Material architectures for gastric residence systems

Abstract

To provide gastric residence systems with precisely tailored material architectures, and methods of making and using such gastric residence systems.SOLUTION: The invention provides gastric residence systems with specifically tailored architectures, and methods for making such systems. Components of the gastric residence systems can be manufactured by three-dimensional printing or by co-extrusion. The ability to construct precise architectures for the systems provides excellent control over drug release, in vivo stability and residence time of the systems.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 342,798, filed May 27, 2016, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to a system that remains in the stomach for extended periods of time for the sustained release of pharmaceutical agents. [Background technology]

[0003] A gastroretentive system is a delivery system for therapeutic agents that remains in the stomach for days to weeks or even longer, during which time a drug or other substance can elute from the system for absorption in the gastrointestinal tract. Examples of such systems are described in WO 2015 / 191920 and WO 2015 / 191925.

[0004] A gastroretentive system is designed to be administered into the stomach of a patient, usually in a capsule that is swallowed, or introduced into the stomach by an alternative method of administration (e.g., feeding tube or stomach tube). Upon dissolution of the capsule in the stomach, the system resides in the stomach and expands or widens to a size that resists elimination by the pyloric sphincter for the desired residence period (such as 3 days, 7 days, 2 weeks, etc.). This requires mechanical stability over the desired residence period. Over the residence period, the system releases a drug or drugs, such as one or more agents, preferably agents with minimal burst release, which requires careful selection of carrier materials for the agents to provide the desired release profile. While remaining in the stomach, the system should not interfere with the normal elimination of food or other stomach contents. The system should be emptied from the stomach at the end of the desired residence time and be easily eliminated from the patient. If the system passes prematurely from the stomach to the small intestine, it should not cause ileus and should be easily eliminated from the patient. These properties require careful selection of the materials from which the system is constructed, as well as the dimensions and configuration of the system.

[0005] The present invention describes advances in the design and manufacture of gastroretentive systems, and in system construction, that allow for the fine tailoring of the substances used in the system. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a gastroretentive system having a precisely tailored material structure that can be administered to a patient's stomach for sustained drug or agent release. The customized structure of the material used in the system allows for greater control of system performance, including drug or agent release in the stomach, system stability, system safety, and residence time in the gastrointestinal tract. Methods of making and using such a gastroretentive system are also provided. [Means for solving the problem]

[0007] In some embodiments, the present invention provides a gastroretentive system for administration to a stomach of a patient comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or salt thereof bound to the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member being bound to the elastomeric component and projecting radially from the elastomeric component, each elongate member having its distal end not bound to the elastomeric component and located at a greater radial distance from the elastomeric component than its proximal end; each elongate member comprising at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween: the segments being the at least one linker region comprises a first linker material and a second linker material, wherein i) the second linker material extends from the outer surface of the at least one linker region into the body of the at least one linker region; or ii) the second linker material extends from the outer surface of the at least one linker region through the body of the at least one linker region to re-emerge on the outer surface; or iii) a portion of the second linker material extends from the outer surface of the at least one linker region into the body of the at least one linker region and a portion of the second linker material extends from the outer surface of the at least one linker region through the body of the at least one linker region to re-emerge on the outer surface.

[0008] In some embodiments, the present invention provides a gastroretentive system for administration to a stomach of a patient comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or salt thereof bound to the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is bound to the elastomeric component and projects radially from the elastomeric component, each elongate member having its distal end not bound to the elastomeric component and located at a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween: the segments are joined by a linker region; and at least one segment is formed from at least one of the elongate members. The segment further comprises a segmented island material, wherein i) the segmented island material extends from the outer surface of the at least one carrier polymer-drug segment into the body of the at least one carrier polymer-drug segment; or ii) the segmented island material extends from the outer surface of the at least one carrier polymer-drug segment through the body of the at least one carrier polymer-drug segment to re-emerge on the outer surface; or iii) a portion of the segmented island material extends from the outer surface of the at least one carrier polymer-drug segment into the body of the at least one carrier polymer-drug segment and a portion of the segmented island material extends from the outer surface of the at least one carrier polymer-drug segment through the body of the at least one carrier polymer-drug segment to re-emerge on the outer surface.

[0009] In some embodiments, the invention encompasses a gastric retention system for administration to a patient's stomach comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or salt thereof associated with the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is associated with the elastomeric component and projects radially from the elastomeric component, each elongate member being unassociated with the elastomeric component and located at a greater radial distance from the elastomeric component than the proximal end; each elongate member is comprised of at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween: at least one segment further comprises a reinforcing material, the reinforcing material extending axially along an interior of the at least one segment; the segments being connected by a linker region. In some embodiments, the reinforcing material extends axially along at least one interior for at least about 90% of the length of the segment. In some embodiments, the reinforcement has a cylindrical, triangular prism, rectangular prism, or regular square prism structure. In some embodiments, the reinforcement has a pie-shaped structure (a triangular structure with one side replaced by the arc of a circle). In some embodiments, the reinforcement has an I-shaped structure or an H-shaped structure. In some embodiments, the reinforcement has a truss structure.

[0010] In some embodiments, the invention encompasses a gastric retention system for administration to a patient's stomach comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or salt thereof associated with the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is associated with the elastomeric component and projects radially from the elastomeric component, each elongate member being free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween: one or more of the elongate members comprises a fenestrated coating on the exterior surface; and the segments are connected by a linker region.

[0011] In some embodiments, the invention encompasses a gastric retention system for administration to a patient's stomach comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or salt thereof associated with the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is associated with the elastomeric component and projects radially from the elastomeric component, each elongate member being free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween: the segments are connected by a linker region having an exterior surface; and the segments of the elongate member have a layered structure comprising at least two layers.

[0012] In some embodiments, the invention encompasses a gastric retention system for administration to a patient's stomach comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or salt thereof associated with the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is associated with the elastomeric component and projects radially from the elastomeric component, each elongate member being unassociated with the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween: the segments are connected by a linker region having an exterior surface; and either a portion of the linker region extends into the segment, or a portion of the segment extends into the linker region, or both portions of the linker region extend into the segment and a portion of the segment extends into the linker region.

[0013] In some embodiments, the invention encompasses a method of manufacturing an elongate member for use in a gastric retention system comprising co-extrusion of the elongate member. Co-extrusion of the elongate member can include co-extrusion of at least two regions comprising carrier polymer-drug formulations, with each region of carrier polymer-drug formulation being separated from an adjacent region of carrier polymer-drug formulation by a linker region. The linker region can comprise a material selected from the group consisting of an enteric linker and a time-dependent linker. In some embodiments, at least one junction between the carrier polymer-drug region and the linker region is co-extruded in an interlocking configuration. In some embodiments, at least one carrier polymer-drug region is co-extruded in an islands-in-the-sea configuration. In some embodiments, at least one linker region is co-extruded in an islands-in-the-sea configuration. In some embodiments, the island component of the islands-in-the-sea configuration can comprise at least one material selected from the group consisting of an enteric polymer and a time-dependent polymer.

[0014] In some embodiments, the invention encompasses a method of manufacturing an elongate member for use in a gastroretentive system, comprising printing the elongate member by additive manufacturing (e.g., three-dimensional printing). Printing the elongate member by three-dimensional printing can include printing at least two regions comprising a carrier polymer-drug formulation, with each region of the carrier polymer-drug formulation being separated from an adjacent region of the carrier polymer-drug formulation by a linker region. The linker region can comprise a material selected from the group consisting of an enteric linker and a time-dependent linker. In some embodiments, at least one junction between the carrier polymer-drug region and the linker region can be printed with an interlocking structure. In some embodiments, at least one carrier polymer-drug region can be printed with an islands-in-the-sea structure. In some embodiments, at least one linker region can be printed with an islands-in-the-sea structure. The island component of the islands-in-the-sea structure can comprise at least one material selected from the group consisting of an enteric polymer and a time-dependent polymer.

[0015] In any of the co-extrusion or three-dimensional printing methods disclosed herein, the carrier polymer of the carrier polymer-drug formulation may be selected from the group consisting of polycaprolactone and polydioxanone.

[0016] In any of the coextrusion or three dimensional printing methods disclosed herein, the drug of the carrier polymer-drug formulation may be selected from the group consisting of analgesics; anti-analgesics; anti-inflammatory drugs; antipyretics; antidepressants; anti-epileptic drugs; anti-schizophrenia drugs; neuroprotective drugs; anti-proliferative drugs; anti-cancer drugs; antihistamines; anti-migraine drugs; hormones; prostaglandins; antibacterial drugs; antibiotics; anti-fungals; anti-virals; anti-parasitic drugs; anti-muscarinics; anxiolytics; bacteriostatics; immunosuppressants; sedatives; hypnotics; antipsychotics; bronchodilators; anti-asthma drugs; cardiovascular drugs; anesthetics; anticoagulants; enzyme inhibitors; steroidal drugs; steroidal or non-steroidal anti-inflammatory drugs; corticosteroids; dopaminergic drugs ; electrolytes; gastrointestinal agents; muscle relaxants; nutrients; vitamins; parasympathomimetics; stimulants; appetite suppressants; anti-narcoleptics; antimalarials; quinine; lumefantrine; chloroquine; amodiaquine; pyrimethamine; proguanil; chlorproguanil-dapsone; sulfonamides; sulfadoxine; sulfamethoxypyridazine; mefloquine; atovaquone; primaquine; halofantrine; doxycycline; clindamycin; artemisinin; artemisinin derivatives; artemether; dihydroartemisinin; arteether; and artesunate. [Brief description of the drawings]

[0017] [Figure 1A] 1 shows the star-shaped design of the gastroretentive system in its unpacked state. [Figure 1B] 1 shows the star design of the gastroretentive system in a compressed or folded state. [Figure 1C] 1 shows the annular design of the gastroretentive system in an unpacked state. [Figure 2A] 1 shows the dimensions of the triangular cross section of an arm or arm segment in the shape of a triangular prism. [Figure 2B] The structure of an arm (elongated member) having a carrier polymer-drug region A and a linker (binding polymer) region B is shown. [Figure 2C]The structure of the arms (elongated members) with triangular cross-sections in the shape of a triangular prism is shown (left). The longitudinal cross-section along the axial length of the arms is shown (right). The carrier polymer-drug regions (i.e., drug-loaded polymer regions) are shown as plain rectangles, the time-dependent linker regions are shown as horizontally striped rectangles, and the enteric linker regions are shown as cross-hatched rectangles. [Figure 2D] An alternative configuration of an arm (elongated member) with a triangular cross section in the shape of a triangular prism is shown (left). A longitudinal cross section along the axial length of the arm is shown (right). The carrier polymer-drug region (i.e., drug-loaded polymer region) is shown as an unmarked rectangle, the time-dependent linker region is shown as a horizontally striped rectangle, and two separate enteric linker regions are shown as cross-hatched rectangles. [Figure 2E] An alternative configuration of an arm (elongated member) with a triangular cross section in the shape of a triangular prism is shown (left). A longitudinal cross section along the axial length of the arm is shown (right). The carrier polymer-drug region (i.e., drug-loaded polymer region) is shown as an unmarked rectangle, the time-dependent linker region is shown as a horizontally striped rectangle, and three separate enteric linker regions are shown as cross-hatched rectangles. [Figure 3A] 1 shows the structure of an elongate member having an "islands in the sea" arrangement of materials in the linker region. [Figure 3B] 1 shows the structure of an elongate member having an "islands in the sea" arrangement of materials in the linker region. [Figure 3C] 3B shows a close-up of the "islands-in-the-sea" arrangement of materials in the linker region of FIG. 3A. [Figure 3D] 1 shows a structure of an elongate member having an "islands in the sea" arrangement of material in the linker region, where the "sea" of the linker region comprises the carrier polymer-drug formulation. [Figure 3E] The structure of the elongate member is shown having an "islands in the sea" arrangement of material in the linker region, where the "sea" of the linker region comprises the carrier polymer-drug formulation and the "islands" have various diameters. [Figure 4A] The structure of the arm segment has an "islands-in-the-sea" arrangement of materials in the linker region and a "lock-and-key" design between the linker region and the carrier polymer-drug region. [Figure 4B] 1 shows an "islands in the sea" arrangement of materials in the linker region and an alternative structure of the arm segment having a "lock and key" design between the linker region and the carrier polymer-drug region. [Figure 4C] 1 shows alternative structures of arm segments with a "lock-and-key" design between the linker region and the carrier polymer-drug (drug-loaded polymer) region, where one of the lock-and-key linkers is a time-dependent linker, while the other is an enteric linker. [Figure 4D] 1 shows alternative structures of arm segments with a "lock-and-key" design between the linker region and the carrier polymer-drug (drug-loaded polymer) region, where one of the lock-and-key linkers is a time-dependent linker, while the other is an enteric linker. [Figure 5A] The structures of segments having "islands in the sea" arrangement of materials in the linker region, and "islands in the sea" arrangement of materials in the carrier polymer-drug region are shown. [Figure 5B] 1 shows the structure of an elongate member having an "islands in the sea" arrangement of carrier polymer-drug substance "islands" in a "sea" of structural polymers joined by a time-dependent linker and an enteric linker. [Figure 6A] 13A-13C show a multi-layered embodiment of a bifurcation segment for use in a gastroretention system. [Figure 6B] 1 shows a multi-layer embodiment of an elongate member having multi-layered carrier polymer-drug segments joined by a time-dependent linker and an enteric linker. [Figure 7A] 1 illustrates an embodiment of a segment having an I-type internal reinforcement. [Figure 7B] 1 illustrates an embodiment of an elongate member having an I-type internal stiffener. [Figure 8A] 1 illustrates an embodiment of a segment having a truss-type internal stiffener. [Figure 8B] 1 illustrates an embodiment of an elongate member having a truss-type internal stiffener. [Figure 9A] 1 illustrates an embodiment of a segment having a fenestrated (perforated) external support. [Figure 9B] 1 illustrates an embodiment of an elongate member having a fenestrated (perforated) external support. [Figure 9C] 1 illustrates an embodiment of an elongate member having a fenestrated (perforated) external support. [Figure 10A] 1 shows the arrangement of elongate arms of an embodiment of a gastric retention system having six elongate arms, with the arms having a triangular cross section. [Figure 10B] 1 shows the arrangement of elongate arms of an embodiment of a gastric retention system having six elongate arms, where the arms have a wedge-shaped cross section. [Figure 10C] 1 shows a gastroretention system in a compacted state with elongated arms with blunt ends. [Figure 11A] A schematic diagram of a suitable structure (spine) for an externally reinforced drug arm is shown. [Figure 11B] FIG. 1 shows a schematic diagram of a suitable structure (exoskeleton) for an externally reinforced drug arm. [Figure 11C] A photograph of the illustrated structure is shown in FIG. 11B. [Figure 11D] 1 shows the effect of external reinforcement on the mechanical strength of the drug arm. [Figure 12A] 1 shows a schematic diagram of the coextrusion method of the present invention. [Figure 12B] 1 shows a schematic diagram of another coextrusion method of the present invention. [Figure 12C] FIG. 12A illustrates an elongated member produced by the coextrusion method of the present invention. [Figure 12D] FIG. 12B illustrates an elongated member produced by the coextrusion method of the present invention. [Figure 13] 4 shows tensile test results of the coextruded arms. [Figure 14] 1 shows the release profiles of tacrolimus over time for various formulations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition A "carrier polymer" is a polymer suitable for loading an agent, such as a drug, for use in the present invention.

[0019] A "pharmaceutical agent" is a substance intended for therapeutic, diagnostic, or nutritional purposes in a patient, individual, or subject. Pharmaceutical agents include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0020] A "dispersing agent" is defined as a substance that aids in minimizing drug particle size and dispersing drug particles in the carrier polymer matrix. That is, dispersing agents help minimize or prevent particle aggregation or flocculation during the manufacture of the system. Thus, dispersing agents have anti-aggregation and anti-flocculation properties and aid in maintaining a uniform distribution of drug particles in the carrier polymer matrix.

[0021] An "excipient" is a substance added to a formulation of a drug that is not itself a drug. Excipients include, but are not limited to, binders, coatings, diluents, disintegrants, emulsifiers, flavors, glidants, lubricants, and preservatives. The specific class of dispersing agents falls within the more general class of excipients.

[0022] An "elastic polymer" or "elastomer" (also called a "high strength polymer") is a polymer that can be distorted from its original shape by an applied force for a period of time, and then substantially return to its original shape once the force is removed.

[0023] A "linking polymer" is a polymer suitable for linking to other polymers, such as linking a first carrier polymer-drug moiety to a second carrier polymer-drug moiety. The linking polymer typically forms a linker region between the other moieties.

[0024] A "time-dependent polymer" or "time-dependent binding polymer" is a polymer that degrades in a time-dependent manner when the gastroretentive system is placed in the stomach. Time-dependent polymers are generally not affected by normal pH fluctuations in the stomach.

[0025] "Substantially constant plasma concentration" refers to a plasma concentration that remains within ±25% of the average plasma concentration measured over the period that the gastroretentive system is retained in the stomach.

[0026] A "hydrophilic therapeutic agent", "hydrophilic drug" or "hydrophilic drug" is a drug that is readily soluble in water. A hydrophilic drug is defined as a drug that has a water solubility of 1 mg / ml or greater. Alternatively, a hydrophilic drug has a log P oct (log partition coefficient P oct , 0.5P oct = (concentration in 1-octanol) / (concentration in HO). oct The pH at which it is measured is 1.6.

[0027] A "hydrophobic therapeutic agent", "hydrophobic drug", or "hydrophobic drug" is a drug that does not dissolve readily in water. A hydrophobic drug is defined as a drug that has a water solubility of less than 1 mg / ml. Alternatively, a hydrophobic drug has a log P oct A hydrophobic therapeutic agent can be defined as a drug that has a log partition coefficient (log 1 / log 2 ). Alternatively, a hydrophobic therapeutic agent can be defined as a drug that has a higher solubility in ethanol than in water. Alternatively, a hydrophobic therapeutic agent can be defined as a drug that has a higher solubility in 40% ethanol / 60% simulated gastric fluid than in 100% simulated gastric fluid.

[0028] "Biocompatibility," when used to describe a substance or system, indicates that the substance or system elicits no, or only minimal and 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.

[0029] A "patient," "individual," or "subject" refers to a mammal, preferably a human or a domestic animal such as a dog or cat. In a preferred embodiment, the patient, individual, or subject is a human.

[0030] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0031] "Treatment" of a disease or disorder with the systems and methods disclosed herein is defined as administering one or more systems disclosed herein to a patient in need thereof, with or without additional agents, to either reduce or eliminate the disease or disorder, or one or more symptoms of the disease or disorder, or to slow the progression of the disease or disorder, or one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder, or one or more symptoms of the disease or disorder. "Inhibition" of a disease or disorder with the systems and methods disclosed herein is defined as administering one or more systems disclosed herein to a patient in need thereof, with or without additional agents, to prevent the clinical symptoms of the disease or disorder, or to prevent the symptoms of adverse symptoms of the disease or disorder. The distinction between treatment and inhibition is that treatment is performed after adverse symptoms of the disease or disorder appear in the patient, but inhibition is performed before adverse symptoms of the disease or disorder appear in the patient. Inhibition may be partial, substantially complete, or complete. Some diseases or disorders are hereditary, so genetic screening can be used to identify patients at risk for the disease or disorder. The systems and methods of the present invention can then be used to treat asymptomatic patients who are at risk for developing clinical symptoms of a disease or disorder to inhibit the onset of adverse symptoms.

[0032] A "therapeutic use" of the systems disclosed herein is defined as the use of one or more systems disclosed herein to treat a disease or disorder, as defined above. A "therapeutically effective amount" of a therapeutic agent, such as a drug, is an amount of the agent that, when administered to a patient, is sufficient to reduce or eliminate either a disease or disorder, or one or more symptoms of a disease or disorder, or slow the progression of a disease or disorder, or one or more symptoms of a disease or disorder, or reduce the severity of a disease or disorder, or one or more symptoms of a disease or disorder. A therapeutically effective amount may be administered to a patient in a single dose or divided and administered in multiple doses.

[0033] A "prophylactic use" of the systems disclosed herein is defined as the use of one or more systems disclosed herein to inhibit a disease or disorder, as defined above. A "prophylactically effective amount" of a therapeutic agent is an amount of agent that, when administered to a patient, is sufficient to inhibit the clinical symptoms of a disease or disorder, or inhibit the symptoms of an adverse manifestation of a disease or disorder. A prophylactically effective amount may be administered to a patient in a single dose or in divided, repeated doses.

[0034] As used herein, the singular forms "a," "an," and "the" include plurals unless otherwise indicated or the context clearly indicates otherwise.

[0035] When the word "about" or "approximately" is used herein to describe a numerical value, it is understood to include both the specified value as well as values ​​reasonably close to the specified value. For example, "about 50°C" or "approximately 50°C" includes both 50°C itself as well as a disclosure of values ​​close to 50°C. Thus, the phrase "about X" or "approximately X" includes a description of the value X itself. When a range is specified, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C," it is understood that both of the values ​​specified by the endpoints are included, and values ​​near each endpoint or endpoint are included toward each endpoint or endpoint; i.e., "approximately 50°C to 60°C" (or "approximately 50°C to 60°C") is equivalent to describing both "50°C to 60°C" and "approximately 50°C to approximately 60°C" (or "approximately 50°C to 60°C").

