Methadone-containing gastroretentive systems

Abstract

There is provided a gastroretentive system comprising at least one drug eluting component comprising methadone or a salt thereof, 30-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer, and a rate controlling release membrane coating the at least one co-extruded drug eluting component. The gastroretentive system comprising the at least one drug eluting component is configured to be retained in the stomach of a human body for at least 48 hours and to release methadone for at least 48 hours, such that the at least one drug eluting component with the rate controlling release membrane is configured to release at least 10% of the methadone or a salt thereof after the first 24 hours of residence in the stomach.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 184,760, filed May 5, 2021, the entire contents of which are incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Grant No. 1UG3DA050310 awarded by the National Institutes of Health. The government has certain rights in the invention. Field

[0003] TECHNICAL FIELD The present disclosure relates to gastroretentive systems, and more particularly to gastroretentive systems containing methadone. [Background technology]

[0004] Methadone is an opioid and μOR agonist approved for the maintenance treatment of opioid use disorder. Methadone alleviates opiate withdrawal symptoms and blocks the euphoric effects of opiates such as heroin, morphine, and codeine, as well as semi-synthetic opioids such as oxycodone and hydrocodone. Methadone maintenance therapy (MMT) has been used since the 1960s and has been shown to promote recovery and prevent deaths.

[0005] Because methadone is a full μOR agonist, it carries a significant risk of accidental overdose and diversion. Therefore, methadone is typically administered on a once-daily schedule under direct observation in a designated clinic. After administration of methadone in a designated clinic, patients may be observed for 15–20 minutes to reduce the risk of drug diversion. Summary of the Invention

[0006] Provided herein is a gastroretentive system containing methadone.Currently, patients who receive methadone for the treatment of opioid use disorder usually take a dose of methadone at a designated clinic every day.Therefore, in order to properly comply with the treatment plan, patients must go to a designated clinic every day to receive a daily dose of methadone.As expected, this is difficult for many patients and is prone to non-compliance.

[0007] The gastroretentive systems containing methadone provided herein are designed to be administered to patients less frequently than conventional maintenance therapy. As described above, methadone is typically administered to patients daily in a monitored environment. However, this places a significant burden not only on patients who must travel to and from a designated clinic every day, but also on designated clinics, which must provide appropriate medication and staff to accommodate patients every day. Therefore, the gastroretentive systems provided herein are designed to provide the same therapeutic effect as daily methadone maintenance therapy even when administered less frequently than once a day. For example, the gastroretentive systems provided herein can be configured to be administered once a week. Throughout the retention period (e.g., 7 days), the gastroretentive systems are configured to slowly release methadone in the patient's stomach. The reduced dose administration frequency reduces the burden on patients who must visit a designated clinic every day and on designated clinics that must accept patients every day during daily methadone maintenance therapy. Therefore, the gastroretentive systems provided herein, which require administration less frequently than daily methadone maintenance therapy, can minimize patient noncompliance and reduce the amount of resources required at designated clinics.

[0008] The gastroretentive systems provided herein can achieve a steady release of methadone throughout the residence period of the gastroretentive system in the patient's stomach only through the combination of a methadone formulation in the drug-eluting segment of the gastroretentive system and a release rate-controlling membrane coating the drug-eluting segment of the gastroretentive system. Without both of these features, the gastroretentive system cannot adequately release methadone in a controlled manner throughout the residence period. For example, if the gastroretentive system is configured to have a 7-day residence period, the methadone formulation in combination with the release rate-controlling membrane coating can control the release of methadone so that methadone continues to be released from the gastroretentive system throughout the entire period, including the 7th (i.e., final) day of the residence period.

[0009] The provided gastroretentive systems are designed to be swallowed by a patient in a compressed configuration and to unfold to an uncompressed configuration upon reaching the patient's stomach. Once opened in the patient's stomach, the gastroretentive system will remain there until gastric fluids in the stomach disrupt the gastroretentive system, allowing it to pass through the remainder of the patient's gastrointestinal system. The gastroretentive system can include one or more linking moieties (e.g., linkers) that link the various components of the gastroretentive system together. The linking moieties can include disintegrating matrices and are designed to dissolve or degrade in the presence of gastric fluid in a controlled manner, allowing the various components of the gastroretentive system to dissociate and pass through the remainder of the patient's gastrointestinal tract. In some embodiments, the gastroretentive system is designed to release the active ingredient (i.e., methadone), dissociate, and be voided from the patient within a controlled time (e.g., 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 1 month) after the patient first ingests the gastroretentive system.

[0010] In some embodiments, the gastroretention system is star-shaped and comprises a central elastomer, three or more arms, and one or more connecting components. The central elastomer of the gastroretention system is the central component of the gastroretention system from which three or more arms extend.

[0011] The three or more arms of the gastroretention system radiate from a central elastomer of the gastroretention system. One or more arms can contain an active pharmaceutical ingredient (i.e., methadone). The number of active arms (i.e., the one or more arms containing the active pharmaceutical ingredient) can depend on the dosage of the gastroretention system. The active arms are configured to release the methadone formulation once the gastroretention system reaches the patient's stomach.

[0012] Thus, provided herein is a gastroretentive system comprising methadone for use in treating patients with opioid use disorder. The described gastroretentive system is designed to be administered to patients less frequently than conventional methadone maintenance therapy. In some embodiments, the gastroretentive system provided herein is designed to be administered to patients once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments, the gastroretentive system provided herein is designed to be administered to patients once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0013] In some embodiments, a gastroretentive system is provided, comprising at least one drug-eluting component comprising methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer, and a release rate-controlling membrane coating the at least one drug-eluting component, wherein the gastroretentive system is configured to be retained in the stomach of a human body for at least 48 hours and to release the methadone for at least 48 hours, and wherein the at least one drug-eluting component with the release rate-controlling membrane is configured to release at least 10% of the methadone or salt thereof after the first 24 hours of residence in the stomach.

[0014] In some embodiments of the gastroretentive system, the gastroretentive system comprises 50-60% by weight of racemic methadone.

[0015] In some embodiments of the gastroretentive system, the gastroretentive system comprises 50-60% levomethadone by weight.

[0016] In some embodiments of the gastroretentive system, the gastroretentive system comprises 1-2% by weight of poloxamer.

[0017] In some embodiments of the gastroretentive system, the poloxamer comprises P407.

[0018] In some embodiments of the gastroretentive system, the release rate controlling membrane comprises polycaprolactone, copovidone, and magnesium stearate.

[0019] In some embodiments of the gastroretentive system, the release rate-controlling membrane comprises 60-90% by weight polycaprolactone.

[0020] In some embodiments of the gastroretentive system, the release rate-controlling membrane comprises 70-75% by weight of polycaprolactone.

[0021] In some embodiments of the gastroretentive system, the release rate controlling membrane comprises 10-40% copovidone by weight.

[0022] In some embodiments of the gastroretentive system, the release rate controlling membrane comprises 20-30% by weight of copovidone.

[0023] In some embodiments of the gastroretentive system, the release rate controlling membrane comprises 1-5% by weight magnesium stearate.

[0024] In some embodiments of the gastroretentive system, the release rate-controlling membrane comprises 1-3% by weight magnesium stearate.

[0025] In some embodiments of the gastroretentive system, at least one drug-eluting component comprises 20 mg to 50 mg of racemic methadone or a salt thereof.

[0026] In some embodiments of the gastroretentive system, at least one drug-eluting component comprises 20-50 mg of levomethadone or a salt thereof.

[0027] In some embodiments of the gastroretention system, the gastroretention system comprises a central elastomer and a plurality of arms, each arm of the plurality of arms comprising a proximal end (anchored to the central elastomer) and a distal end, wherein each arm of the plurality of arms extends radially from the central elastomer, and at least one arm of the plurality of arms comprises at least one drug-eluting component.

[0028] In some embodiments of the gastroretentive system, the plurality of arms comprises six arms.

[0029] In some embodiments of the gastroretentive system, at least two arms of the plurality of arms comprise at least one drug-eluting component.

[0030] In some embodiments of the gastroretentive system, at least three arms of the plurality of arms comprise at least one drug-eluting component.

[0031] In some embodiments of the gastroretentive system, six arms of the plurality of arms comprise at least one drug eluting component.

[0032] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a polymer linker segment attached to a central elastomer, the polymer linker segment comprising polycaprolactone.

[0033] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a first degradable matrix segment attached to a polymer linker segment, the first degradable matrix segment comprising polycaprolactone, an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio), a copolymer of DL-lactide and glycolide (50 / 50 molar ratio), and polyethylene oxide.

[0034] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a first inert segment attached to a first disintegrable matrix segment, the first inert segment comprising polycaprolactone and (BiO)2CO3.

[0035] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a second disintegrable matrix segment attached to a first inert segment, wherein the second disintegrable matrix segment comprises polycaprolactone, hydroxypropylmethylcellulose acetate succinate, and poloxamer.

[0036] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a non-active segment attached to a second disintegrable matrix segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0037] In some embodiments of the gastroretentive system, the drug eluting arm of the plurality of arms comprises a drug eluting component attached to a non-active segment.

[0038] In some embodiments of the gastroretentive system, the area under the curve of the gastroretentive system is between 1000 and 6000 hr·ng / ml.

[0039] In some embodiments, a method of treating an opioid abuse disorder in an individual is provided, comprising administering to the individual a gastroretentive system.

[0040] In some embodiments, a method of making a gastroretentive system is provided, the method comprising extruding at least one drug-eluting component comprising methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer; and applying a release rate controlling membrane to the at least one drug-eluting component, wherein the gastroretentive system is configured to be retained in the stomach of a human body for at least 48 hours and to release methadone for at least 48 hours, and wherein the at least one drug-eluting component with the release rate controlling membrane is configured to release at least 10% of the methadone or salt thereof after the first 24 hours of residence in the stomach.

[0041] In some embodiments of the method, the gastroretentive system comprises 50-60% by weight of racemic methadone.

[0042] In some embodiments of the method, the gastroretentive system comprises 50-60% by weight of levomethadone.

[0043] In some embodiments of the method, the gastroretentive system comprises 1-2% by weight of poloxamer.

[0044] In some embodiments of the method, the poloxamer comprises P407.

[0045] In some embodiments of the method, the release rate controlling membrane comprises polycaprolactone, copovidone, and magnesium stearate.

[0046] In some embodiments of the method, the release rate controlling membrane comprises 60-90% by weight polycaprolactone.

[0047] In some embodiments of the method, the release rate controlling membrane comprises 70-75% by weight polycaprolactone.

[0048] In some embodiments of the method, the release rate controlling membrane comprises 10-40% by weight copovidone.

[0049] In some embodiments of the method, the release rate controlling membrane comprises 20 mg to 30% by weight of copovidone.

[0050] In some embodiments of the method, the release rate controlling membrane comprises 1-5% by weight magnesium stearate.

[0051] In some embodiments of the method, the release rate controlling membrane comprises 1-3% by weight magnesium stearate.

[0052] In some embodiments of the method, at least one drug-eluting component comprises 20-50 mg of racemic methadone or a salt thereof.

[0053] In some embodiments of the method, the at least one drug-eluting component comprises 20-50 mg of levomethadone or a salt thereof.

[0054] In some embodiments of the method, the gastroretention system comprises a central elastomer and a plurality of arms, each arm of the plurality of arms comprising a proximal end (anchored to the central elastomer) and a distal end, wherein each arm of the plurality of arms extends radially from the central elastomer, and at least one arm of the plurality of arms comprises at least one drug-eluting component.

[0055] In some embodiments of the method, the plurality of arms comprises six arms.

[0056] In some embodiments of the method, at least two arms of the plurality of arms comprise at least one drug eluting component.

[0057] In some embodiments of the method, at least three arms of the plurality of arms comprise at least one drug eluting component.

[0058] In some embodiments of the method, six arms of the plurality of arms comprise at least one drug eluting component.

[0059] In some embodiments of the method, each arm of the plurality of arms comprises a polymer linker segment attached to the central elastomer, and the polymer linker segment comprises polycaprolactone.

[0060] In some embodiments of the method, each arm of the plurality of arms comprises a first degradable matrix segment attached to a polymer linker segment, the first degradable matrix segment comprising polycaprolactone, an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio), a copolymer of DL-lactide and glycolide (50 / 50 molar ratio), and polyethylene oxide.

[0061] In some embodiments of the method, each arm of the plurality of arms comprises a first inert segment attached to a first disintegrable matrix segment, the first inert segment comprising polycaprolactone and (BiO)2CO3.

[0062] In some embodiments of the method, each arm of the plurality of arms comprises a second disintegrable matrix segment attached to a first inert segment, wherein the second disintegrable matrix segment comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0063] In some embodiments of the method, each arm of the plurality of arms comprises a non-active segment attached to a second disintegrable matrix segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0064] In some embodiments of the method, a drug eluting arm of the plurality of arms comprises a drug eluting component attached to a non-active segment.

[0065] In some embodiments of the method, the area under the curve of the gastroretentive system is between 1000 and 6000 hr·ng / ml.

[0066] In some embodiments, a gastroretention system is provided comprising a plurality of arms secured to a central elastomer, wherein at least one arm comprises a drug eluting component, each arm comprising a proximal end, a distal end, and an exterior surface therebetween, wherein the proximal end of each arm is attached to the elastomeric component and projects radially from the elastomeric component, and each arm has its distal end not attached to the elastomeric component and located a greater radial distance from the elastomeric component than the proximal end, wherein at least one arm comprising the drug eluting component comprises a polymer linker segment, a first degradable matrix segment attached to the first degradable matrix segment, a first inactive segment attached to the first inactive segment, a second degradable matrix segment attached to the first inactive segment, an inactive segment attached to the second degradable matrix segment, and a drug-eluting component attached to the inactive segment, wherein the drug-eluting component comprises 50-60% by weight of methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer, and wherein the drug-eluting component further comprises a coating comprising a release rate-controlling polymer membrane.

[0067] In some embodiments, any one or more of the features, characteristics, or elements discussed above with respect to any embodiment may be incorporated into any of the other embodiments mentioned above or described elsewhere herein.

[0068] This application contains at least one drawing executed in color. Copies of this patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0069] [Figure 1A] FIG. 1A shows a gastroretentive system having a star configuration, according to some embodiments. [Figure 1B] FIG. 1B illustrates a gastroretention system in a folded configuration, according to some embodiments. [Figure 2] FIG. 2 shows the arrangement of elongate arms of a gastroretention system having six elongate arms, according to some embodiments, where the cross-sections of the arms are wedge-shaped. [Figure 3] FIG. 3 shows a gastroretention system having six active arms, according to some embodiments. [Figure 4] FIG. 4 shows a gastroretention system having four active arms, according to some embodiments. [Figure 5A] FIG. 5A shows the methadone release profiles of coated and uncoated drug eluting segments. [Figure 5B] FIG. 5B shows the methadone release profiles of coated and uncoated drug eluting segments. [Figure 6] FIG. 6 shows the methadone release profiles of gastroretentive systems containing drug-eluting segments coated with various amounts of release rate-controlling membrane. [Figure 7] FIG. 7 shows the methadone release rates of the drug-eluting segments in various simulated fluids (i.e., FASSGF, FED, FaSSIF). [Figure 8A] FIG. 8A shows methadone release following a 1-day ethanol challenge. [Figure 8B] FIG. 8B shows methadone release following a 1-day ethanol challenge. [Figure 9A] FIG. 9A shows methadone release over a 3-day ethanol challenge. [Figure 9B] FIG. 9B shows methadone release over a 3-day ethanol challenge. [Figure 10A] FIG. 10A shows the structure of the active arm of the gastroretentive system used in Example 6. [Figure 10B] FIG. 10B shows the mean methadone plasma concentrations over 10 days following a single oral dose of LYN-014-M (100 mg). [Figure 10C] FIG. 10C shows the mean methadone plasma concentrations after a single oral dose of methadone HCl (10 mg). [Figure 10D] FIG. 10D shows the mean methadone plasma concentrations over 7 days following a single oral dose of LYN-014-M (100 mg). [Figure 11] Figure 11 shows the cumulative release profile using the dissolution test method; and [Figure 12] FIG. 12 shows the cumulative release profile using the in vitro release test method. DETAILED DESCRIPTION OF THE INVENTION

[0070] Detailed Description of Disclosure Described herein are gastroretentive systems containing methadone. In some embodiments, the gastroretentive systems containing methadone provided herein can be used to treat opioid use disorder. In some embodiments, the described gastroretentive systems are designed to be administered less frequently than conventional methadone dosage forms. By reducing the administration frequency, the methadone-containing dosage forms provided herein can increase patient compliance. For example, instead of requiring a patient to visit a designated clinic once a day, as is typically required in conventional methadone maintenance treatment plans, the patient can visit the designated clinic only once every two days, once a week, or once a month (methadone is typically administered to patients at a clinical site to minimize the occurrence of overdose and diversion). This not only reduces the burden on patients by eliminating the need for frequent visits to the designated clinic, but also reduces the burden on designated clinics that must accommodate regular patient visits due to frequent administration. To further reduce the administration frequency, the gastroretentive systems provided herein slowly release the active pharmaceutical ingredient (i.e., methadone) over the residence period. Thus, if the gastroretentive form is designed to have a one week residence time, the active pharmaceutical ingredient (i.e., methadone) is designed to be slowly released in the patient's stomach throughout the one week residence time.

