Gastroretentive systems containing buprenorphine and naloxone

Abstract

A gastroretentive system is provided, comprising at least one co-extruded drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and a rate controlling release membrane coating the at least one co-extruded drug eluting component. The gastroretentive system comprising 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 buprenorphine for at least 48 hours, such that the at least one co-extruded drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of residence in the stomach and to release at least 10% of the naloxone 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 / 184,734, filed May 5, 2021, the entire contents of which are incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant No. 5UG3DA047709 awarded by the National Institutes of Health. The Government has certain rights in the invention.

[0003] Field The present disclosure relates to gastroretentive systems, and more particularly to gastroretentive systems comprising buprenorphine and naloxone. [Background technology]

[0004] Buprenorphine is an opioid medication used to treat opioid use disorder, acute pain, and chronic pain. When used to treat opioid use disorder, buprenorphine can be administered when a patient begins to experience withdrawal symptoms. However, buprenorphine is addictive, and patients may misuse it (i.e., overdose).

[0005] Therefore, buprenorphine is typically used in combination with naloxone. Naloxone is designed to rapidly reverse opioid overdoses. It is an opioid antagonist that binds to opioid receptors and can reverse and block the effects of opioids such as buprenorphine. Combining buprenorphine and naloxone such that the two are inseparable greatly reduces the potential for buprenorphine misuse. The buprenorphine and naloxone combination is typically administered sublingually (e.g., film, tablet). Summary of the Invention

[0006] Summary of disclosure Provided herein is a gastroretentive system comprising buprenorphine and naloxone. Buprenorphine, an opioid, can cause dependency in users and is prone to therapeutic errors (e.g., overdose). Therefore, buprenorphine is usually administered with naloxone, which blocks the action of opioids and reverses the effects of opioid overdose. This combined pharmaceutical composition (e.g., buprenorphine and naloxone) can provide the patient with the therapeutic effects of buprenorphine without the effects that can cause dependence or addiction. Thus, by administering buprenorphine with naloxone, the risk of developing a dependency on buprenorphine and / or overdose is reduced.

[0007] However, a challenge that arises with buprenorphine / naloxone combination dosage forms is that a user or patient may intentionally separate the naloxone from the dosage form and ingest only buprenorphine (e.g., an individual suffering from an opioid use disorder). In doing so, the user may obtain the high of buprenorphine because there is no naloxone present to block the effects of buprenorphine. It is therefore important to design dosage forms containing buprenorphine and naloxone in a manner that prevents or minimizes this possibility.

[0008] Thus, there is provided a gastroretentive system comprising buprenorphine and naloxone for use in treating patients with pain or opioid use disorder. Specifically, the gastroretentive system described herein is formulated to address and minimize the potential for abuse (i.e., removing and ingesting only buprenorphine).

[0009] To minimize the potential for abuse, buprenorphine and naloxone may be formulated within a single component of the gastroretentive system described herein. As described below, the gastroretentive system may include various components, each with a different function. For example, the components of the gastroretentive system provided herein may include a central elastomer and two or more elongated arms. Each elongated arm may include a time-dependent disintegrating matrix and / or an enteroerodible matrix. One or more arms of the gastroretentive system may include a drug-eluting component. As described herein, both buprenorphine and naloxone are provided within the same component of the gastroretentive system to minimize the potential for separation of buprenorphine and naloxone and subsequent therapeutic error (i.e., ingestion of buprenorphine alone). Alternatively, buprenorphine and naloxone may be formulated separately and provided within separate components of the gastroretentive system. However, providing buprenorphine and naloxone in separate components of a gastroretentive system allows a user to separate the two active ingredients and ingest buprenorphine without the naloxone simply by separating the two components from one another. Thus, by incorporating buprenorphine and naloxone in a single component of a gastroretentive system (e.g., a drug-eluting segment), it becomes much more difficult to physically separate these two active ingredients from one another.

[0010] In some embodiments, buprenorphine and naloxone are designed to be released at different rates in the stomach of a patient. For example, naloxone may be released faster than buprenorphine. In some embodiments, buprenorphine and naloxone are designed to be released at similar rates in the stomach of a patient. For example, if a user tries to separate buprenorphine from naloxone in a gastroretentive system by dissolving naloxone from the gastroretentive system outside the body, the user will not be able to recover the original amount of buprenorphine in both a gastroretentive system in which buprenorphine and naloxone have similar release profiles and a gastroretentive system in which buprenorphine and naloxone have different release profiles. If buprenorphine and naloxone have similar release profiles, little, if any, buprenorphine will remain after naloxone is completely dissolved. If naloxone is released faster than buprenorphine, then during the time it takes for all of the naloxone to dissolve from the gastroretentive system, a significant amount of the buprenorphine will have dissolved, and thus a significantly smaller amount of the original buprenorphine will remain. In either case, combining buprenorphine and naloxone in a single component of the gastroretentive system prevents the user from separately withdrawing the entire amount of buprenorphine from the naloxone in the gastroretentive system, minimizing the risk of abuse.

[0011] The gastroretentive system provided is designed to be swallowed by a patient in a compressed configuration and to open to an uncompressed configuration upon arrival in the patient's stomach. Once opened in the patient's stomach, the gastroretentive system will remain in the stomach until the gastric juices of the stomach break down the gastroretentive system, allowing it to pass through the remainder of the patient's gastrointestinal system. The gastroretentive system may include one or more linking moieties (e.g., linkers) that link the various components of the gastroretentive system together. The linking moieties include disintegrating matrices and are designed to dissolve or degrade in the presence of gastric juices 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 releases the active ingredients (i.e., buprenorphine and naloxone), dissociates, and is expelled from the patient after 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.

[0012] 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.

[0013] The three or more arms of the gastroretention system radiate from the central elastomer of the gastroretention system. One or more arms can contain active pharmaceutical ingredients (i.e., buprenorphine and naloxone). The number of active arms (i.e., one or more arms containing active pharmaceutical ingredients) can depend on the dosage of the gastroretention system. In some embodiments, the active arm contains a single buprenorphine / naloxone formulation. In some embodiments, the active arm contains a buprenorphine-naloxone combination formulation and a naloxone-only formulation that are coextruded to form one or more carrier polymer-drug segments (i.e., drug-eluting segments). The active arm is configured to release the buprenorphine / naloxone formulation once the gastroretention system reaches the patient's stomach.

[0014] Accordingly, provided herein is a gastroretentive system comprising buprenorphine and naloxone for use in treating patients with pain or opioid use disorder. The gastroretentive system described is formulated to address and minimize the potential for abuse (i.e., removal and ingestion of buprenorphine alone).

[0015] In some embodiments, a gastroretention system is provided, the gastroretention system comprising at least one co-extruded drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and a rate controlling release membrane coating the at least one co-extruded drug eluting component, wherein the gastroretention system is configured to be retained in a human stomach for at least 48 hours and to release buprenorphine for at least 48 hours, and the at least one co-extruded drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach and to release at least 10% of the naloxone or a salt thereof after the first 24 hours of retention in the stomach.

[0016] In some embodiments of the gastroretentive system, the rate controlling release membrane comprises polycaprolactone and copovidone.

[0017] In some embodiments of the gastroretentive system, the rate controlling release membrane comprises 60-90% by weight polycaprolactone.

[0018] In some embodiments of the gastroretentive system, the rate controlling release membrane comprises 10-40% copovidone by weight.

[0019] In some embodiments of the gastroretentive system, at least one co-extruded drug eluting component comprises a first co-extruded portion comprising naloxone and a second co-extruded portion comprising buprenorphine and naloxone.

[0020] In some embodiments of the gastroretentive system, the first coextruded portion is embedded in the second coextruded portion.

[0021] In some embodiments of the gastroretentive system, the first coextruded portion comprises one or more strands embedded within the second coextruded portion.

[0022] In some embodiments of the gastroretentive system, the first coextruded portion is layered over the second coextruded portion.

[0023] In some embodiments of the gastroretentive system, the first coextruded portion is present in a ratio of 4:1 to the second coextruded portion.

[0024] In some embodiments of the gastroretentive system, the first coextruded portion comprises 35-50% buprenorphine by weight.

[0025] In some embodiments of the gastroretentive system, the first coextruded portion comprises 2-7% naloxone by weight.

[0026] In some embodiments of the gastroretentive system, the first coextruded portion comprises 35-50% by weight polycaprolactone.

[0027] In some embodiments of the gastroretentive system, the first coextruded portion comprises polyethylene glycol and a poloxamer.

[0028] In some embodiments of the gastroretentive system, the second coextruded portion comprises 30-50% naloxone by weight.

[0029] In some embodiments of the gastroretentive system, the second coextruded portion comprises 50-60% by weight polycaprolactone.

[0030] In some embodiments of the gastroretentive system, the second coextrusion portion comprises a poloxamer.

[0031] In some embodiments of the gastroretentive system, at least one co-extruded drug eluting component comprises between 30 mg and 40 mg of buprenorphine or a salt thereof.

[0032] In some embodiments of the gastroretentive system, at least one co-extruded drug eluting component comprises between 8 mg and 15 mg of naloxone or a salt thereof.

[0033] In some embodiments of the gastric retention system, the gastric retention 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 co-extruded drug eluting component.

[0034] In some embodiments of the gastroretentive system, the plurality of arms comprises six arms.

[0035] In some embodiments of the gastroretentive system, at least two of the plurality of arms comprise at least one co-extruded drug eluting component.

[0036] In some embodiments of the gastroretentive system, at least three of the plurality of arms comprise at least one co-extruded drug eluting component.

[0037] In some embodiments of the gastroretentive system, six arms of the plurality of arms comprise at least one co-extruded drug eluting component.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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, said second disintegrable matrix segment comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0042] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a second inert segment attached to a second disintegrable matrix segment, the second inert segment comprising polycaprolactone and (BiO)2CO3.

[0043] In some embodiments of the gastroretentive system, a first arm of the plurality of arms comprises at least one co-extruded drug eluting component attached to a second inert segment.

[0044] In some embodiments of the gastroretentive system, a second arm of the plurality of arms comprises a non-active segment attached to a second inactive segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0045] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a third inactive segment attached to one of the co-extruded drug eluting components or the inactive segments, the third inactive segment comprising polycaprolactone and (BiO)2CO3.

[0046] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a third disintegrable matrix segment attached to a third inert segment, the third disintegrable matrix comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0047] In some embodiments of the gastroretention system, the gastroretention system comprises a filament circumferentially connecting each arm, where the circumferential filament is attached to a third disintegrable matrix segment in each arm.

[0048] In some embodiments, a method of treating an opioid abuse disorder in an individual is provided comprising administering to the individual a gastroretentive system.

[0049] In some embodiments, a method of treating pain in an individual is provided comprising administering to the individual a gastroretentive system.

[0050] In some embodiments, a gastroretention system is provided, the gastroretention system comprising at least one drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and a rate controlling release membrane coating the at least one drug eluting component, wherein the gastroretention system is configured to be retained in a human stomach for at least 48 hours and to release buprenorphine for at least 48 hours, and the at least one drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach and to release at least 10% of the naloxone or a salt thereof within the first 24 hours of retention in the stomach.

[0051] In some embodiments of the gastroretentive system, the rate controlling release membrane comprises polycaprolactone and copovidone.

[0052] In some embodiments of the gastroretentive system, the rate controlling release membrane comprises 60-90% by weight polycaprolactone.

[0053] In some embodiments of the gastroretentive system, the rate controlling release membrane comprises 10-40% copovidone by weight.

[0054] In some embodiments of the gastroretentive system, at least one drug eluting component comprises 35-50% buprenorphine by weight.

[0055] In some embodiments of the gastroretentive system, at least one drug eluting component comprises 2-7% naloxone by weight.

[0056] In some embodiments of the gastroretentive system, at least one drug eluting component comprises 35-50% by weight polycaprolactone.

[0057] In some embodiments of the gastroretentive system, at least one drug eluting component comprises polyethylene glycol and a poloxamer.

[0058] In some embodiments of the gastroretentive system, at least one drug eluting component comprises between 10 mg and 30 mg of buprenorphine or a salt thereof.

[0059] In some embodiments of the gastroretentive system, at least one drug eluting component comprises between 1 mg and 3 mg of naloxone or a salt thereof.

[0060] In some embodiments of the gastric retention system, the gastric retention 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.

[0061] In some embodiments of the gastroretentive system, the plurality of arms comprises six arms.

[0062] In some embodiments of the gastroretentive system, at least two of the plurality of arms comprise at least one drug eluting component.

[0063] In some embodiments of the gastroretentive system, at least three arms of the plurality of arms comprise at least one drug eluting component.

[0064] In some embodiments of the gastroretentive system, six arms of the plurality of arms comprise at least one drug eluting component.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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, the second disintegrable matrix segment comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0069] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a second inert segment attached to a second disintegrable matrix segment, the second inert segment comprising polycaprolactone and (BiO)2CO3.

[0070] In some embodiments of the gastroretentive system, a first arm of the plurality of arms comprises at least one drug eluting component attached to a second inactive segment.

[0071] In some embodiments of the gastroretentive system, a second arm of the plurality of arms comprises a non-active segment attached to a second inactive segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0072] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a third inactive segment attached to one of the drug eluting component or the inactive segment, the third inactive segment comprising polycaprolactone and (BiO)2CO3.

[0073] In some embodiments of the gastroretentive system, each arm of the plurality of arms comprises a third disintegrable matrix segment attached to a third inert segment, the third disintegrable matrix comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0074] In some embodiments of the gastroretention system, the gastroretention system comprises a filament circumferentially connecting each arm, the circumferential filament being attached to a third disintegrable matrix segment in each arm.

[0075] In some embodiments, a method of treating an opioid abuse disorder in an individual is provided comprising administering to the individual a gastroretentive system.

[0076] In some embodiments, a method of treating pain in an individual is provided comprising administering to the individual a gastroretentive system.

[0077] In some embodiments, a gastroretentive system is provided that comprises: 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 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; and wherein at least one arm comprising the drug eluting component comprises: a polymer linker segment, a first disintegrable matrix segment attached to the polymer linker segment, a first disintegrable matrix segment, a first inactive segment attached to the disintegrable matrix segment, a second inactive segment attached to the first inactive segment, a second inactive segment attached to the second disintegrable matrix segment, a drug eluting component attached to the second inactive segment, where the drug eluting component comprises a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and where the drug eluting component further comprises a coating comprising a release rate controlling polymer membrane; a third inactive segment attached to the drug eluting component; a third disintegrable matrix segment attached to the third inactive segment; and a filament circumferentially connecting each arm.

[0078] In some embodiments, a method of making a gastroretentive system is provided, the method comprising co-extruding at least one drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and applying a rate controlling release membrane to the at least one co-extruded drug eluting component, wherein the gastroretentive system is configured to be retained in a human stomach for at least 48 hours and to release buprenorphine for at least 48 hours, and wherein the at least one co-extruded drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach and to release at least 10% of the naloxone or a salt thereof after the first 24 hours of retention in the stomach.

[0079] In some embodiments of the method, the rate controlling release membrane comprises polycaprolactone and copovidone.

[0080] In some embodiments of the method, the rate controlling release membrane comprises 60-90% by weight polycaprolactone.

[0081] In some embodiments of the method, the rate controlling release membrane comprises 10-40% by weight copovidone.

[0082] In some embodiments of the method, the at least one co-extruded drug eluting component comprises a first co-extruded portion comprising naloxone and a second co-extruded portion comprising buprenorphine and naloxone.

[0083] In some embodiments of the method, co-extruding at least one drug eluting component comprises co-extruding a first co-extruded portion embedded in a second co-extruded portion.

[0084] In some embodiments of the method, co-extruding at least one drug eluting component comprises co-extruding strands of a first co-extruded portion embedded within a second co-extruded portion.

[0085] In some embodiments of the method, co-extruding at least one drug eluting component comprises co-extruding a first co-extruded portion layered onto a second co-extruded portion.

[0086] In some embodiments of the method, the first coextrusion portion is present in a 4:1 ratio to the second coextrusion portion.

[0087] In some embodiments of the method, the first coextrusion portion comprises 35-50% by weight buprenorphine.

[0088] In some embodiments of the method, the first coextrusion portion comprises 2-7% by weight naloxone.

[0089] In some embodiments of the method, the first coextrusion portion comprises 35-50% by weight polycaprolactone.

[0090] In some embodiments of the method, the first coextrusion portion comprises polyethylene glycol and a poloxamer.

[0091] In some embodiments of the method, the second coextrusion portion comprises 30-50% by weight naloxone.

[0092] In some embodiments of the method, the second coextrusion portion comprises 50-60% by weight polycaprolactone.

[0093] In some embodiments of the method, the second coextrusion portion comprises a poloxamer.

[0094] In some embodiments of the method, at least one co-extruded drug eluting component comprises between 30 mg and 40 mg of buprenorphine or a salt thereof.

[0095] In some embodiments of the method, at least one co-extruded drug eluting component comprises between 8 mg and 15 mg of naloxone or a salt thereof.

[0096] In some embodiments of the method, the gastric retention 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 co-extruded drug-eluting component.

[0097] In some embodiments of the method, the plurality of arms comprises six arms.

[0098] In some embodiments of the method, at least two of the plurality of arms comprise at least one co-extruded drug eluting component.

[0099] In some embodiments of the method, at least three of the plurality of arms comprise at least one co-extruded drug eluting component.

[0100] In some embodiments of the method, six of the plurality of arms comprise at least one co-extruded drug eluting component.

