Polymer linkers for gastric retention systems

Abstract

Described herein are gastric retention systems and methods for using the systems to deliver drugs to an individual. The gastric retention systems may include a time-dependent polymeric linker and / or an enteric polymeric linker, or a time-dependent and enteric dual-sided polymeric linker. In some embodiments, the time-dependent polymeric linker includes PLGA, optionally including PLA or a support polymer. The enteric polymeric linker includes an enteric polymer, optionally including a support polymer such as PCL or TPU. The time-dependent polymeric linker may degrade in the individual's stomach according to the degradation (i.e., loss of flexural modulus) characteristics described herein, and the enteric polymeric linker may degrade in the individual's intestine according to the other degradation (i.e., loss of flexural modulus) characteristics described herein.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the priority of U.S. Provisional Patent Application No. 62 / 933,226, filed on November 8, 2019. The entire content of the said application is incorporated herein by reference.

[0002] [Description of Research and Development Funded by the Federal Government] The present invention was made under government support awarded by the National Institutes of Health under R01 AI131416. The government has certain rights in this invention.

[0003] The present invention relates to an intragastric retention system for the gastric sustained release of drugs and a method of using the same.

Background Art

[0004] An intragastric retention system is a drug delivery system that remains in the stomach for several days to several weeks, or even longer, during which a drug or other agent can elute from the system and be absorbed in the gastrointestinal tract. Examples of such systems are described in International Patent Applications No. WO 2015 / 191920, No. WO 2015 / 191925, No. WO 2017 / 070612, WO 2017 / 100367, and No. WO 2017 / 205844. Each of these documents is incorporated herein by reference. During the retention period, the system releases an agent, for example, one or more drugs.

[0005] 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.

[0006] This invention describes advances in the design and manufacture of gastric retention systems that enable complex adjustments of the materials and system structure used in the system.

[0007] All publications, patents, patent applications, and published patent applications referenced herein by specific reference are incorporated herein by reference in their entirety. [Overview of the project]

[0008] This specification describes gastric retention systems comprising time-dependent polymer linkers and / or enteric-coated polymer linkers, along with methods for treating patients using these gastric retention systems. Time-dependent polymer linkers degrade under aqueous conditions and act as timers for gastric retention. Enteric-coated polymer linkers degrade rapidly in the small intestine and act as a safety mechanism to limit the risk of intestinal obstruction.

[0009] This specification describes an intragastric retention system comprising one or more first structural members containing a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via polymer linkers, the polymer linkers comprising poly(lactic acid-co-glycolide) (PLGA) and at least one additional linker polymer, the polymer linkers losing 20% ​​or more of their flexural modulus or rupturing after being left at constant temperature at 37°C for 30 days in an aqueous solution of pH 1.6, and the intragastric retention system is retained in the stomach for a period of at least 24 hours.

[0010] In some embodiments of the gastric retention system described above, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6.In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses more than 90% of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6.

[0011] Depending on the embodiment of the gastric retention system, the at least one additional linker polymer may include polylactic acid (PLA), a supported polymer, polycaprolactone (PCL), or thermoplastic polyurethane (TPU). Depending on the embodiment, the supported polymer may include PCL, and the at least one additional linker polymer may include PCL. Depending on the embodiment, the supported polymer may include TPU, and the at least one additional linker polymer may include TPU. Depending on the embodiment, the at least one additional linker polymer may include PLA. Depending on the embodiment, the supported polymer may include PCL or TPU.

[0012] This specification also describes an intragastric retention system comprising one or more first structural members comprising a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via polymer linkers, the polymer linkers comprising (a) poly(lactic acid-co-glycolide) (PLGA) and (b) polylactic acid (PLA), polycaprolactone (PCL), or thermoplastic polyurethane (TPU), and the intragastric retention system is retained in the stomach for a period of at least 24 hours.

[0013] In some embodiments of the gastric retention system, the supported polymer includes PCL, and the polymer linker includes PLGA and PCL. In some embodiments, the supported polymer includes TPU, and the polymer linker includes PLGA and TPU. In some embodiments, the polymer linker includes PLGA and PLA. In some embodiments, the supported polymer includes TPU or PCL.

[0014] In any embodiment of the gastric retention system described above, the PLGA comprises poly(D,L-lactic acid-co-glycolide) (PDLG). In some embodiments, the PLGA comprises acid-terminated PLGA. In some embodiments, the PLGA comprises ester-terminated PLGA. In some embodiments, the PLGA comprises acid-terminated PLGA and ester-terminated PLGA in a ratio of about 1:9 to about 9:1. In some embodiments, the polymer linker comprises about 70% by weight or less of PLGA. In some embodiments, the polymer linker comprises about 30% by weight to about 70% by weight of PLGA.

[0015] In any embodiment of the gastric retention system described above, the polymer linker further comprises an enteric-coated polymer. In some embodiments, the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate (HPMCAS). In some embodiments, the polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5. In some embodiments, the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5. In some embodiments, the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5. In some embodiments, the polymer linker further loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5. In some embodiments, the polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses more than 10% of the flexural modulus that decreases after being left at a constant temperature of 37°C for three days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses more than 20% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution with pH 6.5 at 37°C.In some embodiments, the polymer linker loses more than 40% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 1.6, compared to when it is left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C. In some embodiments, the polymer linker loses more than 60% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 1.6, compared to when it is left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C. In some embodiments, the polymer linker loses more than 80% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 1.6, compared to when it is left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0016] In any embodiment of the gastric retention system described above, one or more first structural members are attached to a second structural member via a polymer linker and a second polymer linker, the second polymer linker comprising an enteric polymer. In some embodiments, the second polymer linker further comprises TPU, PCL, or PLGA. In some embodiments, the second polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0017] This specification further describes an intragastric retention system comprising one or more first structural members comprising a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker, the polymer linker comprising (a) thermoplastic polyurethane (TPU) or poly(lactic acid-co-glycolide) (PLGA), and (b) an enteric polymer, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5, and the intragastric retention system is retained in the stomach for a period of at least 24 hours.

[0018] In some embodiments, the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 1 day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 1 day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker further loses more than 60% of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5. In some embodiments, the polymer linker further loses more than 80% of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5. In some embodiments, the polymer linker loses more than 10% of the flexural modulus that decreases after being left at a constant temperature of 37°C for three days in an aqueous solution of pH 6.5. In some embodiments, the polymer linker loses more than 20% of the flexural modulus that decreases after being left at a constant temperature of 37°C for three days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses more than 40% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 1.6, compared to the decrease after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C. In some embodiments, the polymer linker loses more than 60% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 1.6, compared to the decrease after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.In some embodiments, the polymer linker loses more than 80% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution with pH 6.5 at 37°C.

[0019] In some embodiments, the supported polymer includes TPU, and the one or more polymer linkers include TPU. In some embodiments, the polymer linker further includes polylactic acid (PLA). In some embodiments, the polymer linker includes PLGA. In some embodiments, the PLGA is poly(D,L-lactic acid-co-glycolide) (PDLG). In some embodiments, the PLGA includes acid-terminated PLGA. In some embodiments, the PLGA includes ester-terminated PLGA. In some embodiments, the PLGA contains acid-terminated PLGA and ester-terminated PLGA in a ratio of about 1:9 to about 9:1. In some embodiments, the polymer linker contains about 70% by weight or less of PLGA. In some embodiments, the polymer linker contains about 30% by weight to about 70% by weight of PLGA.

[0020] In some embodiments, the enteric-coated polymer includes hydroxypropyl methylcellulose succinate acetate (HPMCAS).

[0021] Depending on the embodiment, the polymer linker contains approximately 20% to 80% by weight of enteric-coated polymer.

[0022] Depending on the embodiment of the gastric retention system described above, the polymer linker contains about 0.5% to about 20% by weight of a plasticizer. Depending on the embodiment, the plasticizer may include propylene glycol, polyethylene glycol (PEG), butyl triethyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer, or D-α-tocopheryl polyethylene glycol succinate.

[0023] This specification also describes an intragastric retention system comprising one or more first structural members comprising a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker comprising a linker polymer and about 0.5% to about 20% by weight of a plasticizer, and the intragastric retention system is retained in the stomach for a period of at least 24 hours. In some embodiments, the polymer linker comprises about 0.5% to about 12% of a plasticizer. In some embodiments, the linker polymer comprises an enteric polymer.

[0024] In some embodiments of the gastric retention system described above, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 1 day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses more than 40% of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses more than 60% of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses more than 80% of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution with a pH of 6.5. In some embodiments, the polymer linker loses more than 10% of the flexural modulus that would decrease after being left at a constant temperature of 37°C for three days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses more than 20% of the flexural modulus that decreases after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5 compared to being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses more than 40% of the flexural modulus that decreases after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5 compared to being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses more than 60% of the flexural modulus that decreases after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5 compared to being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 1.6.In some embodiments, the polymer linker loses a flexural modulus greater than 80% of the flexural modulus that decreases after being kept at a constant temperature in an aqueous solution at pH 6.5 for 3 days at 37 °C and then in an aqueous solution at pH 1.6 for 3 days at a constant temperature.

[0025] In some embodiments of the above gastric retention system, the enteric polymer includes hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0026] In some embodiments of the above gastric retention system, the polymer linker contains about 20 wt% to about 80 wt% of an enteric polymer.

[0027] In some embodiments of the above gastric retention system, the linker polymer includes the carrier polymer. In some embodiments, the carrier polymer is polycaprolactone (PCL) or thermoplastic polyurethane (TPU). In some embodiments, the linker polymer includes polylactic acid (PLA), polycaprolactone (PCL), or thermoplastic polyurethane (TPU).

[0028] In some embodiments of the gastric retention system described above, the linker polymer includes a time-dependent degradable polymer. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6.In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6. In some embodiments, the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 1.6.

[0029] In some embodiments of the gastric retention system described above, the time-dependent degradable polymer includes poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the PLGA includes poly(D,L-lactic-co-glycolic acid) (PDLG). In some embodiments, the PLGA includes acid-terminated PLGA. In some embodiments, the PLGA includes ester-terminated PLGA. In some embodiments, the PLGA includes acid-terminated PLGA and ester-terminated PLGA in a ratio of about 1:9 to about 9:1. In some embodiments, the polymeric linker includes up to about 70% by weight of PLGA. In some embodiments, the polymeric linker includes from about 30% to about 70% of PLGA.

[0030] In some embodiments of the gastric retention system described above, the plasticizer includes propylene glycol, polyethylene glycol (PEG), tributyltriethyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer, or succinic acid D-α-tocopheryl polyethylene glycol.

[0031] The present specification further describes a gastric retention system including one or more first structural members including a carrier polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymeric linker, the polymeric linker includes (a) a pH-independent degradable polymer, and (b) an enteric polymer, and the gastric retention system is retained in the stomach for a period of at least 24 hours.

[0032] In some embodiments of the gastric retention system described above, the polymeric linker further includes a carrier polymer. In some embodiments, the carrier polymer is TPU or PCL.

[0033] In some embodiments of the gastric retention system described above, the pH-independent degradable polymer includes PLGA. In some embodiments, the PLGA is poly(D,L-lactic acid-co-glycolide) (PDLG). In some embodiments, the PLGA includes acid-terminated PLGA. In some embodiments, the PLGA includes ester-terminated PLGA. In some embodiments, the PLGA contains acid-terminated PLGA and ester-terminated PLGA in a ratio of about 1:9 to about 9:1. In some embodiments, the polymer linker contains about 70% by weight or less of PLGA. In some embodiments, the polymer linker contains about 30% by weight to about 70% by weight of PLGA.

[0034] In some embodiments of the gastric retention system described above, the enteric-coated polymer includes hydroxypropyl methylcellulose succinate acetate (HPMCAS).

[0035] Depending on the embodiment of the gastric retention system described above, the polymer linker contains approximately 20% to 80% by weight of an enteric-coated polymer.

[0036] Depending on the embodiment of the gastric retention system described above, the polymer linker contains about 0.5% to about 20% by weight of a plasticizer. Depending on the embodiment, the plasticizer may include propylene glycol, polyethylene glycol (PEG), butyl triethyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer, or D-α-tocopheryl polyethylene glycol succinate.

[0037] In any of the above embodiments of the gastric retention system, the materials in the polymer linker are homogeneously blended.

[0038] In any of the embodiments of the gastric retention system described above, the polymer linker is substantially free of the drug.

[0039] In any of the embodiments of the gastric retention system described above, the polymer linker further comprises a color-absorbing dye. In some embodiments, the color-absorbing dye comprises iron oxide.

[0040] In any embodiment of the intragastric retention system described above, the system comprises a plurality of first structural members, each first structural member being attached to a second structural member via a separate polymer linker, the second structural member being an elastic central member, the intragastric retention system being configured to fold and be physically constrained during administration, and to assume an open retaining shape when the constrainment is removed, and the change between the folded shape and the open retaining shape is mediated by the elastic central member, which undergoes elastic deformation when the retention structure is in the folded shape and recoils when the intragastric retention structure assumes the open retaining shape. In some embodiments, the intragastric retention system is constrained within a capsule configured to decompose in the stomach.

[0041] In any of the embodiments of the gastric retention system described above, the agent is a drug.

[0042] In any of the embodiments of the gastric retention system described above, the second structural member is an elastic body.

[0043] In any of the embodiments of the gastric retention system described above, the second structural member is a central elastic body, and the one or more first structural members are arms projecting radially from the central elastic body.

[0044] In any of the embodiments of the gastric retention system described above, the gastric retention system is retained in the stomach for at least 48 hours. In any embodiment, the gastric retention system is retained in the stomach for at least 3 days. In any embodiment, the gastric retention system is retained in the stomach for at least 7 days. In any embodiment, the gastric retention system is retained in the stomach for at least 14 days. In any embodiment, the gastric retention system is retained in the stomach for at least 30 days.

[0045] This specification further describes a method for delivering a drug to an individual, which includes deploying one of the gastric retention systems described above into the stomach of the individual. In some embodiments, the individual is a human.

[0046] Any configuration of the embodiments described above and herein can be combined with any of the other embodiments described above and herein where appropriate and practical. [Brief explanation of the drawing]

[0047] [Figure 1A] Figure 1A shows an exemplary star-shaped configuration of the gastric retention system described herein.

[0048] [Figure 1B] Figure 1B shows another exemplary star-shaped configuration of the gastric retention system described herein.

[0049] [Figure 1C] Figure 1C shows an exemplary annular configuration of the gastric retention system described herein.

[0050] [Figure 1D] Figure 1D shows another exemplary annular configuration of the gastric retention system described herein.

[0051] [Figure 2A] Figure 2A shows a portion of the gastric retention system, including an exemplary configuration of a structural member attached to a second structural member via a polymer linker.

[0052] [Figure 2B] Figure 2B shows a portion of the gastric retention system, including another exemplary configuration of a structural member attached to a second structural member via a polymer linker.

[0053] [Figure 2C]Figure 2C shows a portion of the intragastric retention system, including another exemplary configuration of a structural member attached to a second structural member via a polymer linker.

[0054] [Figure 2D] Figure 2D shows a portion of the intragastric retention system, including an exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0055] [Figure 2E] Figure 2E shows a portion of the gastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0056] [Figure 2F] Figure 2F shows a portion of the intragastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0057] [Figure 2G] Figure 2G shows a portion of the intragastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0058] [Figure 2H] Figure 2H shows a portion of the gastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0059] [Figure 2I] Figure 2I shows a portion of the intragastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0060] [Figure 2J] Figure 2J shows a portion of the gastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0061] [Figure 2K] Figure 2K shows a portion of the intragastric retention system, including another exemplary configuration of a structural member attached to a second structural member via two polymer linkers.

[0062] [Figure 3] Figure 3 shows an exemplary method for bonding multiple components together to form an intragastric retention system.

[0063] [Figure 4] Figure 4 shows a method for testing the flexural modulus of a material using a three-point bending test.

[0064] [Figure 5] Figure 5 shows the flexural modulus results at various time points after leaving various time-dependent polymer linkers at constant temperature in simulated gastric juice (FaSSGF) under fasting conditions.

[0065] [Figure 6] Figure 6 shows the results of the flexural modulus of various time-dependent polymer linkers after being left at constant temperature in FaSSGF at various time points.

[0066] [Figure 7] Figure 7 shows the results of the flexural modulus of time-dependent polymer linkers containing different amounts of PLGA after being left at constant temperature in FaSSGF for 3 and 18 days.

[0067] [Figure 8] Figure 8 shows the results of the flexural modulus after pH-independent time-dependent polymer linkers were left at a constant temperature over time in aqueous solutions with different pH values.

[0068] [Figure 9] Figure 9 compares the flexural modulus of enteric-coated polymer linkers left at constant temperature over time in FaSSGF or simulated intestinal fluid under fasting conditions (FaSSIF).

[0069] [Figure 10]Figure 10 compares the flexural modulus over time of enteric-coated polymer linkers containing different amounts of HPMCAS after being left at constant temperature in FaSSIF.

[0070] [Figure 11] Figure 11 compares the flexural moduli of enteric-coated polymer linkers containing different amounts of propylene glycol after being left at constant temperature in FaSSGF or FaSSIF.

[0071] [Figure 12] Figure 12 compares the flexural modulus over time of time-dependent, enteric-coated, dual-function polymer linkers, including enteric-coated polymers (HPMCAS) and pH-independent biodegradable polymers (PLGA), after being left at constant temperature in FaSSGF or FaSSIF.

[0072] [Figure 13A] Figure 13A shows the melt flow indices for various materials having a supported polymer (base polymer), a time-dependent polymer linker, and a plasticizer, or containing an enteric linker within the plasticizer.

[0073] [Figure 13B] Figure 13B shows the melt flow indices of enteric-coated polymer linker materials with different amounts of plasticizer, measured at 120°C and a load of 2.16 kg.

[0074] [Figure 14A] Figure 14A shows the change in tensile strength of the bond after joining enteric-coated polymer linkers with different amounts of plasticizer to a time-dependent linker.

[0075] [Figure 14B] Figure 14B shows the tensile strength of the bonds connecting enteric-coated polymer linkers with different amounts of plasticizer to time-dependent linkers. Values ​​shown in circles represent materials where the increased plasticizer replaces both PCL and HPMCAS, while values ​​shown in squares represent materials with a constant amount of PCL.

[0076] [Figure 15A] Figure 15A shows the flexural modulus of various enteric-coated polymer linker materials after being left at a constant temperature in FaSSGF or FaSSIF.

[0077] [Figure 15B] Figure 15B shows the flexural modulus as a function of time of an enteric-coated polymer linker material containing 60% HPMCAS and 40% TPU after being left at constant temperature in FaSSGF or FaSSIF.

[0078] [Figure 16] Figure 16 shows the gastric retention times of gastric retention systems having enteric-coated polymers mixed with supported (i.e., base) polymers in different amounts.

[0079] [Figure 17A] Figure 17A shows a non-planar compression (CINC) test apparatus that is periodically kept at a constant temperature to maintain the gastric retention system of astrocytes.

[0080] [Figure 17B] Figure 17B is an internal side view of a periodic excitation non-planar compression (CINC) test apparatus, showing the slots where the star-shaped arms are positioned.

[0081] [Figure 18] Figure 18 is a schematic diagram summarizing the stress relaxation test procedure, showing the angles measured to track the degree of linker deformation. Panel A shows the measured angles of linker deformation before the stress relaxation test, Panel B shows the angles after compression and constant temperature standing (4 hours), and Panel C shows the angles after the test.

[0082] [Figure 19A] Figures 19A and 19B show the results of the stress relaxation "window" test. For the three different linkers listed in Table 10, Figure 19A shows the percentage difference in arm angle over time after the window test in the star-shaped arm, and Figure 19B also includes the percentage difference in arm angle after recovery. This data demonstrates clear distinctions in the behavior of the star-shaped and, consequently, the linkers. [Figure 19B] Figures 19A and 19B show the results of the stress relaxation "window" test. For the three different linkers listed in Table 10, Figure 19A shows the percentage difference in arm angle over time after the window test in the star-shaped arm, and Figure 19B also includes the percentage difference in arm angle after recovery. This data demonstrates clear distinctions in the behavior of the star-shaped and, consequently, the linkers.

[0083] [Figure 20] Figure 20 shows the time-dependent, tunable stress relaxation behavior of astrocytes with time-delayed linkers. The properties outlined for time-delayed linker 1 are associated with a gastric retention of 7.2 ± 3.2 days, and the properties outlined for time-delayed linker 2 are associated with a gastric retention of 19.3 ± 3.9 days.

[0084] [Figure 21] Figure 21 shows the results of a multi-day post-astromorphic deformation stress relaxation test in FaSSGF versus FaSSIF. This data was collected using a representative enteric-coated linker 1.