[0071] The particular combination of the methadone formulation for the drug-eluting segment of the gastroretentive system described herein in combination with the release rate-controlling membrane described herein can achieve a gastroretentive system that requires less frequent administration to the patient than conventional methadone maintenance therapy. Without both of these features, the gastroretentive system cannot adequately release methadone in a controlled manner throughout the retention period. For example, if the gastroretentive system is configured to have a 7-day retention period, the methadone formulation in combination with the release rate-controlling membrane coating can control the release of methadone so that methadone continues to be released from the gastroretentive system throughout the retention period, including the 7th (i.e., final) day of the retention period.

[0072] The gastroretention system for administering methadone may be star-shaped. For example, the star-shaped gastroretention system may include a central elastomer, three or more arms, and multiple connecting components (i.e., linkers). The central elastomer may be located at the center of the star, with three or more arms radiating from the central elastomer. The linkers can connect two or more components of the gastroretention system together. For example, the linkers can connect the arms to the central elastomer. The linkers can also connect two arms to each other (e.g., function as elbows for the arms). In some embodiments, the active pharmaceutical ingredient (i.e., methadone) can be provided within the arms (i.e., active arms) of the star. The active arms can include a methadone formulation.

[0073] The following describes a gastroretentive system for administering methadone to a patient. Specifically, this description provides: (1) definitions, (2) gastroretentive system drug delivery mechanisms, (3) gastroretentive system configurations and components, (4) features for improved retention and drug release, (5) carrier polymer-drug segment containing methadone formulations, (6) rate-controlling polymer membranes, (7) gastric residence times, (8) gastroretentive systems containing methadone, and (9) examples.

[0074] definition "Methadone" can be racemic or levomethadone. Levomethadone is approximately twice as potent as racemic methadone. "Methadone" can also refer to salts of methadone, such as methadone HCl or levomethadone HCl.

[0075] A "carrier polymer" is a polymer suitable for blending with an agent, eg, a drug, for use in a gastroretentive system.

[0076] A "drug" is any substance intended for therapeutic, diagnostic, or nutritional use in a patient, individual, or subject. Drugs include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0077] A "dispersing agent" is defined as a substance that aids in minimizing drug particle size and dispersing drug particles within the carrier polymer matrix. That is, dispersing agents help minimize or prevent particle aggregation or agglomeration during the manufacture of the system. Thus, dispersing agents have anti-aggregation and anti-agglomeration activity and help maintain a uniform distribution of drug particles within the carrier polymer matrix.

[0078] An "excipient" is any substance, other than the drug itself, that is added to a drug formulation. Excipients include, but are not limited to, binders, coating agents, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, and preservatives. The specific category of dispersing agents falls within the more general category of excipients.

[0079] An "elastic polymer" or "elastomer" is a polymer that can be deformed from its original shape for a period of time by an applied force, and that returns to substantially its original shape when the applied force is removed.

[0080] A "patient," "individual," or "subject" refers to a mammal, preferably a human, or a domestic animal such as a dog or cat. In the most preferred embodiment, the patient, individual, or subject is a human.

[0081] A "poloxamer" is a block copolymer that has a central polypropylene oxide core with flanking regions of polyethylene oxide on either side of the core.

[0082] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0083] "Treating" a disease or disorder using the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional agents, to a patient in need thereof to 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. "Suppressing" a disease or disorder using the systems and methods disclosed herein is defined as administering one or more of the systems disclosed herein, with or without additional agents, to a patient in need thereof to suppress the clinical symptoms of the disease or disorder or the development of an adverse symptom of the disease. The difference between treatment and suppression is that treatment occurs after adverse symptoms of the disease or disorder appear in a patient, whereas suppression occurs before adverse symptoms of the disease or disorder appear in a patient. Suppression can be partial, substantially total, or total. Some diseases or disorders are inherited, and therefore genetic screening can be used to identify patients at risk for the disease or disorder. The systems and methods disclosed herein can then be used to treat asymptomatic patients who are at risk of developing clinical symptoms of a disease or disorder in order to prevent the onset of any adverse symptoms.

[0084] The "flexural modulus" of a material is an intrinsic property of the material, calculated as the ratio of stress to strain in bending deformation of the material as measured by a three-point bending test. Although the linker is described herein as a component of the gastroretentive system, the flexural modulus of the polymeric material can also be measured independently. For example, the polymer linker of a gastroretentive system may be too short to measure the flexural modulus, but a longer sample of the same material can be used to accurately measure the flexural modulus. The longer sample used to measure the flexural modulus should have the same cross-sectional dimensions (shape and size) as the polymer linker used in the gastroretentive system. Flexural modulus is measured using a three-point bending test according to the ASTM standard three-point bending test (ASTM D790) with a 10 mm distance between supports, further modified to accommodate materials with non-rectangular cross sections. The flexural modulus should be measured with the longest line of symmetry of the polymer linker's cross section positioned vertically and a downward force applied. If the longest line of symmetry of the polymer linker's cross section is perpendicular to one flat edge, one flat edge should be positioned upward. If the cross section of the polymer linker is triangular, the apex of the triangle must point downward. The force and displacement when a downward force is applied are measured, and the slope in the linear region is calculated to calculate the bending modulus.

[0085] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated or the context clearly dictates otherwise.

[0086] When a numerical value is expressed using the term "about" or "approximately" herein, it is understood to include both the specified value and values ​​reasonably close to the specified value. For example, a statement such as "about 50°C" or "approximately 50°C" includes a disclosure of both 50°C itself and values ​​close to 50°C. Thus, the phrase "about X" or "approximately X" includes a disclosure of the value X itself. When a range is indicated, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C," it is understood that both values ​​specified by the endpoints are included, and values ​​close to each or both endpoints are included at each or both endpoints. In other words, "approximately 50°C to 60°C" (or "approximately 50°C to 60°C") is the same as describing both "50°C to 60°C" and "approximately 50°C to about 60°C" (or "approximately 50°C to 60°C").

[0087] With respect to the numerical ranges disclosed herein, any disclosed upper limit for a given ingredient can be combined with any disclosed lower limit for that ingredient to provide a range (provided that the upper limit is greater than the associated lower limit). Each of these combinations of disclosed upper and lower limits is expressly contemplated herein. For example, if ranges of the amount of a particular ingredient are given as 10% to 30%, 10% to 12%, and 15% to 20%, then ranges of 10% to 20% and 15% to 30% are also contemplated, while the combination of a lower limit of 15% with an upper limit of 12% is not possible and therefore not contemplated.

[0088] Unless otherwise specified, percentages of components in a composition are expressed as weight percent or weight / weight percent. Reference to relative weight percentages in a composition is understood to assume that the combined total weight percentages of all components in the composition add up to 100. It is further understood that the relative weight percentages of one or more components can be adjusted up or down to mean that the weight percentages of the components in the composition add up to 100, as long as the weight percentage of a particular component does not exceed the range limit specified for that component.

[0089] Some embodiments described herein are described as "comprising" or "comprises" with respect to various elements. In alternative embodiments, those elements can be described with the transitional phrase "consisting essentially of" or "consists essentially of" applied to those elements. In further alternative embodiments, those elements can be described with the transitional phrase "consisting of" or "consists of" applied to those elements. Thus, for example, if a composition or method is disclosed herein as comprising A and B, alternative embodiments of that composition or method "consisting essentially of A and B," and alternative embodiments of that composition or method "consisting of A and B," are also considered to be disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to various elements can also be described as "comprising" when applied to those elements. Finally, embodiments described as "consisting essentially of" various elements may also be described as "consisting of" as applied to those elements, and vice versa.

[0090] When a composition or system is described as "consisting essentially of" recited elements, the composition or system includes the explicitly recited elements and may include other elements that do not significantly affect the condition being treated (in the case of a composition for treating a condition) or the recited system properties (for a composition comprising a system). However, the composition or system either does not include other elements, other than the explicitly recited elements, that significantly affect the condition being treated (for a composition that constitutes a system), or does not include other elements that significantly affect the system properties (for a composition that comprises a system); or, if the composition or system includes additional elements other than those recited that may significantly affect the condition being treated or the system properties, the composition or system does not include the additional elements in concentrations or amounts sufficient to significantly affect the condition being treated or the system properties. When a method is described as "consisting essentially of" recited steps, the method includes the recited steps and may include other steps that do not significantly affect the condition being treated by the method or the properties of the system produced by the method, but the method does not include other steps, other than the explicitly recited steps, that significantly affect the condition being treated or the system produced.

[0091] The present disclosure provides several embodiments. It is contemplated that any feature of any embodiment may be combined, to the extent possible, with any feature of any other embodiment. Thus, hybrid configurations of the disclosed features are within the scope of the present disclosure.

[0092] In addition to the embodiments and methods disclosed herein, additional embodiments of gastroretentive systems, and methods of making and using such systems, are disclosed in International Patent Application Nos. WO2015 / 191920, WO2015 / 191925, WO2017 / 070612, WO2017 / 100367, and PCT / US2017 / 034856, the entire contents of which are incorporated herein by reference.

[0093] The following abbreviations are used for polymers and other components:

[0094] [Table 1]

[0095] PLURONIC® is a registered trademark of BASF Corporation for polyoxyalkylene ether. In any formulations described herein using trade names, the trade names can be substituted for the generic names. For example, a formulation described as containing 50% Corbion PC17 and 50% Corbion PC04 is understood to describe a formulation containing 50% polycaprolactone with a viscosity of 1.7 dl / g and 50% polycaprolactone with a viscosity of 0.4 dl / g.

[0096] Drug delivery mechanism of gastroretentive systems Gastric retention dosage forms can be designed to be administered to a patient's stomach by swallowing, via a feeding tube, via a stomach tube, etc. In some embodiments, the gastric retention dosage form is folded into a compressed configuration and secured within a capsule. Once the gastric retention dosage form is in place within the stomach, it unfolds from its compressed form to an uncompressed form, allowing it to remain in the stomach for a desired retention time (e.g., 3 days, 7 days, 2 weeks, etc.). Once properly positioned within the stomach, the gastric retention dosage form resists passage through the pyloric valve separating the stomach from the small intestine. The gastric retention dosage form can release a therapeutic agent (i.e., an API or drug) over the retention period via controlled release. While in the stomach, the dosage form should not interfere with the normal passage of food or other stomach contents. After the desired retention time has elapsed, the dosage form exits the stomach (i.e., through the pyloric valve) and is readily voided by the patient.

[0097] To administer the gastroretentive system to a patient, the gastroretentive system can be folded into a form small enough to be swallowed or otherwise administered. In some embodiments, the folded gastroretentive system is held in a capsule or other container that the patient can swallow. In some cases, the gastroretentive system can be delivered to the patient via a gastrostomy tube, a feeding tube, a gastric tube, or other administration route to the stomach. Specific examples of gastroretentive systems can be found in PCT / US2018 / 051816, WO2015 / 191920, WO2017 / 070612, WO2017 / 100367, WO2018 / 064630, WO2017 / 205844, and WO2018 / 227147, each of which is incorporated herein in its entirety.

[0098] Once the gastroretention system reaches the patient's stomach, it can assume an open configuration. The dimensions of the open gastroretention system, if left unchanged, are suitable to prevent the device from passing through the pyloric valve for the duration of its intended gastric retention. In some embodiments, the collapsed gastroretention system can also be secured by a dissolvable retention band or sleeve, which can prevent premature deployment of the gastroretention system in the event of capsule failure.

[0099] While in the stomach, the gastroretentive system accommodates digestion and other normal functions of the stomach or digestive tract. The gastroretentive system does not interfere with or prevent the emptying of chyme (partially digested food) and other stomach contents from the stomach through the pyloric valve and into the duodenum.

[0100] Once released from the capsule into the stomach, the therapeutic agent (e.g., methadone) of the gastroretentive system begins to take effect. In some embodiments, the gastroretentive system comprises multiple carrier polymer-drug components. The carrier polymer-drug component may include a carrier polymer, a pore-forming agent, and a therapeutic agent (or a salt thereof). The multiple carrier polymer-drug components are bound together by one or more coupling polymer components. The therapeutic agent can dissolve from the carrier polymer-drug component into the patient's gastric fluid over the desired residence time in the system. Release of the therapeutic agent is controlled by proper formulation of the carrier polymer-drug component, by the use of a dispersing agent in the carrier polymer-drug component formulation, and by milling the therapeutic agent into particles of the desired size before blending the drug with the carrier polymer and dispersing agent.

[0101] Additionally, a coating can be applied to the outer surface of the gastroretentive system, which can include one or more additional therapeutic agents that can affect the release of the therapeutic agent or the duration of residence in the gastroretentive system.

[0102] Once the desired retention time has elapsed, the gastric retention system is expelled from the stomach. To do so, various components of the gastric retention system are designed to weaken and degrade. The specific dimensions of the system are also taken into consideration. The gastric retention system is designed to resist passage through the pyloric valve in its intact, uncompressed, open configuration. However, the coupling polymer component of the gastric retention system is selected to gradually degrade over the specified retention period in the stomach. If the coupling polymer component is sufficiently weakened by degradation, the gastric retention system loses significant resilience to compression and size reduction and may break down into smaller fragments. The reduced-size dosage form and other small fragments are designed to pass through the pyloric valve. The system then passes through the intestine and is expelled from the patient. In some embodiments, the gastric retention system can be designed to weaken at specific locations so that it can pass through the pyloric valve intact over the retention time without breaking down into multiple small fragments.

[0103] Composition and components of the gastroretentive system Gastroretention systems can be prepared in a variety of configurations. The "star" configuration of the gastroretention system is also known as the "star" (or "asterisk") configuration. An example of a star-shaped system 100 is shown schematically in FIG. 1A. Multiple arms (only one such arm, 108, is labeled for clarity) are attached to a disk-shaped central elastomer 106. The arms shown in FIG. 1A are composed of segments 102 and 103 connected by a coupling polymer or linker region 104 (again, for clarity, these components are labeled on only one arm). This configuration allows the system to be folded or compressed around the central elastomer. FIG. 1B shows a folded configuration 190 of the gastroretention system of FIG. 1A (only two arms are shown in FIG. 1B for clarity). Segments 192 and 193, linker region 194, elastomer 196, and arms 198 in FIG. 1B correspond to segments 102 and 103, linker region 104, elastomer 106, and arms 108 in FIG. 1A, respectively. When collapsed, the overall length of the system is reduced by approximately half, allowing the system to be conveniently placed in a container such as a capsule or other container suitable for oral administration. The gastroretentive system is constrained in a compressed (folded) state by the capsule or other container. When the capsule reaches the stomach, it dissolves, releasing the gastroretentive system. When the capsule or other container is released from its restraint, the gastroretentive system expands to a non-compressed state and is retained in the stomach for the desired retention period.

[0104] Although linker regions 104 are shown slightly larger in diameter than segments 102 and 103 in FIG. 1A, they may be the same diameter as the segments, so that the entirety of arms 102-104-103 has a smooth outer surface.

[0105] In some embodiments, a star system may have arms composed of only one segment attached to a central elastomer by a linker region. This corresponds to Figure 1A, where segment 103 is omitted. The single-segment arm, comprising segment 102, is then directly attached to central elastomer 106 via linker 104. The linker may comprise a coupling polymer or a disintegrating matrix.

[0106] A star system can be described as a gastroretentive system for administration to a patient's stomach, comprising an elastomeric component and at least one carrier polymer-drug component attached to the elastomeric component, the carrier polymer and the drug or a salt thereof, wherein each of the multiple carrier polymer-drug components is an arm having a proximal end, a distal end, and an outer surface therebetween, wherein the proximal end of each arm is attached to the elastomeric component and protrudes radially from the elastomeric component, and each arm has its distal end not attached to the elastomeric component and located at a greater radial distance from the elastomeric component than the proximal end, wherein each arm independently comprises one or more segments, each segment having a proximal end, a distal end, and an outer surface therebetween. In some embodiments, when two or more segments are present in an arm, each segment is attached to an adjacent segment via a linker region. In some embodiments, when two or more segments are present in an arm, one segment is directly attached to another segment without the use of a linker region. The linker region may be a coupling polymer or a degradable matrix. The arms can be attached to the central elastomer via a coupling polymer or a degradable matrix and can have intervening portions of interfacial polymer. A plurality of at least three arms, or multiple arms, with a preferred number of arms being six, although 3, 4, 5, 7, 8, 9, or 10 arms can also be used. The arms should be evenly spaced around the central elastomer. If there are N arms, there will be an angle of approximately 360 / N degrees between adjacent arms.

