Risperidone Dosage Regimen Using a Gastroretentive System

Abstract

Disclosed are administration regimens for gastroretentive systems containing risperidone or a salt thereof. The administration regimens include a regimen in which immediate-release risperidone or a salt thereof is administered for a first period, a gastroretentive system containing immediate-release risperidone or a salt thereof and risperidone or a salt thereof is administered for a second period, and a gastroretentive system containing risperidone or a salt thereof is administered for a third period. Also included are regimens in which immediate-release risperidone or a salt thereof and a gastroretentive system containing risperidone or a salt thereof are administered during a co-administration period, followed by a gastroretentive system containing risperidone or a salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 377,961, filed September 30, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to a dosing regimen for risperidone using a gastroretentive system for sustained gastric release of the active agent. [Background technology]

[0003] A gastroretentive system is a drug delivery system that remains in the stomach for days to weeks or even longer, during which time a drug or other agent can be eluted from the system for absorption in the gastrointestinal tract. Examples of such systems are described in U.S. Patent No. 10,182,985 and International Patent Applications WO2015 / 191920, WO2015 / 191925, WO2017 / 070612, WO2017 / 100367, WO2017 / 205844, and WO2018 / 227147. During the retention period, the system releases a drug, such as one or more drugs.

[0004] Gastroretentive systems for administering risperidone are disclosed in International Patent Applications WO2021 / 092491 and WO2022 / 159529.

[0005] The present invention describes a dosing regimen for risperidone using a gastroretentive system, including in combination with an immediate release dosage form of risperidone. Summary of the Invention

[0006] Risperidone dosage forms are disclosed that incorporate several features to more accurately and consistently control the desired retention time of the gastric retention system, including: 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 greater precision in retention and transit of the gastric retention system, and arms coated with a release rate-controlling polymer film.

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

[0008] [Figure 1A] Figure 1A shows the configuration of the gastroretentive system. [Figure 1B] FIG. 1B is a detailed view of the configuration of the gastric retention portion. [Figure 2A] FIG. 2A shows the configuration of a gastroretentive system dosage form of risperidone. [Figure 2B] FIG. 2B shows another configuration of a gastroretentive system dosage form of risperidone. [Figure 3] FIG. 3 is a graph showing the pharmacokinetics of the gastroretentive system risperidone formulation of Example 1 (upper row: 28 mg formulation, lower row: 14 mg formulation) in humans. [Figure 4] Figure 4 shows the pharmacokinetics of risperidone in patients transitioning from steady-state immediate-release (IR) risperidone to an extended-release (ER) risperidone gastric retentive system. The concentrations of the active moieties (risperidone and 9-hydroxyrisperidone combination) are plotted. The upper curve represents the concentration following administration of the 28 mg ER gastric retentive system, and the lower curve represents the concentration following administration of the 14 mg ER gastric retentive system. Bands representing Cavg and Cmin for the corresponding matched IR groups are superimposed on the curves. [Figure 5A]Figure 5A shows the pharmacokinetics of risperidone administered via the gastroretentive system (ER). Mean concentrations of the active moieties (risperidone and 9-hydroxyrisperidone combined) are plotted ± standard deviation. The top graph shows the 14 mg ER dose, and the bottom graph shows the 28 mg ER dose. Bands representing Cavg and Cmin on the final day of the IR lead-in are superimposed on the graphs. [Figure 5B] Figure 5B shows the concentration of the active ingredient (risperidone and 9-hydroxyrisperidone) following daily IR administration of risperidone at 2 mg (top) and 4 mg (bottom). Bands representing Cavg and Cmin on the final day of IR lead-in are superimposed on the graph. [Figure 6A] Figure 6A compares the mean concentration of the active moiety (the sum of risperidone and 9-hydroxyrisperidone), Cavg, on day 1 (i.e., just before the transition from IR risperidone to the ER risperidone gastroretentive system) and day 15 between IR 2 mg and ER 14 mg, and between IR 4 mg and ER 28 mg. [Figure 6B] Figure 6B shows a comparison of the trough concentrations (Ctau) at the active site (risperidone and 9-hydroxyrisperidone combination) on day 1 (i.e., just before the transition from IR risperidone to the ER risperidone gastric retention system) and day 15 for IR 2 mg vs. ER 14 mg and IR 4 mg vs. ER 28 mg, respectively. [Figure 7] FIG. 7 shows the configuration of a gastroretentive system dosage form of risperidone. [Figure 8A] FIG. 8A shows the configuration of a gastroretentive system dosage form of risperidone. [Figure 8B] FIG. 8B shows another configuration of a gastroretentive system dosage form for risperidone. [Figure 8C] FIG. 8C shows the configuration of a drug-eluting arm in a gastroretentive system dosage form for risperidone. [Figure 8D] FIG. 8D shows the active composite arm in a gastroretentive system dosage form for risperidone. [Figure 8E]FIG. 8E shows the inactive composite arm in a gastroretentive system dosage form for risperidone. [Figure 9A] FIG. 9A shows the configuration of a gastroretentive system dosage form for risperidone. [Figure 9B] FIG. 9B shows the configuration of the drug-eluting arm (with the active arm) in a gastroretentive system dosage form for risperidone. [Figure 9C] FIG. 9C shows the configuration of a non-drug eluting arm (with an inactive arm) in a gastric retention system dosage form for risperidone. [Figure 10A] FIG. 10A shows the configuration of a gastroretentive system dosage form for risperidone. [Figure 10B] FIG. 10B shows the configuration of the drug-eluting arm (with the active arm) in a gastroretentive system dosage form for risperidone. [Figure 10C] FIG. 10C shows the configuration of a non-drug eluting arm (with an inactive arm) in a gastric retention system dosage form for risperidone. [Figure 11A] FIG. 11A shows the configuration of a gastroretentive system dosage form for risperidone. [Figure 11B] FIG. 11B shows the configuration of the drug-eluting arm (with the active arm) in a gastroretentive system dosage form for risperidone. [Figure 11C] FIG. 11C shows the configuration of a non-drug eluting arm (with an inactive arm) in a gastric retention system dosage form for risperidone. [Figure 12] Figure 12 shows the plasma concentrations of risperidone in patients who were initially administered an immediate-release (IR) dosage form for one week (only the last day of administration of the IR dosage form is shown as Day-1). Subsequently, patients were administered a gastroretentive system containing risperidone on days 0, 7, and 14, i.e., weekly. IR administration of risperidone was also administered on days 0-6. [Figure 13A]Figures 13A, 13B, and 13C are graphs of the plasma concentrations of the active moiety in patients. Figure 13A shows the plasma concentrations of 21 subjects who received either a 15 mg dose of risperidone or a 45 mg dose of risperidone. The plasma concentrations of the 45 mg cohort were divided by 3 to normalize the plasma concentrations to the 15 mg dose. [Figure 13B] FIG. 13B shows the plasma concentrations of the 15 mg dose cohort. [Figure 13C] FIG. 13C shows the plasma concentrations of the 45 mg dose cohort. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition A "carrier polymer" is a polymer suitable for blending with an agent, such as a drug, for use in a gastroretentive system.

[0010] "Pharmaceutical" means a substance intended for the treatment, diagnosis, or nutritional supplementation of a patient, individual, or subject. Pharmaceuticals include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0011] A "dispersing agent" is defined as a substance that minimizes drug particle size and aids in the dispersion of drug particles within the carrier polymer matrix. That is, dispersing agents help minimize or prevent particle aggregation or clumping during the manufacturing of the system. Thus, dispersing agents have anti-agglomeration and anti-agglomeration activity and help maintain a uniform distribution of drug particles within the carrier polymer matrix.

[0012] "Excipient" refers to a substance added to a drug formulation, other than the drug itself. Excipients include, but are not limited to, binders, coating agents, diluents, disintegrants, emulsifiers, flavorings, lubricants, and preservatives. The specific category of dispersing agents is included within the more general category of excipients.

[0013] An "elastic polymer" or "elastomer" is a polymer that can be deformed from its original shape by an applied force for a period of time, and that returns to substantially its original shape when the applied force is removed.

[0014] "Nearly constant plasma concentration" means that the plasma concentration measured over the period that the gastroretentive system is retained in the stomach is maintained within two-fold of the mean plasma concentration (i.e., between 50% and 200% of the mean plasma concentration).

[0015] A "substantially constant plasma concentration" refers to a plasma concentration that is within plus or minus 25% of the average plasma concentration measured over the period that the gastroretentive system is in the stomach.

[0016] "Biocompatible," when used to describe a material or system, indicates that the material or system will not cause any adverse reaction, or will cause only minimally acceptable adverse reactions, when in contact with an organism, such as a human. In the context of gastroretentive systems, biocompatibility is evaluated in the environment of the gastrointestinal tract.

[0017] 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.

[0018] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0019] "Treating" a disease or disorder using the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional agents, to a patient in need thereof to alleviate or eliminate either the disease or disorder. It refers to administering one or more of the systems disclosed herein to a patient, with or without additional agents, to alleviate or eliminate either 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. "Suppressing" a disease or disorder using the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional agents, to a patient in need thereof to inhibit the clinical manifestations of the disease or disorder or the manifestations of adverse symptoms of the disease or disorder. The difference between treatment and suppression is that treatment occurs after adverse symptoms of a disease or disorder appear in a patient, whereas suppression occurs before adverse symptoms of a disease or disorder appear in a 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 a disease or disorder. The systems and methods disclosed herein can then be used to treat asymptomatic patients at risk for developing clinical symptoms of a disease or disorder to suppress the onset of adverse symptoms.

[0020] A "therapeutic use" of the systems disclosed herein is defined as the use of 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, such as a drug, is the amount of drug that, when administered to a patient, is sufficient to either reduce or eliminate a disease or disorder or one or more symptoms of a disease or disorder, or to slow the progression of the disease or disorder or one or more symptoms of a disease or disorder, or to reduce the severity of the 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 in multiple doses.

[0021] "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 that, when administered to a patient, is sufficient to inhibit the clinical manifestations of a disease or disorder, or to inhibit the manifestations of adverse symptoms of a disease or disorder. A prophylactically effective amount can be administered to a patient in a single dose or in divided doses.

[0022] 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 gastroretentive system, the flexural modulus of a polymeric material may also be measured independently. For example, the polymeric linker of a gastroretentive system may be too short to measure the flexural modulus, but a long specimen of the same material may be used to accurately measure the flexural modulus. The long specimen used to measure the flexural modulus should have the same cross-sectional dimensions (shape and size) as the polymeric linker used in the gastroretentive system. Flexural modulus is measured using the ASTM standard three-point bending test (ASTM D790), with a 10 mm distance between supports and a modification to accommodate materials with non-rectangular cross sections. The flexural modulus is measured by placing the longest line of symmetry of the polymeric linker's cross section vertically and applying a downward force. If the longest line of symmetry of the polymeric linker's cross section is perpendicular to one flat side, the flat side should be oriented upward. If the cross section of the polymer linker is triangular, the apex of the triangle is oriented downward. When a downward force is applied, the force and displacement are measured, and the slope in the linear region is used to calculate the bending modulus.

[0023] The concentration of the risperidone active moiety is the concentration of risperidone plus the concentration of 9-hydroxyrisperidone. The concentration of the risperidone active moiety is usually measured in plasma.

[0024] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated or the context clearly dictates otherwise.

[0025] When a numerical value is expressed using the term "about" or "approximately," it is understood to include not only the specified value but also values ​​reasonably close to the specified value. For example, the description "about 50°C" or "about 50°C" includes both the disclosure of 50°C itself and values ​​close to 50°C. Thus, the expression "about X" or "approximately X" includes a description of the value X itself. When a range is indicated, such as "about 50°C to 60°C" or "about 50°C to 60°C," it is understood that both values ​​specified by the endpoints are included, and that each endpoint or value close to each endpoint is included; that is, "approximately 50°C to 60°C" (or "about 50°C to 60°C") is equivalent to describing both "50°C to 60°C" and "approximately 50°C to about 60°C" (or "about 50°C to 60°C").

[0026] With respect to the numerical ranges disclosed herein, an upper limit disclosed for a given component can be combined with a lower limit disclosed for that component to provide a range (provided that the upper limit is greater than the lower limit with which it is combined). These combinations of disclosed upper and lower limits are expressly contemplated herein. For example, if a range of amounts for a particular component is stated as 10% to 30%, 10% to 12%, and 15% to 20%, then ranges of 10% to 20% and 15% to 30% are also contemplated, but a combination of a lower limit of 15% with an upper limit of 12% is not contemplated because it is not possible.

[0027] Unless otherwise specified, percentages of components in a composition are expressed as weight percent or weight / weight percent. References to relative weight percent in a composition are understood to assume that the total weight percent of all components in the composition adds up to 100. Furthermore, it is understood that the relative weight percent of one or more components can be adjusted upward or downward so that the total weight percent of the components in the composition adds up to 100, provided that the weight percent of a particular component does not fall outside the limits of the range specified for that component.

[0028] Some embodiments described herein are incorporated by reference to "comprising" or "comprising" with respect to various elements thereof. In alternative embodiments, the elements may be incorporated with the transitional phrase "consisting essentially of" or "consisting essentially of" applied to those elements. In further alternative embodiments, the elements may be described with the transitional phrase "consisting of" or "consisting of" applied to those elements. Thus, for example, if a composition or method is disclosed herein as comprising A and B, alternative embodiments of the composition or method that are "consisting essentially of A and B," and alternative embodiments of the composition or method that are "consisting of A and B," are also considered to be disclosed herein. Similarly, embodiments that are incorporated by reference to "consisting essentially of" or "consisting of" with respect to those various elements may also be incorporated by reference to "consisting of" applied to those elements. Finally, embodiments that are incorporated by reference to "consisting essentially of" with respect to those various elements may also be incorporated by reference to "consisting essentially of" applied to those elements, and vice versa.

[0029] When a composition or system is described as "consisting essentially of" recited elements, the composition or system includes the explicitly recited elements and can include other elements that do not significantly affect the condition being treated (in the case of a composition for treating a condition) or the properties of the recited system (in the case of a composition constituting a system). However, the composition or system does not include other elements, other than the explicitly recited elements, that significantly affect the condition being treated (in the case of a composition for treating a system) or that significantly affect the properties of the system (in the case of a composition constituting a system), or if the composition or system includes extra elements other than the recited elements that may significantly affect the condition being treated or the properties of the system, the composition or system does not include those extra elements in concentrations or amounts sufficient to significantly affect the condition being treated or the properties of the system. When a method is described as "consisting essentially of" recited steps, the method includes the recited steps and can include other steps that do not significantly affect the condition being treated by the method or the properties of the system produced by the method, but the method does not include other steps, other than the explicitly recited steps, that significantly affect the condition being treated or the properties of the system produced by the method.

[0030] The present disclosure provides several embodiments. It is contemplated that any feature from any embodiment can be combined, where possible, with any feature from any other embodiment. In this respect, hybrid configurations of the disclosed features are within the scope of the present disclosure.

[0031] In addition to the embodiments and methods disclosed herein, additional embodiments of gastroretentive systems, and methods of making and using such systems, are disclosed in International Patent Application Nos. WO2015 / 191920, WO2015 / 191925, WO2017 / 070612, WO2017 / 100367, and PCT / US2017 / 034856 (WO2017 / 205844), which are incorporated herein by reference in their entireties.

[0032] The abbreviations for polymers etc. are as follows:

[0033] [Table 1]

[0034] PLURONIC® is a registered trademark of BASF for polyoxyalkylene ether. In formulations described herein using trade names, the trade names can be replaced with generic names. 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 a formulation described herein using a trade name can be replaced with an equivalent component from another manufacturer.

[0035] 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).

[0036] As used herein, unless otherwise specified, "PCL" can refer to polycaprolactone having an intrinsic viscosity midpoint of 1.0 to 2.1 dl / g, for example, 1.7 dl / g, or polycaprolactone having an intrinsic viscosity midpoint of 1.2 dl / g.

[0037] Gastric retention system description Gastroretention systems can be prepared in a variety of configurations. The "star" configuration of a gastroretention system is also known as the "star" (or "asterisk") configuration. An example of a star system 100 is shown schematically in FIG. 1A. Multiple arms (only one such arm, 108, is labeled for clarity) are affixed to a disk-shaped central elastomer 106. The arms depicted in FIG. 1A are composed of segments 102 and 103, which are joined by a coupling polymer or linker region 104, which functions as a linker region (again, for clarity, the component is only shown on one arm). This configuration allows the central elastomer to fold or compress the system. 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 arm 198 in FIG. 1B correspond to segments 102 and 103, linker region 104, elastomer 106, and arm 108, respectively, in FIG. 1A. When folded, the overall length of the system is reduced to approximately half, allowing the system to be conveniently placed in a container such as a capsule 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, releasing the gastroretentive system. When freed from the constraint of the capsule or other container, the gastroretentive system expands to an uncompressed state and remains in the stomach for the desired retention period.

[0038] Linker region 104 is shown in FIG. 1A as being slightly larger in diameter than segments 102 and 103, but it can be the same diameter as the segments so that the entire arm 102-104-103 has a smooth outer surface.

[0039] In some embodiments, the stellate system can have arms containing only one segment attached to a central elastomer by a linker region. This corresponds to FIG. 1A, where segment 103 is omitted. The single-segment arm containing segment 102 is then directly attached to central elastomer 106 via linker 104. The linker can consist of a coupling polymer or a disintegrable matrix.

[0040] A stellate system can be described as a gastroretentive 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, the plurality comprising a carrier polymer and a drug or a salt thereof, wherein each of the plurality of carrier polymer-drug components is an arm comprising a proximal end, a distal end, and an outer surface therebetween; wherein the proximal end of each arm is attached to the elastomeric component and protrudes radially from the elastomeric component, and each arm has its distal end not attached to the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; wherein each arm independently comprises one or more segments, each segment comprising a proximal end, a distal end, and an outer surface therebetween. In some embodiments, when two or more segments are present in an arm, each segment is 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 directly attached to another segment without the use of a linker region. The linker region can be a coupling polymer or a degradable matrix. The arms can be attached to the central elastomer via a coupling polymer or a degradable matrix and can have an intervening polymeric portion. A plurality of at least three arms, or if multiple arms, a preferred number of arms is six, although three, four, five, seven, eight, nine, or ten arms can be used. The arms are preferably evenly spaced around the central elastomer, and if there are N arms, there is an angle of approximately 360 / N degrees between adjacent arms.

[0041] The coupling polymer of the gastroretentive system, which serves as the linker region, is designed to degrade gradually in a controlled manner during the gastric retention period. To avoid ileus if the gastroretentive system passes intact into the small intestine prematurely, the system is designed to degrade more rapidly. This is easily achieved by using an enteric polymer as the coupling 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 coupling polymer as a safety element prevents the undesired passage of the intact gastroretentive system into the small intestine. In the system shown in FIG. 1A, at least the coupling polymer used in coupling 104 is made from such an enteric polymer.

[0042] In further embodiments, time-dependent coupling polymers or linkers can be used. Such time-dependent coupling polymers or linkers degrade in a predictable, time-dependent manner. In some embodiments, the degradation of the time-dependent coupling polymers or linkers may not be affected by the fluctuating pH of the gastrointestinal system.

[0043] In additional embodiments, different types of linkers can be used in the gastroretentive system, i.e., both enteric linkers (or enteric coupling polymers) and time-dependent linkers (or time-dependent coupling 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.

[0044] The width of the linker region is usually from about 100 microns to about 2 millimeters, for example, from about 200 μm to about 2000 μm, from about 300 μm to about 2000 μm, from about 400 μm to about 2000 μm, from about 500 μm to about 2000 μm, from about 600 μm to about 2000 μm, from about 700 μm to about 2000 μm, from about 800 μm to about 2000 μm, or from about 900 μm to about 2000 μm. μm~about 2000μm, about 1000μm~about 2000μm, about 1100μm~about 2000μm, about 1200μm~about 2000μm, about 1300μm~about 200 0μm, about 1400μm to about 2000μm, about 1500μm to about 2000μm, about 1600μm to about 2000μm, about 1700μm to about 2000μm, about 1800μm μm to about 2000 μm, or about 1900 μm to about 2000 μm; about 100 μm to about 1900 μm, about 100 μm to about 1800 μm, about 100 μm to about 1700 μm, about 100 μm to about 1600 μm, about 100 μm to about 1500 μm, about 100 μm to about 1400 μm, about 100 μm to about 1300 μm, about 100 μm to about 1200 μm , about 100 μm to about 1100 μm, about 100 μm to about 1000 μm, about 100 μm to about 900 μm, about 100 μm to about 800 μm, about 100 μm to about 700 μm, about 100 μm to about 600 μm, about 100 μm to about 500 μm, about 100 μm to about 400 μm, about 100 μm to about 300 μm, or about 100 μm to about 200 μm. The width of the linker region can be about 100 μm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1000 μm, about 1100 μm, about 1200 μm, about 1300 μm, about 1400 μm, about 1500 μm, about 1600 μm, about 1700 μm, about 1800 μm, about 1900 μm, or about 200 μm, each value plus or minus 50 μm (±50 μm).

[0045] The central elastomeric polymer of a stearate system is typically not an enteric polymer, although the central elastomeric polymer can be made from such an enteric polymer where desirable and practical.

[0046] The central elastomer should have a specific durometer and compression set. Durometer is important because it determines the folding force of the dosage form and whether it will remain in the stomach; a preferred range is about 60 to about 90A. Compression set should be as low as possible to avoid permanent deformation of the gastroretentive system when stored in a compressed state in a capsule. 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 meeting these requirements is Dow Corning's QP1 series 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 can include 50A or 60A durometer liquid silicone rubber (Shin-Etsu).

[0047] The segments and arms of the gastric retention system can have a circular (in which case the segments are cylindrical), polygonal (e.g., segments having a triangular, rectangular, or square cross-section), or pie-shaped cross-section (in which case the segments are cylindrical). Segments having polygonal or pie-shaped cross-sections, and ends of cylindrical cross-sections that come into contact with gastric tissue, can have rounded corners and edges to enhance in vivo safety. That is, instead of providing a sharp transition between intersecting ends or planes, a circular arc is used to transition from one end or plane to another. Thus, a "triangular cross-section" includes a cross-section having an approximately triangular shape, such as a triangle with rounded corners. Arms with a triangular cross-section 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, fillet edges, or fillet edges.

[0048] In some embodiments, the stellate system is about 30 mm to about 60 mm when deployed (arms extended). In some embodiments, the stellate system is about 41 mm to about 51 mm when deployed. In some embodiments, the stellate system is about 45 mm to about 47 mm when deployed. In some embodiments, the stellate system is about 46 mm when deployed.

[0049] Characteristics of risperidone gastroretentive systems for improved retention and drug release Retention of the gastric retention system for the desired retention period and drug release from the gastric retention system can be improved and made more consistent using 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 greater precision in retention and transit through the gastric retention system; and arms coated with release rate-controlling polymer films.