[0085] [Figure 22A] Figures 22A and 22B show the decay of typical time-delayed linkers and enteric-coated linkers in the relevant media. Figure 22A shows the three-point flexural moduli of time-delayed linkers 1, 2, and 3 in simulated gastric juice under fasting conditions. Figure 22B shows the three-point flexural moduli of enteric-coated linkers 1, 2, and 3 in simulated gastric juice or simulated intestinal juice under fasting conditions. [Figure 22B] Figures 22A and 22B show the decay of typical time-delayed linkers and enteric-coated linkers in the relevant media. Figure 22A shows the three-point flexural moduli of time-delayed linkers 1, 2, and 3 in simulated gastric juice under fasting conditions. Figure 22B shows the three-point flexural moduli of enteric-coated linkers 1, 2, and 3 in simulated gastric juice or simulated intestinal juice under fasting conditions. [Detailed Description of the Invention]

[0086] This specification describes intragastric retention systems, methods for fabricating intragastric retention systems, and methods for delivering drugs to an individual using intragastric retention systems. An intragastric retention system comprises one or more drug-containing structural members attached to a second structural member via one or more polymer linkers. The polymer linkers connecting the drug-containing members to the second member may be enteric-coated linkers (i.e., configured to degrade in the gastric environment), time-dependent linkers (i.e., configured to degrade over time in the gastric environment), or both (i.e., possessing the properties of both an enteric-coated and a time-dependent linker). Some embodiments of the intragastric retention system include two polymer linkers (including an enteric-coated linker and a time-dependent linker) connecting one or more drug-containing members to the second member. If necessary, spacer elements may be separated so as not to directly contact the first and second polymer linkers.

[0087] The intragastric retention system is deployed in the individual's stomach, and the drug contained in the drug-containing component diffuses from the intragastric retention system into the gastric environment over an intragastric retention period, for example, approximately 24 hours or more. Once the drug is depleted from the intragastric retention system, the system must safely exit the gastrointestinal system. The amount of time it takes to exit the stomach must be reliable so that the system does not exit too quickly (potentially resulting in insufficient drug delivery during the intended retention period) or too slowly (potentially causing gastric obstruction or drug overdelivery). Furthermore, if the intragastric retention system moves to the intestines, it must decompose rapidly to avoid intestinal obstruction. Therefore, the polymer linker of the intragastric retention system described herein may be configured to pass from the individual's stomach to the intestines after the intended retention period has ended (time-dependent linker), or to decompose rapidly in the intestinal environment and pass through (enteric-coated linker).

[0088] Components of the gastric retention system (e.g., drug-containing structural members or other structural members, linkers, etc.) are joined by, for example, a thermal bonding process (e.g., laser beam welding or infrared (IR) welding). This process joins dissimilar materials with different intended functional properties (e.g., drug dissolution, weakening or rupture in the intestine, or time-dependent weakening or rupture). However, the materials must be joined by a strong bond that does not unintentionally rupture during gastric retention. As further described herein, the bond strength between the structural element and the polymer linker may be enhanced by including in the polymer linker one or more of the following: (1) a certain amount of plasticizer, (2) a color-absorbing dye, and / or (3) a supported polymer contained in the bonded structural element. definition

[0089] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated or clearly indicated by the context.

[0090] 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."

[0091] "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.

[0092] 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).

[0093] 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.

[0094] "Supported polymers" are polymers that are suitable for blending with drugs and other medications for use in the gastric retention system.

[0095] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0096] 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.

[0097] An "elastic polymer" or "elastic body" 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.

[0098] 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.

[0099] 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.

[0100] "Individual," "patient," 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.

[0101] "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.

[0102] Two polymers of the "same polymer species" refer to two polymers that are composed of one or more identical monomer units (in the case of copolymers), even if their average weight, average molecular weight, intrinsic viscosity, monomer ratio (in the case of copolymers), or other physical properties differ.

[0103] "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 agents, to suppress the clinical manifestation of a disease or disorder, or to suppress the manifestation of adverse symptoms of a disease or disorder. The difference between treatment and suppression is that treatment is performed after adverse symptoms of a disease or disorder have appeared in a patient, while suppression is performed before adverse symptoms of a disease or disorder have appeared in a 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 developing a disease or disorder. The systems and methods disclosed herein can then be used to treat asymptomatic patients at risk of developing clinical symptoms of a disease or disorder in order to suppress the manifestation of any adverse symptoms.

[0104] 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.

[0105] "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.

[0106] Time-dependent materials, such as time-dependent polymers or time-dependent linkers, are materials that decompose over time once the gastric retention system is deployed within the stomach.

[0107] When the absolute numerical property of the first material is described as "within X%" of the corresponding absolute numerical property of the second material having the value "Y", it is understood that the absolute numerical property of the first material may fall within the range of (Y - (X% of Y)) to (Y + (X% of Y)). For example, if a material is described as having a flexural modulus within 30% of the flexural modulus of the material after being left at constant temperature under the second condition, and the material after being left at constant temperature under the second condition has a flexural modulus of 1000 MPa, then the material after being left at constant temperature under the first condition may have a flexural modulus of 700 MPa to 1300 MPa. When the absolute numerical property of the first material is described as "greater than X%" of the corresponding absolute numerical property of the second material having the value "Y", it is understood that the absolute numerical property of the first material may exceed (Y + (X% of Y)). For example, if a material is described as having a flexural modulus greater than 30% of its flexural modulus after being left at a constant temperature under a second condition, and the material after being left at a constant temperature under the second condition has a flexural modulus of 1000 MPa, then the material after being left at a constant temperature under the first condition has a flexural modulus of 1300 MPa. Similarly, if the absolute numerical property of the first material is described as "less than X%" of the corresponding absolute numerical property of the second material having a value of "Y", it is understood that the absolute numerical property of the first material is greater than (Y - (X% of Y)). For example, if a material is described as having a flexural modulus less than 30% of the flexural modulus of the material after being left at a constant temperature under a second condition, and the material after being left at a constant temperature under the second condition has a flexural modulus of 1000 MPa, then the material after being left at a constant temperature under the first condition has a flexural modulus of less than 700 MPa.

[0108] When the relative numerical properties of the first material are described as being "within X%" relative to the corresponding relative numerical properties of the second material having a value of "Y%", it is understood that the relative numerical properties of the first material can fall within the range of (YX)% to (Y+X)% (however, the lower limit cannot be less than 0%, and the upper limit cannot exceed 100%). For example, if it is stated that a material loses 10% or less of its flexural modulus after being left at a constant temperature under the first condition compared to the decrease in its flexural modulus after being left at a constant temperature under the second condition, and the material loses 50% of its flexural modulus after being left at a constant temperature under the second condition, then the material after being left at a constant temperature under the first condition loses 40% to 60% of its flexural modulus. When the relative numerical property of the first material is described as "greater than X%" relative to the corresponding relative numerical property of the second material which has a value of "Y%", it is understood that the relative numerical property of the first material exceeds (Y + X)% (however, the upper limit of the relative numerical property cannot exceed 100%). For example, if it is stated that a material loses more than 10% of its flexural modulus after being left at constant temperature under the first condition compared to the decrease in its flexural modulus after being left at constant temperature under the second condition, and the material loses 50% of its flexural modulus after being left at constant temperature under the second condition, then the material after being left at constant temperature under the first condition loses more than 60% of its flexural modulus. Similarly, if the relative numerical property of the first material is described as being "less than X%" of the corresponding relative numerical property of the second material having a value of "Y%", it is understood that the relative numerical property of the first material is less than (YX)% (however, the lower limit of the relative numerical property cannot be less than 0%). For example, if it is described that a material loses less than 10% of its flexural modulus after being left at constant temperature under the first condition compared to the decrease after being left at constant temperature under the second condition, and that the material loses 50% of its flexural modulus after being left at constant temperature under the second condition, then the material after being left at constant temperature under the first condition loses less than 40% of its flexural modulus.

[0109] Radial force compression test. The radial force compression test using a thoracic mechanism is used to quantify the force required to compress an intact intragastric retention system to a configuration small enough to pass through the pylorus. The instrument used to measure radial force compression (i.e., the thoracic tester) is a Blockwise Model TTR2 tensile tester with a Model RLU124 Twin-Cam® radial compression device, 60 mm (diameter) × 124 mm (length). The intragastric retention system to be measured is placed in the thoracic tester so that the plane of the intragastric retention system is parallel to the thoracic cylinder axis. When testing a star-shaped intragastric retention system with six arms, the tips of four arms are in contact with the inner wall of the thoracic tester, with two arms angled upward and two arms angled downward. The remaining two arms are positioned parallel to the thoracic cylinder axis. As the diameter of the thoracic mechanism decreases, a radial force is applied to the intragastric retention system. The given force measurement is the force required to compress the intragastric retention system to the diameter of the corresponding thoracic mechanism.

[0110] Pull-out force test. The adhesive strength of filaments for the gastric retention system can be tested by a pull-out force test. As previously mentioned, the filaments may be attached to the distal end of the arms. 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 arms along the filament when the gastric retention system is bent by the force of the stomach. Therefore, the pull-out force test described herein can quantify the force required to separate the filament from the distal end of the arm. A gastric retention system with six arms and filaments was prepared, and the arms were separated by cutting the elastic core into six parts. The filaments were cut between each arm. The tensile force required to pull the filament 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.

[0111] 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).

[0112] 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).

[0113] 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".

[0114] Tensile testing. Using an Instron machine with a custom grip (Figure C), the ultimate tensile strength (UTS) of the bond between any combination of stellate components at constant temperature can be evaluated (1) in various constant temperature liquids, (2) after several periods of constant temperature storage, 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, tensile strength can be maximized and ideal stellate performance can be achieved. To test stellate arms with a triangular cross-section, a custom grip with one flat plate and one notch can be used. The vertices of the triangular arms are positioned in the notch, allowing the pressure from the plate to be evenly distributed across the three longitudinal surfaces of the triangular arms. Tensile testing was performed using an Instron 3342 series. A series of hot-melt extruded and thermally bonded equilateral triangular prisms with a 3.33 mm triangular base are gripped by pneumatic operation. 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 the 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 this disclosure.

[0121] 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 WO2017 / 20584, which are incorporated herein by reference in their entirety. Overall structure of the gastric retention system

[0122] The intragastric retention system described herein comprises one or more drug-containing structural members attached to a second structural member via one or more polymer linkers. The polymer linkers used to link the drug-containing members to the second structural member may be enteric-coated polymer linkers, time-dependent polymer linkers, or polymer linkers that are both enteric-coated and time-dependent. The intragastric retention system is configured to remain in the stomach of an individual for a period of intragastric retention (e.g., at least 24 hours), during which time-dependent polymer linkers degrade (i.e., the flexural modulus of the time-dependent polymer linkers decreases) or break. The weakening or breakage of the time-dependent polymer linkers allows the intragastric retention system to pass into the intestines of the individual. In addition, or instead, the intragastric retention system may include enteric-coated polymer linkers that degrade (i.e., the flexural modulus of the enteric-coated polymer linkers decreases) or break in the intestines of the individual after passing through the stomach (even if they pass through too early or after the intended intragastric retention period).

[0123] Gastric retention systems can be prepared in various configurations. The “stellate” configuration of the gastric retention system is also known as a “star-shaped” (or “star”) configuration. An example of a stellate system 100 is schematically shown in Figure 1A. Multiple arms (also called “elongated members”) (only one such arm 102 is numbered for clarity) are attached to a second structural member, namely a central elastic body 104. The arms 102 are joined to the central elastic body 104 via polymer linkers 106 (again, only one polymer linker is numbered for clarity), which function as linker regions. The polymer linkers 106 may be enteric-coated linkers or time-dependent linkers, or may have the properties of both (i.e., both time-dependent and enteric-coated). In this configuration, the system can be folded or compressed at the central elastic body. When folded, the overall length of the system is reduced by approximately half, making it convenient to fit into a container such as a capsule suitable for oral administration. When the capsule reaches the stomach, it dissolves, releasing the gastric retention system. The gastric retention system then unfolds in an uncompressed state and remains in the stomach for the desired retention period.

[0124] Figure 1B shows another embodiment of the star-shaped system 110 having two polymer linkers 112 and 114 that join the arms 116 to a central member 118. The two polymer linkers may be directly joined to one, or, as shown, each may be directly joined to a connecting member 120 that separates the first polymer linker 112 and the second polymer linker 114. The first polymer linker 112, which is close to the central member 118, may be an enteric linker, and the second polymer linker 114, which is distal to the central member 118, may be a time-dependent linker. Alternatively, the first polymer linker 112, which is close to the central member 118, may be a time-dependent linker, and the second polymer linker 114, which is distal to the central member 118, may be an enteric linker. Multiple arms are attached to the central structural member 118 and project radially from there.

[0125] The stellate system can be described as an intragastric retention system for administration to a patient's stomach, comprising an elastic component and three supported polymer-drug components (i.e., “arms” or “elongated members”) attached to this elastic component, containing a supported polymer and a drug or a salt thereof. Each supported polymer-drug component is an arm, having a proximal and distal end, the proximal end of each arm being attached to the elastic component via one or more polymer linkers and projecting radially from the elastic component, and each arm having its distal end not attached to the elastic component, with a radius greater from the elastic component than the proximal end. They are positioned at a greater distance. The polymer linkers may be enteric-coated linkers or time-dependent linkers. The arms can be attached to the central elastic body via polymer linkers or via additional boundary polymer segments. In a star configuration, the gastric retention system may have two, three, four, five, six, seven, eight, nine, or ten or more arms. The arms may be equally spaced around the central elastic body, and if there are N arms, there will be an angle of approximately 360 / N degrees between adjacent arms.

[0126] Figure 1C shows another possible overall configuration of the gastric retention system 130 in an annular configuration. The first arm 132 is joined to the second elongated segment 136 via a polymer linker 134. The second arm may be, for example, an elastic member, which allows the annular system to be configured in a compact state.

[0127] Figure 1D shows another intragastric retention system 140 in an annular configuration. System 140 includes an arm 142 attached to another arm 150 (e.g., around the ring structure) via a first polymer linker 144 and a second polymer linker 148. The first polymer linker 144 and the second polymer linker 148 may be joined directly to each other or via a connecting member 146. Arm 150 may be the same as or different from arm 142. For example, arm 142 may contain a supported polymer and a drug, and arm 150 is an elastic member that allows the ring to be configured in a compressed state. In another example, the connecting member 146 may be an elastic member that allows the ring to be configured in a compressed state.

[0128] Figures 2A-2K show exemplary configurations for attaching a first structural member (e.g., an arm which may contain a drug and a supported polymer) to a second structural member (e.g., an elastic member such as a central member in a star configuration). As will be further described, the exemplary configurations may include one or two polymer linkers, and may include zero, one, two, or three bonding members. Furthermore, the arm may include one or more segments, which may include active or inactive segments.

[0129] Figure 2A shows a portion of the intragastric retention system including an arm 201 which is a polymer linker 202 (which may be an enteric-coated linker, a time-dependent linker, or a time-dependent and enteric-coated dual-function polymer linker) directly attached to a second structural member 203 (e.g., a central member or a central elastic member). The arm 201 may contain a supported polymer and a drug. Depending on the embodiment, the polymer linker 202 may contain the same supported polymer as the arm 201 or the same type of supported polymer.

[0130] Figure 2B shows part of an intragastric retention system including an arm 204 which includes an active segment 205 containing a drug and a supported polymer, and an inactive segment 206 which contains the supported polymer but is substantially free of the drug. The arm 204 is attached to a second structural member 208 (a central member, or central elastic member) via a polymer linker 207 (which may be, for example, an enteric-coated linker, a time-dependent linker, or a time-dependent and enteric-coated dual-function polymer linker). The active segment 205 is distal to the polymer linker 207, the inactive segment 206 is proximal to the polymer linker 207 and directly attached, and the polymer linker 207 is directly attached to the second structural member 208. In some embodiments, the polymer linker 207 contains the same supported polymer as the inactive segment 206 or the same type of supported polymer.

[0131] Figure 2C shows a portion of an intragastric retention system including an arm 209 directly attached to a polymer linker 210 (which may be an enteric-coated linker, a time-dependent linker, or a time-dependent and enteric-coated dual-function polymer linker), the arm being directly attached to a connector 211, the connector being directly attached to a second structural member 212 (e.g., a central member or a central elastic member). The arm 209 may contain a supported polymer and a drug. In some embodiments, the polymer linker 210 contains the same supported polymer as the arm 209 or of the same type. In some embodiments, the connector 211 and the polymer linker 210 contain the same supported polymer as the arm 209 or of the same type.

[0132] Figure 2D shows a portion of the intragastric retention system including an arm 213 directly attached to a first polymer linker 214 (which may be an enteric-coated linker or a time-dependent linker), which is directly attached to a second polymer linker 215 (which is an enteric-coated linker if the first polymer linker 214 is a time-dependent linker, and is a time-dependent linker if the first polymer linker 214 is an enteric-coated linker), which is directly attached to a second structural member 216 (e.g., a central member or a central elastic member). The arm 213 may contain a supported polymer and a drug. In some embodiments, the first polymer linker 214 contains the same supported polymer as the arm 213 or the same type of polymer linker. In some embodiments, the first polymer linker 214 and the second polymer linker 215 contain the same supported polymer as the arm 213 or the same type of supported polymer.

[0133] Figure 2E shows a portion of the intragastric retention system including an arm 217, which is directly attached to a connecting member 218, which is directly attached to a first polymer linker 219, which is directly attached to a second polymer linker 220, which is directly attached to a second structural member 221. The arm 217 contains a supported polymer and a drug. The first polymer linker 219 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 220 may be a time-dependent linker (if the first polymer linker 219 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 219 is a time-dependent linker). The second structural member 221 may be, for example, a central member (e.g., a central elastic member) of the intragastric retention system. The bonding member 218 may contain a supported polymer (for example, the same or similar supported polymer as the arm 217), and the first polymer linker 219 and / or the second polymer linker 220 may contain the same or similar supported polymer.

[0134] Figure 2F shows a portion of the intragastric retention system including an arm 222, which is directly attached to a first polymer linker 223, which is directly attached to a connecting member 224, which is directly attached to a second polymer linker 225, which is directly attached to a second structural member 226. The arm 222 contains a supported polymer and a drug. The first polymer linker 223 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 225 may be a time-dependent linker (if the first polymer linker 223 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 223 is a time-dependent linker). The second structural member 226 may be, for example, a central member of the intragastric retention system (e.g., a central elastic member). In some embodiments, the first polymer linker 223 contains the same or identical supported polymer as the supported polymer present in the arm 222. The binder member 224 positioned between the first polymer linker 223 and the second polymer linker 225 may contain a supported polymer (which may be the same as or of the same type as the supported polymer present in the arm 222), and the first polymer linker 223 and / or the second polymer linker 225 may contain the same as or of the same type as the supported polymer in the binder member 224.

[0135] Figure 2G shows a portion of the intragastric retention system including an arm 227. This arm is directly attached to a first polymer linker 228, which is directly attached to a second polymer linker 229, which is directly attached to a binder 230, which is directly attached to a second structural member 231. The arm 227 contains a supported polymer and a drug. The first polymer linker 228 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 229 may be a time-dependent linker (if the first polymer linker 228 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 228 is a time-dependent linker). The second structural member 231 may be, for example, a central member of the intragastric retention system (e.g., a central elastic member). Depending on the embodiment, the first polymer linker 228 contains the same or the same type of supported polymer as the arm 227. The binder member 230 may contain a supported polymer (which may be the same as or of the same type as the supported polymer in arm 227), and the first polymer linker 228 and / or the second polymer linker 229 may contain the same as or of the same type as the supported polymer in binder member 230.

[0136] Figure 2H shows a portion of the intragastric retention system including an arm 232, which is directly attached to a first connector 233, which is directly attached to a first polymer linker 234, which is directly attached to a second connector 235, which is directly attached to a second polymer linker 236, which is directly attached to a second structural member 237. The arm 232 contains a supported polymer and a drug. The first polymer linker 234 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 236 may be a time-dependent linker (if the first polymer linker 234 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 234 is a time-dependent linker). The second structural member 237 may be, for example, a central member (e.g., a central elastic member) of the intragastric retention system. In some embodiments, the first polymer linker 234 and / or the second polymer linker 236 contain the same or similar supported polymer as the arm 232. In some embodiments, the first binder member 233 and / or the second binder member 235 contain a supported polymer (which may be the same or similar supported polymer in the arm 232), and the first polymer linker 234 and / or the second polymer linker 236 may contain the same or similar supported polymer as the first binder member 233 and / or the second binder member 235.

[0137] Figure 2I shows a portion of the intragastric retention system including an arm 238, which is directly attached to a first binding member 239, which is directly attached to a second polymer linker 240, which is directly attached to a second polymer linker 241, which is directly attached to a second binding member 242, which is directly attached to a second structural member 243. The arm 238 contains a supported polymer and a drug. The first polymer linker 240 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 241 may be a time-dependent linker (if the first polymer linker 240 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 240 is a time-dependent linker). The second structural member 243 may be, for example, a central member (e.g., a central elastic member) of the intragastric retention system. In some embodiments, the first polymer linker 240 and / or the second polymer linker 241 contain the same or similar supported polymer as in the arm 238. In some embodiments, the first binder member 239 and / or the second binder member 242 may contain a supported polymer (which may be the same or similar as the supported polymer in the arm 238), and the first polymer linker 240 and / or the second polymer linker 241 may contain the same or similar supported polymer as in the first binder member 239 and / or the second binder member 242.

[0138] Figure 2J shows a portion of the intragastric retention system including an arm 244, which is directly attached to a first polymer linker 245, which is directly attached to a first binder 246, which is directly attached to a second polymer linker 247, which is directly attached to a second binder 248, which is directly attached to a first structural member 249. The arm 244 contains a supported polymer and a drug. The first polymer linker 245 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 247 may be a time-dependent linker (if the first polymer linker 245 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 245 is a time-dependent linker). The second structural member 249 may be, for example, a central member of the intragastric retention system (e.g., a central elastic member). In some embodiments, the first polymer linker 245 and / or the second polymer linker 247 contain the same or similar supported polymer as the arm 244. In some embodiments, the first binder member 246 and / or the second binder member 248 may contain a supported polymer (which may be the same or similar supported polymer as the arm 244), and the first polymer linker 245 and / or the second polymer linker 247 may contain the same or similar supported polymer as the first binder member 246 and / or the second binder member 248.

