Preparation method of gastric retention system

Abstract

A gastric retention system comprising one or more retention members comprising: at least one drug eluting component; and at least one laser joint component laser welded to the at least one drug eluting component.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application 63 / 506,039, filed June 2, 2023, the entire contents of which are incorporated herein by reference.

[0003] field

[0004] This disclosure generally relates to gastric retention systems, and more particularly to methods for preparing gastric retention systems.

[0005] background

[0006] A gastric retention system is a delivery system for therapeutic agents that are retained in the stomach for several days to several weeks or even longer, during which time the drug or other active agent can be eluted from the system for absorption in the gastrointestinal tract.

[0007] A gastric retention system can be administered to a patient using a capsule, which can be swallowed or introduced into the patient's stomach via an alternative method, such as a feeding tube or gastric tube. When the capsule dissolves in the stomach, the gastric retention system can inflate or expand to the size required to remain in the stomach and prevent passage through the pylorus for the desired retention period. Throughout the desired retention period, the system elutes one or more active agents (e.g., drugs) at the desired rate. At the end of the retention period, the system passes through the pylorus and is cleared from the patient. However, if the system passes through the pylorus before the end of the desired retention period, one or more active agents may not be delivered to the patient as intended. Therefore, the gastric retention system needs to be prepared to keep the system intact until the end of the desired retention period.

[0008] Gastric retention systems typically comprise multiple components with different functions. For example, a gastric retention system may include an elastomeric component that allows the system to be compacted, a drug elution component that elutes the active pharmaceutical ingredient at a desired rate, a time-dependent and enteric component that facilitates the system's degradation at the end of the desired retention time, and an inactive component that helps maintain the system's size and shape. Each of these components may contain multiple different polymers with varying properties. Due to their different compositions, properties, and functions, the polymers used in these components may be difficult to adhere using conventional preparation methods. Therefore, improved methods for preparing gastric retention systems are needed.

[0009] Overview

[0010] As described, a gastric retention system can comprise multiple distinct components for different functions, such as elastomeric components, drug-eluting components, time-dependent and enteric-coated components, and / or inactive components. Connecting these distinct components using conventional manufacturing methods while preserving their individual functions is a challenge. For example, some methods involve overmolding multiple components of the gastric retention system onto each other. However, this can result in a system that is too large to fit into a conventional capsule for administration and may hinder the function of the different components. Components can also be joined using adhesives, but the adhesives used must be safe for human consumption, as the system described herein is designed for patient swallowing. Using adhesives also introduces additional components into the system, thereby introducing additional points of failure.

[0011] Some existing fabrication techniques do not introduce additional components into the system, such as infrared welding or hot plate welding. However, both infrared welding and hot plate welding present their own challenges. For example, certain components of a gastric retention system (e.g., drug elution components) may be temperature-sensitive. The heat provided during infrared welding and hot plate welding may not be concentrated at the interface between components, potentially melting more components than are necessary to join them, thus damaging temperature-sensitive components. Furthermore, infrared welding and hot plate welding typically require welding polymers together to make them similar (e.g., in terms of structure or composition) to produce a strong weld. However, the components used in the gastric retention system described herein comprise a variety of polymers with different functions and properties.

[0012] This paper presents an improved fabrication technique that uses laser welding to adhere components of a gastric retention system. Laser welding uses laser energy to heat the interface between components, causing them to melt and fuse together. The bonds produced by laser welding can be stronger than those produced by other polymer bonding techniques, resulting in a stronger gastric retention system and enhanced protection against rupture and premature pyloric passage. Laser welding can also be advantageous because it can be used to efficiently weld components with different polymer compositions while allowing the different components to maintain their specific functionality. Furthermore, laser welding uses a focused energy beam to weld the components, making it easier to avoid damaging heat-sensitive components, such as drug-eluting components.

[0013] The gastric retention system includes: one or more retainers, each comprising: at least one drug elution component; and at least one laser connector component laser-welded to at least one drug elution component.

[0014] In some embodiments, one or more retainers are connected to an elastomeric component. In some embodiments, the elastomeric component is overmolded onto a first portion of at least one inter-component anchor. In some embodiments, the laser connector component is overmolded onto a second portion of at least one inter-component anchor. In some embodiments, the first retainer is connected to the elastomeric component via the overmolded laser connector component. In some embodiments, at least one laser connector component comprises an inactive component. In some embodiments, the inactive component comprises polycaprolactone. In some embodiments, the inactive component further comprises bismuth subcarbonate. In some embodiments, the inactive component further comprises copovidone. In some embodiments, the inactive component further comprises poloxamer. In some embodiments, the inactive component further comprises a colorant. In some embodiments, at least one laser connector component comprises an enteric disintegrating matrix. In some embodiments, the enteric disintegrating matrix comprises polycaprolactone. In some embodiments, the enteric disintegrating matrix further comprises HPMCAS. In some embodiments, the enteric disintegrating matrix further comprises poloxamer. In some embodiments, at least one laser connector component comprises a time-dependent disintegrating matrix. In some embodiments, the time-dependent disintegrating matrix comprises polycaprolactone. In some embodiments, the time-dependent disintegration matrix further comprises poly(ethylene oxide). In some embodiments, the time-dependent disintegration matrix further comprises 50 / 50DL-lactide / glycolic acid copolymer. In some embodiments, the time-dependent disintegration matrix further comprises iron(III) oxide. In some embodiments, the drug elution component comprises polycaprolactone. In some embodiments, the drug elution component further comprises an active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient includes meloxicam, excipientan, citalopram, clopidogrel, prednisone, aripiprazole, risperidone, buprenorphine, naloxone, montelukast, memantine, digoxin, tamsulosin, ezetimibe, colchicine, loratadine, cetirizine, loperamide, omeprazole, entecavir, doxycycline, ciprofloxacin, azithromycin, antimalarial agents, levothyroxine, methadone, varenicline, contraceptives, stimulants, or nutrients, or one or more of these. In some embodiments, the drug elution component further comprises copovidone. In some embodiments, the drug elution component further comprises poloxamer. In some embodiments, the drug elution component further comprises vitamin E succinate. In some embodiments, the drug elution component further comprises silica. In some embodiments, the drug elution component further comprises a colorant. In some embodiments, the difference between the melt flow index of at least one laser connector component and the melt flow index of at least one drug elution component is greater than 10%. In some embodiments, the difference between the melt flow index of at least one laser connector component and the melt flow index of at least one drug elution component is less than 50%. In some embodiments, the polycaprolactone content of at least one laser connector component is at least 30% by weight.In some embodiments, the polycaprolactone content of at least one laser junction component is at least 40% by weight. In some embodiments, the polycaprolactone content of at least one drug elution component is at least 30% by weight. In some embodiments, the polycaprolactone content of at least one drug elution component is at least 40% by weight. In some embodiments, the polycaprolactone content of at least one laser junction component is less than 50% by weight. In some embodiments, the polycaprolactone content of at least one laser junction component is less than 65% by weight. In some embodiments, the polycaprolactone content of at least one laser junction component is less than 75% by weight. In some embodiments, the polycaprolactone content of at least one drug elution component is less than 50% by weight. In some embodiments, the polycaprolactone content of at least one drug elution component is less than 65% by weight. In some embodiments, the polycaprolactone content of at least one drug elution component is less than 75% by weight. In some embodiments, the melting temperature of at least one drug elution component is within the range of 1-75°C from the melting temperature of at least one laser junction component. In some embodiments, the melting temperature of at least one drug elution component is within 5-50°C of the melting temperature of at least one laser connector component. In some embodiments, the width of the molten zone between the laser-welded components of one or more retainers is 0.5 mm-5 mm. In some embodiments, the width of the molten zone between the laser-welded components of one or more retainers is 1 mm-3 mm. In some embodiments, the depth of the molten zone between the laser-welded components of one or more retainers is at least 90% of the depth of the interface between the laser-welded components. In some embodiments, the depth of the molten zone between the laser-welded components of one or more retainers is at least 95% of the depth of the interface between the laser-welded components. In some embodiments, the gastric retention system receives a score of at least 7 when using a window-circulation funnel test. In some embodiments, the gastric retention system receives a score of at least 10 when using a window-circulation funnel test. In some embodiments, the gastric retention system is configured to be in a stressed configuration during administration and is configured to present an open configuration when in the patient's stomach.

[0015] A method for preparing a gastric retention system, the gastric retention system comprising one or more retainers, each including at least one drug elution component and at least one laser connector component, the method comprising: laser welding at least one drug elution component to at least one laser connector component.

[0016] In some embodiments, the method further includes placing at least one laser connector component and at least one drug elution component in a laser welding holder prior to laser welding. In some embodiments, the method further includes applying a radial force that presses at least one drug elution component onto at least one laser connector component. In some embodiments, the radial force is 5 N-200 N. In some embodiments, the radial force is 10 N-50 N. In some embodiments, the method further includes applying a downward force that presses at least one drug elution component and at least one laser connector component onto the laser welding holder. In some embodiments, the vertical force is 100 N-5000 N. In some embodiments, the vertical force is 200 N-2800 N. In some embodiments, laser welding is performed using a laser with a wavelength of 0.7 µm-2.5 µm. In some embodiments, laser welding is performed using a laser with a wavelength of 1.9 µm-2.0 µm. In some embodiments, laser welding is performed using a laser with a Gaussian energy distribution or a top-cap energy distribution. In some embodiments, laser welding is performed using a laser with a beam diameter of 0.5 mm-5 mm. In some embodiments, laser welding is performed using a laser with a beam diameter of 1 mm to 3 mm. In some embodiments, laser welding is performed in an environment with humidity below 40%. In some embodiments, laser welding is performed in an environment with humidity below 25%. In some embodiments, laser welding is performed in an environment with at least 10% humidity. In some embodiments, laser welding is performed in an environment with at least 15% humidity. In some embodiments, the method further includes laser welding one or more retainers to an elastomeric component, wherein the elastomeric component includes one or more laser connector components configured to laser weld to one or more retainers. In some embodiments, the gastric retention system includes at least two retainers laser welded to the elastomeric component. In some embodiments, the gastric retention system includes at least three retainers laser welded to the elastomeric component. In some embodiments, the gastric retention system includes at least four retainers laser welded to the elastomeric component. In some embodiments, the gastric retention system includes at least five retainers laser welded to the elastomeric component. In some embodiments, the gastric retention system includes at least six retainers laser welded to the elastomeric component. In some embodiments, laser welding at least one drug elution component to at least one laser connector component includes laser welding along a repeating path that connects the respective interfaces between at least one drug elution component and at least one connector on each retainer. In some embodiments, the repeating path is a loop path. In some embodiments, laser welding at least one drug elution component to at least one laser connector component includes round-trip laser welding along the interface between at least one drug elution component and at least one laser connector component.

[0017] The laser welding system comprises: a laser welding support configured to hold components of a gastric retention system in an assembly sequence; at least one radial pressure piston configured to apply a radial force to the gastric retention system in a direction transverse to the seam between each component; at least one vertical pressure piston configured to apply a downward force to the gastric retention system in a direction parallel to the seam between each component; and at least one laser configured to weld the seam between each component of the gastric retention system.