[0036] With respect to the numerical ranges disclosed herein, any disclosed upper limit of an ingredient may be combined with any disclosed lower limit of that ingredient to provide a range (provided that the upper limit is greater than the combined lower limit). Each of these combinations of the disclosed upper and lower limits is expressly contemplated herein. For example, if a range of the amount of a particular ingredient is given as 10%-30%, 10%-12%, and 15%-20%, the ranges 10%-20% and 15%-30% are also contemplated, but the combination of a lower limit of 15% and an upper limit of 12% is not possible and therefore not contemplated.

[0037] Unless otherwise specified, the percentages of components in a composition are expressed as weight percent or weight / weight percent. References to relative weight percents in a composition are understood to assume that the total weight percents of all components in the composition, when combined, total 100. It is further understood that the relative weight percents of one or more components may be adjusted up or down such that the weight percents of the components in a composition, when combined, total 100, provided that the weight percent of any particular component does not fall outside the limits of the range specified for that component.

[0038] Some embodiments described herein are described as "comprising" or "comprises" with respect to various elements thereof. In alternative embodiments, these elements can be described with the transitional phrase "consisting essentially of" or "consists essentially of" when applied to these elements. In further alternative embodiments, these elements can be described with the transitional phrase "consisting of" or "consists of" when applied to these 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 "consist essentially of" and alternative embodiments of the composition or method that "consist essentially of" and "consist of" are also considered to be disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to various elements thereof can also be described as "comprising" when applied to these elements. And, embodiments described as "consisting essentially of" with respect to these various elements can also be described as "consisting of" when applied to those elements, and embodiments described as "consisting of" can also be described as "consisting essentially of" when applied to those elements.

[0039] When a composition or system is described as "consisting essentially of" recited elements, the composition or system contains the elements explicitly recited, and may contain other elements that do not substantially affect the conditions being treated (for compositions for treating conditions) or the properties of the system described (for compositions that include a system). However, the composition or system either does not contain other elements that substantially affect the conditions being treated other than those explicitly recited elements (for compositions for treating a system) or does not contain other elements that substantially affect the properties of the system (for compositions that include a system); or, if the composition or system does not contain additional elements other than those recited that can substantially affect the conditions being treated or the properties of the system, then the composition or system does not contain a concentration or amount of the additional elements sufficient to substantially affect the conditions 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 does not substantially affect the conditions processed by the method or the properties of the system produced by the method, but the method does not include other steps that substantially affect the conditions processed or the system produced other than those steps explicitly recited.

[0040] This disclosure provides several embodiments. Any feature from any embodiment may be combined, where possible, with any feature from any other embodiment. As such, hybrid configurations of the disclosed features are within the scope of the invention.

[0041] In addition to the embodiments and methods disclosed herein, additional embodiments of gastroretentive systems, as well as methods of making and using such systems, are disclosed in International Publication No. WO 2015 / 191920, International Publication No. WO 2015 / 191925, International Publication No. WO 2017 / 070612, and PCT U.S. Patent Application Publication No. 2016 / 065453, the entire contents of which are incorporated herein by reference.

[0042] Overall System Structure The present invention provides, inter alia, components of gastroretention systems designed to provide specific mechanical properties and customized drug release rates during gastric retention. The components described herein are suitable for use in a variety of gastroretention systems, including, but not limited to, star-shaped gastroretention systems and annular gastroretention systems.

[0043] The "stellate" structure of a gastroretentive system is also known as a "star" (or "asterisk") structure. An example of a star-shaped system 100 is shown diagrammatically in FIG. 1A. A number of elongated members or "arms" (for clarity, only one such arm 108 is labeled) are attached to a disk-shaped central elastomer 106. The elongated members or arms depicted in FIG. 1A consist of segments 102 and 103 connected by a linking polymer or linker region 104 (again, for clarity, only one component in one arm is labeled). This structure allows the system to be folded or packed into the central elastomer. FIG. 1B shows a folded structure 190 of the gastroretentive system of FIG. 1A (for clarity, only two arms are shown in FIG. 1B). Segments 192 and 193, linker region 194, elastomer 196, and arm 198 of FIG. 1B correspond to segments 102 and 103, linker region 104, elastomer 106, and arm 108 of FIG. 1A, respectively. When folded, the overall length of the system is reduced by approximately a factor of two, allowing the system to be conveniently placed in a container, such as a capsule or other container suitable for oral administration. When the capsule reaches the stomach, it dissolves, liberating the gastroretentive system. The gastroretentive system then expands to its uncompacted state and remains in the stomach for the desired retention period.

[0044] In some embodiments, a star system may have an elongate member or arm made of only one segment attached to a central elastomer by a linker group, which corresponds to Figure 1A, except for segment 103.

[0045] 1C shows another possible overall structure 120 of the gastroretentive system, which is a ring structure. Segments 122 are joined by a connecting polymer or linker region 124 (for clarity, only one segment and one connecting linkage is labeled). The connecting polymer / linker region in this design must also function as an elastomer, allowing the ring to be twisted into a tightly packed state for placement within a container such as a capsule.

[0046] In one embodiment of the star structure, segments 102 and 103 comprise a carrier polymer loaded with a drug or agent. In one embodiment of the ring structure, segment 122 comprises a carrier polymer loaded with a drug or agent.

[0047] The binding polymer of the gastroretentive system, which serves as the linker region, is designed to gradually disintegrate in a controlled manner during the system's residence time in the stomach. If the gastroretentive system passes prematurely intact into the small intestine, the system is designed to disintegrate much more quickly to avoid intestinal obstruction. This is easily achieved by using an enteric polymer as the binding polymer. Enteric polymers are relatively resistant to the acidic pH levels encountered in the stomach, but dissolve quickly at the higher pH levels found in the duodenum. The use of an enteric binding polymer as a safety element protects against the undesirable condition of the gastroretentive system passing intact into the small intestine. The use of an enteric binding polymer also provides a way to remove the gastroretentive system before its designed residence time; if the system must be removed, the patient can drink a mild alkaline solution, such as sodium bicarbonate solution, or ingest an antacid, such as hydrated magnesium hydroxide (milk of magnesia) or calcium carbonate, which will raise the pH level in the stomach and cause the rapid degradation of the enteric binding polymer. The gastroretentive system can then be broken apart and removed from the patient.In the system shown in Figure 1A, at least the binding polymer 104 used for binding is made from such an enteric polymer.

[0048] In additional embodiments, time-dependent conjugated polymers or linkers can be used that degrade in a predictable, time-dependent manner. In some embodiments, the degradation of the time-dependent conjugated polymers or linkers is not affected by the varying pH of the gastrointestinal system.

[0049] In additional embodiments, different types of linkers can be used in the gastroretentive system; that is, enteric linkers (or enteric binding polymers) and time-dependent linkers (or time-dependent binding polymers) can be used. In some embodiments, one elongate member (arm) of the star-shaped system can use both an enteric linker in some linker regions between the segments and a time-dependent linker in other linker regions between the segments. An example of such an elongate member is shown in FIG. 2C, which uses a time-dependent linker region between the first and second segments and an enteric linker between the second and third segments. Another example of such an elongate member is shown in FIG. 2D, which uses a time-dependent linker region between the first and second segments, an enteric linker between the second and third segments, and another enteric linker between the third and fourth segments. Yet another example of such an elongate member is shown in FIG. 2E, which uses a time-dependent linker region between the first and second segments, an enteric linker between the second and third segments, another enteric linker between the third and fourth segments, and another enteric linker between the fourth and fifth segments. In some embodiments, one elongate member (arm) of the star system can use both one or more enteric linkers and one or more time-dependent linkers at the same junction between the segments; i.e., two or more linker regions connect the segments, at least one linker region is an enteric binding polymer or linker, and at least one linker region is a time-dependent binding polymer or linker. In some embodiments, one elongate member (arm) of the star system can use only one type of linker - i.e., in different junction regions between the segments - either only enteric linkers or only time-dependent linkers, but the star system can use at least one arm with only enteric linkers and at least one arm containing only time-dependent linkers.

[0050] The use of multiple linker regions allows the gastroretentive system to disintegrate into smaller pieces after a desired residence time for easier passage through the gastrointestinal tract. The manufacturing methods described herein, including coextrusion and three-dimensional printing, provide a relatively simple method of adding additional linker regions without complicating the manufacture of the gastroretentive system. In contrast, earlier methods required separate manufacture of each carrier polymer-drug segment and each linker region followed by end-to-end assembly of the regions; in such methods, the addition of each additional linker region requires an additional two-step step of attaching the linker region to the ends of the segments joined by the linker region.

[0051] The linker region is usually about 200 μm to about 2000 μm, about 300 μm to about 2000 μm, about 400 μm to about 2000 μm, about 500 μm to about 2000 μm, about 600 μm to about 2000 μm, about 700 μm to about 2000 μm, about 800 μm to about 2000 μm, about 900 μm to about 2000 μm, about 1000 μm ~2000μm, approximately 1100μm~2000μm, approximately 1200μm~2000μm, approximately 1300μm~2000μm, approximately 1400μm~200 0μm, about 1500μm to about 2000μm, about 1600μm to about 2000μm, about 1700μm to about 2000μm, about 1800μm to about 2000μm, about 1 900 μm to about 2000 μm, about 200 μm to about 1000 μm, about 300 μm to about 1000 μm, about 400 μm to about 1000 μm, about 500 μm to about 1000 μm, about 600 μm to about 1000 μm, about 700 μm to about 1000 μm, about 800 μm to about 1000 μm, or about 900 μm to about 1000 μm; or A width of about 100 microns to about 2 millimeters, such as 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 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 wide, about 1100 μm wide, about 1200 μm wide, about 1300 μm wide, about 1400 μm wide, about 1500 μm wide, about 1600 μm wide, about 1700 μm wide, about 1800 μm wide, about 1900 μm wide, or about 2000 μm wide, although each value can be plus or minus 50 μm (± 50 μm).

[0052] The central elastic polymer of a star system, such as polymer 106 in Figure 1A, is typically not an enteric polymer, however, the central elastic polymer may also be made from such an enteric polymer where desirable and practical. In a ring system, such as shown in Figure 1C, at least one, and preferably all, of the bonds 124 are made from such an enteric polymer.

[0053] The central elastomer should have a particular durometer and compression set. The durometer is weight since it determines the folding force of the dosage form and whether it will remain in the stomach; the preferred range is about 60 to about 90A. The compression set should be as low as possible to avoid having a permanent set of the gastroretentive system when stored in the capsule in its compacted configuration. The preferred range is about 10% to about 20%. A material that meets these requirements is the QPI range of liquid silicone rubbers from Dow Corning. In one embodiment, QPI-270 (70A durometer) can be used.

[0054] System Arm and Segment Design Segment Shape The elongated members, or arms, used in star-shaped delivery systems can have a variety of shapes. Elongated members suitable for star-shaped structures can generally also be used in ring-shaped structures. In some embodiments, the segments forming the arms of the gastric retention system are cylindrical (i.e., they have a circular cross section). In some embodiments, the segments forming the arms of the gastric retention system are rectangular prisms (i.e., they have a rectangular cross section), such as a regular rectangular prism (having a square cross section). In some embodiments, the segments forming the arms of the gastric retention system are triangular prisms (i.e., they have a triangular cross section). Figures 6A, 6B, 7A, 7B, 8A, 8B, 9A, 9B, and 9C show examples of segments that are triangular prisms. Differently shaped arms can be combined in the same gastric retention system, which is desirable and practical. Differently shaped segments can be combined in the same arms of the same gastric retention system, which is desirable and practical. In one embodiment, all of the arms and all of the arm segments in one gastric retention system have the same shape (e.g., all are cylindrical; all are triangular prisms; all are rectangular prisms). A triangular cross-section is shown in the left image of FIG. 10A. The arrangement of triangular cross-sections of the elongate members of a gastric retention system 1030 comprising six elongate members is shown in the right image of FIG. 10A; only one elongate member is labeled (1010). The gastric retention system is enclosed in a container or capsule 1020. The vertices of the hexagon thus formed exert stress on the retaining capsule when the system is in its compacted configuration.

[0055] Arms with polygonal shaped cross sections (such as arms with triangular, rectangular or square cross sections) or arms with sharp angles (such as arms with pie-shaped cross sections) can have rounded corners and contours to improve in vivo safety. That is, instead of having a sharp transition between intersecting edges or faces, an arc is used to transition from one edge or face to another. Thus, a "triangular cross section" includes a cross section that has an approximate triangular shape, such as a triangle with rounded corners. Arms with triangular cross sections include arms with rounded edges and rounded corners at the ends of the arms. An example of an arm cross section with rounded corners is shown in FIG. 2A; the rounded corners are labeled by arrows labeled R1, R2 and R3. Rounded corners and edges are also referred to as filleted corners, filleted corners, filleted edges or filleted edges. Arms with rectangular cross sections include arms with rounded edges and rounded corners at the ends of the arms; a rectangular shape with rounded corners is sometimes referred to as a rectellipse. An arm having a square cross section has rounded edges and rounded corners at the ends of the arm; a square shape with rounded corners is sometimes referred to as a squircle. Thus, in preferred embodiments of any of the systems described herein, all sharp edges or corners of the arms, arm segments, or elongate members are rounded or filleted.

[0056] In a preferred embodiment, the cross-section of the elongate members, or arms, used in the star-shaped intragastric delivery system is a circular cross-section formed by two radii of a cylindrical cylinder in the same plane and at an arc where the radii intersect. The angle between the two radii (the angle at the center of the arc) is preferably about 360° divided by 4, 6, or 8, but may be about 360° divided by any integer between 2 and 12, inclusive. That is, a cross-section described as a circular cross-section resembles a slice of a pie, such as the cross-section shown in the left diagram of FIG. 10B. Such a cross-section of the elongate members in the star-shaped system allows the gastric retention system to have an approximately cylindrical shape when packed together, as shown in the right diagram of FIG. 10B for a gastric retention system 1030 having six elongate members (one elongate member 1010 is labeled) with wedge-shaped cross-sections. Compared to the arrangement in Fig. 10A, the arrangement in Fig. 10B reduces stress on the containing capsule 1020 when the system is in its compact configuration, allowing a higher volume to be used in the elongate member when there is less unused space in the capsule. Elongate members having such cross sections can be manufactured by extrusion through a die having such cross sections. For co-extrusion of multiple regions in a bulk structure such as an extruded slab or ribbon, compression molding or thermoforming can be used to form elongate members having such cross sections from portions of the extruded bulk structure.

[0057] In another preferred embodiment, instead of having a flat surface at the tip, the tip of the end of the elongate member is curved as shown in Figure 10C. Such a configuration allows the system to fit more snugly within the capsule, which aids in manufacturing and storage, and also allows room for additional carrier polymer-drug composition at the tip of the elongate member, efficiently using the total space within the capsule. Figure 10C shows an elastomer 1002, a first segment 1004, a first linker region 1006, a second (or middle) segment 1008, a second linker region 1010, and a third (or final) segment 1012. The end or tip of the final segment 1012 is curved as described to fit within the capsule.

[0058] Segment Composition: Alternative Carrier Polymer-Drug Region and Linker Region FIG. 2A shows a cross-section of one embodiment of an arm in the shape of a solid triangular prism. The triangular cross-section is characterized by sides of widths W1, W2, and W3, corresponding angles θ1, θ2, and θ3 opposite corresponding member sides, and fillet radii of R1, R2, and R3. The arm has a height H1. FIG. 2B shows a side view of this embodiment of an arm. The region marked A consists of carrier polymer-drug, and the region marked B consists of linker material. The length of each region is independent of the length of each other region, labeled L1, L2, L3, L4, and L5; the overall length of the arm is (L1+L2+L3+L4+L5).

[0059] This arm embodiment can be manufactured by extruding material axially from an extrusion device; that is, if one looks at the end of the extrusion device where the extruded arm material emerges, one would see the cross section of Figure 2A. Extrusion entails extruding the carrier polymer-drug region (A region) of appropriate length (e.g., L1, L3, and L5), and then extruding the linker region (B region) of appropriate length (e.g., lengths L2, L4). The final arm embodiment can be assembled by gluing or bonding the segments in the following order: L1, L2, L3, L4, L5.

[0060] Alternatively, the arm embodiment of Figures 2A and 2B can be produced by extruding material from an extrusion device in a direction perpendicular to the longitudinal dimension (longest dimension) of the arm or elongate member. That is, if you look at the face of the extrusion device where the extruded arm material emerges, you will see the cross section of Figure 2B. Extrude the material as a rectangular block or rectangular parallelepiped - i.e., a slab having dimensions H1, (L1+L2+L3+L4+L5), and a third dimension of indefinite length; extrusion of the block is in the direction of this third dimension, so the third dimension can be as long as desired, provided sufficient raw material is fed to the extrusion device to produce the desired dimension. The rectangular block or slab can then be cut at an oblique angle to produce a solid triangular prism. (i.e., the rectangular block is cut at an oblique angle relative to the plane formed by the (L1+L2+L3+L4+L5) sides and the third dimension through which the block is extruded.) If a solid rectangular prism shape for the arms is desired (not shown), the rectangular block can be cut at a 90° angle instead of the oblique angle. If a pie cut is desired, the material is cut at an oblique angle and then the piece is second cut to form a curved arc. Alternatively, if a pie cut is desired, the material is cut into triangular prisms, rectangular prisms, or other shapes of appropriate size and then compression molded or die cut into the desired shape. This coextrusion method is further described below with reference to Example 2, Figures 12A, 12B, 12C, 12D, and 13.

[0061] Segment Composition: "Sea Island" Linker Region Some arm embodiments can be fabricated as carrier polymer-drug segments joined by an "islands in the sea" linker region. Figures 3A, 3B, and 3C show examples of such linker regions. In Figure 3A, segments 304 and 308 are connected by an "islands in the sea" linker region 306, while segments 302 and 304 are connected by another "islands in the sea" linker region (listed above is line segment L2, not otherwise labeled). In an islands in the sea structure of the linker region, the first linker material comprises an "island" indicated by 324 in Figure 3C. A large portion of the second linker material comprises "islands" that exist in the "sea" of the first linker material (one such island 322 is labeled in the column of Figure 3C). The linker region generally conforms to the overall structure of the arm; i.e., if the arm is in the shape of a triangular prism, the linker region will be in the shape of a triangular prism as well.

[0062] The second linker material, or linker material, which forms an island in the sea of ​​the first linker material, can be arranged in the sea in various structures. In Figures 3A and 3B, the island is in the form of a cylinder penetrating the sea in a direction transverse to the general longitudinal (axial) direction of the arm. The inset in Figure 3A shows an island (labeled "C") with a diameter D1. The island region can enter the linker region at one position on the face of the linker region and emerge from another position on the face of the linker region, penetrating the "sea of ​​linker". This structure can be manufactured by co-extrusion or three-dimensional printing. The island enters the linker region at one position on the face of the linker region and stops at the inner part of the linker region; this structure can be manufactured by three-dimensional printing.

[0063] The diameter of the "islands" may be uniform for all islets or may vary between islands, such as the arrangement shown in Figure 3E. The diameter of the islands in the linker region does not exceed the width of the linker region. In one embodiment, the islets independently have a diameter of about 1 μm to about 100 μm, such as about 1 μm to about 90 μm, about 1 μm to about 80 μm, about 1 μm to about 70 μm, about 1 μm to about 60 μm, about 1 μm to about 50 μm, about 1 μm to about 40 μm, about 1 μm to about 30 μm, about 1 μm to about 20 μm, or about 1 μm to about 10 μm; or about 10 μm to about 100 μm, about 20 μm to about 100 μm, about 30 μm to about 100 μm, about 40 μm to about 100 μm, about 50 μm to about 100 μm, about 60 μm to about 100 μm, about 70 μm to about 100 μm, about 80 μm to about 100 μm, or about 90 μm to about 100 μm. The islets independently have a diameter of about 10 μm, about 20 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, or about 100 μm, each value being plus or minus about 5 μm (± 5 μm). The islets independently have a diameter of about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, or about 10 μm.

[0064] In the figures, the islands are illustrated as circles in cross section, but they can be any shape that can be produced by co-extrusion or three-dimensional printing. For non-circular cross sections, the diameter size ranges given above are the size ranges of the longest cross-sectional diameter of the non-circular region (e.g., the major axis if the island is elliptical in shape).

[0065] A variety of materials can be used for the first linker material ("sea"). In one embodiment, the same carrier polymer-drug formulation that forms the segments connected by the linker region can also be used as the first linker material. Such an arrangement is shown in FIG. 3D. This embodiment has the advantage of simplifying coextrusion manufacturing, since the islands only have to be added during the coextrusion of the segments. If this embodiment is manufactured using three-dimensional printing, using a carrier polymer-drug formulation material as the first linker material minimizes the number of different polymer inputs required for three-dimensional printing. This can also provide a relatively strong linker region during the residence period in the stomach.

[0066] In one embodiment, a carrier polymer without a drug can be used as a first linker material that can facilitate bonding between the carrier polymer formulation segment and the linker region.