[0050] Circumferential filament In particular, gastric retention systems having filaments described herein can help improve the gastric retention of the gastric retention system. Specifically, the filaments can help provide more consistent and / or longer gastric retention times. Thus, gastric retention systems provided herein including filaments can provide more predictable and / or controllable gastric retention times. A gastric retention system with a predictable and / or controllable gastric retention time can minimize the risk of the gastric retention system prematurely deploying (e.g., in the esophagus) and causing blockage. 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 deploying later in the gastrointestinal tract (i.e., intestines), or passing through the gastrointestinal tract without deploying at all. In each of these potential scenarios, the therapeutic agent in the gastroretentive dosage form is not delivered to the patient as intended.

[0051] However, it has been demonstrated that star-shaped gastroretentive systems can bend into a shape that allows them to pass through a patient's pylorus prematurely. A gastroretentive system that passes through the pylorus prematurely cannot deliver the therapeutic agent of the gastroretentive system to the patient. Furthermore, premature passage can lead to inconsistency, reduced reliability, and compromised efficacy of the gastroretentive system.

[0052] The characteristics of the circumferential filament are described in International Patent Application PCT / US2020 / 059541 (WO2021 / 092491), which is incorporated herein by reference in its entirety.

[0053] In some embodiments, the filaments are non-degradable. In some embodiments, the filaments comprise a thermoplastic polyurethane such as Pellethane 80A. In some embodiments, the filaments comprise methylene bis(4-phenylisocyanate), poly(tetramethylene oxide), and 1,4-butanediol. In some embodiments, the filaments are degradable. In some embodiments, the filaments comprise poly(lactic-co-glycolic acid). In some embodiments, the filaments comprise polyglycolic acid. In some embodiments, the filaments have a thickness of 0.05 mm, 0.1 mm, 0.15 mm, 0.20 mm, 0.25 mm, 0.30 mm, 0.35 mm, 0.40 mm, 0.45 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, or any one of thicknesses therebetween. In some embodiments, the filaments have a thickness of about 0.20 mm. In some embodiments, the filaments have a thickness of about 0.30 mm.

[0054] In some embodiments, each section of 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, e.g., about 100 to about 110 mm, e.g., about 105 mm.

[0055] Timed linker (timed disintegration matrix) and enteric linker (enteric disintegration matrix) polymer linker The drug-containing structural member is attached to a second structural member (such as a central member, which may be an elastic central member) via one or more linkers. The polymeric linker may interface directly with the drug-containing structural member or may interface with the drug-containing structural member via a linking member. Similarly, the polymeric linker may interface directly with the second structural member or may interface with the second structural member via a coupling 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 interface with each other directly or via a coupling 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.

[0056] The polymer linker typically has a width of about 100 microns to about 3 millimeters, for example, about 200 μm to about 3000 μm, about 300 μm to about 3000 μm, about 400 μm to about 3000 μm, about 500 μm to about 3000 μm, about 600 μm to about 3000 μm, about 700 μm to about 3000 μm, about 800 μm to about 3000 μm, about 900 μm to about 3000 μm, about 1000 μm to about 3000 μm, about 1100 μm to about 3000 μm, about 1200 μm to about 3000 μm, about 1300 μm to about 3000 μm, about 1400 μm to about 3 000 μm, about 1500 μm to about 3000 μm, about 1600 μm to about 3000 μm, about 1700 μm to about 3000 μm, about 1800 μm to about 3000 μm, about 1900 μm to about 3000 μm, about 2000 μm to about 3000 μm, about 2100 μm to about 3000 μm, about 2200 μm to about 3000 μm, about 2300 μm to about 3000 μm, about 2400 μm to about 3000 μm, about 2500 μm to about 3000 μm, about 2600 μm to about 3000 μm, about 2700 μm to about 3000 μm, about 2800 μm to about 3000 μm, or about 2900 μm to about 3000 μm; or about 100 μm to about 200 μm, about 200 μm to about 300 μm, about 300 μm to about 400 μm, about 400 μm to about 500 μm, about 500 μm to about 600 μm, about 600 μm to about 700 μm, about 700 μm to about 800 μm, about 800 μm to about 900 μm, about 900 μm to about 1000 μm, about 1000 μm to about 1100 μm, about 1100 μm to about 1200 μm, about 1200 μm to about 1300 μm, about 1300 μm to about 1400 μm, about 1400 μm to about 1500 μm, about 1500 μm to about 1600 μm, about 1600 μm to about 1700 μm, about 1700 μm to about 1800 μm, about 1800 μm to about 1900 μm, about 1900 μm to about 2000 μm, about 2000 μm to about 2100 μm, about 2100 μm to about 2200 μm, about 2200 μm to about 2300 μm, about 2300 μm to about 2400 μm, about 2400 μm to about 2500 μm, about 2500 μm to about 2600 μm, about 2600 μm to about 2700 μm, about 2700 μm to about 2800 μm, about 2800 μm to about 2900 μm, about 2900 μm to about 3000 μm.The polymer linker may be about 100 μm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1000 μm, about 1100 μm, about 1200 μm, about 1300 μm, about 1400 μm, about 1500 μm, about 1600 μm, about 1700 μm, or about 1800 μm. The ranges are approximately 1800 μm, approximately 1900 μm, approximately 2000 μm, approximately 2100 μm, approximately 2200 μm, approximately 2300 μm, approximately 2400 μm, approximately 2500 μm, approximately 2600 μm, approximately 2700 μm, approximately 2800 μm, approximately 2900 μm, and approximately 3000 μm, and each value is plus or minus 50 μm (±50 μm).

[0057] The cross-section of the polymeric linker can be circular (i.e., circular), oval, 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 attached to the polymeric linker. 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.

[0058] Time-dependent decay 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 placed in an individual's stomach. The time-dependent polymer linker controls the residence time of the gastroretentive system in the stomach. The time-dependent polymer linker is designed to gradually degrade, dissolve, mechanically weaken, or rupture over time. After the desired residence time has elapsed, the time-dependent polymer linker has degraded, dissolved, dissociated, mechanically weakened, or ruptured to an extent that the gastroretentive system can pass through the pyloric valve, exit the gastric environment, enter the small intestine, and ultimately be excreted from the body.

[0059] The time-dependent polymer linker is preferably composed of a pH-independent degradable polymer that degrades under aqueous conditions in a pH-independent or nearly pH-independent manner. Exemplary pH-independent degradable polymers include PLGA, PLA, PCL, polydioxanone, cellulose, or blends or copolymers thereof.

[0060] The time-dependent polymer linker can include polylactic acid-co-glycolide (PLGA).

[0061] In some embodiments, the PLGA of the time-dependent polymer linker comprises an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint between about 0.32 dl / g and about 0.48 dl / g (e.g., about 0.4 dl / g) (e.g., a PLGA sold under the trade name Purasorb® PDLG 5004A available from Corbion). In some embodiments, the PLGA of the time-dependent polymer linker comprises an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint between about 0.32 dl / g and about 0.48 dl / g (e.g., about 0.4 dl / g) (e.g., a PLGA sold under the trade name Purasorb® PDLG 5004A available from Corbion). In some embodiments, the PLGA of the time-dependent polymer linker comprises a mixture of (a) ester-terminated poly(D,L-lactic-co-glycolide) having a lactide monomer to glycolide monomer ratio of about 50:50 (such as PLGA sold by Corbion under the trade name Purasorb® PDLG 5004), and (b) acid-terminated poly(D,L-lactic-co-glycolide) having a lactide monomer to glycolide monomer ratio of about 50:50 (such as PLGA sold by Corbion under the trade name Purasorb® PDLG 5004A).

[0062] The one or more additional linker polymers included in the polymer linker are preferably homogeneously mixed with PLGA. In some embodiments, the one or more additional linker polymers are miscible with PLGA. The one or more additional linker polymers may be non-degradable polymers (i.e., not degradable in the stomach or intestinal environment, or in aqueous solutions at pH 1.6 (representing the stomach environment) or pH 6.5 (representing the intestinal environment)), and are optionally present in the time-dependent polymer linker in an amount such that the time-dependent polymer linker does not cleave during the gastric residence period.

[0063] Attachment of the polymer linker to directly adjacent members can be improved if at least one polymer is common to both the adjacent members and the time-dependent polymer linker. In some embodiments, the at least one common polymer is polycaprolactone (PCL).

[0064] In some embodiments, one or more additional linker polymers comprise PCL. The time-dependent polymer linker may be directly conjugated or bonded to another component of the gastroretentive system (e.g., a structural component comprising a drug and a carrier polymer, a coupling component, an enteric polymer linker, or a core structural component), which may also comprise PCL. This PCL may be the same as or different from the PCL in the time-dependent polymer linker, and may be at the same or different concentrations. The different PCL in the time-dependent polymer linker may differ from the other component directly conjugated or bonded to the time-dependent linker in, for example, the weight-average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when a blend of two or more PCL polymers is used). In some embodiments, the time-dependent disintegrating matrix comprises about 40 wt% to about 50 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 43 wt% to about 47 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 45 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 44.95 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 45 wt% to about 55 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 48 wt% to about 52 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 50 wt% PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 49.95 wt% PCL. In some embodiments, the PCL has a viscosity midpoint between about 1.5 dl / g and about 2.1 dl / g, e.g., about 1.7 dl / g, e.g., Corbion PC17. In some embodiments, the PCL has a viscosity midpoint between about 1.0 dl / g and about 1.4 dl / g, e.g., about 1.2 dl / g, e.g., Corbion PC12.

[0065] The time-dependent polymer linker may further comprise one or more plasticizers, such as polyethylene glycol. The term "polyethylene glycol" is used interchangeably herein with the terms "polyethylene oxide" and "PEO." In some embodiments, the molecular weight of the polyethylene glycol is about 90K to about 110K, for example, 100K (also referred to as 100K or 100kDa). In some embodiments, the time-dependent disintegrating matrix comprises polyethylene glycol with a molecular weight of about 100k (polyethylene glycol 100k). In some embodiments, the time-dependent disintegrating matrix comprises about 0.5 wt% to about 5 wt% polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 1 wt% to about 3 wt% polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 2 wt% polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 1.5 wt% to about 3.5 wt% polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 2.5 wt% polyethylene glycol 100k. Recall 100k is included. In some embodiments, the time-dependent disintegrating matrix includes a color-absorbing dye (also called a colorant or pigment). The color-absorbing dye may be included to enhance bonding or attachment between the polymer linker and other gastroretentive system components. The color-absorbing dye may 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 include the 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 includes from about 0.005 wt% to about 0.2 wt% of the color-absorbing dye. In some embodiments, the time-dependent disintegrating matrix includes from about 0.01 wt% to about 0.1 wt% of the color-absorbing dye.In some embodiments, the time-dependent disintegratable matrix comprises about 0.05 wt% of a color absorbing pigment, hi some embodiments, the color absorbing pigment is E172.

[0066] In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint, about 10 wt% to about 25 wt% of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 10 wt% to about 25 wt% of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 40 wt% to about 50 wt% PCL (e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 1.9 dL / g), about 30 wt% to about 40 wt% of about 0.4 dL / g, about 10 wt% to about 25 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 40 wt% to about 50 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 30 wt% to about 40 wt% of about 0.4 dL / g, about 10 wt% to about 25 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45 wt% to about 55 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 27 wt% to about 37 wt% of about 0.4 dL / g, about 12 wt% to about 22 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45 wt% to about 55 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 33 wt% to about 43 wt% of about 0.4 dL / g, about 5 wt% to about 15 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45 wt% to about 55 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 30 wt% to about 40 wt% of about 0.4 dL / g, about 8 wt% to about 18 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 45 wt% to about 55 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dl / g to about 1.4 dl / g), about 27 wt% to about 37 wt% of about 0.4 dl / g, about 12 wt% to about 22 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% of a color absorbing dye E172.

[0067] In another example of the time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 43 wt % to about 47 wt % PCL, about 33 wt % to about 37 wt % of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint, about 15 wt % to about 20 wt % of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt % to about 20 wt % of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt % to about 3 wt % of polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 43 wt% to about 47 wt% PCL (e.g., PCL having a mid-viscosity of about 1.5 dL / g to about 1.9 dL / g), about 33 wt% to about 37 wt% of about 0.4 dL / g, about 15 wt% to about 20 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt% to about 3 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 43 wt% to about 47 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 33 wt% to about 37 wt% of about 0.4 dL / g, about 15 wt% to about 20 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt% to about 3 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color absorbing dye E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48 wt% to about 52 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 30 wt% to about 34 wt% of about 0.4 dL / g, about 14 wt% to about 18 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt% to about 3 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48 wt% to about 52 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 36 wt% to about 40 wt% of about 0.4 dL / g, about 8 wt% to about 12 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt% to about 3 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48 wt% to about 52 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dL / g to about 1.4 dL / g), about 33 wt% to about 37 wt% of about 0.4 dL / g, about 11 wt% to about 15 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt% to about 3 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color absorbing dye E172. In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 48 wt% to about 52 wt% PCL (e.g., PCL having a mid-viscosity of about 1.0 dl / g to about 1.4 dl / g), about 30 wt% to about 34 wt% of about 0.4 dl / g, about 14 wt% to about 18 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 1.5 wt% to about 3.5 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color absorbing dye E172.

[0068] In another example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 44.95 wt% PCL, about 35 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint 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 comprises about 44.95 wt% PCL (e.g., a PCL having a viscosity midpoint of about 1.7 dL / g, such as Corbion PC 17), about 35 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint 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 is ​​about 44.95 wt% PCL (such as a PCL with a viscosity midpoint of about 1.2 dl / g, such as Corbion PC 12), about 35 wt% of about 0.4 dl / g, about 18 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) with a viscosity midpoint of about 0.4 dl / g, about 2 wt% polyethylene glycol 100k, and about 0.05 wt% of a color absorbing dye, E172.In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix includes about 49.95 wt % PCL (such as a PCL having a viscosity midpoint of about 1.2 dl / g, such as Corbion PC 12), about 32 wt % of a PCL having a viscosity midpoint of about 0.4 dl / g, about 16 wt % of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint 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 (such as a PCL having a viscosity midpoint of about 1.2 dl / g, such as Corbion PC 12), about 38 wt % of a viscosity midpoint of about 0.4 dl / g, about 10 wt % of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint 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 comprises about 49.95 wt% PCL (such as a PCL having a viscosity midpoint of about 1.2 dL / g, such as Corbion PC 12), about 35 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 13 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 13 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint 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 is ​​about 49.95 wt% PCL (such as a PCL with a viscosity midpoint of about 1.2 dl / g, such as Corbion PC 12), about 31.75 wt% PCL with a viscosity midpoint of about 0.4 dl / g, about 15.75 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) with a viscosity midpoint of about 0.4 dl / g, about 2.5 wt% polyethylene glycol 100k, and about 0.05 wt% color absorbing dye E172.

[0069] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 44.95 wt% polycaprolactone (PCL), e.g., a PCL having a medium 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 time-dependent disintegrating matrix comprising about 35.0 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 wt% of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 a time-dependent disintegrating matrix comprising about 2.0 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide, e.g., E172. In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 44.95 wt% Corbion PC17, about 35.0 wt% PDLG 5004A, about 18.0 wt% PDLG 5004, about 2.0 wt% PEO100K, and about 0.05 wt% E172.

[0070] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 44.95 wt% polycaprolactone (PCL), e.g., PCL having a medium viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, such as Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 35.0 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 wt% of an ester copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 a time-dependent disintegrating matrix comprising about 2.0 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide, e.g., E172. In some embodiments, a dosage form for administering one or more drugs includes a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 44.95 wt% Corbion PC12, about 35.0 wt% PDLG 5004A, about 18.0 wt% PDLG 5004, about 2.0 wt% PEO100K, and about 0.05 wt% E172.

[0071] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95 wt% polycaprolactone (PCL), such as Corbion PC12, having a medium viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 32.0 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 16.0 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 a time-dependent disintegrating matrix comprising about 2.0 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide, e.g., E172. In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95 wt% Corbion PC12, about 32.0 wt% PDLG 5004A, about 16.0 wt% PDLG 5004, about 2.0 wt% PEO100K, and about 0.05 wt% E172.

[0072] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95 wt% polycaprolactone (PCL), such as Corbion PC12, having a medium viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 38.0 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 10.0 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 a time-dependent disintegrating matrix comprising about 2.0 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide, e.g., E172. In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95 wt% Corbion PC12, about 38.0 wt% PDLG 5004A, about 10.0 wt% PDLG 5004, about 2.0 wt% PEO100K, and about 0.05 wt% E172.

[0073] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95 wt% polycaprolactone (PCL), e.g., PCL having a medium viscosity of about 1.0 dl / g to about 1.4 dl / g, e.g., 1.2 dl / g, such as Corbion PC12. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 35.0 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 13.0 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 a time-dependent disintegrating matrix comprising about 2.0 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide, e.g., E172. In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95 wt% Corbion PC12, about 35.0 wt% PDLG 5004A, about 13.0 wt% PDLG 5004, about 2.0 wt% PEO100K, and about 0.05 wt% E172.

[0074] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 49.95 wt% polycaprolactone (PCL), e.g., a PCL having a mid-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 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a mid-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 15.75 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 a time-dependent disintegrating matrix comprising about 2.5 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide, such as E172. In some embodiments, a dosage form for administering one or more pharmaceutical agents comprises a gastroretentive system, the gastroretentive system comprising a time-dependent disintegrating matrix comprising about 49.95 wt% Corbion PC12, about 31.75 wt% PDLG 5004A, about 15.75 wt% PDLG 5004, about 2.5 wt% PEO100K, and about 0.05 wt% E172.

[0075] Exemplary amounts of the components of the time-dependent disintegrating matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0076] [Table 2]

[0077] Exemplary amounts of the components of the time-dependent disintegrating matrix are set forth in the table below. It should be understood that amounts are given as approximate weight percent and that when ranges are provided, the amounts are selected to add up to 100%.

[0078] [Table 3]

[0079] Exemplary amounts of the components of the time-dependent disintegrating matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0080] [Table 4]

[0081] Exemplary amounts of the components of the time-dependent disintegrating matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0082] [Table 5]

[0083] Exemplary amounts of ingredients for the time-dependent disintegrating matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0084] [Table 6]

[0085] Exemplary amounts of the components of the time-dependent disintegrating matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0086] [Table 7]

[0087] Exemplary amounts of ingredients for the time-dependent disintegrating matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0088] [Table 8]

[0089] Gastric residence time The gastric retention time of the system is controlled by the degradation, weakening, or cleavage rate of the time-dependent polymer linker in the gastroretentive system. Faster degradation, weakening, or cleavage of the time-dependent polymer linker results in faster passage of the system from the stomach. The retention time of a gastroretentive system is defined as the time between administration of the system to the stomach and emptying of the system from the stomach. In one embodiment, the gastroretentive system has a retention time of about 24 hours, or up to about 24 hours. In one embodiment, the gastroretentive system has a retention time of about 48 hours, or up to about 48 hours. In one embodiment, the gastroretentive system has a retention time of about 72 hours, or up to about 72 hours. In one embodiment, the gastroretentive system has a retention time of about 96 hours, or up to about 96 hours. In one embodiment, the gastroretentive system has a retention time of about 5 days, or up to about 5 days. In one embodiment, the gastroretentive system has a retention time of about 6 days, or up to about 6 days. In one embodiment, the gastroretentive 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 gastroretentive system has a retention time of about 10 days, or up to about 10 days. In one embodiment, the gastroretentive system has a retention time of about 14 days (about 2 weeks), or up to about 14 days (about 2 weeks).

[0090] In one embodiment, the gastroretentive system has a retention time of between about 24 hours and about 7 days. In one embodiment, the gastroretentive system has a retention time of between about 48 hours and about 7 days. In one embodiment, the gastroretentive system has a retention time of between about 72 hours and about 7 days. In one embodiment, the gastroretentive system has a retention time of between about 96 hours and about 7 days. In one embodiment, the gastroretentive system has a retention time of between about 5 days and about 7 days. In one embodiment, the gastroretentive system has a retention time of between about 6 days and about 7 days.

[0091] In one embodiment, the gastroretentive system has a retention time of between about 24 hours and about 10 days. In one embodiment, the gastroretentive system has a retention time of between about 48 hours and about 10 days. In one embodiment, the gastroretentive system has a retention time of between about 72 hours and about 10 days. In one embodiment, the gastroretentive system has a retention time of between about 96 hours and about 10 days. In one embodiment, the gastroretentive system has a retention time of between about 5 days and about 10 days. In one embodiment, the gastroretentive system has a retention time of between about 6 days and about 10 days. In one embodiment, the gastroretentive system has a retention time of between about 7 days and about 10 days.

[0092] In one embodiment, the gastroretentive system has a retention time of about 24 hours to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 48 hours to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 72 hours to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 96 hours to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 5 days to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 6 days to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 7 days to about 14 days. In one embodiment, the gastroretentive system has a retention time of about 10 days to about 14 days.

[0093] The gastroretentive system releases a therapeutically effective amount of the drug (or salt thereof) for at least a portion of the residence time or duration that the system resides in the stomach. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 25% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 50% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 60% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 70% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 75% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 80% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for 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.

[0094] Enteric matrix (enteric linker) The pH-dependent disintegrating matrix provides a safety mechanism for the gastroretentive system. If the gastroretentive system exits the stomach prematurely, i.e., if the time-dependent disintegrating matrix exits the stomach entirely intact, the pH-dependent disintegrating matrix will degrade, dissolve, dissociate, or become mechanically weakened in the high pH environment of the small intestine, allowing the gastroretentive system to pass easily through the small intestine. Furthermore, if the time-dependent disintegrating matrix degrades, dissolves, dissociates, or becomes mechanically weakened in the stomach environment, exposure of the pH-dependent disintegrating matrix to the high pH of the small intestine after the gastroretentive system has passed will result in further weakening and / or degradation of the system in order to allow easy passage through the small intestine.

[0095] To avoid intestinal obstruction if a gastroretentive system passes intact into the small intestine prematurely, it can be designed to degrade more rapidly. This is easily achieved by using an enteric polymer linker that includes an enteric polymer in addition to an additional linker polymer (e.g., a carrier polymer) that weakens or degrades in the intestinal environment. Enteric polymers are relatively resistant to the acidic pH levels encountered in the stomach but rapidly dissolve at the high pH levels found in the duodenum. Using an enteric polymer linker as a safety element can prevent undesired passage of the gastroretentive system into the small intestine. The use of an enteric polymer linker also provides a method for removing the gastroretentive system before its designed residence time. If removal of the gastroretentive system is necessary, 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 will increase the pH level in the stomach and cause rapid degradation of the enteric polymer linker.

[0096] The weakening or degradation of an enteric polymeric linker can be measured based on the loss or failure of the polymeric linker's flexural modulus under given conditions (e.g., enteric or gastric conditions). Enteric linkers weaken, degrade, or break down relatively quickly in the intestinal environment, but retain much of their flexural modulus in the gastric environment. Gastric conditions can be simulated using an aqueous solution such as fasted-state simulated gastric fluid (FaSSGF) at pH 1.6 and 37°C, and intestinal conditions can be simulated using an aqueous solution such as fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5 and 37°C.