[0018] In some embodiments, the laser-welded support comprises aluminum or stainless steel. In some embodiments, the laser-welded support is nickel-plated. In some embodiments, the laser-welded support includes recesses sized and shaped to accommodate components of a gastric retention system. In some embodiments, the top surface of the laser-welded support comprises a silicone layer. In some embodiments, the top surface of the laser-welded support comprises a polytetrafluoroethylene-coated glass layer. In some embodiments, the laser welding system also includes a cap configured to hold components of the gastric retention system in place during laser welding. In some embodiments, the cap comprises silicone or polytetrafluoroethylene-coated glass. In some embodiments, the laser welding system also includes a top layer located on top of the cap. In some embodiments, the top layer comprises quartz glass. In some embodiments, the radial force applied by at least one radial pressure piston is 5-200 N. In some embodiments, the radial force applied by at least one radial pressure piston is 10-50 N. In some embodiments, the downward force applied by at least one vertical pressure piston is 100-5000 N. In some embodiments, the downward force applied by at least one vertical pressure piston is 200-2800 N. In some embodiments, at least one laser has a wavelength of 0.7 µm to 2.5 µm. In some embodiments, at least one laser has a wavelength of 1.9 µm to 2.0 µm. In some embodiments, at least one laser has a Gaussian energy distribution or a top-cap energy distribution. In some embodiments, at least one laser has a beam diameter of 0.5 mm to 5 mm. In some embodiments, at least one laser has a beam diameter of 1 mm to 3 mm. Brief description of the attached diagram

[0020] The invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0021] Figure 1A This shows an open-structured gastric retention system.

[0022] Figure 1B Displaying a folded structure of the gastric retention system.

[0023] Figure 2The gastric retention system is shown, which includes multiple retainers, and the gastric retention system is most likely to exhibit a curved geometry when subjected to forces such as gastric contraction.

[0024] Figures 3A-3C This demonstrates various methods by which the gastric retention system passes through the pylorus before the gastric retention time has elapsed.

[0025] Figure 4A This shows an exemplary Gaussian energy distribution of a laser beam.

[0026] Figure 4B This shows an exemplary top-cap energy distribution of the laser beam.

[0027] Figure 5 This illustrates an exemplary laser-welded gastric retention system.

[0028] Figures 6A-6B This shows an exemplary energy thermal map generated by laser welding a gastric retention system.

[0029] Figures 7A-7B This shows an exemplary energy thermal map generated by oscillating a laser beam around a circular path.

[0030] Figures 8A-8B Example: Exemplary laser welding assembly.

[0031] Figure 9 Example: A laser-welded bracket.

[0032] Figure 10 Example: Exemplary gastric retention system.

[0033] Figure 11 An example of a method for quantifying the welding strength of a gastric retention system.

[0034] Figure 12 The results of tensile tests on gastric retention systems prepared using laser welding and infrared welding are shown.

[0035] Figure 13 This displays the absorbance of different components of a laser-welded gastric retention system.

[0036] Figure 14 This displays the absorbance of different components of a laser-welded gastric retention system.

[0037] Figure 15 This demonstrates the relationship between the window-circulation funnel test results and the total energy of the star-shaped structure in a laser-welded gastric retention system.

[0038] Figure 16 This displays the melting temperature and pressure of different components of a laser-welded gastric retention system.

[0039] Detailed description

[0040] This article describes a method for preparing a gastric retention system. The gastric retention system is designed to remain in the patient's gastrointestinal tract for a predetermined retention time. After the retention time has elapsed, the gastric retention system breaks down into several pieces, small enough to pass through the pylorus. If the gastric retention system breaks down prematurely, the therapeutic agents contained within it may not be delivered to the patient as intended.

[0041] Therefore, gastric retention systems need to be fabricated in a way that ensures the system does not rupture prematurely. This paper presents a method for fabricating a gastric retention system that uses laser welding to thermally connect the components of the system.

[0042] Laser welding uses laser energy to heat the interface between components, causing the components to melt and fuse together at the interface. An exemplary gastric retention system prepared using the laser welding technique described herein may include one or more retainers. Each retainer may include at least one drug elution component and at least one laser connector component laser-welded to the drug elution component. The laser connector component may include a time-dependent or intestinal-disintegrating matrix or an inactive component and may be used to control properties of the gastric retention system (e.g., achieving a predetermined gastric retention time or maintaining the size and shape of the gastric retention system).

[0043] Connecting these different components of a gastric retention system while maintaining their function and integrity can be challenging. For example, overmolding can be used to connect components; however, this may make the system too large to fit into a conventional capsule for administration and may hinder the function of the different components. Adhesives can also be used to connect components, but the adhesives used must be safe for human consumption, and the use of adhesive components introduces additional points of failure into the system. Thermal bonding techniques (such as infrared welding or hot plate welding) can also be used, but these methods may damage heat-sensitive components and may be ineffective unless the components to be welded contain polymers with relatively similar properties.

[0044] The laser welding technology presented in this article can solve one or more of the aforementioned problems. Laser welding can be used to efficiently weld components with different polymer compositions, while allowing the different components to maintain their specific properties and functions. Furthermore, laser welding uses a focused energy beam to weld components, which can help maintain the integrity and functionality of heat-sensitive components. The joints produced by laser welding can also be stronger than those produced using conventional techniques to join components of the gastric retention system, which can enhance protection against system rupture and improve gastric retention.

[0045] definition

[0046] As used herein, a “gastric retention system” is a dosage form containing an active agent and configured to be administered to a patient in a folded configuration. A “gastric retention dosage form” contains a folded gastric retention system and is configured to retain the gastric retention system in the folded configuration until unfolded. For example, gastric retention dosage forms may contain capsules and / or capsule coatings, as described in U.S. Application No. 62 / 821,352, entitled “Capsules and Capsule Coatings for Gastric Residence Dosage Forms” and / or U.S. Application No. 62 / 821,361, entitled “Coatings for Gastric Residence Form”.

[0047] "Carrier polymer" is a polymer suitable for blending with active agents, such as pharmaceuticals, used in this invention.

[0048] "Active agent" refers to any substance used in a patient, individual, or person for therapeutic, diagnostic, or nutritional purposes. Active agents include, but are not limited to, drugs, nutrients, vitamins, and minerals.

[0049] A "dispersant" is defined as a substance that helps minimize the particle size of the surfactant and disperse the surfactant particles within the carrier polymer matrix. In other words, a dispersant helps minimize or prevent particle aggregation or flocculation during system preparation. Therefore, dispersants possess anti-aggregation and anti-flocculation activities and help maintain a uniform distribution of surfactant particles within the carrier polymer matrix.

[0050] "Excipients" are any substances added to an active agent formulation, not the active agent itself. Excipients include, but are not limited to, binders, coating agents, diluents, disintegrants, emulsifiers, flavoring agents, flow aids, lubricants, and preservatives. Specific categories of dispersants fall under the more general category of excipients.

[0051] "Elastic polymers" or "elastomers" (also known as "tensile polymers") are polymers that are able to deform from their original shape for a period of time by an applied force, and then essentially return to their original shape once the applied force is removed.

[0052] "Coupled polymer" is a polymer suitable for coupling any other polymer together, such as coupling a first carrier polymer-activator component to a second carrier polymer-activator component. Coupled polymers typically form joint regions between other components.

[0053] "Time-dependent polymers" or "time-dependent coupling polymers" are polymers that degrade in a time-dependent manner when the gastric retention system is present in the stomach. Time-dependent polymers are generally unaffected by normal pH changes in the stomach.

[0054] "Nearly constant plasma level" refers to plasma levels that remain within twice the average plasma level (i.e., 50% to 200% of the average plasma level) measured during the period when the gastric retention system is in the stomach.

[0055] When used to describe a material or system, "biocompatibility" means that the material or system does not cause adverse reactions, or causes only minimal, tolerable adverse reactions, when in contact with a living organism such as a human. In the context of a gastric retention system, biocompatibility in the gastrointestinal environment is evaluated.

[0056] "Patient," "individual," or "individual" refers to a mammal, preferably a human or a domesticated animal such as a dog or cat. In the most preferred embodiment, the patient, individual, or individual is a human being.

[0057] The “diameter” of the particles used in this article refers to the longest dimension of the particle.

[0058] "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 active agents, to a patient in need to reduce or eliminate the disease or disorder or one or more symptoms of the disease or disorder, or to delay 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.

[0059] "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 active agents, to a patient in need to suppress the clinical manifestations of the disease or disorder, or to suppress the manifestation of adverse symptoms of the disease or disorder. The distinction between treatment and suppression is that treatment occurs after the adverse symptoms of the disease or disorder have appeared in the patient, while suppression occurs before the adverse symptoms of the disease or disorder have appeared in the patient. Suppression can be partial, substantially complete, or complete. Because some diseases or disorders are hereditary, genetic screening can be used to identify patients at risk of developing a 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 in order to suppress the occurrence of any adverse symptoms.

[0060] The "therapeutic use" of the systems disclosed herein is defined as the use of one or more systems disclosed herein to treat a disease or disorder, as defined above. A "therapeuticly effective amount" of a therapeutic agent (e.g., a medicine) is an amount of active agent sufficient, when administered to a patient, to reduce or eliminate the disease or disorder or one or more symptoms of the disease or disorder, or to delay 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. A therapeutically effective amount may be administered to a patient as a single dose, or it may be divided and administered as multiple doses.

[0061] The “preventative use” of the systems disclosed herein is defined as the use of one or more of the systems disclosed herein to suppress a disease or disorder, as defined above. The “preventative effective amount” of the active agent is the amount of active agent sufficient, when administered to a patient, to suppress the clinical manifestations of the disease or disorder or to suppress the manifestation of adverse symptoms of the disease or disorder. The preventative effective amount may be administered to the patient as a single dose, or it may be divided and administered as multiple doses.

[0062] The flexural modulus of a material is an inherent property of the material, calculated as the ratio of stress to strain in the bending deformation of the material, as measured by a three-point bend test. Although the joint is described herein as a component of a gastric retention system, the flexural modulus of the polymer material can be measured separately. For example, a polymer joint in a gastric retention system may be too short to measure its flexural modulus, but a longer sample of the same material can be used to accurately determine 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 joint used in the gastric retention system. The flexural modulus is measured using a three-point bend test according to ASTM standard three-point bend test (ASTM D790), using a 10 mm distance between supports, and further modified to accommodate materials with non-rectangular cross-sections. The longest line of symmetry of the polymer joint's cross-section should be vertically positioned, and the flexural modulus should be measured by applying a downward force. If the longest line of symmetry of the polymer joint's cross-section is perpendicular to a single flat edge, the single flat edge should be positioned upward. If the cross-section of the polymer joint is triangular, the vertices of the triangle should face downward. When a downward force is applied, the force and displacement are measured, and the slope at the linear region is obtained to calculate the flexural modulus.

[0063] As used herein, the singular forms “a,” “an,” and “the” also include the plural forms, unless the context clearly indicates otherwise. It should also be understood that, as used herein, the term “and / or” refers to and includes any and all possible combinations of one or more of the related listed items. It should also be understood that the terms “comprising,” “including,” and / or “containing,” when used herein, specify the presence of the stated feature, integral, step, operation, element, component, and / or unit, but do not preclude the presence or addition of one or more other features, integrals, steps, operations, elements, components, units, and / or groups thereof.

[0064] When the terms “about” or “approximately” are used herein to refer to numerical values, it should be understood that this includes both the specified value and a value reasonably close to the specified value. For example, the description “about 50°C” or “approximately 50°C” includes the 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. If a range is indicated, such as “approximately 50°C-60°C” or “about 50°C-60°C”, it should be understood that this includes both values ​​specified by the endpoints, and for each endpoint or both endpoints, includes a value close to each endpoint or both endpoints; that is, “approximately 50°C-60°C” (or “about 50°C-60°C”) is equivalent to the statements “50°C-60°C” and “approximately 50°C-approximately 60°C” (or “about 50°C-60°C”).

[0065] This application discloses several numerical ranges in the text and figures. The disclosed numerical ranges inherently support any range or value within the disclosed numerical ranges, including endpoints; however, no precise range limitations are specified verbatim in this specification, as this disclosure can be applied throughout the entire disclosed numerical range.