[0067] Polycaprolactone (PCL) is the preferred material for use as the "sea" material. In another embodiment, polydioxanone is used as the "sea" material. In additional embodiments, the "sea" material is selected from the group consisting of hydrophilic cellulose derivatives (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose), cellulose acetate phthalate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymers, polyvinyl alcohol, carboxyvinyl polymers (carbomer), Carbopol® acid carboxy polymers, polycarbophil, polyethylene oxide (Polyox WSR), polysaccharides and derivatives thereof, polyalkylene oxides, polyethylene glycol, chitosan, alginates, pectins, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidone vinyl acetate copolymer, dextrans, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, briar nori, eucheumae, gum arabic, gum ghatti, Karaya gum, arabinogalactan, amylopectin, gelatin, gellan, hyaluronic acid, pullulan, scleroglucan, xanthan, xyloglucan, maleic anhydride copolymer, ethylene maleic anhydride copolymer, polyhydroxyethyl methacrylate, ammonio methacrylate copolymer (Eudragit RL, Eudragit RS, etc.), polyethyl methacrylate (Eudragit NE), Eudragit E (dimethylaminoethyl methacrylate and neutral methacrylate) acrylate-based cationic copolymers), polyacrylic acids such as polymethacrylic acid, methyl methacrylate, and ethyl acrylate, polymethacrylate / polyethacrylates, polylactones such as polycaprolactone, polyanhydrides such as poly[bis(p-carboxyphenoxy)]propane anhydride and polyterephthalic anhydride, polypeptides such as polylysine and polyglutamic acid, DETOSU and hexanediol, decanediol, cyclohexanedimethanol, ethylene glycol,Polyorthoesters such as copolymers with diols such as polyethylene glycol, as well as the polyorthoesters described and disclosed in U.S. Pat. No. 4,304,767, which are incorporated herein by reference, can include starch, particularly pregelatinized starch and starch-based polymers, carbomers, maltodextrins, amylomaltodextrins, dextrans, poly(2-ethyl-2-oxazoline), polyethyleneimine, polyurethanes, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid (PLGA), polyhydroxyalkanoates, polyhydroxybutyric acid, and copolymers, mixtures, blends and combinations thereof.

[0068] In cases where the use of carrier polymer (with or without drug) results in a linker region that does not allow the system to break apart after the desired residence time, another polymer can be used as the first linker material. In one embodiment, an enteric polymer can be used as the first linker material. In one embodiment, a time-dependent polymer can be used as the first linker material. In one embodiment, low molecular weight polycaprolactone is used. In one embodiment, a weakening agent is mixed with the carrier polymer to form the first linker material; for example, carnauba wax, paraffin wax, or RH40 can be mixed with the carrier polymer (such as polycaprolactone) to produce a weakening polymer for use in the linker region.

[0069] A variety of materials are available for use as the second linker material ("island"). In one embodiment, an enteric polymer can be used as the second linker material. In one embodiment, a time-dependent polymer can be used as the second linker material. The "island" material can include one or more of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methacrylic acid methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, shellac, poly(methyl vinyl ether / maleic acid) monoethyl ester, poly(methyl vinyl ether / maleic acid) n-butyl ester, and copolymers, mixtures, blends and combinations thereof.

[0070] For enteric or time-dependent polymers arranged as islands or channels in a sea of ​​hydrophobic structural polymers, the time required for the time-dependent or enteric linker material to degrade or dissolve depends on the rate of water penetration into the polymer matrix. The diffusion time of water into the polymer islands is t~L 2 / 2D, where L is the water penetration distance and D is the diffusivity of water in the polymer. For a given geometry, the water diffusion time can be tailored by changing the diffusivity of the material. The diffusivity of the polymer can be tailored by blending with binders or other polymers. For example, for polymethylmethacrylate capillaries (for water in PMMA, distance L = 1.5 mm and D is approximately 3.35e-8 cm 2 / sec) to the center of the formulation would take approximately 3.9 days. To achieve 1.5 mm of water penetration into the matrix over 8 days, the diffusion rate of water in the polymer is 1.6e-8 cm 2 / seconds is the target.

[0071] Segment composition: Interlocking bonds between carrier polymer-drug and linker regions ("lock-and-key" junctions) The linker region used in the arm may be of a constant dimension along its length, such as the embodiment shown in region B of the arm diagram in FIG. 2B. Alternatively, the linker region may be of a constant dimension along its length, as illustrated in FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D. The linker regions in FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D have portions that extend from the body of the linker region into the carrier polymer-drug substance segment in an interlocking or "lock-and-lock" configuration. In some embodiments, portions of one or more segments of the carrier polymer-drug substance extend from the body of the carrier polymer-drug segment into the linker region, again in an interlocking or "lock-and-lock" configuration. In some embodiments, portions of one or more linker regions extend from the body of the linker region into the carrier polymer-drug segment, and portions of one or more segments of the carrier polymer-drug substance extend from the body of the carrier polymer-drug segment into the linker region.

[0072] The carrier polymer-drug substance and linker region form interlocking bonds by combining protrusions in the linker region with recesses in the carrier polymer-drug substance (such as those shown in Figures 4A, 4B, 4C, and 4D), or by combining protrusions in the carrier polymer-drug substance with recesses in the linker region, or by both combining protrusions in the linker region with recesses in the carrier polymer-drug substance and combining protrusions in the carrier polymer-drug substance with recesses in the linker region. These interlocking bonds provide enhanced bonding between segments comprising the linker region and the carrier polymer-drug substance.

[0073] The linker region in the interlocked bond structure further comprises a sea-island polymer of Figure 4A or Figure 4B. Figures 4C and 4D show interlock linkers without a sea-island polymer. In Figures 4C and 4D, one interlock linker region is a time-dependent linker, while the other interlock linker region is an enteric linker.

[0074] In one embodiment, the interlocking segments are manufactured by three dimensional printing. In one embodiment, the interlocking segments are manufactured by coextrusion.

[0075] Segment Composition: "Island-Sea" Carrier Polymer-Drug Region Some arm embodiments can be produced with carrier polymer-drug segments present in an "islands in the sea" structure. In this embodiment, one or more segment island materials can be used to produce an "islands in the sea" structure in which the carrier polymer-drug formulation includes segment sea material. FIG. 5A shows such a structure, in which both the carrier polymer-drug segment and the linker region have an island-sea structure. However, an island-sea structure can be used for the carrier polymer-drug segment without a linker region with an island-sea structure. That is, an island-sea structure can be used for the carrier polymer-drug segment while using a uniform linker region or a linker region with only one linker material. This allows further tuning of the properties of the gastroretentive system. For example, a channel of a relatively permeable material can be used as the segment island material, allowing liquids, especially water or gastric fluids, to contact a larger amount of the surface area of ​​the carrier polymer-drug segment sea material than only the segment outer surface. Alternatively, an additional drug or drugs can be used as the segment island material for co-administration. The segmented islet material containing the additional drug(s) may be relatively quickly soluble or quickly dissolve if rapid administration of the additional drug is desired when the gastroretentive system is placed in the stomach, or the drug(s) may be slowly eluted from the segmented islet material to gradually co-deliver the additional drug along with the drug contained in the carrier polymer-drug formulation in the segmented islet material.

[0076] FIG. 5B shows another embodiment of an elongate member that includes an islands-in-the-sea structure in the segments between linker regions. In this embodiment, the carrier polymer-drug compound is used as an island in the sea of ​​structural polymer, which significantly relaxes the requirements for the mechanical integrity and stability of the carrier polymer-drug. Soft polymers and waxes can be used as carrier materials, such as Kolliphor RH40, carnauba wax, P407, etc. Degradable polymers, such as polyanhydrides, polyphosphazenes, and polycyanoacrylates, can also be used as carrier polymers. The structural polymer used in this structure should have high Young's modulus, tensile strength, compressive strength, and should also interact well with the carrier polymer-drug compound (i.e., the structural polymer and the carrier polymer should be chemically compatible and have similar melting temperatures). Examples of structural polymers that can be used in this structure are polylactic acid, polycarbonate, polyetheretherketone, polyethylene, and polypropylene.

[0077] Segment Composition: Multilayered Segments In one embodiment, the gastroretentive system utilizes a multi-layered segment. One implementation of a multi-layered segment is shown in FIG. 6A. The segment comprises two or more layers of carrier polymer-drug formulation. This layering allows for different concentrations of drug or agent. A concentration gradient of the drug or agent can be created across the layers to provide a desired release rate of the drug or agent from the segment and / or the overall system.

[0078] In one embodiment, the multi-layered segment comprises two or more layers comprising a carrier polymer-drug formulation, where the concentration of drug or agent in each layer differs from the concentration in one or more adjacent layers of the segment. In one embodiment, the multi-layered segment comprises two or more layers comprising a carrier polymer-drug formulation, where the concentration of drug or agent in each layer decreases with increasing diameter (or distance) from the center of the segment. In one embodiment, the multi-layered segment comprises two or more layers comprising a carrier polymer-drug formulation, where the concentration of drug or agent in each layer increases with increasing diameter (or distance) from the center of the segment.

[0079] For example, a cylindrical segment of carrier polymer-drug formulation is produced having three layers, the first layer comprising a core cylinder of 1 mm diameter. The second layer, which is essentially a cylindrical tube with a circular cross section, has an inner diameter of 1 mm and an outer diameter of 2 mm, and therefore a layer thickness of 1 mm. The third (outer) layer, which is a cylindrical tube with a circular cross section, has an inner diameter of 2 mm and an outer diameter of 3 mm, and also has a layer thickness of 1 mm. For a segment that is 10 mm long, the total volume of the first (core) layer will be about 31.42 cubic millimeters, and the volume of the second layer will be about 94.3 mm3. 3 The volume of the second layer is about 157 mm 3 The volumes of the second and third layers are obtained by calculating the volume of a cylinder with that outer diameter and subtracting the volume of a cylinder with that inner diameter. For example, for the third layer, V = [π × (3 mm) 2 ×10mm]-[π×(2mm) 2x 10 mm]. Thus, the second layer has three times the volume of the first layer and the third layer has five times the volume of the first layer. The drug or agent concentration of the segment layers can be adjusted so that each layer contains approximately the same amount of drug or agent. If the third, most voluminous layer has a concentration of C, then the drug or agent concentration used in the second layer can be 1.67 times C and the drug or agent concentration used in the first layer can be 5 times C. The multi-layer concentration of drug or agent used can be adjusted to provide the desired elution rate of the drug or agent; in the previous example, it may be desirable to use a concentration of 1C in the third (outer) layer, 3C in the second layer, and 15C in the first layer to provide increased elution over time. Alternatively, the elution of the drug or agent can be tapered over time, for example, using a concentration of 1C in the third layer, 1 / 2C in the second layer, and 1 / 4C in the third layer.

[0080] In further embodiments, more than one drug or agent can be used in different carrier polymer-drug formulation layers of multiple multi-layered segments. In one embodiment, a first drug or agent is present in at least one of two or more layers in a segment, and a second drug or agent is present in at least one of two or more layers in a segment. In one embodiment, a first drug or agent is present in at least one of two or more layers in a segment, and one or more additional drugs or agents (i.e., a second drug or agent, a third drug or agent, etc.) are also present in at least one of two or more layers. In one embodiment, only one drug is present in each layer (i.e., each layer contains only one drug). In one embodiment, two or more drugs are present in at least one layer (i.e., one or more layers can contain two or more drugs).

[0081] FIG. 6B shows an embodiment of an elongate member having multiple carrier polymer-drug layers (labeled drug-polymer formulation in the figure). To compensate for the reduced mass transport area as the drug is released from the dosage form surface, formulations with different release rates can be layered to form a multi-layered structure as illustrated in FIG. 6B. Carrier polymer-drug (drug polymer) formulation 1 releases the drug relatively slowly, while formulation 4 releases the drug rapidly; the order of release rates of the formulations is formulation 1<formulation 2<formulation 3<formulation 4. The release rate from each layer and layer thickness can be adjusted to obtain a linear overall release rate from the dosage form. Formulations 1-4 can differ in drug or drug concentration (e.g., formulation 4>formulation 3>formulation 2>drug or drug loading in formulation 1) or excipient concentration.

[0082] Segment Composition: Internal Reinforcement Segments The strength of the segment can be improved by depositing a reinforcing material on the interior portion of the segment, usually in the central region of the segment. When providing the main mechanical support for the segment, the reinforcing material significantly relieves the mechanical requirements of the carrier polymer-drug substance. The reinforcing material extends axially along the segment. Various shapes and structures can be used for the reinforcing material. An I-shaped design, such as that shown in Figures 7A and 7B, provides excellent torsional and bending strength and improves the interaction between the carrier polymer-drug compound and the reinforcing material. A truss structure of the reinforcing material, such as that shown in Figures 8A and 8B, minimizes the amount of reinforcing material required while also providing excellent strength. The reinforcing material can have an I-shaped structure. The reinforcing material can have an H-shaped structure (the H-shape is similar to the I-shape but with a wider flange). The reinforcing material can have a truss structure. The reinforcing material can have a cylindrical structure. The reinforcing material can have a triangular prism structure (i.e., a rod structure with a triangular cross section). The reinforcement may have a "pie-like" structure (i.e., a structure of rods with a "pie-like" cross section, the "pie shape" being represented by a triangle with one side of the triangle replaced by an arc of a circle; the cross section of the arm shown in FIG. 10B is an example of a pie-like cross section). The reinforcement may have a rectangular prism structure or a regular square prism structure (i.e., a structure of rods with a rectangular or square cross section). If the internal reinforcement is polygonal (such as triangular or square) in shape, any or all sharp corners or edges may be rounded or filleted. The reinforcement may comprise a pure carrier polymer, such as polycaprolactone or polydioxanone. The reinforcement may consist essentially of or consist of a pure carrier polymer, such as polycaprolactone or polydioxanone. The reinforcement may comprise a carrier polymer with other components added. The reinforcement material can include a carrier polymer that contains a low concentration of a drug or agent (i.e., the inner carrier polymer reinforcement is a carrier polymer-drug formulation with a lower drug concentration than the surrounding carrier polymer-drug material. The reinforcement material can include a carrier polymer that does not contain a drug or agent.The reinforcing material may comprise another polymer (i.e. a polymer different from the carrier polymer), such as polylactic acid, polycarbonate, polyetheretherketone, polyethylene, or polypropylene. The reinforcing material may be a non-polymeric material.

[0083] The reinforcement can extend axially along substantially the entire length of the segment, or the reinforcement can extend axially along about 50%, at least about 50%, about 60%, at least about 60%, about 70%, at least about 70%, about 80%, at least about 80%, about 90%, at least about 90%, about 95%, or at least about 95% of the entire length of the segment.

[0084] The reinforcement is usually one continuous strip along the interior of the segment, however, two, three or more strips of reinforcement can be used, with the corner strips extending axially along the interior portion of the segment.

[0085] The internal reinforcement material is useful for gastroretentive systems that deliver hydrophobic therapeutic agents or their salts. Due to the low solubility of hydrophobic therapeutic agents or salts, a high percentage of the drug or salt must be formulated together using carrier polymers and other excipients. However, this high percentage of drug or salt can significantly reduce the mechanical strength of the segment. The mechanical strength of the segment can be increased by using the internal reinforcement material. In addition, since the innermost region of the segment is the most difficult region for water or gastric fluid to penetrate, replacing the inner portion of the carrier polymer-therapeutic agent with the reinforcement material has a relatively small effect on the drug delivery properties. The results in Example 4 and Figure 14 show the use of an internal reinforcement segment containing the hydrophobic drug tacrolimus, where the polycaprolactone arms are immersed in a solution containing tacrolimus and polyethylene vinyl acetate.

[0086] In one embodiment, the invention provides a gastric retention system for administration to a patient's stomach comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomeric component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is associated with the elastomeric component and projects radially from the elastomeric component, each elongate member being free from the elastomeric component and positioned a greater radial distance from the elastomeric component than the proximal end; at least one segment further comprises a reinforcing material, the reinforcing material extending axially along an interior of the at least one segment; and the carrier polymer-drug components comprise a hydrophobic therapeutic agent. In further embodiments, the elongate member is attached to the elastomeric component by a linker region; or the elongate member comprises two or more segments, the segments connected by a linker region; or the elongate member is attached to the elastomeric component by a linker region and the elongate member comprises two or more segments, the segments connected by a linker region. Each segment comprises a proximal end, a distal end, and an exterior surface therebetween. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 1 mg / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 500 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 250 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 100 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 50 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 25 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 10 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 5 micrograms / ml in water. In one embodiment, the hydrophobic therapeutic agent has a solubility of less than about 1 microgram / ml in water.In one embodiment, the hydrophobic therapeutic agent has a solubility in water of about 1 microgram / ml to about 1 mg / ml, about 1 microgram / ml to about 500 microgram / ml, about 1 microgram / ml to about 250 microgram / ml, about 1 microgram / ml to about 100 microgram / ml, about 1 microgram / ml to about 50 microgram / ml, about 1 microgram / ml to about 25 microgram / ml, about 1 microgram / ml to about 10 microgram / ml, or about 1 microgram / ml to about 5 microgram / ml.

[0087] The segments containing the reinforcement can be manufactured by any suitable method, such as dip coating (as used in Example 4), coextrusion, or three-dimensional printing.

[0088] Because the mechanical strength of the elongate member or segment is provided primarily by the reinforcing material, and not the carrier polymer, significantly more drug can be used in the carrier polymer-drug mixture while maintaining adequate mechanical strength of the elongate member than could be used without the reinforcing material. Thus, the amount of drug in the carrier polymer-drug mixture can range from about 60% by weight or less, about 50% by weight or less, or about 40% by weight or less, whereas such high percentages would not be achievable without the reinforcing material. Thus, in one embodiment, the amount of drug can be in the range of about 1% to about 60% by weight, about 10% to about 60% by weight, about 20% to about 60% by weight, about 30% to about 60% by weight, about 40% to about 60% by weight, about 50% to about 60% by weight, about 1% to about 50% by weight, about 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 20% by weight, or about 1% to about 10% by weight of the carrier polymer-drug mixture.

[0089] Also, because the reinforcing material provides mechanical strength to the elongated member or segment, additional polymers that may not be suitable for use without the reinforcing material can be used as carrier polymers. Polyethylene vinyl acetate can be used as a carrier polymer when a reinforcing material is used. Poloxamer 407, Pluronic P407, hypromellose, Corifol RH40, polyvinyl caprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), Soluplus (available from BASF; copolymer of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol), copovidone, Eudragit (E, EPO, RS, RL), methyl methacrylate, carnauba wax, poly(methyl vinyl ether-alt-maleic anhydride), polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene stearates, polyvinyl acetate phthalate, alginate, polydextrose, polydioxanone, polybutyl methacrylate, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid (PLGA), and mixtures thereof can also be used as carrier polymers for the reinforcement. Alternatively, the polymers listed as carrier polymers that can be used as carrier polymers without a reinforcing material can also be used as carrier polymers together with a reinforcing material; these polymers, including polycaprolactone and polydioxanone, are shown herein in the section "Carrier Polymers - Carrier Polymers for Drug Components."

[0090] Segment composition: fenestrated or porous coating as external support A fenestrated (perforated) coating or layer, such as that illustrated in Figure 9A, serving as an external support, can be used to improve the strength of the segments. In providing the primary mechanical support for the segments, the coating or external support significantly mitigates the mechanical requirements of the carrier polymer-drug substance. Polymers that degrade quickly enough to achieve linear drug release tend to be poorly structured polymers (polyanhydrides). Thus, the use of a structural polymer shell to reinforce such relatively poorly structured carrier polymers obviates the problems in using such carrier polymers.

[0091] The fenestrations can be adjusted in size, number and location to provide the desired ingress of gastric fluids and the desired release of the drug or agent eluted from the carrier polymer-drug formulation by the gastric fluids.

[0092] 9B shows cross and longitudinal cross sections of an embodiment of an elongate member having a fenestrated coating or layer. The interior may be entirely or primarily the carrier polymer-drug formulation, while the exterior structural polymer provides support. Time dependent or enteric linkers may be used in the elongate member.

[0093] Figure 9C shows another embodiment of an elongate member having a fenestrated coating or layer. This embodiment has less carrier polymer-drug drug in its interior than the embodiment shown in Figure 9B. The cross-sectional area of ​​the pores increases towards the center of the structure. As material dissolves out of the pores, the surface area for drug dissolution increases over time.

[0094] The porous shell can be created by three-dimensional printing. Using an islands-in-a-sea approach, a highly differentiated polymer (e.g., Eudragit E, Pluronic P407) can be printed within a slowly degrading structural polymer shell (e.g., PCL, PLA). Gastric fluids will quickly degrade and / or dissolve the islets, leaving a porous structure that allows the carrier polymer-drug formulation to enter. The size of these islets (and the resulting pores after the islets dissolve) can be from about 10 μm to about 100 μm.