[0101] In some embodiments of the method, each arm of the plurality of arms comprises a polymer linker segment attached to the central elastomer, the polymer linker segment comprising polycaprolactone.

[0102] In some embodiments of the method, each arm of the plurality of arms comprises a first disintegrable matrix segment attached to a polymer linker segment, the first disintegrable 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.

[0103] 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.

[0104] In some embodiments of the method, each arm of the plurality of arms comprises a second disintegrable matrix segment attached to a first inactive segment, the second disintegrable matrix segment comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0105] In some embodiments of the method, each arm of the plurality of arms comprises a second inert segment attached to a second disintegrable matrix segment, the second inert segment comprising polycaprolactone and (BiO)2CO3.

[0106] In some embodiments of the method, a first arm of the plurality of arms comprises at least one co-extruded drug eluting component attached to a second inert segment.

[0107] In some embodiments of the method, a second arm of the plurality of arms comprises a non-active segment attached to a second inactive segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0108] In some embodiments of the method, each arm of the plurality of arms comprises a third inactive segment attached to one of the co-extruded drug eluting components or the inactive segments, the third inactive segment comprising polycaprolactone and (BiO)2CO3.

[0109] In some embodiments of the method, each arm of the plurality of arms comprises a third disintegrable matrix segment attached to a third inert segment, the third disintegrable matrix comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0110] In some embodiments of this method, the gastroretentive system comprises a filament circumferentially connecting each arm, where the circumferential filament is attached to a third disintegrable matrix segment in each arm.

[0111] In some embodiments, a method of making a gastroretentive system is provided, comprising: The method includes co-extruding at least one drug eluting component including a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, applying a rate controlling release membrane to the at least one drug eluting component, and applying a rate controlling release membrane to the at least one drug eluting component, wherein the gastroretentive system is configured to be retained in a stomach of a human body for at least 48 hours and to release buprenorphine for at least 48 hours, and the at least one co-extruded drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach and to release at least 10% of the naloxone or a salt thereof within the first 24 hours of retention in the stomach.

[0112] In some embodiments of the method, the rate controlling release membrane comprises polycaprolactone and copovidone.

[0113] In some embodiments of the method, the rate controlling release membrane comprises 60-90% by weight polycaprolactone.

[0114] In some embodiments of the method, the rate controlling release membrane comprises 10-40% by weight copovidone.

[0115] In some embodiments of the method, at least one drug eluting component comprises 35-50% buprenorphine by weight.

[0116] In some embodiments of the method, the at least one drug eluting component comprises 2-7% naloxone by weight.

[0117] In some embodiments of the method, the at least one drug eluting component comprises 35-50% by weight polycaprolactone.

[0118] In some embodiments of the method, the at least one drug eluting component comprises polyethylene glycol and a poloxamer.

[0119] In some embodiments of the method, at least one drug eluting component comprises between 10 mg and 30 mg of buprenorphine or a salt thereof.

[0120] In some embodiments of the method, the at least one drug eluting component comprises between 1 mg and 3 mg of naloxone or a salt thereof.

[0121] In some embodiments of the method, the gastric retention 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.

[0122] In some embodiments of the method, the plurality of arms comprises six arms.

[0123] In some embodiments of the method, at least two of the plurality of arms comprise at least one drug eluting component.

[0124] In some embodiments of the method, at least three arms of the plurality of arms comprise at least one drug eluting component.

[0125] In some embodiments of the method, six arms of the plurality of arms comprise at least one drug eluting component.

[0126] In some embodiments of the method, each arm of the plurality of arms comprises a polymer linker segment attached to the central elastomer, the polymer linker segment comprising polycaprolactone.

[0127] In some embodiments of the method, each arm of the plurality of arms comprises a first disintegrable matrix segment attached to a polymer linker segment, the first disintegrable 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.

[0128] 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.

[0129] In some embodiments of the method, each arm of the plurality of arms comprises a second disintegrable matrix segment attached to a first inactive segment, the second disintegrable matrix segment comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate, and poloxamer.

[0130] In some embodiments of the method, each arm of the plurality of arms comprises a second inert segment attached to a second disintegrable matrix segment, the second inert segment comprising polycaprolactone and (BiO)2CO3.

[0131] In some embodiments of the method, a first arm of the plurality of arms comprises at least one drug eluting component attached to a second inactive segment.

[0132] In some embodiments of the method, a second arm of the plurality of arms comprises a non-active segment attached to a second inactive segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0133] In some embodiments of the method, each arm of the plurality of arms comprises a third inactive segment attached to one of the drug eluting component or the non-active segment, the third inactive segment comprising polycaprolactone and (BiO)2CO3.

[0134] In some embodiments of the method, each arm of the plurality of arms comprises a third disintegrable matrix segment attached to a third inert segment, the third disintegrable matrix comprising polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0135] In some embodiments of this method, the gastroretentive system comprises a filament circumferentially connecting each arm, where the circumferential filament is attached to a third disintegrable matrix segment in each arm.

[0136] 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 in this specification.

[0137] 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 description of the drawings]

[0138] [Figure 1A] 1 illustrates a gastroretention system having a star configuration, according to some embodiments. [Figure 1B] 1 illustrates a gastroretention system in a folded configuration, according to some embodiments. [Figure 2A] 1 shows an example of a co-extrusion shape of a drug eluting segment according to some embodiments. [Figure 2B] 1 shows an example of a co-extrusion shape of a drug eluting segment according to some embodiments. [Figure 3A] 1 shows a gastroretention system having six active arms, according to some embodiments. [Figure 3B] 1 shows a gastroretention system having four active arms, according to some embodiments. [Figure 3C] 1 shows a gastroretention system having two active arms, according to some embodiments. [Figure 4A] 1 shows the BUP release profile of coated and uncoated drug eluting segments containing BUP-NAL combination formulations. [Figure 4B] 1 shows the NAL release profile of coated and uncoated drug eluting segments containing BUP-NAL combination formulations. [Figure 5A] 1 shows the release profile of a gastroretentive system comprising a buprenorphine-naloxone combination formulation, according to some embodiments. [Figure 5B] 1 shows the release profile of a gastroretentive system comprising a naloxone-only formulation, according to some embodiments. [Figure 6A] 1 shows the release profiles of gastroretentive systems comprising drug-eluting segments co-extruded with BUP-NAL combination formulations and NAL alone formulations, according to some embodiments. [Figure 6B] 1 shows the BUP:NAL mass ratio from the time of administration over a 7-day period for gastroretentive systems comprising drug-eluting segments co-extruded with BUP-NAL combination formulations and NAL alone formulations according to some embodiments. [Figure 7A] 1 shows the mean plasma buprenorphine concentrations in dog plasma following sublingual administration of BUP. [Figure 7B] 1 shows the mean plasma buprenorphine concentrations in dog plasma following administration of a gastroretentive system containing BUP-NAL. [Figure 7C] 1 shows the mean plasma concentrations of norbuprenorphine in dog plasma following administration of a gastroretentive system containing BUP-NAL. [Figure 8A]1 shows the mean buprenorphine plasma concentrations in cynomolgus monkeys following intravenous administration of BUP. [Figure 8B] 1 shows the mean buprenorphine plasma concentrations in cynomolgus monkeys after administration of a gastroretentive system containing BUP-NAL; and [Figure 8C] 1 shows the mean norbuprenorphine plasma concentrations in cynomolgus monkeys following administration of a gastroretentive system containing BUP-NAL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0139] Detailed Description of the Disclosure Described herein is a gastroretentive system comprising buprenorphine and naloxone for treating pain or opioid use disorder. Specifically, the gastroretentive system described is designed to minimize the potential for buprenorphine abuse. This can be accomplished by providing a dosage form comprising buprenorphine and naloxone that does not allow for extraction of buprenorphine and / or naloxone and does not allow buprenorphine to be taken separately.

[0140] The gastroretention system for administering buprenorphine and naloxone 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, and three or more arms may radiate from the central elastomer. The linkers may link two or more components of the gastroretention system together. For example, the linkers may connect the arms to the central elastomer. The linkers may also connect two arms to each other (e.g., function as elbows for the arms). In some embodiments, the active pharmaceutical ingredients (i.e., buprenorphine and naloxone) may be provided within the arms (i.e., active arms) of the star. The active arms may include a single buprenorphine-naloxone combination.

[0141] In some embodiments, the active arm may contain two separate formulations (a buprenorphine-naloxone combination formulation and a naloxone only formulation) that are co-extruded together to form a combined buprenorphine and naloxone formulation. In either case (i.e., a combined formulation that includes a buprenorphine-naloxone formulation, or a naloxone only formulation and a co-extruded buprenorphine-naloxone combination formulation), the likelihood that a user will be able to remove the naloxone from the dosage form and ingest only buprenorphine is small.

[0142] The following describes a gastric retention system for administering buprenorphine and naloxone to a patient. Specifically, the description provides: (1) definitions, (2) gastric retention system drug delivery mechanism, (3) gastric retention system configuration and components, (4) features for improved retention and drug release, (5) carrier polymer-drug segments comprising BUP-NAL combination formulations, (6) carrier polymer-drug segments formed by co-extrusion of a combination of BUP-NAL formulations and NAL alone formulations, (7) rate controlling polymer membranes, (8) gastric retention times, (9) gastric retention systems comprising BUP and NAL, and (10) examples.

[0143] definition A "carrier polymer" is a polymer suitable for blending with a substance, such as a drug, for use in a retention system.

[0144] A "pharmaceutical agent" is any substance intended for therapeutic, diagnostic, or nutritional use in a patient, individual, or subject. Pharmaceutical agents include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0145] A "dispersing agent" is defined as a substance that aids in minimizing the drug particle size and dispersing the drug particles in the carrier polymer matrix. That is, the dispersing agent helps to minimize or prevent particle aggregation or agglomeration during the manufacture of the system. Thus, the dispersing agent has anti-agglomeration and anti-coagulation activity and helps to maintain a uniform distribution of the drug particles in the carrier polymer matrix.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] As used herein, the "diameter" of a particle refers to the longest dimension of the particle.

[0150] 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.

[0151] "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 any of 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 to suppress the development of the disease or adverse symptoms of the disease. The difference between treating and suppressing is that treating occurs after adverse symptoms of the disease or disorder appear in a patient, whereas suppressing 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, so 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 at risk of developing clinical symptoms of a disease or disorder to inhibit the onset of any adverse symptoms.

[0152] 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 gastric retention system, the flexural modulus of the material of the polymeric material can also be measured alone. For example, the polymer linker of the gastric retention 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 gastric retention system. The flexural modulus is measured using a three-point bending test according to the ASTM Standard Three-Point Bend Test (ASTM D790) with a distance between supports of 10 mm, and is further modified to accommodate materials with non-rectangular cross sections. The flexural modulus should be measured with the longest line of symmetry of the cross section of the polymer linker placed vertically and a force applied downward. If the longest line of symmetry of the cross section of the polymer linker is perpendicular to one flat edge, one flat edge should be placed upward. If the cross section of the polymer linker is triangular, the apex of the triangle must face downward. The force and displacement when a downward force is applied are measured, and the bending modulus is calculated by finding the slope in the linear region.

[0153] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated or the context clearly dictates otherwise.

[0154] When a numerical value is expressed using the term "about" or "approximately" in this specification, it is understood that both the specified value and a value reasonably close to the specified value are included. For example, the description "about 50°C" or "approximately 50°C" includes both a disclosure of 50°C itself and a value close to 50°C. Thus, the phrase "about X" or "approximately X" includes a description of the value X itself. When a range is given, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C", it is understood that both values ​​specified at the endpoints are included, and values ​​close to each or both endpoints are included at each or both endpoints. That is, "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").

[0155] With respect to the numerical ranges disclosed herein, any disclosed upper limit for a component can be combined with any disclosed lower limit for that component to provide a range (provided that the upper limit is greater than the lower limit with which it is combined). Each of these combinations of the disclosed upper and lower limits is expressly contemplated herein. For example, if a range of the amount of a particular component is given as 10%-30%, 10%-12%, and 15%-20%, then the ranges of 10%-20% and 15%-30% are also contemplated, while the combination of a lower limit of 15% with an upper limit of 12% is not contemplated, as this is not possible.

[0156] Unless otherwise specified, the percentages of components in a composition are expressed as weight percent or weight / weight percent. It is understood that references to relative weight percentages in a composition assume that the combined total weight percentages of all components in the composition equal 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 equal 100, as long as the weight percentage of a particular component does not exceed the range limit specified for that component.

[0157] Some embodiments described herein are described as "comprising" or "comprises" with respect to various elements. In alternative embodiments, the elements can be described with the transitional phrase "consisting essentially of" or "consists essentially of" applied to those elements. In further alternative embodiments, the 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 the composition or method "consisting essentially of A and B," and alternative embodiments of the 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" with respect to various elements can also be described as "consisting of" as applied to those elements, and vice versa.

[0158] When a composition or system is described as "consisting essentially of" recited elements, the composition or system includes the elements explicitly recited 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 properties of the system being recited (for a composition that comprises a system). However, the composition or system either does not include other elements other than the elements explicitly recited (for compositions of a therapeutic system) that have a significant effect on the condition being treated, or does not include other elements that significantly affect the properties of the system (for compositions that constitute 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 properties of the system, the composition or system does not include the additional elements in a concentration or amount sufficient to significantly affect the condition being treated or the properties of the system. When a method is described as "consisting essentially of" recited steps, the method includes the recited steps and 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 steps explicitly recited that have a significant effect on the condition being treated or the properties of the system produced by the method.

[0159] 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 included within the scope of the present disclosure.

[0160] 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 entireties of which are incorporated by reference herein.

[0161] The following abbreviations are used for polymers and other components:

[0162] [Table 1]

[0163] PLURONIC® is a registered trademark of BASF Corporation for polyoxyalkylene ethers. In any formulation described herein using a trade name, the trade name can be replaced with a generic name. For example, a formulation described as containing 50% Corbion PC17 and 50% Corbion PC04 is understood to describe a formulation containing 50% polycaprolactone with a viscosity of 1.7 dl / g and 50% polycaprolactone with a viscosity of 0.4 dl / g.

[0164] Drug delivery mechanism of gastroretentive systems The gastric retention dosage form can be designed to be administered to the patient's stomach by swallowing, by a feeding tube, by a stomach tube, etc. In some embodiments, the gastric retention dosage form is folded into a compressed configuration and secured in a capsule. Once the gastric retention dosage form is in place in the stomach, the compressed form opens to a non-compressed form and can remain in the stomach for a desired retention time (e.g., 3 days, 7 days, 2 weeks, etc.). Once properly placed in the stomach, the gastric retention dosage form resists passage through the pyloric valve that separates the stomach from the small intestine. The gastric retention dosage form can release the therapeutic agent (i.e., API or drug) over the retention period by controlled release. While present in the stomach, the dosage form cannot 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 easily voided from the patient.

[0165] To administer the gastroretention system to a patient, the gastroretention system can be folded into a form small enough to be swallowed or otherwise administered. In some embodiments, the folded gastroretention system is held in a capsule or other container that the patient can swallow. In some cases, the gastroretention 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 gastroretention systems can be found in PCT / US2018 / 051816, WO2015 / 191920, WO2017 / 070612, WO2017 / 100367, WO2018 / 064630, WO2017 / 205844, WO2018 / 227147, each of which is incorporated herein in its entirety.

[0166] Once the gastric retention system reaches the patient's stomach, it can assume an open configuration. The dimensions of the open gastric retention system, if left unchanged, are suitable to prevent the device from passing through the pyloric valve for the period of time the device is intended to remain in the stomach. In some embodiments, the folded gastric retention system can also be secured by a dissolvable retention band or sleeve, which can prevent premature deployment of the gastric retention system in the event of capsule failure.

[0167] 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 impede the emptying of chyme (partially digested food) and other stomach contents from the stomach through the pyloric valve into the duodenum.

[0168] Once released from the capsule into the stomach, the therapeutic agent (e.g., buprenorphine, naloxone) of the gastroretentive system begins to take effect. In some embodiments, the gastroretentive system comprises a plurality of carrier polymer-drug components. The carrier polymer-drug components may comprise a carrier polymer, a pore-forming agent, and a therapeutic agent (or a salt thereof). The plurality of 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 gastric fluid of the patient over the desired residence time of the system. The release of the therapeutic agent is controlled by the proper formulation of the carrier polymer-drug components, by the use of a dispersing agent in the formulation of the carrier polymer-drug component, and by grinding the therapeutic agent into particles of the desired size before blending the drug with the carrier polymer and dispersing agent.

[0169] Additionally, a coating can be applied to the outer surface of the gastroretentive system. The coating 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.

[0170] Once the desired retention time has elapsed, the gastric retention system is discharged out of the stomach. To do so, various components of the gastric delivery 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 an intact, uncompressed, open configuration. However, the coupling polymer component of the gastric retention system is selected to degrade gradually 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 pieces. The reduced size dosage form and other small pieces are designed to pass through the pyloric valve. The system then passes through the intestine and is discharged 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 many small pieces.

[0171] Composition and components of the gastroretentive system The gastroretention system 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 system 100 is shown diagrammatically in FIG. 1A. A number of 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) that serves as a linker region. This configuration allows the system to be folded or compressed with 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. Upon reaching the stomach, the capsule dissolves, releasing the gastroretentive system. When freed from the constraint of the capsule or other container, the gastroretentive system expands to a non-compressed state and is retained in the stomach for the desired retention period.