[0139] Figure 2K shows a portion of the intragastric retention system including an arm 250, which is directly attached to a first connector 251, which is directly attached to a first polymer linker 252, which is directly attached to a second connector 253, which is directly attached to a second polymer linker 254, which is directly attached to a third connector 255, which is directly attached to a second structural member 256. The arm 250 contains a supported polymer and a drug. The first polymer linker 252 may be an enteric-coated linker or a time-dependent linker, and the second polymer linker 254 may be a time-dependent linker (if the first polymer linker 252 is an enteric-coated linker) or an enteric-coated linker (if the first polymer linker 252 is a time-dependent linker). The second structural member 256 may be, for example, a central member (e.g., a central elastic member) of the intragastric retention system. In some embodiments, the first polymer linker 252 and / or the second polymer linker 254 contain the same or similar supported polymer as the arm 250. In embodiments, the first binder member 251 and / or the second binder member 253 and / or the third binder member 255 contain a supported polymer (which may be the same or similar as the supported polymer in the arm 250), and the first polymer linker 252 and / or the second polymer linker 254 may contain the same or similar supported polymer as the first binder member 251 and / or the second binder member 253 and / or the third binder member 255. Polymer linker

[0140] A drug-containing structural member is attached to a second structural member (which may be a central member, for example, an elastic central member) via one or more linkers. The polymer linkers may be directly bonded to the drug-containing structural member or bonded to the drug-containing structural member via a bonding member. Similarly, the polymer linkers may be directly bonded to the second structural member or bonded via a bonding member. In embodiments in which the drug-containing structural member is connected to the second structural member via two or more polymer linkers, the polymer linkers may be directly bonded to each other or bonded via a bonding member. Enteric linkers and time-dependent linkers, or both, may be used, or the polymer linkers may function as both enteric linkers and time-dependent linkers.

[0141] High polymer linco は、 Typical には、 Width が Approximately 100 micrometers ~ Approximately 3 micrometers, Example えば、 Approximately 200 μm ~ Approximately 3000 μm、 Approximately 300 μm ~ Approximately 3000 μm、 Approximately 400 μm ~ Approximately 3000 μm、 Approximately 500 μm ~ Approximately 3000 μm、 Approximately 600 μm ~ Approximately 3000 μm、 Approximately 700 μm ~ Approximately 3000 μm、 Approximately 800 μm ~ Approximately 3000 μm、 Approximately 900 μm ~ Approximately 3000 μm、 Approximately 1000 μm ~ Approximately 3000 μm、 Approximately 1100 μm ~ Approximately 3000 μm、 Approximately 1200 μm ~ Approximately 3000 μm、 Approximately 1300 μm ~ Approximately 3000 μm、 Approximately 1400 μm ~ approximately 3000 μm, approximately 1500 μm ~ approximately 3000 μm, approximately 1600 μm ~ approximately 3000 μm, approximately 1700 μm ~ approximately 3000 μm, approximately 1800 μm ~ approximately 3000 μm, approximately 1900 μm ~ approximately 3000 μm, approximately 2000 μm ~ approximately 3000 μm, approximately 2100 μm ~ approximately 3000 μm, approximately 2200 μm ~ approximately 3000 μm, approximately 2300 μm ~ approximately 3000 μm, approximately 2400 μm ~ approximately 3000 μm, approximately 2500 μm ~ approximately 3000 μm, approximately 2600 μm ~ approximately 3000 μm, approximately 2700 μm ~ approximately 3000 μm, approximately 2800 μm ~ approximately 3000 μm μm, または approx. 2900 μm ~ approx. 3000 μm, または approx. 100 μm ~ approx. 200 μm ~ approx. 300 μm ~ approx. 400 μm, approx. 400 μm ~ approx. 500 μm, approx. 500 μm ~ approx. 600 μm, approx. 600 μm ~ approx. 700 μm, approx. 700 μm ~ approx. 800 μm, approx. 800 μm ~ approx. 900 μm ~ approx. 1000 μm, approx. 1000 μm ~ approx. 1100 μm, approx. 1100 μm ~ approx. 1200 μm, approx. 1200 μm ~ approx. 1300 μm, approx. 1300 μm ~ approx. 1400 μm, approx. 1400 μm ~ approx. 1500 μm μm, approximately 1500 μm to approximately 1600 μm.Approximately 1600 μm to approximately 1700 μm, approximately 1700 μm to approximately 1800 μm, approximately 1800 μm to approximately 1900 μm, approximately 1900 μm to approximately 2000 μm, approximately 2000 μm to approximately 2100 μm, approximately 2100 μm to approximately 2200 μm, approximately 2200 μm to approximately 2300 μm, about 2300 μm to about 2400 μm, about 2400 μm to about 2500 μm, about 2500 μm to about 2600 μm, about 2600 μm to about 2700 μm, about 2700 μm to about 2800 μm, about 2800 μm to about 2900 μm, about 2900 μm to about 3000 μm. The polymer linker has a width of approximately 100 μm, approximately 200 μm, approximately 300 μm, approximately 400 μm, approximately 500 μm, approximately 600 μm, approximately 700 μm, approximately 800 μm, approximately 900 μm, approximately 1000 μm, approximately 1100 μm, approximately 1200 μm, approximately 1300 μm, approximately 1400 μm, approximately 1500 μm. μm, approximately 1600 μm, approximately 1700 μm. The values ​​are approximately 1800 μm, 1900 μm, 2000 μm, 2100 μm, 2200 μm, 2300 μm, 2400 μm, 2500 μm, 2600 μm, 2700 μm, 2800 μm, 2900 μm, and 3000 μm, and each value may be plus or minus 50 μm (±50 μm).

[0142] The cross-section of the polymer linker may be round (i.e., circular), elliptical, triangular, square, rectangular, pentagonal, hexagonal, or any other polymer shape. In some embodiments, the cross-section of the polymer linker is the same shape as the cross-section of the drug-containing structural member attached to the polymer linker. In some embodiments, the cross-section of the polymer linker has a larger area than the cross-section of the drug-containing structural member, a smaller area than the cross-section of the drug-containing structural member, or an area approximately the same as the cross-section of the attached drug-containing structural member. Time-dependent collapse matrix (time-dependent linker)

[0143] Time-dependent linkers degrade in a predictable, time-dependent manner under aqueous conditions, such as when the intragastric retention system is deployed within the stomach of an individual. Time-dependent polymer linkers control the intragastric retention time of the intragastric retention system. Time-dependent polymer linkers are designed to gradually degrade, dissolve, mechanically weaken, or break down over time. After the desired retention period, the time-dependent polymer linkers degrade, dissolve, dissociate, mechanically weaken, or break down to the extent that the intragastric retention system can pass through the pyloric valve, leave the gastric environment, enter the small intestine, and ultimately be excreted from the body.

[0144] The time-dependent polymer linker preferably comprises a pH-independent biodegradable polymer that degrades in a pH-independent or nearly pH-independent manner under aqueous conditions. Exemplary pH-independent biodegradable polymers include PLGA, PLA, PCL, polydioxanone, cellulose, or blends or copolymers thereof. In some embodiments, the pH-independent biodegradable polymer is PLGA. The pH-independent biodegradable polymer may be, for example, a polymer whose flexural modulus after being kept at constant temperature in an aqueous solution such as pH 6.5, 37°C for 3 days is within 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as pH 1.6, 37°C for 3 days. In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being left at constant temperature in an aqueous solution such as intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 5 days, compared to the flexural modulus after being left at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 5 days. In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being left at constant temperature in an aqueous solution such as intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 7 days, compared to the flexural modulus after being left at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 7 days. In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being left at constant temperature in an aqueous solution such as intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 10 days, compared to the flexural modulus after being left at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 10 days. In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being left at constant temperature in an aqueous solution such as intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 14 days, compared to the flexural modulus after being left at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 14 days.In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as fasted intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 18 days, compared to the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 18 days. In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as fasted intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 18 days, compared to the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 21 days. In some embodiments, the pH-independent biodegradable polymer has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus of 5% of the flexural modulus of 5% of the flexural modulus of 37°C, 37°C, 30%, 20%, 15%, 10%, or 5% of the flexural modulus of 5% of the flexural modulus of 5% of 37°C, 37°C, 37% or 28 days of 37°C, 37% of pH-1.6.

[0145] The weakening or degradation of a time-dependent polymer linker can be measured by referring to the loss or fracture of the polymer linker's flexural modulus under predetermined conditions (e.g., intestinal or gastric conditions). The time-dependent linker weakens in the gastric environment over a selected gastric retention period until it weakens or fractures sufficiently to allow the gastric retention system to exit the stomach. Gastric conditions may be simulated at pH 1.6 and 37°C using an aqueous solution such as fasting-simulated gastric juice (FaSSGF). For example, in some embodiments, a polymer linker loses or fractures about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 99% or more of its flexural modulus after being left at constant temperature for 3 days in an aqueous solution such as FaSSGF at pH 1.6 and 37°C. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C with a pH of 1.6 in an aqueous solution such as FaSSGF for 5 days. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C with a pH of 1.6 in an aqueous solution such as FaSSGF for 10 days. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C with a pH of 1.6 in an aqueous solution such as FaSSGF for 10 days. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C with a pH of 1.6 in an aqueous solution such as FaSSGF for 18 days. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C with a pH of 1.6 in an aqueous solution such as FaSSGF for 18 days.In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C and pH 1.6 in an aqueous solution such as FaSSGF for 24 days. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C and pH 1.6 in an aqueous solution such as FaSSGF for 30 days. In some embodiments, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more, after being left at a constant temperature of 37°C and pH 1.6 in an aqueous solution such as FaSSGF for 60 days.

[0146] In certain gastric retention systems, sustained gastric retention is desired, and rapid degradation of time-dependent polymer linkers is undesirable. Therefore, in some embodiments, the polymer linker loses approximately 80%, 70%, 60%, 50%, 40%, or 30% of its flexural modulus after being left at constant temperature for 3 days in an aqueous solution such as FaSSGF at pH 1.6 and 37°C. In some embodiments, the polymer linker loses approximately 80%, 70%, 60%, 50%, 40%, or 30% of its flexural modulus after being left at constant temperature for 5 days in an aqueous solution such as FaSSGF at pH 1.6 and 37°C. In some embodiments, after leaving the polymer linker in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 7 days, approximately 80% or less, approximately 70% or less, approximately 60% or less, approximately 50% or less, approximately 40% or less, or approximately 30% or less of its flexural modulus is lost. In some embodiments, after leaving the polymer linker in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 10 days, approximately 80% or less, approximately 70% or less, approximately 60% or less, approximately 50% or less, approximately 40% or less, or approximately 30% or less of its flexural modulus is lost. In some embodiments, after leaving the polymer linker in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 14 days, approximately 80% or less, approximately 70% or less, approximately 60% or less, approximately 50% or less, approximately 40% or less, or approximately 30% or less of its flexural modulus is lost.

[0147] The degradation characteristics of time-dependent polymer linkers are determined based on the amount of time-dependently degradable polymer in the time-dependent polymer linker. For example, a larger amount of poly(lactic acid-co-glycolide) (PLGA) may result in a greater loss of flexural modulus over an extended gastric retention period, but may maintain sufficient structural integrity for a short time to retain the gastric retention system in the stomach. As an example, in some embodiments, a polymer linker may lose about 80% or less, about 70%, about 60%, about 50%, about 40%, or about 30% or less of its flexural modulus after being left at constant temperature for 3 days at pH 1.6 in an aqueous solution such as FaSSGF, and may lose or break about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 99% or more of its flexural modulus after being left at constant temperature for 7 days at pH 1.6 in an aqueous solution such as FaSSGF, and about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 99% or more of its flexural modulus.

[0148] In some embodiments, the time-dependent polymer linker is pH-independent, and the polymer linker decomposes in a pH-independent or nearly pH-independent manner under aqueous conditions. The pH-independent time-dependent polymer linker may also be a time-dependent polymer linker in which the flexural modulus after being kept at constant temperature in an aqueous solution such as fasted intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 3 days is within the range of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 3 days. In some embodiments, the pH-independent time-dependent polymer linker has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 5 days, compared to the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 5 days. In some embodiments, the pH-independent time-dependent polymer linker has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 7 days, compared to the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 7 days. In some embodiments, the pH-independent time-dependent polymer linker has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as fasted intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 10 days, compared to the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 10 days. In some embodiments, the pH-independent time-dependent polymer linker has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus after being kept at constant temperature in an aqueous solution such as fasted intestinal fluid (FaSSIF) at pH 6.5 and 37°C for 14 days, compared to the flexural modulus after being kept at constant temperature in an aqueous solution such as FaSSGF at pH 1.6 and 37°C for 14 days.Depending on the embodiment, the pH-independent time-dependent polymer linker has a flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus of 5% of the flexural modulus of 30%, 20%, 15%, 10%, or 5% of the flexural modulus of 5% of the flexural modulus of 5% of the flexural modulus of 5% of the flexural modulus of 5% of 37°C, 37°C, and 30% of pH 1.6.

[0149] Depending on the embodiment, the time-dependent polymer linker has an initial flexural modulus of approximately 100 MPa to approximately 2500 MPa, such as approximately 100 MPa to approximately 2500 MPa, approximately 250 MPa to approximately 500 MPa, approximately 500 mPa to approximately 750 MPa, approximately 750 MPa to approximately 1000 MPa, approximately 1000 MPa to approximately 1250 MPa, approximately 1250 MPa to approximately 1500 MPa, approximately 1500 MPa to approximately 2000 MPa, or approximately 2000 MPa to approximately 2500 MPa.

[0150] The time-dependent polymer linker may contain poly(lactic acid-co-glycolide) (PLGA) and at least one additional linker polymer, preferably homogeneously mixed together. For example, the PLGA and additional linker polymer are homogeneously mixed together before the mixture is extruded and the extruded material is cut to the desired size relative to the polymer linker. Since PLGA is biodegradable in aqueous environments, the amount of PLGA in the polymer linker affects the time-dependent degradation characteristics of the polymer linker and, consequently, the gastric retention system. Generally, a higher weight percentage of PLGA in the polymer linker leads to faster weakening, or degradation, of the polymer linker in an aqueous (e.g., stomach) environment. Similarly, a lower weight percentage of PLGA leads to slower weakening, or degradation, of the polymer linker in an aqueous environment. Any amount of PLGA can be used in the polymer linker, and the amount is selected based on the desired degradation characteristics. For example, depending on the embodiment, the time-dependent polymer linker may contain PLGA in amounts of approximately 99% or less, approximately 98% or less, approximately 95% or less, approximately 90% or less, approximately 85% or less, approximately 80% or less, approximately 75% or less, approximately 70% or less, approximately 65% ​​or less, approximately 60% or less, approximately 55% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, approximately 20% or less, or approximately 10% or less (by weight). Depending on the embodiment, the time-dependent polymer linker may contain PLGA in amounts of approximately 99% or more, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more (by weight). Depending on the embodiment, the time-dependent polymer linker may contain approximately 0.1% to approximately 10% PLGA, approximately 10% to approximately 20% PLGA, approximately 20% to approximately 30% PLGA, approximately 30% to approximately 40% PLGA, approximately 40% to approximately 50% PLGA, approximately 50% to approximately 60% PLGA, approximately 60% to approximately 70% PLGA, approximately 70% to approximately 80% PLGA, approximately 80% to approximately 90% PLGA, or approximately 90% to approximately 99.9% PLGA. Depending on the embodiment, the time-dependent polymer linker may contain approximately 30% or less PLGA. Depending on the embodiment, the time-dependent polymer linker may contain approximately 70% or more PLGA.Depending on the embodiment, the time-dependent polymer linker contains approximately 30% to 70% PLGA.

[0151] The PLGA in the polymer linker may contain poly(D,L-lactic acid-co-glycolide) (PDLG), poly(D-lactic acid-co-glycolide), and / or poly(L-lactic acid-co-glycolide), but PDLG is preferred. The ratio of lactide monomers to glycolide monomers in the copolymer may be about 5:95 to about 95:5, for example, about 5:95 to about 10:90, about 10:90 to about 20:80, about 20:80 to about 35:65, about 35:65 to about 50:50, about 50:50 to about 65:35, about 65:35 to about 80:20, about 80:20 to about 90:10, or about 90:10 to about 95:5.

[0152] The molecular weight of PLGA also affects the rate of polymer decomposition and, consequently, the rate of loss of flexural modulus, with higher molecular weight polymers decomposing more slowly (and thus losing their flexural modulus). Depending on the embodiment, the mass-weighted molecular weight (M) of PLGA may also be affected. w ) is approximately 5,000 Da to approximately 250,000 Da, for example, approximately 5,000 Da to approximately 10,000 Da, approximately 10,000 to approximately 20,000 Da, approximately 20,000 Da to approximately 30,000 Da, approximately 30,000 Da to approximately 50,000 Da, approximately 50,000 Da to approximately 100,000 Da, approximately 100,000 Da to approximately 150,000 Da, approximately 150,000 Da to approximately 200,000 Da, or approximately 200,000 Da to approximately 250,000 Da. Depending on the embodiment, the intrinsic viscosity of PLGA (measured in CHCl3 at 25°C) is between approximately 0.1 dl / g and approximately 1.5 dl / g, for example, between approximately 0.1 dl / g and approximately 0.15 dl / g, approximately 0.15 dl / g and approximately 0.25 dl / g, approximately 0.25 dl / g and approximately 0.5 dl / g, approximately 0.5 dl / g and approximately 0.75 dl / g, approximately 0.75 dl / g and approximately 1.0 dl / g, approximately 1.0 dl / g and approximately 1.25 dl / g, and approximately 1.25 dl / g and approximately 1.5 dl / g.

[0153] The amount or ratio of acid-terminated PLGA to ester-terminated PLGA also affects the degradation, or weakening, rate of the time-dependent polymer linker; the higher the proportion of acid-terminated PLGA, the greater the degradation, or weakening rate, compared to the case where the proportion of ester-terminated PLGA is higher. In some embodiments, the PLGA comprises, essentially comprises, or includes acid-terminated PLGA. In some embodiments, the PLGA comprises, essentially comprises, or includes ester-terminated PLGA. In some embodiments, the PLGA comprises a blend of acid-terminated PLGA and ester-terminated PLGA. For example, depending on the embodiment, the PLGA is a blend of acid-terminated PLGA and ester-terminated PLGA in a ratio of approximately 1:9 to approximately 9:1 (e.g., approximately 1:9 to approximately 1:8, approximately 1:8 to approximately 1:7, approximately 1:7 to approximately 1:6, approximately 1:6 to approximately 1:5, approximately 1:5 to approximately 1:4, approximately 1:4 to approximately 1:3, approximately 1:3 to approximately 1:2, approximately 1:2 to approximately 1:1, approximately 1:1 to approximately 2:1, approximately 2:1 to approximately (Includes 3:1, approximately 3:1 to approximately 4:1, approximately 4:1 to approximately 5:1, approximately 5:1 to approximately 6:1, approximately 6:1 to approximately 7:1, approximately 7:1 to approximately 8:1, approximately 8:1 to approximately 9:1, approximately 9:1, approximately 8:1, approximately 7:1, approximately 6:1, approximately 5:1, approximately 4:1, approximately 3:1, approximately 2:1, approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:6, approximately 1:7, approximately 1:8, or approximately 1:9). Depending on the embodiment, the PLGA includes a blend of acid-terminated PLGA and ester-terminated PLGA in a ratio of approximately 1:1.