[0107] Coupling polymer / linker region The coupling polymer of the gastroretentive system, which serves as the linker region, is designed to gradually degrade in a controlled manner during the system's residence in the stomach. If the gastroretentive system passes too quickly into the small intestine and remains intact, the system is designed to degrade more quickly to avoid ileus. This is easily achieved by using an enteric polymer as the coupling polymer. Enteric polymers are relatively resistant to the acidic pH levels encountered in the stomach but dissolve at the higher pH levels found in the duodenum. The use of an enteric coupling polymer as a safety element prevents unwanted passage of the intact gastroretentive system into the small intestine. In the system shown in FIG. 1A, at least the coupling polymer used in coupling 104 is made from such an enteric polymer.

[0108] In additional embodiments, time-dependent coupling polymers or linkers can be used. Such time-dependent coupling polymers or linkers degrade in a predictable, time-dependent manner. In some embodiments, the degradation of the time-dependent coupling polymers or linkers may not be affected by changes in pH in the gastrointestinal system.

[0109] In additional embodiments, different types of linkers can be used in the gastroretentive system. That is, both enteric linkers (or enteric coupling polymers) and time-dependent linkers (or time-dependent coupling polymers) can be used. In some embodiments, a single multi-segment arm of a star system can use both an enteric linker in some linker regions between segments and a time-dependent linker in other linker regions between segments.

[0110] The linker region typically has a width of about 100 microns to about 2 millimeters, for example, 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, or about 900 μm to about 2000μm, about 1000μm to about 2000μm, about 1100μm to about 2000μm, about 1200μm to about 2000μm, about 1300μm to about 2000μm, about 1 400μm~about 2000μm, about 1500μm~about 2000μm, about 1600μm~about 2000μm, about 1700μm~about 2000μm, about 1800μm~about 20 00 μm, or about 1900 μm to about 2000 μm, or about 100 μm to about 1900 μm, about 100 μm to about 1800 μm, about 100 μm to about 1700 μm, about 100 μm to about 1600 μm, about 100 μm to about 1500 μm, about 100 μm to about 1400 μm, about 100 to about 1300 μm, about 100 μm to about 1200 μm, or about 100 μm to about 1100 μm, about 100 μm to about 1000 μm, about 100 μm to about 900 μm, about 100 μm to about 800 μm, about 100 μm to about 700 μm, about 100 μm to about 600 μm, about 100 μm to about 500 μm, about 100 μm to about 400 μm, about 100 μm to about 300 μm, or about 100 μm to about 200 μm. The linker region can be about 100 μm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1000 μm, about 1100 μm, about 1200 μm, about 1300 μm, about 1400 μm, about 1500 μm, about 1600 μm, about 1700 μm, about 1800 μm, about 1900 μm, or about 2000 μm in width, where each value can be plus or minus 50 μm (±50 μm).

[0111] Central Elastomer The central elastomeric polymer of a star system is typically not an enteric polymer, but the central elastomeric polymer can also be made from such an enteric polymer when desirable and practical.

[0112] The central elastomer must have a specific durometer and compression set. Durometer is important because it determines the folding force of the dosage form and whether it will remain in the stomach. A preferred range is about 60 to about 90A. Compression set should be as small as possible to avoid permanent deformation of the gastroretentive system when stored in a compressed configuration within the capsule. A preferred range is about 10% to about 20%. Liquid silicone rubber is a useful material for the central elastomer. An example of a material that meets these requirements is Dow Corning's QP1 series of liquid silicone rubbers. In any embodiment that includes a central elastomer, QP1-270 (70A durometer) liquid silicone rubber can be used. In some embodiments, the central elastomer can include 50A or 60A durometer liquid silicone rubber (Shin-Etsu Chemical Co., Ltd.).

[0113] Segment / Arm The segments and arms of the gastric retention system can have a cross-section that is circular (in which case the segment is cylindrical), polygonal (such as a segment having a triangular, rectangular, or square cross-section), or pie-shaped (in which case the segment is cylindrical). Segments with polygonal or pie-shaped cross-sections, and the ends of cylindrical sections that come into contact with gastric tissue, can have sharp edges rounded to provide rounded corners and edges for increased in vivo safety. That is, instead of abrupt transitions between intersecting edges or planes, a circular arc is used to transition from one edge or plane to another. Thus, a "triangular cross-section" also includes a cross-section that has an approximately triangular shape, such as a triangle with rounded corners. Arms with a triangular cross-section also include arms with rounded corners or rounded corners at their tips. Rounded corners and edges are also referred to as fillet corners, filleted corners, fillet edges, or filleted edges.

[0114] In some embodiments, the cross-section of the elongate members or arms used in a star-shaped gastric retention system is circular, where the circular cross-section is formed by two radii of a cylinder that lie in the same plane and the arc where the radii intersect. The angle between the two radii (the central angle of the arc) is preferably about 360 degrees divided by 4, 6, or 8, but may also be about 360 degrees divided by any integer between 2 and 12. That is, a cross-section described as a circular cross-section resembles a slice of a pie, such as the cross-section shown on the left side of FIG. 2, and such a shape can be referred to as a pie-shape. Such cross-sections of the elongate members in a star-shaped system allow the gastric retention system to have an approximately cylindrical shape when compressed, as shown on the right side of FIG. 2 for a gastric retention system 1030 having six elongate members (one elongate member 1010 is labeled) with wedge-shaped cross-sections. 2 reduces stress on the containment capsule 1020 when the system is in a compressed configuration compared to an arrangement with elongate members having triangular cross sections, and allows for greater volume to be used for the elongate members because space within the capsule is not wasted. Elongate members having such cross sections can be produced by extrusion through a die having such cross sections. When multiple regions of a bulk structure, such as an extruded slab or ribbon, are co-extruded, compression molding or thermoforming can be used to form elongate members having such cross sections from portions of the extruded bulk structure.

[0115] In some embodiments, the star system is about 30 mm to about 60 mm when deployed (arms extended). In some embodiments, the star system is about 41 mm to about 51 mm when deployed. In some embodiments, the star system is about 45 mm to about 47 mm when deployed. In some embodiments, the star system is about 46 mm when deployed.

[0116] Methadone gastroretentive system functions to enhance retention and drug release Retention of and drug release from gastroretention systems over the desired retention period can be improved and made more consistent by using features described herein, such as filaments wrapped around and connecting the arms of the gastroretention system, the use of timed linkers and enteric linkers that allow for more precise retention and passage of the gastroretention system, and arms coated with release rate-controlling polymeric membranes.

[0117] Circumferential filament In some embodiments, the gastric retention system may include circumferential filaments. A gastric retention system with filaments may help improve the gastric retention of the gastric retention system. Specifically, the filaments may help provide a more consistent and / or longer gastric retention time. Thus, a gastric retention system including filaments may provide a more predictable and / or controllable gastric retention time. A gastric retention system with a predictable and / or controllable gastric retention time may minimize the risk of the gastric retention system deploying prematurely (e.g., in the esophagus) and causing a blockage. A gastric retention system with a predictable and / or controllable gastric retention time may also minimize the possibility of the gastric retention system deploying in the gastrointestinal tract (i.e., intestines) after passing through the stomach, or passing through the gastrointestinal tract without deploying at all. In each of these possible scenarios, the therapeutic agent in the gastrointestinal dosage form is not delivered to the patient as intended.

[0118] However, it has been demonstrated that star-shaped gastroretentive systems can bend into a shape that allows them to pass through the patient's pylorus too early. A gastroretentive system that passes through the pylorus too early cannot deliver the therapeutic agent of the gastroretentive system to the patient. Furthermore, early passage can cause inconsistency, reduce reliability, and compromise the effectiveness of the gastroretentive system.

[0119] The characteristics of the circumferential filament are described in International Patent Application PCT / US2020 / 059541, which is incorporated herein by reference in its entirety.

[0120] Time-dependent linkers (time-degradable matrices) and enteric linkers (enterically degradable matrices) Polymer linkers (eg, timed linkers and / or enteric linkers) and time-dependent linkers are specifically described below.

[0121] polymer linker The drug-containing structural member is attached to a second structural member (e.g., a central member, which may be an elastic central member) via one or more linkers. The polymer linker may contact the drug-containing structural member directly or via a coupling member. Similarly, the polymer linker may contact the second structural member directly or via a coupling member. In embodiments in which the drug-containing structural member is connected to the second structural member via two or more polymer linkers, the polymer linkers may contact each other directly or via a coupling member. One or both of an enteric linker and a time-dependent linker may be used, or a polymer linker may function as both an enteric linker and a time-dependent linker.

[0122] The polymer linker typically has a width of about 100 microns to about 3 millimeters, for example, about 200 μm to about 3000 μm, about 300 μm to about 3000 μm, about 400 μm to about 3000 μm, about 500 μm to about 3000 μm, about 600 μm to about 3000 μm, about 700 μm to about 3000 μm, about 800 μm to about 3000 μm, about 900 μm to about 3000 μm, about 1000 μm to about 3000 μm, about 1100 μm to about 3000 μm, about 1200 μm to about 3000 μm, about 1300 μm to about 3000 μm, about 1400 μm to about 3000 μm. μm, approx. 1500 μm to approx. 3000 μm, approx. 1600 μm to approx. 3000 μm, approx. 1700 μm to approx. 3000 μm, approx. 1800 μm to approx. 3000 μm, approx. 2200μm ~ approx. 3000μm, approx. 2300μm ~ approx. 3000μm, approx. 2400μm ~ approx. 3000μm, approx. 2500μm ~ approx. 30 00μm, approximately 2600μm to approximately 3000μm, approximately 2700μm to approximately 3000μm, approximately 2800μm to approximately 3000μm, or approximately 2 900 μm to about 3000 μm, or about 100 μm to about 200 μm, about 200 μm to about 300 μm, about 300 μm to about 400 μm, about 400 μm to about 500 μm, about 500 μm to about 600 μm, about 600 μm to about 700 μm, about 700 μm to about 800 μm, about 800 μm to about 900 μm, about 900 μm to about 1000 μm, about 1000 μm to about 1100 μm, about 1100 μm to about 1200 μm, about 1200 μm to about 1300 μm, about 1300 μm to about 1400 μm, about 1400 μm to about 1500 μm, about 1500 μm to about 1600 μm, about 1600 μm to about 1700 μm, about 1700 μm to about 1800 μm, about 1800 μm to about 1900 μm, about 1900 μm to about 2000 μm, about 2000 μm to about 2100 μm, about 2100 μm to about 2200 μm, about 2200 μm to about 2300 μm, about 2300 μm to about 2400 μm, about 2400 μm to about 2500 μm, about 2500 μm to about 2600 μm, about 2600 μm to about 2700 μm, about 2700 μm to about 2800 μm, about 2800 μm to about 2900 μm, about 2900 μm to about 3000 μm.The polymer linker may have a width of about 100 μm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1000 μm, about 1100 μm, about 1200 μm, about 1300 μm, about 1400 μm, about 1500 μm, about 1600 μm, about 1700 μm, about 1800 μm, about 2000 μm, about 2100 μm, about 2200 μm, about 2300 μm, about 2400 μm, about 2500 μm, about 2600 μm, about 2700 μm, about 2800 μm, about 2900 μm, about 3000 μm, about 3100 μm, about 3200 μm, about 3300 μm, about 3400 μm, about 3500 μm, about 3600 μm, about 3700 μm, about 3800 μm, about 3900 μm, about 4000 μm, about 4100 μm, about 4200 μm, about 4300 μm, about 4400 μm, about 4500 μm, about 4600 μm, about 4700 μm, about 4800 μm, about 4900 μm, about 5000 μm, about 5100 μm, about 5200 μm, about 5300 μm, about 5400 μm, about 5500 μm, about 5600 μm, about 5700 μm, about 5800 μ The thickness may be about 1000 μm, about 1900 μm, about 2000 μm, about 2100 μm, about 2200 μm, about 2300 μm, about 2400 μm, and the width may be about 2500 μm, about 2600 μm, about 2700 μm, about 2800 μm, about 2900 μm, about 3000 μm, wherein each of the above values ​​may be plus or minus 50 μm (±50 μm).

[0123] The cross-section of the polymer linker can be round (i.e., circular), oval, triangular, square, rectangular, pentagonal, hexagonal, pie-shaped, or any other polymer shape. In some embodiments, the cross-section of the polymer linker is the same shape as the cross-section of the drug-containing structural member attached to the polymer linker. In some embodiments, the cross-section of the polymer linker has an area larger than the cross-section of the drug-containing structural member, an area smaller than the cross-section of the drug-containing structural member, or about the same area as the cross-section of the structural member containing the attached drug.

[0124] In some embodiments, the polymer linker may comprise polylactic acid (PLA), polycaprolactone (PCL), or another suitable polymer.

[0125] Time-dependent disintegration matrix (time-dependent linker) The time-dependent linker degrades predictably and in a time-dependent manner under aqueous conditions, such as when the gastroretentive system is deployed in an individual's stomach. The time-dependent polymer linker controls the residence time of the gastroretentive system in the stomach. The time-dependent polymer linker is designed to gradually degrade, dissolve, mechanically weaken, or break down over time. After the desired residence period, the time-dependent polymer linker degrades, dissolves, dissociates, or mechanically weakens or breaks down to a point that allows the gastroretentive system to pass through the pyloric valve, exit the gastric environment, enter the small intestine, and ultimately be excreted from the body.

[0126] The time-dependent polymer linker preferably comprises a pH-independent degradable polymer that degrades in an aqueous condition in a pH-independent or nearly pH-independent manner. Examples of pH-independent degradable polymers include PLGA, PLA, PCL, polydioxanone, cellulose, or blends or copolymers thereof.

[0127] The time-dependent polymer linker may include poly(lactic acid-co-glycolide) (PLGA).

[0128] In some embodiments, the PLGA of the time-dependent polymer linker comprises a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g) (e.g., PLGA sold under the trade name Purasorb® PDLG5004, available from Corbion). In some embodiments, the PLGA of the time-dependent polymer linker comprises an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.32 dl / g to about 0.48 dl / g (e.g., about 0.4 dl / g) (e.g., PLGA sold under the trade name Purasorb® PDLG5004A, available from Corbion). In some embodiments, the PLGA of the time-dependent polymer linker comprises (a) a mixture of poly(D,L-lactic acid-co-glycolide) having a lactide monomer to glycolide monomer ratio of about 50:50 (e.g., PLGA sold under the trade name Purasorb® PDLG5004, available from Corbion), and (b) acid-terminated poly(D,L-lactic acid-co-glycolide) having a lactide monomer to glycolide monomer ratio of about 50:50 (e.g., PLGA sold under the trade name Purasorb® PDLG5004A, available from Corbion).

[0129] The one or more additional linker polymers contained in the polymer linker can be uniformly mixed with PLGA. In some embodiments, the one or more additional linker polymers are miscible with PLGA. The one or more additional linker polymers can be non-degradable polymers (i.e., they are not degraded in the stomach or intestinal environment, i.e., in an aqueous solution at pH 1.6 (representing the stomach environment) or pH 6.5 (representing the intestinal environment)), and optionally are present in the time-dependent polymer linker in an amount such that the time-dependent polymer linker is not destroyed during the gastric residence period.

[0130] Attachment of the polymer linker to directly adjacent members can be improved if at least one polymer is common to both the adjacent members and the time-dependent polymer linker. In some embodiments, at least one common polymer is polycaprolactone (PCL).

[0131] In some embodiments, one or more additional linker polymers comprise PCL. The time-dependent polymer linker may be directly linked or bonded to another member of the gastric retention system (e.g., a structural member comprising a drug and a carrier polymer, a coupling member, an enteric polymer linker, or a central structural member), which may also comprise PCL. This PCL may be the same as or different from that in the time-dependent polymer linker, and may be at the same or different concentrations. The different PCL in the time-dependent polymer linker may differ from the other member directly linked or bonded to the time-dependent linker in, for example, the weight-average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when a blend of two or more PCL polymers is used). In some embodiments, the time-dependent disintegrating matrix comprises about 40% to about 50% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 43% to about 47% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 45% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 44.95% by weight PCL.