[0066] Regarding the numerical ranges disclosed in this specification, any disclosed upper limit value for a component can be combined with any disclosed lower limit value for that component to provide a range (provided the upper limit value is greater than the lower limit value combined with it). Each of these combinations of the disclosed upper and lower limits is explicitly contemplated herein. For example, if the range of a particular component's amount is given as 10%-30%, 10%-12%, and 15%-20%, then ranges of 10%-20% and 15%-30% are also contemplated, while a combination of a 15% lower limit value and a 12% upper limit value is not possible and therefore not contemplated.

[0067] Unless otherwise stated, percentages of components in a composition are expressed as weight percentages or weight / weight percentages. It should be understood that references to relative weight percentages in a composition presuppose that the total combined weight percentage of all components in the composition is 100. It should also be understood that the relative weight percentages of one or more components may be adjusted upwards or downwards such that the total weight percentage of the components in the composition is 100, provided that the weight percentage of any particular component does not fall outside the limits of the range specified for that component.

[0068] Some embodiments described herein are described with respect to their various elements as “comprising” or “including”. In alternative embodiments, those elements may be described using transitional phrases such as “consisting primarily of” or “consisting substantially of” applied to those elements. In further alternative embodiments, those elements may be described using the transitional phrase “consisting of” applied to those elements. Thus, for example, if a composition or method is disclosed herein to comprise A and B, then alternative embodiments of the composition or method “consisting substantially of A and B” and alternative embodiments of the composition or method “consisting of A and B” are also considered to have been disclosed herein. Similarly, embodiments described with respect to their various elements as “consisting substantially of” or “consisting of” may also be described as “comprising” applied to those elements. Finally, embodiments described with respect to their various elements as “consisting substantially of” may also be described as “consisting of” applied to those elements, and embodiments described with respect to their various elements as “consisting of” may also be described as “consisting substantially of” applied to those elements.

[0069] When a composition or system is described as "consisting substantially of the listed elements," the composition or system comprises the elements expressly listed and may include other elements that do not substantially affect the condition treated (for compositions for treating the condition) or the properties of the system (for compositions comprising the system). However, in addition to those elements expressly listed (for compositions for treating the system), the composition or system does not contain any other elements that do substantially affect the condition treated, or any other elements that do substantially affect the properties of the system (for compositions comprising the system); or, if the composition or system does contain additional elements other than those listed that may substantially affect the condition treated or the properties of the system, the composition or system does not contain those additional elements in sufficient concentration or amount to substantially affect the condition treated or the properties of the system. When a method is described as "consisting substantially of the listed steps," the method includes the listed steps and may include other steps that do not substantially affect the condition treated by the method or the properties of the system produced by the method, but in addition to those steps expressly listed, the method does not include any other steps that substantially affect the condition treated or the system produced.

[0070] This disclosure provides several embodiments. It is conceivable that, where possible, any feature from any embodiment can be combined with any feature from any other embodiment. In this way, hybrid constructions of the disclosed features are within the scope of this invention.

[0071] General principles of the gastric retention system

[0072] This article provides a gastric retention system and a method for preparing said system. The gastric retention system relates to an administration method to a patient's stomach via swallowing or other methods of administration (e.g., tube feeding or nasogastric tube). Once in place in the stomach, the system is retained in the stomach for a desired retention period (e.g., 3 days, 7 days, 2 weeks, etc.). During retention, the system prevents passage through the pylorus, which separates the stomach from the small intestine. The system releases an active agent (e.g., an active pharmaceutical ingredient or drug) into the stomach at a controlled release rate during the retention period. While retained in the stomach, the system may not interfere with the normal passage of food or other gastric contents. Once the desired retention period has passed, the system can pass through the pylorus and be eliminated from the patient. If the system prematurely enters the small intestine from the stomach, it does not cause intestinal obstruction and can be easily eliminated from the patient again.

[0073] To administer the gastric retention system to a patient, the system can be folded into a sufficiently small configuration for swallowing or other administration. In some embodiments, the folded gastric retention system is contained in a capsule or other container that can be swallowed or otherwise administered by the patient. In some embodiments, the capsule may contain at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0074] In some embodiments, the folded gastric retention system can also be secured by a soluble retaining band or sleeve that prevents premature unfolding of the gastric retention system in the event of capsule or other container failure. The gastric retention system folded and held in the folded configuration by the sleeve or band can be encapsulated. In some embodiments, the sleeve or band may contain at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0075] Once the capsule or other container storing the gastric retention system reaches the patient's stomach, the capsule or container dissolves and releases the folded gastric retention system. Upon release, the gastric retention system can unfold and present an open configuration. The open configuration can be star-shaped. The dimensions of the open configuration gastric retention system, while remaining constant, are adapted to prevent the gastric retention system from passing through the pylorus during the desired retention period.

[0076] While in the stomach, the gastric retention system is compatible with the digestive and other normal functions of the stomach or gastrointestinal tract. The gastric retention system does not interfere with or prevent chyme (partially digested food) or other stomach contents from leaving the stomach through the pylorus into the duodenum.

[0077] A gastric retention system releases an active agent (e.g., while in the stomach). The gastric retention system may comprise multiple polymer-active agent components. In one embodiment, the polymer-active agent component comprises a carrier polymer, a dispersant, and an active agent (e.g., an active pharmaceutical ingredient). In another embodiment, the polymer-active agent component comprises a carrier polymer and an active agent. Multiple polymer-active agent components are connected together via one or more laser connector components and / or one or more elastomeric components. During the desired retention time of the system, the active agent is eluted from the carrier polymer-active agent component into the patient's gastric fluid. The release of the active agent is controlled by the appropriate formulation of the carrier polymer-active agent component, including the use of a dispersant in the formulation of the carrier polymer-active agent component and grinding the active agent into particles of a desired size before blending it with the carrier polymer and dispersant. Furthermore, a coating may be applied to the outer surface of the gastric retention system. The coating may include additional reagents or reagents that affect the release of the active agent or the retention time of the gastric retention system.

[0078] Once the desired retention time has elapsed, the gastric retention system exits the stomach. To this end, different components of the gastric retention system are designed to weaken and degrade. The specific size of the system is also considered. In its intact, open form, the gastric retention system is designed to resist passage through the pylorus. However, some of the laser-connecting components of the gastric retention system are chosen to degrade progressively during the designated retention period in the stomach. When the laser-connecting components are sufficiently weakened by degradation, the gastric retention system loses its critical resilience to compression or size reduction and may break down into smaller fragments. The reduced-size system and any smaller fragments are designed to pass through the pylorus. The system then traverses the intestine and is eliminated from the patient's body. In some embodiments, the gastric retention system can be designed to weaken at specific locations such that once the retention time has ended, the gastric retention system can pass through the pyloric valve intact without degrading into numerous smaller pieces.

[0079] Structure of the gastric retention system

[0080] Gastric retention systems can be fabricated in various configurations. Gastric retention systems according to some embodiments of this disclosure include one or more retainers. The retainer may be a component of the gastric retention system that helps prevent premature passage of the pyloric sphincter (e.g., expansion or unfolding within the gastric environment). In some embodiments, the retainer includes at least one drug-eluting component. The drug-eluting component may contain an active agent (an active pharmaceutical ingredient, such as a therapeutic agent). The drug-eluting component may also contain one or more carrier polymers and / or other excipients or additives (e.g., stabilizers or dispersants).

[0081] The drug elution unit can be connected to at least one connector component, for example by laser welding, infrared welding, adhesive bonding, or any other suitable connection method. When the connector component is connected to the drug elution unit using the laser welding technology described herein, the connector component may be referred to as a "laser connector component".

[0082] In some embodiments, the laser connector component may be an inactive component, a time-dependent disintegration matrix component, or an intestinal disintegration matrix component. In some embodiments, the designated retainer may include multiple laser connector components. For example, one or more laser connector components may be laser-welded to a drug elution component of the retainer. In another example, one or more laser connector components may be welded to one or more additional laser connector components within the retainer. In some embodiments, the retainer includes multiple types of laser connector components. For example, the retainer may include one or more inactive components, one or more time-dependent disintegration matrix components, and / or one or more intestinal disintegration matrix components.

[0083] In some implementations, the retainer may not include a drug elution component. A retainer without a drug elution component may include one or more laser connector components.

[0084] In some embodiments, the gastric retention system may include multiple retainers. For example, the gastric retention system may include at least two retainers, at least three retainers, at least four retainers, at least one retainer, or at least six retainers. In some embodiments, one or more retainers may include a drug-eluting component. For example, in a gastric retention system with six retainers, one retainer may include a drug-eluting component while five retainers do not; two retainers may include a drug-eluting component while four retainers do not; three retainers may include a drug-eluting component while three retainers do not; four retainers may include a drug-eluting component while two retainers do not; five retainers may include a drug-eluting component while one retainer does not; or all six retainers may include a drug-eluting component.

[0085] In some embodiments, one or more retainers may be attached to an elastomeric component. The elastomeric component allows the gastric retention system to be compressed, for example, by folding or compressing it to be applied to the stomach via swallowing a container or capsule containing the compressed system. As the capsule dissolves in the stomach, the gastric retention system expands into a shape that prevents the system from passing through the patient's pyloric sphincter for the desired retention time. Therefore, the elastomeric component must be able to be stored in a capsule in a compressible configuration for a reasonable storage period and, upon release from the capsule, expand to its original shape or near-original shape without rupturing due to torque or stress.

[0086] In some embodiments, the elastomeric component may comprise an elastomeric material (also referred to as an elastic polymer or tensile polymer) overmolded onto one or more inter-component anchors. The inter-component anchors are used to connect or anchor different components of the gastric retention system (e.g., the elastomeric component and the retainer) together. In some embodiments, the inter-component anchors may comprise any suitable polymer that adheres well to or bonds well with the components to be connected (e.g., polycarbonate, polyphenylene sulfone, polyphenylene ether-polystyrene blends, polyphenylene ether, polystyrene, or polyetheretherketone). In some embodiments, the inter-component anchor may be "dumbbell-shaped," comprising a relatively thicker flap at one end of the anchor, connected together by a thinner connecting portion. Optionally, the inter-component anchor may have a larger central body from which a first portion and a second portion project in opposite directions. The larger central body may be sized as a retainer of the gastric retention system to form an intermediate region between the central elastomeric component and the remainder of the retainer.

[0087] In some embodiments, the elastomer may be overmolded onto a first portion of an inter-component anchor (e.g., a lobe of a dumbbell-shaped anchor). In some embodiments, direct laser welding of the elastomer to one or more retainers may be challenging. To facilitate attachment of the retainer to the elastomer component, a laser connector component may be overmolded onto a second portion of the inter-component anchor (e.g., a second lobe of a dumbbell). In some embodiments, the laser connector component overmolded onto the inter-component anchor may be an inactive component (e.g., polycaprolactone). The retainer can then be laser welded to the laser connector component to attach the retainer to the elastomer component. In some embodiments, the elastomer component may comprise a plurality of elastomer-overmolded inter-component anchors such that the elastomer holds one lobe of each of the plurality of inter-component anchors together. The laser connector component may be overmolded onto the other lobes of each inter-component anchor such that the plurality of retainers can be laser welded to the elastomer component via the laser connector component.

[0088] In some implementations, the resulting gastric retention system is constructed in a star shape, also known as a "star" or "asterisk" configuration, wherein the elastomeric component is located at the center of the system, and the retainer is an "arm" extending radially outward from the elastomeric component.

[0089] Figure 1A A simplified exemplary star system 100 is shown in the figure. Multiple retainers (only one such retainer 108 is labeled for clarity) are secured to a disc-shaped elastomer component 106. Figure 1A The retainer depicted consists of segments 102 and 103, which are connected by a laser connector component 104 (again, for clarity, this component is only labeled in one retainer). One or both of segments 102 and 103 can be a drug elution component. Segments 102 and / or 103 may optionally be additional laser connector components. Although Figure 1A The laser connector component 104 is shown with a diameter slightly larger than that of segments 102 and 103, but they can have the same diameter as the segments, so that the entire retainer 102-104-103 has a smooth outer surface. Figure 1A The star-shaped structure shown can be folded or compressed at the elastomeric component.

