Dosage forms for gastric retention

Abstract

A gastric retention system for administering risperidone is disclosed. Features that enhance retention in the stomach for a desired retention time and allow for more precise control of retention time are disclosed, including circumferential filaments connecting the arms of the star gastric retention system, an improved time-dependent and enteroerodible matrix (linker), and a release rate modifying polymer coating that is resistant to changes in release rate characteristics during heat-assisted assembly or thermal cycling. Combinations of these features are also disclosed.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 301,041, filed January 19, 2022, and U.S. Provisional Patent Application No. 63 / 368,605, filed July 15, 2022, the entire contents of which are incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under R01 AI131416 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] The present invention relates to a gastroretentive system for sustained release of an active agent, such as a drug, in the stomach, and methods of use thereof. [Background technology]

[0004] A gastroretentive system is a drug delivery system that remains in the stomach for a period of days to 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 U.S. Patent Application No. 10,182,985, and International Application Nos. 2015 / 191920, 2015 / 191925, 2017 / 070612, 2017 / 100367, 2017 / 205844, and 2018 / 227147. Over the retention period, the system releases one or more agents, such as one or more drugs.

[0005] The present invention describes advances in the design, construction, and formulation of gastroretentive systems that provide improved control over drug residence time and release rate. Summary of the Invention

[0006] A gastric retention system dosage form is disclosed that incorporates several features to more precisely and consistently control the desired retention time of the gastric retention system, including the following features: a filament that is wrapped circumferentially around the gastric retention system and connects the arms of the gastric retention system, the use of timed linkers and enteric linkers that allow for more precise retention and movement of the gastric retention system, and the arms that are coated with a release rate modifying polymer film.

[0007] Features of any of the embodiments described above and herein may be combined with any of the other embodiments described above and herein, where appropriate and practical. [Brief description of the drawings]

[0008] [Figure 1A] 1 shows the configuration of a gastric retention system.

[0009] [Figure 1B] FIG. 13 shows a detailed view of the gastroretentive configuration.

[0010] [Figure 2A] 1 shows the composition of a gastroretentive system dosage form for risperidone.

[0011] [Figure 2B] 1 shows another configuration of a gastroretentive system dosage form for risperidone.

[0012] [Diagram 3] 1 depicts a graph of the pharmacokinetics of the risperidone formulation in the gastroretentive system of Example 1 in human subjects (upper curve: 28 mg dosage form, lower curve: 14 mg dosage form).

[0013] [Figure 4]Figure 1 shows the pharmacokinetics of risperidone in a patient who transitioned from steady state with immediate release (IR) risperidone to steady state with an extended release (ER) risperidone gastric retention system. The concentrations of the active moieties (combination of risperidone and 9-hydroxyrisperidone) are plotted. The top curve shows concentrations from administration of 28 mg of the ER gastric retention system, and the bottom curve shows concentrations from administration of 14 mg of the ER gastric retention system. Bands showing the Cavg and Cmin of the corresponding matched IR group are superimposed on the curves.

[0014] [Figure 5A] Figure 1 shows the pharmacokinetics of risperidone administered via a gastroretentive system (ER). Mean concentrations of the active moieties (risperidone and 9-hydroxyrisperidone combined) are plotted + / - standard deviation. The top graph shows a 14 mg ER dose and the bottom graph shows a 28 mg ER dose. Bands showing Cavg and Cmin on the last day of the IR lead-in are superimposed on the graphs.

[0015] [Figure 5B] Concentrations of active moieties (risperidone and 9-hydroxyrisperidone combined) following daily IR administration of 2 mg (top graph) and 4 mg (bottom graph) of risperidone. Bands showing Cavg and Cmin on the last day of IR lead-in are superimposed on the graphs.

[0016] [Figure 6A] The mean concentrations Cavg of the active moiety (the combination of risperidone and 9-hydroxyrisperidone) on day -1 (i.e., just before the transition from the IR risperidone to the ER risperidone gastroretentive system) and on day 15 are presented comparing 2 mg IR with 14 mg ER and 4 mg IR with 28 mg ER.

[0017] [Figure 6B]Trough concentrations Ctau of the active moiety (combination of risperidone and 9-hydroxyrisperidone) on day -1 (i.e., just before the transition from IR risperidone to the ER risperidone gastroretentive system) and on day 15 are shown comparing 2 mg IR with 14 mg ER and 4 mg IR with 28 mg ER.

[0018] [Figure 7] 1 shows the composition of a gastroretentive system dosage form for risperidone.

[0019] [Figure 8A] 1 shows the composition of a gastroretentive system dosage form for risperidone. [Figure 8B] 1 shows another configuration of a gastroretentive system dosage form for risperidone. [Figure 8C] 1 shows the configuration of a drug-eluting arm in a gastroretentive system dosage form for risperidone. [Figure 8D] 1 shows the active composite arm in a gastroretentive system dosage form for risperidone. [Figure 8E] 1 shows an inactive composite arm in a gastroretentive system dosage form for risperidone.

[0020] [Figure 9A] 1 shows the composition of a gastroretentive system dosage form for risperidone. [Figure 9B] 1 shows the configuration of the drug-eluting arm (with the active arm) in a gastric retention system dosage form for risperidone. [Figure 9C] 1 shows the configuration of a non-drug eluting arm (with an inactive arm) in a gastric retention system dosage form for risperidone.

[0021] [Figure 10A] 1 shows the composition of a gastroretentive system dosage form for risperidone. [Figure 10B] 1 shows the configuration of the drug-eluting arm (with the active arm) in a gastric retention system dosage form for risperidone. [Figure 10C]1 shows the configuration of a non-drug eluting arm (with an inactive arm) in a gastric retention system dosage form for risperidone.

[0022] [Figure 11A] 1 shows the composition of a gastroretentive system dosage form for risperidone. [Figure 11B] 1 shows the configuration of the drug-eluting arm (with the active arm) in a gastric retention system dosage form for risperidone. [Figure 11C] 1 shows the configuration of a non-drug eluting arm (with an inactive arm) in a gastric retention system dosage form for risperidone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] definition A "carrier polymer" is a polymer suitable for blending with an agent, such as a drug, for use in a gastroretentive system.

[0024] A "pharmaceutical agent" is any substance intended for therapeutic, diagnostic, or nutritional use in a patient, individual, or subject. Pharmaceutical agents include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0025] A "dispersing agent" is defined as a substance that aids in minimizing the drug particle size and dispersing the drug particles in the carrier polymer matrix. That is, the dispersing agent helps to minimize or prevent particle aggregation or agglomeration during the fabrication of the system. Thus, the dispersing agent has anti-agglomeration and anti-agglomeration activity and helps to maintain a uniform distribution of the drug particles in the carrier polymer matrix.

[0026] An "excipient" is any substance, other than the drug itself, that is added to a drug formulation. Excipients include, but are not limited to, binders, coating agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, and preservatives. The specific category of dispersing agents is included within the more general category of excipients.

[0027] An "elastic polymer" or "elastomer" is a polymer that can be deformed from its original shape under an applied force for a period of time, and then substantially return to its original shape when the applied force is removed.

[0028] "Approximately constant plasma level" refers to a plasma level that remains within two-fold of the average plasma level (i.e., between 50% and 200% of the average plasma level) measured over the period that the gastroretentive system is in the stomach.

[0029] "Substantially constant plasma level" refers to a plasma level that remains within plus or minus 25% of the average plasma level measured over the period that the gastroretentive system is in the stomach.

[0030] "Biocompatibility," when used to describe a material or system, indicates that the material or system will not elicit an adverse reaction, or will elicit only a minimal and acceptable adverse reaction, when in contact with a living organism, such as a human. In the context of gastroretentive systems, biocompatibility is evaluated in the environment of the gastrointestinal tract.

[0031] A "patient," "individual," or "subject" refers to a mammal, preferably a human, or a domestic animal, such as a dog or cat. In the most preferred embodiment, the patient, individual, or subject is a human.

[0032] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0033] "Treatment" of a disease or disorder with the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional agents, to a patient in need thereof to either alleviate or eliminate the disease or disorder, or one or more symptoms of the disease or disorder, or to slow the progression of the disease or disorder, or one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder, or one or more symptoms of the disease or disorder. "Suppression" of a disease or disorder with the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional agents, to a patient in need thereof to inhibit the clinical manifestation of the disease or disorder, or to inhibit the manifestation of adverse symptoms of the disease or disorder. The difference between treatment and suppression is that treatment occurs after adverse symptoms of the disease or disorder appear in the patient, while suppression occurs before adverse symptoms of the disease or disorder appear in the patient. Suppression can be partial, substantially total, or total. Because some diseases or disorders are hereditary, genetic screening can be used to identify patients at risk for the disease or disorder. Asymptomatic patients who are at risk for developing clinical symptoms of the disease or disorder can then be treated using the systems and methods disclosed herein to prevent the appearance of any adverse symptoms.

[0034] 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. A "therapeutically effective amount" of a therapeutic agent, e.g., a drug, is an amount of the agent that, when administered to a patient, is sufficient to alleviate or eliminate any of a disease or disorder or one or more symptoms of a disease or disorder, or to slow the progression of a disease or disorder or one or more symptoms of a disease or disorder, or to reduce the severity of a disease or disorder or one or more symptoms of a disease or disorder. A therapeutically effective amount can be administered to a patient as a single dose, or can be divided and administered as multiple doses.

[0035] "Prophylactic use" of the systems disclosed herein is defined as using one or more of the systems disclosed herein to inhibit a disease or disorder, as defined above. A "prophylactically effective amount" of an agent is an amount of agent sufficient to inhibit the clinical manifestation of a disease or disorder, or inhibit the manifestation of adverse symptoms of a disease or disorder, when administered to a patient. A prophylactically effective amount can be administered to a patient as a single dose, or can be divided and administered as multiple doses.

[0036] The "flexural modulus" of a material is an intrinsic property of the material calculated as the ratio of stress to strain in bending deformation of the material as measured by a three-point bending test. Although the linker is described herein as a component of the gastroretention system, the flexural modulus of the material of the polymeric material may be measured alone. For example, the polymeric linker of the gastroretention system may be too short to measure the flexural modulus, but a longer sample of the same material may be used to accurately determine the flexural modulus. The longer sample used to measure the flexural modulus should be of the same cross-sectional dimension (shape and size) as the polymeric linker used in the gastroretention system. The flexural modulus is measured using the ASTM standard three-point bending test (ASTM D790) with a support distance of 10 mm and a modified three-point bending test to accommodate materials that are not rectangular in cross section. The flexural modulus should be measured by placing the longest line of symmetry of the cross section of the polymeric linker vertically and applying a force downward. If the longest line of symmetry of the cross section of the polymeric linker is perpendicular to one flat side, one flat side should be placed upward. If the cross section of the polymer linker is triangular, the apex of the triangle should be pointing downward. A downward force is applied, the force and displacement are measured, and the slope in the linear region is obtained to calculate the bending modulus.

[0037] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated or the context clearly dictates otherwise.

[0038] When a numerical value is expressed herein using the term "about" or "approximately", it is understood that both the specified value and values ​​reasonably close to the specified value are included. For example, a description of "about 50°C" or "approximately 50°C" includes a disclosure of both 50°C itself and values ​​close to 50°C. Thus, the phrase "about X" or "approximately X" includes a description of the value X itself. When a range is given, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C", it is understood that both values ​​specified by the endpoints are included, and values ​​close to each or both endpoints are included for each or both endpoints; i.e., "approximately 50°C to 60°C" (or "approximately 50°C to 60°C") is equivalent to describing both "50°C to 60°C" and "approximately 50°C to approximately 60°C" (or "approximately 50°C to 60°C").

[0039] With respect to the numerical ranges disclosed herein, any disclosed upper limit for a given ingredient can be combined with any disclosed lower limit 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 the disclosed upper and lower limits is expressly contemplated herein. For example, if the ranges for the amount of a particular ingredient are 10%-30%, 10%-12%, and 15%-20%, then the ranges 10%-20% and 15%-30% are also contemplated, but the combination of a lower limit of 15% with an upper limit of 12% is not possible and is therefore not contemplated.

[0040] Unless otherwise specified, the percentages of components in a composition are expressed as weight percent or weight / weight percent. Reference to a relative weight percent in a composition is understood to mean that the total weight percent of all components in the composition combined is considered to add up to 100. It is further understood that the relative weight percentage of one or more components can be adjusted upward or downward so that the weight percentages of the components in the composition together add up to 100, as long as the weight percentage of any particular component does not fall outside the limits of the range specified for that component.

[0041] Some embodiments described herein are described as "comprising" or "comprises" with respect to their various elements. In alternative embodiments, the elements may be described with the transitional phrase "consisting essentially of" or "consists essentially of" applied to those elements. In further alternative embodiments, the elements may be described with the transitional phrase "consisting of" or "consists of" applied to those elements. Thus, for example, if a composition or method is disclosed herein as comprising A and B, alternative embodiments of that composition or method "consisting essentially of A and B" and alternative embodiments of that composition or method "consisting of A and B" are also considered to be disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to their various elements may also be described as "comprising" applied to those elements. Finally, embodiments described as "consisting essentially of" with respect to their various elements may also be described as "consisting of" applied to those elements, and vice versa.

[0042] When a composition or system is described as "consisting essentially of" listed elements, the composition or system contains the elements explicitly listed and may contain other elements that do not substantially affect the condition being treated (in the case of a composition for treating a condition) or the properties of the described system (in the case of a composition that includes a system). However, the composition or system does not contain any other elements that substantially affect the condition being treated (in the case of a composition for treating a system) or does not contain any other elements that substantially affect the properties of the system (in the case of a composition that includes a system) other than the elements explicitly listed; or, if the composition or system contains additional elements other than the listed elements that may substantially affect the condition being treated or the properties of the system, the composition or system does not contain those additional elements in sufficient concentrations or amounts to substantially affect the condition being treated or the properties of the system. When a method is described as "consisting essentially of" listed steps, the method contains the listed steps and may contain other steps that do not substantially affect the condition being treated by the method or the properties of the system produced by the method, but the method does not contain any other steps other than those explicitly listed that substantially affect the condition being treated or the properties of the system produced by the method.

[0043] The present disclosure provides several embodiments. It is contemplated that any feature from any embodiment may be combined, where possible, with any feature from any other embodiment. In this manner, hybrid configurations of the disclosed features are within the scope of the present disclosure.

[0044] In addition to the embodiments and methods disclosed herein, additional embodiments of gastroretention systems and methods of making and using such systems are disclosed in International Application Nos. 2015 / 191920, 2015 / 191925, 2017 / 070612, 2017 / 100367, and PCT / US2017 / 034856, which are incorporated by reference in their entireties.

[0045] The following abbreviations are used for the polymers and other components:

[0046] [Table 1]

[0047] PLURONIC® is a registered trademark of BASF Corporation for polyoxyalkylene ethers. In any formulation described herein using a trade name, the trade name can be replaced with a generic name. For example, a formulation described as containing 50% Corbion PC17 and 50% Corbion PC04 is understood to describe a formulation containing 50% polycaprolactone with a viscosity of 1.7 dl / g and 50% polycaprolactone with a viscosity of 0.4 dl / g. Any component in any formulation described herein using a trade name can be replaced with an equivalent component from another manufacturer.

[0048] As used herein, unless otherwise specified, "copolymer of DL-lactide and glycolide" is understood to refer to an ester-terminated copolymer of DL-lactide and glycolide, and "poly(D,L-lactic acid-co-glycolide)" is understood to refer to ester-terminated poly(D,L-lactic acid-co-glycolide).

[0049] As used herein, unless otherwise specified, "PCL" can refer to polycaprolactone having various median intrinsic viscosities, such as 1.0-2.1 dl / g, for example, polycaprolactone having a median intrinsic viscosity of 1.7 dl / g or polycaprolactone having a median intrinsic viscosity of 1.2 dl / g.

[0050] Description of the gastroretentive system The gastroretention system can be made in different configurations. The "stellate" configuration of the gastroretention system is also known as the "star" (or "asterisk") configuration. An example of a star system 100 is shown diagrammatically in FIG. 1A. A number of arms (only one arm 108 is numbered for clarity) are fixed to a disk-shaped central elastomer 106. The arms shown in FIG. 1A are composed of segments 102 and 103 and are joined by a linking polymer or linker region 104 that acts as a linker region (again, for clarity, the component is numbered for only one arm). This configuration allows the system to be folded or compressed in the central elastomer. FIG. 1B shows a folded configuration 190 of the gastroretention system of FIG. 1A (only two arms are shown in FIG. 1B for clarity). Segments 192 and 193, linker region 194, elastomer 196, and arms 198 of FIG. 1B correspond to segments 102 and 103, linker region 104, elastomer 106, and arms 108 of FIG. 1A, respectively. When folded, the overall length of the system is reduced by approximately half, and the system can be conveniently placed in a container such as a capsule or other container suitable for oral administration. The gastroretentive system is constrained in a compressed (folded) state by the capsule or other container. When the capsule reaches the stomach, it dissolves and the gastroretentive system is released. When freed from the constraint of the capsule or other container, the gastroretentive system then unfolds to a non-compressed state and is maintained in the stomach for the desired retention period.

[0051] Linker region 104 is shown in FIG. 1A as being slightly larger in diameter than segments 102 and 103, but may be the same diameter as the segments, such that the entirety of arms 102-104-103 have a smooth outer surface.

[0052] In some embodiments, a star system may have an arm composed of only one segment attached to a central elastomer by a linker region. This corresponds to the omission of segment 103 in Figure 1A. The single segment arm, including segment 102, is then attached directly to the central elastomer 106 via linker 104. The linker may comprise a connecting polymer or a collapsible matrix.

[0053] The star system can be described as a gastroretention system for administration to a patient's stomach, comprising an elastomeric component and a plurality of at least three carrier polymer-drug components attached to the elastomeric component, each of the plurality of carrier polymer-drug components comprising a carrier polymer and a drug or a salt thereof, each of the plurality of carrier polymer-drug components comprising a proximal end, a distal end, and an outer surface therebetween, the proximal end of each arm being attached to the elastomeric component and projecting radially from the elastomeric component, each arm having its distal end not attached to the elastomeric component and located at a radial distance from the elastomeric component greater than the proximal end, each arm independently comprising one or more segments, each segment comprising a proximal end, a distal end, and an outer surface therebetween. In some embodiments, when two or more segments are present in an arm, each segment is attached to an adjacent segment via a linker region. In some embodiments, when two or more segments are present in an arm, one segment is attached directly to the other segment without the use of a linker region. The linker region can be a linking polymer or a disintegrating matrix. The arms may be attached to the central elastomer via a linking polymer or a degradable matrix and may have intervening portions of polymer that bond them. For a plurality of at least three arms, or for a plurality of arms, the preferred number of arms is six, although 3, 4, 5, 7, 8, 9, or 10 arms can be used. The arms should be equally spaced around the periphery of the central elastomer, and if there are N arms, there is an angle of about 360 / N degrees between adjacent arms.

[0054] The linking polymer of the gastroretentive system, which serves as the linker region, is designed to degrade gradually in a controlled manner during the system's residence period in the stomach. If the gastroretentive system moves too early in its intact form to the small intestine, the system is designed to degrade much more rapidly to avoid intestinal obstruction. This is easily achieved by using an enteric polymer as the linking polymer. Enteric polymers are relatively resistant to the acidic pH levels encountered in the stomach, but dissolve at the high pH levels found in the duodenum. The use of an enteric linking polymer as a safety element protects the gastroretentive system from undesired migration to the small intestine. In the system shown in FIG. 1A, at least the linking polymer 104 used for linking is made of such an enteric polymer.

[0055] In further embodiments, a time-dependent linking polymer or linker can be used that degrades in a predictable, time-dependent manner. In some embodiments, the degradation of the time-dependent linking polymer or linker may not be affected by the changing pH of the gastrointestinal system.

[0056] In further embodiments, different types of linkers can be used in the gastroretentive system, i.e., both enteric linkers (or enteric linking polymers) and time-dependent linkers (or time-dependent linking polymers) can be used. In some embodiments, a single multi-segment arm of a star system can use both enteric linkers in some linker regions between segments and time-dependent linkers in other linker regions between segments.

[0057] The linker region is typically about 100 microns to about 2 millimeters in width, for example, about 200 um to about 2000 um, about 300 um to about 2000 um, about 400 um to about 2000 um, about 500 um to about 2000 um, about 600 um to about 2000 um, about 700 um to about 2000 um, about 800 um to about 2000 um, about 900 um to about 2000 um, about 1000 um to about 2000 um, about 1100 um to about 2000 um, about 1200 um to about 2000 um, about 1300 um to about 2000 um, about 1400 um to about 2000 um, about 1500 um to about 2000 um, about 1600 um to about 2000 um, about 1700 um to about 2000 um, about 1800 um, and the like. m to about 2000 um, or about 1900 um to about 2000 um; or about 100 um to about 1900 um, about 100 um to about 1800 um, about 100 um to about 1700 um, about 100 um to about 1600 um, about 100 um to about 1500 um, about 100 um to about 1400 um, about 100 to about 1300 um, about 100 um to about 1200 um , about 100 um to about 1100 um, about 100 um to about 1000 um, about 100 um to about 900 um, about 100 um to about 800 um, about 100 um to about 700 um, about 100 um to about 600 um, about 100 um to about 500 um, about 100 um to about 400 um, about 100 um to about 300 um, or about 100 um to about 200 um. The linker region may be about 100 um, about 200 um, about 300 um, about 400 um, about 500 um, about 600 um, about 700 um, about 800 um, about 900 um, about 1000 um, about 1100 um, about 1200 um, about 1300 um, about 1400 um, about 1500 um, about 1600 um, about 1700 um, about 1800 um, about 1900 um, or about 200 um in width, each value may be plus or minus 50 um (±50 um).