[0132] The time-dependent polymer linker can further comprise one or more plasticizers, such as polyethylene glycol. The term "polyethylene glycol" is used interchangeably herein with the terms "polyethylene oxide" and "PEO." In some embodiments, the molecular weight of the polyethylene glycol is about 90K to about 110K, e.g., 100k (also referred to as 100K or 100kDa). In some embodiments, the time-dependent disintegrating matrix comprises polyethylene glycol having a molecular weight of about 100k (polyethylene glycol 100k). In some embodiments, the time-dependent disintegrating matrix comprises about 0.5% to about 5% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 1% to about 3% by weight of polyethylene glycol 100k. In some embodiments, the time-dependent disintegrating matrix comprises about 2% by weight of polyethylene glycol 100k.

[0133] In some embodiments, the time-dependent disintegrating matrix comprises a color-absorbing dye (also called a colorant or pigment). The color-absorbing dye can be included to enhance the bonding or attachment of the polymer linker to other gastroretentive system components. The color-absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced attachment, which increases the tensile strength of the resulting bond. Examples of color-absorbing dyes include iron oxide and carbon black. The time-dependent disintegrating matrix can comprise the color-absorbing dye in an amount of up to about 5%, e.g., up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, up to about 0.1%, or up to about 0.05%. In some embodiments, the time-dependent disintegrating matrix comprises from about 0.005% to about 0.2% by weight of the color-absorbing dye. In some embodiments, the time-dependent disintegrating matrix comprises from about 0.01% to about 0.1% by weight of the color-absorbing dye. In some embodiments, the time-dependent disintegrating matrix comprises about 0.05% by weight of a color absorbing dye, hi some embodiments, the color absorbing dye is E172.

[0134] In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 10% to about 25% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color absorbing dye E172.

[0135] In another example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 43% to about 47% by weight of PCL, about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15% to about 20% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of a color absorbing dye E172.

[0136] In another example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 44.95 wt. % PCL, about 35 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt. % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172.

[0137] In some embodiments, a dosage form for administration of one or more agents comprises a gastroretentive system, wherein the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 44.95% by weight of polycaprolactone (PCL), e.g., PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, such as Corbion PC17. In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 35.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) (e.g., PDLG5004A) having a viscosity midpoint of about 0.32 dL / g to about 0.48 dL / g (e.g., about 0.4 dL / g). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 18.0 wt% copolymer of DL-lactide and glycolide (50 / 50 molar ratio) (e.g., PDLG5004) having a viscosity midpoint of about 0.32 dL / g to about 0.48 dL / g (e.g., about 0.4 dL / g). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 2.0 wt% polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000 (e.g., PEO100K). In some embodiments, the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 0.05 wt% iron oxide (e.g., E172). In some embodiments, the dosage form for administration of one or more pharmaceutical agents comprises a gastroretentive system, wherein the gastroretentive system comprises a time-dependent disintegrating matrix comprising about 44.95% by weight of Corbin PC17, about 35.0% by weight of PDLG5004A, and about 18.0% by weight of PDLG5004, about 2.0% by weight of PEO100K, and about 0.05% by weight of E172.

[0138] Exemplary amounts of components of the time-dependent disintegrating matrix are shown in the table below. Where ranges are provided, the amounts are given as approximate weight percent, with the understanding that the amounts are selected to add up to 100%.

[0139] [Table 2]

[0140] Enterodispersible matrix (enteric linker) The pH-dependent disintegration matrix provides a safety mechanism for the gastroretentive system. If the system exits the stomach too quickly, i.e., if the time-dependent disintegration matrix remains entirely intact, the pH-dependent disintegration matrix will degrade, dissolve, dissociate, or mechanically weaken in the high pH environment of the small intestine, facilitating passage of the gastroretentive system through the small intestine. Furthermore, after passage through the gastroretentive system, once the time-dependent disintegration matrix has degraded, dissolved, dissociated, or mechanically weakened in the gastric environment, exposure of the pH-dependent disintegration matrix to the high pH of the small intestine will further weaken and / or disrupt the system, facilitating passage through the small intestine.

[0141] If a gastroretentive system passes through the small intestine too quickly in its native form, the system can be designed to degrade more quickly to avoid intestinal obstruction. This is achieved by using an enteric polymer linker, which includes an enteric polymer that weakens or degrades in the intestinal environment, in addition to an additional linker polymer (e.g., a carrier polymer). The enteric polymer is relatively resistant to the acidic pH levels encountered in the stomach but rapidly dissolves at the higher pH levels found in the duodenum. The use of an enteric polymer linker as a safety element can prevent the undesired passage of the intact gastroretentive system into the small intestine. The use of an enteric polymer linker also provides a method for removing the gastroretentive system before the planned residence time. If the system needs to be removed, the patient can drink a mildly alkaline solution, such as sodium bicarbonate solution, or take an antacid, such as magnesium hydroxide hydrate (milk of magnesia) or calcium carbonate, which raises the pH level in the stomach and causes rapid degradation of the enteric polymer linker.

[0142] The weakening or degradation of an enteric polymer linker can be measured by reference to the loss or destruction of the polymer linker's flexural modulus under given conditions (e.g., intestinal or gastric conditions). An enteric linker weakens, degrades, or destroys relatively quickly in the intestinal environment, but retains much of its flexural modulus in the gastric environment. Gastric conditions can be simulated using an aqueous solution such as FaSSGF at pH 1.6 and 37°C, while intestinal conditions can be simulated using an aqueous solution such as FaSSIF at pH 6.5 and 37°C.

[0143] In some embodiments, the enteric disintegrating matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, in some embodiments, the enteric disintegrating matrix comprises about 60% to about 70% HPMCAS by weight. In some embodiments, the enteric disintegrating matrix comprises about 62% to about 66% HPMCAS by weight. In some embodiments, the enteric disintegrating matrix comprises about 63.95% HPMCAS by weight.

[0144] The enteric polymer is combined with one or more additional polymers (e.g., one or more carrier polymers) in the enteric linker, preferably in a homogeneous mixture. For example, the enteric polymer and the additional linker polymer can be homogeneously blended together before the mixture is extruded, and the extruded material is cut to the desired size for the polymer linker. In some embodiments, the one or more additional linker polymers are miscible with the enteric polymer. The one or more additional linker polymers may be non-degradable polymers (i.e., not degraded in the stomach or intestinal environment, or in aqueous solutions at pH 1.6 (representing the stomach environment) or pH 6.5 (representing the intestinal environment)).

[0145] The binding of the polymer linker to the immediately adjacent member can be improved if at least one polymer is common to both the adjacent member and the enteric polymer linker. That is, one of the one or more additional linker polymers in the enteric linker can be the same (or the same polymer type) as at least one polymer in the immediately adjacent component (or, optionally, both immediately adjacent components) of the gastroretentive system. For example, when the enteric polymer linker is directly attached to the structural member containing a carrier polymer, in some embodiments, the one or more additional linker polymers also contain the same or different concentration of carrier polymer (in addition to PLGA in the time-dependent polymer linker). Examples of carrier polymers include, but are not limited to, polylactic acid (PLA) and polycaprolactone (PCL), particularly those described herein.

[0146] In some embodiments, one or more additional linker polymers in the enteric linker comprise PCL. The enteric polymer linker may be directly linked or bonded to another member of the gastroretentive system (e.g., a structural member comprising a drug and a carrier polymer, a coupling member, a time-dependent polymer linker, or a central structural member), which may also comprise PCL, which may be the same PCL as in the enteric polymer linker or a different PCL from that in the enteric polymer linker, at the same or different concentrations. The different PCL in the enteric polymer linker may differ from the other member directly linked or bonded to the enteric linker, for example, in the weight-average molecular weight of the PCL, the intrinsic viscosity of the PCL, or the proportion of PCL (e.g., when a blend of two or more PCL polymers is used). In some embodiments, the enteric disintegrating matrix comprises about 30% to about 40% by weight of PCL. In some embodiments, the enteric disintegrating matrix comprises about 32% to about 37% by weight of PCL. In some embodiments, the enteroerodible matrix comprises about 34% PCL by weight, hi some embodiments, the enteroerodible matrix comprises about 33.95% PCL by weight.

[0147] The enteroerodible matrix may further comprise one or more plasticizers, such as poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the enteroerodible matrix comprises about 0.5% to about 5% by weight of poloxamer. In some embodiments, the enteroerodible matrix comprises about 1% to about 3% by weight of poloxamer. In some embodiments, the enteroerodible matrix comprises about 2% by weight of poloxamer.

[0148] In some embodiments, the enteroerodible matrix comprises a color-absorbing dye (also called a colorant or pigment). The color-absorbing dye can be included to enhance bonding or attachment of the polymer linker to other gastroretentive system components. The color-absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced attachment, increasing the tensile strength of the resulting bond. Examples of color-absorbing dyes include iron oxide and carbon black. The enteric polymer linker can comprise a color-absorbing dye in an amount of up to about 5%, e.g., up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, or up to about 0.1%. In some embodiments, the enteroerodible matrix comprises the color-absorbing dye triiron tetroxide in an amount of about 0.01% to about 0.2% by weight. In some embodiments, the enteroerodible matrix comprises the color-absorbing dye triiron tetroxide in an amount of about 0.05% to about 0.15% by weight. In some embodiments, the enteroerodible matrix comprises about 0.1% by weight of the color absorbing dye iron oxide.

[0149] In some embodiments, the enteroerodible matrix comprises about 59% to about 69% HPMCAS by weight, about 29% to about 39% PCL by weight, and about 0.5% to about 5% poloxamer (e.g., P407) by weight. Optionally, the enteroerodible matrix further comprises an iron oxide, e.g., about 0.01% to about 0.2% iron oxide (e.g., E172) by weight.

[0150] In some embodiments, the enteroerodible matrix comprises about 62% to about 66% HPMCAS by weight, about 32% to about 36% PCL by weight, and about 1% to about 3% poloxamer (e.g., P407) by weight. Optionally, the enteroerodible matrix further comprises an iron oxide, for example, about 0.05% to about 0.15% iron oxide (e.g., E172) by weight.

[0151] In some embodiments, the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (e.g., P407). Optionally, the enteroerodible matrix further comprises iron oxide, for example, about 0.1% by weight iron oxide (e.g., E172).

[0152] In some embodiments, the dosage form for administration of one or more agents comprises a gastroretentive system, wherein the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 33.95% by weight of polycaprolactone (PCL), such as a PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbin PC 17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 63.95% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises about 2.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H-(OCHCH)-(O-CH(CH)CH)-(OCHCH)-OH (wherein x and z are about 101, and y is about 56), such as poloxamer 407 (P407, a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer having a polyoxypropylene molecular weight of about 4000 and a polyoxyethylene content of about 70%. In some embodiments, the gastroretentive system comprises a pH-dependent disintegrating matrix comprising about 0.1% by weight of iron oxide (e.g., E172). In some embodiments, the dosage form for administration of one or more agents comprises a gastroretentive system, wherein the gastroretentive system comprises about 33.95% by weight of Corbin It comprises a pH-dependent disintegrating matrix comprising PC17, about 63.95% by weight of HPMCAS-MG, about 2.0% by weight of P407, and about 0.1% by weight of E172.

[0153] Examples of amounts of components of an enteroerodible matrix are shown in the table below. When ranges are provided, the amounts are given as approximate weight percentages, with the understanding that the amounts are selected to add up to 100%.

[0154] [Table 3]

[0155] Arm tip collapsible matrix In some embodiments, the gastroretentive system comprises an arm comprising a third disintegrating matrix in addition to the time-dependent disintegrating matrix and the enterodisintegrating matrix. In some embodiments, the third disintegrating matrix is ​​the filament-retaining segment (i.e., the segment to which the filament is attached). In some embodiments, the third disintegrating matrix is ​​the distal portion of the retention system arm, i.e., the tip of the arm.

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

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

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

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

[0160] In some embodiments, the third disintegrable matrix comprises a color-absorbing dye (also called a colorant or pigment). The color-absorbing dye can be included to enhance the bonding or attachment of the polymer linker to other gastroretentive system components. The color-absorbing dye can absorb heat during laser welding, infrared welding, or other heat-induced attachment, which increases the tensile strength of the resulting bond. Examples of color-absorbing dyes include iron oxide and carbon black. The third disintegrable matrix can comprise the color-absorbing dye in an amount of up to about 5%, e.g., up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, or up to about 0.1%. In some embodiments, the third disintegrable matrix comprises about 0.01% to about 0.5% by weight of the color-absorbing dye. In some embodiments, the third disintegrable matrix comprises about 0.05% to about 0.15% by weight of the color-absorbing dye. In some embodiments, the third disintegrable matrix comprises about 0.1% by weight of a color-absorbing dye. In some embodiments, the third disintegrable matrix comprises about 0.025% ferric oxide and about 0.075% FD&C Red 40. In some embodiments, the third disintegrable matrix comprises about 0.025% ferric oxide and about 0.075% FD&C Red 40.

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

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

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

[0164] Exemplary amounts of components of the third disintegrable matrix are shown in the table below: Where ranges are provided, the amounts are given as approximate weight percent, with the understanding that the amounts are selected to add up to 100%.

[0165] [Table 4]

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

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

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

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

[0170] In some embodiments, the inert segment comprises a color absorbing dye (also referred to as a colorant or pigment). The inert segment may comprise the color absorbing dye in an amount of up to about 5%, e.g., up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, up to about 0.1%, or up to about 0.05%. In some embodiments, the inert segment comprises from about 0.005% to about 0.2% by weight of the color absorbing dye. In some embodiments, the inert segment comprises from about 0.01% to about 0.1% by weight of the color absorbing dye. In some embodiments, the color absorbing dye is FD&C Blue #1 Alum Lake.

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

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

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

[0174] Exemplary amounts of components of one embodiment of the inactive segment (e.g., inactive spacer) are shown in the table below. In some embodiments, the formulations provided in the table immediately below are referred to as "inactive segments." The inactive segments must not contain radioactive materials. When ranges are provided, the amounts are given as approximate weight percent, with the understanding that the amounts are selected to add up to 100%.

[0175] [Table 5]

[0176] In some embodiments, the gastroretention system comprises one or more inactive segments, wherein the inactive segments comprise one or more radiopaque materials, hi some embodiments, the gastroretention system comprises one or more inactive segments, wherein the inactive segments are radiopaque segments.

[0177] In some embodiments, the inactive segment comprises a polymer common to other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 65% to about 75% by weight of PCL. In some embodiments, the inactive segment comprises about 68% to about 72% by weight of PCL. In some embodiments, the inactive segment comprises about 70% by weight of PCL.

[0178] In some embodiments, the inactive segments comprise a radiopaque material. In some embodiments, the inactive segments comprise a radiopaque material, wherein the radiopaque material is (BiO)2CO3. In some embodiments, the inactive segments comprise (BiO)2CO3. In some embodiments, the inactive segments comprise about 25% to about 35% (BiO)2CO3 by weight. In some embodiments, the inactive segments comprise about 28% to about 32% (BiO)2CO3 by weight. In some embodiments, the inactive segments comprise about 30% (BiO)2CO3 by weight.

[0179] In some embodiments, the inactive segments comprise about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3. In some embodiments, the inactive segments comprise about 68% to about 72% by weight PCL and about 28% to about 32% by weight (BiO)2CO3. In some embodiments, the inactive segments comprise about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0180] Exemplary amounts of components of one embodiment of the inactive segment (e.g., the rPCL segment) are shown in the table below. When ranges are provided, the amounts are given as approximate weight percent, with the understanding that the amounts are selected to add up to 100%.

[0181] [Table 6]

[0182] Carrier polymer containing methadone formulation - drug segment (drug eluting segment) The carrier polymer-drug segment or drug-eluting segment releases the drug in a controlled manner during the gastroretentive system's residence in the stomach. The carrier polymer is mixed with the drug and formed into segments, which are then assembled with other components described herein to produce the gastroretentive system. Compositions of such carrier polymer-drug blends are provided below for specific drug formulations, including those containing methadone.

[0183] In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system containing about 10 mg to about 320 mg of methadone. In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system containing about 50 mg to about 300 mg of methadone. In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system containing about 320, about 300, about 280, about 260, about 240, about 220, about 200, about 180, about 160, about 140, about 120, about 100, about 80, about 60, about 40, or about 20 mg or less of methadone. In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system comprising about 10, about 20, about 40, about 60, about 80, about 100, about 120, or about 140 mg, about 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300 mg or more of methadone.

