Gastric retention system with filaments that improve gastric retention

Abstract

To provide a gastric retention system, and more specifically, a gastric retention system having filaments that improve gastric retention. [Solution] A gastric retention system is provided, comprising a core, a plurality of arms connected to the core at their proximal ends via a plurality of linker components, and filaments connecting each of the plurality of arms circumferentially, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially from their proximal ends.

Description

Cross-reference of related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 933,211, filed on 8 November 2019, and U.S. Provisional Patent Application No. 62 / 992,075, filed on 19 March 2020. The entire contents of those applications are incorporated herein by reference. [Technical Field]

[0002] This disclosure relates to a gastric retention system, and more particularly to a gastric retention system having filaments that improve gastric retention. [Background technology]

[0003] Intragastric retention systems are drug delivery systems that remain in the stomach for several days, several weeks, or even longer periods, during which time the drug or other medication can be eluted from the system for absorption in the gastrointestinal tract. Examples of such systems are described in International Patent Application Nos. WO2015 / 191920, WO2015 / 191925, WO2017 / 070612, WO2017 / 100367, and PCT / US2017 / 034856.

[0004] A gastric retention system is typically designed to be administered to a patient's stomach in the form of a capsule, either swallowed or introduced into the stomach by another method of administration (e.g., a feeding tube or gastric tube). Once the capsule dissolves in the stomach, the system expands or unfolds to a size that allows it to remain in the stomach for a desired retention period (e.g., 3 days, 7 days, 2 weeks) and resist passage through the pyloric sphincter. This requires mechanical stability over the desired retention period. During the retention period, the system releases a drug, such as one or more drugs, preferably with minimal explosive release; however, careful selection of the drug-carrying material is necessary to impart the desired release characteristics. While in the stomach, the system must not obstruct the normal passage of food or other stomach contents. Once the desired retention period is complete, the system must be easily expelled from the patient. If the system passes too quickly from the stomach into the small intestine, it must not cause intestinal obstruction and must also be easily expelled from the patient. These characteristics necessitate careful selection of the materials constituting the system, as well as its dimensions and arrangement. [Overview of the Initiative]

[0005] Provided in this disclosure of a circular filament is a gastric retention system including a filament for improving gastric retention, and a method for preparing a gastric retention form with a filament. In particular, the gastric retention system with a filament described herein helps to improve gastric retention of the retention system. Specifically, the filament helps to provide a more consistent and / or longer retention time. Thus, the gastric retention system provided herein, including a filament, provides a more predictable and / or controllable retention time. A gastric retention system with a predictable and / or controllable retention time can minimize the risk of the retention system developing too quickly (e.g., in the esophagus) and causing obstruction. A gastric retention system with a predictable and / or controllable retention time can also minimize the possibility of the retention system passing through the stomach and subsequently developing in the gastrointestinal tract (i.e., the intestines), or passing through the gastrointestinal tract without developing at all. In each of these possible scenarios, the therapeutic agent in a retention-type dosage form may not be delivered to the patient as intended.

[0006] Depending on the embodiment, the gastric retention system is provided, comprising a core, a plurality of arms connected to the core at their proximal ends via a plurality of linker components, and filaments connecting each of the plurality of arms circumferentially, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially from the proximal end.

[0007] In one embodiment of this gastric retention system, the filament connects the distal ends of each of the plurality of arms in a circumferential direction.

[0008] In some embodiments of this gastric retention system, the plurality of arms include at least three arms.

[0009] In one embodiment of this gastric retention system, the plurality of arms are configured to carry the active pharmaceutical ingredient.

[0010] In this embodiment of the gastric retention system, the multiple arms carry 40-60% of the active pharmaceutical ingredient.

[0011] Depending on the embodiment of this gastric retention system, the linker component may decompose, dissolve, dissociate, or be mechanically weakened in the gastric environment.

[0012] In some embodiments of this gastric retention system, the gastric retention system is configured to fold during administration and to open when it is in the patient's stomach.

[0013] In some embodiments of this gastric retention system, the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system assumes the open configuration.

[0014] In one embodiment of this gastric retention system, the gastric retention system has a multi-armed star shape in the open configuration.

[0015] Depending on the embodiment of this intragastric retention system, the force required to compress the intragastric retention system to a configuration small enough to pass through a 20 mm diameter opening, as measured by radial testing, is at least 1.5 times greater than the force required to compress an intragastric retention system without filaments to a configuration small enough to pass through the opening.

[0016] In one embodiment of this gastric retention system, when the gastric retention system is left at a constant temperature in a pH 1.6 environment for three days and then measured, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is greater than 1 N.

[0017] In some embodiments of this intragastric retention system, when measured after leaving the intragastric retention system in a constant temperature environment at pH 6.5 for 3 days, the pulling force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

[0018] In some embodiments of this intragastric retention system, the distal end of each arm of the plurality of arms contains an enteric material.

[0019] In some embodiments of this intragastric retention system, the filament contains one or more of an elastic polymer, a biodegradable polymer, and a plasticizer.

[0020] In some embodiments of this intragastric retention system, the enteric material at the distal end of each arm contains a polymer, an enteric polymer, a plasticizer, and an acid.

[0021] In some embodiments of this intragastric retention system, the polymer contains polycaprolactone or TPU.

[0022] In some embodiments of this intragastric retention system, the enteric polymer contains hydroxypropyl methylcellulose acetate succinate.

[0023] In some embodiments of this intragastric retention system, the plasticizer contains propylene glycol.

[0024] In some embodiments of this intragastric retention system, the acid contains stearic acid.

[0025] In some embodiments of this intragastric retention system, the distal end of each arm contains a notch, and the filament is disposed within the notch at each distal end.

[0026] In one embodiment of this gastric retention system, the filament is fixed by overlapping its first end and its second end within a first notch, and the first end and the second end are fixed by extending the first and second ends of the filament.

[0027] In one embodiment of this gastric retention system, each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, wherein the first segment has greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

[0028] In some embodiments of this intragastric retention system, when measured using a throttling test mechanism, the force required to compress the intragastric retention system to a configuration small enough to pass through a 20 mm diameter opening is at least 1.2 times greater than the force required to compress an intragastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

[0029] In some embodiments of this gastric retention system, the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0030] In some embodiments of this gastric retention system, the second polymer composition comprises one or more of the following: polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

[0031] In some embodiments of this gastric retention system, the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens upon exposure to an aqueous environment.

[0032] In one embodiment of this gastric retention system, the first segment is directly connected to the second segment of each of the plurality of arms.

[0033] In one embodiment of this gastric retention system, the first segment is connected to the second segment via a linker.

[0034] In one embodiment of this gastric retention system, the first segment constitutes 20–50% of the length of at least one of the plurality of arms, the length of which is measured from the proximal end to the distal end of the first arm, the proximal end being close to the core.

[0035] In one embodiment of this gastric retention system, the second segment constitutes 50–80% of the length of at least the first arm of the plurality of arms, the length of which 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 core.

[0036] In some embodiments of this intragastric retention system, the number of fatigue cycles required for rupture of the intragastric retention system, as measured using a double funnel test, is at least 25% greater than the number of fatigue cycles required for rupture of an intragastric retention system having an arm containing only the first polymer composition.

[0037] In one embodiment of this intragastric retention system, the intragastric retention system is configured to be enclosed in a capsule when in a folded configuration to form an intragastric retention dosage form suitable for administration to a patient, and the intragastric retention dosage form is configured to release the intragastric retention system in the patient's stomach to take on an open configuration.

[0038] Depending on the embodiment of this gastric retention system, the gastric retention system may be used to treat a patient.

[0039] Depending on the embodiment of this gastric retention system, the patient may be a human or a dog.

[0040] Depending on the embodiment, the gastric retention system is provided, which includes a plurality of arms connected at their proximal ends, and a filament connecting the distal ends of each of the plurality of arms in a circumferential direction, wherein the plurality of arms extend radially from the proximal end.

[0041] In one embodiment of this gastric retention system, the gastric retention system includes a core, and each of the plurality of arms is connected to the core at its proximal end.

[0042] In some embodiments of this gastric retention system, the plurality of arms include at least three arms.

[0043] In one embodiment of this gastric retention system, the plurality of arms are configured to carry the active pharmaceutical ingredient.

[0044] In this embodiment of the gastric retention system, the multiple arms carry 40-60% of the active pharmaceutical ingredient.

[0045] Depending on the embodiment of this gastric retention system, it may include a plurality of linker components, one of which connects one of which arms to the core.

[0046] Depending on the embodiment of this gastric retention system, each of the multiple linker components may be broken down, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0047] In some embodiments of this gastric retention system, the gastric retention system is configured to fold during administration and to open when it is in the patient's stomach.

[0048] In some embodiments of this gastric retention system, the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system assumes the open configuration.

[0049] In one embodiment of this gastric retention system, the gastric retention system has a multi-armed star shape in the open configuration.

[0050] Depending on the embodiment of this intragastric retention system, the force required to compress the intragastric retention system to a configuration small enough to pass through a 20 mm diameter opening, as measured by radial testing, is at least 1.5 times greater than the force required to compress an intragastric retention system without filaments to a configuration small enough to pass through the opening.

[0051] In one embodiment of this gastric retention system, when the gastric retention system is left at a constant temperature in a pH 1.6 environment for three days and then measured, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is greater than 1 N.

[0052] In one embodiment of this gastric retention system, when the gastric retention system is left at a constant temperature in a pH 6.5 environment for three days and then measured, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

[0053] In one embodiment of this gastric retention system, the distal end of each of the plurality of arms contains an enteric-coated material.

[0054] In some embodiments of this gastric retention system, the filament comprises one or more of the following: an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0055] In some embodiments of this gastric retention system, the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0056] In some embodiments of this gastric retention system, the polymer comprises polycaprolactone or TPU.

[0057] In some embodiments of this gastric retention system, the enteric-coated polymer includes hydroxypropyl methylcellulose succinate acetate.

[0058] In some embodiments of this gastric retention system, the plasticizer includes propylene glycol.

[0059] In some embodiments of this gastric retention system, the acid includes stearic acid.

[0060] In one embodiment of this gastric retention system, the distal end of each arm includes a notch, and the filament is positioned within the notch at each distal end.

[0061] In one embodiment of this gastric retention system, the filament is fixed by overlapping its first end and its second end within a first notch, and the first and second ends are fixed by either a stopper or a heat-expanding process.

[0062] In one embodiment of this gastric retention system, each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, wherein the first segment has greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

[0063] In some embodiments of this intragastric retention system, when measured using a throttling test mechanism, the force required to compress the intragastric retention system to a configuration small enough to pass through a 20 mm diameter opening is at least 1.2 times greater than the force required to compress an intragastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

[0064] In some embodiments of this gastric retention system, the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0065] In some embodiments of this gastric retention system, the second polymer composition comprises one or more of the following: polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

[0066] In some embodiments of this gastric retention system, the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens upon exposure to an aqueous environment.

[0067] In one embodiment of this gastric retention system, the first segment is directly connected to the second segment of at least the first arm of the plurality of arms.

[0068] In one embodiment of this gastric retention system, the first segment is connected to the second segment via a linker component.

[0069] In some embodiments of this gastric retention system, the first segment constitutes at least 20-50% of the length of the first arm, which is measured from the proximal end to the distal end of the first arm, with the proximal end being close to the core.

[0070] In one embodiment of this intragastric retention system, the second segment constitutes 50–80% of the length of at least one arm, the length of which is measured from the proximal end to the distal end of the at least one arm, the proximal end being close to the core.

[0071] In some embodiments of this intragastric retention system, the number of fatigue cycles required for rupture of the intragastric retention system, as measured using a double funnel test, is at least 25% greater than the number of fatigue cycles required for rupture of an intragastric retention system having an arm containing only the first polymer composition.

[0072] In one embodiment of this intragastric retention system, the intragastric retention system is configured to be enclosed in a capsule when in a folded configuration to form an intragastric retention dosage form suitable for administration to a patient, and the intragastric retention dosage form is configured to release the intragastric retention system in the patient's stomach to take on an open configuration.

[0073] Depending on the embodiment of this gastric retention system, the gastric retention system may be used to treat a patient.

[0074] Depending on the embodiment of this gastric retention system, the patient may be a human or a dog.

[0075] Depending on the embodiment, the present invention provides a method for manufacturing an intragastric retention system, comprising: a plurality of arms connected to a core at their proximal ends via a plurality of linker components, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially; cutting notches into each of the plurality of arms to form notches in each arm; winding a filament circumferentially around the intragastric retention system such that the filament is positioned within each notch of each arm; and closing each notch to secure the filament within each notch.

[0076] In one embodiment of this method, the filament connects the distal ends of each of the plurality of arms in the circumferential direction.

[0077] In some embodiments of this method, the plurality of arms include at least three arms.

[0078] In some embodiments of this method, the plurality of arms are configured to carry the active pharmaceutical ingredient.

[0079] In some embodiments of this method, the multiple arms carry 40-60% of the active pharmaceutical ingredient.

[0080] Depending on the embodiment of this method, the linker component may be decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0081] In some embodiments of this method, the gastric retention system is configured to be folded during administration and to be open when it is in the patient's stomach.

[0082] In some embodiments of this method, the core undergoes elastic deformation when the intragastric retention system is in the folded configuration and recoils when the intragastric retention system takes the open configuration.

[0083] Depending on the embodiment of this method, the gastric retention system has a multi-armed star shape in the open configuration.

[0084] Depending on the embodiment of this method, closing each notch includes at least one of stopping or heating.

[0085] In some embodiments of this method, the force required to compress the gastric retention system to a configuration small enough to pass through a 20 mm diameter opening, as measured by radial testing, is at least 1.5 times greater than the force required to compress a filamentless gastric retention system to a configuration small enough to pass through the opening.

[0086] In some embodiments of this method, when the gastric retention system is left at constant temperature in a pH 1.6 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0087] In some embodiments of this method, when the gastric retention system is left at a constant temperature in a pH 6.5 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

[0088] In some embodiments of this method, the distal end of each of the plurality of arms contains an enteric-coated material.

[0089] Depending on the embodiment of this method, the filament comprises one or more of the following: an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0090] In some embodiments of this method, the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0091] In some embodiments of this method, the polymer includes polycaprolactone.

[0092] In some embodiments of this method, the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate.

[0093] Depending on the embodiment of this method, the plasticizer includes propylene glycol.

[0094] In some embodiments of this method, the acid includes stearic acid.

[0095] In some embodiments of this method, each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, wherein the first segment has greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

[0096] In some embodiments of this method, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through a 20 mm diameter opening is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

[0097] In some embodiments of this method, the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0098] Depending on the embodiment of this method, the second polymer composition comprises one or more of the following: polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

[0099] In some embodiments of this method, the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

[0100] In some embodiments of this method, the first segment is directly connected to the second segment of at least one arm.

[0101] In some embodiments of this method, the first segment is connected to the second segment via a linker component.

[0102] In some embodiments of this method, the first segment constitutes 20 to 50% of the length of the at least one arm, the length of which 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 core.

[0103] In some embodiments of this method, the second segment constitutes 50-80% of the length of the at least one arm, the length of which 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 core.

[0104] In some embodiments of this method, when measured using a double funnel test, the number of fatigue cycles required for rupture of the intragastric retention system is at least 25% greater than the number of fatigue cycles required for rupture of an intragastric retention system having an arm containing only the first polymer composition.

[0105] In some embodiments of this method, the gastric retention system is configured to be enclosed in a capsule when 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 to take on an open configuration.

[0106] Depending on the embodiment of this method, the intragastric retention system may be used to treat a patient.

[0107] Depending on the embodiment of this method, the patient may be a human or a dog.

[0108] Depending on the embodiment, the present invention provides a method for manufacturing an intragastric retention system, comprising: manufacturing an intragastric retention system comprising a plurality of arms connected to a core at their proximal ends via a plurality of linker components, wherein one of the plurality of linker components corresponds to each arm of the plurality of arms, and the plurality of arms extend radially; manufacturing one plurality of tips for each arm of the plurality of arms, and filaments attached to each tip of the plurality of tips; and connecting each tip of the plurality of tips to one arm of the plurality of arms to form an intragastric retention system including filaments.

[0109] Depending on the embodiment of this method, the fabrication of multiple chips and filaments may involve injection molding. [Brief explanation of the drawing]

[0110] The present invention will be described below, simply as an example, with reference to the attached drawings. The drawings are as follows:

[0111] [Figure 1A] Figures 1A, 1B, and 1C show various gastric retention system configurations according to several embodiments. [Figure 1B] Figures 1A, 1B, and 1C show various gastric retention system configurations according to several embodiments. [Figure 1C] Figures 1A, 1B, and 1C show various gastric retention system configurations according to several embodiments.

[0112] [Figure 2] Figure 2 shows a gastric retention system in several embodiments, comprising multiple arms and a curved geometric shape that most readily allows for gastric retention when compressed by forces such as gastric contraction.

[0113] [Figure 3A] Figures 3A, 3B, and 3C illustrate various ways in which the gastric retention system may pass through the pylorus before dissolving, according to several embodiments. [Figure 3B] Figures 3A, 3B, and 3C illustrate various ways in which the gastric retention system may pass through the pylorus before dissolving, according to several embodiments. [Figure 3C] Figures 3A, 3B, and 3C illustrate various ways in which the gastric retention system may pass through the pylorus before dissolving, according to several embodiments.

[0114] [Figure 4A]Figures 4A and 4B illustrate several embodiments of intragastric retention systems with filaments and methods that may help prevent the filaments from passing through the pylorus prematurely. [Figure 4B] Figures 4A and 4B illustrate several embodiments of intragastric retention systems with filaments and methods that may help prevent the filaments from passing through the pylorus prematurely.

[0115] [Figure 5A] Figures 5A and 5B show two different configurations of a gastric retention system including a filament, according to several embodiments. [Figure 5B] Figures 5A and 5B show two different configurations of a gastric retention system including a filament, according to several embodiments.

[0116] [Figure 6A] Figures 6A, 6B, and 6C illustrate the steps for preparing a filament-attached intragastric retention system according to several embodiments. [Figure 6B] Figures 6A, 6B, and 6C illustrate the steps for preparing a filament-attached intragastric retention system according to several embodiments. [Figure 6C] Figures 6A, 6B, and 6C illustrate the steps for preparing a filament-attached intragastric retention system according to several embodiments.

[0117] [Figure 7] Figure 7 shows two methods for fixing the filament according to several embodiments.

[0118] [Figure 8] Figure 8 shows several embodiments of a method for manufacturing an intragastric retention system.

[0119] [Figure 9] Figure 9 shows a method for testing radial compression using a throttling mechanism according to several embodiments.

[0120] [Figure 10A] Figures 10A and 10B show the withdrawal force tests of filament-equipped intragastric retention systems according to several embodiments. [Figure 10B] Figures 10A and 10B show the withdrawal force tests of filament-equipped intragastric retention systems according to several embodiments.

[0121] [Figure 11] Figure 11 shows radial force data for gastric retention systems without filaments and gastric retention systems with filaments, according to several embodiments.

[0122] [Figure 12] Figure 12 shows radial force data for several embodiments of intragastric retention systems, including a flexible arm without a filament, and an intragastric retention system having a filament and a rigid arm.

[0123] [Figure 13] Figure 13 shows the withdrawal force data for an intragastric retention system including a filament and an enteric-coated tip (Formulation 14) according to several embodiments.

[0124] [Figure 14] Figure 14 shows the withdrawal force data for an intragastric retention system including a filament and enteric-coated tip (Formulation 15) according to several embodiments.

[0125] [Figure 15] Figure 15 shows filament pull-out force data for intragastric retention systems with filaments attached using different fixation methods in several embodiments.

[0126] [Figure 16] Figure 16 shows several embodiments of intragastric retention systems with filaments prepared for visualization while in the stomach of a dog.

[0127] [Figure 17A] Figure 17A shows several embodiments of a compression / folding gastric retention system, including a filament sleeved on the arm side.

[0128] [Figure 17B] Figure 17B shows several embodiments of a sleeve-shaped compression / folding gastric retention system containing a filament.

[0129] [Figure 17C] Figure 17C shows several embodiments of a compression / folding gastric retention system including a filament sleeved on the core side.

[0130] [Figure 17D] Figure 17D shows several embodiments of a sleeve-shaped compression / folding gastric retention system containing a filament.

[0131] [Figure 17E] Figure 17E shows several embodiments of a compression / folding intragastric retention system that includes a filament, has a sleeve attached to the arm side, and is encapsulated in a two-piece capsule.

[0132] [Figure 17F] Figure 17F shows several embodiments of a compression / folding intragastric retention system that includes a filament, has a sleeve attached to the arm side, and is encapsulated in a two-piece capsule.

[0133] [Figure 17G] Figure 17G shows several embodiments of an encapsulated, compressed / foldable intragastric retention system.

[0134] [Figure 18A]Figure 18A shows the ability of elastic or inelastic filaments to increase the resistance of the stellate gastric retention system to compression.

[0135] [Figure 18B] Figure 18B shows the adhesion strength of a biodegradable suture to the enteric-coated tip of the gastric retention system over time in a simulated gastric environment. Detailed description of the invention

[0136] This specification describes a gastric retention system having a filament and a method for fabricating such a system. As described above, the gastric retention system is designed to remain in the gastrointestinal tract for a predetermined time. After a certain time (e.g., a predetermined retention time), the gastric retention system breaks down into several components small enough to pass through the pylorus. However, if the gastric retention system becomes small enough to bend and pass through the patient's pylorus too quickly, the therapeutic agent of the gastric retention system will not be properly administered to the patient.

[0137] Therefore, the intragastric retention system provided herein includes a filament connecting the distal ends of each arm of the intragastric retention system. This filament may help prevent the intragastric retention system from passing through the pylorus before a predetermined retention time has elapsed.

[0138] Typically, the intragastric retention system is administered in a folded, closed, or collapsed configuration. Once inside the patient's stomach, the intragastric retention system unfolds and takes on an open configuration. When the intragastric retention system is physically opened (i.e., unfolded), it becomes a dosage form (i.e., an open intragastric retention system) that is too large in effective dimensions to pass through the patient's pyloric valve (i.e., the opening between the stomach and the small intestine). A deployed or unfolded intragastric retention system can remain in the patient's stomach for a predetermined period (e.g., 24 hours, 48 ​​hours, 7 days, 10 days, etc.).

[0139] However, one challenge, particularly with regard to the gastric retention system, is ensuring a consistent and accurate retention time. A gastric retention system that passes through the pylorus too quickly cannot deliver the intended amount of medication, compromising the effectiveness and reliability of the gastric retention system.

[0140] Therefore, the intragastric retention systems provided herein are designed for more consistent and accurate residence times within the patient's stomach. In particular, intragastric retention systems containing filaments provided herein are likely to resist premature passage through the pylorus. Thus, the intragastric retention systems provided herein are likely to provide consistent and accurate residence times and improve the effectiveness and reliability of intragastric retention systems. definition

[0141] As used herein, “intragastric retention system” is a dosage form containing a therapeutic agent and configured to be administered to a patient in a folded configuration. “Intragastric retention dosage form” includes a folded intragastric retention system and is configured to keep the intragastric retention system in a folded configuration until deployed. For example, an intragastric retention dosage form may include a capsule and / or capsule coating as described in U.S. Patent Application No. 62 / 821,352, entitled “Capsule and Capsule Coating for Intragastric Retention Dosage Form” and / or U.S. Patent No. 62 / 821,361, entitled “Coating for Intragastric Retention Dosage Form.”

[0142] A "supported polymer" is a polymer suitable for blending with pharmaceuticals such as drugs for use in the present invention.

[0143] "Medicine" is any substance intended for therapeutic, diagnostic, or nutritional use in a patient, individual, or subject. Medicines include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0144] A "dispersant" is defined as a substance that helps minimize the particle size of a drug and disperse drug particles within a carrier polymer matrix. In other words, dispersants help minimize or prevent particle aggregation or soft aggregation during system fabrication. Thus, dispersants possess anti-aggregating and anti-soft-aggregating activities and help maintain a uniform distribution of drug particles within the carrier polymer matrix.

[0145] Excipients are any substances added to a drug formulation that are not the drug itself. Excipients include, but are not limited to, binders, coatings, diluents, disintegrants, emulsifiers, fragrances, flow enhancers, lubricants, and preservatives. Dispersants are a specific category that falls under the more general category of excipients.

[0146] An "elastic polymer" or "elastic body" (also called an elongated polymer) is a polymer that can be deformed from its original shape by an applied force for a certain period of time, and then returns to substantially its original shape when the applied force is removed.

[0147] A "linking polymer" is a polymer suitable for linking any other polymers together (for example, linking a first supported polymer-pharmaceutical component to a second supported polymer-pharmaceutical component). Linking polymers generally form linker regions between other components.

[0148] Time-dependent polymers, or time-dependent linked polymers, are polymers that degrade in a time-dependent manner once the gastric retention system is established in the stomach. Time-dependent polymers are generally unaffected by normal pH changes in the stomach.

[0149] A "nearly constant plasma level" refers to a plasma level that remains within twice the average plasma level measured over the period the gastric retention system resides in the stomach (i.e., between 50% and 200% of the average plasma level).

[0150] "Substantially constant plasma levels" refers to plasma levels that remain within ±25% of the average plasma level measured over the period the gastric retention system resides in the stomach.

[0151] A "hydrophilic therapeutic agent," "hydrophilic drug," or "hydrophilic substance" is a drug that dissolves easily in water. A hydrophilic drug is defined as a drug with a water solubility of 1 mg / ml or more. Alternatively, a hydrophilic drug may be defined as a drug with a log Poct (logarithm of the partition coefficient Poct; Poct = (concentration in 1-octanol) / (concentration in H2O)) of less than 0.5 in a 1-octanol / water system. The pH at which solubility or log Poct is measured is 1.6, which is close to the environment of the stomach.

[0152] A "hydrophobic therapeutic agent," "hydrophobic agent," or "hydrophobic drug" is a drug that is poorly soluble in water. A hydrophobic agent is defined as a drug with a water solubility of less than 1 mg / ml. Alternatively, a hydrophobic agent may be defined as a drug with a log Poct (logarithm of the partition coefficient Poct) greater than 1 in a 1-octanol / water system. Alternatively, a hydrophobic therapeutic agent may be defined as a drug that has higher solubility in ethanol than in water. Alternatively, a hydrophobic therapeutic agent may be defined as a drug that has higher solubility in 40% ethanol / 60% simulated gastric fluid than in 100% simulated gastric fluid.

