Gastric residence system with filaments for improved gastric residence

Abstract

A gastric residence system is provided that includes a core; a plurality of arms connected proximally to the core by a plurality of linker assemblies, one linker assembly of the plurality of linker assemblies corresponding to each arm of the plurality of arms and the plurality of arms extending radially from proximal, and a filament circumferentially connecting each arm of the plurality of arms.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 933,211, filed November 8, 2019, and U.S. Provisional Application No. 62 / 992,075, filed March 19, 2020. The entire contents of these applications are incorporated herein by reference. Invention Field

[0003] This invention relates to gastric retention systems, and more particularly to gastric retention systems having filaments for improving gastric retention. Background of the Invention

[0005] A gastric-resident system is a delivery system for active agents that remains in the stomach for days to weeks, or even longer, during which time the drug or other active agent can be eluted from the system for absorption in the gastrointestinal tract. Examples of such systems are described in international patent applications WO 2015 / 191920, WO 2015 / 191925, WO 2017 / 070612, WO 2017 / 100367 and PCT / US2017 / 034856.

[0006] A gastric retention system is designed to be administered to a patient's stomach, typically in the form of a swallowed capsule, or introduced into the stomach via another method of administration (e.g., a feeding tube or gastric tube). When the capsule dissolves in the stomach, the system expands or unfolds to a size that allows it to remain in the stomach and prevent passage through the pyloric sphincter for the desired retention period (e.g., 3 days, 7 days, 2 weeks, etc.). This requires mechanical stability during the desired retention period. During retention, the system releases one or more active agents, such as one or more drugs, preferably with minimal burst release, which requires careful selection of the carrier material of the active agent to provide the desired release properties. While residing in the stomach, the system should not interfere with the normal passage of food or other gastric contents. The system should be expelled from the stomach at the end of the desired retention time and should be easily cleared from the patient. If the system prematurely enters the small intestine from the stomach, it should not cause intestinal obstruction and should also be easily cleared from the patient. These characteristics require careful selection of the materials constituting the system, as well as the size and arrangement of the system. Invention Overview

[0008] A gastric retention system comprising filaments for improving gastric retention and a method for preparing a gastric retention form having filaments are provided. The gastric retention system having filaments described herein particularly helps to improve gastric retention. Specifically, the filaments can help provide a more consistent and / or longer gastric retention time. Therefore, the gastric retention system comprising filaments provided herein can provide a more predictable and / or controllable gastric retention time. A gastric retention system with predictable and / or controllable gastric retention time minimizes the risk of the gastric retention system unfolding too early (e.g., in the esophagus) and causing obstruction. A gastric retention system with predictable and / or controllable gastric retention time also minimizes 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 intended.

[0009] In some embodiments, a gastric retention system is provided, comprising: a core; a plurality of arms connected proximally to the core via a plurality of connector assemblies, wherein one connector assembly corresponds to each arm of the plurality of arms and the plurality of arms extend radially from the proximal end; and filaments circumferentially connecting each arm of the plurality of arms.

[0010] In some embodiments of this gastric retention system, the filament is circumferentially connected to the distal ends of each of the plurality of arms.

[0011] In some embodiments of this gastric retention system, the multiple arms comprise at least three arms.

[0012] In some embodiments of this gastric residence system, the multiple arms are configured to be loaded with pharmaceutically active ingredients.

[0013] In some embodiments of this gastric retention system, the multiple arms contain a 40-60% load of the active pharmaceutical ingredient.

[0014] In some embodiments of this gastric residency system, the connector assembly is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

[0015] In some embodiments of this gastric retention system, the gastric retention system is configured to fold during administration and to be in an open configuration when in the patient's stomach.

[0016] In some embodiments of the gastric residence system, the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rewinds when the gastric residence system is in an open configuration.

[0017] In some embodiments of this gastric retention system, the gastric retention system has a multi-armed star shape in an open construction.

[0018] In some embodiments of this gastric retention system, the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times that required to compress a gastric retention system without filaments to a size small enough to pass through the opening, as measured using a radial test.

[0019] In some embodiments of this gastric retention system, when the gastric retention system is incubated at pH 1.6 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0020] In some embodiments of the gastric retention system, when the gastric retention system is incubated at pH 6.5 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is less than 2 N.

[0021] In some embodiments of this gastric residency system, the distal end of each of the multiple arms contains enteric material.

[0022] In some embodiments of this gastric retention system, the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0023] In some embodiments of this gastric residency system, the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0024] In some embodiments of this gastric retention system, the polymer comprises polycaprolactone or TPU.

[0025] In some embodiments of this gastric residency system, the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

[0026] In some embodiments of this gastric residency system, the plasticizer comprises propylene glycol.

[0027] In some embodiments of this gastric residency system, the acid comprises stearic acid.

[0028] In some embodiments of this gastric retention system, the distal end of each arm includes a notch and the filament is located within the notch at each distal end.

[0029] In some embodiments of this gastric retention system, the filament is secured by overlapping the first end and the second end of the filament within a first notch, and the first end and the second end are secured by expanding the first end and the second end of the filament.

[0030] In some embodiments of the gastric retention system, each of the plurality of arms includes a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a greater stiffness than the second segment, as measured using a three-point bending test according to ASTM D790.

[0031] In some embodiments of the gastric retention system, the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times that required to compress a gastric retention system having an arm containing only the first polymer composition to a size small enough to pass through the opening, as measured using an iris test mechanism.

[0032] In some embodiments of this gastric residence system, the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0033] In some embodiments of the gastric residence system, the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

[0034] In some embodiments of this gastric retention system, the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

[0035] In some embodiments of the gastric retention system, the first section is directly connected to the second section of each of the plurality of arms.

[0036] In some embodiments of the gastric retention system, the first segment is connected to the second segment via a connector.

[0037] In some embodiments of the gastric residence system, the first segment comprises 20-50% of the length of at least the first arm of the plurality of arms, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

[0038] In some embodiments of the gastric residence system, the second segment comprises 50-80% of the length of at least the first arm of the plurality of arms, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

[0039] In some embodiments of the gastric residence system, the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

[0040] In some embodiments of the gastric retention system, the gastric retention system is configured to be encapsulated in a capsule when the gastric retention system is in a folded configuration to form a gastric retention dosage form suitable for administration to a patient, and the gastric retention dosage form is configured to release the gastric retention system in the patient's stomach, thereby allowing the gastric retention to be in an open configuration.

[0041] In some implementations of this gastric residency system, the gastric residency system is used to treat patients.

[0042] In some implementations of this gastric residency system, the patient is a human or a dog.

[0043] In some embodiments, a gastric retention system is provided, comprising: a plurality of arms connected to a proximal end, the plurality of arms extending radially from the proximal end; and filaments circumferentially connected to the distal ends of each of the plurality of arms.

[0044] In some embodiments of the gastric residency system, the gastric residency system includes a core, wherein each of the plurality of arms is connected to the core at its proximal end.

[0045] In some embodiments of this gastric retention system, the multiple arms comprise at least three arms.

[0046] In some embodiments of this gastric residence system, the multiple arms are configured to be loaded with pharmaceutically active ingredients.

[0047] In some embodiments of this gastric retention system, the multiple arms contain a 40-60% load of the active pharmaceutical ingredient.

[0048] In some embodiments of the gastric residency system, the gastric residency system includes a plurality of connector assemblies, wherein one of the plurality of connector assemblies connects one arm of the plurality of arms to the core.

[0049] In some embodiments of the gastric residency system, each of the multiple connector components is degraded, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0050] In some embodiments of this gastric retention system, the gastric retention system is configured to fold during administration and to be in an open configuration when in the patient's stomach.

[0051] In some embodiments of the gastric residence system, the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rewinds when the gastric residence system is in an open configuration.

[0052] In some embodiments of this gastric retention system, the gastric retention system has a multi-armed star shape in an open construction.

[0053] In some embodiments of this gastric retention system, the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times that required to compress a gastric retention system without filaments to a size small enough to pass through the opening, as measured using a radial test.

[0054] In some embodiments of this gastric retention system, when the gastric retention system is incubated at pH 1.6 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0055] In some embodiments of the gastric retention system, when the gastric retention system is incubated at pH 6.5 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is less than 2 N.

[0056] In some embodiments of this gastric residency system, the distal end of each of the multiple arms contains enteric material.

[0057] In some embodiments of this gastric retention system, the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0058] In some embodiments of this gastric residency system, the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0059] In some embodiments of this gastric retention system, the polymer comprises polycaprolactone or TPU.

[0060] In some embodiments of this gastric residency system, the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

[0061] In some embodiments of this gastric residency system, the plasticizer comprises propylene glycol.

[0062] In some embodiments of this gastric residency system, the acid comprises stearic acid.

[0063] In some embodiments of this gastric retention system, the distal end of each arm includes a notch and the filament is located within the notch at each distal end.

[0064] In some embodiments of the gastric retention system, the filament is secured by overlapping the first end and the second end of the filament within a first notch, and the first end and the second end are secured by either knotting or thermal flaring.

[0065] In some embodiments of the gastric retention system, each of the plurality of arms includes a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a greater stiffness than the second segment, as measured using a three-point bending test according to ASTM D790.

[0066] In some embodiments of the gastric retention system, the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times that required to compress a gastric retention system having an arm containing only the first polymer composition to a size small enough to pass through the opening, as measured using an iris test mechanism.

[0067] In some embodiments of this gastric residence system, the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0068] In some embodiments of the gastric residence system, the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

[0069] In some embodiments of this gastric retention system, the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

[0070] In some embodiments of the gastric retention system, the first segment is directly connected to a second segment of at least the first arm of the plurality of arms.

[0071] In some embodiments of the gastric retention system, the first segment is connected to the second segment via a connector assembly.

[0072] In some embodiments of this gastric residency system, the first segment comprises at least 20-50% of the length of the first arm, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

[0073] In some embodiments of the gastric residence system, the second segment comprises 50-80% of the length of the at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

[0074] In some embodiments of the gastric residence system, the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

[0075] In some embodiments of the gastric retention system, the gastric retention system is configured to be encapsulated in a capsule when the gastric retention system is in a folded configuration to form a gastric retention dosage form suitable for administration to a patient, and the gastric retention dosage form is configured to release the gastric retention system in the patient's stomach, thereby allowing the gastric retention system to have an open configuration.

[0076] In some implementations of this gastric residency system, the gastric residency system is used to treat patients.

[0077] In some implementations of this gastric residency system, the patient is a human or a dog.

[0078] In some embodiments, a method of manufacturing a gastric residence system is provided, the method comprising preparing a gastric residence system comprising a plurality of arms connected proximally to the nucleus by a plurality of connector assemblies, one connector assembly corresponding to each arm of the plurality of arms and the plurality of arms extending radially; making cuts in each arm of the plurality of arms to form notches in each arm; circumferentially winding a filament around the gastric residence system such that the filament is located within a notch in each arm; and closing the notches to secure the filament within the notches.

[0079] In some embodiments of the method, the filament is circumferentially connected to the distal ends of each of the plurality of arms.

[0080] In some implementations of this method, the plurality of arms comprises at least three arms.

[0081] In some embodiments of the method, the multiple arms are configured to be loaded with a pharmaceutically active ingredient.

[0082] In some embodiments of this method, the multiple arms contain a 40-60% load of the active pharmaceutical ingredient.

[0083] In some embodiments of the method, the connector component is degraded, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0084] In some embodiments of the method, the gastric residency system is configured to fold during administration and to be in an open configuration when in the patient's stomach.

[0085] In some embodiments of the method, the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rewinds when the gastric residence system is in an open configuration.

[0086] In some implementations of this method, the gastric residence system has a multi-armed star shape in an open construction.

[0087] In some embodiments of the method, closing the gaps includes at least one of knotting or heating.

[0088] In some embodiments of the method, the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times that required to compress a gastric retention system without filaments to a size small enough to pass through the opening, as measured using a radial test.

[0089] In some embodiments of the method, when the gastric residence system is incubated at pH 1.6 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0090] In some embodiments of the method, when the gastric residence system is incubated at pH 6.5 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is less than 2 N.

[0091] In some embodiments of the method, the distal end of each of the plurality of arms contains enteric material.

[0092] In some embodiments of the method, the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0093] In some embodiments of the method, the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0094] In some embodiments of the method, the polymer comprises polycaprolactone.

[0095] In some embodiments of the method, the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

[0096] In some embodiments of this method, the plasticizer comprises propylene glycol.

[0097] In some embodiments of the method, the acid comprises stearic acid.

[0098] In some embodiments of the method, each of the plurality of arms includes a first segment containing a first polymer composition and a second segment containing a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured using a three-point bending test according to ASTM D790.

[0099] In some embodiments of the method, the force required to compress the gastric residence system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times that required to compress a gastric residence system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening, as measured using an iris test mechanism.

[0100] In some embodiments of the method, the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0101] In some embodiments of the method, the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

[0102] In some embodiments of the method, the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens when exposed to an aqueous environment.

[0103] In some embodiments of the method, the first segment is directly connected to the second segment of the at least one arm.

[0104] In some implementations of the method, the first segment is connected to the second segment via a connector assembly.

[0105] In some embodiments of the method, the first segment comprises 20-50% of the length of the at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

[0106] In some embodiments of the method, the second segment comprises 50-80% of the length of the at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

[0107] In some embodiments of the method, the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having only an arm containing the first polymer composition, as measured using a double funnel test.

[0108] In some embodiments of the method, the gastric residence system is configured to be encapsulated in a capsule when the gastric residence system is in a folded configuration to form a gastric residence dosage form suitable for administration to a patient, and the gastric residence dosage form is configured to release the gastric residence system in the patient's stomach, thereby allowing the gastric residence system to be in an open configuration.

[0109] In some implementations of this method, the gastric residency system is used to treat patients.

[0110] In some implementations of this method, the patient is a human or a dog.

[0111] In some embodiments, a method of manufacturing a gastric residency system is provided, the method comprising preparing a gastric residency system including a plurality of arms connected proximally to the nucleus by a plurality of connector assemblies, one connector assembly corresponding to each arm of the plurality of arms and the plurality of arms extending radially; preparing a plurality of tips and filaments, one tip of each arm of the plurality of arms, wherein the filaments are connected to each tip of the plurality of tips; and connecting each tip of the plurality of tips to the arms of the plurality of arms to form a gastric residency system including the filaments.

[0112] In some embodiments of this method, the preparation of multiple tips and filaments includes injection molding.

[0113] Brief description of the attached figures

[0114] The invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0115] Figure 1A-1C This illustrates the construction of various gastric residency systems according to some implementation schemes;

[0116] Figure 2 This illustrates a multi-arm gastric retention system according to some implementations and the curvature geometry that the gastric retention system may most readily exhibit when compressed by forces such as gastric contractions.

[0117] Figures 3A-3C This demonstrates various methods by which a gastric resident system, according to some implementation schemes, can pass through the pylorus before dissolution;

[0118] Figure 4A and 4B This illustrates a gastric retention system with filaments according to some implementation schemes, and how the filaments can help prevent premature passage through the pylorus;

[0119] Figure 5A and 5B This illustrates two different constructions of a gastric resident system including filaments, according to some implementation schemes;

[0120] Figures 6A-6C This illustrates the steps for preparing a gastric retention system with filaments according to some embodiments;

[0121] Figure 7 This illustrates two methods for fixing the filament according to some implementation schemes;

[0122] Figure 8 This illustrates a method for manufacturing a gastric resident system according to some implementation schemes;

[0123] Figure 9 This demonstrates a method for testing radial compression using the iris mechanism according to some implementation schemes;

[0124] Figure 10A and Figure 10B Showing pull-out force tests of a gastric retention system with filaments according to some implementation schemes;

[0125] Figure 11 Shows radial force data for gastric retention systems without and with filaments according to some implementation schemes;

[0126] Figure 12 Shows radial force data for a gastric retention system without filaments and including a flexible arm, and a gastric retention system with filaments and a rigid arm, according to some embodiments.

[0127] Figure 13 Showing pull-out force data for a gastric retention system including filaments and enteric tips (Formula 14) according to some implementation schemes;

[0128] Figure 14 Showing pull-out force data for a gastric retention system including filaments and enteric tips (Formula 15) according to some implementation schemes;

[0129] Figure 15 This displays filament pull-out force data for gastric retention systems with different fixation methods according to several implementation schemes; and

[0130] Figure 16 This image shows a gastric resident system with filaments, according to some implementation schemes, ready for visualization in a dog's stomach.

[0131] Figure 17A Showing a compression / folding stomach retention system including filaments fitted on the side of the arm, according to some embodiments;

[0132] Figure 17B This illustrates a compression / folding stomach retention system including filament sheaths according to some implementation schemes;

[0133] Figure 17C Showing a compression / folding gastric retention system including filaments fitted on the nuclear side, according to some embodiments;

[0134] Figure 17D This illustrates a compression / folding stomach retention system including filament sheaths according to some implementation schemes;

[0135] Figure 17E The illustration shows a compression / folding gastric retention system, comprising filaments and fitted onto the arm side, according to some embodiments, which is encapsulated in two-piece capsules;

[0136] Figure 17F The illustration shows a compression / folding gastric retention system, comprising filaments and fitted onto the arm side, according to some embodiments, which is encapsulated in two-piece capsules;

[0137] Figure 17G This shows a packaged compression / folding stomach retention system according to some implementation schemes.

[0138] Figure 18A This demonstrates the ability of elastic or inelastic filaments to improve the compressibility of the stellate gastric retention system.

[0139] Figure 18B The adhesion strength of the biodegradable suture to the enteric tip of the gastric residence system changes over time in a simulated gastric environment. Invention Details

[0141] This article describes a gastric retention system with filaments and a method for preparing such a system. As described above, the gastric retention system is designed to remain in the gastrointestinal tract for a predetermined period of time. After a period of time (e.g., a predetermined retention time), the gastric retention system breaks down into several small pieces sufficient to pass through the pylorus. However, if the gastric retention system is bent into a structure small enough to pass through the patient's pylorus prematurely, the therapeutic agent of the gastric retention system is not properly administered to the patient.

[0142] Therefore, the gastric retention system provided herein includes filaments connecting the distal ends of the arms of the gastric retention system. These filaments help prevent the gastric retention system from passing through the pylorus before the predetermined retention time expires.

[0143] Gastric retention systems are typically administered in a folded, closed, or collapsed configuration. When the gastric retention system enters a patient's stomach, it unfolds into an open configuration. This physical opening or unfolding of the gastric retention system produces a dosage form of an effective size (i.e., an open-configuration gastric retention system) that is too large to pass through the patient's pyloric valve (the opening between the stomach and small intestine). An unfolded or expanded gastric retention system can remain in the patient's stomach for a predetermined period of time (e.g., 24 hours, 48 ​​hours, 7 days, 10 days, etc.).

[0144] However, a particular challenge with gastric residency systems is ensuring consistent and accurate residency time. Gastroretention systems that pass through the pylorus too early fail to deliver the intended dose of therapeutic agent, sacrificing the efficacy and reliability of the system.

[0145] Therefore, the gastric retention system presented in this paper was designed to achieve a more consistent and accurate residence time in the patient's stomach. The gastric retention system comprising filaments presented in this paper is particularly likely to prevent premature passage through the pylorus. Thus, the gastric retention system presented in this paper is more likely to provide a consistent and accurate residence time, improving the efficacy and reliability of the gastric retention system.

[0146] definition

[0147] As used herein, a “gastric retention system” is a dosage form containing a therapeutic agent and configured for administration to a patient in a folded configuration. A “gastric retention dosage form” includes a folded gastric retention system and is configured to retain the gastric retention system in a folded configuration until unfolded. For example, a gastric retention dosage form may include capsules and / or capsule coatings as described in U.S. Application No. 62 / 821,352 entitled “Capsules and Capsule Coatings for Gastric Retention Dosage Forms” and / or U.S. Application No. 62 / 821,361 entitled “Coatings for Gastric Retention Dosage Forms”.

[0148] "Carrier polymer" is a polymer suitable for blending with active agents, such as pharmaceuticals, used in this invention.

[0149] "Active agent" is any substance intended for use in the treatment, diagnosis, or nutrition of a patient, individual, or subject. Active agents include, but are not limited to, pharmaceuticals, nutrients, vitamins, and minerals.

[0150] A "dispersant" is defined as a substance that helps minimize the particle size of an active agent and disperse the active agent particles within a carrier polymer matrix. In other words, the dispersant helps minimize or prevent particle aggregation or flocculation during system manufacturing. Therefore, the dispersant possesses anti-aggregation and anti-flocculation activities and helps maintain a uniform distribution of active agent particles within the carrier polymer matrix.

[0151] "Excipients" are any substances added to an active agent formulation but not to the active agent itself. Excipients include, but are not limited to, binders, coating agents, diluents, disintegrants, emulsifiers, flavoring agents, flow aids, lubricants, and preservatives. The specific category of dispersants falls under the more general category of excipients.

[0152] "Elastic polymer" or "elastomer" (also known as "stretch polymer") is a polymer that can be deformed from its original shape by an applied force for a period of time, and then substantially return to its original shape once the applied force is removed.

[0153] A "coupling polymer" is a polymer suitable for coupling any other polymer together, such as coupling a first carrier polymer-surfactant component to a second carrier polymer-surfactant component. Coupling polymers typically form linker regions between other components.

[0154] "Time-dependent polymers" or "time-dependent coupling polymers" are polymers that degrade in a time-dependent manner as the gastric resident system unfolds in the stomach. Time-dependent polymers are generally unaffected by normal pH changes in the stomach.

[0155] "Largely constant plasma levels" means that plasma levels measured during the period that the gastric residence system remains in the stomach are kept within twice the average plasma level (i.e., between 50% and 200% of the average plasma level).

[0156] "Substantially constant plasma levels" means that plasma levels measured during the period that the gastric residence system resides in the stomach remain within ±25% of the mean plasma level.

[0157] "Hydrophilic therapeutic agent," "hydrophilic active agent," or "hydrophilic drug" is an active agent that is readily soluble in water. A hydrophilic active agent is defined as an active agent with a solubility of 1 mg / ml or greater in water. Alternatively, a hydrophilic active agent can be defined as an active agent with a solubility of log P in a 1-octanol / water system. oct (log allocation coefficient P) oct , where P oct The ratio of (concentration in 1-octanol) to (concentration in H₂O) of an active agent is less than 0.5. Measure solubility or log P. oct Its pH is 1.6, which is close to the stomach environment.

[0158] A "hydrophobic therapeutic agent," "hydrophobic active agent," or "hydrophobic drug" is an active agent that is poorly soluble in water. A hydrophobic active agent is defined as an active agent with a solubility in water of less than 1 mg / ml. Alternatively, a hydrophobic active agent can be defined as an active agent with a solubility of log P in a 1-octanol / water system. oct An active agent with a log partition coefficient greater than 1. Alternatively, a hydrophobic therapeutic agent can be defined as an active agent that has higher solubility in ethanol than in water. Alternatively, a hydrophobic therapeutic agent can be defined as an active agent that has higher solubility in 40% ethanol / 60% simulated gastric fluid than in 100% simulated gastric fluid.

[0159] When used to describe a material or system, "biocompatible" means that when exposed to an organism such as a human, the material or system will not cause adverse reactions or will cause only minimal, tolerable adverse reactions. In the context of this gastrointestinal resident system, biocompatibility is evaluated in the gastrointestinal environment.

[0160] "Patient," "individual," or "subject" refers to a mammal, preferably a human or a domesticated animal such as a dog or cat. In the most preferred embodiment, the patient, individual, or subject is a human.

[0161] The “diameter” of the particles used in this article refers to the longest dimension of the particle.

[0162] "Treating" a disease or disorder using the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional active agents, to a patient in need of such treatment to reduce or eliminate the disease or disorder or one or more symptoms of the disease or disorder, or to delay the progression of the disease or disorder or one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder or one or more symptoms of the disease or disorder. "Inhibiting" a disease or disorder using the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional active agents, to a patient in need of such treatment to inhibit the clinical manifestations of the disease or disorder or to inhibit the manifestation of adverse symptoms of the disease or disorder. The difference between treatment and inhibition is that treatment occurs after adverse symptoms of the disease or disorder have manifested in the patient, while inhibition occurs before adverse symptoms of the disease or disorder have manifested in the patient. Inhibition can be partial, substantially complete, or complete. Because some diseases or disorders are hereditary, genetic screening can be used to identify patients at risk for the disease or disorder. The system and method of the present invention can then be used to treat asymptomatic patients at risk of developing clinical symptoms of the disease or disorder, in order to suppress the occurrence of any adverse symptoms.

[0163] The "therapeutic use" of the systems disclosed herein is defined as the use of one or more systems disclosed herein to treat a disease or disorder as defined above. A "therapeutic effective amount" of a therapeutic agent, such as a drug, is an amount of active agent sufficient, when administered to a patient, to reduce or eliminate the disease or disorder or one or more symptoms of the disease or disorder, or to delay the progression of the disease or disorder or one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder or one or more symptoms of the disease or disorder. A therapeutic effective amount may be administered to a patient as a single dose, or it may be divided and administered as multiple doses.

[0164] The “preventive use” of the systems disclosed herein is defined as the use of one or more systems disclosed herein to suppress a disease or disorder as defined above. The “preventive effective amount” of the active agent is the amount of active agent sufficient, when administered to a patient, to suppress the clinical manifestations of the disease or disorder or to suppress the manifestation of adverse symptoms of the disease or disorder. The preventive effective amount may be administered to a patient as a single dose, or it may be divided and administered as multiple doses.

[0165] The flexural modulus of a material is an inherent property of the material, calculated as the ratio of stress to strain measured by a three-point bend test during the bending deformation of the material. Although the connector, as described herein, is a component of the gastric retention system, the flexural modulus of the material containing a polymer can be measured separately. For example, the polymer connector in the gastric retention system may be too short to measure the flexural modulus, but a longer sample of the same material can be used to accurately determine the flexural modulus. The longer sample used to measure the flexural modulus should have the same cross-sectional dimensions (shape and size) as the polymer connector used in the gastric retention system. The flexural modulus is measured using a three-point bend test according to the ASTM standard three-point bend test (ASTM D790) using a 10 mm support spacing and further modified to accommodate materials with non-rectangular cross-sections. The longest line of symmetry of the polymer connector's cross-section should be set perpendicularly and the flexural modulus should be measured by applying a downward force. If the longest line of symmetry of the polymer connector's cross-section is perpendicular to a single flat edge, that single flat edge should be set upwards. If the cross-section of the polymer connector is triangular, the apex of the triangle should face downwards. As a downward force is applied, the force and displacement are measured, and the slope of the linear region is obtained to calculate the flexural modulus.

[0166] The singular forms “a,” “an,” and “the” used in this document include plural references unless otherwise specified or the context clearly indicates otherwise.

[0167] When the term “about” or “approximately” is used herein to express numerical values, it should be understood that it includes both the specified value and a value reasonably close to the specified value. For example, the description of “about 50°C” or “approximately 50°C” includes both the stated value of 50°C and a value close to 50°C. Thus, the phrase “about X” or “approximately X” includes the description of the numerical value X itself. If a range is given, such as “about 50-60°C” or “about 50-60°C”, it should be understood that it includes both the value specified at the endpoint and, for each endpoint or both endpoints, a value close to each endpoint or both endpoints; that is, “about 50-60°C” (or “about 50-60°C”) is equivalent to describing both “50-60°C” and “about 50°C to about 60°C” (or “about 50-60°C”).