[0095] The fenestrated layer may comprise a material strong enough to provide structural support, such as a thick layer of carrier polymer lacking a therapeutic agent. The fenestrated layer may comprise a pure carrier polymer, such as polycaprolactone or polydioxanone. The fenestrated layer may consist essentially of or consist of a pure carrier polymer, such as polycaprolactone or polydioxanone. The fenestrated layer may comprise a carrier polymer with other components added. The fenestrated layer may comprise a carrier polymer with a low concentration of drug or agent (i.e., the inner carrier polymer fenestrated layer is a carrier polymer-drug formulation with a lower drug concentration than the surrounding carrier polymer-drug material. The fenestrated layer may comprise a carrier polymer that does not contain a drug or agent. The fenestrated layer may comprise another polymer (i.e., a different polymer than the carrier polymer), such as polylactic acid, polycarbonate, polyetheretherketone, polyethylene, or polypropylene. The fenestrated layer may be a non-polymeric material.

[0096] In some embodiments, the fenestrated layer can have a thickness of about 100 micrometers to about 1,000 micrometers, such as a thickness of about 200 micrometers to about 900 micrometers, about 300 micrometers to about 800 micrometers, about 400 micrometers to about 700 micrometers, about 400 micrometers to about 600 micrometers, or about 500 micrometers. In some embodiments, the fenestrated layer can have a thickness of about 100 micrometers to about 900 micrometers, about 100 micrometers to about 800 micrometers, about 100 micrometers to about 700 micrometers, about 100 micrometers to about 600 micrometers, about 100 micrometers to about 500 micrometers, about 100 micrometers to about 400 micrometers, about 100 micrometers to about 300 micrometers, about 100 micrometers to about 250 micrometers, about 100 micrometers to about 200 micrometers, about 100 micrometers to about 300 micrometers, about 100 micrometers to about 25 ...250 micrometers, about 100 micrometers to about 250 micrometers, about 100 micrometers to about 250 micrometers, about 100 micrometers to about 250 or about 200 micrometers to about 1,000 micrometers, about 300 micrometers to about 1,000 micrometers, about 400 micrometers to about 1,000 micrometers, about 500 micrometers to about 1,000 micrometers, about 600 micrometers to about 1,000 micrometers, about 700 micrometers to about 1,000 micrometers, about 800 micrometers to about 1,000 micrometers, or about 900 micrometers to about 1,000 micrometers. In some embodiments, the fenestrated layer can have a thickness of about 200, about 300, about 400 micrometers, about 500, about 600, about 700, about 800, or about 900 micrometers.

[0097] Segment composition: External reinforcement layer or exoskeleton as external support The strength of the segments can also be improved by the use of an "exoskeleton" or external reinforcement layer that acts as an external support. This external reinforcement layer is similar to a fenestrated coating, but does not completely surround the segment outer surface. Although the external reinforcement layer does not need to be fenestrated because it does not completely surround the segment outer surface, the external reinforcement layer can be fenestrated if desired. Thus, in one embodiment, the external reinforcement layer is not fenestrated; in another embodiment, the external reinforcement layer is fenestrated. When having a fenestrated coating, the external reinforcement layer significantly eases the mechanical requirements of the carrier polymer-drug substance by providing the primary mechanical support for the segment. Segments with external reinforcement layers are described in Example 1, Figures 11A, 11B, 11C, and 11D.

[0098] The external reinforcement layer can be applied to a portion of the surface of the segment such that it covers about 10%, about 20%, about 25%, about 30%, about 33%, about 40%, about 50%, about 60%, about 67%, about 70%, about 75%, about 80%, or about 90% of the segment. However, if the external reinforcement layer covers 100% of the segment, it will need to be fenestrated to allow for elution of the therapeutic agent, thus resulting in a fenestrated shell as described above. The external reinforcement layer should extend along a significant amount of the length of the segment to provide sufficient reinforcement; for example, it should extend at least about 75%, at least about 80%, at least about 90%, or preferably at least about 95% of the length of the segment.

[0099] The external reinforcing layer can be tailored to the shape of the segment or elongated member to be reinforced. For example, for an elongated member or "arm" with a triangular cross section, such as the cross section shown in the left image of FIG. 2A (i.e., the elongated member is a triangular prism), the external reinforcing layer can be applied to one side of the elongated member, covering about one third or about 33% of the surface of the elongated member. An external reinforcing layer covering one side of a triangular prism has a width equal to the length of the elongated member and a height equal to the width of the triangular side to which it is applied; such an external reinforcing layer is rectangular in shape, the rectangle being a parallelogram forming one side of the elongated member. For example, a reinforcing layer applied to the leftmost side of the arm cross section illustrated in FIG. 2A for the arm illustrated in FIG. 2B has a length equal to (L1+L2+L3+L4+L5) and a height equal to W2. The reinforcing layer can be applied to two sides of the elongated member, covering about two thirds or 67% of the surface of the elongated member. For elongated members having a square or rectangular cross section, a rectangular reinforcing layer can be added to one, two, or three sides of the elongated member. Generally, for elongated members in the shape of a cylinder, a reinforcing layer in the shape of a parallelogram can be applied to the elongated member including the sides of the elongated member. Different shapes can be used for elongated members having different surface configurations; for example, a curved reinforcing layer can be used to cover the curved portion of the surface of the cross section shown in the left diagram of FIG. 10B.

[0100] The reinforcing material can comprise a material that is strong enough to provide structural support, such as a thick layer of carrier polymer that is devoid of therapeutic agent. The reinforcing material can comprise a pure carrier polymer, such as polycaprolactone or polydioxanone. The reinforcing material can consist essentially of or consist of a pure carrier polymer, such as polycaprolactone or polydioxanone. The reinforcing material can comprise a carrier polymer with other components added. The reinforcing material can comprise a carrier polymer that contains a low concentration of drug or agent (i.e., an internal carrier polymer reinforcement is a carrier polymer-drug blend with a lower drug concentration than the surrounding carrier polymer-drug material. The reinforcing material can comprise a carrier polymer that does not contain a drug or agent. The reinforcing material can comprise another polymer (i.e., a different polymer than the carrier polymer), such as polylactic acid, polycarbonate, polyetheretherketone, polyethylene, or polypropylene. The reinforcing material can be a non-polymeric material.

[0101] In some embodiments, the reinforcing material can have a thickness of about 100 micrometers to about 1,000 micrometers, such as a thickness of about 200 micrometers to about 900 micrometers, about 300 micrometers to about 800 micrometers, about 400 micrometers to about 700 micrometers, about 400 micrometers to about 600 micrometers, or about 500 micrometers. In some embodiments, the reinforcing material can have a thickness of about 100 micrometers to about 900 micrometers, about 100 micrometers to about 800 micrometers, about 100 micrometers to about 700 micrometers, about 100 micrometers to about 600 micrometers, about 100 micrometers to about 500 micrometers, about 100 micrometers to about 400 micrometers, about 100 micrometers to about 300 micrometers, about 100 micrometers to about 250 micrometers, about 100 micrometers to about 200 micrometers, about 100 micrometers to about 300 micrometers, about 100 micrometers to about 350 micrometers, about 100 micrometers to about 400 micrometers, about 100 micrometers to about 500 micrometers, about 100 micrometers to about 600 micrometers, about 100 micrometers to about 700 micrometers, about 100 micrometers to about 800 micrometers, about 100 micrometers to about 900 micrometers, about 100 micrometers to about 100 micrometers to about 100 micrometers to about 250 micrometers, about 100 micrometers to about 300 micrometers, about 100 micrometers to about 250 or about 200 micrometers to about 1,000 micrometers, about 300 micrometers to about 1,000 micrometers, about 400 micrometers to about 1,000 micrometers, about 500 micrometers to about 1,000 micrometers, about 600 micrometers to about 1,000 micrometers, about 700 micrometers to about 1,000 micrometers, about 800 micrometers to about 1,000 micrometers, or about 900 micrometers to about 1,000 micrometers. In some embodiments, the reinforcement can have a thickness of about 200, about 300, about 400, about 500, about 600, about 700, about 800, or about 900 micrometers.

[0102] System Dimensions The system must be configurable to a compacted state having dimensions that allow the patient to swallow it (or for the system to be introduced into the stomach by alternative methods such as a feeding tube or stomach tube). Typically, the system is held in a compacted state by a container such as a capsule. Upon entering the stomach, the system is released from the container and expands, i.e., to an expanded configuration having dimensions that prevent the system from passing through the pyloric sphincter and thus allow retention of the system in the stomach.

[0103] Therefore, the system should be capable of being placed into a standard size capsule of the type commonly used in pharmacies. Standard capsule sizes used in the United States are shown in Table 1 below (see "Draft Guidance for Industry on Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules" at URL www.regulations.gov / #!documentDetail;D=FDA-2013-N-1434-0002). Because these are the outer dimensions of the capsule and there are slight dimensional variations between capsule manufacturers, the system should be capable of being constructed to be approximately 0.5-1 mm smaller than the outer dimensions shown in Table 1 and approximately 1-2 mm shorter in length than those shown in Table 1.

[0104] [Table 1]

[0105] The capsules can be made from materials known in the art, such as gelatin or hydroxypropylmethylcellulose, In one embodiment, the capsules are made from a material that dissolves in the gastric environment but not in the oral or esophageal environment, which prevents premature release of the system before it reaches the stomach.

[0106] In one embodiment, the system is folded or compressed into a tight fit to fit into a capsule. Once the capsule dissolves in the stomach, the system assumes a structure suitable for gastric retention. The preferred capsule sizes are 00 and 00el (00el size capsules have an approximate length and an approximate width of the 000 capsule), which results in constraints on the length and diameter of the folded system.

[0107] Once released from the container, the system is in an expanded state with dimensions suitable for preventing the gastroretention system from passing through the pyloric sphincter. In one embodiment, the system has at least two dimensions, each of which is at least 2 cm long; i.e., the gastroretention system is greater than at least about 2 cm in at least two perpendicular directions. In one embodiment, the perimeter of the system in its expanded state, when projected onto a plane, has two perpendicular dimensions, each of which is at least 2 cm long. The two perpendicular dimensions can independently have lengths of about 2 cm to about 7 cm, about 2 cm to about 6 cm, about 2 cm to about 5 cm, about 2 cm to about 4 cm, about 2 cm to about 3 cm, about 3 cm to about 7 cm, about 3 cm to about 6 cm, about 3 cm to about 5 cm, about 3 cm to about 4 cm, about 4 cm to about 7 cm, about 4 cm to about 6 cm, about 4 cm to about 5 cm, or about 4 cm to about 4 cm. These dimensions prevent the gastroretention system from passing through the pyloric sphincter.

[0108] For star-shaped polymer systems having N arms (N is 3 or more), the arms can have dimensions such that the system has at least two perpendicular dimensions, each having a length as described above. These two perpendicular dimensions are selected as described above to promote retention of the gastroretentive system. The number of arms in a star-shaped (stellate) gastroretentive system should be at least 3. The number of arms can be 3, 4, 5, 6, 7, 8, 9, or 10. The number of arms can be 4, 5, 6, 7, or 8. The preferred number of arms (elongated members) for a star-shaped gastroretentive system is 6.

[0109] The system is designed to eventually break apart in the stomach at the end of the desired residence time. Once the binding polymer breaks down, the remaining components of the system are of a size that allows the system to pass through the pyloric sphincter, small intestine, and large intestine. Ultimately, the system is eliminated from the body by excretion or by eventual complete dissolution of the system in the small intestine and large intestine.

[0110] System Polymer Composition The selection of the individual polymers for the carrier polymer, the binding polymer, and the elastomer will affect the therapeutic agent elution rate (which depends on the carrier polymer, as well as other factors), the residence time of the system (which depends on the degradation of either of the polymers, primarily the binding polymer), the uncoupling time of the system when it enters the small intestine (which depends primarily on the enteric degradation rate of the binding polymer, as described herein), and the useful life of the system in its compacted form (which depends primarily on the properties of the elastomer). Because the system is administered to the gastrointestinal tract, all of the system components should be biocompatible with the gastrointestinal environment.

[0111] The rate at which a therapeutic agent dissolves from a carrier polymer-drug component is influenced by many factors, including the composition and properties of the carrier polymer, which itself may be a mixture of several polymeric and non-polymeric components; the properties of the therapeutic agent, such as hydrophilicity / hydrophobicity, charge state, pKa, and hydrogen bonding ability; and the properties of the gastric environment. In the aqueous environment of the stomach, it is difficult but challenging to avoid burst release of a therapeutic agent, especially a hydrophilic drug (burst release refers to a high initial delivery of an active pharmaceutical ingredient relative to the initial deployment of the system in the stomach), and to maintain sustained release of the drug over a period of days to weeks.

[0112] The residence time of the system in the stomach is adjusted by the binding polymer used in the linker region. The mechanical action and fluctuating pH in the stomach eventually weaken the enteric binding polymer, so the system eventually disintegrates in the stomach despite the use of an enteric polymer. A binding polymer that degrades in a time-dependent manner in the stomach can also be used to adjust the time it takes for the system to break apart, and therefore the residence time. Once the system breaks apart, it enters the intestine and is then excreted.

[0113] The elastomer used in the system is important to the shelf life of the system. When the system is compacted, the elastomer is subjected to mechanical stress. The stress can then cause polymer creep, which if excessive enough, can prevent the system from returning to its expanded structure when released from the capsule or other container; this in turn leads to premature emptying of the system from the stomach. Polymer creep can also be temperature dependent, therefore the expected storage conditions of the system need to be considered when selecting the elastomer and other polymeric components.

[0114] The system components and polymers should not swell or should swell very little in the gastric environment: the components should swell no more than about 20%, no more than about 10%, or preferably no more than about 5% when in the gastric environment over the period of residence.

[0115] Carrier Polymers - Carrier Polymers for Drug Components The carrier polymer-drug component contains a therapeutic agent (or a salt of a therapeutic agent) that is eluted from the gastroretentive system in the gastric environment. The therapeutic agent is compounded with the carrier polymer to produce a carrier polymer-drug mixture. This mixture can be formed into a desired shape or shapes for use as the carrier polymer-drug component of the system column.

[0116] Preferably, the carrier polymer has the following properties: The carrier polymer should be thermoplastic to allow extrusion using hot melt extrusion or 3D printing techniques. The carrier polymer has high enough melt strength and viscosity to be extrudable into the required shape. The carrier polymer has a low melt temperature (e.g., less than about 120°C) to avoid exposing the drug or agent to high temperatures during manufacture. The carrier polymer should have sufficient mechanical strength (Young's modulus, compressive strength, tensile strength) to avoid disintegration in the stomach during the desired residence time. The carrier polymer should be capable of forming a stable blend with the drug, therapeutic agent, drug, excipient, dispersant, and other additives.

[0117] Suitable carrier polymers for use in the present invention include hydrophilic cellulose derivatives (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose), cellulose acetate phthalate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymers, polyvinyl alcohol, carboxyvinyl polymers (carbomers), Carbopol® acidic carboxy polymers, polycarbophil, polyethylene oxide (Polyox WSR), polysaccharides and derivatives thereof, polyalkylene oxides, polyethylene glycol, chitosan, alginates, pectins, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidone vinyl acetate copolymer, dextrans, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, briarweed, eucheumae, gum arabic, gum ghatti, karaya gum, arabinogalactan, amylopectin, zeaxanthin ... Latin, gellan, hyaluronic acid, pullulan, scleroglucan, xanthan, xyloglucan, maleic anhydride copolymers, ethylene maleic anhydride copolymers, polyhydroxyethyl methacrylate, ammonio methacrylate copolymers (Eudragit RL, Eudragit RS, etc.), polyethyl methacrylate (Eudragit NE), Eudragit E (cationic copolymers based on (dimethylamino)ethyl methacrylate and neutral methacrylate esters), polymethacrylic acid, methyl methacrylate, and Polyacrylic acids such as ethyl acrylate, polymethacrylates / polyethacrylates, polylactones such as polycaprolactone, polyanhydrides such as poly[bis(p-carboxyphenoxy)]propane anhydride and polyterephthalic anhydride, polypeptides such as polylysine and polyglutamic acid, polyorthoesters such as copolymers of DETOSU with diols such as hexanediol, decanediol, cyclohexanedimethanol, ethylene glycol, and polyethylene glycol, and the like, as well as copolymers of DETOSU with diols such as hexanediol, decanediol, cyclohexanedimethanol, ethylene glycol, and polyethylene glycol ... decanediol, decanediol, decanediol, decanediol, decanediol, decanediol, decanediol, decanediol, decanediol, decanediol, decanediol, decanedPolyorthoesters described and disclosed in US Pat. No. 767, incorporated herein by reference, include, but are not limited to, starch, particularly pregelatinized starch and starch-based polymers, carbomers, maltodextrins, amylomaltodextrins, dextrans, poly(2-ethyl-2-oxazoline), polyethyleneimine, polyurethane, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid (PLGA), polyhydroxyalkanoates, polyhydroxybutyric acid, and copolymers, mixtures, blends, and combinations thereof. Polycaprolactone (PCL) is a preferred carrier polymer. In another embodiment, polydioxanone is used as the carrier polymer.

[0118] Other excipients can be added to the carrier polymer to modify the release of the therapeutic agent. Such excipients can be added in an amount of about 1% to 15%, preferably about 5% to 10%, more preferably about 5% or about 10%. Examples of such excipients include Poloxamer 407 (available as Corifol P407, Sigma catalog #62035); Pluronic P407; Eudragit E, Eudragit EPO (available from Evonik); Hypromellose (available from Sigma, catalog #H3785), Corifol RH40 (available from Sigma, catalog #07076), polyvinylcaprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), and Soluplus (available from BASF; a copolymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol). Preferred soluble excipients include Eudragit E, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl alcohol (PVA). Preferred poorly soluble excipients include Eudragit RS and Eudragit RL. Preferred poorly soluble, swellable excipients include crospovidone, croscarmellose, hypromellose acetate succinate (HPMCAS), and carbopol.

[0119] Carrier Polymer-Drug Component Manufacturing Method Compounding temperatures for incorporating therapeutic agents into a polymer matrix typically range from about 80°C to about 120°C, although higher or lower temperatures may be used for polymers that are best compounded at temperatures outside that range. If a particular size of drug particles is used and it is desired to maintain the particle size during and after compounding, compounding can be done at a temperature below the melting point of the drug to maintain the desired size of the drug. Alternatively, a temperature that melts both the polymer and the drug can be used. The compounding temperature should be below the decomposition temperature of the drug. In one embodiment, less than about 0.05% of the drug is degraded during manufacturing. In one embodiment, less than about 0.04% of the drug is degraded during manufacturing. In one embodiment, less than about 0.03% of the drug is degraded during manufacturing. In one embodiment, less than about 0.02% of the drug is degraded during manufacturing. In one embodiment, less than about 0.01% of the drug is degraded during manufacturing.

[0120] Hot melt extrusion can be used to prepare carrier polymer-drug components. Single screw or preferably twin screw methods can be used. As mentioned above, if it is desired to maintain particle size during and after compounding, a carrier polymer that can melt at a temperature that does not degrade the drug should be used. Alternatively, a temperature that melts both the polymer and the drug can be used.

[0121] A melt and cast process can also be used to prepare the carrier polymer-drug component. The carrier polymer and therapeutic drug, as well as any other desired ingredients, are mixed together. The carrier polymer is melted, the melt is mixed so that the drug particles are uniformly distributed in the melt, poured into a mold, and allowed to cool.

[0122] Solution casting methods can also be used to prepare carrier polymer-drug components. The polymer is dissolved in a solvent and particles of therapeutic agent are added. If the size of the drug particles is to be maintained, a solvent that does not dissolve the drug particles should be used to avoid variations in the size characteristics of the particles; otherwise, a solvent that dissolves both the polymer and drug particles can be used. The solvent-carrier polymer-drug particle mixture (or solvent-carrier polymer-drug solution) is then mixed to distribute the particles evenly (or the solution is thoroughly mixed), poured into a mold, and the solvent is allowed to evaporate.

[0123] Preparation of Feed Polymer for Three-Dimensional Printing Three-dimensional printing is often accomplished by feeding a print head with rods or fibers of solid material that are melted, deposited, and then solidified in a technique known as fused deposition modeling (sometimes called extrusion deposition modeling); see U.S. Patent Nos. 5,121,329 and 5,340,433. The carrier polymer-drug component manufacturing methods described herein can also be used to produce feed materials that can be used for the three-dimensional printing manufacture of components of gastroretentive systems.

[0124] Therapeutic Drug Particle Size and Milling Control of particle size used in gastroretentive systems is important for both optimal therapeutic agent release and mechanical stability of the system. The therapeutic agent particle size affects the surface area of ​​drug available for dissolution when gastric fluids permeate the carrier polymer-drug component of the system. Also, when the "arms" (elongated members) of the system are relatively thin in diameter (e.g., 1-5 mm), the presence of drug particles with a size greater than a few percent of the arm diameter results in weaker arms both before the drug elutes from the device and after elution when voids are left in the spaces previously occupied by the drug particles. Such weakening of the arms is disadvantageous as it can result in premature disintegration and expulsion of the system before the end of the desired residence period.

[0125] In one embodiment, the therapeutic agent particles used for loading into the carrier polymer-drug component are smaller than about 100 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 75 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 50 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 40 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 30 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 25 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 20 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 10 microns in diameter. In some embodiments, the therapeutic agent particles are smaller than about 5 microns in diameter.