[0058] The central elastic polymer of a star system is typically not an enteric polymer, although the central elastic polymer may be made from such an enteric polymer where desirable and practical.

[0059] The central elastomer should have a particular durometer and compression set. The durometer is important as it determines the folding force of the dosage form and whether it will remain in the stomach, with a preferred range of about 60 to about 90A. The compression set should be as low as possible so that the gastroretentive system does not become permanently deformed when stored in the capsule in a compressed configuration. A preferred range is about 10% to about 20%. Liquid silicone rubber is a useful material for the central elastomer. An example of a material that meets these requirements is Dow Corning's QP1 range of liquid silicone rubber. In any embodiment having a central elastomer, QP1-270 (70A durometer) liquid silicone rubber can be used. In some embodiments, the central elastomer may include 50A or 60A durometer liquid silicone rubber (Shin Etsu).

[0060] The segments and arms of the gastric retention system can have a cross-section in the shape of a circle (in which case the segment is cylindrical), a polygon (e.g., a segment having a triangular, rectangular, or square cross-section), or a sector cross-section (in which case the segment is a cylindrical section). Segments with polygonal or sector cross-sections, and ends of cylindrical sections that will come into contact with gastric tissue, can have their sharp edges rounded to provide rounded corners and edges for increased in vivo safety. That is, rather than a sharp transition between intersecting edges or planes, an arc is used to transition from one edge or plane to another. Thus, a "triangular cross-section" includes a cross-section that has a generally triangular shape, such as a triangle with rounded corners. Arms with triangular cross-sections include arms with rounded edges and rounded corners at the ends of the arms. Rounded corners and edges are also referred to as fillet corners, filleted corners, fillet edges, or filleted edges.

[0061] In some embodiments, the star system is about 30 mm to about 60 mm when unfolded (arms deployed). In some embodiments, the star system is about 41 mm to about 51 mm when unfolded. In some embodiments, the star system is about 45 mm to about 47 mm when unfolded. In some embodiments, the star system is about 46 mm when unfolded.

[0062] Features for improving retention and drug release in gastroretentive systems Retention of and drug release from the gastric retention system over the desired retention period can be improved and made more consistent using the features described herein, such as filaments wrapped circumferentially around the gastric retention system and connecting the arms of the gastric retention system, the use of timed linkers and enteric linkers that allow for more precise retention and movement of the gastric retention system, and arms coated with release rate controlling polymer films.

[0063] Circumferential filaments In this disclosure of circumferential filaments, gastric retention systems including filaments for improved gastric retention and methods of making gastric retention forms with filaments are provided. In particular, gastric retention systems with filaments described herein can help improve the gastric retention of the gastric retention system. Specifically, the filaments can help provide a more consistent gastric retention time and / or a longer gastric retention time. Thus, gastric retention systems provided herein including filaments can provide a more predictable and / or controllable gastric retention time. A gastric retention system with a predictable and / or controllable gastric retention time can minimize the risk of the gastric retention system deploying too early (e.g., in the esophagus) and causing obstruction. A gastric retention system with a predictable and / or controllable gastric retention time can also minimize the possibility of the gastric retention system passing through the stomach and later deploying in the gastrointestinal tract (i.e., intestines) or passing through the gastrointestinal tract without being deployed at all. In each of these possible scenarios, the therapeutic agent in the gastroretentive dosage form is not delivered to the patient as intended.

[0064] However, it has been demonstrated that star-shaped gastroretention systems can bend into a configuration that allows them to pass through the patient's pylorus too early. A gastroretention system that passes through the pylorus too early cannot deliver the therapeutic agent of the gastroretention system to the patient. Furthermore, premature passage can cause inconsistency, unreliability, and compromise the effectiveness of the gastroretention system.

[0065] Circumferential filament features are described in International Application No. PCT / US2020 / 059541, which is incorporated by reference in its entirety.

[0066] In some embodiments, the filaments are non-disintegrating filaments. In some embodiments, the filaments include a thermoplastic polyurethane, such as Pellethane 80A. In some embodiments, the filaments include methylene bis(4-phenylisocyanate), poly(tetramethylene oxide), and 1,4-butanediol. In some embodiments, the filaments are disintegrating filaments. In some embodiments, the filaments include poly(lactic-co-glycolic acid). In some embodiments, the filaments include polyglycolic acid. In some embodiments, the filaments have a thickness of about 0.05 mm, about 0.1 mm, about 0.15 mm, about 0.20 mm, about 0.25 mm, about 0.30 mm, about 0.35 mm, about 0.40 mm, about 0.45 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, or any thickness therebetween. In some embodiments, the filaments have a thickness of about 0.20 mm. In some embodiments, the filament thickness is about 0.30 mm.

[0067] In some embodiments, each section of the filament connecting two adjacent arms can be about 20 to about 25 mm long, e.g., about 21 to about 24 mm long, e.g., about 22.8 mm long. In some embodiments, the circumferential filament can have a total length of about 95 to about 120 mm, or a total length of about 100 to about 150 mm, e.g., a total length of about 105 mm.

[0068] Time-delayed linker (time-delayed disintegrating matrix) and enteric linker (enteric disintegrating matrix) Polymer Linker The drug-containing structural member is attached to the second structural member (e.g., a central member, which may be an elastic central member) via one or more linkers. The polymeric linker may be directly bonded to the drug-containing structural member or may be bonded to the drug-containing structural member via a linking member. Similarly, the polymeric linker may be directly bonded to the second structural member or may be bonded via a linking member. In embodiments in which the drug-containing structural member is connected to the second structural member via two or more polymeric linkers, the polymeric linkers may be bonded directly to each other or may be bonded via a linking member. Either or both of an enteric linker and a time-dependent linker may be used, or a polymeric linker may function as both an enteric linker and a time-dependent linker.

[0069] The polymer linker typically has a width of about 100 microns to about 3 mm, for example, about 200 um to about 3000 um, about 300 um to about 3000 um, about 400 um to about 3000 um, about 500 um to about 3000 um, about 600 um to about 3000 um, about 700 um to about 3000 um, about 800 um to about 3000 um, about 900 um to about 3000 um, about 1000 um to about 3000 um, about 1100 um to about 3000 um, about 1200 um to about 3000 um, about 1300 um to about 3000 um, about 1400 um to about 3 000um, about 1500um to about 3000um, about 1600um to about 3000um, about 1700um to about 3000um, about 1800um to about 3000um, about 1900um to about 3000um, about 2000um to about 3000um, about 2100um to about 3000um, about 2200um to about 3000um, about 2300um to about 3000um, about 2400um to about 3000um, about 2500um to about 3000um, about 2600um to about 3000um, about 2700um to about 3000um, about 2800um to about 3000um, or about 2900um to about 3000um; or about 100um to about 200um, about 200um to about 300um, about 300um to about 400um, about 400um to about 500um, about 500um to about 600um, about 600um to about 700um, about 700um to about 800um, about 800um to about 900um, about 900um to about 1000um, about 1000um to about 1100um, about 1100um to about 1200um, about 1200um to about 1300um, about 1300um to about 1400um, about 1400um to about 1500um, about 1500um to about 1600 um, about 1600 um to about 1700 um, about 1700 um to about 1800 um, about 1800 um to about 1900 um, about 1900 um to about 2000 um, about 2000 um to about 2100 um, about 2100 um to about 2200 um, about 2200 um to about 2300 um, about 2300 um to about 2400 um, about 2400 um to about 2500 um, about 2500 um to about 2600 um, about 2600 um to about 2700 um, about 2700 um to about 2800 um, about 2800 um to about 2900 um, about 2900 um to about 3000 um.The polymer linker may have a range of about 100 um, about 200 um, about 300 um, about 400 um, about 500 um, about 600 um, about 700 um, about 800 um, about 900 um, about 1000 um, about 1100 um, about 1200 um, about 1300 um, about 1400 um, about 1500 um, about 1600 um, about 1700 um, about 1800 um, about 1900 um, about 2000 um, about 2100 um, about 2200 um, about 2300 um, about 2400 um, about 2500 um, about 2600 um, about 2700 um, about 2800 um, about 2900 um, about 3000 um, and each value may be plus or minus 50 um (±50 um).

[0070] The cross-section of the polymeric linker may be round (i.e., circular), elliptical, triangular, square, rectangular, pentagonal, hexagonal, or any other polymeric shape. In some embodiments, the cross-section of the polymeric linker is the same shape as the cross-section of the drug-containing structural member to which it is attached. In some embodiments, the cross-section of the polymeric linker has an area larger than the cross-section of the drug-containing structural member, an area smaller than the cross-section of the drug-containing structural member, or approximately the same area as the cross-section of the drug-containing structural member to which it is attached.

[0071] Time-dependent disintegration matrix (time-dependent linker) The time-dependent linker degrades in a predictable, time-dependent manner under aqueous conditions, such as when the gastroretentive system is deployed in the stomach of an individual. The time-dependent polymeric linker controls the residence time of the gastroretentive system in the stomach. The time-dependent polymeric linker is designed to gradually degrade, dissolve, mechanically weaken, or break down over time. After the desired residence period, the time-dependent polymeric linker degrades, dissolves, dissociates, or mechanically weakens or breaks down to a degree that allows the gastroretentive system to pass through the pyloric valve, exit the gastric environment into the small intestine, and ultimately exit the body.

[0072] The time-dependent polymeric linker preferably comprises a pH-independent degradable polymer, which degrades in an aqueous condition in a pH-independent or approximately pH-independent manner. Exemplary pH-independent degradable polymers include PLGA, PLA, PCL, polydioxanone, cellulose, or blends or copolymers thereof.

[0073] The time-dependent polymeric linker can include poly(lactic acid-co-glycolide) (PLGA).

[0074] In some embodiments, the PLGA of the time-dependent polymeric linker comprises an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity between about 0.32 dl / g and about 0.48 dl / g (e.g., about 0.4 dl / g) (e.g., PLGA sold under the trade name Purasorb® PDLG 5004 available from Corbion). In some embodiments, the PLGA of the time-dependent polymeric linker comprises an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity between about 0.32 dl / g and about 0.48 dl / g (e.g., about 0.4 dl / g) (e.g., PLGA sold under the trade name Purasorb® PDLG 5004A available from Corbion). In some embodiments, the PLGA of the time-dependent polymeric linker comprises a mixture of (a) ester-terminated poly(D,L-lactic acid-co-glycolide) having a ratio of about 50:50 lactide and glycolide monomers (e.g., PLGA sold under the trade name Purasorb® PDLG 5004, available from Corbion) and (b) acid-terminated poly(D,L-lactic acid-co-glycolide) having a ratio of about 50:50 lactide and glycolide monomers (e.g., PLGA sold under the trade name Purasorb® PDLG 5004A, available from Corbion).

[0075] The one or more additional linker polymers contained in the polymeric linker are preferably mixed homogeneously with PLGA.In some embodiments, the one or more additional linker polymers are miscible with PLGA.The one or more additional linker polymers can be non-degradable polymers (i.e., they are not degraded in gastric or intestinal environments, or in aqueous solutions at pH 1.6 (representing gastric environment) or pH 6.5 (representing intestinal environment)), and are optionally present in the time-dependent polymeric linker in an amount such that the time-dependent polymeric linker is not destroyed during the gastric residence period.

[0076] Attachment of the polymeric linker to directly adjacent members may be improved when at least one polymer is common to both the adjacent members and the time-dependent polymeric linker, hi some embodiments, the at least one common polymer is polycaprolactone (PCL).

[0077] In some embodiments, the one or more additional linker polymers include PCL. The time-dependent polymeric linker may be directly bonded or attached to another member of the gastric retention system (e.g., a structural member comprising a drug and a carrier polymer, a linking member, an enteric polymeric linker, or a central structural member), which may include PCL, which may be the same as the PCL in the time-dependent polymeric linker or a different PCL from the PCL in the polymeric linker, and may be at the same concentration or at a different concentration. The different PCL in the time-dependent polymeric linker and the other member directly bonded or attached to the time-dependent linker may differ, for example, in the weight average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when a blend of two or more PCL polymers is used). In some embodiments, the time-dependent disintegrating matrix includes about 40% to about 50% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix includes about 43% to about 47% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix includes about 45% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 44.95% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 45% to about 55% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 48% to about 52% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 50% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 49.95% by weight of PCL. In some embodiments, the PCL has a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., about 1.7 dl / g (e.g., Corbion PC17). In some embodiments, the PCL has a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., about 1.2 dl / g (e.g., Corbion PC12).

[0078] The time-dependent polymeric linker may further comprise one or more plasticizers, such as polyethylene glycol. The term "polyethylene glycol" is used herein interchangeably with the terms "polyethylene oxide" and "PEO". In some embodiments, the molecular weight of the polyethylene glycol is about 90K to about 110K, such as 100K (also referred to as 100K or 100kDa). In some embodiments, the time-dependent disintegrating matrix comprises polyethylene glycol having a molecular weight of about 100k (polyethylene glycol 100k). In some embodiments, the time-dependent disintegrating matrix comprises about 0.5% to about 5% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 1% to about 3% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 2% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 1.5% to about 3.5% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 2.5% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises a color absorbing dye (also referred to as a colorant or pigment). The color absorbing dye may be included to enhance the bonding or attachment of the polymeric linker to other gastroretentive system components. The color absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced attachment, thereby increasing the tensile strength of the resulting bond. Exemplary color absorbing dyes include iron oxide and carbon black. The time-dependent disintegrating matrix may comprise a color absorbing dye in an amount of 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%, up to about 0.1%, or up to about 0.05%. In some embodiments, the time-dependent disintegrating matrix comprises about 0.005% to about 0.2% by weight of the color absorbing dye. In some embodiments, the time-dependent disintegratable matrix comprises from about 0.01% to about 0.1% by weight of a color absorbing dye.In some embodiments, the time-dependent disintegratable matrix comprises about 0.05% by weight of a color absorbing dye, hi some embodiments, the color absorbing dye is E172.

[0079] In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 40% to about 50% by weight PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 40% to about 50% by weight of PCL (e.g., PCL having a median viscosity of about 1.5 dl / g to about 1.9 dl / g), about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 40% to about 50% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45% to about 55% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 27% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 12% to about 22% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45% to about 55% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 33% to about 43% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 5% to about 15% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45% to about 55% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 8% to about 18% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45% to about 55% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 27% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 12% to about 22% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172.

[0080] In another example of the time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 43% to about 47% by weight PCL, about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 15% to about 20% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 43% to about 47% by weight of PCL (e.g., PCL having a median viscosity of about 1.5 dl / g to about 1.9 dl / g), about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 15% to about 20% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 43% to about 47% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 15% to about 20% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48% to about 52% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 30% to about 34% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 14% to about 18% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48% to about 52% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 36% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 8% to about 12% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48% to about 52% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 11% to about 15% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48% to about 52% by weight of PCL (e.g., PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g), about 30% to about 34% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 14% to about 18% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1.5% to about 3.5% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of color absorbing dye E172.

[0081] In another example of the time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 44.95% by weight PCL, about 35% by weight acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 44.95 wt. % PCL (e.g., a PCL having a median viscosity of about 1.7 dl / g, e.g., Corbion PC 17), about 35 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18 wt. % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 44.95 wt. % PCL (e.g., a PCL having a median viscosity of about 1.2 dl / g, e.g., Corbion PC 12), about 35 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18 wt. % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 49.95 wt. % PCL (e.g., a PCL having a median viscosity of about 1.2 dl / g, e.g., Corbion PC 12), about 32 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 16 wt. % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 49.95 wt. % PCL (e.g., a PCL having a median viscosity of about 1.2 dl / g, e.g., Corbion PC 12), about 38 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10 wt. % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 49.95 wt. % PCL (e.g., a PCL having a median viscosity of about 1.2 dl / g, e.g., Corbion PC 12), about 35 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 13 wt. % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 49.95% by weight PCL (e.g., a PCL having a median viscosity of about 1.2 dl / g, e.g., Corbion PC 12), about 31.75% by weight acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 15.75% by weight ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2.5% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172.

[0082] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 44.95% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 35.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004A. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 18.0% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the gastroretentive system comprises about 2.0% by weight of a polyethylene glycol, such as a polyethylene glycol having an average molecular weight of 100,000, such as PEO. 100KIn some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 44.95% by weight of Corbion PC17, about 35.0% by weight of PDLG 5004A, about 18.0% by weight of PDLG 5004, about 2.0% by weight of PEO. 100K and about 0.05% by weight of E172.

[0083] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 44.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, e.g., Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 35.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g, e.g., about 0.4 dl / g, e.g., PDLG 5004A. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 18.0% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the gastroretentive system comprises about 2.0% by weight of polyethylene glycol, such as polyethylene glycol having an average molecular weight of 100,000, such as PEO. 100KIn some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 44.95% by weight of Corbion PC12, about 35.0% by weight of PDLG 5004A, about 18.0% by weight of PDLG 5004, about 2.0% by weight of PEO. 100K and about 0.05% by weight of E172.

[0084] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, e.g., Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 32.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g, e.g., about 0.4 dl / g, e.g., PDLG 5004A. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 16.0% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the gastroretentive system comprises about 2.0% by weight of a polyethylene glycol, such as a polyethylene glycol having an average molecular weight of 100,000, such as PEO. 100KIn some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95% by weight of Corbion PC12, about 32.0% by weight of PDLG 5004A, about 16.0% by weight of PDLG 5004, about 2.0% by weight of PEO. 100K and about 0.05% by weight of E172.

[0085] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, e.g., Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 38.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g, e.g., about 0.4 dl / g, e.g., PDLG 5004A. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 10.0% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the gastroretentive system comprises about 2.0% by weight of a polyethylene glycol, such as a polyethylene glycol having an average molecular weight of 100,000, such as PEO. 100KIn some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95% by weight of Corbion PC12, about 38.0% by weight of PDLG 5004A, about 10.0% by weight of PDLG 5004, about 2.0% by weight of PEO. 100K and about 0.05% by weight of E172.

[0086] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, e.g., Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 35.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g, e.g., about 0.4 dl / g, e.g., PDLG 5004A. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 13.0% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the gastroretentive system comprises about 2.0% by weight of a polyethylene glycol, such as a polyethylene glycol having an average molecular weight of 100,000, such as PEO. 100KIn some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95% by weight of Corbion PC12, about 35.0% by weight of PDLG 5004A, about 13.0% by weight of PDLG 5004, about 2.0% by weight of PEO. 100K and about 0.05% by weight of E172.

[0087] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, e.g., Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 31.75% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g, e.g., about 0.4 dl / g, e.g., PDLG 5004A. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 15.75% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the gastroretentive system comprises about 2.5% by weight of polyethylene glycol, such as polyethylene glycol having an average molecular weight of 100,000, such as PEO. 100KIn some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95% by weight of Corbion PC12, about 31.75% by weight of PDLG 5004A, about 15.75% by weight of PDLG 5004, about 2.5% by weight of PEO. 100K and about 0.05% by weight of E172.

[0088] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0089] [Table 2]

[0090] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0091] [Table 3]

[0092] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0093] [Table 4]

[0094] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0095] [Table 5]

[0096] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0097] [Table 6]

[0098] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0099] [Table 7]

[0100] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0101] [Table 8]

[0102] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0103] [Table 9]

[0104] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0105] [Table 10]

[0106] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0107] [Table 11]

[0108] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0109] [Table 12]

[0110] Exemplary amounts of the components of the time-dependent disintegratable matrix are provided in the table below. It is understood that the amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0111] [Table 13]

[0112] The time-dependent disintegration matrix disclosed herein can be used as the time-dependent disintegration matrix in any of the gastroretentive systems disclosed herein.

[0113] Gastric residence time The gastric retention time of the system is controlled by the rate of degradation or weakening or breakage of the time-dependent polymeric linker in the gastric retention system. The faster the degradation or weakening or breakage of the time-dependent polymeric linker, the faster the passage of the system from the stomach. The retention time of the gastric retention system is defined as the time between administration of the system to the stomach and the system being emptied from the stomach. In one embodiment, the gastric retention system has a retention time of about 24 hours, or up to about 24 hours. In one embodiment, the gastric retention system has a retention time of about 48 hours, or up to about 48 hours. In one embodiment, the gastric retention system has a retention time of about 72 hours, or up to about 72 hours. In one embodiment, the gastric retention system has a retention time of about 96 hours, or up to about 96 hours. In one embodiment, the gastric retention system has a retention time of about 5 days, or up to about 5 days. In one embodiment, the gastric retention system has a retention time of about 6 days, or up to about 6 days. In one embodiment, the gastroretention system has a retention time of about 7 days (about 1 week), or up to about 7 days (about 1 week). In one embodiment, the gastroretention system has a retention time of about 10 days, or up to about 10 days. In one embodiment, the gastroretention system has a retention time of about 14 days (about 2 weeks), or up to about 14 days (about 2 weeks).

[0114] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 5 days to about 7 days. In one embodiment, the gastric retention system has a retention time of about 6 days to about 7 days.

[0115] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 5 days to about 10 days. In one embodiment, the gastric retention system has a retention time of about 6 days to about 10 days. In one embodiment, the gastric retention system has a retention time of about 7 days to about 10 days.