[0168] For the numerical ranges disclosed in this specification, any upper limit disclosed for a component may be combined with any lower limit disclosed for that component to provide a range (provided the upper limit is greater than the lower limit to which the desired combination is made). Each of these combinations of disclosed upper and lower limits is explicitly considered herein. For example, if the range of a particular component's amount is given as 10-30%, 10-12%, and 15-20%, then the ranges of 10-20% and 15-30% are also considered, while the combination of a 15% lower limit and a 12% upper limit is not possible and is therefore not considered.

[0169] Unless otherwise stated, percentages of components in a composition are expressed as weight percentages or weight / weight percentages. It should be understood that references to relative weight percentages in a composition assume that the sum of the combined total weight percentages of all components in the composition is 100. It should further be understood that the relative weight percentages of one or more components may be adjusted upwards or downwards such that the sum of the weight percentages of the components in the composition is 100, provided that the weight percentage of any particular component does not exceed the limits given for that component.

[0170] The partition behavior of the surfactant between the polycaprolactone phase (PCL phase) and the simulated gastric juice phase (SGF phase) can be measured to obtain the partition coefficient PPCL-SGF between the two phases. Log PPCL-SGF can also be calculated. A 5:1 mixture of polycaprolactone diol (MW530):ethyl acetate can be used as the PCL phase, and fasted simulated gastric juice (FaSSGF) can be used as the SGF phase, such that PPCL-SGF = (concentration in polycaprolactone diol) / (concentration in FaSSGF).

[0171] Some embodiments described herein are described with respect to their various elements as “comprising” or “including”. In alternative embodiments, those elements may be described using the transitional phrase “consistently composed of…” applied to those elements. In other alternative embodiments, those elements may be described using the transitional phrase “composed of…” applied to those elements. Thus, for example, if a composition or method is disclosed herein to comprise A and B, then alternative embodiments of the composition or method “consistently composed of A and B” and alternative embodiments of the composition or method “consisting of A and B” are also considered to have been disclosed herein. Similarly, embodiments whose various elements are described as “consistently composed of…” or “composed of…” may also be described as “comprising” applied to those elements. Finally, embodiments whose various elements are described as “consistently composed of…” may also be described as “composed of…” applied to those elements, and embodiments whose various elements are described as “composed of…” may also be described as “consistently composed of…” applied to those elements.

[0172] When a composition or system is described as "consisting substantially of" the listed elements, the composition or system contains the explicitly listed elements and may contain other elements that do not substantially affect the condition to be treated (for a composition treating the condition) or the performance of the described system (for a composition containing the system). However, the composition or system does not contain any other elements besides those explicitly listed that substantially affect the condition to be treated (for a composition treating the system) or any other elements that substantially affect the performance of the system (for a composition containing the system); or if the composition or system does contain additional elements besides those listed that may substantially affect the condition to be treated or the performance of the system, then the composition or system does not contain those additional elements in concentrations or amounts sufficient to substantially affect the condition to be treated or the performance of the system. When a method is described as "consisting substantially of" the listed steps, the method contains the listed steps and may contain other steps that do not substantially affect the condition treated by the method or the performance of the system produced by the method, but the method does not contain any other steps besides those explicitly listed that substantially affect the condition to be treated or the system produced.

[0173] This disclosure provides several embodiments. Where possible, any feature from any embodiment can be combined with any feature from any other embodiment. In this way, mixed configurations of the disclosed features are within the scope of the invention.

[0174] In addition to the embodiments and methods disclosed herein, additional embodiments of the gastric residency system and methods of manufacturing and using such systems are disclosed in International Patent Application Nos. WO 2015 / 191920, WO 2015 / 191925, WO 2017 / 070612, WO 2017 / 100367 and PCT / US2017 / 034856, which are incorporated herein by reference in their entirety.

[0175] gastric resident system

[0176] This document provides arms and segments for use in a gastric retention system, which may include filaments to help prevent premature passage of the gastric retention system through the pylorus. An overall gastric retention system construction is described below, and each of the three main components of the gastric retention system is described in detail: an elastomer (i.e., a central elastomer or core), arms (i.e., elongated members, carrier polymers, or carrier polymer-activator components), and coupling polymers (i.e., connectors, connector regions, or connector assemblies). More specifically, this article describes the overall system architecture; system dimensions; residence time; evaluation of release characteristics; gastric delivery pharmacokinetics of the gastric residence system; dissolution properties, bioavailability, and pharmacokinetics of the gastric residence system; elastomers; carrier polymers for segments and arms (carrier polymer-active agent components); carrier polymer-active agent / active agent salt combinations with excipients and other additives; active agents for the gastric residence system; high active agent loading in arms and segments; dispersants for regulating active agent release and polymer blend stability; stabilizers for the gastric residence system; coupling polymers; filaments for improving gastric residence; gastric residence systems including arms with controlled stiffness; and the system polymer composition.

[0177] Gastroretention formulations can be designed for administration to the patient's stomach via swallowing, feeding tube, or gastric tube. Once in place, a gastroretention formulation can remain in the stomach for the desired duration (e.g., 3 days, 7 days, 2 weeks, etc.). Properly positioned gastroretention formulations prevent passage through the pyloric valve, which separates the stomach from the small intestine. Gastroretention formulations can deliver the therapeutic agent (i.e., an API or drug) in a controlled-release manner during the retention time. While residing in the stomach, the formulation must not interfere with the normal passage of food or other gastric contents. Once the desired retention time has elapsed, the formulation is expelled from the stomach (i.e., through the pyloric valve) and is readily cleared from the patient's body.

[0178] To administer a gastric retention system to a patient, the system may be folded into a form small enough to be swallowed or otherwise administered. In some embodiments, the folded gastric retention system is contained in a capsule or other container that can be swallowed by the patient. In some cases, the gastric retention system may be delivered to the patient via a gastrostomy tube, feeding tube, gastric tube, or other route of administration to the stomach. Specific examples of gastric retention systems can be found in PCT / US2018 / 051816, WO2015 / 191920, WO 2017 / 070612, WO 2017 / 100367, WO 2018 / 064630, WO 2017 / 205844, and WO2018 / 227147, each of which is incorporated herein by reference in its entirety.

[0179] Once the gastric retention system reaches the patient's stomach, it can be in an open configuration. An open gastric retention system, when its dimensions remain unchanged, is suitable for preventing the device from passing through the pyloric valve for the desired period of time. In some embodiments, the folded gastric retention system can also be secured by a soluble clamping band or sleeve that can prevent premature unfolding of the gastric retention system in the event of capsule rupture. The folded gastric retention system, which retains its folded structure with a sleeve or band, can be encapsulated in a capsule. In some embodiments of this gastric retention dosage form, the sleeve comprises at least one of gelatin, hydroxypropyl methylcellulose, or amylopectin. In some embodiments of this gastric retention dosage form, the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or amylopectin. Thus, in one embodiment, the gastric retention system includes a core; a plurality of arms proximally connected to the core by a plurality of connector assemblies, one connector assembly corresponding to each arm of the plurality of arms and the plurality of arms extending radially from the proximal end; and filaments circumferentially connecting each arm of the plurality of arms. The gastric retention system may further include a sheath, wherein the sheath at least surrounds a portion of the folded gastric retention system. The gastric retention system may further include a capsule encapsulating the folded gastric retention system. In any of these embodiments, the sheath may contain at least one of gelatin, hydroxypropyl methylcellulose, or amylopectin. In any of these embodiments, the capsule may contain at least one of gelatin, hydroxypropyl methylcellulose, or amylopectin. In any of these embodiments, the sheath may contain at least one of gelatin, hydroxypropyl methylcellulose, or amylopectin, and the capsule may contain at least one of gelatin, hydroxypropyl methylcellulose, or amylopectin.

[0180] While in the stomach, this gastric retention system is compatible with the digestive and other normal functions of the stomach or gastrointestinal tract. This gastric retention system does not interfere with or impede the passage of chyme (partially digested food) or other gastric contents emptied from the stomach through the pyloric sphincter into the duodenum.

[0181] Once released from the capsule into the stomach, the therapeutic agent of the gastric retention system begins to take effect. In some embodiments, the gastric retention system comprises multiple carrier polymer-active agent components. The carrier polymer-active agent components may contain a carrier polymer, a pore-forming agent, and a therapeutic agent (or a salt thereof). These multiple carrier polymer-active agent components are linked together by one or more coupling polymer components. During the desired residence time of the system, the therapeutic agent can be eluted from the carrier polymer-active agent components into the patient's gastric fluid. The release of the therapeutic agent is controlled by a suitable formulation of the carrier polymer-active agent components, including by using a dispersant in the formulation of the carrier polymer-active agent components and by grinding the therapeutic agent into particles of the desired size, followed by blending the active agent with the carrier polymer and the dispersant.

[0182] Alternatively, the coating can be applied to the outer surface of the gastric residence system. The coating may include additional therapeutic agents or active agents that may affect the release of therapeutic agents or the residence period of the gastric residence system.

[0183] Once the required residence time has elapsed, the gastric residence system is expelled from the stomach. For this purpose, the various components of the gastric delivery system are designed to be weakened and degraded. The specific size of the system is also considered. In its fully open construction, the gastric residence system is designed to prevent passage through the pyloric valve. However, the coupling polymer components of the gastric residence system are selected such that they gradually degrade within the stomach during the prescribed residence period. When the coupling polymer components are sufficiently weakened through degradation, the gastric residence system loses significant compressive resilience or shrinks in size and breaks down into smaller pieces. The reduced-size dosage form and any smaller pieces are designed to pass through the pyloric valve. The system then passes through the intestine and is cleared from the patient. In some embodiments, the gastric residence system may be designed to be weakened at specific locations such that once the residence time has elapsed, the gastric residence system can pass intact through the pyloric valve without breaking down into many smaller pieces.

[0184] Overall system structure

[0185] Gastric resident systems can be fabricated with different configurations. The "star-shaped" configuration of a gastric resident system is also known as a "star-shaped" (or "asterisk") configuration. An example of a star-shaped system 100 is illustrated in [illustration missing]. Figure 1A In the middle, multiple arms (only one arm 108 is shown for clarity) are fixed to the disc-shaped central elastic body 106. Figure 1A The arm shown is composed of segments 102 and 103 connected by coupling polymers or connector regions 104 (these components are again labeled only in one arm for clarity). This configuration allows the system to fold or compress at the central elastomer. Figure 1B show Figure 1A The folded structure of the gastric resident system 190 (for clarity) Figure 1B Only two arms are shown in the image. Figure 1B Sections 192 and 193, connector section 194, elastomer 196, and arm 198 respectively correspond to Figure 1A The system comprises sections 102 and 103, a connector section 104, an elastomer 106, and an arm 108. When folded, the overall length of the system is reduced by approximately half, and the system can be easily placed into a container such as a capsule or other suitable for oral administration. When the capsule reaches the stomach, it dissolves, releasing the gastric retention system. The gastric retention system then unfolds to its uncompressed state, maintaining the desired residence time in the stomach.

[0186] Although the connector region 104 is in Figure 1A The diameter shown is slightly larger than that of segments 102 and 103, but they can have the same diameter as these segments, thus giving the entire arm 102-104-103 a smooth outer surface.

[0187] In some embodiments, the star-shaped system may have an arm consisting of only one segment, which is connected to the central elastomer via a connecting body region. This corresponds to omitting segment 103. Figure 1A At this point, the single-segment arm containing segment 102 is directly connected to the central elastomer 106 via connector 104. These connectors may contain coupling polymers or disintegrating matrices.

[0188] A star-shaped system can be described as a gastric retention system administered to a patient's stomach, comprising an elastomeric component and at least three carrier polymer-activator components attached to the elastomeric component, the latter comprising a carrier polymer and an activator or a salt thereof, wherein each of the multiple carrier polymer-activator components is an arm comprising a proximal end, a distal end, and an outer surface therebetween; wherein the proximal end of each arm is attached to and radially protrudes from the elastomeric component, and the distal end of each arm is not attached to the elastomeric component and is located at a greater radial distance from the elastomeric component than the proximal end; wherein each arm independently comprises one or more segments, each segment comprising a proximal end, a distal end, and an outer surface therebetween. In some embodiments, when two or more segments are present in an arm, each segment is connected to an adjacent segment via a connector region. In some embodiments, when two or more segments are present in an arm, one segment is directly connected to another segment without using a connector region. The connector region may be a coupling polymer or a disintegrating matrix. These arms can be attached to the central elastomer via a coupling polymer or a disintegrating matrix and can have an interfacial polymer middle portion. For more than three arms, or for multiple arms, the preferred number of arms is six, but three, four, five, seven, eight, nine, or ten arms can be used. These arms should be equidistant from the central elastomer; if there are N arms, there will be an angle of approximately 360 / N degrees between adjacent arms.

[0189] Figure 1CThis illustrates another possible overall configuration 120 for the gastric retention system, which is a ring-shaped structure. Segment 122 is connected by a coupling polymer or linker region 124 (only one segment and one coupling connection are shown for clarity). The coupling polymer / linker region in this design must also act as an elastomer so that the ring can be twisted into a compressed state and placed into a container such as a capsule.

[0190] In one embodiment of the star-shaped configuration, segments 102 and 103 comprise a carrier polymer blended with an active agent or drug. In one embodiment of the ring-shaped configuration, segment 122 comprises a carrier polymer blended with an active agent or drug.

[0191] The coupling polymer used as the connective tissue in this gastric resident system is designed to degrade gradually in a controlled manner during the system's residence time in the stomach. If the gastric resident system prematurely enters the small intestine intact, it is designed to degrade much faster to avoid intestinal obstruction. This can be easily achieved by using an enteric polymer as the coupling polymer. Enteric polymers are relatively tolerant of the acidic pH levels encountered in the stomach but dissolve rapidly at the higher pH levels in the duodenum. The use of enteric coupling polymers as a safety element prevents the intact gastric resident system from undesirably entering the small intestine. The use of enteric coupling polymers also provides a way to remove the gastric resident system before its designed residence time; if removal is necessary, the patient can drink a weakly alkaline solution, such as sodium bicarbonate solution, or take an antacid such as hydrated magnesium hydroxide (milk magnesia) or calcium carbonate, which will raise the pH level in the stomach and cause the enteric coupling polymer to degrade rapidly. The gastric resident system will then disintegrate and be cleared from the patient's body. Figure 1A In the system shown, at least the coupling polymer used for coupling agent 104 is made of this type of enteric polymer.

[0192] In additional embodiments, a time-dependent coupling polymer or linker may be used. This time-dependent coupling polymer or linker degrades in a predictable time-dependent manner. In some embodiments, the degradation of this time-dependent coupling polymer or linker may be unaffected by pH changes in the gastrointestinal system.

[0193] In additional embodiments, different types of connectants can be used in the gastric residency system. That is, both enteric connectants (or enteric coupling polymers) and time-dependent connectants (or time-dependent coupling polymers) can be used. In some embodiments, a single multi-segment arm of the star-shaped system can use enteric connectants in some connectant regions between segments and time-dependent connectants in other connectant regions between segments.

[0194] The connectant region is typically about 100 micrometers to about 2 millimeters wide, such as approximately 200-2000 μm, approximately 300-2000 μm, approximately 400-2000 μm, approximately 500-2000 μm, approximately 600-2000 μm, approximately 700-2000 μm, approximately 800-2000 μm, approximately 900-2000 μm, approximately 1000-2000 μm, approximately 1100-2000 μm, approximately 1200-2000 μm, approximately 1300-2000 μm, approximately 1400-2000 μm, approximately 1500-2000 μm, approximately 1600-2000 μm, approximately 1700-2000 μm, and approximately 1800-2000 μm. 00μm or approximately 1900-2000μm; or approximately 100-1900μm, approximately 100-1800μm, approximately 100-1700μm, approximately 100-1600μm, approximately 100-1500μm, approximately 100-1400μm, approximately 100-1300μm, approximately 100-1200μm, approximately 100-1100μm, approximately 100-1000μm, approximately 100-900μm, approximately 100-800μm, approximately 100-700μm, approximately 100-600μm, approximately 100-500μm, approximately 100-400μm, approximately 100-300μm or approximately 100-200μm. The connector region can be approximately 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1000 μm, 1100 μm, 1200 μm, 1300 μm, 1400 μm, 1500 μm, 1600 μm, 1700 μm, 1800 μm, 1900 μm, or 2000 μm wide, with each value being plus or minus 50 μm (±50 μm).

[0195] The central elastomeric polymer of a star-shaped system is not typically an enteric polymer; however, if desired and feasible, the central elastomeric polymer may be made from the enteric polymer.

[0196] The central elastomer should have specific hardness and compression set. Hardness is important because it determines the folding force of the dosage form and whether it will remain in the stomach; a preferred range is about 60-90 A. Compression set should be as low as possible to avoid permanent deformation of the gastric retention system when stored in the capsule with its compression structure. A preferred range is about 10-20%. Materials meeting these requirements are the QP1 series of liquid silicone rubbers from Dow Corning. In any embodiment with a central elastomer, QP1-270 (70 A hardness) liquid silicone rubber can be used. In some embodiments, the central elastomer may comprise liquid silicone rubber (Shin Etsu) with a hardness of 50 A or 60 A.

[0197] The segments and arms of this gastric retention system can have circular cross-sections (in which case the segments are cylindrical), polygonal cross-sections (such as segments with triangular, rectangular, or square cross-sections), or sectoral cross-sections (in which case the segments are cylindrical). The ends of segments with polygonal or sectoral cross-sections, as well as the ends of cylindrical segments that contact gastric tissue, can be rounded to provide rounded corners and edges, improving in vivo safety. That is, instead of sharp transitions between intersecting edges or planes, rounded arcs are used to transition from one edge or plane to another. Thus, a "triangular cross-section" includes a cross-section that is generally triangular, such as a triangle with rounded corners. An arm with a triangular cross-section includes an arm in which the edges are rounded and the corners at the arm's ends are rounded. Rounded corners and edges are also called chamfers, rounded corners, beveled edges, or rounded edges.

[0198] However, it has been shown that a star-shaped gastric retention system can bend into a structure that allows premature passage through the patient's pylorus. Premature passage through the pylorus prevents the delivery of therapeutic agents to the patient. Furthermore, premature passage causes inconsistencies, unreliability, and compromises the efficacy of the gastric retention system.

[0199] Figure 2 This diagram shows a stellate gastric retention system with multiple arms. An example of a curved configuration is shown on the right side of the figure. Due to forces within the stomach (e.g., peristalsis), the gastric retention system can be curved into configurations that allow premature passage through the pylorus, such as... Figure 2 As shown.

[0200] Other possible bending structures are shown in Figures 3A-3C In China. Specifically, Figures 3A-3C This diagram illustrates three different configurations that could allow premature passage through the pylorus. As shown in the figures, the stiffer arm of the gastric retention system remains straight. However, because the nucleus of each gastric retention system is more flexible than the arm, it can bend. This bending of the nucleus allows the gastric retention system to have a stiffer arm for premature passage through the patient's pylorus.

[0201] like Figure 3A As shown, a gastric retention system 302a is illustrated with a curved configuration having three arms passing through the pyloric opening. Figure 3B A gastric resident system 302b is shown in a curved configuration with two arms passing through the pyloric opening. Figure 3C A gastric resident system 302c is shown with a curved structure resembling a shuttlecock and having a core passing through the pyloric opening.

[0202] Therefore, this article describes a gastric retention system comprising filaments. The filaments are circumferentially wound around the gastric retention system and connected to the arms of the gastric retention system, for example, to help prevent premature passage through the patient's pylorus. The filaments and the gastric retention system comprising the filaments are described in more detail with respect to the arms of the gastric retention system and the coupling polymer.

[0203] System size

[0204] The system must be able to be compressed, and its size must allow the patient to swallow it (or allow it to be introduced into the stomach via an alternative means such as a feeding tube or gastrostomy tube). The system is typically kept compressed in a container such as a capsule. Upon entering the stomach, the system is then released from the container and becomes uncompressed, i.e., expanded, with a size that prevents the system from passing through the pyloric sphincter, thus allowing it to remain in the stomach.

[0205] Therefore, the system should be able to fit into standard-sized capsules of commonly used types in pharmacies. Standard capsule sizes used in the United States are provided in the capsule table below (see “Draft Guidance for Industry on Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules”, URL www.regulations.gov / #!documentDetail; D=FDA-2013-N-1434-0002). Since these are the external dimensions of the capsules and because sizes vary slightly among capsule manufacturers, the system should be constructed to be approximately 0.5–1 mm smaller in outer diameter than shown and approximately 1–2 mm shorter in length than shown in the capsule table.

[0206] Capsule Table

[0207]

[0208]

[0209] The capsule can be made of materials well known in the art, such as gelatin or hydroxypropyl methylcellulose. In one embodiment, the capsule is made of a material that dissolves in the gastric environment but does not dissolve in the oral or esophageal environment, which prevents the system from being released prematurely before reaching the stomach.

[0210] In one implementation, for example, Figure 1B The system is folded or compressed into a compacted state as shown to be inserted into the capsule. Once the capsule dissolves in the stomach, the system, for example, is... Figure 1AThe configuration shown is suitable for gastric retention. Preferred capsule sizes are 00 and 00el (a 00el capsule has approximately the length of a 000 capsule and approximately the width of a 00 capsule), which in turn constrains the length and diameter of the folding system.

[0211] Once released from the container, the system is sized to prevent the gastric residing system from passing through the pyloric sphincter in an uncompressed state. In one embodiment, the system has at least two vertical dimensions, each at least 2 cm long; that is, the gastric residing system is at least about 2 cm long in at least two vertical directions. In another embodiment, when protruding onto a plane, the circumference of the system in its uncompressed state has two vertical dimensions, each at least 2 cm long. These two vertical dimensions can independently have lengths of about 2-7 cm, about 2-6 cm, about 2-5 cm, about 2-4 cm, about 2-3 cm, about 3-7 cm, about 3-6 cm, about 3-5 cm, about 3-4 cm, about 4-7 cm, about 4-6 cm, about 4-5 cm, or about 4-4 cm. These dimensions prevent the gastric residing system from passing through the pyloric sphincter. For a star-shaped polymer with N arms (where N is greater than or equal to 3, such as N=6), these arms can have dimensions such that the system has at least two vertical dimensions, each with the lengths described above. These two vertical dimensions were selected as described above to facilitate the retention of the gastric retention system.

[0212] The system is designed to disintegrate in the stomach at the end of the desired residence time (residence period), at which point the remaining components of the system are sized to allow the system to pass through the pyloric sphincter, small intestine, and large intestine. Finally, the system is cleared from the body either by defecation or by its eventual complete dissolution in the small and large intestines. Therefore, the coupling polymer or disintegrating matrix is ​​incorporated into the gastric residence system of the present invention, the latter being constructed such that, at the end of the desired residence period, when the coupling polymer or disintegrating matrix is ​​destroyed or dissolved, the uncoupled components of the gastric residence system have a size suitable for passage through the pyloric sphincter and clearance from the digestive tract.

[0213] Duration of stay

[0214] The residence time of the gastric residence system is defined as the time between its application to the stomach and its removal from the stomach. In one embodiment, the gastric residence system has a residence time of about 24 hours or at most about 24 hours. In one embodiment, the gastric residence system has a residence time of about 48 hours or at most about 48 hours. In one embodiment, the gastric residence system has a residence time of about 72 hours or at most about 72 hours. In one embodiment, the gastric residence system has a residence time of about 96 hours or at most about 96 hours. In one embodiment, the gastric residence system has a residence time of about 5 days or at most about 5 days. In one embodiment, the gastric residence system has a residence time of about 6 days or at most about 6 days. In one embodiment, the gastric residence system has a residence time of about 7 days (about 1 week) or at most about 7 days (about 1 week). In one embodiment, the gastric residence system has a residence time of about 10 days or at most about 10 days. In one implementation, the gastric residence system has a residence time of about 14 days (about 2 weeks) or at most about 14 days (about 2 weeks).

[0215] In one embodiment, the gastric residency system has a residency time of approximately 24 hours to approximately 7 days. In one embodiment, the gastric residency system has a residency time of approximately 48 hours to approximately 7 days. In one embodiment, the gastric residency system has a residency time of approximately 72 hours to approximately 7 days. In one embodiment, the gastric residency system has a residency time of approximately 96 hours to approximately 7 days. In one embodiment, the gastric residency system has a residency time of approximately 5-7 days. In one embodiment, the gastric residency system has a residency time of approximately 6-7 days.

[0216] In one embodiment, the gastric residency system has a residency time of approximately 24 hours to approximately 10 days. In one embodiment, the gastric residency system has a residency time of approximately 48 hours to approximately 10 days. In one embodiment, the gastric residency system has a residency time of approximately 72 hours to approximately 10 days. In one embodiment, the gastric residency system has a residency time of approximately 96 hours to approximately 10 days. In one embodiment, the gastric residency system has a residency time of approximately 5-10 days. In one embodiment, the gastric residency system has a residency time of approximately 6-10 days. In one embodiment, the gastric residency system has a residency time of approximately 7-10 days.

[0217] In one embodiment, the gastric residency system has a residency time of approximately 24 hours to approximately 14 days. In one embodiment, the gastric residency system has a residency time of approximately 48 hours to approximately 14 days. In one embodiment, the gastric residency system has a residency time of approximately 72 hours to approximately 14 days. In one embodiment, the gastric residency system has a residency time of approximately 96 hours to approximately 14 days. In one embodiment, the gastric residency system has a residency time of approximately 5 to 14 days. In one embodiment, the gastric residency system has a residency time of approximately 6 to 14 days. In one embodiment, the gastric residency system has a residency time of approximately 7 to 14 days. In one embodiment, the gastric residency system has a residency time of approximately 10 to 14 days.

[0218] The gastric residence system releases a therapeutically effective amount of the active agent (or its salt) during at least a portion of the residence time or residence period while the system is residing in the stomach. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 25% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 50% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 60% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 70% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 75% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 80% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 85% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or its salt) for at least about 90% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or a salt thereof) for at least about 95% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or a salt thereof) for at least about 98% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the active agent (or a salt thereof) for at least about 99% of the residence time.

[0219] Evaluation of release characteristics

[0220] The release characteristics of the active agent from the segment, arm, and gastric residence system can be evaluated using various assays. Assays for active agent release are described in detail in the examples. In vitro release of the active agent from the segment, arm, and gastric residence system can be measured by immersing the segment, arm, or gastric residence system in a liquid such as water, 0.1N HCl, fasting-state simulated gastric juice (FaSSGF), or feeding-state simulated gastric juice (FeSSGF). Fasting-state simulated gastric juice (FaSSGF) is preferred for the release assay. Simulated gastric juice refers to either fasting-state simulated gastric juice (FaSSGF) or feeding-state simulated gastric juice (FeSSGF); when a specified limit is measured in simulated gastric juice (SGF), if the limit is maintained in either fasting-state simulated gastric juice (FaSSGF) or feeding-state simulated gastric juice (FeSSGF), the limit is met. For example, if a segment is defined as releasing at least 10% of the active agent in simulated gastric fluid within the first 24 hours, then the limit is satisfied if the segment releases at least 10% of the active agent in simulated gastric fluid in a fasting state within the first 24 hours or if the segment releases at least 10% of the active agent in simulated gastric fluid in a feeding state within the first 24 hours.