[0090] Figure 1B show Figure 1A The folded structure of the gastric retention system 190 (for clarity, Figure 1B Only two retainers are shown in the example. Figure 1B Sections 192 and 193, laser connector component 194, elastomer component 196, and retainer 198 respectively correspond to Figure 1AThe system comprises sections 102 and 103, a laser connector component 104, an elastomer component 106, and a retainer 108. When folded, the total length of the gastric retention system is reduced by approximately half, and the system can be conveniently placed in a container, such as a capsule or other container suitable for oral administration. The gastric retention system is confined in a compressed state (folded state) by the capsule or other container. When the capsule reaches the stomach, the capsule dissolves, thereby releasing the gastric retention system. After the capsule or other container releases its restraints, the gastric retention system unfolds into its uncompressed state, retaining in the stomach for the desired retention period.

[0091] However, it has been demonstrated that the stellate gastric retention system can bend into a structure that allows premature passage through the patient's pylorus. Premature passage through the pylorus prevents the delivery of the gastric retention system's active agents to the patient. Furthermore, premature passage leads to inconsistencies in the gastric retention system, resulting in its unreliability and impairing its efficacy.

[0092] Figure 2 This illustrates a star-shaped gastric retention system with multiple retainers. An example of a curved construction is shown. Figure 2 The right side. Due to forces within the stomach (such as peristalsis), the gastric retention system can bend into various configurations, such as... Figure 2 As shown, this could lead to premature passage through the pylorus.

[0093] Other possible bending structures such as Figures 3A-3C As shown. In particular, Figures 3A-3C Three different configurations of the gastric retention system are shown, which could allow premature passage through the pylorus. As shown in each figure, the relatively rigid retainer of the gastric retention system remains straight. However, because the elastomeric component of the gastric retention system is more flexible than the retainer, it can bend. This bending of the elastomeric component can allow the gastric retention system with the relatively rigid retainer to pass prematurely through the patient's pylorus.

[0094] like Figure 3A As shown, the gastric retention system 302a is shown in a curved configuration with three retainers that lead to the pyloric opening. Figure 3B The gastric retention system 302b, which exhibits a curved structure, has two retainers that allow passage through the pyloric opening. Figure 3C The gastric retention system 302c is shown to have a curved structure similar to a badminton shuttlecock and has an elastomeric component that leads to the opening of the pylorus.

[0095] To help prevent premature passage through the pylorus, the gastric retention system can be assembled using the laser welding technique described herein. The laser-welded components of the gastric retention system together strengthen the interfaces between the components, making them resistant to breakage and premature passage through the pylorus.

[0096] Laser welding of the gastric retention system

[0097] As described above, the gastric retention system described herein can be assembled using laser welding technology. For example, individual components of a retainer (e.g., one or more drug elution components and / or laser connector components) can be laser welded together to form the retainer. Laser welding can also be used to attach the retainer to an elastomeric component to form a larger gastric retention system (e.g., a star-shaped system). Using laser welding to connect components of a gastric retention system can offer several improvements over conventional techniques. For example, even if components have different compositions, properties, and / or functions, laser welding can create a strong bond between components, whereas conventional techniques may require components to contain similar polymers for effective adhesion. Laser welding also does not introduce any additional components into the gastric retention system, minimizing the number of points of failure in the system and avoiding the introduction of components incompatible with human consumption. Furthermore, laser welding can be applied in a manner that prevents damage to heat-sensitive components, such as drug elution components containing active pharmaceutical ingredients.

[0098] Various laser systems can be used for laser welding components of gastric retention systems. In some embodiments, near-infrared lasers can be used. The wavelength of this laser can be approximately 1000-3000 nm, approximately 1500-2500 nm, approximately 1800-2000 nm, or approximately 1940 nm. In some embodiments, the wavelength of the laser used can be selected based on the absorbance of the polymer to be welded. In some embodiments, the laser system can be a Dukane laser welder. In some embodiments, the laser source model can be an IPG TLM-120-WC-Y12 laser or a Sakar PE 2000 AC laser. In some embodiments, the laser scanning head can be a SCANcube 10 or a Raylase 11532 scanning head. In some embodiments, a single laser scanning head can be used to weld a single gastric retention system. In some embodiments, multiple laser scanning heads (e.g., dual laser scanning heads) can be used to weld multiple gastric retention systems simultaneously.

[0099] In some implementations, the laser beam may have a Gaussian energy distribution. For a beam with a Gaussian energy distribution, the highest energy concentration is located at the center of the beam, and the energy concentration decreases radially outwards. An exemplary Gaussian energy distribution is shown below. Figure 4A As shown in the diagram. In some embodiments, the laser beam may have a flat-top or "top-cap" energy distribution. For a beam with a top-cap energy distribution, the energy concentration is flat and uniform across the entire beam width, with sharp edges, where the energy concentration rapidly drops to zero. An exemplary top-cap energy distribution is shown below. Figure 4B As shown in the diagram. In some implementations, other laser beam distributions may be used, such as diffraction energy distributions or inverse-Gaussian energy distributions.

[0100] In some implementations, the laser beam can have a diameter or spot size of about 0.5-5 mm, about 0.75-4 mm, or about 1-3 mm. Different beam diameters can be used depending on the objectives of the laser welding process. For example, using a larger beam diameter may be more efficient than using a smaller beam and can ensure that the weld melts the entire interface. On the other hand, if the parts being welded together are very small, a smaller diameter laser beam may be more desirable because it may be easier to control and can achieve welding of individual interfaces. However, if the beam diameter is too small, the beam may become too concentrated and burn through the parts being welded.

[0101] The power and energy of the laser can vary depending on the composition of the components being welded. For example, the power and energy used for laser welding a laser joint component to a drug elution component can differ from the power and energy used for laser welding a laser joint component to another laser joint component. In some embodiments, the laser power can be about 10-1200 W, about 20-1000 W, or about 30-800 W. In some embodiments, the laser power can be at least about 10 W, at least about 20 W, or at least about 30 W. In some embodiments, the laser power can be less than about 1200 W, less than about 1000 W, or less than about 800 W. In some embodiments, the laser energy can be about 10-750 J, about 30-500 J, or about 40-450 J. In some embodiments, the laser energy can be at least about 10 J, at least about 30 J, or at least about 40 J. In some embodiments, the laser energy can be less than about 750 J, less than about 500 J, or less than about 450 J.

[0102] In some embodiments, the laser speed can vary depending on the amount of energy desired to be applied to a particular interface. For example, if an interface requires more energy to weld, the laser power can be kept constant while the speed is reduced, thereby increasing the time it takes for the laser to reach any given point. In some embodiments, the laser speed can be about 500-5000 mm / s, about 700-4500 mm / s, or about 900-4000 mm / s. In some embodiments, the laser speed can be at least about 500 mm / s, at least about 700 mm / s, at least about 1000 mm / s, at least about 2000 mm / s, at least about 3000 mm / s, at least about 3500 mm / s, at least about 4000 mm / s, or at least about 5000 mm / s. In some implementations, the laser velocity may be less than about 5000 mm / s, less than about 4000 mm / s, 3500 mm / s, less than about 3000 mm / s, less than about 2000 mm / s, less than about 1000 mm / s, less than about 700 mm / s, or less than about 500 mm / s.

[0103] In some embodiments, the characteristics of the laser beam can be selected to ensure that the beam effectively heats the entire weld interface from beginning to end. In some embodiments, the beam is configured to heat about 90-100% of the interface. In some embodiments, the beam is configured to heat at least about 90%, at least about 95%, or at least about 99% of the interface. If only the top of the interface receiving direct contact from the laser melts, the weld may be weak and / or incomplete, which could lead to breakage of the retainer in the gastric retention system. In some embodiments, this consideration can be balanced with the desire to avoid burning the top of the interface.

[0104] In some embodiments, a laser beam with a diameter of 3 mm and a top-cap energy distribution can be used. The energy of the beam can be uniform within the 3 mm diameter range, which will melt not only the interface between the parts to be welded, but also some or all of the parts themselves. In some embodiments, the laser beam can create a molten zone of about 0.5-5 mm, about 0.75-4 mm, or about 1-3 mm between the parts being laser welded. In some embodiments, the molten zone between the laser-welded parts can be at least about 0.5 mm, at least about 0.75 mm, or at least about 1 mm. In some embodiments, the molten zone between the laser-welded parts can be less than about 5 mm, less than about 4 mm, or less than about 3 mm.

[0105] In some embodiments, melting some or all of the components may be advantageous. For example, in some embodiments, the components to be welded together may each contain a polyester, such as PCL. The polymer regions (e.g., PCL regions) of the components may be oriented along an axis (e.g., along the extrusion axis). Using PCL as an example, when the components melt, the crystalline PCL melts, resulting in the PCL regions being randomly oriented. If only a portion of the components melts, that portion may have randomly oriented PCL regions; suitably, the unmelted portions of the components may have uniformly oriented PCL regions. Differences in orientation may cause those portions to break or bend at their intersections. Therefore, for some components, it may be desirable to melt all the components during laser welding, not just the interfaces between the components. However, this may not be suitable for all components. For example, drug-eluting components may not be completely melted to avoid damaging the active pharmaceutical ingredient.

[0106] In some implementations, if the gastric retention system comprises multiple corresponding interfaces that need to be welded together (e.g., a star-shaped structure comprising multiple retainers), the laser beam can move along repeating paths, such as annular paths. For example, for a star-shaped system, the laser beam can move along annular paths symmetrically near the center of the star-shaped system, and can trace the same interface on each retainer of the star-shaped system, such that as the laser beam moves along the annular path, the corresponding interfaces on the different retainers are heated. The laser beam can be configured to follow multiple repeating paths to laser weld a specified system, wherein each repeating path corresponds to a different set of interfaces to be welded. In some implementations, for a specified star-shaped system, the laser beam can be configured to follow at least one repeating path, at least two repeating paths, at least three repeating paths, at least four repeating paths, at least five repeating paths, or at least six repeating paths. In some implementations, the repeating paths can be welded in a radially outward sequence from the center of the system (e.g., the first repeating path may weld the interface closest to the elastomeric component, while subsequent repeating paths weld interfaces farther from the elastomeric component). For example, in Figure 5 The example illustrates a laser-welded star-shaped system, in which the annular path corresponding to interface 502 can be laser-welded first, the annular path corresponding to interface 504 can be laser-welded second, and the annular path corresponding to interface 506 can be laser-welded third, and so on. In other embodiments, repeating paths can be welded to move radially inward from the outer edge of the system to the center of the system.

[0107] In some embodiments, the laser beam may pass around a designated repeating path multiple times to ensure that welding is completed before moving to another repeating path (i.e., ensuring that the laser beam melts the entire interface between the welded parts). In some embodiments, the laser beam may pass around the designated path approximately 10-2000 times, approximately 25-1500 times, or approximately 40-1300 times. In some embodiments, the laser beam may pass around the designated path at least approximately 10 times, at least approximately 25 times, or at least approximately 40 times. In some embodiments, the laser beam may pass around the designated path less than approximately 2000 times, less than approximately 1500 times, or less than approximately 1300 times.

[0108] In some embodiments, the laser beam may follow a designated path for approximately 1-10 seconds, approximately 2-8 seconds, or approximately 3-6 seconds. In some embodiments, the laser beam may follow a designated path for at least approximately 1 second, at least approximately 2 seconds, or at least approximately 3 seconds. In some embodiments, the laser beam may follow a designated path for less than approximately 10 seconds, less than approximately 8 seconds, or less than approximately 6 seconds.