[0154] In some embodiments, the time-dependent polymer linker PLGA contains an acid-terminated poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 50:50 and an intrinsic viscosity of 0.16 dl / g to 0.24 dl / g (for example, PLGA sold under the trade names Purasorb® PDLG 5002A or Purasorb® PDLG 5002A Y, respectively, available from Corbion). In some embodiments, the time-dependent polymer linker PLGA contains poly(D,L-lactic acid-co-glycolide) with a lactide monomer-to-glycolide monomer ratio of approximately 50:50 (e.g., PLGA sold by Corbion under the trademark name Purasorb® PDLG 5004). In some embodiments, the time-dependent polymer linker PLGA contains acid-terminated poly(D,L-lactic acid-co-glycolide) with a lactide monomer-to-glycolide monomer ratio of approximately 50:50 (e.g., PLGA sold by Corbion under the trademark name Purasorb® PDLG 5004A). In some embodiments, the time-dependent polymer linker PLGA contains poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 50:50 and an intrinsic viscosity of 0.8 dl / g to 1.2 dl / g (e.g., PLGA sold under the trademark Purasorb® PDLG 5010, available from Corbion).In some embodiments, the time-dependent polymer linker PLGA contains poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 55:45 and an intrinsic viscosity of 0.4 dl / g to 0.6 dl / g (e.g., PLGA sold under the trade name Purasorb® PDLG 5505G, available from Corbion). In some embodiments, the time-dependent polymer linker PLGA contains acid-terminated poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 75:25 and an intrinsic viscosity of 0.16 dl / g to 0.24 dl / g (e.g., PLGA sold under the trade name Purasorb® PDLG 7502A, available from Corbion). In some embodiments, the time-dependent polymer linker PLGA includes poly(D,L-lactic acid-co-glycolide) (PLGA available from Corbion under the trade name Purasorb® PDLG 7502) having a lactide monomer-glycolide monomer-lactic acid ratio of approximately 75:25 and an intrinsic viscosity of 0.16 dl / g to 0.24 dl / g. In some embodiments, the time-dependent polymer linker PLGA includes poly(D,L-lactic acid-co-glycolide) (for example, PLGA available from Corbion under the trade name Purasorb® PDLG 7507 Y) having a lactide monomer-to-glycolide monomer ratio of approximately 75:25 and an intrinsic viscosity of 0.65 dl / g to 0.95 dl / g. In some embodiments, the time-dependent polymer linker PLGA contains poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 75:25 and an intrinsic viscosity of 0.56 dl / g to 0.84 dl / g (e.g., PLGA sold under the trade name Purasorb® PDLG 7507, available from Corbion).In some embodiments, the time-dependent polymer linker PLGA comprises poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 75:25 and an intrinsic viscosity of 0.85 dl / g to 1.05 dl / g (e.g., PLGA available from Corbion under the trade name Purasorb® PDLG 7510). In some embodiments, the time-dependent polymer linker PLGA comprises poly(D,L-lactic acid-co-glycolide) having a lactide monomer-to-glycolide monomer ratio of approximately 65:35 and an intrinsic viscosity of 0.32 dl / g to 0.44 dl / g (PLGA available from Evonik under the trade name Resomer® RG 653 H). In some embodiments, the time-dependent polymer linker PLGA comprises a mixture of two or more of the above PDLG polymers. For example, in some embodiments, the time-dependent polymer linker PLGA comprises (a) a mixture of poly(D,L-lactic acid-co-glycolides) with a lactide monomer-to-glycolide monomer ratio of approximately 50:50 (e.g., PLGA, available from Corbion under the trade name Purasorb® PDLG 5004), and (b) a mixture of acid-terminated poly(D,L-lactic acid-co-glycolides) with a lactide monomer-to-glycolide monomer ratio of approximately 50:50 (e.g., PLGA, available from Corbion under the trade name Purasorb® PDLG 5004A).

[0155] One or more additional linker polymers contained in the polymer linker are preferably homogeneously mixed with PLGA. Depending on the embodiment, one or more additional linker polymers are miscible with PLGA. One or more additional linker polymers are non-degradable polymers (i.e., they do not decompose in the gastric or intestinal environment, or in aqueous solutions at pH 1.6 (representing the gastric environment) or pH 6.5 (representing the intestinal environment)) and may be present in the time-dependent polymer linker in an amount that does not cleave the time-dependent polymer linker during its gastric retention period.

[0156] The bonding of a polymer linker to directly adjacent members may be improved if at least one polymer is common to both the adjacent members and the time-dependent polymer linker. That is, one of the one or more additional linker polymers in the time-dependent linker may be the same (or the same polymer species) as at least one polymer in the directly adjacent members (or both directly adjacent members, as required) of the gastric retention system. For example, if the time-dependent polymer linker is directly bonded to a structural member containing a supported polymer, depending on the embodiment, one or more additional linker polymers also contain the supported polymer (in addition to PLGA in the time-dependent polymer linker) at the same or different concentrations. Exemplary supported polymers include, but are not limited to, polylactic acid (PLA), polycaprolactone (PCL), and thermoplastic polyurethane (TPU), among others described herein.

[0157] Depending on the embodiment, one or more additional linker polymers are PLA, for example, PLA as described herein with respect to supported polymers. Depending on the embodiment, the time-dependent polymer linker comprises about 99% or less, about 98% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, or about 10% or less (by weight) of PLA. Depending on the embodiment, the time-dependent polymer linker contains approximately 99% or more, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more (by weight) of PLA. Depending on the embodiment, the time-dependent polymer linker may contain approximately 0.1% to approximately 10% PLA, approximately 10% to approximately 20% PLA, approximately 20% to approximately 30% PLA, approximately 30% to approximately 40% PLA, approximately 40% to approximately 50% PLA, approximately 50% to approximately 60% PLA, approximately 60% to approximately 70% PLA, approximately 70% to approximately 80% PLA, approximately 80% to approximately 90% PLA, or approximately 90% to approximately 99.9% PLA. Depending on the embodiment, the time-dependent polymer linker may contain approximately 30% or less PLA. Depending on the embodiment, the time-dependent polymer linker may contain approximately 70% or more PLA. Depending on the embodiment, the time-dependent polymer linker may contain approximately 30% to approximately 70% PLA. PLGA may be further included with PLA and may constitute the remainder of the time-dependent polymer linker, but additional agents (plasticizers, colorants, or other agents may be further included).

[0158] Depending on the embodiment, the time-dependent polymer linker may contain 10-90%, 20-80%, 30-70%, 40-60%, 45-55%, 48-52%, or 50% PLA by weight. Depending on the embodiment, the time-dependent polymer linker may contain 10-50%, 20-40%, 25-35%, 28-32%, or 30% PLA by weight. Depending on the embodiment, the time-dependent polymer linker may contain 10-40%, 15-35%, 20-28%, 22-26%, or 24% PLA by weight.

[0159] Depending on the embodiment, one or more additional linker polymers include PCL. The time-dependent polymer linker may be directly bonded to or connected to other components of the gastric retention system (e.g., structural components containing the drug and supporting polymer, binding components, enteric-coated polymer linker, or central structural components), which may contain PCL, which may be the same as the PCL in the time-dependent polymer linker or different from the PCL in the polymer linker, and may be the same or different in concentration. If the PCL in the time-dependent polymer linker is different from the PCL in other components directly bonded to or connected to the time-dependent linker, they may differ in, for example, the weight-average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when using a blend of two or more PCL polymers).

[0160] Depending on the embodiment, the time-dependent polymer linker contains approximately 99% or less, approximately 98% or less, approximately 95% or less, approximately 90% or less, approximately 85% or less, approximately 80% or less, approximately 75% or less, approximately 70% or less, approximately 65% ​​or less, approximately 60% or less, approximately 55% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, approximately 20% or less, or approximately 10% or less (by weight) of PCL. Depending on the embodiment, the time-dependent polymer linker contains approximately 99% or more, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more (by weight) of PCL. Depending on the embodiment, the time-dependent polymer linker may contain about 0.1% to about 10% PCL, about 10% to about 20% PCL, about 20% to about 30% PCL, about 30% to about 40% PCL, about 40% to about 50% PCL, about 50% to about 60% PCL, about 60% to about 70% PCL, about 70% to about 80% PCL, about 80% to about 90% PCL, or about 90% to about 99.9% PCL. Depending on the embodiment, the time-dependent polymer linker may contain about 30% or less PLA. Depending on the embodiment, the time-dependent polymer linker may contain about 70% or more PLA. Depending on the embodiment, the time-dependent polymer linker may contain about 30% to about 70% PCL. PLGA may be further included with PCL and may constitute the remainder of the time-dependent polymer linker, but additional agents (e.g., plasticizers, colorants, or other agents) may also be included.

[0161] Depending on the embodiment, one or more additional linker polymers include TPU. The time-dependent polymer linker may be directly bonded or coupled to other components of the gastric retention system (e.g., structural components containing the drug and supporting polymer, binding components, enteric-coated polymer linker, or central structural components), which also include TPU, which may be the same TPU as in the time-dependent polymer linker or a different TPU from that in the polymer linker, and may be at the same or different concentrations. The different TPUs in the time-dependent polymer linker and the other components directly bonded or coupled to the time-dependent linker may differ, for example, in the weight-average molecular weight of the TPU, the intrinsic viscosity of the TPU, or the proportion of TPU (e.g., if a blend of two or more TPU polymers is used). Suitable commercially available TPU polymers include Pathway® TPU Polymer (The Lubrizol Corporation), Tecoflex® (The Lubrizol Corporation), Tecophilic® (The Lubrizol Corporation), Carbonhatane® (The Lubrizol Corporation), Texin® (Covestro), and NEUSoft® (PolyOne).

[0162] Depending on the embodiment, the time-dependent polymer linker may contain TPU in amounts of approximately 99% or less, approximately 98% or less, approximately 95% or less, approximately 90% or less, approximately 85% or less, approximately 80% or less, approximately 75% or less, approximately 70% or less, approximately 65% ​​or less, approximately 60% or less, approximately 55% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, approximately 20% or less, or approximately 10% or less by weight. Depending on the embodiment, the time-dependent polymer linker may contain TPU in amounts of approximately 99% or more, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more by weight. Depending on the embodiment, the time-dependent polymer linker may contain approximately 0.1% to 10% TPU, approximately 10% to 20% TPU, approximately 20% to 30% TPU, approximately 30% to 40% TPU, approximately 40% to 50% TPU, approximately 50% to 60% TPU, approximately 60% to 70% TPU, approximately 70% to 80% TPU, approximately 80% to 90% TPU, or approximately 90% to 99.9% TPU. Depending on the embodiment, the time-dependent polymer linker may contain approximately 30% or less TPU. Depending on the embodiment, the time-dependent polymer linker may contain approximately 70% or more TPU. Depending on the embodiment, the time-dependent polymer linker may contain approximately 30% to 70% TPU. Depending on the embodiment, the time-dependent polymer linker may contain approximately 30% to 70% PLA. PLGA may be further included with TPU and may constitute the remainder of the time-dependent polymer linker, but may also include additional agents (plasticizers, color-absorbing dyes, or other agents).

[0163] The time-dependent polymer linker may further contain one or more plasticizers, which can help cut the extruded polymer linker material to the desired size and help bind or adhere the time-dependent polymer linker to other components of the gastric retention system. Exemplary plasticizers include, but are not limited to, propylene glycol, polyethylene glycol (PEG), butyl triethyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer (e.g., Poloxamer 407, "P407"), or D-α-tocopheryl polyethylene glycol succinate. The term "polyethylene glycol" is used herein interchangeably with the terms "polyethylene oxide" and "PEO". Depending on the embodiment, the molecular weight of polyethylene glycol ranges from approximately 200 Da to approximately 8,000,000 Da (also known as 8000 K or 8000 kDa), for example, approximately 200 Da to approximately 400 Da, approximately 400 Da to approximately 800 Da, approximately 800 Da to approximately 1600 Da, approximately 1600 Da to approximately 2500 Da, approximately 2500 Da to approximately 5000 Da. The ranges are approximately Da~10K, approximately 10K~20K, approximately 20K~50K, approximately 50K~100K, approximately 100K~200K, approximately 200K~400K, approximately 400K~800K, approximately 800K~1000K, approximately 1000K~2000K, approximately 2000K~4000K, approximately 4000K~6000K, or approximately 6000K~8000K. Depending on the embodiment, the polymer linker may contain up to 20% plasticizer, for example, up to 18% plasticizer, up to 15% plasticizer, up to 12% plasticizer, up to 10% plasticizer, up to 8% plasticizer, up to 6% plasticizer, up to 4% plasticizer, up to 3% plasticizer, up to 2% plasticizer, or up to 1% plasticizer. Depending on the embodiment, the polymer linker may contain about 0.5% to about 20% plasticizer, for example, about 0.5% to about 1%, about 1% to about 2%, about 2% to about 3%, about 3% to about 5%, about 5% to about 7%, about 7% to about 10%, about 10% to about 12%, about 12% to about 15%, about 15% to about 18%, or about 18% to about 20% plasticizer.

[0164] Depending on the embodiment, the time-dependent polymer linker may include a color-absorbing dye (also referred to as a colorant or pigment). The color-absorbing dye may be included to enhance the binding or adhesion of the polymer linker to other components of the gastric retention system. The color-absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced adhesion, thereby increasing the tensile strength of the resulting bond. Exemplary color-absorbing dyes include iron oxide and carbon black. The time-dependent polymer linker may contain the color-absorbing dye in amounts up to about 5%, e.g., up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, or up to about 0.1%.

[0165] The time-dependent polymer linker may contain one or more additional excipients as needed. For example, the time-dependent polymer linker may contain a pologen such as a sugar (e.g., lactose, sucrose, glucose), a salt (e.g., NaCl), sodium starch glycolate (SSG), or any other suitable substance. The pologen may dissolve rapidly in an aqueous environment, thereby allowing the aqueous solution to facilitate contact with the inner portion of the polymer linker. Other excipients include flow aids such as vitamin E succinate or silicon dioxide silicide (e.g., Cab-O-Sil), which may be included in the polymer blend to facilitate handling of the material before extrusion.

[0166] In one example of a time-dependent polymer linker, the polymer linker comprises about 75% to about 90% PLGA and about 10% to about 25% PLA (e.g., about 85% PLGA and about 15% PLA). The PLA may be, for example, PLDL or PDL. The PLGA may be, for example, poly(D,L-lactic acid-co-glycolide) with a lactide monomer to glycoside monomer ratio of about 50:50 to about 75:25 (e.g., about 65:35), and / or may have an intrinsic viscosity between about 0.1 dl / g and about 0.7 dl / g (e.g., about 0.3 dl / g and about 0.5 dl / g).

[0167] In another example of a time-dependent polymer linker, the polymer linker contains approximately 40% to 70% PLGA and approximately 30% to 60% supported polymer (e.g., approximately 55% PLGA and 45% PLA). The supported polymer may be, for example, TPU or PCL. PLGA may be, for example, (1) poly(D,L-lactic acid-co-glycolide) with a lactide monomer-to-glycolide monomer ratio of approximately 65:35 to approximately 95:5 (e.g., approximately 75:25) and / or have an intrinsic viscosity of approximately 0.1 dl / g to approximately 0.5 dl / g (e.g., approximately 0.15 dl / g to approximately 0.25 dl / g); (2) poly(D,L-lactic acid-co-glycolide) with a lactide monomer-to-glycolide monomer ratio of approximately 25:75 to approximately 75:25 (e.g., approximately 50:50) and / or have an intrinsic viscosity of approximately 0.5 dl / g to approximately 1.5 dl / g (e.g., approximately 0.8 dl / g to approximately 1.2 It may have an intrinsic viscosity between dl / g; or (3) poly(D,L-lactic acid-co-glycolide) in which the ratio of lactide monomer to glycolide monomer is about 65:35 to about 95:5 (e.g., about 75:25), and / or it may have an intrinsic viscosity between about 0.3 dl / g to about 1.2 dl / g (e.g., about 0.5 dl / g to about 0.9 dl / g).

[0168] In another example of a time-dependent polymer linker, the polymer linker comprises about 35% to about 65% (e.g., about 50%) of a supported polymer, about 35% to about 65% (e.g., about 53%) of PDLG, and about 2% of polyethylene glycol (e.g., polyethylene glycol 100K), and optionally further iron oxide (e.g., about 0.01% to about 0.25%). The supported polymer may be, for example, TPU or PCL.

[0169] In another example of a time-dependent polymer linker, the polymer linker comprises about 35% to about 45% (e.g., about 40%) of a supported polymer (e.g., TPU or PCL) and about 55% to about 65% (e.g., about 60%) of PLGA. The PLGA may be, for example, acid-terminated PLGA.

[0170] In another example of a time-dependent polymer linker, the polymer linker comprises about 40% to about 50% (e.g., about 45%) of a supported polymer (e.g., TPU or PCL), about 48% to about 58% (e.g., about 53%) of PLGA, and about 1% to about 3% (e.g., about 2%) of polyethylene glycol (e.g., about 100K polyethylene glycol). The PLGA may be, for example, acid-terminated PLGA.

[0171] In another example of a time-dependent polymer linker, the polymer linker contains about 40% to about 50% (e.g., about 45%) of a supported polymer (e.g., TPU or PCL) and about 48% to about 58% (e.g., about 53%) of PLGA, where the PLGA consists of acid-terminated PLGA and ester-terminated PLGA in a ratio of about 4:1 to about 1:1, e.g., about 2:1. If necessary, the polymer linker may also contain about 1% to about 3% (e.g., about 2%) of polyethylene glycol (e.g., polyethylene glycol 100K) and / or iron oxide (e.g., about 0.01% to about 0.2%, particularly about 0.05% to about 0.1%).

[0172] In another example of a time-dependent polymer linker, the polymer linker comprises approximately 45% to approximately 55% (e.g., approximately 50%) of a supported polymer (e.g., TPU or PCL) and approximately 45% to approximately 55% (e.g., approximately 50%) of PLGA. The PLGA may be, for example, acid-terminated PLGA.

[0173] In another example of a time-dependent polymer linker, the polymer linker comprises approximately 45% to 55% (e.g., approximately 50%) of a supported polymer (e.g., TPU or PCL), approximately 40% to 50% (e.g., approximately 45%) of PLGA, and approximately 2% to 7% (e.g., approximately 5%) of polyethylene oxide (e.g., polyethylene glycol 100K). The PLGA may be, for example, acid-terminated PLGA.

[0174] In some embodiments, the time-dependent polymer linker may contain approximately 10% or more, approximately 20% or more, approximately 30% or more, approximately 40% or more, approximately 50% or more, approximately 60% or more, approximately 70% or more, or approximately 80% or more by weight of PLGA. In some embodiments, the time-dependent polymer linker may contain approximately 90% or less, approximately 80% or less, approximately 70% or less, approximately 60% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, or approximately 20% or less by weight of PLGA.

[0175] Depending on the embodiment, the time-dependent polymer linker may contain 50-90%, 60-80%, 65-75%, 68-72%, or 70% PLGA by weight. Depending on the embodiment, the time-dependent polymer linker may contain 40-72%, 45-67%, 50-62%, 54-58%, or 56% PLGA by weight. Depending on the embodiment, the time-dependent polymer linker may contain 30-70%, 40-60%, 45-55%, 48-52%, or 50% PLGA by weight. Depending on the embodiment, the time-dependent polymer linker may contain 20-60%, 30-50%, 35-45%, 38-42%, or 40% PLGA by weight.

[0176] Depending on the embodiment, the time-dependent polymer linker containing PLGA may include lactic acid / glycolic acid ratios of 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5. gastric emptying time

[0177] The gastric residence time of the system is controlled by the rate of degradation, weakening, or rupture of time-dependent polymer linkers in the gastric residence system. Faster degradation, weakening, or rupture of time-dependent polymer linkers leads to faster passage of the system from the stomach. The residence time of a gastric residence system is defined as the time between the administration of the system to the stomach and the exit of the system from the stomach. In one embodiment, the gastric residence system has a residence time of about 24 hours, or up to about 24 hours. In one embodiment, the gastric residence system has a residence time of about 48 hours, or up to about 48 hours. In one embodiment, the gastric residence system has a residence time of about 72 hours, or up to about 72 hours. In one embodiment, the gastric residence system has a residence time of about 96 hours, or up to about 96 hours. In one embodiment, the gastric residence system has a residence time of about 5 days, or up to about 5 days. In one embodiment, the intragastric retention system has a retention time of approximately 6 days, or a retention time of up to approximately 6 days. In one embodiment, the intragastric retention system has a retention time of approximately 7 days (approximately 1 week), or a retention time of up to approximately 7 days (approximately 1 week). In one embodiment, the intragastric retention system has a retention time of approximately 10 days, or a maximum retention time of approximately 10 days. In one embodiment, the intragastric retention system has a retention time of approximately 14 days (approximately 2 weeks), or a maximum retention time of approximately 14 days (approximately 2 weeks).

[0178] In one embodiment, the gastric retention system has a residence time between approximately 24 hours and approximately 7 days. In one embodiment, the gastric retention system has a residence time between approximately 48 hours and approximately 7 days. In one embodiment, the gastric retention system has a residence time between approximately 72 hours and approximately 7 days. In one embodiment, the gastric retention system has a residence time between approximately 96 hours and approximately 7 days. In one embodiment, the gastric retention system has a residence time between approximately 5 days and approximately 7 days. In one embodiment, the gastric retention system has a residence time between approximately 6 days and approximately 7 days.

[0179] In one embodiment, the intragastric retention system has a residence time between approximately 24 hours and approximately 10 days. In one embodiment, the intragastric retention system has a residence time between approximately 48 hours and approximately 10 days. In one embodiment, the intragastric retention system has a residence time between approximately 72 hours and approximately 10 days. In one embodiment, the intragastric retention system has a residence time between approximately 96 hours and approximately 10 days. In one embodiment, the intragastric retention system has a residence time between approximately 5 days and approximately 10 days. In one embodiment, the intragastric retention system has a residence time between approximately 6 days and approximately 10 days. In one embodiment, the intragastric retention system has a residence time between approximately 7 days and approximately 10 days.

[0180] In one embodiment, the gastric retention system has a residence time between approximately 24 hours and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 48 hours and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 72 hours and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 96 hours and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 5 days and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 6 days and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 7 days and approximately 14 days. In one embodiment, the gastric retention system has a residence time between approximately 10 days and approximately 14 days.

[0181] 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. Enteric-disintegrating matrix (enteric-coated linker)

[0182] If the gastric retention system passes into the small intestine early and intact, it can be designed to break down much more rapidly to avoid intestinal obstruction. This is easily achieved by using enteric-coated polymer linkers, including enteric polymers, in addition to additional linker polymers (e.g., supported polymers) that weaken or break down in the intestinal environment. Enteric polymers are relatively resistant to the acidic pH levels encountered in the stomach but dissolve rapidly at the higher pH levels found in the duodenum. By using enteric-coated polymer linkers as a safe element, it is possible to prevent the intact gastric retention system from moving into the small intestine in an undesirable manner. The use of enteric-coated polymer linkers also provides a way to remove the gastric retention system before its designed retention time. If the system needs to be removed, the patient can drink a weakly alkaline solution, such as a sodium bicarbonate solution, or take an antacid such as hydrated magnesium hydroxide (magnesia milk) or calcium carbonate, which can raise the pH level in the stomach and cause rapid breakdown of the enteric-coated polymer linker.