[0221] Ethanol burst release is typically determined as follows: the segment, arm, or gastric retention system is immersed in a solution of 40% ethanol and 60% fasting simulated gastric juice for 1 hour, and then the same segment, arm, or gastric retention system is immersed in 100% fasting simulated gastric juice for the remainder of the test period, and the release of the active agent is measured at appropriate time points. This test is designed to simulate the effects of alcoholic beverages consumed by patients with the gastric retention system of the present invention deployed in their stomachs.

[0222] While segmental, arm, or gastric-resident systems can be used for in vitro assays, segmental assays are the most convenient for rapidly evaluating release characteristics. When performing in vitro assays to compare release rates under different conditions (e.g., comparing release in 100% FaSSGF with release in 40% ethanol / 60% FaSSGF), the comparison solutions are maintained at the same temperature, such as room temperature, 25°C, or 37°C. For these comparisons, room temperature (ambient temperature) is preferred; in one embodiment, the ambient temperature does not drop below 20°C or above 25°C (but it can fluctuate between 20-25°C).

[0223] In vivo testing can be performed on animals such as dogs (e.g., beagles or hounds) and pigs. For in vivo testing, a gastric-resident system is used because individual segments or arms are not retained in the animal's stomach. Blood samples can be obtained at appropriate time points, and stomach contents can be sampled via cannulation or other techniques if necessary.

[0224] Clinical trials conducted in humans, in accordance with appropriate laws, regulations, and official agency guidelines, also provide in vivo data.

[0225] Gastric delivery pharmacokinetics of the gastric residence system

[0226] Compared to the bioavailability of conventional oral formulations of active agents, these systems provide a higher bioavailability by AUC after administration of the gastric retention systems of the present invention. inf The measured bioavailability of the active agent is high. These systems also provide for the maintenance of approximately constant or substantially constant plasma levels of the active agent.

[0227] The relative bioavailability (FREL) of two different formulations, namely formulation A and formulation B, is defined as:

[0228] F REL =100×(AUC) A × Dosage B ) / (AUC B × Dosage A )

[0229] AUC A It is the area under the curve for formula A, AUC B It is the area under the curve for formulation B, and the dosage. A This refers to the dosage of formula A used. B This refers to the dosage of formulation B used. AUC (Area Under the Active Agent Plasma Concentration-Time Curve) is typically measured at the same time (t) after administration of each formulation to provide the relative bioavailability of the formulation at the same time point. inf AUC refers to the AUC measured or calculated over an "infinite" time period, that is, from the start of initial administration until the plasma level of the active agent drops to a negligible level.

[0230] In one embodiment, the gastric retention system of the present invention provides a substantially constant plasma level of the active agent, which may be at or above the trough level of the plasma level of the active agent when administered daily in a conventional oral formulation (i.e., the C10 level of the active agent administered daily in an immediate-release formulation). min The levels of the active agent are at or below the peak plasma levels when administered daily in the regular oral formulation (i.e., the C60 levels of the active agent administered daily in the immediate-release formulation). max In some embodiments, the substantially constant plasma level of the active agent provided by the gastric residence system of the present invention can be the peak plasma level of the active agent when administered daily in a conventional oral formulation (i.e., the C60% of the active agent administered daily in an immediate-release formulation). max The active agent provided by the gastric retention system of the present invention is approximately 50-90% of the average plasma level of the active agent when administered daily in a conventional oral formulation (i.e., the C0.05 of the active agent administered daily in an immediate-release formulation). aveThe active agent provided by the gastric retention system of the present invention is substantially constant in plasma, and may be at or above the trough level of the active agent plasma level when administered daily in a conventional oral formulation (i.e., the C10 level of the active agent administered daily in an immediate-release formulation). min ), such as C min Approximately 100-150%.

[0231] The gastric retention system of the present invention can provide a bioavailability of the active agent released from the system that is at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the bioavailability provided by an immediate-release form containing the same amount of the active agent. As shown above, this is achieved by measuring the area under the plasma concentration-time curve (AUC). inf )Measure bioavailability.

[0232] Dissolution properties, bioavailability and pharmacokinetics of the gastric residence system

[0233] Dissolution: The gastric residence system described herein provides a smooth release of the active agent or its pharmaceutically acceptable salt over an extended period of time. The system is designed to release a therapeutically effective amount of the active agent or its salt in the stomach during the residence period. The release of the active agent (or its salt) can be measured in vitro or in vivo to establish the dissolution properties (elution properties, release rate) of the active agent (or its salt) from a given residence system in a specific environment. Dissolution properties can be defined as the percentage of the original amount of the active agent (or its salt) present in the system that is eluted from the system over a given period of time.

[0234] Therefore, in some embodiments, the active agent (or its salt) contained in the gastric residence system may have a 10-20% release dissolution property in a given environment between 0 and 24 hours. That is, within 24 hours after the gastric residence system is initially introduced into the environment of interest, 10-20% of the initial active agent (or its salt) contained in the system is eluted from the system.

[0235] The environment of interest can be 1) the patient's stomach (i.e., the internal environment) or 2) a simulated gastric juice (i.e., the external environment).

[0236] Compared to the bioavailability of conventional oral formulations of the active agent (or its salt), these systems, upon administration of the gastric retention systems of the present invention, provide bioavailability by AUC. inf These systems measure high bioavailability of the active agent (or its salt). They also provide for the maintenance of substantially constant plasma levels of the active agent (or its salt).

[0237] The parameters of interest for release include linearity of release during the residence period in the gastric residence system, the standard deviation of release during the residence period (which is related to linearity of release; a standard deviation of zero indicates that release is linear throughout the residence period), release during the initial 6-hour residence period (i.e., burst release after initial administration), and the total release of the active agent (or its salt) during the residence period. A residence period of 7 days is preferred, but other periods such as 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, or 14 days are also useful.

[0238] Linearity of release of the active agent (or its salt) during the residence period refers to the amount released within each 24-hour residence period. For a 7-day residence period, what is desirable is the amount of active agent (or its salt) released daily, i.e., maximizing the linearity of release of the active agent (or its salt). This will minimize the standard deviation of daily release of the active agent or active agent salt during the residence period. In some embodiments, the variability (or standard deviation) of daily release of the active agent (or its salt) in the gastric residence system during the residence period is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. In some embodiments, the residence period may be about 3 days, about 7 days, about 10 days, or about 2 weeks.

[0239] To maintain predictable and stable release properties, minimizing burst release, i.e., release during the initial residence period (e.g., 6, 12, or 24 hours after administration of a gastric residence system), is desirable. If T is the total release of the active agent (or its salts) during the residence period (in mass) and D is the number of days in the residence period, then fully linear release would mean the release of approximately T / D mass of the active agent (or its salts) per day. If the burst release is measured during the first 6 hours, linear release properties would result in the release of 0.25 × T / D mass of the active agent (or its salts) within the first 6 hours. In terms of the percentage of the total active agent (or its salts) released during the D-day residence period, linear release is approximately 100 / D% of the active agent (or its salts) per day, and 25 / D% in the first 6 hours. (Note that 100% here refers to the total amount of active agent (or its salts) released, regardless of how much active agent (or its salts) was in the initial formulation). Therefore, for a 7-day residence period, the linear release in the first 6 hours would be approximately 3.6% of the total amount of active agent (or its salt) released over the 7-day period.

[0240] In some embodiments, during the initial 6-hour residence period following administration, the gastric residence system releases approximately 0.2-2 times T / D of the total mass T of the active agent (or its salt) released during the D-day residence period, or approximately 0.2-1.75 times T / D of the total mass T of the active agent (or its salt) released during the D-day residence period, or approximately 0.2-1.5 times T / D of the total mass T of the active agent (or its salt) released during the D-day residence period, or approximately 0.2-1.25 times T / D of the total mass T of the active agent (or its salt) released during the D-day residence period. The total mass T of the surfactant (or its salt) is approximately 0.2-1 times T / D, or the total mass T of the surfactant (or its salt) released during the D-day residence period is approximately 0.2-0.8 times T / D, or approximately 0.2-0.75 times T / D, or approximately 0.2-0.7 times T / D, or approximately 0.2-0.6 times T / D, or approximately 0.2-0.5 times T / D, or approximately 0.2-0.4 times T / D, or approximately 0.2-0.3 times T / D, or approximately 0.25-2 times T / D, or approximately 0.3-2 times T / D, or approximately 0.4-2 times T / D, or approximately 0.5-2 times T / D, or approximately 0.6 times T / D. -2 times T / D or approximately 0.7-2 times T / D or approximately 0.25-1.5 times T / D or approximately 0.3-1.5 times T / D or approximately 0.4-1.5 times T / D or approximately 0.5-1.5 times T / D or approximately 0.6-1.5 times T / D or approximately 0.7-1.5 times T / D or approximately 0.25-1.25 times T / D or approximately 0.3-1.25 times T / D or approximately 0.4-1.25 times T / D or approximately 0.5-1.25 times T / D or approximately 0.6-1.25 times T / D or approximately 0.7-1.25 times T / D or approximately 0.25-1 times T / D or approximately 0.3-1 times T / D or approximately 0.4-1 times T / D or approximately 0.5-1 times T / D or approximately 0.6-1 times T / D or approximately 0.7-1 times T / D or approximately 0.25 times T / D or approximately 0.25-0.8 times T / D or approximately 0.3-0.8 times T / D or approximately 0.4-0.8 times T / D or approximately 0.5-0.8 times T / D or approximately 0.6-0.8 times T / D or approximately 0.7-0.8 times T / D or approximately 0.8 times T / D, approximately 1 times T / D, approximately 1.25 times T / D, approximately 1.5 times T / D or approximately 2 times T / D.

[0241] In some embodiments of the gastric residence system, during the initial 6-hour residence period after administration, the gastric residence system releases approximately 2-10%, or approximately 3-10%, or approximately 4-10%, or approximately 5-10%, or approximately 6-10%, or approximately 7-10%, or approximately 8-10%, or approximately 9-10%, or approximately 2-9%, or approximately 2-8%, or approximately 2-7%, or approximately 2-6%, or approximately 2-5%, or approximately 2-4%, or approximately 2-3% of the total mass of the active agent (or its salt) released during the residence period.

[0242] In some embodiments of the gastric residence system, the gastric residence system has a residence period of approximately 7 days, during which, during the initial 6-hour residence period after administration, the gastric residence system releases approximately 2-10%, or approximately 3-10%, or approximately 4-10%, or approximately 5-10%, or approximately 6-10%, or approximately 7-10%, or approximately 8-10%, or approximately 9-10%, or approximately 2-9%, or approximately 2-8%, or approximately 2-7%, or approximately 2-6%, or approximately 2-5%, or approximately 2-4%, or approximately 2-3% of the total mass of the active agent (or its salt) released during the 7-day residence period.

[0243] In some embodiments, during the initial 24-hour residence period after administration, the gastric residence system releases approximately 10-35%, or approximately 10-30%, or approximately 10-25%, or approximately 10-20%, or approximately 10-15%, or approximately 15-35%, or approximately 15-35%, or approximately 15-30%, or approximately 20-30%, or approximately 25-35%, or approximately 25-30%, or approximately 30-35% of the total mass of the active agent (or its salt) released during the residence period.

[0244] In some embodiments, the gastric residence system has a residence period of about 7 days, during which the gastric residence system releases about 10-35%, or about 10-30%, or about 10-25%, or about 10-20%, or about 10-15%, or about 15-35%, or about 15-35%, or about 20-30%, or about 25-35%, or about 25-30%, or about 30-35% of the total mass of the active agent (or its salt) released during the 7-day residence period.

[0245] elastomer

[0246] An elastomer (also known as an elastic polymer or stretching polymer) enables the gastric retention system to be compressed, such as folded or compressed, into a form suitable for application to the stomach by swallowing a container or capsule containing the compression system. When the capsule dissolves in the stomach, the gastric retention system expands to a shape that prevents the system from passing through the patient's pyloric sphincter for the desired system retention period. Therefore, the elastomer must be able to be stored in a capsule in a compressed configuration for a reasonable shelf life and expand to or substantially expand to its original shape upon release from the capsule. In one embodiment, the elastomer is a silicone elastomer. In one embodiment, the elastomer is formed from liquid silicone rubber (LSR), for example, as sold in the form of Dow Corning QP-1 liquid silicone rubber kits. In one embodiment, the elastomer is cross-linked polycaprolactone. In one embodiment, the elastomer is an enteric polymer, such as those listed in the enteric polymers table. In some embodiments, the coupling polymer used in the system is also an elastomer. The elastomer is preferably used as the central polymer in a star-shaped or star-shaped design of the gastric retention system.

[0247] In one embodiment, both the coupling polymer and the elastomer are enteric polymers that cause the system to break down more completely into carrier polymer-active agent tablets if the system enters the intestine or if the patient drinks a mildly alkaline solution to induce the system to pass through.

[0248] Examples of elastomers that can be used include silicones, such as those formed using the Dow Corning QP-1 kit; urethane-crosslinked polycaprolactone; poly(acryloyl 6-aminohexanoic acid) (PA6ACA); poly(ethyl methacrylate-co-acrylate) (EUDRAGIT L 100-55); and mixtures of poly(acryloyl 6-aminohexanoic acid) (PA6ACA) and poly(ethyl methacrylate-co-acrylate) (EUDRAGIT L 100-55).

[0249] Flexible coupling polymers, i.e., elastomeric coupling polymers or elastomers, are used as the central polymer in star-shaped or star-shaped designs of gastric residence systems. A particularly preferred elastomer for use as the central elastomer with a star-shaped or star-shaped configuration is silicone rubber. Liquid silicone rubber (LSR) can be readily molded and cured into the desired shape. The Dow Corning QP-1 series, comprising crosslinked dimethyl and methyl-vinylsiloxane copolymers and reinforced silica, is an example of such silicone rubber polymers (see, for example, the website www.dowcorning.com / DataFiles / 090276fe8018ed07.pdf). Segmentless arms or arms containing segments of the carrier polymer-activator component can then be attached to this central silicone rubber elastomer. Another elastomer that can be used as the central elastomer in a star-shaped design is crosslinked polycaprolactone.

[0250] Specific constructions of gastric residency systems are disclosed in International Patent Application No. WO 2017 / 100367, and any of those constructions can be used in the gastric residency system disclosed herein. The carrier polymer (carrier polymer-active agent component) is used for the segments and arms.

[0251] The segments and arms of the gastric residence system contain a carrier polymer-active agent component, which contains an active agent (or a pharmaceutically acceptable salt of an active agent) to be eluted from the gastric environment of the gastric residence system. The active agent is incorporated into the carrier polymer to form a carrier polymer-active agent mixture. This mixture can be shaped into one or more desired shapes for use as the carrier polymer-active agent component in the system. After a drug or drug salt is incorporated into the carrier polymer to form a carrier polymer-drug mixture, the drug or drug salt is distributed or dispersed throughout the blend. If excipients, antioxidants, or other components are included in the carrier polymer-drug blend, they will also be distributed or dispersed throughout the blend.

[0252] The choice of carrier material for the active agent or its pharmaceutically acceptable salt in a gastric residence system affects the drug release properties during gastric residence. The carrier polymer can be thermoplastic to allow extrusion using hot melt extrusion or 3D printing techniques. They can also have sufficiently high melt strength and viscosity to enable extrusion into the required geometry. They can have low melt temperatures (e.g., less than about 120°C) to avoid exposing the active agent or drug to high temperatures during manufacturing. They can have sufficient mechanical strength (Young's modulus, compressive strength, tensile strength) to prevent rupture in the stomach during the desired residence period. They should be able to form stable blends with the active agent, therapeutic agent, drug, excipient, dispersant, and other additives.

[0253] Exemplary carrier polymers suitable for use in this invention include, but are not limited to, hydrophilic cellulose derivatives (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose), cellulose acetate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymers, polyvinyl alcohol, and carboxyvinyl polymers (carbomer). Acidic carboxyl polymers, polycarboxylic acid, polyoxyethylene (Polyox WSR), polysaccharides and their derivatives, polyoxyethylene, polyethylene glycol, chitosan, alginate, pectin, acacia gum, tragacanth gum, guar gum, locust bean gum, vinylpyrrolidone vinyl acetate copolymer, dextran, natural gums, agar, agarose, sodium alginate, carrageenan, fucoidan, red algae gum, laminarin, hypnea, eucheuma, gum arabic, gum arabic, guilargine, arabinoglactan, starch, gelatin, gellan gum, hyaluronic acid, amylopectin, sclerotium dextran, xanthan gum, xyloglucan, maleic anhydride copolymer, ethylene maleic anhydride copolymer, poly(hydroxyethyl methacrylate), ammonium methacrylate copolymers (such as Eudragit RL or Eudragit). RS), poly(ethyl acrylate-methyl methacrylate) (Eudragit NE), Eudragit E (a cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylate), polyacrylic acid, polymethacrylate / polyethyl acrylate such as polymethacrylate, methyl methacrylate and ethyl acrylate, polylactone such as polycaprolactone, polyanhydride such as poly[bis-(p-carboxyphenoxy)propane anhydride], polyterephthalic anhydride, polypeptides such as polylysine, polyglutamic acid, poly(orthoesters) such as DETOSU and copolymers with glycols such as hexanediol, decanediol, cyclohexanediol, ethylene glycol, polyethylene glycol and those poly(orthoesters) described and disclosed in U.S. Patent No. 4,304,767 incorporated herein by reference, starch, especially pregelatinized starch and starch-based polymers, carbomer, maltodextrin, starch maltodextrin (amylomaltodextrin), dextran, poly(2-ethyl-2- Poly(hydroxyacetic acid), polyethyleneimine, polyurethane, polylactic acid, poly(hydroxyacetic acid), poly(lactic-co-hydroxyacetic acid) (PLGA), polyhydroxyalkanoates, polyhydroxybutyrate, poly(ethylene-co-vinyl acetate), and their copolymers, mixtures, blends, and combinations thereof. Polycaprolactone (PCL) and / or thermoplastic polyurethane are preferred carrier polymers. In some embodiments, poly(p-dioxanone) is used as the carrier polymer. In any embodiment of the gastric residence system, the carrier polymer used in the gastric residence system may comprise polycaprolactone, such as linear polycaprolactone with a number average molecular weight (Mn) ranging from about 60-100 kilodaltons (kDa); 75-85 kDa; or about 80 kDa; or about 45-55 kDa; or about 50-110,000 kDa; or about 80-110,000 kDa.

[0254] Furthermore, drug release can be modulated by various excipients included in the carrier polymer-active agent component. Soluble excipients include P407, Eudragit E, PEG, polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA). Insoluble wicking excipients include Eudragit RS and Eudragit RL. Degradable excipients include PLA, PLGA, PLA-PCL, poly(p-dioxanone), and linear copolymers of caprolactone and glycolide; multiaxial block copolymers of glycolide, caprolactone, and trimethylene carbonate; multiaxial block copolymers of glycolide, trimethylene carbonate, and lactide; multiaxial block copolymers of glycolide, trimethylene carbonate, and polypropylene succinate; multiaxial block copolymers of caprolactone, lactide, glycolide, and trimethylene carbonate; multiaxial block copolymers of glycolide, trimethylene carbonate, and caprolactone; and linear block copolymers of lactide, caprolactone, and trimethylene carbonate, such as linear copolymers of caprolactone (95%) and glycolide (5%); glycolide (68%). Multiaxial block copolymers of caprolactone (29%) and trimethylene carbonate (3%); multiaxial block copolymers of glycolide (86%), trimethylene carbonate (9%) and lactide (5%); multiaxial block copolymers of glycolide (70%), trimethylene carbonate (27%) and polypropylene succinate (2%); multiaxial block copolymers of caprolactone (35%), lactide (34%), glycolide (17%) and trimethylene carbonate (14%); multiaxial block copolymers of glycolide (55%), trimethylene carbonate (25%) and caprolactone (20%); and linear block copolymers of lactide (39%), caprolactone (33%) and trimethylene carbonate (28%). Insoluble, swelling excipients include polyvinyl acetate (PVAc), croscarmellose, croscarmellose carboxymethyl cellulose, HPMCAS, and linear block copolymers of p-dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethyl carbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol; such as p-dioxanone (8... Linear block copolymers of lactide (0%) and ethylene glycol (20%); linear block copolymers of lactide (60%) and ethylene glycol (40%); linear block copolymers of lactide (68%), ethylene glycol (20%), trimethyl carbonate (10%) and caprolactone (2%); linear block copolymers of lactide (88%), lactide (8%) and ethylene glycol (4%); linear block copolymers of lactide (67%), polyethylene glycol (28%) and ethylene glycol (5%). Surfactants include lecithin, taurine, SDS, Soluplus, fatty acids, and Kolliphor RH40.

[0255] Other excipients can be added to the carrier polymer to adjust the release of the surfactant. These excipients can be added in amounts of about 1-75%, about 5-50%, or about 5% or about 30%. Examples of such excipients include poloxamer 407 (available as Kolliphor P407, Sigma catalog number 62035), polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol, CAS number 9003-11-6; H-(OCH2CH2) x -(O-CH(CH3)CH2) y -(OCH2CH2) z -OH, where x and z are about 101 and y is about 56); Pluronic P407; Eudragit E, Eudragit EPO (available from Evonik); hydroxypropyl methylcellulose (available from Sigma, catalog number H3785), Kolliphor RH40 (available from Sigma, catalog number 07076), polyvinyl caprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), and Soluplus (available from BASF; a copolymer of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol). Preferred soluble excipients include Eudragit E, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl alcohol (PVA). Preferred insoluble excipients include Eudragit RS and Eudragit RL. Preferred insoluble, swellable excipients include crospovidone, crospovidone carboxymethyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), and carboplatin. EUDRAGIT RS and EUDRAGIT RL are registered trademarks of Evonik (Darmstadt, Germany) of a copolymer of ethyl acrylate, methyl methacrylate, and a quaternary ammonium methacrylate (trimethylammonium ethyl methacrylate chloride), having a molar ratio of ethyl acrylate, methyl methacrylate, and trimethylammonium ethyl methacrylate of […]. In RL, the ratio is approximately 1:2:0.2 and in The ratio in RS is approximately 1:2:0.1. Preferred insoluble, swellable excipients include croscarmellose, croscarmellose carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carbopol, and linear block copolymers of p-dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethyl carbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol; such as p-dioxanone... Linear block copolymers of cyclohexanone (80%) and ethylene glycol (20%); linear block copolymers of lactide (60%) and ethylene glycol (40%); linear block copolymers of lactide (68%), ethylene glycol (20%), trimethyl carbonate (10%) and caprolactone (2%); linear block copolymers of lactide (88%), glycolide (8%) and ethylene glycol (4%); linear block copolymers of glycolide (67%), polyethylene glycol (28%) and ethylene glycol (5%).

[0256] Other examples of excipients that can be used in the segments of this gastric residency system are listed in the excipient table below.

[0257] Excipient list

[0258]

[0259]

[0260] Carrier polymer-activator / activator salt combination with excipients and other additives

[0261] Blends of carrier polymer-activator or carrier polymer-activator salts can contain a variety of excipients and other additives. Table CPE-1 below lists combinations of excipients and other additives that can be used in combination with an activator or its salt and a carrier polymer in a composition constituting an arm or segment of a gastric resident system. These excipients and other additives can be combined with an activator or its salt (wherein the activator or activator salt constitutes about 10-60% by weight of the composition) and a carrier polymer such as polycaprolactone to form the remainder of the composition. Excipients include the following substances that can be used alone or in any combination in an amount of about 1-30% by weight of the composition, such as about 5-20% by weight: Kolliphor P407 (poloxamer 407, polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol), Eudragit RS (poly[ethyl acrylate, methyl methacrylate, trimethylammonium methacrylate chloride] 1:2:0.1), Eudragit RL (poly[ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride] 1:2:0.2), PDO (polydioxanone), PEG-PCL, SIF (FaSSIF / FaSSGF powder from BioRelevant), EPO (dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer), KollidonVA64 (vinylpyrrolidone-vinyl acetate copolymer at a mass ratio of 6:4), polyvinyl acetate, polyvinylpyrrolidone.

[0262] Other additives include silica (e.g., about 0.1-5% by weight of the composition, such as about 0.1-1% or about 0.5%) and antioxidants, such as α-tocopherol (e.g., about 0.1-5% by weight of the composition, such as about 0.1-1% or about 0.5%). The rows in the table below indicate formulations of excipients and other additives used with the carrier polymer and the active agent or its salts.

[0263] Table CPE-1

[0264]

[0265]

[0266] Table CPE-2 lists the specific amounts of excipients and other additives that can be used in combination with the active agent or its salt and carrier polymer in the composition constituting the arm or segment of the gastric resident system.

[0267] The amounts listed in Table CPE-2 can be varied by ±20% for each component (e.g., 0.5% silica can vary between 0.4% and 0.6% silica, since 20% of 0.5% is 0.1%). The rows in the table below represent formulations of excipients and other additives used with the carrier polymer and the active agent or its salts.

[0268] Table CPE-2

[0269]

[0270]

[0271] Active agents for the gastric resident system

[0272] Active agents (e.g., pharmaceutical active ingredients, therapeutic agents) that can be applied to or administered via the gastrointestinal tract can be used in the gastric retention system of the present invention. The active agent is blended with the carrier polymer and any other excipients or other additives added to the carrier mixture to form a segment for use in the gastric retention system. Active agents include, but are not limited to, drugs, prodrugs, biological products, and any other substances that can be administered to produce a beneficial effect on a disease or injury.

[0273] Active agents that can be used in the gastric resident system of this invention include statins, such as rosuvastatin; nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam; selective serotonin reuptake inhibitors (SSRIs), such as etanercept and citalopram; blood thinners, such as clopidogrel; steroids, such as prednisone; antipsychotics, such as aripiprazole and risperidone; analgesics, such as buprenorphine; opioid antagonists, such as naloxone; antiasthmatics, such as montelukast; antidementia drugs, such as memantine; cardiac glycosides, such as digoxin; alpha-blockers, such as tamsulosin; and cholesterol. Absorption inhibitors, such as ezetimibe; antigout medications, such as colchicine; antihistamines, such as loratadine and cetirizine; opioids, such as loperamide; proton pump inhibitors, such as omeprazole; antiviral drugs, such as entecavir; antibiotics, such as doxycycline, ciprofloxacin, and azithromycin; antimalarial drugs; levothyroxine; drug abuse treatments, such as methadone and varenicline; contraceptives; and nutrients, such as folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, biotin, plant extracts, phytohormones, and other vitamins or minerals. Biological products that can be used as active agents in the gastric resident system of this invention include proteins, peptides, polynucleotides, and hormones. Exemplary categories of active agents include, but are not limited to, analgesics; anti-analgesics; anti-inflammatory drugs; antipyretics; antidepressants; antiepileptics; antipsychotics; neuroprotective agents; antiproliferative agents, such as anticancer drugs; antihistamines; antimigraines; hormones; prostaglandins; antimicrobial agents, such as antibiotics, antifungals, antivirals, and antiparasitics; antimuscarinic agents; anxiolytics; bacteriostatic agents; immunosuppressants; sedatives; hypnotics; antipsychotics; bronchodilators; antiasthmatics; cardiovascular drugs; anesthetics; anticoagulants; enzyme inhibitors; steroids; and steroids or nonsteroidal anti-inflammatory drugs. Drugs; corticosteroids; dopaminergic drugs; electrolytes; gastrointestinal drugs; muscle relaxants; nutritional supplements; vitamins; parasympathomimetic drugs; appetite suppressants; anti-narcoleptics; and antimalarial drugs, such as quinine, fluorenol, chloroquine, amodiaquine, pyrimethamine, chlorguanidine, chlorpromazine-dapsone, sulfonamides (e.g., sulfadoxine and sulfamethoxazole), mefloquine, atovaquinone, primaquine, halopanthracene, doxycycline, clindamycin, artemisinin, and artemisinin derivatives (e.g., artemether, dihydroartemisinin, artesyl ether, and artesunate). The term "active agent" includes salts, solvates, polymorphs, and cocrystals of the above substances. In some embodiments, the active agent is selected from cetirizine, rosuvastatin, etanercept, citalopram, risperidone, olanzapine, donepezil, and ivermectin. In some implementations, the active agent is an active agent used to treat neuropsychiatric disorders, such as antipsychotics or antidementia drugs like memantine.