[0109] Once the laser beam has completed welding the designated path, the gastric retention system can be allowed to cool in situ before welding the subsequent path. In some embodiments, the gastric retention system can be allowed to cool for approximately 1-20 seconds, approximately 5-15 seconds, or approximately 8-10 seconds before starting to weld the next path. In some embodiments, the gastric retention system can be allowed to cool for at least approximately 1 second, at least approximately 5 seconds, or at least approximately 8 seconds before starting to weld the next path. In some embodiments, the gastric retention system can be allowed to cool for less than approximately 20 seconds, less than approximately 15 seconds, or less than approximately 10 seconds before starting to weld the next path.

[0110] In some implementations, the laser settings can be varied for different paths. For example, the laser energy and / or power required for laser welding of a drug elution component and a laser connector component may differ from the energy and / or power required for laser welding of two laser connector components. Figure 6A Exemplary thermal maps showing the energy supplied to different parts of a star-shaped system. As shown, the path energy after different interface groups of the star varies based on the energy requirements of the laser-welded interfaces.

[0111] In some implementations, one or more interfaces of the gastric retention system can be welded individually, rather than welded along a repetitive path around the gastric retention system. For example, some retainers of the gastric retention system may include a drug elution component, while others may not. Therefore, interfaces on the drug elution retainers may not have corresponding interfaces on other retainers. Thus, certain interfaces on the drug elution retainers can be welded individually. Examples of individually welded interfaces include... Figure 6A and Figure 6B As shown at the top. In some embodiments, the interfaces to be welded individually are welded by moving the laser beam back and forth on a single interface before moving to another interface. This type of weld may be referred to herein as a "hexagonal weld". In some embodiments, the laser beam may pass through a single interface in the hexagonal weld about 10-1000 times, about 25-500 times, or about 50-400 times. In some embodiments, the laser beam may pass through a single interface in the hexagonal weld at least about 10 times, at least about 25 times, or at least about 50 times. In some embodiments, the laser beam may pass through a single interface in the hexagonal weld less than about 1000 times, less than about 500 times, or less than about 400 times.

[0112] In some embodiments, to avoid burning the welded components, the laser beam can "oscillate" near the welded interface. When the beam oscillates, it does not move entirely along the seam between the welded components, but rather moves around the seam in a regular or irregular pattern. Therefore, oscillating the beam can effectively increase the beam diameter. In some embodiments, the oscillation radius of the oscillating beam can be about 0.5-10 mm, about 0.7-5 mm, or about 1-3 mm. In some embodiments, the oscillation radius of the oscillating beam can be at least about 0.5 mm, at least about 0.7 mm, or at least about 1 mm. In some embodiments, the oscillation radius of the oscillating beam can be less than about 10 mm, less than about 5 mm, or less than about 3 mm. Oscillation can be used with beams having any energy distribution, including Gaussian energy distributions or top-cap energy distributions.

[0113] In some implementations, oscillating beams may create "hot spots" and "cold spots" in the energy distribution of the beam. For example, a "hot spot" may be created if the oscillation pattern causes the laser beam to repeatedly hit the same location. Similarly, a "cold spot" may be created if the oscillation pattern causes the laser beam to hit certain locations less frequently or skip them completely (e.g., if a helical oscillation pattern is used). Figure 7A and 7B An exemplary circular path with a swing is shown. (e.g.) Figure 7AAs shown, a beam oscillating in a spiral pattern creates a "cold spot" in the middle of the spiral. The occurrence of hot and / or cold spots can be controlled by changing the laser speed or the oscillation frequency. For example, if the laser speed and / or oscillation frequency decreases (e.g., from... Figure 7A The 3000 mm / s shown is as follows Figure 7B As shown in the figure of 400 mm / s, hot and / or cold spots may blur together, resulting in a more uniform energy distribution. In some embodiments, the oscillation frequency can be about 500-5000 Hz, about 1000-4000 Hz, or about 1200-3200 Hz. In some embodiments, the oscillation frequency can be at least about 500 Hz, at least about 1000 Hz, or at least about 1200 Hz. In some embodiments, the oscillation frequency can be less than about 5000 Hz, less than about 4000 Hz, or less than about 3200 Hz.

[0114] In some implementations, oscillation can be used to intentionally create hot and / or cold spots. For example, if two materials to be welded melt at different temperatures, an oscillation pattern may be desirable, which imparts more energy to the material melting at the higher temperature and less energy to the material melting at the lower temperature.

[0115] In some embodiments, the relative humidity of the environment in which laser welding is performed can be controlled. If the parts to be laser welded absorb water before laser welding, the weld strength may be weakened. Therefore, controlling the relative humidity of the laser welding environment is desirable; however, laser welding can still be effective at higher relative humidity levels than those concerned herein. In some embodiments, maintaining at least a certain level of humidity in the room is desirable because if the humidity is too low, the laser-welded parts may become brittle and / or may experience increased electrostatic adsorption. In some embodiments, the relative humidity during the laser welding process can be about 10-40%, about 12-35%, or about 15-25%. In some embodiments, the relative humidity during the laser welding process can be below about 40%, below about 35%, below about 30%, below about 25%, below about 20%, or below about 15%. In some embodiments, the relative humidity during the laser welding process can be at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, or at least about 35%. In some implementations, the laser-welded components are exposed to relative humidity in the environment, wherein the laser welding is carried out for less than 1 hour, less than 45 minutes, less than 30 minutes, less than 25 minutes, or less than 20 minutes.

[0116] In some embodiments, the gastric retention system can be cooled once all interfaces of the system have been welded. The gastric retention system can be cooled in situ (e.g., within the laser welding support of the welding system) or moved before cooling (e.g., removed from the laser welding support). In some embodiments, the gastric retention system can be passively cooled using ambient air. In some embodiments, the gastric retention system can be actively cooled (e.g., by an air cooling system). In some embodiments, the gastric retention system can be allowed to cool for approximately 10 seconds to 5 minutes, approximately 30 seconds to 4 minutes, approximately 1 to 3 minutes, or approximately 2 minutes.

[0117] Laser welding components

[0118] Laser welding assemblies can be used to fix components of a system to be welded (e.g., a gastric retention system) in situ during laser welding. An exemplary laser welding assembly for a star-shaped gastric retention system is shown below. Figure 8A and 8B As shown in the diagram. The laser welding assembly 800 may include a laser welding support 802 having recesses sized and shaped to receive components of the gastric retention system 804 (e.g., a star-shaped object). The recesses of the laser welding support 802 may be covered by a liner 806. The laser welding assembly 800 may also include a top layer 808 configured to fix components of the gastric retention system 804 in situ during laser welding, and a separate glass layer 810 situated above the top layer 808. The laser welding assembly 800 may also include a vertical pressure clamp 812 and one or more radial pressure clamps 814, which may be configured to apply vertical and radial forces, respectively, during laser welding.

[0119] The laser welding assembly 800 includes a laser welding holder 802 having recesses sized and shaped to receive components of the gastric retention system. The laser welding holder 802 can be circular (e.g., like a hockey puck), polygonal (e.g., triangular, square, or rectangular), irregular, or any other suitable shape. The laser welding holder 802 helps maintain the geometry of the components during laser welding by preventing the various components of the gastric retention system 804 from flowing in the molten state. The laser welding holder 802 can be formed of a metal, such as stainless steel (e.g., 3000 series stainless steel) or aluminum (e.g., 5000 series or 6000 series aluminum). In some embodiments, for example, the laser welding holder 802 can be chemically nickel-plated.

[0120] In some implementations, the laser welding support 802 is circular or hockey puck-shaped, such as... Figure 9As shown in the diagram. In some embodiments, the laser welding bracket 802 may be at least about 11 mm thick, at least about 12 mm thick, at least about 13 mm thick, at least about 14 mm thick, at least about 15 mm thick, at least about 16 mm thick, at least about 17 mm thick, at least about 18 mm thick, or at least about 19 mm thick. In some embodiments, the laser welding bracket 802 may be less than about 20 mm thick, less than about 19 mm thick, less than about 18 mm thick, less than about 17 mm thick, less than about 16 mm thick, less than about 15 mm thick, less than about 14 mm thick, less than about 13 mm thick, or less than about 12 mm thick. In some embodiments, the diameter of the laser welding bracket 802 may be at least about 35 mm, at least about 40 mm, at least about 45 mm, or at least about 50 mm. In some embodiments, the diameter of the laser welding bracket may be less than about 52 mm, less than about 47 mm, less than about 42 mm, or less than about 37 mm.

[0121] In some embodiments, the upper surface of the laser-welded support 802, including the grooves, may be covered with a liner 806. The liner 806 may be a non-stick layer and may comprise silicone (e.g., liquid silicone rubber, such as Dow Corning QP1-250 liquid silicone rubber, 50A hardness), polytetrafluoroethylene, ceramic, or any other suitable non-stick material. The liner 806, combined with the laser-welded support 802, can prevent the gastric retention system 804 from adhering to the laser-welded support 802 during removal. The liner 806 can also help prevent the molten components of the gastric retention system 804 from flowing during laser welding. Furthermore, the liner 806 can mitigate spatter during the welding process. In some embodiments, the liner 806 may be at least about 0.75 mm thick, at least about 0.80 mm thick, at least about 0.85 mm thick, at least about 0.90 mm thick, or at least about 0.95 mm thick. In some implementations, the liner 806 may be less than about 1 mm thick, less than about 0.95 mm thick, less than about 0.90 mm thick, less than about 0.85 mm thick, or less than about 0.80 mm thick.

[0122] In some embodiments, the laser welding assembly 800 may further include a top layer 808 configured to hold the gastric retention system 804 in situ within a recess of the laser welding support 802. In some embodiments, the top layer 808 may comprise a non-stick material to prevent the gastric retention system 804 from adhering to the top layer 808 once laser welding is complete. The top layer 808 may comprise silicone (e.g., Specialty Silicone Products SSP-2390-40 silicone sheet, 40A hardness tester), glass, polytetrafluoroethylene, ceramic, or any other suitable non-stick material. The length and width of the top layer 808 may match the length and width of the top of the laser welding support 802. For example, if the laser welding support 802 has a circular cross-section, the diameter of the top layer 808 may match the diameter of the laser welding support 802. In some embodiments, the top layer 808 may be at least about 0.025 mm thick, at least about 0.027 mm thick, at least about 0.029 mm thick, at least about 0.031 mm thick, or at least about 0.033 mm thick. In some implementations, the top layer 808 may be less than about 0.035, less than about 0.033, less than about 0.031, less than about 0.029, or less than about 0.027 in thickness.

[0123] In some embodiments, the laser welding assembly 800 may further include a glass layer 810 located on top of the top layer 808. The glass layer 810 may be formed of quartz (e.g., Momentive Quartz 124). In some embodiments, the glass layer 810 may have a thickness of at least about 0.05, at least about 0.10, or at least about 0.15. In some embodiments, the glass layer 810 may have a thickness of less than about 0.20, less than about 0.15, or less than about 0.10.

[0124] In some embodiments, the laser welding assembly 800 may include one or more vertical pressure clamps 812 configured to apply force to one or more portions of the laser welding assembly 800 during laser welding to prevent flow of molten gastric retention system components. The vertical pressure clamps 812 may apply a downward force. The downward force applied during welding may be about 100-5000 N, about 150-3000 N, or about 200-2800 N. In some embodiments, the downward force applied during welding may be at least about 100 N, at least about 200 N, or at least about 250 N. In some embodiments, the downward force applied during welding may be less than about 5000 N, less than about 4000 N, less than about 3000 N, or less than about 2800 N.