[0153] When used to describe a material or system, "biocompatibility" indicates that the material or system does not induce adverse reactions, or causes only minimally acceptable adverse reactions, when in contact with living organisms such as humans. In the context of the gastric retention system, biocompatibility is assessed in the gastrointestinal environment.

[0154] "Patient," "individual," or "subject" refers to a mammal, preferably a human, or a domestic animal such as a dog or a cat. In the most preferred embodiment, the patient, individual, or subject is a human.

[0155] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0156] "Treatment" of a disease or disorder by the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein to a patient in need, with or without additional drugs, to alleviate or eliminate the disease or disorder, or one or more symptoms of the disease or disorder, or to slow 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. "Suppression" of a disease or disorder by the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein to a patient in need, with or without additional drugs, to suppress the clinical manifestation of the disease or disorder, or to suppress the manifestation of adverse symptoms of the disease or disorder. The difference between treatment and suppression is that treatment is performed after adverse symptoms of the disease or disorder have appeared in the patient, while suppression is performed before adverse symptoms of the disease or disorder have appeared in the patient. Suppression may be performed partially, substantially entirely, or entirely. Since some diseases or disorders are hereditary, genetic screening can be used to identify patients at risk of disease or disorder. Next, the system and method of the present invention can be used to treat asymptomatic patients at risk of developing clinical symptoms of a disease or disorder in order to suppress the appearance of any adverse symptoms.

[0157] The “therapeutic use” of the systems disclosed herein is defined as using one or more of the systems disclosed herein to treat a disease or disorder, as defined above. The “therapeutic effective dose” of a therapeutic agent, such as a drug, is the amount of the drug that, when administered to a patient, reduces or eliminates any of the symptoms of a disease or disorder or one or more of the symptoms of a disease or disorder, slows the progression of any of the symptoms of a disease or disorder or one or more of the symptoms of a disease or disorder, or reduces the severity of any of the symptoms of a disease or disorder or one or more of the symptoms of a disease or disorder. The therapeutic effective dose may be administered to a patient as a single dose or in divided doses.

[0158] "Prophylactic use" of the systems disclosed herein is defined as using one or more of the systems disclosed herein to suppress a disease or disorder, as defined above. A "prophylactically effective dose" of a drug is the amount of drug sufficient, when administered to a patient, to suppress the clinical manifestation of a disease or disorder, or to suppress the manifestation of adverse symptoms of a disease or disorder. A prophylactically effective dose may be administered as a single dose or in divided doses.

[0159] The "flexural modulus" of a material is a material-specific property calculated as the ratio of stress to strain in the bending deformation of the material, measured by a three-point bending test. While linkers are described herein as components of an intragastric retention system, the flexural modulus of polymer materials may be measured independently. For example, a polymer linker in an intragastric retention system may be too short to measure the flexural modulus; however, a longer sample of the same material may be used to accurately determine the flexural modulus. The longer sample used for measuring the flexural modulus should preferably have the same cross-sectional dimensions (shape and size) as the polymer linker used in the intragastric retention system. The flexural modulus is measured using a three-point bending test (ASTM D790) in accordance with the ASTM standard, with a distance of 10 mm between supports and modified to accommodate materials with non-rectangular cross-sections. It is preferable to position the longest symmetry line of the polymer linker's cross-section perpendicular and apply a downward force to measure the flexural modulus. If the longest symmetry line of the polymer linker's cross-section is perpendicular to a flat side, it is preferable to position the flat side upwards. If the cross-section of the polymer linker is triangular, ensure that the vertex of the triangle points downwards. While applying a downward force, measure the force and displacement, determine the inclination in the linear region, and calculate the flexural modulus.

[0160] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated or clearly indicated by the context.

[0161] In this specification, when a numerical value is expressed using the term "approximately," it shall include both the specified value and a value that is reasonably close to the specified value. For example, the expression "approximately 50°C" includes both the disclosure of 50°C itself and a value that is close to 50°C. Therefore, the expression "approximately X" includes a description of the value X itself. Furthermore, when a range is indicated, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C," it shall include the value specified at each endpoint and a value that is close to each endpoint or both endpoints. In other words, "approximately 50°C to 60°C" is equivalent to stating both "50°C to 60°C" and "approximately 50°C to approximately 60°C."

[0162] With respect to the numerical ranges disclosed herein, any upper limit disclosed for a given ingredient can be combined with any lower limit disclosed for that ingredient to provide a range (provided that the upper limit is greater than the lower limit with which it is combined). Each of these combinations of disclosed upper and lower limits is expressly assumed herein. For example, if the formulation ranges for a given ingredient are 10% to 30%, 10% to 12%, and 15% to 20%, then 10% to 20% and 15% to 30% are also assumed, but the combination of a lower limit of 15% and an upper limit of 12% is not assumed because it is impossible.

[0163] Unless otherwise specified, the percentage of components in a composition is expressed as weight percentage or weight / weight percentage. Naturally, when discussing relative weight percentages in a composition, it is assumed that the total weight percentage of all components in the composition is 100. Furthermore, the relative weight percentages of one or more components may be adjusted upward or downward so that the total weight percentages of the components in the composition equal 100, provided that the weight percentage of any particular component does not fall outside the specified range limits for that component.

[0164] The distribution behavior of a drug between the polycaprolactone phase (PCL phase) and the simulated gastric juice phase (SGF phase) can be measured to obtain the drug distribution coefficient PPCL-SGF between the two phases. The logarithmic PPCL-SGF can also be calculated. A 5:1 mixture of polycaprolactone diol (MW 530) and ethyl acetate can be used as the PCL phase, and simulated gastric juice in a fasted state (FaSSGF) can be used as the SGF phase, where PPCL-SGF = (concentration in polycaprolactone diol) / (concentration in FaSSGF).

[0165] In the embodiments described herein, the terms “includes” or “includes” are used with respect to various elements. In some alternative embodiments, those elements may be described with the transitional phrase “essentially from” or “essentially from” used with those elements. In some further alternative embodiments, those elements may be described with the transitional phrase “includes” or “consists of” used with those elements. Thus, for example, if a composition or method is disclosed herein as including A and B, then alternative embodiments of that composition or method “essentially consisting of A and B” and alternative embodiments of that composition or method “including A and B” are also deemed to be disclosed herein. Similarly, embodiments described as “essentially including” or “including” with respect to various elements also include “including” used with those elements. Finally, embodiments invoked as “essentially including” with respect to various elements also include “including” used with those elements, and embodiments described as “including” with respect to various elements may also be described as “essentially consisting of” used with those elements.

[0166] Where a composition or system is described as “essentially derived” from the enumerated elements, the composition or system may include the explicitly enumerated elements and other elements that do not substantially affect the condition being treated (for compositions for treating a condition), or the properties of the system described (for compositions constituting a system). However, the composition or system may not include any other elements other than the explicitly enumerated elements that substantially affect the condition being treated (for compositions for treating a system), or any other elements that substantially affect the properties of the system (for compositions constituting a system), or, if the composition or system includes additional elements other than the enumerated elements that could substantially affect the condition being treated or the properties of the system, the composition or system may not include any additional elements, concentrations, or amounts that substantially affect the condition being treated or the properties of the system. Where a method is described as “essentially derived” from the enumerated steps, the method may include the enumerated steps and other steps that do not materially affect the properties of the condition being treated or the system produced by the method, but the method does not include any other steps other than the explicitly enumerated steps that materially affect the condition being treated or the system produced.

[0167] This disclosure provides several embodiments. Any configuration from any embodiment is intended to be combined with any configuration from any other embodiment, where possible. In this aspect, hybrid configurations of the disclosed configurations are within the scope of the invention.

[0168] In addition to the embodiments and methods disclosed herein, additional embodiments of intragastric retention systems, as well as methods for manufacturing and using such systems, are disclosed in international patent applications WO2015 / 191920, WO2015 / 191925, WO2017 / 070612, WO2017 / 100367, and PCT / US2017 / 034856, which are incorporated herein by reference in their entirety. Intragastric retention system

[0169] This specification provides arms and segments used in intragastric retention systems, which may include filaments that help prevent the intragastric retention system from passing too quickly through the pylorus. Below is a description of the overall structure of the intragastric retention system, as well as a detailed description of each of the three main components of the intragastric retention system: the elastic body (i.e., the central elastic body or core), the arms (i.e., elongated members, supported polymers, or supported polymer-drug components), and the linking polymers (i.e., linkers, linker regions, or linker components). More specifically, this specification describes the overall configuration of the system; the dimensions of the system; residence time; evaluation of release characteristics; intragastric pharmacokinetics of the intragastric retention system; solubility, bioavailability, and pharmacokinetics of the intragastric retention system; elasticity; supporting polymers for segments and arms (supporting polymer-drug components); combinations of supporting polymers-drugs / drug salts with excipients and other additives; drugs used in the intragastric retention system; high drug load capacity of arms and segments; dispersants for regulating drug release and stability of polymer formulations; stabilizers used in the intragastric retention system; linking polymers; filaments for improving intragastric retention; intragastric retention systems including arms with regulated stiffness; and the polymer composition of the system.

[0170] Intragastric retention formulations can be designed to be administered to a patient's stomach via swallowing, a feeding tube, or a nasogastric tube. Once placed in the stomach, an intragastric retention formulation can remain there for a desired residence time (e.g., 3 days, 7 days, 2 weeks, etc.). A properly placed intragastric retention formulation resists passage through the pyloric valve separating the stomach from the small intestine. The intragastric retention formulation can release the therapeutic agent (i.e., API or drug) in a controlled release manner over the residence period. While in the stomach, the formulation should not interfere with the normal passage of food or other stomach contents. Once the desired residence time is over, the formulation is easily expelled from the patient by exiting the stomach (i.e., passing through the pyloric valve).

[0171] For administering an intragastric retention system to a patient, the system can be folded into a form small enough to be swallowed or otherwise administered. Depending on the embodiment, the folded intragastric retention system may be contained in a capsule or other container that can be swallowed by the patient. In some cases, the intragastric retention system may be delivered to the patient's stomach via a gastrostomy tube, feeding tube, nasogastric tube, or other route of administration. Specific examples of intragastric retention systems are described in PCT / US2018 / 051816, WO 2015 / 191920, WO 2017 / 070612, WO 2017 / 100367, WO 2018 / 064630, WO 2017 / 205844, and WO 2018 / 227147. Each of these documents is incorporated herein in its entirety.

[0172] The intragastric retention system can assume an open configuration upon reaching the patient's stomach. The dimensions of the open intragastric retention system are suitable for preventing the device from passing through the pyloric valve for the duration it is intended to remain in the stomach, if left unchanged. In some embodiments, the folded intragastric retention system may be secured with a dissolvable retaining band or sleeve, which can prevent the intragastric retention system from deploying prematurely in the event of a capsule malfunction. The intragastric retention system, folded and held in a folded configuration with a sleeve or band, may be encapsulated in a capsule. In some embodiments of the intragastric retention dosage form, the sleeve comprises at least one of gelatin, hydroxypropyl methylcellulose, and pullulan. In some embodiments of the intragastric retention dosage form, the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, and pullulan. Accordingly, in one embodiment, the intragastric retention system includes a core, a plurality of arms connected to the core at their proximal ends via a plurality of linker components, and filaments connecting each of the plurality of arms circumferentially, where one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially from the proximal end. This intragastric retention system may further include a sleeve enclosing at least a portion of the folded intragastric retention system. This intragastric retention system may further include a capsule enclosing the folded intragastric retention system. This intragastric retention system may further include a sleeve enclosing at least a portion of the folded intragastric retention system, and may further include a capsule enclosing the folded intragastric retention system. In any of these embodiments, the sleeve may contain at least one of gelatin, hydroxypropyl methylcellulose, and pullulan. In any of these embodiments, the capsule may contain at least one of gelatin, hydroxypropyl methylcellulose, and pullulan. In any of these embodiments, the sleeve may contain at least one of gelatin, hydroxypropyl methylcellulose, and pullulan, and the capsule may contain at least one of gelatin, hydroxypropyl methylcellulose, and pullulan.

[0173] While present in the stomach, the gastric retention system is compatible with the digestion and other normal functions of the stomach or gastrointestinal tract. The gastric retention system does not interfere with or obstruct the passage of porridge (partially digested food) or other stomach contents through the pyloric valve into the duodenum.

[0174] Once released from the capsule into the stomach, the therapeutic agent in the gastric retention system begins to exert its effects. In some embodiments, the gastric retention system comprises multiple supported polymer-pharmaceutical components. The supported polymer-pharmaceutical components may comprise a supported polymer, a pore-forming agent, and a therapeutic agent (or a salt thereof). Multiple supported polymer-pharmaceutical components are linked together by one or more linked polymer components. The therapeutic agent may be eluted from the supported polymer-pharmaceutical components into the patient's gastric juice over a desired residence time in the system. The release of the therapeutic agent is controlled by appropriate formulation of the supported polymer-pharmaceutical components, for example, by using a dispersant in the formulation of the supported polymer-pharmaceutical components, and by crushing the therapeutic agent into particles of a desired size before mixing the drug with the supported polymer and dispersant.

[0175] Additionally, a coating may be applied to the outer surface of the gastric retention system. This coating may contain additional therapeutic agents or agents that can affect the release of therapeutic agents or the retention period of the gastric retention system.

[0176] Once the desired residence time has elapsed, the intragastric delivery system exits the stomach. To this end, various components of the gastric delivery system are designed to weaken and break down. The specific dimensions of the system are also taken into consideration. In an unchanged, open configuration, the intragastric delivery system is designed to resist passage through the pyloric valve. However, the linked polymer components of the intragastric delivery system are selected to gradually break down over a specific period of residence in the stomach. Once the linked polymer components have weakened sufficiently through breakdown, the intragastric delivery system loses significant resilience against compression or reduction in size and can break down into smaller components. The reduced dosage form and any smaller components are designed to pass through the pyloric valve. The system then passes through the intestines and is expelled from the patient. In some embodiments, the intragastric delivery system may be designed to weaken at specific locations so that, after the residence time has elapsed, the intragastric delivery system can pass through the pyloric valve unchanged without breaking down into numerous smaller fragments. Overall system configuration

[0177] The gastric retention system can be prepared in different configurations. The “stellate” configuration of the gastric retention system is also known as the “star-shaped” (or “star”) configuration. An example of a stellate system 100 is schematically shown in Figure 1A. Multiple arms (for clarity, only one arm is numbered 108) are attached to a plate-like central elastic body 106. The arms depicted in Figure 1A consist of segments 102 and 103 and are joined by a linking polymer or linker region 104 that functions as a linker region (again, for clarity, only one arm is numbered). This configuration allows the system to be folded or compressed at the position of the central elastic body. Figure 1B shows the folded configuration 190 of the gastric retention system of Figure 1A (for clarity, only two arms are illustrated in Figure 1B). Segments 192 and 193, linker region 194, elastic body 196, and arm 198 in Figure 1B correspond to segments 102 and 103, linker region 104, elastic body 106, and arm 108 in Figure 1A, respectively. When folded, the overall length of the system is reduced by approximately half, and the system can be conveniently placed in a container such as a capsule suitable for oral administration. When the capsule reaches the stomach, the capsule dissolves, and the gastric retention system is released. The gastric retention system then unfolds into an uncompressed state and remains in the stomach for a desired retention period.

[0178] The linker region 104 is shown in Figure 1A with a diameter slightly larger than segments 102 and 103, but it can be made to have the same diameter as the segments so that the entire arm 102-104-103 has a smooth outer surface.

[0179] In some embodiments, the star-shaped system may have an arm consisting of only one segment, attached to the central elastic body in the linker region. This corresponds to Figure 1A, in which segment 103 is omitted. The single-segment arm, including segment 102, is directly attached to the central elastic body 106 via linker 104. The linker may contain a linking polymer or a disintegrating matrix.

[0180] The stellate system is an intragastric retention system administered to a patient's stomach, comprising an elastic component and at least three supported polymer-drug components attached to the elastic component, each containing a supported polymer and a drug or a salt thereof, wherein each of these supported polymer-drug components is an arm including a proximal end, a distal end and an outer surface between them. The proximal end of each arm is attached to the elastic component and projects radially from the elastic component, and each arm has a distal end that is not attached to the elastic component and is located at a greater radial distance from the elastic component than the proximal end. Each arm independently includes one or more segments, each segment including a proximal end, a distal end and an outer surface between them. In some embodiments, when two or more segments are present in an arm, each segment is attached to an adjacent segment via a linker region. In some embodiments, when two or more segments are present in an arm, one segment is attached directly to the other segments without using a linker region. The linker region may be a linking polymer or a disintegrating matrix. The arms are attached to the central elastic body via linking polymers or a disintegrating matrix and may have intervening portions of boundary polymers. For at least three arms, the preferred number of arms is six, but 3, 4, 5, 7, 8, 9, or 10 arms can be used. The arms are preferably arranged at equal intervals around the central elastic body, and if there are N arms, there will be an angle of approximately 360 / N degrees between adjacent arms.

[0181] Figure 1C shows another possible overall configuration 120 for the intragastric retention system, which is an annular configuration. Segments 122 are joined by linking polymers or linker regions 124 (for clarity, only one segment and one coupling linkage are numbered). The linking polymer / linker regions in this design also need to function as elastic bodies so that the ring can be twisted and compressed for placement in a container such as a capsule.

[0182] In one embodiment of the stellate structure, segments 102 and 103 contain a supported polymer blended with a drug or pharmaceutical agent. In one embodiment of the cyclic structure, segment 122 contains a supported polymer blended with a drug or pharmaceutical agent.

[0183] The linking polymer of the intragastric retention system, which functions as a linker region, is designed to be gradually broken down in a controlled manner during the retention period of the intragastric retention system. To avoid intestinal obstruction if the intragastric retention system passes into the small intestine intact prematurely, the system is designed to break down much more rapidly. This can be easily achieved by using enteric-coated polymers as the linking polymer. Enteric-coated polymers are relatively resistant to the acidic pH of the stomach but dissolve rapidly at the higher pH of the duodenum. By using enteric-coated linking polymers as a safe element, it is possible to prevent the intact intragastric retention system from undesirably entering the small intestine. The use of enteric-coated linking polymers also provides a method for removing the intragastric retention system before the designed retention time. If the system needs to be removed, the patient can drink a weakly alkaline solution such as sodium bicarbonate solution or take an antacid such as magnesium hydroxide (magnesia milk) or calcium carbonate, which will raise the pH level in the stomach and cause the enteric-coated linking polymer to break down rapidly. The intragastric retention stem will then break down and be excreted from the patient. In the system shown in Figure 1A, at least the linking polymer used in coupling 104 is made from such an enteric-coated polymer.

[0184] In further embodiments, time-dependent linking polymers or linkers can be used. Such time-dependent linking polymers or linkers degrade in a predictable time-dependent manner. Depending on the embodiment, the degradation of the time-dependent linking polymer or linker may not be affected by the changing pH of the gastrointestinal system.

[0185] In further embodiments, different types of linkers can be used in the gastric retention system. That is, both enteric-coated linkers (or enteric-coated linked polymers) and time-dependent linkers (or time-dependent linked polymers) can be used. Depending on the embodiment, a single multi-segment arm of the astrocyte system can use both enteric-coated linkers in some linker regions between segments and time-dependent linkers in other linker regions between segments.

[0186] The linker region is typically about 100 microns to 2 millimeters wide, for example, about 200 μm to 2000 μm, about 300 μm to 2000 μm, about 400 μm to 2000 μm, about 500 μm to 2000 μm, about 600 μm to 2000 μm, about 700 μm to 2000 μm, about 800 μm to 2000 μm, 900 μm to 2000 μm, about 1000 μm to 2000 μm, about 1100 μm to 2000 μm, about 1200 μm to 2000 μm, about 1300 μm to 2000 μm, about 1400 μm to 2000 μm, about 1500 μm to 2000 μm, about 1600 μm~about 2000 μm, about 1700 μm~about 2000 μm, about 1800 μm~about 2000 μm, or about 1900 μm~about 2000 μm, or about 100 μm~about 1900 μm, about 100 μm~about 1800 μm, about 100 μm~about 1700 μm, about 100 μm~Approx. 1600 μm, Approx. 100 μm~Approx. 1500 μm, Approx. 100 μm~Approx. 1400 μm, Approx. 100 μm~Approx. 1300 μm, Approx. 100 μm~Approx. 1200 μm, Approx. μm, approx. 100 μm ~ approx. 800 The ranges are μm, approximately 100 μm to 700 μm, approximately 100 μm to 600 μm, approximately 100 μm to 500 μm, approximately 100 μm to 400 μm, approximately 100 μm to 300 μm, or approximately 100 μm to 200 μm. The linker region may have a width of 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, with each value being plus or minus 50 μm (±50 μm).

[0187] While the central elastic polymers of astrocyte systems are not typically enteric polymers, central elastic polymers can also be made from such enteric polymers when desirable and practical.

[0188] The central elastic body preferably has a specific hardness and compression set. Hardness is important as it determines the folding force of the dosage form and whether it will remain in the stomach, and the preferred range is about 60 to about 90A. The compression set is desirable to be as low as possible to avoid the gastric retention system having permanent deformation when stored in the capsule in its compressed configuration. The preferred range is about 10% to about 20%. An example of a material that meets these requirements is the QP1 series of liquid silicone rubber from Dow Corning. In any embodiment having a central elastic body, QP1-270 (70A hardness) liquid silicone rubber can be used. Depending on the embodiment, the central elastic body may include liquid silicone rubber (Shin Etsu) with a hardness of 50A or 60A.

[0189] The segments and arms of the gastric retention system can have cross-sections of circular (in which case the segment is cylindrical), polygonal (e.g., segments with triangular, rectangular, or square cross-sections), or pie-shaped (in which case the segment is cylindrical). The ends of segments with polygonal or cylindrical cross-sections, or cylindrical segments that come into contact with gastric tissue, can have rounded corners or edges for safety. That is, instead of having sharp transitions between intersecting edges or faces, arcs are used for transitions from one edge or face to another. Thus, a “triangular cross-section” includes cross-sections that have an almost triangular shape, such as a triangle with rounded corners. Arms with a triangular cross-section include arms with rounded edges, and arms with rounded corners at the ends of the arms. Rounded corners or edges are also called fillet corners, filleted corners, filleted edges, etc.

[0190] However, it has been demonstrated that star-shaped intragastric retention systems can be bent to allow premature passage through the patient's pylorus. An intragastric retention system that passes through the pylorus prematurely cannot deliver the therapeutic agent for the intragastric retention system to the patient. Furthermore, premature passage causes inconsistencies, lacks reliability, and impairs the effectiveness of the intragastric retention system.

[0191] Figure 2 shows a star-shaped intragastric retention system with multiple arms. An example of a curved configuration is shown on the right side of the figure. Due to intragastric forces (e.g., peristaltic forces), the intragastric retention system may bend into the configuration shown in Figure 2, allowing for earlier passage through the pylorus.

[0192] Other possible bent configurations are shown in Figures 3A–3C. Specifically, Figures 3A–3C show three different possible configurations of intragastric retention systems that can allow for earlier passage through the pylorus. As shown in each figure, the relatively rigid arms of the intragastric retention system remain straight. However, the core of each intragastric retention system has greater flexibility than the arms and can therefore bend. The bending of the core allows the intragastric retention system with relatively rigid arms to pass through the patient's pylorus earlier.

[0193] As shown in Figure 3A, the intragastric retention system 302a is shown in a curved configuration having three arms that enter the pyloric orifice. Figure 3B shows the intragastric retention system 302b in a curved configuration having two arms that enter the pyloric orifice. Figure 3C shows the intragastric retention system 302c in a curved configuration similar in shape to a shuttlecock and having a core that enters the pyloric orifice.

[0194] Accordingly, what is described herein is an intragastric retention system including filaments. The filaments, which are wound circumferentially around the intragastric retention system and connect the arms of the intragastric retention system, help, for example, prevent premature passage through the patient's pylorus. The filaments and the intragastric retention system including the filaments will be described in more detail with respect to the arms and connecting polymers of the intragastric retention system. System dimensions

[0195] The system must be able to take on a compressed state of dimensions that allow the patient to swallow it (or to introduce it into the stomach by other means, such as a feeding tube or gastric tube). Generally, the system is kept compressed in a container such as a capsule. Once in the stomach, the system is released from the container and takes on an uncompressed state, i.e., an expanded structure with dimensions that prevent the system from passing through the pyloric sphincter and allow it to be held in the stomach.

[0196] Therefore, the system must be able to fit into standard-sized capsules of the types commonly used in pharmaceuticals. The standard capsule sizes used in the United States are shown 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)). These are the outer dimensions of the capsules, and since dimensions vary slightly depending on the capsule manufacturer, the system must be able to be configured to be approximately 0.5–1 mm smaller than the outer diameter shown and approximately 1–2 mm shorter than the length shown in the capsule table. [Table 1]

[0197] Capsules can be made from materials well known in the art, such as gelatin or hydroxypropyl methylcellulose. In one embodiment, capsules are made from a material that dissolves in the gastric environment but not in the oral or esophageal environment, preventing the system from being released prematurely before reaching the stomach.

[0198] In one embodiment, the system is folded or compressed to fit into a capsule, for example, in the manner shown in Figure 1B. Once the capsule dissolves in the stomach, the system takes on a configuration suitable for retention in the stomach, for example, in the manner shown in Figure 1A. Preferred capsule dimensions are 00 and 00el (a capsule of size 00el has approximately the length of a 000 capsule and approximately the width of a 00 capsule), which imposes constraints on the length and diameter of the folded system.

[0199] When released from the container, the system takes an uncompressible state with dimensions suitable for preventing the intragastric retention system from passing through the pyloric sphincter. In one embodiment, the system has at least two vertical dimensions, each at least 2 cm in length. That is, the intragastric retention system has at least about 2 cm in length in at least two vertical directions. In another embodiment, the perimeter of the uncompressed system has two vertical dimensions, each at least 2 cm in length when projected onto a plane. These two vertical dimensions may independently have lengths of about 2 cm to about 7 cm, about 2 cm to about 6 cm, about 2 cm to about 5 cm, about 2 cm to about 4 cm, about 2 cm to about 3 cm, about 3 cm to about 7 cm, about 3 cm to about 6 cm, about 3 cm to about 5 cm, about 3 cm to about 4 cm, about 4 cm to about 7 cm, about 4 cm to about 6 cm, about 4 cm to about 5 cm, or about 4 cm to about 4 cm. These dimensions prevent the intragastric retention system from passing through the pyloric sphincter. In the case of a star-shaped polymer having N arms (where N is 3 or greater, e.g., N = 6), the arms may have dimensions such that the system has at least two vertical dimensions, each of which is the length described above. These two vertical dimensions are selected as described above to facilitate retention of the gastric retention system.