[0126] In one embodiment, at least about 80% of the therapeutic agent particles used for loading into the carrier polymer-drug component are smaller than about 100 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 75 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 50 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 40 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 30 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 25 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 20 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 10 microns in diameter. In some embodiments, at least about 80% of the therapeutic agent particles are smaller than about 5 microns in diameter.

[0127] In one embodiment, at least about 80% of the mass of the therapeutic agent particles used for loading into the carrier polymer-drug component have a size of about 1 micron diameter to about 100 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 75 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 50 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 40 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 30 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 25 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 20 microns diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 1 micron diameter to about 10 microns diameter. In some embodiments, at least about 80% by mass of the therapeutic agent particles have a size between about 1 micron in diameter and about 5 microns in diameter.

[0128] In one embodiment, at least about 80% of the mass of the therapeutic agent particles used for loading into the carrier polymer-drug component have a size of about 2 microns to about 100 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 75 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 50 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 40 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 30 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 25 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 20 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 2 microns to about 10 microns in diameter. In some embodiments, at least about 80% by mass of the therapeutic agent particles have a size between about 2 microns in diameter and about 5 microns in diameter.

[0129] In one embodiment, at least about 80% of the mass of the therapeutic agent particles used for loading into the carrier polymer-drug component have a size of about 5 microns to about 100 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 75 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 50 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 40 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 30 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 25 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 20 microns in diameter. In some embodiments, at least about 80% of the mass of the therapeutic agent particles have a size of about 5 microns to about 10 microns in diameter.

[0130] The particle size of the therapeutic agent can be easily adjusted by milling. Several milling techniques are available to reduce larger particles to the desired size of smaller particles. Fluid energy milling is a dry milling technique that uses interparticle collisions to reduce particle size. A type of fluid energy mill called an air jet mill projects air into a cylindrical chamber in such a way as to maximize collisions between therapeutic agent particles. Ball milling utilizes the rotation of a cylindrical chamber around its main axis. The therapeutic agent and abrasives (steel balls made from chrome steel or CR-NI steel; ceramic balls such as zirconia; or plastic polyamides) collide reducing the drug particle size. Ball milling can be performed either dry or with a liquid added to the cylinder where the therapeutic agent and abrasives are poorly soluble in the liquid. Further information on milling can be found in the chapter by RW Lee et al. entitled "Particle Size Reduction" in Water-Insoluble Drug Formulation, Second Edition (Ron Liu, editor), Boca Raton, Florida: CRC Press, 2008; and the chapter by AW Brzeczko et al. entitled "Granulation of Poorly Water-Soluble Drugs", in Handbook of Pharmaceutical Granulation Technology, Third Edition (Dilip M. Parikh, editor), Boca Raton, Florida: CRC Press / Taylor & Francis Group, 2010 (and other sections of the Handbook). Fluid energy milling (i.e., air jet milling) is the preferred milling method as it is more amenable to scale-up compared to other dry milling techniques such as ball milling.

[0131] Flour Additives Substances can be added to the therapeutic agent during milling to help obtain particles of the desired size and minimize aggregation during handling. Silica (silicon dioxide, SiO2) is a preferred milling additive because it is inexpensive, widely available, and non-toxic. Other additives that can be used include calcium phosphate, powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, talc, polyvinylpyrrolidone, cellulose ethers, polyethylene glycol, polyvinyl alcohol, and surfactants. Hydrophobic particles, particularly those less than 5 microns in size, are particularly prone to agglomeration, and hydrophilic additives are used when milling such particles. A milling additive such as silica at a weight / weight ratio of about 0.1% to about 5%, or about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, or about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, or about 5% can be used in the fluid milling or ball milling.

[0132] Particle Sizing After milling, the particles are passed through a mesh of appropriate size to obtain particles of the desired size. To obtain particles of the maximum desired size, the particles are passed through a mesh with holes of the maximum desired size; particles that are too large are left on the mesh and particles that pass through the mesh have the maximum desired size. To obtain particles of the minimum desired size, the particles are passed through a mesh with holes of the minimum desired size; particles that pass through the mesh are too small and the desired particles are retained on the mesh.

[0133] Dispersing agents for controlling therapeutic agent release and stability of polymer formulations The use of a dispersant in a carrier polymer-drug component offers many advantages. The dissolution rate of a therapeutic agent from a carrier polymer-drug component is influenced by many factors, including the composition and properties of the carrier polymer (which itself may contain multiple polymeric and non-polymeric components); the physical and chemical properties of the therapeutic agent; and the gastric environment, as discussed above. Avoiding burst release of a therapeutic agent, especially a hydrophilic drug, and maintaining a sustained release of the therapeutic agent over the residence period are important properties of the system. The use of a dispersant according to the present invention allows for better control of the release rate and suppression of burst release. The burst release and release rate can be adjusted by using different concentrations of the dispersant.

[0134] Dispersants that can be used in the present invention include: silicon dioxide (silica, SiO2) (hydrophilic fumed); stearates such as calcium stearate and magnesium stearate; microcrystalline cellulose; carboxymethylcellulose; hydrophobic colloidal silica; hypromellose; magnesium aluminum silicate; phospholipids; polyoxyethylene stearate; zinc acetate; alginic acid; lectin; fatty acids; sodium lauryl sulfate; and non-toxic metal oxides such as aluminum oxide. Porous inorganic materials and polar inorganic materials can be used. Hydrophilic fumed silicon dioxide is the preferred dispersant.

[0135] In addition to their aggregation / flocculation inhibition effect, dispersants can help prevent phase separation during manufacture and / or storage of the system. This is particularly useful for systems manufactured by hot melt extrusion methods.

[0136] The weight / weight ratio of dispersing agent to therapeutic agent substance can be about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 4%, about 2% to about 3%, about 3% to about 4%, about 4% to about 5%, or about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, or about 5%.

[0137] When administering a gastroretentive system, a dispersing agent may also be used to adjust the burst release amount during the initial period. In an embodiment of a gastroretentive system to be administered once every week, the burst release over about the first 6 hours after the initial administration is less than about 8%, preferably less than about 6%, of the total amount of drug in the system. In an embodiment of a gastroretentive system to be administered once every 3 days, the burst release over about the first 6 hours after the initial administration is less than about 12%, preferably less than about 10% of the total amount of drug in the system. In an embodiment of a gastroretentive system to be administered once every day, the burst release over about the first 6 hours after the initial administration is less than about 40%, preferably less than about 30% of the total amount of drug in the system. In general, if a new gastroretentive system is administered every D days and the total mass of drug is M, the gastroretentive system releases less than about [0.5 times M divided by D], preferably less than about [M divided by D multiplied by 0.4], or less than about [M divided by D multiplied by 3 / 8], and more preferably less than about [M divided by D multiplied by 0.3], over about the first 6 hours after the first administration. In a further embodiment, the gastroretentive system releases at least about [M divided by D multiplied by 0.25] over about the first 6 hours after the first administration, i.e., the system releases at least about one-quarter of the daily dosage over the first quarter of the first day of administration.

[0138] Binding Polymer A binding polymer is used to bind one or more carrier polymer-drug components to one or more carrier polymer-drug components, to bind one or more carrier polymer-drug components to one or more elastomeric components, or to bind one or more elastomeric components to one or more elastomeric components. The binding polymer thus forms a linker region between the other components of the system. Enteric and time-dependent polymers are preferred for use as binding polymers.

[0139] Under acidic conditions such as those encountered in the stomach, enteric polymers are relatively insoluble, but are soluble under low acidity to basic conditions encountered in the small intestine. Since the pH of the first part of the small intestine, the duodenum, ranges from about 5.4 to 6.1, enteric polymers that dissolve at about pH 5 or higher can be used as binding polymers. When the gastric retention system passes unchanged through the pyloric valve, the enteric binding polymer dissolves and the components bound by the binding polymer break apart to allow the retention system to pass through the small intestine and large intestine. Therefore, to avoid possible intestinal obstruction, the gastric retention system is designed to rapidly uncouple in the intestinal environment by dissolution of the binding polymer within 48 hours, preferably within 24 hours, more preferably within 12 hours, and even more preferably within 1 to 2 hours. During treatment, if the gastric retention system must be removed quickly for any reason, the patient can drink a weakly basic aqueous solution (such as a bicarbonate solution) to induce fast-acting uncoupling of the gastric retention system.

[0140] Suitable binding polymers include, but are not limited to, cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methacrylic acid methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, and copolymers, mixtures, blends and combinations thereof.Some of the enteric polymers that can be used in the present invention are listed in Table 2 together with their dissolution pH. (See Mukherji, Gour and Clive G. Wilson, "Enteric Coating for Colonic Delivery," Chapter 18 of Modified-Release Drug Delivery Technology (editors Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts), Drugs and the Pharmaceutical Sciences Volume 126, New York:Marcel Dekker, 2002). Preferably, an enteric polymer is used that is soluble at a pH no greater than about 5 or about 5.5. Methacrylic acid-ethyl acrylate copolymer (sold under the trade name Eudragit L100-55; Eudragit is a registered trademark of Evonik Rohm GmbH, Darmstadt, Germany) is a preferred enteric polymer. Cellulose acetate phthalate, cellulose acetate succinate, and hydroxypropyl methylcellulose phthalate are also suitable enteric polymers.

[0141] In one embodiment, the enteric polymer used in the gastric retention system dissolves at a pH greater than about 4. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH greater than about 5. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH greater than about 6. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH greater than about 7. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH greater than about 7.5. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 4 to about 5. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 4 to about 6. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 4 to about 7. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 4 to about 7.5. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 5 to about 6. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 5 to about 7. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 5 to about 7.5. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 6 to about 7. In some embodiments, the enteric polymer used in the gastric retention system dissolves at a pH of about 6 to about 7.

[0142] [Table 2]

[0143] Additional preferred polymers for use as binding polymers are time-dependent polymers, i.e., polymers that degrade in a time-dependent manner in gastric environment.For example, triacetin degrades in a time-dependent manner over 7 days in simulated gastric fluid, while plastoid B retains its strength over a period of 7 days in simulated gastric fluid.Therefore, a time-dependent degrading polymer can be easily produced by mixing plastoid B and triacetin; the degradation time of plastoid B-triacetin mixture can be extended by increasing the amount of plastoid B used in the mixture, while the degradation time can be decreased by increasing the amount of plastoid B used in the mixture.

[0144] A variety of time-dependent mechanisms are available. Water-soluble time-dependent polymers break down when water penetrates the polymer. Examples of such polymers are hydroxypropyl methylcellulose and polyvinyl acetate. Acid-soluble time-dependent polymers break down over time in an acidic environment. Examples include Eudragit EPO. Time-dependent polymers can use water-soluble plasticizers; when the plasticizer is released, the remaining polymer becomes brittle and breaks down under the forces of the stomach. Examples of such polymers include triacetin and triethyl citrate.

[0145] In some embodiments, the carrier polymer-drug component is an elongate member comprised of segments bonded together by an enteric polymer. In some embodiments, the carrier polymer-drug component is bonded to the elastomeric component of the system by an enteric polymer. In any of these embodiments, when an enteric polymer is used for both segment-to-segment bonding and elongate member-to-elastomeric component bonding, the enteric polymer used for segment-to-segment bonding may be the same enteric polymer as the enteric polymer used for bonding the elongate member-to-elastomeric component, or the enteric polymer used for segment-to-segment bonding may be a different enteric polymer than the enteric polymer used for bonding the elongate member-to-elastomeric component. The enteric polymers used for segment-to-segment bonding may all be the same enteric polymer or may all be different enteric polymers, and some of the enteric polymers in the segment-to-segment bonding may be the same and some of the enteric polymers in the segment-to-segment bonding may be different. That is, the enteric polymer(s) used for each segment-segment bond and the enteric polymer used to bond the elongate member to the elastomeric component may be selected independently.

[0146] In any of the embodiments of the gastroretentive system described herein, the binding polymer or linker can include hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polycaprolactone (PCL). These blends can be used to produce a disintegrating linker or disintegrating matrix. The ratio of HPMCAS to polycaprolactone in the disintegrating linker or disintegrating matrix can be about 80% HPMCAS:20% PCL to about 20% HPMCAS:80% PCL. The ratio of HPMCAS to polycaprolactone was about 80% HPMCAS:20% PCL to about 20% HPMCAS:80% PCL; about 70% HPMCAS:30% PCL to about 30% HPMCAS:70% PCL; about 60% HPMCAS:40% PCL to about 40% HPMCAS:60% PCL; about 80% HPMCAS:20% PCL to about 50% HPMCAS:50% PCL; about 80% HPMCAS:20% PCL to about 60% HPMCAS:40% PCL; about 70% HPMCAS:30% PCL to about 50% HPMCAS:50% PCL; about 70% HPMCAS:30% PCL to about 60% HPMCAS:40% PCL; about 2 It may be 0% HPMCAS:80% PCL to about 40% HPMCAS:60% PCL; about 20% HPMCAS:80% PCL to about 50% HPMCAS:50% PCL; about 30% HPMCAS:70% PCL to about 40% HPMCAS:60% PCL; about 30% HPMCAS:70% PCL to about 50% HPMCAS:50% PCL; or about 80% HPMCAS:20% PCL, about 70% HPMCAS:30% PCL, about 60% HPMCAS:40% PCL, about 50% HPMCAS:50% PCL, about 40% HPMCAS:60% PCL, about 30% HPMCAS:70% PCL, or about 20% HPMCAS:80% PCL.The linker may further comprise a plasticizer selected from the group consisting of triacetin, triethyl citrate, tributyl citrate, poloxamer, polyethylene glycol, polypropylene glycol, diethyl phthalate, dibutyl sebacate, glycerin, castor oil, acetyl triethyl citrate, acetyl tributyl citrate, polyethylene glycol monomethyl ether, sorbitol, sorbitan, sorbitol-sorbitan mixtures, and diacetylated monoglycerides.

[0147] Linkers are selected to weaken sufficiently after a certain period of time to allow the gastro-retentive system to reach a point where it uncouples, crosses the pylorus, and exits the stomach after a desired residence time, i.e., they weaken to a point where it uncouples, or where the gastro-retentive system can cross the pylorus, referred to as the uncoupling or pylorus crossing point. Thus, in one embodiment, a linker is used that uncouples after about 2 days in the human stomach; after about 3 days in the human stomach; after about 4 days in the human stomach; after about 5 days in the human stomach; after about 6 days in the human stomach; after about 7 days in the human stomach; after about 8 days in the human stomach; after about 9 days in the human stomach; after about 10 days in the human stomach; or after about 2 weeks in the human stomach. In one embodiment, a linker is used that uncouples after about 2 days in the dog stomach; after about 3 days in the dog stomach; after about 4 days in the dog stomach; after about 5 days in the dog stomach; after about 6 days in the dog stomach; after about 7 days in the dog stomach; after about 8 days in the dog stomach; after about 9 days in the dog stomach; after about 10 days in the dog stomach; or after about 2 weeks in the dog stomach. In one embodiment, a linker is used that uncouples after about 2 days in the pig stomach; after about 3 days in the pig stomach; after about 4 days in the pig stomach; after about 5 days in the pig stomach; after about 6 days in the pig stomach; after about 7 days in the pig stomach; after about 8 days in the pig stomach; after about 9 days in the pig stomach; after about 10 days in the pig stomach; or after about 2 weeks in the pig stomach. In one embodiment, a linker is used that uncouples after about 2 days in fasted simulated gastric fluid; after about 3 days in fasted simulated gastric fluid; after about 4 days in fasted simulated gastric fluid; after about 5 days in fasted simulated gastric fluid; after about 6 days in fasted simulated gastric fluid; after about 7 days in fasted simulated gastric fluid; after about 8 days in fasted simulated gastric fluid; after about 9 days in fasted simulated gastric fluid; after about 10 days in fasted simulated gastric fluid; or after about 2 weeks in fasted simulated gastric fluid. In one embodiment, a linker is used that uncouples after about 2 days in fed artificial gastric fluid; after about 3 days in fed artificial gastric fluid; after about 4 days in fed artificial gastric fluid; after about 5 days in fed artificial gastric fluid; after about 6 days in fed artificial gastric fluid; after about 7 days in fed artificial gastric fluid; after about 8 days in fed artificial gastric fluid; after about 9 days in fed artificial gastric fluid; after about 10 days in fed artificial gastric fluid; or after about 2 weeks in fed artificial gastric fluid.In one embodiment, a linker is used that uncouples after about 2 days in water at pH 2; after about 3 days in water at pH 2; after about 4 days in water at pH 2; after about 5 days in water at pH 2; after about 6 days in water at pH 2; after about 7 days in water at pH 2; after about 8 days in water at pH 2; after about 9 days in water at pH 2; after about 10 days in water at pH 2; or after about 2 weeks in water at pH 2. In one embodiment, a linker is used that uncouples after about 2 days in water at pH 1; after about 3 days in water at pH 1; after about 4 days in water at pH 1; after about 5 days in water at pH 1; after about 6 days in water at pH 1; after about 7 days in water at pH 1; after about 8 days in water at pH 1; after about 9 days in water at pH 1; after about 10 days in water at pH 1; or after about 2 weeks in water at pH 1.

[0148] Uncoupling or pyloric passage occurs in humans, dogs, or pigs when the system leaves the stomach, i.e., passes through the pylorus. For in vitro measurements in simulated gastric fluid or acidic water, uncoupling or pyloric passage occurs when the linker weakens to the point where it disintegrates under the normal compressive forces of the stomach, which are usually about 0.1 Newtons to 0.2 Newtons. The bond strength (breaking point) can be measured by any relevant test that serves to test the binding capacity, i.e., the force required to break the linker, such as the four-point bending test (ASTM D790) described in Example 18 of WO 2017 / 070612, or Examples 12, 13, 15, 17, or 18 of PCT / US2016 / 065453. In one embodiment, uncoupling or pyloric passage is reached when the linker uncouples with a force of about 0.2 N. In another embodiment, the uncoupling or pylorus crossing point is reached when the linker uncouples with a force of about 0.1 N.

[0149] Elastomer The elastomer (also called elastic or high strength polymer) allows the gastroretentive system to be compacted, such as by folding or compacting into a form suitable for administration into the stomach by swallowing a container or capsule containing the compacted system. Upon dissolution of the capsule in the stomach, the gastroretentive system expands into a shape that prevents the system from passing through the patient's pyloric sphincter for the desired residence time of the system. Thus, the elastomer must be capable of being stored in a compacted structure in a capsule for a reasonable shelf life and expanding back to its original shape, or approximately its original shape. In one embodiment, the elastomer is a silicone elastomer. In one embodiment, the elastomer is produced from a liquid silicone rubber, such as that sold in Dow Corning QP-1 Liquid Silicone Rubber Kit. In one embodiment, the elastomer is a crosslinked polycaprolactone. In one embodiment, the elastomer is an enteric polymer, such as those listed in Table 2. In some embodiments, the binding polymer(s) used in the system are also elastomers. Elastomers are preferred for use as the central polymer in star-shaped or stellate designs of gastroretentive systems.

[0150] In one embodiment, both the binding polymer and the elastomer are enteric polymers that provide more complete disintegration of the system into carrier polymer-drug particles when the system enters the intestine or when the patient drinks a weakly basic solution to induce excretion of the system.

[0151] Examples of elastomers that can be used include silicones, such as those formed using the Dow Corning QP-1 kit; urethane crosslinked polycaprolactone; poly(6-aminocaproic acid acryloyl) (PA6ACA); methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55); and mixtures of poly(6-aminocaproic acid acryloyl) (PA6ACA) and methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55).

[0152] Other System Characteristics Stabilization of therapeutic drugs Many therapeutic agents are prone to oxidative degradation when exposed to reactive oxygen species that may be present in the stomach. Thus, the therapeutic agents contained in the system may be subject to oxidation due to the long residence of the system in the stomach and the sustained release period of the drug from the system. Therefore, it is desirable to stabilize the drug to inhibit oxidative and other degradation.

[0153] Antioxidant stabilizers that can be included in the system to reduce or inhibit oxidation of the therapeutic agent include alpha-tocopherol (about 0.01 to about 0.05% (v / v)), ascorbic acid (about 0.01% to about 0.1% (w / v)), ascorbyl palmitate (about 0.01% to about 0.1% (w / v)), butylated hydroxytoluene (about 0.01% to about 0.1% (w / w)), butylated hydroxyanisole (about 0.01% to about 0.1% (w / w)), and fumaric acid (up to 3600 ppm).

[0154] Certain therapeutic agents are sensitive to pH, especially at the low pH found in the gastric environment. Stabilizer compounds that can be included in the system to reduce or inhibit degradation of the therapeutic agent at low pH include calcium carbonate, calcium lactate, sodium phosphate, and sodium bicarbonate. These are typically used in amounts of about 2% (w / w) or less.

[0155] Antioxidant stabilizers, pH stabilizers, and other stabilizer compounds are incorporated into the polymer containing the therapeutic agent by incorporating the stabilizer(s) into the molten carrier polymer-drug mixture. The stabilizer(s) can also be incorporated into the molten carrier polymer before incorporating the therapeutic agent into the polymer-stabilizer mixture; the stabilizer(s) can also be incorporated with the therapeutic agent before formulating the therapeutic agent-stabilizer mixture incorporated into the carrier polymer; the stabilizer(s), therapeutic agent, and molten carrier polymer can also be incorporated simultaneously. The therapeutic agent can also be incorporated into the molten carrier polymer before incorporating the stabilizer(s) into the polymer-drug mixture.