[0172] Linker regions 104 are shown slightly larger in diameter than segments 102 and 103 in FIG. 1A, but they may be the same diameter as the segments, so that the entirety of arms 102-104-103 have a smooth outer surface.

[0173] In some embodiments, a star system may have an arm composed of only one segment attached to a central elastomer by a linker region. This corresponds to FIG. 1A with segment 103 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 disintegrable matrix.

[0174] A star system can be described as a gastroretentive system for administration to a patient's stomach, comprising an elastomer component and at least one carrier polymer-drug component comprising a carrier polymer and a drug or a salt thereof attached to the elastomer component, wherein each of the plurality of carrier polymer-drug components is an arm having a proximal end, a distal end, and an outer surface thereof, wherein the proximal end of each arm is attached to the elastomer component and projects radially from the elastomer component, and each arm having its distal end is not attached to the elastomer component and is located at a greater radial distance from the elastomer component than the proximal end, wherein each arm independently comprises one or more segments, each segment comprising a proximal end, a distal end, and an outer surface therebetween. In some embodiments, when there are two or more segments in an arm, each segment is attached to an adjacent segment via a linker region. In some embodiments, when there are two or more segments in an arm, one segment is attached directly to the other segment without the use of a linker region. The linker region may be a coupling polymer or a disintegrating matrix. The arms may be attached to the central elastomer via a coupling polymer or a degradable matrix and may have an intervening portion of an interfacial polymer. If there are a plurality of at least three arms, or multiple arms, the preferred number of arms is six, although 3, 4, 5, 7, 8, 9, or 10 arms may be used. The arms should be equally spaced around the periphery of the central elastomer. If there are N arms, there will be an angle of approximately 360 / N degrees between adjacent arms.

[0175] Coupling polymer / linker region The coupling polymer of the gastroretentive system, which functions as a linker region, is designed to degrade gradually in a controlled manner during the system's residence period 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 intestinal obstruction. This is easily accomplished 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 can prevent the undesired passage of the intact gastroretentive system into the small intestine. In the system shown in FIG. 1A, at least the coupling polymer used for coupling 104 is made from such an enteric polymer.

[0176] In additional embodiments, time-dependent coupling polymers or linkers can be used. Such time-dependent coupling polymers or linkers degrade in a predictable and time-dependent manner. In some embodiments, the degradation of time-dependent coupling polymers or linkers may not be affected by changes in pH of the gastrointestinal system.

[0177] 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.

[0178] 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, 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, 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).

[0179] Center 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 where desirable and practical.

[0180] The central elastomer must have a certain durometer hardness and compression set. Durometer hardness 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. The compression set should be as small as possible to avoid permanent deformation of the gastroretentive system when stored in a compressed configuration in a capsule. A preferred range is about 10% to about 20%. Liquid silicone rubber is a useful material for the central elastomer. An example of a material that meets these requirements is Dow Corning's QP1 series of liquid silicone rubber. In any embodiment that includes a central elastomer, QP1-270 (durometer hardness 70A) 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.).

[0181] Segment / Arm The segments and arms of the gastric retention system can have a cross-section in the shape of a circle (where the segment is cylindrical), a polygon (such as a segment having a triangular, rectangular, or square cross-section), or a pie-shaped cross-section (where the segment is cylindrical in cross-section). The segments having polygonal or pie-shaped cross-sections, and the ends of the cylindrical sections that will come into contact with the stomach tissue, can have sharp edges rounded to provide rounded corners and edges for increased in vivo safety. That is, instead of making 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 having an approximate triangular shape, such as a triangle with rounded corners. Arms with a triangular cross-section also include arms with rounded corners and arms with rounded corners at their tips. Rounded corners and edges are also referred to as fillet corners, filleted corners, fillet edges, or filleted edges.

[0182] In some embodiments, the star system is about 30 mm to about 60 mm when unfolded (with arms extended). In some embodiments, the star system is about 41 mm to about 51 mm when unfolded. In some embodiments, the star system is about 45 mm to about 47 mm when unfolded. In some embodiments, the star system is about 46 mm when unfolded.

[0183] Functions of the buprenorphine / naloxone gastroretentive system to enhance retention and drug release Retention of and drug release from a gastric retention system over a desired retention period can be improved and made more consistent by using the features described herein, such as filaments wrapped around and connecting the arms of the gastric retention system, the use of timed linkers and enteric linkers that allow for more precise retention and passage through the gastric retention system, and arms coated with release rate controlling polymeric membranes.

[0184] Circumferential filament A gastric retention system having filaments as described herein 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 provided herein including filaments may provide a more predictable and / or controllable gastric retention time. A gastric retention system having 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 having 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 of the gastroretentive dosage form is not delivered to the patient as intended.

[0185] 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. Additionally, early passage can cause inconsistency, making the system less reliable and less effective.

[0186] The characteristics of the circumferential filament are described in International Patent Application PCT / US2020 / 059541, which is incorporated herein by reference in its entirety.

[0187] Time-dependent linkers (time-degradable matrices) and enteric linkers (enteric degradable matrices) Polymer linkers (eg, timed linkers and / or enteric linkers) and time-dependent linkers are specifically described below.

[0188] Polymer Linkers The drug-containing structural member is attached to the second structural member (e.g., the central member, which may be an elastic central member) through one or more linkers. The polymer linker may be in direct contact with the drug-containing structural member or in contact with the drug-containing structural member through a coupling member. Similarly, the polymer linker may be in direct contact with the second structural member or in contact with the coupling member. In embodiments in which the drug-containing structural member is connected to the second structural member through two or more polymer linkers, the polymer linkers may be in direct contact with each other or in contact with each other through a coupling member. One or both of the enteric linker and the time-dependent linker may be used, or the polymer linker may function as both the enteric linker and the time-dependent linker.

[0189] 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, and the like. 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, about 2600μm to about 3000μm, about 2700μm to about 3000μm, about 2800μm to about 3000μm, or about 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, and about 2900 μm to about 3000 μm.The polymer linker may be about 100 μm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1000 μm, about 1100 μm, about 1200 μm, about 1300 μm, about 1400 μm, about 1500 μm, about 1600 μm, about 1700 μm, about 1800 μm, about 2000 μm, about 2200 μm, about 2400 μm, about 2600 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 μm, about 5900 μm, about 6000 μm, about 6100 μm, about 6200 μm, about The thickness may be about 100 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, where each of said values ​​may be plus or minus 50 μm (± 50 μm).

[0190] The cross-section of the polymer linker can be round (i.e., circular), elliptical, triangular, square, rectangular, pentagonal, hexagonal, or any other polymer shape. In some embodiments, the cross-section of the polymer linker is the same shape as the cross-section of the drug-containing structural member attached to the polymer linker. In some embodiments, the cross-section of the polymer linker has 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.

[0191] In some embodiments, the polymer linker may include polylactic acid (PLA), polycaprolactone (PCL), or another suitable polymer.

[0192] 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 gastroretention system is deployed in an individual's stomach. The time-dependent polymer linker controls the residence time of the gastroretention 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 gastroretention system to pass through the pyloric valve, exit the gastric environment, enter the small intestine, and ultimately be expelled from the body.

[0193] 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.

[0194] The time-dependent polymer linker may include poly(lactic acid-co-glycolide) (PLGA).

[0195] 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 ratio of lactide and glycolide monomers of about 50:50 (e.g., PLGA sold under the trade name Purasorb® PDLG5004, available from Corbion), and (b) an acid-terminated poly(D,L-lactic acid-co-glycolide) having a ratio of lactide and glycolide monomers of about 50:50 (e.g., PLGA sold under the trade name Purasorb® PDLG5004A, available from Corbion).

[0196] The one or more additional linker polymers included in the polymer linker can be homogeneously mixed with PLGA. In some embodiments, the one or more additional linker polymers are miscible with PLGA. The one or more additional linker polymers can be non-degradable polymers (i.e., do not degrade in stomach or intestinal environment, i.e., in aqueous solution at pH 1.6 (representing stomach environment) or pH 6.5 (representing 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.

[0197] 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, hi some embodiments, at least one common polymer is polycaprolactone (PCL).

[0198] In some embodiments, one or more additional linker polymers include PCL. The time-dependent polymer linker may be directly connected or bonded to another member of the gastric retention system (e.g., a structural member including a drug and a carrier polymer, a coupling member, an enteric polymer linker, or a central structural member), which may also include PCL, which may be the same PCL as in the time-dependent polymer linker or a different PCL from that in the polymer linker, and which may be at the same concentration or at different concentrations. The different PCL in the time-dependent polymer linker may differ from the other member directly connected or bonded to the time-dependent 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 time-dependent disintegrating matrix includes about 40% to about 50% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix includes about 43% to about 47% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix includes about 45% by weight of PCL. In some embodiments, the time-dependent disintegrating matrix comprises about 44.95% by weight PCL.

[0199] The time-dependent polymer linker may further comprise one or more plasticizers, such as polyethylene glycol. The term "polyethylene glycol" is used interchangeably herein with the terms "polyethylene oxide" and "PEO". In some embodiments, the molecular weight of the polyethylene glycol is about 90K to about 110K, e.g., 100k (also referred to as 100K or 100kDa). In some embodiments, the time-dependent disintegrating matrix comprises polyethylene glycol with a molecular weight of about 100k (polyethylene glycol 100k). In some embodiments, the time-dependent disintegrating matrix comprises about 0.5% 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.

[0200] In some embodiments, the time-dependent disintegrating matrix includes a color absorbing dye (also called a colorant or pigment). A color absorbing dye can be included to enhance the bond 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 include a color absorbing dye in an amount of up to about 5%, such as up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, up to about 0.1%, or up to about 0.05%. In some embodiments, the time-dependent disintegrating matrix includes about 0.005% to about 0.2% by weight of the color absorbing dye. In some embodiments, the time-dependent disintegrating matrix includes about 0.01% to about 0.1% by weight of the color absorbing dye. In some embodiments, the time-dependent disintegratable matrix comprises about 0.05% by weight of a color absorbing dye, hi some embodiments, the color absorbing dye is E172.

[0201] In one example of a time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 40% to about 50% by weight PCL, about 30% to about 40% by weight 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 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 polyethylene glycol 100k, and about 0.005% to about 0.2% by weight color absorbing dye E172.

[0202] In another example of the time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 43% to about 47% by weight PCL, about 33% to about 37% by weight 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 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 polyethylene glycol 100k, and about 0.01% to about 0.1% by weight color absorbing dye E172.

[0203] In another example of the time-dependent disintegrating matrix, the time-dependent disintegrating matrix comprises about 44.95% by weight PCL, about 35% by weight acid terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 18% by weight copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172.

[0204] In some embodiments, the 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 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 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% 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 (e.g., about 0.4 dl / g). In some embodiments, the gastroretentive system comprises about 2.0% by weight of polyethylene glycol, e.g., polyethylene glycol having an average molecular weight of 100,000 (e.g., PEO 100K In some embodiments, the gastroretentive system comprises a time-dependent disintegration matrix comprising about 0.05% 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 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 PEO. 100K and about 0.05% by weight of E172.

[0205] Exemplary amounts of components of the time-dependent disintegratable matrix are set forth 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%.

[0206] [Table 2]

[0207] Enterolytic matrix (enteric linker) The pH-dependent disintegration matrix provides a safety mechanism for the gastroretentive system. If the system leaves the stomach too early, 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, once the time-dependent disintegration matrix has degraded, dissolved, dissociated, or mechanically weakened in the gastric environment after passage through the gastroretentive system, exposure of the pH-dependent disintegration matrix to the high pH of the small intestine provides further weakening and / or destruction of the system, facilitating passage through the small intestine.

[0208] If a gastroretentive system passes through the small intestine in its native form too quickly, the system can be designed to degrade more quickly to avoid intestinal obstruction. This is accomplished 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., carrier polymer). The enteric polymer is relatively resistant to the acidic pH levels encountered in the stomach, but dissolves rapidly 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 an intact gastroretentive system into the small intestine. The use of an enteric polymer linker also provides a method for removing the gastroretentive system prior to 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.

[0209] The weakening or degradation of the enteric polymer linker can be measured by reference to the loss or destruction of the flexural modulus of the polymer linker under given conditions (e.g., intestinal conditions or gastric conditions). The enteric linker weakens, degrades, or is destroyed 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, and intestinal conditions can be simulated using an aqueous solution such as FaSSIF at pH 6.5 and 37°C.

[0210] In some embodiments, the enteric disintegrating matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, in some embodiments, the enteric disintegrating matrix comprises about 60% to about 70% by weight of HPMCAS. In some embodiments, the enteric disintegrating matrix comprises about 62% to about 66% by weight of HPMCAS. In some embodiments, the enteric disintegrating matrix comprises about 63.95% by weight of HPMCAS.

[0211] The enteric polymer is combined with one or more additional polymers (e.g., one or more carrier polymers) in the enteric linker, preferably in a homogeneous mixture. For example, the enteric polymer and the additional linker polymer can be homogeneously blended together before the mixture is extruded, and the extruded material is cut into the desired size for the 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 can 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)).

[0212] When at least one polymer is common to both adjacent members and the enteric polymer linker, the binding of the polymer linker to the directly adjacent member can be improved. 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 directly adjacent component (or optionally both directly adjacent components) of the gastroretentive system. For example, when the enteric polymer linker is directly attached to the structural member that includes a carrier polymer, in some embodiments, the one or more additional linker polymers also include 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), especially among those described herein.

[0213] In some embodiments, one or more additional linker polymers in the enteric linker include PCL. The enteric polymer linker may be directly connected or bonded to another member of the gastroretentive system (e.g., a structural member including a drug and a carrier polymer, a coupling member, a time-dependent polymer linker, or a central structural member), which may also include PCL, which may be the same PCL in the enteric polymer linker or a different PCL from that in the enteric polymer linker, and may be at the same concentration or a different concentration. The different PCL in the enteric polymer linker may differ from the other member directly connected 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 includes about 30% to about 40% by weight of PCL. In some embodiments, the enteric disintegrating matrix includes about 32% to about 37% by weight of PCL. In some embodiments, the enteric erodible matrix comprises about 34% PCL by weight.In some embodiments, the enteric erodible matrix comprises about 33.95% PCL by weight.

[0214] 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.

[0215] In some embodiments, the enterodisintegrable matrix includes a color absorbing dye (also called a colorant or pigment). A 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 may 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 may include 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 enterodisintegrable matrix includes the color absorbing dye triferric oxide from about 0.01% to about 0.2% by weight. In some embodiments, the enterodisintegrable matrix includes the color absorbing dye triferric oxide from 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 ferric oxide.

[0216] In some embodiments, the enterodisintegrable matrix comprises about 59% to about 69% HPMCAS, about 29% to about 39% PCL, and about 0.5% to about 5% poloxamer (e.g., P407) by weight. Optionally, the enterodisintegrable matrix further comprises an iron oxide, such as about 0.01% to about 0.2% iron oxide (e.g., E172) by weight.

[0217] In some embodiments, the enteric disintegrating matrix comprises about 62% to about 66% HPMCAS, about 32% to about 36% PCL, and about 1% to about 3% poloxamer (e.g., P407) by weight. Optionally, the enteric disintegrating matrix further comprises an iron oxide, such as about 0.05% to about 0.15% iron oxide (e.g., E172) by weight.

[0218] 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 an iron oxide, such as about 0.1% by weight iron oxide (e.g., E172).

[0219] 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 disintegration 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, such as Corbin PC17. In some embodiments, the gastroretentive system comprises a pH-dependent disintegration matrix comprising about 63.95% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the gastroretentive system comprises 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 are 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 disintegration 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 The composition comprises a pH-dependent disintegration matrix comprising PC17, about 63.95% by weight HPMCAS-MG, about 2.0% by weight P407, and about 0.1% by weight E172.

[0220] Exemplary amounts of components of an enteroerodible matrix are set forth 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%.

[0221] [Table 3]

[0222] Arm tip collapsible matrix In some embodiments, the gastroretentive system comprises an arm comprising a third disintegrable matrix in addition to the time-dependent disintegrable matrix and the enterodisintegrable matrix. In some embodiments, the third disintegrable matrix is ​​the filament-retaining segment (i.e., the segment to which the filament is attached). In some embodiments, the third disintegrable matrix is ​​the distal portion of the retention system arm, i.e., the tip of the arm.

[0223] In some embodiments, the third disintegrating matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, in some embodiments, the third disintegrating matrix comprises about 60% to about 70% by weight of HPMCAS. In some embodiments, the third disintegrating matrix comprises about 63% to about 67% by weight of HPMCAS. In some embodiments, the third disintegrating matrix comprises about 64.9% by weight of HPMCAS.

[0224] In some embodiments, the third disintegrating matrix comprises a polymer in common with one or other segments in the gastroretentive system arms. In some embodiments, the third disintegrating matrix comprises polycaprolactone (PCL). In some embodiments, the third disintegrating matrix comprises about 25% to about 35% by weight PCL. In some embodiments, the third disintegrating matrix comprises about 28% to about 32% by weight PCL. In some embodiments, the third disintegrating matrix comprises about 30% by weight PCL.

[0225] 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.

[0226] In some embodiments, the third disintegrating matrix can further include one or more plasticizers, such as propylene glycol. In some embodiments, the third disintegrating matrix includes about 1% to about 5% by weight of propylene glycol. In some embodiments, the third disintegrating matrix includes about 2% to about 3% by weight of propylene glycol. In some embodiments, the third disintegrating matrix includes about 2.5% by weight of propylene glycol.