[0116] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 5 days to about 14 days. In one embodiment, the gastric retention system has a retention time of about 6 days to about 14 days. In one embodiment, the gastric retention system has a retention time of about 7 days to about 14 days. In one embodiment, the gastric retention system has a retention time of about 10 days to about 14 days.

[0117] The gastric retention system releases a therapeutically effective amount of the agent (or salt thereof) during at least a portion of the residence time or period during which the system resides in the stomach. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 25% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 50% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 60% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 70% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 75% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 80% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) during at least about 85% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 90% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 95% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 98% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 99% of the residence time.

[0118] Enterolytic matrix (enteric linker) The pH-dependent disintegration matrix provides a safety mechanism for the gastroretentive system. If the system is emptied from the stomach too early, i.e., if all of the time-dependent disintegration matrix is ​​emptied from the stomach intact, the pH-dependent disintegration matrix will degrade, dissolve, dissociate, or be mechanically weakened in the high pH environment of the small intestine, allowing the gastroretentive system to pass through the small intestine easily. In addition, if the time-dependent disintegration matrix degrades, dissolves, dissociates, or is mechanically weakened in the gastric environment, the pH-dependent disintegration matrix will be exposed to the high pH of the small intestine after passage of the gastroretentive system, further weakening and / or destruction of the system for easy passage through the small intestine.

[0119] If the gastroretentive system migrates too early in its intact form to the small intestine, the system can be designed to degrade much more rapidly to avoid intestinal obstruction. This is easily accomplished by using an enteric polymeric linker that includes an enteric polymer that weakens or degrades in the intestinal environment in addition to an additional linker polymer (e.g., carrier polymer). The enteric polymer is relatively resistant to the acidic pH levels encountered in the stomach, but dissolves rapidly at the high pH levels found in the duodenum. The use of an enteric polymeric linker as a safety element protects the gastroretentive system from undesired migration to the small intestine. The use of an enteric polymeric linker also provides a manner of removing the gastroretentive system before its designed residence time. If the system needs to be removed, the patient can drink a mildly alkaline solution, such as sodium bicarbonate solution, or take an antacid, such as hydrated magnesium hydroxide (milk of magnesia) or calcium carbonate, which raises the pH level in the stomach and causes rapid degradation of the enteric polymeric linker.

[0120] The weakening or degradation of the enteric polymeric linker can be measured based on the loss or failure of the flexural modulus of the polymeric linker under given conditions (e.g., intestinal or gastric conditions). The enteric linker weakens, degrades, or fails relatively quickly in the intestinal environment, but retains much of its flexural modulus in the gastric environment. Gastric conditions can be simulated using an aqueous solution such as fasted simulated gastric fluid (FaSSGF) at pH 1.6 and 37°C, and intestinal conditions can be simulated using an aqueous solution such as fasted simulated intestinal fluid (FaSSIF) at pH 6.5 and 37°C.

[0121] In some embodiments, the enteric disintegrating matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, in some embodiments, the enteric disintegrating matrix comprises about 60% to about 70% by weight of HPMCAS. In some embodiments, the enteric disintegrating matrix comprises about 62% to about 66% by weight of HPMCAS. In some embodiments, the enteric disintegrating matrix comprises about 63.95% by weight of HPMCAS.

[0122] The enteric polymer is combined with one or more additional polymers (e.g., one or more carrier polymers) in the enteric linker, preferably in a homogeneous mixture. For example, the enteric polymer and the additional linker polymer can be homogeneously blended together before the mixture is extruded and the extruded material is cut into the desired size for the polymeric linker. In some embodiments, the one or more additional linker polymers are miscible with the enteric polymer. The one or more additional linker polymers can be non-degradable polymers (i.e., not degraded 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)).

[0123] The binding of the polymer linker to the immediately adjacent member may be improved when at least one polymer is common to both the adjacent member and the enteric polymer linker. That is, one of the one or more additional linker polymers in the enteric linker can be the same (or the same polymer type) as at least one polymer in the immediately adjacent component (or optionally both immediately adjacent components) of the gastroretentive system. For example, when the enteric polymer linker is directly bound to the structural member that includes a carrier polymer, in some embodiments, the one or more additional linker polymers also include a carrier polymer (in addition to PLGA in the time-dependent polymer linker) at the same or different concentration. Exemplary carrier polymers include, but are not limited to, polylactic acid (PLA), polycaprolactone (PCL), and thermoplastic polyurethane (TPU), among others described herein.

[0124] In some embodiments, one or more additional linker polymers in the enteric linker include PCL. The enteric polymer linker may be directly conjugated or bonded to another member of the gastroretentive system (e.g., a structural member comprising a drug and a carrier polymer, a linking member, a time-dependent polymer linker, or a central structural member), which may include PCL, which may be the same as the PCL in the enteric polymer linker or a different PCL from the PCL in the enteric polymer linker, and may be at the same concentration or a different concentration. The different PCL in the enteric polymer linker and the other member directly conjugated or bonded to the enteric linker may differ, for example, in the weight average molecular weight of PCL, the intrinsic viscosity of PCL, or the proportion of PCL (e.g., when a blend of two or more PCL polymers is used). In some embodiments, the enteric disintegrating matrix includes about 30% to about 40% by weight of PCL. In some embodiments, the enteric disintegrating matrix includes about 32% to about 37% by weight of PCL. In some embodiments, the enteroerodible matrix comprises about 34% PCL by weight.In some embodiments, the enteroerodible matrix comprises about 33.95% PCL by weight.

[0125] The enteroerodible matrix may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the enteroerodible matrix comprises about 0.5% to about 5% by weight of a poloxamer. In some embodiments, the enteroerodible matrix comprises about 1% to about 3% by weight of a poloxamer. In some embodiments, the enteroerodible matrix comprises about 2% by weight of a poloxamer.

[0126] In some embodiments, the enteroerodible matrix includes a color absorbing dye (also called a colorant or pigment). The color absorbing dye may be included to enhance the bonding or attachment of the polymeric linker to other gastroretentive system components. The color absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced attachment, thereby increasing the tensile strength of the resulting bond. Exemplary color absorbing dyes include iron oxide and carbon black. The enteric polymeric linker may include a color absorbing dye in an amount of up to about 5%, such as 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%. In some embodiments, the enteroerodible matrix includes about 0.01% to about 0.2% by weight of the color absorbing dye E172. In some embodiments, the enteroerodible matrix includes about 0.05% to about 0.15% by weight of the color absorbing dye E172. In some embodiments, the enteroerodible matrix comprises about 0.1% by weight of the color absorbing dye E172.

[0127] In some embodiments, the enteroerodible matrix comprises about 59% to about 69% HPMCAS, about 29% to about 39% PCL, and about 0.5% to about 5% poloxamer (such as P407) by weight. Optionally, the enteroerodible matrix further comprises an iron oxide, for example, about 0.01% to about 0.2% iron oxide (such as E172) by weight.

[0128] In some embodiments, the enteroerodible matrix comprises about 62% to about 66% HPMCAS, about 32% to about 36% PCL, and about 1% to about 3% poloxamer (such as P407) by weight. Optionally, the enteroerodible matrix further comprises an iron oxide, for example, about 0.05% to about 0.15% iron oxide (such as E172) by weight.

[0129] In some embodiments, the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407).Optionally, the enteroerodible matrix further comprises an iron oxide, for example about 0.1% by weight iron oxide (such as E172).

[0130] In some embodiments, the enterodisintegrable matrix comprises about 59% to about 69% HPMCAS by weight, about 29% to about 39% PCL by weight, and about 0.5% to about 5% poloxamer (such as P407) by weight.

[0131] In some embodiments, the enterodisintegrable matrix comprises about 62% to about 66% HPMCAS by weight, about 32% to about 36% PCL by weight, and about 1% to about 3% poloxamer (such as P407) by weight.

[0132] In some embodiments, the enteroerodible matrix comprises about 64% HPMCAS, about 34% PCL, and about 2% poloxamer (such as P407) by weight.

[0133] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 33.95% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 63.95% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 2.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 0.1% by weight of an iron oxide, such as E172. In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 33.95% by weight Corbion PC17, about 63.95% by weight HPMCAS-MG, about 2.0% by weight P407, and about 0.1% by weight E172.

[0134] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM1 are provided in the table below. It is understood that amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0135] [Table 14]

[0136] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 64% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 2.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of Corbion PC17, about 64% by weight of HPMCAS-MG, and about 2.0% by weight of P407.

[0137] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM2 are provided in the table below. The amounts are given as approximate weight percentages, and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0138] [Table 15]

[0139] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 64% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 2% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of Corbion PC17, about 64% by weight of HPMCAS-MG, and about 2.0% by weight of P407.

[0140] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM3 are provided in the table below. It is understood that amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0141] [Table 16]

[0142] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 41.5% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 56.5% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 2% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 41.5% by weight of Corbion PC17, about 56.5% by weight of HPMCAS-MG, and about 2% by weight of P407.

[0143] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM4 are provided in the table below. It is understood that amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0144] [Table 17]

[0145] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 49% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 49% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 2% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 49% by weight of Corbion PC17, about 49% by weight of HPMCAS-MG, and about 2% by weight of P407.

[0146] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM5 are provided in the table below. It is understood that amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0147] [Table 18]

[0148] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 62% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 4% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of Corbion PC17, about 62% by weight of HPMCAS-MG, and about 4% by weight of P407.

[0149] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM6 are provided in the table below. The amounts are given as approximate weight percentages, and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0150] [Table 19]

[0151] In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 34% by weight of polycaprolactone (PCL), e.g., PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbion PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 32% by weight of hypromellose acetate succinate, e.g., HPMCAS-MG. In some embodiments, the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 32% by weight of VA64 (copovidone). In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 2% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer with a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegration matrix comprising about 34% by weight of Corbion PC17, about 32% by weight of HPMCAS-MG, about 32% by weight of VA64, and about 2% by weight of P407.

[0152] Exemplary amounts of the components of enteric disintegrating matrix formulation E-DM7 are provided in the table below. The amounts are given as approximate weight percentages, and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0153] [Table 20]

[0154] Collapsible Filament In some embodiments, the gastric retention system includes arms connected by one or more filaments. In some embodiments, the filaments are disintegrating filaments. In some embodiments, the gastric retention system includes arms connected at distal tips by one or more filaments. In some embodiments, the filaments circumferentially connect the arms. In some embodiments, the filaments are disintegrating filaments. In some embodiments, the filaments comprise one or more of poly(lactic-co-glycolic acid), polyglycolic acid, polylactic acid, polydioxanone, polycaprolactone, polytrimethylene carbonate, cellulose, or any blends and copolymers thereof. In some embodiments, the filaments comprise poly(lactic-co-glycolic acid). In some embodiments, the filaments comprise polyglycolic acid. In some embodiments, the filament has a thickness of about 0.05 mm, about 0.1 mm, about 0.15 mm, about 0.20 mm, about 0.25 mm, about 0.30 mm, about 0.35 mm, about 0.40 mm, about 0.45 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, or any thickness therebetween. In some embodiments, the filament has a thickness of about 0.20 mm. In some embodiments, the filament has a thickness of about 0.30 mm. In some embodiments, the filament is a Bondek Suture 2-0. In some embodiments, the filament is a Bondek Suture 3-0.

[0155] Further collapsible matrix as arm tip In some embodiments, the gastroretentive system comprises an arm that comprises a third disintegrable matrix in addition to the time-dependent disintegrable matrix and the enterodisintegrable matrix. In some embodiments, the third disintegrable matrix is ​​the filament-retaining segment (i.e., the segment to which the filament is attached). In some embodiments, the third disintegrable matrix is ​​the distal segment of the retention system arm, i.e., the tip of the arm. In some embodiments, the third disintegrable matrix is ​​referred to as outer disintegrable matrix tip enteric-coated PCL (ODMTEP).

[0156] In some embodiments, the third disintegrating matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, in some embodiments, the third disintegrating matrix comprises about 60% to about 70% by weight of HPMCAS. In some embodiments, the third disintegrating matrix comprises about 63% to about 67% by weight of HPMCAS. In some embodiments, the third disintegrating matrix comprises about 64.9% by weight of HPMCAS.

[0157] In some embodiments, the third disintegrating matrix comprises a polymer common to either one of the segments in the gastroretentive system arms. In some embodiments, the third disintegrating matrix comprises polycaprolactone (PCL). In some embodiments, the third disintegrating matrix comprises about 25% to about 35% by weight PCL. In some embodiments, the third disintegrating matrix comprises about 28% to about 32% by weight PCL. In some embodiments, the third disintegrating matrix comprises about 30% by weight PCL.

[0158] In some embodiments, the third disintegrating matrix comprises one or more acids, such as stearic acid. In some embodiments, the third disintegrating matrix comprises about 1% to about 5% by weight of stearic acid. In some embodiments, the third disintegrating matrix comprises about 2% to about 3% by weight of stearic acid. In some embodiments, the third disintegrating matrix comprises about 2.5% by weight of stearic acid.

[0159] In some embodiments, the third disintegrable matrix may further comprise one or more plasticizers, such as propylene glycol. In some embodiments, the third disintegrable matrix comprises about 1% to about 5% by weight propylene glycol. In some embodiments, the third disintegrable matrix comprises about 2% to about 3% by weight propylene glycol. In some embodiments, the third disintegrable matrix comprises about 2.5% by weight propylene glycol.

[0160] In some embodiments, the third disintegrable matrix includes a color absorbing dye (also called a colorant or pigment). The color absorbing dye may be included to enhance the bonding or attachment of the polymeric linker to other gastroretentive system components. The color absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced attachment, thereby increasing the tensile strength of the resulting bond. Exemplary color absorbing dyes include iron oxide and carbon black. The third disintegrable matrix may include a color absorbing dye in an amount of up to about 5%, such as 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%. In some embodiments, the third disintegrable matrix includes about 0.01% to about 0.5% by weight of the color absorbing dye. In some embodiments, the third disintegrable matrix includes about 0.05% to about 0.15% by weight of the color absorbing dye. In some embodiments, the third disintegrative matrix comprises about 0.1% by weight of a color absorbing pigment. In some embodiments, the third disintegrative matrix comprises about 0.025% ferric oxide and about 0.075% FD&C Red 40. In some embodiments, the third disintegrative matrix comprises about 0.025% ferric oxide and about 0.075% FD&C Red 40.

[0161] In some embodiments, the third disintegrable matrix comprises about 60% to about 70% HPMCAS, about 25% to about 35% PCL, about 1% to about 5% propylene glycol, and about 1% to about 5% stearic acid by weight. Optionally, the third disintegrable matrix further comprises about 0.01% to about 0.5% iron oxide by weight.

[0162] In some embodiments, the third disintegrable matrix comprises about 63% to about 67% HPMCAS, about 28% to about 32% PCL, about 2% to about 3% propylene glycol, and about 2% to about 3% stearic acid by weight. Optionally, the third disintegrable matrix further comprises about 0.05% to about 0.15% iron oxide by weight.

[0163] In some embodiments, the third disintegrating matrix comprises 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, and about 2.5% by weight stearic acid. Optionally, the third disintegrating matrix further comprises about 0.1% by weight iron oxide, such as about 0.025% ferric oxide and about 0.075% FD&C Red 40.

[0164] Exemplary amounts of the components of the third disintegrable matrix are provided in the table below. The amounts are given as approximate weight percent, and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0165] [Table 21]

[0166] Inactive Segments In some embodiments, the gastroretentive system comprises one or more inactive segments, hi some embodiments, the inactive segments comprise one or more radiopaque materials.

[0167] In some embodiments, the inactive segment comprises a polymer in common with other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 61% to about 71% by weight PCL. In some embodiments, the inactive segment comprises about 64% to about 69% by weight PCL. In some embodiments, the inactive segment comprises about 66.5% by weight PCL. In some embodiments, the inactive segment comprises about 66.45% by weight PCL.

[0168] In some embodiments, the inactive segment comprises a vinylpyrrolidone-vinyl acetate copolymer (i.e., copovidone, e.g., Kollidon VA64) in a weight ratio of 6:4. In some embodiments, the inactive segment comprises about 27% to about 37% by weight copovidone. In some embodiments, the inactive segment comprises about 30% to about 34% by weight copovidone. In some embodiments, the inactive segment comprises about 32% by weight copovidone.

[0169] The inactive segments may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the inactive segments comprise from about 0.2% to about 4% by weight of a poloxamer. In some embodiments, the inactive segments comprise from about 0.5% to about 2.5% by weight of a poloxamer. In some embodiments, the inactive segments comprise about 1.5% by weight of a poloxamer.

[0170] In some embodiments, the inactive segments include a color absorbing dye (also called a colorant or pigment). The inactive segments may include a color absorbing dye in an amount of up to about 5%, such as 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%, up to about 0.1%, or up to about 0.05%. In some embodiments, the inactive segments include from about 0.005% to about 0.2% by weight of the color absorbing dye. In some embodiments, the inactive segments include from about 0.01% to about 0.1% by weight of the color absorbing dye. In some embodiments, the inactive segments include about 0.05% by weight of the color absorbing dye. In some embodiments, the color absorbing dye is FD&C Blue #1.

[0171] In some embodiments, the inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, and about 0.2% to about 4% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1.

[0172] In some embodiments, the inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, and about 0.5% to about 2.5% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1.

[0173] In some embodiments, the inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, and about 1.5% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.05% by weight of the color absorbing dye FD&C Blue #1.

[0174] Exemplary amounts of components of one embodiment of the inactive segment (e.g., inactive spacer) are provided in the table below. The amounts are given as approximate weight percent, and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0175] [Table 22]

[0176] In some embodiments, the inactive segment comprises a polymer in common with other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 35% to about 45% by weight PCL. In some embodiments, the inactive segment comprises about 38% to about 42% by weight PCL. In some embodiments, the inactive segment comprises about 40% by weight PCL. In some embodiments, the inactive segment comprises about 33.995% by weight PCL.

[0177] In some embodiments, the inactive segment comprises a vinylpyrrolidone-vinyl acetate copolymer (i.e., copovidone, e.g., Kollidon VA64) in a weight ratio of 6:4. In some embodiments, the inactive segment comprises about 37% to about 47% by weight copovidone. In some embodiments, the inactive segment comprises about 40% to about 44% by weight copovidone. In some embodiments, the inactive segment comprises about 42% by weight copovidone.

[0178] The inactive segments may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the inactive segments comprise from about 1% to about 5% by weight of a poloxamer. In some embodiments, the inactive segments comprise from about 2% to about 4% by weight of a poloxamer. In some embodiments, the inactive segments comprise about 3% by weight of a poloxamer.

[0179] The inactive segment may include one or more plasticizers, such as polyethylene glycol. The term "polyethylene glycol" is used herein interchangeably with the terms "polyethylene oxide" and "PEO." In some embodiments, the molecular weight of the polyethylene glycol is about 90K to about 110K, such as 100K (also referred to as 100K or 100kDa). In some embodiments, the inactive segment includes polyethylene glycol having a molecular weight of about 100k (polyethylene glycol 100k). In some embodiments, the inactive segment includes about 10% to about 20% by weight of polyethylene glycol 100k. In some embodiments, the inactive segment includes about 13% to about 17% by weight of polyethylene glycol 100k. In some embodiments, the inactive segment includes about 15% by weight of polyethylene glycol 100k.

[0180] In some embodiments, the inactive segments include a color absorbing pigment (also called a colorant or pigment). In some embodiments, the inactive segments may include a color absorbing pigment in an amount of up to about 1%, such as up to about 0.5%, up to about 0.4%, up to about 0.3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, up to about 0.1%, or up to 0.005%. In some embodiments, the inactive segments include from about 0.0005% to about 0.2% by weight of the color absorbing pigment. In some embodiments, the inactive segments include from about 0.001% to about 0.01% by weight of the color absorbing pigment. In some embodiments, the inactive segments include about 0.005% by weight of the color absorbing pigment. In some embodiments, the color absorbing pigment is an iron oxide (e.g., E172).

[0181] In some embodiments, the inactive segment is about 35% to about 45% by weight PCL, about 37% to about 47% by weight copovidone, about 10% to about 20% by weight polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000, e.g., PEO 100K , about 1% to about 5% by weight of a poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, for example, about 0.0005% to about 0.02% by weight of the color absorbing dye E172.

[0182] In some embodiments, the inactive segment comprises about 38% to about 42% by weight PCL, about 40% to about 44% by weight copovidone, about 13% to about 17% by weight polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000, e.g., PEO100K, about 2% to about 4% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, e.g., about 0.001% to about 0.01% by weight color absorbing dye E172.

[0183] In some embodiments, the inactive segment comprises about 39.995% by weight PCL, about 42% by weight copovidone, about 15% by weight PEO100K, and about 3% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.005% by weight color absorbing dye E172.

[0184] Exemplary amounts of components of one embodiment of the inactive segment (e.g., inactive spacer) are provided in the table below. The amounts are given as approximate weight percent, and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0185] [Table 23]

[0186] In some embodiments, the gastric retention system comprises one or more inactive segments, wherein the inactive segments comprise one or more radiopaque materials, hi some embodiments, the gastric retention system comprises one or more inactive segments, wherein the inactive segments are radiopaque segments.

[0187] In some embodiments, the inactive segment comprises a polymer in common with other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 65% to about 75% by weight PCL. In some embodiments, the inactive segment comprises about 68% to about 72% by weight PCL. In some embodiments, the inactive segment comprises about 70% by weight PCL.