[0183] The weakening or degradation of an enteric-coated polymer linker can be measured based on the loss or fracture of the polymer linker's flexural modulus under specified conditions (e.g., intestinal or gastric conditions). Enteric-coated linkers weaken, decompose, or fracture relatively quickly in the intestinal environment, but retain much of their flexural modulus in the gastric environment. Gastric conditions may be simulated using an aqueous solution such as FaSSGF at pH 1.6 and 37°C, and intestinal conditions may be simulated using an aqueous solution such as FaSSIF at pH 6.5 and 37°C. For example, in some embodiments, an enteric-coated polymer linker may lose or fracture about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 99% or more of its flexural modulus after being left at constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5 and 37°C. In some embodiments, the enteric-coated polymer linker loses or breaks approximately 60% or more of its flexural modulus after being left at a constant temperature of 37°C and pH 6.5 for 24 hours in an aqueous solution such as FaSSIF. In some embodiments, the enteric-coated polymer linker loses or breaks approximately 60% or more of its flexural modulus after being left at a constant temperature of 37°C and pH 6.5 for 2 days in an aqueous solution such as FaSSIF. In some embodiments, after being left at a constant temperature of 37°C, pH 6.5, in an aqueous solution such as FaSSIF for 3 days, the enteric-coated polymer linker loses or breaks approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus. In some embodiments, after being left at a constant temperature of 37°C, pH 6.5, in an aqueous solution such as FaSSIF for 4 days, the enteric-coated polymer linker loses approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus or breakage. In some embodiments, the enteric-coated polymer linker loses or breaks approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C for 5 days in an aqueous solution such as FaSSIF at pH 6.5.

[0184] In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C at pH 1.6 in an aqueous solution such as FaSSGF for 5 days. In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C at pH 1.6 in an aqueous solution such as FaSSGF for 7 days. In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C at pH 1.6 in an aqueous solution such as FaSSGF for 14 days. In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C at pH 1.6 in an aqueous solution such as FaSSGF for 18 days. In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C and pH 1.6 in an aqueous solution such as FaSSGF for 24 days.In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C at pH 1.6 in an aqueous solution such as FaSSGF for 45 days. In some embodiments, the enteric-coated polymer linker retains approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more of its flexural modulus after being left at a constant temperature of 37°C at pH 1.6 in an aqueous solution such as FaSSGF for 60 days.

[0185] In some embodiments, the enteric polymer linker loses or breaks approximately 60% or more of its flexural modulus or fracture strength after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5 such as FaSSIF, and retains approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.6 such as FaSSIF.

[0186] Enteric-coated polymer linkers weaken more quickly or significantly under intestinal conditions than under gastric conditions. For example, in some embodiments, after being left at constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, the enteric-coated polymer linker loses its flexural modulus by more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of pH After leaving an aqueous solution of 1.6 FaSSGF or similar at constant temperature for 12 hours, approximately 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, or 90% to 95%, or any consecutive combination of these ranges. Depending on the embodiment, the enteric polymer linker loses approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of its flexural modulus after being left at a constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, or pH After leaving an aqueous solution of FaSSGF, etc., at constant temperature for 24 hours, the flexural modulus is lost by approximately 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, or 90% to 95%, or a continuous combination of these ranges.Depending on the embodiment, the enteric polymer linker loses approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of its flexural modulus after being left at a constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, or pH After leaving an aqueous solution of FaSSGF, etc., of 1.6 at a constant temperature for 36 hours, the flexural modulus is lost by approximately 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, or 90% to 95%, or a continuous combination within that range. Depending on the embodiment, the enteric-coated polymer linker loses approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of its flexural modulus after being left at a constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, or pH Loss of approximately 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, or 90% to 95%, or a continuous combination of these ranges, after being left at constant temperature for 2 days in an aqueous solution such as 1.6 FaSSGF.Depending on the embodiment, the enteric-coated polymer linker loses approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of its flexural modulus after being left at a constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, or pH Loss of approximately 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, or 90% to 95%, or a continuous combination of these ranges, after being left at constant temperature for 3 days in an aqueous solution such as 1.6 FaSSGF. Depending on the embodiment, the enteric polymer linker loses approximately 5% or more, approximately 10% or more, approximately 15% or more, approximately 20% or more, approximately 25% or more, approximately 30% or more, approximately 35% or more, approximately 40% or more, approximately 50% or more, approximately 55% or more, approximately 60% or more, approximately 65% ​​or more, approximately 70% or more, approximately 75% or more, approximately 80% or more, approximately 85% or more, approximately 90% or more, or more than 95% of its flexural modulus after being left at a constant temperature for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, or pH After being left at constant temperature for 4 days in an aqueous solution of 1.6 FaSSGF or the like, the flexural modulus is lost by approximately 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, or 90% to 95%, or a continuous combination of these ranges.

[0187] Depending on the embodiment, the enteric polymer linker has an initial flexural modulus of approximately 100 MPa to approximately 2500 MPa, for example, approximately 100 MPa to approximately 250 MPa, approximately 250 MPa to approximately 500 MPa, approximately 500 mPa to approximately 750 MPa, approximately 750 MPa to approximately 1000 MPa, approximately 1000 MPa to approximately 1250 MPa, approximately 1250 MPa to approximately 1500 MPa, approximately 1500 MPa to approximately 2000 MPa, or approximately 2000 MPa to approximately 2500 MPa.

[0188] Exemplary enteric-coated polymers that can be used in the present invention are listed in the Enteric-Coated Polymer Table (Table 1) 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. [Table 1]

[0189] The amount of enteric polymer contained in the enteric polymer linker can be selected based on the desired linker weakening or decomposition properties. For example, the polymer linker may contain about 1% to about 99% enteric polymer, such as about 1% to about 5%, about 5% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 99%. Depending on the embodiment, the enteric polymer linker may contain less than 20% enteric polymer. Depending on the embodiment, the enteric-coated polymer linker may contain less than 15% enteric polymer. Depending on the embodiment, the enteric-coated linker may contain less than 10% enteric polymer. Depending on the embodiment, the enteric-coated linker may contain 80% or more enteric polymer. Depending on the embodiment, the enteric-coated linker may contain 85% or more enteric polymer. Depending on the embodiment, the enteric-coated linker may contain more than 90% enteric polymer. Depending on the embodiment, the enteric-coated linker may contain approximately 20% to approximately 80% enteric polymer.

[0190] In some embodiments, the enteric polymer contains (acetic acid / succinate) hydroxypropyl methylcellulose (HPMCAS). For example, in some embodiments, the polymer linker contains about 1% to about 99% HPMCAS, for example, about 1% to about 5% HPMCAS, about 5% to about 10% HPMCAS, about 10% to about 20% HPMCAS, about 20% to about 30% HPMCAS, about 30% to about 40% HPMCAS, about 40% to about 50% HPMCAS, about 50% to about 60% HPMCAS, about 60% to about 70% HPMCAS, about 70% to about 80% HPMCAS, about 80% to about 90% HPMCAS, or about 90% to about 99% HPMCAS. In some embodiments, the enteric polymer linker contains less than 20% HPMCAS. In some embodiments, the enteric polymer linker contains less than 15% HPMCAS. Depending on the embodiment, the enteric-coated polymer linker may contain less than 10% HPMCAS. Depending on the embodiment, the enteric-coated linker may contain more than 80% HPMCAS. Depending on the embodiment, the enteric-coated linker may contain more than 85% HPMCAS. Depending on the embodiment, the enteric-coated linker may contain more than 90% HPMCAS. Depending on the embodiment, the enteric-coated linker may contain approximately 20% to approximately 80% HPMCAS.

[0191] The enteric polymer is preferably bonded in a homogeneous mixture with one or more additional polymers (e.g., one or more supported polymers) in the enteric linker. For example, the enteric polymer and the additional linker polymer may be homogeneously mixed together before the mixture is extruded and the extruded material is cut to the desired size relative to the polymer linker. Depending on the embodiment, one or more additional linker polymers are miscible with the enteric polymer. One or more additional linker polymers may be non-degradable polymers (i.e., they do not decompose in the gastric or intestinal environment, or in aqueous solutions with pH 1.6 (representing the gastric environment) or pH 6.5 (representing the intestinal environment)).

[0192] The binding of a polymer linker to a directly adjacent member may be improved if at least one polymer is common to both the adjacent member and the enteric polymer linker. That is, one of one or more additional linker polymers in the enteric linker may be the same (or the same polymer species) as at least one polymer in the directly adjacent member (or both directly adjacent members, if necessary) of the gastric retention system. For example, if the enteric polymer linker is directly bound to a structural member containing a supported polymer, depending on the embodiment, one or more additional linker polymers also contain the supported polymer (in addition to PLGA in the time-dependent polymer linker) at the same or different concentrations. Exemplary supported polymers include, but are not limited to, polylactic acid (PLA), polycaprolactone (PCL), and thermoplastic polyurethane (TPU), among others described herein.

[0193] In some embodiments, one or more additional linker polymers in the enteric polymer linker are PLA, for example, PLA as described herein with respect to the supported polymer. In some embodiments, the enteric polymer linker comprises about 99% or less by weight, about 98% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, or about 10% or less of PLA. Depending on the embodiment, the enteric polymer linker may contain approximately 99% or more by weight of PLA, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 0.1% to approximately 10% PLA, approximately 10% to approximately 20% PLA, approximately 20% to approximately 30% PLA, approximately 30% to approximately 40% PLA, approximately 40% to approximately 50% PLA, approximately 50% to approximately 60% PLA, approximately 60% to approximately 70% PLA, approximately 70% to approximately 80% PLA, approximately 80% to approximately 90% PLA, or approximately 90% to approximately 99.9% PLA. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 30% or less PLA. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 70% or more PLA. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 30% to approximately 70% PLA. Enteric polymers (e.g., HPMCAS) may be included along with PLA and may constitute the remainder of the enteric polymer linker, but additional agents (e.g., plasticizers, colorants, or other agents) may also be included.

[0194] Depending on the embodiment, one or more additional linker polymers in the enteric-coated linker include PCL. The enteric-coated polymer linker may be directly bonded to or connected to other components of the gastric retention system (e.g., structural components including the drug and carrier polymer, binding components, time-dependent polymer linkers, or central structural components), which may contain PCL, which may be the same PCL as in the enteric-coated polymer linker or a different PCL, and may be the same or a different concentration. If the PCL in the enteric-coated polymer linker differs from that in other components directly bonded to or connected to the enteric-coated linker, for example, the weight-average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when two or more PCL polymers are blended and used) may differ.

[0195] Depending on the embodiment, the enteric polymer linker may contain approximately 99% or less by weight, approximately 98% or less, approximately 95% or less, approximately 90% or less, approximately 85% or less, approximately 80% or less, approximately 75% or less, approximately 70% or less, approximately 65% ​​or less, approximately 60% or less, approximately 55% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, approximately 20% or less, or approximately 10% or less of PCL. Depending on the embodiment, the enteric polymer linker may contain approximately 99% or more by weight, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more of PCL. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 0.1% to approximately 10% PCL, approximately 10% to approximately 20% PCL, approximately 20% to approximately 30% PCL, approximately 30% to approximately 40% PCL, approximately 40% to approximately 50% PCL, approximately 50% to approximately 60% PCL, approximately 60% to approximately 70% PCL, approximately 70% to approximately 80% PCL, approximately 80% to approximately 90% PCL, or approximately 90% to approximately 99.9% PCL. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 30% or less PLA. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 70% or more PLA. Depending on the embodiment, the enteric-coated polymer linker may contain approximately 30% to approximately 70% PCL. Enteric-coated polymers (e.g., HPMCAS) may be included along with PCL and may constitute the remainder of the enteric-coated polymer linker, although additional agents (e.g., plasticizers, colorants, or other agents) may also be included.

[0196] Depending on the embodiment, one or more additional linker polymers in the enteric polymer linker include TPU. The enteric polymer linker may be directly bonded or connected to other components of the gastric retention system (e.g., structural components including the drug and supported polymer, binding components, time-dependent polymer linkers, or central structural components), which may contain TPU, which may be the same TPU as in the enteric polymer linker or a different TPU, and may be the same or a different concentration. Different TPUs in the enteric polymer linker and other components directly bonded or connected to the enteric polymer linker may differ, for example, in the weight-average molecular weight of the TPU, the intrinsic viscosity of the TPU, or the proportion of TPU (e.g., when using a blend of two or more TPU polymers). Suitable commercially available TPU polymers include Pathway® TPU polymer (The Lubrizol Corporation), Tecoflex® (The Lubrizol Corporation), Tecophilic® (The Lubrizol Corporation), Carbonhatane® (The Lubrizol Corporation), Texin® (Covestro), and NEUSoft® (PolyOne). Furthermore, suitable types of TPU polymers for polymer linkers include aliphatic TPU, aliphatic polyether TPU, aromatic TPU, and polycarbonate polyurethane.

[0197] Depending on the embodiment, the enteric polymer linker may contain, by weight, approximately 99% or less, approximately 98% or less, approximately 95% or less, approximately 90% or less, approximately 85% or less, approximately 80% or less, approximately 75% or less, approximately 70% or less, approximately 65% ​​or less, approximately 60% or less, approximately 55% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, approximately 20% or less, or approximately 10% or less of TPU. Depending on the embodiment, the enteric polymer linker may contain, by weight, approximately 99% or more, approximately 98% or more, approximately 95% or more, approximately 90% or more, approximately 85% or more, approximately 80% or more, approximately 75% or more, approximately 70% or more, approximately 65% ​​or more, approximately 60% or more, approximately 55% or more, approximately 50% or more, approximately 40% or more, approximately 30% or more, approximately 20% or more, or approximately 10% or more of TPU. Depending on the embodiment, the enteric polymer linker may contain approximately 0.1% to 10% TPU, approximately 10% to 20% TPU, approximately 20% to 30% TPU, approximately 30% to 40% TPU, approximately 40% to 50% TPU, approximately 50% to 60% TPU, approximately 60% to 70% TPU, approximately 70% to 80% TPU, approximately 80% to 90% TPU, or approximately 90% to 99.9% TPU. Depending on the embodiment, the enteric polymer linker may contain approximately 30% or less TPU. Depending on the embodiment, the enteric polymer linker may contain approximately 70% or more TPU. Depending on the embodiment, the enteric polymer linker may contain approximately 30% to 70% TPU. Depending on the embodiment, the enteric polymer linker may contain approximately 30% to 70% PLA. Enteric polymers (e.g., HMPCAS) may be further included with TPU and may constitute the remainder of the enteric polymer linker, but additional agents (e.g., plasticizers, color-absorbing dyes, or other agents) may also be included.

[0198] Depending on the embodiment, the enteric polymer linker may contain 1-40%, 5-35%, 10-30%, 15-25%, 18-22%, or 20% TPU by weight.

[0199] The enteric-coated polymer linker may further contain one or more plasticizers, which can help cut the extruded polymer linker material to the desired size and help bind or adhere the enteric-coated polymer linker to other components of the gastric retention system. Examples of plasticizers include, but are not limited to, propylene glycol, polyethylene glycol (PEG), triethylbutyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer (e.g., Poloxamer 407, or "P407"), or D-α-tocopheryl polyethylene glycol succinate. Depending on the embodiment, the molecular weight of polyethylene glycol may range from about 200 Da to about 8,000,000 Da (also known as 8000 K or 8000 kDa), for example, about 200 Da to about 400 Da, about 400 Da to about 800 Da, about 800 Da to about 1600 Da, about 1600 Da to about 2500 Da, about 2500 Da to about 5000 Da, and about 5000 Da is approximately 10K, approximately 10K to approximately 20K, approximately 20K to approximately 50K, approximately 50K to approximately 100K, approximately 100K to approximately 200K, approximately 200K to approximately 400K, approximately 400K to approximately 800K, approximately 800K to approximately 1000K, approximately 1000K to approximately 2000K, approximately 2000K to approximately 4000K, approximately 4000K to approximately 6000K, or approximately 6000K to approximately 8000K. Depending on the embodiment, the polymer linker may contain up to 20% plasticizer, for example, up to 18% plasticizer, up to 15% plasticizer, up to 12% plasticizer. The polymer linker contains up to 10% plasticizer, up to 8% plasticizer, up to 6% plasticizer, up to 4% plasticizer, up to 3% plasticizer, up to 2% plasticizer, or up to 1% plasticizer. Depending on the embodiment, the polymer linker contains about 0.5% to about 15% plasticizer, for example, about 0.5% to about 1%, about 1% to about 2%, about 2% to about 3%, about 3% to about 5%, about 5% to about 7%, about 7% to about 10%, about 10% to about 12%, about 12% to about 15%, about 15% to about 18%, or about 18% to about 20% plasticizer.

[0200] Depending on the embodiment, the enteric polymer linker may contain a color-absorbing dye (also called a colorant or pigment). The color-absorbing dye may be included to enhance the binding or adhesion of the polymer linker to other gastric retention system components. The color-absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced adhesion, thereby increasing the tensile strength of the resulting bond. Exemplary color-absorbing dyes include iron oxide and carbon black. The enteric polymer linker may contain a color-absorbing dye in amounts up to about 5%, e.g., up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, or up to about 0.1%.

[0201] Enteric-coated polymer linkers may contain one or more additional excipients as needed. For example, enteric-coated polymer linkers may contain pologens, specifically sugars (e.g., lactose, sucrose, glucose), salts (e.g., NaCl), sodium starch glycolate (SSG), or any other suitable substance. Pologens may dissolve rapidly in an aqueous environment, thereby allowing the aqueous solution to facilitate contact with the inner portion of the polymer linker. Other excipients may include flow aids such as vitamin E succinate or silicon dioxide silicide (e.g., Cab-O-Sil), which may be included in the polymer blend to facilitate handling of the material before extrusion.

[0202] Depending on the embodiment, the enteric polymer linker comprises about 30% to about 80% HPMCAS and about 20% to about 70% supported polymer (e.g., TPU or PCL). If necessary, the enteric polymer linker further comprises propylene glycol (e.g., about 10% to about 14% propylene glycol).

[0203] Depending on the embodiment, the enteric polymer linker comprises about 55% to about 65% (e.g., about 60%) HPMCAS and about 35% to about 45% (e.g., about 40%) of a supported polymer (e.g., TPU or PCL).

[0204] Depending on the embodiment, the enteric polymer linker comprises about 35% to about 45% (e.g., about 40%) HPMCAS, about 45% to about 55% (e.g., about 50%) a supported polymer (e.g., TPU or PCL), and propylene glycol (e.g., about 8% to about 12% propylene glycol, specifically about 10% propylene glycol).

[0205] Depending on the embodiment, the enteric polymer linker may contain approximately 43% to approximately 53% (e.g., approximately 48%) HPMCAS, approximately 35% to approximately 45% (e.g., approximately 40%) of a supported polymer (e.g., TPU or PCL), and propylene glycol (e.g., approximately 10% to approximately 14% propylene glycol, specifically approximately 12% propylene glycol).

[0206] Depending on the embodiment, the enteric polymer linker comprises about 51% to about 61% (e.g., about 56%) HPMCAS, about 25% to about 35% (e.g., about 30%) a supported polymer (e.g., TPU or PCL), and propylene glycol (e.g., about 12% to about 16% propylene glycol, specifically about 14% propylene glycol).

[0207] Depending on the embodiment, the enteric polymer linker comprises about 52% to about 62% (e.g., about 57%) HPMCAS, about 35% to about 45% (e.g., about 40%) a supported polymer (e.g., TPU or PCL), and propylene glycol (e.g., about 1% to about 5% propylene glycol, specifically about 3% propylene glycol).

[0208] Depending on the embodiment, the enteric polymer linker comprises approximately 49% to approximately 59% (e.g., approximately 54%) HPMCAS, approximately 35% to approximately 45% (e.g., approximately 40%) of a supported polymer (e.g., TPU or PCL), and propylene glycol (e.g., approximately 4% to approximately 8% propylene glycol, specifically approximately 6% propylene glycol).

[0209] Depending on the embodiment, the enteric polymer linker comprises about 45% to about 55% (e.g., about 50%) HPMCAS and about 45% to about 55% (e.g., about 55%) of a supported polymer (e.g., TPU or PCL). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%).

[0210] Depending on the embodiment, the enteric polymer linker comprises about 55% to about 65% (e.g., about 60%) HPMCAS and about 35% to about 45% (e.g., about 40%) of a supported polymer (e.g., TPU or PCL). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%).

[0211] Depending on the embodiment, the enteric polymer linker comprises about 53% to about 63% (e.g., about 58%) HPMCAS, about 33% to about 43% (e.g., about 38%) of a supported polymer (e.g., TPU or PCL), and about 2% to about 6% (e.g., about 4%) of polyethylene glycol (e.g., polyethylene glycol 100K). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) of iron oxide.

[0212] Depending on the embodiment, the enteric polymer linker comprises about 31% to about 41% (e.g., about 36%) HPMCAS, about 31% to about 41% (e.g., about 36%) a supported polymer (e.g., TPU or PCL), and about 23% to about 33% (e.g., about 28%) TEC. Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) iron oxide.