[0227] In some embodiments, the third disintegrable matrix includes a color absorbing dye (also called a colorant or pigment). A color absorbing dye can be included to enhance the bond 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 include a color absorbing dye in an amount of up to about 5%, such as up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, or up to about 0.1%. In some embodiments, the third disintegrable matrix includes about 0.01% to about 0.5% by weight of the color absorbing dye. In some embodiments, the third disintegrable matrix includes about 0.05% to about 0.15% by weight of the color absorbing dye. In some embodiments, the third 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.

[0228] In some embodiments, the third disintegrable matrix comprises about 60% to about 70% HPMCAS, about 25% to about 35% PCL, about 1% to about 5% propylene glycol, and about 1% to about 5% stearic acid by weight. Optionally, the third disintegrable matrix further comprises about 0.01% to about 0.5% iron oxide by weight.

[0229] In some embodiments, the third disintegrable matrix comprises about 63% to about 67% HPMCAS, about 28% to about 32% PCL, about 2% to about 3% propylene glycol, and about 2% to about 3%. Optionally, the third disintegrable matrix further comprises about 0.05% to about 0.15% iron oxide by weight.

[0230] In some embodiments, the third disintegrating matrix comprises 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, and about 2.5% by weight stearic acid. Optionally, the third disintegrating matrix further comprises about 0.1% by weight iron oxide, such as about 0.025% ferric oxide, and about 0.075% FD&C Red 40.

[0231] Exemplary amounts of the components of the third disintegrable matrix are set forth 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%.

[0232] [Table 4]

[0233] 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.

[0234] In some embodiments, the inactive segment comprises a common polymer with other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 61% to about 71% by weight 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.

[0235] 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.

[0236] The inactive segment may further comprise one or more plasticizers, such as a poloxamer (e.g., poloxamer 407, or "P407"). In some embodiments, the inactive segment comprises about 0.2% to about 4% by weight of a poloxamer. In some embodiments, the inactive segment comprises about 0.5% to about 2.5% by weight of a poloxamer. In some embodiments, the inactive segment comprises about 1.5% by weight of a poloxamer.

[0237] In some embodiments, the inactive segment comprises a color absorbing dye (also called a colorant or pigment). The inactive segment may comprise a color absorbing dye in an amount of up to about 5%, for example, up to about 4%, up to about 3%, up to about 2%, up to about 1%, up to about 0.5%, up to about 0.3%, up to about 0.2%, up to about 0.1%, or up to about 0.05%. In some embodiments, the inactive segment comprises about 0.005% to about 0.2% by weight of the color absorbing dye. In some embodiments, the inactive segment comprises about 0.01% to about 0.1% by weight of the color absorbing dye. In some embodiments, the inactive segment comprises about 0.05% by weight of the color absorbing dye. In some embodiments, the color absorbing dye is FD&C Blue #1 Alum Lake.

[0238] In some embodiments, the inactive segment comprises about 61% to about 71% by weight PCL, about 27% to about 37% by weight copovidone, and about 0.2% to about 4% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.005% to about 0.2% by weight of the color absorbing dye FD&C Blue #1 Alum Lake.

[0239] In some embodiments, the inactive segment comprises about 64% to about 69% by weight PCL, about 30% to about 34% by weight copovidone, and about 0.5% to about 2.5% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.01% to about 0.1% by weight of the color absorbing dye FD&C Blue #1 Alum Lake.

[0240] In some embodiments, the inactive segment comprises about 66.45% by weight PCL, about 32% by weight copovidone, and about 1.5% by weight poloxamer. Optionally, the inactive segment further comprises a color absorbing dye, such as about 0.05% by weight of the color absorbing dye FD&C Blue #1 Alum Lake.

[0241] Exemplary amounts of components of one embodiment of the inactive segment (e.g., ineffective spacer) are shown in the following table: 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%.

[0242] [Table 5]

[0243] In some embodiments, the gastric retention system comprises one or more inactive segments, wherein the inactive segments comprise one or more radiopaque materials, hi some embodiments, the gastric retention system comprises one or more inactive segments, wherein the inactive segments are radiopaque segments.

[0244] In some embodiments, the inactive segment comprises a common polymer with other segments in the gastroretentive system. In some embodiments, the inactive segment comprises polycaprolactone (PCL). In some embodiments, the inactive segment comprises about 65% to about 75% by weight PCL. In some embodiments, the inactive segment comprises about 68% to about 72% by weight PCL. In some embodiments, the inactive segment comprises about 70% by weight PCL.

[0245] In some embodiments, the inactive segment comprises a radiopaque material. In some embodiments, the inactive segment comprises a radiopaque material, where the radiopaque material is (BiO)2CO3. In some embodiments, the inactive segment comprises (BiO)2CO3. In some embodiments, the inactive segment comprises about 25% to about 35% (BiO)2CO3 by weight. In some embodiments, the inactive segment comprises about 28% to about 32% (BiO)2CO3 by weight. In some embodiments, the inactive segment comprises about 30% (BiO)2CO3 by weight.

[0246] 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.

[0247] 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 percentages, with the understanding that the amounts are selected to add up to 100%.

[0248] [Table 6]

[0249] Carrier polymer containing a combination formulation of buprenorphine and naloxone - drug segment (drug eluting segment) The carrier polymer-drug segment or drug eluting segment releases the drug in a controlled manner during the period that the gastroretentive system is retained in the stomach. The carrier polymer is mixed with the drug and formed into segments that are then assembled with other components described herein to produce the gastroretentive system. Compositions of such carrier polymer-drug blends are provided below for certain drug formulations, including formulations that include a combination of buprenorphine and naloxone.

[0250] Both active agents, buprenorphine and naloxone, are incorporated into a single segment or component of the gastroretentive system, i.e., the drug-eluting segment. This is designed so that a user cannot easily tamper with the gastroretentive system to remove naloxone so that only buprenorphine can be ingested. Alternatively, the gastroretentive system can be designed such that buprenorphine and naloxone are provided as separate components of the gastroretentive system. However, this would facilitate tampering, as the user would be able to physically separate the two components (i.e., the buprenorphine component and the naloxone component) and ingest only the buprenorphine component. Thus, the described drug-eluting segment or component includes both buprenorphine and naloxone.

[0251] In some embodiments, the buprenorphine and naloxone of the drug eluting segment may be released at similar rates. In some embodiments, the buprenorphine and naloxone of the drug eluting segment may be released at different rates. For example, naloxone may be released from the drug eluting segment faster than buprenorphine. In either case, the fact that buprenorphine and naloxone are combined in a single component of the gastroretentive system (i.e., the drug eluting segment) greatly minimizes the separation of naloxone from buprenorphine by the user. For example, a user may attempt to elute naloxone from an external gastroretentive system and ingest the remaining buprenorphine. However, in a gastroretentive system in which buprenorphine and naloxone have similar release profiles, once naloxone is completely eluted, little, if any, buprenorphine remains. In the case of gastroretentive systems in which naloxone is released faster than buprenorphine, a significant amount of buprenorphine will dissolve in the time it takes for naloxone to completely dissolve from the gastroretentive system. Thus, the user will be left with significantly less buprenorphine than was originally present in the gastroretentive system. In either case, abuse of the gastroretentive system is minimized.

[0252] The dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 10 mg to about 150 mg of buprenorphine. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 40 mg to about 115 mg of buprenorphine. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 150, about 140, about 130, about 120, about 110, about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, or about 20 mg or less of buprenorphine. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, or about 140 mg or more of buprenorphine.

[0253] In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 1 mg to about 40 mg of naloxone. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 3.5 mg to about 10 mg of naloxone. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 mg or less of naloxone. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastric retention system comprising about 1, about 5, about 10, about 15, about 20, about 25, about 30, or about 35 mg or more of naloxone.

[0254] In some embodiments, the dosage form comprises a gastroretentive system, wherein the gastroretentive system comprises one or more drug eluting segments, each of the one or more drug eluting segments comprising about 10 mg to about 30 mg of buprenorphine and about 1 mg to about 5 mg of naloxone. In some embodiments, each drug eluting segment comprises no more than about 30, 25, 20, or 15 mg of buprenorphine. In some embodiments, each drug eluting segment comprises no less than about 10, 15, 20, or 25 mg of naloxone.

[0255] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 30% to about 55% buprenorphine by weight. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 55, about 50, about 45, about 40, or about 35% or less buprenorphine by weight. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 30, about 35, about 40, about 45, or about 50% or more buprenorphine by weight.

[0256] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.5% to about 10% naloxone by weight. In some embodiments, the buprenorphine-naloxone combination formulation comprises less than about 10, about 7.5, about 5, about 2.5, or about 1% naloxone by weight. In some embodiments, the buprenorphine-naloxone combination formulation comprises more than about 0.5, about 1, about 2.5, about 5, or about 7.5% naloxone by weight.

[0257] In some embodiments, the combination buprenorphine and naloxone formulation may include a naloxone (NAL) to buprenorphine (BUP) ratio of about 1:1 to about 1:20 NAL:BUP. In some embodiments, the ratio may be about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, or about 1:20 NAL:BUP. In some embodiments, the amount of buprenorphine in a combination formulation of buprenorphine and naloxone can be about 20, about 18, about 15, about 12, about 10, about 8, about 5, about 4, about 3, or about 2 times the weight of naloxone or less. In some embodiments, the amount of buprenorphine in a combination formulation of buprenorphine and naloxone can be about 1, about 2, about 3, about 4, about 5, about 8, about 10, about 12, about 15, or about 18 times the weight of naloxone or more. In some embodiments, the ratio of NAL:BUP can depend on the release characteristics of each active ingredient.

[0258] The buprenorphine-naloxone combination formulation comprises about 30% to 50% by weight polycaprolactone (PCL), such as a PCL having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g, such as Corbin PC 17. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 50, about 45, about 40, or about 35% by weight or less PCL. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 30, about 35, about 40, or about 45% by weight or more PCL.

[0259] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 1% to about 15% by weight polyethylene oxide (PEO) (e.g., PEO 100KIn some embodiments, the buprenorphine-naloxone combination formulation comprises about 15, about 12.5, about 10, about 7.5, about 5, or about 2.5% by weight or less of PEO. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 1, about 2.5, about 5, about 7.5, about 10, about 12.5% ​​by weight or more of PEO.

[0260] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 1% to about 5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407. In some embodiments, the buprenorphine-naloxone combination formulation comprises no more than about 5, about 4, about 3, or about 2% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as poloxamer 407. In some embodiments, the buprenorphine-naloxone combination formulation comprises 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.

[0261] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.1% to about 5% by weight of vitamin E succinate. In some embodiments, the buprenorphine-naloxone combination formulation may comprise about 5, about 4, about 3, about 2, about 1, about 0.5, or about 0.1% by weight or less of vitamin E succinate. In some embodiments, the buprenorphine-naloxone combination formulation may comprise about 0.01, about 0.1, about 0.5, about 1, about 2, about 3, or about 4% by weight or more of vitamin E succinate.

[0262] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.1% to about 1% by weight colloidal silicon dioxide (SiO2).

[0263] In some embodiments, where the buprenorphine-naloxone combination formulation comprises about 35% to about 50% buprenorphine by weight, the buprenorphine-naloxone combination formulation comprises about 1% to about 7% naloxone by weight, about 35% to about 58% polycaprolactone (PCL), such as a PCL having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g, such as Corbin PC 17. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 1% to about 15% PEO, such as PEO 100K In some embodiments, the buprenorphine-naloxone combination formulation comprises about 2% to about 4% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.2% to about 0.8% by weight of vitamin E succinate. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.2% to about 0.8% by weight of colloidal silicon dioxide (SiO2).

[0264] In some embodiments, the buprenorphine-naloxone combination formulation comprises about 42% by weight buprenorphine, said buprenorphine-naloxone combination formulation comprising about 3.7% by weight naloxone, 43.3% by weight polycaprolactone (PCL), such as a PCL having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g, such as Corbin PC 17. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 7% by weight PEO, such as PEO. 100KIn some embodiments, the buprenorphine-naloxone combination formulation comprises about 3.0% by weight of poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56, such as poloxamer 407. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.5% by weight of vitamin E succinate. In some embodiments, the buprenorphine-naloxone combination formulation comprises about 0.5% by weight of colloidal silicon dioxide (SiO2).

[0265] In some embodiments, the drug-eluting segment comprising the buprenorphine-naloxone combination formulation may be formed by extruding the buprenorphine-naloxone combination formulation, hi some embodiments, the buprenorphine-naloxone combination formulation may be extruded to form a drug-eluting segment or component comprising a circular, triangular, or square cross-section.

[0266] Examples of amounts of ingredients for some embodiments of buprenorphine-naloxone combination formulations are provided in the table below. In some embodiments, a buprenorphine-naloxone combination 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%. "Pharm. accept. salt" refers to a pharma- ceutically acceptable salt thereof.

[0267] [Table 7]

[0268] In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5 to about 90% of the total buprenorphine content of the drug eluting segment within the first 24 hours of residence. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination 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 buprenorphine content of the drug eluting segment within the first 24 hours of residence. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination 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 buprenorphine content of the drug eluting segment within the first 24 hours of residence. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5 to about 90% of the total buprenorphine content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination 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 buprenorphine content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination 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 buprenorphine content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising a combination buprenorphine-naloxone formulation may release from about 5 to about 70% of the total buprenorphine content of the drug eluting segment after the first 48 hours of residence.In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65% or more of the total buprenorphine content of the drug eluting segment after the first 48 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total buprenorphine content of the drug eluting segment after the first 48 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5 to about 50% of the total buprenorphine content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total buprenorphine content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total buprenorphine content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5 to about 30% of the total buprenorphine content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5, 10, 15, 20, or 25% or more of the total buprenorphine content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 30, 25, 20, 15, or 10% or less of the total buprenorphine content of the drug eluting segment after the first 96 hours of dwell.In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5 to about 20% of the total buprenorphine content of the drug eluting segment after the first 120 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5, 10, or 15% or more of the total buprenorphine content of the drug eluting segment after the first 120 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 20, 15, or 10% or less of the total buprenorphine content of the drug eluting segment after the first 120 hours of dwell.

[0269] In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release from about 5 to about 100% of the total naloxone content of the drug eluting segment within the first 24 hours of residence. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more of the total naloxone content of the drug eluting segment within the first 24 hours of residence. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total naloxone content of the drug eluting segment within the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0 to about 50% of the total naloxone content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total naloxone content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5% or less of the total naloxone content of the drug eluting segment after the first 24 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0 to about 50% of the total naloxone content of the drug eluting segment after the first 48 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total naloxone content of the drug eluting segment after the first 48 hours of dwell.In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5% or less of the total naloxone content of the drug eluting segment after the first 48 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0 to about 50% of the total naloxone content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total naloxone content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5% or less of the total naloxone content of the drug eluting segment after the first 72 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0 to about 50% of the total naloxone content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release about 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total naloxone content of the drug eluting segment after the first 96 hours of dwell. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release no more than about 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5% of the total naloxone content of the drug eluting segment after the first 96 hours of residence. In some embodiments, the drug eluting segment comprising the buprenorphine-naloxone combination formulation may release from about 0 to about 50% of the total naloxone content of the drug eluting segment after the first 120 hours of residence.In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total naloxone content of the drug eluting segment after the first 120 hours of dwell. In some embodiments, the drug eluting segment comprising a buprenorphine-naloxone combination formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5% or less of the total naloxone content of the drug eluting segment after the first 120 hours of dwell.

[0270] Carrier polymer-drug segment (drug eluting segment) formed by co-extrusion of buprenorphine-naloxone combination formulation with naloxone alone formulation In some embodiments, as described above, during the manufacture of the carrier polymer-drug segment (i.e., drug-eluting segment) of the gastroretentive system, a naloxone-only formulation can be prepared and co-extruded with the buprenorphine-naloxone combination formulation. By co-extruding a naloxone-only formulation with a buprenorphine and naloxone combination formulation, the release profile of naloxone may be better controlled. Controlling the release profile of naloxone from the gastroretentive dosage form helps minimize the possibility of therapeutic error (i.e., dissolving naloxone only to ingest the remaining buprenorphine). Thus, the following describes individual naloxone formulations that can be co-extruded with the buprenorphine-naloxone combination formulations described immediately above.

[0271] As used herein, the term "naloxone only" means that the formulation does not contain buprenorphine. However, a "naloxone only" formulation may contain any number of other ingredients.

[0272] Both active agents, buprenorphine and naloxone, are incorporated into a single segment or component of the gastroretentive system, i.e., the drug-eluting segment. This is designed so that a user cannot easily tamper with the gastroretentive system to remove naloxone so that only buprenorphine can be ingested. Alternatively, the gastroretentive system can be designed such that buprenorphine and naloxone are provided as separate components of the gastroretentive system. However, this would facilitate tampering, as the user would be able to physically separate the two components (i.e., the buprenorphine component and the naloxone component) and ingest only the buprenorphine component. Thus, the described drug-eluting segment or component includes both buprenorphine and naloxone.

[0273] In some embodiments, the buprenorphine and naloxone of the drug eluting segment may be released at similar rates. In some embodiments, the buprenorphine and naloxone of the drug eluting segment may be released at different rates. For example, naloxone may be released from the drug eluting segment faster than buprenorphine. In either case, the fact that buprenorphine and naloxone are combined in a single component of the gastroretentive system (i.e., the drug eluting segment) greatly minimizes the separation of naloxone from buprenorphine by the user. For example, a user may attempt to elute naloxone from an external gastroretentive system and ingest the remaining buprenorphine. However, in a gastroretentive system in which buprenorphine and naloxone have similar release profiles, once naloxone is completely eluted, little, if any, buprenorphine remains. In the case of gastroretentive systems in which naloxone is released faster than buprenorphine, a significant amount of buprenorphine will dissolve in the time it takes for naloxone to completely dissolve from the gastroretentive system. Thus, the user will be left with significantly less buprenorphine than was originally present in the gastroretentive system. In either case, abuse of the gastroretentive system is minimized.