[0184] In some embodiments, the dosage form comprises a gastroretentive system, wherein the gastroretentive system comprises one or more drug-eluting segments, each of which comprises about 10 mg to about 60 mg of methadone. In some embodiments, each drug-eluting segment comprises about 60, about 50, about 40, about 30, or about 20 mg or less of methadone. In some embodiments, each drug-eluting segment comprises about 10, about 20, about 30, about 40, or about 50 mg or more of methadone.

[0185] In some embodiments, the methadone formulation comprises about 40% to about 70% methadone by weight. In some embodiments, the methadone formulation comprises about 70, 65, 60, 55, 50, or about 45% or less methadone by weight. In some embodiments, the methadone formulation comprises about 40, 45, 50, 55, 60, or about 65% or more methadone by weight.

[0186] The methadone formulation comprises about 30% to 50% by weight of polycaprolactone (PCL), e.g., a PCL having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbin PC 17. In some embodiments, the methadone formulation comprises about 50, about 45, about 40, or about 35% by weight or less of PCL. In some embodiments, the methadone formulation comprises about 30, about 35, about 40, or about 45% by weight or more of PCL.

[0187] In some embodiments, the methadone formulation comprises about 0.1% to about 5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCHCH)-(O-CH(CH)CH)-(OCHCH)-OH, where x and z are about 101 and y is about 56, such as poloxamer 407. In some embodiments, the methadone formulation comprises about 5, about 4, about 3, about 2, about 1, or about 0.5% by weight or less of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as poloxamer 407. In some embodiments, the methadone formulation comprises about 0.1, about 0.5, about 1, about 2, about 3, or about 4% by weight or more of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as poloxamer 407.

[0188] In some embodiments, the methadone formulation comprises about 50% to about 60% by weight methadone, the methadone formulation comprises about 35% to about 50% by weight polycaprolactone (PCL), e.g., a PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbin PC 17. In some embodiments, the methadone formulation comprises about 50% to about 60% by weight methadone, the methadone formulation comprises about 0.5% to about 3% by weight poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H—(OCH2CH2)x—(O—CH(CH3)CH2)y—(OCH2CH2)z—OH (where x and z are about 101, and y is about 56), e.g., poloxamer 407.

[0189] In some embodiments, the methadone formulation comprises about 56% by weight methadone, the methadone formulation comprises about 42.5% by weight polycaprolactone (PCL), e.g., a PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbin PC 17. In some embodiments, the methadone formulation comprises about 56% by weight methadone, the methadone formulation comprises about 1.5% by weight poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H—(OCH2CH2)x—(O—CH(CH3)CH2)y—(OCH2CH2)z—OH (where x and z are about 101, and y is about 56), e.g., poloxamer 407.

[0190] In some embodiments, the drug-eluting segment comprising the methadone formulation may be formed by extruding the methadone formulation, hi some embodiments, the methadone formulation may be extruded to form a drug-eluting segment or component comprising a circular, triangular, wedge- or pie-shaped, or square cross-section.

[0191] Examples of component amounts for some embodiments of methadone formulations are provided in the table below. In some embodiments, a methadone formulation is used in the drug-eluting segment (and no additional formulation is used), and these amounts correspond to the amounts in the drug-eluting segment. When ranges are provided, the amounts are given as approximate weight percent, with the understanding that the amounts are selected to add up to 100%. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt thereof.

[0192] [Table 7]

[0193] In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5 to about 90% of the total methadone content of the drug eluting segment within the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85% or more of the total methadone content of the drug eluting segment within the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total methadone content of the drug eluting segment within the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5 to about 90% of the total methadone content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85% or more of the total methadone content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total methadone content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5 to about 70% of the total methadone content of the drug eluting segment after the first 48 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65% or more of the total methadone content of the drug eluting segment after the first 48 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total methadone content of the drug eluting segment after the first 48 hours of dwell.In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5 to about 50% of the total methadone content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total methadone content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total methadone content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5 to about 30% of the total methadone content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5, 10, 15, 20, or 25% or more of the total methadone content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 30, 25, 20, 15, or 10% or less of the total methadone content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5 to about 20% of the total methadone content of the drug eluting segment after the first 120 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 5, 10, or 15% or more of the total methadone content of the drug eluting segment after the first 120 hours of dwell. In some embodiments, the drug eluting segment comprising a methadone formulation may release about 20, 15, or 10% or less of the total methadone content of the drug eluting segment after the first 120 hours of dwell.

[0194] In some embodiments, the length of the drug eluting segment can be 1 to 16 mm, 10 to 14 mm, or 4 to 8 mm. In some embodiments, the length of the drug eluting segment can be 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 mm or less. In some embodiments, the length of the drug eluting segment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mm or more.

[0195] Rate-Controlling Polymer Membrane A release rate-controlling polymer membrane can be coated onto a component of a gastroretentive system that releases an agent, such as a drug. In some embodiments, the release rate-controlling polymer membrane controls the burst release of the active ingredient of the drug-eluting segment and linearizes the release of the active ingredient. Components coated with the release rate-controlling polymer membrane disclosed herein have substantially the same release rate characteristics before and after exposure to heat, which occurs during heat-assisted assembly of the gastroretentive system. The composition, parameters, advantages, features, uses, and release profiles of the release rate-controlling polymer membrane are disclosed in International Patent Application PCT / US2020 / 059541, which is incorporated herein in its entirety. In some embodiments, one or more segments of a composite arm (e.g., a composite arm including a drug-eluting segment or a composite arm excluding a drug-eluting segment) are coated with a release rate-controlling membrane. In some embodiments, the drug-eluting segment is coated with a release rate-controlling membrane.

[0196] In some embodiments, the drug-eluting segment of the gastroretentive system may comprise 1-30% by weight of the release rate controlling membrane. In some embodiments, the drug-eluting segment of the gastroretentive system may comprise 5-15% by weight of the release rate controlling membrane. In some embodiments, the drug-eluting segment of the gastroretentive system may comprise 30, 25, 20, 15, 10, or 5% by weight or less of the release rate controlling membrane. In some embodiments, the drug-eluting segment of the gastroretentive system may comprise 1, 5, 10, 15, 20, or 25% by weight or more of the release rate controlling membrane. In some embodiments, the amount of coating is measured as the coating weight gain. The coating weight gain (cwg) is measured when the coating or release rate controlling membrane is applied by a scalable spray coating process. The coating weight gain is the difference in weight of the drug-eluting segment before and after the addition of the coating (i.e., the release rate controlling membrane). The weight percentages provided above may be measured as the coating weight percentage gain.

[0197] A variety of polymers can be used to form the release rate controlling polymer membrane comprising PCL. In some embodiments, the release rate controlling polymer membrane comprises about 70% to about 80% by weight of PCL. In some embodiments, the release rate controlling polymer membrane comprises about 73% to about 77% by weight of PCL. In some embodiments, the release rate controlling polymer membrane comprises about 73.5% by weight of PCL. In some embodiments, the release rate controlling polymer membrane comprises about 80, 79, 78, 77, 76, 75, 74, 73, 72, or 71% by weight or less of PCL. In some embodiments, the release rate controlling polymer membrane comprises 70, 71, 72, 73, 74, 75, 76, 77, 78, or 79% by weight or more of PCL.

[0198] Other excipients can be added to the carrier polymer to modify the release of a drug, such as copovidone (VA64). In some embodiments, the release rate controlling polymer membrane comprises about 20% to about 30% by weight of VA64. In some embodiments, the release rate controlling polymer membrane comprises about 23% to about 27% by weight of VA64. In some embodiments, the release rate controlling polymer membrane comprises about 24.5% by weight of VA64. In some embodiments, the release rate controlling polymer membrane comprises 30, 29, 28, 27, 26, 25, 24, 23, 22, or 21% or less by weight of VA64. In some embodiments, the release rate controlling polymer membrane comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29% or more by weight of VA64.

[0199] In some embodiments, the release rate controlling polymer membrane comprises 1-5% by weight magnesium stearate. Magnesium stearate is a coating processing aid that prevents the arms from adhering to each other during spray coating. In some embodiments, the release rate controlling membrane comprises 5, 4, 3, or 2% by weight or less magnesium stearate. In some embodiments, the release rate controlling membrane comprises 1, 2, 3, or 4% by weight or more magnesium stearate.

[0200] The release rate-controlling membrane can be applied using a scalable spray coating process. The PCL of the coating firmly adheres to the PCL-based drug-polymer layer, providing a diffusion barrier to transport and preventing the risk of burst release. The copovidone content can be adjusted (e.g., 24.5%) so that a coating of appropriate depth (weight percent) above the drug-polymer layer supports transport throughout the coating at a stable rate in various aqueous media. The sustained-release coating provides a rate-controlling membrane for drug transport from the drug-polymer layer, thereby linearizing the release rate of methadone HCl.

[0201] Gastric residence time The gastric retention time of the present system is controlled by the rate of degradation, weakening, or breakdown of the time-dependent polymer linker in the gastric retention system. The faster the degradation, weakening, or breakdown of the time-dependent polymer linker, the faster the system passes from the stomach. The retention time of a gastric retention system is defined as the time between administration of the system to the stomach and emptying of the system from the stomach. In one embodiment, the gastric retention system has a retention time of about 24 hours, or up to about 24 hours. In one embodiment, the gastric retention system has a retention time of about 48 hours, or up to about 48 hours. In one embodiment, the gastric retention system has a retention time of about 72 hours, or up to about 72 hours. In one embodiment, the gastric retention system has a retention time of about 96 hours, or up to about 96 hours. In one embodiment, the gastric retention system has a retention time of about 5 days, or up to about 5 days. In one embodiment, the gastric retention system has a retention time of about 6 days, or up to about 6 days. In one embodiment, the gastroretentive system has a retention time of about 7 days (about 1 week), or up to about 7 days (about 1 week). In one embodiment, the gastroretentive system has a retention time of about 10 days, or up to about 10 days. In one embodiment, the gastroretentive system has a retention time of about 14 days (about 2 weeks), or up to about 14 days (about 2 weeks).

[0202] 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.

[0203] 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.

[0204] 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.

[0205] The gastroretentive system releases a therapeutically effective amount of the drug (or salt thereof) for at least a portion of the residence time or duration that the system is present in the stomach. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 25% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 50% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 60% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 70% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 75% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 80% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the drug (or salt thereof) for at least about 85% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 90% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 95% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 98% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 99% of the residence time.

[0206] Methadone-containing gastroretentive systems In some embodiments, star-shaped dosage forms for administering methadone can comprise arms, which in turn comprise 1) a carrier polymer-drug arm segment, 2) one or more enteric linkers, 3) one or more time-dependent linkers, 4) an inactive segment, 5) one or more radioactive (inactive) segments, and / or 6) other optional spacers. The arms are connected to the elastomeric core in a star-shaped device configuration. Typically, six arms are used in star-shaped dosage forms. In some embodiments, when six arms are used in a star-shaped dosage form, any one of 1, 2, 3, 4, 5, or 6 arms comprises a carrier polymer-drug arm segment. In some embodiments, when six arms are used in a star-shaped dosage form, three arms comprise a carrier polymer-drug arm segment. In some embodiments, when six arms are used in a star-shaped dosage form, six arms comprise a carrier polymer-drug arm segment. In some embodiments, when six arms are used in a star-shaped dosage form, two arms comprise a carrier polymer-drug arm segment. In some embodiments where six arms are used in the star-shaped dosage form, four arms comprise a carrier polymer-drug arm segment.

[0207] The carrier polymer-drug arm segment of the methadone dosage form can comprise methadone (or a pharmaceutically acceptable salt thereof), polycaprolactone, and poloxamer 407 (P407). In some embodiments, six arms are typically used in a star-shaped dosage form, with one, two, three, four, five, or six of the arms comprising a carrier polymer-drug arm segment. In some embodiments, three of the arms comprise a carrier polymer-drug arm segment. In some embodiments, six of the arms comprise a carrier polymer-drug arm segment. In some embodiments, two of the arms can comprise a carrier polymer-drug arm segment. In some embodiments, four of the arms can comprise a carrier polymer-drug arm segment. In some embodiments, the arm that does not comprise a carrier drug-polymer segment instead comprises an inactive segment. In some embodiments, the total amount of drug contained in the dosage form is one, two, three, four, five, or six times the amount of drug contained in a single arm. In some embodiments, the total amount of drug contained in the dosage form is three times the amount of drug contained in a single arm. In some embodiments, the total amount of drug contained in the dosage form is six times the amount of drug contained in a single arm. In some embodiments, the total amount of drug contained in the dosage form is four times the amount of drug contained in a single arm. The total weight of methadone, a pharmaceutically acceptable salt of methadone, or a salt of methadone in the star-shaped dosage form can range from 10 mg to about 320 mg of methadone. In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system containing about 50 mg to about 300 mg of methadone. In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system containing about 320, 300, 280, 260, 240, 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, or 20 mg or less of methadone. In some embodiments, the dosage form for administration of methadone comprises a gastroretentive system comprising about 10, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 mg or more of methadone.

[0208] The inactive arm segments of the dosage form can comprise polycaprolactone (PCL), a radiopaque material, and optionally a colorant. The polycaprolactone used can have a viscosity of about 1.5 dL / g to about 1.9 dL / g, e.g., about 1.7 dL / g. The radiopaque material can be (BiO)2CO3. Any pharmaceutically acceptable colorant can be used. An example of a colorant that can be used includes FD&C Blue #5.

[0209] The non-active arm segment (eg, non-radioactive) may comprise polycaprolactone, copovidone (VA64), poloxamer (P407), and an optional colorant.

[0210] The enterodispersible matrix of the dosage form may comprise polycaprolactone (PCL), hydroxypropylmethylcellulose acetate succinate (HPMCAS), poloxamer 407 (P407), and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dL / g to about 1.9 dL / g, for example, about 1.7 dL / g. The HPMCAS used may be MG grade (M grade: about 7-11% acetyl content, about 10-14% succinoyl content, about 21-25% methoxyl content, about 5-9% hydroxypropoxy content; G grade: granular). Any pharmaceutically acceptable colorant may be used. An example of a colorant that can be used is iron oxide.

[0211] The time-dependent disintegrating matrix of the methadone dosage form can comprise poly(D,L-lactide-co-glycolide) (PLGA), polyethylene oxide (PEO), and optionally a colorant. The poly(D,L-lactide-co-glycolide) can have a viscosity range of about 0.32 to 0.44 dL / g with a lactide:glycolide molar ratio of about 75:25. The polyethylene oxide used can have a viscosity of about 60,000 MW to about 125,000 MW, e.g., about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0212] The central elastomer of the methadone dosage form can have a durometer hardness of about 40 A to about 60 A, for example, a durometer hardness of about 45 A to about 55 A, or a durometer hardness of about 50 A. The central elastomer can be made from a liquid silicone rubber, for example, the central elastomer can include cured liquid silicone rubber.

[0213] In some embodiments, the assembled arms of the methadone gastric retention dosage form can be attached to the central elastomer with a polymer linker segment. The polymer linker segment can serve as the point of attachment between the assembled arms and the central elastomer. In some embodiments, the polymer linker segment can attach the central elastomer to the time-dependent disintegrating matrix segment of the arms. In some embodiments, the polymer linker comprises a polycaprolactone such as PCL, e.g., Corbin PC17, having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g. In some embodiments, the polymer linker is adjacent to the central elastomer.

[0214] In some embodiments, the gastroretentive system further comprises a release rate controlling membrane comprising about 73.5% by weight of polycaprolactone (PCL), e.g., PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbion PC17. In some embodiments, the release rate controlling membrane further comprises about 24.5% by weight of copovidone, e.g., VA64. In some embodiments, the release rate controlling membrane further comprises about 2.0% by weight of magnesium stearate.

[0215] Examples of amounts of various components of dosage forms are set forth in the table below: Where ranges are provided, the amounts are given as approximate weight percentages, with the understanding that the amounts are selected to add up to 100%.

[0216] [Table 8]

[0217] [Table 9]

[0218] [Table 10]

[0219] [Table 11]

[0220] The assembled arms comprise 1) a polymer linker segment, 2) a first degradable matrix segment, 3) a second degradable matrix segment, 4) a first inactive segment, and 5) a drug eluting segment, where the drug eluting segment comprises a carrier polymer and methadone or a salt thereof, which can be arranged in various orders, starting from the proximal end attached to the central elastomer and proceeding to the distal end: (polymer linker segment) (first degradable matrix segment) (second degradable segment) (first inactive segment) (drug eluting segment).

[0221] In some embodiments, one or more arms of the gastroretentive system may not include a drug eluting segment. For example, an arm assembled without a drug eluting segment may include 1) a polymer linker segment, 2) a first degradable matrix segment, 3) a second degradable segment, and 4) a first inactive segment, which may be arranged in various orders. One such order begins at the proximal end attached to the central elastomer and proceeds to the distal end: (polymer linker segment) (first degradable matrix segment) (first inactive segment) (second degradable segment) (first inactive segment).