[0274] In some embodiments, the active agent may exclude adamantane drugs. In some embodiments, the active agent may exclude one or more of the following active agents: memantine; adamantane; adapromine; nitromemantine; rimantadine; bromelain; nelamissen; or tremantine; or a pharmaceutically acceptable salt of memantine, adamantane, adapromine, nitromemantine, rimantadine, bromelain, or tremantine. In some embodiments, the active agent may exclude memantine. In some embodiments, the active agent may exclude a salt of memantine or a pharmaceutically acceptable salt of memantine.

[0275] The active agent can be used in any suitable crystalline form, or in an amorphous form, or in both crystalline and amorphous forms in the gastric retention system of the present invention. That is, the active agent or drug particles contained in the gastric retention system can be used in crystalline form, in amorphous form, or in a mixture of crystalline (single crystalline or multiple crystalline) and amorphous forms to provide the desired release rate or desired physical or chemical properties.

[0276] Gastrointestinal residency systems are well-suited for treating diseases and disorders where patient adherence is difficult; therefore, in some implementations, gastrointestinal residency systems are used to treat diseases or disorders in which patients have problems adhering to medication regimens. These diseases and disorders include neuropsychiatric disorders, dementia and other disorders and disorders affecting memory, Alzheimer's disease, psychosis, schizophrenia, and paranoia. Therefore, active agents that can be used in gastrointestinal residency systems include, but are not limited to, antidementia drugs, anti-Alzheimer's drugs, and antipsychotics.

[0277] Exemplary hydrophilic surfactants that can be used in the system include risperidone, cetirizine, memantine, and olanzapine. Exemplary hydrophobic surfactants that can be used in the system include aripiprazole, ivermectin, rosuvastatin, citalopram, and entapril.

[0278] In some embodiments, the active agent or its salt (e.g., a drug) constitutes about 10-40% by weight of the arm or segment, and thus the carrier polymer and any other components of the arm or segment blended into the carrier polymer together constitute the remainder by weight of the arm or segment. In some embodiments, the active agent or its salt constitutes about 10-35% by weight, about 10-30% by weight, about 10-25% by weight, about 10-20% by weight, about 10-15% by weight, about 15-40% by weight, about 20-40% by weight, about 25-40% by weight, about 30-40% by weight, about 35-40% by weight, about 15-35% by weight, about 20-35% by weight, or about 25-40% by weight of the arm or segment.

[0279] Other embodiments of the arm or segment in which the active agent or its salt accounts for more than about 40% by weight are described below under “High Active Agent Loading in Arms and Segments”.

[0280] Highly active agent loading in arms and segments

[0281] In some embodiments of the invention, an arm or a segment constituting an arm may have a high loading of an active agent or a pharmaceutically acceptable salt thereof. “High loading” generally means an arm or segment in which the active agent or salt (e.g., a drug) constitutes more than about 40% by weight and therefore the carrier polymer and any other components of the arm or segment blended into the carrier polymer together constitute less than about 60% by weight of the arm or segment. Any components of the arm or segment not blended into the carrier polymer are not included in the weight percentage calculation; for example, if the arm has one or more disintegrating matrices dispersed between the segments of the arm, the weight of such matrices will not be included as part of the arm's weight percentage calculation of the active agent. Once the loading of the active agent is increased to about 60%, it becomes increasingly difficult to properly blend the active agent with the carrier polymer, and phase separation of the active agent and polymer tends to occur. Therefore, the loading of the active agent in the arm or segment should not exceed about 60% of the total weight of the arm.

[0282] Therefore, in some embodiments, the amount of the active agent in the arm or the segment constituting the arm may be at least about 40%, at least about 45%, at least about 50%, at least about 55%, or about 60% by weight. In some embodiments, the amount of the active agent in the arm or the segment constituting the arm may be about 40-60%, about 45-60%, about 50-60%, about 55-60%, about 40-55%, about 40-50%, or about 40-45% by weight. In some embodiments, the amount of the active agent in the arm or the segment constituting the arm may be about 25-60%, about 30-60%, or about 35-60% by weight. In some embodiments, the amount of the active agent in the arm or the segment constituting the arm may be about 51-60%, about 52-60%, about 53-60%, about 54-60%, about 55-60%, about 56-60%, or about 57-60% by weight. In some embodiments, the active agent or its pharmaceutically acceptable salt may be present in an amount of about 67-150% by weight of the carrier polymer.

[0283] The combination of highly active agent or active agent salt loading with a polymer membrane that controls the release rate provides an increased amount of active agent or active agent salt to the gastric residence system while maintaining good release kinetics during the residence period of the system.

[0284] Dispersants used to regulate surfactant release and polymer blend stability

[0285] The use of dispersants in the carrier polymer-active agent component offers numerous advantages. The elution rate of the active agent from the carrier polymer-active agent component is influenced by many factors mentioned above, including the composition and properties of the carrier polymer (which itself may contain various polymer and non-polymer components); the physical and chemical properties of the active agent; and the gastric environment. Avoiding burst release of the active agent, especially hydrophilic active agents, and maintaining a sustained release of the active agent during the effective release or residence period are important characteristics of the system. Using the dispersant of the present invention allows for better control of the release rate and inhibition of burst release. Burst release and release rate can be adjusted by using different concentrations of dispersant. For example, different concentrations of different dispersants and different excipients can regulate the burst release of cetirizine in simulated gastric fluid.

[0286] Dispersants that can be used in this invention include silica (silica, SiO2) (hydrophilic igneous silica); stearates, such as calcium stearate and magnesium stearate; microcrystalline cellulose; carboxymethyl cellulose; hydrophobic colloidal silica; hydroxypropyl methylcellulose; magnesium aluminum silicate; phospholipids; polyoxyethylene stearate; zinc acetate; alginate; lecithin; fatty acids; sodium lauryl sulfate; and non-toxic metal oxides, such as alumina. Porous inorganic materials and polar inorganic materials can be used. Hygrophilic igneous silica is a preferred dispersant. A particularly useful silica is trademarked by Cabot Corporation (Boston, Massachusetts, USA). M-5P (CAS#112945-52-5) is for sale; it has a capacity of approximately 200m. 2 / g±15m 2 Hydrophilic ignited silica with a BET surface area of ​​ / g. The product has a sieve residue of less than about 0.02% on a 45-micron sieve. Typical primary aggregate size is about 150-300 nm, while individual particle size can be about 5-50 nm.

[0287] In addition to its anti-aggregation / anti-flocculation activity, this dispersant helps prevent phase separation during the manufacturing and / or storage of the system. This is particularly useful for systems manufactured via hot melt extrusion.

[0288] The weight ratio of dispersant to surfactant can be approximately 0.1-5%, approximately 0.1-4%, approximately 0.1-3%, approximately 0.1-2%, approximately 0.1-1%, approximately 1-5%, approximately 1-4%, approximately 1-3%, approximately 1-2%, approximately 2-4%, approximately 2-3%, approximately 3-4%, approximately 4-5%, or approximately 0.1%, approximately 0.5%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, or approximately 5%.

[0289] The dispersant may comprise about 0.1-4% of the carrier polymer-active agent component, such as about 0.1-3.5%, about 0.1-3%, about 0.1-2.5%, about 0.1-2%, about 0.1-1.5%, about 0.1-1%, about 0.1-0.5%, or about 0.2-0.8%.

[0290] When this gastric residency system is administered, the dispersant can also be used to regulate the burst release of the active agent or its pharmaceutically acceptable salt during the initial phase. In an embodiment of a gastric residency system administered once weekly, the burst release within approximately 6 hours after initial administration is less than about 8% of the total amount of the active agent (or its salt) in the system, preferably less than about 6%. In an embodiment of a gastric residency system administered every three days, the burst release within approximately 6 hours after initial administration is less than about 12% of the total amount of the active agent (or its salt) in the system, preferably less than about 10%. In an embodiment of a gastric residency system administered daily, the burst release within approximately 6 hours after initial administration is less than about 40% of the total amount of the active agent (or its salt) in the system, preferably less than about 30%. Generally, if a new gastric retention system is administered every D days and the total mass of the active agent (or its salt) is M, the gastric retention system releases less than about [(M / D) × 0.5], preferably less than about [(M / D) × 0.4] or less than about [(M / D) × 3 / 8], more preferably less than about [(M / D) × 0.3], within approximately the first 6 hours after initial administration. In other embodiments, the gastric retention system releases at least about [(M / D) × 0.25] within approximately the first 6 hours after initial administration, i.e., within the first quarter of the first day of administration, the system releases at least about one-quarter of the daily dose.

[0291] Stabilizers for the gastric residency system

[0292] Many surfactants are readily oxidized and degraded when exposed to reactive oxygen species that may be present in the stomach. Because the system resides in the stomach for extended periods and the release period of surfactants from the system is prolonged, surfactants contained within the system may oxidize. Therefore, it is desirable to include stabilizers or preservatives in the system to stabilize the surfactants and prevent oxidation and other degradation.

[0293] Stabilizers, such as antioxidants including tocopherols, α-tocopherol, ascorbic acid, ascorbate palmitate, butylated hydroxytoluene, butylated hydroxyanisole, and fumaric acid, may comprise about 0.1-4% of the carrier polymer-active agent component, for example, about 0.1-3.5%, about 0.1-3%, about 0.1-2.5%, about 0.1-2%, about 0.1-1.5%, about 0.1-1%, about 0.1-0.5%, or about 0.2-0.8%.

[0294] Antioxidant stabilizers that may be included in the system to reduce or prevent oxidation of the active agent include α-tocopherol (about 0.01-0.05% v / v), ascorbic acid (about 0.01-0.1% w / v), palmitic ascorbate (about 0.01-0.1% w / v), butylated hydroxytoluene (about 0.01-0.1% w / w), butylated hydroxyanisole (about 0.01-0.1% w / w), and fumaric acid (up to 3600 ppm). Vitamin E, tocopherol, vitamin E esters, tocopherol esters, ascorbic acid, or carotene such as α-tocopherol, vitamin E succinate, α-tocopherol succinate, vitamin E acetate, α-tocopherol acetate, vitamin E nicotinate, α-tocopherol nicotinate, vitamin E linoleate, or α-tocopherol linoleate can be used as antioxidant stabilizers.

[0295] Some surfactants may be pH sensitive, especially at low pH levels present in the gastric environment. Buffering compounds or pH stabilizers that can be included in the system to reduce or prevent surfactant degradation at low pH levels include calcium carbonate, calcium lactate, calcium phosphate, sodium phosphate, and sodium bicarbonate. They are typically used at a maximum of about 2% w / w. The buffering compound or pH stabilizer may constitute about 0.1-4% of the carrier polymer-surfactant component, such as about 0.1-3.5%, about 0.1-3%, about 0.1-2.5%, about 0.1-2%, about 0.1-1.5%, about 0.1-1%, about 0.1-0.5%, or about 0.2-0.8%.

[0296] Antioxidant stabilizers, pH stabilizers, and other stabilizer compounds are blended into polymers containing surfactants (or their pharmaceutically acceptable salts) by blending stabilizers into molten carrier polymer-surfactant or surfactant salt mixtures. The stabilizer can be blended into the molten carrier polymer, and then the surfactant (or its salt) can be blended into the polymer-stabilizer mixture; alternatively, the stabilizer can be blended with the surfactant (or its salt), and then the blended surfactant (or its salt)-stabilizer mixture can be formulated into the carrier polymer; or the stabilizer, surfactant (or its salt), and molten carrier polymer can be blended simultaneously. Alternatively, the surfactant (or its salt) can be blended with the molten carrier polymer, and then the stabilizer can be blended into the polymer-surfactant or surfactant salt mixture.

[0297] In one embodiment, after a gastric residence period of approximately 24 hours, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized. In one embodiment, after a gastric residence period of approximately 48 hours, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized. In one embodiment, after a gastric residence period of approximately 72 hours, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized. In one embodiment, after a gastric residence period of approximately 96 hours, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized. In one embodiment, after a gastric residence period of approximately 5 days, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized. In some embodiments, after a gastric residence period of approximately 1 week, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized. In some embodiments, after a gastric residence period of approximately 2 weeks, less than 10% of the active agent (or its salt) remaining in the system is degraded or oxidized.

[0298] In one embodiment, after a gastric residence period of approximately 24 hours, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation. In one embodiment, after a gastric residence period of approximately 48 hours, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation. In one embodiment, after a gastric residence period of approximately 72 hours, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation. In one embodiment, after a gastric residence period of approximately 96 hours, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation. In one embodiment, after a gastric residence period of approximately 5 days, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation. In some embodiments, after a gastric residence period of approximately 1 week, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation. In some embodiments, after a gastric residence period of approximately 2 weeks, less than 5% of the active agent (or its salt) remains in the system, resulting in degradation or oxidation.

[0299] Coupling polymers

[0300] The coupling polymer is used to link one or more carrier polymer-active agent components (i.e., arms or segments of arms) to one or more carrier polymer-active agent components, to one or more carrier polymer-active agent components (i.e., cores), or to one or more elastomer components. Thus, the coupling polymer forms a linker region between the other components of the system. Enteric polymers and time-dependent polymers are preferably used as coupling polymers. In some embodiments, enteric polymers are used as coupling polymers. In some embodiments, pH-resistant time-dependent polymers (i.e., less sensitive to pH changes than enteric polymers) are used as coupling polymers. In some embodiments, both enteric polymers and time-dependent polymers less sensitive to pH changes than enteric polymers are used as coupling polymers.

[0301] Enteric polymers are relatively insoluble under acidic conditions, such as those encountered in the stomach, but soluble under weakly acidic to alkaline conditions encountered in the small intestine. Enteric polymers that dissolve at approximately pH 5 or higher can be used as coupling polymers because the initial segment of the small intestine—the duodenum—has a pH range of approximately 5.4–6.1. If the gastric resident system passes intact through the pyloric valve, the enteric coupling polymer will dissolve and the components linked by the coupling polymer will disintegrate, thus allowing the resident system to pass through the small and large intestines. Therefore, the gastric resident system is designed to rapidly uncouple in the intestinal environment through the dissolution of the coupling polymer.

[0302] A “pH-resistant time-dependent polymer” (or equivalently, a “pH-resistant time-dependent polymer”) means a time-dependent polymer that still possesses sufficient mechanical strength to bind the components together even after the enteric polymer has degraded to the point where it no longer binds the components together. In some embodiments, after exposure to a solution at approximately pH 7–pH 8, the time-dependent polymer retains approximately the same binding capacity, i.e., approximately 100% of its binding strength, after exposure to a solution at approximately pH 2–pH 3, wherein such exposure is for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, after exposure to a solution at approximately pH 7–pH 8, the time-dependent polymer retains at least approximately 90% of its binding strength after exposure to a solution at approximately pH 2–pH 3, wherein such exposure is for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, after exposure to a solution at approximately pH 7–pH 8, the time-dependent polymer retains at least approximately 75% of its bond strength after exposure to a solution at approximately pH 2–pH 3, wherein such exposure is for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, after exposure to a solution at approximately pH 7–pH 8, the time-dependent polymer retains at least approximately 60% of its bond strength after exposure to a solution at approximately pH 2–pH 3, wherein such exposure is for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, after exposure to a solution at approximately pH 7–pH 8, the time-dependent polymer retains at least approximately 50% of its bond strength after exposure to a solution at approximately pH 2–pH 3, wherein such exposure is for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, after exposure to a solution at approximately pH 7–pH 8, the time-dependent polymer retains at least approximately 25% of its bond strength after exposure to a solution at approximately pH 2–pH 3, wherein such exposure is approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, the time-dependent polymer resists fracture under flexural forces of approximately 0.2 Newtons (N), approximately 0.3 N, approximately 0.4 N, approximately 0.5 N, approximately 0.75 N, approximately 1 N, approximately 1.5 N, approximately 2 N, approximately 2.5 N, approximately 3 N, approximately 4 N, or approximately 5 N after exposure to a solution at approximately pH 7–pH 8, wherein such exposure is approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. Bond strength can be measured by any relevant test used to test coupling ability, such as the four-point bending test (ASTM D790).

[0303] Exemplary coupling polymers include, but are not limited to, cellulose acetate, cellulose succinate, methylcellulose phthalate, ethyl hydroxycellulose phthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylate copolymer, methacrylate-methacrylate-octyl acrylate copolymer, and copolymers, mixtures, blends, and combinations thereof. A number of enteric polymers that can be used in this invention and their solubility pH are listed in the enteric polymer table (see Mukherji, Gour, and Clive G. Wilson, “Enteric Coating for Colonic Delivery,” Modified-Release Drug Delivery Technology, Chapter 18 (edited by Michael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts), Drugs and the Pharmaceutical Sciences, Vol. 126, New York: Marcel Dekker, 2002). Enteric polymers that dissolve at a pH of not more than about 5 or about 5.5 are preferred. Poly(ethyl methacrylate-co-acrylate) (sold under the trade name EUDRAGIT L100-55; EUDRAGIT is Evonik) GmbH, Darmstadt (a registered trademark in Germany) is a preferred enteric polymer. Another preferred enteric polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS; Ashland, Inc., Covington, Kentucky, USA), which has an adjustable pH threshold of about 5.5-7.0. Cellulose acetate, cellulose acetate succinate, and hydroxypropyl methylcellulose phthalate are also suitable enteric polymers.

[0304] In one embodiment, the enteric polymer used in the gastric resident system dissolves at a pH higher than about 4. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH higher than about 5. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH higher than about 6. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH higher than about 7. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH higher than about 7.5. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH of about 4-5. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH of about 4-6. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH of about 4-7. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH of about 4-7.5. In some embodiments, the enteric polymer used in the gastric resident system dissolves at a pH of about 5-6. In some embodiments, the enteric polymer used in the gastric resident system is dissolved at a pH of about 5-7. In some embodiments, the enteric polymer used in the gastric resident system is dissolved at a pH of about 5-7.5. In some embodiments, the enteric polymer used in the gastric resident system is dissolved at a pH of about 6-7. In some embodiments, the enteric polymer used in the gastric resident system is dissolved at a pH of about 6-7.5.

[0305] Enteric polymer surface

[0306]

[0307]

[0308] Additional preferred polymers for use as coupling polymers are time-dependent polymers, i.e., polymers that degrade in a time-dependent manner in the gastric environment. For example, the liquid plasticizer glyceryl triacetate is released from the polymer formulation in a time-dependent manner within 7 days in simulated gastric fluid, while Plastoid B retains its strength within the simulated gastric fluid for 7 days. Therefore, a time-dependent polymer can be readily prepared by mixing Plastoid B and glyceryl triacetate; the degradation time of the Plastoid B-glyceryl triacetate mixture can be prolonged by increasing the amount of Plastoid B in the mixture (i.e., using less glyceryl triacetate in the mixture), while the degradation time can be reduced by decreasing the amount of Plastoid B in the mixture (i.e., using more glyceryl triacetate in the mixture).

[0309] Various time-dependent mechanisms are available. Water-soluble time-dependent polymers decompose as water permeates the polymer. Examples of such polymers are hydroxypropyl methylcellulose and polyvinyl acetate. Acid-soluble time-dependent polymers decompose over time in acidic environments. Examples include Eudragit EPO. Time-dependent polymers can use water-soluble plasticizers; as the plasticizer is released, the remaining polymer becomes brittle and breaks under gastric force. Examples of such polymers include triglycerides and triethyl citrate.

[0310] In some embodiments, the carrier polymer-activator component is an arm composed of segments linked by an enteric polymer. In some embodiments, the carrier polymer-activator component is linked to the elastomer component of the system via an enteric polymer. In any of these embodiments, when the enteric polymer is used for both segment-to-segment connections and for connecting the arm to the elastomer component, the enteric polymer used for segment-to-segment connections may be the same enteric polymer as the enteric polymer used for connecting the arm to the elastomer component, or the enteric polymer used for segment-to-segment connections may be a different enteric polymer than the enteric polymer used for connecting the arm to the elastomer component. The enteric polymers used for segment-to-segment connections may be all the same, or all different, or some of the enteric polymers in the segment-to-segment connections may be the same and some may be different. That is, the enteric polymers used for each segment-to-segment connection and the enteric polymer used for connecting the arm to the elastomer component can be selected independently.

[0311] In some embodiments, the carrier polymer-drug component is attached to the segmentless arm of the elastomeric component of the system via an enteric polymer, a time-dependent linker, or a disintegration matrix, or any combination of an enteric polymer, a time-dependent linker, and / or a disintegration matrix.

[0312] In any embodiment of the gastric residency system described herein, the coupling polymer or linker may comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polycaprolactone (PCL). These blends may be used to form disintegrating linkers or disintegrating matrices. The ratio of HPMCAS to PCL in the disintegrating linker or disintegrating matrix may be approximately 80% HPMCAS:20% PCL or 20% HPMCAS:80% PCL. The ratio of HPMCAS to polycaprolactone can be approximately 80% HPMCAS: 20% PCL; approximately 70% HPMCAS: 30% PCL; approximately 60% HPMCAS: 40% PCL; approximately 80% HPMCAS: 20% PCL; approximately 50% HPMCAS: 50% PCL; approximately 80% HPMCAS: 20% PCL; approximately 70% HPMCAS: 30% PCL; approximately 70% HPMCAS: 30% PCL; approximately 20% HPMCAS: 40% PCL; approximately 20% HPMCAS: 8 ... HPMCAS: 50% PCL; about 30% HPMCAS: 70% PCL-40% HPMCAS: 60% PCL; about 30% HPMCAS: 70% PCL-50% HPMCAS: 50% PCL; or about 80% HPMCAS: 20% PCL, about 70% HPMCAS: 30% PCL, about 60% HPMCAS: 50% PCL, about 40% HPMCAS: 60% PCL, about 30% HPMCAS: 70% PCL or about 20% HPMCAS: 80% PCL. The linker may further comprise a plasticizer selected from the following: glyceryl triacetate, triethyl citrate, tributyl citrate, poloxamer, polyethylene glycol, polypropylene glycol, diethyl phthalate, dibutyl sebacate, glycerin, castor oil, acetylated triethyl citrate, acetylated tributyl citrate, polyethylene glycol monomethyl ether, sorbitol, dehydrated sorbitol, a mixture of sorbitol and dehydrated sorbitol, and diacetylated monoglyceride.

[0313] The connectors are selected to be sufficiently weakened after a specified period of time to allow the gastric resident system to reach their uncoupling point and exit the stomach through the pylorus after the desired residence period, or to be sufficiently weakened so that the gastric resident system is no longer retained in the stomach; that is, the connectors are weakened to the uncoupling point (uncoupling point) or to the point where the gastric resident system can pass through the pylorus (pyloric passage point or passage point). Thus, in one embodiment, connectors that uncouple after approximately 2 days in the human stomach; approximately 3 days in the human stomach; approximately 4 days in the human stomach; approximately 5 days in the human stomach; approximately 6 days in the human stomach; approximately 7 days in the human stomach; approximately 8 days in the human stomach; approximately 9 days in the human stomach; approximately 10 days in the human stomach; or approximately two weeks in the human stomach are used. In one embodiment, the connectant is used after approximately 2 days in the dog's stomach; approximately 3 days in the dog's stomach; approximately 4 days in the dog's stomach; approximately 5 days in the dog's stomach; approximately 6 days in the dog's stomach; approximately 7 days in the dog's stomach; approximately 8 days in the dog's stomach; approximately 9 days in the dog's stomach; approximately 10 days in the dog's stomach; or approximately 2 weeks in the dog's stomach. In one embodiment, the connectant is used after approximately 2 days in the pig's stomach; approximately 3 days in the pig's stomach; approximately 4 days in the pig's stomach; approximately 5 days in the pig's stomach; approximately 6 days in the pig's stomach; approximately 7 days in the pig's stomach; approximately 8 days in the pig's stomach; approximately 9 days in the pig's stomach; approximately 10 days in the pig's stomach; or approximately 2 weeks in the pig's stomach. In one implementation, the connector is used after approximately 2 days of fasting simulated gastric juice; approximately 3 days of fasting simulated gastric juice; approximately 4 days of fasting simulated gastric juice; approximately 5 days of fasting simulated gastric juice; approximately 6 days of fasting simulated gastric juice; approximately 7 days of fasting simulated gastric juice; approximately 8 days of fasting simulated gastric juice; approximately 9 days of fasting simulated gastric juice; approximately 10 days of fasting simulated gastric juice; or approximately 2 weeks of fasting simulated gastric juice. In one embodiment, the linker is used after approximately 2 days in a fed simulated gastric juice; approximately 3 days in a fed simulated gastric juice; approximately 4 days in a fed simulated gastric juice; approximately 5 days in a fasting simulated gastric juice; approximately 6 days in a fasting simulated gastric juice; approximately 7 days in a fed simulated gastric juice; approximately 8 days in a fed simulated gastric juice; approximately 9 days in a fed simulated gastric juice; approximately 10 days in a fed simulated gastric juice; or approximately 2 weeks in a fed simulated gastric juice. In one embodiment, the linker is uncoupled after approximately 2 days in water at pH 2; approximately 3 days in water at pH 2; approximately 4 days in water at pH 2; approximately 5 days in water at pH 2; approximately 6 days in water at pH 2; approximately 7 days in water at pH 2; approximately 8 days in water at pH 2; approximately 9 days in water at pH 2; approximately 10 days in water at pH 2; or approximately 2 weeks in water at pH 2.In one embodiment, the linker is used after approximately 2 days in water at pH 1; approximately 3 days in water at pH 1; approximately 4 days in water at pH 1; approximately 5 days in water at pH 1; approximately 6 days in water at pH 1; approximately 7 days in water at pH 1; approximately 8 days in water at pH 1; approximately 9 days in water at pH 1; approximately 10 days in water at pH 1; or approximately 2 weeks in water at pH 1.

[0314] When the system is expelled from the stomach, i.e., when it passes through the pylorus, an uncoupling or pyloric passage point occurs in humans, dogs, or pigs. For in vitro measurements in simulated gastric juice or acidic water, the uncoupling or pyloric passage point occurs when the connector weakens to the point where it breaks under normal compressive forces in the stomach (typically about 0.1–0.2 Newtons). The connection strength (break point) can be measured by any relevant test used to test coupling capability, i.e., the force required to break the connector, such as the four-point bending test (ASTM D790) described in Example 18 of WO2017 / 070612 or Examples 12, 13, 15, 17, or 18 of WO2017 / 1003671. In one embodiment, the uncoupling or pyloric passage point is reached when the connector uncouples under a force of about 0.2 N. In another embodiment, the uncoupling or pyloric passage point is reached when the connector uncouples under a force of about 0.1 N.