[0274] In some embodiments, the gastroretentive system comprises one or more co-extruded drug eluting segments, each of which comprises a buprenorphine-naloxone combination formulation and a co-extruded naloxone-only formulation. In some embodiments, the co-extruded drug eluting segment comprises about 20 to about 50% by weight of buprenorphine. In some embodiments, the co-extruded drug eluting segment comprises about 5 to about 20% by weight of total naloxone (i.e., naloxone from the naloxone-only formulation and naloxone from the buprenorphine-naloxone combination formulation). In some embodiments, the co-extruded drug eluting segment comprises about 50, 45, 40, 35, 30, or 25% by weight or less of buprenorphine. In some embodiments, the co-extruded drug eluting segment comprises about 20, 25, 30, 35, 40, or 45% by weight or more of buprenorphine. In some embodiments, the co-extruded drug eluting segment comprises about 20, 15, or 10% by weight or less of total naloxone. In some embodiments, the coextruded drug eluting segment comprises greater than or equal to about 5, 10, or 15% total naloxone by weight.

[0275] In some embodiments, the coextruded drug eluting segment may be prepared using a buprenorphine-naloxone combination formulation as described above with reference to a drug eluting segment that includes only an extruded buprenorphine-naloxone combination formulation (not including a naloxone-only formulation). For example, examples of amounts of components of some embodiments of a buprenorphine-naloxone combination formulation used in a coextruded drug eluting segment are provided 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%. "Pharm. accept. salt" refers to a pharma- ceutically acceptable salt thereof.

[0276] [Table 8]

[0277] Naloxone-only formulations include naloxone or a salt thereof (i.e., naloxone hydrochloride) in an amount of about 5-60, 10-55, 20-50, or 30-50% naloxone or a salt thereof by weight. In some embodiments, naloxone-only formulations may include about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, or about 10% or less naloxone or a salt thereof by weight. In some embodiments, naloxone-only formulations may include about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, or about 55% or more naloxone by weight.

[0278] The naloxone-only formulation comprises about 30% to 70% by weight of carrier polymer. For example, the carrier polymer can comprise polycaprolactone (PCL), such as 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 naloxone-only formulation comprises about 70, about 65, about 60, about 55, about 50, about 45, about 40, or about 35% by weight or less of carrier polymer. In some embodiments, each drug-eluting segment comprises about 30, about 35, about 40, about 45, about 50, about 55, about 60, or about 65% by weight or more of carrier polymer.

[0279] In some embodiments, the naloxone-only formulation includes one or more excipients. For example, the naloxone-only formulation can include one or more plasticizers, such as poloxamers (e.g., poloxamer 407, or "P407"). In some embodiments, the naloxone-only formulation can include about 0.5 to about 10% by weight of a plasticizer. In some embodiments, the naloxone-only formulation can include about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1% by weight or less of a plasticizer. In some embodiments, the naloxone-only formulation can include about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, or about 9% by weight or more of a plasticizer.

[0280] In some embodiments, the naloxone alone formulation contains about 0.1% to about 5% by weight of vitamin E succinate. In some embodiments, the combination formulation may contain about 5, about 4, about 3, about 2, about 1, about 0.5, or about 0.1% by weight or less of vitamin E succinate. In some embodiments, the combination formulation may contain about 0.01, about 0.1, about 0.5, about 1, about 2, about 3, or about 4% by weight or more of vitamin E succinate.

[0281] In some embodiments, the naloxone-only formulation comprises about 0.1% to about 1% by weight colloidal silicon dioxide (SiO2).

[0282] Examples of amounts of components for several embodiments of naloxone-only formulations used in the coextruded drug-eluting segment are provided 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%. "Pharm. accept. salt" refers to a pharma- ceutically acceptable salt thereof.

[0283] [Table 9]

[0284] The naloxone alone formulation described above can be coextruded with the buprenorphine-naloxone formulation described above to form a coextruded drug-eluting segment containing both the buprenorphine-naloxone combination formulation and the naloxone alone formulation. In some embodiments, the coextruded drug-eluting segment can be formed with a ratio of buprenorphine-naloxone combination formulation to naloxone alone formulation ("BN:NAL") of about 1:1 to about 20:1 BN:NAL. In some embodiments, the ratio can be about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, or about 20:1 BN:NAL.

[0285] The buprenorphine-naloxone formulation may be coextruded with the naloxone-only formulation in various configurations. In some embodiments, the two formulations (or "portions") may be extruded such that one formulation (e.g., the naloxone-only formulation) is embedded within the second formulation (e.g., the buprenorphine-naloxone formulation), as shown in FIG. 2A. FIG. 2A shows a cross-section of a drug-eluting segment that includes one formulation embedded throughout the second formulation. The first formulation may include one or more strands embedded within the second formulation. In some embodiments, the two formulations may be coextruded as a multi-layer drug-eluting segment, for example, as shown in FIG. 2B. For example, the multi-layer drug-eluting segment may include multiple layers of the buprenorphine-naloxone formulation alternating with the naloxone-only formulation. In some embodiments, the multi-layer drug-eluting segment may include 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more layers. In some embodiments, the multi-layer drug eluting segment may comprise no more than 12, 10, 9, 8, 7, 6, 5, 4, or 3 layers.

[0286] Examples of amounts of components of some embodiments of the drug eluting segment, including a naloxone-only formulation and a coextruded buprenorphine-naloxone combination formulation, are provided in the table below. In some embodiments, a buprenorphine-naloxone combination formulation and a naloxone-only formulation are used in the drug eluting segment (no additional formulations are used), and these amounts correspond to the amounts of 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 pharma- ceutically acceptable salt thereof.

[0287] [Table 10]

[0288] In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release from about 5 to about 90% of the total buprenorphine content of the coextruded drug eluting segment within the first 24 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only 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 buprenorphine content of the coextruded drug eluting segment within the first 24 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only 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 buprenorphine content of the co-extruded drug eluting segment within the first 24 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5 to about 90% of the total buprenorphine content of the co-extruded drug eluting segment after the first 24 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only 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 buprenorphine content of the coextruded drug eluting segment after the first 24 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only 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 buprenorphine content of the coextruded drug eluting segment after the first 24 hours of residence.In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5 to about 70% of the total buprenorphine content of the co-extruded drug eluting segment after the first 48 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65% or more of the total buprenorphine content of the co-extruded drug eluting segment after the first 48 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total buprenorphine content of the co-extruded drug eluting segment after the first 48 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5 to about 50% of the total buprenorphine content of the co-extruded drug eluting segment after the first 72 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total buprenorphine content of the coextruded drug eluting segment after the first 72 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total buprenorphine content of the coextruded drug eluting segment after the first 72 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5 to about 30% of the total buprenorphine content of the coextruded drug eluting segment after the first 96 hours of residence.In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5, 10, 15, 20, or 25% or more of the total buprenorphine content of the coextruded drug eluting segment after the first 96 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 30, 25, 20, 15, or 10% or less of the total buprenorphine content of the coextruded drug eluting segment after the first 96 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5 to about 20% of the total buprenorphine content of the coextruded drug eluting segment after the first 120 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5, 10, or 15% or more of the total buprenorphine content of the coextruded drug eluting segment after the first 120 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 20, 15, or 10% or less of the total buprenorphine content of the coextruded drug eluting segment after the first 120 hours of residence.

[0289] In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5 to about 90% of the total naloxone content of the coextruded drug eluting segment within the first 24 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only 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 naloxone content of the coextruded drug eluting segment within the first 24 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only 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 naloxone content of the co-extruded drug eluting segment within the first 24 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5 to about 90% of the total naloxone content of the co-extruded drug eluting segment after the first 24 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only 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 naloxone content of the coextruded drug eluting segment after the first 24 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only 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 naloxone content of the coextruded drug eluting segment after the first 24 hours of residence.In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5 to about 70% of the total naloxone content of the co-extruded drug eluting segment after the first 48 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65% or more of the total naloxone content of the co-extruded drug eluting segment after the first 48 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total naloxone content of the co-extruded drug eluting segment after the first 48 hours of residence. In some embodiments, a co-extruded drug eluting segment comprising a buprenorphine-naloxone combination formulation co-extruded with a naloxone-only formulation may release about 5 to about 50% of the total naloxone content of the co-extruded drug eluting segment after the first 72 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5, 10, 15, 20, 25, 30, 35, 40, or 45% or more of the total naloxone content of the coextruded drug eluting segment after the first 72 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 50, 45, 40, 35, 30, 25, 20, 15, or 10% or less of the total naloxone content of the coextruded drug eluting segment after the first 72 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5 to about 30% of the total naloxone content of the coextruded drug eluting segment after the first 96 hours of residence.In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5, 10, 15, 20, or 25% or more of the total naloxone content of the coextruded drug eluting segment after the first 96 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 30, 25, 20, 15, or 10% or less of the total naloxone content of the coextruded drug eluting segment after the first 96 hours of residence. In some embodiments, the coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5 to about 20% of the total naloxone content of the coextruded drug eluting segment after the first 120 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 5, 10, or 15% or more of the total naloxone content of the coextruded drug eluting segment after the first 120 hours of residence. In some embodiments, a coextruded drug eluting segment comprising a buprenorphine-naloxone combination formulation coextruded with a naloxone-only formulation may release about 20, 15, or 10% or less of the total naloxone content of the coextruded drug eluting segment after the first 120 hours of residence.

[0290] Rate Controlling Polymer Membrane The release rate controlling polymer membrane can be coated on the component of the gastroretentive system that releases the 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. The components coated with the release rate controlling polymer membrane disclosed herein have substantially the same release rate characteristics before and after exposure to heat that occurs during the 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 the composite arm (e.g., the composite arm including the drug eluting segment or the composite arm excluding the 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.

[0291] A variety of polymers can be used to form the release rate controlling polymeric membrane comprising PCL. In some embodiments, the release rate controlling polymeric membrane comprises about 70% to about 80% by weight of PCL. In some embodiments, the release rate controlling polymeric membrane comprises about 73% to about 77% by weight of PCL. In some embodiments, the release rate controlling polymeric membrane comprises about 73.5% by weight of PCL. In some embodiments, the release rate controlling polymeric membrane comprises about 80, 79, 78, 77, 76, 75, 74, 73, 72, or 71% or less by weight of PCL. In some embodiments, the release rate controlling polymeric membrane comprises 70, 71, 72, 73, 74, 75, 76, 77, 78, or 79% or more by weight of PCL.

[0292] Other excipients can be added to the carrier polymer to modify the release of the drug, such as copovidone (VA64). In some embodiments, the release rate modifying polymer membrane comprises about 20% to about 30% by weight of VA64. In some embodiments, the release rate modifying polymer membrane comprises about 23% to about 27% by weight of VA64. In some embodiments, the release rate modifying polymer membrane comprises about 24.5% by weight of VA64. In some embodiments, the release rate modifying 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 modifying polymer membrane comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29% or more by weight of VA64.

[0293] In some embodiments, the release rate controlling polymeric membrane comprises 1-5% by weight magnesium stearate. In some embodiments, the release rate controlling membrane comprises less than 5, 4, 3, or 2% by weight magnesium stearate. In some embodiments, the release rate controlling membrane comprises more than 1, 2, 3, or 4% by weight magnesium stearate.

[0294] Gastric residence time The gastric retention time of the system is controlled by the rate of degradation or weakening or breakage of the time-dependent polymer linker in the gastric retention system. The faster the time-dependent polymer linker degrades or weakens or breaks, the faster the system passes from the stomach. The retention time of the gastric retention system is defined as the time between administration of the system to the stomach and the 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 gastroretention system has a retention time of about 7 days (about 1 week), or up to about 7 days (about 1 week). In one embodiment, the gastroretention system has a retention time of about 10 days, or up to about 10 days. In one embodiment, the gastroretention system has a retention time of about 14 days (about 2 weeks), or up to about 14 days (about 2 weeks).

[0295] 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.

[0296] 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.

[0297] 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.

[0298] The gastric retention system releases a therapeutically effective amount of the agent (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 agent (or salt thereof) for at least about 25% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 50% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 60% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 70% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 75% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (or salt thereof) for at least about 80% of the residence time. In one embodiment, the system releases a therapeutically effective amount of the agent (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.

[0299] Gastroretentive systems containing buprenorphine and naloxone In some embodiments, the star-shaped dosage form for administering buprenorphine and naloxone can include arms, which in turn include 1) a carrier polymer-drug arm segment, 2) one or more enteric linkers, 3) one or more time-dependent linkers, 4) a non-active segment, and / or 5) other optional spacers. The arms are connected to the elastomeric core in a star-shaped device configuration. Typically, six arms are used in the star-shaped dosage form. In some embodiments, when six arms are used in the star-shaped dosage form, any one of 1, 2, 3, 4, 5, or 6 arms includes a carrier polymer-drug arm segment. In some embodiments, when six arms are used in the star-shaped dosage form, three arms include a carrier polymer-drug arm segment. In some embodiments, when six arms are used in the star-shaped dosage form, six arms include a carrier polymer-drug arm segment. In some embodiments, when six arms are used in the star-shaped dosage form, two arms include 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.

[0300] The carrier polymer-drug arm segment of the buprenorphine and naloxone dosage forms may be a polymer that is capable of carrying buprenorphine (or a pharma- ceutical acceptable salt thereof), naloxone (or a pharma-ceutical acceptable salt thereof), polycaprolactone, polyethylene oxide (PEO 100K), poloxamer 407 (P407), silica (SiO2), and vitamin E succinate (vitE). In some embodiments, six arms are typically used in the star-shaped dosage form, with either 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 a non-active 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 buprenorphine, pharmacy acceptable salt of buprenorphine, or salt of buprenorphine in the star-shaped dosage form can range from 10 mg to about 150 mg of buprenorphine. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 40 mg to about 115 mg of buprenorphine. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 150, about 140, about 130, about 120, about 110, about 100, about 90, about 80, about 70 or less, about 60, about 50, about 40, about 30, or about 20 mg or less of buprenorphine.In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, or about 140 mg or more of buprenorphine. The total weight of naloxone, pharma- ceutically acceptable salt of naloxone, or salt of naloxone in the star-shaped dosage form can range from about 1 mg to about 60 mg of naloxone. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 3.5 mg to about 10 mg of naloxone. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 mg or less of naloxone. In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system comprising about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, or about 55 mg or more of naloxone.

[0301] The non-active arm segment of the dosage form may comprise polycaprolactone (PCL), a radiopaque material, and optionally a colorant. The polycaprolactone used may have a viscosity of about 1.5 dL / g to about 1.9 dL / g, for example about 1.7 dL / g. The radiopaque material may be (BiO)2CO3. Any medicamentously acceptable colorant may be used. An example of a colorant that may be used includes FD&C Blue #5.

[0302] The enterodisintegrable 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 medicamentously acceptable colorant may be used. Examples of colorants that may be used include triferric oxide.

[0303] The time-dependent disintegrating matrix of the buprenorphine-naloxone dosage form can include 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 molar ratio of lactide:glycolide of about 75:25. The polyethylene oxide used can be about 60,000 MW to about 125,000 MW, for example about 90,000 MW to 110,000 MW, or about 100,000 MW.

[0304] The central elastomer of the buprenorphine-naloxone dosage form can have a durometer hardness of about 40 A to about 60 A, such as 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.

[0305] In some embodiments, the assembled arms of the buprenorphine-naloxone gastric retention dosage form can be attached to the central elastomer with a polymer linker segment. The polymer linker segment can serve as an attachment point 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.

[0306] In some embodiments, the gastroretentive system further comprises a release rate controlling membrane comprising about 73.5% 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, such as Corbion PC17. In some embodiments, the release rate controlling membrane further comprises about 24.5% by weight of copovidone, such as VA64. In some embodiments, the release rate controlling membrane further comprises about 2.0% by weight of magnesium stearate.

[0307] Examples of amounts of various components of the dosage forms are set forth 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%.

[0308] [Table 11]

[0309] [Table 12]

[0310] [Table 13]

[0311] [Table 14]

[0312] [Table 15]

[0313] The assembled arms include 1) a polymer linker segment, 2) a first disintegrable matrix segment, 3) a second disintegrable matrix segment, 4) a drug eluting segment comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and 5) a third disintegrable matrix segment that can be arranged in a variety of sequences. One such sequence begins at the proximal end attached to the central elastomer and proceeds to the distal end: (polymer linker segment) (first disintegrable matrix segment) (second disintegrable matrix segment) (drug eluting segment) (third disintegrable matrix segment).

[0314] 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 disintegrable matrix segment, 3) a second disintegrable matrix segment, 4) a first inactive segment, and 5) a third disintegrable matrix segment, which may be arranged in various orders. One such order is starting from the proximal end attached to the central elastomer and proceeding to the distal end: (polymer linker segment) (first disintegrable matrix segment) (second disintegrable matrix segment) (first inactive segment)) (third disintegrable matrix segment).