[0222] The approximate dimensions of the segment lengths on each arm are shown below: An optional rPCL spacer (inactive segment) about 0.2-2 mm, e.g., about 0.5 mm wide, can be inserted between any two of the following components, or added to the outer tip of the assembled arm, or between the inner tip of the assembled arm and the elastomer core.

[0223] [Table 12]

[0224] Examples of gastroretentive systems The following gastroretention systems are examples to better illustrate certain embodiments of the systems described herein. These examples are merely illustrative and are not intended to limit the gastroretention systems described herein. Those skilled in the art will be able to contemplate additional configurations of gastroretention systems in light of the disclosure provided.

[0225] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug-eluting segment, wherein the arm comprises: (a) a polymeric linker segment according to any of the above embodiments; (b) a time-disintegrating matrix according to any of the above embodiments; (c) a first inactive segment according to any of the above embodiments; (d) an enteroerodible matrix according to any of the above embodiments; (e) a first inactive segment according to any of the above embodiments; and (f) a drug-eluting segment according to any of the above embodiments. The polymeric linker can be attached to the central elastomer. In some embodiments, a second inactive segment can be located between the enteroerodible segment and the first inactive segment.

[0226] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, wherein the arm can be attached to a central elastomer, and the arm comprises one or more of: (a) a polymer linker segment, (b) a time-disintegrating matrix, (c) a first inactive segment, (d) an enteroerodible matrix, (e) a first inactive segment, and (f) a drug eluting segment, wherein: the central elastomer comprises a liquid silicone rubber (LSR) having a durometer hardness of about 40 to about 65; (a) the polymer linker segment comprises 100% by weight of PCL; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 10% to about 25% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color-absorbing dye E172; (c) the first inactive segment comprises about 65% to about 75% by weight of PCL and about 25% to about 35% by weight of (BiO)CO; (d) the enterodisintegrable matrix comprises about 60% to about 70% by weight of HPMCAS, about 30% to about 40% by weight of PCL, and about 0.5% to about 5% by weight of a poloxamer (e.g., P407), and optionally about 0.01% to about 0.5% by weight of an iron oxide (e.g., E172); (e) a first inactive segment comprising about 60% to about 70% by weight of PCL, and about 25% to about 40% by weight of VA64, about 0.5% to about 2.5% by weight of P407, and about 0.005% to about 0.2% by weight of a pigment or colorant; (f) The drug-eluting segment comprises about 50% to about 60% by weight methadone, about 35% to about 50% by weight PCL, and about 0.5% to about 5% by weight P407.

[0227] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, wherein the arm can be attached to a central elastomer, and the arm comprises one or more of: (a) a polymer linker segment, (b) a time-disintegrating matrix, (c) a first inactive segment, (d) an enterodisintegrating matrix, (e) a first inactive segment, and (f) a drug eluting segment, wherein: the central elastomer comprises a liquid silicone rubber (LSR) having a durometer hardness of about 45 to about 55; (a) the polymer linker segment comprises 100% by weight of PCL; (b) a time-dependent disintegrating matrix comprising about 43% to about 47% by weight of PCL, about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15% to about 20% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of a color absorbing dye E172; (c) the first inactive segment comprises about 68% to about 72% by weight of PCL and 28% to about 32% by weight of (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 37% by weight of PCL, and about 1% to about 3% by weight of a poloxamer (e.g., P407), and optionally about 0.05% to about 0.15% by weight of an iron oxide (e.g., E172); (e) a first inactive segment comprising about 62% to about 68% by weight of PCL, and 30% to about 35% by weight of VA64, about 1% to about 2% by weight of P407, and about 0.01% to about 0.1% by weight of a pigment or colorant; (f) The drug-eluting segment comprises about 52% to about 58% by weight of methadone, about 40% to about 45% by weight of PCL, and about 1% to about 2% by weight of P407.

[0228] In some embodiments, the gastroretentive system comprises at least one arm comprising a drug eluting segment, wherein the arm can be attached to a central elastomer, and the arm comprises one or more of: (a) a polymer linker segment, (b) a time-disintegrating matrix, (c) a first inactive segment, (d) an enterodisintegrating matrix, (e) a first inactive segment, and (f) a drug eluting segment, wherein: the central elastomer comprises a liquid silicone rubber (LSR) having a durometer hardness of about 50; (a) the polymer linker segment comprises 100% by weight of PCL; (b) a time-dependent disintegrating matrix comprising about 44.95 wt. % PCL, about 35 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt. % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172; (c) the first inactive segment comprises about 68% to about 72% by weight of PCL and about 28% to about 32% by weight of (BiO)CO; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (e.g., P407), and optionally about 0.1% by weight iron oxide (e.g., E172); (e) a first, inactive segment comprising about 66.45% by weight of PCL, and about 32% by weight of VA64, about 1.5% by weight of P407, and about 0.05% by weight of a pigment or colorant; (f) The drug-eluting segment comprises about 55.9% by weight methadone, about 42.6% by weight PCL, and about 1.5% by weight P407.

[0229] In some embodiments, the gastroretentive system comprises at least one arm other than the drug-eluting segment, wherein the arm can be attached to a central elastomer, and the arm comprises one or more of: (a) a polymer linker segment; (b) a time-degradable matrix; (c) a first inactive segment; (d) an enteroerodible matrix; (e) a first inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a durometer hardness of about 40 to about 65; (a) the polymer linker segment comprises 100% by weight of PCL; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, about 30% to about 40% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 10% to about 25% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 0.5% to about 5% by weight of polyethylene glycol 100k, and about 0.005% to about 0.2% by weight of a color-absorbing dye E172; (c) the first inactive segment comprises about 65% to about 75% by weight of PCL and about 25% to about 35% by weight of (BiO)CO; (d) the enterodisintegrable matrix comprises about 60% to about 70% by weight of HPMCAS, about 30% to about 40% by weight of PCL, and about 0.5% to about 5% by weight of a poloxamer (e.g., P407), and optionally about 0.01% to about 0.5% by weight of an iron oxide (e.g., E172); (e) The first inactive segment comprises about 61% to about 71% by weight of PCL, about 27% to about 37% by weight of VA64, about 0.2% to about 4% by weight of P407, and about 0.005% to about 0.2% by weight of a pigment or colorant.

[0230] In some embodiments, the gastroretentive system comprises at least one arm other than the drug-eluting segment, wherein the arm can be attached to a central elastomer, and the arm comprises one or more of: (a) a polymer linker segment; (b) a time-degradable matrix; (c) a first inactive segment; (d) an enteroerodible matrix; (e) a first inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a durometer hardness of about 45 to about 55; (a) the polymer linker segment comprises 100% by weight of PCL; (b) a time-dependent disintegrating matrix comprising about 43% to about 47% by weight of PCL, about 33% to about 37% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 15% to about 20% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 1% to about 3% by weight of polyethylene glycol 100k, and about 0.01% to about 0.1% by weight of a color absorbing dye E172; (c) the first inactive segment comprises about 68% to about 72% by weight of PCL and 28% to about 32% by weight of (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 37% by weight of PCL, and about 1% to about 3% by weight of a poloxamer (e.g., P407), and optionally about 0.05% to about 0.15% by weight of an iron oxide (e.g., E172); (e) The first inactive segment comprises about 64% to about 69% by weight of PCL, about 30% to about 34% by weight of VA64, about 0.5% to about 2.5% by weight of P407, and about 0.01% to about 0.1% by weight of a pigment or colorant.

[0231] In some embodiments, the gastroretentive system comprises at least one arm other than the drug-eluting segment, wherein the arm can be attached to a central elastomer, and the arm comprises one or more of: (a) a polymer linker segment; (b) a time-degradable matrix; (c) a first inactive segment; (d) an enteroerodible matrix; (e) a first inactive segment; the central elastomer comprises a liquid silicone rubber (LSR) having a durometer hardness of about 50; (a) the polymer linker segment comprises 100% by weight of PCL; (b) a time-dependent disintegrating matrix comprising about 44.95 wt. % PCL, about 35 wt. % acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 18 wt. % copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dL / g, about 2 wt. % polyethylene glycol 100k, and about 0.05 wt. % color absorbing dye E172; (c) the first inactive segment comprises about 70 wt. % PCL and about 30 wt. % (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (e.g., P407), and about 0.1% by weight iron oxide (e.g., E172); (e) The first, inactive segment comprises about 66.45% by weight PCL, about 32% by weight VA64, about 1.5% by weight P407, and about 0.05% by weight pigment or colorant.

[0232] In any of the above embodiments, the arms may be attached to the central elastomer at the polymer linker segment, i.e., the polymer linker segment is at the proximal end of the arm.

[0233] In some embodiments, a dosage form for administration of methadone comprises a gastroretentive system, wherein the gastroretentive system comprises 1 to 5 inactive segments (e.g., one per arm, for a total of 1 to 5 arms, including an inactive segment). In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 66.45% by weight polycaprolactone (PCL), e.g., a PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbin PC17. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 32.0% by weight copovidone, e.g., VA64. In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 1.5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H-(OCHCH)-(O-CH(CH)CH)-(OCHCH)-OH, where x and z are about 101, and y is about 56, e.g., poloxamer 407 (P407). In some embodiments, the gastroretentive system comprises a first inactive segment comprising about 0.005% by weight of an iron oxide (e.g., E172).

[0234] In some embodiments, a gastroretentive system dosage form for administration of one or more pharmaceutical agents can comprise a radiopaque segment, wherein the segment comprises about 70% by weight polycaprolactone (PCL), e.g., PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, such as Corbin PC17. In some embodiments, the gastroretentive system comprises a radiopaque segment comprising about 30% by weight (BiO)2CO3. In some embodiments, the gastroretentive system comprises about 70% by weight Corbin PC17 and a radiopaque (inert) segment comprising 30% by weight (BiO)2CO3.

[0235] In some embodiments, a gastric retention system dosage form for administering methadone comprises a central elastomer. In some embodiments, the gastric retention system dosage form comprises a drug-eluting segment comprising about 46.6 mg of methadone per drug-eluting arm. In some embodiments, the gastric retention system dosage form comprises a drug-eluting segment comprising about 16.09 mg of methadone per drug-eluting arm. In some embodiments, the gastric retention system further comprises a release rate-controlling membrane comprising about 73.5% by weight of polycaprolactone (PCL), e.g., PCL having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g, e.g., Corbion PC17. In some embodiments, the release rate-controlling membrane further comprises about 24.5% by weight of copovidone, e.g., VA64. In some embodiments, the release rate-controlling membrane also comprises about 2% by weight of magnesium stearate. In some embodiments, the gastroretentive system further comprises a time-dependent disintegrating matrix comprising about 44.95% by weight of polycaprolactone (PCL), e.g., PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbion PC17. In some embodiments, the time-dependent disintegrating matrix further comprises about 35.0% by weight of an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio), e.g., PDLG5004A, having a viscosity midpoint of about 0.32 dL / g to about 0.48 dL / g (e.g., about 0.4 dL / g). In some embodiments, the time-dependent disintegrating matrix further comprises about 18.0% by weight of a copolymer of DL-lactide and glycolide (50 / 50 molar ratio), e.g., PDLG5004, having a viscosity midpoint of about 0.32 dL / g to about 0.48 dL / g (e.g., about 0.4 dL / g). In some embodiments, the time-dependent disintegrating matrix further comprises about 2.0% by weight of polyethylene glycol, such as polyethylene glycol with an average molecular weight of 100,000, e.g., PEO100K. In some embodiments, the time-dependent disintegrating matrix further comprises about 0.05% by weight of iron oxide, e.g., E172.In some embodiments, the gastroretentive system further comprises a pH-dependent disintegrating matrix comprising about 33.95% by weight of polycaprolactone (PCL), e.g., a PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbion PC17. In some embodiments, the pH-dependent disintegrating matrix further comprises about 63.95% by weight of hypromellose acetate succinate, e.g., HPMCAS-MG. In some embodiments, the pH-dependent disintegrating matrix further comprises about 2.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH (where x and z are about 101, and y is about 56), e.g., poloxamer 407 (P407). In some embodiments, the pH-dependent disintegrating matrix further comprises about 0.1% by weight of an iron oxide, e.g., E172. In some embodiments, the gastroretentive system further comprises one or more inactive segments. In some embodiments, the gastroretentive system further comprises a radiopaque segment comprising about 70% by weight polycaprolactone (PCL), e.g., PCL having a viscosity midpoint of about 1.5 dL / g to about 2.1 dL / g, e.g., Corbin PC17. In some embodiments, the radiopaque segment comprises about 30% by weight (BiO)2CO3. In some embodiments, the gastroretentive system further comprises one or more polymer linker segments comprising about 100% by weight polycaprolactone (PCL). In some embodiments, the polymer linker segments are located at the proximal ends of the arms and immediately adjacent to the central elastomer.

[0236] In some embodiments, the gastroretention system has one arm that includes a drug eluting segment and five arms that do not include a drug eluting segment. In some embodiments, the gastroretention system has two arms that include a drug eluting segment and four arms that do not include a drug eluting segment. In some embodiments, the gastroretention system has three arms that include a drug eluting segment and three arms that do not include a drug eluting segment. In some embodiments, the gastroretention system has four arms that include a drug eluting segment and two arms that do not include a drug eluting segment. In some embodiments, the gastroretention system has five arms that include a drug eluting segment and one arm that does not include a drug eluting segment. In some embodiments, the gastroretention system has six arms that include a drug eluting segment.

[0237] Central Elastomer The central elastomer provides the gastroretentive system with the ability to be compressed into a compressed form, which can be placed into a capsule or other suitable containment structure for administration to a subject.

[0238] In some embodiments, a dosage form for administration of one or more pharmaceutical agents comprises a gastroretentive system, wherein the gastroretentive system comprises a central elastomer comprising liquid silicone rubber (LSR). In some embodiments, the LSR has a durometer hardness of about 45 to about 60.

[0239] In some embodiments, a dosage form for administration of one or more pharmaceutical agents comprises a gastroretentive system, wherein the gastroretentive system comprises a central elastomer comprising liquid silicone rubber (LSR). In some embodiments, the LSR has a durometer hardness of about 45 to about 55.

[0240] In some embodiments, a dosage form for administration of one or more pharmaceutical agents comprises a gastroretentive system, wherein said gastroretentive system comprises a central elastomer comprising liquid silicone rubber (LSR). In some embodiments, the LSR has a durometer hardness of about 50. [Example]

[0241] The present disclosure is further illustrated by the following non-limiting examples.

[0242] Example 1: Methadone Dosage Form (Sustained Release Gastroretentive System) In this example, a dosage form according to the present invention comprises a gastroretentive system, said gastroretentive system being formulated to contain methadone.

[0243] The gastroretention system includes a central elastomer that provides the gastroretention system with the ability to be compressed into a compacted configuration. The gastroretention system illustrated in this example is another different arrangement of a "star" configuration. In one example of a methadone-loaded gastroretention system, the star includes six arms, each containing a drug-eluting segment.

[0244] Figure 3 is labeled to show the various elements of this configuration. System 300 includes a central elastomeric core 310 in the shape of a "star" with six short branches. Arm segment 380 is attached to one of the short star branches. Segment 380 is followed, in order, by segment 360, segment 370, segment 350, segment 330, and segment 340.

[0245] The average size of the gastroretentive systems is about 46 mm, with the length of each segment ranging from about 0.5 mm to about 11.8 mm. The table below provides a list of the length of each segment of the active arm (i.e., the arm containing the drug-eluting segment) in the gastroretentive systems. Each range or value below can be considered to be "about" the stated range or value, or to exactly match the stated range or value.

[0246] [Table 13]

[0247] The central elastomeric core 310 comprises liquid silicone rubber (LSR) having a 50 durometer hardness.

[0248] In this example, the dosage form provided herein includes six arms, each containing a drug-eluting segment, wherein the dosage form contains approximately 280 mg of methadone for administration. The methadone is contained in the carrier polymer-drug segment 340 (e.g., the drug-eluting segment). The drug-eluting segment contains approximately 55.9% by weight methadone, approximately 42.6% by weight Corbin PC17, and approximately 1.5% by weight P407. The present application also contemplates variations of this dosage form in which the number and / or length of the drug-eluting segments are increased to achieve higher doses of drug, e.g., methadone.

[0249] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 360, and a pH-dependent disintegration matrix or linker, referred to as segment 350. The gastroretentive system further comprises a structural segment 370 and a polymer linker segment 380.