[0125] In some embodiments, the laser welding assembly 800 may include one or more radial pressure clamps 814 configured to apply radial forces to the laser welding assembly 800. In some embodiments, radial forces can be applied to each retainer of the stellate gastric retention system 804 using pistons located at the ends of each recess in the laser welding holder 802. In some embodiments, the radial force applied by each piston can be about 5-200 N, about 8-100 N, or about 10-50 N. In some embodiments, the radial force applied by each piston can be at least about 5 N, at least about 8 N, or at least about 10 N. In some embodiments, the radial force applied by each piston can be less than about 200 N, less than about 100 N, or less than about 50 N.

[0126] The piston used to apply radial force can be wider or narrower than the retainer, forming a tapered shape. In some embodiments, the width of the piston can be selected based on whether the retainer of the gastric retention system 804 extends beyond the edge of the laser-welded support 802. For example, if the retainer is shorter than the radius of the laser-welded support 802, a piston wider than the retainer can be used, while if the retainer is longer than the radius of the laser-welded support 802 and extends beyond the edge of the laser-welded support 802, a piston narrower than the retainer can be used.

[0127] In some implementations, radial and downward forces can be applied incrementally to prevent the gastric retention system 804 from popping out of the groove in the laser welding support 802 or deforming before welding. For example, a relatively low downward force (e.g., about 20 PSI) can be applied via the vertical pressure clamp 812. Then, a relatively high radial force (e.g., about 65 PSI) can be applied via the radial piston of the radial pressure clamp 814. Subsequently, a larger downward force (e.g., about 80 PSI) can be applied via the vertical pressure clamp 812. The radial force can then be reduced (e.g., to about 15 PSI), at which point the welding process can begin.

[0128] Material selection for laser welding

[0129] Some polymers may be difficult to laser weld together, which can result in poor weld strength (and consequently, poor gastric retention). Therefore, the composition and / or properties of different components of a laser welding system (e.g., a gastric retention system) can be selected to facilitate laser welding of the components.

[0130] In some embodiments, each component of the gastric retention system (e.g., each laser connector component and / or drug elution component) may contain a generic polymer. "Generic polymer" can refer to a polymer present in the same form in each component (e.g., a polymer with the same molecular weight in each component), or it can be a polymer with the same experimental formula but different molecular formulas in different components (e.g., polymers with different molecular weights in different components). The generic polymer present in each component may include polyesters (e.g., polycaprolactone (PCL)), thermoplastic copolyesters, thermoplastic polyurethanes, thermoplastic polyamides, thermoplastic vulcanizates, styrene block copolymers, polyethylene covinyl acetate, or polylactic acid. Including a generic polymer in each component of the retention system can improve weld strength between components because similar polymers are easier to laser weld together. For example, polymers can be considered "similar" if they meet the following conditions: they belong to the same type or category (e.g., thermoplastics, thermosets, elastomers, etc.), have similar melting temperatures (e.g., melting temperatures differing from each other by about 100°C), and / or have similar viscosities at their melting temperatures and pressures (e.g., viscosities differing from each other by about 50%). Therefore, including a generic polymer in each component of the gastric retention system to improve weld strength can improve gastric retention by preventing component breakage and premature passage of the system through the pylorus.

[0131] In some embodiments, the PCL can be a generic polymer present in each component of the retainer of the gastric retention system. In some embodiments, the PCL can be present as PCL12, PCL17, or any other suitable form of PCL. In some embodiments, each component can contain at least about 30% by weight of PCL, at least about 35% by weight of PCL, at least about 40% by weight of PCL, at least about 45% by weight of PCL, or at least about 50% by weight of PCL. In some embodiments, each component can contain less than about 75% by weight of PCL, less than about 65% by weight of PCL, or less than about 50% by weight of PCL.

[0132] In some embodiments, adjacent components (i.e., components to be laser-welded together) may have similar viscosities or melt flow indices. Laser-welding polymers with similar viscosities or melt flow indices can result in less phase separation than laser-welding polymers with drastically different viscosities or melt flow indices, which may improve weld strength. Typically, polymers may be difficult to laser-weld together unless they have extremely close melt flow indices (e.g., melt flow indices differing from each other by less than 10%). However, by using the laser welding techniques described herein, components comprising polymers with significantly different melt flow indices can be laser-welded together. In some embodiments, the difference between the melt flow indices of the components to be laser-welded can be at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30%. In some embodiments, the difference between the melt flow indices of the components to be laser-welded can be less than about 50%, less than about 45%, less than about 40%, or less than about 35%.

[0133] In some embodiments, adjacent components may also have relatively similar melting temperatures. In some embodiments, adjacent components to be laser welded together may have melting temperatures that differ from each other by approximately 75°C, approximately 60°C, approximately 50°C, approximately 40°C, approximately 30°C, approximately 20°C, approximately 10°C, or approximately 5°C.

[0134] In some implementations, the composition of the retaining components can be modified to bring the viscosity, melt flow index, and / or melting temperature of adjacent components closer together, thereby facilitating laser welding. For example, one or more excipients can be added to the laser joint component or the drug-eluting component to alter (e.g., increase) the amount of laser energy that the component can absorb. Excipients may include one or more of iron oxide, colorants, or any other suitable absorption-enhancing materials. In another example, a plasticizer (e.g., poloxamer, such as P407) can be added to the thicker component of two components laser-welded together to reduce the viscosity of the thicker component and bring the viscosity of the components closer together.

[0135] Drug elution component composition - activator

[0136] As described above, a gastric retention system may include one or more retainers having at least one drug elution component. The drug elution component of the retainer contains an active agent (an active pharmaceutical ingredient, such as a therapeutic agent). In some embodiments, the active agent in the drug elution component is a drug, prodrug, biological product, or any other substance that can be administered to produce a beneficial effect against disease or injury. Exemplary active agents that may be used in the gastric retention system described herein include, but are not limited to, statin drugs such as rosuvastatin; nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam; selective serotonin reuptake inhibitors (SSRIs) such as exipram and citalopram; blood thinners such as clopidogrel; steroids such as prednisone; antipsychotics such as aripiprazole and risperidone; analgesics such as buprenorphine; opioid antagonists such as naloxone; antiasthmatics such as montelukast; antidementia drugs such as memantine; cardiac glycosides such as digoxin; alpha blockers such as tamsulosin; and cholesterol. Absorption inhibitors, such as ezetimibe; antigout medications, such as colchicine; antihistamines, such as loratadine and cetirizine; opioids, such as loperamide; proton pump inhibitors, such as omeprazole; antiviral agents, such as entecavir; antibiotics, such as doxycycline, ciprofloxacin, and azithromycin; antimalarial agents; levothyroxine; substance abuse medications, such as methadone and varenicline; contraceptives; stimulants, such as caffeine; and nutrients, such as folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, biotin, plant extracts, phytohormones, and other vitamins or minerals. Biological products that can be used as active agents in the gastric retention system of this invention include proteins, peptides, polynucleotides, and hormones. Exemplary categories of active agents include, but are not limited to, analgesics; anti-analgesics; anti-inflammatory drugs; antipyretics; antidepressants; antiepileptics; antipsychotics; neuroprotective agents; antiproliferative agents, such as anticancer agents; antihistamines; antimigraines; hormones; prostaglandins; antimicrobial agents, such as antibiotics, antifungals, antivirals, and antiparasitics; antimuscarinic agents; anxiolytics; bacteriostatic agents; immunosuppressants; sedatives; hypnotics; antipsychotics; bronchodilators; antiasthmatics; cardiovascular drugs; anesthetics; anticoagulants; enzyme inhibitors; steroids; and more. Steroid or nonsteroidal anti-inflammatory agents; corticosteroids; dopaminergic agents; electrolytes; gastrointestinal drugs; muscle relaxants; nutritional supplements; vitamins; parasympathomimetic agents; stimulants; appetite suppressants; antisedatives; and antimalarial drugs, such as quinine, fluorenol, chloroquine, amodiaquine, pyrimethamine, chlorguanidine, chlorpromazine-dapsone, sulfonamides (e.g., sulfadoxine and sulfamethoxazole), mefloquine, atovaquinone, primaquine, halopanthracene, doxycycline, clindamycin, artemisinin, and artemisinin derivatives (e.g., artemether, dihydroartemisinin, artesyl ether, and artesunate). The term "active agent" includes salts, solvates, polymorphs, and cocrystals of the above substances.In some embodiments, the active agent is selected from cetirizine, rosuvastatin, exipram, citalopram, risperidone, olanzapine, donepezil, and ivermectin. In some embodiments, the active agent is an active agent used to treat neuropsychiatric disorders, such as an antipsychotic agent, such as risperidone.

[0137] The active agent can be used in any suitable crystal form, or in an amorphous form, or in one or more crystal forms and an amorphous form. That is, the active agent or drug particles contained in the drug elution component of the retainer can be used in a crystal form, an amorphous form, or a mixture of crystal forms (single crystal or polycrystalline) and an amorphous form in order to provide a desired release rate or desired physical or chemical properties.

[0138] Gastric retention systems are well-suited for treating diseases and disorders where patient adherence is difficult, and thus, in some embodiments, the gastric retention systems described herein are used to treat diseases or disorders where patient adherence to medication regimens is problematic. Such diseases and disorders include neuropsychiatric disorders, dementia and other diseases and disorders affecting memory, Alzheimer's disease, psychosis, schizophrenia, and paranoia. Therefore, active agents that can be used in the drug-eluting components of the retention system include, but are not limited to, antidementia agents, anti-Alzheimer's agents, and antipsychotic agents.

[0139] Exemplary hydrophilic surfactants that can be used include risperidone, cetirizine, memantine, and olanzapine. Exemplary hydrophobic surfactants that can be used include aripiprazole, ivermectin, rosuvastatin, citalopram, and exciplopram.

[0140] In some embodiments, the surfactant may be loaded into the retainer or retainer segment in an amount of about 10% to about 80% of the weight of the retainer or retainer segment. The surfactant / API loading may be about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 30% to about 70%, or about 40% to about 60% of the weight of the retainer or retainer segment.

[0141] In some embodiments, the active agent constitutes about 10% to about 40% of the weight of the retainer or retainer segment, and the carrier polymer thereunder, together with any other components of the retainer or retainer segment blended into the carrier polymer, constitutes the remaining weight of the retainer or retainer segment. In some embodiments, the active agent or a salt thereof constitutes about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, about 15% to about 40%, about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 35% to about 40%, about 15% to about 35%, about 20% to about 35%, or about 25% to about 40% of the weight of the retainer or retainer segment.

[0142] In some embodiments, the retainer or a segment contained therein may have a high surfactant loading. "High loading" typically refers to a retainer or a segment containing an surfactant that constitutes approximately 40% to approximately 80% of the weight of the retainer or segment. Any component of the retainer or segment not blended into the carrier polymer is not included in the weight percentage calculation; for example, if the retainer has one or more disintegrating matrices dispersed between segments of the retainer, the weight of such matrices may not be included as part of the retainer weight in the calculation of the surfactant weight percentage in the retainer.

[0143] In some embodiments, the amount of active agent by weight in the retainer or a section of the retainer may be at least about 40%, at least about 45%, at least about 50%, at least about 55%, or about 60%. In some embodiments, the amount of active agent by weight in the retainer or a section of the retainer may be about 40% to about 60%, about 45% to about 60%, about 50% to about 60%, about 55% to about 60%, about 40% to about 55%, or about 40% to about 45%. In some embodiments, the amount of active agent by weight in the retainer or a section of the retainer may be about 25% to about 60%, about 30% to about 60%, or about 35% to about 60%. In some embodiments, the amount of active agent by weight in the retainer or a section of the retainer may be about 51% to about 60%, about 52% to about 60%, about 53% to about 60%, about 54% to about 60%, about 55% to about 60%, about 56% to about 60%, or about 57% to about 60%.

[0144] The combination of high surfactant loading and polymer films with controlled release rates provides an increased amount of surfactant to the gastric retention system while maintaining good release kinetics during the system's retention period.