[0097] 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 wt% to about 70 wt% HPMCAS. In some embodiments, the enteric disintegrating matrix comprises about 62 wt% to about 66 wt% HPMCAS. In some embodiments, the enteric disintegrating matrix comprises about 63.95 wt% HPMCAS.

[0098] The enteric polymer is combined with one or more additional polymers (such as one or more carrier polymers) in the enteric linker, preferably in a homogeneous mixture. For example, the enteric polymer and the additional linker polymers can be homogeneously blended together before the mixture is extruded and the extruded material is cut to 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., they do not degrade 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)).

[0099] Attachment of the polymer linker to the immediately adjacent member can 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 of the same polymer type) as at least one polymer in the immediately adjacent member (or, optionally, both immediately adjacent members) of the gastroretentive system. For example, when the enteric polymer linker is directly attached to a structural member comprising a carrier polymer, in some embodiments, the one or more additional linker polymers also comprise a carrier polymer (in addition to PLGA in the time-dependent polymer linker) at the same or different concentrations. Exemplary carrier polymers include, but are not limited to, polylactic acid (PLA), polycaprolactone (PCL), and thermoplastic polyurethane (TPU), among others described herein.

[0100] In some embodiments, one or more additional linker polymers in the enteric linker comprise PCL. The enteric polymer linker may be directly conjugated or bonded to another component of the gastroretentive system (e.g., a structural component comprising a drug and a carrier polymer, a coupling component, a time-dependent polymer linker, or a core structural component), and this component may also comprise PCL. This PCL may be the same as or different from the PCL in the enteric polymer linker, and may be at the same or different concentrations. The different PCL in the enteric polymer linker may differ from the other component directly conjugated or bonded to the enteric linker in, for example, the weight-average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when a blend of two or more PCL polymers is used). In some embodiments, the enterically disintegrating matrix comprises about 30 wt% to about 40 wt% PCL. In some embodiments, the enterically disintegrating matrix comprises about 32 wt% to about 37 wt% PCL. In some embodiments, the enteroerodible matrix comprises about 34 wt% PCL, hi some embodiments, the enteroerodible matrix comprises about 33.95 wt% PCL.

[0101] The enteric disintegrating matrix may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the enteric disintegrating matrix comprises about 0.5 wt% to about 5 wt% poloxamer. In some embodiments, the enteric disintegrating matrix comprises about 1 wt% to about 3 wt% poloxamer. In some embodiments, the enteric disintegrating matrix comprises about 2 wt% poloxamer.

[0102] In some embodiments, the enteric disintegrating matrix includes a color-absorbing dye (also called a colorant or pigment). The color-absorbing dye may be included to enhance bonding or adhesion between the polymer linker and other gastroretentive system components. The color-absorbing dye may absorb heat during laser welding, infrared welding, or other heat-induced bonding, thereby increasing the tensile strength of the resulting bond. Exemplary color-absorbing dyes include iron oxide and carbon black. The enteric polymer linker may include the 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%, or up to about 0.1%. In some embodiments, the enteric disintegrating matrix includes about 0.01 wt% to about 0.2 wt% of the color-absorbing dye E172. In some embodiments, the enteric disintegrating matrix includes about 0.05 wt% to about 0.15 wt% of the color-absorbing dye E172. In some embodiments, the enteric disintegrable matrix comprises about 0.1 wt% of color absorbing dye E172.

[0103] In some embodiments, the enteroerodible matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (such as P407). Optionally, the enteroerodible matrix further comprises an iron oxide, for example, about 0.01 wt% to about 0.2 wt% iron oxide (such as E172).

[0104] In some embodiments, the enteroerodible matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (such as P407). Optionally, the enteroerodible matrix further comprises an iron oxide, for example, about 0.05 wt% to about 0.15 wt% iron oxide (such as E172).

[0105] In some embodiments, the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (such as P407). Optionally, the enteroerodible matrix further comprises an iron oxide, for example, about 0.1 wt% iron oxide (such as E172).

[0106] In some embodiments, the enteroerodible matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (such as P407).

[0107] In some embodiments, the enteroerodible matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (such as P407).

[0108] In some embodiments, the enteroerodible matrix comprises about 64 wt% HPMCAS, about 34 wt% PCL, and about 2 wt% poloxamer (such as P407).

[0109] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising about 33.95 wt% polycaprolactone (PCL), e.g., a PCL having a medium viscosity of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbion PC 17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegrating matrix, such as HPMCAS-MG, comprising about 63.95 wt% hypromellose acetate succinate. In some embodiments, the gastroretentive system is about 2.0 wt% 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, e.g., Poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer having a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 0.1 wt% iron oxide, e.g., E172. In some embodiments, a dosage form for administering one or more agents comprises the gastroretentive system, and the gastroretentive system comprises about 33.95 wt% Corbion It comprises a pH-dependent disintegrating matrix comprising PC17, about 63.95 wt% HPMCAS-MG, about 2.0 wt% P407, and about 0.1 wt% E172.

[0110] Exemplary amounts of the components of the enteroerodible matrix are set forth in the table below. The amounts are given as approximate weight percentages, but it should be understood that where ranges are provided, the amounts are selected to add up to 100%.

[0111] [Table 9]

[0112] In some embodiments, a dosage form for administering one or more agents comprises a gastroretentive system, the gastroretentive system comprising a pH-dependent disintegrating matrix comprising about 34 wt% polycaprolactone (PCL), such as PCL with a medium 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 disintegrating matrix comprising about 64 wt% hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system is about 2.0 wt% poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H-(OCHCH)-(O-CH(CH)CH)-(OCHCH)-OH, where x and z are about 101 and y is about 56, e.g., poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer having a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%). In some embodiments, a dosage form for administering one or more agents comprises the gastroretentive system, wherein the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 34 wt% Corbion PC17, about 64 wt% HPMCAS-MG, and about 2.0 wt% P407.

[0113] Exemplary amounts of the components of the enteroerodible matrix are set forth in the table below. The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0114] [Table 10]

[0115] Collapsing Filament In some embodiments, the gastric retention system comprises arms connected by one or more filaments. In some embodiments, the filaments are disintegrating filaments. In some embodiments, the gastric retention system comprises arms connected at their 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 0.05 mm, 0.1 mm, 0.15 mm, 0.20 mm, 0.25 mm, 0.30 mm, 0.35 mm, 0.40 mm, 0.45 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, or any one of thicknesses 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 Bondek Suture 2-0. In some embodiments, the filament is Bondek Suture 3-0.

[0116] Further disintegrating matrix as arm tips In some embodiments, the gastroretentive system comprises an arm that includes a third disintegrating matrix in addition to the time-dependent disintegrating matrix and the enteric-disintegrating matrix. In some embodiments, the third disintegrating matrix is ​​the filament-retaining segment (i.e., the segment to which the filament is attached). In some embodiments, the third disintegrating matrix is ​​the distal segment of the retention system arm, i.e., the tip of the arm. In some embodiments, the third disintegrating matrix is ​​referred to as outer disintegrating matrix tip enteric-coated PCL (ODMTEP).

[0117] In some embodiments, the third disintegrable matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, in some embodiments, the third disintegrable matrix comprises about 60 wt% to about 70 wt% HPMCAS. In some embodiments, the third disintegrable matrix comprises about 63 wt% to about 67 wt% HPMCAS. In some embodiments, the third disintegrable matrix comprises about 64.9 wt% HPMCAS.

[0118] In some embodiments, the third disintegrating matrix comprises a polymer common to one or more segments in the gastroretention system arms. In some embodiments, the third disintegrating matrix comprises polycaprolactone (PCL). In some embodiments, the third disintegrating matrix comprises about 25 wt% to about 35 wt% PCL. In some embodiments, the third disintegrating matrix comprises about 28 wt% to about 32 wt% PCL. In some embodiments, the third disintegrating matrix comprises about 30 wt% PCL.

[0119] 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 wt% to about 5 wt% stearic acid. In some embodiments, the third disintegrating matrix comprises about 2 wt% to about 3 wt% stearic acid. In some embodiments, the third disintegrating matrix comprises about 2.5 wt% stearic acid.

[0120] 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 wt% to about 5 wt% propylene glycol. In some embodiments, the third disintegrable matrix comprises about 2 wt% to about 3 wt% propylene glycol. In some embodiments, the third disintegrable matrix comprises about 2.5 wt% propylene glycol.

[0121] 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 bonding or adhesion between the polymer linker and other gastroretentive system components. The color-absorbing dye may 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 the 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%, or up to about 0.1%. In some embodiments, the third disintegrable matrix includes about 0.01 wt% to about 0.5 wt% of the color-absorbing dye. In some embodiments, the third disintegrable matrix includes about 0.05 wt% to about 0.15 wt% of the color-absorbing dye. In some embodiments, the third disintegrable matrix comprises about 0.1 wt% color absorbing pigment. In some embodiments, the third disintegrable matrix comprises about 0.025% ferric oxide and about 0.075% FD&C Red 40. In some embodiments, the third disintegrable matrix comprises about 0.025% ferric oxide and about 0.075% FD&C Red 40.

[0122] In some embodiments, the third disintegrable matrix comprises about 60 wt% to about 70 wt% HPMCAS, about 25 wt% to about 35 wt% PCL, about 1 wt% to about 5 wt% propylene glycol, and about 1 wt% to about 5 wt% stearic acid. Optionally, the third disintegrable matrix further comprises about 0.01 wt% to about 0.5 wt% iron oxide.

[0123] In some embodiments, the third disintegrable matrix comprises about 63 wt% to about 67 wt% HPMCAS, about 28 wt% to about 32 wt% PCL, about 2 wt% to about 3 wt% propylene glycol, and about 2 wt% to about 3 wt% stearic acid. Optionally, the third disintegrable matrix further comprises about 0.05 wt% to about 0.15 wt% iron oxide.

[0124] In some embodiments, the third disintegrable matrix comprises 64.9 wt% HPMCAS, about 30 wt% PCL, about 2.5 wt% propylene glycol, and about 2.5 wt% stearic acid. Optionally, the third disintegrable matrix further comprises about 0.1 wt% iron oxide, e.g., about 0.025% ferric oxide, and about 0.075% FD&C Red 40.

[0125] Exemplary amounts of the components of the third disintegrative matrix are set forth in the table below. Amounts are given in approximate weight percent with the understanding that when ranges are provided, the amounts are selected to add up to 100%.

[0126] [Table 11]

[0127] 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.

[0128] In some embodiments, the inactive segment comprises a polymer common to other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 61 wt% to about 71 wt% PCL. In some embodiments, the inactive segment comprises about 64 wt% to about 69 wt% PCL. In some embodiments, the inactive segment comprises about 66.5 wt% PCL. In some embodiments, the inactive segment comprises about 66.45 wt% PCL.

[0129] In some embodiments, the inactive segment comprises a 6:4 weight ratio of vinylpyrrolidone-vinyl acetate copolymer (i.e., copovidone, such as Kollidon VA64). In some embodiments, the inactive segment comprises about 27 wt% to about 37 wt% copovidone. In some embodiments, the inactive segment comprises about 30 wt% to about 34 wt% copovidone. In some embodiments, the inactive segment comprises about 32 wt% copovidone.

[0130] The inactive segment may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the inactive segment comprises from about 0.2 wt% to about 4 wt% poloxamer. In some embodiments, the inactive segment comprises from about 0.5 wt% to about 2.5 wt% poloxamer. In some embodiments, the inactive segment comprises about 1.5 wt% poloxamer.

[0131] In some embodiments, the inactive segments comprise a color absorbing dye (also referred to as a colorant or pigment). The inactive segments 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 inactive segments comprise from about 0.005 wt% to about 0.2 wt% of the color absorbing dye. In some embodiments, the inactive segments comprise from about 0.01 wt% to about 0.1 wt% of the color absorbing pigment. In some embodiments, the inactive segments comprise about 0.05 wt% of the color absorbing dye. In some embodiments, the color absorbing dye is FD&C Blue #1.

[0132] In some embodiments, the inactive segment comprises about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, and about 0.2 wt% to about 4 wt% poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.005 wt% to about 0.2 wt% of the color absorbing dye FD&C Blue #1.

[0133] In some embodiments, the inactive segment comprises about 64% to about 69% by weight of PCL, about 30% to about 34% by weight of copovidone, and about 0.5% to about 2.5% by weight of 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.

[0134] In some embodiments, the inactive segment comprises about 66.45 wt% PCL, about 32 wt% copovidone, and about 1.5 wt% poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.05 wt% of the color absorbing dye FD&C Blue #1.

[0135] Exemplary amounts of components of one embodiment of the inert segment (e.g., inert spacer) are set forth in the table below. The amounts are given as approximate weight percent, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0136] [Table 12]

[0137] In some embodiments, the inactive segment comprises a polymer common to other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 35 wt% to about 45 wt% PCL. In some embodiments, the inactive segment comprises about 38 wt% to about 42 wt% PCL. In some embodiments, the inactive segment comprises about 40 wt% PCL. In some embodiments, the inactive segment comprises about 33.995 wt% PCL.

[0138] In some embodiments, the inactive segment comprises a 6:4 weight ratio of vinylpyrrolidone-vinyl acetate copolymer (i.e., copovidone, such as Kollidon VA64). In some embodiments, the inactive segment comprises about 37 wt% to about 47 wt% copovidone. In some embodiments, the inactive segment comprises about 40 wt% to about 44 wt% copovidone. In some embodiments, the inactive segment comprises about 42 wt% copovidone.

[0139] The inactive segment may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the inactive segment comprises about 1 wt% to about 5 wt% poloxamer. In some embodiments, the inactive segment comprises about 2 wt% to about 4 wt% poloxamer. In some embodiments, the inactive segment comprises about 3 wt% poloxamer.

[0140] The inert segment may comprise one or more plasticizers, such as polyethylene glycol. The term "polyethylene glycol" is used interchangeably herein with the terms "polyethylene oxide" and "PEO." In some embodiments, the molecular weight of the polyethylene glycol is about 90K to about 110K, e.g., 100K (also referred to as 100K or 100kDa). In some embodiments, the inert segment comprises polyethylene glycol with a molecular weight of about 100k (polyethylene glycol 100k). In some embodiments, the inert segment comprises about 10 wt% to about 20 wt% polyethylene glycol 100k. In some embodiments, the inert segment comprises about 13 wt% to about 17 wt% polyethylene glycol 100k. In some embodiments, the inert segment comprises about 15 wt% polyethylene glycol 100k.

[0141] In some embodiments, the inactive segments comprise a color absorbing dye (also referred to as a colorant or pigment). In some embodiments, the inactive segments may comprise a color absorbing dye in an amount of up to about 1%, e.g., 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 about 0.005%. In some embodiments, the inactive segments comprise from about 0.0005 wt% to about 0.2 wt% of the color absorbing dye. In some embodiments, the inactive segments comprise from about 0.001 wt% to about 0.01 wt% of the color absorbing pigment. In some embodiments, the inactive segments comprise about 0.005 wt% of the color absorbing pigment. In some embodiments, the color absorbing dye is iron oxide (e.g., E172).

[0142] In some embodiments, the inert segment comprises about 35% to about 45% by weight of PCL, about 37% to about 47% by weight of copovidone, about 10% to about 20% by weight of polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000, e.g., PEO100K, and about 1% to about 5% by weight of poloxamer. Optionally, the inert segment further comprises a color absorbing dye, e.g., about 0.0005% to about 0.02% by weight of the color absorbing dye E172.

[0143] In some embodiments, the inert segment comprises about 38% to about 42% by weight of PCL, about 40% to about 44% by weight of copovidone, about 13% to about 17% by weight of polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000 such as PEO100K, and about 2% to about 4% by weight of poloxamer. Optionally, the inert segment further comprises a color absorbing dye, e.g., about 0.001% to about 0.01% by weight of the color absorbing dye E172.

[0144] In some embodiments, the inactive segment comprises about 39.995 wt% PCL, about 42 wt% copovidone, about 15 wt% PEO100K, and about 3 wt% poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.005 wt% color absorbing dye E172.

[0145] Exemplary amounts of ingredients for one embodiment of an inert segment (e.g., an inert spacer) are shown in the table below. The amounts are given as approximate weight percent, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0146] [Table 13]

[0147] In some embodiments, the gastroretention system comprises one or more inactive segments, wherein the inactive segments comprise one or more radiopaque materials. In some embodiments, the gastroretention system comprises an inactive segment, wherein the inactive segment is a radiopaque segment.

[0148] In some embodiments, the inactive segment comprises a polymer common to other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 65 wt% to about 75 wt% PCL. In some embodiments, the inactive segment comprises about 68 wt% to about 72 wt% PCL. In some embodiments, the inactive segment comprises about 70 wt% PCL.

[0149] In some embodiments, the inactive segments comprise a radiopaque material. In some embodiments, the inactive segments consist of a radiopaque material, and the radiopaque material is (BiO)2CO3. In some embodiments, the inactive segments comprise (BiO)2CO3. In some embodiments, the inactive segments comprise about 25 wt% to about 35 wt% (BiO)2CO3. In some embodiments, the inactive segments comprise about 28 wt% to about 32 wt% (BiO)2CO3. In some embodiments, the inactive segments comprise about 30 wt% (BiO)2CO3.

[0150] In some embodiments, the inactive segments comprise about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3. In some embodiments, the inactive segments comprise about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3. In some embodiments, the inactive segments comprise about 70 wt% PCL and about 30 wt% (BiO)2CO3.

[0151] Exemplary amounts of ingredients for one embodiment of an inactive segment (e.g., an rPCL segment) are shown in the table below. The amounts are given as approximate weight percent, but it should be understood that when a range is provided, the amounts are selected to add up to 100%.

[0152] [Table 14]

[0153] Carrier polymers - Drug segment (drug-eluting segment) The carrier polymer-drug segment (drug-eluting segment) releases the drug in a controlled manner during the gastroretentive system's residence in the stomach. The carrier polymer is blended with the drug, formed into a segment, and then combined with other components described herein to produce the gastroretentive system. The composition of such carrier polymer-drug blends is shown below for specific drug formulations containing risperidone.

[0154] In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 10 mg to about 35 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 10 mg to about 20 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 14 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 20 mg to about 35 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system, and the gastroretentive system comprises about 28 mg of risperidone.

[0155] In some embodiments, the dosage form comprises a gastroretentive system, the gastroretentive system comprising a drug-eluting segment comprising about 14 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system, the gastroretentive system comprising a drug-eluting segment comprising about 28 mg of risperidone. In some embodiments, the drug-eluting segment comprises about 30 wt% to about 40 wt% risperidone, and the drug-eluting segment comprises about 51 wt% to about 61 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the drug-eluting segment comprises about 2 wt% to about 8 wt% vinylpyrrolidone-vinyl acetate copolymer, e.g., Kollidon VA64. In some embodiments, the drug eluting segment comprises about 1 wt % to about 5 wt % 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. In some embodiments, the drug eluting segment comprises about 0.1 wt % to about 1 wt % vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.1 wt % to about 1 wt % colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.01 wt % to about 0.5 wt % pigment.

[0156] In some embodiments, the drug eluting segment comprises about 33 wt% to about 37 wt% risperidone, and the drug eluting segment comprises about 54 wt% to about 58 wt% polycaprolactone (PCL), e.g., 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 wt% to about 6 wt% vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 2 wt% to about 4 wt% 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. In some embodiments, the drug eluting segment comprises about 0.2 wt% to about 0.8 wt% vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.2 wt% to about 0.8 wt% colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.05 wt% to about 0.2 wt% pigment.

[0157] In some embodiments, the drug eluting segment comprises about 35 wt% risperidone, and the drug eluting segment comprises about 55.9 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 5.0 wt% vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 3.0 wt% 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. In some embodiments, the drug eluting segment comprises about 0.5 wt% vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.5 wt% colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.1 wt% pigment.

[0158] 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, e.g., FD&C Yellow 5 Aluminum Lake, in an amount of about 0.05 wt% based on the total weight of the drug-eluting segment, such as benzenemethanaminium, N-ethyl-N-(4-(ethyl((3-sulfophenyl)methyl)amino)phenyl)(2-sulfophenyl)methylene)-2,5-cyclohexadiene, e.g., FD&C Blue 1 Aluminum Lake. 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 wt%. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13% by weight.

[0159] In some embodiments, the drug-eluting segment comprises about 30 wt% to about 40 wt% risperidone, about 51 wt% to about 61 wt% PCL, about 2 wt% to about 8 wt% VA64, about 1 wt% to about 5 wt% P407, about 0.1 wt% to about 1 wt% vitamin E succinate, about 0.1 wt% to about 1 wt% SiO2, and about 0.01 wt% to about 0.5 wt% pigment.

[0160] In some embodiments, the drug-eluting segment comprises about 33 wt% to about 37 wt% risperidone, about 54 wt% to about 58 wt% PCL, about 4 wt% to about 6 wt% VA64, about 2 wt% to about 4 wt% P407, about 0.2 wt% to about 0.8 wt% vitamin E succinate, about 0.2 wt% to about 0.8 wt% SiO2, and about 0.05 wt% to about 0.15 wt% pigment.

[0161] In some embodiments, the drug-eluting segment comprises about 35.0 wt% risperidone, 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. In some embodiments, the pigment comprises FD&C Yellow 5 Aluminum Lake in an amount of about 0.05 wt% based on the total weight of the drug-eluting segment and FD&C Blue 1 Aluminum Lake in an amount of 0.05 wt% based on 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 wt%. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13 wt%. Exemplary amounts of components for one embodiment of the carrier polymer-arm segment (drug-eluting segment) are shown in the table below. Amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt thereof.

[0162] [Table 15]

[0163] Although the drug-eluting segments above are described as risperidone formulations, they are not so limited and may be used in combination with other drugs by replacing some or all of the risperidone component and / or other components with the other drugs.

[0164] In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 12 mg to about 60 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 12 mg to about 36 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 12 mg to about 20 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 16 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 28 mg to about 36 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system, and the gastroretentive system comprises about 32 mg of risperidone. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system comprising about 44 mg to about 52 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system, and the gastroretentive system comprises about 48 mg of risperidone.

[0165] In some embodiments, the dosage form comprises a gastroretentive system, the gastroretentive system comprising a drug-eluting segment comprising about 16 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system, the gastroretentive system comprising a drug-eluting segment comprising about 32 mg of risperidone. In some embodiments, the drug-eluting segment comprises about 30 wt% to about 40 wt% risperidone, and the drug-eluting segment comprises about 51 wt% to about 61 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the drug-eluting segment comprises about 2 wt% to about 8 wt% vinylpyrrolidone-vinyl acetate copolymer, e.g., Kollidon VA64. In some embodiments, the drug eluting segment comprises about 1 wt % to about 5 wt % 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. In some embodiments, the drug eluting segment comprises about 0.1 wt % to about 1 wt % vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.1 wt % to about 1 wt % colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.01 wt % to about 0.5 wt % pigment.