[0250] The time-dependent disintegrating matrix (segment 360) comprises approximately 44.95% by weight of Corbin PC17, approximately 35% by weight of an acid-terminated copolymer of DL-lactide and glycolide (PDLG5004A), approximately 18% by weight of a copolymer of DL-lactide and glycolide (PDLG5004), approximately 2% by weight of polyethylene glycol 100k, and approximately 0.05% by weight of a color-absorbing dye E172. The pH-dependent disintegrating matrix (segment 350) comprises approximately 63.95% by weight of HPMCAS, approximately 33.95% by weight of Corbin PC17, approximately 2% by weight of P407, and approximately 0.1% by weight of a color-absorbing dye E172. The structural segment 370 can be a radiopaque PCL segment comprising approximately 70% by weight of PCL and approximately 30% by weight of (BiO)2CO3.

[0251] The inactive segment (segment 430) comprises about 66.45% by weight Corbin PC17, about 32.0% by weight VA64, about 1.5% by weight PCL, and about 0.05% by weight FD&C Blue 1 aluminum lake.

[0252] Segment 380 at the proximal end of each arm is a polymer linker segment comprising approximately 100% PCL by weight.

[0253] In some embodiments, each drug arm is coated with a release rate-controlling membrane. Specifically, the coating comprises about 73.5% by weight of Corbin PC17, about 24.5% by weight of VA64, and about 2% magnesium stearate, and is applied in an amount of about 5-20% of the pre-coat weight of the segment. In some embodiments, the release rate-controlling membrane may be applied in an amount of no more than 20, 18, 16, 14, 12, 10, 8, or 6% of the pre-coat weight of the segment. In some embodiments, the release rate-controlling membrane may be applied in an amount of no more than 5, 6, 8, 10, 12, 14, 16, or 18% of the pre-coat weight of the segment.

[0254] The gastroretentive system is assembled as described in Example 1 of International Patent Application No. PCT / US2020 / 059541 and then placed into an appropriately sized capsule. The dosage form described herein differs from the gastroretentive system previously described in International Patent Application No. PCT / US2020 / 059541 and from another gastroretentive system previously designated as LYN-005.

[0255] In another example of a gastroretentive system incorporating methadone, the star shape includes four arms each containing a drug-eluting segment and two arms without a drug-eluting segment. The present application also contemplates other gastroretentive systems including six arms, of which one, two, three, four, five, or six contain a drug-eluting segment.

[0256] The various elements of this configuration are labeled in Figure 4. System 400 includes a central elastomeric core 410 in the shape of a "star" with six short branches.

[0257] For the arm containing the drug-eluting segment, segment 480 of the arm is attached to one short star branch, followed in order by segment 460, first segment 470, segment 450, second segment 470, segment 430, and segment 440.

[0258] For arms that do not include a drug-eluting segment, segment 480 of the arm is attached to one short star branch, followed in order by segment 460, first segment 470, segment 450, second segment 470, and segment 430.

[0259] The average size of a gastroretentive system is about 46 mm, with the length of each segment ranging from about 0.5 mm to about 14 mm. The table below lists the length of each segment in a gastroretentive system. Each range or value below can be considered to be "about" the stated range or value, or to exactly match the stated range or value.

[0260] [Table 14]

[0261] The central elastomeric core 410 comprises liquid silicone rubber (LSR) having a 50 durometer hardness.

[0262] In this example, the dosage form provided herein includes six arms, four of which contain a drug-eluting segment, wherein the dosage form contains approximately 187 mg of methadone for administration. In some embodiments, each drug-eluting segment can contain approximately 46.7 mg of methadone HCl. In some embodiments, each drug-eluting segment can contain approximately 46.5 mg of levomethadone HCl. The methadone is contained in the carrier polymer-drug segment 440 (e.g., the drug-eluting segment). The drug-eluting segment contains approximately 55.9% by weight methadone, approximately 42.6% by weight Corbin PC17, and approximately 1.5% by weight P407. The present application also contemplates variations of this dosage form in which the number and / or length of the drug-eluting segments are increased to achieve higher doses of a drug, e.g., methadone.

[0263] The two drug-free arms each contain a larger inactive segment (segment 430) than the inactive segment of the drug-eluting segment. Inactive segments 430 each contain approximately 66.45% by weight Corbin PC17, approximately 32.0% by weight VA64, approximately 1.5% by weight P407, and approximately 0.05% by weight FD&C Blue 1 aluminum lake.

[0264] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 460, and a pH-dependent disintegration matrix or linker, referred to as segment 450. The gastroretentive system further comprises structural segment 470.

[0265] The time-dependent disintegrating matrix (segment 460) comprises approximately 44.95% by weight of Corbin PC17, approximately 35% by weight of an acid-terminated copolymer of DL-lactide and glycolide (PDLG5004A), approximately 18% by weight of a copolymer of DL-lactide and glycolide (PDLG5004), approximately 2% by weight of polyethylene glycol 100k, and approximately 0.05% by weight of a color-absorbing dye E172. The pH-dependent disintegrating matrix (segment 450) comprises approximately 63.95% by weight of HPMCAS, approximately 33.95% by weight of Corbin PC17, approximately 2% by weight of P407, and approximately 0.1% by weight of a color-absorbing dye E172 (iron tetroxide). The structural segment 470 can be a radiopaque PCL segment comprising approximately 70% by weight of PCL and approximately 30% by weight of (BiO)2CO3.

[0266] Segment 480 at the proximal end of each arm is a polymer linker segment comprising approximately 100% PCL by weight.

[0267] In some embodiments, each drug arm is coated with a release rate-controlling membrane. Specifically, the coating comprises about 73.5% by weight of Corbin PC17, about 24.5% by weight of VA64, and about 2% magnesium stearate, and is applied in an amount of about 5-20% of the pre-coat weight of the segment. In some embodiments, the release rate-controlling membrane may be applied in an amount of 20, 18, 16, 14, 12, 10, 8, or 6% or less of the pre-coat weight of the segment. In some embodiments, the release rate-controlling membrane may be applied in an amount of 5, 6, 8, 10, 12, 14, 16, or 18% or more of the pre-coat weight of the segment.

[0268] The gastroretentive system is assembled as described in Example 1 of International Patent Application No. PCT / US2020 / 059541 and then placed into an appropriately sized capsule. The dosage forms described herein differ from the gastroretentive system previously described in International Patent Application No. PCT / US2020 / 059541 and from another gastroretentive system previously designated as LYN-005.

[0269] In another example of a methadone-combined gastroretentive system, the star shape includes two arms each containing a drug-eluting segment and four arms without a drug-eluting segment. The present application also contemplates other gastroretentive systems including six arms, of which one, two, three, four, five, or six contain a drug-eluting segment.

[0270] Example 2: Methadone dosage form containing four arms containing drug-eluting segments (extended-release gastroretentive system) In this second example of a methadone dosage form, the dosage form includes a gastroretentive system, which is formulated to contain methadone. However, unlike the dosage form of Example 1, the dosage form of this example includes a total of six arms, only four of which each contain a drug-eluting segment. In this example, the dosage form includes a 187 mg dose of methadone.

[0271] The gastroretention system of Example 2 includes a central elastomer that provides the gastroretention system with the ability to be compressed into a compressed configuration.

[0272] The gastroretentive system of Figure 4 (as opposed to Figure 3) more closely resembles one containing a 187 mg dose of methadone. Figure 4 is labeled to show the various elements of the configuration. System 400 includes a central elastomeric core 410 that is in the shape of a "star" with six short branches.

[0273] For the arm containing the drug-eluting segment, segment 480 of the arm is attached to one short star branch, followed in order by segment 460, first segment 470, segment 450, second segment 470, segment 430, and segment 440.

[0274] For arms that do not contain a drug-eluting segment, segment 480 of the arm is attached to one short star branch. Segment 480 is followed, in order, by segment 460, first segment 470, segment 450, second segment 470, and segment 430. Segments 480, 460, 470, 450, and 430 correspond to segments 380, 360, 370, 350, and 330, respectively, in Figure 3.

[0275] The gastroretention system is assembled by placing a sleeve (size 0 capsule, transparent, body only) over the convergent distal ends of the star arms (when the star is in its compressed configuration). Once the sleeve is in place, the sleeved gastroretention system is encapsulated in a size 00EL white opaque (2% TiO2) capsule.

[0276] In another example of a methadone-containing gastroretentive system, the star shape includes two arms each containing a drug-eluting segment and four arms without a drug-eluting segment. The present application also contemplates other gastroretentive systems including six arms, of which one, two, three, four, five, or six comprise drug-eluting segments.

[0277] Example 3: Evaluation of methadone release from coated and uncoated dosage forms 5A and 5B show the methadone release profiles of different batches of gastroretentive systems containing the same methadone formulation. Specifically, the methadone combination formulations used in the dosage forms are as follows:

[0278] [Table 15]

[0279] Furthermore, all gastroretentive systems in this study had arms with wedge-shaped cross-sectional areas. The drug elution components for each study were as follows:

[0280] [Table 16]

[0281] Coating PC17 contains 73.5 wt% PCL, 24.5 wt% VA64, and 2 wt% magnesium stearate.

[0282] As shown in Figure 5A, the coated dosage form can delay methadone release by controlling the burst release from the drug-eluting segment. Furthermore, Figure 5B shows that for MET16DB1, a 7.0% PC17 coating linearized the release (relative to the target release), while for MET16DevRun, linearization of cumulative release occurred at a 13.6% PC17 coating.

[0283] Example 4: Comparison of release rate-controlling membrane coating weights Figure 6 shows the release profiles of gastroretentive dosage forms containing methadone and release rate-modifying membranes with various coating weights. As shown, Figure 6 shows the progression of linearization of cumulative release of methadone HCl when coated with 7.1 wt%, 10.8 wt%, 12.6 wt%, and 13.3 wt% PC17 coatings. The coated PC17 contains 73.5 wt% PCL, 24.5 wt% VA64, and 2 wt% magnesium stearate. The MET16 matrix coated with 13.6% PC17 provides the best linearized cumulative release profile (compared to the target release). The MET16 formulations of the tested gastroretentive systems are shown in the table below.

[0284] [Table 17]

[0285] Example 5: Testing of fed-fasting vehicles Figure 7 shows the methadone release profile of the gastroretentive system in different simulated gastric fluids. Fasted-state simulated gastric fluid (FaSSGF), fed, and fasted-state intestinal fluid (FaSSIF) were tested, as indicated. The gastroretentive systems tested included the methadone formulations described above in Examples 2 and 3. The drug-eluting segment was coated with a release rate-controlling membrane of 7 coating weight percent gain (cwg). The coating PC17 included 73.5 wt% PCL, 24.5 wt% VA64, and 2 wt% magnesium stearate.

[0286] Example 6: Day 0 and 3 Day EtOH Challenge Methadone release was tested in the presence of ethanol for gastroretentive systems containing methadone. The gastroretentive systems tested included methadone and the release rate controlling membranes described in Examples 2, 3, and 4 above.

[0287] Figures 8A and 8B show the results of the ethanol challenge on day 0. During this challenge, samples were initially incubated in FaSSGF for 2 hours. Next, samples were subjected to FaSSGF containing 5% or 20% EtOH. The medium was sampled every 30 minutes for 2 hours and replenished with the respective EtOH-supplemented FaSSGF medium. After the challenge, the medium was replaced with FaSSGF. Aliquots were subsequently taken at 6, 24, 48, 96, and 168 hours.

[0288] Figures 9A and 9B show the results of the ethanol challenge on day 3. Starting on the first day of the challenge, samples were subjected to initial FaSSGF incubation for three days. Aliquots were taken at 6, 24, and 48 hours. On day 3, an aliquot was taken at 72 hours, and the medium was replaced with FaSSGF supplemented with 5% or 20% EtOH for a total of two hours. The medium was sampled every 30 minutes and replenished with the respective EtOH-supplemented FaSSGF medium. After the challenge, the medium was replaced with FaSSGF. Aliquots were subsequently taken at 96 and 168 hours.

[0289] Example 7: Testing in Beagle Dogs The release of methadone administered in a gastroretentive dosage form was tested in beagle dogs as described below, and the results are shown in Figures 10B-10D.

[0290] Male beagle dogs were fasted overnight prior to dose administration.

[0291] Methadone HCl 10 mg tablets were administered orally on Study Day 1 and Study Day 8. For Study Day 8 dosing, dogs were treated with 50 mg fluconazole tablets 12 hours before and 12 hours after dosing. (Methadone is rapidly metabolized in dogs, so fluconazole (a CYP3A4 inhibitor) was administered to reduce this metabolism and allow for adequate plasma methadone quantitation. The IR data shown in the report are from Study Day 8.) Plasma samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, and 48 hours after dosing.

[0292] LYN-014-M containing 100 mg of methadone HCl was administered orally to dogs treated with fluconazole as described above on Study Day 22 and daily thereafter through Study Day 30. Plasma samples were collected pre-dose and at 2, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose. The arms of the LYN-014-M gastroretentive system are shown in Figure 10A (where 1090 represents the polycaprolactone segment, 1060 represents the time-dependent disintegrating matrix segment, 1070 represents the radiopaque PCL segment, 1050 represents the pH-dependent disintegrating matrix segment, 1030 represents the inactive segment, and 1040 represents the carrier polymer-drug segment). As shown, the drug-eluting segment contains 16.09 mg of methadone, and the arms include an inactive segment at the distal end (connected to the drug-eluting MET16-RB). Additionally, the star-shaped arms include a polymeric linking member (PCL) on the proximal end directly connected to the central elastomer (not shown), a time-disintegrating matrix segment connected to the polymeric linker, an inactive segment connected to the time-disintegrating matrix segment, an enterodisintegrating segment connected to the inactive segment, an inactive segment connected to the inactive segment, a drug-eluting segment connected to the inactive segment, and an inactive segment connected to the drug-eluting segment.

[0293] Sample extracts were prepared by protein precipitation from plasma, and methadone concentrations were measured using LC / MS / MS. Pharmacokinetic parameters were calculated by noncompartmental analysis.

[0294] The mean plasma PK parameters for methadone HCl (10 mg) and LYN-014-M (100 mg methadone) and individual plasma PK parameters are shown in the following table. As shown, after a single oral dose of a 10 mg methadone IR tablet, methadone was rapidly absorbed, reaching Tmax between 1 and 8 hours post-dose. The mean systemic exposure was 32.0 ng / mL and 317 h for Cmax and AUCtau, respectively. *ng / mL, with a mean half-life of 8 hours.

[0295] After a single oral dose of 100 mg of LYN-014-M, Cmax (29.5 ng / mL) was delayed (Tmax 24-144 hours) compared with IR (Tmax 1-8 hours). The dose-normalized AUCtau of the LYN-014-M dose was comparable to that of IR (average 28.2 hours for the LYN-014-M and IR forms, respectively). * ng / mL and 31.7h * ng / mL).

[0296] Thus, a single oral (PO) dose of LYN-014-M resulted in measurable plasma concentrations of methadone for more than 7 days after dosing in dogs. When compared to a single dose of methadone HClIR tablets, LYN-014-M demonstrated similar exposure as assessed by Cmax and AUC.

[0297] [Table 18]

[0298] [Table 19]

[0299] The table below shows the presence of the gastroretentive system in each of the six dogs (1006-1011) during the study period. "Days" (i.e., Days 1-28) are counted from the day the star was administered, counting as Day 1. "Test Days" (i.e., Test Days 22-49) are counted from the day the first IR methadone dose was administered. The number in the "Broken" cell refers to the number of arms still attached to the star in the stomach.

[0300] [Table 20]

[0301] [Table 21]

[0302] FIG. 10B shows plasma concentration versus time for a single oral dose of LYN-014-M (methadone 100 mg) over a 10-day period.

[0303] The plasma concentration versus time relationship for a single oral dose of methadone HCl (10 mg) is shown in Figure 10C.

[0304] The plasma concentration versus time relationship for a single oral dose of LYN-014-M (methadone 100 mg) over a 7-day period is shown in Figure 10D.

[0305] Example 7: Determination of release profiles using assay and purity methods Gastroretentive systems containing 187 mg levomethadone HCl ER capsules were tested for assay and purity after manufacture and repeated testing after 3 and 6 months of storage at 25°C / 60% RH and 3 months of storage at 30°C / 65% RH. The test methods used were consistent with the "Assay and Purity" method described in the "Release Profile Test Method" section below. The levomethadone HCl content at the initial test was 100% of the labeled content (187 mg). No significant changes were observed at 3 or 6 months. Levomethadone HCl degradants were not detectable initially or at any stable time point and were reported as less than 0.1% / not detected. The release profile of levomethadone HCl from the formulation remained controlled at all time points without burst.