[0145] Drug elution component composition - carrier polymer

[0146] In some embodiments, the active agent in the drug elution component can be blended with the carrier polymer. The resulting mixture can be formed into a desired shape or used as the shape of the drug elution component in the gastric retention system described herein. After the active agent is blended into the carrier polymer to form a carrier polymer-active agent mixture, the active agent is distributed or dispersed throughout the blend. If excipients, antioxidants, or other components are included in the carrier polymer-active agent blend, they will also be distributed or dispersed throughout the blend.

[0147] The choice of carrier material for the active agent in a gastric retention system affects the drug release profile during gastric retention. The carrier polymer can be thermoplastic to allow for extrusion using hot melt extrusion or 3D printing techniques. They can also have sufficiently high melt strength and viscosity to enable extrusion into the desired geometry. They may have a low melting temperature (e.g., less than about 120°C) to avoid exposing the active agent to high temperatures during preparation. They can have sufficient mechanical strength (Young's modulus, compressive strength, tensile strength) to prevent rupture in the stomach during the desired retention period. Furthermore, they should be able to form stable blends with the active agent, therapeutic agent, drug substance, excipients, dispersants, and other additives.

[0148] Exemplary carrier polymers suitable for the gastric retention systems described herein include, but are not limited to, hydrophilic cellulose derivatives (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose), cellulose acetate, poly(vinylpyrrolidone), ethylene / vinyl alcohol copolymer, poly(vinyl alcohol), carboxyvinyl polymers (carbomer), Carbopol® acidic carboxypolymers, polycarbofil, and poly(ethylene oxide) (Polyox) WSR), polysaccharides and their derivatives, polyoxyethylene, polyethylene glycol, chitosan, alginate, pectin, gum arabic, tragacanth gum, guar gum, cowpea gum, vinylpyrrolidone-vinyl acetate copolymer, dextran, natural gums, agar, agarose, sodium alginate, carrageenan, fucoidan, red algae gum, kelp polysaccharide, *Hypnea*, *Euphorbia milii*, gum arabic, Indian gum, *Erythrina variegata* gum, aminoglucan, amylopectin, gelatin, gellan gum, hyaluronic acid, pullulan, stearin, xanthan gum, xylose dextran, maleic anhydride copolymer, ethylene maleic anhydride copolymer, poly(hydroxyethyl methacrylate), ammonium methacrylate copolymer (e.g., Eudragit RL or Eudragit RS), poly(ethyl acrylate-methyl methacrylate) (Eudragit NE), Eudragit E (Catonic copolymers based on dimethylaminoethyl methacrylate and neutral methacrylate), poly(acrylic acid), polymethacrylate / polyethyl acrylate such as poly(methacrylic acid), methyl methacrylate and ethyl acrylate, polylactone such as poly(caprolactone), polyanhydride such as poly[bis-(p-carboxyphenoxy)propionic anhydride], poly(terephthalic anhydride), polypeptides such as polylysine, polyglutamic acid, poly(orthoesters) such as DETOSU and glycols such as hexanediol, decanediol, cyclohexanediol, ethylene glycol, polyethylene glycol, and those poly(orthoesters) described and disclosed by reference in U.S. Patent 4,304,767, incorporated herein by reference, starch, especially pregelatinized starch and starch-based polymers, carbomer, maltodextrin, starch maltodextrin, dextran, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane, poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid) (PLGA), polyhydroxyalkanoates, polyhydroxybutyrates, poly(ethylene-co-vinyl acetate) and their copolymers, mixtures, blends and combinations. Polycaprolactone (PCL) and / or thermoplastic polyurethanes are preferred carrier polymers. In some embodiments, polydioxanone is used as the carrier polymer.In any embodiment of the gastric retention system, the carrier polymer used for the gastric retention system may comprise polycaprolactone, for example, linear polycaprolactone having a number-average molecular weight (Mn) ranging from about 60 kilodaltons (kDa) to about 100 kDa; 75 kDa to 85 kDa; or about 80 kDa; or about 45 kDa to about 55 kDa; or about 50 kDa to about 110,000 kDa or about 80 kDa to about 110,000 kDa.

[0149] Drug system component composition - excipients and other additives

[0150] Furthermore, the release of the active agent from the drug elution component can be modulated by a variety of excipients contained within the drug elution component. Soluble excipients include P407, Eudragit E, PEG, polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA). Insoluble wicking excipients include Eudragit RS and Eudragit RL. Degradable excipients include PLA, PLGA, PLA-PCL, polydioxanone, and linear copolymers of caprolactone and glycolide; multiaxial block copolymers of glycolide, caprolactone, and trimethylene carbonate; multiaxial block copolymers of glycolide, trimethylene carbonate, and lactide; multiaxial block copolymers of glycolide, trimethylene carbonate, and polypropylene succinate; multiaxial block copolymers of caprolactone, lactide, glycolide, and trimethylene carbonate; multiaxial block copolymers of glycolide, trimethylene carbonate, and caprolactone; and linear block copolymers of lactide, caprolactone, and trimethylene carbonate; for example, linear copolymers of caprolactone (95%) and glycolide (5%); glycolide (68%), Multiaxial block copolymers of caprolactone (29%) and trimethylene carbonate (3%); multiaxial block copolymers of glycolide (86%), trimethylene carbonate (9%) and lactide (5%); multiaxial block copolymers of glycolide (70%), trimethylene carbonate (27%) and polypropylene succinate (2%); multiaxial block copolymers of caprolactone (35%), lactide (34%), glycolide (17%) and trimethylene carbonate (14%); multiaxial block copolymers of glycolide (55%), trimethylene carbonate (25%) and caprolactone (20%); and linear block copolymers of lactide (39%), caprolactone (33%) and trimethylene carbonate (28%). Insoluble expandable excipients include polyvinyl acetate (PVAc), crospovidone, crosslinked carboxymethyl cellulose, HPMCAS, and linear block copolymers of dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethyl carbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol; for example, dioxanone (80%). Linear block copolymers of ethylene glycol (20%), lactide (60%), and ethylene glycol (40%); linear block copolymers of lactide (68%), ethylene glycol (20%), trimethyl carbonate (10%), and caprolactone (2%); linear block copolymers of lactide (88%), lactide (8%), and ethylene glycol (4%); and linear block copolymers of lactide (67%), polyethylene glycol (28%), and ethylene glycol (5%). Surfactants include lecithin, taurine, SDS, Soluplus, fatty acids, and Kolliphor RH40.

[0151] Other excipients can be added to the carrier polymer to regulate the release of the surfactant. The amount of such excipients added is approximately 1%-75%, approximately 5%-50%, approximately 5%, or approximately 30%. Examples of such excipients include poloxamer 407 (available as Kolliphor P407, Sigma Cat #62035), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), CAS No. 9003-11-6; H—(OCH2CH2)x-(O-CH(CH3)CH2)y-(OCH2CH2)z-OH, where x and z are about 101 and y is about 56); Pluronic P407; Eudragit E, Eudragit EPO (purchased from Evonik); hydroxypropyl methylcellulose (purchased from Sigma, Cat #H3785), Kolliphor RH40 (purchased from Sigma, Cat #07076), polyvinylcaprolactam, polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), and Soluplus. (Purchased from BASF; a copolymer of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol). Preferred soluble excipients include Eudragit E, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl alcohol (PVA). Preferred insoluble excipients include Eudragit RS and Eudragit RL. Preferred insoluble expandable excipients include cross-linked povidone, cross-linked carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and carboplatin. EUDRAGIT RS and EUDRAGIT RL are registered trademarks of Evonik (Darmstadt, Germany) for copolymers of ethyl acrylate, methyl methacrylate and methacrylate with quaternary ammonium groups (trimethylammonium ethyl methacrylate chloride); having a molar ratio of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate of about 1:2:0.2 (in Eudragit®) and about 1:2:0.1 (in Eudragit® RS).Preferred insoluble expandable excipients include crospovidone, crosslinked carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboplatin, and linear block copolymers of dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethyl carbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol; for example, dioxanone ( Linear block copolymers of 80% lactide and ethylene glycol (20%); linear block copolymers of 60% lactide and ethylene glycol (40%); linear block copolymers of 68% lactide, ethylene glycol (20%), trimethyl carbonate (10%) and caprolactone (2%); linear block copolymers of 88% lactide, 8% glycol and ethylene glycol (4%); linear block copolymers of 67% glycolide, 28% polyethylene glycol and 5% ethylene glycol.

[0152] Other examples of excipients that can be used in drug elution components of gastric retention systems are listed in the excipient table below.

[0153] Excipient list

[0154]

[0155] Table CPE-1 lists combinations of excipients and other additives that can be used in combination with active agents and carrier polymers in the drug elution component of a gastric retention system. These excipients and other additives can be combined with active agents (which constitute about 10% to about 60% of the composition by weight) and carrier polymers such as polycaprolactone to form the remainder of the composition. The excipients include the following components, which may be used alone or in any combination, in amounts ranging from about 1% to about 30% by weight of the composition, for example, about 5% to about 20%: Kolliphor P407 (poloxamer 407, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), Eudragit RS (poly[ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride] 1:2:0.1), Eudragit RL (poly[ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride] 1:2:2:0.2), PDO (polydioxanone), PEG-PCL, SIF (FaSSIF / FaSSGF powder from BioRelevant), EPO (dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer), Kollidon VA64 (vinylpyrrolidone-vinyl acetate copolymer in a mass ratio of 6:4), polyvinyl acetate, and polyvinylpyrrolidone.

[0156] Other additives include silica (e.g., about 0.1% to about 5% by weight of the composition, such as about 0.1% to 1% or about 0.5%) and antioxidants, such as α-tocopherol (e.g., about 0.1% to about 5% by weight of the composition, such as about 0.1% to 1% or about 0.5%). Each row in the table below represents the formulation of excipients and other additives used with the carrier polymer and surfactant.

[0157] Table CPE-1

[0158]

[0159] Table CPE-2 lists the specific amounts of excipients and other additives that can be used in combination with active agents and carrier polymers in the drug elution component of the gastric retention system retainer.

[0160] The amounts listed in Table CPE-2 can be varied between ±20% for each component (e.g., 0.5% silica can be varied between 0.4% and 0.6% silica, such as 0.1% for 20% of 0.5%). Each row in the table below represents a formulation of excipients and other additives used with the carrier polymer and surfactant.

[0161] Table CPE-2

[0162]

[0163] Drug elution component composition - dispersant as excipient

[0164] In some embodiments, the excipients included in the drug elution component may include dispersants. The use of dispersants in drug elution components offers several advantages. The elution rate of the active agent from the drug elution component is influenced by many factors, including the composition and properties of the carrier polymer (which itself may contain a variety of polymeric and non-polymeric components); the physical and chemical properties of the active agent; and the gastric environment. Avoiding burst release of the active agent (especially hydrophilic active agents) and maintaining a sustained release of the active agent during the effective release or retention period are important characteristics of this system. The application of dispersants allows for better control of the release rate and suppression of burst release. Burst release and release rate can be modulated by using different concentrations of dispersant. For example, different dispersants and different excipients at different concentrations can modulate the burst release of cetirizine in simulated gastric fluid.

[0165] Dispersants that can be used in drug elution components include: silica (SiO2) (hydrophilic fumes); stearates, such as calcium stearate and magnesium stearate; microcrystalline cellulose; carboxymethyl cellulose; hydrophobic colloidal silica; hydroxypropyl methylcellulose; magnesium aluminum silicate; phospholipids; polyoxyethylene stearate; zinc acetate; alginate; lecithin; fatty acids; sodium dodecyl sulfate; and non-toxic metal oxides, such as alumina. Porous inorganic materials and polar inorganic materials can be used. Hydrophilic fumes silica is a preferred dispersant. A particularly useful silica is sold by Cabot Corporation (Boston, Mass., USA) under the registered trademark CAB-O-SIL® M-5P (CAS #112945-52-5), which is a hydrophilic fumes silica with a BET surface area of ​​approximately 200 m² / g ± 15 m² / g. The product has a residue of less than approximately 0.02% on a 45-micron sieve. Typical major aggregate sizes range from approximately 150 to approximately 300 nm, while individual particle sizes can range from approximately 5 nm to approximately 50 nm.