[0188] In some embodiments, the inactive segments include a radiopaque material. In some embodiments, the inactive segments include a radiopaque material, and the radiopaque material is (BiO)2CO3. In some embodiments, the inactive segments include (BiO)2CO3. In some embodiments, the inactive segments include about 25% to about 35% (BiO)2CO3 by weight. In some embodiments, the inactive segments include about 28% to about 32% (BiO)2CO3 by weight. In some embodiments, the inactive segments include about 30% (BiO)2CO3 by weight.

[0189] In some embodiments, the inactive segments include about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3. In some embodiments, the inactive segments include about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)2CO3. In some embodiments, the inactive segments include about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0190] Exemplary amounts of components of one embodiment of an inactive segment (e.g., an rPCL segment) are provided in the table below. The amounts are given as approximate weight percent, and when ranges are provided, it is understood that the amounts are selected to add up to 100%.

[0191] [Table 24]

[0192] Carrier polymer - drug segment (drug eluting segment) The carrier polymer-drug segment or drug eluting segment releases the drug in a controlled manner during the period that the gastroretentive system is retained in the stomach. The carrier polymer is blended with the drug and formed into a segment, which is then assembled with other components described herein to produce the gastroretentive system. The compositions of such carrier polymer-drug blends provided below can be used for any drug suitable for administration in a gastroretentive system. A specific example is provided for the drug risperidone.

[0193] In some embodiments, where the drug eluting segment comprises about 30% to about 40% by weight of drug, the drug eluting segment comprises about 51% to about 61% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 2% to about 8% by weight of a vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 1% to about 5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as Poloxamer 407. In some embodiments, the drug eluting segment comprises about 0.1% to about 1% by weight of vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.1% to about 1% by weight of colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.01% to about 0.5% by weight of a pigment.

[0194] In some embodiments, where the drug eluting segment comprises about 33% to about 37% by weight of drug, the drug eluting segment comprises about 54% to about 58% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 4% to about 6% by weight of a vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 2% to about 4% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as Poloxamer 407. In some embodiments, the drug eluting segment comprises about 0.2% to about 0.8% by weight of vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.2% to about 0.8% by weight of colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.05% to about 0.2% by weight of a pigment.

[0195] In some embodiments, where the drug eluting segment comprises about 35% by weight of drug, the drug eluting segment comprises about 55.9% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 5.0% by weight of a vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 3.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as Poloxamer 407. In some embodiments, the drug eluting segment comprises about 0.5% by weight of vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.5% by weight colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.1% by weight pigment.

[0196] In some embodiments, the pigment comprises aluminum, 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-4-((4-sulfophenyl)azo)-1H-pyrazole-3-carboxylic acid complex, such as FD&C Yellow 5 Aluminum Lake, in an amount of about 0.05% by weight of the total weight of the drug eluting segment, and benzenemethanaminium, N-ethyl-N-(4-((4-ethyl((3-sulfophenyl)methyl)amino)phenyl)(2-sulfophenyl)methylene)-2,5-cyclohexadiene, such as FD&C Blue 1 Aluminum Lake, in an amount of 0.05% by weight of the total weight of the drug eluting segment. FD&C Yellow 5 Aluminum Lake and FD&C Blue 1 Aluminum Lake are approved food color additives. In some embodiments, the amount of dye in FD&C Yellow 5 Aluminum Lake is about 14-16% by weight. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13% by weight.

[0197] In some embodiments, the drug eluting segment comprises about 30% to about 40% drug by weight, about 51% to about 61% PCL, about 2% to about 8% VA64, about 1% to about 5% P407, about 0.1% to about 1% vitamin E succinate, about 0.1% to about 1% SiO2, and about 0.01% to about 0.5% pigment by weight.

[0198] In some embodiments, the drug eluting segment comprises about 33% to about 37% by weight of drug, about 54% to about 58% by weight of PCL, about 4% to about 6% by weight of VA64, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinate, about 0.2% to about 0.8% by weight of SiO2, and about 0.05% to about 0.15% by weight of pigment.

[0199] In some embodiments, the drug eluting segment comprises about 35.0% by weight of drug, about 55.9% by weight of PCL, about 5.0% by weight of VA64, about 3.0% by weight of P407, about 0.5% by weight of Vitamin E succinate, about 0.5% by weight of SiO2, and about 0.1% by weight of pigment. In some embodiments, the pigment comprises FD&C Yellow 5 Aluminum Lake in an amount of about 0.05% by weight of the total weight of the drug eluting segment, and FD&C Blue 1 Aluminum Lake in an amount of 0.05% by weight of the total weight of the drug eluting segment. FD&C Yellow 5 Aluminum Lake and FD&C Blue 1 Aluminum Lake are approved food color additives. In some embodiments, the amount of pigment in FD&C Yellow 5 Aluminum Lake is about 14-16% by weight. In some embodiments, the amount of pigment in FD&C Blue 1 Aluminum Lake is about 11-13% by weight. Exemplary amounts of the components of one embodiment of the carrier polymer-arm segment (drug eluting segment) are provided in the following table. Amounts are given as approximate percentages by weight, and when ranges are provided, it is understood that such amounts are selected to add up to 100%. "Pharmaceutically acceptable salt" refers to a pharma-ceutically acceptable salt thereof.

[0200] [Table 25]

[0201] In some embodiments, the dosage form for administering the drug comprises a gastric retention system comprising about 12 mg to about 60 mg of drug. In some embodiments, the dosage form for administering the drug comprises a gastric retention system comprising about 12 mg to about 36 mg of drug. In some embodiments, the dosage form for administering the drug comprises a gastric retention system comprising about 12 mg to about 20 mg of drug.

[0202] In some embodiments, where the drug eluting segment comprises about 30% to about 40% by weight of drug, the drug eluting segment comprises about 51% to about 61% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 2% to about 8% by weight of a vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 1% to about 5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as Poloxamer 407. In some embodiments, the drug eluting segment comprises about 0.1% to about 1% by weight of vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.1% to about 1% by weight of colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.01% to about 0.5% by weight of a pigment.

[0203] In some embodiments, where the drug eluting segment comprises about 33% to about 37% by weight of drug, the drug eluting segment comprises about 54% to about 58% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 4% to about 6% by weight of a vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 2% to about 4% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as Poloxamer 407. In some embodiments, the drug eluting segment comprises about 0.2% to about 0.8% by weight of vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.2% to about 0.8% by weight of colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.05% to about 0.2% by weight of a pigment.

[0204] In some embodiments, where the drug eluting segment comprises about 35% by weight of drug, the drug eluting segment comprises about 55.9% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 5.0% by weight of a vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 3.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as Poloxamer 407. In some embodiments, the drug eluting segment comprises about 0.5% by weight of vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.5% by weight colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.1% by weight pigment.

[0205] In some embodiments, the pigment comprises aluminum, 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-4-((4-sulfophenyl)azo)-1H-pyrazole-3-carboxylic acid complex, such as FD&C Yellow 5 Aluminum Lake, in an amount of about 0.05% by weight of the total weight of the drug eluting segment, and benzenemethanaminium, N-ethyl-N-(4-((4-ethyl((3-sulfophenyl)methyl)amino)phenyl)(2-sulfophenyl)methylene)-2,5-cyclohexadiene, such as FD&C Blue 1 Aluminum Lake, in an amount of 0.05% by weight of the total weight of the drug eluting segment. FD&C Yellow 5 Aluminum Lake and FD&C Blue 1 Aluminum Lake are approved food color additives. In some embodiments, the amount of dye in FD&C Yellow 5 Aluminum Lake is about 14-16% by weight. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13% by weight.

[0206] In some embodiments, the drug eluting segment comprises about 30% to about 40% drug by weight, about 51% to about 61% PCL, about 2% to about 8% VA64, about 1% to about 5% P407, about 0.1% to about 1% vitamin E succinate, about 0.1% to about 1% SiO2, and about 0.01% to about 0.5% pigment by weight.

[0207] In some embodiments, the drug eluting segment comprises about 33% to about 37% by weight of drug, about 54% to about 58% by weight of PCL, about 4% to about 6% by weight of VA64, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinate, about 0.2% to about 0.8% by weight of SiO2, and about 0.05% to about 0.15% by weight of pigment.

[0208] In some embodiments, the drug eluting segment comprises about 35.0% by weight of drug, about 55.9% by weight of PCL, about 5.0% by weight of VA64, about 3.0% by weight of P407, about 0.5% by weight of Vitamin E succinate, about 0.5% by weight of SiO2, and about 0.1% by weight of pigment. In some embodiments, the pigment comprises FD&C Yellow 5 Aluminum Lake in an amount of about 0.05% by weight of the total weight of the drug eluting segment, and FD&C Blue 1 Aluminum Lake in an amount of 0.05% by weight of the total weight of the drug eluting segment. FD&C Yellow 5 Aluminum Lake and FD&C Blue 1 Aluminum Lake are approved food color additives. In some embodiments, the amount of dye in FD&C Yellow 5 Aluminum Lake is about 14-16% by weight. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13% by weight.

[0209] Exemplary amounts of components of one embodiment of the carrier polymer-arm segment (drug eluting segment) are provided in the table below. The amounts are given as approximate weight percent, and when ranges are provided, it is understood that the amounts are selected to add up to 100%. "Pharmaceutically acceptable salt" refers to a pharma-ceutically acceptable salt thereof.

[0210] [Table 26]

[0211] In some embodiments, star-shaped dosage forms for administering drugs can include arms, which include 1) carrier polymer-drug arm segments, 2) inert arm segments, 3) one or more enteric linkers, 4) one or more time-dependent linkers, 5) release rate controlling films, and / or 6) other optional spacers. The arms are connected to the elastomeric core in a star device configuration. Typically, six arms are used in star dosage forms. In some embodiments where six arms are used in star dosage forms, any one of 1, 2, 3, 4, 5, or 6 arms includes a carrier polymer-drug arm segment. In some embodiments where six arms are used in star dosage forms, three arms include a carrier polymer-drug arm segment. In some embodiments where six arms are used in star dosage forms, six arms include a carrier polymer-drug arm segment.

[0212] The carrier polymer-drug arm segment of the dosage form may comprise a drug (or a pharma- ceutically acceptable salt thereof), polycaprolactone, copovidone (VA64), poloxamer 407 (P407), silica (SiO2), vitamin E succinate (vitE), and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g. Any pharma- ceutically acceptable colorant may be used. Examples of colorants that may be used include FD&C Red 40 Aluminum Lake, FD&C Yellow 5 Aluminum Lake, or an approximately equal blend of the two. In some embodiments, typically six arms are used in the star dosage form, with either 1, 2, 3, 4, 5, or 6 of these arms comprising a carrier polymer-drug arm segment. In some embodiments, three of the arms comprise a carrier polymer-drug arm segment. In some embodiments, six of the arms comprise a carrier polymer-drug arm segment. In some embodiments, the total amount of drug in the dosage form is 1, 2, 3, 4, 5, or 6 times the amount of drug in a single arm. In some embodiments, the total amount of drug in the dosage form is 3 times the amount of drug in a single arm. In some embodiments, the total amount of drug in the dosage form is 6 times the amount of drug in a single arm. The total amount of drug by weight can range from about 2 mg to about 200 mg, depending on the dosage of drug required.

[0213] The inactive arm segments of the dosage form may comprise polycaprolactone (PCL), a radiopaque material, and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g. The radiopaque material may be (BiO)2CO3. Any pharma- ceutically acceptable colorant may be used. An example of a colorant that may be used is FD&C Blue #5.

[0214] The enterodisintegrable matrix of the dosage form may comprise polycaprolactone (PCL), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poloxamer 407 (P407), and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g. The HPMCAS used may be MG grade (M grade: about 7-11% acetyl content, about 10-14% succinoyl content, about 21-25% methoxyl content, about 5-9% hydroxypropoxy content; G grade: granular). Any pharma- ceutically acceptable colorant may be used. An example of a colorant that may be used is triferric oxide.

[0215] The time-dependent disintegrating matrix of the dosage form may comprise poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and optionally a colorant. The poly(D,L-lactide-co-glycolide) may have a lactide:glycolide molar ratio of about 75:25 and a viscosity range of about 0.32 to 0.44 dl / g. The polyethylene oxide used may be about 60,000 MW to about 125,000 MW, for example about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0216] The time-dependent disintegrating matrix of the dosage form may include polycaprolactone (PCL), poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and optionally a colorant. The PCL may have a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., about 1.7 dl / g (e.g., Corbion PC17). The PCL may have a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., about 1.2 dl / g (e.g., Corbion Purasorb® PC12). The poly(D,L-lactide-co-glycolide) may have a molar ratio of lactide:glycolide of about 50:50 and a viscosity range of about 0.32 to 0.44 dl / g. The polyethylene oxide used can be from about 60,000 MW to about 125,000 MW, for example from about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0217] The release rate controlling film of the dosage form may include polycaprolactone (PCL), copovidone (such as VA64), and magnesium stearate. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g.

[0218] The central elastomer of the dosage form can have a durometer hardness of about 40 A to about 60 A, for example, a durometer hardness of about 45 A to about 55 A, or a durometer hardness of about 50 A. The central elastomer can be made from a liquid silicone rubber, for example, the central elastomer can include cured liquid silicone rubber.

[0219] Exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0220] [Table 27]

[0221] The assembled arms may include 1) a first inactive segment, 2) a first disintegrable matrix segment, 3) a second inactive segment, 4) a second disintegrable matrix segment, 5) a third inactive segment, 6) a fourth inactive segment, 7) a drug eluting segment comprising a carrier polymer and a drug or a salt thereof, further comprising a coating comprising a release rate modifying polymer film, 8) an optional fifth inactive segment, and 9) a third disintegrable matrix segment, which may be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (first disintegrable matrix segment) (second inactive segment) (second disintegrable matrix segment) (third inactive segment) (fourth inactive segment) (drug eluting segment) (optional fifth inactive segment) (third disintegrable matrix segment). In some embodiments, the fourth inactive segment is an inactive spacer. In some embodiments, the first, second, third, and optional fifth inactive segments are rPCL spacers. An optional rPCL spacer (inactive segment) of about 0.2-2 mm length, e.g., about 0.5 mm length, can be inserted between any two of the above components, added to the outer tip of the assembled arms, or added between the inner tip of the assembled arms and the elastomeric core.

[0222] Approximate dimensions of the lengths of segments on an exemplary drug eluting arm are provided below.

[0223] [Table 28]

[0224] Approximate dimensions of length and thickness of segments on an exemplary drug eluting arm are provided below.

[0225] [Table 29]

[0226] Approximate dimensions of length and thickness of segments on an exemplary drug eluting arm are provided below.

[0227] [Table 30]

[0228] The assembled arms can include 1) a first inert segment, 2) a first disintegrable matrix segment, 3) a second inert segment, 4) a second disintegrable matrix segment, 5) a third inert segment, 6) a fourth inert segment, 7) an optional fifth inert segment, and 8) a third disintegrable matrix segment, which can be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (first inert segment) (first disintegrable matrix segment) (second inert segment) (second disintegrable matrix segment) (third inert segment) (fourth inert segment) (optional fifth inert segment) (third disintegrable matrix segment). Approximate dimensions of the length of the segments on each arm are provided below. An optional rPCL spacer (inactive segment) of about 0.2-2 mm length, for example about 0.5 mm length, can be inserted between any two components of the arms, added to the outer tip of the assembled arms, or added between the inner tip of the assembled arms and the elastomeric core. It will be understood that this embodiment of the assembled arms lacks a drug eluting segment and can be used when it is desirable to use one or more non-drug eluting arms for the dosage form.

[0229] Approximate dimensions of the lengths of the segments on exemplary non-drug eluting arms are provided below.

[0230] [Table 31]

[0231] Approximate dimensions of length and thickness of segments on an exemplary non-drug eluting arm are provided below.

[0232] [Table 32]

[0233] Approximate dimensions of length and thickness of segments on an exemplary non-drug eluting arm are provided below.

[0234] [Table 33]

[0235] Approximate dimensions of the lengths of segments on an exemplary drug eluting arm are provided below.

[0236] [Table 34]

[0237] Exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0238] [Table 35]

[0239] The assembled arms may include 1) a first inactive segment, 2) a first disintegrable matrix segment, 3) a second inactive segment, 4) a second disintegrable matrix segment, 5) a third inactive segment, 6) a fourth inactive segment, 7) a drug eluting segment comprising a carrier polymer and a drug or a salt thereof, further comprising a coating comprising a release rate modifying polymer film, 8) an optional sixth inactive segment, and 9) a fifth inactive segment, which may be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (first disintegrable matrix segment) (second inactive segment) (second disintegrable matrix segment) (third inactive segment) (fourth inactive segment) (drug eluting segment) (optional sixth inactive segment) (fifth inactive segment). In some embodiments, the fourth inactive segment is an inactive spacer. In some embodiments, the first, second, third, and optional sixth inactive segments are rPCL spacers. In some embodiments, the fifth inactive segment is an inactive spacer. An optional rPCL spacer (inactive segment) of about 0.2-2 mm length, for example about 0.5 mm length, can be inserted between any two of the above components, added to the outer tip of the assembled arms, or added between the inner tip of the assembled arms and the elastomeric core.

[0240] Approximate dimensions of the lengths of segments on an exemplary drug eluting arm are provided below.

[0241] [Table 36]

[0242] Approximate dimensions of length and thickness of segments on an exemplary drug eluting arm are provided below.

[0243] [Table 37]

[0244] Approximate dimensions of length and thickness of segments on an exemplary drug eluting arm are provided below.

[0245] [Table 38]

[0246] The assembled arms can include 1) a first inactive segment, 2) a first collapsible matrix segment, 3) a second inactive segment, 4) a second collapsible matrix segment, 5) a third inactive segment, 6) a fourth inactive segment, 7) an optional sixth inactive segment, and 8) a fifth inactive segment, which can be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (first inactive segment) (first collapsible matrix segment) (second inactive segment) (second collapsible matrix segment) (third inactive segment) (fourth inactive segment) (optional sixth inactive segment) (fifth inactive segment). Approximate dimensions of the length of the segments on each arm are provided below. An optional rPCL spacer (inactive segment) of about 0.2-2 mm length, for example about 0.5 mm length, can be inserted between any two of the above components, added to the outer tip of the assembled arms, or added between the inner tip of the assembled arms and the elastomeric core. In some embodiments, the fourth inactive segment is an inactive spacer. In some embodiments, the first, second, third, and optional sixth inactive segments are rPCL spacers. In some embodiments, the fifth inactive segment is an inactive spacer. It will be understood that this embodiment of the assembled arms lacks a drug eluting segment and can be used when it is desirable to use one or more non-drug eluting arms for the dosage form.

[0247] Approximate dimensions of the lengths of the segments on exemplary non-drug eluting arms are provided below.

[0248] [Table 39]

[0249] In some embodiments, the star-shaped dosage form may include arms, which include 1) a carrier polymer-drug arm segment, 2) an inactive arm segment, 3) one or more enteric linkers, 4) one or more time-dependent linkers, 5) a release rate controlling film, and / or 6) other optional spacers. The arms are connected to the elastomeric core in a star device configuration. Typically, six arms are used in a star dosage form. In some embodiments where six arms are used in a star dosage form, any one of 1, 2, 3, 4, 5, or 6 arms includes a carrier polymer-drug arm segment. In some embodiments where six arms are used in a star dosage form, one arm includes a carrier polymer-drug arm segment. In some embodiments where six arms are used in a star dosage form, two arms include a carrier polymer-drug arm segment. In some embodiments where six arms are used in a star dosage form, three arms include a carrier polymer-drug arm segment. In some embodiments where six arms are used in the star dosage form, the six arms comprise a carrier polymer-drug arm segment.

[0250] The carrier polymer-drug arm segment of the dosage form may comprise a drug (or a pharma- ceutically acceptable salt thereof), polycaprolactone, copovidone (VA64), poloxamer 407 (P407), silica (SiO2), vitamin E succinate (vitE), and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g. Any pharma- ceutically acceptable colorant may be used. Examples of colorants that may be used include FD&C Red 40 Aluminum Lake, FD&C Yellow 5 Aluminum Lake, or an approximately equal blend of the two. In some embodiments, typically six arms are used in the star dosage form, and either one, two, three, four, five, or six of these arms comprise a carrier polymer-drug arm segment. In some embodiments, one of the arms comprises a carrier polymer-drug arm segment. In some embodiments, two of the arms comprise a carrier polymer-drug arm segment. In some embodiments, three of the arms comprise a carrier polymer-drug arm segment. In some embodiments, six of the arms comprise a carrier polymer-drug arm segment. In some embodiments, the total amount of drug in the dosage form is 1, 2, 3, 4, 5, or 6 times the amount of drug in a single arm. In some embodiments, the total amount of drug in the dosage form is the same as the amount of drug in a single arm. In some embodiments, the total amount of drug in the dosage form is three times the amount of drug in a single arm. In some embodiments, the total amount of drug in the dosage form is six times the amount of drug in a single arm. The total weight of the drug or a pharma- ceutically acceptable salt thereof in the star dosage form can be in the range of about 1 mg to about 200 mg, for example, about 10 mg to about 200 mg, or about 50 mg to about 200 mg, or about 100 mg to about 200 mg, or about 150 mg to about 200 mg, or about 1 mg to about 150 mg, or about 1 mg to about 50 mg, or about 1 mg to about 25 mg, or about 50 mg to about 150 mg, or about 100 mg to about 150 mg, or about 50 mg to about 100 mg, or about 150 mg to about 200 mg.

[0251] The inactive arm segments of the dosage form may comprise polycaprolactone (PCL), a radiopaque material, and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g. The radiopaque material may be (BiO)2CO3. Any pharma- ceutically acceptable colorant may be used. An example of a colorant that may be used is FD&C Blue #5.