[0200] The system is designed to eventually break down in the stomach at the end of a desired residence time (retention period), at which point the remaining components of the system are sized to pass through the pyloric sphincter, small intestine, and large intestine. Finally, the system is expelled from the body by defecation or by the system finally dissolving completely in the small and large intestine. Thus, the linking polymer or disintegrating substrate is arranged in the gastric retention system of the present invention in such a configuration that, at the end of the desired residence period in which the linking polymer or disintegrating substrate breaks down or dissolves, the unlinked components of the gastric retention system are sized to pass through the pyloric sphincter and be expelled from the digestive tract. Duration of stay

[0201] The residence time of an intragastric system is defined as the time between the administration of the system to the stomach and its emptiness from the stomach. In one embodiment, the intragastric system has a residence time of approximately 24 hours or a maximum of approximately 24 hours. In one embodiment, the intragastric system has a residence time of approximately 48 hours or a maximum of approximately 48 hours. In one embodiment, the intragastric system has a residence time of approximately 72 hours or a maximum of approximately 72 hours. In one embodiment, the intragastric system has a residence time of approximately 96 hours or a maximum of approximately 96 hours. In one embodiment, the intragastric system has a residence time of approximately 5 days or a maximum of approximately 5 days. In one embodiment, the intragastric system has a residence time of approximately 6 days or a maximum of approximately 6 days. In one embodiment, the intragastric system has a residence time of approximately 7 days (approximately 1 week) or a maximum of approximately 7 days (approximately 1 week). In one embodiment, the intragastric system has a residence time of approximately 10 days or a maximum of approximately 10 days. In one embodiment, the gastric retention system has a retention time of approximately 14 days (approximately 2 weeks) or a maximum of approximately 14 days (approximately 2 weeks).

[0202] In one embodiment, the gastric retention system has a residence time of approximately 24 hours to approximately 7 days. In one embodiment, the gastric retention system has a residence time of approximately 48 hours to approximately 7 days. In one embodiment, the gastric retention system has a residence time of approximately 72 hours to approximately 7 days. In one embodiment, the gastric retention system has a residence time of approximately 96 hours to approximately 7 days. In one embodiment, the gastric retention system has a residence time of approximately 5 days to approximately 7 days. In one embodiment, the gastric retention system has a residence time of approximately 6 days to approximately 7 days.

[0203] In one embodiment, the gastric retention system has a residence time of approximately 24 hours to approximately 10 days. In one embodiment, the gastric retention system has a residence time of approximately 48 hours to approximately 10 days. In one embodiment, the gastric retention system has a residence time of approximately 72 hours to approximately 10 days. In one embodiment, the gastric retention system has a residence time of approximately 96 hours to approximately 10 days. In one embodiment, the gastric retention system has a residence time of approximately 5 days to approximately 10 days. In one embodiment, the gastric retention system has a residence time of approximately 6 days to approximately 10 days. In one embodiment, the gastric retention system has a residence time of approximately 7 days to approximately 10 days.

[0204] In one embodiment, the gastric retention system has a residence time of approximately 24 hours to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 48 hours to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 72 hours to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 96 hours to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 5 days to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 6 days to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 7 days to approximately 14 days. In one embodiment, the gastric retention system has a residence time of approximately 10 days to approximately 14 days.

[0205] The gastric retention system releases a therapeutically effective amount of drug (or its salt) during at least a portion of the retention time or period during which the system remains in the stomach. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 25% of the retention time. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 50% of the retention time. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 60% of the retention time. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 70% of the retention time. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 75% of the retention time. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 80% of the retention time. In one embodiment, the system releases a therapeutically effective amount of drug (or its salt) for at least about 85% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the drug (or its salt) for at least about 90% of the residence time. In another embodiment, the system releases a therapeutically effective amount of the drug (or its salt) for at least about 95% of the residence time. In yet another embodiment, the system releases a therapeutically effective amount of the drug (or its salt) for at least about 98% of the residence time. In yet another embodiment, the system releases a therapeutically effective amount of the drug (or its salt) for at least about 99% of the residence time. Evaluation of release characteristics

[0206] The drug release characteristics from segments, arms, and the gastric retention system can be evaluated using various tests. Drug release tests are described in detail in the examples. Drug release in vitro from segments, arms, and the gastric retention system can be measured by immersing the segments, arms, or gastric retention system in a liquid, such as water, 0.1N HCl, fasted simulated gastric juice (FaSSGF), or fed simulated gastric juice (FeSSGF). Fasted simulated gastric juice (FaSSGF) is preferred for release tests. Simulated gastric juice refers to either fasted simulated gastric juice (FaSSGF) or fed simulated gastric juice (FeSSGF), and if measurement with simulated gastric juice (SGF) is restricted, that restriction is satisfied if either fasted simulated gastric juice (FaSSGF) or fed simulated gastric juice (FeSSGF) is used. For example, if a segment is shown to release at least 10% of the drug in simulated gastric juice during the first 24 hours, this restriction is met if that segment releases at least 10% of the drug in simulated gastric juice during the first 24 hours in a fasted state, or if that segment releases at least 10% of the drug in simulated gastric juice during the first 24 hours in a fed state.

[0207] Generally, a segment, arm, or intragastric retention system is immersed for one hour in a solution of 40% ethanol and 60% fasted simulated gastric fluid, and then the same segment, arm, or intragastric retention system is immersed for the remainder of the test period in 100% fasted simulated gastric fluid, and the release of the drug at appropriate time points is measured to determine the explosive release in ethanol. This test is designed to simulate the effects of alcoholic beverage consumption by a patient with the intragastric retention system of the present invention deployed in their stomach.

[0208] In vitro testing can be performed using segments, arms, or gastric retention systems, but segments are most convenient for rapid evaluation of release characteristics. When performing in vitro testing to compare release rates under different conditions (e.g., release with 100% FaSSGF and release with 40% ethanol / 60% FaSSGF), the comparison solutions should be kept at the same temperature, e.g., room temperature, 25°C, or 37°C. Room temperature (ambient temperature) is preferred for comparison. In one embodiment, the ambient temperature does not fall below 20°C or exceed 25°C (however, it may fluctuate between 20°C and 25°C).

[0209] In vivo studies can be performed in animals such as dogs (e.g., beagles and hounds) and pigs. A gastric retention system is used in in vivo studies because individual segments or arms are not supposed to be retained in the animal's stomach. Blood samples can be obtained at appropriate times, and gastric contents can be collected by cannula or other techniques, if desired.

[0210] Clinical trials in humans conducted in accordance with appropriate laws, regulations, and institutional guidelines also provide in vivo data. Intragastric drug kinetics of the gastric retention system

[0211] The gastric retention system of the present invention provides the area under the plasma concentration curve (AUC) after administration of the system. inf When measured using this method, it provides a higher bioavailability of the drug compared to conventional oral formulations. The system further provides the maintenance of a nearly constant or substantially constant plasma concentration of the drug.

[0212] The relative bioavailability (F) of two different formulations, formulation A and formulation B. REL )of F REL = 100 × (AUC A × Dose B ) / (AUC B × Dose A ) This is defined as follows. In the formula, AUC Ais the area under the curve of formulation A, AUC B is the area under the curve of formulation B, and the dose A is the dosage of formulation A used, the dose B is the dosage of formulation B used. To obtain the relative bioavailability of the formulations at the same time point, usually, the area under the curve AUC of the plot of the plasma concentration of the drug against time is measured at the same time (t) after administration of each formulation. AUC inf refers to the AUC measured or calculated over a period of "infinite" time, i.e., the period starting from the first administration and ending when the plasma concentration of the drug has dropped to a negligible amount.

[0213] In one embodiment, the substantially constant plasma drug concentration provided by the gastric retention system of the present invention is the trough value of the plasma drug concentration when administered once a day with a conventional oral formulation (i.e., the minimum blood concentration (C min )) of the drug administered once a day with an immediate-release formulation), and above the peak plasma drug concentration when administered once a day with a conventional oral formulation (i.e., the maximum blood concentration (C max )) of the drug administered once a day with an immediate-release formulation, and may be in the range below. Depending on the embodiment, the substantially constant plasma drug concentration provided by the gastric retention system of the present invention is about 50% to about 90% of the peak plasma drug concentration when administered once a day with a conventional oral formulation (i.e., the C max ) of the drug administered once a day with an immediate-release formulation. The substantially constant plasma drug concentration provided by the gastric retention system of the present invention may be about 75% to about 125% of the average plasma drug concentration when administered once a day with a conventional oral formulation (i.e., the C ave ) of the drug administered once a day with an immediate-release formulation. The substantially constant plasma drug concentration provided by the gastric retention system of the present invention is the trough value of the plasma drug concentration when administered once a day with a conventional oral formulation (i.e., the C min ) of the drug administered once a day with an immediate-release formulation, and above, for example, about 100% to about 150% of C min .

[0214] The gastric retention system of the present invention provides a bioavailability of the drug 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 obtained from an immediate-release form containing the same amount of drug. As described above, the area under the plasma concentration-time curve (AUC) inf Bioavailability is measured using ). Solubility, bioavailability, and pharmacokinetics of the gastric retention system

[0215] Dissolution: The gastric retention systems described herein provide stable release of a drug or a pharmaceutically acceptable salt thereof over a long period. The system is designed to release a therapeutically effective amount of the drug or a salt thereof during its retention in the stomach. The release of the drug (or salt thereof) can be measured in vitro or in vivo to establish the dissolution characteristics (elution characteristics, release rate) of the drug (or salt thereof) from a given retention system in a specific environment. Dissolution characteristics can be identified by the proportion of the original amount of the drug (or salt thereof) present in the system that dissolves from the system over a given period.

[0216] Therefore, depending on the embodiment, the drug (or its salt) contained in the gastric retention system may have a solubility characteristic of releasing 10-20% over a period of 0-24 hours in a given environment. That is, 10-20% of the initial drug (or its salt) contained in the system will leach out of the system within a 24-hour period after the gastric retention system is first introduced into the target environment.

[0217] The target environment may be either 1) the patient's stomach (i.e., the in vivo environment) or 2) simulated gastric juice (i.e., the extra vivo environment).

[0218] The gastric retention system of the present invention has an AUC after administration of the system. inf When measured, it provides a higher bioavailability of the drug (or its salt) compared to conventional oral formulations. The system further provides the maintenance of substantially constant plasma concentrations of the drug (or its salt).

[0219] The variables of interest regarding release include the linearity of release over the residence period of the gastric retention system, the standard deviation of release over the residence period (related to the linearity of release, where a standard deviation of zero indicates that release is linear over the entire residence period), release over the first six hours of retention (i.e., explosive release at the time of initial administration), and total release of the drug (or its salt) over the residence period. A preferred residence period is 7 days, but other periods, such as 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, or 14 days, may be useful.

[0220] The linearity of drug (or its salt) release during the residence period refers to the amount released per 24-hour residence period. For a 7-day residence period, it is desirable that approximately that amount of drug (or its salt) is released daily (i.e., the linearity of drug (or its salt) release is maximized). This minimizes the standard deviation of daily drug or drug salt release during the residence period. Depending on the embodiment, the intragastric release system may have a daily drug (or its salt) release variation (or standard deviation) of less than approximately 100%, less than approximately 90%, less than approximately 80%, less than approximately 70%, less than approximately 60%, less than approximately 50%, less than approximately 40%, less than approximately 30%, less than approximately 25%, less than approximately 20%, less than approximately 15%, less than approximately 10%, or less than approximately 5% during the residence period. Depending on the embodiment, the residence period may be approximately 3 days, approximately 7 days, approximately 10 days, or approximately 2 weeks.

[0221] To maintain predictable and stable release characteristics, it is desirable to minimize explosive release, i.e., release during the initial period of residence (e.g., 6, 12, or 24 hours after administration of the intragastric retention system). If T is the total release (in mass units) of the drug (or its salt) during the residence period and D is the number of days of the residence period, then a perfectly linear release means that approximately T / D mass of the drug (or its salt) is released per day. If the period during which explosive release is measured is the first 6 hours, then, as a result of linear release characteristics, the amount of drug (or its salt) released in the first 6 hours will be 0.25 x T / D mass. Regarding the percentage of the total amount of drug (or its salt) released during a D-day residence period, linear release is approximately 100 / D% of the drug (or its salt) per day, and linear release in the first 6 hours is 25 / D%. (Note that in this context, 100% refers to the total amount of drug (or its salt) released, regardless of the amount of drug (or its salt) contained in the initial formulation. Therefore, for a 7-day residence period, linear release in the first 6 hours is approximately 3.6% of the total amount of drug (or its salt) released over the 7-day period.)

[0222] Depending on the embodiment, during the first 6 hours of retention after administration, the gastric retention system releases approximately 0.2 to 2 times the T / D ratio of the total mass T of the drug (or its salt) released during the D-day retention period, or approximately 0.2 to 1.75 times the T / D ratio of the total mass T of the drug (or its salt) released during the D-day retention period, or approximately 0.2 to 1.5 times the T / D ratio of the total mass T of the drug (or its salt) released during the D-day retention period, or approximately 0.2 to 1.25 times the T / D ratio of the total mass T of the drug (or its salt) released during the D-day retention period, or approximately 0.2 to 1 time the T / D ratio of the total mass T of the drug (or its salt) released during the D-day retention period. Approximately 0.2 to approximately 0.8 times, or approximately 0.2 to approximately 0.75 times T / D, or approximately 0.2 to approximately 0.7 times T / D, or approximately 0.2 to approximately 0.6 times T / D, or approximately 0.2 to approximately 0.5 times T / D, or approximately 0.2 to approximately 0.4 times T / D, or approximately 0.2 to approximately 0.3 times T / D, or approximately 0.25 to approximately 2 times T / D, or approximately 0.3 to approximately 2 times T / D, or approximately 0.4 to approximately 2 times T / D, or Approximately 0.5 to 2 times T / D, or approximately 0.6 to 2 times T / D, or approximately 0.7 to 2 times T / D, or approximately 0.25 to 1.5 times T / D, or approximately 0.3 to 1.5 times T / D, or approximately 0.4 to 1.5 times T / D, or approximately 0.5 to 1.5 times T / D, or approximately 0.6 to 1.5 times T / D, or approximately 0.7 to 1.5 times T / D, or approximately 0.25 to 1.25 times, or approximately 0.3 to 1.25 times T / D, or approximately 0.4 to 1.25 times T / D, or approximately 0.5 to 1.25 times T / D, or approximately 0.6 to 1.25 times T / D, or approximately 0.7 to 1.25 times T / D, or approximately 0.25 to 1 times T / D, or approximately 0.3 to 1 times T / D, or approximately 0.4 to 1 times T / D, or approximately 0.5 to 1 times T / D, or approximately 0.0 of T / D. 6 to approximately 1x, or approximately 0.7 to approximately 1x of T / D, or approximately 0.25x of T / D, or approximately 0.25 to approximately 0.8x of T / D, or approximately 0.3 to approximately 0.8x of T / D, or approximately 0.4 to approximately 0.8x of T / D, or approximately 0.5 to approximately 0.8x of T / D, or approximately 0.6 to approximately 0.8x of T / D, or approximately 0.7 to approximately 0.8x of T / D, or approximately 0.8x of T / D, approximately 1x of T / D, approximately 1x of T / D.It emits 25 times the amount of fuel, approximately 1.5 times the T / D ratio, or approximately 2 times the T / D ratio.

[0223] Depending on the embodiment of the gastric retention system, during the first six hours of retention after administration, the gastric retention system releases approximately 2% to 10%, or approximately 3% to 10%, or approximately 4% to 10%, or approximately 5% to 10%, or approximately 6% to 10%, or approximately 7% to 10%, or approximately 8% to 10%, or approximately 9% to 10%, or approximately 2% to 9%, or approximately 2% to 8%, or approximately 2% to 7%, or approximately 2% to 6%, or approximately 2% to 5%, or approximately 2% to 4%, or approximately 2% to 3%.

[0224] Depending on the embodiment of the intragastric retention system, if the intragastric retention system has a retention period of approximately 7 days, during the first 6 hours of retention after administration, the intragastric retention system will release approximately 2% to approximately 10%, or approximately 3% to approximately 10%, or approximately 4% to approximately 10%, or approximately 5% to approximately 10%, or approximately 6% to approximately 10%, or approximately 7% to approximately 10%, or approximately 8% to approximately 10%, or approximately 9% to approximately 10%, or approximately 2% to approximately 9%, or approximately 2% to approximately 8%, or approximately 2% to approximately 7%, or approximately 2% to approximately 6%, or approximately 2% to approximately 5%, or approximately 2% to approximately 4%, or approximately 2% to approximately 3%.

[0225] Depending on the embodiment, during the first 24 hours of residence after administration, the gastric retention system releases approximately 10% to approximately 35%, or approximately 10% to approximately 30%, or approximately 10% to approximately 25%, or approximately 10% to approximately 20%, or approximately 10% to approximately 15%, or approximately 15% to approximately 35%, or approximately 15% to approximately 35%, or approximately 15% to approximately 35%, or approximately 15% to approximately 30%, or approximately 20% to approximately 30%, or approximately 25% to approximately 35%, or approximately 25% to approximately 30%, or approximately 30% to approximately 35%.

[0226] Depending on the embodiment, if the gastric retention system has a retention period of approximately 7 days, during the first 24 hours of retention after administration, the gastric retention system will release approximately 10% to approximately 35%, or approximately 10% to approximately 30%, or approximately 10% to approximately 25%, or approximately 10% to approximately 20%, or approximately 10% to approximately 15%, or approximately 15% to approximately 35%, or approximately 15% to approximately 35%, or approximately 15% to approximately 35%, or approximately 15% to approximately 30%, or approximately 20% to approximately 30%, or approximately 25% to approximately 35%, or approximately 25% to approximately 30%, or approximately 30% to approximately 35%. Elastic body

[0227] An elastic material (also called an elastic polymer or stretchable polymer) can be used to compress the gastric retention system (for example, by folding or compressing) into a form suitable for administration to the stomach by swallowing a container or capsule containing the compressed 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 retention period. Therefore, the elastic material must be able to be stored in a compressed configuration within the capsule for a reasonable shelf life and be able to expand to its original or nearly original shape when released from the capsule. In one embodiment, the elastic material is a silicone elastic material. In one embodiment, the elastic material is formed from liquid silicone rubber (LSR), such as that sold in the Dow Corning QP-1 liquid silicone rubber kit. In one embodiment, the elastic material is cross-linked polycaprolactone. In one embodiment, the elastic material is an enteric polymer, such as those listed in the table of enteric polymers. In some embodiments, the linking polymer used in the system is also an elastic material. The elastic material is preferred for use as the central polymer in the star-shaped, or astral, design of the gastric retention system.

[0228] In one embodiment, by making both the linking polymer and the elastic body enteric-coated polymers, the system is more completely broken down into supported polymer-drug components when the system enters the intestines or when the patient drinks a slightly alkaline solution to facilitate the passage of the system.

[0229] Examples of elastic materials that can be used include silicone, urethane crosslinked polycaprolactone, poly(acryloyl 6-aminocaproic acid) (PA6ACA), poly(methacrylate-co-acrylate) (EUDRAGIT L 100-55), and mixtures of poly(acryloyl 6-aminocaproic acid) (PA6ACA) and poly(methacrylate-co-acrylate) (EUDRAGIT L 100-55), such as those formed using the Dow Corning QP-1 kit.

[0230] Flexible linking polymers, i.e., elastic linking polymers or elastic bodies, are used as the central polymer in star-shaped or astral designs of gastric retention systems. Silicone rubber is a particularly preferred elastic body for use as the central elastic body in astral or star-shaped configuration. Liquid silicone rubber (LSR) can be easily molded and cured into the desired shape. The Dow Corning QP-1 series, including 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). Undivided arms, or arms containing segments of supported polymer-pharmaceutical components, can then be attached to the central silicone rubber elastic body. Another elastic body that can be used as the central elastic body in astral designs is crosslinked polycaprolactone.

[0231] The specific configurations of the gastric retention system are disclosed in International Patent Application No. WO2017 / 100367, and any of these configurations can be used in the gastric retention system disclosed herein. Supported polymers for segments and arms (supported polymers - pharmaceutical components)

[0232] The segments and arms of the gastric retention system include a supported polymer-drug component containing a drug (or a pharmaceutically acceptable salt of the drug) that elutes from the gastric retention system in the gastric environment. The drug is compounded into a supported polymer to form a supported polymer-drug mixture. This mixture can be formed into one or more desired shapes for use in the system as a supported polymer-drug component. After compounding the drug or drug salt into the supported polymer to form a supported polymer-drug mixture, the drug or drug salt is distributed or dispersed throughout the compounded mixture. If excipients, antioxidants, or other components are included in the supported polymer-drug formulation, they are also distributed or dispersed throughout the compounded mixture.

[0233] The choice of a supporting material for a drug or a pharmaceutically acceptable salt in the gastric retention system affects the drug release characteristics during gastric retention. The supporting polymer may be thermoplastic to allow extrusion using hot-melt extrusion or 3D printing techniques. It may also have sufficiently high melt strength and viscosity to allow extrusion into the desired shape. To prevent the drug or substance from being exposed to high temperatures during manufacturing, the supporting polymer may have a low melting point (e.g., below about 120°C). To avoid rupture in the stomach during the desired retention period, the supporting polymer may have sufficient mechanical strength (Young's modulus, compressive strength, tensile strength). Furthermore, the supporting polymer must be able to form stable formulations with drugs, therapeutic agents, medicinal substances, excipients, dispersants, and other additives.

[0234] Exemplary supported polymers suitable for use in the present invention include, but are not limited to, hydrophilic cellulose derivatives (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose), cellulose phthalate acetate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymer, polyvinyl alcohol, carboxyvinyl polymer (carbomer), Carbopol® acidic carboxypolymer, polycarbophil, polyethylene oxide (Polyox WSR), polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycol, chitosan, alginates, pectin, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidone / vinyl acetate copolymer, dextran, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellan, laminaran, genus Ivanophyllum, genus Ivanophyllum, gum arabic, ghati gum, karaya gum, albinogalactan, amylopectin, gelatin, gellan, hyaluronic acid, pullulan, scleroglucan, xanthan gum, xyloglucan, maleic anhydride copolymer, ethylene / maleic anhydride copolymer, polyhydroxyethyl methacrylate, ammoniacease copolymer (such as Eudragit RL or Eudragit RS), poly(ethyl acrylate-methyl methacrylate) (Eudragit NE), Eudragit Poly(orthoesters) (US 4,304,) such as poly(orthoesters) (US 4,304,)Examples include polyorthoesters described and disclosed in Patent No. 767 (which are incorporated herein by reference), starch, particularly pregelatinized starch, and starch-based polymers, carbomers, maltodextrins, amylomaltodextrins, dextran, poly(2-ethyl-2-oxazoline), polyethyleneimines, polyurethanes, polylactic acid, polyglycolic acid, poly(lactic acid-co-glycolic acid) (PLGA), polyhydroxyalkanoates, polyhydroxybutyrates, poly(ethylene-co-vinyl acetate), and copolymers, mixtures, formulations, and combinations thereof. Polycaprolactone (PCL) and / or thermoplastic polyurethanes are preferred supporting polymers. In some embodiments, polydioxanone is used as the supporting polymer. In any embodiment of the intragastric retention system, the supported polymer used in the intragastric retention system includes polycaprolactone, for example, linear polycaprolactone having a number-average molecular weight (Mn) range of about 60 kDa to about 100 kDa, 75 kDa to 85 kDa, about 80 kDa, about 45 kDa to about 55 kDa, about 50 kDa to about 110,000 kDa, or about 80 kDa to about 110,000 kDa.

[0235] Furthermore, drug release can be regulated by various excipients contained in the supported polymer-drug component. Soluble excipients include P407, Eudragit E, PEG, polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA). Insoluble water-conducting excipients include Eudragit RS and Eudragit RL. Examples of degradable excipients include PLA, PLGA, PLA-PCL, polydioxanone, 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, for example, linear copolymer of caprolactone (95%) and glycolide (5%). Examples include: multiaxial block copolymers of glycolide (68%), 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%).Examples of insoluble, swelling excipients include polyvinyl acetate (PVAc), crospovidone, croscarmellose, HPMCAS, and linear block copolymers of dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethylcarbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; and linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol, for example, di Examples include linear block copolymers of oxanone (80%) and ethylene glycol (20%); linear block copolymers of lactide (60%) and ethylene glycol (40%); linear block copolymers of lactide (68%), ethylene glycol (20%), trimethylcarbonate (10%), and caprolactone (2%); linear block copolymers of lactide (88%), glycolide (8%), and ethylene glycol (4%); and linear block copolymers of glycolide (67%), polyethylene glycol (28%), and ethylene glycol (5%). Examples of surfactants include lecithin, taurocholate, SDS, Soluplus, fatty acids, and Kolliphor RH40.

[0236] Other excipients may be added to the supported polymer to adjust the release of the drug. Such excipients may be added in amounts of about 1% to 75%, about 5% to 50%, or about 5% or 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 (x and z are about 101, and y is about 56); Pluronic P407; Eudragit E, Eudragit EPO (available from Evonik); hypromellose (available from Sigma, catalog number H3785), Kolliphor Examples of suitable excipients include RH40 (available from Sigma, catalog no. 07076), polyvinylcaprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), and Soluplus (available from BASF, a copolymer of polyvinylcaprolactam, 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 swelling excipients include crospovidone, croscarmellose, hypromellose succinate acetate (HPMCAS), and Carbopol. EUDRAGIT RS and EUDRAGIT RL are registered trademarks of Evonik (Darmstadt, Germany) for copolymers of ethyl acrylate, methyl methacrylate, and methacrylate ester having a quaternary ammonium group (trimethylammonium methacrylate chloride). The molar ratio of ethyl acrylate, methyl methacrylate, and trimethylammonium methacrylate is approximately 1:2:0.2 for EUDRAGIT RL and approximately 1:2:0.1 for Eudragit® RS.Preferred insoluble and swelling excipients include crospovidone, croscarmellose, hypromellose succinate acetate (HPMCAS), carbopol, and linear block copolymers of 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, glycol, and ethylene glycol; linear block copolymers of glycol, polyethylene glycol, and ethylene glycol, for example. Examples include linear block copolymers of dioxanone (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%), and linear block copolymers of glycolide (67%), polyethylene glycol (28%), and ethylene glycol (5%).