[0315] The approximate dimensions of the length of the segments on each arm are given below. An optional rPCL spacer (inactive segment) of about 0.2-2 mm, e.g., about 0.5 mm width, may be inserted between any two of the following components or may be added to the outer tip of the assembled arm or between the inner tip of the assembled arm and the elastomeric core. It will be understood that this embodiment of the assembled arm lacks a drug eluting segment and may be used when it is desirable to use one or more non-drug eluting arms in the dosage form.

[0316] [Table 16]

[0317] 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.

[0318] 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 of the inactive segment, (d) an enterodisintegrating matrix according to any of the above embodiments, (e) a second inactive segment according to any of the above embodiments of the inactive segment, (f) a drug eluting segment according to any of the above embodiments, (g) a third inactive segment according to any of the above embodiments of the inactive segment, and (h) a third disintegrating matrix according to any of the above embodiments. The polymeric linker segment can be attached to the central elastomer.

[0319] 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 polymeric linker segment, (b) a time-disintegrating matrix, (c) a first inert segment, (d) an enteroerodible matrix, (e) a second inert segment, (f) a drug eluting segment, (g) a third inert segment, and (h) a third disintegrating matrix, 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 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 PCL and about 25% to about 35% by weight (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 second inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (f) the drug eluting segment comprises about 35% to about 50% by weight of buprenorphine, about 1% to about 7% by weight of naloxone, about 35% to about 50% by weight of PCL, about 1% to about 15% by weight of PEO100K, about 1% to about 5% by weight of P407, about 0.1% to about 1% by weight of vitamin E succinic acid, and about 0.1% to about 1% by weight of SiO2; (g) a third inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3; and / or (h) The third disintegrable matrix comprises about 60% to about 70% by weight HPMCAS, about 25% to about 35% by weight PCL, about 1% to about 5% by weight propylene glycol, and about 1% to about 5% by weight stearic acid, and optionally about 0.01% to about 0.5% by weight iron oxide.

[0320] 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 polymeric linker segment, (b) a time-disintegrating matrix, (c) a first inert segment, (d) an enteroerodible matrix, (e) a second inert segment, (f) a drug eluting segment, (g) a third inert segment, and (h) a third disintegrating matrix, 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 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 PCL and 28% to about 32% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 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 second inactive segment comprising about 68% to about 72% by weight PCL and 28% to about 32% by weight (BiO)CO; (f) the drug eluting segment comprises about 40% to about 45% by weight of buprenorphine, about 2% to about 6% by weight of naloxone, about 40% to about 45% by weight of PCL, about 5% to about 10% by weight of PEO100K, about 2% to about 4% by weight of P407, about 0.2% to about 0.8% by weight of vitamin E succinic acid, and about 0.2% to about 0.8% by weight of SiO2; (g) a third inactive segment comprising about 68% to about 72% by weight PCL and 28% to about 32% by weight (BiO)CO; and / or (h) The third disintegrable matrix comprises about 63% to about 67% by weight HPMCAS, about 28% to about 32% by weight PCL, about 2% to about 3% by weight propylene glycol, and about 2% to about 3% by weight stearic acid.

[0321] 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 polymeric linker segment, (b) a time-disintegrating matrix, (c) a first inert segment, (d) an enteroerodible matrix, (e) a second inert segment, (f) a drug eluting segment, (g) a third inert segment, and (h) a third disintegrating matrix, 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 PCL; (b) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight acid terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 18% by weight copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (c) the first inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (e.g., P407), and about 0.1% by weight iron oxide (e.g., E172); (e) a second inactive segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3; (f) the drug eluting segment comprises about 42 wt.% buprenorphine, about 3.7 wt.% naloxone, about 7 wt.% PEO100K, about 43.3 wt.% PCL, about 3.0 wt.% P407, about 0.5 wt.% Vitamin E succinate, and about 0.5 wt.% SiO; (g) a third inactive segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3; and / or (h) A third disintegrating matrix comprises 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, and about 2.5% by weight stearic acid, and optionally about 0.1% by weight iron oxide, e.g., about 0.025% ferric oxide, and 0.075% FD&C Red 40.

[0322] 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 inert segment, (d) an enteroerodible matrix, (e) a second inert segment, (f) a third inert segment, (g) a third inert segment, and (h) a third degradable matrix, 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 PCL; (b) the time-disintegrating matrix comprises about 40% to about 50% by weight of PCL, 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 PCL and about 25% to about 35% by weight (BiO)2CO3; (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 second inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)CO; (f) a third inactive segment comprising 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; (g) a fourth inactive segment comprising about 65% to about 75% by weight PCL and about 25% to about 35% by weight (BiO)2CO3; and / or (h) The third disintegrable matrix comprises about 60% to about 70% by weight HPMCAS, about 25% to about 35% by weight PCL, about 1% to about 5% by weight propylene glycol, and about 1% to about 5% by weight stearic acid, and optionally about 0.01% to about 0.5% by weight iron oxide.

[0323] 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 inert segment, (d) an enteroerodible matrix, (e) a second inert segment, (f) a third inert segment, (g) a third inert segment, and (h) a third degradable matrix, 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 PCL; (b) a time-dependent disintegrating matrix comprising about 43% to about 47% by weight PCL, about 33% to about 37% by weight 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 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 polyethylene glycol 100k, and about 0.01% to about 0.1% by weight color absorbing dye E172; (c) the first inactive segment comprises about 68% to about 72% by weight PCL and 28% to about 32% by weight (BiO)CO; (d) the enterodisintegrable matrix comprises about 62% to about 66% by weight of HPMCAS, about 32% to about 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 second inactive segment comprising about 68% to about 72% by weight PCL and 28% to about 32% by weight (BiO)CO; (f) a third inactive segment comprising about 64% to about 69% by weight PCL, about 30% to about 34% by weight VA64, about 0.5% to about 2.5% by weight P407, and about 0.01% to about 0.1% by weight pigment or colorant; (g) a fourth inactive segment comprising about 68% to about 72% by weight PCL and 28% to about 32% by weight (BiO)2CO3; and / or (h) The third disintegrable matrix comprises about 63% to about 67% by weight HPMCAS, about 28% to about 32% by weight PCL, about 2% to about 3% by weight propylene glycol, and about 2% to about 3% by weight stearic acid.

[0324] 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 polymeric segment, (b) a time-disintegrating matrix, (c) a first inert segment, (d) an enteroerodible matrix, (e) a second inert segment, (f) a third inert segment, (g) a third inert segment; (h) a third disintegrating matrix, 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 PCL; (b) a time-dependent disintegrating matrix comprising about 44.95% by weight PCL, about 35% by weight acid terminated copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 18% by weight copolymer of DL-lactide and glycolide (50 / 50 molar ratio) having a viscosity midpoint of about 0.4 dl / g, about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172; (c) the first inactive segment comprises about 70% by weight PCL and about 30% by weight (BiO)2CO3; (d) the enteroerodible matrix comprises about 63.95% by weight HPMCAS, about 33.95% by weight PCL, and about 2% by weight poloxamer (e.g., P407), and about 0.1% by weight iron oxide (e.g., E172); (e) a second inactive segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3; (f) a third inactive segment comprising about 6.45% by weight PCL, about 32% by weight VA64, about 1.5% by weight P407, and about 0.05% by weight pigment or colorant; (g) a fourth inactive segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3; and / or (h) A third disintegrating matrix comprises 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, and about 2.5% by weight stearic acid, and optionally about 0.1% by weight iron oxide, e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40.

[0325] 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 the proximal end of the arm.

[0326] In some embodiments, the dosage form for administration of buprenorphine and naloxone comprises a gastroretentive system, wherein the gastroretentive system comprises 1-5 inactive segments (e.g., 1 per arm, 1-5 total 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 non-active segment comprising about 1.5% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, e.g., H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101, and y is about 56, such as poloxamer 407 (P407). In some embodiments, the gastroretentive system comprises a first non-active segment comprising about 0.005% by weight of an iron oxide (e.g., E172).

[0327] In some embodiments, a gastroretention system dosage form for administration of one or more agents can include a radiopaque segment, wherein the segment comprises about 70% by weight of polycaprolactone (PCL), such as Corbin PC17, having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g. In some embodiments, the gastroretention system comprises a radiopaque segment comprising about 30% by weight of (BiO)2CO3. In some embodiments, the gastroretention system comprises a radiopaque segment comprising about 70% by weight of Corbin PC17, and 30% by weight of (BiO)2CO3.

[0328] In some embodiments, the gastroretentive system dosage form for administration of buprenorphine and naloxone comprises a central elastomer and a drug-eluting segment comprising 20 mg of buprenorphine and about 1.75 mg of naloxone. In some embodiments, the gastroretentive system further comprises a release rate controlling membrane comprising about 73.5% 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, such as Corbion PC17. In some embodiments, the release rate controlling membrane further comprises about 24.5% by weight of copovidone, such as 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), such as a 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 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), such as 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), such as PDLG5004 ... a polyethylene glycol having an average molecular weight of 100,000, such as PEO 100KIn some embodiments, the time-dependent disintegrating matrix further comprises about 0.05% by weight of iron oxide, such as E172. In some embodiments, the gastroretentive system further 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, such as Corbion PC17. In some embodiments, the pH-dependent disintegrating matrix further comprises about 63.95% by weight of hypromellose acetate succinate, such as HPMCAS-MG. In some embodiments, the pH-dependent disintegrating matrix further comprises about 2.0% by weight of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) polymer, such as H-(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH (where x and z are about 101, and y are about 56), such as poloxamer 407 (P407). In some embodiments, the pH-dependent disintegrating matrix further comprises about 0.1% by weight of an iron oxide, such as E172. In some embodiments, the gastroretentive system further comprises one or more non-active segments. In some embodiments, the gastroretentive system further comprises a radiopaque segment comprising about 70% by weight of polycaprolactone (PCL), such as a PCL having a viscosity midpoint of about 1.5 dl / g to about 2.1 dl / g, such as Corbin PC17. In some embodiments, the radiopaque segment comprises about 30% by weight of (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.

[0329] In some embodiments, the gastric retention 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 gastric retention 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 gastric retention 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 gastric retention 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 gastric retention 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 gastric retention system has six arms that include a drug eluting segment.

[0330] Center 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.

[0331] 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.

[0332] 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 45 to about 55.

[0333] 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. EXAMPLES

[0334] The present disclosure is further illustrated by the following non-limiting examples.

[0335] Example 1: Buprenorphine-naloxone dosage form (extended release gastroretentive system) In this embodiment, a dosage form according to the present invention comprises a gastroretentive system, said gastroretentive system being formulated to contain buprenorphine and naloxone.

[0336] 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 buprenorphine-naloxone combination gastroretention system, the star includes six arms, each of which includes a drug eluting segment.

[0337] 3A 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, first segment 370, segment 350, second segment 370, segment 340, and third segment 370. At the distal end of each arm is segment 320.

[0338] The average size of the gastroretention system is about 46 mm, with the length of each segment ranging from about 0.5 mm to about 8.4 mm. The following table provides a listing of the length of each segment of the active arm (i.e., the arm containing the drug eluting segment) in the gastroretention 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.

[0339] [Table 17]

[0340] The central elastomeric core 310 comprises a liquid silicone rubber (LSR) having a 50 durometer hardness.

[0341] In this example, the dosage form provided herein includes six arms, each containing a drug eluting segment, where the dosage form contains about 115 mg of buprenorphine and about 10 mg of naloxone for administration. The buprenorphine and naloxone are contained in a carrier polymer-drug segment 340 (e.g., a drug eluting segment). The drug eluting segment is comprised of about 45% by weight buprenorphine, about 4.5% by weight naloxone, about 39.5% by weight Corbin PC17, about 3.0% by weight P407, about 7% by weight PEO 100K , about 0.5% by weight Vitamin E succinate, and about 0.5% by weight SiO2. The application also contemplates variations of this dosage form having increased numbers and / or lengths of drug-eluting segments to achieve higher doses of drugs, such as buprenorphine and / or naloxone.

[0342] 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.

[0343] The time-dependent disintegrating matrix (segment 360) comprises about 44.95% by weight Corbin PC17, about 35% by weight acid terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 350) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbin PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 370 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0344] At the distal end of each arm is a third disintegrable matrix, which also optionally has filaments attached thereto, thereby circumferentially connecting the arms. The third disintegrable matrix (segment 320) comprises about 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, about 2.5% by weight stearic acid, and about 0.1% by weight iron oxide (e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40).

[0345] Segment 380 at the proximal end of each arm is a polymeric linker segment comprising approximately 100% by weight PCL.

[0346] In some embodiments, each drug arm is coated with a release rate controlling membrane, specifically, the coating comprises about 73.5% by weight Corbin PC17, about 24.5% by weight VA64, and about 2% magnesium stearate, and is applied in an amount of about 1% of the pre-coat weight of the segment.

[0347] 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.

[0348] In another example of a buprenorphine-naloxone compounded gastroretentive system, the star contains four arms, each of which contains a drug eluting segment, and two arms that do not contain a drug eluting segment. The application also contemplates other gastroretentive systems that contain six arms, of which one, two, three, four, five, or six arms contain a drug eluting segment.

[0349] 3B is labeled to show the various elements of this configuration. System 400 includes a central elastomeric core 410 that is in the shape of a "star" having six short branches.

[0350] In the case of an arm that includes 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, segment 440, and third segment 470. The distal end of each drug-containing arm has segment 420.

[0351] 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 by segment 460, first segment 470, segment 450, second segment 470, segment 430, and third segment 470. The distal end of each drug-free arm has segment 420.

[0352] 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 8.4 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.

[0353] [Table 18]

[0354] The central elastomeric core 410 comprises a liquid silicone rubber (LSR) having a 50 durometer hardness.

[0355] In this example, the dosage form provided herein includes six arms, four of which include a drug-eluting segment, where the dosage form includes about 80 mg of buprenorphine and about 7 mg of naloxone for administration. The buprenorphine and naloxone are included in the carrier polymer-drug segment 440 (e.g., the drug-eluting segment). The drug-eluting segment includes about 45% by weight buprenorphine, about 4.5 mg of naloxone, about 39.5% by weight Corbin PC17, about 7% by weight PEO100K, about 3% by weight P407, about 0.5% by weight Vitamin E succinate, and about 0.5% by weight SiO2. The application also contemplates variations of this dosage form with increased number and / or length of drug-eluting segments to achieve higher doses of drugs, such as buprenorphine and / or naloxone.

[0356] The two arms not containing drug contain a non-active segment (segment 430), each of which contains about 66.45% by weight Corbin PC17, about 32.0% by weight VA64, about 1.5% by weight P407, and about 0.05% by weight FD&C Blue 1 aluminum lake.

[0357] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 460, as well as a pH-dependent disintegration matrix or linker, referred to as segment 450. The gastroretentive system further comprises structural segment 470.

[0358] The time-dependent disintegrating matrix (segment 460) comprises about 44.95% by weight Corbin PC17, about 35% by weight acid terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 450) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbin PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 470 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0359] At the distal end of each arm is a third disintegrable matrix, which also optionally has filaments attached thereto, thereby circumferentially connecting the arms. The third disintegrable matrix (segment 420) comprises about 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, about 2.5% by weight stearic acid, and about 0.1% by weight iron oxide (e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40).

[0360] Segment 480 at the proximal end of each arm is a polymer linker segment that comprises about 100% PCL by weight.

[0361] In some embodiments, each drug arm is coated with a release rate controlling membrane, specifically, the coating comprises about 73.5% by weight Corbin PC17, about 24.5% by weight VA64, and about 2% magnesium stearate, and is applied in an amount of about 1% of the precoat weight of the segment.

[0362] 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.

[0363] In another example of a buprenorphine-naloxone combination gastroretentive system, the star includes two arms each containing a drug eluting segment and four arms that do not contain a drug eluting segment. The application also contemplates other gastroretentive systems that include six arms, any one of which, 1, 2, 3, 4, 5, through 6, contains a drug eluting segment.

[0364] 3C is labeled to show the various elements of this configuration. System 500 includes a central elastomeric core 510 that is in the shape of a "star" having six short branches.

[0365] In the case of an arm that includes a drug-eluting segment, segment 580 of the arm is attached to one short star branch. Segment 580 is followed, in order, by segment 560, first segment 570, segment 550, second segment 570, segment 540, and third segment 570. The distal end of each drug-containing arm has segment 520.

[0366] For arms that do not contain a drug eluting segment, segment 580 of the arm is attached to one short star branch. Segment 580 is followed by segment 560, first segment 570, segment 550, second segment 570, segment 530, and third segment 570. The distal end of each drug-free arm has segment 520.

[0367] 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 8.4 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.

[0368] [Table 19]

[0369] The central elastomeric core 510 comprises a liquid silicone rubber (LSR) having a 50 durometer hardness.

[0370] In this example, the dosage form provided herein includes six arms, two of which include a drug-eluting segment, where the dosage form includes about 40 mg of buprenorphine and about 3.5 mg of naloxone for administration. The buprenorphine and naloxone are included in the carrier polymer-drug segment 540 (e.g., the drug-eluting segment). The drug-eluting segment includes about 45% by weight buprenorphine, about 4.5 mg of naloxone, about 39.5% by weight Corbin PC17, about 7% by weight PEO100K, about 3% by weight P407, about 0.5% by weight Vitamin E succinate, and about 0.5% by weight SiO2. The application also contemplates variations of this dosage form with increased number and / or length of drug-eluting segments to achieve higher doses of drugs, such as buprenorphine and / or naloxone.