[0166] In some embodiments, the drug eluting segment comprises about 33 wt% to about 37 wt% risperidone, and the drug eluting segment comprises about 54 wt% to about 58 wt% polycaprolactone (PCL), e.g., 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 wt% to about 6 wt% vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 2 wt% to about 4 wt% 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. In some embodiments, the drug eluting segment comprises about 0.2 wt% to about 0.8 wt% vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.2 wt% to about 0.8 wt% colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.05 wt% to about 0.2 wt% pigment.

[0167] In some embodiments, the drug eluting segment comprises about 35 wt% risperidone, and the drug eluting segment comprises about 55.9 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the drug eluting segment comprises about 5.0 wt% vinylpyrrolidone-vinyl acetate copolymer, such as Kollidon VA64. In some embodiments, the drug eluting segment comprises about 3.0 wt% 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. In some embodiments, the drug eluting segment comprises about 0.5 wt% vitamin E succinate. In some embodiments, the drug eluting segment comprises about 0.5 wt% colloidal silicon dioxide (SiO2). In some embodiments, the drug eluting segment comprises about 0.1 wt% pigment.

[0168] 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, e.g., FD&C Yellow 5 Aluminum Lake, in an amount of about 0.05 wt % based on the total weight of the drug-eluting segment, and benzenemethanaminium, N-ethyl-N-(4-(ethyl((3-sulfophenyl)methyl)amino)phenyl)(2-sulfophenyl)methylene)-2,5-cyclohexadiene, e.g., FD&C Blue 1 Aluminum Lake, in an amount of 0.05 wt % based on 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 wt %. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13% by weight.

[0169] In some embodiments, the drug-eluting segment comprises about 30 wt% to about 40 wt% risperidone, about 51 wt% to about 61 wt% PCL, about 2 wt% to about 8 wt% VA64, about 1 wt% to about 5 wt% P407, about 0.1 wt% to about 1 wt% vitamin E succinate, about 0.1 wt% to about 1 wt% SiO2, and about 0.01 wt% to about 0.5 wt% pigment.

[0170] In some embodiments, the drug-eluting segment comprises about 33 wt% to about 37 wt% risperidone, about 54 wt% to about 58 wt% PCL, about 4 wt% to about 6 wt% VA64, about 2 wt% to about 4 wt% P407, about 0.2 wt% to about 0.8 wt% vitamin E succinate, about 0.2 wt% to about 0.8 wt% SiO2, and about 0.05 wt% to about 0.15 wt% pigment.

[0171] In some embodiments, the drug-eluting segment comprises about 35.0 wt% risperidone, 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. In some embodiments, the pigment comprises FD&C Yellow 5 Aluminum Lake in an amount of about 0.05 wt% based on the total weight of the drug-eluting segment and FD&C Blue 1 Aluminum Lake in an amount of 0.05 wt% based on 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 wt%. In some embodiments, the amount of dye in FD&C Blue 1 Aluminum Lake is about 11-13 wt%.

[0172] Exemplary amounts of components for one embodiment of the carrier polymer-arm segment (drug-eluting segment) are shown in the table below. Amounts are given as approximate weight percent, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt thereof.

[0173] [Table 16]

[0174] Although the drug-eluting segments above are described as risperidone formulations, they are not so limited and may be used in combination with other drugs by replacing some or all of the risperidone component and / or other components with the other drugs.

[0175] In some embodiments, a star-shaped dosage form for administering risperidone can comprise arms, which comprise, in order, 1) a carrier polymer-drug arm segment; 2) an inert arm segment; 3) one or more enteric linkers; 4) one or more time-dependent linkers; 5) a release rate-modifying film; and / or 6) other optional spacers. The arms are connected to the elastomeric core in a stearate arrangement. Typically, six arms are used for stearate dosage forms. In some embodiments where six arms are used for a stearate dosage form, any one of 1, 2, 3, 4, 5, or 6 arms constitutes a carrier polymer-drug arm segment. In some embodiments where six arms are used for a stearate dosage form, three arms constitute a carrier polymer-drug arm segment. In some embodiments where six arms are used for a star-shaped dosage form, six arms constitute a carrier polymer-drug arm segment.

[0176] The carrier polymer-drug arm segment of the risperidone dosage form can comprise risperidone (or a pharmaceutically acceptable salt thereof), polycaprolactone, copovidone (VA64), poloxamer 407 (P407), silica (SiO), vitamin E succinate (vitE), and, optionally, a colorant. The calcium salt of risperidone can be used for the carrier polymer-drug arm segment. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, e.g., about 1.7 dL / g. Any pharmaceutically acceptable colorant can be used. Examples of colorants that can be used include FD&C Red 40 aluminum lake, FD&C Yellow 5 aluminum lake, or approximately equal blends thereof. In some embodiments, six arms are typically used in star-shaped dosage forms, with either 1, 2, 3, 4, 5, or 6 of the arms comprising the carrier polymer-drug arm segment. In some embodiments, three of the arms comprise the 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 weight of risperidone, a pharmaceutically acceptable salt of risperidone, or a calcium salt of risperidone in the star-shaped dosage form can be in the range of about 2 mg to about 50 mg, for example, about 4 mg to about 30 mg, or about 10 mg to about 20 mg, or about 20 mg to about 30 mg, or about 25 mg to about 35 mg, or about 12 mg to about 16 mg, or about 26 mg to about 30 mg, or about 3 mg to about 5 mg, or about 8 mg to about 10 mg, or about 13 mg to about 15 mg, or about 17 mg to about 20 mg, or about 22 mg to about 24 mg, or about 27 mg to about 29 mg.In some embodiments, the total weight of risperidone, a pharmaceutically acceptable salt of risperidone, or a calcium salt of risperidone in the star-shaped dosage form is about 14 mg or about 28 mg.

[0177] The inactive arm segments of the risperidone dosage form can comprise polycaprolactone (PCL), a radiopaque material, and optionally a colorant. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, e.g., about 1.7 dL / g. The radiopaque material can be (BiO)2CO3. Any pharmaceutically acceptable colorant can be used. An example of a colorant that can be used is FD&C Blue #5.

[0178] The enteric disintegrating matrix of the risperidone dosage form can contain polycaprolactone (PCL), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poloxamer 407 (P407), and, optionally, a colorant. The polycaprolactone used can 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 can be MG grade (M grade: acetyl content about 7-11%, succinoyl content about 10-14%, methoxyl content about 21-25%, hydroxypropoxy content about 5-9%; G grade: granular). Any pharmaceutically acceptable colorant can be used. An example of a colorant that can be used is ferric oxide.

[0179] The time-dependent disintegration matrix of the risperidone dosage form can comprise poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and, optionally, a colorant. The poly(D,L-lactide-co-glycolide) can 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 can have a molecular weight of about 60,000 MW to about 125,000 MW, e.g., about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0180] The time-dependent disintegration matrix of the risperidone dosage form can comprise polycaprolactone (PCL), poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and, optionally, a colorant. The PCL can have a medium viscosity of about 1.5 dL / g to about 2.1 dL / g, e.g., 1.7 dL / g, such as Corbion PC17. The poly(D,L-lactide-co-glycolide) can have a lactide:glycolide molar ratio of about 50:50 with a viscosity range of about 0.32 to 0.44 dL / g. The polyethylene oxide used can have a molecular weight of about 60,000 MW to about 125,000 MW, e.g., about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0181] The release rate controlling film of the risperidone dosage form can include polycaprolactone (PCL), copovidone (such as VA64), and magnesium stearate. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, for example, about 1.7 dL / g.

[0182] The central elastomer of the risperidone dosage form can have a durometer of about 40 A to about 60 A, for example, a durometer of about 45 A to about 55 A, or a durometer of about 50 A. The central elastomer can be made from a liquid silicone rubber, for example, the central elastomer can comprise a cured liquid silicone rubber.

[0183] Exemplary amounts of various components of risperidone dosage forms are set forth in the table below. The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0184] [Table 17-1]

[0185] [Table 17-2]

[0186]

Table 17-3

[0187]

Table 17-4

[0188]

Table 17-5

[0189]

Table 17-6

[0190] 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) a drug-eluting segment, the drug-eluting segment comprising a carrier polymer and risperidone or a salt thereof, and the drug-eluting segment further comprising a coating comprising a release rate-controlling polymer film, 8) an optional fifth inert segment, and 9) a third disintegrable matrix segment, which can be arranged in various orders. One such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first inert segment) (first disintegrable matrix segment) (second inert segment) (second disintegrable matrix segment) (third inert segment) (fourth inert segment) (drug-eluting segment) (optional fifth inert segment) (third disintegrable matrix segment). In some embodiments, the fourth inert segment is an inert spacer. In some embodiments, the first, second, third, and optional fifth inactive segments are rPCL spacers. An optional rPCL spacer (inactive segment) approximately 0.2-2 mm in length, e.g., approximately 0.5 mm in 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.

[0191] The approximate dimensions of the length of an exemplary drug-eluting arm segment are shown below.

[0192] [Table 18]

[0193] The approximate dimensions of the length and thickness of an exemplary drug-eluting arm segment are shown below.

[0194] [Table 19]

[0195] The approximate dimensions of the length and thickness of an exemplary drug-eluting arm segment are shown below.

[0196] [Table 20]

[0197] 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 proceeding to 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 for the length of each arm segment are shown below. An optional rPCL spacer (inactive segment) about 0.2-2 mm in length, e.g., about 0.5 mm in 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 desired to use one or more non-drug-eluting arms for the risperidone dosage form.

[0198] The approximate dimensions of the length of exemplary non-drug eluting arm segments are shown below:

[0199] [Table 21]

[0200] The approximate dimensions of the length and thickness of exemplary non-drug eluting arm segments are shown below:

[0201] [Table 22]

[0202] The approximate dimensions of the length and thickness of exemplary non-drug eluting arm segments are shown below:

[0203] [Table 23]

[0204] The approximate dimensions of the length of an exemplary drug-eluting arm segment are shown below.

[0205] [Table 24]

[0206] Although the above gastroretentive systems or dosage forms are described as risperidone formulations, they are not so limited and can be used in combination with other drugs by replacing the risperidone-containing segments and / or the inactive segments with segments containing other drugs.

[0207] Exemplary amounts of various components of risperidone dosage forms are set forth in the table below. It should be understood that amounts are given as approximate weight percentages and that when ranges are provided, the amounts are selected to add up to 100%.

[0208] [Table 25-1]

[0209]

Table 25-2

[0210]

Table 25-3

[0211]

Table 25-4

[0212]

Table 25-5

[0213]

Table 25-6

[0214] 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) a drug-eluting segment, the drug-eluting segment comprising a carrier polymer and risperidone or a salt thereof, and the drug-eluting segment further comprising a coating comprising a release rate-controlling polymer film, 8) an optional sixth inert segment, and 9) a fifth inert segment, which can be arranged in various orders. One such order is, starting from the proximal end attached to the central elastomer and proceeding to the distal end: (first inert segment) (first disintegrable matrix segment) (second inert segment) (second disintegrable matrix segment) (third inert segment) (fourth inert segment) (drug-eluting segment) (optional sixth inert segment) (fifth inert segment). In some embodiments, the fourth inert segment is an inert 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) about 0.2-2 mm in length, e.g., about 0.5 mm in 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.

[0215] The approximate dimensions of the length of an exemplary drug-eluting arm segment are shown below.

[0216] [Table 26]

[0217] The approximate dimensions of the length and thickness of an exemplary drug-eluting arm segment are shown below.

[0218] [Table 27]

[0219] The approximate dimensions of the length and thickness of an exemplary drug-eluting arm segment are shown below.

[0220] [Table 28]

[0221] 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 sixth inert segment; and 8) a fifth inert segment, which can be arranged in various orders. One such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first inert segment) (first disintegrable matrix segment) (second inert segment) (second disintegrable matrix segment) (third inert segment) (fourth inert segment) (optional sixth inert segment) (fifth inert segment). Approximate lengths of the segments of each arm are shown below. An optional rPCL spacer (inactive segment) about 0.2 to 2 mm in length, e.g., about 0.5 mm in 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 desired to use one or more non-drug-eluting arms for the risperidone dosage form.

[0222] The approximate dimensions of the length of exemplary non-drug eluting arm segments are shown below:

[0223] [Table 29]

[0224] Although the above gastroretentive systems or dosage forms are described as risperidone formulations, they are not so limited and can be used in combination with other drugs by replacing the risperidone-containing segments and / or the inactive segments with segments containing other drugs.

[0225] In some embodiments, a star-shaped dosage form for administering risperidone can comprise arms, which comprise, in order, 1) a carrier polymer-drug arm segment; 2) an inert arm segment; 3) one or more enteric linkers; 4) one or more time-dependent linkers; 5) a release rate-modifying film; and / or 6) other optional spacers. The arms are connected to the elastomeric core in a stellate arrangement. Typically, six arms are used for stellate dosage forms. In some embodiments where six arms are used for stellate dosage forms, any one of 1, 2, 3, 4, 5, or 6 arms constitutes a carrier polymer-drug arm segment. In some embodiments where six arms are used for star-shaped dosage forms, one arm constitutes a carrier polymer-drug arm segment. In some embodiments where six arms are used for star-shaped dosage forms, two arms constitute a carrier polymer-drug arm segment. In some embodiments where six arms are used for star-shaped dosage forms, three arms constitute a carrier polymer-drug arm segment. In some embodiments where six arms are used in the stellate dosage form, the six arms comprise the carrier polymer-drug arm segment.

[0226] The carrier polymer-drug arm segment of a risperidone dosage form can comprise risperidone (or a pharmaceutically acceptable salt thereof), polycaprolactone, copovidone (VA64), poloxamer 407 (P407), silica (SiO), vitamin E succinate (vitE), and, optionally, a colorant. A calcium salt of risperidone can be used for the carrier polymer-drug arm segment. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, e.g., about 1.7 dL / g. Any pharmaceutically acceptable colorant can be used. Examples of colorants that can be used include FD&C Red 40 aluminum lake, FD&C Yellow 5 aluminum lake, or an approximately equal blend thereof. In some embodiments, six arms are typically used in a star-shaped dosage form, with either one, two, three, four, five, or six of the arms comprising the carrier polymer-drug arm segment. In some embodiments, one of the arms comprises the 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 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 weight of risperidone, a pharmaceutically acceptable salt of risperidone, or a calcium salt of risperidone in the star-shaped dosage form can be in the range of about 2 mg to about 60 mg, e.g., about 4 mg to about 50 mg, or about 10 mg to about 20 mg, or about 20 mg to about 30 mg, or about 25 mg to about 35 mg, or about 14 mg to about 18 mg, or about 30 mg to about 34 mg, about 46 mg to about 50 mg, or about 3 mg to about 5 mg, or about 8 mg to about 10 mg, or about 13 mg to about 15 mg, or about 15 mg to about 17 mg, or about 17 mg to about 20 mg, or about 22 mg to about 24 mg, or about 27 mg to about 29 mg, or about 31 mg to about 33 mg, or about 47 mg to about 49 mg. In some embodiments, the total weight of risperidone, a pharmaceutically acceptable salt of risperidone, or a calcium salt of risperidone in the star-shaped dosage form is about 16 mg, about 32 mg, or about 48 mg.

[0227] The inactive arm segment of the risperidone dosage form can comprise polycaprolactone (PCL), a radiopaque material, and optionally a colorant. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, e.g., about 1.7 dL / g. The radiopaque material can be (BiO)2CO3. Any pharmaceutically acceptable colorant can be used. An example of a colorant that can be used is FD&C Blue #5.

[0228] The enteric disintegration matrix of the risperidone dosage form can include polycaprolactone (PCL), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and poloxamer 407 (P407). The polycaprolactone used can 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 can be MG grade (M grade: acetyl content about 7-11%, succinoyl content about 10-14%, methoxyl content about 21-25%, hydroxypropoxy content about 5-9%; G grade: granular).

[0229] In some embodiments, the filament is circumferentially wrapped around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament circumferentially wrapped around the gastric retention system and connecting one or more arms of the risperidone dosage form can be a disintegrating filament. In some embodiments, the filament comprises poly(lactic-co-glycolic acid) and / or polyglycolic acid.

[0230] The time-dependent disintegration matrix of the risperidone dosage form can comprise polycaprolactone (PCL), poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and, optionally, a colorant. The PCL can have a medium viscosity of about 1.0 dL / g to about 1.4 dL / g, e.g., 1.2 dL / g, such as Corbion PC12. The poly(D,L-lactide-co-glycolide) can have a lactide:glycolide molar ratio of about 50:50 with a viscosity range of about 0.32 to 0.44 dL / g. The polyethylene oxide used can have a molecular weight of about 60,000 MW to about 125,000 MW, e.g., about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0231] The release rate controlling film of the risperidone dosage form can include polycaprolactone (PCL), copovidone (such as VA64), and magnesium stearate. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, for example, about 1.7 dL / g.

[0232] The central elastomer of the risperidone dosage form can have a durometer of about 40 A to about 60 A, for example, a durometer of about 45 A to about 55 A, or a durometer of about 50 A. The central elastomer can be made from a liquid silicone rubber; for example, the central elastomer can comprise a cured liquid silicone rubber.

[0233] In one embodiment, exemplary amounts for the various components of a risperidone dosage form are set forth in the following table: The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0234] [Table 30-1]

[0235] [Table 30-2]

[0236] [Table 30-3]

[0237] [Table 30-4]

[0238] [Table 30-5]

[0239] In one embodiment, exemplary amounts for the various components of a risperidone dosage form are set forth in the following table: The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0240] [Table 31-1]

[0241] [Table 31-2]

[0242] [Table 31-3]

[0243] [Table 31-4]

[0244] [Table 31-5]

[0245] In one embodiment, exemplary amounts of the various components of a risperidone dosage form are provided in the table below. The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0246] [Table 32-1]

[0247] [Table 32-2]

[0248] [Table 32-3]

[0249] [Table 32-4]

[0250] [Table 32-5]

[0251] In one embodiment, exemplary amounts for the various components of a risperidone dosage form are set forth in the following table: The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0252] [Table 33-1]

[0253] [Table 33-2]

[0254] [Table 33-3]

[0255] [Table 33-4]

[0256] [Table 33-5]

[0257] In one embodiment, exemplary amounts for the various components of a risperidone dosage form are set forth in the following table: The amounts are given as approximate weight percentages, but it should be understood that when ranges are provided, the amounts are selected to add up to 100%.

[0258] [Table 34-1]

[0259] [Table 34-2]

[0260] [Table 34-3]

[0261] [Table 34-4]

[0262] [Table 34-5]

[0263] The assembled arms may comprise: 1) a first disintegrating matrix; 2) a first inert segment; 3) a second disintegrating matrix; 4) a second inert segment; 5) a drug-eluting segment, the drug-eluting segment comprising a carrier polymer and risperidone or a salt thereof, and the drug-eluting segment further comprising a coating comprising a release rate-controlling polymer film; and 6) a third inert segment, which may be arranged in various orders. One such order is starting from the proximal end attached to the central elastomer and proceeding to the distal end: (first disintegrating matrix) (first inert segment) (second disintegrating matrix) (second inert segment) (drug-eluting segment) (third inert segment). In some embodiments, the third inert segment is an inert spacer. In some embodiments, the first and second inert segments are rPCL spacers. An optional rPCL spacer (inactive segment) approximately 0.2-2 mm in length, e.g., approximately 0.5 mm in 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 elastomer core.

[0264] The approximate dimensions of the length of an exemplary drug-eluting arm segment are shown below.

[0265] [Table 35]

[0266] The approximate dimensions of the length and thickness of an exemplary drug-eluting arm segment are shown below.

[0267] [Table 36]

[0268] The approximate dimensions of the length and thickness of an exemplary drug-eluting arm segment are shown below.

[0269] [Table 37]

[0270] The assembled arms can include 1) a first disintegrating matrix; 2) a first inert segment; 3) a second disintegrating matrix; 4) a second inert segment; and 5) a third inert segment, which can be arranged in various orders. One such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first disintegrating matrix) (first inert segment) (second disintegrating matrix) (second inert segment) (third inert segment). An optional rPCL spacer (inert segment) approximately 0.2 to 2 mm in length, e.g., approximately 0.5 mm in 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 inert segment is an inert spacer. It will be understood that the assembled arms of this embodiment lack a drug-eluting segment and can be used when it is desired to use one or more non-drug-eluting arms with the risperidone dosage form.

[0271] Approximate dimensions for the length of exemplary non-drug eluting arm segments are shown below.

[0272] [Table 38]

[0273] The approximate dimensions of the length and thickness of exemplary non-drug eluting arm segments are shown below.

[0274] [Table 39]

[0275] The approximate dimensions of the length and thickness of exemplary non-drug eluting arm segments are shown below.

[0276] [Table 40]

[0277] Although the above gastroretentive systems or dosage forms are described as risperidone formulations, they are not so limited and can be used in combination with other drugs by replacing the risperidone-containing segment and / or the inactive segment(s) with segments containing the other drugs.

[0278] 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. The gastroretention systems described, shown as risperidone formulations, are not so limited and can be used with other drugs by replacing the risperidone-containing segment and / or replacing the inactive segment with a segment containing another drug. Any of the gastroretention systems disclosed herein can be used as a gastroretention system for administration to an individual in the methods disclosed herein.

[0279] 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 inactive segment 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.

[0280] 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 inactive segment embodiments above (such as any one of IS-1, IS-2, or IS-3), (b) a time-disintegrating matrix as described in any of the embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (c) at least one arm comprising a drug-eluting segment, (d) a second inactive segment as described in any of the inactive segment embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (e) a second inactive segment as described in any of the inactive segment embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (f) a second inactive segment as described in any of the embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (g) a second inactive segment as described in any of the embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (h) a second inactive segment as described in any of the embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (i) a second inactive segment as described in any of the embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (j ... (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 inactive segment 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 disintegrating matrix (e.g., ODMTEP) as described in any of the above inactive segment 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 described segments may be arranged in any order. One such sequence begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first inactive segment) (timed disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (third disintegrating matrix segment).Another such sequence begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first inactive segment) (timed disintegration matrix) (second inactive segment) (enteric matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (fifth inactive segment) (third disintegration matrix segment). The first inactive segment can be attached to the central elastomer.

[0281] 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 the following: (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 durometers; (a) the first inactive segment comprises about 65 wt % to about 75 wt % PCL and about 25 wt % to about 35 wt % (BiO)2CO3; (b) the timed disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 10 wt% to about 25 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 10 wt% to about 25 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% color absorbing dye E172; (c) a second, inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2COdf3; (d) the enterodispersible matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407), and optionally about 0.01 wt% to about 0.2 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (f) the drug-eluting segment is about 30 wt% to about 40 wt% risperidone, about 51 wt% to about 61 wt% PCL, about 2 wt% to about 8 wt% VA64, about 1 wt% to about 5 wt% P407, about 0.1 wt% to about 1 wt% vitamin E succinate, about 0.1 wt% to about 1 wt% SiO2, and about 0.01 wt% to about 0.5 wt% pigment; (g) a fourth inactive segment comprising about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1; and / or (h) The third disintegrating matrix comprises about 60 wt% to about 70 wt% HPMCAS, about 25 wt% to about 35 wt% PCL, about 1 wt% to about 5 wt% propylene glycol, and about 1 wt% to about 5 wt% stearic acid, and optionally about 0.01 wt% to about 0.5 wt% iron oxide.