[0237] Further examples of excipients that can be used in the gastric retention system segment are shown in the following excipient table. [Table 2]

[0238] Formulations of supported polymers-drugs or supported polymers-drug salts may contain a variety of excipients and other additives. Table 1 of the following CPE shows combinations of excipients and other additives that can be used in combination with a drug or a salt thereof and a supported polymer in compositions constituting an arm or segment of an arm of the gastric retention system. These excipients and other additives can be used in combination with a drug or a salt thereof (the drug or drug salt constitutes about 10% to about 60% by weight of the composition) and a supported polymer such as polycaprolactone that constitutes the remainder of the composition. The following can be used individually or in any combination in amounts ranging from about 1% to about 30% (e.g., about 5% to about 20%) of the composition by weight as excipients: namely, 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 methacrylate chloride] 1:2:0.2), PDO (polydioxanone), PEG-PCL, SIF (BioRelevant's FaSSIF / FaSSGF powder), EPO (dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer), Kollidon VA64 (vinylpyrrolidone-vinyl acetate copolymer (mass ratio 6: 4)) Examples include polyvinyl acetate and polyvinyl pyrrolidine.

[0239] Other additives include silicon dioxide (for example, constituting about 0.1% to about 5% by weight of the composition, e.g., about 0.1% to 1% or about 0.5%) and antioxidants, such as alpha-tocopherol (for example, constituting about 0.1% to about 5% by weight of the composition, e.g., about 0.1% to 1% or about 0.5%). Each row in the table below represents the formulation of excipients and other additives used with the supported polymer and the drug or its salts. [Table 3]

[0240] Table 2 of the CPE table shows specific amounts of excipients and other additives that can be used in combination with drugs or salts thereof and supported polymers in compositions constituting the arms or segments of the gastric retention system.

[0241] The amounts shown in Table 2 of the CPE may vary by ±20% of each component (for example, 0.5% silica may vary between 0.4% and 0.6% silica, since 20% of 0.5% is 0.1%). Each row in the table below represents the formulation of excipients and other additives used with the supported polymer and the drug or its salts. [Table 4-1] [Table 4-2]

[0242] Drugs that can be administered into or via the gastrointestinal tract (e.g., active pharmaceutical ingredients, therapeutic agents) can be used in the gastric retention system of the present invention. The drug is blended with a supported polymer and other excipients or other additives to the supported polymer to form segments used in the gastric retention system. Drugs include, but are not limited to, drugs, prodrugs, biologics, and any other substances that can be administered to produce a beneficial effect against disease or injury.

[0243] Drugs that can be used in the gastric retention system of the present invention include statins such as rosuvastatin; nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam; selective serotonin reuptake inhibitors (SSRIs) such as escitalopram and citalopram; anticoagulants such as clopidogrel; steroids such as prednisone; antipsychotics such as aripiprazole and risperidone; analgesics such as buprenorphine; opioid antagonists such as naloxone; anti-asthmatics such as montelukast; anti-dementia drugs such as memantine; cardiac glycosides such as digoxin; alpha-blockers such as tamsulosin; and cholesterol-lowering drugs such as ezetimibe. Examples of drugs that can be used as pharmaceuticals in the gastric retention system of the present invention include: steroid absorption inhibitors; gout preventive drugs such as colchicine; antihistamines such as loratadine and cetirizine; opioids such as loperamide; proton pump inhibitors such as omeprazole; antiviral agents such as entecavir; antibiotics such as doxycycline, ciprofloxacin, and azithromycin; antimalarial agents; levothyroxine; drug abuse treatments such as methadone and varenicline; contraceptives; stimulants such as caffeine; and nutrients such as folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, biotin, plant extracts, plant hormones, and other vitamins and minerals. Examples of biological preparations that can be used as pharmaceuticals in the gastric retention system of the present invention include proteins, polypeptides, polynucleotides, and hormones.Examples of drug classes include antiproliferative agents such as analgesics, anti-analgesics, anti-inflammatory agents, antidepressants, antiepileptic agents, antipsychotics, neuroprotective agents, and anticancer agents; antihistamines, anti-migraine agents; hormones, prostaglandins; antibacterial agents such as antibiotics, antifungal agents, antiviral agents, and antiparasitic agents; antimuscarinic agents, anxiolytics, bacteriostatic agents, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthmatics, cardiovascular drugs, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroids or non-steroidal anti-inflammatory drugs, corticosteroids, dopamine agonists, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional supplements, vitamins, parasympathomimetic agents, stimulants, analgesics, and anti-involuntary motility drugs. These include, but are not limited to, antimalarial drugs (quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides (sulfadoxine, sulfamethoxypyridazine, etc.), mefloquine, atovaquone, primaquine, halofantrine, doxycycline, clindamycin, artemisinin, and artemisinin derivatives (artemether, dihydroartemisinin, arteether, artesunate, etc.). The term “drug” includes salts, solvates, polymorphs, and cocrystals of the aforementioned substances. In some embodiments, the drug is selected from the group consisting of cetirizine, rosuvastatin, escitalopram, citalopram, risperidone, olanzapine, donepezil, and ivermectin. In some embodiments, the drug is a drug used to treat neuropsychiatric disorders, such as an antipsychotic or antidementia drug, e.g., memantine.

[0244] In some embodiments, the drug may exclude drugs of the genus adamantane. In some embodiments, the drug may exclude memantine, amantadine, adapromine, nitromemantine, rimantadine, bromantane, neramexane, or tromantadine, or one or more pharmaceutically acceptable salts of memantine, amantadine, adapromine, nitromemantine, rimantadine, bromantane, or tromantadine. In some embodiments, the drug may exclude memantine. In some embodiments, the drug may exclude salts of memantine or pharmaceutically acceptable salts of memantine.

[0245] The drug can be used in any suitable crystalline form, amorphous form, or both crystalline and amorphous forms in the gastric retention system of the present invention. That is, the drug or drug particles contained in the gastric retention system can be used in crystalline form, amorphous form, or as a mixture of crystalline form (single or multiple crystalline forms) and amorphous form, providing a desired release rate or desired physical or chemical properties.

[0246] Intragastric retention systems are highly suitable for use in the treatment of diseases and disorders in which patient adherence to medication is difficult, and therefore, depending on the embodiment, intragastric retention systems are used to treat diseases or disorders in which adherence to the patient's medication plan is problematic. Such diseases and disorders include neuropsychiatric disorders and disorders, dementia and other diseases and disorders affecting memory, Alzheimer's disease, psychosis, schizophrenia, and paranoid disorders. Therefore, drugs that can be used in intragastric retention systems include, but are not limited to, antidementia drugs, anti-Alzheimer's drugs, and antipsychotic drugs.

[0247] Examples of exemplary hydrophilic agents that can be used in the system include risperidone, cetirizine, memantine, and olanzapine. Examples of exemplary hydrophobic agents that can be used in the system include aripiprazole, ivermectin, rosuvastatin, citalopram, and escitalopram.

[0248] In some embodiments, the drug or a salt thereof (e.g., a pharmacokinetic) accounts for about 10% to about 40% of the weight of the arm or segment, and therefore the supported polymer and other components of the arm or segment incorporated into the supported polymer together constitute the weight of the remainder of the arm or segment. In some embodiments, the drug or a salt thereof constitutes about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, about 15% to about 40%, about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 35% to about 40%, 15% to about 35%, about 20% to about 35%, or about 25% to about 40% by weight of the arm or segment.

[0249] Further embodiments of the arm or segment in which the drug or a salt thereof constitutes more than approximately 40% by weight of the arm or segment are described below in "High Drug Loading Properties of Arms and Segments". High drug load capacity of arms and segments

[0250] In some embodiments of the present invention, an arm, or a segment constituting an arm, may have high load capacity for a drug or a pharmaceutically acceptable salt thereof. “High load capacity” generally means an arm or segment in which the drug or a salt thereof (e.g., a drug) constitutes more than about 40% by weight of the arm or segment, and therefore the supported polymer, and any other components of the arm or segment incorporated into the supported polymer, constitute less than about 60% by weight of the arm or segment. Components of the arm or segment not incorporated into the supported polymer are not included in the calculation of weight percentages. For example, if an arm has one or more disintegrating substrates dispersed between the segments of the arm, the weight of such substrates is not included as part of the weight of the arm when calculating the weight percentage of the drug in the arm. An increase in the drug load to about 60% makes it increasingly difficult to properly incorporate the drug into the supported polymer, and phase separation between the drug and the polymer becomes more likely. Therefore, the amount of drug loaded onto an arm or segment should not exceed about 60% of the total weight of the arm.

[0251] Therefore, depending on the embodiment, the amount of drug in the arm or the segment constituting the arm may constitute at least about 40%, at least about 45%, at least about 50%, at least about 55%, or about 60% by weight. Depending on the embodiment, the amount of drug in the arm or the segment constituting the arm may constitute about 40% to about 60%, about 45% to about 60%, about 50% to about 60%, about 55% to about 60%, about 40% to about 55%, about 40% to about 50%, or about 40% to about 45% by weight. Depending on the embodiment, the amount of drug in the arm or the segment constituting the arm may constitute about 25% to about 60%, about 30% to about 60%, or about 35% to about 60% by weight. Depending on the embodiment, the amount of the drug in the arm or the segment constituting the arm may constitute about 51% to about 60%, about 52% to about 60%, about 53% to about 60%, about 54% to about 60%, about 55% to about 60%, about 56% to about 60%, or about 57% to about 60% by weight. Depending on the embodiment, the drug or a pharmaceutically acceptable salt thereof is present in a weight of about 67% to about 150% of the weight of the supported polymer.

[0252] By combining the high load-bearing capacity of the drug or drug salt with a release rate-adjusting polymer film, this system provides an intragastric retention system in which the amount of the drug or drug salt is increased while maintaining good release dynamics throughout the system's residence period. Dispersants for regulating drug release and stability of polymer formulations

[0253] Using a dispersant in the carrier polymer-drug component creates many advantages. The dissolution rate of the drug from the carrier polymer-drug component is affected by many factors such as the composition and properties of the carrier polymer (which may itself contain multiple polymer components and non-polymer components), the physical and chemical properties of the drug, and the gastric environment, as previously pointed out. Avoiding the explosive release of drugs, especially hydrophilic drugs, and maintaining the sustained release of the drug over the effective release period or residence period is an important feature of the system. By using the dispersant according to the present invention, the release rate can be better adjusted and the explosive release can be suppressed. The explosive release and release rate can be adjusted using dispersants at various concentrations. For example, the explosive release of cetirizine in simulated gastric juice may be adjusted using various dispersants and various excipients at various concentrations.

[0254] Dispersants that can be used in the present invention include silicon dioxide (silica, SiO2) (hydrophilic fume), stearates such as calcium stearate and magnesium stearate, microcrystalline cellulose, carboxymethyl cellulose, hydrophobic colloidal silica, hypromellose, magnesium aluminum silicate, phospholipids, polyoxyethylene stearate, zinc acetate, alginic acid, lecithin, fatty acids, sodium lauryl sulfate, non-toxic metal oxides such as aluminum oxide, etc. Porous inorganic materials and polar inorganic materials can be used. Hydrophilic fumed silicon dioxide is a preferred dispersant. One particularly useful silicon dioxide is sold under the registered trademark CAB-O-SIL® M-5P (CAS# 112945-52-5) by Cabot Corporation (Boston, Massachusetts, USA), which is hydrophilic fumed silicon dioxide having a BET surface area of about 200 m 2 / g ± 15 m 2 / g, and the mesh residue of this product sieved through a 45-micron sieve is less than about 0.02%. The size of typical primary aggregates is about 150 to about 300 nm, and the individual particle size may be in the range of about 5 nm to 50 nm.

[0255] In addition to anti-aggregation / anti-coagulation activity, the dispersant helps prevent phase separation during the manufacture and / or storage of the system. This is particularly useful for the manufacture of the system by hot melt extrusion.

[0256] The weight / weight ratio of the dispersant to the pharmaceutical substance may be from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 4%, from about 4% to about 5%, or about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4% or about 5%.

[0257] The dispersant may constitute from about 0.1% to about 4% of the carrier polymer-drug component, such as from about 0.1% to about 3.5%, from about 0.1% to about 3%, from about 0.1% to about 2.5%, from about 0.1% to about 2%, from about 0.1% to about 1.5%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, or from about 0.2% to about 0.8%.

[0258] Dispersants can also be used to regulate the explosive release of the drug or its pharmaceutically acceptable salt during the initial period of administration of the intragastric retention system. In embodiments of the intragastric retention system administered once a week, the explosive release in the first approximately 6 hours after the initial administration is less than approximately 8%, preferably less than approximately 6%, of the total amount of the drug (or its salt) in the system. In embodiments of the intragastric retention system administered once every three days, the explosive release in the first approximately 6 hours after the initial administration is less than approximately 12%, preferably less than approximately 10%, of the total amount of the drug (or its salt) in the system. In embodiments of the intragastric retention system administered once a day, the explosive release in the first approximately 6 hours after the initial administration is less than approximately 40%, preferably less than approximately 30%, of the total amount of the drug (or its salt) in the system. Generally, when a new intragastric retention system is administered every D days, and the total mass of the drug (or its salt) is M, the intragastric retention system releases approximately less than [(M / D) × 0.5], preferably less than [(M / D) × 0.4], or approximately less than [(M / D) × 3 / 8], more preferably approximately [(M / D) × 0.3], in the first approximately 6 hours after the initial administration. In a further embodiment, the intragastric retention system releases at least approximately [(M / D) × 0.25] in the first approximately 6 hours after the initial administration. That is, the system releases at least approximately 1 / 4 of the daily dose in the first quartile of the first day of administration. Stabilizers used in the gastric retention system

[0259] Many drugs are susceptible to oxidative degradation when exposed to reactive oxygen species that may be present in the stomach. Drugs contained in a system can thus oxidize during the system's prolonged presence in the stomach and the prolonged release period from the system. Therefore, it is desirable to include stabilizers or preservatives in the system to stabilize the drug and prevent oxidative degradation and other forms of degradation.

[0260] Stabilizers, such as antioxidants like tocopherol, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, and fumaric acid, may constitute about 0.1% to about 4%, for example, about 0.1% to about 3.5%, about 0.1% to about 3%, about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.5%, or about 0.2% to about 0.8% of the supported polymer-pharmaceutical component.

[0261] Antioxidant stabilizers that can be included in a system to reduce or prevent the oxidation of drugs include alpha-tocopherol (approximately 0.01–0.05% v / v), ascorbic acid (approximately 0.01–0.1% w / v), ascorbyl palmitate (approximately 0.01–0.1% w / v), butylated hydroxytoluene (approximately 0.01–0.1% w / w), butylated hydroxyanisole (approximately 0.01–0.1% w / w), and fumaric acid (up to 3600 ppm). As antioxidant stabilizers, vitamin E, tocopherol, vitamin E ester, tocopherol ester, ascorbic acid, or carotene, such as α-tocopherol, vitamin E succinate, α-tocopherol succinic acid, vitamin E acetate, α-tocopherol acetate, vitamin E nicotinic acid, α-tocopherol nicotinic acid, vitamin E linoleic acid, or α-tocopherol linoleic acid can be used.

[0262] Certain drugs may be pH sensitive, especially at low pH levels present in the gastric environment. Buffers, or pH-stabilizing compounds, that can be included in the system to reduce or prevent drug degradation at low pH include calcium carbonate, calcium lactate, calcium phosphate, sodium phosphate, and sodium bicarbonate. Generally, these are used in amounts up to approximately 2% w / w. The buffer or pH-stabilizing compound may constitute approximately 0.1% to 4% of the supported polymer-drug component, for example, approximately 0.1% to 3.5%, 0.1% to 3%, 0.1% to 2.5%, 0.1% to 2%, 0.1% to 1.5%, 0.1% to 1%, 0.1% to 0.5%, or 0.2% to 0.8%.

[0263] Antioxidant stabilizers, pH stabilizers, and other stabilizer compounds are incorporated into polymers containing a drug (or a pharmaceutically acceptable salt thereof) by incorporating the stabilizers into a mixture of a molten supported polymer and the drug or drug salt. The stabilizers may be incorporated into the molten supported polymer first, and then the drug (or its salt) may be incorporated into the polymer-stabilizer mixture; or the stabilizers may be incorporated into the drug (or its salt) first, and then the combined drug (or its salt)-stabilizer mixture may be incorporated into the supported polymer; or the stabilizers, the drug (or its salt), and the molten supported polymer may be mixed simultaneously.

[0264] In one embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 24 hours of gastric retention. In another embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 48 hours of gastric retention. In yet another embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 72 hours of gastric retention. In yet another embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 96 hours of gastric retention. In yet another embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 5 days of gastric retention. In yet another embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 1 week of gastric retention. In yet another embodiment, less than 10% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 2 weeks of gastric retention.

[0265] In one embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 24 hours of gastric retention. In another embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 48 hours of gastric retention. In yet another embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 72 hours of gastric retention. In yet another embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 96 hours of gastric retention. In yet another embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 5 days of gastric retention. In yet another embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 1 week of gastric retention. In yet another embodiment, less than 5% of the drug (or its salt) remaining in the system decomposes or oxidizes after approximately 2 weeks of gastric retention. Linked polymer

[0266] Linking polymers are used to link one or more supported polymer-pharmaceutical components (i.e., arms or segments of arms) to one or more supported polymer-pharmaceutical components, to link one or more supported polymer-pharmaceutical components to one or more elastic components (i.e., cores), or to link one or more elastic components to one or more elastic components. Thus, the linking polymers form linker regions between other components of the system. Enteric polymers and time-dependent polymers are preferred for use as linking polymers. In some embodiments, enteric polymers are used as linking polymers. In some embodiments, pH-tolerant, i.e., time-dependent polymers that are less sensitive to pH changes than enteric polymers are used as linking polymers. In some embodiments, both enteric polymers and time-dependent polymers that are less sensitive to pH changes than enteric polymers are used as linking polymers.

[0267] Enteric-coated polymers are relatively insoluble under acidic conditions, such as those found in the stomach, but soluble under the low-acid to basic conditions found in the small intestine. Enteric-coated polymers that dissolve at pH 5 or higher can be used as linking polymers because the pH of the duodenum, the first compartment of the small intestine, is in the range of approximately 5.4 to 6.1. If the gastric retention system passes through the pyloric valve unchanged, the enteric-coated linking polymer dissolves, and the components linked by the linking polymer break down, allowing the retention system to pass through the small and large intestines. Therefore, the gastric retention system should be designed so that the linkage is rapidly broken by the dissolution of the linking polymer in the intestinal environment.

[0268] A "pH-tolerant time-dependent polymer" (or equivalently, a "pH-tolerant time-dependent polymer") means that even under conditions where enteric-coated polymers decompose to the point where they can no longer bond components, the time-dependent polymer still possesses sufficient mechanical strength to bond components. In some embodiments, the time-dependent polymer retains approximately 100% of its bonding ability, i.e., its bonding strength, after exposure to a solution of approximately pH 7 to approximately pH 8, compared to exposure to a solution of approximately pH 2 to approximately pH 3 (exposure durations of approximately 1 hour, 1 day, 3 days, or 1 week). In some embodiments, the time-dependent polymer retains approximately 90% of its bonding strength after exposure to a solution of approximately pH 7 to approximately pH 8, compared to exposure to a solution of approximately pH 2 to approximately pH 3 (exposure durations of approximately 1 hour, 1 day, 3 days, or 1 week). In some embodiments, the time-dependent polymer retains approximately 75% of the bond strength it has after exposure to a solution of approximately pH 2 to approximately pH 3 after exposure to a solution of approximately pH 7 to approximately pH 8 (exposure durations of approximately 1 hour, 1 day, 3 days, or 1 week). In some embodiments, the time-dependent polymer retains approximately 60% of the bond strength it has after exposure to a solution of approximately pH 2 to approximately pH 3 after exposure to a solution of approximately pH 7 to approximately pH 8 (exposure durations of approximately 1 hour, 1 day, 3 days, or 1 week). In some embodiments, the time-dependent polymer retains approximately 50% of the bond strength it has after exposure to a solution of approximately pH 2 to approximately pH 3 after exposure to a solution of approximately pH 7 to approximately pH 8 (exposure durations of approximately 1 hour, 1 day, 3 days, or 1 week). In some embodiments, the time-dependent polymer retains approximately 25% of the bond strength it had after exposure to a solution of approximately pH 2 to approximately pH 3 after exposure to a solution of approximately pH 7 to approximately pH 8 (exposure durations are approximately 1 hour, 1 day, 3 days, or 1 week). In some embodiments, the time-dependent polymer resists fracture to bending forces of approximately 0.2 Newtons (N), 0.3 N, 0.4 N, 0.5 N, 0.75 N, 1 N, 1.5 N, 2 N, 2.5 N, 3 N, 4 N, or 5 N after exposure to a solution of approximately pH 7 to approximately pH 8 (exposure durations are approximately 1 hour, 1 day, 3 days, or 1 week).The joint strength can be measured using any relevant test that helps test the jointing ability, such as the four-point bending test (ASTM D790).

[0269] Exemplary linked polymers include, but are not limited to, cellulose phthalate acetate, cellulose succinate acetate, methylcellulose phthalate, ethyl hydroxycellulose phthalate, polyvinyl phthalate acetate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymers, styrene-maleic acid monoester copolymers, methacrylic acid-methyl methacrylate copolymers, methyl acrylate-methacrylic acid copolymers, methacrylate-methacrylic acid-octyl acrylate copolymers, and copolymers, mixtures, formulations, and combinations thereof. Some enteric polymers that can be used in the present invention are shown in the Table of Enteric Polymers along with their dissolution pH. (See Mukherji, Gour and Clive G. Wilson, "Enteric Coating for Colonic Delivery," Chapter 18 of Modified-Release Drug Delivery Technology (editors Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts), Drugs and the Pharmaceutical Sciences (Volume 126, New York. Marcel Dekker, 2002). Preferably, an enteric polymer that dissolves at a pH not exceeding about 5 or about 5.5 is used. Poly(methacrylate-co-ethyl acrylate) (marketed under the trade name EUDRAGIT L 100-55; EUDRAGIT is a registered trademark of Evonik Rohm GmbH, Darmstadt, Germany) is a preferred enteric polymer. Another preferred enteric polymer is hydroxypropyl methylcellulose succinate acetate (hypromellose acetate succinate or HPMCAS; Ashland, Inc., Covington, It is from Kentucky, USA, and has an adjustable pH cutoff of approximately 5.5 to 7.0. Cellulose phthalate acetate, cellulose succinate acetate, and hydroxypropyl methylcellulose phthalate are also suitable enteric-coated polymers.

[0270] In one embodiment, the enteric polymer used in the gastric retention system dissolves at a pH greater than approximately 4. In another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH greater than approximately 5. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH greater than approximately 6. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH greater than approximately 7. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH greater than approximately 7.5. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH of approximately 4 to approximately 5. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH of approximately 4 to approximately 6. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH of approximately 4 to approximately 7. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH of approximately 4 to approximately 7.5. In yet another embodiment, the enteric polymer used in the gastric retention system dissolves at a pH of approximately 5 to approximately 6. Depending on the embodiment, the enteric-coated polymer used in the gastric retention system dissolves at a pH of approximately 5 to approximately 7. Depending on the embodiment, the enteric-coated polymer used in the gastric retention system dissolves at a pH of approximately 5 to approximately 7.5. Depending on the embodiment, the enteric-coated polymer used in the gastric retention system dissolves at a pH of approximately 6 to approximately 7. Depending on the embodiment, the enteric-coated polymer used in the gastric retention system dissolves at a pH of approximately 6 to approximately 7.5. [Table 5]

[0271] A further preferred polymer to be used as a linking polymer is a time-dependent polymer, i.e., a polymer that degrades in a time-dependent manner in the gastric environment. For example, the liquid plasticizer triacetin is released from the polymer formulation in a time-dependent manner over 7 days in simulated gastric juice, while Plastoid B retains its strength over 7 days in simulated gastric juice. Therefore, a time-dependently degrading polymer can be easily prepared by mixing Plastoid B and triacetin. The degradation time of the Plastoid B-triacetin mixture can be extended by increasing the amount of Plastoid B used in the mixture (i.e., using less triacetin in the mixture), and the degradation time can be shortened by decreasing the amount of Plastoid B used in the mixture (i.e., using more triacetin in the mixture).

[0272] Various time-dependent mechanisms can be utilized. Water-soluble time-dependent polymers decompose when water penetrates the polymer. Examples of such polymers include hydroxypropyl methylcellulose and polyvinyl acetate. Acid-soluble time-dependent polymers decompose over time in an acidic environment. An example is Eudragit EPO. Time-dependent polymers may also utilize water-soluble plasticizers. Once the plasticizer is released, the remaining polymer becomes brittle and decomposes under the force of water. Examples of such polymers include triacetin and triethyl citrate.

[0273] In some embodiments, the polymer-drug component is an arm composed of segments linked by an enteric polymer. In some embodiments, the polymer-drug component is attached to the elastomeric component of the system by an enteric polymer. In any of these embodiments, when the enteric polymer is used for both the attachment between segments and the attachment of the arm to the elastomeric component, the enteric polymer used for the attachment between segments may be the same enteric polymer as the enteric polymer used for the attachment of the arm to the elastomeric component, or the enteric polymer used for the attachment between segments may be a different enteric polymer from the enteric polymer used for the attachment of the arm to the elastomeric component. The enteric polymers used for the attachment between segments may all be the same enteric polymer, or they may all be different enteric polymers, or some of the enteric polymers for the attachment between segments may be the same and some may be different. That is, the enteric polymer used for each attachment between segments and the enteric polymer used for the attachment of the arm to the elastomeric component can be selected independently.