[0315] The gastric residency system can reach the pyloric passage point without any or all connectors actually breaking. If the connectors weaken or degrade to the point where they can no longer hold the gastric residency system in the stomach, the gastric residency system will pass through the pylorus and enter the small intestine (pyloric passage point or transit point) even if one, some, or all of the connectors do not break. In some embodiments, connectors weakened to the transit point are used after approximately 2 days in the human stomach; approximately 3 days in the human stomach; approximately 4 days in the human stomach; approximately 5 days in the human stomach; approximately 6 days in the human stomach; approximately 7 days in the human stomach; approximately 8 days in the human stomach; approximately 9 days in the human stomach; approximately 10 days in the human stomach; or approximately 2 weeks in the human stomach. In some embodiments, the connective tissue is weakened to the point of penetration after approximately 2 days in the dog's stomach; approximately 3 days in the dog's stomach; approximately 4 days in the dog's stomach; approximately 5 days in the dog's stomach; approximately 6 days in the dog's stomach; approximately 7 days in the dog's stomach; approximately 8 days in the dog's stomach; approximately 9 days in the dog's stomach; approximately 10 days in the dog's stomach; or approximately 2 weeks in the dog's stomach. In some embodiments, the connective tissue is weakened to the point of penetration after approximately 2 days in the pig's stomach; approximately 3 days in the pig's stomach; approximately 4 days in the pig's stomach; approximately 5 days in the pig's stomach; approximately 6 days in the pig's stomach; approximately 7 days in the pig's stomach; approximately 8 days in the pig's stomach; approximately 9 days in the pig's stomach; approximately 10 days in the pig's stomach; or approximately 2 weeks in the pig's stomach. In some implementations, the connection is weakened to a point after approximately 2 days in a fasting simulated gastric juice; approximately 3 days in a fasting simulated gastric juice; approximately 4 days in a fasting simulated gastric juice; approximately 5 days in a fasting simulated gastric juice; approximately 6 days in a fasting simulated gastric juice; approximately 7 days in a fasting simulated gastric juice; approximately 8 days in a fasting simulated gastric juice; approximately 9 days in a fasting simulated gastric juice; approximately 10 days in a fasting simulated gastric juice; or approximately 2 weeks in a fasting simulated gastric juice. In some implementations, the connection is weakened to a point-by-point connector after approximately 2 days in simulated gastric juice of a fed state; approximately 3 days in simulated gastric juice of a fed state; approximately 4 days in simulated gastric juice of a fed state; approximately 5 days in simulated gastric juice of a fed state; approximately 6 days in simulated gastric juice of a fed state; approximately 7 days in simulated gastric juice of a fed state; approximately 8 days in simulated gastric juice of a fed state; approximately 9 days in simulated gastric juice of a fed state; approximately 10 days in simulated gastric juice of a fed state; or approximately 2 weeks in simulated gastric juice of a fed state. In some implementations, the connection weakens to a point after approximately 2 days in water at pH 2; approximately 3 days in water at pH 2; approximately 4 days in water at pH 2; approximately 5 days in water at pH 2; approximately 6 days in water at pH 2; approximately 7 days in water at pH 2; approximately 8 days in water at pH 2; approximately 9 days in water at pH 2; approximately 10 days in water at pH 2; or approximately 2 weeks in water at pH 2.In some implementations, the connection weakens to a point after approximately 2 days in water at pH 1; approximately 3 days in water at pH 1; approximately 4 days in water at pH 1; approximately 5 days in water at pH 1; approximately 6 days in water at pH 1; approximately 7 days in water at pH 1; approximately 8 days in water at pH 1; approximately 9 days in water at pH 1; approximately 10 days in water at pH 1; or approximately 2 weeks in water at pH 1.

[0316] Filaments for improving gastric retention

[0317] The following describes a gastric retention system with filaments. As detailed below, the filaments in the gastric retention system help prevent premature passage of the system through the patient's pylorus. Therefore, the filaments and the gastric retention system with filaments described herein can help improve the efficacy and reliability of gastric retention systems.

[0318] A filamentous gastric retention system can prevent it from prematurely passing through the patient's pylorus. This article describes how filamentous gastric retention systems help minimize the risk of premature passage of the gastric retention system through the patient's pylorus.

[0319] The filaments can be attached to the distal end of the arm of the gastric resident system. Figure 4A and 4B The diagram illustrates how the filament affects the most common bends and pyloric passage patterns of the complete gastric residence system. The filament, for example, can prevent one or both arms from prematurely entering the pylorus. It also maintains the spacing between the arms, which alters the bend geometry and increases the force required to compress the gastric residence system into a configuration small enough to prematurely pass through the pylorus.

[0320] For example, Figure 4A The gastric resident system 400a includes a central core 402a and a plurality of arms 404a, as shown, each arm 404a extending radially from the central core 402a. Each arm 404a is connected to the core 402a at its proximal end. Filaments 406a are connected to the distal ends 404a of each arm, as shown. Figure 4A The gastric residence system 400a is shown in an open configuration. As shown, when the gastric residence system 400a remains in an open configuration, the filament 406a helps prevent the gastric residence system 400a from passing through the pylorus prematurely.

[0321] Figure 4B The gastric retention system 400b is shown in a curved configuration. The gastric retention system 400b includes a core 402b, arms 404b, and filaments 406b. As shown, even though the gastric retention system 400b is curved into a configuration that might allow premature passage through the patient's pylorus (see...), Figure 3BThe filament 408b helps prevent the device from passing through. The filament 408b is particularly flexible and stretchable, which allows it to maintain its integrity, although gastric forces may cause the gastric retention system 400b to bend and twist.

[0322] In some embodiments, the gastric retention system may include tips located distal to one or more arms. These tips may comprise an enteric polymer composition. The filament may be attached to each arm via the distal tip. These tips may be configured to detach from the rest of the arm when in the gastric environment. In particular, these tips may be configured to detach from the arm, which allows the filament to also detach from the gastric retention system. This detachment may be fine-tuned so that the tip and filament detach once a predetermined gastric retention time has elapsed, thereby allowing the gastric retention system to detach and pass through the patient's pylorus upon the expiration of the predetermined gastric retention time. If the tip and / or filament detach too early, there is a risk that the gastric retention system will prematurely pass through the patient's pylorus.

[0323] In some embodiments, the arm tip may comprise one or more polymers, an enteric coating material, a plasticizer, and an acid. Suitable polymers may include polycaprolactone and / or thermoplastic polyurethanes (e.g., Lubrizol's Pathway). TM In some embodiments, the composition of the arm tip may be the same as that of the connector assembly. In some embodiments, the composition of the arm tip may differ from that of the connector assembly. In some embodiments, the arm tip may contain 10-50% by weight of polymer. In some embodiments, the arm tip may contain less than 50% by weight, less than 40% by weight, less than 30% by weight, or less than 20% by weight of polymer. In some embodiments, the arm tip may contain more than 10% by weight, more than 20% by weight, more than 30% by weight, or more than 40% by weight of polymer.

[0324] In some embodiments, the enteric material of the arm tip may comprise an enteric polymer. Suitable enteric polymers include, for example, cellulose acetate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, polyvinyl acetate phthalate, methacrylate-methyl methacrylate copolymer (1:1), methacrylate-methyl methacrylate copolymer (2:1), methacrylate-ethyl acrylate copolymer (2:1), shellac, hydroxypropyl methylcellulose acetate succinate, poly(methyl vinyl ether / maleic acid) monoethyl ester, or poly(methyl vinyl ether / maleic acid) n-butyl ester. In some embodiments, the arm tip may comprise 20-90% by weight of the enteric material. In some embodiments, the arm tip may comprise less than 90% by weight, less than 80% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, or less than 30% by weight of the enteric material. In some embodiments, the arm tip may contain more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, more than 60% by weight, more than 70% by weight, or more than 90% by weight of enteric material.

[0325] Suitable plasticizers may include propylene glycol, P407, triethyl citrate, triglyceride triacetate, dibutyl sebacate, and / or polyethylene glycol. In some embodiments, the arm tip may contain 1-20% by weight of plasticizer. In some embodiments, the arm tip may contain less than 20% by weight, less than 15% by weight, less than 10% by weight, or less than 5% by weight of plasticizer. In some embodiments, the arm tip may contain more than 1% by weight, more than 5% by weight, more than 10% by weight, or more than 15% by weight of plasticizer.

[0326] Suitable acids may include stearic acid or other fatty acids. In some embodiments, the tip may contain 1-20% by weight or 1-10% by weight of acid. In some embodiments, the tip may contain less than 20% by weight, less than 15% by weight, less than 10% by weight, or less than 5% by weight of acid. In some embodiments, the tip may contain more than 1% by weight, more than 5% by weight, more than 10% by weight, or more than 15% by weight of acid.

[0327] Figure 5A and 5B This illustrates two different configurations of a stomach-residence system having filaments connected at the distal ends of each arm to the tips. Specifically, Figure 5AThis illustrates a gastric residency system 500a comprising a core 502a and six arms 504a. Each arm 504a includes a distal end 510a. In some embodiments, each arm 504a may be connected to the core 502a via a connector 512a. As shown, filaments 508a are connected to each arm 504a at a tip 510a. In some embodiments, a single filament 508a may be circumferentially wound around the gastric residency system 500a and connected to each arm at a tip 510a. In some embodiments, multiple filaments 508a may be connected to each arm 504a of the gastric residency system 500a.

[0328] Figure 5B The display shows a gastric resident system 500b having a core 502b, six arms 504b, and a tip 510b at the distal end of each arm 504b. Unlike Figure 5A The gastric residence system 500a and gastric residence system 500b include a connector 512b connecting an arm 504b to a core 502b and a connector 512b connecting two segments of the arm 504b. As shown, filaments 508b are connected to each arm 504b at a tip 510b. In some embodiments, a single filament 508b may be circumferentially wound around the gastric residence system 500a and connected to each arm at a tip 510a. In some embodiments, multiple filaments 508b may be connected to each arm 504b of the gastric residence system 500b.

[0329] Filaments used to improve gastric retention may include elastic polymers and / or bioabsorbable polymers.

[0330] Suitable elastic polymers may include polyurethane (Lubrizol Pellethane, Pathways, Tecoflex, carbothane), polyamide-polyether block copolymer (Pebax), poly(ethylene-co-vinyl acetate) (PEVAc), polyvinyl acetate, polysiloxane, and / or combinations thereof. In some embodiments, the filament may contain 10-90 wt%, 20-80 wt%, or 30-70 wt% of the elastic polymer. In some embodiments, the filament may contain less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, or less than 20 wt% of the elastic polymer. In some embodiments, the filament may contain more than 10 wt%, more than 20 wt%, more than 30 wt%, more than 40 wt%, more than 50 wt%, more than 60 wt%, more than 70 wt%, or more than 80 wt% of the elastic polymer.

[0331] Suitable bioabsorbable polymers may include poly(lactic-co-hydroxyacetic acid) (PLGA), polycaprolactone (PCL), polylactic acid (PLA), PCL-PLA copolymer, polydioxanone, polytrimethylene carbonate, PCL-polyhydroxyacetic acid copolymer, polyglycerol sebacate, polyanhydride, polyphosphazene, poly(alkyl cyanoacrylate), polyamino acids, polypropylene fumarate, and / or combinations thereof. In some embodiments, the filament may contain 10-90 wt%, 20-80 wt%, or 30-70 wt% of the bioabsorbable polymer. In some embodiments, the filament may contain less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, or less than 20 wt% of the bioabsorbable polymer. In some embodiments, the filament may contain more than 10% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, more than 60% by weight, more than 70% by weight, or more than 80% by weight of bioabsorbable polymer.

[0332] In some embodiments, the filament may include a plasticizer. Suitable plasticizers may include propylene glycol, P407, triethyl citrate, glyceryl triacetate, dibutyl sebacate, and / or polyethylene glycol. In some embodiments, the filament may contain 0.1-20% by weight or 1-10% by weight of plasticizer. In some embodiments, the filament may contain less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, or less than 1% by weight of plasticizer. In some embodiments, the filament may contain more than 0.1% by weight, more than 1% by weight, more than 5% by weight, more than 10% by weight, or more than 15% by weight of plasticizer.

[0333] The length of the filament can be measured as the length between the arms or, for an embodiment including a single filament wrapped around the perimeter of the gastric residence system, as the total length of the circumferentially wound filament. In either case, the filament length depends on the size and number of arms of the gastric residence system. For example, for a star-shaped gastric residence system comprising six arms, the length of a single circumferentially wound filament can be 100-150 mm, 110-140 mm, or 120-130 mm. The length of the filament between any two adjacent arms in the six arms can be 18-24 mm or 20-22 mm.

[0334] In some embodiments, the filament made of Pellethane tubing can be stretched between two adjacent arms to create tension in the filament between the arms. For a star-shaped stomach retention system comprising six arms, the length of a single circumferentially wound filament containing Pellethane tubing can be 90-130 mm or 100-120 mm. The length of the filament between any two adjacent arms in the six arms can be 18-22 mm.

[0335] The cross-sectional shape of the filament can be any of many shapes, including but not limited to circular, elliptical, rectangular, or toroidal. The thickness or diameter of the filament can be 100-1000 micrometers, preferably 200-400 micrometers. In some embodiments, the thickness or diameter of the filament can be less than 1000 micrometers, less than 800 micrometers, less than 600 micrometers, less than 400 micrometers, or less than 200 micrometers. In some embodiments, the thickness or diameter of the filament can be greater than 100 micrometers, greater than 200 micrometers, greater than 400 micrometers, greater than 600 micrometers, or greater than 800 micrometers.

[0336] In embodiments including filaments with rectangular cross-sections, the width of the filament (i.e., the longer side of the rectangular cross-section) can be 1-4 mm. In some embodiments, the width can be less than 4 mm, less than 3 mm, or less than 2 mm. In some embodiments, the width can be greater than 2 mm, greater than 3 mm, or greater than 4 mm.

[0337] The force required to compress a gastric residence system with filaments can be quantified using a radial compression test, described in detail in the "Test Methods" section below. In some embodiments, the force required to compress a gastric residence system with filaments can be 1.25 to 5 times the force required to compress a gastric residence system without filaments to the same compression diameter. In some embodiments, the force required to compress a gastric residence system with filaments can be less than 5 times, less than 4 times, less than 3 times, or less than 2 times the force required to compress a gastric residence system without filaments to the same compression diameter. In some embodiments, the force required to compress a gastric residence system with filaments can be greater than 1.25 times, greater than 2 times, greater than 3 times, or greater than 4 times the force required to compress a gastric residence system without filaments to the same compression diameter.

[0338] The force required to separate the filament from the arm tip can be quantified using a pull-out force test, described in detail in the "Test Methods" section below. In some embodiments, the force required to separate the filament from its corresponding arm tip can be 0.5-10 N or 2-6 N. In some embodiments, the force required to separate the filament from its corresponding arm tip can be less than 10 N, less than 9 N, less than 8 N, less than 7 N, less than 6 N, less than 5 N, less than 4 N, less than 3 N, less than 2 N, or less than 1 N. In some embodiments, the force required to separate the filament from its corresponding arm tip can be greater than 0.5 N, greater than 1 N, greater than 2 N, greater than 3 N, greater than 4 N, greater than 5 N, greater than 6 N, greater than 7 N, greater than 8 N, or greater than 9 N. In some embodiments, the force required to separate the filament from its corresponding arm tip may decrease as the gastric retention system remains in the gastric environment for longer periods.

[0339] In some embodiments, the force required to separate a filament from its corresponding arm tip may depend on the method used to secure the filament end (i.e., a knotted, heated, or unsecured end). In some embodiments, the force required to separate a filament with a knotted end from its corresponding arm tip may be greater than the force required to separate a filament with a heated end from its corresponding arm tip. In some embodiments, the forces required to separate a filament with a knotted end from its corresponding arm tip and the forces required to separate a filament with a heated end from its corresponding arm tip may be greater than the force required to separate an unmodified filament (i.e., unsecured) from its corresponding arm tip.

[0340] Including a stomach-residence system with arms having controlled stiffness

[0341] In some implementations, the gastric retention system described herein may additionally include an arm with controlled thickness to help prevent the gastric retention system from prematurely passing through the patient's pylorus.

[0342] By controlling the stiffness of elements (such as arms) that widen / extend the device to its open configuration, the risk of premature passage of the gastric retention system through the pylorus can be minimized. Therefore, a gastric retention system with arms of controlled stiffness can help improve the effectiveness and reliability of the system. Additionally, a gastric retention system with arms of controlled stiffness can help prevent the system from bending into a configuration that allows premature passage through the pylorus.

[0343] Gastric retention systems with arms of controlled stiffness require greater force to bend the system into a configuration suitable for premature passage through the pylorus. Gastric retention systems with any component (such as an arm) having controlled stiffness are described, which can widen or extend the system into its open configuration to help minimize the risk of premature passage through the patient's pylorus.

[0344] A stomach-residence system with arms of controlled stiffness is defined as a system comprising one or more arms, at least a portion of which is made of a flexible material. In some embodiments, the one or more arms may include a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the second segment is more flexible than the first segment.

[0345] In some embodiments, the one or more arms extend radially. The proximal end of the one or more arms may be connected to the nucleus. In some embodiments, the gastric residency system may include a plurality of radially extending arms. In some embodiments, the gastric residency system may include a plurality of arms, each connected to the nucleus at its proximal end, the plurality of arms extending radially from the nucleus. In some embodiments, the gastric residency system may include a plurality of arms, each arm including a first segment and a second segment.

[0346] The first polymer composition of the flexible arm of the gastric resident system may comprise a stiffer polymer. Suitable polymers may include polycaprolactone, polylactic acid, poly(lactic-co-hydroxyacetic acid), HPMCAS, high-stiffness TPU, and / or combinations thereof. Other examples may include hydrophilic cellulose derivatives (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose), cellulose acetate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymers, polyvinyl alcohol, carboxyvinyl polymers (carbomer), etc. Acidic carboxyl polymers, polycarboxylic acid, polyoxyethylene (Polyox WSR), polysaccharides and their derivatives, polyoxyethylene, polyethylene glycol, chitosan, alginate, pectin, acacia gum, tragacanth gum, guar gum, locust bean gum, vinylpyrrolidone vinyl acetate copolymer, dextran, natural gums, agar, agarose, sodium alginate, carrageenan, fucoidan, red algae gum, kelp, alfalfa, euryale ferox, gum arabic, gum arabic, arabinogalactan, starch, gelatin, gellan gum, hyaluronic acid, amylopectin, sclerotium dextran, xanthan gum, xyloglucan, maleic anhydride copolymer, ethylene maleic anhydride copolymer, poly(hydroxyethyl methacrylate), ammonium methacrylate copolymers (such as Eudragit RL or Eudragit RS), poly(ethyl acrylate-methyl methacrylate) (Eudragit NE), Eudragit E (a cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylate), polyacrylic acid, polymethacrylate / polyethyl acrylate such as polymethacrylate, methyl methacrylate and ethyl acrylate, polylactone such as polycaprolactone, polyanhydride such as poly[bis-(p-carboxyphenoxy)propane anhydride], polyterephthalic anhydride, polypeptides such as polylysine, polyglutamic acid, poly(orthoesters) such as DETOSU and copolymers with glycols such as hexanediol, decanediol, cyclohexanediol, ethylene glycol, polyethylene glycol and those poly(orthoesters) described and disclosed in U.S. Patent No. 4,304,767 incorporated herein by reference, starch, especially pregelatinized starch and starch-based polymers, carbomer, maltodextrin, starch maltodextrin, dextran, poly(2-ethyl-2- Poly(hydroxyacetic acid), poly(lactic acid), poly(co-hydroxyacetic acid) (PLGA), polyhydroxyalkanoates, polyhydroxybutyrates, and copolymers, mixtures, blends, and combinations thereof. In some embodiments, the first section may also comprise one or more therapeutic agents or pharmaceutically active ingredients (APIs).

[0347] In some embodiments, the first polymer composition may contain 10-90 wt% or 50-70 wt% polycaprolactone. In some embodiments, the first polymer composition may contain less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, or less than 20 wt% polycaprolactone. In some embodiments, the first polymer composition may contain more than 20 wt%, more than 30 wt%, more than 40 wt%, more than 50 wt%, more than 60 wt%, more than 70 wt%, or more than 80 wt% polycaprolactone.

[0348] In some embodiments, the first polymer composition may contain 10-90 wt% or 30-70 wt% of a therapeutic agent or API. In some embodiments, the first polymer composition may contain less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, or less than 20 wt% of a therapeutic agent or API. In some embodiments, the first polymer composition may contain more than 20 wt%, more than 30 wt%, more than 40 wt%, more than 50 wt%, more than 60 wt%, more than 70 wt%, or more than 80 wt% of a therapeutic agent or API.

[0349] The second polymer composition of the arm of the gastric resident system disclosed herein may comprise a main polymer that is flexible relative to the polymer of the first polymer composition. For example, suitable more "flexible" polymers may include one or more of polyurethane, polyether-polyamide copolymers, thermoplastic elastomers, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymers, polypropylene carbonate, polyglycerol sebate, polyethylene-co-vinyl acetate, and polysiloxanes. In some embodiments, the second polymer composition of the arm may actually comprise the same main polymer as the first polymer composition. For example, the second polymer composition may comprise polycaprolactone. However, unlike the first polymer composition, the second polymer composition may additionally comprise a soluble material (e.g., crosslinked povidone, poloxamer). Therefore, upon hydration (e.g., within the stomach), the second polymer composition softens, resulting in a less rigid second polymer composition in the second segment than the first polymer composition in the first segment. Suitable commercially available polymers may include Pathway. TM TPU polymer (The Lubrizol Corporation), Tecoflex TM (The Lubrizol Corporation),Tecophilic TM (The Lubrizol Corporation), Carbothane TM (The Lubrizol Corporation) (The Lubrizol Corporation) (Arkema) (Covestro), Chronoflex (AdvanSource Biomaterials), NEUSoft TM (PolyOne) and TPE (Teknor Apex).

[0350] In some embodiments, the second polymer composition may contain 10-90 wt% or 40-70 wt% of a main polymer. In some embodiments, the second polymer composition may contain less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, or less than 20 wt% of a main polymer. In some embodiments, the second polymer composition may contain more than 20 wt%, more than 30 wt%, more than 40 wt%, more than 50 wt%, more than 60 wt%, more than 70 wt%, or more than 80 wt% of a main polymer.

[0351] In some embodiments, the second polymer composition may additionally include one or more water-soluble excipients (which may include one or more polymers in addition to the aforementioned main polymer). Suitable water-soluble excipients may include crosslinked povidone, poloxamer, and / or polyethylene oxide. Suitable commercially available water-soluble excipients may include Kolliphor P407 (poloxam 407, polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol), PEG-PCL, SIF (FaSSIF / FaSSGF powder from BioRelevant), EPO (dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer), Kollidon VA64 (vinylpyrrolidone-vinyl acetate copolymer in a 6:4 mass ratio), and polyvinylpyrrolidone.

[0352] The second polymer composition may contain 5-70% by weight or 10-40% by weight of water-soluble excipients. In some embodiments, the second polymer composition may contain less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, or less than 10% by weight of water-soluble excipients. In some embodiments, the second polymer composition may contain more than 5% by weight, more than 10% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, or more than 60% by weight of water-soluble excipients.

[0353] In some embodiments, the second polymer composition may contain additional excipients. For example, the second polymer composition may contain basic bismuth carbonate, silica, vitamin E succinate, iron oxide, polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam graft copolymer. Sodium starch glycolate and / or hydroxypropyl cellulose. In some embodiments, the second polymer composition may contain 10-70% by weight or 20-50% by weight of excipients. In some embodiments, the second polymer composition may contain less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, or less than 20% by weight of excipients. In some embodiments, the second polymer composition may contain more than 10% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, or more than 60% by weight of excipients.

[0354] In some embodiments, the second polymer composition may additionally contain a therapeutic agent or API. The second polymer composition may contain 20-80% by weight or 40-60% by weight of a therapeutic agent or API. In some embodiments, the second polymer composition may contain less than 80% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, or less than 30% by weight of a therapeutic agent or API. In some embodiments, the second polymer composition may contain more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, more than 60% by weight, or more than 70% by weight of a therapeutic agent or API.

[0355] Some polymeric materials that can be used to produce arms with controlled stiffness can offer additional advantages in thermal stability. For example, gastric residence systems may experience temperature variations during transport and distribution. Transport data indicate that the temperature limit for goods in some climate zones can approach 60°C (Singh et al., Packag. Technol. Sci. 2012; 25:149-160). The polymers constituting the gastric residence system should be physically stable at this temperature if they are to be transported without cold chain packaging and storage.

[0356] Polycaprolactone is the preferred polymer for the stiffer arms (or stiff / first segment), and thermoplastic polyurethane is the preferred polymer for producing arms with controlled stiffness (i.e., the second segment). Polycaprolactone-based arms are physically stable when exposed to temperatures up to 55°C, but melt if they reach 60°C. When stored in capsules, the arms that begin to melt may adhere to each other and prevent the gastric retention system from unfolding in the stomach. Thermoplastic polyurethanes such as Pathway PY-PT72AE offer improved thermal stability. Pathway PY-PT72AE is an amorphous material that softens at elevated temperatures without undergoing a clear melt transition.

[0357] When a gastric retention system with a stiffer arm is compressed (e.g., by gastric electro-wave or radial compression test), the compressive force is transferred to the more flexible core of the gastric retention system, resulting in a curved structure that allows the patient's pylorus (i.e., an opening with a diameter of 20 mm) to pass through.

[0358] Conversely, when a gastric retention system comprising a relatively flexible arm (i.e., having a first segment and a second segment) is compressed, the second segment absorbs some of the compressive force. Therefore, the compressive force is not transferred to the core of the gastric retention system with the relatively flexible arm as is the case with a gastric retention system having a stiffer arm. To compress the stiff inner segment of the arm to pyloric size, a greater force is required due to the shorter lever arm connected to the flexible core. This may mean that a gastric retention system with a relatively flexible arm requires a greater compressive force to bend it into a structure small enough to pass through the patient's pylorus (i.e., an opening with a diameter of 20 mm).

[0359] As the second segment of the arm of the gastric retention system with controlled stiffness increases relative to the first segment, so too does the compressive force required to compress the gastric retention system into a curved structure small enough to pass through the pylorus (i.e., an opening with a diameter of 20 mm). (This is provided that the dimensions of the hard inner portion and the core remain larger than the pyloric diameter.)

[0360] The ratio of the first segment to the second segment of the relatively flexible arm can vary. If the first segment is too large compared to the second segment, the compressive force may be transferred to the core of the gastric resident system too early, allowing the compressive force to compress the gastric resident system into a tortuous structure small enough to prematurely pass through the pylorus. If the second segment is too large compared to the first segment, the second segment may be too easily bent under compressive force, allowing these forces to compress the gastric resident system into a tortuous structure small enough to prematurely pass through the pylorus. Both situations result in the gastric resident system being less effective at preventing premature passage through the pylorus as needed.