[0252] The enterodisintegrable matrix of the dosage form may include polycaprolactone (PCL), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and poloxamer 407 (P407). The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g. The HPMCAS used may be MG grade (M grade: about 7-11% acetyl content, about 10-14% succinoyl content, about 21-25% methoxyl content, about 5-9% hydroxypropoxy content; G grade: granular).

[0253] In some embodiments, the filament is wrapped circumferentially around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament wrapped circumferentially around the gastric retention system and connecting one or more arms of the dosage form can be a disintegrating filament. In some embodiments, the filament comprises poly(lactic-co-glycolic acid) and / or polyglycolic acid.

[0254] The time-dependent disintegrating matrix of the dosage form may comprise polycaprolactone (PCL), poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and optionally a colorant. The PCL may have a median viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., about 1.2 dl / g (e.g., Corbion PC12). The poly(D,L-lactide-co-glycolide) may have a molar ratio of lactide:glycolide of about 50:50 and a viscosity range of about 0.32 to 0.44 dl / g. The polyethylene oxide used may be about 60,000 MW to about 125,000 MW, e.g., about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0255] The release rate controlling film of the dosage form may include polycaprolactone (PCL), copovidone (such as VA64), and magnesium stearate. The polycaprolactone used may have a viscosity of about 1.5 dl / g to about 1.9 dl / g, for example about 1.7 dl / g.

[0256] The central elastomer of the dosage form can have a durometer hardness of about 40 A to about 60 A, for example, a durometer hardness of about 45 A to about 55 A, or a durometer hardness of about 50 A. The central elastomer can be made from a liquid silicone rubber, for example, the central elastomer can include cured liquid silicone rubber.

[0257] In one embodiment, exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0258] [Table 40]

[0259] In one embodiment, exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0260] [Table 41]

[0261] In one embodiment, exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0262] [Table 42]

[0263] In one embodiment, exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0264] [Table 43]

[0265] In one embodiment, exemplary amounts of the various components of the dosage form are provided in the table below. It is understood that the amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0266] [Table 44]

[0267] The assembled arms may include 1) a first disintegrable matrix, 2) a first inactive segment, 3) a second disintegrable matrix, 4) a second inactive segment, 5) a drug eluting segment comprising a carrier polymer and a drug or a salt thereof, further comprising a coating comprising a release rate modifying polymer film, and 6) a third inactive segment, which may be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first disintegrable matrix) (first inactive segment) (second disintegrable matrix) (second inactive segment) (drug eluting segment) (third inactive segment). In some embodiments, the third inactive segment is an inactive spacer. In some embodiments, the first and second inactive segments are rPCL spacers. An optional rPCL spacer (inactive segment) of about 0.2-2 mm length, for example about 0.5 mm length, can be inserted between any two of the above components, added to the outer tip of the assembled arms, or added between the inner tip of the assembled arms and the elastomeric core.

[0268] Approximate dimensions of the lengths of segments on an exemplary drug eluting arm are provided below.

[0269] [Table 45]

[0270] Approximate dimensions of length and thickness of segments on an exemplary drug eluting arm are provided below.

[0271] [Table 46]

[0272] Approximate dimensions of length and thickness of segments on an exemplary drug eluting arm are provided below.

[0273] [Table 47]

[0274] The assembled arms can include 1) a first disintegrating matrix, 2) a first inactive segment, 3) a second disintegrating matrix, 4) a second inactive segment, and 5) a third inactive segment, which can be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (first disintegrating matrix) (first inactive segment) (second disintegrating matrix) (second inactive segment) (third inactive segment). An optional rPCL spacer (inactive segment) of about 0.2-2 mm length, for example about 0.5 mm length, can be inserted between any two of the following components, added to the outer tip of the assembled arms, or added between the inner tip of the assembled arms and the elastomer core. In some embodiments, the third inactive segment is an inactive spacer. It will be understood that this embodiment of the assembled arms lacks a drug eluting segment and can be used when it is desirable to use one or more non-drug eluting arms for the dosage form.

[0275] Approximate dimensions of the lengths of the segments on exemplary non-drug eluting arms are provided below.

[0276] [Table 48]

[0277] Approximate dimensions of length and thickness of segments on an exemplary non-drug eluting arm are provided below.

[0278] [Table 49]

[0279] Approximate dimensions of length and thickness of segments on an exemplary non-drug eluting arm are provided below.

[0280] [Table 50]

[0281] Exemplary Gastroretentive Systems The following gastroretention systems are illustrative to better illustrate certain embodiments of the systems described herein. These examples are merely illustrative and are not intended to limit the gastroretention systems described herein. Those skilled in the art will be able to contemplate additional configurations of gastroretention systems in light of the disclosure provided. Any described gastroretention systems herein shown as formulated with risperidone are not so limited and can be used with other drugs by replacing the risperidone-containing segments and / or inactive segments with segments containing other drugs in dosages and amounts appropriate for the particular drug.

[0282] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising (a) a first inactive segment as described in any of the above inactive segment embodiments, (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments, (c) a second inactive segment as described in any of the above inactive segment embodiments, (d) an enterodisintegrating matrix as described in any of the above inactive segment embodiments, (e) a third inactive segment as described in any of the above inactive segment embodiments, (f) a drug eluting segment as described in any of the above embodiments, (g) a fourth inactive segment as described in any of the above inactive segment embodiments, and (h) a third disintegrating matrix as described in any of the above embodiments. The first inactive segment may be attached to the central elastomer.

[0283] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising: (a) a first inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6); (c) a second inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (d) The drug-eluting arm includes an enterodisintegrable matrix (e.g., E-DM1 or E-DM2) as described in any of the above embodiments, (e) a third inactive segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above inactive segment embodiments, (f) a drug-eluting segment (e.g., CP-1) as described in any of the above embodiments, (g) a fourth inactive segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above inactive segment embodiments, and (h) a third disintegrable matrix (e.g., ODMTEP) as described in any of the above embodiments. The drug-eluting arm may include an optional fifth inactive segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above inactive segment embodiments. The segments described may be arranged in any order. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterodisintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (third disintegrating matrix segment). Another such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterodisintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (fifth inactive segment) (third disintegrating matrix segment).A first inactive segment can be attached to the central elastomer.

[0284] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising: (a) a first inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3); (b) a time-disintegrating matrix described in any of the embodiments described herein (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6, T-DM7, T-DM8, T-DM9, T-DM10, T-DM11, or T-DM12); (c) a second inactive segment described in any of the embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3); (d) a drug eluting segment described in any of the embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3); The drug-eluting arm comprises an enterodisintegrable matrix (e.g., E-DM1, E-DM2, E-DM3, E-DM4, E-DM5, E-DM6, E-DM7, or E-DM8) as described in any of the embodiments of the inactive segment described herein, (e) a third inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the embodiments of the inactive segment described herein, (f) a drug-eluting segment (e.g., CP-1) as described in any of the embodiments of the inactive segment described herein, (g) a fourth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the embodiments of the inactive segment described herein, and (h) a third disintegrable matrix (e.g., ODMTEP) as described in any of the embodiments of the inactive segment described herein. The drug-eluting arm may comprise an optional fifth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the embodiments of the inactive segment described herein. The described segments may be arranged in any order. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (third disintegrating matrix segment).Another such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterodisintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (fifth inactive segment) (third disintegrating matrix segment). The first inactive segment may be attached to the central elastomer.

[0285] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enterodisintegrating matrix, (e) a third inactive segment, (f) a drug eluting segment, (g) a fourth inactive segment, and (h) a third disintegrating matrix; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color absorbing dye E172; (c) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 59% to about 69% by weight of HPMCAS, about 29% to about 39% by weight of PCL, and about 0.5% to about 5% by weight of a poloxamer (e.g., P407), and optionally about 0.01% to about 0.2% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (f) the drug eluting segment comprises about 30% to about 40% by weight of drug, about 51% to about 61% by weight of PCL, about 2% to about 8% by weight of VA64, about 1% to about 5% by weight of P407, about 0.1% to about 1% by weight of vitamin E succinate, about 0.1% to about 1% by weight of SiO2, and about 0.01% to about 0.5% by weight of pigment; (g) the fourth inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1; and / or (h) the third disintegrable matrix comprises about 60% to about 70% by weight HPMCAS, about 25% to about 35% by weight PCL, about 1% to about 5% by weight propylene glycol, and about 1% to about 5% by weight stearic acid, and optionally about 0.01% to about 0.5% by weight iron oxide.

[0286] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enterodisintegrating matrix, (e) a third inactive segment, (f) a drug eluting segment, (g) a fourth inactive segment, and (h) a third disintegrating matrix; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (b) the time-dependent disintegrating matrix comprises from about 43% to about 47% by weight of PCL, from about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 15% to about 20% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 1% to about 3% by weight of polyethylene glycol 100k, and from about 0.01% to about 0.1% by weight of a color absorbing dye E172; (c) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 36% by weight of PCL, and about 1% to about 3% by weight of a poloxamer (e.g., P407), and optionally about 0.05% to about 0.15% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (f) the drug eluting segment comprises about 33% to about 37% by weight of drug, about 54% to about 58% by weight of PCL, about 4% to about 6% by weight of VA64, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinate, about 0.2% to about 0.8% by weight of SiO2, and about 0.05% to about 0.15% by weight of pigment; (g) the fourth inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1; and / or (h) the third disintegrable matrix comprises about 63% to about 67% by weight HPMCAS, about 28% to about 32% by weight PCL, about 2% to about 3% by weight propylene glycol, and about 2% to about 3% by weight stearic acid, and optionally about 0.05% to about 0.15% by weight iron oxide.

[0287] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enterodisintegrating matrix, (e) a third inactive segment, (f) a drug eluting segment, (g) a fourth inactive segment, and (h) a third disintegrating matrix; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) the first inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (b) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.005% to about 0.2% by weight, e.g., 0.05%, of a color absorbing dye E172; (c) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407), and about 0.1% by weight iron oxide (such as E172); (e) the third inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (f) the drug-eluting segment comprises about 35.0 wt.% drug, about 55.9 wt.% PCL, about 5.0 wt.% VA64, about 3.0 wt.% P407, about 0.5 wt.% vitamin E succinate, about 0.5 wt.% SiO2, and about 0.1 wt.% pigment; (g) the fourth inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye FD&C Blue #1; and / or (h) the third disintegrable matrix comprises 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, and about 2.5% by weight stearic acid, and optionally about 0.1% by weight iron oxide, e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40.

[0288] In some embodiments, the gastroretention system comprises at least one arm that does not comprise a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment as described in any of the above inactive segment embodiments; (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments; (c) a second inactive segment as described in any of the above inactive segment embodiments; (d) an enterodisintegrating matrix as described in any of the above embodiments; (e) a third inactive segment as described in any of the above inactive segment embodiments; (f) a drug-free segment as described in any of the above embodiments; (g) a fourth inactive segment as described in any of the above inactive segment embodiments; and (h) a third disintegrating matrix as described in any of the above embodiments.

[0289] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, where the drug-free arm may be attached to a central elastomer, and the arm comprises one or more of: (a) a first inactive segment as described in any of the above inactive segment embodiments; (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments; (c) a second inactive segment as described in any of the above inactive segment embodiments; (d) an enterodisintegrating matrix as described in any of the above embodiments; (e) a third inactive segment as described in any of the above inactive segment embodiments; (f) a fourth inactive segment as described in any of the above inactive segment embodiments; and (g) a third disintegrating matrix as described in any of the above embodiments.

[0290] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, and the drug-free arm may be attached to a central elastomer, and the arm comprises: (a) a first inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6); (c) a second inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, IS-3, IS-4, IS-5, IS-6, IS-7, IS-8, IS-9, IS-10, IS-11, IS-12, IS-13, IS-14, IS-15, IS-16, IS-17, IS-18, IS-19, IS-20, IS-21, IS-22, IS-23, IS-24, IS-25, IS-26, IS-27, IS-28, IS-29, IS-30, IS-31, IS-32, IS-33, IS-34, IS-35, IS-36, IS-37, IS-38, IS-39, IS-40, IS-41, IS-42, IS-43, IS-44, IS-45, IS-46, IS-47, IS-48, IS-49, IS-50, IS-51, IS-52, IS-53, IS-54, IS-55, IS-56, IS-57, IS-58, IS-59, IS-60, IS-61, IS-62, IS-63, IS-64, IS-65, IS-65, IS-66, IS-67, IS-6 (e) a third inactive segment described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3); (d) an enterodisintegrable matrix described in any of the above embodiments (e.g., E-DM1 or E-DM2); (e) a third inactive segment described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3); (f) a fourth inactive segment described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3); and (g) a third disintegrable matrix described in any of the above embodiments (e.g., ODMTEP). The drug-free arm may include an optional fifth inactive segment described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3). The segments described may be arranged in any order. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterolytic matrix) (third inactive segment) (fourth inactive segment) (third disintegrating matrix segment). Another such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterolytic matrix) (third inactive segment) (fourth inactive segment) (fifth inactive segment) (third disintegrating matrix segment).A first inactive segment can be attached to the central elastomer.

[0291] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, and the drug-free arm may be attached to a central elastomer, and the arm comprises: (a) a first inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3); (b) a time-disintegrating matrix described in any of the embodiments described herein (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6, T-DM7, T-DM8, T-DM9, T-DM10, T-DM11, or T-DM12); (c) a second inactive segment described in any of the embodiments described herein (e.g., The drug-free arm may include one or more of the following: (a) an enterodisintegrable matrix described in any of the embodiments described herein (e.g., E-DM1, E-DM2, E-DM3, E-DM4, E-DM5, E-DM6, E-DM7, or E-DM8); (b) a third inactive segment described in any of the embodiments described herein (e.g., IS-1, IS-2, or IS-3); (c) a fourth inactive segment described in any of the embodiments described herein (e.g., IS-1, IS-2, or IS-3); and (d) a third disintegrable matrix described in any of the embodiments described herein (e.g., ODMTEP). The drug-free arm may include an optional fifth inactive segment described in any of the embodiments described herein (e.g., IS-1, IS-2, or IS-3). The segments described may be arranged in any order. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (third disintegrating matrix segment).Another such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (fifth inactive segment) (third disintegrating matrix segment). The first inactive segment may be attached to the central elastomer.

[0292] In some embodiments that can be combined with any of the embodiments herein, the filament is circumferentially wrapped around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament that is circumferentially wrapped around the gastric retention system and connects one or more arms of the dosage form can be a non-disintegrating filament. In some embodiments, the filament comprises a thermoplastic polyurethane. In some embodiments, the filament comprises methylene bis(4-phenylisocyanate), poly(tetramethylene oxide), and / or 1,4-butanediol.

[0293] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enterodisintegrating matrix, (e) a third inactive segment, (f) a fourth inactive segment, and (g) a third disintegrating matrix; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color absorbing dye E172; (c) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 59% to about 69% by weight of HPMCAS, about 29% to about 39% by weight of PCL, and about 0.5% to about 5% by weight of a poloxamer (e.g., P407), and optionally about 0.01% to about 0.2% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (f) the fourth inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1; and / or (g) the third disintegrable matrix comprises about 60% to about 70% by weight HPMCAS, about 25% to about 35% by weight PCL, about 1% to about 5% by weight propylene glycol, and about 1% to about 5% by weight stearic acid, and optionally about 0.01% to about 0.5% by weight iron oxide.

[0294] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enterodisintegrating matrix, (e) a third inactive segment, (f) a fourth inactive segment, and (g) a third disintegrating matrix; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (b) the time-dependent disintegrating matrix comprises from about 43% to about 47% by weight of PCL, from about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 15% to about 20% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 1% to about 3% by weight of polyethylene glycol 100k, and from about 0.01% to about 0.1% by weight of a color absorbing dye E172; (c) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 36% by weight of PCL, and about 1% to about 3% by weight of a poloxamer (e.g., P407), and optionally about 0.05% to about 0.15% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (f) the fourth inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1; and / or (g) the third disintegrable matrix comprises about 63% to about 67% by weight HPMCAS, about 28% to about 32% by weight PCL, about 2% to about 3% by weight propylene glycol, and about 2% to about 3% by weight stearic acid, and optionally about 0.05% to about 0.15% by weight iron oxide.

[0295] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enterodisintegrating matrix, (e) a third inactive segment, (f) a fourth inactive segment, and (g) a third disintegrating matrix; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) the first inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (b) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (c) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407), and about 0.1% by weight iron oxide (such as E172); (e) the third inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (f) the fourth inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight of the color absorbing dye FD&C Blue #1; and / or (g) the third disintegrating matrix comprises 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, and about 2.5% by weight stearic acid, and optionally about 0.1% by weight iron oxide, e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40.

[0296] In some embodiments according to any of the gastroretention systems described herein, the gastroretention system comprises at least one arm comprising a drug eluting segment, the arm further comprising a fifth optional inactive segment, the fifth optional inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0297] In any of the above embodiments, the arms may be attached to the central elastomer at a first inactive segment, i.e., the first inactive segment is the proximal end of the arm.

[0298] The table below provides a listing of the length of each segment in the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value itself.

[0299] [Table 51]

[0300] For further embodiments, the following table provides a listing of the length of each segment of the drug eluting arm in a gastroretentive system. Each range or value below can be considered to be "about" the recited range or value, or to be the recited range or value exactly.

[0301] [Table 52]

[0302] The following gastroretentive systems are illustrative to better illustrate certain embodiments of the systems described herein.

[0303] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising (a) a first inactive segment as described in any of the above inactive segment embodiments, (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments, (c) a second inactive segment as described in any of the above inactive segment embodiments, (d) an enterodisintegrating matrix as described in any of the above inactive segment embodiments, (e) a third inactive segment as described in any of the above inactive segment embodiments, (f) a fourth inactive segment as described in any of the above inactive segment embodiments, (g) a drug eluting segment as described in any of the above embodiments, and (h) a fifth inactive segment as described in any of the above embodiments. The first inactive segment may be attached to a central elastomer.

[0304] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising: (a) a first inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6); (c) a second inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (d) a drug eluting segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); The drug-eluting arm includes an enterodisintegrable matrix (e.g., E-DM1 or E-DM2) as described in any of the embodiments, (e) a third inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the inactive segment embodiments above, (f) a fourth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the inactive segment embodiments above, (g) a drug-eluting segment as described in any of the embodiments above, and (h) a fifth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the embodiments above. The drug-eluting arm may include an optional sixth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) as described in any of the inactive segment embodiments above. The described segments may be arranged in various orders. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteroerodible matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (fifth inactive segment). One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteroerodible matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (optional sixth inactive segment) (fifth inactive segment).A first inactive segment can be attached to the central elastomer.

[0305] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising: (a) a first inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3); (b) a time-disintegrating matrix described in any of the embodiments described herein (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6, T-DM7, T-DM8, T-DM9, T-DM10, T-DM11, or T-DM12); (c) a second inactive segment described in any of the embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3); (d) a drug eluting segment described herein (e.g., any one of IS-1, IS-2, or IS-3); The drug eluting arm includes an enterodisintegrable matrix as described in any of the embodiments described herein (e.g., E-DM1, E-DM2, E-DM3, E-DM4, E-DM5, E-DM6, E-DM7, or E-DM8), (e) a third inactive segment as described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3), (f) a fourth inactive segment as described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3), (g) a drug eluting segment as described in any of the embodiments described herein, and (h) a fifth inactive segment as described in any of the embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3). The drug eluting arm may include an optional sixth inactive segment as described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3). The described segments may be arranged in various orders. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (fifth inactive segment).One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterolytic matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (optional sixth inactive segment) (fifth inactive segment). The first inactive segment may be attached to the central elastomer.

[0306] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteroerodible matrix, (e) a third inactive segment, (f) a fourth inactive segment, (g) a drug eluting segment, and (h) a fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172; (c) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 59% to about 69% by weight of HPMCAS, about 29% to about 39% by weight of PCL, and about 0.5% to about 5% by weight of a poloxamer (e.g., P407), and optionally about 0.01% to about 0.2% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (f) the fourth inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1; (g) the drug eluting segment comprises about 30% to about 40% by weight of drug, about 51% to about 61% by weight of PCL, about 2% to about 8% by weight of VA64, about 1% to about 5% by weight of P407, about 0.1% to about 1% by weight of vitamin E succinate, about 0.1% to about 1% by weight of SiO2, and about 0.01% to about 0.5% by weight of pigment; and / or (h) the fifth inactive segment comprises about 35% to about 45% by weight PCL, about 37% to about 47% by weight copovidone, about 10% to about 20% by weight polyethylene glycol, about 1% to about 5% by weight poloxamer, and optionally about 0.0005% to about 0.02% by weight color absorbing dye E172.

[0307] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteroerodible matrix, (e) a third inactive segment, (f) a fourth inactive segment, (g) a drug eluting segment, and (h) a fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (b) the time-dependent disintegrating matrix comprises from about 43% to about 47% by weight of PCL, from about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 15% to about 20% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 1% to about 3% by weight of polyethylene glycol 100k, and from about 0.01% to about 0.1% by weight of color absorbing dye E172; (c) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 36% by weight of PCL, and about 1% to about 3% by weight of a poloxamer (e.g., P407), and optionally about 0.05% to about 0.15% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (f) the fourth inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1; (g) the drug eluting segment comprises about 33% to about 37% by weight of drug, about 54% to about 58% by weight of PCL, about 4% to about 6% by weight of VA64, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinate, about 0.2% to about 0.8% by weight of SiO2, and about 0.05% to about 0.15% by weight of pigment; and / or (h) the fifth inactive segment comprises about 38% to about 42% by weight PCL, about 40% to about 44% by weight copovidone, about 13% to about 17% by weight polyethylene glycol, about 2% to about 4% by weight poloxamer, and optionally about 0.001% to about 0.01% by weight color absorbing dye E172.