[0156] In one embodiment, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 24 hours of gastric residence. In one embodiment, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 48 hours of gastric residence. In one embodiment, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 72 hours of gastric residence. In one embodiment, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 96 hours of gastric residence. In one embodiment, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 5 days of gastric residence. In some embodiments, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 1 week of gastric residence. In some embodiments, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 2 weeks of gastric residence. In some embodiments, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 3 weeks of gastric residence. In some embodiments, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 4 weeks of gastric residence. In some embodiments, less than about 10% of the therapeutic agent remaining in the system is degraded or oxidized after about 1 month of gastric residence.

[0157] In one embodiment, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 24 hours of gastric residence. In one embodiment, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 48 hours of gastric residence. In one embodiment, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 72 hours of gastric residence. In one embodiment, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 96 hours of gastric residence. In one embodiment, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 5 days of gastric residence. In some embodiments, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 1 week of gastric residence. In some embodiments, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 2 weeks of gastric residence. In some embodiments, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 3 weeks of gastric residence. In some embodiments, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 4 weeks of gastric residence, hi some embodiments, less than about 5% of the therapeutic agent remaining in the system is degraded or oxidized after about 1 month of gastric residence.

[0158] Therapeutic Agents for Use in Gastroretentive Systems Therapeutic agents that can be administered to or through the gastrointestinal tract can be used in the gastroretentive system of the present invention. Therapeutic agents include, but are not limited to, drugs, prodrugs, biologics, and any other substances that can be administered to obtain a beneficial effect against a disease or injury. Therapeutic agents that can be used in the gastroretentive system of the present invention include statins such as rosuvastatin; nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam; selective serotonin reuptake inhibitors (SSRIs) such as escitalopram and citalopram; anticoagulants such as clopidogrel; steroids such as prednisone; antipsychotics such as aripiprazole and risperidone; analgesics such as buprenorphine; opioid antagonists such as naloxone; antiasthmatics such as montelukast; antidementia drugs such as memantine; cardiac glycosides such as digoxin; alpha blockers such as tamsulosin; cholesterol blockers such as ezetimibe. These include: cholesteatomatase inhibitors; anti-gout treatments such as colchicine; antihistamines such as loratadine and cetirizine; opioids such as loperamide; proton pump inhibitors such as omeprazole; antivirals such as entecavir; antibiotics such as doxycycline, ciprofloxacin, and azithromycin; antimalarials; levothyroxine; drug abuse treatments such as methadone and varenicline; contraceptives; stimulants such as caffeine; and nutrients such as folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, biotin, plant extracts, plant hormones, and other vitamins or minerals. Biologics that can be used as therapeutic agents in the gastroretentive system of the present invention include proteins, polypeptides, polynucleotides, and hormones.Suitable classes of therapeutic agents include analgesics; anti-analgesics; anti-inflammatory drugs; antipyretics; antidepressants; anti-epileptic drugs; anti-schizophrenia drugs; neuroprotective drugs; anti-proliferative drugs such as anti-cancer drugs; antihistamines; anti-migraine drugs; hormones; prostaglandins; antibacterial drugs such as antibiotics; anti-fungal drugs; anti-viral drugs and anti-parasitic drugs; anti-muscarinics; anxiolytic drugs; bacteriostatic drugs; immunosuppressants; sedatives; hypnotics; antipsychotic drugs; bronchodilators; anti-asthma drugs; cardiovascular drugs; anesthetics; anticoagulants; enzyme inhibitors; steroidal drugs; steroidal or non-steroidal anti-inflammatory drugs; corticosteroids; dopamine agonists; electrolytes; gastrointestinal drugs; muscle relaxants. These include, but are not limited to, laxatives; nutrients; vitamins; parasympathomimetics; stimulants; appetite suppressants; antihypersomnia medications; and antimalarials such as quinine; lumefantrine; chloroquine; amodiaquine; pyrimethamine; proguanil; chlorproguanil-dapsone; sulfonamides (such as sulfadoxine and sulfamethoxypyridazine); mefloquine; atovaquone; primaquine; halofantrine; doxycycline; clindamycin; artemisinin; and artemisinin derivatives (such as artemether, dihydroartemisinin, arteether, and artesunate). The term "therapeutic agent" includes salts, solvates, polymorphs, and cocrystals of the foregoing. In certain embodiments, the therapeutic agent is selected from the group consisting of cetirizine, rosuvastatin, escitalopram, citalopram, risperidone, olanzapine, donezepil, and ivermectin. In some embodiments, the therapeutic agent is one used for the treatment of a neuropsychiatric disorder, such as an antipsychotic or an anti-dementia agent, such as memantine.

[0159] Targeted therapeutic drug category The gastroretentive system is well suited for use in treating diseases and disorders where patient compliance is a challenge, and thus in some embodiments, the gastroretentive system is used to treat diseases and disorders where patient compliance to drug regimens is an issue, including neuropsychiatric diseases and disorders, dementia and other diseases and disorders that affect memory, Alzheimer's disease, psychosis, schizophrenia, and delusional disorders. Thus, therapeutic agents that can be used in the gastroretentive system include, but are not limited to, anti-dementia drugs, anti-Alzheimer's drugs, and anti-psychotic drugs.

[0160] Hydrophilic Therapeutic Agents Suitable hydrophilic therapeutic agents that can be used in the system include risperidone, cetirizine, memantine, and olanzapine.

[0161] Hydrophobic Therapeutic Agents Suitable hydrophobic therapeutic agents that can be used in the system include tacrolimus, ivermectin, rosuvastatin, citalopram, and escitalopram.

[0162] Low-dosage drugs Drugs and other therapeutic agents administered in relatively low doses, such as about 1 mg / day or less, about 0.5 mg / day, or about 0.1 mg / day, are also well suited for use in the gastroretentive system of the present invention. Examples of such drugs that can be used in the gastroretentive system include, but are not limited to, levothyroxine, low-dose contraceptives, and vitamins and other nutrients, such as vitamin A, vitamin D, vitamin K, folate, vitamin B12, and biotin.

[0163] Residence time The residence time of a gastric retention system is defined as the time from administration of the system to the stomach until the system leaves the stomach. In one embodiment, the gastric retention system has a residence time of about 24 hours, or less than about 24 hours. In one embodiment, the gastric retention system has a residence time of about 48 hours, or less than about 48 hours. In one embodiment, the gastric retention system has a residence time of about 72 hours, or less than about 72 hours. In one embodiment, the gastric retention system has a residence time of about 96 hours, or less than about 96 hours. In one embodiment, the gastric retention system has a residence time of about 5 days, or less than about 5 days. In one embodiment, the gastric retention system has a residence time of about 6 days, or less than about 6 days. In one embodiment, the gastric retention system has a residence time of about 7 days, or less than about 7 days. In one embodiment, the gastric retention system has a residence time of about 10 days, or less than about 10 days. In one embodiment, the gastroretention system has a retention time of about 14 days, or less than about 14 days. In one embodiment, the gastroretention system has a retention time of about 3 weeks, or less than about 3 weeks. In one embodiment, the gastroretention system has a retention time of about 4 weeks, or less than about 4 weeks. In one embodiment, the gastroretention system has a retention time of about 1 month, or less than about 1 month.

[0164] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of about 5 days to about 7 days. In one embodiment, the gastric retention system has a retention time of about 6 days to about 7 days.

[0165] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of about 5 days to about 10 days. In one embodiment, the gastric retention system has a retention time of about 6 days to about 10 days. In one embodiment, the gastric retention system has a retention time of about 7 days to about 10 days.

[0166] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of about 5 days to about 14 days. In one embodiment, the gastric retention system has a retention time of about 6 days to about 14 days. In one embodiment, the gastric retention system has a retention time of about 7 days to about 14 days. In one embodiment, the gastric retention system has a retention time of about 10 days to about 14 days.

[0167] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 5 days to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 6 days to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 7 days to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 10 days to about 3 weeks. In one embodiment, the gastric retention system has a retention time of about 14 days to about 3 weeks.

[0168] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 5 days to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 6 days to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 7 days to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 10 days to about 4 weeks. In one embodiment, the gastric retention system has a retention time of about 14 days to about 4 weeks. In one embodiment, the gastroretentive system has a retention time of about 3 weeks to about 4 weeks.

[0169] In one embodiment, the gastric retention system has a retention time of about 24 hours to about 1 month. In one embodiment, the gastric retention system has a retention time of about 48 hours to about 1 month. In one embodiment, the gastric retention system has a retention time of about 72 hours to about 1 month. In one embodiment, the gastric retention system has a retention time of about 96 hours to about 1 month. In one embodiment, the gastric retention system has a retention time of about 5 days to about 1 month. In one embodiment, the gastric retention system has a retention time of about 6 days to about 1 month. In one embodiment, the gastric retention system has a retention time of about 7 days to about 1 month. In one embodiment, the gastric retention system has a retention time of about 10 days to about 1 month. In one embodiment, the gastric retention system has a retention time of about 14 days to about 1 month. In one embodiment, the gastroretentive system has a retention time of about 3 weeks to about 1 month.

[0170] The gastric retention system releases a therapeutically effective amount of the therapeutic agent for at least a portion of the residence time, or the residence period during which the system is present in the stomach. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 25% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 50% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 60% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 70% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 75% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 80% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 85% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 90% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 95% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 98% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the therapeutic agent for at least about 99% of the residence time.

[0171] radiopaque The system is optionally radiopaque so that the system can be located by abdominal x-ray if necessary. In some embodiments, one or more materials used in the construction of the system are sufficiently radiopaque for x-ray visualization. In other embodiments, a radiopaque material is added to one or more materials of the system, or coated on one or more materials of the system, or added to a small portion of the system. Examples of suitable radiopaque materials are barium sulfate, bismuth subcarbonate, bismuth oxychloride, and bismuth trioxide. Preferably, these materials should not be compounded into the polymers used to construct the gastroretentive system so as not to alter the therapeutic agent release from the carrier polymer or the desired properties of other system polymers. Metal striping or chips on a small portion of the system components, such as tungsten, can also be used.

[0172] System manufacturing / assembly: 3D printing Three-dimensional printing of components of the gastroretentive system, such as arms or arm segments, is performed using commercially available equipment. Three-dimensional printing has been used for pharmaceutical formulations; see Khaled et al., "Desktop 3D printing of controlled release pharmaceutical bilayer tablets," International Journal of Pharmaceutics 461:105- 111 (2014); US Patent No. 7,276,252; Alhnan et al., "Emergence of 3D Printed Dosage Forms: Opportunities and Challenges," Pharm. Res., May 18, 2016, PubMed PMID: 27194002); Yu et al., "Three-dimensional printing in pharmaceutics: promises and problems," J. Pharm. Sci. 97(9):3666-3690 (2008); and Ursan et al., "Three-dimensional drug printing: A structured review," J. Am. Pharm. Assoc. 53(2):136-44 (2013).

[0173] The initial feedstock for three-dimensional printing is a polymer or polymer blend (e.g., an enteric polymer, a time-dependent polymer, or a blend of one or more drugs, agents, excipients, etc. with an enteric polymer(s), enteric polymer(s), or time-dependent polymer). The polymer or components to be used for one region of the segment or elongate member to be produced are mixed and pelletized using a hot melt extrusion process. The polymer or blended polymer material is extruded through a circular die to create a cylindrical fiber wrapped around a spool.

[0174] Multiple spools are fed into a 3D printer (Hyrel Printer available from Hyrel 3D, Norcross, GA, USA) and fed into its representative print head. The print head heats up, melts the material at the nozzle, and places a thin layer of material (polymer or polymer blend) at a specific location on the piece being produced. The material cools and hardens within seconds, and the next layer is added until the structure is fully formed. The quality of the formulation depends on the feed rate, nozzle temperature, and printer resolution, and the feed rate and nozzle temperature can be adjusted to obtain the desired quality.

[0175] Three-dimensional printing can be used to produce individual elongated members, or segments of elongated members. Three-dimensional printing can be used to produce bulk structures, such as compressed "slabs" similar to those produced by the coextrusion methods described herein. The bulk structures can also be cut into individual pieces (i.e., individual elongated members or individual segments) as needed.

[0176] In some embodiments, three-dimensional printing of an elongate member is contemplated to produce a complete elongate member or an "arm" of a gastroretention system. In some embodiments, three-dimensional printing of a segment of an elongate member is contemplated to produce a segment of an elongate member or an "arm" of a gastroretention system. In some embodiments, an elongate member or a segment thereof is produced by three-dimensional printing of adjacent portions of a carrier polymer-drug formulation and a linker material in a bulk structure, such as a slab structure. Following three-dimensional printing, the bulk structure can be cut into portions having the desired shape of the elongate member or a segment thereof. Following three-dimensional printing, the bulk structure can be compression molded into portions having the desired shape of the elongate member or a segment thereof.

[0177] System manufacturing / assembly: Co-extrusion The components of the gastroretentive system can be manufactured by coextrusion. Most of the various structures for the segments described herein, such as the "islands in the sea" structures, can be manufactured by either three-dimensional printing or coextrusion. However, coextrusion is less expensive and can be performed in a continuous manner, as opposed to three-dimensional printing, which is generally performed in a batch manner.

[0178] Coextrusion of "islands in the sea" structures is used in the textile industry and optical fiber manufacturing, but is rarely applied in biomedical systems, see U.S. Patent Nos. 3,531,368; 3,716,614; 4,812,012; and Haslauer et al., J. Biomed. Mater. Res. B Appl. Biomater. 103(5):1050-8 (2015).

[0179] Co-extrusion of components of the gastroretentive system, such as elongated members (arms) or segments of elongated members (arms), can be performed using commercially available equipment in combination with customized co-extrusion plumbing and customized dies for the desired configuration. The initial feedstock for co-extrusion is a polymer or polymer blend (e.g., an enteric polymer, a time-dependent polymer, or a blend of one or more drugs, agents, excipients, etc. with an enteric polymer(s), enteric polymer(s), or time-dependent polymer). The polymer or components to be used for one region of the segment or elongated member to be produced are mixed and pelletized using a hot melt extrusion process. The polymer pellets thus formed are placed in a hopper on a single screw extruder and dried to remove surface moisture. The pellets are gravimetrically fed into individual single screw extruders, where they are melted and pressurized for co-extrusion.

[0180] A suitable molten polymer is then pumped through a custom designed die with multiple channels to form the required shape. The composite polymer block is cooled (water, air, or bath) and cut or stamped into the desired shape, including but not limited to shapes such as triangular prisms, rectangular prisms, or cylindrical sections (pie wedges).

[0181] In some embodiments, co-extrusion of elongate members is contemplated to produce complete elongate members or "arms" of a gastroretentive system. In some embodiments, co-extrusion of segments of elongate members is contemplated to produce segments of elongate members or "arms" of a gastroretentive system. In some embodiments, elongate members or segments thereof are produced by co-extrusion of adjacent portions of carrier polymer-drug formulation and linker material in a bulk structure, such as a slab structure. Following co-extrusion, the bulk structure can be cut into portions having elongate members or segments thereof of the desired shape. For example, a segment-linker-segment bulk or slab structure is cut at an angle perpendicular to the co-extrusion direction. Following co-extrusion, the bulk structure can be compression molded into portions having elongate members or segments thereof of the desired shape.

[0182] Figures 12A and 12B illustrate such a co-extrusion method in schematic form. Figure 12A shows the co-extrusion of an elongate member or "arm" with three segments and two linkers. Extruder 1202 extrudes one "ribbon" of material (extruded in the direction indicated by arrow 1250) comprising three segment ribbon strip regions 1210, 1212, and 1214 comprising a carrier polymer-drug formulation, i.e., a formulation including a carrier polymer, a therapeutic agent or a salt thereof, and any desired excipients. Ribbon strip regions 1210, 1212, and 1214 comprising the carrier polymer-drug formulation are separated by ribbon strip regions 1220 and 1222 comprising a linker formulation, i.e., a formulation including a linker polymer(s) or a binding polymer(s). The ribbon can be cut along dotted line 1230 to separate ribbon pieces 1240 to form segment-linker-segment elongate members or "arms" 1260 shown in Figure 12C. After cutting, ribbon strip region 1210 of piece 1240 in Figure 12A becomes segment 1280 of arm 1260 in Figure 12C, ribbon strip region 1212 becomes segment 1282 of arm 1260 in Figure 12C, and ribbon strip region 1214 becomes segment 1284 of arm 1260 in Figure 12C, while ribbon strip region 1220 in Figure 12A becomes linker 1290 of arm 1260 in Figure 12C, and ribbon strip region 1222 in Figure 12A becomes linker 1292 of arm 1260 in Figure 12C. The ribbon strip 1240 may be cut to form square or rectangular segments, triangles to form triangular segments, or cut and then punched with a die into the desired shape.

[0183] FIG. 12B illustrates the co-extrusion of an arm with one linker connecting two segments. Extruder 1202 extrudes a "ribbon" of material (extruded in the direction indicated by arrow 1250) comprising two segment ribbon strip regions 1210 and 1212 comprising a carrier polymer-drug formulation, i.e., a formulation of a carrier polymer, a therapeutic agent or salt thereof, and any desired excipients. The two ribbon strip regions 1210 and 1212 comprising the carrier polymer-drug formulation are separated by ribbon strip region 1220 comprising a linker formulation, i.e., a formulation including a linker polymer(s) or a linking polymer(s). The ribbon can be cut along dotted line 1230 to cut out pieces of ribbon 1240 to form segment-linker-segment elongated members or "arms" 1260 shown in FIG. 12D. After cutting, ribbon strip region 1210 of piece 1240 in FIG. 12B becomes segment 1280 of arm 1260 in FIG. 12D, ribbon strip region 1212 becomes segment 1282 of arm 1260 in FIG. 12D, and ribbon strip region 1220 in FIG. 12B becomes linker 1290 of arm 1260 in FIG. 12D. Ribbon strip 1240 may be cut to form square or rectangular segments, cut into triangles to form triangular segments, or cut and then punched with a die to the desired shape. Co-extrusion in this manner provides elongate members or "arms" with stronger bonds at the segment-linker junctions compared to heat welding separate portions of the segments and the linker, as shown in Example 2 and FIG. 13.

[0184] An elongate member or "arm" with only one segment and linker, i.e., a segment-linker portion, can be similarly produced. This is equivalent to omitting segment ribbon 1212 from the extrusion illustrated in FIG. 12B to produce an arm lacking segment 1282 in FIG. 12D. Similarly, an elongate member or "arm" with multiple linkers and segments, such as a segment-linker-segment-linker-segment structure, can be produced by extrusion of appropriate regions. All of the segments can be the same in composition, all of the segments can be different in composition, some of the segments can be the same in composition while others are different in composition. Similarly, all of the linkers can be the same in composition, all of the linkers can be different in composition, some of the linkers can be the same in composition while others are different in composition.

[0185] An elongate member or arm can be made with one, two, three, four, or five segments. If an elongate member is made with one segment, a linker can be attached to one end of the elongate member. If an elongate member is made with multiple segments, a linker is positioned between and joined to any two segments. If desired, an elongate member can have a linker at one end of the elongate member, i.e., one end of the elongate member can be terminated or "capped" with a linker; this is equivalent to omitting ribbon 1214 from FIG. 12A to make the arm of FIG. 12C lacking segment 1284.

[0186] The overall length of the elongate members is typically about 10 mm to about 20 mm, and therefore the length of the segments in the elongate members after cutting from the ribbon (such as the elongate members shown in Figures 12C and 12D) plus the length of the linkers should also be in the range of about 10 mm to about 20 mm. Preferred ranges for the elongate members are about 12 mm to about 20 mm, about 14 mm to about 20 mm, about 14 mm to about 18 mm, or about 14 mm to about 16 mm. Subject to the constraint that the length of all segments and linkers of an elongate member should be in the range of about 10 mm to about 20 mm, or within a preferred sub-range, the segments may be in the range of about 2 mm to about 20 mm in length, about 2 mm to about 18 mm in length, about 2 mm to about 16 mm in length, about 2 mm to about 14 mm in length, about 2 mm to about 12 mm in length, about 2 mm to about 10 mm in length, about 2 mm to about 8 mm in length, about 2 mm to about 6 mm in length, or about 2 mm to about 4 mm in length. Subject to the constraint that the length of all segments and linkers of the elongate member should be in the range of about 10 mm to about 20 mm, or within a preferred sub-range, the linker region of the elongate member may be in the range of about 50 microns to about 2 mm in length, about 100 microns to about 2 mm in length, about 250 microns to about 2 mm in length, about 500 microns to about 2 mm in length, about 750 microns to about 2 mm in length, about 1 mm to about 2 mm in length, about 1.25 mm to about 2 mm in length, about 1.5 mm to about 2 mm in length; or about 1.75 mm to about 2 mm in length. In some embodiments, the linker region can range from about 50 microns to about 1.75 mm in length, from about 50 microns to about 1.5 mm in length, from about 50 microns to about 1.25 mm in length, from about 50 microns to about 1 mm in length, from about 50 microns to about 750 microns in length, from about 50 microns to about 500 microns in length, from about 50 microns to about 250 microns in length, or from about 50 microns to about 100 microns in length.