[0361] The effective ratio of the first segment to the second segment of the flexible arm of the gastric retention system can vary. In some embodiments, the first segment can occupy 10-90% of the arm length (measured from proximal to distal). In some embodiments, the first segment can occupy less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20% of the arm length. In some embodiments, the first segment can occupy more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80% of the arm length. In some embodiments, the second segment can occupy 10-90% of the arm length (measured from proximal to distal). In some embodiments, the second segment can occupy less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20% of the arm length. In some implementations, the second section may account for more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80% of the arm length.

[0362] System polymer composition

[0363] The choice of polymers used for the carrier polymer, coupling polymer, and elastomer affects many properties of the system, such as the drug elution rate (depending on the carrier polymer and other factors), the system's residence time (depending on the degradation of any polymer, primarily the coupling polymer), the uncoupling time if the system enters the intestine (as discussed herein, primarily depending on the intestinal degradation rate of the coupling polymer), and the shelf life of the system in its compressed form (primarily depending on the properties of the elastomer). Since the system is administered to the gastrointestinal tract, all system components should be biocompatible with the gastrointestinal environment.

[0364] The rate of drug elution from the carrier polymer-drug component is influenced by a variety of factors, including the composition and properties of the carrier polymer, which itself can be a mixture of several polymeric and non-polymeric components; the properties of the drug, such as hydrophilicity / hydrophobicity, charge state, pKa, and hydrogen bonding ability; and the nature of the gastric environment. Avoiding burst release of drugs, especially hydrophilic drugs (where burst release refers to the high initial delivery of the active drug component as the system initially unfolds in the stomach) and maintaining sustained drug release over several days to a week or two weeks is challenging in the aqueous environment of the stomach.

[0365] The residence time of this system in the stomach is modulated by selecting the coupling polymer used in the linker region. Although enteric coupling polymers are used, the system eventually decomposes in the stomach because the mechanical action and fluctuating pH of the stomach ultimately weaken the enteric coupling polymers. Coupling polymers that degrade in the stomach in a time-dependent manner can also be used to regulate the time until the system disintegrates, thereby modulating the residence time. Once the system disintegrates, it enters the intestine and is then eliminated.

[0366] The elastomer used in the system is crucial to the system's shelf life. When the system is compressed, the elastomer is subjected to mechanical stress. This stress can then cause polymer creep, which, if strong enough, can prevent the system from returning to its uncompressed state when released from a capsule or other container; this, in turn, can cause the system to pass through the stomach prematurely. Polymer creep can also be temperature-dependent, so the system's intended storage conditions must be considered when selecting the elastomer and other polymer components.

[0367] The system components and polymers should not swell or should have minimal swelling in the gastric environment. When in the gastric environment during the residence period, the swelling of the components should not exceed about 20%, not exceed about 10%, or preferably not exceed about 5%.

[0368] The systems are optionally radiopaque, allowing them to be located by abdominal X-rays if necessary. In some embodiments, one or more of the materials used to construct the system are sufficiently radiopaque for X-ray visualization. In other embodiments, radiopaque substances are incorporated into one or more materials of the system, coated onto one or more materials of the system, or incorporated into a small portion of the system. Examples of suitable radiopaque substances are barium sulfate, basic bismuth carbonate, bismuth oxychloride, and bismuth trioxide. Preferably, these materials should not be blended into the polymer used to construct the gastric residence system to avoid altering the release of the drug from the carrier polymer or the desired properties of other system polymers. Metal strips or tips, such as tungsten, may also be used on a small portion of the system components.

[0369] Manufacturing methods and treatment methods

[0370] Various manufacturing methods and treatment methods are described below. In particular, detailed descriptions are provided for: system manufacturing / assembly: 3D printing; system manufacturing / assembly: co-extrusion; surfactant particle size and grinding; methods for manufacturing carrier polymer-surfactant (or surfactant salt) components; system manufacturing / assembly: fixing arms to a central elastomer; system manufacturing / assembly; methods for manufacturing gastric resident systems with filaments; methods for treatment using gastric resident systems; and cassettes and articles of manufacture.

[0371] System manufacturing / assembly: 3D printing

[0372] 3D printing of components such as arms or arm segments of the gastric retention system is performed using commercially available equipment. 3D printing has been used in drug preparation; see Khaled et al., “Desktop 3D printing of controlled release pharmaceutical bilayer tablets”, International Journal of Pharmaceutics 461:105-111 (2014); US Patent No. 7,276,252; Alhnan et al., “Emergence of 3D Printed Dosage Forms: Opportunities and Challenges”, Pharm. Res., May 18, 2016, PubMed PMID:27194002); Yu et al., “Three-dimensional printing in pharmaceutics: promises and problems”, J. Pharm. Sci. 97(9):3666-3690 (2008); and Ursan et al., “Three-dimensional drug printing: A structured review”, J. Am. Pharm. Assoc. 53(2):136-44 (2013).

[0373] The initial raw material used for 3D printing is a polymer or polymer blend (e.g., enteric polymer, time-dependent polymer, or blend of one or more activators, activator salts, drugs, excipients, etc., with a carrier polymer, enteric polymer, or time-dependent polymer). The polymer or components to be used for a region of the segment or arm to be manufactured are mixed and granulated by hot melt extrusion. The polymer or polymer blend is extruded through a circular die, producing cylindrical fibers wound onto a spool.

[0374] Multiple spools are fed into a 3D printer (e.g., a Hyrel Printer, purchased from Hyrel 3D, Norcross, Georgia, USA) to feed them into its representative printhead. The printhead heats and melts the material at the nozzle, covering the part being manufactured with a thin layer of material (polymer or polymer blend) at specific locations. This material cools and hardens within seconds, allowing the next layer to be added until a complete structure is formed. The quality of the formulation depends on the feed rate, nozzle temperature, and printer resolution; the feed rate and nozzle temperature can be adjusted to achieve the desired quality.

[0375] 3D printing can be used to manufacture individual arms or segments of arms. It can also be used to prepare bulk structures, such as consolidated "slabs," similar to those prepared via the co-extrusion method described herein. This bulk structure can then be cut into individual parts (i.e., individual arms or segments) as needed.

[0376] In some embodiments of the invention, it is contemplated that the entire arm of the gastric resident system be produced by 3D printing. In some embodiments of the invention, it is contemplated that segments of the arm of the gastric resident system be produced by 3D printing segments of the arm. In some embodiments, the arm or a segment thereof is produced by constructing adjacent portions of a bulk structure, such as a slab, of a 3D printing carrier polymer-activator or polymer-activator salt blend and a connectant material. After 3D printing, the bulk structure is cut into parts of the arm or segment thereof having the desired shape. After 3D printing, portions of the bulk structure may be compressed into parts of the arm or segment thereof having the desired shape.

[0377] 3D printing is typically performed by feeding rods or fibers of solid material into a printhead, where it is melted and deposited using a technique called fused deposition modeling (sometimes also called extrusion deposition), followed by solidification; see U.S. Patent Nos. 5,121,329 and 5,340,433. The method described herein for manufacturing carrier polymer-drug components can also be used to manufacture feedstocks, which can be used to manufacture components of gastric resident systems via 3D printing.

[0378] System manufacturing / assembly: co-extrusion

[0379] Components of this gastric resident system can be manufactured via co-extrusion. Most of the various constructions of the sections discussed in this paper, such as the “island in the sea” construction, can be manufactured using either 3D printing or co-extrusion. However, unlike 3D printing, which is typically operated as a batch method, co-extrusion is less expensive and can be operated as a continuous method.

[0380] The co-extrusion of this "island in the sea" structure is used in the textile industry and for the production of optical fibers, but rarely in biomedical systems. See U.S. Patent Nos. 3,531,368; 3,716,614; 4,812,012; and Haslauer et al., J. Biomed. Mater. Res. B Appl. Biomater. 103(5):1050-8 (2015)).

[0381] Co-extrusion of components of the gastric resident system, such as arms or segments of arms, can be performed using commercially available equipment combined with custom co-extrusion tubing and custom dies for the desired configuration. The initial feedstock for co-extrusion is a polymer or polymer blend (e.g., enteric polymer, time-dependent polymer, or blend of one or more active agents, pharmaceuticals, excipients, etc., with a carrier polymer, enteric polymer, or time-dependent polymer). The polymer or components to be used for a segment or region of the arm to be manufactured are mixed and granulated using a hot-melt extrusion process. The resulting polymer granules are fed into a hopper above a single-screw extruder and dried to remove surface moisture. The granules are then gravimetrically fed into individual single-screw extruders, where they are melted and pressurized for co-extrusion.

[0382] The appropriate molten polymer is then pumped through a custom-designed die with multiple channels, in which they are formed into the desired geometry. The composite polymer block is then cooled (water-cooled, air-cooled, or both) and cut or stamped into the desired shape, including but not limited to shapes such as triangular prisms, rectangular prisms, or cylindrical cross-sections (sector wedges).

[0383] In some embodiments of the invention, it is contemplated that the entire arm of the gastric residence system be produced by co-extrusion. In some embodiments of the invention, it is contemplated that segments of the arm of the gastric residence system be produced by co-extrusion of the arm segments. In some embodiments, the arm or a segment thereof is produced by co-extruding adjacent portions of a carrier polymer-activator or carrier polymer-activator salt blend and a linker material in a bulk construction such as a slab construction. After co-extrusion, the bulk construction is cut into components of the arm or segment thereof having the desired shape. After co-extrusion, portions of the bulk construction may be compressed into components of the arm or segment thereof having the desired shape.

[0384] In some embodiments, the arm or its segment is produced as follows: adjacent portions of a carrier polymer-activator or carrier polymer-activator salt blend and a linker material are co-extruded in a bulk configuration such as a slab configuration, while simultaneously co-extruded one or more additional polymers, linker materials, or both a carrier polymer-activator (or activator salt) blend and a linker material within the carrier polymer-activator or carrier polymer-activator salt blend. The co-extrusion of the additional one or more polymers, linker materials, or both a carrier polymer-activator (or activator salt) blend and a linker material within the carrier polymer-activator or carrier polymer-activator salt blend can be carried out in an island configuration. After co-extrusion, the bulk configuration can be cut into components of the arm or its segment having the desired shape. After co-extrusion, portions of the bulk configuration can be compression molded into components of the arm or its segment having the desired shape.

[0385] Surfactant particle size and grinding

[0386] Controlling the particle size used in this gastric residence system is important for both optimal release of the surfactant and the mechanical stability of the system. The surfactant particle size affects the surface area available for dissolution as gastric fluid permeates into the carrier polymer-surfactant segment of the system. Furthermore, due to the relatively thin diameter of the system arms (e.g., 1-5 mm), the presence of surfactant particles exceeding the arm diameter by several percentage points before and after elution creates weaker arms, leaving gaps in the spaces previously occupied by the surfactant particles. This weakening of the arms is detrimental because it can lead to premature system rupture and passage before the desired residence period ends.

[0387] In one embodiment, the surfactant particles used for blending into the carrier polymer-surfactant component have a diameter of less than about 100 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 75 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 50 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 40 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 30 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 25 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 20 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 10 micrometers. In another embodiment, the surfactant particles have a diameter of less than about 5 micrometers.

[0388] In one embodiment, at least about 80% of the surfactant particles used for blending into the carrier polymer-surfactant component have a diameter of less than about 100 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 75 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 50 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 40 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 30 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 25 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 20 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 10 micrometers. In another embodiment, at least about 80% of the surfactant particles have a diameter of less than about 5 micrometers.

[0389] In one embodiment, at least about 80% by mass of the surfactant particles used to blend into the carrier polymer-surfactant component has a size of about 1-100 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-75 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-50 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-40 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-30 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-25 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-20 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-10 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 1-5 micrometers in diameter.

[0390] In one embodiment, at least about 80% by mass of the surfactant particles used to blend into the carrier polymer-surfactant component has a size of about 2-100 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-75 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-50 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-40 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-30 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-25 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-20 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-10 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 2-5 micrometers in diameter.

[0391] In one embodiment, at least about 80% by mass of the surfactant particles used for blending into the carrier polymer-surfactant component has a size of about 5-100 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-75 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-50 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-40 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-30 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-25 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-20 micrometers in diameter. In another embodiment, at least about 80% by mass of the surfactant particles has a size of about 5-10 micrometers in diameter.

[0392] The particle size of surfactants can be easily adjusted by grinding. Several grinding techniques can be used to reduce larger particles to smaller particles of the desired size. Fluid energy milling is a dry grinding technique that uses inter-particle collisions to reduce particle size. One type of fluid energy mill, called an air jet mill, injects air into a cylindrical chamber in a way that maximizes collisions between surfactant particles. Ball mills use a rolling cylindrical chamber that rotates around its spindle. The surfactant and abrasive material (such as steel balls made of chromium steel or CR-NI steel; ceramic balls, such as zirconium oxide; or plastic polyamide) collide, resulting in a reduction in the particle size of the surfactant. Ball milling can be carried out in a dry state or with a liquid added to the cylinder, in which the surfactant and abrasive material are insoluble. More information on milling is described in the following sections: RWLee et al., “Particle Size Reduction,” Water-Insoluble Drug Formulation, 2nd ed. (edited by Ron Liu), Boca Raton, Florida: CRC Press, 2008; and AWBrzeczko et al., “Granulation of Poorly Water-Soluble Drugs,” Handbook of Pharmaceutical Granulation Technology, 3rd ed. (edited by Dilip M. Parikh), Boca Raton, Florida: CRC Press / Taylor & Francis Group, 2010 (and other sections in the handbook). Fluid energy milling (i.e., air jet milling) is the preferred milling method because it is more suitable for scaling up compared to other dry milling techniques such as ball milling.

[0393] Substances that help obtain particles of the desired size and minimize aggregation during the grinding process can be added to the active agent material. Silica (silica, SiO2) is a preferred grinding additive because it is inexpensive, widely available, and non-toxic. Other additives that can be used include silica, calcium phosphate, powdered cellulose, colloidal silica, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, talc, polyvinylpyrrolidone, cellulose ether, polyethylene glycol, polyvinyl alcohol, and surfactants. Specifically, hydrophobic particles with a diameter less than 5 micrometers are particularly prone to agglomeration, and hydrophilic additives are used when grinding such particles. Grinding additives such as silica can be used in fluid mills or ball mills at a weight ratio of about 0.1-5%, or about 0.1-4%, about 0.1-3%, about 0.1-2%, about 0.1-1%, about 1-5%, about 1-4%, about 1-3%, about 1-2%, or about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, or about 5%.

[0394] After grinding, the particles can be passed through a sieve of suitable size to obtain particles of the desired size. To obtain particles with the desired maximum size, the particles are passed through a sieve with holes of the desired maximum size; excessively large particles will remain on the sieve, and the particles passing through the sieve will have the desired maximum size. To obtain particles with the desired minimum size, the particles are passed through a sieve with holes of the desired minimum size; particles passing through the sieve will be too small, and the desired particles will remain on the sieve. Method for manufacturing the carrier polymer-activator (or activation salt) component.

[0395] The blending temperature for incorporating an active agent (or its pharmaceutical salt) into a polymer matrix is ​​typically in the range of about 80-120°C; however, for polymers that blend best at temperatures outside this range, higher or lower temperatures may be used. When using active agent (or its salt) particles of a specific size and it is desirable to maintain the particle size during and after blending, blending can be carried out at a temperature below the melting point of the active agent (or its salt) to maintain the desired particle size. Otherwise, temperatures that melt both the polymer and the active agent (or its salt) can be used. The blending temperature should be below the degradation temperature of the active agent (or its salt). In one embodiment, less than about 2% of the active agent (or its salt) degrades during manufacturing. In one embodiment, less than about 1.5% of the active agent (or its salt) degrades during manufacturing. In one embodiment, less than about 1% of the active agent (or its salt) degrades during manufacturing. In one embodiment, less than about 0.75% of the active agent (or its salt) degrades during manufacturing. In one embodiment, less than about 0.5% of the active agent (or its salt) degrades during manufacturing. In one embodiment, less than about 0.4% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.3% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.2% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.15% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.1% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.05% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.04% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.03% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.02% of the surfactant (or its salt) degrades during manufacturing. In one embodiment, less than about 0.01% of the surfactant (or its salt) degrades during manufacturing.

[0396] Hot melt extrusion can be used to prepare carrier polymer-activator (or activator salt) components. A single-screw or preferably twin-screw system can be used. It should be noted that if it is necessary to maintain particle size during and after blending, a carrier polymer melted at a temperature that does not degrade the activator or its salt should be used. Otherwise, a temperature at which both the polymer and the activator or its salt are melted can be used.

[0397] Melting and casting can also be used to prepare a carrier polymer-activator (or its salt) component. The carrier polymer and the activator (or its salt), along with any other desired components, are mixed together. The carrier polymer is melted and the melt is mixed so that the activator (or its salt) particles are uniformly distributed throughout the melt. The mixture is then poured into a mold and allowed to cool.

[0398] Solvent casting can also be used to prepare carrier polymer-surfactant (or its salt) components. The polymer is dissolved in a solvent and then surfactant (or its salt) particles are added. To maintain the size of the surfactant (or its salt) particles, a solvent that does not dissolve the surfactant (or its salt) particles should be used to avoid altering the particle size characteristics; otherwise, a solvent that dissolves both the polymer and the surfactant (or its salt) particles can be used. The solvent-carrier polymer-surfactant (or its salt) particle mixture (or solvent-carrier particle-surfactant / surfactant salt solution) is then mixed until the particles are uniformly distributed (or the solution is thoroughly mixed), poured into a mold, and the solvent is evaporated.

[0399] System manufacturing / assembly: fixing the arm to the central elastomer

[0400] For stellate gastric resident systems, such as Figure 1A The star-shaped gastric retention system shown has arms that can be attached to a central elastomer in various ways. The central polymer can be cast or molded using short "asterisk" arms, and a connecting polymer can be used to attach the arms to the asterisk arms of the central elastomer. Alternatively, the central elastomer can be molded in a mold with the proximal end of the arm protruding therein. The elastomer solidifies, cures, or otherwise hardens into its desired form, wherein a portion of the arm extends into the body of the central elastomer. Alternatively, the central elastomer can be fabricated with cavities into which the arms can be securely inserted.

[0401] Therefore, the present invention includes a method for preparing a gastric retention system, the method comprising preparing at least three arms formed of a material comprising any drug-carrier polymer-excipient formulation disclosed herein; and attaching the arms to a central elastomer to form the gastric retention system. The arms may comprise at least one segment of a polymer membrane having a controlled release rate. The arms of the gastric retention system project radially from the central elastomer, for example, in a hub-and-spoke arrangement. A preferred number of arms is six. However, star-shaped systems with three, four, five, seven, or eight arms may also be used.

[0402] In some embodiments, the arm comprising any carrier polymer-activator formulation can be thermally welded, solvent-welded, or otherwise fixed to other elements, including a disintegrating matrix, coupling polymer, or interface polymer, and then attached to the central elastomer. In some embodiments, the arm is directly fixed to the central elastomer. The disintegrating matrix, coupling polymer, or interface polymer segment can be welded or otherwise fixed to the central elastomer and then fixed to the arm.

[0403] In some embodiments, an arm containing any drug-carrier polymer-excipient formulation as disclosed herein can be heat-welded to a polycaprolactone segment, such as a short polycaprolactone "asterisk" arm anchored to a central elastomer. The linker segment can be welded to this short "asterisk" arm, and then the drug-carrier polymer-excipient formulation arm can be anchored to it. A stronger weld is obtained by heat-welding the drug-carrier polymer-excipient formulation arm to a MW 80,000PCL segment at a temperature of 140-170°C, followed by cooling at 8°C for 24 hours. Therefore, in one embodiment, attaching an arm comprising any of the drug-carrier polymer-excipient formulations disclosed herein to a central elastomer to form a gastric residence system may include thermally welding the arm to other system components, such as an asterisk arm or other segments comprising at least about 90%, at least about 95%, or at least about 99% polycaprolactone (e.g., MW 80,000 PCL), at a temperature of about 140–170°C, followed by cooling the welded component attached to the other system components at a temperature of about 2–14°C, such as about 5–10°C or about 8°C, for about 12–48 hours. Alternatively, the other system components may be connector elements.

[0404] System manufacturing / assembly

[0405] Once the arms of the gastric residence system are secured to the central elastomer, the system is ready to be folded into its compressed configuration and encapsulated for storage, transport, and final administration. The system can be folded and encapsulated in appropriately sized and material capsules by automated mechanical methods or manually. Further details regarding the manufacture and assembly of the gastric residence system and its packaging into capsules can be found in International Patent Application Nos. WO 2015 / 191920, WO 2015 / 191925, WO2017 / 070612, WO 2017 / 100367 and PCT / US2017 / 034856.

[0406] Method for manufacturing a gastric retention system with filaments

[0407] As described, the filament of the gastric retention system can be attached to the tip of the arm of the gastric retention system. If improperly attached, the arm may move along the filament when the gastric retention system is compressed / bent, which may sacrifice the filament's ability to help prevent the gastric retention system from prematurely passing through the pylorus. Therefore, a method for manufacturing a gastric retention system with filaments is described below.

[0408] In some implementations, filaments can be attached to the arms of a pre-assembled gastric retention system via incisions, winding, and end forming. The gastric retention system can be assembled at the distal ends of each arm using specially designed tips. Each tip of each arm can be incised with a razor blade or circular saw to form a shape such as... Figure 6A The gap shown. Figure 6BThe diagram shows filaments that have been circumferentially wound around the arms of the gastric retention system and connect the notches. In some embodiments, the filaments can be wound using a winding device with controlled tension. Figure 6C The notch is shown to have been closed and rounded to secure the filament. In some embodiments, the notch can be closed using a device that applies heat and pressure to each arm end via a heated die, thereby leaving a circular surface at the arm end.

[0409] After the filament is wound to connect two or more arms, the end of the filament can be secured. Figure 7 This illustrates two different methods for securing the ends of the filament. The two ends of the filament can initially be secured by overlapping them within a notch in a single arm. Because the gastric retention system bends within the stomach during gastric retention, tension is applied to the filament, and the two free filament ends may slip out of the notch and detach from the arm. Therefore, to better secure the filament ends, they can be expanded by knotting and / or heat flaring. In some embodiments, the ends of the filament may be knotted and / or heated before being attached to the gastric retention system.

[0410] In some implementations, the filament can be attached to multiple arm tips before the arm tips are attached to the rest of the gastric retention system. For example, the filament and arm tips can be manufactured by injection molding or insert molding (e.g., overmolding the tip onto an existing filament). Figure 8 An example of a manufacturing method is shown, including forming the filament and arm tip by injection molding. As shown, a gastric retention system 852 can be inserted into the injection-molded filament and arm tip (850). The gastric retention system 852 can be welded to the filament and arm tip 850 to form a complete gastric retention system having a filament 854.

[0411] Methods of treating gastric resident system

[0412] A gastric retention system can be used to treat conditions requiring the administration of a drug or active agent over an extended period. In a preferred embodiment, the gastric retention system is administered to a human. For long-term administration of an active agent or drug for months, years, or indefinite periods, regular administration of the gastric retention system, such as once a week or every two weeks, can provide significant advantages in terms of patient compliance and convenience. Therefore, the gastric retention system of the present invention can be administered once every 3 days, once every 5 days, once a week, once every 10 days, or once every 2 weeks. The administration frequency is set to correspond to the designed gastric retention period of the administered gastric retention system, such that a new gastric retention system is administered approximately at the same time after its retention period has elapsed and is expelled from the stomach.

[0413] Once the gastric retention system is administered to a patient, it provides a continuous release of the active agent or drug during the gastric retention period. After the gastric retention period, the system degrades and is expelled from the stomach. Therefore, for a system with a one-week gastric retention period, the patient will swallow (or otherwise administer to the stomach) a new system weekly. Thus, in one embodiment, a method of treating a patient with the gastric retention system of the present invention—the active agent or drug in which it is administered—for a total required treatment period T-total (where T-total is the required treatment length in days) comprising introducing a new gastric retention system into the patient's stomach every D days by oral administration or other methods during the total required treatment period. The number of gastric retention systems administered to the patient will be (T-total) / (D days). For example, if a patient needs to be treated for a year (T-total = 365 days) and the gastric residence period of the system is 7 days (D days = 7 days), then approximately 52 gastric residence systems will be administered to the patient over 365 days, as a new system is administered every 7 days.

[0414] Alternatively, the patient may swallow (or otherwise administer to the stomach) a new gastric resident system at the end of its effective release period. The “effective release period” or “effective release time” is the time it takes for the gastric resident system to release an effective amount of the active agent contained in the system. Therefore, in one embodiment, a method of treating a patient with the gastric resident system of the present invention—with an effective release period of E days (where E days is the effective release period in days) for a total required treatment period T-total (where T-total is the required treatment length in days) includes introducing a new gastric resident system into the patient's stomach every E days by oral administration or other methods during the total required treatment period. The number of gastric resident systems administered to the patient will be (T-total) / E days. For example, if a patient needs to be treated for one year (T-total = 365 days) and the effective release period of the system is 7 days (E days = 7 days), then approximately 52 gastric resident systems will be administered to the patient over 365 days, as a new system is administered every 7 days.

[0415] Medicine boxes and manufactured goods

[0416] This document also provides a kit for treating patients with the gastric residence system of the present invention. The kit may contain, for example, a sufficient number of gastric residence systems for periodic administration to the patient over the desired total treatment period. If the total treatment time in days is (T - total) and the gastric residence system has a residence period of D days, then the kit will contain a plurality of gastric residence systems equal to ((T - total) / (D days)) (rounded to an integer) for administration once every D days. Alternatively, if the total treatment time in days is (T - total) and the gastric residence system has an effective release period of E days, then the kit will contain a plurality of gastric residence systems equal to ((T - total) / (E days)) (rounded to an integer) for administration once every E days. The kit may contain, for example, several gastric residence systems in a container (where the container may be a capsule), and may optionally also contain printed or computer-readable instructions regarding the dosing regimen, treatment duration, or other information related to the use of the gastric residence system and / or the active agent and / or drug contained in the gastric residence system. For example, if the total treatment period prescribed for the patient is 1 year and the gastric retention system has a 1-week retention period or a 1-week effective release period, the kit may contain 52 capsules, each containing one gastric retention system, and the kit may also include instructions to swallow one capsule on the same day of the week (e.g., every Saturday).

[0417] The invention also includes an article of manufacture comprising a sufficient number of gastric residency systems for periodic administration to a patient over the desired total treatment period, and optionally includes instructions for use regarding the dosing regimen, duration of treatment, or other information relating to the use of the gastric residency system and / or the active agent or drug contained in the gastric residency system. The article of manufacture may be supplied in suitable packaging, such as a dispenser, tray, or other packaging that facilitates administration of the gastric residency system to the patient at prescribed intervals.