[0274] In some embodiments, the polymer-drug component is an integral arm attached to the elastomeric component of the system by an enteric polymer, a time-dependent linker, or a disintegrating matrix, or by any combination of an enteric polymer, a time-dependent linker, and / or a disintegrating matrix.

[0275] In any of the gastric retention systems described herein, the linking polymer or linker may contain hydroxypropyl methylcellulose succinate acetate (HPMCAS) and polycaprolactone (PCL). These formulations can be used to form a disintegrating linker or disintegrating substrate. The HPMCAS:polycaprolactone ratio in the disintegrating linker or disintegrating substrate is approximately 80% HPMCAS:20% PCL to approximately 20% HPMCAS:80% PCL. The HPMCAS:polycaprolactone ratio is approximately 80% HPMCAS:20% PCL, approximately 20% HPMCAS:80% PCL, approximately 70% HPMCAS:30% PCL, approximately 30% HPMCAS:70% PCL, approximately 60% HPMCAS:40% PCL, approximately 40% HPMCAS:60% PCL, approximately 80% HPMCAS:20% PCL, approximately 50% HPMCAS:50% PCL, approximately 80% HPMCAS:20% PCL, approximately 60% HPMCAS:40% PCL, approximately 70% HPMCAS:30% PCL, approximately 50% HPMCAS:50% PCL, approximately 70% HPMCAS:30% PCL, approximately 60% HPMCAS:40% PCL, approximately 20% HPMCAS:80% PCL, approximately 40% HPMCAS:60% PCL, approximately 20% HPMCAS:80% PCL to approximately 50% HPMCAS:50% PCL, approximately 30% HPMCAS:70% PCL to approximately 40% HPMCAS:60% PCL, approximately 30% HPMCAS:70% PCL to approximately 50% HPMCAS:50% PCL, or approximately 80% HPMCAS:20% PCL, approximately 70% HPMCAS:30% PCL, approximately 60% HPMCAS:40% PCL, approximately 50% HPMCAS:50% PCL, approximately 40% HPMCAS:60% PCL, approximately 30% HPMCAS:70% PCL, or approximately 20% HPMCAS:80% PCL.The linker may further contain a plasticizer selected from the group consisting of triacetin, triethyl citrate, tributyl citrate, poloxamer, polyethylene glycol, polypropylene glycol, diethyl phthalate, dibutyl sebacate, glycerin, castor oil, acetyl triethyl citrate, acetyl tributyl citrate, polyethylene glycol monomethyl ether, sorbitol, sorbitan, sorbitol-sorbitan mixtures, and diacetylated monoglycerides.

[0276] The linker is selected to weaken sufficiently after a specified period of time, or to weaken so that the gastric retention system can no longer be retained in the stomach, in order to reach a point where it can break down and pass through the pylorus and leave the stomach after a desired retention period. That is, the linker weakens to a point where the linkage is broken (separation point) or a point where the gastric retention system can pass through the pylorus (pyloric passage point, or passage point). Thus, in one embodiment, a linker is used that separates in the human stomach after about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, or about 2 weeks. In one embodiment, a linker is used that separates in the stomach of a dog after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks. In another embodiment, a linker is used that separates in the stomach of a pig after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks. In one embodiment, a linker is used that separates in simulated gastric juice under fasting conditions after approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days, or approximately 2 weeks. In one embodiment, a linker is used that separates in simulated gastric juice under feeding conditions after approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days, or approximately 2 weeks.In one embodiment, a linker is used that separates in pH 2 water after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks. In another embodiment, a linker is used that separates in pH 1 water after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks.

[0277] In humans, dogs, or pigs, the separation or pyloric passage point occurs when the system leaves the stomach, i.e., when it passes through the pylorus. In in vitro measurements with simulated gastric fluid or acidic water, the separation or pyloric passage point occurs when the linker weakens to the point where it breaks under the normal compressive force of the stomach (typically about 0.1 to 0.2 Newtons). The linkage strength (breaking point) can be measured by any relevant test that helps test the linkage ability, i.e., the force required to break the linker, 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 / 100367. In one embodiment, the separation or pyloric passage point is reached when the linker separates with a force of about 0.2 N. In another embodiment, the separation or pyloric passage point is reached when the linker separates with a force of about 0.1 N.

[0278] The gastric retention system may reach the pyloric passage point without any linkers actually rupturing. If the linkers weaken or break down to the point where they can no longer hold the gastric retention system in the stomach, the gastric retention system passes through the pylorus and into the small intestine (pyloric passage point or passage point), even if one, some, or all of the linkers do not rupture. Depending on the embodiment, linkers are used that weaken to the passage point after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks in the human stomach. Depending on the embodiment, a linker is used that weakens to a passpoint after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks in the stomach of a dog. Depending on the embodiment, a linker is used that weakens to a passpoint after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks in the stomach of a pig. Depending on the embodiment, a linker is used that weakens to a pass point after approximately 2 days in a fasted state of simulated gastric juice, approximately 3 days in a fasted state of simulated gastric juice, approximately 4 days in a fasted state of simulated gastric juice, approximately 5 days in a fasted state of simulated gastric juice, approximately 6 days in a fasted state of simulated gastric juice, approximately 7 days in a fasted state of simulated gastric juice, approximately 8 days in a fasted state of simulated gastric juice, approximately 9 days in a fasted state of simulated gastric juice, approximately 10 days in a fasted state of simulated gastric juice, or approximately 2 weeks in a fasted state of simulated gastric juice. Depending on the embodiment, a linker is used that weakens to a pass point after approximately 2 days in simulated gastric juice under feeding conditions, approximately 3 days in simulated gastric juice under feeding conditions, approximately 4 days in simulated gastric juice under feeding conditions, approximately 5 days in simulated gastric juice under feeding conditions, approximately 6 days in simulated gastric juice under feeding conditions, approximately 7 days in simulated gastric juice under feeding conditions, approximately 8 days in simulated gastric juice under feeding conditions, approximately 9 days in simulated gastric juice under feeding conditions, approximately 10 days in simulated gastric juice under feeding conditions, or approximately 2 weeks in simulated gastric juice under feeding conditions.Depending on the embodiment, a linker is used that weakens to its passpoint after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks in pH 2 water. Depending on the embodiment, a linker is used that weakens to its passpoint after approximately 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 2 weeks in pH 2 water. Filaments to improve gastric retention

[0279] The following is a description of a filament-equipped intragastric retention system. As will be described in detail below, the filament in a filament-equipped intragastric retention system helps prevent the intragastric retention system from passing through the patient's pylorus prematurely. Therefore, the filament and filament-equipped intragastric retention system described herein help improve the effectiveness and reliability of the intragastric retention system.

[0280] A gastric retention system with a filament can prevent the gastric retention system from passing through the patient's pylorus prematurely. Described herein is a gastric retention system that includes a filament that helps minimize the risk of the gastric retention system passing through the patient's pylorus prematurely.

[0281] The filaments may be attached to the distal ends of the arms of the intragastric retention system. Figures 4A and 4B show how the inclusion of filaments affects the most common bending and passage modes of an intact intragastric retention system through the pylorus. In particular, the filaments can prevent, for example, one or two arms from entering the pylorus prematurely. The filaments also maintain the spacing between the arms, alter the bending shape, and increase the force required to compress the intragastric retention system into a configuration small enough to pass through the pylorus prematurely.

[0282] For example, the intragastric retention system 400a in Figure 4A includes a central core 402a and multiple arms. As shown, each arm 404a of the multiple arms extends radially from the central core 402. Each arm 404 is attached to the core 402a at its proximal end. A filament 406a is shown attached to the distal end of each arm 404a. Figure 4A shows the intragastric retention system 400a in an open configuration. As shown, when the intragastric retention system 400a remains in an open configuration, the filament 406a helps prevent the intragastric retention system 400a from passing through the pylorus prematurely.

[0283] Figure 4B shows a curved configuration of the intragastric retention system 400b. The intragastric retention system 400b includes a core 402b, an arm 404b, and a filament 406b. As shown, even if the intragastric retention system 400b is curved in a configuration that allows it to pass through the patient's pylorus early (see Figure 3B), the filament 406b can help prevent the device from passing through. In particular, the filament 406b is flexible and stretchable so that it can maintain its integrity despite the gastric forces that may bend or distort the intragastric retention system 400b.

[0284] In some embodiments, the intragastric retention system may include a tip located at the distal end of one or more arms. The tip may be composed of an enteric polymer composition. Filaments may be connected to each arm via the distal tip. The tip may be configured to separate from the rest of the arm when in the gastric environment. In particular, the tip may be configured to separate from the arm, allowing the filament to separate from the intragastric retention system as well. This separation can be fine-tuned so that the tip and filament separate as a predetermined intragastric retention time approaches completion, and the intragastric retention system separates and passes through the patient's pylorus at the completion of the predetermined intragastric retention time. If the tip and / or filament separate too early, there is a risk that the intragastric retention system will pass through the patient's pylorus prematurely.

[0285] Depending on the embodiment, the arm tip may contain one or more polymers, enteric coatings, plasticizers, and acids. Suitable polymers may include polycaprolactone and / or thermoplastic polyurethane (e.g., Lubrizol's Pathway®). Depending on the embodiment, the composition of the arm tip may be the same as that of the linker component. Depending on the embodiment, the composition of the arm tip may be different from that of the linker component. Depending on the embodiment, the arm tip may contain 10 to 50% by weight of polymer. Depending on the embodiment, 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. Depending on the embodiment, 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.

[0286] Depending on the embodiment, the enteric material at the tip of the arm may be composed of an enteric polymer. For example, suitable enteric polymers include cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, polyphthalate acetate, methacrylic acid-methyl methacrylate copolymer (1:1), methacrylic acid-methyl methacrylate copolymer (2:1), methacrylic acid-ethyl acrylate copolymer (2:1), shellac, (acetic acid / succinate) hydroxypropyl methylcellulose, poly(methyl vinyl ether / maleic acid) monoethyl ester, or poly(methyl vinyl ether / maleic acid) n-butyl ester. Depending on the embodiment, the tip of the arm may contain 20 to 90% by weight of the enteric material. Depending on the embodiment, the tip of the arm may contain 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. Depending on the embodiment, the tip of the arm 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-coated material.

[0287] Suitable plasticizers include propylene glycol, P407, triethyl citrate, triacetin, dibutyl sebacate, and / or polyethylene glycol. Depending on the embodiment, the arm tip may contain 1 to 20% by weight of the plasticizer. Depending on the embodiment, 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 the plasticizer. Depending on the embodiment, 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 the plasticizer.

[0288] Suitable acids may include stearic acid or other fatty acids. Depending on the embodiment, the arm tip may contain 1 to 20% by weight or 1 to 10% by weight of acid. Depending on the embodiment, 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 acid. Depending on the embodiment, 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 acid.

[0289] Figures 5A and 5B show two different configurations of an intragastric retention system with filaments connected to a tip at the distal end of each arm. In particular, Figure 5A shows an intragastric retention system 500a including a core 502a and six arms 504a. Each arm 504a includes a tip 510a at its distal end. In some embodiments, each arm 504a may be connected to the core 502a via a linker 512a. As shown, a filament 508a connects each arm 504a at its tip 510a. In some embodiments, a single filament 508a may be wound circumferentially around the intragastric retention system 500a and connected to each arm at its tip 510a. In some embodiments, multiple filaments 508a may connect each arm 504a of the intragastric retention system 500a.

[0290] Figure 5B shows an intragastric retention system 500b having a core 502b, six arms 504b, and a tip 510b at the distal end of each arm 504b. Unlike the intragastric retention system 500a in Figure 5A, this intragastric retention system 500b includes a linker 512b connecting the arms 504b to the core 502b and another linker 512b connecting two segments of the arms 504b. As shown, a filament 508b connects each arm 504b at its tip 510b. In some embodiments, a single filament 508b may be wound circumferentially around the intragastric retention system 500a and connected to each arm at its tip 510a. In some embodiments, multiple filaments 508b may connect each arm 504b of the intragastric retention system 500b.

[0291] To improve gastric retention, the filaments may contain elastic polymers and / or bioabsorbable polymers.

[0292] Suitable elastic polymers include polyurethanes (Lubrizol Pellethane, Pathways, Tecoflex, carbonhane), polyamide-polyether block copolymers (Pebax), poly(ethylene-co-vinyl acetate) (PEVAc), vinyl acetate, silicones, and / or combinations thereof. Depending on the embodiment, the filament may contain 10-90% by weight, 20-80% by weight, or 30-70% by weight of the elastic polymer. Depending on the embodiment, the filament may contain 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, less than 30% by weight, or less than 20% by weight of the elastic polymer. Depending on the embodiment, 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 the elastic polymer.

[0293] Suitable bioabsorbable polymers include poly(lactic acid-co-glycolic acid) (PLGA), polycaprolactone (PCL), polylactic acid (PLA), PCL-PLA copolymer, polydioxanone, polytrimethylene carbonate, PCL-polyglycolic acid copolymer, polyglycerol polysebacate, anhydride polymers, polyphosphazene, alkyl polycyanoacrylate, polyamino acids, propylene polyfumarate, and / or combinations thereof. Depending on the embodiment, the filament may contain 10-90% by weight, 20-80% by weight, or 30-70% by weight of the bioabsorbable polymer. Depending on the embodiment, the filament may contain 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, less than 30% by weight, or less than 20% by weight of the bioabsorbable polymer. Depending on the embodiment, the filament contains 10% by weight or more, 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 a bioabsorbable polymer.

[0294] In some embodiments, the filament may contain a plasticizer. For example, suitable plasticizers may include propylene glycol, P407, triethyl citrate, triacetin, dibutyl sebacate, and / or polyethylene glycol. In some embodiments, the filament may contain 0.1 to 20% by weight of a plasticizer, or 1 to 10% by weight of a 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 a 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 a plasticizer.

[0295] The length of the filament can be measured as the length between each arm, or, in embodiments including a single filament wrapping around the periphery of the intragastric retention system, as the total length of the filament wrapped around the periphery. In any case, the length of the filament depends on the size of the intragastric retention system and the number of arms. For example, in the case of a star-shaped intragastric retention system including six arms, the length of a single circumferentially wound filament may be 100-150 mm, 110-140 mm, or 120-130 mm. Also, the length of the filament between any two adjacent arms of the six arms may be 18-24 mm or 20-22 mm.

[0296] In some embodiments, the filament made from the pelletan tube may be stretched between two adjacent arms to create tension in the filament between the arms. If the star-shaped intragastric retention system includes six arms, the length of a single circumferentially wound filament containing the pelletan tube may be 90–130 mm or 100–120 mm. The length of the filament between any two adjacent arms of the six arms can be 18–22 mm.

[0297] The cross-sectional shape of the filament may include, but is not limited to, a circle, ellipse, rectangle, or annular shape. The thickness, or diameter, of the filament may be 100 to 1000 microns, preferably 200 to 400 microns. Depending on the embodiment, the thickness, or diameter, of the filament may be less than 1000 microns, less than 800 microns, less than 600 microns, less than 400 microns, or less than 200 microns. Depending on the embodiment, the thickness, or diameter, of the filament may be greater than 100 microns, greater than 200 microns, greater than 400 microns, greater than 600 microns, or greater than 800 microns.

[0298] In some embodiments, including a filament having a rectangular cross-section, the width of the filament (i.e., the longer side of the rectangular cross-section measurement) may be between 1 and 4 mm. In some embodiments, the width may be less than 4 mm, less than 3 mm, or less than 2 mm. In some embodiments, the width may be greater than 2 mm, greater than 3 mm, or greater than 4 mm.

[0299] The force required to compress a filamented intragastric retention system can be quantified using the radial compression test described in detail in the "Test Method" section below. Depending on the embodiment, the force required to compress a filamented intragastric retention system may be 1.25 to 5 times the force required to compress an intragastric retention system without a filament to the same compression diameter. Depending on the embodiment, the force required to compress a filamented intragastric retention system may be less than 5 times, less than 4 times, less than 3 times, or less than 2 times the force required to compress an intragastric retention system without a filament to the same compression diameter. Depending on the embodiment, the force required to compress a filamented intragastric retention system may be more than 1.25 times, more than 2 times, more than 3 times, or more than 4 times the force required to compress an intragastric retention system without a filament to the same compression diameter.

[0300] The force required to separate the filament from the arm tip can be quantified using the pull-out force test, which is described in detail in the "Test Method" section below. Depending on the embodiment, the force required to separate the filament from its corresponding arm tip may be 0.5 to 10 N or 2 to 6 N. Depending on the embodiment, the force required to separate the filament from its corresponding arm tip may 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. Depending on the embodiment, the force required to separate the filament from its corresponding arm tip may 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. Depending on the embodiment, the force required to separate the filament from its corresponding arm tip may decrease as the gastric retention system remains in the gastric environment longer.

[0301] In some embodiments, the force required to separate a filament from its corresponding arm tip may depend on the method used to secure the end of the filament (i.e., knot, heating, or no secured 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 force required to separate a filament with a knotted end, and the force 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 (i.e., unsecured) filament from its corresponding arm tip. Intragastric retention system including arms with adjusted rigidity

[0302] Depending on the embodiment, the gastric retention system described herein may further include an arm having an adjusted diameter to prevent the gastric retention system from passing through the patient's pylorus too quickly.

[0303] By controlling the stiffness of the elements (e.g., arms) of the intragastric retention system that expand / extend the device to its open configuration, the risk of premature passage of the intragastric retention system through the pylorus can be minimized. Therefore, an intragastric retention system with controlled stiffness arms helps to improve the efficacy and reliability of the intragastric retention system. Furthermore, an intragastric retention system with controlled stiffness arms can help prevent the intragastric retention system from bending into a configuration that allows it to pass through the pylorus prematurely.

[0304] A gastric retention system with controlled rigidity arms requires more force to bend into a configuration suitable for premature passage through the pylorus. The description relates to a gastric retention system with controlled rigidity of any member that can widen or expand the gastric retention system into its open configuration (e.g., arms) to help minimize the risk of the gastric retention system prematurely passing through the patient's pylorus.

[0305] A gastric retention system having controlled rigidity arms is defined as a system comprising one or more arms having at least a portion of an arm made of a flexible material. Depending on the embodiment, one or more arms may comprise a first segment comprising a first polymer composition and a second segment comprising a second polymer composition, the second segment being more flexible than the first segment.

[0306] In some embodiments, one or more arms extend radially. The proximal ends of one or more arms may be connected to a core. In some embodiments, the intragastric retention system may include a plurality of radially extending arms. In some embodiments, the intragastric retention system may include a plurality of arms connected to a core at the proximal end of each arm, with the plurality of arms extending radially from the core. In some embodiments, the intragastric retention system may include a plurality of arms, each arm may include a first segment and a second segment.

[0307] The first polymer composition of the flexible arm of the gastric retention system may include relatively rigid polymers. For example, suitable polymers may include polycaprolactone, polylactic acid, poly(lactic acid-co-glycolic acid), HPMCAS, high-rigidity TPU, and / or combinations thereof. Other examples include hydrophilic cellulose derivatives (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium-carboxymethylcellulose), cellulose phthalate acetate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymer, polyvinyl alcohol, carboxyvinyl polymer (carbomer), acidic carboxypolymer Carbopol®, polycarbophil, polyethylene oxide (Polyox WSR),Polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycol, chitosan, arginate, pectin, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidone-vinyl acetate copolymer, dextran, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, fercellaran, laminaran, hypnea, euthuma, acacia gum, gatti gum, karaya gum, albinogratan, amylopectin, gelatin, gellan, hyaluronic acid, pullulan, scleroglucan, xane, xyloglucan, maleic anhydride copolymer, ethylene maleic anhydride copolymer, polyhydroxyethyl methacrylate, ammoniacease copolymer (e.g., Eudragit RL or Eudragit RS), poly(ethyl acrylate-methyl methacrylate) (Eudragit NE), Eudragit E (cationic copolymer based on dimethylaminoethylmethyl acrylate and neutral methylacrylic acid ester), polymethacrylate / polyethacrylate (e.g., polymethacrylate, methyl methacrylate, and ethyl acrylate), polymethacrylate / polyethacrylate, polylactones such as polycaprolactone, anhydride polymers such as poly[bis-(p-carboxyphenoxy)-propane anhydride], polyterephthalic acid anhydride, polypeptides such as polylysine and polyglutamic acid, polyorthoesters, polyorthoesters such as copolymers of DETOSU with diols such as hexanediol, decanediol, cyclohexanedimethanol, ethylene glycol, polyethylene glycol, and other polyorthoesters incorporated herein by reference, U.S. 4,304,This includes the polyorthoesters described and disclosed in Patent No. 767, starches, particularly pre-gelatinized starches, and starch polymers, carbomers, maltodextrins, amylomaltodextrins, dextrans, poly(2-ethyl-2-oxazoline), polyethyleneimines, polyurethanes, polylactic acid, polyglycolic acid, poly(lactic acid-co-glycolic acid) (PLGA), polyhydroxyalkanoates, polyhydroxybutyrates, and copolymers, mixtures, blends, and combinations thereof. Depending on the embodiment, the first segment may include one or more therapeutic agents or active pharmaceutical ingredients (APIs).

[0308] In some embodiments, the first polymer composition may contain 10 to 90% by weight or 50 to 70% by weight of polycaprolactone. In some embodiments, the first polymer composition may contain 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, less than 30% by weight, or less than 20% by weight of polycaprolactone. In some embodiments, the first 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, more than 70% by weight, or more than 80% by weight of polycaprolactone.

[0309] Depending on the embodiment, the first polymer composition may contain 10 to 90% by weight or 30 to 70% by weight of a therapeutic agent or API. Depending on the embodiment, the first polymer composition may contain 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, less than 30% by weight, or less than 20% by weight of a therapeutic agent or API. Depending on the embodiment, the first 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, more than 70% by weight, or more than 80% by weight of a therapeutic agent or API.

[0310] The second polymer composition of the arm of the intragastric retention system disclosed herein may include a first polymer that is flexible relative to the polymer of the first polymer composition. For example, suitable relatively "flexible" polymers may include one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastomer, thermoplastic polyurethane, polycaprolactone polylactic acid copolymer, polytrimethylene carbonate, polyglycerol polysebacate, polyethylene-co-vinyl acetate, and silicone. Depending on the embodiment, the second polymer composition of the arm may actually include the same first polymer as the first polymer composition. For example, the second polymer composition may include polycaprolactone. However, unlike the first polymer composition, the second polymer composition may further include a soluble material (e.g., copovidone, poloxamer). Thus, upon hydration (e.g., in the stomach), the second polymer composition softens, and the stiffness of the second polymer composition of the second segment is lower than that of the first polymer composition of the first segment. Suitable commercially available polymers include Pathway® TPU polymer (The Lubrizol Corporation), Tecoflex® (The Lubrizol Corporation), Tecophilic® (The Lubrizol Corporation), Carbonhatane® (The Lubrizol Corporation), Isoplast® (The Lubrizol Corporation), Pebax® (Arkema), Texin® (Covestro), Chronoflex (AdvanSource Biomaterials), NEUSoft® (PolyOne), and Medalist® TPEs (Teknor Apex).

[0311] Depending on the embodiment, the second polymer composition may contain 10 to 90% by weight or 40 to 70% by weight of the primary polymer. Depending on the embodiment, the second polymer composition may contain 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, less than 30% by weight, or less than 20% by weight of the primary polymer. Depending on the embodiment, 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, more than 70% by weight, or more than 80% by weight of the primary polymer.

[0312] Depending on the embodiment, the second polymer composition may additionally contain one or more water-soluble excipients (which may include one or more polymers relative to the first polymer described above). For example, suitable water-soluble excipients include copovidone, poloxamer, and / or polyethylene oxide. Suitable commercially available water-soluble excipients include Kolliphor P407 (poloxamer 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), Coridone VA64 (vinylpyrrolidone-vinyl acetate copolymer in a mass ratio of 6:4), and polyvinylpyrrolidine.

[0313] The second polymer composition may contain 5 to 70% by weight or 10 to 40% by weight of a water-soluble excipient. Depending on the embodiment, 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 a water-soluble excipient. Depending on the embodiment, 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 a water-soluble excipient.

[0314] Depending on the embodiment, the second polymer composition may contain additional excipients. For example, the second polymer composition may contain bismuth carbonate, silica, vitamin E succinate, iron oxide, polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam graft copolymer (Soluplus®), sodium starch glycolate, and / or hydroxypropyl cellulose. Depending on the embodiment, the second polymer composition may contain 10 to 70% by weight or 20 to 50% by weight of excipients. Depending on the embodiment, 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. Depending on the embodiment, 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.

[0315] Depending on the embodiment, the second polymer composition may further 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. Depending on the embodiment, 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. Depending on the embodiment, 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.

[0316] Polymer materials useful for creating arms with controlled rigidity sometimes offer additional advantages in terms of thermal stability. For example, intragastric retention systems can be subjected to temperature changes during shipping and distribution. Shipping data suggests that extreme fluctuations in cargo temperature can approach 60°C in certain climates (Singh et al, Packag.Technol.Sci. 2012; 25: 149-160). Polymers constituting intragastric retention systems must be physically stable at this temperature if shipped without cold chain packaging or storage.

[0317] Polycaprolactone is a preferred polymer for relatively rigid arms (or rigid / first segment), while thermoplastic polyurethanes are preferred polymers for creating arms with controlled rigidity (i.e., second segment). Polycaprolactone-based arms are physically stable even when exposed to high temperatures of 55°C, but melt when they reach 60°C. When stored in capsules, the arms that begin to melt can stick together, preventing the gastric retention system from unfolding in the stomach. Suitable polymers may include customizable thermoplastic polyurethanes with a hardness range of 62A to 83D, such as Pathway® TPU polymer (The Lubrizol Corporation). Thermoplastic polyurethanes such as Pathway PY-PT72AE improve thermal stability. Pathway PY-PT72AE is an amorphous material and does not undergo a clear melt transition, but it softens at high temperatures.

[0318] When a gastric retention system, which includes relatively rigid arms, is compressed (for example, by gastric peristalsis or radial compression testing), the compressive force is transmitted to the more flexible core of the gastric retention system, causing it to bend into a configuration that allows it to pass through the patient's pylorus (i.e., a 20 mm diameter opening).