[0282] 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 the following: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteric disintegrating 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 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (b) the time-dependent disintegrating matrix comprises about 43 wt % to about 47 wt % PCL, about 33 wt % to about 37 wt % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt % to about 20 wt % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt % to about 20 wt % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % color-absorbing dye E172; (c) a second, inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407), and optionally about 0.05 wt% to about 0.15 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% ((BiO)2CO3); (f) drug-eluting segment is about 33 wt% to about 37 wt% risperidone, about 54 wt% to about 58 wt% PCL, about 4 wt% to about 6 wt% VA64, about 2 wt% to about 4 wt% P407, about 0.2 wt% to about 0.8 wt% vitamin E succinate, about 0.2 wt% to about 0.8 wt% SiO2, and about 0.05 wt% to about 0.15 wt% pigment; (g) a fourth inactive segment comprising about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1; and / or (h) The third disintegrating matrix comprises about 63 wt% to about 67 wt% HPMCAS, about 28 wt% to about 32 wt% PCL, about 2 wt% to about 3 wt% propylene glycol, and about 2 wt% to about 3 wt% stearic acid, and optionally about 0.05 wt% to about 0.15 wt% iron oxide.

[0283] 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 the following: (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 contains about 70 wt% PCL and about 30 wt% (BiO)2CO3; (b) a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprising about 44.95 wt% PCL, about 35 wt% PCL having a viscosity midpoint of about 0.4 dL / g, about 18 wt% DL-lactide and glycolide copolymer (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt%, for example about 0.05%, of a color absorbing dye E172; (c) the second inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407) and about 0.1 wt% iron oxide (e.g., E172); (e) the third inactive segment contains about 70 wt% PCL and about 30 wt% (BiO)2CO3; (f) the drug-eluting segment comprises about 35.0 wt% risperidone, 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) a fourth inactive segment comprising about 66.45 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1; and / or (h) The third disintegrating matrix comprises 64.9 wt% HPMCAS, about 30 wt% PCL, about 2.5 wt% propylene glycol, and about 2.5 wt% stearic acid, and optionally about 0.1 wt% iron oxide, e.g., about 0.025% ferric oxide, and about 0.075% FD&C Red 40.

[0284] In some embodiments, the gastroretentive system comprises at least one arm excluding the drug-eluting segment, wherein the arm may be attached to the central elastomer, and the arm comprises one or more of the following: (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-free segment as described in any of the above inactive segment 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.

[0285] In some embodiments, the gastroretentive system comprises at least one arm excluding the drug-eluting segment, wherein the drug-free arm may be attached to a central elastomer, and the arm comprises one or more of the following: (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.

[0286] In some embodiments, the gastroretentive system comprises at least one arm excluding the drug-eluting segment, wherein the drug-free arm may be attached to a central elastomer, the arm comprising one or more of the following: (a) a first inactive segment (such as any one of IS-1, IS-2, or IS-3) as described in any of the inactive segment embodiments above; (b) a time-disintegrating matrix (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, or T-DM6) as described in any of the inactive segment embodiments above; (c) a second inactive segment (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, or T-DM6) as described in any of the inactive segment embodiments above; (d) a second inactive segment (e.g., IS-1, IS-2, or IS-3) described in any of the above embodiments, (e.g., E-DM1 or E-DM2) an enterodisintegrable matrix (e.g., E-DM1 or E-DM2) described in any of the above embodiments, (f) a fourth inactive segment (e.g., IS-1, IS-2, or IS-3) described in any of the above embodiments, and (g) a third disintegrable matrix (e.g., ODMTEP) described in any of the above embodiments. The drug-free arm may also include an optional fifth inactive segment (e.g., IS-1, IS-2, or IS-3) described in any of the above embodiments. The described segments may be arranged in any order. One such sequence begins at the proximal end attached to the central elastomer and proceeds to 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 begins at the proximal end attached to the central elastomer and proceeds to 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 can be attached to the central elastomer.

[0287] In some embodiments that can be combined with any of the embodiments herein, a 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 risperidone dosage form can be a non-degradable 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.

[0288] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug eluting segment, which arm may be attached to the central elastomer, and which arm comprises one or more of the following: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteric-disintegrating 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 wt % to about 75 wt % PCL and about 25 wt % to about 35 wt % (BiO)2CO3; (b) the timed disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 10 wt% to about 25 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 10 wt% to about 25 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% color absorbing dye E172; (c) a second, inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407), and optionally about 0.01 wt% to about 0.2 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1; and / or (g) The third disintegrating matrix comprises about 60 wt% to about 70 wt% HPMCAS, about 25 wt% to about 35 wt% PCL, about 1 wt% to about 5 wt% propylene glycol, and about 1 wt% to about 5 wt% stearic acid, and optionally about 0.01 wt% to about 0.5 wt% iron oxide.

[0289] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug eluting segment, which arm may be attached to the central elastomer, and which arm comprises one or more of the following: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteric-disintegrating 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 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (b) the time-dependent disintegrating matrix comprises about 43 wt % to about 47 wt % PCL, about 33 wt % to about 37 wt % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt % to about 20 wt % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt % to about 20 wt % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % color-absorbing dye E172; (c) a second, inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407), and optionally about 0.05 wt% to about 0.15 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1; and / or (g) The third disintegrating matrix comprises about 63 wt% to about 67 wt% HPMCAS, about 28 wt% to about 32 wt% PCL, about 2 wt% to about 3 wt% propylene glycol, and about 2 wt% to about 3 wt% stearic acid, and optionally about 0.05 wt% to about 0.15 wt% iron oxide.

[0290] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to the central elastomer, and which arm comprises one or more of the following: (a) a first inactive segment, (b) a time-disintegrating matrix, (c) a second inactive segment, (d) an enteric-disintegrating 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 contains about 70 wt% PCL and about 30 wt% (BiO)2CO3; (b) a time-dependent disintegrating matrix, the time-dependent disintegrating matrix being about 44.95 wt % PCL, about 35 wt % PCL having a viscosity midpoint of about 0.4 dL / g, about 18 wt % DL-lactide and glycolide copolymer (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt % polyethylene glycol 100k, and about 0.05 wt % color absorbing dye E172; (c) the second inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407) and about 0.1 wt% iron oxide (e.g., E172); (e) the third inactive segment contains about 70 wt% PCL and about 30 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 66.45 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1; and / or (g) A third disintegrating matrix comprises 64.9 wt% HPMCAS, about 30 wt% PCL, about 2.5 wt% propylene glycol, and about 2.5 wt% stearic acid, and optionally about 0.1 wt% iron oxide, e.g., about 0.025% ferric oxide, and about 0.075% FD&C Red 40.

[0291] In some embodiments of any of the gastroretentive systems described herein, the gastroretentive 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 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 70 wt% PCL and about 30 wt% (BiO)2CO3.

[0292] In any of the above-described embodiments, the arms may be attached to the central elastomer at the first inactive segment, i.e., the first inactive segment is the proximal end of the arm.

[0293] The table below lists the length of each segment in the gastroretentive system. Each range or value below can be considered to be "approximately" the indicated range or value, or exactly the indicated range or value.

[0294] [Table 41]

[0295] For further embodiments, the following table provides a list of the length of each segment in the drug-eluting arm of a gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or the indicated range or value itself.

[0296] [Table 42]

[0297] Although the above gastroretentive systems are described as risperidone formulations, they are not so limited and can be used in combination with other drugs by replacing the risperidone-containing segment and / or the inactive segment with segments containing other drugs.

[0298] The following gastroretentive systems are exemplary to better illustrate certain embodiments of the systems described herein.

[0299] 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 can be attached to the central elastomer.

[0300] 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 inactive segment embodiments above (such as any one of IS-1, IS-2, or IS-3), (b) a time-disintegrating matrix as described in any of the embodiments above (such as any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (c) at least one arm comprising a drug-eluting segment, (d) a second inactive segment as described in any of the inactive segment embodiments above (such as 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-59, IS-59, IS-59, IS-59, IS-59, IS-59, IS-59, IS-59, IS-51, IS-52, IS-53, IS-54, IS-55, IS-5 (e) an enteric disintegration 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 fourth inactive segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above inactive segment embodiments; (g) a drug-eluting segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above embodiments; and (h) a fifth inactive segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above embodiments. The drug-eluting arm may also include an optional sixth inactive segment (e.g., IS-1, IS-2, or IS-3) as described in any of the above inactive segment embodiments. The described segments may be arranged in various orders. One such sequence begins at the proximal end, which is attached to the central elastomer, and proceeds to the distal end: (first inactive segment) (timed disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (fifth inactive segment).One such sequence begins at the proximal end, which is attached to the central elastomer, and proceeds to the distal end: (first inactive segment) (time-disintegrating matrix) (second inactive segment) (enteric disintegrating matrix) (third inactive segment) (fourth inactive segment) (drug-eluting segment) (optional sixth inactive segment) (fifth inactive segment). The first inactive segment can be attached to the central elastomer.

[0301] 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 the following: (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, (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 wt % to about 75 wt % PCL and about 25 wt % to about 35 wt % (BiO)2CO3; (b) the timed disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% color-absorbing dye E172; (c) a second, inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407), and optionally about 0.01 wt% to about 0.2 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1; (g) the drug-eluting segment is comprised of about 30 wt% to about 40 wt% risperidone, about 51 wt% to about 61 wt% PCL, about 2 wt% to about 8 wt% VA64, about 1 wt% to about 5 wt% P407, about 0.1 wt% to about 1 wt% vitamin E succinate, about 0.1 wt% to about 1 wt% SiO2, and about 0.01 wt% to about 0.5 wt% pigment, and / or (h) The fifth inactive segment comprises about 35 wt% to about 45 wt% PCL, about 37 wt% to about 47 wt% copovidone, about 10 wt% to about 20 wt% polyethylene glycol, about 1 wt% to about 5 wt% poloxamer, and optionally about 0.0005 wt% to about 0.02 wt% color absorbing dye E172.

[0302] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm being attachable to the central elastomer, the arm comprising one or more of the following: (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, (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 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (b) a time-dependent disintegrating matrix comprising about 43 wt % to about 47 wt % PCL, about 15 wt % to about 20 wt % of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % of a color-absorbing dye E172; (c) a second, inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407), and optionally about 0.05 wt% to about 0.15 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1; (g) the drug-eluting segment is about 33 wt% to about 37 wt% risperidone, about 54 wt% to about 58 wt% PCL, about 4 wt% to about 6 wt% VA64, about 2 wt% to about 4 wt% P407, about 0.2 wt% to about 0.8 wt% vitamin E succinate, about 0.2 wt% to about 0.8 wt% SiO2, and about 0.05 wt% to about 0.15 wt% pigment, and / or (h) The fifth inactive segment comprises about 38 wt% to about 42 wt% PCL, about 40 wt% to about 44 wt% copovidone, about 13 wt% to about 17 wt% polyethylene glycol, about 2 wt% to about 4 wt% poloxamer, and optionally about 0.001 wt% to about 0.01 wt% color absorbing dye E172.

[0303] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, the arm being attachable to the central elastomer, the arm comprising one or more of the following: (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, (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 contains about 70 wt% PCL and about 30 wt% (BiO)2CO3; (b) a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprising about 44.95 wt% PCL, about 35 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt%, for example about 0.05%, of a color-absorbing dye E172; (c) the second inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407) and about 0.1 wt% iron oxide (e.g., E172); (e) the third inactive segment contains about 70 wt% PCL and about 30 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 66.45 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1; (g) the drug-eluting segment comprises about 35.0 wt% risperidone, 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 wt% PCL, about 42 wt% copovidone, about 15 wt% polyethylene glycol, about 3 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye E172.

[0304] In some embodiments, the gastroretention system comprises at least one arm, excluding the drug-eluting segment, which may be attached to a central elastomer, and which comprises one or more of the following: (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 enteric-disintegrating 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 inactive segment embodiments.

[0305] In some embodiments, the gastroretentive system comprises at least one arm excluding the drug-eluting segment, wherein the arm comprises: (a) a first inactive segment as described in any of the inactive segment embodiments above (e.g., any one of IS-1, IS-2, or IS-3), (b) a time-disintegrating matrix as described in any of the embodiments above (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, e.g., any one of T-DM2, T-DM3, T-DM4, T-DM5, T-DM6), (c) a second inactive segment as described in any of the inactive segment embodiments above. (d) an enterodispersible matrix (e.g., E-DM1 or E-DM2) described in any of the above embodiments; (e) a third inactive segment (e.g., IS-1, IS-2, or IS-3) described in any of the above inactive segment embodiments; (f) a fourth inactive segment (e.g., IS-1, IS-2, or IS-3) described in any of the above inactive segment embodiments; and (g) a fifth inactive segment (e.g., IS-1, IS-2, or IS-3) described in any of the above embodiments. The non-drug-containing arm may also include an optional sixth inactive segment as described in any of the above inactive segment embodiments (e.g., IS-1, IS-2, or IS-3). The described segments can be arranged in various orders. One such sequence begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first inactive segment) (timed disintegration matrix) (second inactive segment) (enteric disintegration matrix) (third inactive segment) (fourth inactive segment) (fifth inactive segment). One such sequence begins at the proximal end attached to the central elastomer and proceeds to the distal end: (first inactive segment) (timed disintegration matrix) (second inactive segment) (enteric disintegration matrix) (third inactive segment) (fourth inactive segment) (optional sixth inactive segment) (fifth inactive segment).The first inactive segment can be attached to the central elastomer.

[0306] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to a central elastomer, which arm comprises one or more of the following: (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 fifth inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometers; (a) the first inactive segment comprises about 65 wt % to about 75 wt % PCL and about 25 wt % to about 35 wt % (BiO)2CO3; (b) the timed disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% color-absorbing dye E172; (c) a second, inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407), and optionally about 0.01 wt% to about 0.2 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1; and / or (g) The fifth inactive segment comprises about 35 wt% to about 45 wt% PCL, about 37 wt% to about 47 wt% copovidone, about 10 wt% to about 20 wt% polyethylene glycol, about 1 wt% to about 5 wt% poloxamer, and optionally about 0.0005 wt% to about 0.02 wt% color absorbing dye E172.

[0307] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to the central elastomer, and which arm comprises one or more of the following: (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 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 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (b) a time-dependent disintegrating matrix comprising about 43 wt % to about 47 wt % PCL, about 15 wt % to about 20 wt % of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % of a color-absorbing dye E172; (c) a second, inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (d) the enterodispersible matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407), and optionally about 0.05 wt% to about 0.15 wt% iron oxide (e.g., E172); (e) a third inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (f) a fourth inactive segment comprising about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1; and / or (g) The fifth inactive segment comprises about 38 wt% to about 42 wt% PCL, about 40 wt% to about 44 wt% copovidone, about 13 wt% to about 17 wt% polyethylene glycol, about 2 wt% to about 4 wt% poloxamer, and optionally about 0.001 wt% to about 0.01 wt% color absorbing dye E172.

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

[0309] In some embodiments of any of the gastroretentive systems described herein, the gastroretentive 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 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3. In some embodiments, the fifth optional inactive segment comprises about 70 wt% PCL and about 30 wt% (BiO)2CO3.

[0310] In any of the above-described embodiments, the arms may be attached to the central elastomer at the first inactive segment, i.e., the first inactive segment is the proximal end of the arm.

[0311] The table below lists the length of each segment in the drug-eluting arm of the intragastric placement system. Each range or value below can be considered to be "about" the indicated range or value, or the indicated range or value itself.

[0312] [Table 43]

[0313] The table below lists the length of each section of the drug-free arm of the gastroretentive system. Each range or value below can be considered to be "about" the stated range or value, or the stated range or value itself.

[0314] [Table 44]

[0315] Although the above gastroretentive systems are described as risperidone formulations, they are not so limited and can be used in combination with other drugs by replacing the risperidone-containing segment(s) and / or replacing the inactive segment(s) with segments containing the other drugs.

[0316] The following gastroretentive systems are exemplary to better illustrate the system embodiments described herein.

[0317] 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 enteric 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.

[0318] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug-eluting segment, the arm comprising: (a) a time-disintegrating matrix according to 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 according to any of the above inactive segment embodiments (e.g., any one of IS-1, IS-2, IS-3), (c) an enterodisintegrating matrix according to 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 as described in any of the inactive segment embodiments above (such as any one of IS-1, IS-2, or IS-3). The described segments may be arranged in any order. One such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (time-disintegrating matrix) (first inactive segment) (enteric disintegrating matrix) (second inactive segment) (drug-eluting segment) (third inactive segment). Another such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (time-disintegrating matrix) (first inactive segment) (enteric disintegrating matrix) (second inactive segment) (drug-eluting segment) (optional fourth inactive segment) (third inactive segment). The time-disintegrating matrix may be attached to the central elastomer.

[0319] In some embodiments, the filament is circumferentially wrapped around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament circumferentially wrapped around the gastric retention system and connecting one or more arms of the risperidone dosage form can be a disintegrating filament. In some embodiments, the filament comprises poly(lactic-co-glycolic acid) and / or polyglycolic acid.

[0320] 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 the following: (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 timed disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% color-absorbing dye E172; (b) the first inactive segment comprises about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407); (d) a second, inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (e) the drug-eluting segment is from about 30 wt% to about 40 wt% risperidone, from about 51 wt% to about 61 wt% PCL, from about 2 wt% to about 8 wt% VA64, from about 1 wt% to about 5 wt% P407, from about 0.1 wt% to about 1 wt% vitamin E succinate, from about 0.1 wt% to about 1 wt% SiO2, and from about 0.01 wt% to about 0.5 wt% pigment, and / or (f) The third inactive segment comprises about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1.

[0321] 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 the following: (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 timed disintegrating matrix comprises about 45 wt % to about 55 wt % PCL, about 27 wt % to about 37 wt % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 10 wt % to about 22 wt % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt % to about 5 wt % polyethylene glycol 100k, and about 0.005 wt % to about 0.2 wt % color-absorbing dye E172; (b) the first inactive segment comprises about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407); (d) a second, inactive segment comprising about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (e) the drug-eluting segment is from about 30 wt% to about 40 wt% risperidone, from about 51 wt% to about 61 wt% PCL, from about 2 wt% to about 8 wt% VA64, from about 1 wt% to about 5 wt% P407, from about 0.1 wt% to about 1 wt% vitamin E succinate, from about 0.1 wt% to about 1 wt% SiO2, and from about 0.01 wt% to about 0.5 wt% pigment, and / or (f) The third inactive segment comprises about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1.

[0322] 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 the following: (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 43 wt % to about 47 wt % PCL, about 33 wt % to about 37 wt % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 0.4 dl / g, about 15 wt % to about 20 wt % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 0.4 dl / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % color-absorbing dye E172; (b) a first inactive segment comprising about 68 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407); (d) a second, inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (e) the drug-eluting segment is about 33 wt% to about 37 wt% risperidone, about 54 wt% to about 58 wt% PCL, about 4 wt% to about 6 wt% VA64, about 2 wt% to about 4 wt% P407, about 0.2 wt% to about 0.8 wt% vitamin E succinate, about 0.2 wt% to about 0.8 wt% SiO2, and about 0.05 wt% to about 0.15 wt% pigment, and / or (f) The third inactive segment comprises about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1.

[0323] 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 the following: (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, wherein the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometers; (a) a time-dependent disintegrating matrix comprising about 48 wt % to about 52 wt % PCL, about 14 wt % to about 18 wt % of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % of a color-absorbing dye E172; (b) a first inactive segment comprising about 68 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407); (d) a second, inactive segment comprising about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3; (e) the drug-eluting segment comprises about 33 wt% to about 37 wt% risperidone, about 54 wt% to about 58 wt% PCL, about 4 wt% to about 6 wt% VA64, about 2 wt% to about 4 wt% P407, about 0.2 wt% to about 0.8 wt% vitamin E succinate, about 0.2 wt% to about 0.8 wt% SiO2, and about 0.05 wt% to about 0.15 wt% pigment; and / or (f) The third inactive segment comprises about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1.

[0324] 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 the following: (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, the time-dependent disintegrating matrix comprising about 44.95 wt% PCL, about 35 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt% polyethylene glycol 100k, and about 0.05 wt% color-absorbing dye E172; (b) the second, inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (c) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407); (d) the second inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (e) the drug-eluting segment is about 35.0 wt% risperidone, 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 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1.

[0325] 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 the following: (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, the time-dependent disintegrating matrix comprising about 49.95 wt% PCL, about 32 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 16 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 16 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt% polyethylene glycol 100k, and about 0.05 wt% color-absorbing dye E172; (b) the second, inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (c) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407); (d) the second inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (e) the drug-eluting segment is about 35.0 wt% risperidone, 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 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1.

[0326] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which may be attached to a central elastomer, and which comprises one or more of the following: (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 enteroerodible 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.

[0327] In some embodiments, the gastroretentive system comprises at least one arm excluding the drug-eluting segment, the arm comprising: (a) a time-disintegrating matrix (e.g., any one of T-DM1, T-DM2, T-DM3, T-DM4, T-DM5, and T-DM6) as described in any of the above embodiments, (b) a first inactive segment (e.g., any one of IS-1, IS-2, and IS-3) as described in any of the above inactive segment embodiments, (c) an enteric-disintegrating matrix (e.g., E-DM1 or E-DM2) as described in any of the above embodiments, (d) a second inactive segment (e.g., any one of IS-1, IS-2, and IS-3) as described in any of the above inactive segment embodiments, and (e) a third inactive segment (e.g., any one of IS-1, IS-2, and IS-3) as described in any of the above inactive segment embodiments. The drug-free arm may comprise an optional fourth inactive segment (e.g., any one of IS-1, IS-2, and IS-3) as described in any of the above inactive segment embodiments. The described segments can be arranged in any order. One such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (time-disintegrating matrix) (first inert segment) (enteric disintegrating matrix) (second inert segment) (third inert segment). Another such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (time-disintegrating matrix) (first inert segment) (enteric disintegrating matrix) (second inert segment) (optional fourth inert segment) (third inert segment). The time-disintegrating matrix can be attached to the central elastomer.

[0328] In some embodiments, the filament is circumferentially wrapped around the gastric retention system (e.g., by connecting the distal ends of each arm). The filament circumferentially wrapped around the gastric retention system and connecting one or more arms of the risperidone dosage form can be a disintegrating filament. In some embodiments, the filament comprises poly(lactic-co-glycolic acid) and / or polyglycolic acid.

[0329] In some embodiments, the gastroretentive system comprises at least one arm excluding the drug-eluting segment, wherein the arm may be attached to the central elastomer, the arm comprising one or more of the following: (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 timed disintegrating matrix comprises about 40 wt% to about 50 wt% PCL, about 30 wt% to about 40 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 4 dl / g, about 10 wt% to about 25 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a midpoint viscosity of about 0.4 dl / g, about 0.5 wt% to about 5 wt% polyethylene glycol 100k, and about 0.005 wt% to about 0.2 wt% color-absorbing dye E172; (b) the first inactive segment comprises about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407); (d) the second inactive segment comprises about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)CO; and / or (e) The third inactive segment comprises about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1.