[0418] Test methods

[0419] Three-point bend test: The “flexural modulus” of a material is an inherent property of the material, calculated as the ratio of stress to strain measured by a three-point bend test during bending deformation of the material. Although the connector, as described herein, is a component of the gastric retention system, the flexural modulus of the material containing polymers can be measured separately. For example, the polymer connector in the gastric retention system may be too short to measure the flexural modulus, but a longer sample of the same material can be used to accurately determine the flexural modulus. The longer sample used to measure the flexural modulus should have the same cross-sectional dimensions (shape and size) as the polymer connector used in the gastric retention system. The flexural modulus is measured using the three-point bend test according to the ASTM standard three-point bend test (ASTM D790) using a 10 mm support spacing and further modified to accommodate materials with non-rectangular cross-sections. The longest line of symmetry of the polymer connector’s cross-section should be set perpendicularly and the flexural modulus should be measured by applying a downward force. If the longest line of symmetry of the polymer connector’s cross-section is perpendicular to a single flat edge, that single flat edge should be set upward. If the cross-section of the polymer connector is triangular, the apex of the triangle should face downward. As a downward force is applied, the force and displacement are measured, and the slope of the linear region is obtained to calculate the flexural modulus.

[0420] Radial force compression test: Figure 9 This demonstrates a radial force compression test utilizing the iris mechanism. Specifically, Figure 9 The illustrated gastric retention system 902 comprises a circumferentially wound filament of a star-shaped gastric retention system including six arms. The instrument used to measure radial force compression (i.e., an iris scanner) is a Model RLU124 Twin-Cam. TM Radial compression stage, Blockwise Model TTR2 tensile testing machine with dimensions of 60mm D×124mm L.

[0421] The gastric retention system is placed into the iris transducer such that the plane of the gastric retention system is parallel to the axis of the iris cylinder. Four arm tips are inserted into contact with the inner wall of the iris transducer (in the case of a gastric retention system with six arms), with two arms tilted upwards and two arms tilted downwards. The two additional arms are oriented parallel to the axis of the iris cylinder.

[0422] Pull-out force test: Figure 10A and 10B This paper presents a method for testing the adhesion strength of a filament. As previously described, the filament can be attached to the distal end of an arm. In cases where a single filament is attached to more than two arms, the filament can be attached to the distal end of each arm to prevent the arm from moving along the filament when the stomach force bends the stomach-residence system. Therefore, the pull-out force test described herein can quantify the amount of force required to separate the filament from the distal end of the arm.

[0423] A stomach-residence system with six arms and a filament was prepared, and the arms were separated by cutting the elastomer core into six parts. The filament was then cut between each arm. The pull force required to pull the filament out of each arm tip was measured using an Instron 3340 series universal testing system by clamping the base of the arm and one end of the filament.

[0424] Double-funnel durability test: The double-funnel test can be used to quantify the durability and / or failure modes of a gastric residence system. The durability of the gastric residence system can help prevent premature rupture or weakening (and early passage through the pylorus) due to repetitive gastric electrical waves / forces. To test a gastric residence system using the double-funnel test, the system under test is clamped at its center (i.e., the core) by a ring connected to a linear actuator. The gastric residence system is repeatedly moved up and down into facing cone-shaped cavities, causing the arms of the gastric residence system to bend back and forth relative to the core. The cone-shaped cavities face each other such that the apexes of the cones are opposite each other and the bases of the cones are close to each other. This up-and-down movement is repeated hundreds of times or until the gastric residence system ruptures. Different specific failure modes can include rupture at the connection point (e.g., arm to core or first segment to second segment) or tearing of the polysiloxane core. The number of cycles until failure and the force required to bend the gastric residence system can be quantified. This test can be performed at body temperature using the gastric residence system immersed in an aqueous medium (e.g., simulated gastric juice).

[0425] Planar circumferential bending durability test: The planar circumferential test can be used to quantify the durability and / or failure modes of a gastric residence system. This test can be performed, in particular, by placing the gastric residence system on a disk with four clamps, each in contact with an arm of the system. The clamps are connected to a rotary actuator that applies force to the circumferentially moving arm. This movement causes the arm to unfold within the plane of the gastric residence system. This movement is repeated for hundreds of cycles or until the gastric residence system ruptures. Different specific failure modes can include rupture at the connection point (e.g., arm to core or first segment to second segment) or tearing of the polysiloxane core. The number of cycles until failure and the force required to bend the gastric residence system can be quantified. This test can be performed at body temperature with the gastric residence system immersed in an aqueous medium (e.g., simulated gastric juice).

[0426] Melt Flow Index (MFI): The Melt Flow Index (MFI) is a measure of viscosity at low shear, expressed as the number of grams of material flowing through a die over 10 minutes at a set temperature and applied weight. These measurements are performed using a Ray-Ran 6MPCA advanced melt flow system with a 2.16 kg weight (but a range of standardized weights can be used) and according to ASTM D1238 Procedure A, “Standard Test Method for Melt Flow Rates of Thermoplastics by Extrusion Plastometer”.

[0427] Tensile testing: An Instron machine with custom fixtures (Figure C) can be used to evaluate the ultimate tensile strength (UTS) of any combination of star-shaped components: (1) in a wide variety of incubation media; (2) after several incubations; and (3) at room temperature or body temperature (37–40 °C). A low ultimate tensile strength indicates a potential failure point for the star. Tensile strength can be maximized for ideal star performance using formulation and process optimization.

[0428] To test a star-shaped arm with a triangular cross-section, a custom fixture with a flat plate and a notched plate can be used. The apex of the triangular arm is located within the notch to distribute the pressure from the plate more evenly across the three length directions of the triangular arm.

[0429] Tensile testing was performed using the Instron 3342 series. A series of thermoplasticized, thermobonded equilateral triangular prisms with 3.33mm triangular bases were pneumatically clamped. The crosshead moved upward at a rate of 5-500mm / min, depending on the elasticity of the test material. The instrument recorded force (N) v. displacement (mm) and divided the maximum force by the cross-sectional area at the interface to calculate the ultimate tensile strength (stress).

[0430] Drug release rate assay: The drug release rate was tested in fasting simulated gastric fluid (FaSSGF). FaSSGF was prepared according to the manufacturer's instructions (biorelevant.com) as follows: 975 mL of deionized water and 25 mL of 1N hydrochloric acid were mixed in a 1 L glass media bottle. The pH was adjusted to 1.6 as needed using 1N HCl or NaOH. 2.0 g of NaCl was added and mixed. Just before use, 60 mg of Biorelevant powder was added to the solution. The composition of FaSSGF is taurine (0.08 mM), phospholipids (0.02 mM), sodium (34 mM), and chloride ions (59 mM). The carrier polymer-active agent composition was molded into a drug-loaded polymer arm by blending and extruding the polymer powder and the active pharmaceutical ingredient. The arm was coated with a polymer membrane to adjust the release rate by dissolving the membrane polymer in a suitable solvent—usually ethyl acetate or acetone—and pan-coating or dip-coating the arm in the solution of the membrane polymer. The coated arm was then placed in a container containing FaSSGF and incubated at 37°C, typically sampled at least four times over a 7-day period. Drug concentration was determined by HPLC. Samples were stored at 4°C for no more than 3 days prior to analysis. At each measurement point, to maintain leak conditions, the entire volume of release medium was replaced with fresh solution pre-equilibrated to 37°C. Example

[0431] Example 1: The radial force required to compress the gastric retention system to various iris diameters was tested using the radial force test described in detail above. For example... Figure 11 As shown, gastric receptacle systems with and without filaments were tested. As indicated, the difference in force required to compress the gastric receptacle system with and without filaments increases as the compression diameter decreases. The results indicate that at compression diameters small enough for the gastric receptacle system to prematurely pass through the pylorus (i.e., diameters of 20 mm and smaller), the force required to compress the gastric receptacle system with filaments is at least twice that required to compress the gastric receptacle system without filaments.

[0432] Example 2: The radial force required to compress the gastric residence system to various iris diameters was tested using the radial force test described in detail above. Specifically, gastric residence systems with and without filaments and relatively flexible arms (compared to the gastric residence system tested in Example 1) were tested. Like the gastric residence system tested in Example 1, Figure 12 The difference in force required to compress a gastric retention system with filaments and one without filaments increases as the compression diameter decreases. Furthermore, as shown in the figure, the force required to compress a gastric retention system with filaments to a compression diameter small enough to prematurely pass through the pylorus (i.e., 20 mm and smaller) is approximately 1.5 times that required to compress a gastric retention system without filaments to the same compression diameter.

[0433] Example 3: Testing the pull force required to separate the filament from the arm tip under various incubation settings. For example... Figure 13 As shown, the pull-out force of the filament attached to the arm tip with formulation 14 (as shown in Table 1) was tested using the pull-out force testing procedure described in detail above. The tip containing this formulation was designed to remain attached to the filament in a highly acidic or gastric environment and to detach or slip from the filament in the intestinal environment as the gastric residence system component passes through the patient's intestine. Adhesion was measured after incubating the samples in fasting simulated gastric fluid (FaSSGF, pH 1.6) or fasting simulated intestinal fluid (FaSSIF, pH 6.5) for 1 day and 3 days. As shown in the figure, the incubation duration (i.e., 1 day or 3 days) only slightly affected the pull-out force of the samples incubated in fasting simulated gastric fluid and fasting simulated intestinal fluid. However, the pull-out force varied significantly between the two simulated solutions. The pull-out force of the sample incubated in fasting simulated gastric fluid was approximately twice that of the sample incubated in fasting simulated intestinal fluid.

[0434] Table 1. Ingredients of the Arm Tip Formula

[0435] Formula 1 Formula 6 Formula 14 Formula 15 PCL (by weight) 30 30 30 30 HPMC AS MG (wt%) 64.9 49.9 64.9 59.9 Plasticizer (wt%) Propylene glycol, 5 P407，10 Propylene glycol, 2.5 Propylene glycol, 5 Stearic acid (wt%) 0 0 2.5 5

[0436] Example 4: Testing the pull force required to separate the filament from the arm tip under various incubation settings. For example... Figure 14 As shown, the pull-out force of a filament attached to an arm tip having formulation 15 (as shown in Table 1) was tested using the pull-out force testing procedure described in detail above. The tip containing this formulation was designed to remain attached to the filament in a highly acidic or gastric environment and to detach or slip from the filament in the intestinal environment as the gastric resident system components pass through the patient's intestines. Adhesion was measured after incubating samples in fasting simulated gastric fluid (FaSSGF, pH 1.6) or fasting simulated intestinal fluid (FaSSIF, pH 6.5) for 1 day and 3 days. As shown in the figure, the incubation duration (i.e., 1 day or 3 days) only slightly affected the pull-out force of samples incubated in fasting simulated gastric fluid. However, the pull-out force of a sample incubated in fasting simulated intestinal fluid for 3 days was approximately 75% of that of a sample incubated for only 1 day. Additionally, the pull-out force of a sample incubated in fasting simulated gastric fluid was approximately at least 20% greater than that of a sample incubated in fasting simulated intestinal fluid.

[0437] Example 5: Test the pull force required to separate the filament from the arm tip for both knotted and heated filament ends. Figure 15The results of this experiment are shown. Samples were incubated in simulated gastric fluid for 3 days under fasting conditions. As shown in the figure, samples with knotted filament ends required the greatest force to separate the filament from the arm tip. Samples with heated flared filament ends required less force to separate the filament from the arm tip compared to knotted filament ends, but more force than the control sample (neither knotted nor heated). As shown in the figure, the pull force required to separate knotted filament ends was approximately at least 1.5 times that required to separate heated filament ends from the arm tip and approximately 5 times that required to separate control (i.e., unknotted and unheated) filament ends from the arm tip.

[0438] Example 6: Testing gastric retention of a gastric retention system comprising filaments in dogs. Figure 16 The image shows a gastric retention system 1602 comprising filaments 1608 with knotted ends. Radiopaque tubes / markers 1660 are placed on the filaments 1608 between the arm tips 1610. The location and integrity of the gastric retention system can be determined via X-ray imaging using two or more radiopaque tubes / markers 1660. The radiopaque tubes / markers 1660 contain bismuth blended into a polymer matrix. Specifically, bismuth-loaded polycaprolactone is molded into tubes and loaded onto the filaments between the arms during filament assembly. The radiopaque tubes are free to slide along the filaments and can detach from the filaments if the filament ends slide out of the star-shaped structure. In animal studies, filament integrity is tracked on X-rays by observing the visible number and orientation of the radiopaque tubes.

[0439] The gastric retention system was assembled using arm tips 1610 containing enteric-coated formulation 14 (see Table 1) via incision, wrapping, and rounding. Incisions were made in arm tips 1610 using a circular saw. Pellethane filaments were cut to the required length, radiopaque tubes were loaded onto the filaments, and the ends of the filaments were knotted. The filaments were added to the gastric retention system by connecting notches at the arm ends, thus placing a radiopaque marker between each arm. The notches were then sealed by applying pressure using a heated die (85°C, 25 psi, 30 seconds). The gastric retention system was loaded into hydroxypropyl methylcellulose capsules and administered orally to beagle dogs. The gastric retention system was visualized daily by X-ray for up to one week. The number of polycaprolactone tubes visible on X-ray is shown in Table 2. In two of the three dogs, the mesh remained intact for more than one week. In the third gastric retention system, the two radiopaque tubes separated from the star-shaped structure on day 7, and the star-shaped structure was expelled from the body by day 8. Data shows that the filaments made of these materials are durable enough to support a week-long stomach stay.

[0440] Table 2. Gastric retention in Beagles, tested using a gastric retention system with long filaments.

[0441] animal# Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 1005 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 1006 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 1007 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 4 / 6 0 / 6

[0442] Example 7: Evaluation of the ability of filaments to prevent intact gastric retention of a star-shaped gastric retention system in a canine model. A dosage form with an outer diameter of 37 mm was assembled using a 40A hardness polysiloxane core, an enteric matrix, and PCL-based placebo arms. The arms included radiopaque markers for X-ray tracking of gastric retention. The dosage form was loaded into coated HPMC capsules and administered to 5 beagle dogs. As a first-instance study, a gastric retention system without filaments was administered. Gastric retention time ranged from 1 to 7 days, with an average of 3.2 days. X-ray imaging showed an intact star-shaped structure in the intestine, indicating that the dosage form was able to be completely expelled from the stomach. This star-shaped structure was chosen to evaluate the ability of the filaments to improve gastric retention time by preventing complete passage through the pylorus, as the inclusion of filaments in the dosage form was intended to help prevent complete passage. A similar star-shaped structure (40 core, 37 mm outer diameter, PCL-based arms) was assembled, and filaments were attached to the ends of each arm. The filament is a flexible Pellethane tube with a hardness of 80A, an OD of approximately 400 micrometers, and an ID of approximately 250 micrometers. The dosage form was folded into coated HPMC capsules and administered to 5 beagle dogs. X-ray imaging showed gastric retention times ranging from 4 to 10 days, with an average of 6.4 days. The addition of the filament prolonged the gastric retention time of the dosage form, which would otherwise pass completely through the pylorus.

[0443] Example 8: Testing the deployment time of a gastric retention system comprising filaments cascaded and sleeved on the arm side and the deployment time of a gastric retention system comprising filaments cascaded and sleeved on the core side. Specifically, some gastric retention systems, such as star-shaped gastric retention systems, are configured to be compressed / folded at the core. Therefore, when compressed / folded, the gastric retention system has an arm side (e.g., composed of filaments cascaded and sleeved on the core side). Figure 17A The arrows indicate the side of the nucleus and the nuclear side (e.g., by the side of the nucleus). Figure 17C (The arrow in the text indicates the side). The embodiment described herein tests the deployment time of a gastric retention system that is compressed and fitted onto the arm side and a gastric retention system that is compressed and fitted onto the nucleus side.

[0444] Figure 17A-17G Different sheathing and encapsulation configurations are shown for gastric retention systems that include filaments. Specifically, Figure 17A The sleeve 1712A shows a compression / folding gastric retention system 1710A fitted onto the arm side. The compression / folding gastric retention system 1710A includes filaments between the arms of the gastric retention system. Therefore, the filaments of the gastric retention system are covered by the sleeve 1712A. Figure 17B The stomach retention system 1710A is fitted onto the arm side of the stomach retention system 1712A to form a fitted compression / folding stomach retention system 1740B. Figure 17C The compression / folding gastric retention system 1710C is shown. However, the compression / folding gastric retention system 1710C is shown fitted onto the core side of the gastric retention system with a sleeve 1712C. Figure 17DThe image shows the compression / folding of the gastric retention system 1710D, which is fitted onto the nuclear side of the gastric retention system using a sleeve 1712C. Therefore, unlike... Figure 17B The mesh of the sleeved compression / folding stomach retention system 1740B and compression / folding stomach retention system 1710C is not covered by the sleeve 1712C in the sleeved compression / folding stomach retention system 1740D.

[0445] Figure 17E and 17F Different encapsulation configurations are shown for the compression / folding stomach retention system of the sleeve. Figure 17E The 1740E and its folding / compression gastric retention system Figure 17F The compression / folding gastric retention system 1740F is fitted onto the arm side of the gastric retention system. Furthermore, Figure 17E The gastric retention system 1740E shown is packaged in two capsules. The cap of the two capsules is shown—cap 1716E encapsulates the gastric retention system on its core side, and the body of the two capsules is shown—body 1714E encapsulates the gastric retention system on its arm side. Figure 17F The 1740F gastric retention system, as shown in the display case, is packaged with two capsules. However, unlike... Figure 17E As such, Figure 17F The compression / folding gastric retention system 1740F is packaged with the two-piece capsule body 1714F on the core side and the caps of the two-piece capsules 1716F on the arm side of the gastric retention system.

[0446] Figure 17G The 1742G shows the packaged compression / folding stomach retention system.

[0447] The sleeves used in these experiments were size 0 VCaps Plus HPMC. The sleeved gastric retention systems were then encapsulated in VCaps Plus HPMC capsules. Table 3 below shows the unfolding time data for the arm-side sleeved gastric retention systems, and Table 4 shows the unfolding time data for the core-side sleeved gastric retention systems. The data in both Tables 3 and 4 were obtained using a rocker test at pH 7, as described in further detail below.

[0448] Table 3. Arm sleeve deployment time

[0449] capsule# Deployment time (min) 1 95.3 2 78.7 3 83.6 4 68.6 5 67.0 average 78.6 StDev 11.6

[0450] Table 4. Results of nuclear lateral sleeve deployment

[0451] capsule# Deployment time (min) 1 87.8 2 130.2 3 107.7 4 81.9 5 55.6 6 71.0 7 101.0 8 84.8 9 85.7 10 59.0 average 86.5 StDev 22.5

[0452] As shown in Tables 3 and 4, the deployment times of the nuclear-side and arm-side gastric retention systems are similar. Although the average deployment time of the nuclear-side system is slightly longer than that of the arm-side system, the difference is not statistically significant. Therefore, the deployment times of the arm-side system and the nuclear-side system should theoretically be the same based on the data in Tables 3 and 4.

[0453] Example 9: Biodegradable sutures can be used as filaments to improve the gastric retention performance of this gastric retention system. The biodegradable sutures can be elastic or inelastic. Furthermore, the biodegradable sutures can be bioabsorbable. In some cases, the biodegradable sutures are attached to the enteric-coating tip of the stellate arm.

[0454] To evaluate the effect of the elasticity of the outer filaments on the resistance of the star-shaped structure to compression to a size that can pass through the pylorus, a star-shaped gastric retention system was assembled using filaments of various elasticities. Polyurethane elastomer (Pellethane tubing) was used as the elastic filament material, and polyglycolic acid sutures were used as the non-elastic filaments. The filaments were connected to the enteric tips of the star-shaped arms via slits, winding, and rounding. The radial force required to compress the star-shaped structure to a diameter of 20 mm was then measured using an iris tester.

[0455] like Figure 18A As shown, both filament materials improve the compressibility of the star-shaped structure compared to one without filaments. Furthermore, the star-shaped structure with a non-elastic mesh exhibits greater compressibility than that with an elastic mesh.

[0456] Furthermore, the adhesion strength of PLGA sutures to the star-shaped arms with enteric tips was evaluated by measuring pull-out force after incubation. A star-shaped gastric retention system was assembled using enteric tips and filaments made of polyurethane elastomer (Pellethane) or PLGA sutures. The filaments were attached to the enteric tips of the star-shaped arms via incision, winding, and rounding. The adhesion of the filaments to the star-shaped arms was measured before and after incubation in simulated gastric fluid in a fasting state for indicated time periods (0 days, 1 day, 4 days, or 7 days).

[0457] like Figure 18B As shown, the adhesion of both types of filaments was strongest at the early time point and decreased at the later time point, consistent with the observed hydration and softening of the enteric-coated tip material. More importantly, both the polyurethane elastomer and PLGA filament materials maintained adhesion strength above the 1N target for at least 7 days.

[0458] Exemplary Implementation

[0459] Implementation Scheme 1. A gastric resident system, comprising:

[0460] nuclear;

[0461] Multiple arms connected proximally to the core via multiple connector assemblies, one connector assembly corresponding to each arm of the multiple arms and the multiple arms extending radially from the proximity; and filaments circumferentially connecting each arm of the multiple arms.

[0462] Implementation Scheme 2. The gastric retention system of Implementation Scheme 1, wherein the filament is circumferentially connected to the distal ends of each of the plurality of arms.

[0463] Implementation scheme 3. The gastric resident system of implementation scheme 1 or 2, wherein the plurality of arms includes at least 3 arms.

[0464] Implementation Scheme 4. A gastric retention system of any one of Implementation Schemes 1-3, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

[0465] Implementation Scheme 5. A gastric retention system of any one of Implementation Schemes 1-4, wherein the plurality of arms contains a 40-60% load of the active pharmaceutical ingredient.

[0466] Implementation Scheme 6. A gastric residency system of any one of Implementation Schemes 1-5, wherein the connector component is degraded, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0467] Implementation Scheme 7. A gastric retention system of any one of Implementation Schemes 1-6, wherein the gastric retention system is configured to fold during administration and to have an open configuration when in the patient's stomach.

[0468] Implementation Scheme 8. The gastric residence system of Implementation Scheme 7, wherein the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rewinds when the gastric residence system is in an open configuration.

[0469] Implementation Scheme 9. A gastric residence system of any one of Implementation Schemes 1-8, wherein the gastric residence system has a multi-armed star shape in an open structure.

[0470] Implementation Scheme 10. A gastric retention system of any one of Implementation Schemes 1-9, wherein the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times the force required to compress a gastric retention system without filaments to a size small enough to pass through the opening, as measured by radial testing.

[0471] Implementation Scheme 11. A gastric retention system of any one of Implementation Schemes 2-10, wherein when the gastric retention system is incubated in an environment of pH 1.6 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0472] Implementation Scheme 12. A gastric retention system of any one of Implementation Schemes 2-11, wherein the pull force required to separate the filament from the distal end of the first arm of the plurality of arms when the gastric retention system is incubated in an environment of pH 6.5 for 3 days is less than 2N.

[0473] Implementation Scheme 13. A gastric resident system of any one of Implementation Schemes 1-12, wherein the distal end of each of the plurality of arms comprises an enteric material.

[0474] Implementation Scheme 14. A gastric residence system of any one of Implementation Schemes 1-13, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0475] Implementation Scheme 15. The gastric residence system of Implementation Scheme 13 or 14, wherein the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0476] Implementation Scheme 16. The gastric residence system of Implementation Scheme 15, wherein the polymer comprises polycaprolactone or TPU.

[0477] Implementation Scheme 17. The gastric residence system of Implementation Scheme 15 or 16, wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

[0478] Implementation scheme 18. A gastric resident system of any one of implementation schemes 15-17, wherein the plasticizer comprises propylene glycol.

[0479] Implementation scheme 19. A gastric resident system of any one of implementation schemes 15-18, wherein the acid comprises stearic acid.

[0480] Implementation Scheme 20. A gastric retention system of any one of Implementation Schemes 1-19, wherein the distal end of each arm includes a notch and the filament is located within the notch at each distal end.

[0481] Implementation Scheme 21. The gastric retention system of Implementation Scheme 20, wherein the filament is secured by overlapping the first end and the second end of the filament within a first notch and the first end and the second end are secured by expanding the first end and the second end of the filament.

[0482] Implementation Scheme 22. A gastric residence system of any one of Implementation Schemes 1-21, wherein each arm of the plurality of arms includes a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured by a three-point bending test according to ASTM D790.

[0483] Implementation Scheme 23. The gastric residence system of Implementation Scheme 22, wherein the force required to compress the gastric residence system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times the force required to compress a gastric residence system having an arm containing only the first polymer composition to a size small enough to pass through the opening, as measured using an iris test mechanism.

[0484] Implementation Scheme 24. A gastric residence system of Implementation Scheme 22 or 23, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS and TPU.

[0485] Implementation Scheme 25. A gastric residence system of any one of Implementation Schemes 22-24, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

[0486] Implementation Scheme 26. A gastric retention system of any one of Implementation Schemes 22-25, wherein the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

[0487] Implementation Scheme 27. A gastric retention system of any one of Implementation Schemes 22-26, wherein the first segment is directly connected to the second segment of each of the plurality of arms.

[0488] Implementation Scheme 28. A gastric retention system of any one of Implementation Schemes 22-27, wherein the first segment is connected to the second segment via a connector.

[0489] Implementation Scheme 29. A gastric resident system of any one of Implementation Schemes 22-28, wherein the first segment comprises 20-50% of the length of at least the first arm of the plurality of arms, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

[0490] Implementation Scheme 30. A gastric resident system of any one of Implementation Schemes 22-29, wherein the second segment comprises 50-80% of the length of at least the first arm of the plurality of arms, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

[0491] Implementation Scheme 31. A gastric residence system of any one of Implementation Schemes 22-30, wherein the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

[0492] Implementation Scheme 32. A gastric retention system of any one of Implementation Schemes 1-31, wherein the gastric retention system is configured to be encapsulated in a capsule when the gastric retention system is in a folded configuration to form a gastric retention dosage form suitable for administration to a patient, and the gastric retention dosage form is configured to release the gastric retention system in the patient's stomach, thereby allowing the gastric retention system to be in an open configuration.

[0493] Implementation scheme 33. A gastric retention system of any one of implementation schemes 1-32, wherein the gastric retention system is used to treat a patient.

[0494] Implementation scheme 34. The gastric resident system of implementation scheme 33, wherein the patient is a human or a dog.

[0495] Implementation Scheme 35. A gastric resident system, comprising:

[0496] Multiple arms connected to the proximal end, the multiple arms extending radially from the proximal end; and

[0497] The filaments at the distal ends of each arm of the plurality of arms are circumferentially connected.

[0498] Implementation Scheme 36. The gastric resident system of Implementation Scheme 35, including a core, wherein each arm of the plurality of arms is connected to the core at its proximal end.

[0499] Implementation scheme 37. The gastric residence system of implementation scheme 35 or 36, wherein the plurality of arms comprises at least 3 arms.

[0500] Implementation scheme 38. The gastric residence system of implementation scheme 35 or 36, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

[0501] Implementation Scheme 39. A gastric retention system of any one of Implementation Schemes 35-38, wherein the plurality of arms contains a 40-60% load of the active pharmaceutical ingredient.

[0502] Implementation Scheme 40. A gastric resident system of any one of Implementation Schemes 36-39, comprising a plurality of connector assemblies, wherein one of the plurality of connector assemblies connects one arm of the plurality of arms to the core.

[0503] Implementation Scheme 41. The gastric residency system of Implementation Scheme 40, wherein each of the plurality of connector components is degraded, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0504] Implementation Scheme 42. A gastric retention system of any one of Implementation Schemes 35-41, wherein the gastric retention system is configured to fold during administration and to have an open configuration when in the patient's stomach.