[0319] Conversely, when an intragastric retention system containing a relatively flexible arm (i.e., having a first segment and a second segment) is compressed, the second segment absorbs part of the compressive force. Therefore, the compressive force is not transmitted to the core of the intragastric retention system with a relatively flexible arm in the same way as in the case of an intragastric retention system with a relatively rigid arm. A greater force is required to compress the rigid inner segment of the arm to the size of the pylorus, because the lever arm attached to the flexible core is short. This may mean that an intragastric retention system with a relatively flexible arm requires a greater compressive force to bend it into a configuration small enough to pass through the patient's pylorus (i.e., a 20 mm diameter opening).

[0320] As the second segment of the arm of an intragastric retention system with a rigidity-adjusted arm becomes longer than the first segment, the compressive force required to compress the intragastric retention system into a fold configuration small enough to pass through the pylorus (i.e., a 20 mm diameter opening) also increases (only if the length of the rigid inner portion and core is greater than the diameter of the pylorus).

[0321] The ratio of the first segment of the relatively flexible arm to the second segment of the arm may be changed. If the first segment is too large compared to the second segment, the compressive force may be transmitted too quickly to the core of the intragastric retention system, potentially compressing the system into a curved configuration large enough to allow it to pass through the pylorus prematurely. If the second segment is too large compared to the first segment, the second segment may bend too easily under compressive force, allowing the force to compress the intragastric retention system into a curved configuration large enough to allow it to pass through the pylorus prematurely. In either scenario, the intragastric retention system is not expected to have the effect of preventing premature passage through the pylorus.

[0322] The effective ratio of the first segment to the second segment of the flexible arm of the gastric retention system may be varied. In some embodiments, the first segment may constitute 10 to 90% of the arm length (measured from the proximal end to the distal end). In some embodiments, the first segment may constitute 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 may constitute 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more of the arm length. In some embodiments, the second segment may constitute 10 to 90% of the arm length (when measured from the proximal end to the distal end). Depending on the embodiment, the second segment may comprise 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. Depending on the embodiment, the second segment may comprise 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more of the arm length. System polymer composition

[0323] The selection of individual polymers for the supported polymer, linking polymer, and elastic material affects many properties of the system, such as the drug dissolution rate (dependent on the supported polymer and other factors), the residence time of the system (dependent on the degradation of any of the polymers, mainly the linking polymer), the separation time of the system as it passes through the intestines (primarily dependent on the rate of degradation of the linking polymer in the intestines, as described herein), and the shelf life of the system in compressed form (primarily dependent on the properties of the elastic material). Since the system is administered into the gastrointestinal tract, all components of the system must be biocompatible with the gastrointestinal environment.

[0324] The rate of drug dissolution from supported polymer-drug components is influenced by many factors, such as the composition and properties of the supported polymer, which itself may be a mixture of several polymeric or non-polymeric components; the properties of the drug, such as hydrophilic / hydrophobicity, charge state, pKa, and hydrogen bonding ability; and the properties of the gastric environment. In the aqueous environment of the stomach, it is difficult to avoid explosive release of drugs, especially hydrophilic drugs (explosive release refers to a high initial delivery amount of the active pharmaceutical ingredient when the system is first deployed to the stomach) and to maintain a sustained release of the drug over a period of several days to one or two weeks.

[0325] The residence time of the system in the stomach is controlled by the selection of the linking polymer used in the linker region. Even with enteric-coated linking polymers, the system ultimately degrades in the stomach because the stomach's mechanical action and fluctuating pH ultimately weaken the enteric-coated linking polymer. It is also possible to control the time it takes for the system to degrade in the stomach, and thus the residence time, by using linking polymers that degrade in a time-dependent manner. Once the system degrades, it passes through to the intestines and is then excreted.

[0326] The elastic materials used in a system are crucial to its shelf life. When the system is compressed, the elastic materials are subjected to mechanical stress. This stress can further cause polymer creep. If the creep is widespread enough, it can prevent the system from returning to its incompressible configuration when released from the capsule or other container. This, in turn, can lead to the system passing through the stomach more quickly. Since polymer creep is also temperature-dependent, the expected storage conditions of the system must also be considered when selecting the elastic materials and other polymer components.

[0327] The system components and polymers must not swell, or swell minimally, in the gastric environment. During the residence period in the gastric environment, the components should swell by approximately 20% or less, approximately 10% or less, or preferably approximately 5% or less.

[0328] If necessary, the system may be radiopaque, thereby allowing positioning by abdominal radiography. In some embodiments, one or more of the materials used to construct the system are sufficiently radiopaque to be visualized by radiography. In other embodiments, radiopaque material is added to one or more of the materials in the system, coated to one or more of the materials in the system, or added to a small portion of the system. Examples of suitable radiopaque materials are barium sulfate, bismuth subcarbonate, bismuth chloride oxide, and bismuth trioxide. It is preferable not to incorporate these materials into the polymers used to construct the gastric retention system so as not to alter drug release from the supported polymer or other desired properties of the system polymer. Metal striping or tips, such as tungsten, may be used on small portions of the system components. Manufacturing method and treatment method

[0329] The following is a description of various manufacturing and treatment methods. In particular, it includes detailed descriptions of system manufacturing / assembly: 3D printing, system manufacturing / assembly: co-extrusion, drug particle size and grinding, manufacturing method of supported polymer-drug (or drug salt) components, system manufacturing / assembly: attachment of arms to central elastic body, system manufacturing / assembly, manufacturing method of intragastric retention system with filaments, treatment methods using intragastric retention system, and kits and manufactured products. System manufacturing / assembly: 3D printing

[0330] Three-dimensional printing of components of the gastric retention system, such as arms or arm segments, is performed using commercially available equipment. Three-dimensional printing has been used in the preparation of pharmaceuticals (see Khaled et al., “Desktop 3D printing of controlled release pharmaceutical bilayer tablets,” International Journal of Pharmaceutics 461:105-111 (2014); U.S. 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)).

[0331] The initial raw material for 3D printing is a polymer or polymer compound (e.g., enteric polymer, time-dependent polymer, or a compound of a supported polymer, enteric polymer, or time-dependent polymer with one of the following: a drug, drug salt, pharmacokinetic, excipient, etc.). The polymer or component to be used in one area of ​​the segment or arm to be manufactured is mixed and pelletized by hot-melt extrusion. The polymer or compounded polymer material is extruded through a circular mold to produce cylindrical fibers wound on a spool.

[0332] Multiple spools are fed into a 3D printer (such as the Hyrel Printer, available from Hyrel 3D, Norcross, Georgia, USA) and then fed into a typical printhead. The printhead is heated, the material is melted at the nozzle, and thin layers of the material (polymer or polymer compound) are placed at specific locations on the part to be manufactured. The material cools and hardens within seconds, and subsequent layers are added until the complete structure is formed. The quality of the formulation depends on the feeding rate, nozzle temperature, and printer resolution, and the desired quality can be obtained by adjusting the feeding rate and nozzle temperature.

[0333] Individual arms or segments of arms can be manufactured using three-dimensional printing. Bulk structures, such as solidified "slabs," similar to those prepared by the co-extrusion method described herein, can also be prepared using three-dimensional printing. If necessary, the bulk structure may be cut into individual parts (i.e., individual arms or individual segments).

[0334] In some embodiments of the present invention, the entire arm of the intragastric retention system may be fabricated by three-dimensional printing of the arm. In some embodiments of the present invention, segments of the arm of the intragastric retention system may be fabricated by three-dimensional printing of the arm segments. In some embodiments, the arm or segments are fabricated by three-dimensional printing of adjacent portions of a bulk structure, such as a thick plate, consisting of a supported polymer-drug or supported polymer-drug salt compound and a linker material. Following three-dimensional printing, the bulk structure may be cut into pieces having the desired shape of the arm or segments. Following three-dimensional printing, a portion of the bulk structure may be compression-molded into pieces having the desired shape of the arm or segments.

[0335] Three-dimensional printing is often achieved by feeding a rod or fiber of solid material into a printhead, where it is melted and deposited using a technique known as fusion deposition (sometimes called extrusion deposition), and then allowed to solidify (see U.S. Patents 5,121,329 and 5,340,433). The methods described herein for the manufacture of supported polymer-drug components can also be used to produce feed materials that can be used for the three-dimensional printing of components of the gastric retention system. System manufacturing / assembly: Co-extrusion

[0336] Components of the gastric retention system may be manufactured by co-extrusion. Most of the various segment configurations described herein (such as island-in-the-sea configurations) can be manufactured by both 3D printing and co-extrusion. However, co-extrusion is less expensive and can be carried out in a continuous process, unlike 3D printing which is generally performed in a batch process.

[0337] Co-extrusion of "sea-island" structures is used in the textile industry and for the fabrication of optical fibers, but has little application in biomedical systems. See U.S. Patents 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).

[0338] Commercially available equipment can be used in combination with dedicated co-extrusion piping and molds for the desired configuration to co-extrude components of the gastric retention system, such as arms or segments of arms. The initial feed material for co-extrusion is a polymer or polymer compound (e.g., enteric polymer, time-dependent polymer, or a compound of a supported polymer, enteric polymer, or time-dependent polymer with one of the following: a drug, drug salt, pharmacologic agent, excipient, etc.). The polymer or component to be used for one region of the segment or arm to be manufactured is mixed and pelletized by hot-melt extrusion. The polymer pellets thus formed are placed in a hopper on a single-screw extruder and dried to remove surface moisture. The pellets are weighed and fed into individual single-screw extruders, where they are melted and pressurized for co-extrusion.

[0339] Next, the appropriate molten polymer is pumped into a specially designed mold having multiple channels to form the required shape. The composite polymer block is cooled (water-cooled, air-cooled, or both) and cut or molded into the desired shape (such as, but not limited to, triangular prisms, prismatic prisms, or cylindrical fragments (pi-shaped wedges)).

[0340] In some embodiments of the present invention, the entire arm of the intragastric retention system may be manufactured by co-extrusion of the arm. In some embodiments of the present invention, segments of the arm of the intragastric retention system may be manufactured by co-extrusion of the arm segments. In some embodiments, an arm or segment is manufactured by co-extruding adjacent portions of a bulk composition such as a thick plate, consisting of a supported polymer-pharmaceutical or supported polymer-pharmaceutical salt compound and a linker material. Following co-extrusion, the bulk composition may be cut into pieces having the desired shape of the arm or segment. Following co-extrusion, a portion of the bulk composition may be compression-molded into pieces having the desired shape of the arm or segment. Depending on the embodiment, adjacent portions of a supported polymer-agent or supported polymer-agent salt compound and linker material are co-extruded in a bulk configuration such as a plate configuration, while additional polymers contained in both the supported polymer-agent or supported polymer-agent salt compound, linker material, or supported polymer-agent (or agent salt) compound and linker material are also co-extruded to produce an arm or segment thereof. The co-extrusion of additional polymers with both the supported polymer-agent or supported polymer-agent salt compound, linker material, or supported polymer-agent (or agent salt) compound and linker material may be carried out in a sea-island configuration. Following co-extrusion, the bulk configuration may be cut into pieces having the desired shape of an arm or segment thereof. Following co-extrusion, a portion of the bulk configuration may be compression-molded into pieces having the desired shape of an arm or segment thereof. Drug particle size and grinding

[0341] Adjusting the particle size used in intragastric retention systems is crucial for both optimal drug release and the mechanical stability of the system. Drug particle size affects the surface area of ​​the drug available for dissolution when gastric juice penetrates the system's supported polymer-drug segment. Furthermore, because the system's arms are relatively small in diameter (e.g., 1-5 mm), the presence of drug particles larger than a few percent of the arm diameter weakens the arms, both before drug elution from the device and after elution, leaving voids in the spaces previously occupied by the drug particles. Such arm weakening is undesirable as it can lead to premature rupture and passage of the system before the desired retention period is complete.

[0342] In one embodiment, the drug particles used to be incorporated into the supported polymer-drug component are smaller than approximately 100 microns in diameter. In another embodiment, the drug particles are smaller than approximately 75 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 50 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 40 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 30 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 25 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 20 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 10 microns in diameter. In yet another embodiment, the drug particles are smaller than approximately 5 microns in diameter.

[0343] In one embodiment, at least about 80% of the drug particles used to be incorporated into the supported polymer-drug component are smaller than about 100 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 75 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 50 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 40 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 30 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 25 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 20 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 10 microns in diameter. In another embodiment, at least about 80% of the drug particles are smaller than about 5 microns in diameter.

[0344] In one embodiment, at least about 80% of the mass of drug particles used to be incorporated into the supported polymer-drug component has a diameter of about 1 to about 100 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 75 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 50 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 40 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 30 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 25 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 20 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 1 to about 10 microns. In another embodiment, at least about 80% of the mass of the drug particles have a size of about 1 to 5 microns in diameter.

[0345] In one embodiment, at least about 80% of the mass of drug particles used to be incorporated into the supported polymer-drug component has a diameter of about 2 to about 100 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 75 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 50 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 40 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 30 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 25 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 20 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 2 to about 10 microns. In another embodiment, at least about 80% of the mass of the drug particles have a size of about 2 to 5 microns in diameter.

[0346] In one embodiment, at least about 80% of the mass of drug particles used to be incorporated into the supported polymer-drug component has a diameter of about 5 to about 100 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 75 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 50 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 40 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 30 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 25 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 20 microns. In another embodiment, at least about 80% of the mass of drug particles has a diameter of about 5 to about 10 microns.

[0347] Grinding allows for easy adjustment of the particle size of pharmaceuticals. Several grinding techniques can be used to reduce the size of large particles to the desired size. Fluid energy grinding is a dry grinding technique that reduces particle size by utilizing collisions between particles. A type of fluid energy grinding called air jet grinding involves injecting air into a cylindrical chamber in a manner that maximizes collisions between pharmaceutical particles. Ball mills utilize a rotating cylindrical chamber that rotates around a main spindle. The pharmaceutical and abrasive material (such as steel balls made of chromium steel or CR-NI steel, ceramic balls such as zirconia, or plastic polyamide) collide, reducing the particle size of the pharmaceutical. Ball milling can be performed in a dry state, or a liquid that does not dissolve either the pharmaceutical or the abrasive material may be added to the cylinder. Further information on granulation can be found in the chapter entitled “Particle Size Reduction” by RW Lee et al. in Water-Insoluble Drug Formulation, Second Edition (Ron Liu, editor), Boca Raton, Florida: CRC Press, 2008, and in the chapter entitled “Granulation of Poorly Water-Soluble Drugs” by AW Brzeczko et al. (and other parts of the same handbook) in Handbook of Pharmaceutical Granulation Technology, Third Edition (Dilip M. Parikh, editor), Boca Raton, Florida: CRC Press / Taylor & Francis Group, 2010. Fluid energy granulation (i.e., air jet granulation) is a preferred granulation method because it is easier to scale up compared to other dry granulation techniques such as ball mills.

[0348] During grinding, substances can be added to pharmaceutical materials to help obtain particles of the desired size and minimize aggregation during handling. Silica (silicon dioxide, 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 silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, talc, polyvinylpyrrolidone, cellulose ether, polyethylene glycol, polyvinyl alcohol, and surfactants. Hydrophobic particles, in particular, are especially prone to aggregation, and hydrophilic additives should be used when grinding such particles. Grinding additives such as silica can be used in fluid grinding or ball milling at a weight ratio of approximately 0.1% to 5%, or approximately 0.1% to 4%, 0.1% to 3%, 0.1% to 2%, 0.1% to 1%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or approximately 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5%.

[0349] After grinding, the particles can be passed through a mesh of the appropriate size to obtain particles of the desired size. To obtain the largest desired particle size, the particles are passed through a mesh with holes of the desired largest size. Particles that are too large remain on the mesh, and the particles that pass through the mesh are of the desired largest size. To obtain the smallest desired particle size, the particles are passed through a mesh with holes of the desired smallest size. Particles that are too small pass through the mesh, and the desired particles remain on the mesh. Method for manufacturing supported polymer-pharmaceutical (or pharmaceutical salt) components

[0350] The compounding temperature for incorporating a drug (or a pharmaceutically acceptable salt thereof) into a polymer substrate is typically in the range of about 80°C to about 120°C, but higher or lower temperatures may be used for polymers that are optimally compounded at temperatures outside this range. If drug (or salt thereof) particles of a specific size are used and it is desirable to maintain the particle size during and after compounding, compounding may be carried out at a temperature lower than the melting point of the drug (or salt thereof) to maintain the desired particle size. Otherwise, a temperature that melts both the polymer and the drug (or salt thereof) may be used. The compounding temperature must be lower than the decomposition temperature of the drug (or salt thereof). In one embodiment, less than about 2% of the drug (or salt thereof) decomposes during manufacturing. In one embodiment, less than about 1.5% of the drug (or salt thereof) decomposes during manufacturing. In one embodiment, less than about 1% of the drug (or salt thereof) decomposes during manufacturing. In one embodiment, less than about 0.75% of the drug (or salt thereof) decomposes during manufacturing. In one embodiment, less than about 0.5% of the drug (or salt thereof) decomposes during manufacturing. In one embodiment, less than approximately 0.4% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.3% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.2% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.15% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.1% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.05% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.04% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.03% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.02% of the drug (or its salt) decomposes during manufacturing. In one embodiment, less than approximately 0.01% of the drug (or its salt) decomposes during manufacturing.

[0351] Supported polymer-agent (or agent salt) components can be prepared using hot-melt extrusion molding. A single-screw, or preferably a twin-screw, system can be used. As mentioned above, if it is desirable to maintain particle size during or after compounding, a supported polymer that can be melted at a temperature that does not decompose either the agent or its salt should be used. Otherwise, a temperature that melts both the polymer and the agent or its salt can be used.

[0352] Supported polymer-pharmaceutical (or salt thereof) components can also be prepared by melting and casting. The supported polymer and the pharmaceutical (or salt thereof), along with any other desired components, are mixed together. The supported polymer is melted, the molten material is mixed so that the pharmaceutical (or salt thereof) particles are uniformly dispersed in the molten material, the mixture is poured into a mold, and cooled.

[0353] Supported polymer-drug (or its salt) components can also be prepared using solvent casting. The polymer is dissolved in a solvent, and the drug (or its salt) particles are added. If the size of the drug (or its salt) particles needs to be maintained, a solvent that does not dissolve the drug (or its salt) particles should be used to avoid changes in the particle size properties. Otherwise, a solvent that dissolves both the polymer and the drug (or its salt) particles can be used. The solvent-supported polymer-drug (or its salt) particle mixture (i.e., solvent-supported particle-drug / drug salt solution) is then mixed to uniformly disperse the particles (i.e., the solution is thoroughly mixed), poured into a mold, and the solvent is evaporated. System manufacturing / assembly: Attaching the arms to the central elastic body.

[0354] In the case of a stellate gastric retention system as shown in Figure 1A, the arms of the gastric retention system can be attached to the central elastic body in several ways. The central polymer can be cast or molded into short "stellate" arms, and the arms can be fixed to the stellate arms of the central elastic body using a linker polymer. Alternatively, the central elastic body may be formed in a form in which the proximal ends of the arms protrude. The elastic body hardens by solidification, curing, or other means to obtain the desired shape in which a portion of the arms extends into the body of the central elastic body. Alternatively, the central elastic body may be made with a cavity into which the arms can be securely inserted.

[0355] Accordingly, the present invention encompasses a method for fabricating an intragastric retention system, comprising fabricating at least three arms formed from a material comprising any drug-carrying polymer-excipient formulation disclosed herein, and attaching the arms to a central elastic body to form an intragastric retention system. The arms may include at least one segment having a polymer film that modulates the release rate. The arms of the intragastric retention system protrude radially from the central elastic body in a "hub and spoke" arrangement. A preferred number of arms is six; however, a star-shaped system having three, four, five, seven, or eight arms may also be used.

[0356] In some embodiments, an arm containing any supported polymer-pharmaceutical formulation may be fixed to other elements, such as a disintegrating substrate, a linking polymer, or an intervening polymer, by heat welding, solvent welding, or other means, and then these are fixed to a central elastic body. In some embodiments, the arm is fixed directly to the central elastic body. The disintegrating substrate, linking polymer, or intervening polymer segment may be fixed to the central elastic body by welding or other means before the arm is fixed.

[0357] Depending on the embodiment, an arm containing any drug-supported polymer-excipient formulation disclosed herein may be heat-welded to a polycaprolactone segment, such as a short polycaprolactone "star" arm attached to a central elastic body. Alternatively, a linker segment may be welded to a short "star" arm before fixing the drug-supported polymer-excipient formulation arm. A stronger weld was obtained by heat-welding the drug-supported polymer-excipient formulation arm to an MW 80,000 PCL segment at a temperature of 140°C to 170°C and then cooling at 8°C for 24 hours. Accordingly, in one embodiment, forming an intragastric retention system by attaching an arm containing any drug-carrying polymer-excipient formulation disclosed herein to a central elastic body may involve heat-welding the arm to other system components, such as a star-shaped arm or other segment containing 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°C to about 170°C, and then cooling the welded member attached to the other system components at about 12 to about 48 hours at about 2°C to about 14°C, for example, about 5°C to about 10°C, or about 8°C. Alternatively, the other system components may be linker elements. System manufacturing / assembly

[0358] Once the arms of the intragastric retention system are secured to the central elastic body, the system folds into a compressed configuration and is ready to be encapsulated for storage, transport, and final administration. The system can be folded by an automated mechanical process or by hand and placed into a capsule of appropriate size and material. Details relating to the manufacture and assembly of the intragastric retention system, as well as the encapsulation of the intragastric retention system, are described in International Patent Applications WO2015 / 191920, WO2015 / 191925, WO2017 / 070612, WO2017 / 100367, and PCT / US2017 / 034856. Method for manufacturing a gastric retention system having filaments

[0359] As already explained, the filaments of the intragastric retention system may be connected to the tips of the arms of the intragastric retention system. If not properly connected, when the intragastric retention system is compressed / bent, the arms may translate along the filaments, impairing the filaments' ability to prevent premature passage of the intragastric retention system into the pylorus. Therefore, the following describes a method for manufacturing an intragastric retention system with filaments.

[0360] In some embodiments, the filament may be attached to the arms of a pre-assembled intragastric retention system by notching, wrapping, and end forming. The intragastric retention system may be assembled using specially formed tips at each distal end of each arm. Each tip of each arm can be notched with a razor or circular saw, as shown in Figure 6A, to form a notch at the tip. Figure 6B shows the filament wound circumferentially around the arms of the intragastric retention system and fed from each notch. In some embodiments, the filament can be wound using a winding device with controlled tension. Figure 6C shows the notches closed and rounded to secure the filament. In some embodiments, the notches may be closed using a fastener that applies heat and pressure to the ends of each arm with a heated die, leaving a rounded surface at the ends of the arms.

[0361] After winding the filament and connecting two or more arms, the ends of the filament can be secured. Figure 7 shows two different methods for securing both ends of the filament. The two ends of the filament can initially be secured by overlapping them within a notch in one arm. If the gastric retention system bends within the stomach during gastric retention, tension will be applied to the filament, and the two free ends of the filament may slip through the notch and detach from the arm. Therefore, to secure the filament ends more firmly, they are expanded by knotting and / or heating. In some embodiments, the ends of the filament may be knotted and / or heated before being attached to the gastric retention system.

[0362] In some embodiments, the filament may be attached to multiple arm tips before the arm tip is attached to the rest of the gastric retention system. For example, the filament and arm tip may be manufactured by injection molding or insert molding (e.g., overmolding the tip onto an existing filament). Figure 8 shows an example of a manufacturing process that includes forming the filament and arm tip by injection molding. As shown, the gastric retention system 852 may 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 completed gastric retention system having the filament 854. Treatment methods using the gastric retention system

[0363] A gastric retention system can be used to treat conditions requiring long-term administration of drugs or medications. In a preferred embodiment, the gastric retention system is administered to a human. For long-term administration of drugs or medications taken for months, years, or indefinitely, administering the gastric retention system regularly (e.g., once a week or once every two weeks) can provide significant advantages in patient adherence to medication and convenience. Therefore, the gastric retention system of the present invention may be administered every three days, every five days, once a week, once every ten days, or once every two weeks. The administration frequency is time-adjusted to match the designed gastric retention period of the gastric retention system being administered, so that a new gastric retention system is administered approximately simultaneously with the exit of the gastric retention system after its retention period.

[0364] When an intragastric retention system is administered to a patient, the system continuously releases the drug or substance over its intragastric retention period. After the intragastric retention period, the system disintegrates and exits the stomach. Therefore, if the system has an intragastric retention period of one week, the patient swallows (or is otherwise administered to the stomach) a new system every week. Thus, in one embodiment, a method of treating a patient with a drug or substance in an intragastric retention system of the present invention, having an intragastric retention period of "days D" (days D being the intragastric retention period in days) over a desired total treatment period "total T" (where total T is the desired treatment length in days), includes introducing a new intragastric retention system into the patient's stomach every D days over the desired total treatment period by oral administration or other means. The number of intragastric retention systems administered to the patient is "total T" divided by "D days". For example, if a patient's treatment is desired to last one year (total T = 365 days), and the gastric retention period of the system is 7 days (days D = 7 days), then administering a new system every 7 days would result in the patient receiving approximately 52 gastric retention systems over 365 days.

[0365] Alternatively, the patient may swallow (or be administered to the stomach by other means) a new intragastric retention system at the end of the effective release period of the intragastric retention system. The “effective release period” or “effective release time” is the time it takes for the intragastric retention system to release an effective amount of the drug contained in the system. Thus, in one embodiment, a method of treating a patient with a drug in a system of the present invention, using an intragastric retention system of the present invention having an effective release period of “days E” (days E being the effective release period in days) over a desired total treatment period “total T” (total T being the desired length of treatment in days), includes introducing a new intragastric retention system into the patient’s stomach by oral administration or other means every E days over the desired total treatment period. The number of intragastric retention systems administered to the patient is the number obtained by dividing “total T” by “E days”. For example, if a patient's treatment is desired for one year (total T = 365 days) and the effective release period of the system is 7 days (days E = 7 days), then a new system would be administered once every 7 days, resulting in approximately 52 intragastric retention systems being administered to the patient over 365 days. Kits and manufactured products

[0366] Kits for treating patients with the intragastric retention systems of the present invention are also provided herein. The kit may include, for example, a sufficient number of intragastric retention systems to be administered regularly to a patient over a desired total treatment period. If the total treatment period in days is "Total T" and the intragastric retention systems have an intragastric retention period of "D days", then for administration every D days, the kit includes a number of intragastric retention systems equal to ("Total T" ÷ "D days") (rounded to the nearest integer). Alternatively, if the total treatment period in days is "Total T" and the intragastric retention systems have an effective release period of "E days", then for administration every E days, the kit includes a number of intragastric retention systems equal to ("Total T" ÷ "E days") (rounded to the nearest integer). The kit may, for example, contain several intragastric retention systems in a container (the container may be a capsule), and may also include, as necessary, printed or computer-readable instructions regarding a dosage plan, treatment duration, or other information about the use of the intragastric retention system and / or the drugs or medications contained in the intragastric retention system. For example, if a patient's predetermined total treatment duration is one year and the intragastric retention system has a retention period of one week or an effective release period of one week, the kit may contain 52 capsules, each containing one intragastric retention system, along with instructions to take one capsule once a week on the same day (for example, every Saturday).