[0213] Depending on the embodiment, the enteric polymer linker comprises about 59% to about 69% (e.g., about 64%) HPMCAS, about 29% to about 39% (e.g., about 34%) of a supported polymer (e.g., TPU or PCL), and about 1% to about 3% (e.g., about 2%) of poloxamer (e.g., P407). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) of iron oxide.

[0214] Depending on the embodiment, the enteric polymer linker comprises about 59% to about 69% (e.g., about 64%) HPMCAS, about 29% to about 39% (e.g., about 34%) of a supported polymer (e.g., TPU or PCL), and about 1% to about 3% (e.g., about 2%) of polyethylene glycol (e.g., polyethylene glycol 100K). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) of iron oxide.

[0215] Depending on the embodiment, the enteric polymer linker comprises about 65% to about 75% (e.g., about 70%) HPMCAS and about 25% to about 35% (e.g., about 30%) of a supported polymer (e.g., TPU or PCL). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) of iron oxide.

[0216] Depending on the embodiment, the enteric polymer linker comprises about 79% to about 89% (e.g., about 84%) HPMCAS, about 9% to about 19% (e.g., about 14%) of a supported polymer (e.g., TPU or PCL), and about 1% to about 3% (e.g., about 2%) of polyethylene glycol (e.g., polyethylene glycol 100K). Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) of iron oxide.

[0217] Depending on the embodiment, the enteric polymer linker comprises about 70% to about 80% (e.g., about 75%) HPMCAS, about 10% to about 20% (e.g., about 15%) of a supported polymer (e.g., TPU or PCL), and about 5% to about 15% (e.g., about 10%) of TEC. Optionally, the enteric polymer linker further comprises iron oxide, for example, about 0.01% to about 0.2% (specifically about 0.05% to about 0.1%) of iron oxide. Time-dependent, enteric-coated, dual-function polymer linker

[0218] In some embodiments, the gastric retention system includes a polymer linker having both time-dependent and enteric properties. That is, the time-dependent and enteric-coated dual-function polymer linker weakens or degrades in both the gastric and intestinal environments, but the weakening and degradation of the linker is faster in the intestinal environment than in the gastric environment. This type of linker can be obtained, for example, by including a mixture of a pH-independent degradable polymer such as PLGA and an enteric polymer such as HPMCAS.

[0219] For example, depending on the embodiment, when a polymer linker is left at a constant temperature of 37°C for 12 hours in an aqueous solution such as FaSSIF at pH 6.5, it loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more. When left at a constant temperature of 37°C for 12 hours in an aqueous solution such as FaSSGF at pH 1.6, it retains approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more. When left at a constant temperature of 37°C for 7 days in an aqueous solution such as FaSSGF at pH 1.6, it loses approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more. Depending on the embodiment, after being left at a constant temperature of 37°C for 24 hours in an aqueous solution such as FaSSIF at pH 6.5, the polymer linker loses or breaks approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more. After being left at a constant temperature of 37°C for 24 hours in an aqueous solution such as FaSSGF at pH 1.6, it retains approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more. Furthermore, after being left at a constant temperature of 37°C for 7 days in an aqueous solution such as FaSSGF at pH 1.6, it loses approximately 60% or more of its flexural modulus, approximately 70% or more, approximately 80% or more, approximately 90% or more, approximately 95% or more, or approximately 99% or more.

[0220] Depending on the embodiment, the time-dependent and enteric-coated bifunctional polymer linker has an initial flexural modulus of approximately 100 MPa to approximately 2500 MPa, for example, approximately 100 MPa to approximately 2500 MPa, approximately 100 MPa to approximately 250 MPa, approximately 250 MPa to approximately 500 MPa, approximately 500 MPa to approximately 750 MPa, approximately 750 MPa to approximately 1000 MPa, approximately 1000 MPa to approximately 1250 MPa, approximately 1250 MPa to approximately 1500 MPa, approximately 1500 MPa to approximately 2000 MPa, or approximately 2000 MPa to approximately 2500 MPa.

[0221] In some embodiments, the time-dependent and enteric-coated dual-function polymer linker includes PLGA. Examples of PLGA included in the time-dependent and enteric-coated dual-function polymer linker are as described above in relation to the time-dependent polymer linker. In some embodiments, the time-dependent and enteric-coated dual-function polymer linker includes PLGA in amounts of about 60% or less, about 55% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, or about 10% or less by weight. In some embodiments, the time-dependent and enteric-coated dual-function polymer linker includes PLGA in amounts of about 50% or more, about 40% or more, about 30% or more, about 20% or more, or about 10% or more by weight. Depending on the embodiment, the time-dependent and enteric-coated bifunctional polymer linker may contain about 5% to about 60% PLGA, for example, about 5% to about 10% PLGA, about 10% to about 20% PLGA, about 20% to about 30% PLGA, about 30% to about 40% PLGA, about 40% to about 50% PLGA, or about 50% to about 60% PLGA.

[0222] Depending on the embodiment, the time-dependent and enteric-coated dual-function polymer linker contains an enteric polymer such as HPMCAS in an amount of about 60% or less, about 55% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, or about 10% or less by weight. Depending on the embodiment, the time-dependent and enteric-coated dual-function polymer linker contains PLGA in an amount of about 50% or more, about 40% or more, about 30% or more, about 20% or more, or about 10% or more by weight. Depending on the embodiment, the time-dependent and enteric-coated dual-function polymer linker contains an enteric polymer such as HPMCAS in an amount of about 5% to about 60%, for example, about 5% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, or about 50% to about 60%.

[0223] Depending on the embodiment, the time-dependent and enteric-coated bifunctional polymer linker comprises about 40% to about 80% HPMCAS and about 20% to about 60% PLGA. Optionally, the polymer linker further comprises, for example, about 5% to about 40% of a supported polymer (e.g., PLA, TPU, or PCL). Structural members

[0224] The gastric retention system includes one or more structural members (e.g., “arms”), which are attached to a second member (e.g., a central member, which may be an elastic member) via one or more polymer linkers (e.g., a time-dependent polymer linker, an enteric polymer linker, both a time-dependent polymer linker and an enteric polymer linker, or a time-dependent and enteric bifaceted polymer linker). The structural members include a supported polymer and a drug (e.g., a pharmaceutical drug). In some embodiments, the structural members are divided into multiple segments. For example, the structural members may include one or more active segments (e.g., segments containing a drug) and one or more inactive segments. Embodiments having two or more active segments may have identical or different active segments (e.g., a first active segment containing a first drug and a second active segment containing a second drug). In some embodiments, the active and inactive segments include a general supported polymer or a general type of supported polymer.

[0225] The segments and arms of the gastric retention system may have a circular cross-section (in which case the segment is cylindrical), a polygonal cross-section (such as a segment having a triangular, rectangular, or square cross-section), or a pie-shaped cross-section (in which case the segment is a cylindrical fragment). To enhance in vivo safety, the sharp edges of segments with polygonal or pie-shaped cross-sections, and the ends of cylindrical fragments that come into contact with gastric tissue, may be rounded to create rounded corners and edges. That is, the transition from one edge or face to another is made using an arc, rather than an acute angle between intersecting edges or faces. Therefore, a “triangular cross-section” generally encompasses a triangular shape, such as a triangular cross-section with rounded corners. An arm with a triangular cross-section includes an arm with rounded edges, and the corners at the ends of the arm are rounded. Rounded corners and edges are also called chamfered angles, chamfered edges, or chamfered sides. The cross-sections of the segments and arms may coincide with the cross-sections of one or more polymer linkers used to attach the arms to a second (e.g., central) member. Supported polymer-drug segment (drug-eluting segment)

[0226] A supported polymer-drug segment or drug-eluting segment releases a drug in a controlled manner during the duration that the gastric retention system is present in the stomach. The supported polymer is blended with the drug to form a segment, which is then assembled with other components described herein to produce the gastric retention system. This mixture can be formed into a desired shape for use as a supported polymer-drug component in the system. After mixing the drug with the supported polymer to form a supported polymer-drug mixture, the drug or drug salt is distributed or dispersed throughout the combined mixture. If excipients, antioxidants, or other components are included in the supported polymer-drug formulation, they are also distributed or dispersed throughout the combined mixture.

[0227] Examples of supported polymers that may be included in the drug segment are described in further detail herein.

[0228] Drugs that can be administered into or via the gastrointestinal tract can be used in the gastric retention system of the present invention. The drug is mixed with a supported polymer and any excipient or other additive of the supported polymer to form segments for use in the gastric retention system. Drugs include, but are not limited to, drugs, prodrugs, biological preparations, and any other substances that can be administered to produce a beneficial effect against disease or injury. 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 such as ezetimibe. Examples of drugs that can be used as pharmaceutical agents in the gastric retention system of the present invention include: drug absorption inhibitors; antigout 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 pharmaceutical agents 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 certain embodiments, the drug is selected from the group including cetirizine, rosuvastatin, escitalopram, citalopram, risperidone, olanzapine, donepezil, and ivermectin. In other embodiments, the drug is one used to treat neuropsychiatric disorders, such as antipsychotics or antidementia agents such as memantine.

[0229] 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.

[0230] 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 15%, preferably about 5% to 10%, more preferably about 5% or about 10%. Examples of such excipients include Poloxamer 407 (available as Kolliphor P407, Sigma catalog no. 62035), polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol, CAS no. 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 no. 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%). Inactive segment

[0231] The arms of the gastric retention system may include one or more inactive segments that are drug-free or substantially drug-free. "Substantially drug-free" means that the drug is not present, or that trace amounts of the drug may be present due to diffusion from or binding to adjacent components, or due to the normal handling, packaging, or storage of the gastric retention system, but the polymer or other material used to form the inactive segment does not contain the drug.

[0232] The inert segment may contain a supported polymer, which may be the same supported polymer (or the same type of supported polymer) or a different supported polymer (or a different type of supported polymer) used in the active supported polymer-agent segment or one or more polymer linkers described herein. Exemplary supported polymers are further described herein. In some embodiments, the supported polymer contained in the inert segment is thermoplastic polyurethane (TPU). In some embodiments, the supported polymer contained in the inert segment is polycaprolactone (PCL). Supported polymer

[0233] Preferably, the supported polymer has the following properties: The supported polymer should be thermoplastic so that it can be extruded using hot-melt extrusion or 3D printing technology. The supported polymer should also have sufficiently high melt strength and viscosity so that it can be extruded into the desired shape. The supported polymer should have a low melting point (e.g., less than about 120°C) to avoid the drug or drug being exposed to high temperatures during manufacturing. The supported polymer should have sufficient mechanical strength (Young's modulus, compressive strength, tensile strength) to avoid rupture in the stomach during the desired residence period. The supported polymer should 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, and copolymers, mixtures, formulations, and combinations thereof. Polycaprolactone (PCL) is a preferred supported polymer. In another embodiment, polydioxanone is used as the supported polymer. In any embodiment of the gastric retention system, the supported polymer used in the gastric retention system may include a linear polycaprolactone having a number-average molecular weight (Mn) range of approximately 60 kDa to approximately 100 kDa, 75 kDa to 85 kDa, or approximately 80 kDa, or approximately 45 kDa to approximately 55 kDa, or approximately 50 kDa to approximately 110,000 kDa, or approximately 80 kDa to approximately 110,000 kDa.

[0235] In some embodiments, the supported polymer includes polylactic acid (PLA). PLA may include, essentially consist of, or consist of poly(L-lactide), poly(D-lactide), poly(D,L-lactide), or combinations thereof or copolymers thereof (such as L-lactide / D,L-lactide copolymer (PLDL) or L-lactide / D-lactide copolymer (PLD)). Depending on the embodiment, the intrinsic viscosity of this PLA (measured in CHCl3 at 25°C) is approximately 0.1 dl / g to approximately 6.5 dl / g, for example, approximately 0.1 dl / g to approximately 0.15 dl / g, approximately 0.15 dl / g to approximately 0.25 dl / g, approximately 0.25 dl / g to approximately 0.5 dl / g, approximately 0.5 dl / g to approximately 0.75 dl / g, approximately 0.75 dl / g to approximately 1.0 dl / g, approximately 1.0 dl / g to approximately 1.25 dl / g, approximately 1.25 dl / g to approximately 1.5 dl / g, approximately 1.5 dl / g to approximately 2.0 dl / g, approximately 2.0 to approximately 2.5 dl / g, and approximately 2.5 dl / g to approximately 3.0 The values ​​are approximately dl / g, 3.0 dl / g to 3.5 dl / g, 3.5 dl / g to 4.0 dl / g, 4.0 dl / g to 4.5 dl / g, 4.5 dl / g to 5.0 dl / g, 5.0 dl / g to 5.5 dl / g, 5.5 dl / g to 6.0 dl / g, or 6.0 dl / g to 6.5 dl / g. Depending on the embodiment, the ratio of L-lactide monomers to D,L-lactide monomers in the PLDL copolymer is in the range of approximately 5:95 to approximately 95:5, for example, approximately 5:95 to approximately 10:90, approximately 10:90 to approximately 20:80, approximately 20:80 to approximately 35:65, approximately 35:65 to approximately 50:50, approximately 50:50 to approximately 65:35, approximately 65:35 to approximately 80:20, approximately 80:20 to approximately 90:10, or approximately 90:10 to approximately 95:5. Depending on the embodiment, the ratio of L-lactide monomers to D-lactide monomers in the PLD copolymer is in the range of about 5:95 to about 95:5, for example, about 5:95 to about 10:90, about 10:90 to about 20:80, about 20:80 to about 35:65, about 35:65 to about 50:50, about 50:50 to about 65:35, about 65:35 to about 80:20, about 80:20 to about 90:10, or about 90:10 to about 95:5.Depending on the embodiment, the PLA may include a poly(L-lactide) having an intrinsic viscosity of 0.9 dl / g to 1.2 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PL10). Depending on the embodiment, the PLA may include a poly(L-lactide) having an intrinsic viscosity of 1.5 dl / g to 2.0 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PL18). Depending on the embodiment, the PLA may include a poly(L-lactide) having an intrinsic viscosity of 2.0 dl / g to 2.7 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PL24). Depending on the embodiment, the PLA may include a poly(L-lactide) having an intrinsic viscosity of 2.7 dl / g to 3.6 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PL32). Depending on the embodiment, the PLA may include a poly(L-lactide) having an intrinsic viscosity of 3.2 dl / g to 4.3 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PL38). Depending on the embodiment, the PLA may include a poly(L-lactide) having an intrinsic viscosity of 4.3 dl / g to 5.5 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PL49). Depending on the embodiment, the PLA may include a poly(L-lactide) (for example, a polymer sold under the trade name Purasorb® PL65) having an intrinsic viscosity of 5.5 dl / g to 7.5 dl / g (measured in CHCl3 at 25°C). Depending on the embodiment, the PLA may include a poly(D-lactide) (for example, a polymer sold under the trade name Purasorb® PD24) having an intrinsic viscosity of 2.0 dl / g to 2.8 dl / g (measured in CHCl3 at 25°C). Depending on the embodiment, the PLA may include a poly(D-lactide) (for example, a polymer sold under the trade name Purasorb® PD38) having an intrinsic viscosity of 3.2 dl / g to 4.3 dl / g (measured in CHCl3 at 25°C).Depending on the embodiment, the PLA may include a poly(D,L-lactide) having an intrinsic viscosity of 0.4 dl / g to 0.6 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PDL05). Depending on the embodiment, the PLA may include a poly(D,L-lactide) having an intrinsic viscosity of 1.6 dl / g to 2.4 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PDL20). Depending on the embodiment, the PLA may include a poly(D,L-lactide) having an intrinsic viscosity of 3.5 dl / g to 5.5 dl / g (measured in CHCl3 at 25°C) (for example, a polymer sold under the trade name Purasorb® PDL45). Depending on the embodiment, the PLA may contain PLDL (for example, a polymer sold under the trade name Purasorb® PLDL 7024) having an L-lactide:D,L-lactide ratio of approximately 70:30 and an intrinsic viscosity of 2.0 dl / g to 2.8 dl / g (measured in CHCl3 at 25°C). Depending on the embodiment, the PLA may contain PLDL (for example, a polymer sold under the trade name Purasorb® PLDL 7028) having an L-lactide:D,L-lactide ratio of approximately 70:30 and an intrinsic viscosity of 2.3 dl / g to 3.3 dl / g (measured in CHCl3 at 25°C). Depending on the embodiment, the PLA may contain PLDL (for example, a polymer sold under the trade name Purasorb® PLDL 7038) having an L-lactide:D,L-lactide ratio of approximately 70:30 and an intrinsic viscosity of 3.3 dl / g to 4.3 dl / g (measured in CHCl3 at 25°C). Depending on the embodiment, the PLA may contain PLDL (for example, a polymer sold under the trade name Purasorb® PLDL 7060) having an L-lactide:D,L-lactide ratio of approximately 70:30 and an intrinsic viscosity of 5.5 dl / g to 6.5 dl / g (measured in CHCl3 at 25°C). Depending on the embodiment, the PLA contains PLDL (for example, a polymer sold under the trade name Purasorb® PLDL 8038) having an L-lactide:D,L-lactide ratio of approximately 80:20 and an intrinsic viscosity of 3.3 dl / g to 4.3 dl / g (measured in CHCl3 at 25°C).Depending on the embodiment, the PLA contains PLDL (for example, a polymer sold under the trade name Purasorb® PLDL 8058) having an L-lactide:D,L-lactide ratio of approximately 80:20 and an intrinsic viscosity of 5.2 dl / g to 6.3 dl / g (measured in CHCl3 at 25°C).

[0236] In some embodiments, the supported polymer is PCL. For example, in some embodiments, the PCL has an intrinsic viscosity of about 1.5 to about 1.9 dl / g (e.g., PCL available from Corbion, sold under the trade name Purasorb® PC 17). Second structural member and central member

[0237] Structural members are attached to a second structural member, such as a central member. That is, one or more structural members may radiate outwards from the central member, for example, in a star-shaped configuration. The second structural member or the central member may be an elastic member. This allows the intragastric retention system to be configured between a folded, reduced configuration (e.g., during delivery of the intragastric retention system) and an expanded configuration (e.g., during intragastric retention).

[0238] This elastic member may be made from an elastic polymer. Although elastic polymers are generally not enteric polymers, the central elastic polymer may be made from such an enteric polymer if it is desirable and practical.

[0239] The indentation hardness of the elastic member determines the folding force of the dosage form and whether it will remain in the stomach. A preferred range is approximately 60 to 90A. The compression set should be as low as possible so that the gastric retention system does not permanently deform when stored in a capsule in a compressed configuration. A preferred range is approximately 10% to 20%. A material that satisfies these requirements is Dow Corning's QP1 series of liquid silicone rubber. QP1-270 (indentation hardness 70A) liquid silicone rubber can be used in any embodiment having a central elastic body.

[0240] An elastic material (also called an elastic polymer, elastic polymer, or tension 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 system 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 (Table 1). In some embodiments, the linking polymer used in the system is also an elastic material. Elastic materials are preferred for use as the central polymer in the star-shaped, or stellate, design of the gastric retention system.

[0241] 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. Other connecting members

[0242] Each component of the gastric retention system is attached directly or via one or more connecting members. The connecting members may be inert (i.e., drug-free or substantially drug-free), but may contain a supported polymer, which may be the same (or homogeneous) as the supported polymer contained in the adjacent member (or segment), or a different (or heterogeneous) supported polymer from the supported polymer contained in the adjacent member (or segment).

[0243] In some embodiments, the coupling member separates the first segment of the arm from the second segment of the arm. For example, in some embodiments, the coupling member separates the active segment of the arm from the inactive segment of the arm. The coupling member separating the two segments may be sandwiched directly between the two segments. In some embodiments, the first segment, the second segment, and the coupling member separating the two segments (such as one in direct contact with the two segments) comprise the same supported polymer, such as PCL, TPU, PLA, or other supported polymers described herein.

[0244] In some embodiments, the binder separates the arm from the polymer linker (e.g., a time-dependent polymer linker, an enteric polymer linker, or a time-dependent and enteric dual-function polymer linker). The binder that separates the polymer linker from the arm can be directly bonded to the arm and the polymer linker. In some embodiments, the binder contains the same (or the same type) supported polymer as the arm and / or the same (or the same type) supported polymer as the polymer linker at the interfacial joint (i.e., one or more additional polymers in the polymer linker may be general supported polymers or general supported polymer species). For example, in some embodiments, the arm, polymer linker, and binder between the arms include PCL. In some embodiments, the arm, polymer linker, and binder between the arms include TPU. In some embodiments, the arm, polymer linker, and binder between the arms include PLA.

[0245] In some embodiments, a binder separates the first polymer linker from the second polymer linker. The binder separating the first polymer linker from the second polymer linker may be directly connected to both polymer linkers. In some embodiments, the first and second polymer linkers and the binder between the polymer linkers include common polymers (or polymers of a common type) such as PCL, TPU, or PLA.

[0246] In some embodiments, a bonding member separates the polymer linker from a second structural member (e.g., a centrally elastic member). The bonding member may, for example, be in direct contact with both the second structural member and the polymer linker. Exemplary gastric retention system

[0247] The following gastric retention systems are illustrative to more specifically illustrate certain embodiments of the systems described herein. These examples are illustrative and not intended to limit the gastric retention systems described herein. Those skilled in the art may, in view of the provided disclosure, conceive of additional configurations of gastric retention systems.