[0505] Implementation Scheme 43. The gastric residence system of Implementation Scheme 42, wherein the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rewinds when the gastric residence system is in an open configuration.

[0506] Implementation scheme 44. A gastric residence system of any one of implementation schemes 35-43, wherein the gastric residence system has a multi-armed star shape in an open structure.

[0507] Implementation Scheme 45. A gastric retention system of any one of Implementation Schemes 35-44, wherein the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times the force required to compress a gastric retention system without filaments to a size small enough to pass through the opening, as measured by radial testing.

[0508] Implementation Scheme 46. A gastric retention system of any one of Implementation Schemes 35-45, wherein when the gastric retention system is incubated in an environment of pH 1.6 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0509] Implementation Scheme 47. A gastric retention system of any one of Implementation Schemes 35-46, wherein the pull force required to separate the filament from the distal end of the first arm of the plurality of arms when the gastric retention system is incubated in an environment of pH 6.5 for 3 days is less than 2N.

[0510] Implementation scheme 48. A gastric retention system of any one of implementation schemes 35-47, wherein the distal end of each of the plurality of arms comprises an enteric material.

[0511] Implementation Scheme 49. A gastric residence system of any one of Implementation Schemes 35-48, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0512] Implementation scheme 50. The gastric residence system of implementation scheme 48 or 49, wherein the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0513] Implementation Scheme 51. The gastric residence system of Implementation Scheme 50, wherein the polymer comprises polycaprolactone or TPU.

[0514] Implementation Scheme 52. The gastric residence system of Implementation Scheme 50 or 51, wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

[0515] Implementation scheme 53. A gastric resident system of any one of implementation schemes 50-52, wherein the plasticizer comprises propylene glycol.

[0516] Implementation scheme 54. A gastric resident system of any one of implementation schemes 50-53, wherein the acid comprises stearic acid.

[0517] Implementation scheme 55. A gastric retention system of any one of implementation schemes 35-54, wherein the distal end of each arm includes a notch and the filament is located within the notch at each distal end.

[0518] Implementation Scheme 56. A gastric retention system of Implementation Scheme 55, wherein the filament is secured by overlapping the first end and the second end of the filament within a first notch and the first end and the second end are secured by either knotting or thermal flaring.

[0519] Implementation Scheme 57. A gastric residence system of any one of Implementation Schemes 35-56, wherein each arm of the plurality of arms includes a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured by a three-point bending test according to ASTM D790.

[0520] Implementation Scheme 58. The gastric residence system of Implementation Scheme 57, wherein the force required to compress the gastric residence system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times the force required to compress a gastric residence system having an arm containing only the first polymer composition to a size small enough to pass through the opening, as measured using an iris test mechanism.

[0521] Implementation Scheme 59. The gastric residence system of Implementation Scheme 57 or 58, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS and TPU.

[0522] Implementation Scheme 60. A gastric residence system of any one of Implementation Schemes 57-59, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

[0523] Implementation Scheme 61. A gastric residence system of any one of Implementation Schemes 57-60, wherein the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

[0524] Implementation Scheme 62. A gastric retention system of any one of Implementation Schemes 57-61, wherein the first segment is directly connected to a second segment of at least the first arm of the plurality of arms.

[0525] Implementation Scheme 63. A gastric retention system of any one of Implementation Schemes 57-62, wherein the first segment is connected to the second segment via a connector assembly.

[0526] Implementation Scheme 64. A gastric resident system of any one of Implementation Schemes 57-63, wherein the first segment comprises at least 20-50% of the length of the first arm, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

[0527] Implementation Scheme 65. A gastric resident system of any one of Implementation Schemes 57-64, wherein the second segment comprises 50-80% of the length of the at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

[0528] Implementation Scheme 66. A gastric residence system of any one of Implementation Schemes 57-65, wherein the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

[0529] Implementation Scheme 67. A gastric residence system of any one of Implementation Schemes 35-66, wherein the gastric residence system is configured to be encapsulated in a capsule when the gastric residence system is in a folded configuration to form a gastric residence dosage form suitable for administration to a patient, and the gastric residence dosage form is configured to release the gastric residence system in the patient's stomach, thereby allowing the gastric residence system to be in an open configuration.

[0530] Implementation scheme 68. A gastric residence system of any one of implementation schemes 35-67, wherein the gastric residence system is used to treat a patient.

[0531] Implementation scheme 69. The gastric resident system of implementation scheme 68, wherein the patient is a human or a dog.

[0532] Implementation Scheme 70. A method for manufacturing a gastric resident system, comprising:

[0533] Prepare a gastric residence system comprising a plurality of arms proximal to the nucleus via a plurality of connector assemblies, one connector assembly corresponding to each of the plurality of arms and the plurality of arms extending radially;

[0534] Make cuts in each of the multiple arms to create notches in each arm;

[0535] The filament is wound circumferentially around the gastric retention system such that the filament is located within the notches of each arm; and the notches are closed to secure the filament within the notches.

[0536] Implementation Scheme 71. The method of Implementation Scheme 70, wherein the filament is circumferentially connected to the distal ends of each of the plurality of arms.

[0537] Implementation Scheme 72. The method of Implementation Scheme 70 or 71, wherein the plurality of arms comprises at least 3 arms.

[0538] Implementation Scheme 73. The method of any one of Implementation Schemes 70-72, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

[0539] Implementation Scheme 74. The method of any one of Implementation Schemes 70-73, wherein the plurality of arms comprises a 40-60% loading of the active pharmaceutical ingredient.

[0540] Implementation Scheme 75. The method of any one of Implementation Schemes 70-74, wherein the connector component is degraded, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0541] Implementation Scheme 76. The method of any one of Implementation Schemes 70-75, wherein the gastric residence system is configured to fold during administration and to have an open configuration when in the patient's stomach.

[0542] Implementation Scheme 77. The method of Implementation Scheme 76, wherein the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rewinds when the gastric residence system is in an open configuration.

[0543] Implementation scheme 78. The method of any one of implementation schemes 70-77, wherein the gastric residence system has a multi-armed star shape in an open structure.

[0544] Implementation Scheme 79. The method of any one of Implementation Schemes 70-78, wherein closing each gap includes at least one of knotting or heating.

[0545] Implementation scheme 80. The method of any one of implementation schemes 70-79, wherein the force required to compress the gastric retention system into a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times the force required to compress a gastric retention system without filaments into a configuration small enough to pass through the opening, as tested using a radial test.

[0546] Implementation Scheme 81. The method of any one of Implementation Schemes 70-80, wherein when the gastric residence system is incubated in an environment of pH 1.6 for 3 days, the pull force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0547] Implementation Scheme 82. The method of any one of Implementation Schemes 70-81, wherein the pull force required to separate the filament from the distal end of the first arm of the plurality of arms when measured after incubating the gastric residence system in an environment of pH 6.5 for 3 days is less than 2N.

[0548] Implementation Scheme 83. The method of any one of Implementation Schemes 70-82, wherein the distal end of each of the plurality of arms comprises an enteric material.

[0549] Implementation Scheme 84. The method of any one of Implementation Schemes 70-83, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0550] Implementation Scheme 85. The method of any one of Implementation Schemes 70-84, wherein the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0551] Implementation Scheme 86. The method of Implementation Scheme 85, wherein the polymer comprises polycaprolactone.

[0552] Implementation Scheme 87. The method of Implementation Scheme 85 or 86, wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

[0553] Implementation scheme 88. The method of any one of implementation schemes 85-87, wherein the plasticizer comprises propylene glycol.

[0554] Implementation scheme 89. The method of any one of implementation schemes 85-88, wherein the acid comprises stearic acid.

[0555] Implementation Scheme 90. The method of any one of Implementation Schemes 70-89, wherein each arm of the plurality of arms includes a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured by a three-point bending test according to ASTM D790.

[0556] Implementation Scheme 91. The method of Implementation Scheme 90, wherein the force required to compress the gastric residence system into a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times the force required to compress a gastric residence system having an arm containing only the first polymer composition into a configuration small enough to pass through the opening, as measured using an iris test mechanism.

[0557] Implementation Scheme 92. The method of Implementation Scheme 90 or 91, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS and TPU.

[0558] Implementation Scheme 93. The method of any one of Implementation Schemes 90-92, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

[0559] Implementation Scheme 94. The method of any one of Implementation Schemes 90-93, wherein the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

[0560] Implementation Scheme 95. The method of any one of Implementation Schemes 90-94, wherein the first segment is directly connected to the second segment of the at least one arm.

[0561] Implementation Scheme 96. The method of any one of Implementation Schemes 90-95, wherein the first segment is connected to the second segment via a connecting body assembly.

[0562] Implementation Scheme 97. The method of any one of Implementation Schemes 90-96, wherein the first segment accounts for 20-50% of the length of the at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

[0563] Implementation Scheme 98. The method of any one of Implementation Schemes 90-97, wherein the second segment accounts for 50-80% of the length of the at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

[0564] Implementation Scheme 99. The method of any one of Implementation Schemes 90-98, wherein the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

[0565] Implementation Scheme 100. The method of any one of Implementation Schemes 90-99, wherein the gastric residence system is configured to be encapsulated in a capsule when the gastric residence system is in a folded configuration to form a gastric residence dosage form suitable for administration to a patient, and the gastric residence dosage form is configured to release the gastric residence system in the patient's stomach, thereby allowing the gastric residence system to be in an open configuration.

[0566] Implementation Scheme 101. A gastric residence system prepared using the method of any one of Implementation Schemes 70-100, wherein the gastric residence system is used to treat a patient.

[0567] Implementation scheme 102. The gastric resident system of implementation scheme 101, wherein the patient is a human or a dog.

[0568] Implementation Scheme 103. A method for manufacturing a gastric resident system, comprising:

[0569] Prepare a gastric residence system comprising a plurality of arms proximal to the nucleus via a plurality of connector assemblies, wherein one connector assembly corresponds to each of the plurality of arms and the plurality of arms extend radially.

[0570] Prepare a plurality of tips and filaments, each arm of the plurality of arms having one tip, wherein the filaments are connected to each tip of the plurality of tips;

[0571] The tips of the plurality of tips are connected to the arms of the plurality of arms to form a stomach-residing system including filaments.

[0572] Implementation scheme 104. The method of implementation scheme 103, wherein the preparation of multiple tips and filaments includes injection molding.

[0573] Unless otherwise defined, all process terms, symbols, and other technical and scientific terms or specialized expressions used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or convenience of reference, and the introduction of such definitions herein is not necessarily construed as indicating a significant difference from the meaning commonly understood in the art.

[0574] In this document, the use of "about" to refer to a value or parameter includes (and describes) changes relating to that value or parameter itself. For example, a description relating to "about X" includes a description of "X".

[0575] The singular forms “a,” “an,” and “the” used herein are intended to include the plural forms as well, unless the context clearly specifies otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any and all possible combinations of one or more of the associated enumerated items. Furthermore, it should be understood that the terms “comprising,” “including,” and / or “containing,” when used herein, expressly specify the presence of the stated feature, integer, step, operation, element, component, and / or unit, but do not preclude the presence or inclusion of one or more other features, integers, steps, operations, elements, components, units, and / or groups thereof.

[0576] This application discloses several ranges of numbers in the text and accompanying drawings. The disclosed ranges of numbers inherently support any range or value within the disclosed ranges of numbers, including endpoints, even if precise range limits are not described verbatim in the specification, because this disclosure can be implemented throughout the entire disclosed range of numbers.

[0577] For ease of explanation, the foregoing description has been based on specific embodiments. However, the illustrative discussion above is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many changes and variations are possible in light of the foregoing teachings. Embodiments have been chosen and described to best explain the technical principles and their practical application. This enables other skilled in the art to best utilize the various modified techniques and various embodiments suitable for the particular application considered.

[0578] Although this disclosure and embodiments have been fully described 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 this disclosure and embodiments as defined in the claims.

Claims

1. A gastric resident system, comprising: nuclear; Multiple arms are connected to the core proximally via multiple connector assemblies, one connector assembly corresponding to each arm of the multiple arms, the multiple arms comprising at least three arms, and the multiple arms extending radially from the proximity to the distal end, each arm of the multiple arms including a separate tip at its distal end. and The filaments at the individual tips of the plurality of arms are circumferentially connected. The gastric retention system is configured to fold during administration and to be in an open configuration when in the patient's stomach. The filaments are configured to prevent the gastric retention system from passing through the patient's pylorus before the predetermined gastric retention time expires. The gastric retention system described herein has a multi-armed star shape in an open construction.

2. The gastric residence system of claim 1, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

3. The gastric retention system of claim 1, wherein the plurality of arms comprises a 40-60% pharmaceutically active ingredient load.

4. The gastric residency system of claim 1, wherein the connector component is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

5. The gastric residency system of claim 2, wherein the connector assembly is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

6. The gastric residence system of claim 3, wherein the connector component is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

7. The gastric residence system according to any one of claims 1-6, wherein the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rebounds when the gastric residence system is in an open configuration.

8. The gastric retention system according to any one of claims 1-6, wherein the force required to compress the gastric retention system into a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times the force required to compress a gastric retention system without filaments into a configuration small enough to pass through the opening, as measured using a radial test.

9. The gastric retention system according to any one of claims 1-6, wherein the pull force required to separate the filament from the individual tip of the first arm of the plurality of arms when measured after the gastric retention system has been incubated in an environment of pH 1.6 for 3 days is greater than 1 N.

10. The gastric retention system according to any one of claims 1-6, wherein the pull force required to separate the filament from the individual tip of the first arm of the plurality of arms when measured after the gastric retention system has been incubated at pH 6.5 for 3 days is less than 2 N.

11. The gastric retention system according to any one of claims 1-6, wherein the individual tip of each of the plurality of arms comprises an enteric material.

12. The gastric residence system according to any one of claims 1-6, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

13. The gastric residence system of claim 11, wherein the enteric material at the individual tip of each arm comprises a polymer different from the enteric polymer, an enteric polymer, a plasticizer, and an acid.

14. The gastric residence system of claim 12, wherein the enteric material at the individual tip of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid, which are different from enteric polymers.

15. The gastric residence system of claim 13, wherein the polymer, which is different from the enteric polymer, comprises polycaprolactone or TPU.

16. The gastric residence system of claim 14, wherein the polymer, which is different from the enteric polymer, comprises polycaprolactone or TPU.

17. The gastric residence system according to any one of claims 13-16, wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

18. The gastric residence system according to any one of claims 13-16, wherein the plasticizer comprises propylene glycol.

19. The gastric resident system according to any one of claims 13-16, wherein the acid comprises stearic acid.

20. A gastric retention system according to any one of claims 1-6, wherein the individual tip of each arm includes a notch and the filament is located within the notch of each individual tip.

21. The gastric retention system of claim 20, wherein the filament is secured by overlapping a first end and a second end of the filament within a first notch, and the first end and the second end are secured by knotting the first end and the second end or by thermal flaring to expand the first end and the second end of the filament.

22. The gastric retention system according to any one of claims 1-6, wherein each of the plurality of arms comprises a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured by a three-point bending test according to ASTM D790.

23. The gastric retention system of claim 22, wherein the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times the force required to compress a gastric retention system having an arm containing only the first polymer composition to a size small enough to pass through the opening, as measured using an iris testing mechanism.

24. The gastric residence system of claim 22, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

25. The gastric residence system of claim 22, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

26. The gastric residence system of claim 25, wherein the polyurethane comprises thermoplastic polyurethane.

27. The gastric residence system of claim 22, wherein the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

28. The gastric retention system of claim 22, wherein the first section is directly connected to a second section of each of the plurality of arms.

29. The gastric retention system of claim 22, wherein the first segment is connected to the second segment via a connector.

30. The gastric residence system of claim 22, wherein the first segment comprises 20-50% of the length of at least the first arm of the plurality of arms, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

31. The gastric residence system of claim 22, wherein the second segment comprises 50-80% of the length of at least the first arm of the plurality of arms, wherein the length is measured from the proximal end of the first arm to the distal end of the first arm, the proximal end being close to the nucleus.

32. The gastric residence system of claim 22, wherein the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

33. The gastric residence system according to any one of claims 1-6, wherein the gastric residence system is configured to be encapsulated in a capsule when the gastric residence system is in a folded configuration to form a gastric residence dosage form suitable for administration to a patient, and the gastric residence dosage form is configured to release the gastric residence system in the patient's stomach, thereby allowing the gastric residence system to be in an open configuration.

34. The gastric retention system according to any one of claims 1-6, wherein the gastric retention system is used to treat a patient.

35. The gastric residency system of claim 34, wherein the patient is a human or a dog.

36. A gastric resident system, comprising: A plurality of arms connected to the proximal end, the plurality of arms extending radially from the proximal end, the plurality of arms comprising at least 3 arms; and A filament circumferentially connected to the individual tips located at the distal ends of each of the plurality of arms. The gastric retention system is configured to fold during administration and to be in an open configuration when in the patient's stomach. The filaments are configured to prevent the gastric retention system from passing through the patient's pylorus before the predetermined gastric retention time expires. The gastric retention system described herein has a multi-armed star shape in an open construction.

37. The gastric residence system of claim 36, comprising a core, wherein each arm of the plurality of arms is connected to the core at its proximal end.

38. The gastric residence system of claim 36, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

39. The gastric residence system of claim 37, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

40. The gastric retention system of claim 36, wherein the plurality of arms comprises a 40-60% pharmaceutically active ingredient load.

41. A gastric resident system according to any one of claims 37-40, comprising a plurality of connector assemblies, wherein one of the plurality of connector assemblies connects one arm of the plurality of arms to the core.

42. The gastric residency system of claim 41, wherein each of the plurality of connector components is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

43. A gastric residence system according to any one of claims 36-40, wherein the core undergoes elastic deformation when the gastric residence system is in a folded configuration and rebounds when the gastric residence system is in an open configuration.

44. A gastric retention system according to any one of claims 36-40, wherein the force required to compress the gastric retention system into a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times the force required to compress a gastric retention system without filaments into a configuration small enough to pass through the opening, as measured using a radial test.

45. The gastric retention system according to any one of claims 36-40, wherein the pull force required to separate the filament from the individual tip of the first arm of the plurality of arms when measured after the gastric retention system has been incubated at pH 1.6 for 3 days is greater than 1 N.

46. ​​The gastric retention system according to any one of claims 36-40, wherein the pull force required to separate the filament from the individual tip of the first arm of the plurality of arms when measured after the gastric retention system has been incubated at pH 6.5 for 3 days is less than 2 N.

47. The gastric retention system according to any one of claims 36-40, wherein the individual tip of each of the plurality of arms comprises an enteric material.

48. The gastric residence system according to any one of claims 36-40, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

49. The gastric residence system of claim 47, wherein the enteric material at the individual tip of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid, which are different from enteric polymers.

50. The gastric residence system of claim 48, wherein the enteric material at the individual tip of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid, which are different from enteric polymers.

51. The gastric residence system of claim 49, wherein the polymer, which is different from the enteric polymer, comprises polycaprolactone or TPU.

52. The gastric residence system of claim 50, wherein the polymer, which is different from the enteric polymer, comprises polycaprolactone or TPU.

53. The gastric residency system according to any one of claims 49-52, wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

54. The gastric residence system according to any one of claims 49-52, wherein the plasticizer comprises propylene glycol.

55. The gastric resident system according to any one of claims 49-52, wherein the acid comprises stearic acid.

56. A gastric retention system according to any one of claims 36-40, wherein the individual tip of each arm includes a notch and the filament is located within the notch of each individual tip.

57. The gastric retention system of claim 56, wherein the filament is secured by overlapping a first end and a second end of the filament within a first notch and the first end and the second end are secured by one of knotting or thermal flaring.

58. A gastric retention system according to any one of claims 36-40, wherein each of the plurality of arms comprises a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured by a three-point bending test according to ASTM D790.

59. The gastric retention system of claim 58, wherein the force required to compress the gastric retention system to a size small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times the force required to compress a gastric retention system having an arm containing only the first polymer composition to a size small enough to pass through the opening, as measured using an iris testing mechanism.

60. The gastric residence system of claim 58, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

61. The gastric residence system of claim 58, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

62. The gastric residence system of claim 61, wherein the polyurethane comprises thermoplastic polyurethane.

63. The gastric retention system of claim 58, wherein the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

64. The gastric retention system of claim 58, wherein the first segment is directly connected to a second segment of at least the first arm of the plurality of arms.

65. The gastric retention system of claim 58, wherein the first segment is connected to the second segment via a connector assembly.

66. The gastric residence system of claim 58, wherein the first segment comprises at least 20-50% of the length of the first arm, wherein the length is measured from the proximal end to the distal end of the first arm, the proximal end being close to the nucleus.

67. The gastric residence system of claim 58, wherein the second segment comprises 50-80% of the length of at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

68. The gastric residence system of claim 58, wherein the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

69. A gastric retention system according to any one of claims 36-40, wherein the gastric retention system is configured to be encapsulated in a capsule when the gastric retention system is in a folded configuration to form a gastric retention dosage form suitable for administration to a patient, and the gastric retention dosage form is configured to release the gastric retention system in the patient's stomach, thereby allowing the gastric retention system to be in an open configuration.

70. A gastric retention system according to any one of claims 36-40, wherein the gastric retention system is used to treat a patient.

71. The gastric residency system of claim 70, wherein the patient is a human or a dog.

72. A method of manufacturing a gastric resident system, comprising: A gastric retention system is prepared comprising a plurality of arms connected proximally to the nucleus via a plurality of connector assemblies, one connector assembly corresponding to each arm of the plurality of arms, the plurality of arms comprising at least three arms and extending radially from proximal to distal, each arm of the plurality of arms having a separate tip at its distal end, wherein the gastric retention system is configured to fold during administration and configured to have an open configuration when in the patient's stomach; Individual cuts are made at the individual tips of each of the plurality of arms to form notches in the individual tips of each arm; filaments are circumferentially wound around the gastric retention system such that the filaments are located within the notches at the individual tips of each arm; and Seal the notches to secure the filaments within them. The filaments are configured to prevent the gastric retention system from passing through the patient's pylorus before the predetermined gastric retention time expires. The gastric retention system described herein has a multi-armed star shape in an open construction.

73. The method of claim 72, wherein the plurality of arms are configured to be loaded with a pharmaceutically active ingredient.

74. The method of claim 72, wherein the plurality of arms comprises a 40-60% pharmaceutical active ingredient load.

75. The method of claim 72, wherein the connector assembly is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

76. The method of claim 73, wherein the connector assembly is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

77. The method of claim 74, wherein the connector assembly is degraded, dissolved, disintegrated, or mechanically weakened in the gastric environment.

78. The method of any one of claims 72-77, wherein the core undergoes elastic deformation when the gastric residence system is in a folded configuration and springs back when the gastric residence system is in an open configuration.

79. The method according to any one of claims 72-77, wherein closing each notch comprises at least one of knotting or heating.

80. The method of any one of claims 72-77, wherein the force required to compress the gastric retention system into a configuration small enough to pass through an opening of 20 mm in diameter is at least 1.5 times the force required to compress a gastric retention system without filaments into a configuration small enough to pass through the opening, as measured using a radial test.

81. The method of any one of claims 72-77, wherein the pull force required to separate the filament from the individual tip of the first arm of the plurality of arms when measured after the gastric retention system has been incubated at pH 1.6 for 3 days is greater than 1 N.

82. The method according to any one of claims 72-77, wherein the pull force required to separate the filament from the individual tip of the first arm of the plurality of arms when measured after the gastric retention system has been incubated at pH 6.5 for 3 days is less than 2 N.

83. The method according to any one of claims 72-77, wherein the individual tip of each of the plurality of arms comprises an enteric material.

84. The method according to any one of claims 72-77, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

85. The method of any one of claims 83, wherein the enteric material at the individual tip of each arm comprises a polymer different from the enteric polymer, an enteric polymer, a plasticizer, and an acid.

86. The method of claim 84, wherein the enteric material at the individual tip of each arm comprises a polymer different from the enteric polymer, an enteric polymer, a plasticizer, and an acid.

87. The method of claim 85, wherein the polymer, which is different from the enteric polymer, comprises polycaprolactone.

88. The method of claim 86, wherein the polymer, which is different from the enteric polymer, comprises polycaprolactone.

89. The method of any one of claims 85-88, wherein the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate.

90. The method according to any one of claims 85-88, wherein the plasticizer comprises propylene glycol.

91. The method according to any one of claims 85-88, wherein the acid comprises stearic acid.

92. The method of any one of claims 72-77, wherein each of the plurality of arms comprises a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, wherein the first segment has a stiffness greater than that of the second segment, as measured using a three-point bending test according to ASTM D790.

93. The method of claim 92, wherein the force required to compress the gastric retention system into a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times the force required to compress a gastric retention system having an arm containing only the first polymer composition into a configuration small enough to pass through the opening, as measured using an iris testing mechanism.

94. The method of claim 92, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

95. The method of claim 92, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, polycaprolactone / polylactic acid copolymer, polypropylene carbonate, polyglycerol sebacate, and polysiloxane.

96. The method of claim 95, wherein the polyurethane comprises thermoplastic polyurethane.

97. The method of claim 92, wherein the second polymer composition comprises at least polycaprolactone and a soluble material to form a material that softens upon exposure to an aqueous environment.

98. The method of claim 92, wherein the first segment is directly connected to a second segment of at least one arm.

99. The method of claim 92, wherein the first segment is connected to the second segment via a connector assembly.

100. The method of claim 92, wherein the first segment comprises 20-50% of the length of at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

101. The method of claim 92, wherein the second segment comprises 50-80% of the length of at least one arm, wherein the length is measured from the proximal end of the at least one arm to the distal end of the at least one arm, the proximal end being close to the nucleus.

102. The method of claim 92, wherein the number of fatigue cycles required to destroy the gastric residence system is at least 25% greater than the number of fatigue cycles required to destroy a gastric residence system having an arm containing only the first polymer composition, as measured using a double funnel test.

103. The method of claim 92, wherein the gastric residence system is configured to be encapsulated in a capsule when the gastric residence system is in a folded configuration to form a gastric residence dosage form suitable for administration to a patient, and the gastric residence dosage form is configured to release the gastric residence system in the patient's stomach, thereby allowing the gastric residence system to be in an open configuration.

104. A gastric retention system prepared using the method of any one of claims 72-103, wherein the gastric retention system is used to treat a patient.

105. The gastric residency system of claim 104, wherein the patient is a human or a dog.

106. A method of manufacturing a gastric resident system, comprising: Prepare a gastric retention system comprising a plurality of arms proximally connected to the nucleus via a plurality of connector assemblies, one connector assembly corresponding to each arm of the plurality of arms, the plurality of arms comprising at least three arms and extending radially, wherein the gastric retention system is configured to fold during administration and configured to be in an open configuration when in a patient's stomach; prepare a plurality of individual tips and filaments, each arm of the plurality of arms having a single tip, wherein the filaments are connected to each individual tip of the plurality of individual tips; Each individual tip of the plurality of tips is connected to an arm of the plurality of arms to form a stomach-residence system including filaments. The filaments are configured to prevent the gastric retention system from passing through the patient's pylorus before the predetermined gastric retention time expires. The gastric retention system described herein has a multi-armed star shape in an open construction.

107. The method of claim 106, wherein preparing the plurality of individual tips and filaments includes injection molding.

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