[0330] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to the central elastomer, and which arm comprises one or more of the following: (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, wherein the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 40 to about 65 durometer; (a) the timed disintegrating matrix comprises about 45 wt % to about 55 wt % PCL, about 27 wt % to about 37 wt % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 10 wt % to about 22 wt % ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 0.5 wt % to about 5 wt % polyethylene glycol 100k, and about 0.005 wt % to about 0.2 wt % color-absorbing dye E172; (b) the first inactive segment comprises about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 59 wt% to about 69 wt% HPMCAS, about 29 wt% to about 39 wt% PCL, and about 0.5 wt% to about 5 wt% poloxamer (e.g., P407); (d) the second inactive segment comprises about 65 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)CO; and / or (e) The third inactive segment comprises about 61 wt% to about 71 wt% PCL, about 27 wt% to about 37 wt% copovidone, about 0.2 wt% to about 4 wt% poloxamer, and optionally about 0.005 wt% to about 0.2 wt% color absorbing dye FD&C Blue #1.

[0331] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to a central elastomer, and which arm comprises one or more of the following: (a) a time-disintegrating matrix, (b) a first inert segment, (c) an enteroerodible matrix, (d) a second inert segment, and (e) a third inert 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 wt% to about 47 wt% PCL, about 33 wt% to about 37 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt% to about 20 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15 wt% to about 20 wt% of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1 wt% to about 3 wt% polyethylene glycol 100k, and about 0.01 wt% to about 0.1 wt% of a color-absorbing dye E172; (b) a first inactive segment comprising about 68 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407); (d) the second inactive segment comprises about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)CO; and / or (e) The third inactive segment comprises about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1.

[0332] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to a central elastomer, and which arm comprises one or more of the following: (a) a time-disintegrating matrix, (b) a first inert segment, (c) an enteroerodible matrix, (d) a second inert segment, and (e) a third inert segment. the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 45 to about 55 durometer; (a) a time-dependent disintegrating matrix comprising about 48 wt % to about 52 wt % PCL, about 14 wt % to about 18 wt % of an ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 1 wt % to about 3 wt % polyethylene glycol 100k, and about 0.01 wt % to about 0.1 wt % of a color-absorbing dye E172; (b) a first inactive segment comprising about 68 wt % to about 72 wt % PCL and about 28 wt % to about 32 wt % (BiO)2CO3; (c) the enterodisintegrable matrix comprises about 62 wt% to about 66 wt% HPMCAS, about 32 wt% to about 36 wt% PCL, and about 1 wt% to about 3 wt% poloxamer (e.g., P407); (d) the second inactive segment comprises about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)CO; and / or (e) The third inactive segment comprises about 64 wt% to about 69 wt% PCL, about 30 wt% to about 34 wt% copovidone, about 0.5 wt% to about 2.5 wt% poloxamer, and optionally about 0.01 wt% to about 0.1 wt% color absorbing dye FD&C Blue #1.

[0333] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to the central elastomer, and which arm comprises one or more of the following: (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, wherein The central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprising about 44.95 wt% PCL, about 35 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt% polyethylene glycol 100k, and about 0.05 wt% color-absorbing dye E172; (b) the second, inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (c) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407); (d) the second inactive segment comprises about 70 wt % PCL and about 30 wt % (BiO)2CO3; and / or (e) The third inactive segment comprises about 66.45 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1.

[0334] In some embodiments, the gastroretentive system comprises at least one arm, excluding the drug-eluting segment, which arm may be attached to a central elastomer, which arm comprises one or more of the following: (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, wherein the central elastomer comprises a liquid silicone rubber (LSR) having a hardness of about 50 durometer; (a) a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprising about 49.95 wt% PCL, about 32 wt% acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 16 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 16 wt% ester-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt% polyethylene glycol 100k, and about 0.05 wt% color-absorbing dye E172; (b) the second, inactive segment contains about 70 wt % PCL and about 30 wt % (BiO)2CO3; (c) the enteroerodible matrix comprises about 63.95 wt% HPMCAS, about 33.95 wt% PCL, and about 2 wt% poloxamer (e.g., P407); (d) the second inactive segment comprises about 70 wt % PCL and about 30 wt % (BiO)2CO3; and / or (e) The third inactive segment comprises about 66.45 wt% PCL, about 32 wt% copovidone, about 1.5 wt% poloxamer, and optionally about 0.05 wt% color absorbing dye FD&C Blue #1.

[0335] In some embodiments of any of the gastroretentive systems described herein, the gastroretentive 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 wt% to about 75 wt% PCL and about 25 wt% to about 35 wt% (BiO)2CO3. In some embodiments, the fourth optional inactive segment comprises about 68 wt% to about 72 wt% PCL and about 28 wt% to about 32 wt% (BiO)2CO3. In some embodiments, the fourth optional inactive segment comprises about 70 wt% PCL and about 30 wt% ((BiO)2CO3).

[0336] In any of the above-described embodiments, the arms may be attached to the central elastomer at the first inactive segment, i.e., the first inactive segment is the proximal end of the arm.

[0337] The table below lists the length of each segment in the drug-eluting arm of the intragastric placement system. Each range or value below can be considered to be "about" the indicated range or value, or the indicated range or value itself.

[0338] [Table 45]

[0339] The table below lists the length and thickness of each segment in the drug-eluting arm of the intragastric placement system. Each range or value below can be considered to be "about" the indicated range or value, or the indicated range or value itself.

[0340] [Table 46]

[0341] The table below lists the length and thickness of each segment in the drug-eluting arm of the intragastric placement system. Each range or value below can be considered to be "about" the indicated range or value, or the indicated range or value itself.

[0342] [Table 47]

[0343] The table below lists the length of each section 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 the indicated range or value itself.

[0344] [Table 48]

[0345] The table below lists the length and width of each segment of the drug-free arm of the gastroretentive system. Each range or value below can be considered to be "approximate" to the indicated range or value, or exactly the indicated range or value.

[0346] [Table 49]

[0347] The table below lists the length and thickness of each drug-free arm segment of the gastroretentive system. Each range or value below can be considered to be "about" the indicated range or value, or the indicated range or value itself.

[0348] [Table 50]

[0349] In some embodiments according to any of the systems described herein, the thickness of a segment is determined by the longest straight line within a cross section of the segment. In some embodiments where the cross section of the segment is a circle, the thickness is defined by the diameter of the circle. In some embodiments where the cross section of the segment is a square or rectangle, 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.

[0350] Although the above gastroretentive systems are described as risperidone formulations, they are not so limited and can be used in combination with other drugs by replacing the risperidone-containing segment and / or the inactive segment with segments containing other drugs.

[0351] In some embodiments, a dosage form for administering risperidone 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 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 32.0 wt% copovidone, such as VA64. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 1.5 wt% 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 wt% iron oxide, such as E172. In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 39.995 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 42.0 wt% copovidone, such as VA64. In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 15.0 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, such as PEO(100K).In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 3.0 wt% 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 wt% iron oxide, such as E172. In some embodiments, the dosage form for administering risperidone comprises a gastroretentive system, wherein the gastroretentive system comprises one or two inactive segments. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 66.45 wt% Corbion PC17, about 32.0 wt% VA 64, about 1.5 wt% P407, and about 0.05 wt% FD&C Blue 1 aluminum lake. In some embodiments, the gastroretentive system comprises a second inactive segment comprising about 39.995 wt% Corbion PC17, about 42.0 wt% VA 64, about 15.0 wt% PEO100K, about 3.0 wt% P407, and about 0.005 wt% E172.

[0352] In some embodiments, a gastroretention system dosage form for administering one or more drugs can include a radiopaque segment, the segment comprising about 70 wt% polycaprolactone (PCL), such as Corbion PC17, having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g. In some embodiments, the gastroretention system comprises a radiopaque segment comprising about 30 wt% (BiO)2CO3. In some embodiments, the gastroretention system comprises a radiopaque segment comprising about 70 wt% Corbion PC17 and about 30 wt% (BiO)2CO3.

[0353] In some embodiments, a gastroretentive system dosage form for administering risperidone comprises a central elastomer and a drug-eluting segment comprising about 14 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system, the drug-eluting segment comprising about 28 mg of risperidone. In some embodiments, the gastroretentive system further comprises a release rate controlling film comprising about 73.5 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the release rate controlling film further comprises about 24.5 wt% copovidone, such as VA64. In some embodiments, the release rate controlling film further comprises about 2.0 wt% magnesium stearate. In some embodiments, the gastroretentive system further comprises a time-dependent disintegration matrix comprising about 44.95 wt% polycaprolactone (PCL), e.g., PCL having a medium viscosity of about 1.5 dL / g to about 2.1 dL / g, such as Corbion PC17. In some embodiments, the time-dependent disintegration matrix further comprises about 35.0 wt% of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint 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 disintegration matrix further comprises about 18.0 wt% of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a medium 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 wt% polyethylene glycol, e.g., polyethylene glycol with an average molecular weight of 100,000, e.g., PEO100K. In some embodiments, the time-dependent disintegrating matrix further comprises about 0.05 wt% iron oxide, e.g., E172.In some embodiments, the gastroretentive system further comprises a pH-dependent disintegrating matrix comprising about 33.95 wt% polycaprolactone (PCL), e.g., PCL having a medium viscosity of about 1.5 dL / g to about 2.1 dL / g, such as Corbion PC17. In some embodiments, the pH-dependent disintegrating matrix further comprises about 63.95 wt% hypromellose acetate succinate, e.g., HPMCAS-MG. In some embodiments, the pH-dependent disintegrating matrix further comprises about 2.0 wt% 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 pH-dependent disintegrating matrix further comprises about 0.1 wt% 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 wt% polycaprolactone (PCL), e.g., PCL having a viscosity midpoint between about 1.5 dL / g and about 2.1 dL / g, such as Corbion PC17. In some embodiments, the radiopaque segment comprises about 30 wt% (BiO)2CO3. In some embodiments, a dosage form for administering risperidone comprises a gastroretentive system comprising a central elastomer and a drug-eluting segment comprising about 14 mg of risperidone. In some embodiments, the dosage form comprises a gastroretentive system comprising a drug-eluting segment comprising about 28 mg of risperidone. In some embodiments, the gastroretentive system further comprises a release rate modifying film comprising about 73.5 wt% Corbion PC17, about 24.5 wt% VA64, and about 2.0 wt% Mg stearate.In some embodiments, the gastroretentive system further comprises a time-dependent disintegration matrix comprising about 44.95 wt% Corbion PC17, about 35.0 wt% PDLG 5004A, about 18.0 wt% PDLG 5004, about 2.0 wt% PEO100K, and about 0.05 wt% E172. In some embodiments, the gastroretentive system further comprises a pH-dependent disintegration matrix comprising about 33.95 wt% Corbion PC17, about 63.95 wt% HPMCAS-MG, about 2.0 wt% P407, and about 0.1 wt% E172. In some embodiments, the gastroretentive system further comprises one or more inert segments. In some embodiments, the gastroretentive system further comprises a radiopaque segment comprising about 70 wt% Corbion PC17 and about 30 wt% (BiO)2CO3.

[0354] In some embodiments, the gastroretention system has three arms that include a drug-eluting segment and three arms that do not, hi some embodiments, the gastroretention system has six arms that include a drug-eluting segment.

[0355] In some embodiments according to any of the systems described herein, the thickness of a segment is determined by the longest straight line within a cross section of the segment. In some embodiments where the cross section of the segment is a circle, the thickness is defined by the diameter of the circle. In some embodiments where the cross section of the segment is a square or rectangle, 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.

[0356] In some embodiments of any of the systems described herein, the thickness of the segments across the star arms is uniform. In some embodiments of any of the systems described herein, the thickness of the segments across the star arms is about 2.8 mm to about 3.7 mm, optionally about 3.1 mm to about 3.5 mm, and more optionally about 3.3 mm.

[0357] In some embodiments of any of the systems described herein, the thickness of one or more segments at the distal end of the arm (farthest from the star core) is less than the thickness of the remaining proximal segments in the arm; optionally, the thickness of the proximal segments may be uniform. In some embodiments of 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 of 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 thickness of the most distal segment is about 3.1 mm, and the remaining segments of the arm are about 3.3 mm thick.

[0358] Central Elastomer The central elastomer provides the gastroretentive system with the ability to be compressed into a compressed configuration, which can be placed into a capsule or other suitable containing structure for administration to a subject.

[0359] 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 durometers.

[0360] 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 durometers.

[0361] 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 60 durometers.

[0362] 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 50 durometers.

[0363] Velocity Modulating Polymer Film The release rate controlling polymer film can be coated onto a component of a gastroretentive system that releases a drug, such as a pharmaceutical agent. Components coated with the release rate controlling polymer films 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 controlling polymer film are disclosed in International Patent Application PCT / US2020 / 059541 (WO2021 / 092491), which is incorporated herein in its entirety. In some embodiments, one or more segments of a composite arm (e.g., a composite arm including a drug-eluting segment or a composite arm excluding a drug-eluting segment) are coated with a release rate controlling film. In some embodiments, the drug-eluting segment is coated with a release rate controlling film. In some embodiments, one or more inactive segments are coated with a release rate controlling film. In some embodiments, the release rate controlling film is applied in an amount of about 0.5% to about 10%, or about 1% to about 5%, e.g., about 2% to about 4%, of the pre-coating weight of the segments (such as the drug eluting segment and / or inactive segment(s)). In some embodiments, the release rate controlling film is applied in an amount of about 2.3% to about 3%, e.g., about 2.6%, of the pre-coating weight of the segments (such as the drug eluting segment and / or inactive segment(s)). In some embodiments, the release rate controlling film is applied in an amount of about 2.4% to about 3.2%, e.g., about 2.8%, of the pre-coating weight of the segments (such as the drug eluting segment and / or inactive segment(s)).

[0364] 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 wt% to about 78 wt% PCL. In some embodiments, the release rate controlling polymer film comprises about 71 wt% to about 76 wt% PCL. In some embodiments, the release rate controlling polymer film comprises about 73.5 wt% PCL.

[0365] Other excipients can be added to the carrier polymer to modify the release of drugs such as copovidone (VA64). In some embodiments, the release rate modifying polymer film comprises about 20 wt% to about 30 wt% VA64. In some embodiments, the release rate modifying polymer film comprises about 22 wt% to about 27 wt% VA64. In some embodiments, the release rate modifying polymer film comprises about 24.5 wt% VA64.

[0366] The release rate controlling film can include one or more dispersing agents, such as magnesium stearate. In some embodiments, the release rate controlling polymer film includes about 0.5 wt% to about 5 wt% magnesium stearate. In some embodiments, the release rate controlling polymer film includes about 1 wt% to about 3 wt% magnesium stearate. In some embodiments, the release rate controlling polymer film includes about 2 wt% magnesium stearate.

[0367] In some embodiments, the release rate controlling polymer film comprises about 68 wt% to about 78 wt% PCL, about 20 wt% to about 30 wt% VA64, and about 0.5 wt% to about 5 wt% magnesium stearate. In some embodiments, the release rate controlling polymer film comprises about 71 wt% to about 76 wt% PCL, about 22 wt% to about 27 wt% VA64, and about 1 wt% to about 3 wt% magnesium stearate. In some embodiments, the release rate controlling polymer film comprises about 73.5 wt% PCL, about 24.5 wt% VA64, and about 2 wt% magnesium stearate.

[0368] Exemplary amounts of components of the release rate controlling film are set forth in the table below. The amounts are given as approximate weight percentages, but it should be understood that where ranges are provided, the amounts are selected to add up to 100%.

[0369] [Table 51]

[0370] Encapsulation of gastroretentive systems As mentioned above, one example of a star system 100 is shown schematically in FIG. 1A, and the described configuration allows the system to be folded or compressed with a central elastomer. FIG. 1B shows the folded configuration 190 of the gastrostomy system of FIG. 1A (for clarity, only two arms are shown in FIG. 1B). When folded, the overall length of the system is reduced by approximately half, allowing the system to be conveniently placed into a container such as a capsule or other container suitable for oral administration.

[0371] In some embodiments, the capsule consists of a narrow 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 a sleeve over the narrow capsule bottom to cover the wider capsule top. In some embodiments, the system is oriented within the capsule so that the star core is located toward the capsule bottom and the distal tips of the star arms (and any circumferential filaments) are located toward 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 so that the star core is located toward the capsule top and the distal tips of the star arms (and any circumferential filaments) are located toward the capsule bottom, i.e., the capsule sleeve covers the star core. In some embodiments, the core-side sleeve provides better compatibility with the collapsible filament stabilization ring and ensures proper alignment of the stabilization ring filaments within the capsule for full deployment.

[0372] In some embodiments, the capsule size is 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 contains any one of the following: 1%, 2%, 3%, 4%, or 5% titanium dioxide. In some embodiments, the capsule is a white, opaque HPMC capsule (size 00EL) containing 2% titanium dioxide. In some embodiments, the capsule is a white, opaque HPMC capsule (size 00EL) containing 3% titanium dioxide.

[0373] In some embodiments, the gastroretentive system is assembled as described in Example 1 of International Patent Application PCT / US2020 / 059541 (WO2021 / 092491) and then placed into a capsule of appropriate size.

[0374] In some embodiments, the gastroretentive system is assembled and then placed into a capsule of appropriate size, as described in International Patent Application PCT / US2020 / 023704 (WO2020 / 191229).

[0375] In some embodiments, the gastroretentive system is assembled and then placed into a capsule of appropriate size, as described in International Patent Application PCT / US2020 / 023710 (WO2020 / 191231).

[0376] The entire contents of international applications PCT / US2020 / 059541 (WO2021 / 092491), PCT / US2020 / 023704 (WO2020 / 191229), and PCT / US2020 / 023710 (WO2020 / 191231) are incorporated herein by reference.

[0377] Sustained release pharmaceutical dosage forms In some embodiments of any one of the risperidone dosage forms described herein, the gastroretentive system allows for the sustained release of risperidone (e.g., including risperidone and any of its active metabolite forms).

[0378] Any gastroretentive system containing risperidone or a suitable amount thereof can be used in the dosing regimens disclosed herein, including, but not limited to, the gastroretentive systems for the administration of risperidone disclosed in International Patent Applications WO2021 / 092491 and WO2022 / 159529, the entire contents of which are incorporated herein by reference.

[0379] In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of at least about 7.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of at least about 6.5 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of at least about 4.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of at least about 3.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of at least about 2.5 ng / mL after about 120 hours. In one embodiment, administration of about 14 mg of risperidone to a human results in a plasma concentration of at least about 2.0 ng / mL after about 144 hours.

[0380] In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of not more than about 27.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of not more than about 22.5 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of not more than about 21.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of not more than about 21.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of not more than about 20.0 ng / mL after about 120 hours. In one embodiment, administration of about 14 mg of risperidone to a human results in a plasma concentration of about 17.0 ng / mL or less after about 144 hours.

[0381] In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of about 7.0 ng / mL to about 27.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of about 6.5 ng / mL to about 22.5 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of about 4.5 ng / mL to about 21.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 14 mg of risperidone to a human results in a plasma concentration of about 3.0 ng / mL to about 21.0 ng / mL after about 96 hours. In one embodiment, administration of about 14 mg of risperidone to a human results in a plasma concentration of about 2.5 ng / mL to about 20.0 ng / mL after about 120 hours. In one embodiment, administration of about 14 mg of risperidone to a human results in a plasma concentration of about 2.0 ng / mL to about 17.0 ng / mL after about 144 hours.

[0382] In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of at least about 20.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of at least about 16.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of at least about 14.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of at least about 12.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of at least about 9.0 ng / mL after about 120 hours. In one embodiment, administration of about 28 mg of risperidone to a human results in a plasma concentration of at least about 6.0 ng / mL after about 144 hours.

[0383] In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of not more than about 39.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of not more than about 39.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of not more than about 38.0 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of not more than about 35.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of not more than about 30.0 ng / mL after about 120 hours. In one embodiment, administration of about 28 mg of risperidone to a human results in a plasma concentration of about 25.0 ng / mL or less after about 144 hours.

[0384] In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of about 20.0 ng / mL to about 39.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of about 16.0 ng / mL to about 39.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of about 14.5 ng / mL to about 38.0 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 28 mg of risperidone to a human results in a plasma concentration of about 12.0 ng / mL to about 35.0 ng / mL after about 96 hours. In one embodiment, administration of about 28 mg of risperidone to a human results in a plasma concentration of about 9.0 ng / mL to about 30.0 ng / mL after about 120 hours. In one embodiment, administration of about 28 mg of risperidone to a human results in a plasma concentration of about 6.0 ng / mL to about 25.0 ng / mL after about 144 hours.

[0385] In any of these embodiments, administration of the gastric retention dosage form can occur after administering immediate-release risperidone for at least 7 days, for example, administering about 2 mg of immediate-release risperidone for at least about 7 days, or administering about 4 mg of immediate-release risperidone for at least about 7 days, or administering about 6 mg of immediate-release risperidone for at least about 7 days.

[0386] In some embodiments of any one of the risperidone dosage forms described herein, the gastroretentive system allows for the sustained release of risperidone (e.g., including risperidone and any of its active metabolite forms).

[0387] In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of at least about 7.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of at least about 6.5 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of at least about 4.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of at least about 3.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of at least about 2.5 ng / mL after about 120 hours. In one embodiment, administration of about 15 mg of risperidone to a human results in a plasma concentration of at least about 2.0 ng / mL after about 144 hours.

[0388] In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of not more than about 27.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 22.5 ng / mL or less after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 21.5 ng / mL or less after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 21.0 ng / mL or less after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 20.0 ng / mL or less after about 120 hours. In one embodiment, administration of about 15 mg of risperidone to a human results in a plasma concentration of about 17.0 ng / mL or less after about 144 hours.

[0389] In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 7.0 ng / mL to about 27.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 6.5 ng / mL to about 22.5 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 4.5 ng / mL to about 21.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 15 mg of risperidone to a human results in a plasma concentration of about 3.0 ng / mL to about 21.0 ng / mL after about 96 hours. In one embodiment, administration of about 15 mg of risperidone to a human results in a plasma concentration of about 2.5 ng / mL to about 20.0 ng / mL after about 120 hours. In one embodiment, administration of about 15 mg of risperidone to a human results in a plasma concentration of about 2.0 ng / mL to about 17.0 ng / mL after about 144 hours.

[0390] In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of at least about 20.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of at least about 16.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of at least about 14.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of at least about 12.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of at least about 9.0 ng / mL after about 120 hours. In one embodiment, administration of about 30 mg of risperidone to a human results in a plasma concentration of at least about 6.0 ng / mL after about 144 hours.

[0391] In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of not more than about 39.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of not more than about 39.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of not more than about 38.0 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of not more than about 35.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of not more than about 30.0 ng / mL after about 120 hours. In one embodiment, administration of about 30 mg of risperidone to a human results in a plasma concentration of about 25.0 ng / mL or less after about 144 hours.