[0308] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteroerodible matrix, (e) a third inactive segment, (f) a fourth inactive segment, (g) a drug eluting segment, and (h) a fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) the first inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (b) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.005% to about 0.2% by weight, e.g., 0.05%, of a color absorbing dye E172; (c) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407), and about 0.1% by weight iron oxide (such as E172); (e) the third inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (f) the fourth inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight of the color absorbing dye FD&C Blue #1; (g) the drug-eluting segment comprises about 35.0 wt.% drug, about 55.9 wt.% PCL, about 5.0 wt.% VA64, about 3.0 wt.% P407, about 0.5 wt.% Vitamin E succinate, about 0.5 wt.% SiO2, and about 0.1 wt.% pigment; and / or (h) the fifth inactive segment comprises about 39.995% by weight PCL, about 42% by weight copovidone, about 15% by weight polyethylene glycol, about 3% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye E172.

[0309] In some embodiments, the gastroretention system comprises at least one arm that does not comprise a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment as described in any of the above inactive segment embodiments; (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments; (c) a second inactive segment as described in any of the above inactive segment embodiments; (d) an enterodisintegrating matrix as described in any of the above inactive segment embodiments; (e) a third inactive segment as described in any of the above inactive segment embodiments; (f) a fourth inactive segment as described in any of the above inactive segment embodiments; and (g) a fifth inactive segment as described in any of the above embodiments.

[0310] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, the arm comprising (a) a first inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3), (b) a time-disintegrating matrix as described in any of the above inactive segment embodiments (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (c) a second inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3), (d) a second inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3), (e) a second inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3), (f) a second inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3), (g) a second inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3), (h) a second inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3), (i) a second inactive segment as described in any of the above inactive segment embodiments (i.e., IS-1, IS-2, or IS-3), (j ... 3), (d) an enterodispersible matrix as described in any of the above embodiments (e.g., E-DM1 or E-DM2), (e) a third inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3), (f) a fourth inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3), and (g) a fifth inactive segment as described in any of the above embodiments (e.g., any one of IS-1, IS-2, or IS-3). The drug-free arm may include an optional sixth inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3). The segments described may be arranged in various orders. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteroerodible matrix) (third inactive segment) (fourth inactive segment) (fifth inactive segment). One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteroerodible matrix) (third inactive segment) (fourth inactive segment) (optional sixth inactive segment) (fifth inactive segment). The first inactive segment may be attached to the central elastomer.

[0311] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, the arm comprising (a) a first inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3), (b) a time-disintegrating matrix described in any of the embodiments described herein (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6, T-DM7, T-DM8, T-DM9, T-DM10, T-DM11, or T-DM12), (c) a second inactive segment described in any of the embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3), (d) an enteroerodible matrix as described in any of the embodiments described herein (e.g., E-DM1, E-DM2, E-DM3, E-DM4, E-DM5, E-DM6, E-DM7, or E-DM8); (e) a third inactive segment as described in any of the embodiments of the inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3); (f) a fourth inactive segment as described in any of the embodiments of the inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3); and (g) a fifth inactive segment as described in any of the embodiments of the inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3). The drug-free arm may include an optional sixth inactive segment as described in any of the embodiments of the inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3). The described segments can be arranged in various orders. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (fifth inactive segment).One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enterolytic matrix) (third inactive segment) (fourth inactive segment) (optional sixth inactive segment) (fifth inactive segment). The first inactive segment may be attached to the central elastomer.

[0312] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteroerodible matrix, (e) a third inactive segment, (f) a fourth inactive segment, and (g) a fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172; (c) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 59% to about 69% by weight of HPMCAS, about 29% to about 39% by weight of PCL, and about 0.5% to about 5% by weight of a poloxamer (e.g., P407), and optionally about 0.01% to about 0.2% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (f) the fourth inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1; and / or (g) the fifth inactive segment comprises about 35% to about 45% by weight PCL, about 37% to about 47% by weight copovidone, about 10% to about 20% by weight polyethylene glycol, about 1% to about 5% by weight poloxamer, and optionally about 0.0005% to about 0.02% by weight color absorbing dye E172.

[0313] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteroerodible matrix, (e) a third inactive segment, (f) a fourth inactive segment, and (g) a fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (b) the time-dependent disintegrating matrix comprises from about 43% to about 47% by weight of PCL, from about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 15% to about 20% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 1% to about 3% by weight of polyethylene glycol 100k, and from about 0.01% to about 0.1% by weight of color absorbing dye E172; (c) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 36% by weight of PCL, and about 1% to about 3% by weight of a poloxamer (e.g., P407), and optionally about 0.05% to about 0.15% by weight of an iron oxide (e.g., E172); (e) the third inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (f) the fourth inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1; and / or (g) the fifth inactive segment comprises about 38% to about 42% by weight PCL, about 40% to about 44% by weight copovidone, about 13% to about 17% by weight polyethylene glycol, about 2% to about 4% by weight poloxamer, and optionally about 0.001% to about 0.01% by weight color absorbing dye E172.

[0314] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteroerodible matrix, (e) a third inactive segment, (f) a fourth inactive segment, and (g) a fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) the first inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (b) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (c) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407), and about 0.1% by weight iron oxide (such as E172); (e) the third inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (f) the fourth inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight of the color absorbing dye FD&C Blue #1; and / or (g) the fifth inactive segment comprises about 39.995% by weight PCL, about 42% by weight copovidone, about 15% by weight polyethylene glycol, about 3% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye E172.

[0315] In some embodiments according to any of the gastroretention systems described herein, the gastroretention system comprises at least one arm comprising a drug eluting segment, the arm further comprising a fifth optional inactive segment, the fifth optional inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0316] In any of the above embodiments, the arms may be attached to the central elastomer at a first inactive segment, i.e., the first inactive segment is the proximal end of the arm.

[0317] The following table provides a listing of the length of each segment of the drug eluting arm in a gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0318] [Table 53]

[0319] The following table provides a listing of the length of each segment of the drug-free arm in the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value itself.

[0320] [Table 54]

[0321] The following gastroretentive systems are exemplary to better illustrate the system embodiments described herein.

[0322] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising (a) a time-disintegrating matrix as described in any of the above embodiments, (b) a first inactive segment as described in any of the above inactive segment embodiments, (c) an enterodisintegrating matrix as described in any of the above embodiments, (d) a second inactive segment as described in any of the above inactive segment embodiments, (e) a drug eluting segment as described in any of the above embodiments, and (f) a third inactive segment as described in any of the above inactive segment embodiments. The time-disintegrating matrix may be attached to the central elastomer.

[0323] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising: (a) a time-disintegrating matrix as described in any of the above embodiments (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6); (b) a first inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (c) an enterodisintegrating matrix as described in any of the above embodiments (e.g., E-DM1 or E-DM2); (d) a second inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3); (e) a drug eluting segment as described in any of the above embodiments (e.g., CP-1); and (f) a third inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3). The drug eluting arm may include an optional fourth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) described in any of the above inactive segment embodiments. The described segments may be arranged in any order. One such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (time-degradable matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (drug eluting segment) (third inactive segment). Another such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (time-degradable matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (drug eluting segment) (optional fourth inactive segment) (third inactive segment). The time-degradable matrix may be attached to the central elastomer.

[0324] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm comprising (a) a time disintegrating matrix described in any of the embodiments described herein (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6, T-DM7, T-DM8, T-DM9, T-DM10, T-DM11, or T-DM12), (b) a first inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (c) a second inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (d) a second inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (e) a second inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (f) a second inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (g) a second inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (h) a second inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (i) a second inactive segment described in any of the embodiments of the inactive segment described herein (i.e., any one of IS-1, IS-2, or IS-3), (j) a second inactive segment described in any of the embodiments of the inactive segment described herein (i.e., any one of IS-1, IS-2, or IS-3), (j) a second inactive The drug eluting arm comprises an enterodisintegrable matrix as described herein (e.g., E-DM1, E-DM2, E-DM3, E-DM4, E-DM5, E-DM6, E-DM7, or E-DM8), (d) a second inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3), (e) a drug eluting segment as described herein (e.g., CP-1), and (f) a third inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3). The drug eluting arm may comprise an optional fourth inactive segment as described herein (e.g., any one of IS-1, IS-2, or IS-3), (e.g., any one of IS-1, IS-2, or IS-3). The segments described may be arranged in any order. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (time-degradable matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (drug-eluting segment) (third inactive segment). Another such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (time-degradable matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (drug-eluting segment) (optional fourth inactive segment) (third inactive segment). The time-degradable matrix may be attached to the central elastomer.

[0325] In some embodiments, the filament is wrapped circumferentially around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament wrapped circumferentially around the gastric retention system and connecting one or more arms of the dosage form can be a disintegrating filament. In some embodiments, the filament comprises poly(lactic-co-glycolic acid) and / or polyglycolic acid.

[0326] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172; (b) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 59% by weight to about 69% by weight of HPMCAS, about 29% by weight to about 39% by weight of PCL, and about 0.5% by weight to about 5% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (e) the drug eluting segment comprises about 30% to about 40% by weight of drug, about 51% to about 61% by weight of PCL, about 2% to about 8% by weight of VA64, about 1% to about 5% by weight of P407, about 0.1% to about 1% by weight of vitamin E succinate, about 0.1% to about 1% by weight of SiO2, and about 0.01% to about 0.5% by weight of pigment; and / or (f) the third inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1.

[0327] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the time-disintegrating matrix comprises about 45% to about 55% by weight of PCL, about 27% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 22% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color absorbing dye E172; (b) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 59% by weight to about 69% by weight of HPMCAS, about 29% by weight to about 39% by weight of PCL, and about 0.5% by weight to about 5% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (e) the drug eluting segment comprises about 30% to about 40% by weight of drug, about 51% to about 61% by weight of PCL, about 2% to about 8% by weight of VA64, about 1% to about 5% by weight of P407, about 0.1% to about 1% by weight of vitamin E succinate, about 0.1% to about 1% by weight of SiO2, and about 0.01% to about 0.5% by weight of pigment; and / or (f) the third inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1.

[0328] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the time-dependent disintegrating matrix comprises from about 43% to about 47% by weight of PCL, from about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 15% to about 20% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, from about 1% to about 3% by weight of polyethylene glycol 100k, and from about 0.01% to about 0.1% by weight of a color absorbing dye E172; (b) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 62% by weight to about 66% by weight of HPMCAS, about 32% by weight to about 36% by weight of PCL, and about 1% by weight to about 3% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (e) the drug eluting segment comprises about 33% to about 37% by weight of drug, about 54% to about 58% by weight of PCL, about 4% to about 6% by weight of VA64, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinate, about 0.2% to about 0.8% by weight of SiO2, and about 0.05% to about 0.15% by weight of pigment; and / or (f) the third inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1.

[0329] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the time-dependent disintegrating matrix comprises about 48% to about 52% by weight of PCL, about 30% to about 34% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 14% to about 18% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of a color absorbing dye E172; (b) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 62% by weight to about 66% by weight of HPMCAS, about 32% by weight to about 36% by weight of PCL, and about 1% by weight to about 3% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (e) the drug eluting segment comprises about 33% to about 37% by weight of drug, about 54% to about 58% by weight of PCL, about 4% to about 6% by weight of VA64, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinate, about 0.2% to about 0.8% by weight of SiO2, and about 0.05% to about 0.15% by weight of pigment; and / or (f) the third inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1.

[0330] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (b) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (c) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407); (d) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (e) the drug-eluting segment comprises about 35.0 wt.% drug, about 55.9 wt.% PCL, about 5.0 wt.% VA64, about 3.0 wt.% P407, about 0.5 wt.% Vitamin E succinate, about 0.5 wt.% SiO2, and about 0.1 wt.% pigment; and / or (f) the third inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye FD&C Blue #1.

[0331] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) a time-dependent disintegrating matrix comprising about 49.95% by weight PCL, about 32% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 16% by weight an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (b) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (c) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407); (d) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (e) the drug-eluting segment comprises about 35.0 wt.% drug, about 55.9 wt.% PCL, about 5.0 wt.% VA64, about 3.0 wt.% P407, about 0.5 wt.% Vitamin E succinate, about 0.5 wt.% SiO2, and about 0.1 wt.% pigment; and / or (f) the third inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye FD&C Blue #1.

[0332] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix as described in any of the above embodiments, (b) a first inactive segment as described in any of the above inactive segment embodiments, (c) an enterodisintegrating matrix as described in any of the above embodiments, (d) a second inactive segment as described in any of the above inactive segment embodiments, and (e) a third inactive segment as described in any of the above inactive segment embodiments. The time-disintegrating matrix may be attached to the central elastomer.

[0333] In some embodiments, the gastroretentive system comprises at least one arm that does not comprise a drug eluting segment, the arm comprising (a) a time-disintegrating matrix as described in any of the above embodiments (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (b) a first inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3), (c) an enterodisintegrating matrix as described in any of the above embodiments (e.g., E-DM1 or E-DM2), (d) a second inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3), and (e) a third inactive segment as described in any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, or IS-3). The drug eluting arm may include an optional fourth inactive segment (e.g., any one of IS-1, IS-2, or IS-3) described in any of the above inactive segment embodiments. The described segments may be arranged in any order. One such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (time-degradable matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (third inactive segment). Another such order is, starting from the proximal end attached to the central elastomer and moving toward the distal end, (time-degradable matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (optional fourth inactive segment) (third inactive segment). The time-degradable matrix may be attached to the central elastomer.

[0334] In some embodiments, the gastroretentive system comprises at least one arm that does not contain a drug eluting segment, and the arm comprises (a) a time-disintegrating matrix described in any of the embodiments described herein (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6, T-DM7, T-DM8, T-DM9, T-DM10, T-DM11, or T-DM12), (b) a first inactive segment described in any of the embodiments of the inactive segment described herein (e.g., any one of IS-1, IS-2, or IS-3), (c) an enteroerodible matrix described in any of the embodiments described herein (e.g., E-DM1, E-DM2, E-DM3, E-DM4, E-DM5, E-DM6, E-DM7, or E-DM8), (d) a second inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3), and (e) a third inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3). The drug-eluting arm may include an optional fourth inactive segment described in any of the inactive segment embodiments described herein (e.g., any one of IS-1, IS-2, or IS-3). The described segments may be arranged in any order. One such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (time-disintegrating matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (third inactive segment). Another such sequence is, starting from the proximal end attached to the central elastomer and moving towards the distal end, (time-disintegrating matrix) (first inactive segment) (enterolytic matrix) (second inactive segment) (optional fourth inactive segment) (third inactive segment). The time-disintegrating matrix may be attached to the central elastomer.

[0335] In some embodiments, the filament is wrapped circumferentially around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament wrapped circumferentially around the gastric retention system and connecting one or more arms of the dosage form can be a disintegrating filament. In some embodiments, the filament comprises poly(lactic-co-glycolic acid) and / or polyglycolic acid.

[0336] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, (e) a drug eluting segment, and (f) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 25% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of color absorbing dye E172; (b) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 59% by weight to about 69% by weight of HPMCAS, about 29% by weight to about 39% by weight of PCL, and about 0.5% by weight to about 5% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; and / or (e) the third inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1.

[0337] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, and (e) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the time-disintegrating matrix comprises about 45% to about 55% by weight of PCL, about 27% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 10% to about 22% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color absorbing dye E172; (b) the first inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 59% by weight to about 69% by weight of HPMCAS, about 29% by weight to about 39% by weight of PCL, and about 0.5% by weight to about 5% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; and / or (e) the third inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, about 0.2% to about 4% by weight poloxamer, and optionally about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1.

[0338] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, and (e) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the time-dependent disintegrating matrix comprises about 43% to about 47% by weight of PCL, about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 15% to about 20% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of a color absorbing dye E172; (b) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 62% by weight to about 66% by weight of HPMCAS, about 32% by weight to about 36% by weight of PCL, and about 1% by weight to about 3% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; and / or (e) the third inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1.

[0339] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, and (e) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) the time-dependent disintegrating matrix comprises about 48% to about 52% by weight of PCL, about 30% to about 34% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 14% to about 18% by weight of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of a color absorbing dye E172; (b) the first inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; (c) the enterodisintegrable matrix comprises about 62% by weight to about 66% by weight of HPMCAS, about 32% by weight to about 36% by weight of PCL, and about 1% by weight to about 3% by weight of a poloxamer (such as P407); (d) the second inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)CO; and / or (e) the third inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, about 0.5% to about 2.5% by weight poloxamer, and optionally about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1.

[0340] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, and (e) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 18% by weight an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (b) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (c) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407); (d) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; and / or (e) the third inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye FD&C Blue #1.

[0341] In some embodiments, the gastroretentive system comprises at least one arm that does not include a drug eluting segment, the arm may be attached to a central elastomer, the arm comprising one or more of: (a) a time-disintegrating matrix, (b) a first inactive segment, (c) an enteroerodible matrix, (d) a second inactive segment, and (e) a third inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) a time-dependent disintegrating matrix comprising about 49.95% by weight PCL, about 32% by weight an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 16% by weight an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (b) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)CO; (c) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (such as P407); (d) the second inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; and / or (e) the third inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, about 1.5% by weight poloxamer, and optionally about 0.05% by weight color absorbing dye FD&C Blue #1.

[0342] In some embodiments according to any of the gastroretention systems described herein, the gastroretention system comprises at least one arm comprising a drug eluting segment, the arm further comprising a fourth optional inactive segment, the fourth optional inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3. In some embodiments, the fourth optional inactive segment comprises about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)2CO3. In some embodiments, the fourth optional inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0343] In any of the above embodiments, the arms may be attached to the central elastomer at a first inactive segment, i.e., the first inactive segment is the proximal end of the arm.

[0344] The following table provides a listing of the length of each segment of the drug eluting arm in a gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0345] [Table 55]

[0346] The table below provides a listing of the length and thickness of each segment of the drug eluting arm in the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0347] [Table 56]

[0348] The table below provides a listing of the length and thickness of each segment of the drug eluting arm in the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0349] [Table 57]

[0350] The following table provides a listing of the length of each segment of the drug-free arm in the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value itself.

[0351] [Table 58]

[0352] The following table provides a listing of the length and thickness of each segment of the drug-free arm of the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value itself.

[0353] [Table 59]

[0354] The following table provides a listing of the length and thickness of each segment of the drug-free arm of the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value itself.

[0355] [Table 60]

[0356] In some embodiments according to any of the systems described herein, the thickness of a segment is determined by the longest straight line in the cross section of the segment. In some embodiments where the cross section of the segment is circular, the thickness is defined by the diameter of the circle. In some embodiments where the cross section of the segment is square or rectangular, the thickness is defined by the diagonal of the square or rectangle. In some embodiments where the cross section of the segment is an equilateral triangle, the thickness is defined by the sides of the equilateral triangle.

[0357] In some embodiments, the dosage form for administering the agent comprises a gastroretentive system, the gastroretentive system comprising one or two inactive segments. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 66.495% by weight polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 32.0% by weight copovidone, such as VA64. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 1.5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, e.g., poloxamer 407 (P407). In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 0.005% by weight of an iron oxide, e.g., E172. In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 39.995% by weight of a polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbion PC17. In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 42.0% by weight copovidone, e.g., VA64. In some embodiments, the gastroretentive system comprises about 15.0% by weight polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000, e.g., PEO. 100KIn some embodiments, the gastroretentive system comprises a second inactive segment comprising about 3.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407). In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 0.005% by weight of an iron oxide, such as E172. In some embodiments, the dosage form for administering the agent comprises a gastroretentive system, and the gastroretentive system comprises one or two inactive segments. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 66.45% by weight Corbion PC17, about 32.0% by weight VA 64, about 1.5% by weight P407, and about 0.05% by weight aluminum lake FD&C Blue 1. In some embodiments, the gastroretentive system comprises about 39.995% by weight Corbion PC17, about 42.0% by weight VA 64, about 15.0% by weight PEO. 100K %, about 3.0% by weight P407, and about 0.005% by weight E172.

[0358] In some embodiments, a gastric retention system dosage form for administering one or more drugs can include a radiopaque segment, the segment including about 70% by weight polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the gastric retention system includes a radiopaque segment including about 30% by weight (BiO)2CO3. In some embodiments, the gastric retention system includes a radiopaque segment including about 70% by weight Corbion PC17 and about 30% by weight (BiO)2CO3.