[0306] [Table 22]

[0307] Example 8: Determination of release profile using chiral purity method Gastroretentive systems containing 187 mg levomethadone hydrochloride ER capsules were tested for chiral purity after manufacturing, and the test was repeated after 3 and 6 months of storage at 25°C / 60% RH, and after 3 months of storage at 30°C / 65% RH. The test method used was consistent with the "Chiral Purity" method described in the "Release Profile Test Method" section below. The amount of the opposite enantiomer, dextromethadone, remained constant at 0.2%. This level is observed in the purchased levomethadone hydrochloride drug substance, and its stability does not change during manufacturing.

[0308] [Table 23]

[0309] Example 9: Determination of release profiles using dissolution methods After manufacturing, dissolution was performed in a gastroretentive system containing 187 mg levomethadone hydrochloride ER capsules, and the test was repeated after 3 and 6 months of storage at 25°C / 60% RH and after 3 months of storage at 30°C / 65% RH. The test method used was consistent with the "Dissolution" method described in the "Release Profile Test Method" section below. As shown in Figure 11, no statistically significant trends were found. The release profile of levomethadone hydrochloride from the formulation remained controlled without burst at all time points.

[0310] Example 10: Determination of release profiles using in vitro release methods In vitro release testing by the "In Vitro Release (IVR)" test method described in the "Release Profile Test Method" section below was performed on the coated intermediates to evaluate the release profile in a gastric environment and determine the effect of the dosage form entering the intestine early while continuing to release drug. Testing was performed by starting in a biorelevant medium (FaSSGF) simulating fasted gastric conditions and transferring samples to a medium representing fasted intestinal conditions (FaSSIF) after 1, 3, or 5 days. As shown in Figure 12, no significant changes in the release profile were observed.

[0311] Release Profile Test Method Assay and Purity: A portion of the gastroretentive system or drug product containing the API (e.g., levomethadone hydrochloride) is cut / removed and dissolved in stabilized tetrahydrofuran. Ethanol is added as a countersolvent to obtain a 5% tetrahydrofuran 95% ethanol solution containing the API (e.g., levomethadone). The solution is diluted as necessary and filtered. Samples are analyzed for levomethadone hydrochloride content and degradation products by HPLC according to the method conditions in the table below. The detection limit for this method is 0.1% of the nominal levomethadone peak area.

[0312] [Table 24]

[0313] Chiral purity (method adapted from Ph.Eur. monograph): The portion of the gastroretentive system (or drug product) containing the API (e.g., levomethadone hydrochloride) is cleaved / removed from the drug product and dissolved in stabilized tetrahydrofuran. Mobile phase is added as a countersolvent to obtain a 5% tetrahydrofuran 95% mobile phase solution containing the API (e.g., levomethadone). The solution is diluted as necessary and filtered. The sample is analyzed by chiral HPLC to confirm the identity of the API (e.g., levomethadone) and to quantify the presence of the opposite enantiomer relative to the API (e.g., levomethadone) content. The HPLC method conditions are shown in the table below.

[0314] [Table 25]

[0315] Dissolution: Dissolutions performed on levomethadone drug products were performed according to USP standards using the dissolution parameters listed in the table below. <711> was completed according to the

[0316] [Table 26]

[0317] Samples are taken over a period of one week and analyzed by HPLC using the following conditions:

[0318] [Table 27]

[0319] In Vitro Release (IVR): IVR is performed on levomethadone intermediates in various biorelevant media. The term "intermediate" refers to the drug-loaded polymer segment (coated or uncoated), not the entire gastroretentive system. One drug-loaded polymer sample is added to 30 mL of biorelevant media and placed in a shaking incubator set at 37°C and 200 rpm. Samples are taken over 2-7 days and sampled for HPLC analysis (method conditions below). The sample is transferred to 30 mL of fresh media and returned to the shaking incubator to continue testing.

[0320] [Table 28]

[0321] [Table 29]

[0322] Embodiment 1. 1. A gastroretentive system comprising at least one drug-eluting component comprising methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer, and a release rate-controlling membrane coating the at least one drug-eluting component, wherein the gastroretentive system is configured to be retained in the stomach of a human body for at least 48 hours and to release methadone for at least 48 hours, and the at least one drug-eluting component with the release rate-controlling membrane is configured to release at least 10% of the methadone or salt thereof after the first 24 hours of residence in the stomach.

[0323] Embodiment 2. The gastroretentive system of embodiment 1, comprising 50-60% by weight of racemic methadone.

[0324] Embodiment 3. The gastroretentive system of embodiment 1, comprising 50-60% by weight of levomethadone.

[0325] Embodiment 4. A gastroretentive system according to any one of embodiments 1 to 3, comprising 1 to 2% by weight of poloxamer.

[0326] Embodiment 5. The gastroretentive system of any one of embodiments 1 to 4, wherein the poloxamer comprises P407.

[0327] Embodiment 6. A gastroretentive system described in any one of embodiments 1 to 5, wherein the release rate-controlling membrane comprises polycaprolactone, copovidone, and magnesium stearate.

[0328] Embodiment 7. The gastroretentive system of embodiment 6, wherein the release rate-controlling membrane comprises 60 to 90% by weight of polycaprolactone.

[0329] Embodiment 8. A gastroretentive system according to embodiment 6 or 7, wherein the release rate-controlling membrane comprises 70 to 75% by weight of polycaprolactone.

[0330] Embodiment 9. A gastroretentive system described in any one of embodiments 6 to 8, wherein the release rate-controlling membrane comprises 10 to 40% by weight of copovidone.

[0331] Embodiment 10. A gastroretentive system described in any one of embodiments 6 to 9, wherein the release rate-controlling membrane comprises 20 to 30% by weight of copovidone.

[0332] Embodiment 11. A gastroretentive system described in any one of embodiments 6 to 10, wherein the release rate-controlling membrane comprises 1 to 5% by weight of magnesium stearate.

[0333] Embodiment 12. A gastroretentive system described in any one of embodiments 6 to 11, wherein the release rate-controlling membrane comprises 1 to 3% by weight of magnesium stearate.

[0334] Embodiment 13. The gastroretentive system of any one of embodiments 1 to 12, wherein the at least one drug-eluting component comprises 20 mg to 50 mg of racemic methadone or a salt thereof.

[0335] Embodiment 14. The gastroretentive system of any one of embodiments 1 to 12, wherein the at least one drug-eluting component comprises 20 mg to 50 mg of levomethadone or a salt thereof.

[0336] Embodiment 15. A gastric retention system according to any one of embodiments 1 to 14, wherein the gastric retention system comprises a central elastomer and a plurality of arms, each of the plurality of arms comprising a proximal end (anchored to the central elastomer) and a distal end, wherein each of the plurality of arms extends radially from the central elastomer, and at least one of the plurality of arms comprises the at least one drug-eluting component.

[0337] Embodiment 16. A gastric retention system as described in embodiment 15, wherein the plurality of arms comprises six arms.

[0338] Embodiment 17. A gastroretentive system described in embodiment 15 or 16, wherein at least two arms of the plurality of arms comprise a drug-eluting component of the at least one drug-eluting component.

[0339] Embodiment 18. A gastroretentive system described in embodiment 15 or 16, wherein at least three arms of the plurality of arms comprise a drug-eluting component of the at least one drug-eluting component.

[0340] Embodiment 19. A gastroretentive system described in embodiment 15 or 16, wherein six arms of the plurality of arms contain a drug-eluting component of the at least one drug-eluting component.

[0341] Embodiment 20. A gastric retention system described in any of embodiments 15 to 19, wherein each arm of the plurality of arms comprises a polymer linker segment attached to the central elastomer, and the polymer linker segment comprises polycaprolactone.

[0342] Embodiment 21. The gastric retention system described in embodiment 20, wherein each arm of the plurality of arms comprises a first degradable matrix segment attached to the polymer linker segment, and the first degradable matrix segment comprises polycaprolactone, an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio), a copolymer of DL-lactide and glycolide (50 / 50 molar ratio), and polyethylene oxide.

[0343] Embodiment 22. The gastroretentive system described in embodiment 21, wherein each arm of the plurality of arms comprises a first inactive segment attached to the first disintegrable matrix segment, and the first inactive segment comprises polycaprolactone and (BiO)2CO3.

[0344] Embodiment 23. The gastric retention system described in embodiment 22, wherein each arm of the plurality of arms comprises a second disintegrable matrix segment attached to the first inactive segment, and the second disintegrable matrix segment comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0345] Embodiment 24. The gastroretentive system described in embodiment 23, wherein each arm of the plurality of arms comprises a non-active segment attached to the second disintegrable matrix segment, and the non-active segment comprises polycaprolactone, copovidone, and poloxamer.

[0346] Embodiment 25. A gastroretentive system as described in embodiment 24, wherein a drug-eluting arm of the plurality of arms comprises a drug-eluting component attached to the inactive segment.

[0347] Embodiment 26. A gastric retention system according to any one of embodiments 1 to 25, wherein the area under the curve of the gastric retention system is 1000 to 6000 hr·ng / ml.

[0348] Embodiment 27. A method of treating an opioid abuse disorder in an individual, comprising administering to the individual a gastroretentive system described in any one of Embodiments 1 to 26.

[0349] Embodiment 28. A method for making a gastroretentive system, comprising: extracting at least one drug-eluting component comprising methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer; and applying a release rate controlling membrane to the at least one drug-eluting component, wherein the gastroretentive system is configured to be retained in the stomach of a human body for at least 48 hours and to release methadone for at least 48 hours, and wherein the at least one drug-eluting component with the release rate controlling membrane is configured to release at least 10% of the methadone or salt thereof after the first 24 hours of residence in the stomach.

[0350] Embodiment 29. The method of embodiment 28, wherein the gastroretentive system comprises 50-60% by weight of racemic methadone.

[0351] Embodiment 30. The method of embodiment 28, wherein the gastroretentive system comprises 50-60% by weight of levomethadone.

[0352] Embodiment 31. The method of any one of embodiments 28 to 30, wherein the gastroretentive system comprises 1 to 2% by weight of poloxamer.

[0353] Embodiment 32. The method of any one of embodiments 28 to 31, wherein the poloxamer comprises P407.

[0354] Embodiment 33. The method of any one of embodiments 28 to 32, wherein the release rate-controlling membrane comprises polycaprolactone, copovidone, and magnesium stearate.

[0355] Embodiment 34. The method of embodiment 33, wherein the release rate-controlling membrane comprises 60 to 90% by weight of polycaprolactone.

[0356] Embodiment 35. The method of embodiment 33 or 34, wherein the release rate-controlling membrane comprises 70 to 75% by weight of polycaprolactone.

[0357] Embodiment 36. The method of any one of embodiments 33 to 35, wherein the release rate-controlling membrane comprises 10 to 40% by weight of copovidone.

[0358] Embodiment 37. The method of any one of embodiments 33 to 36, wherein the release rate-controlling membrane comprises 20 to 30% by weight of copovidone.

[0359] Embodiment 38. The method of any one of embodiments 33 to 37, wherein the release rate-controlling membrane comprises 1 to 5% by weight of magnesium stearate.

[0360] Embodiment 39. The method of any one of embodiments 33 to 38, wherein the release rate-controlling membrane comprises 1 to 3% by weight of magnesium stearate.

[0361] Embodiment 40. The method of any one of embodiments 28 to 39, wherein the at least one drug-eluting component comprises 20 mg to 50 mg of racemic methadone or a salt thereof.

[0362] Embodiment 41. The method of any one of embodiments 28 to 39, wherein the at least one drug-eluting component comprises 20 mg to 50 mg of levomethadone or a salt thereof.

[0363] Embodiment 42. The method of any of embodiments 28 to 41, wherein the gastric retention system comprises a central elastomer and a plurality of arms, each of the plurality of arms comprising a proximal end (anchored to the central elastomer) and a distal end, wherein each of the plurality of arms extends radially from the central elastomer, and at least one of the plurality of arms comprises at least one drug-eluting component.

[0364] Embodiment 43. The method of embodiment 42, wherein the plurality of arms comprises six arms.

[0365] Embodiment 44. The method of embodiment 42 or 43, wherein at least two arms of the plurality of arms comprise a drug-eluting component of the at least one drug-eluting component.

[0366] Embodiment 45. The method of embodiment 42 or 43, wherein at least three arms of the plurality of arms comprise a drug-eluting component of the at least one drug-eluting component.

[0367] Embodiment 46. The method of embodiment 42 or 43, wherein six arms of the plurality of arms comprise a drug-eluting component of the at least one drug-eluting component.

[0368] Embodiment 47. The method of any one of embodiments 42 to 46, wherein each arm of the plurality of arms comprises a polymer linker segment attached to a central elastomer, and the polymer linker segment comprises polycaprolactone.

[0369] Embodiment 48. The method of embodiment 47, wherein each arm of the plurality of arms comprises a first degradable matrix segment attached to a polymer linker segment, and the first degradable matrix segment comprises polycaprolactone, an acid-terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio), a copolymer of DL-lactide and glycolide (50 / 50 molar ratio), and polyethylene oxide.

[0370] Embodiment 49. The method of embodiment 48, wherein each arm of the plurality of arms comprises a first inert segment attached to the first disintegrable matrix segment, and the first inert segment comprises polycaprolactone and (BiO)2CO3.

[0371] Embodiment 50. The method of embodiment 49, wherein each arm of the plurality of arms comprises a second disintegrable matrix segment attached to the first inactive segment, and the second disintegrable matrix segment comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0372] Embodiment 51. The method of embodiment 50, wherein each arm of the plurality of arms comprises a non-effective segment attached to the second disintegrable matrix segment, and the non-effective segment comprises polycaprolactone, copovidone, and poloxamer.

[0373] Embodiment 52. The method of embodiment 51, wherein a drug-eluting arm of the plurality of arms comprises a drug-eluting component attached to the non-active segment.

[0374] Embodiment 53. The method of any one of embodiments 28 to 52, wherein the area under the curve of the gastroretention system is 1000 to 6000 hr·ng / ml.

[0375] Embodiment 54. 1. A gastroretentive system comprising a plurality of arms affixed to a central elastomer, at least one arm comprising a drug eluting component, each arm comprising a proximal end, a distal end, and an exterior surface therebetween, wherein the proximal end of each arm is attached to the elastomer component and projects radially from the elastomer component, and each arm has its distal end not attached to the elastomer component and located a greater radial distance from the elastomer component than the proximal end, wherein the at least one arm comprising a drug eluting component comprises a polymer linker segment, a first polymer linker segment attached to the polymer linker segment, a first inactive segment attached to the first disintegrating matrix segment; a second disintegrating matrix segment attached to the first inactive segment; an inactive segment attached to the second disintegrating matrix segment; and the drug-eluting component attached to the inactive segment, wherein the drug-eluting component comprises 50-60% by weight of methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer, and wherein the drug-eluting component further comprises a coating comprising a release rate-controlling polymer membrane.

[0376] The foregoing description has set forth example systems, methods, techniques, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of exemplary implementations.

[0377] In the description herein, terms such as first, second, etc. are used to describe various elements, but these elements should not be limited by these terms, and these terms are used only to distinguish one element from another.

Claims

1. at least one drug eluting component comprising methadone or a salt thereof, 35-50% by weight of polycaprolactone, and 0.5-3% by weight of poloxamer; a release rate controlling membrane coating said at least one drug eluting component, wherein the gastroretentive system is configured to remain in the stomach of a human body for at least 48 hours and to release methadone for at least 48 hours, and wherein the at least one drug-eluting component having a release rate controlling membrane is configured to release at least 10% of the methadone or a salt thereof after the first 24 hours of retention in the stomach.

2. 10. The gastroretentive system of claim 1, comprising 50-60% by weight of racemic methadone.

3. 10. The gastroretentive system of claim 1 comprising 50-60% by weight of levomethadone.

4. 2. The gastroretentive system of claim 1, comprising 1-2% by weight of poloxamer.

5. The gastroretentive system of claim 1 , wherein the poloxamer comprises P407.

6. 2. The gastroretentive system of claim 1, wherein the release rate controlling membrane comprises polycaprolactone, copovidone, and magnesium stearate.

7. The gastroretentive system of claim 6, wherein the release rate controlling membrane comprises 60-90% by weight of polycaprolactone.

8. The gastroretentive system of claim 6 or 7, wherein the release rate controlling membrane comprises 70-75% by weight of polycaprolactone.

9. The gastroretentive system of claim 6, wherein the release rate controlling membrane comprises 10-40% by weight of copovidone.

10. The gastroretentive system of claim 6, wherein the release rate controlling membrane comprises 20-30% by weight of copovidone.

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