[0248] In one example of an intragastric retention system, the system comprises several structural members including an active segment containing a supported polymer homogeneously mixed with a drug, arms extending radially from a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA), and at least one additional polymer (e.g., PLA or supported polymer), wherein the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature of 37°C for 14 days in an aqueous solution of pH 1.6, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0249] In another example of an intragastric retention system, the system includes an active segment containing a supported polymer homogeneously mixed with a drug, as well as several structural members, including arms extending radially from a central elastic member via a time-dependent polymer linker containing a pH-independent degradable polymer (e.g., PLGA) and a supported polymer. The time-dependent polymer linker is directly bonded to the segment of the structural member containing the supported polymer homogeneously mixed with the drug, and the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature in an aqueous solution of pH 1.6 at 37°C for 14 days, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent degradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the time-dependent polymer linker may contain a plasticizer, for example, about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0250] In another example of an intragastric retention system, the system includes a plurality of structural members, each containing a binding member and an active segment containing a supported polymer uniformly mixed with a drug; arms extending radially from a central elastic member attached via a time-dependent polymer linker of a pH-independent biodegradable polymer (e.g., PLGA); and the supported polymer. The time-dependent polymer linker is directly bonded to the binding member, which separates the active segment from the time-dependent polymer linker, and the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature in an aqueous solution of pH 1.6 at 37°C for 14 days, and the intragastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the time-dependent polymer linker may contain a plasticizer, for example, about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0251] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with a drug-homogeneously mixed PCL polymer, a pH-independent biodegradable polymer (e.g., PLGA), and a time-dependent polymer linker containing PCL, from which arms extend radially. The time-dependent polymer linker loses more than 80% of its flexure or breaks after being left at constant temperature for 14 days at 37°C in an aqueous solution of pH 1.6, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0252] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with PCL homogeneously mixed with a drug, and arms extending radially from a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and PCL. The time-dependent polymer linker is directly bonded to the segment of the structural member containing the PCL homogeneously mixed with the drug, and the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature in an aqueous solution of pH 1.6 at 37°C for 14 days, causing the intragastric retention system to remain in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the time-dependent polymer linker may contain a plasticizer, for example, about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0253] In another example of an intragastric retention system, the system includes a binding member containing PCL, a plurality of structural members containing an active segment homogeneously mixed with a drug and a supported polymer, and arms attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and PCL, from which arms extend radially. The time-dependent polymer linker is directly bonded to the binding member of the structural member, the binding member separates the active segment from the time-dependent polymer linker, the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature in an aqueous solution of pH 1.6 at 37°C for 14 days, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the time-dependent polymer linker may contain a plasticizer, for example, about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0254] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment comprising a TPU polymer homogeneously mixed with a drug, and arms attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and TPU, from which arms extend radially. The time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature for 14 days at 37°C in an aqueous solution of pH 1.6, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0255] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with a drug homogeneously mixed with TPU, and arms attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and TPU, from which arms extend radially. The time-dependent polymer linker is directly bonded to the segment of the structural member containing the drug homogeneously mixed with TPU, and after being left at constant temperature in an aqueous solution of pH 1.6 at 37°C for 14 days, the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the time-dependent polymer linker may contain a plasticizer, for example, about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0256] In another example of an intragastric retention system, the system includes multiple structural members, each containing a binding member containing TPU and an active segment containing a supported polymer homogeneously mixed with a drug, as well as arms attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and TPU, from which arms extend radially. The time-dependent polymer linker is directly bonded to the binding member of the structural member, which separates the active segment from the time-dependent polymer linker, and the time-dependent polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature in an aqueous solution of pH 1.6 at 37°C for 14 days, and the intragastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the time-dependent polymer linker may contain a plasticizer, for example, about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0257] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with a supported polymer homogeneously mixed with a drug, as well as arms attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and PLA, from which arms extend radially. The intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0258] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment homogeneously mixed with a drug and PCL, as well as arms attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and PCL, from which the intragastric retention system remains in the stomach for at least 24 hours. Depending on the embodiment, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. Depending on the embodiment, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0259] In another example of an intragastric retention system, the system comprises multiple structural members, each containing an active segment homogeneously mixed with a drug and TPU, attached to a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and TPU, extending radially from there. The intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0260] In another example of an intragastric retention system, the system includes a plurality of structural members, each containing an active segment with a supported polymer homogeneously mixed with a drug, and arms attached to a central elastic member via time-dependent polymer linkers containing a pH-independent biodegradable polymer (e.g., PLGA) and PLA, from which arms extend radially. The time-dependent polymer linkers are directly bonded to the segments of the structural members containing the supported polymer homogeneously mixed with the drug, and the intragastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linkers contain 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linkers contain a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0261] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment homogeneously mixed with a drug and PCL, as well as arms extending radially from a central elastic member via a time-dependent polymer linker containing a pH-independent biodegradable polymer (e.g., PLGA) and PCL. The time-dependent polymer linker is directly bonded to the segment of the structural member containing the drug-independent biodegradable PCL, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or mixtures thereof. In some embodiments, the polymer linker contains 70% or less PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0262] In another example of an intragastric retention system, the system includes a plurality of structural members including an active segment that includes TPU homogeneously mixed with a drug, as well as a time-dependent polymer linker that includes a pH-independent degradable polymer (e.g., PLGA) and TPU and is attached to a central elastic member via the time-dependent polymer linker and includes arms that radially extend therefrom. The time-dependent polymer linker is directly bonded to a segment of the structural member that includes TPU homogeneously mixed with the drug, and the intragastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent degradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. In some embodiments, the polymer linker includes 70% or less PLGA (e.g., from about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker includes a plasticizer, e.g., from about 0.5% to about 20% plasticizer (specifically from about 0.5% to about 12% plasticizer).

[0263] In another example of an intragastric retention system, the system includes a plurality of structural members including an active segment that includes a carrier polymer homogeneously mixed with a binding member and a drug, as well as a time-dependent polymer linker that includes a pH-independent degradable polymer (e.g., PLGA) and PLA and is attached to a central elastic member via the time-dependent polymer linker and includes arms that radially extend therefrom. The time-dependent polymer linker is directly bonded to the binding member, and the binding member separates the active segment from the time-dependent polymer linker, and the intragastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent degradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. In some embodiments, the polymer linker includes 70% or less PLGA (e.g., from about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker includes a plasticizer, e.g., from about 0.5% to about 20% plasticizer (specifically from about 0.5% to about 12% plasticizer).

[0264] In another embodiment of the gastric retention system, the system includes a plurality of structural members including an active segment containing a binding member comprising PCL and a carrier polymer uniformly mixed with a drug, and a central elastic member attached via a time-dependent polymer linker comprising a pH-independent degradable polymer (e.g., PLGA) and PCL, and having arms extending radially therefrom. The time-dependent polymer linker is directly attached to the binding member, which separates the active segment from the time-dependent polymer linker, and the gastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent degradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. In some embodiments, the polymer linker includes 70% or less of PLGA (e.g., about 30% to about 70% of PLGA). Optionally, the time-dependent polymer linker includes a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically, about 0.5% to about 12% plasticizer).

[0265] In another embodiment of the gastric retention system, the system includes a plurality of structural members including an active segment containing a binding member comprising TPU and a carrier polymer homogeneously mixed with a drug, and a central elastic member attached via a time-dependent polymer linker comprising a pH-independent degradable polymer (e.g., PLGA) and TPU, and having arms extending radially therefrom. The time-dependent polymer linker is directly attached to the binding member, which separates the active segment from the time-dependent polymer linker, and the gastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the pH-independent degradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. In some embodiments, the polymer linker includes 70% or less of PLGA (e.g., about 30% to about 70% PLGA). Optionally, the time-dependent polymer linker includes a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically, about 0.5% to about 12% plasticizer).

[0266] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with a drug and TPU, as well as arms attached to a central elastic member via an enteric polymer linker containing an enteric polymer and TPU, from which arms extend radially. The polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the enteric polymer is HMPCAS. If necessary, the enteric polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12%).

[0267] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with a drug and TPU homogeneously mixed, as well as arms attached to a central elastic member via an enteric polymer linker containing an enteric polymer and TPU, from which arms extend radially. The enteric polymer linker is directly bonded to the active segment containing TPU, and after being left at constant temperature in an aqueous solution of pH 6.5 at 37°C for 3 days, the polymer linker loses more than 80% of its flexural modulus or breaks, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the enteric polymer is HMPCAS. If necessary, the enteric polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0268] In another example of an intragastric retention system, the system includes a plurality of structural members, each comprising a binding member containing a TPU and an active segment containing a supported polymer uniformly mixed with a drug, as well as arms extending radially from a central elastic member via an enteric polymer linker containing an enteric polymer and TPU, the enteric polymer linker being directly bonded to the binding member, and the polymer linker losing more than 80% of its flexural modulus or rupturing after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5, the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the enteric polymer is HMPCAS. If necessary, the enteric polymer linker contains a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12%).

[0269] In another example of an intragastric retention system, the system comprises several structural members, each containing an active segment with a drug and a supported polymer uniformly mixed; the arms are attached to a central elastic member via an enteric polymer linker containing an enteric polymer and PLGA, extending radially from there, the polymer linker losing more than 80% of its flexural modulus or rupturing after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the enteric polymer linker contains a supported polymer. In some embodiments, the supported polymer is PCL and the enteric polymer linker constitutes PCL. In some embodiments, the supported polymer is TPU and the enteric polymer linker constitutes TPU. In some embodiments, the enteric polymer is HMPCAS. In some embodiments, the pH-independent biodegradable polymer contains acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. Depending on the embodiment, the polymer linker may contain 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the enteric polymer linker may contain about 0.5% to about 20% plasticizer (e.g., about 0.5% to about 12% plasticizer).

[0270] In another example of an intragastric retention system, the system includes multiple structural members, each containing an active segment with a supported polymer uniformly mixed with a drug, as well as arms attached to a central elastic member via an enteric polymer linker containing an enteric polymer and PLGA, from which arms extend radially. The enteric polymer linker is directly bonded to the active segment constituting the supported polymer, and the polymer linker loses more than 80% of its flexural modulus or breaks after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5, and the intragastric retention system remains in the stomach for at least 24 hours. In some embodiments, the enteric polymer is HMPCAS. In some embodiments, the enteric polymer linker contains the supported polymer. In some embodiments, the supported polymer is PCL and the enteric polymer linker contains PCL. In some embodiments, the supported polymer is TPU and the enteric polymer linker contains TPU. In some embodiments, the pH-independent biodegradable polymer contains acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. Depending on the embodiment, the polymer linker may contain 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the enteric polymer linker may contain a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer).

[0271] In another example of an intragastric retention system, the system includes a plurality of structural members, each comprising a binding member and an active segment containing a supported polymer uniformly mixed with a drug, as well as arms extending radially and attached to a central elastic member via enteric polymer linkers containing an enteric polymer and PLGA. The enteric polymer linkers are directly bonded to the binding member, and after being left at constant temperature at 37°C for 3 days in an aqueous solution of pH 6.5, the polymer linkers lose more than 80% of their flexural modulus or rupture, and the intragastric retention system remains in the stomach for a period of at least 24 hours. In some embodiments, the enteric polymer is HMPCAS. In some embodiments, the binding member and enteric polymer linkers contain a supported polymer. In some embodiments, the binding member and enteric polymer linkers contain PCL. In some embodiments, the binding member and enteric polymer linkers contain TPU. In some embodiments, the pH-independent biodegradable polymer includes acid-terminated PLGA, ester-terminated PLGA, or a mixture thereof. Depending on the embodiment, the polymer linker may contain 70% or less PLGA (e.g., about 30% to about 70% PLGA). If necessary, the enteric polymer linker may contain a plasticizer, e.g., about 0.5% to about 20% plasticizer (specifically about 0.5% to about 12% plasticizer). System dimensions

[0272] 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 nasogastric tube). Generally, the system is kept in a compressed state by 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.

[0273] Therefore, the system needs to be able to fit into standard-sized capsules of the type commonly used in pharmaceuticals. Standard capsule sizes used in the United States are shown in the capsule table (Table 2). These are the outer dimensions of the capsules, and since dimensions vary slightly depending on the capsule manufacturer, the system needs to be able to take a configuration that is approximately 0.5 to 1 mm smaller than the outer diameter shown and approximately 1 to 2 mm shorter than the length shown in the capsule table (Table 2). [Table 2]

[0274] 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.

[0275] In one embodiment, the system is folded or compressed to fit into a capsule. Once the capsule dissolves in the stomach, the system takes on a configuration suitable for retention within the stomach, for example, as shown in Figures 1A to 1D.

[0276] 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. radiopaque

[0277] The system may be radiopaque so that it can be positioned by abdominal X-ray if necessary. In some embodiments, one or more of the materials used to construct the system are sufficiently radiopaque to be visualized by X-ray. 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 the 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 of gastric retention systems Manufacturing of system components

[0278] Components of the gastric retention system, such as structural members (or member segments), linkers, and / or other connecting members, can be manufactured by hot-melt extrusion, co-extrusion, and / or three-dimensional printing. Commercially available equipment can be used in combination with dedicated co-extruder piping and molds for the desired configuration to co-extrude components of the gastric retention system. 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.

[0279] 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 die-cut into the desired shape (such as, but not limited to, triangular prisms, prismatic prisms, or cylindrical fragments (pi-shaped wedges)). Generally, the material is extruded to a thickness of about 0.2 mm to about 2.0 mm.

[0280] In some embodiments of the present invention, the entire elongated component of the gastric retention system, i.e., the "arm," may be manufactured by co-extrusion of the arm. In some embodiments of the present invention, segments of the elongated component of the gastric retention system, i.e., the "arm," may be manufactured by co-extrusion of the arm segments. In some embodiments, an arm or its segments 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 its segments. Following co-extrusion, a portion of the bulk composition may be compression-molded into pieces having the desired shape of the arm or its segments.

[0281] 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 slab 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. 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.

[0282] Plasticizers, such as in particular propylene glycol, polyethylene glycol (PEG), triethylbutyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer (e.g., Poloxamer 407 or "P407"), or succinic acid D-α-tocopheryl polyethylene glycol may be included in the coextruded polymer formulation, which can assist in cutting the extruded material into the desired size or shape. In some embodiments, the molecular weight of the polyethylene glycol is from about 200 Da to about 8,000,000 Da (also referred to as 8000K or 8000 kDa), for example, from about 200 Da to about 400 Da, from about 400 Da to about 800 Da, from about 800 Da to about 1600 Da, from about 1600 Da to about 2500 Da, from about 2500 Da to about 5000 Da, from about 5000 Da to about 10K, from about 10K to about 20K, from about 20K to about 50K, from about 50K to about 100K, from about 100K to about 200K, from about 200K to about 400K, from about 400K to about 800K, from about 800K to about 1000K, from about 1000K to about 2000K, from about 2000K to about 4000K, from about 4000K to about 6000K, or from about 6000K to about 8000K. In some embodiments, the coextruded polymer may contain up to 20% plasticizer, such as up to 18% plasticizer, up to 15% plasticizer, up to 12% plasticizer, up to 10% plasticizer, up to 8% plasticizer, up to 6% plasticizer, up to 4% plasticizer, up to 3% plasticizer, up to 2% plasticizer, or up to 1% plasticizer. In some embodiments, the coextruded polymer contains from about 0.5% to about 15% plasticizer, for example, from about 0.5% to about 1%, from about 1% to about 2%, from about 2% to about 3%, from about 3% to about 5%, from about 5% to about 7%, from about 7% to about 10%, from about 10% to about 12%, from about 12% to about 15%, from about 15% to about 18%, or from about 18% to about 20% plasticizer. Assembly of system components

[0283] Various components of a gastric retention system or polymer assembly can be attached to each other in various ways. One convenient method of attachment is thermal welding, which involves heating a first surface of a first component to a first temperature to provide a first heated surface, heating a second surface of a second component to a second temperature to provide a second heated surface, and then bringing the first heated surface into contact with the second heated surface (or equivalently, bringing the second heated surface into contact with the first heated surface). The first and second temperatures may be the same, or they may be different depending on the properties of the first and second components being welded. Heating of the first or second surface can be done by bringing each surface into contact with a metal platen (a flat metal plate) at the respective temperature. To facilitate manufacturing, a dual-temperature platen can be used, where the first end of the platen is at a first temperature and the second end is at a second temperature. The first surface is pressed against the first end of the platen, the second surface against the second end of the platen, and then the platen is removed, allowing the resulting first heated surface to come into contact with the resulting second heated surface. The contacted heated surfaces are pressed together with some force or pressure to ensure adhesion after cooling (the applied force or pressure is maintained as needed during the cooling process). Thermal welding is also called thermal fusion.

[0284] Another method for attaching various components of the gastric retention system, i.e., polymer assemblies, is infrared welding. Infrared welding is performed by bringing the first surface of a first component into contact with the second surface of a second component, irradiating the area of ​​the contact surface with infrared light while applying force or pressure to maintain contact between the two surfaces, and then cooling the attached components (the applied force or pressure is maintained during the cooling process as needed).

[0285] After each welding process, a heat treatment process may be employed as needed to increase the strength of the welded joint. The welded first and second parts can be heat-treated by placing them in an oven set to a third temperature (if the parts are heat-welded, the third temperature may be the same as the first temperature, the same as the second temperature, or different from the first and second temperatures used in the heat welding). The welded first and second parts can be subjected to infrared heat treatment by irradiating the welded area with infrared radiation. Unlike heat treatment in an oven where the entire first and second parts are heated, infrared heat treatment has the advantage of being able to irradiate locally.

[0286] Any combination of welding and heat treatment can be used. The parts can be heat-welded and then heat-treated in an oven, heat-welded and then heat-treated with infrared heat, heat-welded and then heat-treated in an oven, or heat-welded and then heat-treated with infrared heat.

[0287] Figure 3 shows an exemplary method for joining components together to form an intragastric retention system. Pre-cut polymer linkers (e.g., enteric-coated linkers or time-dependent linkers) are laser or IR welded to an elastic core material. The polymer linkers can be formed, for example, by hot-melt extruding the material and cutting it to the desired length. Next, a hot-melt extruded arm containing a supported polymer mixed with the drug is laser or IR welded to the polymer linker, thereby forming the star-shaped structure of the intragastric retention system.

[0288] By firmly attaching the components of the gastric retention system to one another, optimal system performance can be obtained when deployed in an individual's stomach. Insufficient welding or other attachment conditions of the system components may sever the interfaces between the system components, which may cause part or all of the system to pass through the pyloric valve and enter the intestines before the desired gastric retention period is completed. Several mechanisms for reinforcing the attachment of system components have been identified, and any one or more of these may be utilized in any of the gastric system components, such as the polymer linkers described herein (e.g., time-dependent polymer linkers and / or enteric polymer linkers).

[0289] System components can be enriched with plasticizers to enhance adhesion (e.g., welding) to adjacent components. For example, the plasticizer may be contained in a polymer linker (e.g., a time-dependent linker, an enteric linker, or a dual time-dependent and enteric linker) to strengthen the welding interface between the polymer linker and the immediately adjacent component (a structural member containing a supported polymer and a drug (or its active or inactive segment), a bonding member, another polymer linker, or a second structural member (e.g., an elastic core member)). In certain embodiments, too much plasticizer may result in a weaker welding interface compared to a lower amount of plasticizer. Therefore, depending on the embodiment, the plasticizer in the system component (e.g., polymer linker) may include up to 20% plasticizer, for example, up to 18% plasticizer, up to 15% plasticizer, up to 12% plasticizer, up to 10% plasticizer, up to 8% plasticizer, up to 6% plasticizer, up to 4% plasticizer, up to 3% plasticizer, up to 2% plasticizer, or up to 1% plasticizer. Depending on the embodiment, the system component (e.g., polymer linker) may include about 0.5% to about 15% plasticizer, for example, about 0.5% to about 1%, about 1% to about 2%, about 2% to about 3%, about 3% to about 5%, about 5% to about 7%, about 7% to about 10%, about 10% to about 12%, about 12% to about 15%, about 15% to about 18%, or about 18% to about 20% plasticizer. Examples of plasticizers include propylene glycol, polyethylene glycol (PEG), triethylbutyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer (e.g., Poloxamer 407, "P407"), and D-α-tocopheryl polyethylene glycol succinate.Depending on the embodiment, the molecular weight of polyethylene glycol ranges from approximately 200 Da to approximately 8,000,000 Da (also known as 8000 K or 8000 kDa), for example, approximately 200 Da to approximately 400 Da, approximately 400 Da to approximately 800 Da, approximately 800 Da to approximately 1600 Da, approximately 1600 Da to approximately 2500 Da, approximately 2500 Da to approximately 5000 Da, and approximately 5000 The ranges are approximately Da~10K, approximately 10K~20K, approximately 20K~50K, approximately 50K~100K, approximately 100K~200K, approximately 200K~400K, approximately 400K~800K, approximately 800K~1000K, approximately 1000K~2000K, approximately 2000K~4000K, approximately 4000K~6000K, or approximately 6000K~8000K.

[0290] Incorporating color absorbers into system components can strengthen attachment (e.g., welding) to adjacent components. Welding involves heating components, such as using infrared energy. Color absorbers absorb heat and act as blackbody radiation, allowing for a uniform distribution of their heads at the welded joint, thereby improving the strength and durability of the weld. Examples of color absorbers include iron oxide and carbon black.