[0359] In some embodiments, the gastroretentive system dosage form for administering a drug comprises a central elastomer and further comprises a release rate controlling film comprising about 73.5% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbion PC17. In some embodiments, the release rate controlling film further comprises about 24.5% by weight of copovidone, e.g., VA64. In some embodiments, the release rate controlling film further comprises about 2.0% by weight of Mg stearate. In some embodiments, the gastroretentive system further comprises a time-dependent disintegrating matrix comprising about 44.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbion PC17. In some embodiments, the time-dependent disintegrating matrix further comprises about 35.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004A. In some embodiments, the time-dependent disintegrating matrix further comprises about 18.0% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a median viscosity of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g), such as PDLG 5004. In some embodiments, the time-dependent disintegrating matrix further comprises about 2.0% by weight of a polyethylene glycol, such as a polyethylene glycol having an average molecular weight of 100,000, such as PEO 100KIn some embodiments, the time-dependent disintegrating matrix further comprises about 0.05% by weight of iron oxide, e.g., E172. In some embodiments, the gastroretentive system further comprises a pH-dependent disintegrating matrix comprising about 33.95% by weight of polycaprolactone (PCL), e.g., a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbion PC17. In some embodiments, the pH-dependent disintegrating matrix further comprises about 63.95% by weight of hypromellose acetate succinate, e.g., HPMCAS-MG. In some embodiments, the pH-dependent disintegrating matrix further comprises about 2.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407 (P407). In some embodiments, the pH-dependent disintegrating matrix further comprises about 0.1% by weight of an iron oxide, such as E172. In some embodiments, the gastroretentive system further comprises one or more inactive segments. In some embodiments, the gastroretentive system further comprises a radiopaque segment comprising about 70% by weight of polycaprolactone (PCL), such as a PCL having a median viscosity of about 1.5 dl / g to about 2.1 dl / g, such as Corbion PC17. In some embodiments, the radiopaque segment comprises about 30% (BiO)2CO3 by weight. In some embodiments, a dosage form for administering a drug comprises a gastroretention system, the gastroretention system comprises a central elastomer and further comprises a release rate modifying film comprising about 73.5% Corbion PC17, about 24.5% VA64, and about 2.0% Mg stearate by weight. In some embodiments, the gastroretention system comprises about 44.95% Corbion PC17, about 35.0% PDLG 5004A, about 18.0% PDLG 5004, about 2.0% PEO by weight. 100Kand about 0.05% by weight E172. In some embodiments, the gastroretentive system further comprises a pH-dependent disintegration matrix comprising about 33.95% by weight Corbion PC17, about 63.95% by weight HPMCAS-MG, about 2.0% by weight P407, and about 0.1% by weight E172. In some embodiments, the gastroretentive system further comprises one or more inactive segments. In some embodiments, the gastroretentive system further comprises a radiopaque segment comprising about 70% by weight Corbion PC17, and about 30% by weight (BiO)2CO3.

[0360] In some embodiments, the gastric retention system has three arms that include a drug eluting segment and three arms that do not include a drug eluting segment, hi some embodiments, the gastric retention system has six arms that include a drug eluting segment.

[0361] In some embodiments according to any of the systems described herein, the thickness of a segment is determined by the longest straight line in the cross section of the segment. In some embodiments where the cross section of the segment is circular, the thickness is defined by the diameter of the circle. In some embodiments where the cross section of the segment is square or rectangular, the thickness is defined by the diagonal of the square or rectangle. In some embodiments where the cross section of the segment is an equilateral triangle, the thickness is defined by the sides of the equilateral triangle.

[0362] In some embodiments according to any of the systems described herein, the thickness of the segment across the star arm is uniform. In some embodiments according to any of the systems described herein, the thickness of the segment across the star arm is about 2.8 mm to about 3.7 mm, optionally about 3.1 mm to 3.5 mm, more optionally about 3.3 mm.

[0363] In some embodiments according to any of the systems described herein, the thickness of one or more segments at the distal end of the arm (furthest from the star core) is less than the thickness of the remaining proximal segments of the arm, and optionally the thickness of the proximal segments can be uniform. In some embodiments according to any of the systems described herein, the thickness of the most distal segment is about 2.4 mm to about 3.4 mm, and the thickness of the remaining segments of the arm is about 2.8 mm to about 3.7 mm. In some embodiments, the thickness of the most distal segment is about 2.8 mm to about 3.1 mm, and the thickness of the remaining segments of the arm is about 3.1 mm to about 3.5 mm. In some embodiments according to any of the systems described herein, the thickness of the most distal segment is about 2.9 mm to about 3.2 mm, and the thickness of the remaining segments of the arm is about 3.2 mm to about 3.5 mm. In some embodiments, the thickness of the most distal segment is about 2.9 mm to about 3.15 mm, and the thickness of the remaining segments of the arm is about 3.2 mm to about 3.4 mm. In some embodiments, the distal most segment is about 3.1 mm thick, with the remaining segments of the arm being about 3.3 mm thick.

[0364] Center Elastomer The central elastomer provides the gastroretentive system with the ability to be compressed into a compressed configuration, such that the gastroretentive system can be placed into a capsule or other suitable containing structure for administration to a subject.

[0365] In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a central elastomer comprising liquid silicone rubber (LSR), in some embodiments, the LSR has a hardness of about 45 to about 60 durometer.

[0366] In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a central elastomer comprising liquid silicone rubber (LSR), in some embodiments, the LSR has a hardness of about 45 to about 55 durometer.

[0367] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a central elastomer comprising liquid silicone rubber (LSR), in some embodiments, the LSR has a hardness of about 60 durometer.

[0368] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a central elastomer comprising liquid silicone rubber (LSR), in some embodiments, the LSR has a hardness of about 50 durometer. Speed ​​Control Polymer Film

[0369] The release rate modifying polymer film can be coated on the components of the gastroretentive system that release agents such as drugs. The components coated with the release rate modifying polymer film disclosed herein have substantially the same release rate characteristics before and after exposure to heat generated during heat-assisted assembly of the gastroretentive system. The composition, parameters, advantages, features, uses, and release profiles of the release rate modifying polymer film are disclosed in International Application PCT / US2020 / 059541, which is incorporated herein in its entirety. In some embodiments, one or more segments of the composite arm (e.g., a composite arm that includes a drug eluting segment or a composite arm that does not include a drug eluting segment) are coated with a release rate modifying film. In some embodiments, the drug eluting segment is coated with a release rate modifying film. In some embodiments, one or more inactive segments are coated with a release rate modifying film. In some embodiments, the release rate controlling film is applied in an amount of about 1% to about 5%, about 2% to about 4%, or about 2.3% to about 3%, such as about 2.6%, of the precoating weight of the segments (e.g., drug eluting segments and / or inactive segments). In some embodiments, the release rate controlling film is applied in an amount of about 2.4% to about 3.2%, such as about 2.8%, of the precoating weight of the segments (e.g., drug eluting segments and / or inactive segments).

[0370] A variety of polymers, including PCL, can be used to form the release rate controlling polymer film. In some embodiments, the release rate controlling polymer film comprises about 68% to about 78% by weight PCL. In some embodiments, the release rate controlling polymer film comprises about 71% to about 76% by weight PCL. In some embodiments, the release rate controlling polymer film comprises about 73.5% by weight PCL.

[0371] Other excipients, such as copovidone (VA64), can be added to the carrier polymer to modify the release of the drug. In some embodiments, the release rate modifying polymer film comprises about 20% to about 30% by weight of VA64. In some embodiments, the release rate modifying polymer film comprises about 22% to about 27% by weight of VA64. In some embodiments, the release rate modifying polymer film comprises about 24.5% by weight of VA64.

[0372] The release rate controlling film may include one or more dispersing agents, such as magnesium stearate. In some embodiments, the release rate controlling polymer film includes from about 0.5% to about 5% by weight magnesium stearate. In some embodiments, the release rate controlling polymer film includes from about 1% to about 3% by weight magnesium stearate. In some embodiments, the release rate controlling polymer film includes about 2% by weight magnesium stearate.

[0373] In some embodiments, the release rate controlling polymer film comprises about 68% to about 78% by weight PCL, about 20% to about 30% by weight VA64, and about 0.5% to about 5% by weight magnesium stearate. In some embodiments, the release rate controlling polymer film comprises about 71% to about 76% by weight PCL, about 22% to about 27% by weight VA64, and about 1% to about 3% by weight magnesium stearate. In some embodiments, the release rate controlling polymer film comprises about 73.5% by weight PCL, about 24.5% by weight VA64, and about 2% by weight magnesium stearate.

[0374] Exemplary amounts of the components of the release rate controlling film are provided in the table below. The amounts are given as approximate weight percent and it is understood that when ranges are provided, the amounts are selected to add up to 100%.

[0375] [Table 61]

[0376] Encapsulation of gastroretentive systems As mentioned above, one example of a star system 100 is shown diagrammatically in Figure 1A, and the configuration described above allows the system to be folded or compressed in a central elastomer. Figure 1B shows a folded configuration 190 of the gastroretentive system of Figure 1A (for clarity, only two arms are shown in Figure 1B). When folded, the overall length of the system is reduced by approximately half, and the system can be conveniently placed into a container such as a capsule or other container suitable for oral administration.

[0377] In some embodiments, the capsule includes a narrower portion (hereinafter referred to as the "capsule bottom") and a wider portion (hereinafter referred to as the "capsule cap", "capsule top", or "capsule sleeve"), and the capsule is closed by placing the wider capsule top over the narrower capsule bottom. In some embodiments, the system is oriented within the capsule such that the star core is located closer to the capsule bottom and the distal tips of the star arms (and any circumferential filaments) are located closer to the capsule top, i.e., the capsule sleeve covers the distal tips of the star arms. In some embodiments, the system is oriented within the capsule such that the star core is located closer to the capsule top and the distal tips of the star arms (and any circumferential filaments) are located closer to the capsule bottom, i.e., the capsule sleeve covers the star core. In some embodiments, the core sleeve enhances compatibility of the collapsible filaments with the stabilization ring, ensuring proper placement of the stabilization ring filaments within the capsule for full deployment.

[0378] In some embodiments, the capsule is size 000, 00, 0, 1, 2, 3, 4, or 5. In some embodiments, the capsule size is 00EL. In some embodiments, the capsule is an HPMC capsule. In some embodiments, the capsule comprises any one of about 1%, about 2%, about 3%, about 4%, or about 5% titanium dioxide. In some embodiments, the capsule is a white opaque HPMC capsule (size 00EL) with 2% titanium dioxide. In some embodiments, the capsule is a white opaque HPMC capsule (size 00EL) with 3% titanium dioxide.

[0379] In some embodiments, the gastroretentive system is assembled as described in Example 1 of International Application No. PCT / US2020 / 059541 and then placed into a capsule of appropriate size.

[0380] In some embodiments, the gastroretentive system is assembled as described in International Application No. PCT / US2020 / 023704 and then placed into a capsule of appropriate size.

[0381] In some embodiments, the gastroretentive system is assembled and then placed into an appropriately sized capsule as described in International Application No. PCT / US2020 / 023710.

[0382] The entire contents of International Applications Nos. PCT / US2020 / 059541, PCT / US2020 / 023704, and PCT / US2020 / 023710 are incorporated by reference into this specification. EXAMPLES

[0383] The present disclosure is further illustrated by the following non-limiting examples. Although the examples show dosage forms of risperidone, it is understood that other drugs may be used in the dosage forms and the amounts of drugs are adjusted as necessary for proper dosing.

[0384] Example 1: Risperidone dosage form (extended release gastric retention system) In this example, a dosage form according to the present invention comprises a gastroretentive system, and the gastroretentive system is formulated to include risperidone.

[0385] The gastroretention system includes a central elastomer that provides the gastroretention system with the ability to be compressed into a compressed configuration. The gastroretention system described in this example is another variation of a "star" configuration. In one example of a gastroretention system formulated with risperidone, the star includes six arms, each of which includes a drug-eluting segment.

[0386] 2A is numbered to show the various elements of this configuration. System 1300 includes a central elastomeric core 1310 in the shape of an "asterisk" with six short branches. Arm segment 1370 is attached to one of the short asterisk branches. Segment 1370 is followed in order by segment 1360, second segment 1370, segment 1350, third segment 1370, segment 1340, segment 1330, and fourth segment 1370. The distal end of each arm has segment 1320.

[0387] The gastroretention system has an average size of about 46 mm, with each segment having a length ranging from about 0.5 mm to about 8.0 mm. Table I below provides a list of the length of each segment in the gastroretention system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value itself.

[0388] [Table 62]

[0389] The gastroretention system has an average size of about 46 mm, with each segment having a length ranging from about 0.5 mm to about 8.0 mm. Table IA below provides a list of the length of each segment in an exemplary gastroretention system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0390] [Table 63]

[0391] The central elastomeric core 1310 comprises liquid silicone rubber (LSR) having a hardness of 50 durometer.

[0392] In this example, the dosage form provided herein includes six arms, each of which includes a drug-eluting segment, and the dosage form includes about 28 mg of risperidone for administration. The risperidone is included in the carrier polymer-drug segment 1330 (e.g., the drug-eluting segment). The drug-eluting segment includes about 35.0% by weight risperidone, about 55.9% by weight Corbion PC17, about 5.0% by weight VA64, about 3.0% by weight P407, about 0.5% by weight vitamin E succinate, about 0.5% by weight SiO2, and about 0.1% by weight pigment. The pigment includes about 0.05% FD&C Yellow 5 aluminum lake (14-16%) and about 0.05% FD&C Blue 1 aluminum lake (11-13%). The application also contemplates variations of this dosage form in which the number and / or length of the drug-eluting segments are increased to achieve higher doses of the drug, e.g., risperidone.

[0393] Additionally, each arm includes an inactive segment 1340. The inactive segment 1340 includes about 66.45% by weight Corbion PC17, about 32.0% by weight VA 64, about 1.5% by weight P407, and about 0.05% by weight FD&C Blue 1 Aluminum Lake.

[0394] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 1360, and a pH-dependent disintegration matrix or linker, referred to as segment 1350. In addition, the gastroretentive system comprises structural segment 1370.

[0395] The time-dependent disintegrating matrix (segment 1360) comprises about 44.95% by weight Corbion PC17, about 35% by weight acid-terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 1350) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbion PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 1370 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0396] Segment 1320 at the distal end of each arm is a third disintegrable matrix to which a filament is also optionally attached, such that the filaments circumferentially connect the arms. The third disintegrable matrix (segment 1320) comprises about 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, about 2.5% by weight stearic acid, and about 0.1% by weight iron oxide (e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40).

[0397] In the gastroretentive system, each drug arm is coated with a release rate modifying film. Specifically, the coating comprises about 73.5% by weight of Corbion PC17, about 24.5% by weight of VA64, and about 2.0% by weight of Mg stearate, and is applied in an amount of about 4.5% of the precoat weight of the segment (i.e., segments 1320, 1330, and 1340).

[0398] The gastroretentive system is assembled and then placed into a capsule of appropriate size as described in Example 1 of International Application PCT / US2020 / 059541. The dosage form described herein differs from the gastroretentive system previously described in International Application PCT / US2020 / 059541, as well as another gastroretentive system previously designated as LYN-005.

[0399] In another example of a gastroretentive system in which risperidone is formulated, the star contains three arms, each of which contains a drug eluting segment, and three of which does not contain a drug eluting segment. Other gastroretentive systems containing six arms, in which any of arms 1, 2, 3, 4, 5-6 contain a drug eluting segment, are also contemplated in the present application.

[0400] 2B is numbered to show the various elements of this configuration. System 1400 includes a central elastomeric core 1410 in the shape of an "asterisk" with six short prongs.

[0401] For the arms that include a drug eluting segment, segment 1470 of the arm is attached to one short asterisk branch. Segment 1470 is followed, in order, by segment 1460, second segment 1470, segment 1450, third segment 1470, segment 1440, segment 1430, and fourth segment 1470. The distal end of each drug-containing arm has segment 1420.

[0402] For arms that do not contain a drug eluting segment, segment 1470 of the arm is attached to one short asterisk branch. Segment 1470 is followed by segment 1460, a second segment 1470, segment 1450, a third segment 1470, and segment 1480. The distal end of each drug-free arm has segment 1420.

[0403] The gastroretention system has an average size of about 46 mm, with each segment having a length ranging from about 0.5 mm to about 10.9 mm. Table II below provides a list of the length of each segment in the gastroretention system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0404] [Table 64]

[0405] The gastroretention system has an average size of about 46 mm, with each segment having a length ranging from about 0.5 mm to about 10.9 mm. Table IIA below provides a list of the length of each segment in an exemplary gastroretention system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0406] [Table 65]

[0407] The central elastomeric core 1410 comprises liquid silicone rubber (LSR) having a hardness of 50 durometer.

[0408] In this example, the dosage form provided herein includes six arms, half of which (three arms) each include a drug-eluting segment, and the dosage form includes about 14 mg of risperidone for administration. The three drug-containing arms can be arranged alternately around the circumference of the star. The risperidone is included in the carrier polymer-drug segment 1430 (e.g., drug-eluting segment). The drug-eluting segment includes about 35.0% by weight risperidone, about 55.9% by weight Corbion PC17, about 5.0% by weight VA64, about 3.0% by weight P407, about 0.5% by weight Vitamin E succinate, about 0.5% by weight SiO2, and about 0.1% by weight pigment. The pigment includes about 0.05% FD&C Yellow 5 aluminum lake (14-16%) and about 0.05% FD&C Blue 1 aluminum lake (11-13%). Also contemplated in the present application are variations of this dosage form in which the number and / or length of drug-eluting segments are increased to achieve higher doses of drug, eg, risperidone.

[0409] Additionally, each arm includes an inactive segment (segment 1440 for the drug-containing arm and segment 1480 for the drug-free arm). Inactive segment 1440 or 1480 each includes about 66.45% by weight Corbion PC17, about 32.0% by weight VA 64, about 1.5% by weight P407, and about 0.05% by weight FD&C Blue 1 Aluminum Lake.

[0410] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 1460, and a pH-dependent disintegration matrix or linker, referred to as segment 1450. In addition, the gastroretentive system comprises a structural segment 1470.

[0411] The time-dependent disintegrating matrix (segment 1460) comprises about 44.95% by weight Corbion PC17, about 35% by weight acid-terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 1450) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbion PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 1470 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0412] Segment 1420 at the distal end of each arm is a third disintegrable matrix to which a filament is also optionally attached, such that the filaments circumferentially connect the arms. The third disintegrable matrix (segment 1420) comprises about 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, about 2.5% by weight stearic acid, and about 0.1% by weight iron oxide (e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40).

[0413] In the gastroretentive system, each drug arm is coated with a release rate modifying film. Specifically, the coating comprises about 73.5% by weight Corbion PC17, about 24.5% by weight VA64, and about 2.0% by weight Mg stearate, and is applied in an amount of about 4.5% of the precoat weight of the segment (i.e., segments 1420, 1430, 1440, and 1480).

[0414] The gastroretentive system is assembled and then placed into a capsule of appropriate size as described in Example 1 of International Application PCT / US2020 / 059541. The dosage form described herein differs from the gastroretentive system previously described in International Application PCT / US2020 / 059541, as well as another gastroretentive system previously designated as LYN-005.

[0415] Human studies Patients being treated for schizophrenia or schizoaffective disorder were administered immediate release (IR) risperidone tablets (2 mg or 4 mg based on the patient's current antipsychotic medication (APD) dose) for 15 days, and then randomized 3:1 to receive either IR risperidone-matched placebo or a risperidone-containing gastroretentive system described herein (14 mg or 28 mg risperidone), or a gastroretentive system-matched placebo and IR risperidone (2 mg or 4 mg; 4 patients per group) for 3 weeks. The gastroretentive system was administered once weekly. IR risperidone was administered once daily.

[0416] Following administration of the gastroretentive system, systemic exposure to the risperidone active moieties (risperidone and 9-hydroxyrisperidone combined) increased with increasing dose, with exposure observed throughout the dosing period, and peak concentrations generally observed within the first 3 days of dosing.

[0417] The dosage forms were administered to humans and plasma samples were collected from the participants. The pharmacokinetics of the risperidone dosage form formulations in subjects are shown in Figure 3 (upper curve: 28 mg dosage form; lower curve: 14 mg dosage form). Specifically, the plasma concentrations of the active moieties risperidone and 9-hydroxy-risperidone (the active metabolite of risperidone) were plotted over a 7-day period.

[0418] This formulation of a risperidone sustained release gastroretentive system demonstrated drug release over a 7 day period for both the 14 mg and 28 mg risperidone dosage forms described in this Example 1.

[0419] Example 2: Three-week study of a risperidone dosage form (extended release gastroretentive system) Methods: A multipharmaceutical, randomized, parallel-group, placebo-controlled study was conducted that enrolled 32 clinically stable patients with a primary diagnosis of schizophrenia or schizoaffective disorder. Patients were administered immediate-release (IR) risperidone tablets (2 mg or 4 mg based on the patient's current antipsychotic medication dose) for a 13-day lead-in period ("IR lead-in"), and then randomized 3:1 to receive either IR risperidone-matched placebo and a risperidone gastric retention system with the appropriate risperidone loading described in Example 1 (14 mg or 28 mg risperidone; 12 patients per group), or a risperidone gastric retention system-matched placebo and IR risperidone (2 mg or 4 mg; 4 patients per group) for 3 weeks.

[0420] The risperidone gastric retention system dose for patients receiving a 2 mg / day IR lead-in was 14 mg. The risperidone gastric retention system dose for patients receiving a 4 mg / day IR lead-in was 28 mg. Patients in the risperidone gastric retention system-matched placebo / IR risperidone group received the same IR dose administered during the IR lead-in.

[0421] The risperidone gastric retention system was administered once weekly (3 times in total). IR risperidone was administered once daily. Primary endpoints were pharmacokinetics after administration of the risperidone gastric retention system capsule and after IR risperidone, and incidence of adverse events (AEs). Secondary endpoints were pharmacokinetics after switching from IR risperidone to the risperidone gastric retention system. Pharmacokinetic analysis was performed using a noncompartmental model.

[0422] Plasma samples were analyzed by LCMS for risperidone and its active metabolite, 9-OH-risperidone. The sum of risperidone and 9-OH-risperidone is referred to as the risperidone active moiety. In the pharmacokinetic analysis, plasma concentrations of the active moiety observed during the 3-week dosing period were compared to concentrations observed during the last day of the IR lead-in (day -1).