[0367] The present invention also includes a product comprising a sufficient number of intragastric retention systems to be administered to a patient regularly over a desired total treatment period, and including, optionally, instructions regarding the administration plan, treatment period, or other information regarding the use of the intragastric retention systems and / or the drugs or substances contained in the intragastric retention systems. The product may be supplied in appropriate packaging, such as a dispenser, tray, or other packaging that assists the patient in administering the intragastric retention systems at predetermined intervals. Test method

[0368] Three-point bending test. The "flexural modulus" of a material is an intrinsic property of the material, calculated as the ratio of stress to strain during bending deformation of the material, as measured by a three-point bending test. In this specification, linkers are described as components of an intragastric retention system, but the flexural modulus of polymer materials may be measured independently. For example, a polymer linker in an intragastric retention system may be too short to measure the flexural modulus, but a longer sample of the same material may be used to accurately determine the flexural modulus. It is desirable that the longer sample used to measure the flexural modulus has the same cross-sectional dimensions (shape and size) as the polymer linker used in the intragastric retention system. The flexural modulus is measured using a three-point bending test that conforms to the ASTM standard three-point bending test (ASTM D790), with a distance of 10 mm between supports, and is modified to accommodate materials with non-rectangular cross-sections. It is desirable to place the longest line of symmetry of the polymer linker's cross-section perpendicular and apply a downward force to measure the flexural modulus. If the longest line of symmetry of the polymer linker's cross-section is perpendicular to a flat side, it is preferable to position the flat side above. If the cross-section of the polymer linker is triangular, ensure that the vertex of the triangle points downwards. While applying a downward force, measure the force and displacement, determine the inclination in the linear region, and calculate the flexural modulus.

[0369] Radial force compression test: Figure 9 shows a radial force compression test using a thoracic mechanism. Specifically, the gastric retention system 902 shown in Figure 9 contains a circumferentially wound filament in a nearly stellate gastric retention system with six arms. The equipment used to measure radial force compression (i.e., thoracic testing machine) was a Blockwise Model TTR2 Tensile Testing Machine and a Model RLU124 Twin-Cam® Radial Compression Station, 60 mm D x 124 mm L.

[0370] The gastric retention system to be measured was placed in the thoracic testing machine so that the plane of the gastric retention system was parallel to the axis of the thoracic cylinder. Four arm tips were placed in contact with the inner wall of the thoracic testing machine (in the case of a gastric retention system with six arms), with two arms angled upward and two arms angled downward. Two additional arms were oriented parallel to the axis of the thoracic cylinder.

[0371] Pull-out force test: Figures 10A and 10B show a method for testing the adhesive strength of a filament. As previously mentioned, the filament may be attached to the distal end of the arm. When a single filament connects two or more arms, the filament may be attached to the distal end of each arm to prevent translation of the arm along the filament when the gastric retention system is bent by the force of the stomach. Thus, the pull-out force test described herein can quantify the force required to separate the filament from the distal end of the arm.

[0372] A gastric retention system with six arms and filaments was prepared, and the arms were separated by cutting an elastic core into six sections. The filaments were cut between each arm. The tensile force required to pull the filament out from the tip of each arm was measured using an Instron 3340 series universal tester by gripping the base of the arm and one end of the filament.

[0373] Double Funnel Durability Test. The double funnel test is used to quantify the durability and / or failure modes of an intragastric retention system. The durability of an intragastric retention system helps prevent premature rupture or weakening of the system due to repeated gastric waves / forces (and premature passage through the pylorus). To test an intragastric retention system using the double funnel test, the system to be tested is grasped by a ring attached to a linear actuator at its center (i.e., core). The intragastric retention system is moved up and down into a conical cavity, and the arms of the intragastric retention system are repeatedly bent back and forth relative to the core. The conical cavities face each other so that the apex of the cones faces each other and the base of each cone is close to each other. This up and down movement is repeated for several hundred cycles, or until the intragastric retention system ruptures. Different specific rupture modes include rupture at connection points (e.g., between the arms and core or between the first and second segments) or tearing of the silicone core. The number of cycles until rupture and the force required to bend the gastric retention system may be quantified. The test may be performed at body temperature with the gastric retention system immersed in an aqueous medium (e.g., simulated gastric fluid).

[0374] Planar Circumferential Bend Durability Test. Planar circumferential testing is used to quantify the durability and / or failure modes of intragastric retention systems. In particular, the planar circumferential bend durability test can test an intragastric retention system by positioning the system on a pack having four grips, each in contact with the arms of the intragastric retention system. The grips are connected to rotary actuators that apply a circumferential force to the arms. This motion causes the arms to spread in the plane of the intragastric retention system. This motion is repeated for several hundred cycles, or until the intragastric retention system breaks. Different specific failure modes include fracture at connection points (e.g., between arms and core or between the first and second segments) or tearing of the silicone core. The number of cycles to fracture and the force required to bend the intragastric retention system may be quantified. The test may be performed at body temperature with the intragastric retention system immersed in an aqueous medium (e.g., simulated gastric fluid).

[0375] Melt Flow Index (MFI). The Melt Flow Index (MFI) is a measure of viscosity at low shear, and is measured as the number of grams of material flowing through the die in 10 minutes at a set temperature and applied weight. These measurements are performed using the Ray-Ran 6MPCA Advanced Melt Flow System with a weight of 2.16 kg (however, this can be within a standardized weight range), following procedure A of ASTM D1238 "Standard Test Method for Melt Flow Rates of Thermoplastics by Extrusion Plastometer".

[0376] Tensile testing. Using an Instron machine with a custom grip (Figure C), the ultimate tensile strength (UTS) of the bonds between any combination of star-shaped components under constant temperature conditions can be evaluated (1) in various constant temperature solutions, (2) after several constant temperature periods, and (3) at room temperature or body temperature (37-40°C). Low ultimate tensile strength indicates the potential fracture point of the star. By optimizing the formulation and experimental process, the tensile strength can be maximized and ideal star-shaped performance can be achieved.

[0377] To test a stellate arm with a triangular cross-section, a custom-made grip consisting of a flat plate and a notch can be used. The vertices of the triangular arm are positioned to fit into the notch, allowing the pressure from the plate to be evenly distributed across the three longitudinal surfaces of the triangular arm.

[0378] Tensile tests were performed using the Instron 3342 series. A series of hot-melt extruded and thermally bonded equilateral triangular prisms with 3.33 mm triangular bases are gripped by pneumatic action. The crosshead is moved upward at a rate of 5 to 500 mm / min, depending on the elasticity of the test material. The measuring instrument records force (N) versus displacement (mm), and the ultimate tensile strength (stress) is calculated by dividing the maximum force by the cross-sectional area of ​​the interface.

[0379] Drug release rate test. The drug release rate was tested in fasting-simulated gastric juice (FaSSGF). FaSSGF was prepared as follows, according to the manufacturer's instructions (biorelevant.com): 975 mL of deionized water and 25 mL of 1N hydrochloric acid were mixed in a 1 L glass medium bottle. The pH was adjusted to 1.6 using 1N HCl or NaOH as needed. 2.0 g of NaCl was added and mixed. Immediately before use, 60 mg of Biorelevant powder was mixed into the solution. The composition of FaSSGF was taurocholic acid (0.08 mM), phospholipid (0.02 mM), sodium (34 mM), and chloride (59 mM). Supported polymer -- The drug composition was formed into drug-supported polymer arms by blending polymer powder and active pharmaceutical ingredients and extruding the mixture. The arms were coated with a release rate-controlled polymer film by pan-coating or dip-coating them with a solution of the film polymer, which was dissolved in a suitable solvent, typically ethyl acetate or acetone. The coated arms were then placed in a container containing FaSSGF and left at a constant temperature of 37°C, and sampled at least four times over a typical 7-day period. The drug content was measured by HPLC. Samples were stored at 4°C for no more than 3 days prior to analysis. At each measurement point, the entire volume of the release medium was replaced with a fresh solution pre-equilibrated at 37°C to maintain sink conditions. [Examples]

[0380] Example 1: The radial force required to compress the intragastric retention system to various constriction diameters was tested using the radial force testing machine described in detail earlier. As shown in Figure 11, intragastric retention systems with and without filaments were tested. As shown in the figure, the discrepancy between the force required to compress the intragastric retention system with filaments and the intragastric retention system without filaments increases as the compressed diameter decreases. As a result, it was found that for compression diameters small enough that the intragastric retention device passes through the pylorus (i.e., diameter 20 mm or less), the force required to compress the intragastric retention device with filaments is at least twice the force required to compress the intragastric retention device without filaments.

[0381] Example 2: The radial force required to compress the intragastric retention system to various constriction diameters was tested using the radial force tests described in detail earlier. In particular, intragastric retention systems with and without filaments, and with relatively flexible arms (compared to the intragastric retention system tested in Example 1), were tested. Similar to the intragastric retention system tested in Example 1, Figure 12 shows that the discrepancy between the force required to compress the intragastric retention system with filaments and the intragastric retention system without filaments increases as the compressed diameter decreases. Furthermore, as shown in the figure, the force required to compress the intragastric retention system with filaments to a compression diameter small enough to pass through the pylorus early (i.e., a diameter of 20 mm or less) is at least twice as large as the force required to compress the intragastric retention system without filaments to the same compression diameter.

[0382] Example 3: The pull-out force required to separate the filament from the arm tip was tested under various constant temperature settings. As shown in Figure 13, the pull-out force was tested on a filament connected to an arm tip having Formulation 14 (shown in Table 1), following the pull-out force test procedure described in detail earlier. The tip containing this Formulation is designed to remain attached to the filament in a highly acidic environment, i.e., the stomach environment, and to separate or slide away from the filament as each component of the gastric retention system passes through the patient's intestines in the intestinal environment. The adhesion force was measured after keeping the samples at constant temperature for 1 day and 3 days in simulated fasting gastric fluid (FaSSGF, pH 1.6) or simulated fasting intestinal fluid (FaSSIF, pH 6.5). As shown in the figure, the length of constant temperature storage (i.e., 1 day or 3 days) had only a slight effect on the pull-out force of the samples kept at constant temperature in simulated fasting gastric fluid and simulated fasting intestinal fluid. However, the pull-out force differed significantly between the two simulated fluids. The extraction force of a sample left at a constant temperature in simulated gastric fluid under fasting conditions was approximately twice that of a sample left at a constant temperature in simulated intestinal fluid under fasting conditions. [Table 6]

[0383] Example 4: The pull-out force required to separate the filament from the arm tip was tested under various constant temperature settings. As shown in Figure 14, the pull-out force was tested using a filament connected to an arm tip having Formulation 15 (shown in Table 1), following the pull-out force test procedure described in detail earlier. The tip containing this Formulation is designed to remain attached to the filament in a highly acidic environment, i.e., the stomach environment, and to separate or slide away from the filament as each component of the gastric retention system passes through the patient's intestines in the intestinal environment. The adhesion force was measured after the samples were left at constant temperature for 1 day and 3 days in simulated fasting gastric fluid (FaSSGF, pH 1.6) or simulated fasting intestinal fluid (FaSSIF, pH 6.5). As shown in the figure, the length of constant temperature storage (i.e., 1 day or 3 days) had only a slight effect on the pull-out force of the samples left at constant temperature in simulated fasting gastric fluid. However, the suction force of the samples left at constant temperature for 3 days was approximately 75% of the suction force of the samples left at constant temperature for only 1 day in simulated fasting intestinal fluid. Furthermore, the extraction force of a sample left at constant temperature in simulated gastric fluid under fasting conditions is at least 20% greater than the extraction force of a sample left at constant temperature in simulated intestinal fluid under fasting conditions.

[0384] Example 5: The pull force required to separate the filament from the arm tip was tested for both knotted and heated filament ends. Figure 15 shows the results of this test. The samples were left at constant temperature for 3 days in simulated gastric fluid under fasting conditions. As shown in the figure, the sample with a knot at the filament end required the greatest force to separate the filament from the arm tip. Also, the sample with a heated and widened filament tip required less force to pull the filament away from the arm tip than the sample with a knotted filament tip, but greater force than the control sample (neither knotted nor heated). As shown in the figure, the pull force required to separate the knotted filament end was at least about 1.5 times the pull force required to separate the heated filament end from the arm tip, and about 5 times the pull force required to separate the control (i.e., knotless and unheated) filament end from the arm tip.

[0385] Example 6: The gastric retention of a filament-containing intragastric retention system was tested in dogs. Figure 16 shows an intragastric retention system 1602 containing a filament 1608 with a knotted end. Radiopaque tubes / markers 1660 were placed on the filament 1608 between each arm tip 1610. Using two or more radiopaque tubes / markers 1660, the location and integrity of the intragastric retention system could be identified in vivo by radiographic imaging. The radiopaque tubes / markers 1660 were composed of a polymer matrix compounded with bismuth. Specifically, polycaprolactone compounded with bismuth was molded into tubes, and during filament assembly, the tubes were passed through the filaments between each arm. The radiopaque tubes slid freely along the filaments, and when the ends of the filaments slid off the astrocytes, the tubes could slide off the filaments. In animal experiments, the integrity of the filaments was tracked by observing the number and orientation of radiopaque tubes visible on X-rays.

[0386] The intragastric retention system was assembled at the arm tip 1610 containing enteric-coated formulation 14 (see Table 1) by cutting, winding, and rounding, as shown in Figures 5A-5C. The arm tip 1610 was notched with a circular saw. Pelletan filaments were cut to length, radiopaque tubing was threaded through the filaments, and the ends of the filaments were tied. The filaments were added to the intragastric retention system by feeding them through the notches at the arm tips so that one radiopaque marker was positioned between each arm. The notches were then closed by applying pressure from a heated die (85°C, 25 psi, 30 seconds). The intragastric retention system was filled into hydroxypropyl methylcellulose capsules and administered orally to beagle dogs. The intragastric retention system was visualized by X-ray daily for one week. The number of polycaprolactone tubes visible by X-ray is shown in Table 2. In two of the three dogs, the web remained intact for more than one week. In the third intragastric retention system, two radiopaque tubes separated from the astrocyte by day 7, and the astrocyte detached from the body by day 8. The filaments containing these materials were shown to be durable enough to support intragastric retention for one week. [Table 7]

[0387] Example 7: The ability of a filament to prevent a star-shaped intragastric retention system from passing through the stomach unchanged was evaluated in a canine model. A dosage form with a silicone core with an indentation hardness of 40A, an enteric-coated substrate, and a placebo arm based on PCL was assembled to have an outer diameter of 37 mm. The arm contained a radiopaque marker to track intragastric retention by X-ray. The dosage form was filled into coated HPMC capsules and administered to five beagle dogs. In the first test, the intragastric retention system was administered without the filament. Intragastric retention time ranged from 1 to 7 days, with an average of 3.2 days. X-ray images showed an unchanged astrocyte in the intestine, suggesting that the dosage form exited the stomach unchanged. This astrocyte configuration was chosen to evaluate the ability of the filament to resist unchanged passage and improve intragastric retention time, as the addition of the filament to the dosage form is intended to help the dosage form resist passing through the pylorus unchanged. Similar star-shaped structures (40A core, 37 mm outer diameter, PCL-based arms) were assembled, and filaments were attached to the ends of each arm. The filaments were flexible pelletan tubes with a compression hardness of 80A, an outer diameter of approximately 400 microns, and an inner diameter of approximately 250 microns. The dosage form was folded and placed in a coated HPMC capsule and administered to five beagle dogs. X-ray images showed that the gastric retention time ranged from 4 to 10 days, with an average of 6.4 days. The addition of filaments was able to extend the gastric retention time of the dosage form, which would normally pass through the pylorus unchanged.

[0388] Example 8: The unfolding time of an intragastric retention system containing a filament and sleeved on the arm side was tested, as was the unfolding time of an intragastric retention system containing a filament and sleeved on the core side. Specifically, some intragastric retention systems, such as star-shaped intragastric retention systems, are configured to be compressed / folded at the core. Thus, when compressed / folded, the intragastric retention system has an arm side (e.g., the side indicated by the arrow in Figure 17A) and a core side (e.g., the side indicated by the arrow in Figure 17C). The examples described herein test the unfolding time of a sleeved intragastric retention system compressed on the arm side and a sleeved intragastric retention system compressed on the core side.

[0389] Figures 17A to 17G show different sleeve and compression configurations for intragastric retention systems containing filaments. Specifically, Figure 17A shows intragastric retention system 1710A sleeved on the arm side with sleeve 1712A and compressed / folded. Compressed / folded intragastric retention system 1710A contains filaments between each arm of the intragastric retention system. Thus, the filaments of the intragastric retention system are covered with sleeve 1712A. Figure 17B shows intragastric retention system 1710A sleeved with sleeve 1712A on the arm side of the intragastric retention system to form sleeved and compressed / folded intragastric retention system 1740B. Figure 17C shows compressed / folded intragastric retention system 1710C. However, it is shown that compressed / folded intragastric retention system 1710C is sleeved on the core side of the intragastric retention system having sleeve 1712C. Figure 17D shows that the compressed / folded intragastric retention system 1710D is sleeved with sleeve 1712C on the core side of the intragastric retention system. Thus, unlike the sleeved compressed / folded intragastric retention system 1740B in Figure 17B, in the sleeved compressed / folded intragastric retention system 1740D, the webbing of the compressed / folded intragastric retention system 1710C is not covered with sleeve 1712C.

[0390] Figures 17E and 17F show different encapsulation configurations for sleeved compressed / folded intragastric retention systems. Both the sleeved compressed / folded intragastric retention system 1740E in Figure 17E and the sleeved compressed / folded intragastric retention system 1740F in Figure 17F are sleeved on the arm side of the intragastric retention system. Furthermore, Figure 17E shows the sleeved intragastric retention system 1740E enclosed in a two-piece capsule. The lid 1716E of the two-piece capsule encapsulates the sleeved intragastric retention system on its core side, and the body 1714E of the two-piece capsule encapsulates the sleeved intragastric retention system on its sleeved arm side. Figure 17F shows the sleeved intragastric retention system 1740F enclosed in a two-piece capsule. However, unlike that in Figure 17E, the sleeved compression / folding intragastric retention system 1740F in Figure 17F is encapsulated by the two-piece capsule body 1714F encapsulating the core side and the two-piece capsule lid 1716F encapsulating the sleeved arm side of the intragastric retention system.

[0391] Figure 17G shows an encapsulated, sleeved, compressed / folded intragastric retention system 1742G.

[0392] The sleeves used in these tests were VCaps Plus HPMC size 0. The sleeved intragastric retention systems were then encapsulated in VCaps Plus HPMC capsules. Table 3 shows the deployment time data for the arm-side sleeved intragastric retention system, and Table 4 shows the deployment time data for the core-side sleeved intragastric retention system. Both Tables 3 and 4 were obtained using the pH 7 deployment (Rocker) test, which is described in more detail below. [Table 8] [Table 9]

[0393] As shown in Tables 3 and 4, the deployment times of the core-sleeved intragastric retention system and the arm-sleeved intragastric retention system are similar. The average deployment time of the core-sleeved intragastric retention system is slightly longer than that of the arm-sleeved intragastric retention system, but the difference is not statistically significant. Therefore, based on the data in Tables 3 and 4, the deployment times of the arm-sleeved intragastric retention system and the core-sleeved intragastric retention system are approximately the same.

[0394] Example 9: A biodegradable suture can be used as a filament to enhance the gastric retention characteristics of the gastric retention system. The biodegradable suture may be elastic or inelastic. Furthermore, the biodegradable suture may be bioabsorbable. In some embodiments, the biodegradable suture is attached to the enteric-coated tip of a stellate arm.

[0395] To evaluate the effect of the elasticity of the outer filament on the resistance of the stellate to compression to a size that can pass through the pylorus, a stellate intragastric retention system was constructed using filaments with different elasticity. Polyurethane elastic material (pelletan tubing) was used as the elastic filament material, and polyglycolic acid sutures were used as the inelastic filament material. The filaments were attached to the enteric-coated tip of the stellate arm by methods such as notching, winding, and rolling. The radial force required to compress the stellate to a diameter of 20 mm was measured using a throttling machine.

[0396] As shown in Figure 18A, all filament materials increased the compression resistance of the astral structures compared to those without filaments. Furthermore, astral structures with inelastic webs exhibited greater compression resistance than astral structures with elastic webs.

[0397] Furthermore, the adhesive strength of PLGA sutures to stellate arms with enteric-coated tips was evaluated by measuring the pull-out force after constant temperature storage. The stellate intragastric retention system was assembled to the enteric-coated tip using a filament made from either polyurethane elastic material (Pellethane) or PLGA suture. The filament was attached to the enteric-coated tip of the stellate arm by notching, winding, and rounding. The adhesion of the filament to the stellate arm was measured before and after constant temperature storage in simulated gastric fluid under fasting conditions for specified periods (days 0, 1, 4, and 7).

[0398] As shown in Figure 18B, the adhesion of both types of filaments was strongest at an early stage and decreased at a later stage, consistent with the hydration and softening of the enteric-coated tip material observed. More importantly, both the polyurethane elastomer and the PLGA filament material maintained an adhesive strength of 1N or higher for at least 7 days. Exemplary Embodiments

[0399] Action 1 Core, Multiple arms connected to the core at the proximal end via multiple linker components, and Filaments connecting each arm of the plurality of arms in the circumferential direction. Includes, One of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially from the proximal end. Gastric retention system.

[0400] Embodiment 2: The gastric retention system according to Embodiment 1, wherein the filament connects the distal ends of each of the plurality of arms in the circumferential direction.

[0401] Embodiment 3: The gastric retention system according to Embodiment 1 or 2, wherein the plurality of arms include at least three arms.

[0402] Embodiment 4: The gastric retention system according to any one of Embodiments 1 to 3, wherein the plurality of arms are configured to carry a pharmaceutical active ingredient.

[0403] Embodiment 5: The gastric retention system according to any one of Embodiments 1 to 4, wherein the plurality of arms carry 40-60% of the active pharmaceutical ingredient.

[0404] Embodiment 6: The gastric retention system according to any one of Embodiments 1 to 5, wherein the linker component is decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0405] Embodiment 7: The gastric retention system according to any one of Embodiments 1 to 6, wherein the gastric retention system is configured to be folded during administration and to be in an open configuration when it is in the patient's stomach.

[0406] Embodiment 8: The gastric retention system according to Embodiment 7, wherein the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system takes the open configuration.

[0407] Embodiment 9 The gastric retention system according to any one of Embodiments 1 to 8, wherein the gastric retention system has a multi-arm star shape in the open configuration.

[0408] Embodiment 10: The gastric retention system according to any one of Embodiments 1 to 9, wherein, as measured by radial testing, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times greater than the force required to compress a gastric retention system without filaments to a configuration small enough to pass through the opening.

[0409] Embodiment 11: The gastric retention system according to any one of Embodiments 2 to 10, wherein, when the gastric retention system is left at constant temperature in a pH 1.6 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0410] Embodiment 12: The gastric retention system according to any one of Embodiments 2 to 11, wherein, after being left at constant temperature in a pH 6.5 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

[0411] Embodiment 13: The gastric retention system according to any one of Embodiments 1 to 12, wherein the distal end of each of the plurality of arms contains an enteric-coated material.

[0412] Embodiment 14: The gastric retention system according to any one of Embodiments 1 to 13, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0413] Embodiment 15 The gastric retention system according to Embodiment 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.

[0414] Embodiment 16: The gastric retention system according to Embodiment 15, wherein the polymer comprises polycaprolactone or TPU.

[0415] Embodiment 17: The gastric retention system according to Embodiment 15 or 16, wherein the enteric polymer comprises hydroxypropyl methylcellulose succinate acetate.

[0416] Embodiment 18: The gastric retention system according to any one of Embodiments 15 to 17, wherein the plasticizer comprises propylene glycol.

[0417] Embodiment 19: The gastric retention system according to any one of Embodiments 15 to 18, wherein the acid comprises stearic acid.

[0418] Embodiment 20: The gastric retention system according to any one of Embodiments 1 to 19, wherein the distal end of each arm includes a notch, and the filament is positioned within the notch of each distal end.

[0419] Embodiment 21 The gastric retention system according to Embodiment 20, wherein the first end and the second end of the filament are overlapped and fixed within a first notch, and the first end and the second end are extended and fixed together.

[0420] Embodiment 22 The gastric retention system according to any one of Embodiments 1 to 21, wherein each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, the first segment having greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

[0421] Embodiment 23 The gastric retention system according to Embodiment 22, wherein, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

[0422] Embodiment 24 The gastric retention system according to Embodiment 22 or 23, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0423] Embodiment 25 The gastric retention system according to any one of Embodiments 22 to 24, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

[0424] Embodiment 26 The gastric retention system according to any one of Embodiments 22 to 25, wherein the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

[0425] Embodiment 27: The gastric retention system according to any one of embodiments 22 to 26, wherein the first segment is directly connected to the second segment of each of the plurality of arms.

[0426] Embodiment 28: An intragastric retention system according to any one of embodiments 22 to 27, wherein the first segment is connected to the second segment via a linker.

[0427] Embodiment 29 The intragastric retention system according to any one of Embodiments 22 to 28, wherein the first segment constitutes 20 to 50% of the length of at least the first arm of the plurality of arms, and this 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 core.

[0428] Embodiment 30 The gastric retention system according to any one of Embodiments 22 to 29, wherein the second segment constitutes 50 to 80% of the length of at least the first arm of the plurality of arms, and this 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 core.