[0187] In some embodiments, the elongate member or segments thereof are produced by coextrusion of adjacent portions of the carrier polymer-drug formulation and linker material in a bulk structure, such as a slab structure, simultaneously with coextrusion of additional polymers or polymers of the carrier polymer-drug formulation, linker material, or both the carrier polymer-drug formulation and linker material. Coextrusion of additional polymers or polymers of the carrier polymer-drug formulation, linker material, or both the carrier polymer-drug formulation and linker material can be performed in an islands-in-the-sea structure. Following coextrusion, the bulk structure can be cut into portions having the desired shape of the elongate member or segments thereof. Following coextrusion, the bulk structure can be compression molded into portions having the desired shape of the elongate member or segments thereof.

[0188] Co-extrusion of elongated members according to the method described in this invention offers beneficial advantages over other methods of manufacturing elongated members. When segments are manufactured by mono-extrusion of carrier polymer-drug formulations through a die having the cross-sectional shape of the segment or elongated member in a "straight line", i.e., so that the elongated member or segment exits the extruder along its long axis, the segments must be cut to the appropriate length and then require additional post-extrusion steps to secure the linker and additional segments. In contrast, by using the co-extrusion method described herein, the entire elongated member is manufactured as one co-extruded unit in a ribbon, which is cut into pieces at the appropriate points (and subsequently punched into pieces cut to different shapes, if necessary), and the elongated member is immediately obtained without the need for further post-extrusion assembly steps. Eliminating the extra steps reduces the manufacturing cost of the elongated members. It also allows for the production of elongated members at a faster rate than linear extrusion. As described in Example 2, co-extrusion allows for high-throughput and scalable manufacturing of composite arms. Coextrusion of composite ribbons at about 12 inches (about 30.5 cm) per minute produces about 180 3.33 mm wide elongated members or "arms" per minute, while linear (single-component) extrusion of axial elongated members or "arms" at the same linear speed produces less than six arms per minute and also requires a post-extrusion step of assembling the segments into elongated members by incorporating linkers (such as disintegrable matrices) between the segments. In addition, as shown in Example 2, elongated members produced by coextrusion have stronger linker-segment joints than elongated members produced by linear extrusion and heat welding of the linkers and segments.

[0189] Thus, in one embodiment, the coextrusion process of the invention provides a coextrusion rate of about or at least about 30 or less elongated members per minute, such as about 30 to about 500 elongated members per minute, or about 50 to about 500, about 100 to about 500, about 150 to about 500, about 180 to about 500, about 200 to about 500, about 300 to about 500, or about 400 to about 500 elongated members per minute; or about 50 to about 400, about 50 to about 300, about 50 to about 200, or about 50 to about 180 elongated members per minute. Methods are provided for co-extruding elongate members as an assembly of segments and linkers at a rate sufficient to produce up to 50, about or at least about 100, about or at least about 150, about or at least about 180, about or at least about 200, about or at least about 300, about or at least about 400, or about or at least about 500 elongate members per minute. In any of the foregoing embodiments, the arms are about 1-5 mm wide, such as about 2 mm wide and 4 mm wide. In any of the foregoing embodiments, the arms are produced from a single co-extrusion apparatus.

[0190] In one embodiment, the coextrusion of the present invention is conducted at a coextrusion rate sufficient to produce elongated members at a rate that is about or at least about 5 times faster, about 10 times faster, about 20 times faster, about 30 times faster, or about 50 times faster than one-component extrusion at the same linear extrusion rate, or about 5 to about 10 times, about 5 to about 20 times, about 5 to about 30 times, or about 5 to about 50 times faster than one-component extrusion at the same linear extrusion rate.

[0191] As the ribbon is extruded, it is cooled from the temperature required for extrusion to room temperature, or additional cooling is applied to increase the cooling rate or to cool the ribbon below room temperature. Once the ribbon reaches a temperature at which it can be cut, it is cut to produce the elongate members. If the elongate members are to be punched into the desired shapes after cutting, the ribbon may be cut while still somewhat flexible, i.e., before it has completely cooled. Alternatively, the ribbon may be produced in substantial lengths (e.g., 12 inches or 30 cm) and stored, and later cut into the desired elongate members for assembly into the gastroretentive system.

[0192] In addition to producing elongate members with carrier polymer-drug segments and linkers, coextrusion can be used to produce elongate members with reinforcements. For example, the reinforced elongate member shown in FIG. 11A can be produced by coextrusion of drug-loaded polymer (carrier polymer-drug component) and structural polymer (reinforcement). The cross-sectional view on the left of FIG. 11A represents a die pattern that can be used to produce a reinforced coextruded segment of a triangular elongate member reinforced on one side. Other patterns of coextrusion that can be used include coextrusion to produce elongate members of any cross-sectional shape with reinforcements on the surface, such as a triangular elongate member reinforced on two sides of the triangular elongate member.

[0193] Gastric delivery pharmacokinetics for gastroretentive systems The gastroretentive system of the present invention has been shown to provide a significant improvement in the bioavailability of a therapeutic agent compared to conventional oral formulations, with an AUC 無限 The system provides high bioavailability of the therapeutic agent as measured by the plasma concentration of the therapeutic agent.

[0194] Relative bioavailability of two different formulations, Formulation A and Formulation B, F 相対 is defined as follows: F 相対 =100×(AUC A ×Dose B ) / (AUC B ×Dose A ) In the formula, AUC A is the area under the curve for formulation A, AUC B is the area under the curve for formulation B, and dose A is the dose of formulation A used, and dose B is the dose of formulation B used. AUC, the area under the curve of therapeutic drug plasma concentration versus time, is usually measured at the same time (t) after administration of each formulation to obtain the relative bioavailability of the formulations at the same time point. AUC 無限represents the AUC measured or calculated over the "infinite" time period, i.e., the final time period starting with the first dose at which the plasma concentration of the therapeutic agent declines to negligible amounts.

[0195] In one embodiment, the substantially constant plasma concentration of a therapeutic agent provided by the gastroretentive system of the present invention is greater than the trough plasma concentration of the therapeutic agent when administered daily in a conventional oral formulation (i.e., the C of the therapeutic agent administered daily in an immediate release formulation). 最小 ) from the above, the peak plasma concentration of a therapeutic agent when administered daily in a conventional oral formulation (i.e., the C 最大 In some embodiments, the substantially constant plasma concentration of a therapeutic agent provided by the gastroretentive systems of the present invention can range from the peak plasma concentration of the therapeutic agent when administered daily in a conventional oral formulation (i.e., the C of the therapeutic agent administered daily in an immediate release formulation). 最大 The substantially constant plasma concentration of a therapeutic agent provided by the gastric retention system of the present invention can be about 50% to about 90% of the average plasma concentration of a therapeutic agent when administered daily in a conventional oral dosage form (i.e., the C of a therapeutic agent administered daily in an immediate release dosage form). 平均 The substantially constant plasma concentration of the therapeutic agent provided by the gastric retention system of the present invention can be about 75% to about 125% of the C 最小 100% to about 150% of the trough mean plasma concentration of a therapeutic agent when administered daily in a conventional oral formulation (i.e., the C of a therapeutic agent administered daily in an immediate release formulation) 最小 ) or more.

[0196] The gastroretentive systems of the present invention can provide a bioavailability of a therapeutic agent released from the system that is at least about 50%, at least about 60%, at least about 70%, or at least about 80% of that provided by an immediate release form containing the same amount of therapeutic agent. As indicated above, bioavailability can be measured using the area under the plasma concentration-time curve (AUC 無限 ) is measured.

[0197] Treatment Methods Using Gastric Retention Systems A gastroretentive system can be used to treat conditions requiring administration of a therapeutic agent over an extended period of time. For long-term administration of a therapeutic agent for months, years, or indefinitely, administration of the gastroretentive system once a week, once every two weeks, or once a month can offer significant advantages in terms of patient compliance and convenience.

[0198] Once the gastroretentive system is administered to the patient, the system provides sustained release of the therapeutic agent over the gastroretentive period. After the gastroretentive period, the system degrades and leaves the stomach. Thus, for a system with a gastroretentive period of one week, the patient would swallow (or otherwise administer to the stomach) a new system every week. Thus, in one embodiment, a method of treating a patient with a gastroretentive system of the present invention having a gastroretentive period of D days (D days being the gastroretentive period days) over the entire desired treatment period T total (T total being the desired treatment period days) containing a therapeutic agent in the system includes introducing a new gastroretentive system into the patient's stomach by oral administration or other means every D days over the entire desired treatment period. The number of gastroretentive systems administered to the patient is the quotient of (T total) divided by (D days). For example, if it is desired to treat a patient for one year (T total = 365 days) and the gastric retention period of the system is 7 days (D day = 7 days), then a new system would be administered once every 7 days, so that approximately 52 gastric retention systems would be administered to the patient over the 365 days.

[0199] Kits and Articles of Manufacture Also provided herein is a kit for the treatment of a patient with the gastroretention system of the present invention. The kit may, for example, contain a sufficient number of gastroretention systems for regular administration to a patient over the entire desired treatment period. If the total number of treatment days (Ttotal) and the gastroretention system has a residence time of (Dday), for administration per Dday, the kit contains a number of gastroretention systems equal to (Ttotal divided by (Dday)) (rounded to the nearest whole number). The kit may, for example, contain several gastroretention systems in a container (which may be a capsule) and, if desired, may contain printed or computer readable instructions for use, duration of treatment, or other information regarding the use of the gastroretention system and / or the therapeutic agent contained in the gastroretention system. For example, if the patient's prescribed total treatment duration is one year and the gastroretentive system has a one week retention time, the kit may contain 52 capsules, each containing one gastroretentive system, along with instructions to swallow one capsule once each week on the same day (e.g., every Saturday).

[0200] Also encompassed by the invention is an article of manufacture that includes a sufficient number of gastroretentive systems for regular administration to a patient over the entire desired treatment period, and optionally includes directions for use, duration of treatment, or other information regarding the use of the gastroretentive systems and / or the therapeutic agent contained therein. The article of manufacture may be provided in suitable packaging, such as a dispenser, tray, or other packaging that assists the patient in administering the gastroretentive systems at prescribed intervals.

[0201] Preferred Embodiments The present invention will be further illustrated by the following embodiments, the features of each of which may, where necessary and practicable, be combined with any of the other embodiments.

[0202] Embodiment 1. 1. A gastroretentive system for administration to a stomach of a patient, the gastroretentive system comprising: a plurality of at least three carrier polymer-drug components comprising an elastomeric component and a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomeric component; Each of the plurality of carrier polymer-drug components is an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is coupled to the elastomeric component and projects radially from the elastomeric component, and each elongate member has its distal end free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween; the segments are joined by a linker region having an exterior surface; At least one of the linker regions comprises a first linker agent and a second linker agent:

[0203] i) the second linker material extends from the outer surface of at least one linker region into the body of at least one linker region; or ii) the second linker material extends from the exterior surface of the at least one linker region through the body of the at least one linker region to re-emerge on the exterior surface; or iii) a gastroretentive system, wherein a portion of the second linker material extends from the outer surface of the at least one linker region into the body of the at least one linker region, and wherein a portion of the second linker material extends from the outer surface of the at least one linker region through the body of the at least one linker region to re-emerge on the outer surface.

[0204] Embodiment 2. 1. A gastroretentive system for administration to a stomach of a patient, the gastroretentive system comprising: a plurality of at least three carrier polymer-drug components comprising an elastomeric component and a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomeric component; Each of the plurality of carrier polymer-drug components is an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is coupled to the elastomeric component and projects radially from the elastomeric component, and each elongate member has its distal end free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween; the segments are joined by linker regions; and At least one segment further comprises a segment island material: i) the segment island material extends from the outer surface of at least one carrier polymer-drug segment into the body of at least one carrier polymer-drug segment; or ii) the segment island material extends from the exterior surface of at least one carrier polymer-drug segment through the body of at least one carrier polymer-drug segment to re-emerge on the exterior surface; or iii) A gastric retention system, wherein portions of the segmented island material extend from the outer surface of at least one carrier polymer-drug segment into the body of at least one carrier polymer-drug segment, and portions of the segmented island material extend from the outer surface of at least one carrier polymer-drug segment through the body of at least one carrier polymer-drug segment to re-emerge on the outer surface.

[0205] Embodiment 3. 1. A gastroretentive system for administration to a stomach of a patient, the gastroretentive system comprising: a plurality of at least three carrier polymer-drug components comprising an elastomeric component and a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomeric component; Each of the plurality of carrier polymer-drug components is an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is coupled to the elastomeric component and projects radially from the elastomeric component, and each elongate member has its distal end free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween; A gastroretentive system, wherein at least one segment further comprises a reinforcing material, the reinforcing material extending axially along an interior of the at least one segment; and the segments are connected by a linker region.

[0206] Embodiment 4. A gastric retention system as described in embodiment 3, wherein the reinforcement material extends axially along at least one interior portion for at least about 90% of the length of the segment.

[0207] Embodiment 5. A gastric retention system as described in embodiment 3 or embodiment 4, wherein the reinforcing material has an I-shaped structure or an H-shaped structure.

[0208] Embodiment 6. A gastric retention system as described in embodiment 3 or embodiment 4, wherein the reinforcement material has a truss structure.

[0209] Embodiment 7. 1. A gastroretentive system for administration to a stomach of a patient, the gastroretentive system comprising: a plurality of at least three carrier polymer-drug components comprising an elastomeric component and a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomeric component; Each of the plurality of carrier polymer-drug components is an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is coupled to the elastomeric component and projects radially from the elastomeric component, and each elongate member has its distal end free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween; one or more of the elongate members further includes a fenestrated coating on an exterior surface; and A gastroretentive system, wherein the segments are linked by linker regions.

[0210] Embodiment 8. 1. A gastroretentive system for administration to a stomach of a patient, the gastroretentive system comprising: an elastomer component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomer component, each of the plurality of carrier polymer-drug components being an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is coupled to the elastomeric component and projects radially from the elastomeric component, and each elongate member has its distal end free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween; the segments are joined by a linker region having an exterior surface; The gastroretentive system, wherein the segment of the elongate member has a multi-layered structure comprising at least two layers.

[0211] EMBODIMENT 9. 1. A gastroretentive system for administration to a stomach of a patient, the gastroretentive system comprising: 1. A gastroretentive system for administration to a stomach of a patient comprising an elastomeric component and a plurality of at least three carrier polymer-drug components comprising a carrier polymer and a therapeutic agent or a salt thereof associated with the elastomeric component, Each of the plurality of carrier polymer-drug components is an elongate member having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is coupled to the elastomeric component and projects radially from the elastomeric component, and each elongate member has its distal end free from the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end; each elongate member comprises at least two segments, each segment having a proximal end, a distal end, and an exterior surface therebetween; the segments are joined by a linker region having an exterior surface; A gastroretentive system in which a portion of the linker region extends into the segment, or a portion of the segment extends into the linker region, or both portions of the linker region extend into the segment and a portion of the segment extends into the linker region.

[0212] EMBODIMENT 10. co-extruding the elongate members; A method of making said elongate member for use in a gastroretentive system comprising:

[0213] Embodiment 11. co-extruding the elongate members Coextrusion of at least two regions comprising a carrier polymer-drug formulation, each region of the carrier polymer-drug formulation being separated from an adjacent region of the carrier polymer-drug formulation by a linker region. 11. The method of embodiment 10, comprising:

[0214] Embodiment 12. 12. The method of embodiment 11, wherein the carrier polymer of the carrier polymer-drug formulation is selected from the group consisting of polycaprolactone and polydioxanone.

[0215] Embodiment 13. The drug of the carrier polymer-drug formulation may be selected from the group consisting of analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, anti-epileptic drugs, anti-schizophrenia drugs, neuroprotective drugs, anti-proliferative drugs, anti-cancer drugs, antihistamines, anti-migraine drugs, hormones, prostaglandins, antimicrobial drugs, antibiotics, anti-fungal drugs, anti-viral drugs, anti-parasitic drugs, anti-muscarinics, anxiolytic drugs, bacteriostatic drugs, immunosuppressants, sedatives, hypnotics, anti-psychotic drugs, bronchodilators, anti-asthmatic drugs, cardiovascular drugs, anesthetic drugs, anticoagulants, enzyme inhibitors, steroidal drugs, steroidal or non-steroidal anti-inflammatory drugs, corticosteroid drugs, dopaminergic drugs, electrolytes, gastrointestinal drugs, and muscle relaxants. The method of embodiment 11 or embodiment 12, wherein the therapeutic agent is selected from the group consisting of: nutritional supplements; vitamins; parasympathomimetics; stimulants; appetite suppressants; antisomnia medications; antimalarials; quinine; lumefantrine; chloroquine; amodiaquine; pyrimethamine; proguanil; chlorproguanil-dapsone; sulfonamides; sulfadoxine; sulfamethoxypyridazine; mefloquine; atovaquone; primaquine; halofantrine; doxycycline; clindamycin; artemisinin; artemisinin derivatives; artemether; dihydroartemisinin; arteether; and artesunate.

[0216] Embodiment 14. The method of any one of embodiments 11 to 13, wherein the linker region comprises a substance selected from the group consisting of an enteric linker and a time-dependent linker.

[0217] EMBODIMENT 15. The method of any one of embodiments 11 to 14, wherein at least one junction between the carrier polymer-drug region and the linker region is coextruded in an interlocking configuration.

[0218] EMBODIMENT 16. The method of any one of embodiments 11-15, wherein at least one carrier polymer-drug region is coextruded in an islands-in-the-sea configuration.

[0219] EMBODIMENT 17. 17. The method according to any one of embodiments 11 to 16, wherein at least one linker region is coextruded in an islands-in-the-sea configuration.

[0220] Embodiment 18. 18. The method of embodiment 16 or embodiment 17, wherein the islands of the islands-in-the-sea structure comprise at least one material selected from the group consisting of enteric polymers and time-dependent polymers.

[0221] EMBODIMENT 19. A method of manufacturing said elongate member for use in a gastroretentive system comprising:

[0222] Printing long and thin parts using three-dimensional printing.

[0223] EMBODIMENT 20. 20. The method of claim 19, wherein co-extruding the elongate members comprises:

[0224] Printing at least two regions comprising a carrier polymer-drug formulation, each region of the carrier polymer-drug formulation being separated from an adjacent region of the carrier polymer-drug formulation by a linker region.

[0225] EMBODIMENT 21. 21. The method of embodiment 20, wherein the carrier polymer of the carrier polymer-drug formulation is selected from the group consisting of polycaprolactone and polydioxanone.

[0226] EMBODIMENT 22. The drug of the carrier polymer-drug formulation may be selected from the group consisting of analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, anti-epileptic drugs, anti-schizophrenia drugs, neuroprotective drugs, anti-proliferative drugs, anti-cancer drugs, antihistamines, anti-migraine drugs, hormones, prostaglandins, antimicrobial drugs, antibiotics, anti-fungal drugs, anti-viral drugs, anti-parasitic drugs, anti-muscarinics, anxiolytic drugs, bacteriostatic drugs, immunosuppressants, sedatives, hypnotics, anti-psychotic drugs, bronchodilators, anti-asthmatic drugs, cardiovascular drugs, anesthetic drugs, anticoagulants, enzyme inhibitors, steroidal drugs, steroidal or non-steroidal anti-inflammatory drugs, corticosteroid drugs, dopaminergic drugs, electrolytes, gastrointestinal drugs, muscle relaxants. The method of embodiment 20 or 21, wherein the antihypertensive agent is selected from the group consisting of laxatives; nutrients; vitamins; parasympathomimetics; stimulants; appetite suppressants; antihypersomnia medications; antimalarials; quinine; lumefantrine; chloroquine; amodiaquine; pyrimethamine; proguanil; chlorproguanil-dapsone; sulfonamides; sulfadoxine; sulfamethoxypyridazine; mefloquine; atovaquone; primaquine; halofantrine; doxycycline; clindamycin; artemisinin; artemisinin derivatives; artemether; dihydroartemisinin; arteether; and artesunate.

[0227] EMBODIMENT 23. The method of any one of embodiments 20 to 22, wherein the linker region comprises a substance selected from the group consisting of an enteric linker and a time-dependent linker.

[0228] EMBODIMENT 24. 24. The method of any one of embodiments 20 to 23, wherein at least one junction between the carrier polymer-drug region and the linker region is printed with an interlocking structure.

[0229] 25. 25. The method of any one of embodiments 20-24, wherein at least one carrier polymer-drug region is printed in an islands-in-the-sea structure.

[0230] 26. 26. The method according to any one of embodiments 20 to 25, wherein at least one linker region is printed in an islands-in-a-sea structure.

[0231] EMBODIMENT 27. 27. The method of embodiment 25 or 26, wherein the islands of the islands-in-the-sea structure comprise at least one material selected from the group consisting of enteric polymers and time-dependent polymers.

[0232] 28. The method of any one of embodiments 20-27, wherein the linker uncouples after about 7 days in fasted artificial gastric fluid.

[0233] 29. A method of manufacturing said elongate member for use in a gastroretentive system comprising:

[0234] Producing the elongated member by additive manufacturing.