[0392] In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of about 20.0 ng / mL to about 39.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of about 16.0 ng / mL to about 39.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of about 14.5 ng / mL to about 38.0 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 30 mg of risperidone to a human results in a plasma concentration of about 12.0 ng / mL to about 35.0 ng / mL after about 96 hours. In one embodiment, a gastric retention dosage form containing about 30 mg of risperidone administered to a human results in a plasma concentration of about 9.0 ng / mL to about 30.0 ng / mL after about 120 hours. In one embodiment, a gastric retention dosage form containing about 30 mg of risperidone administered to a human results in a plasma concentration of about 6.0 ng / mL to about 25.0 ng / mL after about 144 hours.

[0393] In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of at least about 20.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of at least about 16.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of at least about 14.5 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of at least about 12.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of at least about 9.0 ng / mL after about 120 hours. In one embodiment, administration of about 45 mg of risperidone to a human results in a plasma concentration of at least about 6.0 ng / mL after about 144 hours.

[0394] In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of not more than about 39.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of not more than about 39.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of not more than about 38.0 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of not more than about 35.0 ng / mL after about 96 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of not more than about 30.0 ng / mL after about 120 hours. In one embodiment, administration of about 45 mg of risperidone to a human results in a plasma concentration of about 25.0 ng / mL or less after about 144 hours.

[0395] In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of about 20.0 ng / mL to about 39.0 ng / mL after about 24 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of about 16.0 ng / mL to about 39.0 ng / mL after about 48 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of about 14.5 ng / mL to about 38.0 ng / mL after about 72 hours. In one embodiment, administration of a gastric retention dosage form containing about 45 mg of risperidone to a human results in a plasma concentration of about 12.0 ng / mL to about 35.0 ng / mL after about 96 hours. In one embodiment, administration of about 45 mg of risperidone to a human results in a plasma concentration of about 9.0 ng / mL to about 30.0 ng / mL after about 120 hours. In one embodiment, administration of about 45 mg of risperidone to a human results in a plasma concentration of about 6.0 ng / mL to about 25.0 ng / mL after about 144 hours.

[0396] In any of these embodiments, administration of the gastric retention dosage form can occur after administering immediate-release risperidone for at least 7 days, for example, administering about 2 mg of immediate-release risperidone for at least about 7 days, or administering about 4 mg of immediate-release risperidone for at least about 7 days, or administering about 6 mg of immediate-release risperidone for at least about 7 days.

[0397] In additional embodiments, an immediate release dosage form of risperidone can be administered to an individual for a first period of time, then one or more gastroretentive systems comprising an immediate release dosage form of risperidone and risperidone can be administered to the individual for a second period of time, and then one or more gastroretentive systems comprising risperidone can be administered to the individual for a third period of time. The first period of time can be between about 1 day and about 4 weeks, e.g., between about 3 days and about 4 weeks, about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, or between any two of these periods, e.g., between about 1 day and about 1 week, about 1 week and about 2 weeks, about 1 week and about 3 weeks, or about 1 week and about 4 weeks.

[0398] The first period is followed by a second period during which the individual is administered both an immediate-release dosage form of risperidone and one or more gastroretentive systems containing risperidone. The second period can be about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks, or between any two of these periods, such as between about 1 day and about 3 days, between about 1 day and about 1 week, between about 3 days and about 1 week, between about 1 week and about 2 weeks, between about 1 week and about 3 weeks, between about 1 week and about 4 weeks, between about 1 week and about 5 weeks, or between about 1 week and about 6 weeks.

[0399] After the second period, a third period occurs, during which one or more gastroretentive systems are administered to the individual. The third period can vary widely depending on how long the individual requires treatment. Because many psychiatric and / or neurological disorders may require lifelong treatment, the third period can be indefinite. Alternatively, the third period can be about 1 week, about 1 month, about 3 months, about 6 months, about 9 months, about 1 year, about 2 years, about 3 years, about 5 years, or about 10 years, or between any two of these periods, such as between about 1 week and about 1 year, between about 1 month and about 1 year, between about 3 months and about 6 months, between about 3 months and about 1 year, between about 1 year and about 2 years, or between about 1 year and about 5 years.

[0400] The immediate release dosage form of risperidone administered to the individual over the first period of time comprises about 1 mg to about 10 mg of risperidone, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, or an amount between any two of these doses.

[0401] The immediate release dosage form of risperidone administered to the individual over the second period comprises about 1 mg to about 10 mg of risperidone, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, or an amount between any two of these doses.

[0402] The one or more gastroretentive systems containing risperidone can contain from about 10 mg to about 60 mg of risperidone, for example, about 10 mg of risperidone, about 15 mg of risperidone, about 20 mg of risperidone, about 25 mg of risperidone, about 30 mg of risperidone, about 35 mg of risperidone, about 40 mg of risperidone, about 45 mg of risperidone, about 50 mg of risperidone, about 55 mg of risperidone, about 60 mg of risperidone, or an amount between any two of the foregoing amounts.

[0403] The immediate-release form of risperidone can be administered to the individual once daily.

[0404] The gastroretentive system containing risperidone can be administered to an individual periodically over a second period of time, depending on the retention period of the gastroretentive system or the period during which sufficient drug is released from the gastroretentive system. In one embodiment, the gastroretentive system is administered once weekly during the second period of time. In one embodiment, the gastroretentive system contains about 15 mg of risperidone and is administered once weekly during the second period of time. In one embodiment, the gastroretentive system contains about 15 mg of risperidone and is administered once weekly during the second period of time, and the immediate-release risperidone is administered in an amount of about 1 mg per day during the second period of time. In one embodiment, the gastroretentive system contains about 30 mg of risperidone and is administered once weekly during the second period of time. In one embodiment, the gastroretentive system contains about 30 mg of risperidone and is administered once weekly during the second period of time, and the immediate-release risperidone is administered in an amount of about 2 mg per day during the second period of time. In one embodiment, the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the second time period. In one embodiment, the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the second time period, and the immediate-release risperidone is administered in an amount of about 3 mg per day during the second time period.

[0405] The gastroretentive system containing risperidone can be administered to an individual periodically over a third period of time depending on the retention time of the gastroretentive system or the period during which sufficient drug is released from the gastroretentive system. In one embodiment, the gastroretentive system is administered once weekly during the third period of time. In one embodiment, the gastroretentive system contains about 15 mg of risperidone and is administered once weekly during the third period of time. In one embodiment, the gastroretentive system contains about 30 mg of risperidone and is administered once weekly during the third period of time. In one embodiment, the gastroretentive system contains about 45 mg of risperidone and is administered once weekly during the third period of time.

[0406] In one embodiment, immediate-release risperidone is administered daily in an amount of about 2 mg during a first period of time; immediate-release risperidone is administered daily in an amount of about 1 mg during a second period of time, the gastroretentive system comprises about 15 mg of risperidone and is administered once weekly during the second period of time; and the gastroretentive system comprises about 15 mg of risperidone and is administered once weekly during a third period of time.

[0407] In one embodiment, immediate-release risperidone is administered daily in an amount of about 4 mg during a first period of time; immediate-release risperidone is administered daily in an amount of about 2 mg during a second period of time, the gastroretentive system comprises about 30 mg of risperidone and is administered once weekly during the second period of time; and the gastroretentive system comprises about 30 mg of risperidone and is administered once weekly during a third period of time.

[0408] In one embodiment, immediate-release risperidone is administered daily in an amount of about 6 mg during a first period of time; immediate-release risperidone is administered daily in an amount of about 3 mg during a second period of time, the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the second period of time, and the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during a third period of time.

[0409] In additional embodiments, risperidone can be administered to an individual by a method comprising administering to the individual an immediate release dosage form of risperidone and one or more gastroretentive systems comprising risperidone for a co-administration period; and then administering to the individual one or more gastroretentive systems comprising risperidone for a subsequent period.

[0410] The co-administration period can be about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks, or between any two of these periods, for example, between about 1 day and about 3 days, between about 1 day and about 1 week, between about 3 days and about 1 week, between about 1 week and about 2 weeks, between about 1 week and about 3 weeks, between about 1 week and about 4 weeks, between about 1 week and about 5 weeks, or between about 1 week and about 6 weeks.

[0411] The co-administration period is followed by a subsequent period during which one or more gastroretentive systems are administered to the individual. This subsequent period can vary substantially depending on how long the individual requires treatment. Because many psychiatric and / or neurological disorders may require lifelong treatment, this subsequent period can be indefinite. Alternatively, this subsequent period can be about 1 week, about 1 month, about 3 months, about 6 months, about 9 months, about 1 year, about 2 years, about 3 years, about 5 years, or about 10 years, or between any two of these periods, e.g., between about 1 week and about 1 year, between about 1 month and about 1 year, between about 3 months and about 6 months, between about 3 months and about 1 year, between about 1 year and about 2 years, or between about 1 year and about 5 years.

[0412] The immediate release dosage form of risperidone administered to an individual over the co-administration period comprises about 1 mg to about 10 mg of risperidone, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, or an amount between any two of these doses.

[0413] The one or more gastroretentive systems containing risperidone can contain about 10 mg to about 60 mg of risperidone, for example, about 10 mg of risperidone, about 15 mg of risperidone, about 20 mg of risperidone, about 25 mg of risperidone, about 30 mg of risperidone, about 35 mg of risperidone, about 40 mg of risperidone, about 45 mg of risperidone, about 50 mg of risperidone, about 55 mg of risperidone, about 60 mg of risperidone, or an amount between the two aforementioned amounts.

[0414] The immediate-release form of risperidone can be administered to the individual once daily.

[0415] The gastroretentive system containing risperidone can be administered to an individual periodically throughout the co-administration period, depending on the retention period of the gastroretentive system or the period during which sufficient drug is released from the gastroretentive system. In one embodiment, the gastroretentive system is administered once weekly during the co-administration period. In one embodiment, the gastroretentive system contains about 15 mg of risperidone and is administered once weekly during the co-administration period. In one embodiment, the gastroretentive system contains about 15 mg of risperidone and is administered once weekly during the co-administration period, and the immediate-release risperidone is administered in an amount of about 1 mg per day during the co-administration period. In one embodiment, the gastroretentive system contains about 30 mg of risperidone and is administered once weekly during the co-administration period. In one embodiment, the gastroretentive system contains about 30 mg of risperidone and is administered once weekly during the co-administration period, and the immediate-release risperidone is administered in an amount of about 2 mg per day during the co-administration period. In one embodiment, the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the co-administration period. In one embodiment, the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the co-administration period, and the immediate-release risperidone is administered in an amount of about 3 mg daily during the co-administration period.

[0416] The gastroretentive system containing risperidone can be administered to an individual periodically over a subsequent period depending on the retention time of the gastroretentive system or the time period during which sufficient drug is released from the gastroretentive system. In one embodiment, the gastroretentive system is administered once weekly during the subsequent period. In one embodiment, the gastroretentive system contains about 15 mg of risperidone and is administered once weekly during the subsequent period. In one embodiment, the gastroretentive system contains about 30 mg of risperidone and is administered once weekly during the subsequent period. In one embodiment, the gastroretentive system contains about 45 mg of risperidone and is administered once weekly during the subsequent period.

[0417] In one embodiment, immediate-release risperidone is administered daily in an amount of about 1 mg during the co-administration period, and the gastroretentive system comprises about 15 mg of risperidone and is administered once weekly during the co-administration period; and the gastroretentive system comprises about 15 mg of risperidone and is administered once weekly during the subsequent period.

[0418] In one embodiment, immediate-release risperidone is administered daily in an amount of about 2 mg during the co-administration period, and the gastroretentive system comprises about 30 mg of risperidone and is administered once weekly during the co-administration period; and the gastroretentive system comprises about 30 mg of risperidone and is administered once weekly during the subsequent period.

[0419] In one embodiment, immediate-release risperidone is administered daily in an amount of about 3 mg during the co-administration period, and the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the co-administration period; and the gastroretentive system comprises about 45 mg of risperidone and is administered once weekly during the subsequent period.

[0420] The subject of risperidone administration may have a psychiatric or neurological disorder. The psychiatric or neurological disorder may be schizophrenia. The psychiatric or neurological disorder may be bipolar disorder. The psychiatric or neurological disorder may be hyperirritability associated with autistic disorder.

[0421] Immediate release dosage form for co-administration with a gastroretentive system During any co-administration period in which both an immediate-release dosage form of risperidone or a salt thereof and one or more gastroretentive systems containing risperidone or a salt thereof are administered to an individual, the immediate-release dosage form can be combined with a gastroretentive system to form an immediate-release-gastroretentive system combination dosage form. The immediate-release dosage form can be combined with a gastroretentive system in various configurations. In a first configuration, a capsule containing a gastroretentive system can be coated on the outside with a coating containing risperidone or a salt thereof, and the coating containing risperidone or a salt thereof is an immediate-release form of risperidone or a salt thereof. When the drug-coated capsule reaches the stomach, the coating containing risperidone or a salt thereof dissolves and can be absorbed. In a second configuration, the immediate-release form of risperidone or a salt thereof can be placed in a capsule containing a gastroretentive system, for example, as a powder, gel, tablet, or other form suitable for inclusion in a capsule. Upon dissolution of the capsule in the stomach, the immediate-release form of risperidone or a salt thereof is released along with the gastroretentive system. The immediate-release risperidone or salt thereof is then absorbed. In a third configuration, the gastroretentive system can have a layer, segment, or patch of immediate-release risperidone or its salt in addition to the sustained-release risperidone or salt thereof contained in the gastroretentive system. When the gastroretentive system is released in the stomach, the immediate-release risperidone or salt thereof dissolves and can then be absorbed.

[0422] The immediate release dosage form of risperidone or a salt thereof administered to an individual over the co-administration period can contain from about 1 mg to about 10 mg of risperidone or a salt thereof, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, or an amount between any two of these doses.

[0423] Enumerated Embodiments The embodiments listed below are representative of some aspects of the present disclosure and may, where practical, be combined with other features disclosed herein.

[0424] Embodiment 1. A gastroretentive system comprising: six arms fixed to a central elastomer, at least one arm comprising a drug-eluting segment; each arm includes a proximal end, a distal end, and an outer surface therebetween; wherein the proximal end of each arm is attached to and projects radially from the central elastomer, and each arm has its distal end not attached to the central elastomeric component and is located a greater radial distance from the central elastomeric component than the proximal end; wherein at least one arm comprising a drug eluting segment comprises: First inactive segment; a first disintegrable matrix segment attached to a first inert segment; a second inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the second inert segment; a third inert segment attached to the second disintegrable matrix segment; a fourth inactive segment attached to the third inactive segment; a drug eluting segment attached to the fourth inert segment, the drug eluting segment comprising a carrier polymer and risperidone or a salt thereof, the drug eluting segment further comprising a coating comprising a release rate modifying polymer film; an optional fifth inactive segment attached to the drug-eluting segment; and a third disintegrable matrix segment attached to the optional fifth inert segment, if present, or attached to the drug-eluting segment, if the optional fifth inert segment is not present; and A filament connects each arm circumferentially.

[0425] Embodiment 2. A gastroretentive system comprising: six arms fixed to a central elastomer, at least one arm comprising a drug-eluting segment; each arm includes a proximal end, a distal end, and an outer surface therebetween; wherein the proximal end of each arm is attached to the elastomeric component and protrudes radially from the elastomeric component, and each arm has its distal end not attached to the elastomeric component and is located a greater radial distance from the elastomeric component than the proximal end; wherein at least one arm comprising a drug eluting segment comprises: First inactive segment; a first disintegrable matrix segment attached to a first inert segment; a second inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the second inert segment; a third inert segment attached to the second disintegrable matrix segment; a fourth inactive segment attached to the third inactive segment; a drug eluting segment attached to the fourth inert segment, the drug eluting segment comprising a carrier polymer and risperidone or a salt thereof, the drug eluting segment further comprising a coating comprising a release rate modifying polymer film; an optional fifth inactive segment accompanying the drug-eluting segment; a third disintegrable matrix segment attached to an optional fifth inert segment; and A filament connects each arm circumferentially.

[0426] Embodiment 3. A gastric retention system according to embodiment 1 or 2, wherein the first inactive segment is attached to the central elastomer.

[0427] Embodiment 4. A gastric retention system according to any one of embodiments 1 to 3, wherein the segments are in the order listed from the proximal end to the distal end of the arms comprising the drug eluting segment, the first inactive segment being at the proximal end of the arms comprising the drug eluting segment, the first inactive segment being attached to the central elastomer, and the third disintegrable matrix segment being at the distal end of the arms comprising the drug eluting segment.

[0428] Embodiment 5. A gastric retention system according to any one of embodiments 1 to 4, wherein at least one arm excludes a drug-eluting segment.

[0429] Embodiment 6. At least one arm, excluding the drug eluting segment, First inactive segment; a first disintegrable matrix segment attached to a first inert segment; a second inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the second inert segment; a third inert segment attached to the second disintegrable matrix segment; a fourth inactive segment attached to the third inactive segment; an optional fifth inactive segment attached to the fourth inactive segment; and a third disintegrable matrix segment attached to any fifth inert segment, if present, or attached to the fourth inert segment, if any fifth inert segment is not present; and Filaments connecting the arms in the circumferential direction 6. The gastric retention system of embodiment 5, comprising:

[0430] Embodiment 7. At least one arm, excluding the drug eluting segment, First inactive segment; a first disintegrable matrix segment attached to a first inert segment; a second inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the second inert segment; a third inert segment attached to the second disintegrable matrix segment; a fourth inactive segment attached to the third inactive segment; an optional fifth inactive segment attached to the fourth inactive segment; and a third disintegrable matrix segment attached to an optional fifth inert segment; 6. The gastric retention system of embodiment 5, comprising:

[0431] Embodiment 8. A gastroretention system according to embodiment 6 or 7, wherein the first inactive segment is attached to the central elastomer.

[0432] Embodiment 9. The gastric retention system of embodiment 8, wherein the segments are in the order listed from the proximal end to the distal end of the arm excluding the drug eluting segment, the first inactive segment is at the proximal end of the arm excluding the drug eluting segment, the first inactive segment is attached to the central elastomer, and the third disintegrable matrix segment is at the distal end of the arm excluding the drug eluting segment.

[0433] Embodiment 10. A gastroretentive system comprising: six arms secured to a central elastomer, at least one arm comprising a drug-eluting segment; each arm includes a proximal end, a distal end, and an outer surface therebetween; wherein the proximal end of each arm is attached to the elastomeric component and protrudes radially from the elastomeric component, and each arm has its distal end not attached to the elastomeric component and is located a greater radial distance from the elastomeric component than the proximal end; wherein at least one arm comprising a drug eluting segment comprises: First inactive segment; a first disintegrable matrix segment attached to a first inert segment; a second inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the second inert segment; a third inert segment attached to the second disintegrable matrix segment; a fourth inactive segment attached to the third inactive segment; a drug eluting segment attached to the fourth inert segment, the drug eluting segment comprising a carrier polymer and risperidone or a salt thereof, the drug eluting segment further comprising a coating comprising a release rate modifying polymer film; a fifth inactive segment attached to the drug-eluting segment; and An optional filament circumferentially connects each arm.

[0434] Embodiment 11. A gastric retention system according to embodiment 10, wherein the first inactive segment is attached to the central elastomer.

[0435] Embodiment 12. A gastric retention system as described in embodiment 10 or 11, wherein the segments are in the order listed from the proximal end to the distal end of the arm that constitutes the drug eluting segment, with the first inactive segment being at the proximal end of the arm that constitutes the drug eluting segment, the first inactive segment being attached to the central elastomer, and the fifth inactive segment being at the distal end of the arm that constitutes the drug eluting segment.

[0436] Embodiment 13. A gastric retention system according to any one of embodiments 10 to 12, wherein at least one arm excludes a drug-eluting segment.

[0437] Embodiment 14. At least one arm, excluding the drug eluting segment, First inactive segment; a first disintegrable matrix segment attached to a first inert segment; a second inert segment attached to the first disintegrable matrix segment; a second disintegrable matrix segment attached to the second inert segment; a third inert segment attached to the second disintegrable matrix segment; a fourth inactive segment attached to the third inactive segment; and A fifth inactive segment attached to a fourth inactive segment 14. The gastric retention system of embodiment 13, comprising:

[0438] Embodiment 15. A gastric retention system according to embodiment 14, wherein the first inactive segment is attached to the central elastomer.

[0439] Embodiment 16. A gastric retention system as described in embodiment 15, wherein the segments are in the order listed from the proximal end to the distal end of the arm excluding the drug eluting segment, with the first inactive segment being at the proximal end of the arm excluding the drug eluting segment, the first inactive segment being attached to the central elastomer, and the fifth inactive segment being at the distal end of the arm excluding the drug eluting segment.

[0440] Embodiment 17. A gastric retention system according to any one of embodiments 1 to 16, wherein three arms constitute a drug-eluting segment and three arms exclude a drug-eluting segment.

[0441] Embodiment 18. A gastric retention system described in any one of embodiments 1 to 16, wherein all of the arms constitute a drug-eluting segment.

[0442] Embodiment 19. The first inactive segment comprises: (a) polycaprolactone (PCL), optionally having about 68 wt % to about 72 wt % of the first inactive segment; and / or (b) (BiO)2CO3, optionally wherein the first inactive segment comprises about 28 wt% to about 32 wt% (BiO)2CO3. 19. A gastric retention system according to any one of embodiments 1 to 18, comprising:

[0443] Embodiment 20. A gastroretentive system according to any one of embodiments 1 to 19, wherein the first disintegrating matrix segment comprises a time-dependent disintegrating matrix.

[0444] Embodiment 21. The first disintegrable matrix segment comprises: (a) polycaprolactone (PCL), optionally wherein the first disintegrable matrix comprises about 43 wt % to about 47 wt % PCL; and / or (b) an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g; optionally, the first disintegrable matrix is ​​about 33 wt% to about 37 wt% of the acid-terminated copolymer of DL-lactide and glycolide; and / or (c) a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g; optionally, the first disintegrable matrix comprises about 15 wt% to about 20 wt% of the copolymer of DL-lactide and glycolide; (d) polyethylene oxide, optionally having a molecular weight of about 100,000 MW (PEO 100k), and further optionally, wherein the segments comprise about 1 wt % to about 3 wt % polyethylene oxide; (e) optionally a colorant, optionally wherein the first disintegrable matrix comprises about 0.01 wt % to about 0.1 wt % of the colorant. 21. A gastric retention system according to any one of embodiments 1 to 20, comprising:

[0445] Embodiment 22. The gastroretentive system of any one of embodiments 1 to 21, wherein the second inactive segment comprises: (a) polycaprolactone (PCL), optionally having about 68 wt % to about 72 wt % PCL in the second inactive segment; and / or (b) (BiO)2CO3, optionally a second inactive segment comprising about 28 wt% to about 32 wt% (BiO)2CO3.

[0446] Embodiment 23. The gastroretentive system of any one of embodiments 1 to 22, wherein the second disintegrable matrix segment comprises an enterodisintegrable matrix.