[0371] The two arms not containing drug contained a non-active segment (segment 530), which each contained about 66.45% by weight Corbin PC17, about 32.0% by weight VA64, about 1.5% by weight P407, and about 0.05% by weight FD&C Blue 1 aluminum lake.

[0372] The gastroretentive system further comprises a time-dependent disintegration matrix or linker, referred to as segment 560, and a pH-dependent disintegration matrix or linker, referred to as segment 550. The gastroretentive system further comprises a structural segment 570.

[0373] The time-dependent disintegrating matrix (segment 560) comprises about 44.95% by weight Corbin PC17, about 35% by weight acid terminated copolymer of DL-lactide and glycolide (PDLG5004A), about 18% by weight copolymer of DL-lactide and glycolide (PDLG5004), about 2% by weight polyethylene glycol 100k, and about 0.05% by weight color absorbing dye E172. The pH-dependent disintegrating matrix (segment 550) comprises about 63.95% by weight HPMCAS, about 33.95% by weight Corbin PC17, about 2% by weight P407, and about 0.1% by weight color absorbing dye E172. The structural segment 570 can be a radiopaque PCL segment comprising about 70% by weight PCL and about 30% by weight (BiO)2CO3.

[0374] At the distal end of each arm is a third disintegrable matrix, which also optionally has filaments attached thereto, thereby circumferentially connecting the arms. The third disintegrable matrix (segment 520) comprises about 64.9% by weight HPMCAS, about 30% by weight PCL, about 2.5% by weight propylene glycol, about 2.5% by weight stearic acid, and about 0.1% by weight iron oxide (e.g., about 0.025% ferric oxide and about 0.075% FD&C Red 40).

[0375] Segment 580 at the proximal end of each arm is a polymer linker segment comprising about 100% by weight PCL.

[0376] In some embodiments, each drug arm is coated with a release rate controlling membrane, specifically, the coating comprises about 73.5% by weight Corbin PC17, about 24.5% by weight VA64, and about 2% magnesium stearate, and is applied in an amount of about 1% of the precoat weight of the segment.

[0377] 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.

[0378] Example 2: Evaluation of BUP release from coated and uncoated dosage forms 4A and 4B show the BUP and NAL release profiles, respectively, for a dosage form that includes a drug-eluting segment that includes a buprenorphine-naloxone combination formulation. Specifically, the buprenorphine-naloxone combination formulation used in the dosage form is as follows:

[0379] [Table 20]

[0380] The gastroretentive dosage form used in this study contained six arms, each of which contained a drug-eluting segment. Each dosage form contained 170 mg of BUP. The dosage form contained a central elastomer of 50A silicone. Each arm contained, in that order, a polymer linker segment, a time-dependent disintegrating matrix, an enteroerodible matrix, a radiopaque polycaprolactone segment, a non-active segment, a drug-eluting segment, and a radiopaque polycaprolactone segment (where the polymer linker segment was attached to the central elastomer). The total diameter of the uncompressed dosage form was 46 mm. The drug-eluting segments were fabricated and compression molded using a Haake mini-CTW conical twin-screw compounder.

[0381] The dosage form was coated with a 1% PCL:VA64 75:25 coating. As shown in Figure 3A, the coated dosage form can control the burst release and linearize the BUP release of the drug elution segment from the combination formulation. Figure 3B shows that NAL is completely released from the combination formulation after 1 day.

[0382] Example 3: Comparison of release profiles of buprenorphine-naloxone combination formulations and naloxone alone formulations 5A and 5B show the release profiles of a buprenorphine-naloxone combination formulation (FIG. 5A) compared to a naloxone-only formulation (FIG. 5B). As shown, FIG. 5A shows the release profile of BUP and NAL released from the buprenorphine-naloxone combination formulation. NAL is completely released after only 1 day. BUP is completely released in 7 days. FIG. 5B shows that naloxone is almost completely released from the naloxone-only formulation after 7 days. The formulations of the buprenorphine-naloxone combination formulation and the naloxone-only formulation are as follows:

[0383] [Table 21]

[0384] [Table 22]

[0385] Example 4: Coextruded drug eluting segments with buprenorphine-naloxone combination formulation and naloxone alone formulation As described herein, some gastroretentive dosage forms include drug-eluting segments co-extruded with buprenorphine-naloxone combination formulations and naloxone-only formulations. Figures 6A and 6B show the release profiles of BUP and NAL, respectively, from the co-extruded drug-eluting segments and the mass ratios from the associated co-extruded drug-eluting segments over the first 7 days after ingestion.

[0386] Specifically, Figure 6A shows the predicted release profile of a coextruded drug eluting segment containing a buprenorphine-naloxone combination formulation and a naloxone-only formulation coextruded in a 4:1 ratio. The dotted line represents the predicted naloxone release from the coextruded drug eluting segment, and the solid line shows the predicted buprenorphine release from the coextruded drug eluting segment. The buprenorphine-naloxone formulation and the naloxone-only formulation are the same as those provided in Example 3 above. As shown, the coextruded drug eluting segment achieves similar release profiles for both buprenorphine and naloxone over a 7-day dwell period. FIG. 6B shows that the predicted release rates of buprenorphine and naloxone from the coextruded drug eluting segments as shown in FIG. 6A would achieve the buprenorphine to naloxone mass ratios shown in FIG. 6B. (For the commercially available oral dosage form (Suboxone), when injected intravenously, the most intense withdrawal symptoms were observed at a BUP:NAL mass ratio of 4:1.)

[0387] Example 5: Drug release study in beagle dogs The release of BUP and NAL when administered sublingually was compared to the release of BUP and NAL when administered using the gastroretentive dosage forms described herein, and the results are provided in Figures 7A-7C.

[0388] A total of four female beagle dogs (approximately 7-12 kg at time of dosing) were selected from the sponsor-designated animal population at the study facility. All animals were fasted overnight prior to both Dose 1 and Dose 2. After Dose 1, animals were given food back at least 1 hour after recovery from anesthesia. For Dose 2, animals were given a small amount of dog chow approximately 30 (± 5) minutes prior to dosing and food was returned to animals 1 hour after dosing. The final study design is shown in the table below.

[0389] [Table 23]

[0390] On Day 1, each animal was sedated with dexmedetomidine (16.8 mcg / kg, intravenous). After sedation, each animal's head was positioned and Dose 1 (buprenorphine HCL) was administered into the sublingual cavity for a 10 minute exposure period. After the exposure period, Dose 1 was washed and wiped from the sublingual cavity, and each animal was administered Antisedan (200 mcg / kg, intramuscular) to reverse sedation. Dose 2 test article LYN-013 was received from the sponsor in a ready-to-use form. LYN-013 contains a 50A central elastomer with an enteroerodible matrix (time-dependent disintegration), and 6 x BUP / Nal drug arms with a final diameter of approximately 46 mm (consistent with the dosage form described with respect to Figure 3A above and the table below).

[0391] [Table 24]

[0392] On day 16, each animal was administered a capsule dose containing the dosage form detailed in the table above by manual oral dosing. Immediately after dosing, each animal was given a small amount of canned food loosely packed into an approximately 1-inch sized ball to facilitate swallowing of the capsule.

[0393] All dosing was completed without incident. Dose administration data, including animal weights, are shown in the table below.

[0394] [Table 25]

[0395] X-rays were taken to demonstrate the stomach and intestines to determine the location of the dosage form within the gastrointestinal system. To confirm capsule dissolution, radiographs were taken 30 minutes after dose administration on day 16. Further x-rays were taken daily through day 8, on day 10, and three times weekly thereafter, or as needed, until images confirmed that the entire dosage form had passed through the body.

[0396] All blood samples were collected by venipuncture of a peripheral vein. At each time point, 1 mL of whole blood was collected into tubes containing K3EDTA anticoagulant. Whole blood samples with K3EDTA were stored on wet ice before processing for plasma. Samples were centrifuged at 2200 x g for 10 minutes at 5°C ± 3°C to isolate plasma. Plasma samples were transferred to individual polypropylene tubes in a 96-well plate format, immediately placed on dry ice, and stored at a nominal -80°C until shipment. Actual blood collection times were as follows:

[0397] [Table 26]

[0398] Collected samples were shipped via same-day courier to Charles River Laboratories, Worcester, Mass. Plasma samples were analyzed for buprenorphine, norbuprenorphine, and naloxone concentrations (buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide were tracked) using appropriate analytical procedures by LCMS.

[0399] Figure 7A shows the mean plasma concentration of BUP in dog plasma after sublingual administration of BUP-HCL. Figure 7B shows the mean plasma concentration of BUP in dog plasma after administration of a gastroretentive dosage form of BUP (LYN-013). Figure 7C shows the mean plasma concentration of norbuprenorphine (the major active metabolite of buprenorphine) after administration of a gastroretentive dosage form of BUP (LYN-013). This study shows sustained BUP plasma levels of greater than about 1 ng / mL for over one week after administration of a single oral capsule.

[0400] Example 6: BUP / NAL release study in cynomolgus monkeys This report includes two single-dose pharmacokinetic studies (LYN-190-BUP, LYN-213-BUP).

[0401] In each study, monkeys were fasted overnight prior to dosing. In the LYN-190-BUP study, a 0.03 mg / kg intravenous bolus dose of buprenorphine HCL was administered to four monkeys, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. In the LYN-213-BUP study, a 172 / 17.2 mg buprenorphine / naloxone capsule of LYN-013 was administered orally to four monkeys, and plasma samples were collected pre-dose and at 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, and 216 hours after dosing.

[0402] In each study, sample extracts were prepared by protein precipitation from plasma and concentrations of buprenorphine, norbuprenorphine (active metabolite), and naloxone (abuse deterrent) were measured using LC / MS / MS. Pharmacokinetic parameters of buprenorphine and norbuprenorphine (when available) were calculated by noncompartmental analysis.

[0403] After intravenous administration of 0.03 mg / kg buprenorphine HCL to monkeys, the extrapolated initial plasma concentration (C0) was 17.3 ng / mL. The area under the concentration-time curve from time zero to the time of the last sample (AUClast) was 24.7 hr *ng / mL, and the terminal half-life (t1 / 2) was 1.62 hours.

[0404] Following a single dose of 172 / 17.2 mg buprenorphine / naloxone, LYN-013 demonstrated measurable plasma buprenorphine concentrations for 9 days after dosing, while norbuprenorphine levels were measurable through the fifth day and naloxone was below the limit of quantification in all samples (except one). The median Tmax for buprenorphine was 72 hours, and the Cmax was 4.85 ng / mL. The AUClast for buprenorphine was 350 hr. * The absolute oral bioavailability (F) was 1.1%. Norbuprenorphine reached Tmax at 60 hours, and Cmax and AUClast were low (2.72 ng / mL and 151 hr, respectively). * ng / mL).

[0405] The following table shows the individual and mean plasma PK parameters of intravenous BUP-HCL and LYN-013 (buprenorphine and norbuprenorphine).

[0406] [Table 27]

[0407] 8A-8C show plasma concentrations versus time following single oral doses of BUP-HCL (intravenous) (FIG. 8A) and LYN-013 (FIGS. 8B and 8C).

[0408] Implementation Embodiment 1. A gastroretention system comprising at least one co-extruded drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and a rate controlling release membrane coating the at least one co-extruded drug eluting component, wherein the gastroretention system is configured to be retained in a human stomach for at least 48 hours and to release buprenorphine for at least 48 hours, and wherein the at least one co-extruded drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach, and to release at least 10% of the naloxone or a salt thereof after the first 24 hours of retention in the stomach.

[0409] Embodiment 2. The gastroretentive system of embodiment 1, wherein the rate-controlling release membrane comprises polycaprolactone and copovidone.

[0410] Embodiment 3. The gastric retention system of embodiment 2, wherein the rate-controlling release membrane comprises 60-90% by weight of polycaprolactone.

[0411] Embodiment 4. The gastric retention system of embodiment 2 or 3, wherein the rate-controlling release membrane comprises 10 to 40% by weight of copovidone.

[0412] Embodiment 5. A gastroretentive system described in any of embodiments 1 to 4, wherein the at least one co-extruded drug-eluting component comprises a first co-extruded portion comprising naloxone and a second co-extruded portion comprising buprenorphine and naloxone.

[0413] Embodiment 6. A gastroretentive system as described in embodiment 5, wherein the first coextruded portion is embedded in the second coextruded portion.

[0414] Embodiment 7. A gastroretentive system described in embodiment 5 or 6, wherein the first coextruded portion comprises one or more strands embedded within the second coextruded portion.

[0415] Embodiment 8. A gastroretentive system as described in embodiment 5, wherein the first coextruded portion is layered on top of the second coextruded portion.

[0416] Embodiment 9. A gastroretentive system described in any of embodiments 5 to 8, wherein the first coextruded portion is present in a ratio of 4:1 to the second coextruded portion.

[0417] Embodiment 10. A gastroretentive system described in any of embodiments 5 to 9, wherein the first coextruded portion contains 35 to 50% by weight buprenorphine.

[0418] Embodiment 11. A gastroretentive system described in any one of embodiments 5 to 10, wherein the first coextruded portion contains 2 to 7% by weight of naloxone.

[0419] Embodiment 12. A gastroretentive system described in any one of embodiments 5 to 11, wherein the first coextruded portion contains 35 to 50 weight % polycaprolactone.

[0420] Embodiment 13. A gastroretentive system described in any one of embodiments 5 to 12, wherein the first coextrusion portion comprises polyethylene glycol and poloxamer.

[0421] Embodiment 14. A gastroretentive system described in any one of embodiments 5 to 13, wherein the second coextruded portion contains 30 to 50% by weight of naloxone.

[0422] Embodiment 15. A gastroretentive system described in any one of embodiments 5 to 14, wherein the second coextruded portion comprises 50 to 60% by weight of polycaprolactone.

[0423] Embodiment 16. A gastroretentive system described in any one of embodiments 5 to 15, wherein the second coextrusion portion comprises a poloxamer.

[0424] Embodiment 17. A gastroretentive system described in any one of embodiments 1 to 16, wherein the at least one co-extruded drug-eluting component comprises 30 mg to 40 mg of buprenorphine or a salt thereof.

[0425] Embodiment 18. A gastroretentive system described in any one of embodiments 1 to 17, wherein the at least one co-extruded drug-eluting component comprises 8 mg to 15 mg of naloxone or a salt thereof.

[0426] Embodiment 19. A gastric retention system as described in any of embodiments 1 to 18, 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, each of the plurality of arms extending radially from the central elastomer, and at least one of the plurality of arms comprising the at least one co-extruded drug-eluting component.

[0427] Embodiment 20. A gastric retention system as described in embodiment 19, wherein the plurality of arms comprises six arms.

[0428] Embodiment 21. A gastric retention system as described in embodiment 19 or 20, wherein at least two of the plurality of arms comprise a co-extruded drug-eluting component of the at least one co-extruded drug-eluting component.

[0429] Embodiment 22. A gastric retention system as described in embodiment 19 or 20, wherein at least three of the plurality of arms comprise a co-extruded drug-eluting component of the at least one co-extruded drug-eluting component.

[0430] Embodiment 23. A gastric retention system as described in embodiment 19 or 20, wherein six of the plurality of arms comprise a co-extruded drug-eluting component of the at least one co-extruded drug-eluting component.

[0431] Embodiment 24. A gastric retention system described in any of embodiments 19 to 23, 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.

[0432] Embodiment 25. The gastric retention system of embodiment 24, wherein each arm of the plurality of arms comprises a first disintegrable matrix segment attached to the polymer linker segment, and the first disintegrable 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.

[0433] Embodiment 26. The gastric retention system of embodiment 25, wherein each arm of the plurality of arms comprises a first inactive segment attached to the first disintegrable matrix segment, the first inactive segment comprising polycaprolactone and (BiO)2CO3.

[0434] Embodiment 27. The gastric retention system of embodiment 26, 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.

[0435] Embodiment 28. The gastric retention system of embodiment 27, wherein each arm of the plurality of arms comprises a second inactive segment attached to the second disintegrable matrix segment, the second inactive segment comprising polycaprolactone and (BiO)2CO3.

[0436] Embodiment 29. The gastric retention system of embodiment 28, wherein a first arm of the plurality of arms comprises at least one co-extruded drug eluting component attached to the second inactive segment.

[0437] Embodiment 30. The gastric retention system of embodiment 28, wherein a second arm of the plurality of arms comprises a non-active segment attached to the second inactive segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0438] Embodiment 31. A gastric retention system as described in embodiment 29 or 30, wherein each arm of the plurality of arms comprises a third inactive segment attached to one of the co-extruded drug-eluting components or inactive segments, the third inactive segment comprising polycaprolactone and (BiO)2CO3.

[0439] Embodiment 32. The gastric retention system of embodiment 31, wherein each arm of the plurality of arms comprises a third disintegrable matrix segment attached to the third inactive segment, and the third disintegrable matrix comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0440] Embodiment 33. A gastric retention system as described in embodiment 32, comprising a filament circumferentially connecting each arm, wherein the circumferential filament is attached to the third disintegrable matrix segment of each arm.

[0441] Embodiment 34. A method for treating an opioid abuse disorder in an individual, comprising administering to the individual a gastroretentive system described in any one of embodiments 1 to 33.

[0442] EMBODIMENT 35. A method for treating pain in an individual, comprising administering to the individual a gastroretentive system described in any one of embodiments 1 to 33.

[0443] Embodiment 36. A gastric retention system comprising at least one drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and a rate controlling release membrane coating the at least one drug eluting component, wherein the gastric retention system is configured to be retained in the stomach of a human body for at least 48 hours and to release buprenorphine for at least 48 hours, and wherein the at least one drug eluting component having the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach, and to release at least 10% of the naloxone or a salt thereof within the first 24 hours of retention in the stomach.