[0235] EMBODIMENT 30. 30. The method of embodiment 29, wherein manufacturing the elongate member by additive manufacturing comprises:

[0236] The preparation of at least two regions comprising a carrier polymer-drug formulation, each region of the carrier polymer-drug formulation being separated from an adjacent region of the carrier polymer-drug formulation by a linker region.

[0237] EMBODIMENT 31. The method of embodiment 30, wherein the carrier polymer of the carrier polymer-drug formulation is selected from the group consisting of polycaprolactone and polydioxanone.

[0238] EMBODIMENT 32. The drug of the carrier polymer-drug formulation may be selected from the group consisting of analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, anti-epileptic drugs, anti-schizophrenia drugs, neuroprotective drugs, anti-proliferative drugs, anti-cancer drugs, antihistamines, anti-migraine drugs, hormones, prostaglandins, antimicrobial drugs, antibiotics, anti-fungal drugs, anti-viral drugs, anti-parasitic drugs, anti-muscarinics, anxiolytic drugs, bacteriostatic drugs, immunosuppressants, sedatives, hypnotics, anti-psychotic drugs, bronchodilators, anti-asthmatic drugs, cardiovascular drugs, anesthetic drugs, anticoagulants, enzyme inhibitors, steroidal drugs, steroidal or non-steroidal anti-inflammatory drugs, corticosteroid drugs, dopaminergic drugs, electrolytes, gastrointestinal drugs, muscle relaxants. The method of embodiment 30 or 31, wherein the antihypertensive agent is selected from the group consisting of laxatives; nutrients; vitamins; parasympathomimetics; stimulants; appetite suppressants; antihypersomnia medications; antimalarials; quinine; lumefantrine; chloroquine; amodiaquine; pyrimethamine; proguanil; chlorproguanil-dapsone; sulfonamides; sulfadoxine; sulfamethoxypyridazine; mefloquine; atovaquone; primaquine; halofantrine; doxycycline; clindamycin; artemisinin; artemisinin derivatives; artemether; dihydroartemisinin; arteether; and artesunate.

[0239] EMBODIMENT 33. The method of any one of embodiments 30 to 32, wherein the linker region comprises a substance selected from the group consisting of an enteric linker and a time-dependent linker.

[0240] EMBODIMENT 34. The method of any one of embodiments 30 to 33, wherein at least one junction between the carrier polymer-drug region and the linker region is made with an interlocking structure.

[0241] EMBODIMENT 35. The method of any one of embodiments 30-34, wherein at least one carrier polymer-drug region is prepared in an islands-in-the-sea structure.

[0242] EMBODIMENT 36. 36. The method according to any one of embodiments 30 to 35, wherein at least one linker region is made in an islands-in-a-sea structure.

[0243] 37. 37. The method of embodiment 35 or 36, wherein the islands of the islands-in-the-sea structure comprise at least one material selected from the group consisting of enteric polymers and time-dependent polymers.

[0244] 38. The method of any one of embodiments 30-37, wherein the linker uncouples after about 7 days in fasted artificial gastric fluid. EXAMPLES

[0245] The invention is further illustrated by the following non-limiting examples.

[0246] Example 1: Reinforced Drug Arms Containing Structural Polymers Dosage forms with high drug loading are structurally fragile and further weaken hydration in the gastric environment. Therefore, it is difficult to successfully achieve 7-day gastric retention for high drug loading formulations. A bilayer structure with an external reinforcement layer surrounding the high drug loading formulation is fabricated to understand the effect on maintaining the mechanical strength of the dosage form and compare its performance under external mechanical stress.

[0247] To make the reinforcement layer, black iron oxide pigment doped PCL was extruded as a ribbon about 500 micrometers thick and cut into 20 mm long pieces. By holding the two layers in close contact with each other, a thin 100% black PCL layer was compression molded onto one side of the 38% drug-loaded arm, incubated at 75°C for 10 minutes in a dryer, and then compressed together. Using this method, a spine reinforcement structure was made in which the carrier polymer-drug formulation had a spine-type reinforcement layer on one side; a schematic diagram of this structure is shown in Figure 11A. Using this method, an exoskeleton reinforcement structure was made in which the carrier polymer-drug formulation had an exoskeleton-type reinforcement layer on all three sides; a schematic diagram of this structure is shown in Figure 11B, and a photograph of the exoskeleton reinforcement arm is shown in Figure 11C. The mechanical strength of the reinforced high drug loading samples was compared with the non-reinforced high drug loading samples for both reinforcement structures (spine and exoskeleton) before and after 24 hours of four-point bending incubation in FaSSGF.

[0248] The results show that in the pre-incubation condition, for both reinforcement structures, the reinforcement structures make the high drug-loading arms more ductile as they withstand higher bending forces, as shown in the table in Figure 11 D. Upon incubation, the reinforcement layers help to strengthen and maintain the stiffness of the high drug-loading formulation, which is important for extended gastric retention periods.

[0249] As discussed in the section "System Manufacturing / Assembly: Coextrusion," the reinforcing elongate members can be manufactured by coextrusion of the reinforcing material and carrier polymer-drug blends instead of manufacturing the reinforcing material and carrier polymer-drug components separately and compressing them together.

[0250] Example 2: Coextrusion Compared to Single Component Extrusion and Thermal Bonding-Effect on Weld Strength Composite arms consisting of two 1.5 mm segments of disintegrated matrix (DM) (equivalent to elements 1290 and 1292 in FIG. 12C) adjacent to three 4 mm to 6.5 mm segments of PCL (equivalent to elements 1280, 1282, and 1284 in FIG. 12C) were produced in a two-step process by coextrusion and then cut perpendicular to the flow (extrusion) direction to obtain arms with rectangular cross-sections as shown in FIG. 12A. Ribbons were produced using a standard laboratory-scale two-component coextruder consisting of two 5 / 8 inch single screw style extruders coupled with a coextrusion head that allows the polymer to flow from both extruders arranged in a specific orientation. An example of an elongated member (arm) produced by coextrusion and cutting is illustrated in FIG. 12C.

[0251] Pure 80k PCL was loaded into one extruder and a disintegrating matrix (DM) formulation (60% 80k PCL / 40% HPMCAS-MG) was loaded into the other extruder. The melt flow rate set point was adjusted so that the DM flow rate was set to approximately 20% of the PCL flow rate. The molten ribbon exiting the coextrusion head was guided onto a Teflon belt conveyor to provide support for the ribbon and to harden before handling. The ribbon had cross-sectional dimensions of 3.5 mm x 20.5 mm. The ribbon was cut perpendicular to the extrusion direction to produce composite arms 20.5 mm long, 4 mm wide, and 3.5 mm high.

[0252] For comparison, an arm was fabricated using a heat weld to join a previously extruded segment of PCL and the same DM formulation. The extruded 80k PCL arm was cut into 1 cm pieces. One end of the 1 cm PCL segment was melted by contacting it with a heating element at 100° C. for 5 seconds, and one end of the DM segment was melted by contacting it with a heating element at 170° C. for 10 seconds. The two melted ends were gently pressed together for approximately 2 seconds, and the resulting head was flattened along the weld. Using clippers, the joined DM segment was cut to a length of 2 mm. The unwelded end of the DM segment was joined to a second 1 cm PCL segment by repeating the heat weld process.

[0253] The weld strength of the coextruded and heat-sealed arms was compared by observing the location where samples containing one linker region adjacent to two PCL segments were torn under tensile stress. The coextruded and heat-sealed arms were incubated in FaSSGF for three different periods: 1 day, 4 days, and 7 days. For all three incubation periods, the arms were removed from the FaSSGF solution at each time point, washed with DI water, and wiped dry. The weld strength of the five post-incubation arms was tested for each condition by performing tensile tests on a linear stage tensile tester. The average stage speed of the tested pulls was set to 0.0796 mm / s, and the maximum stage displacement varied between samples depending on the yield point.

[0254] The data in Figure 13 show that for all incubation periods, over 80% of the heat sealed arms cleaved at the weld and not within the linker, whereas no coextrusion arms cleaved at the weld and over 80% cleaved within the linker. Cracks within the linker were not observed in the heat sealed arms, which failed at the weld interface, indicating that the coextrusion arms have a strong interface between the linker and drug formulation.

[0255] Example 3: Production Rate Coextrusion Compared to Single Component Extrusion with Thermal Bonding The coextrusion process carried out as described in Example 2 allows for high throughput, scalable production of composite arms. Coextrusion of composite ribbons at about 12 inches per minute produced about 180 3.33 mm wide arms per minute. Extrusion of axial arms at the same linear speed would produce more than six arms per minute and require additional processing to incorporate disintegrating matrix segments.

[0256] Example 4: Two-layer structure with an inner reinforcement layer and an API-loaded outer layer to achieve complete release of a hydrophobic API Formulation of a hydrophobic drug in a bulk matrix limits hydration of the matrix core and achieves only approximately 50% total release at day 7. A bilayer structure was fabricated with a hydrophobic active pharmaceutical ingredient (API) in an outer layer surrounding a structural PCL core. Empty PCL arms were immersed in a solution containing tacrolimus and polyethylene vinyl acetate (PEVA) (30% (w / v) in dichloromethane). Tacrolimus:PEVA ratios of 1:1, 1:2, and 2:1 were evaluated. The dip application resulted in a weight gain of approximately 10-20% and a deposition of approximately 6 mg tacrolimus on the surface of the PCL structural element.

[0257] To test the release in vitro under simulated physiological conditions, fasting artificial gastric fluid (FaSSGF) was prepared according to the manufacturer's instructions (www.biorelevant.com: see also WO 2017 / 070612, especially Examples 3 and 7). Each coated drug arm was incubated in 10 mL release medium in a shaking incubator at 37° C. for 7 days. The drug content in the release medium was routinely analyzed by HPLC after 6 hours, 24 hours, and then daily for up to 7 days. At each stage, the entire volume of the release medium was replaced with fresh medium. Nearly 100% tacrolimus was released from formulations containing 1:1 and 2:1 tacrolimus:PEVA ratios after 7 days of incubation in vitro. The release profiles of tacrolimus versus time are shown for the various formulations in FIG. 14.

[0258] Example 5: Island-in-sea coextrusion Coextrusion was used to produce model rectangular ribbons that could serve as precursors for segment-linker-segment composite arms, with each arm comprising a linker region consisting of an array of cylindrical "islands in the sea" adjacent to a segment of carrier polymer-drug formulation. The islands in the sea extended from one exterior surface to the opposite surface. Polypropylene was used as the model island material, and PCL was used to model the sea material of the linker. PCL was also used to model the carrier polymer-drug formulation. Ribbons were produced using a standard laboratory-scale two-component coextruder consisting of two 5 / 8 inch single screw style extruders coupled with a coextrusion head that allowed the polymers to flow from both extruders arranged in a specific orientation. The coextrusion head was designed to produce ribbons with cross-sectional dimensions of approximately 3.5 x 20 mm, consisting of a PCL region approximately 4.5 mm wide and a linker region approximately 2 mm wide with eight cylindrical polypropylene islands (each approximately 250 μm in diameter) in a sea of ​​PCL adjacent on each side. Pure 80k PCL was loaded into one extruder and polypropylene was loaded into the other. The melt flow rate set point, including the polypropylene flow rate, was set to approximately 8% of the PCL flow rate. The molten ribbon exiting the coextrusion head was guided onto a Teflon belt conveyor to provide support for the ribbon and to harden before handling.

[0259] Example 6: Sea Island: Ribbon Cutting The cured precursor ribbon produced in Example 4 is then cut into the desired shape as needed. The ribbon was cut perpendicular to the extrusion direction to produce composite arms of the desired shape (e.g., triangular or pie-shaped cross-section).

[0260] The disclosures of all publications, patents, patent applications, and published patent applications referenced herein by a specific citation are incorporated herein by reference in their entirety. Web site references that use the initial "World Wide Web" in the Uniform Resource Locator (URL) can be accessed by replacing "World Wide Web" with "www."

[0261] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of a clear understanding, it will be apparent to those skilled in the art that certain changes and modifications can be practiced. Therefore, the specification and examples should not be construed as limiting the scope of the invention.

Claims

1. 1. A gastroretentive system for administration to a stomach of a patient, comprising: an elastomeric component and at least three coextruded elongate members; at least one elongate member comprises a carrier polymer-drug component comprising a carrier polymer and a therapeutic agent or a salt thereof, said carrier polymer and said therapeutic agent being bound to said elastomeric component; each of the at least three elongate members having a proximal end, a distal end and an exterior surface therebetween; the proximal end of each elongate member is bonded to the elastomeric component and projects radially from the elastomeric component, and each elongate member has a distal end thereof that is not bonded to the elastomeric component and is located a greater radial distance from the elastomeric component than the proximal end; Each elongate member independently includes three or more segments; a first segment of the three or more segments and a second segment of the three or more segments are linked by a first linker, and a second segment of the three or more segments and a third segment of the three or more segments are linked by a second linker, wherein one of the first linker and the second linker is a time-dependent linker and the other is an enteric linker; wherein the time-dependent linker comprises one or more materials selected from the group consisting of low molecular weight polycaprolactone, Plastoid B, triacetin, Eudragit EPO, and triethyl citrate; A gastroretentive system, wherein the elastomer component, the first segment, the first linker, the second segment, the second linker, and the third segment are linked in this order.

2. The gastroretentive system of claim 1 , wherein the time-dependent linker weakens or decouples after 7 days in fasted simulated gastric fluid.

3. The gastric retention system of claim 1 or 2, wherein the time-dependent linker comprises one or more attenuators selected from carnauba wax, paraffin wax, and corriphor RH40, and the attenuators are one or more selected from carnauba wax, paraffin wax, and corriphor RH40.

4. The gastroretentive system of any one of claims 1 to 3, wherein the time-dependent linker comprises plastoid B and triacetin.

5. The carrier polymer may be polyethylene vinyl acetate (PEVA), poloxamer 407, Pluronic® P407, hypromellose, Corifol RH40, polyvinyl caprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), Soluplus (a copolymer of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol), copovidone, Eudragit (E, EPO, RS, RL), methyl methacrylate, carnauba wax, poly( methyl vinyl ether-alt-maleic anhydride), polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene stearates, polyvinyl acetate phthalate, alginates, polydextrose, polydioxanone, polybutyl methacrylate, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid (PLGA), hydrophilic cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymers, polyvinyl alcohol, carboxyvinyl polymers (carbomers), Carbopol® acidic carboxy polymers, polycarbophil, polyethylene oxide (Polyox WSR), polysaccharides and their derivatives, polyalkylene oxides, chitosan, alginates, pectins, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidone vinyl acetate copolymers, dextrans, natural rubber, agar, alginates, Galose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, briar nori, eucheuma muricatum, gum arabic, gum ghatti, karaya gum, arabinogalactan, amylopectin, gelatin, gellan, hyaluronic acid, pullulan, scleroglucan, xanthan, xyloglucan, maleic anhydride copolymer, ethylene maleic anhydride copolymer, polyhydroxyethyl methacrylate, ammonio methacrylate copolymer, Eudragit RL, Eudragit RS, polyethyl methacrylate acrylate (Eudragit NE),Eudragit E (cationic copolymers based on (dimethylamino)ethyl methacrylate and neutral methacrylate esters), polyacrylic acid, polymethacrylates / polyethacrylates, polymethacrylic acid, methyl methacrylate, and ethyl acrylate, polylactones, polycaprolactones, polyanhydrides, poly[bis(p-carboxyphenoxy)]propane anhydride, polyterephthalic anhydride, polypeptides, polylysine, polyglutamic acid, polyorthoesters, copolymers of DETOSU and diols; DETOSU and hexanediol, ... The gastroretentive system of any one of claims 1 to 4, comprising a polymer selected from the group consisting of candiol, cyclohexanedimethanol, ethylene glycol, or copolymers with polyethylene glycol; starch, pregelatinized starch, starch-based polymers, carbomers, maltodextrins, amylomaltodextrins, dextrans, poly(2-ethyl-2-oxazoline), polyethyleneimine, polyurethane, polyhydroxyalkanoates, polyhydroxybutyric acid, and copolymers, mixtures, blends, and combinations thereof.

6. The gastroretentive system of any one of claims 1 to 5, wherein the carrier polymer comprises polyethylene vinyl acetate (PEVA).

7. The gastroretentive system of any one of claims 1 to 6, wherein the time-dependent linker and / or the enteric linker comprises a degradable matrix.

8. The gastroretentive system of any one of claims 1 to 7, wherein each elongate member is attached to the elastomeric component by a linker region.

9. The gastroretentive system of claim 8 , wherein the linker region comprises a disintegrable matrix.

10. 1. A gastroretentive system for administration to a stomach of a patient, comprising an elastomeric component and at least three co-extruded elongate members, at least one of the elongate members comprising a carrier polymer-drug component comprising a carrier polymer and a therapeutic agent or a salt thereof, the carrier polymer and the therapeutic agent being bound to the elastomeric component; each of the at least three elongate members having a proximal end, a distal end, and an exterior surface therebetween; the proximal end of each elongate member is bonded to the elastomeric component and projects radially from the elastomeric component, and each elongate member has a distal end thereof that is not bonded to the elastomeric component and is located a greater radial distance from the elastomeric component than the proximal end; Each elongate member independently includes three or more segments; a first segment of the three or more segments and a second segment of the three or more segments are linked by a first linker, and a second segment of the three or more segments and a third segment of the three or more segments are linked by a second linker, wherein one of the first linker and the second linker is a time-dependent linker and the other is an enteric linker; wherein the time-dependent linker comprises one or more materials selected from the group consisting of low molecular weight polycaprolactone, Plastoid B, triacetin, Eudragit EPO, and triethyl citrate; wherein the elastomer component, the first segment, the first linker, the second segment, the second linker, and the third segment are linked in this order; A gastroretentive system, wherein the therapeutic agent or a salt thereof comprises a hydrophobic drug.

11. The carrier polymer may be polyethylene vinyl acetate (PEVA), poloxamer 407, Pluronic® P407, hypromellose, Corifol RH40, polyvinyl caprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), Soluplus (a copolymer of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol), copovidone, Eudragit (E, EPO, RS, RL), methyl methacrylate, carnauba wax, poly( methyl vinyl ether-alt-maleic anhydride), polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene stearates, polyvinyl acetate phthalate, alginates, polydextrose, polydioxanone, polybutyl methacrylate, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid (PLGA), hydrophilic cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, ethylene / vinyl alcohol copolymers, polyvinyl alcohol, carboxyvinyl polymers (carbomers), Carbopol® acidic carboxy polymers, polycarbophil, polyethylene oxide (Polyox WSR), polysaccharides and their derivatives, polyalkylene oxides, chitosan, alginates, pectins, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidone vinyl acetate copolymers, dextrans, natural rubber, agar, alginates, Galose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, briar nori, eucheuma muricatum, gum arabic, gum ghatti, karaya gum, arabinogalactan, amylopectin, gelatin, gellan, hyaluronic acid, pullulan, scleroglucan, xanthan, xyloglucan, maleic anhydride copolymer, ethylene maleic anhydride copolymer, polyhydroxyethyl methacrylate, ammonio methacrylate copolymer, Eudragit RL, Eudragit RS, polyethyl methacrylate acrylate (Eudragit NE),Eudragit E (cationic copolymers based on (dimethylamino)ethyl methacrylate and neutral methacrylate esters), polyacrylic acid, polymethacrylate / polyethacrylates, polymethacrylic acid, methyl methacrylate, and ethyl acrylate, polylactone, polycaprolactone, polyanhydrides, poly[bis(p-carboxyphenoxy)]propane anhydride, polyterephthalic anhydride, polypeptides, polylysine, polyglutamic acid, polyorthoesters, copolymers of DETOSU and diols; DETOSU and hexanediol.

11. The gastroretentive system of claim 10, comprising a polymer selected from the group consisting of: copolymers with glycerol, decanediol, cyclohexanedimethanol, ethylene glycol, or polyethylene glycol; starch, pregelatinized starch, starch-based polymers, carbomers, maltodextrins, amylomaltodextrins, dextrans, poly(2-ethyl-2-oxazoline), polyethyleneimine, polyurethane, polyhydroxyalkanoates, polyhydroxybutyrates, and copolymers, mixtures, blends, and combinations thereof.

12. The gastroretentive system of claim 10 , wherein the carrier polymer comprises polyethylene vinyl acetate (PEVA).

13. The gastroretentive system of any one of claims 10 to 12, wherein the hydrophobic drug has a solubility in water of less than 100 μg / ml.

14. The gastroretentive system of any one of claims 10 to 13, wherein the hydrophobic drug is tacrolimus.

15. A method for producing at least one elongate member comprising a carrier polymer-drug component as defined in any one of claims 1 to 14, comprising the steps of: A method of manufacturing comprising co-extruding the elongate member, said co-extruding comprising co-extruding a carrier polymer-therapeutic agent or carrier polymer-therapeutic agent salt combination, and a reinforcing material.

16. A method of manufacturing an elongate member for use in the gastroretentive system of any one of claims 1 to 15, comprising co-extruding the elongate member.

17. The method of claim 16, wherein co-extruding the elongate members comprises co-extruding a carrier polymer-therapeutic agent or carrier polymer-therapeutic agent salt combination, and a reinforcing material.

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