[0423] Results: After administration of the risperidone gastric retention system, systemic exposure to the risperidone active moiety (combined concentration of risperidone and 9-hydroxyrisperidone) increased with increasing dose of the risperidone gastric retention system. Exposure was observed throughout the entire dosing period, with peak concentrations generally observed within the first 3 days of dosing. Peak exposure with the risperidone gastric retention system was lower than that with IR risperidone; see Figure 4, day -1 (in Figure 4, n=12 in the 14 mg group; one patient withdrew 24 hours after the first dose; one patient withdrew 4 hours after the third dose; n=11 in the 28 mg group; one patient withdrew 48 hours after the second dose; one patient excluded due to erratic absorption for unknown reasons). Examination of pre-dose concentrations suggested that steady state was achieved before the third dose of the risperidone gastric retention system.

[0424] Plasma concentrations of the active moiety in patients receiving the risperidone gastroretentive system generally remained above or close to the steady-state trough concentration observed during the IR lead-in, i.e., at t=0; see Figures 4 and 5A. (In Figures 4 and 5A, n=12 in the 14 mg group; one patient withdrew 24 hours after the first dose; one patient withdrew 4 hours after the third dose. In Figure 5A, n=11 in the 28 mg group; one patient withdrew 48 hours after the second dose; one patient was excluded due to erratic absorption of unknown origin).

[0425] Subjects receiving risperidone gastroretentive system-matched placebo and IR risperidone demonstrated active moiety concentrations consistent with those observed during the IR lead-in; see FIG. 5B. (In FIG. 5B, n=4 in the 2 mg group; n=4 in the 4 mg group, with one patient weaning 96 hours after the first dose.

[0426] Exposure to the active moiety in subjects receiving the risperidone gastric retention system and the IR risperidone-matched placebo was assessed by comparing the mean concentration (Cavg) and trough concentration (Ctau) over a one-week period following administration of the third risperidone gastric retention system dose and the last day of the IR lead-in. The Cavg and Ctau values ​​were generally similar for administration of the IR and risperidone gastric retention systems at both dose levels (i.e., 2 mg IR / 14 mg risperidone gastric retention system and 4 mg / IR / 28 mg risperidone gastric retention system); see Figures 6A and 6B.

[0427] The risperidone gastroretentive system was well tolerated, with approximately 85% of subjects completing all three doses. No serious events or SAEs were reported.

[0428] Example 3: Risperidone dosage form (extended release gastric retention system) In this example, a dosage form according to the present invention comprises a gastroretentive system, and the gastroretentive system is formulated to include risperidone.

[0429] The gastroretention system includes a central elastomer that provides the gastroretention system with the ability to be compressed into a compressed configuration. The gastroretention system described in this example is another variation of a "star" configuration. In one example of a gastroretention system formulated with risperidone, the star includes six arms, each of which includes a drug-eluting segment.

[0430] Figure 7 is numbered to show the various elements of this configuration. System 700 includes a central elastomeric core 710 in the shape of an "asterisk" with six short branches. Segments 711 are inert polycaprolactone linker segments at the end of each branch of the core to facilitate attachment of the arms.

[0431] For the arms that include a drug eluting segment, segment 770 of the arm is attached to one short asterisk branch. Segment 770 is followed in order by segment 760, a second segment 770, segment 750, a third segment 770, segment 740, and segment 730. The distal end of each arm has segment 720.

[0432] For arms that do not contain a drug eluting segment, segment 1470 of the arm is attached to one short asterisk branch. Segment 770 is followed by segment 760, a second segment 770, segment 750, a third segment 770, and segment 780. The distal end of each drug-free arm has segment 720.

[0433] The gastroretention system has an average size of about 46 mm, with each segment having a length ranging from about 0.5 mm to about 8.0 mm. Table A below provides a list of the length of each segment in the gastroretention system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0434] [Table 66]

[0435] In the gastroretentive system, the cross section of the arm can be oval, circular, rectangular, square, or triangular. In one exemplary system, the cross section of the arm can be an equilateral triangle, with the sides of the triangle being about 3.0 mm to 3.5 mm, for example about 3.3 mm. In one exemplary system, the cross section of the arm can be a square or a rectangle, with the diagonal of the square or rectangle being about 3.0 mm to 3.5 mm, for example about 3.3 mm. In one exemplary system, the cross section of the arm can be a circle, with the diameter of the circle being about 3.0 mm to 3.5 mm, for example about 3.3 mm.

[0436] The central elastomeric core 710 comprises liquid silicone rubber (LSR) having a hardness of 50 durometer.

[0437] In this example, the dosage form provided herein includes six arms, half of which (three arms) each include a drug-eluting segment, and the dosage form includes about 14 mg of risperidone for administration. The three drug-containing arms can be arranged alternately around the circumference of the star. The risperidone is included in the carrier polymer-drug segment 730 (e.g., drug-eluting segment). The drug-eluting segment includes about 35.0% by weight risperidone, about 55.9% by weight Corbion PC17, about 5.0% by weight VA64, about 3.0% by weight P407, about 0.5% by weight Vitamin E succinate, about 0.5% by weight SiO2, and about 0.1% by weight pigment. The pigment includes about 0.05% FD&C Yellow 5 aluminum lake (14-16%) and about 0.05% FD&C Blue 1 aluminum lake (11-13%). Also contemplated in the present application are variations of this dosage form in which the number and / or length of drug-eluting segments are increased to achieve higher doses of drug, eg, risperidone.

[0438] Additionally, each arm includes two inactive segments. The first inactive segment is designated segment 740 for the drug-containing arm and segment 780 for the drug-free arm. The first inactive segment 740 or 780 each includes about 66.45% by weight Corbion PC17, about 32.0% by weight VA 64, about 1.5% by weight P407, and about 0.05% by weight FD&C Blue 1 aluminum lake. The second inactive segment 720 at the distal end of each arm, to which a filament may be optionally attached, includes about 39.995% by weight Corbion PC17, about 42.0% by weight VA 64, about 15.0% by weight PEO100k, about 3.0% by weight P407, and about 0.05% by weight ferric oxide E172.

[0439] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 760, and a pH-dependent disintegration matrix or linker, referred to as segment 750. In addition, the gastroretentive system comprises a structural segment 770.

[0440] The time-dependent disintegrating matrix (segment 760) comprises about 44.95% by weight Corbion PC17, about 35% by weight acid-terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 750) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbion PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 770 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0441] In the gastroretentive system, each drug arm is coated with a release rate modifying film. Specifically, the coating comprises about 73.5% by weight Corbion PC17, about 24.5% by weight VA64, and about 2.0% by weight Mg stearate, and is applied in an amount of about 2.3% to about 3%, e.g., about 2.6%, of the precoat weight of the segment (i.e., segments 720, 730, 740, and 780).

[0442] The gastroretentive system is assembled and then placed into a capsule of appropriate size as described in Example 1 of International Application PCT / US2020 / 059541. The dosage form described herein differs from the gastroretentive system previously described in International Application PCT / US2020 / 059541, as well as another gastroretentive system previously designated as LYN-005.

[0443] In another example of a gastroretentive system in which risperidone is formulated, the star contains six arms, each of which contains a drug-eluting segment. Other gastroretentive systems containing six arms, where any of the arms, 1, 2, 3, 4, 5, or 6, contains a drug-eluting segment, are also contemplated in the present application.

[0444] Although the gastroretentive systems described are shown formulated with risperidone, they are not so limited and can be used with other drugs by replacing the risperidone-containing segments and / or the inactive segments with segments containing other drugs.

[0445] Example 4: Risperidone dosage form (sustained release gastric retention system) In this example, a dosage form according to the present invention comprises a gastroretentive system, and the gastroretentive system is formulated to include risperidone.

[0446] The gastroretention system includes a central elastomer that provides the gastroretention system with the ability to be compressed into a compressed configuration. The gastroretention system described in this example is another variation of a "star" configuration. In one example of a gastroretention system formulated with risperidone, the star includes six arms, each of which includes a drug-eluting segment.

[0447] Figures 8A and 8B are numbered to show the various elements of two such configurations. As shown in Figures 8A and 8B, systems 800.1 and 800.2 each include a central elastomeric core 810 in the shape of an "asterisk" with six short branches. Figure 8C shows one arm attached to the central elastomeric core 810. Segments 811 are inert polycaprolactone linker segments at the end of each branch of the core to facilitate attachment of the arms.

[0448] For arms that include a drug-eluting segment, segment 870 of the arm is attached to one short asterisk branch. Segment 870 is followed in sequence by segment 860, second segment 870, segment 850, third segment 870, segment 840, segment 830, and fourth segment 870. The distal end of each drug-containing arm has segment 820. Figure 8D shows an active composite arm (distal end of drug-eluting arm) that includes, in sequence, segment 840, segment 830, fourth segment 870, and distal segment 820. As shown in Figures 8C and 8D, the active composite arm can measure approximately 14.0 mm and can be trimmed down to approximately 12.5 mm.

[0449] For arms that do not include a drug eluting segment, segment 870 of the arm is attached to one short asterisk branch. Segment 870 is followed by segment 860, second segment 870, segment 850, third segment 870, and segment 880. The distal end of each drug-free arm has segment 820. Figure 8E shows an inactive composite arm (the distal end of a non-drug eluting arm) that in turn includes segment 880 and distal segment 820. The inactive composite arm can measure approximately 14.0 mm and can be trimmed down to approximately 12.5 mm.

[0450] The gastroretention system has an average size of about 46 mm, with each segment having a length ranging from about 0.5 mm to about 8.5 mm. Table B below provides a list of the length of each segment in the gastroretention system. Each range or value below can be considered to be "about" the indicated range or value, or to be the indicated range or value.

[0451] [Table 67]

[0452] In the gastroretentive system, the cross section of the arm can be oval, circular, rectangular, square, or triangular. In one exemplary system, the cross section of the arm can be an equilateral triangle, with the sides of the triangle being about 3.0 mm to 3.5 mm, for example about 3.3 mm. In one exemplary system, the cross section of the arm can be a square or a rectangle, with the diagonal of the square or rectangle being about 3.0 mm to 3.5 mm, for example about 3.3 mm. In one exemplary system, the cross section of the arm can be a circle, with the diameter of the circle being about 3.0 mm to 3.5 mm, for example about 3.3 mm.

[0453] The central elastomeric core 810 comprises liquid silicone rubber (LSR) having a hardness of 50 durometer.

[0454] In one example, the dosage form provided herein includes six arms each including a drug-eluting segment, and the dosage form includes about 28 mg of risperidone for administration (FIG. 8A). In one example, the dosage form provided herein includes three arms each including a drug-eluting segment, and the dosage form includes about 14 mg of risperidone for administration (FIG. 8B). The risperidone is included in the carrier polymer-drug segment 830 (e.g., the drug-eluting segment). The drug-eluting segment includes about 35.0% by weight risperidone, about 55.9% by weight Corbion PC17, about 5.0% by weight VA64, about 3.0% by weight P407, about 0.5% by weight vitamin E succinate, about 0.5% by weight SiO2, and about 0.1% by weight pigment. The pigments include about 0.05% FD&C Yellow 5 Aluminum Lake (14-16%) and about 0.05% FD&C Blue 1 Aluminum Lake (11-13%).Also contemplated in the present application are variations of this dosage form in which the number and / or length of drug-eluting segments are increased to achieve higher doses of drug, e.g., risperidone.

[0455] Additionally, each arm includes an inactive segment (segment 840 for the drug-containing arm and segment 880 for the drug-free arm). Inactive segment 840 or 880 each includes about 66.45% by weight Corbion PC17, about 32.0% by weight VA 64, about 1.5% by weight P407, and about 0.05% by weight FD&C Blue 1 Aluminum Lake.

[0456] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 860, and a pH-dependent disintegration matrix or linker, referred to as segment 850. In addition, the gastroretentive system comprises structural segment 870.

[0457] The time-dependent disintegrating matrix (segment 860) comprises about 44.95% by weight Corbion PC17, about 35% by weight acid-terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 850) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbion PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 870 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0458] Segment 820 at the distal end of each arm is a third disintegrable matrix to which a filament is also optionally attached, such that the filament circumferentially connects the arms. The third disintegrable matrix (segment 820) comprises about 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, about 2.5% by weight stearic acid, and about 0.1% by weight iron oxide (e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40). The filament can comprise a material having a Shore hardness of about 70A to 85A, such as polyurethane having a hardness of 80A. The filament can comprise polyurethane, such as Pellethane 80A. Each section of the filament connecting two adjacent arms can be about 20 to about 25 mm long, such as about 21 to about 24 mm long. The total length of the filament, such as polyurethane (such as Pellethane 80A), may be about 100 mm to 150 mm, for example about 105 mm.

[0459] In the gastroretentive system, each drug arm is coated with a release rate modifying film. Specifically, the coating comprises about 73.5% by weight Corbion PC17, about 24.5% by weight VA64, and about 2.0% by weight Mg stearate, and is applied in an amount of about 2.3% to about 3%, e.g., about 2.6%, of the precoat weight of the segment (i.e., segments 830, 840, and 880).

[0460] The gastroretentive system is assembled and then placed into a capsule of appropriate size as described in Example 1 of International Application PCT / US2020 / 059541. The dosage form described herein differs from the gastroretentive system previously described in International Application PCT / US2020 / 059541, as well as another gastroretentive system previously designated as LYN-005.

[0461] In another example of a gastroretention system in which risperidone is formulated, the stellate comprises four arms each comprising a drug eluting segment and two arms without a drug eluting segment. In another example of a gastroretention system in which risperidone is formulated, the stellate comprises two arms each comprising a drug eluting segment and four arms without a drug eluting segment. Other gastroretention systems comprising six arms, in which any of 1, 2, 3, 4, 5, or 6 of the arms comprises a drug eluting segment, are also contemplated in the present application.

[0462] Although the gastroretentive systems described are shown formulated with risperidone, they are not so limited and can be used with other drugs by replacing the risperidone-containing segments and / or the inactive segments with segments containing other drugs.

[0463] Example 5: Risperidone dosage form (sustained release gastric retention system) In this example, a dosage form according to the present invention comprises a gastroretentive system, and the gastroretentive system is formulated to include risperidone.

[0464] The gastroretention system includes a central elastomer that provides the gastroretention system with the ability to be compressed into a compressed configuration. The gastroretention system described in this example is another variation of a "star" configuration. In one example of a gastroretention system formulated with risperidone, the star includes six arms, each of which includes a drug-eluting segment.

[0465] Figure 9A is numbered to show the various elements of this configuration. System 900 includes a central elastomeric core 910 in the shape of an "asterisk" with six short branches. Segments 911 are inert polycaprolactone linker segments ("third shots") at the end of each branch of the core to facilitate attachment of the arms.

[0466] For arms that include a drug eluting segment, segment 960 of the arm is attached to one sh...

Claims

1. 1. A gastroretentive system comprising: six arms secured to a central elastomer, at least one arm comprising a drug-eluting segment; each arm including a proximal end, a distal end, and an outer surface therebetween, the proximal end of each arm being attached to and projecting radially from the central elastomer, and each arm having its distal end not attached to the central elastomer and located a greater radial distance from the central elastomer than the proximal end; the at least one arm comprising a drug eluting segment; a first disintegrable matrix segment; and a first inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the first inert segment; a second inert segment attached to the second disintegrable matrix segment; the drug eluting segment attached to the second inert segment, the drug eluting segment comprising a carrier polymer and a drug or a salt thereof, and further comprising a coating comprising a release rate controlling polymer film; a third inactive segment attached to the drug-eluting segment; and six arms fixed to a central elastomer, and a filament connecting each arm in the circumferential direction; 1. A gastroretentive system comprising:

2. A gastric retention system as described in claim 1, wherein the drug is a drug other than risperidone.

3. 3. The gastric retention system of claim 1 or 2, wherein the segments are in the following order from the proximal end to the distal end of the arm containing the drug eluting segment, the first disintegrable matrix segment being at the proximal end of the arm containing the drug eluting segment, the first disintegrable matrix segment being attached to the central elastomer, and the third inactive segment being at the distal end of the arm containing the drug eluting segment.

4. 10. The gastroretentive system of claim 1, wherein at least one arm does not include a drug-eluting segment.

5. the at least one arm not including a drug eluting segment, a first disintegrable matrix segment; and a first inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the first inert segment; a second inert segment attached to the second disintegrable matrix segment; a third inactive segment attached to the second inactive segment; and a filament connecting each arm in the circumferential direction; The gastroretentive system of claim 4, comprising:

6. 6. The gastric retention system of claim 5, wherein the segments are in the following order from the proximal end to the distal end of the arm that does not contain a drug eluting segment, the first disintegrable matrix segment being at the proximal end of the arm that does not contain a drug eluting segment, the first disintegrable matrix segment being attached to the central elastomer, and the third inactive segment being at the distal end of the arm that does not contain a drug eluting segment.

7. (a) one arm comprises the drug eluting segment and five arms do not comprise the drug eluting segment; or (b) two arms contain the drug eluting segment and four arms do not contain the drug eluting segment; or (c) three arms include the drug eluting segment and three arms do not include the drug eluting segment; The gastroretentive system of claim 1 .

8. The gastroretentive system of claim 1 , wherein the first disintegrating matrix segment comprises a time-dependent disintegrating matrix.

9. The first inactive segment comprises: (a) polycaprolactone (PCL), optionally wherein the first inactive segment comprises about 68% to about 72% by weight of PCL; and / or (b) (BiO) ２ CO ３ [Optionally, the first inactive segment is about 28% to about 32% by weight of (BiO) ２ CO ３ Including 10. The gastroretentive system of claim 1, comprising:

10. 10. The gastroretentive system of claim 1, wherein the second disintegrable matrix segment comprises an enteroerodible matrix.

11. The second disintegrable matrix comprises: (a) polycaprolactone (PCL) [optionally, the second disintegrable matrix comprises about 32% to about 36% by weight of PCL]; and / or (b) hydroxypropyl methylcellulose acetate succinate (HPMCAS) [optionally, the second disintegrable matrix comprises about 62% to about 66% by weight of HPMCAS]; and / or (c) a polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymer (optionally, the second disintegrable matrix comprises about 1% to about 3% by weight of the PEG-PPG-PEG block copolymer); 10. The gastroretentive system of claim 1, comprising:

12. The second inactive segment comprises: (a) polycaprolactone (PCL), and / or (b) (BiO) ２ CO ３ [Optionally, the second inactive segment is about 28% to about 32% by weight of (BiO) ２ CO ３ Including 10. The gastroretentive system of claim 1, comprising:

13. the third inactive segment (a) polycaprolactone (PCL), and / or (b) copovidone (optionally, the third inactive segment comprises about 30% to about 34% copovidone by weight); and / or (c) polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymer, optionally wherein the third inactive segment comprises from about 0.5% to about 2.5% by weight of the PEG-PPG-PEG block copolymer; and / or (d) an optional colorant, wherein the third inactive segment optionally comprises from about 0.01% to about 0.1% by weight of the colorant.

10. The gastroretentive system of claim 1, comprising:

14. the drug eluting segment (a) a drug (optionally, the drug-eluting segment comprises about 30% to about 40% drug by weight); and / or (b) polycaprolactone (PCL), optionally wherein the segment comprises about 51% to about 61% by weight of PCL; and / or (c) copovidone (optionally, the segment comprises about 2% to about 8% copovidone by weight); and / or (d) polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymers, optionally wherein the segment comprises from about 1% to about 5% by weight of PEG-PPG-PEG block copolymer; and / or (e) Vitamin E succinate (optionally, the segment comprises about 0.1% to about 1% by weight of Vitamin E succinate); and / or (f) colloidal silicon dioxide (SiO ２ ) [Optionally, the segment is about 0.1 wt % to about 1 wt % SiO ２ and / or (g) an optional colorant, wherein said segment optionally comprises from about 0.01% to about 0.5% by weight of said colorant; 10. The gastroretentive system of claim 1, comprising:

15. the proximal ends of the proximal segments of the arms are attached to the central elastomer via an inert polycaprolactone (PCL) linker; and optionally (a) the proximal segment of the arm is the first inactive segment; or (b) the proximal segment of the arm is the first disintegrable matrix; The gastroretentive system of claim 1 .

16. 10. The gastric retention system of claim 1, wherein the central elastomer comprises silicone rubber, and optionally, the central elastomer has a durometer hardness of about 45A to about 55A.

17. 2. The gastroretentive system of claim 1, wherein one or more segments of the arm are coated with a release rate controlling polymer film, optionally the release rate controlling polymer film comprising about 71% to about 76% by weight of PCL, about 22% to about 27% by weight of VA64, and about 1% to about 3% by weight of magnesium stearate.

18. A disintegrating matrix for use in a gastric retention system, comprising: (a) about 40% to about 50% by weight of a polycaprolactone having a median viscosity of about 1.2 dl / g; (b) about 48% to about 58% by weight of an acid-terminated copolymer of DL-lactide and glycolide (PDLG) having a median viscosity of about 0.2 dl / g; (c) from about 0% to about 5% by weight of an ester-terminated copolymer of DL-lactide and glycolide (PDLG) having a median viscosity of about 0.2 dl / g; (d) about 0.5% to about 5% by weight of polyethylene oxide having a molecular weight of about 100,000 (PEO 100k), and (e) optionally, from about 0.005% to about 0.2% by weight of a colorant; A disintegrable matrix comprising:

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