[0444] Embodiment 37. The gastroretentive system of embodiment 36, wherein the rate-controlling release membrane comprises polycaprolactone and copovidone.

[0445] Embodiment 38. The gastric retention system described in embodiment 37, wherein the rate-controlling release membrane comprises 60 to 90% by weight of polycaprolactone.

[0446] Embodiment 39. The gastroretentive system of embodiment 36 or 37, wherein the rate-controlling release membrane comprises 10 to 40% by weight of copovidone.

[0447] Embodiment 40. A gastroretentive system described in any of embodiments 36 to 39, wherein the at least one drug-eluting component comprises 35 to 50% by weight of buprenorphine.

[0448] Embodiment 41. A gastroretentive system described in any one of embodiments 36 to 40, wherein the at least one drug-eluting component comprises 2 to 7% by weight of naloxone.

[0449] Embodiment 42. A gastroretentive system described in any one of embodiments 36 to 41, wherein the at least one drug-eluting component comprises 35 to 50% by weight polycaprolactone.

[0450] Embodiment 43. A gastroretentive system described in any one of embodiments 36 to 42, wherein the at least one drug-eluting component comprises polyethylene glycol and poloxamer.

[0451] Embodiment 44. A gastroretentive system described in any of embodiments 36 to 43, wherein the at least one drug-eluting component comprises 10 mg to 30 mg of buprenorphine or a salt thereof.

[0452] Embodiment 45. A gastroretentive system described in any one of embodiments 36 to 44, wherein the at least one drug-eluting component comprises 1 mg to 3 mg of naloxone or a salt thereof.

[0453] EMBODIMENT 46. A gastric retention system as described in any of embodiments 36 to 45, 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, each of the plurality of arms extending radially from the central elastomer, and at least one of the plurality of arms comprising at least one drug-eluting component.

[0454] Embodiment 47. A gastric retention system as described in embodiment 46, wherein the plurality of arms includes six arms.

[0455] Embodiment 48. A gastric retention system as described in embodiment 46 or 47, wherein at least two of the plurality of arms contain a drug-eluting component of the at least one drug-eluting component.

[0456] Embodiment 49. A gastric retention system as described in embodiment 46 or 47, wherein at least three of the plurality of arms contain a drug-eluting component of the at least one drug-eluting component.

[0457] Embodiment 50. A gastric retention system as described in embodiment 46 or 47, wherein six of the plurality of arms contain a drug-eluting component of the at least one drug-eluting component.

[0458] Embodiment 51. A gastroretentive system of any of embodiments 46 to 50, wherein each arm of the plurality of arms comprises a polymer linker segment attached to a central elastomer, the polymer linker segment comprising polycaprolactone.

[0459] Embodiment 52. The gastric retention system of embodiment 51, wherein each arm of the plurality of arms comprises a first disintegrable matrix segment attached to a polymer linker segment, and the first disintegrable 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.

[0460] Embodiment 53. The gastric retention system of embodiment 52, wherein each arm of the plurality of arms comprises a first inactive segment attached to the first disintegrable matrix segment, the first inactive segment comprising polycaprolactone and (BiO)2CO3.

[0461] Embodiment 54. The gastric retention system described in embodiment 53, 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.

[0462] Embodiment 55. The gastric retention system described in embodiment 54, wherein each arm of the plurality of arms comprises a second inactive segment attached to a second disintegrable matrix segment, the second inactive segment comprising polycaprolactone and (BiO)2CO3.

[0463] Embodiment 56. A gastric retention system as described in embodiment 55, wherein a first arm of the plurality of arms comprises a drug eluting component of the at least one drug eluting component attached to the second inactive segment.

[0464] Embodiment 57. The gastric retention system of embodiment 55, wherein a second arm of the plurality of arms comprises a non-active segment attached to the second inactive segment, the non-active segment comprising polycaprolactone, copovidone, and poloxamer.

[0465] Embodiment 58. A gastric retention system as described in embodiment 56 or 57, wherein each arm of the plurality of arms comprises a third inactive segment attached to one of the drug eluting components or non-active segments, and the third inactive segment comprises polycaprolactone and (BiO)2CO3.

[0466] Embodiment 59. The gastric retention system described in embodiment 58, wherein each arm of the plurality of arms comprises a third disintegrable matrix segment attached to the third inactive segment, and the third disintegrable matrix comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0467] Embodiment 60. A gastric retention system as described in embodiment 59, comprising a filament circumferentially connecting each arm, wherein the circumferential filament is attached to the third disintegrable matrix segment of each arm.

[0468] Embodiment 61. A method for treating an opioid abuse disorder in an individual, comprising administering to said individual a gastroretentive system described in any one of embodiments 36 to 60.

[0469] Embodiment 62. A method for treating pain in an individual, comprising administering to the individual a gastric retention system described in any one of embodiments 36 to 60.

[0470] Embodiment 63. 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 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 a drug eluting component comprises: a polymer linker segment; a first disintegrable matrix segment attached to the polymer linker segment; a first inert segment attached to said first disintegrable matrix segment; said first inert segment. a second disintegrable matrix segment attached to the second disintegrable matrix segment; a second inactive segment attached to the second disintegrable matrix segment; the drug eluting component attached to the second inactive segment, wherein the drug eluting component comprises a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and wherein the drug eluting component further comprises a coating comprising a release rate controlling polymer membrane; a third inactive segment attached to the drug eluting component; a third disintegrable matrix segment attached to the third inactive segment; and a filament circumferentially connecting each arm.

[0471] Embodiment 64. A method for making a gastroretentive system comprising co-extruding at least one drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and applying a rate controlling release membrane to the at least one co-extruded drug eluting component, wherein the gastroretentive system is configured to be retained in a human stomach for at least 48 hours and to release buprenorphine for at least 48 hours, and wherein the at least one co-extruded drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach, and to release at least 10% of the naloxone or a salt thereof after the first 24 hours of retention in the stomach.

[0472] Embodiment 65. The method of embodiment 64, wherein the rate controlling release membrane comprises polycaprolactone and copovidone.

[0473] Embodiment 66. The method of embodiment 65, wherein the rate-controlling release membrane comprises 60 to 90% by weight of polycaprolactone.

[0474] Embodiment 67. The method of embodiment 65 or 66, wherein the rate-controlling release membrane comprises 10 to 40% by weight of copovidone.

[0475] Embodiment 68. The method of any of embodiments 64 to 67, wherein the at least one co-extruded drug-eluting component comprises a first co-extruded portion comprising naloxone and a second co-extruded portion comprising buprenorphine and naloxone.

[0476] Embodiment 69. The method of embodiment 68, wherein coextruding the at least one drug eluting component comprises coextruding the first coextruded portion embedded in the second coextruded portion.

[0477] Embodiment 70. The method of embodiment 68 or 69, wherein coextruding the at least one drug eluting component comprises coextruding strands of the first coextruded portion embedded in the second coextruded portion.

[0478] Embodiment 71. The method of embodiment 68, wherein coextruding the at least one drug eluting component comprises coextruding the first coextruded portion layered on the second coextruded portion.

[0479] Embodiment 72. The method of any one of embodiments 68 to 71, wherein the first coextruded portion is present in a ratio of 4:1 to the second coextruded portion.

[0480] Embodiment 73. The method of any one of embodiments 68 to 72, wherein the first coextrusion portion comprises 35 to 50% by weight buprenorphine.

[0481] Embodiment 74. The method of any one of embodiments 68 to 73, wherein the first coextrusion portion comprises 2 to 7% by weight naloxone.

[0482] Embodiment 75. The method of any one of embodiments 68 to 74, wherein the first coextruded portion comprises 35 to 50 weight percent polycaprolactone.

[0483] Embodiment 76. The method of any one of embodiments 68 to 75, wherein the first coextrusion portion comprises polyethylene glycol and poloxamer.

[0484] Embodiment 77. The method of any one of embodiments 68 to 76, wherein the second coextrusion portion comprises 30 to 50% by weight naloxone.

[0485] Embodiment 78. The method of any one of embodiments 68 to 77, wherein the second coextruded portion comprises 50 to 60 weight percent polycaprolactone.

[0486] Embodiment 79. The method of any one of embodiments 68 to 78, wherein the second coextrusion portion comprises a poloxamer.

[0487] Embodiment 80. The method of any one of embodiments 64 to 79, wherein the at least one co-extruded drug-eluting component comprises 30 mg to 40 mg of buprenorphine or a salt thereof.

[0488] Embodiment 81. The method of any one of embodiments 64 to 80, wherein the at least one co-extruded drug-eluting component comprises between 8 mg and 15 mg of naloxone or a salt thereof.

[0489] Embodiment 82. A method according to any of embodiments 64 to 81, 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 co-extruded drug-eluting component.

[0490] Embodiment 83. The method of embodiment 82, wherein the plurality of arms comprises six arms.

[0491] Embodiment 84. The method of embodiment 82 or 83, wherein at least two of the plurality of arms comprise a co-extruded drug eluting component of the at least one co-extruded drug eluting component.

[0492] Embodiment 85. The method of embodiment 82 or 83, wherein at least three of the plurality of arms comprise a co-extruded drug eluting component of the at least one co-extruded drug eluting component.

[0493] Embodiment 86. The method of embodiment 82 or 83, wherein six of the plurality of arms comprise a co-extruded drug eluting component of the at least one co-extruded drug eluting component.

[0494] Embodiment 87. The method of any of embodiments 82 to 86, 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.

[0495] Embodiment 88. The method of embodiment 87, wherein each arm of the plurality of arms comprises a first disintegrable matrix segment attached to the polymer linker segment, and the first disintegrable 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.

[0496] Embodiment 89. The method of embodiment 88, wherein each arm of the plurality of arms comprises a first inactive segment attached to the first disintegrable matrix segment, the first inactive segment comprising polycaprolactone and (BiO)2CO3.

[0497] Embodiment 90. The method of embodiment 89, 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.

[0498] Embodiment 91. The method of embodiment 90, wherein each arm of the plurality of arms comprises a second inactive segment attached to the second disintegrable matrix segment, the second inactive segment comprising polycaprolactone and (BiO)2CO3.

[0499] Embodiment 92. The method of embodiment 91, wherein a first arm of the plurality of arms comprises at least one co-extruded drug eluting component attached to the second inactive segment.

[0500] Embodiment 93. The method of embodiment 91, wherein a second arm of the plurality of arms comprises a non-active segment attached to the second inactive segment, and the non-active segment comprises polycaprolactone, copovidone, and poloxamer.

[0501] Embodiment 94. The method of embodiment 92 or 93, wherein each arm of the plurality of arms comprises a third inactive segment attached to one of the co-extruded drug eluting components or non-active segments, the third inactive segment comprising polycaprolactone and (BiO)2CO3.

[0502] Embodiment 95. The method of embodiment 94, wherein each arm of the plurality of arms comprises a third disintegrable matrix segment attached to the third inactive segment, and the third disintegrable matrix comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0503] Embodiment 96. The method of embodiment 95, comprising a filament circumferentially connecting each arm, the circumferential filament being attached to the third disintegrable matrix segment of each arm.

[0504] Embodiment 97. A method of making a gastroretentive system comprising extruding at least one drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof, and applying a rate controlling release membrane to the at least one drug eluting component, wherein the gastroretentive system is configured to remain in a human stomach for at least 48 hours and to release buprenorphine for at least 48 hours, and wherein the at least one drug eluting component with the rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of residence in the stomach, and to release at least 10% of the naloxone or a salt thereof within the first 24 hours of residence in the stomach.

[0505] Embodiment 98. The method of embodiment 97, wherein the rate controlling release membrane comprises polycaprolactone and copovidone.

[0506] Embodiment 99. The method of embodiment 98, wherein the rate-controlling release membrane comprises 60 to 90% by weight of polycaprolactone.

[0507] Embodiment 100. The method of embodiment 98 or 99, wherein the rate-controlling release membrane comprises 10 to 40% by weight of copovidone.

[0508] Embodiment 101. The method of any of embodiments 97-100, wherein the at least one drug-eluting component comprises 35-50% by weight buprenorphine.

[0509] Embodiment 102. The method of any one of embodiments 97 to 101, wherein the at least one drug eluting component comprises 2 to 7% by weight naloxone.

[0510] Embodiment 103. The method of any one of embodiments 97 to 102, wherein the at least one drug-eluting component comprises 35 to 50 weight percent polycaprolactone.

[0511] Embodiment 104. The method of any one of embodiments 97 to 103, wherein the at least one drug eluting component comprises polyethylene glycol and poloxamer.

[0512] Embodiment 105. The method of any of embodiments 97 to 104, wherein the at least one drug-eluting component comprises 10 mg to 30 mg of buprenorphine or a salt thereof.

[0513] Embodiment 106. The method of any one of embodiments 97 to 105, wherein the at least one drug eluting component comprises 1 mg to 3 mg of naloxone or a salt thereof.

[0514] Embodiment 107. A method according to any of embodiments 97 to 106, 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, each of the plurality of arms extending radially from the central elastomer, and at least one of the plurality of arms comprising the at least one drug-eluting component.

[0515] Embodiment 108. The method of embodiment 107, wherein the plurality of arms comprises six arms.

[0516] Embodiment 109. The method of embodiment 107 or 108, wherein at least two of the plurality of arms contain a drug eluting component of the at least one drug eluting component.

[0517] Embodiment 110. The method of embodiment 107 or 108, wherein at least three of the plurality of arms contain a drug eluting component of the at least one drug eluting component.

[0518] Embodiment 111. The method of embodiment 107 or 108, wherein six of the plurality of arms contain a drug eluting component of the at least one drug eluting component.

[0519] Embodiment 112. The method of any of embodiments 107 to 111, 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.

[0520] Embodiment 113. The method of embodiment 112, wherein each arm of the plurality of arms comprises a first disintegrable matrix segment attached to the polymer linker segment, and the first disintegrable 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.

[0521] Embodiment 114. The method of embodiment 113, wherein each arm of the plurality of arms comprises a first inactive segment attached to the first disintegrable matrix segment, the first inactive segment comprising polycaprolactone and (BiO)2CO3.

[0522] Embodiment 115. The method of embodiment 114, 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.

[0523] Embodiment 116. The method of embodiment 115, wherein each arm of the plurality of arms comprises a second inactive segment attached to the second disintegrable matrix segment, the second inactive segment comprising polycaprolactone and (BiO)2CO3.

[0524] Embodiment 117. The method of embodiment 116, wherein a first arm of the plurality of arms comprises a drug eluting component of the at least one drug eluting component attached to the second inactive segment.

[0525] Embodiment 118. The method of embodiment 117, wherein a second arm of the plurality of arms comprises a non-active segment attached to the second inactive segment, and the non-active segment comprises polycaprolactone, copovidone, and poloxamer.

[0526] Embodiment 119. The method of embodiment 117 or 118, wherein each arm of the plurality of arms comprises a third inactive segment attached to one of the drug eluting component or the non-active segments, and the third inactive segment comprises polycaprolactone and (BiO)2CO3.

[0527] Embodiment 120. The method of embodiment 119, wherein each arm of the plurality of arms comprises a third disintegrable matrix segment attached to the third inactive segment, and the third disintegrable matrix comprises polycaprolactone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), stearic acid, and polypropylene glycol.

[0528] Embodiment 121. The method of embodiment 120, comprising a filament circumferentially connecting each arm, the circumferential filament being attached to the third disintegrable matrix segment of each arm.

[0529] The foregoing description has set forth example systems, methods, techniques, parameters, etc. It should be recognized, however, that such description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary implementations.

[0530] In the present description, terms such as first, second, etc. are used to describe various elements, but these elements should not be limited by these terms. These terms are used only to distinguish one element from another.

Claims

1. at least one co-extruded drug eluting component comprising a carrier polymer, buprenorphine or a salt thereof, and naloxone or a salt thereof; a rate controlling release membrane coating said at least one co-extruded drug eluting component, wherein the gastroretention system is configured to remain in the stomach of a human body for at least 48 hours and to release buprenorphine for at least 48 hours, and wherein the at least one co-extruded drug eluting component having a rate controlling release membrane is configured to release at least 10% of the buprenorphine or a salt thereof after the first 24 hours of retention in the stomach and to release at least 10% of the naloxone or a salt thereof after the first 24 hours of retention in the stomach.

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

3. The gastroretentive system of claim 2, wherein the rate-controlling release membrane comprises 60-90% by weight of polycaprolactone.

4. The gastroretentive system of claim 2 or 3, wherein the rate-controlling release membrane comprises 10-40% by weight of copovidone.

5. 2. The gastroretentive system of claim 1, wherein the at least one co-extruded drug eluting component comprises a first co-extruded portion comprising naloxone and a second co-extruded portion comprising buprenorphine and naloxone.

6. The gastroretentive system of claim 5 , wherein the first coextruded portion is embedded in the second coextruded portion.

7. The gastroretentive system of claim 5 or 6, wherein the first coextruded portion comprises one or more strands embedded within the second coextruded portion.

8. The gastroretentive system of claim 5 , wherein the first coextruded portion is layered over the second coextruded portion.

9. The gastroretentive system of claim 5 , wherein the first coextruded portion is present in a ratio of 4:1 to the second coextruded portion.

10. The gastroretentive system of claim 5 , wherein the first coextruded portion comprises 35-50% by weight buprenorphine.

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