[0429] Embodiment 31: The gastric retention system according to any one of Embodiments 22 to 30, wherein, when measured using a double funnel test, the number of fatigue cycles required for the rupture of the gastric retention system is at least 25% greater than the number of fatigue cycles required for the rupture of the gastric retention system having an arm containing only the first polymer composition.

[0430] Embodiment 32 The gastric retention system according to any one of Embodiments 1 to 31, wherein the gastric retention system is configured to be enclosed in a capsule when 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 to take an open configuration.

[0431] Embodiment 33: The gastric retention system according to any one of Embodiments 1 to 32, wherein the gastric retention system is used for the treatment of a patient.

[0432] Embodiment 34: The intragastric retention system according to Embodiment 33, wherein the patient is a human or a dog.

[0433] Embodiment 35 Multiple arms connected at the proximal end, and Filaments connecting the distal ends of each of the plurality of arms in the circumferential direction. Includes, The aforementioned multiple arms extend radially from the proximal end. Gastric retention system.

[0434] Embodiment 36: The gastric retention system according to Embodiment 35, comprising a core, wherein each of the plurality of arms is connected to the core at the proximal end of each arm.

[0435] Embodiment 37 The gastric retention system according to Embodiment 35 or 36, wherein the plurality of arms include at least three arms.

[0436] Embodiment 38: The gastric retention system according to Embodiment 35 or 36, wherein the plurality of arms are configured to carry a pharmaceutical active ingredient.

[0437] Embodiment 39: The gastric retention system according to any one of Embodiments 35 to 38, wherein the plurality of arms carry 40-60% of the active pharmaceutical ingredient.

[0438] Embodiment 40 A gastric retention system according to any one of embodiments 36 to 39, comprising a plurality of linker components, wherein one of the plurality of linker components connects one of the plurality of arms to the core.

[0439] Embodiment 41: The gastric retention system according to Embodiment 40, wherein each of the plurality of linker components is decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0440] Embodiment 42 The gastric retention system according to any one of Embodiments 35 to 41, wherein the gastric retention system is configured to be folded during administration and to be in an open configuration when it is in the patient's stomach.

[0441] Embodiment 43 The gastric retention system according to Embodiment 42, wherein the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system takes the open configuration.

[0442] Embodiment 44 The gastric retention system according to any one of embodiments 35 to 43, wherein the gastric retention system has a multi-arm star shape in the open configuration.

[0443] Embodiment 45: The gastric retention system according to any one of embodiments 35 to 44, wherein, as measured by radial testing, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times greater than the force required to compress a gastric retention system without filaments to a configuration small enough to pass through the opening.

[0444] Embodiment 46: The gastric retention system according to any one of embodiments 35 to 45, wherein, when the gastric retention system is measured after being left at constant temperature in a pH 1.6 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0445] Embodiment 47: The gastric retention system according to any one of embodiments 35 to 46, wherein, when the gastric retention system is left at constant temperature in a pH 6.5 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

[0446] Embodiment 48: The gastric retention system according to any one of embodiments 35 to 47, wherein the distal end of each of the plurality of arms contains an enteric-coated material.

[0447] Embodiment 49: The gastric retention system according to any one of Embodiments 35 to 48, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0448] Embodiment 50 The gastric retention system according to Embodiment 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.

[0449] Embodiment 51: The gastric retention system according to Embodiment 50, wherein the polymer comprises polycaprolactone or TPU.

[0450] Embodiment 52: The gastric retention system according to Embodiment 50 or 51, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate.

[0451] Embodiment 53: The gastric retention system according to any one of Embodiments 50 to 52, wherein the plasticizer comprises propylene glycol.

[0452] Embodiment 54: The gastric retention system according to any one of Embodiments 50 to 53, wherein the acid comprises stearic acid.

[0453] Embodiment 55: The gastric retention system according to any one of embodiments 35 to 54, wherein the distal end of each arm includes a notch, and the filament is positioned within the notch of each distal end.

[0454] Embodiment 56: The gastric retention system according to Embodiment 55, wherein the first end and the second end of the filament are overlapped and fixed within a first notch, and the first end and the second end are fixed by either a stopper or a heat-expanding process.

[0455] Embodiment 57 The gastric retention system according to any one of embodiments 35 to 56, wherein each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, the first segment having greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

[0456] Embodiment 58 The gastric retention system according to Embodiment 57, wherein, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

[0457] Embodiment 59 The gastric retention system according to Embodiment 57 or 58, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0458] Embodiment 60 The gastric retention system according to any one of Embodiments 57 to 59, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

[0459] Embodiment 61 The gastric retention system according to any one of Embodiments 57 to 60, wherein the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

[0460] Embodiment 62 The gastric retention system according to any one of embodiments 57 to 61, wherein the first segment is directly connected to the second segment of at least the first arm of the plurality of arms.

[0461] Embodiment 63: An intragastric retention system according to any one of embodiments 57 to 62, wherein the first segment is connected to the second segment via a linker component.

[0462] Embodiment 64 The gastric retention system according to any one of Embodiments 57 to 63, wherein the first segment constitutes at least 20 to 50% of the length of the first arm, and this 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 core.

[0463] Embodiment 65 The gastric retention system according to any one of Embodiments 57 to 64, wherein the second segment constitutes 50 to 80% of the length of at least one arm, the length of which 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 core.

[0464] Embodiment 66: A gastric retention system according to any one of Embodiments 57 to 65, wherein, when measured using a double funnel test, the number of fatigue cycles required for the rupture of the gastric retention system is at least 25% greater than the number of fatigue cycles required for the rupture of a gastric retention system having an arm containing only the first polymer composition.

[0465] Embodiment 67 The gastric retention system according to any one of embodiments 35 to 66, wherein the gastric retention system is configured to be enclosed in a capsule when 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 to take an open configuration.

[0466] Embodiment 68 The gastric retention system according to any one of embodiments 35 to 67, wherein the gastric retention system is used for the treatment of a patient.

[0467] Embodiment 69: The intragastric retention system according to Embodiment 68, wherein the patient is a human or a dog.

[0468] Embodiment 70 A method for manufacturing an intragastric retention system, To create an intragastric retention system comprising a plurality of arms connected to a core at their proximal ends via a plurality of linker components, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially. To make a notch in each of the aforementioned multiple arms, The filament is wound circumferentially around the gastric retention system such that the filament is positioned within each notch of each arm, and Close each notch to secure the filament within each notch. Methods that include...

[0469] Embodiment 71 The method according to Embodiment 70, wherein the filament connects the distal ends of each of the plurality of arms in the circumferential direction.

[0470] Embodiment 72 The method according to Embodiment 70 or 71, wherein the plurality of arms include at least three arms.

[0471] Embodiment 73 The method according to any one of embodiments 70 to 72, wherein the plurality of arms are configured to carry a pharmaceutical active ingredient.

[0472] Embodiment 74 The method according to any one of Embodiments 70 to 73, wherein the plurality of arms carry 40 to 60% of the active pharmaceutical ingredient.

[0473] Embodiment 75 The method according to any one of Embodiments 70 to 74, wherein the linker component is decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

[0474] Embodiment 76 The method according to any one of embodiments 70 to 75, wherein the gastric retention system is configured to be folded during administration and to take an open configuration when it is in the patient's stomach.

[0475] Embodiment 77 The method according to Embodiment 76, wherein the core undergoes elastic deformation when the intragastric retention system is in the folded configuration and recoils when the intragastric retention system takes the open configuration.

[0476] Embodiment 78 The method according to any one of embodiments 70 to 77, wherein the gastric retention system has a multi-armed star shape in the open configuration.

[0477] Embodiment 79 The method according to any one of embodiments 70 to 78, wherein closing each notch includes at least one of stopping or heating.

[0478] Embodiment 80 The method according to any one of Embodiments 70 to 79, wherein, as measured by radial testing, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times greater than the force required to compress a filamentless gastric retention system to a configuration small enough to pass through the opening.

[0479] Embodiment 81 The method according to any one of Embodiments 70 to 80, wherein, when the gastric retention system is left at constant temperature in a pH 1.6 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

[0480] Embodiment 82 The method according to any one of Embodiments 70 to 81, wherein, after the gastric retention system has been left at constant temperature in a pH 6.5 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is less than 2 N.

[0481] Embodiment 83 The method according to any one of embodiments 70 to 82, wherein the distal end of each of the plurality of arms contains an enteric-coated material.

[0482] Embodiment 84 The method according to any one of Embodiments 70 to 83, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

[0483] Embodiment 85 The method according to Embodiments 70 to 84, wherein the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

[0484] Embodiment 86: The method according to Embodiment 85, wherein the polymer comprises polycaprolactone.

[0485] Embodiment 87 The method according to Embodiment 85 or 86, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate.

[0486] Embodiment 88 The method according to any one of Embodiments 85 to 87, wherein the plasticizer comprises propylene glycol.

[0487] Embodiment 89 The method according to any one of Embodiments 85 to 88, wherein the acid comprises stearic acid.

[0488] Embodiment 90 The method according to any one of Embodiments 70 to 89, wherein each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, the first segment having greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

[0489] Embodiment 91 The method according to Embodiment 90, wherein, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

[0490] Embodiment 92 The method according to Embodiment 90 or 91, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

[0491] Embodiment 93 The method according to any one of Embodiments 90 to 92, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

[0492] Embodiment 94 The method according to any one of Embodiments 90 to 93, wherein the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

[0493] Embodiment 95 The method according to any one of embodiments 90 to 94, wherein the first segment is directly connected to the second segment of at least one arm.

[0494] Embodiment 96 The method according to any one of embodiments 90 to 95, wherein the first segment is connected to the second segment via a linker component.

[0495] Embodiment 97 The method according to any one of embodiments 90 to 96, wherein the first segment constitutes 20 to 50% of the length of the at least one arm, and this 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 core.

[0496] Embodiment 98 The method according to any one of embodiments 90 to 97, wherein the second segment constitutes 50 to 80% of the length of the at least one arm, and this 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 core.

[0497] Embodiment 99 The method according to any one of Embodiments 90 to 98, wherein, when measured using a double funnel test, the number of fatigue cycles required for rupture of the intragastric retention system is at least 25% greater than the number of fatigue cycles required for rupture of an intragastric retention system having an arm containing only the first polymer composition.

[0498] Embodiment 100 The method according to any one of Embodiments 90 to 99, wherein the intragastric retention system is configured to be enclosed in a capsule when in a folded configuration to form an intragastric retention dosage form suitable for administration to a patient, and the intragastric retention dosage form is configured to release the intragastric retention system in the patient's stomach to take an open configuration.

[0499] Embodiment 101: An intragastric retention system prepared by any one of Embodiments 70-100 for use in the treatment of a patient.

[0500] Embodiment 102: The intragastric retention system according to Embodiment 101, wherein the patient is a human or a dog.

[0501] Embodiment 103 A method for manufacturing an intragastric retention system, To create an intragastric retention system comprising a plurality of arms connected to a core at their proximal ends via a plurality of linker components, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially. To manufacture one or more chips for each of the multiple arms, and filaments attached to each of the multiple chips, and Each of the multiple chips is connected to one of the multiple arms to form a gastric retention system including a filament. Methods that include...

[0502] Embodiment 104 The method according to Embodiment 103, wherein the fabrication of multiple chips and filaments includes injection molding.

[0503] Unless otherwise defined, all technical terms, notations, and other scientific and technical terms or vocabulary used herein shall have the same meaning as that generally understood by a person skilled in the art in which the claims relate. Where applicable, terms that have a commonly understood meaning are defined herein for clarity and / or for ease of reference. The inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from the commonly understood meaning in the art.

[0504] In this specification, when a value or variable is described as "approximately," it includes (and describes) the variation in that value or variable itself. For example, the statement "approximately X" also includes the statement "X."

[0505] Where used herein, the singular forms “a,” “an,” and “the” also include the plural forms unless the context clearly indicates otherwise. Furthermore, where used herein, the term “and / or” refers to and encompasses any possible combination of one or more of the enumerated items concerned. Furthermore, where used herein, the terms “includes, including, comprises, and / or comprising” identify the existence of the described features, integers, processes, operations, components, ingredients, and / or units, but do not exclude the existence or addition of one or more other features, integers, processes, operations, components, ingredients, units, and / or groups thereof.

[0506] This application discloses several numerical ranges in the text and figures. Since this disclosure is enforceable across the entire disclosed numerical range, the disclosed numerical ranges essentially support any range or value (including the values ​​at both ends) that falls within that disclosed numerical range, even if the exact range limitation is not stated verbatim in the specification.

[0507] In the above description, specific embodiments have been referenced for illustrative purposes. However, the above exemplary descriptions are not intended to be exhaustive or to limit the invention to the exact form disclosed. Many modifications and variations are possible considering the above teachings. Embodiments have been selected and described to best illustrate the principles of the art and their practical applications. This will enable those skilled in the art to best utilize the art and its various embodiments with various modifications tailored to specific intended uses.

[0508] While the present disclosure and examples have been fully described with reference to the accompanying figures, various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are included within the scope of the present disclosure and examples as defined by the claims.

Claims

1. core, Multiple arms connected to the core at the proximal end via multiple linker components, and Filaments connecting each arm of the plurality of arms in the circumferential direction. Includes, One of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially from the proximal end. Intragastric retention system.

2. The gastric retention system according to claim 1, wherein the filament connects the distal ends of each of the plurality of arms in the circumferential direction.

3. The gastric retention system according to claim 1 or 2, wherein the plurality of arms include at least three arms.

4. The gastric retention system according to any one of claims 1 to 3, wherein the plurality of arms are configured to carry a pharmaceutical active ingredient.

5. The gastric retention system according to any one of claims 1 to 4, wherein the plurality of arms carry 40 to 60% of the active pharmaceutical ingredient.

6. The gastric retention system according to any one of claims 1 to 5, wherein the linker component is decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

7. The gastric retention system according to any one of claims 1 to 6, wherein the gastric retention system is configured to be folded during administration and to be in an open configuration when it is in the patient's stomach.

8. The gastric retention system according to claim 7, wherein the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system takes the open configuration.

9. The gastric retention system according to any one of claims 1 to 8, wherein the gastric retention system has a multi-arm star shape in the open configuration.

10. The gastric retention system according to any one of claims 1 to 9, wherein, as measured by radial testing, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times greater than the force required to compress a gastric retention system without filaments to a configuration small enough to pass through the opening.

11. The gastric retention system according to any one of claims 2 to 10, wherein, when the gastric retention system is left at constant temperature in a pH 1.6 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

12. The gastric retention system according to any one of claims 2 to 11, wherein, after being left at a constant temperature in a pH 6.5 environment for 3 days, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

13. The gastric retention system according to any one of claims 1 to 12, wherein the distal end of each of the plurality of arms contains an enteric-coated material.

14. The gastric retention system according to any one of claims 1 to 13, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

15. The gastric retention system according to claim 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.

16. The gastric retention system according to claim 15, wherein the polymer comprises polycaprolactone or TPU.

17. The gastric retention system according to claim 15 or 16, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate.

18. The gastric retention system according to any one of claims 15 to 17, wherein the plasticizer comprises propylene glycol.

19. The gastric retention system according to any one of claims 15 to 18, wherein the acid comprises stearic acid.

20. The gastric retention system according to any one of claims 1 to 19, wherein the distal end of each arm includes a notch, and the filament is positioned within the notch of each distal end.

21. The gastric retention system according to claim 20, wherein the first end and the second end of the filament are overlapped and fixed within a first notch, and the first end and the second end are extended and fixed together.

22. The gastric retention system according to any one of claims 1 to 21, wherein each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, the first segment having greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

23. The gastric retention system according to claim 22, wherein, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

24. The gastric retention system according to claim 22 or 23, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

25. The gastric retention system according to any one of claims 22 to 24, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

26. The gastric retention system according to any one of claims 22 to 25, wherein the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

27. The gastric retention system according to any one of claims 22 to 26, wherein the first segment is directly connected to the second segment of each of the plurality of arms.

28. The gastric retention system according to any one of claims 22 to 27, wherein the first segment is connected to the second segment via a linker.

29. The gastric retention system according to any one of claims 22 to 28, wherein the first segment constitutes 20 to 50% of the length of at least the first arm of the plurality of arms, and this 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 core.

30. The gastric retention system according to any one of claims 22 to 29, wherein the second segment constitutes 50 to 80% of the length of at least the first arm of the plurality of arms, and this 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 core.

31. The gastric retention system according to any one of claims 22 to 30, wherein, when measured using a double funnel test, the number of fatigue cycles required for the rupture of the gastric retention system is at least 25% greater than the number of fatigue cycles required for the rupture of the gastric retention system having an arm containing only the first polymer composition.

32. The gastric retention system according to any one of claims 1 to 31, wherein the gastric retention system is configured to be enclosed in a capsule when 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 to take on an open configuration.

33. The gastric retention system according to any one of claims 1 to 32, wherein the gastric retention system is used for the treatment of a patient.

34. The gastric retention system according to claim 33, wherein the patient is a human or a dog.

35. Multiple arms connected at the proximal end, and Filaments connecting the distal ends of each of the plurality of arms in the circumferential direction. Includes, The aforementioned multiple arms extend radially from the proximal end. Intragastric retention system.

36. The gastric retention system according to claim 35, comprising a core, wherein each of the plurality of arms is connected to the core at the proximal end of each arm.

37. The gastric retention system according to claim 35 or 36, wherein the plurality of arms include at least three arms.

38. The gastric retention system according to claim 35 or 36, wherein the plurality of arms are configured to carry a pharmaceutical active ingredient.

39. The gastric retention system according to any one of claims 35 to 38, wherein the plurality of arms carry 40 to 60% of the active pharmaceutical ingredient.

40. The gastric retention system according to any one of claims 36 to 39, comprising a plurality of linker components, wherein one of the plurality of linker components connects one of the plurality of arms to the core.

41. The gastric retention system according to claim 40, wherein each of the plurality of linker components is decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

42. The gastric retention system according to any one of claims 35 to 41, wherein the gastric retention system is configured to be folded during administration and to be in an open configuration when it is in the patient's stomach.

43. The gastric retention system according to claim 42, wherein the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system takes the open configuration.

44. The gastric retention system according to any one of claims 35 to 43, wherein the gastric retention system has a multi-arm star shape in the open configuration.

45. The gastric retention system according to any one of claims 35 to 44, wherein, as measured by radial testing, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times greater than the force required to compress a gastric retention system without filaments to a configuration small enough to pass through the opening.

46. The gastric retention system according to any one of claims 35 to 45, wherein, when the gastric retention system is left at constant temperature in a pH 1.6 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

47. The gastric retention system according to any one of claims 35 to 46, wherein, when the gastric retention system is left at a constant temperature in a pH 6.5 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

48. The gastric retention system according to any one of claims 35 to 47, wherein the distal end of each of the plurality of arms contains an enteric-coated material.

49. The gastric retention system according to any one of claims 35 to 48, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

50. The gastric retention system according to claim 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.

51. The gastric retention system according to claim 50, wherein the polymer comprises polycaprolactone or TPU.

52. The gastric retention system according to claim 50 or 51, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate.

53. The gastric retention system according to any one of claims 50 to 52, wherein the plasticizer comprises propylene glycol.

54. The gastric retention system according to any one of claims 50 to 53, wherein the acid comprises stearic acid.

55. The gastric retention system according to any one of claims 35 to 54, wherein the distal end of each arm includes a notch, and the filament is positioned within the notch of each distal end.

56. The gastric retention system according to claim 55, wherein the first end and the second end of the filament are overlapped and fixed within a first notch, and the first end and the second end are fixed by either a knotting or heat spreading process.

57. The gastric retention system according to any one of claims 35 to 56, wherein each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, the first segment having greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

58. The gastric retention system according to claim 57, wherein, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

59. The gastric retention system according to claim 57 or 58, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

60. The gastric retention system according to any one of claims 57 to 59, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

61. The gastric retention system according to any one of claims 57 to 60, wherein the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

62. The gastric retention system according to any one of claims 57 to 61, wherein the first segment is directly connected to the second segment of at least the first arm of the plurality of arms.

63. The gastric retention system according to any one of claims 57 to 62, wherein the first segment is connected to the second segment via a linker component.

64. The gastric retention system according to any one of claims 57 to 63, wherein the first segment constitutes at least 20 to 50% of the length of the first arm, the length of which 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 core.

65. The gastric retention system according to any one of claims 57 to 64, wherein the second segment constitutes 50 to 80% of the length of at least one arm, the length of which 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 core.

66. The gastric retention system according to any one of claims 57 to 65, wherein, when measured using a double funnel test, the number of fatigue cycles required for the rupture of the gastric retention system is at least 25% greater than the number of fatigue cycles required for the rupture of the gastric retention system having an arm containing only the first polymer composition.

67. The gastric retention system according to any one of claims 35 to 66, wherein the gastric retention system is configured to be enclosed in a capsule when 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 to take on an open configuration.

68. The gastric retention system according to any one of claims 35 to 67, wherein the gastric retention system is used for the treatment of a patient.

69. The gastric retention system according to claim 68, wherein the patient is a human or a dog.

70. A method for manufacturing a gastric retention system, To create an intragastric retention system comprising a plurality of arms connected to a core at their proximal ends via a plurality of linker components, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially. To make a notch in each of the aforementioned multiple arms, The filament is wound circumferentially around the gastric retention system such that the filament is positioned within each notch of each arm, and Close each notch to secure the filament within each notch. Methods that include...

71. The method according to claim 70, wherein the filament connects the distal ends of each of the plurality of arms in the circumferential direction.

72. The method according to claim 70 or 71, wherein the plurality of arms include at least three arms.

73. The method according to any one of claims 70 to 72, wherein the plurality of arms are configured to carry a pharmaceutical active ingredient.

74. The method according to any one of claims 70 to 73, wherein the plurality of arms carry 40 to 60% of the active pharmaceutical ingredient.

75. The method according to any one of claims 70 to 74, wherein the linker component is decomposed, dissolved, dissociated, or mechanically weakened in the gastric environment.

76. The method according to any one of claims 70 to 75, wherein the gastric retention system is configured to be folded during administration and to be in an open configuration when it is in the patient's stomach.

77. The method according to claim 76, wherein the core undergoes elastic deformation when the gastric retention system is in the folded configuration and recoils when the gastric retention system takes the open configuration.

78. The gastric retention system according to any one of claims 70 to 77, wherein the open configuration has a multi-armed star shape.

79. The method according to any one of claims 70 to 78, wherein closing each notch includes at least one of stopping or heating.

80. The method according to any one of claims 70 to 79, wherein, as measured by radial testing, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.5 times greater than the force required to compress a filamentless gastric retention system to a configuration small enough to pass through the opening.

81. The method according to any one of claims 70 to 80, wherein, when the gastric retention system is left at constant temperature in a pH 1.6 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm of the plurality of arms is greater than 1 N.

82. The method according to any one of claims 70 to 81, wherein, when the gastric retention system is left at a constant temperature in a pH 6.5 environment for 3 days and then measured, the pull-out force required to separate the filament from the distal end of the first arm among the plurality of arms is less than 2 N.

83. The method according to any one of claims 70 to 82, wherein the distal end of each of the plurality of arms contains an enteric-coated material.

84. The method according to any one of claims 70 to 83, wherein the filament comprises one or more of an elastic polymer, a bioabsorbable polymer, and a plasticizer.

85. The method according to claims 70 to 84, wherein the enteric material at the distal end of each arm comprises a polymer, an enteric polymer, a plasticizer, and an acid.

86. The method according to claim 85, wherein the polymer comprises polycaprolactone.

87. The method according to claim 85 or 86, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate.

88. The method according to any one of claims 85 to 87, wherein the plasticizer comprises propylene glycol.

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

90. The method according to any one of claims 70 to 89, wherein each of the plurality of arms comprises a first segment containing a first polymer composition and a second segment containing a second polymer composition, the first segment having greater stiffness than the second segment when measured by a three-point bending test according to ASTM D790.

91. The method according to claim 90, wherein, when measured using a throttling test mechanism, the force required to compress the gastric retention system to a configuration small enough to pass through an opening with a diameter of 20 mm is at least 1.2 times greater than the force required to compress a gastric retention system having an arm containing only the first polymer composition to a configuration small enough to pass through the opening.

92. The method according to claim 90 or 91, wherein the first polymer composition comprises one or more of PCL, PLA, PLGA, HPMCAS, and TPU.

93. The method according to any one of claims 90 to 92, wherein the second polymer composition comprises one or more of polyurethane, polyether-polyamide copolymer, thermoplastic elastic material, thermoplastic polyurethane, polycaprolactone-polylactic acid copolymer, polytrimethylene carbonate, polysebacate glycerol, and silicone.

94. The method according to any one of claims 90 to 93, wherein the second polymer composition comprises at least polycaprolactone and a soluble material, forming a material that softens when exposed to an aqueous environment.

95. The method according to any one of claims 90 to 94, wherein the first segment is directly connected to the second segment of at least one arm.

96. The method according to any one of claims 90 to 95, wherein the first segment is connected to the second segment via a linker component.

97. The method according to any one of claims 90 to 96, wherein the first segment constitutes 20 to 50% of the length of the at least one arm, and this 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 core.

98. The method according to any one of claims 90 to 97, wherein the second segment constitutes 50 to 80% of the length of the at least one arm, and this 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 core.

99. The method according to any one of claims 90 to 98, wherein, when measured using a double funnel test, the number of fatigue cycles required for rupture of the intragastric retention system is at least 25% greater than the number of fatigue cycles required for rupture of an intragastric retention system having an arm containing only the first polymer composition.

100. The method according to any one of claims 90 to 99, wherein the gastric retention system is configured to be enclosed in a capsule when 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 to take on an open configuration.

101. A gastric retention system, manufactured by the method of any one of claims 70 to 100, for use in the treatment of a patient.

102. The gastric retention system according to claim 101, wherein the patient is a human or a dog.

103. A method for manufacturing a gastric retention system, To create an intragastric retention system comprising a plurality of arms connected to a core at their proximal ends via a plurality of linker components, wherein one of the plurality of linker components corresponds to each of the plurality of arms, and the plurality of arms extend radially. To manufacture one or more chips for each of the multiple arms, and filaments attached to each of the multiple chips, and Each of the multiple chips is connected to one of the multiple arms to form a gastric retention system including a filament. Methods that include...

104. The method according to claim 103, wherein the production of multiple chips and filaments includes injection molding.

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