[0447] Embodiment 24. The gastroretentive system of any one of embodiments 1 to 23, wherein the second disintegrable matrix comprises: (a) polycaprolactone (PCL), optionally wherein the second disintegrable matrix comprises about 32 wt % to about 36 wt % PCL; and / or (b) hydroxypropyl methylcellulose succinate (HPMCAS); optionally, the second disintegrable matrix is ​​about 62 wt% to about 66 wt% HPMCAS; and / or (c) a polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymer, optionally wherein the second disintegrable matrix comprises about 1 wt % to about 3 wt % of the PEG-PPG-PEG block copolymer; and / or (d) Optionally, a colorant; optionally, the second disintegrable matrix comprises about 0.05 wt% to about 0.15 wt% of a colorant.

[0448] Embodiment 25. The gastroretentive system of any one of embodiments 1 to 24, wherein the third inactive segment comprises: (a) polycaprolactone (PCL), optionally having a third inactive segment of about 68 wt % to about 72 wt % PCL; and / or (b) (BiO)2CO3, optionally a third inactive segment comprising about 28 wt% to about 32 wt% (BiO)2CO3.

[0449] Embodiment 26. The gastroretentive system of any one of embodiments 1 to 25, wherein the fourth inactive segment comprises: (a) polycaprolactone (PCL), optionally wherein the fourth inactive segment comprises about 64 wt % to about 69 wt % PCL; and / or (b) copovidone; optionally, the fourth inactive segment comprises about 30 wt% to about 34 wt% copovidone; and / or (c) a polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymer, optionally wherein the fourth inert segment comprises about 0.5 wt % to about 2.5 wt % of the PEG-PPG-PEG block copolymer; and / or (d) Optionally, a colorant. Optionally, the fourth inactive segment comprises about 0.01 wt% to about 0.1 wt% of a colorant.

[0450] Embodiment 27. The gastroretentive system of any one of embodiments 10-26, wherein the fifth inactive segment comprises: (a) polycaprolactone (PCL), optionally wherein the fifth inactive segment comprises about 38 wt % to about 42 wt % PCL; and / or (b) copovidone; optionally, the fifth inactive segment comprises about 40 wt% to about 44 wt% copovidone; and / or (c) polyethylene glycol, optionally wherein the fifth inert segment comprises about 13 wt% to about 17 wt% polyethylene glycol; and / or (d) a polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymer, optionally wherein the fifth inactive segment comprises about 2 wt % to about 4 wt % of the PEG-PPG-PEG block copolymer; and / or (e) Optionally, a colorant. Optionally, the fifth inactive segment comprises about 0.01 wt% to about 0.1 wt% of a colorant.

[0451] Embodiment 28. The gastroretentive system of any one of embodiments 1-9 and 17-26, wherein the optional fifth inactive segment comprises: (a) polycaprolactone (PCL), optionally having a fifth inactive segment of about 68 wt % to about 72 wt % PCL; and / or (b) (BiO)2CO3, optionally with a fifth inactive segment of about 28 wt% to about 32 wt% (BiO)2CO3.

[0452] Embodiment 29. The gastroretentive system of any one of embodiments 1 to 28, wherein the third disintegrable matrix segment comprises: (a) polycaprolactone (PCL), optionally wherein the second disintegrable matrix comprises about 28 wt % to about 32 wt % PCL; and / or (b) hydroxypropyl methylcellulose succinate (HPMCAS); optionally, the second disintegrable matrix comprises about 63 wt% to about 67 wt% HPMCAS; and / or (c) stearic acid, optionally wherein the second disintegrable matrix comprises about 2 wt% to about 3 wt% stearic acid; and / or (d) polypropylene glycol, optionally, the second disintegrable matrix comprises about 2 wt % to about 3 wt % polypropylene glycol; and / or (e) optional colorant; optionally, the segment comprises about 0.05 wt % to about 0.15 wt % of a colorant.

[0453] Embodiment 30. The gastroretentive system of any one of embodiments 1-29, wherein the drug eluting segment comprises: (a) risperidone, optionally the drug-eluting segment comprises about 33 wt% to about 37 wt% risperidone; and / or (b) polycaprolactone (PCL), optionally wherein the segment comprises about 54 wt% to about 58 wt% PCL; and / or (c) copovidone, optionally wherein the segment comprises about 4 wt% to about 6 wt% copovidone; and / or (d) a polyethylene glycol-polypropylene glycol-polyethylene glycol (PEG-PPG-PEG) block copolymer, optionally wherein the segment comprises about 2 wt % to about 4 wt % of the PEG-PPG-PEG block copolymer; and / or (e) vitamin E succinate, optionally the segment comprising about 0.2 wt% to about 0.8 wt% vitamin E succinate; and / or (f) colloidal silicon dioxide (SiO2), optionally wherein the segment comprises about 0.2 wt% to about 0.8 wt% SiO2; and / or (g) an optional colorant; optionally, the segment comprises about 0.05 wt % to about 0.15 wt % of a colorant.

[0454] Embodiment 31. A gastric retention system comprising: six arms secured to a central elastomer, at least one arm comprising a drug-eluting segment; each arm includes a proximal end, a distal end, and an outer surface therebetween; wherein the proximal end of each arm is attached to and protrudes radially from the central elastomer, and each arm has its distal end not attached to the central elastomer and is located a greater radial distance from the central elastomer than the proximal end; wherein at least one arm comprising a drug eluting segment comprises: First disintegrable matrix segment; a first inert segment attached to a 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 drug eluting segment attached to the second inert segment, the drug eluting segment comprising a carrier polymer and risperidone or a salt thereof, the drug eluting segment further comprising a coating comprising a release rate modifying polymer film; a third inactive segment attached to the drug-eluting segment; and A filament connects each arm circumferentially.

[0455] Embodiment 32. A gastroretentive system according to embodiment 31, wherein the first disintegrable matrix segment is attached to the central elastomer.

[0456] Embodiment 33. A gastric retention system according to embodiment 31 or 32, wherein the segments are in the order listed from the proximal end to the distal end of the arm comprising the drug eluting segment, the first disintegrable matrix segment being at the proximal end of the arm comprising the drug eluting segment, the first disintegrable matrix segment being attached to the central elastomer, and the third inactive seg...

Claims

1. 1. A method of administering risperidone or a salt thereof to an individual, comprising: administering to the individual one or more combined immediate-release-gastric retention system dosage forms of risperidone or salts thereof for a first period of time; administering one or more gastroretentive systems comprising risperidone or a salt thereof to the individual for a second period of time; A method comprising:

2. 10. The method of claim 1, wherein the first period of time is between about 1 day and about 4 weeks.

3. 10. The method of claim 1, wherein the first period of time is between about 1 week and about 2 weeks.

4. 10. The method of claim 1, wherein the first period of time is between about 1 day and about 1 week.

5. 10. The method of claim 1, wherein the first period of time is about one week.

6. 6. The method of any one of claims 1 to 5, wherein the second period of time is between about 1 week and about 1 year.

7. 6. The method of any one of claims 1 to 5, wherein the second period of time is between about 3 months and about 1 year.

8. The method of any one of claims 1 to 5, wherein the second period of time continues indefinitely.

9. 9. The method of any one of claims 1 to 8, wherein the gastroretentive system is contained in a capsule, and the capsule comprises a coating comprising immediate-release risperidone or a salt thereof.

10. The method of any one of claims 1 to 8, wherein the gastroretentive system is contained in a capsule, and the capsule further comprises an immediate release form of risperidone or a salt thereof.

11. The method of any one of claims 1 to 8, wherein the gastroretentive system comprises an immediate-release risperidone or salt thereof layer, segment, or patch.

12. 12. The method of any one of claims 1 to 11, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over a first period of time comprises from about 1 mg to about 10 mg of risperidone or a salt thereof.

13. 13. The method of claim 12, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the first period comprises about 2 mg, about 4 mg, or about 6 mg of risperidone or a salt thereof.

14. The method of any one of claims 1 to 13, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises from about 10 mg to about 60 mg of risperidone or a salt thereof.

15. 15. The method of claim 14, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises about 15 mg, about 30 mg, or about 45 mg of risperidone or a salt thereof.

16. 16. The method of any one of claims 1 to 15, wherein one or more gastroretentive systems comprising risperidone or a salt thereof are administered to the individual weekly during the second period.

17. 1. A method of administering risperidone or a salt thereof to an individual, comprising: administering an immediate release dosage form of risperidone or a salt thereof to the individual for a first period of time; administering to the individual an immediate release dosage form of risperidone or a salt thereof and one or more gastroretentive systems comprising risperidone or a salt thereof for a second period of time; and administering to the individual one or more gastroretentive systems comprising risperidone or a salt thereof for a third period of time. A method comprising:

18. 18. The method of claim 17, wherein the first period of time is between about 1 day and about 4 weeks.

19. 20. The method of claim 18, wherein the first period of time is between about 1 week and about 2 weeks.

20. 20. The method of claim 18, wherein the first period of time is between about 1 day and about 1 week.

21. 20. The method of claim 18, wherein the first period of time is about one week.

22. 22. The method of any one of claims 17 to 21, wherein the second period of time is between about 1 week and about 6 weeks.

23. 23. The method of claim 22, wherein the second period of time is between about 1 week and about 3 weeks.

24. 23. The method of claim 22, wherein the second period of time is about one week.

25. 25. The method of any one of claims 17 to 24, wherein the third period of time is between about 1 week and about 1 year.

26. 25. The method of any one of claims 17 to 24, wherein the third period of time is between about 3 months and about 1 year.

27. 25. The method of any one of claims 17 to 24, wherein the third period of time continues indefinitely.

28. 28. The method of any one of claims 17 to 27, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over a first period of time comprises from about 1 mg to about 10 mg of risperidone or a salt thereof.

29. 29. The method of claim 28, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the first period of time comprises about 2 mg, about 4 mg, or about 6 mg of risperidone or a salt thereof.

30. 30. The method of any one of claims 17-29, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the second period of time comprises from about 1 mg to about 10 mg of risperidone or a salt thereof.

31. 31. The method of claim 30, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the second period comprises about 1 mg, about 2 mg, or about 3 mg of risperidone or a salt thereof.

32. 32. The method of any one of claims 17 to 31, wherein the immediate release dosage form of risperidone or a salt thereof is administered to the individual daily during a first period of time, daily during a second period of time, or daily during both the first and second period of time.

33. 33. The method of any one of claims 17 to 32, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises from about 10 mg to about 60 mg of risperidone or a salt thereof.

34. 34. The method of claim 33, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises about 15 mg, about 30 mg, or about 45 mg of risperidone or a salt thereof.

35. 35. The method of any one of claims 17 to 34, wherein one or more gastroretentive systems comprising risperidone or a salt thereof are administered to the individual weekly during the second time period, weekly during the third time period, or weekly during the second and third time periods.

36. 28. The method of any one of claims 17-27, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 2 mg during a first time period; immediate-release risperidone or a salt thereof is administered daily in an amount of about 1 mg during a second time period, the gastroretentive system comprising about 15 mg of risperidone or a salt thereof is administered once weekly during the second time period; and the gastroretentive system comprising about 15 mg of risperidone or a salt thereof is administered once weekly during a third time period.

37. 28. The method of any one of claims 17-27, wherein immediate-release risperidone or its salt is administered daily in an amount of about 4 mg during a first period of time; immediate-release risperidone or its salt is administered daily in an amount of about 2 mg during a second period of time, and the gastroretentive system comprises about 30 mg of risperidone or its salt, administered once weekly during the second period of time; and the gastroretentive system comprises about 30 mg of risperidone or its salt, administered once weekly during a third period of time.

38. 28. The method of any one of claims 17-27, wherein immediate-release risperidone or its salt is administered daily in an amount of about 6 mg during a first period of time; immediate-release risperidone or its salt is administered daily in an amount of about 3 mg during a second period of time, and the gastroretentive system comprises about 45 mg of risperidone or its salt, administered once weekly during the second period of time; and the gastroretentive system comprises about 45 mg of risperidone or its salt, administered once weekly during a third period of time.

39. 1. A method of administering risperidone or a salt thereof to an individual, comprising: administering to the individual an immediate release dosage form of risperidone or a salt thereof and one or more gastroretentive systems comprising risperidone or a salt thereof for a co-administration period; and administering one or more gastroretentive systems containing risperidone or a salt thereof to the individual over a subsequent period of time. A method comprising:

40. 40. The method of claim 39, wherein the co-administration period is between about 1 week and about 6 weeks.

41. 41. The method of claim 40, wherein the co-administration period is between about 1 week and about 3 weeks.

42. 41. The method of claim 40, wherein the co-administration period is about 1 week.

43. 43. The method of any one of claims 39 to 42, wherein the subsequent period is between about one week and about one year.

44. 43. The method of any one of claims 39 to 42, wherein the subsequent period is between about 3 months and about 1 year.

45. 43. The method of any one of claims 39 to 42, wherein the subsequent period continues indefinitely.

46. 46. ​​The method of any one of claims 39-45, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the co-administration period comprises from about 1 mg to about 10 mg of risperidone or a salt thereof.

47. 47. The method of claim 46, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the co-administration period comprises about 1 mg, about 2 mg, or about 3 mg of risperidone or a salt thereof.

48. 48. The method of any one of claims 39 to 47, wherein an immediate release dosage form of risperidone or a salt thereof is administered to the individual daily during the co-administration period.

49. 49. The method of any one of claims 39 to 48, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises from about 10 mg to about 60 mg of risperidone or a salt thereof.

50. 50. The method of claim 49, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises about 15 mg, about 30 mg, or about 45 mg of risperidone or a salt thereof.

51. 51. The method of any one of claims 39 to 50, wherein one or more gastroretentive systems comprising risperidone or a salt thereof are administered to the individual weekly during the co-administration period, weekly thereafter, or weekly during the co-administration period and thereafter.

52. 46. ​​The method of any one of claims 39-45, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 1 mg during the co-administration period, and the gastroretentive system comprises about 15 mg of risperidone or a salt thereof and is administered once weekly during the co-administration period; and the gastroretentive system comprises about 15 mg of risperidone or a salt thereof and is administered once weekly during the subsequent period.

53. 46. ​​The method of any one of claims 39-45, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 2 mg during the co-administration period, the gastroretentive system comprises about 30 mg of risperidone or a salt thereof and is administered once weekly during the co-administration period; and the gastroretentive system comprises about 30 mg of risperidone or a salt thereof and is administered once weekly during the subsequent period.

54. 46. ​​The method of any one of claims 39-45, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 3 mg during the co-administration period, and the gastroretentive system comprises about 45 mg of risperidone or a salt thereof and is administered once weekly during the co-administration period; and the gastroretentive system comprises about 45 mg of risperidone or a salt thereof and is administered once weekly during the subsequent period.

55. 1. A method of administering risperidone or a salt thereof to an individual, comprising: administering an immediate release dosage form of risperidone or a salt thereof to the individual for a first period of time; and administering to the individual one or more gastroretentive systems comprising risperidone or a salt thereof for a second period of time. A method comprising:

56. 56. The method of claim 55, wherein the first period of time is between about 1 day and about 4 weeks.

57. 57. The method of claim 56, wherein the first period of time is between about 1 week and about 2 weeks.

58. 57. The method of claim 56, wherein the first period of time is between about 1 day and about 1 week.

59. 57. The method of claim 56, wherein the first period of time is about one week.

60. 60. The method of any one of claims 55 to 59, wherein the second period of time is between about 1 week and about 1 year.

61. 61. The method of any one of claims 55-60, wherein the second period of time is between about 3 months and about 1 year.

62. 60. The method of any one of claims 55 to 59, wherein the second period of time continues indefinitely.

63. 63. The method of any one of claims 55-62, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over a first period of time comprises from about 1 mg to about 10 mg of risperidone or a salt thereof.

64. 64. The method of claim 63, wherein the immediate release dosage form of risperidone or a salt thereof administered to the individual over the first period of time comprises about 2 mg, about 4 mg, or about 6 mg of risperidone or a salt thereof.

65. 65. The method of any one of claims 55 to 64, wherein an immediate release dosage form of risperidone or a salt thereof is administered to the individual daily during the first period of time.

66. 66. The method of any one of claims 55 to 65, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprises from about 10 mg to about 60 mg of risperidone or a salt thereof.

67. 67. The method of claim 66, wherein the one or more gastroretentive systems comprising risperidone or a salt thereof comprise about 15 mg, about 30 mg, or about 45 mg of risperidone or a salt thereof.

68. 68. The method of any one of claims 55 to 67, wherein one or more gastroretentive systems comprising risperidone or a salt thereof are administered to the individual weekly during the second period of time.

69. 63. The method of any one of claims 55-62, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 2 mg during a first time period; and the gastroretentive system comprises about 15 mg of risperidone or a salt thereof and is administered once weekly during a second time period.

70. 63. The method of any one of claims 55-62, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 4 mg during a first time period; and the gastroretentive system comprises about 30 mg of risperidone or a salt thereof and is administered once weekly during a second time period.

71. 63. The method of any one of claims 55-62, wherein immediate-release risperidone or a salt thereof is administered daily in an amount of about 6 mg during a first time period; and the gastroretentive system comprises about 45 mg of risperidone or a salt thereof and is administered once weekly during a second time period.

72. A gastroretentive system for weekly oral administration to a patient, comprising an extended release formulation comprising an amount of risperidone or a salt thereof and a carrier polymer, the extended release formulation further comprising one or more excipients and a release rate controlling polymer film; a) the amount of risperidone or a salt thereof is about 15-45 mg, and the plasma Cmax of (risperidone + 9-hydroxyrisperidone) from once-weekly oral administration into a gastroretentive system at steady state is about 80 ng / mL or less; or b) the amount of risperidone or a salt thereof is about 15-45 mg and the plasma Cavg of (risperidone + 9-hydroxyrisperidone) is 15 ng / mL or greater when administered orally once weekly in a gastroretentive system at steady state; or c) A gastroretentive system containing risperidone or a salt thereof in an amount of about 15 to 45 mg, wherein the plasma concentration of (risperidone + 9-hydroxyrisperidone) at steady state 168 hours after administration is 8 ng / mL or greater when administered orally once weekly to the gastroretentive system.

73. A gastroretentive system for weekly oral administration to a patient, comprising an extended release formulation comprising an amount of risperidone or a salt thereof and a carrier polymer, the extended release formulation further comprising one or more excipients and a release rate controlling polymer film; a) the amount of risperidone or a salt thereof is about 15 mg, and the plasma Cmax of (risperidone + 9-hydroxyrisperidone) from once-weekly oral administration into a gastroretentive system at steady state is about 30 ng / mL or less; or b) the amount of risperidone or a salt thereof is about 15 mg and the plasma Cavg of (risperidone + 9-hydroxyrisperidone) from once-weekly oral administration into a gastroretentive system at steady state is 15 ng / mL or greater; or c) A gastroretentive system containing approximately 15 mg of risperidone or a salt thereof, wherein the plasma concentration of (risperidone + 9-hydroxyrisperidone) at steady state 168 hours after administration is 8 ng / mL or greater when administered orally once weekly to the gastroretentive system.

74. A gastroretentive system for weekly oral administration to a patient, comprising an extended release formulation comprising an amount of risperidone or a salt thereof and a carrier polymer, the extended release formulation further comprising one or more excipients and a release rate controlling polymer film; a) the amount of risperidone or a salt thereof is about 45 mg and the plasma Cmax of (risperidone + 9-hydroxyrisperidone) from once-weekly oral administration into a gastroretentive system at steady state is less than or equal to about 80 ng / mL; or b) the amount of risperidone or a salt thereof is about 45 mg and the plasma Cavg of (risperidone + 9-hydroxyrisperidone) from once-weekly oral administration into a gastroretentive system at steady state is greater than or equal to 30 ng / mL; or c) A gastroretentive system comprising an amount of risperidone or a salt thereof of about 45 mg, and a plasma concentration of (risperidone + 9-hydroxyrisperidone) of 20 ng / mL or greater at steady state 168 hours after administration from a once-weekly oral administration to the gastroretentive system.

75. 1. A gastroretentive system for administration to the stomach of a patient, comprising: an elastomer component; At least one carrier polymer-drug component comprising a carrier polymer and risperidone or a pharmaceutically acceptable salt thereof. Including, at least one carrier polymer-drug component comprises a release rate controlling polymer film; the carrier polymer-drug component comprises an elongated member having a proximal end, a distal end, and an exterior surface therebetween; a proximal end of the elongated member is attached to the elastomeric component and protrudes radially from the elastomeric component, the elongated member having a distal end not attached to the elastomeric component and positioned at a greater radial distance from the elastomeric component than the proximal end; The gastroretentive system is configured to have a compressed form within the container suitable for oral administration or administration via a feeding tube; and an uncompressed form upon release from the container within the patient's stomach.

76. The gastroretentive system of claim 75, wherein the release rate controlling polymer film comprises one or more polyester materials having repeating units of the form -R1-O-C(=O)-, where R1 is selected from the group consisting of C1-C12 alkylene groups, ethers containing 2 to 12 carbon atoms, and polyethers containing 3 to 12 carbon atoms.

77. 77. The gastroretentive system of claim 75 or 76, wherein the release rate controlling polymer film is polycaprolactone.

78. 77. The gastroretentive system of claim 75 or 76, wherein the release rate controlling polymer film is polydioxanone.

79. The gastroretentive system of any one of claims 75 to 78, wherein the elastomer is concave-convex, monoconcave, biconcave, or toroidal.

80. The gastric retention system of any one of claims 75 to 79, wherein the elastomer comprises a material selected from the group consisting of silicone rubber, polysiloxane, polydimethylsiloxane, silicone rubber mixed with silica, polysiloxane mixed with silica, and polydimethylsiloxane mixed with silica.

81. The gastroretentive system of any one of claims 75 to 80, wherein the carrier polymer comprises polycaprolactone.

82. The gastroretentive system of any one of claims 75 to 81, wherein the extension member further comprises a disintegrable matrix.

83. The gastroretentive system of any one of claims 75 to 82, wherein each of the plurality of carrier polymer-drug component is an arm, and one or more of the arms comprises two or more segments.

84. The gastroretentive system of claim 83, wherein each segment of the two or more segments is connected to an adjacent segment via a linker region.

85. The gastroretentive system of claim 83, wherein each segment of the two or more segments is directly bonded to an adjacent segment without the use of a linker region.

86. The gastroretentive system of claim 84, wherein the linker region comprises a coupling polymer or a degradable matrix.

87. 85. The gastroretentive system of claim 83 or 84, wherein one or more of the arms are attached to the central elastomer via a coupling polymer or a degradable matrix.

88. 88. The gastric retention system of claim 87, wherein one or more of the arms attached to the central elastomer via a coupling polymer or an erodible matrix further comprises an intervening portion comprising an interfacing polymer.

89. 89. The method of any one of claims 1 to 88, wherein the individual has a psychiatric or neurological disorder.

90. 90. The method of claim 89, wherein the psychiatric or neurological disorder is schizophrenia.

91. 90. The method of claim 89, wherein the psychiatric or neurological disorder is bipolar disorder.

92. 90. The method of claim 89, wherein the psychiatric or neurological disorder is irritability associated with autistic disorder.

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