[0291] Including a general polymer (e.g., a general supported polymer) or a general type of polymer (e.g., a general type of supported polymer) between joined components of the gastric retention system can improve the strength of welded joints between directly adjacent components. For example, depending on the embodiment, the polymer linker (e.g., a time-dependent linker, an enteric polymer linker, or a dual time-dependent and enteric polymer linker) includes a general polymer or a general type of polymer (a structural member, a bonding member, another polymer linker, or a second structural member (e.g., an elastic core member) containing a supported polymer and a drug (or its active or inactive segment) between directly adjacent components. The general polymer may be, for example, PCL or a certain type of PCL, TPU or a certain type of TPU, or PLA or a certain type of PLA.

[0292] Directly adjacent or welded parts may have similar melt flow indices at the welding temperature, in which case the welding between the joined gastric retention system parts can be enhanced. The melt flow index is a measure of viscosity determined by the number of grams of material flowing through the capillary in 10 minutes at a set temperature and load. The melt flow index can be measured, for example, using a load of 2.16 kg according to the method described in ASTM D1238. In some embodiments, the melt flow indices of two gastric retention system parts welded to each other may differ by only 50%, 40%, 30%, 20%, or 10% or less from the lower of the two parts' melt flow indices. In some embodiments, the welding temperature of the two parts may be between approximately 120°C and approximately 200°C, for example, approximately 120°C to approximately 140°C, approximately 140°C to approximately 160°C, approximately 160°C to approximately 180°C, or approximately 180°C to approximately 200°C. Treatment methods using the gastric retention system

[0293] 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.

[0294] 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 each 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 the number obtained by dividing "total T)" 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.

[0295] 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

[0296] 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).

[0297] 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. Exemplary Embodiments

[0298] The following embodiments are illustrative and are not intended to limit the scope of the invention as described herein.

[0299] Embodiment 1 An intragastric retention system comprising one or more first structural members comprising a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker, and the polymer linker comprises poly(lactic acid-co-glycolide) (PLGA) and at least one additional linker polymer. The polymer linker, after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6, loses more than 20% of its flexural modulus or breaks. The gastric retention system is a gastric retention system that is retained in the stomach for a period of at least 24 hours.

[0300] Embodiment 2: The intragastric retention system according to Embodiment 1, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0301] Embodiment 3: The intragastric retention system according to Embodiment 1, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 16.

[0302] Embodiment 4: The intragastric retention system according to Embodiment 1, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0303] Embodiment 5: The intragastric retention system according to Embodiment 1, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0304] Embodiment 6: The intragastric retention system according to any one of Embodiments 1 to 5, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0305] Embodiment 7: The intragastric retention system according to any one of Embodiments 1 to 5, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0306] Embodiment 8: The intragastric retention system according to any one of Embodiments 1 to 5, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0307] Embodiment 9: The intragastric retention system according to any one of Embodiments 1 to 5, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0308] Embodiment 10: The intragastric retention system according to any one of Embodiments 1 to 5, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0309] Embodiment 11: The intragastric retention system according to any one of Embodiments 1 to 10, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution of pH 1.6.

[0310] Embodiment 12: The intragastric retention system according to any one of Embodiments 1 to 10, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution of pH 1.6.

[0311] Embodiment 13: The intragastric retention system according to any one of Embodiments 1 to 10, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution of pH 1.6.

[0312] Embodiment 14: The intragastric retention system according to any one of Embodiments 1 to 10, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution of pH 1.6.

[0313] Embodiment 15: The intragastric retention system according to any one of Embodiments 1 to 10, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution of pH 1.6.

[0314] Embodiment 16: The intragastric retention system according to any one of Embodiments 1 to 15, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.6.

[0315] Embodiment 17: The intragastric retention system according to any one of Embodiments 1 to 15, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.6.

[0316] Embodiment 18: The intragastric retention system according to any one of Embodiments 1 to 15, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.6.

[0317] Embodiment 19: The intragastric retention system according to any one of Embodiments 1 to 15, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.6.

[0318] Embodiment 20: The intragastric retention system according to any one of Embodiments 1 to 15, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.6.

[0319] Embodiment 21: The intragastric retention system according to any one of Embodiments 1 to 20, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.6.

[0320] Embodiment 22 The intragastric retention system according to any one of Embodiments 1 to 20, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.6.

[0321] Embodiment 23: The intragastric retention system according to any one of Embodiments 1 to 20, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.6.

[0322] Embodiment 24: The intragastric retention system according to any one of Embodiments 1 to 20, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.6.

[0323] Embodiment 25: The intragastric retention system according to any one of Embodiments 1 to 20, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.6.

[0324] Embodiment 26 The gastric retention system according to any one of Embodiments 1 to 25, wherein the at least one additional linker polymer comprises polylactic acid (PLA), a supported polymer, polycaprolactone (PCL), or thermoplastic polyurethane (TPU).

[0325] Embodiment 27: The gastric retention system according to any one of Embodiments 1 to 25, wherein the supported polymer comprises PCL, and the at least one additional linker polymer comprises PCL.

[0326] Embodiment 28: The gastric retention system according to any one of Embodiments 1 to 25, wherein the supported polymer comprises TPU, and the at least one additional linker polymer comprises TPU.

[0327] Embodiment 29: The gastric retention system according to any one of Embodiments 1 to 25, wherein the at least one additional linker polymer comprises PLA.

[0328] Embodiment 30: The gastric retention system according to Embodiment 29, wherein the supported polymer comprises PCL or TPU.

[0329] Embodiment 31 A gastric retention system comprising one or more first structural members containing a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker, the polymer linker is (a) Poly(lactic acid-co-glycolide) (PLGA), and (b) comprising polylactic acid (PLA), polycaprolactone (PCL), or thermoplastic polyurethane (TPU), The gastric retention system is a gastric retention system that is retained in the stomach for a period of at least 24 hours.

[0330] Embodiment 32: The gastric retention system according to Embodiment 31, wherein the supported polymer comprises PCL, and the polymer linker comprises PLGA and PCL.

[0331] Embodiment 33: The gastric retention system according to Embodiment 31, wherein the supported polymer comprises TPU, and the polymer linker comprises PLGA and TPU.

[0332] Embodiment 34: The intragastric retention system according to Embodiment 31, wherein the polymer linker comprises PLGA and PLA.

[0333] Embodiment 35: The gastric retention system according to Embodiment 34, wherein the supported polymer comprises TPU or PCL.

[0334] Embodiment 36 The gastric retention system according to any one of Embodiments 1 to 35, wherein the PLGA comprises poly(D,L-lactic acid-co-glycolide) (PDLG).

[0335] Embodiment 37: The gastric retention system according to any one of Embodiments 1 to 36, wherein the PLGA includes an acid-terminated PLGA.

[0336] Embodiment 38: The gastric retention system according to any one of Embodiments 1 to 37, wherein the PLGA includes an ester-terminated PLGA.

[0337] Embodiment 39: The gastric retention system according to any one of Embodiments 1 to 38, wherein the PLGA comprises acid-terminated PLGA and ester-terminated PLGA in a ratio of approximately 1:9 to approximately 9:1.

[0338] Embodiment 40: The gastric retention system according to any one of Embodiments 1 to 39, wherein the polymer linker contains approximately 70% by weight or less of PLGA.

[0339] Embodiment 41: The intragastric retention system according to any one of Embodiments 1 to 40, wherein the polymer linker contains approximately 30% to approximately 70% by weight of PLGA.

[0340] Embodiment 42 The intragastric retention system according to any one of Embodiments 1 to 41, wherein the polymer linker further comprises an enteric-coated polymer.

[0341] Embodiment 43 The gastric retention system according to Embodiment 42, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate (HPMCAS).

[0342] Embodiment 44: The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0343] Embodiment 45 The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0344] Embodiment 46 The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0345] Embodiment 47 The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker further loses more than 80% of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0346] Embodiment 48 The intragastric retention system according to any one of Embodiments 1 to 47, wherein the polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0347] Embodiment 49 The intragastric retention system according to any one of Embodiments 1 to 47, wherein the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0348] Embodiment 50 The intragastric retention system according to any one of Embodiments 1 to 47, wherein the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0349] Embodiment 51 The intragastric retention system according to any one of Embodiments 1 to 47, wherein the polymer linker further loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0350] Embodiment 52 The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker loses more than 10% of the flexural modulus that decreases after being left at constant temperature in an aqueous solution of pH 6.5 at 37°C for 3 days compared to when it is left at constant temperature in an aqueous solution of pH 1.6 for 3 days.

[0351] Embodiment 53 The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker loses more than 20% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0352] Embodiment 54: The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker loses more than 40% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0353] Embodiment 55 The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker loses more than 60% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0354] Embodiment 56: The intragastric retention system according to any one of Embodiments 1 to 43, wherein the polymer linker loses more than 80% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0355] Embodiment 57 The gastric retention system according to any one of Embodiments 1 to 56, wherein one or more first structural members are attached to a second structural member via the polymer linker and the second polymer linker, the second polymer linker comprising an enteric polymer.

[0356] Embodiment 58 The gastric retention system according to Embodiment 57, wherein the second polymer linker further comprises TPU, PCL, or PLGA.

[0357] Embodiment 59 The gastric retention system according to Embodiment 57 or 58, wherein the second polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0358] Embodiment 60 A gastric retention system comprising one or more first structural members containing a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker, the polymer linker is (a) Thermoplastic polyurethane (TPU) or poly(lactic acid-co-glycolide) (PLGA), and (b) Contains enteric polymer, The aforementioned polymer linker, after being left at a constant temperature of 37°C for 3 days in an aqueous solution with a pH of 6.5, loses more than 20% of its flexural modulus or breaks. The gastric retention system is a gastric retention system that is retained in the stomach for a period of at least 24 hours.

[0359] Embodiment 61: The intragastric retention system according to Embodiment 60, wherein the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0360] Embodiment 62: The intragastric retention system according to Embodiment 60, wherein the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0361] Embodiment 63: The intragastric retention system according to Embodiment 60, wherein the polymer linker further loses more than 80% of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0362] Embodiment 64: The intragastric retention system according to any one of Embodiments 60 to 63, wherein the polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0363] Embodiment 65 The intragastric retention system according to any one of Embodiments 60 to 63, wherein the polymer linker further loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0364] Embodiment 66: The intragastric retention system according to any one of Embodiments 60 to 63, wherein the polymer linker further loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0365] Embodiment 67 The intragastric retention system according to any one of Embodiments 60 to 63, wherein the polymer linker further loses more than 80% of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0366] Embodiment 68 The intragastric retention system according to Embodiment 60, wherein the polymer linker loses more than 10% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0367] Embodiment 69: The intragastric retention system according to Embodiment 60, wherein the polymer linker loses more than 20% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0368] Embodiment 70 The intragastric retention system according to Embodiment 60, wherein the polymer linker loses more than 40% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0369] Embodiment 71 The intragastric retention system according to Embodiment 60, wherein the polymer linker loses more than 60% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0370] Embodiment 72 The intragastric retention system according to Embodiment 60, wherein the polymer linker loses more than 80% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0371] Embodiment 73: The gastric retention system according to any one of Embodiments 60 to 72, wherein the supported polymer comprises TPU and the one or more polymer linkers comprises TPU.

[0372] Embodiment 74: The gastric retention system according to any one of Embodiments 60 to 72, wherein the polymer linker includes PLGA.

[0373] Embodiment 75 The gastric retention system according to Embodiment 74, wherein the polymer linker further comprises polylactic acid (PLA).

[0374] Embodiment 76: The gastric retention system according to Embodiment 74 or 75, wherein the PLGA is poly(D,L-lactic acid-co-glycolide) (PDLG).

[0375] Embodiment 77: The gastric retention system according to any one of Embodiments 74 to 76, wherein the PLGA includes an acid-terminated PLGA.

[0376] Embodiment 78: The gastric retention system according to any one of Embodiments 74 to 77, wherein the PLGA includes an ester-terminated PLGA.

[0377] Embodiment 79: The gastric retention system according to any one of Embodiments 74 to 78, wherein the PLGA comprises acid-terminated PLGA and ester-terminated PLGA in a ratio of about 1:9 to about 9:1.

[0378] Embodiment 80: The intragastric retention system according to any one of Embodiments 74 to 79, wherein the polymer linker contains approximately 70% by weight or less of PLGA.

[0379] Embodiment 81: The intragastric retention system according to any one of Embodiments 74 to 80, wherein the polymer linker contains approximately 30% to approximately 70% by weight of PLGA.

[0380] Embodiment 82 The gastric retention system according to any one of Embodiments 60 to 81, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate (HPMCAS).

[0381] Embodiment 83: The intragastric retention system according to any one of Embodiments 60 to 82, wherein the polymer linker contains approximately 20% to approximately 80% by weight of an enteric-coated polymer.

[0382] Embodiment 84: The gastric retention system according to any one of Embodiments 1 to 83, wherein the polymer linker contains approximately 0.5% to approximately 20% by weight of a plasticizer.

[0383] Embodiment 85 The gastric retention system according to Embodiment 84, wherein the plasticizer comprises propylene glycol, polyethylene glycol (PEG), butyl triethyl citrate (TBC), dibutyl sebacate (DBS), triacetin, triethyl citrate (TEC), poloxamer, or D-α-tocopheryl polyethylene glycol succinate.

[0384] Embodiment 86 A gastric retention system comprising one or more first structural members containing a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker containing a linker polymer and about 0.5% to about 20% by weight of a plasticizer, The gastric retention system is a gastric retention system that is retained in the stomach for a period of at least 24 hours.

[0385] Embodiment 87: The gastric retention system according to Embodiment 86, wherein the polymer linker contains approximately 0.5% to approximately 12% plasticizer.

[0386] Embodiment 88: The gastric retention system according to Embodiment 86 or 87, wherein the linker polymer includes an enteric-coated polymer.

[0387] Embodiment 89: The intragastric retention system according to Embodiment 88, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0388] Embodiment 90: The intragastric retention system according to Embodiment 88, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0389] Embodiment 91: The intragastric retention system according to Embodiment 88, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0390] Embodiment 92: The intragastric retention system according to Embodiment 88, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

[0391] Embodiment 93 The intragastric retention system according to any one of Embodiments 88 to 92, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0392] Embodiment 94: The intragastric retention system according to any one of Embodiments 88 to 92, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0393] Embodiment 95 The intragastric retention system according to any one of Embodiments 88 to 92, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0394] Embodiment 96 The intragastric retention system according to any one of embodiments 88 to 92, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.5.

[0395] Embodiment 97: The intragastric retention system according to Embodiment 88, wherein the polymer linker loses more than 10% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0396] Embodiment 98 The intragastric retention system according to Embodiment 88, wherein the polymer linker loses more than 20% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0397] Embodiment 99: The intragastric retention system according to Embodiment 88, wherein the polymer linker loses more than 40% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0398] Embodiment 100 The intragastric retention system according to Embodiment 88, wherein the polymer linker loses more than 60% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0399] Embodiment 101 The intragastric retention system according to Embodiment 88, wherein the polymer linker loses more than 80% of the flexural modulus that decreases after being left at constant temperature for 3 days in an aqueous solution of pH 6.5 at 37°C.

[0400] Embodiment 102 The gastric retention system according to any one of Embodiments 88 to 101, wherein the enteric polymer comprises hydroxypropyl methylcellulose succinate acetate (HPMCAS).

[0401] Embodiment 103 The intragastric retention system according to any one of Embodiments 88 to 102, wherein the polymer linker contains approximately 20% to approximately 80% by weight of an enteric-coated polymer.

[0402] Embodiment 104: The gastric retention system according to any one of Embodiments 86 to 103, wherein the linker polymer includes the supported polymer.

[0403] Embodiment 105: The gastric retention system according to Embodiment 104, wherein the supported polymer is polycaprolactone (PCL) or thermoplastic polyurethane (TPU).

[0404] Embodiment 106 The gastric retention system according to any one of Embodiments 86 to 103, wherein the linker polymer comprises polylactic acid (PLA), polycaprolactone (PCL), or thermoplastic polyurethane (TPU).

[0405] Embodiment 107: The gastric retention system according to any one of Embodiments 86 to 106, wherein the linker polymer includes a time-dependent degradable polymer.

[0406] Embodiment 108 The intragastric retention system according to any one of Embodiments 86 to 107, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0407] Embodiment 109 The intragastric retention system according to any one of Embodiments 86 to 107, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0408] Embodiment 110 The intragastric retention system according to any one of Embodiments 86 to 107, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0409] Embodiment 111 The intragastric retention system according to any one of Embodiments 86 to 107, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0410] Embodiment 112 The intragastric retention system according to any one of Embodiments 86 to 107, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.6.

[0411] Embodiment 113 The intragastric retention system according to any one of Embodiments 86 to 112, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0412] Embodiment 114: The intragastric retention system according to any one of Embodiments 86 to 112, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0413] Embodiment 115 The intragastric retention system according to any one of Embodiments 86 to 112, wherein the polymer linker loses 60% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0414] Embodiment 116: The intragastric retention system according to any one of Embodiments 86 to 112, wherein the polymer linker loses 80% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0415] Embodiment 117: The intragastric retention system according to any one of Embodiments 86 to 112, wherein the polymer linker loses 90% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.6.

[0416] Embodiment 118 The intragastric retention system according to any one of Embodiments 86 to 117, wherein the polymer linker loses ...

Claims

1. An intragastric retention system comprising one or more first structural members comprising a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker comprising acid-terminated poly(D,L-lactic acid-co-glycolide) (PDLG) and at least one additional linker polymer, The aforementioned polymer linker, after being left at a constant temperature of 37°C for 30 days in an aqueous solution with a pH of 1.6, loses more than 20% of its flexural modulus or breaks. The gastric retention system is a gastric retention system that is retained in the stomach for a period of at least 24 hours.

2. An intragastric retention system comprising one or more first structural members containing a supported polymer and a drug, wherein the one or more first structural members are attached to a second structural member via a polymer linker, the polymer linker is (a) Acid-terminated poly(D,L-lactate-co-glycolide) (PDLG), and (b) comprising polylactic acid (PLA), polycaprolactone (PCL), or thermoplastic polyurethane (TPU), The gastric retention system is a gastric retention system that is retained in the stomach for a period of at least 24 hours.

3. The aforementioned polymer linker is (a) Acid-terminated poly(D,L-lactate-co-glycolide) (PDLG), and (b) Polycaprolactone (PCL) The gastric retention system according to claim 2, including the above.

4. The intragastric retention system according to any one of claims 1 to 3, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.

6.

5. The intragastric retention system according to any one of claims 1 to 3, wherein the polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.

6.

6. The intragastric retention system according to any one of claims 1 to 3, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 14 days in an aqueous solution of pH 1.

6.

7. The intragastric retention system according to any one of claims 1 to 3, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 7 days in an aqueous solution of pH 1.

6.

8. The intragastric retention system according to any one of claims 1 to 3, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.

6.

9. The intragastric retention system according to any one of claims 1 to 3, wherein the polymer linker further loses 10% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 1.

6.

10. The gastric retention system according to any one of claims 1 to 9, wherein one or more first structural members are attached to the second structural member via the polymer linker and the second polymer linker, and the second polymer linker comprises an enteric polymer.

11. The gastric retention system according to claim 10, wherein the second polymer linker further loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.

5.

12. The gastric retention system according to claim 10, wherein the second polymer linker loses 40% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.

5.

13. The gastric retention system according to claim 10, wherein the second polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for one day in an aqueous solution of pH 6.

5.

14. The intragastric retention system according to claim 2 or 3, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 30 days in an aqueous solution of pH 1.

6.

15. The intragastric retention system according to claim 2 or 3, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 21 days in an aqueous solution of pH 1.

6.

16. Including multiple first structural members, Each first structural member is attached to the second structural member via a separate polymer linker. The second structural member is an elastic central member, The gastric retention system is configured to fold and be physically restrained during administration, and to take on an open retaining shape when the restraint is removed, and The change between the folded shape and the open retaining shape is mediated by the elastic central member, which undergoes elastic deformation when the retention structure is in the folded shape and reacts when the gastric retention structure takes on the open retaining shape. The gastric retention system according to any one of claims 1 to 15.

17. The gastric retention system according to claim 16, wherein the gastric retention system is confined within a capsule configured to be broken down in the stomach.

18. The gastric retention system according to any one of claims 1 to 17, wherein the agent is a drug.

19. The gastric retention system according to any one of claims 1 to 18, wherein the second structural member is an elastic body.

20. The gastric retention system according to claim 1, wherein the at least one linker polymer comprises polylactic acid (PLA), a supported polymer, polycaprolactone (PCL), or thermoplastic polyurethane (TPU).

21. The gastric retention system according to claim 1, wherein the supported polymer comprises PCL, and the at least one additional linker polymer comprises PCL.

22. The intragastric retention system according to any one of claims 1 to 5, wherein the polymer linker further comprises an enteric polymer.

23. The gastric retention system according to claim 22, wherein the enteric-coated polymer comprises hydroxypropyl methylcellulose succinate acetate (HPMCAS).

24. The intragastric retention system according to claim 22, wherein the polymer linker loses 20% or more of its flexural modulus or breaks after being left at a constant temperature of 37°C for 3 days in an aqueous solution of pH 6.5.

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