[0166] In addition to anti-aggregation / anti-flocculation activity, dispersants can also help prevent phase separation in gastric retention systems during preparation and / or storage. This is particularly useful for systems prepared via hot melt extrusion.

[0167] The weight / weight ratio of dispersant to surfactant can be about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 4%, about 2% to about 3%, about 3% to about 4%, about 4% to about 5%, or about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, or about 5%.

[0168] The dispersant may comprise approximately 0.1% to approximately 4% of the drug elution component, for example, approximately 0.1% to approximately 3.5%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 2.5%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 1.5%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 0.5%, or approximately 0.2% to approximately 0.8%.

[0169] During the initial application of the gastric retention system, the dispersant can also be used to regulate the burst release of the active agent. In an embodiment of a gastric retention system applied once weekly, the burst release within approximately 6 hours after initial application is less than about 8% of the total amount of the active agent in the system, preferably less than about 6% of the total amount of the active agent in the system. In an embodiment of a gastric retention system applied every 3 days, the burst release within approximately 6 hours after initial application is less than about 12% of the total amount of the active agent in the system, preferably less than about 10% of the total amount of the active agent in the system. In an embodiment of a gastric retention system applied once daily, the burst release within approximately 6 hours after initial application is less than about 40% of the total amount of the active agent in the system, preferably less than about 30% of the total amount of the active agent in the system. Typically, if a new gastric retention system is administered once every D days, and the total mass of the active agent is M, the gastric retention system will release less than about [(M divided by D) multiplied by 0.5], preferably less than about [(M divided by D) multiplied by 0.4] or less than about [(M divided by D) multiplied by 3 / 8], more preferably less than about [(M divided by D) multiplied by 0.3], within approximately the first 6 hours after initial administration. In a further embodiment, the gastric retention system will release at least about [(M divided by D) multiplied by 0.25], meaning that the system releases at least about one-quarter of the daily dose within the first quarter of the first day of administration.

[0170] Drug elution component composition - stabilizer as excipient

[0171] In some embodiments, the excipients included in the drug elution component may include stabilizers. Many active agents tend to undergo oxidative degradation when exposed to reactive oxygen species that may be present in the stomach. Therefore, active agents included in the drug elution component of a gastric retention system may oxidize, due to the prolonged residence time of the system in the stomach and the prolonged release time of the active agents from the system. Therefore, it is desirable to include stabilizers or preservatives in the system to stabilize the active agents and thus prevent oxidation and other degradation.

[0172] Stabilizers, such as antioxidants including tocopherol, α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, and fumaric acid, may comprise about 0.1% to about 4% of the drug eluent, for example, about 0.1% to about 3.5%, about 0.1% to about 3%, about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.5%, or about 0.2% to about 0.8%.

[0173] Antioxidant stabilizers that can be included in the gastric retention system described herein to reduce or prevent the oxidation of active agents include α-tocopherol (about 0.01-0.05% v / v), ascorbic acid (0.01-0.1% w / v), ascorbyl palmitate (0.01-0.1% w / v), butylated hydroxytoluene (0.01-0.1% w / w), butylated hydroxyanisole (0.01-0.1% w / w), and fumaric acid (up to 3600 ppm). Vitamin E, tocopherol, vitamin E esters, tocopheryl esters, ascorbic acid, or carotene such as α-tocopherol, vitamin E succinate, α-tocopherol succinate, vitamin E acetate, α-tocopherol acetate, vitamin E nicotinate, α-tocopherol nicotinate, vitamin E linoleate, or α-tocopherol linoleate can be used as antioxidant stabilizers.

[0174] Some active agents can be pH sensitive, especially in the low pH environment of the stomach. Buffering or pH-stabilizing compounds that can be included in the system to reduce or prevent degradation of the active agent at low pH include calcium carbonate, calcium lactate, calcium phosphate, sodium phosphate, and sodium bicarbonate. The amount of buffering or pH-stabilizing compounds is typically no more than about 2% w / w. Buffering or pH-stabilizing compounds can constitute about 0.1% to about 4% of the drug elution component, for example, about 0.1% to about 3.5%, about 0.1% to about 3%, about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.5%, or about 0.2% to about 0.8%.

[0175] Antioxidant stabilizers, pH stabilizers, and other stabilizer compounds are blended into a polymer containing an active agent by blending stabilizers into a molten carrier polymer-activator mixture. The stabilizer can be blended into the molten carrier polymer before blending the active agent into the polymer-stabilizer mixture; or the stabilizer can be blended with the active agent before formulating the blended active agent-stabilizer mixture in the carrier polymer; or the stabilizer, active agent, and molten carrier polymer can be blended simultaneously. The active agent can also be blended with the molten carrier polymer before blending the stabilizer into the polymer-activator mixture.

[0176] In one embodiment, after a gastric retention period of approximately 24 hours, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 48 hours, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 72 hours, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 96 hours, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 5 days, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized. In some embodiments, after a gastric retention period of approximately 1 week, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized. In some embodiments, after a gastric retention period of approximately 2 weeks, less than approximately 10% of the remaining active agent in the gastric retention system is degraded or oxidized.

[0177] In one embodiment, after a gastric retention period of approximately 24 hours, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 48 hours, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 72 hours, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 96 hours, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized. In one embodiment, after a gastric retention period of approximately 5 days, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized. In some embodiments, after a gastric retention period of approximately 1 week, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized. In some embodiments, after a gastric retention period of approximately 2 weeks, less than approximately 5% of the remaining active agent in the gastric retention system is degraded or oxidized.

[0178] Laser connector components

[0179] The retainer of the gastric retention system may include one or more laser connector components. The laser connector components may be laser-welded to one or more drug elution components, adjacent laser connector components, or elastomeric components. In some embodiments, the laser connector components may be or may include inactive components (e.g., inert components for maintaining the geometry and size of the gastric retention system) or disintegration matrices, such as time-dependent disintegration matrices or intestinal disintegration matrices.

[0180] Laser connector component composition - gut and time-dependent disintegration matrix

[0181] As described above, the laser connector component can be used to connect one or more drug elution components to one or more elastomer components, additional drug elution components, or additional laser connector components; or to connect one or more laser connector components to one or more drug elution components, one or more additional laser connector components, or one or more elastomer components. Thus, the laser connector component connects multiple components of the system (e.g., multiple components of a retainer). In some embodiments, the laser connector component may comprise one or more intestinal or time-dependent disintegration matrices. The disintegration matrix may comprise: one or more intestinal polymers designed to disintegrate gradually in a controlled manner during the system's retention in the stomach; and / or one or more pH-resistant time-dependent polymers, i.e., less sensitive to pH changes than intestinal polymers. In some embodiments, intestinal polymers and time-dependent polymers less sensitive to pH changes than intestinal polymers may be used.

[0182] In some embodiments, the laser connector component may include an intestinal disintegrating matrix comprising an intestinal polymer designed to disintegrate gradually in a controlled manner during the system's retention in the stomach. This system is designed to disintegrate more rapidly to avoid intestinal obstruction should the gastric retention system prematurely enter the small intestine intact. The intestinal polymer is relatively resistant to the acidic pH levels encountered in the stomach but dissolves at the higher pH levels found in the duodenum. The use of the intestinal polymer as a safety element prevents the unintended entry of the intact gastric retention system into the small intestine.

[0183] Intestinal polymers are relatively insoluble under acidic conditions, such as those encountered in the stomach, but are soluble in the small intestine under conditions ranging from slightly acidic to alkaline. Intestinal polymers that dissolve at approximately pH 5 or higher can be used for intestinal disintegration matrix components, as the pH range of the duodenum, the initial segment of the small intestine, is approximately 5.4–6.1. If the gastric retention system passes intact through the pyloric valve, the intestinal polymer dissolves, and the components linked by the intestinal polymer break down, allowing the retention system to pass through the small and large intestines. Therefore, the gastric retention system is designed to rapidly uncouple in the intestinal environment by dissolving the intestinal polymer.

[0184] Exemplary enteric polymers include, but are not limited to, cellulose acetate succinate, methyl phthalate, ethyl hydroxy phthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylate copolymer, methacrylate-methacrylate-octyl acrylate copolymer, and copolymers, mixtures, blends, and combinations thereof. Some of the enteric polymers that can be used in this invention and their solubility pH are listed in the enteric polymer table. (See Mukherji, Gour, and Clive G. Wilson, “Enteric Coating for Colonic Delivery,” Modified-Release Drug Delivery Technology, Chapter 18 (edited by Michael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts), Drugs and the Pharmaceutical Sciences, Vol. 126, New York: Marcel Dekker, 2002.). Preferably, enteric polymers that dissolve at a pH not exceeding about 5 or about 5.5 are used. Poly(ethyl methacrylate-co-ethyl acrylate) (sold under the trade name EUDRAGIT L 100-55; EUDRAGIT is a registered trademark of Evonik Rohm GmbH, Darmstadt, Germany) is a preferred enteric polymer. Another preferred enteric polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS; Ashland, Inc., Covington, Ky., USA), which has an adjustable pH cutoff of about 5.5 to about 7.0. Cellulose phthalate, cellulose acetate succinate, and hydroxypropyl methyl cellulose phthalate are also suitable enteric polymers.

[0185] In one embodiment, the intestinal polymer for the gastric retention system dissolves at a pH above about 4. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH above about 5. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH above about 6. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH above about 7. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH above about 7.5. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH of about 4 to about 5. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH of about 4 to about 6. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH of about 4 to about 7. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH of about 4 to about 7.5. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH of about 5 to about 6. In some embodiments, the intestinal polymer for the gastric retention system dissolves at a pH of about 5 to about 7.5. In some embodiments, the intestinal polymer used in the gastric retention system is dissolved at pH 6 to about 7. In some embodiments, the intestinal polymer used in the gastric retention system is dissolved at pH 6 to about 7.5.

[0186] Intestinal polymer surface

[0187]

[0188] In some embodiments, the retainer of the gastric retention system comprises multiple segments connected by an intestinal disintegrating matrix. In some embodiments, the drug elution component of the gastric retention system is connected to the elastomeric component of the system via one or more intestinal disintegrating matrices. In any of these embodiments, when the intestinal disintegrating matrix is ​​used for segment-to-segment connections and for connecting the retainer to the elastomeric component, the intestinal polymer used for segment-to-segment connections may be the same as the intestinal polymer used for connecting the retainer to the elastomeric component, or the intestinal polymer used for segment-to-segment connections may be different from the intestinal polymer used for connecting the retainer to the elastomeric component. The intestinal polymers used for segment-to-segment connections may all be the same, or they may all be different, or some intestinal polymers in the segment-to-segment connections may be the same, and some intestinal polymers in the segment-to-segment connections may be different. That is, the intestinal polymer used for each segment-to-segment connection and the intestinal polymer used to connect the retainer to the elastomeric component can be selected independently.

[0189] In some embodiments, instead of or in addition to one or more enterodisintegrating matrices, the gastric retention system may comprise one or more time-dependent disintegrating matrices. The time-dependent disintegrating matrices may comprise one or more time-dependent polymers or connectors, i.e., polymers that degrade in a time-dependent manner in the gastric environment. For example, the liquid plasticizer triacetin is released from the polymer formulation in a time-dependent manner in simulated gastric fluid over seven days, while Plastoid B retains its strength in simulated gastric fluid over seven days. Therefore, a time-dependent polymer can be conveniently prepared by mixing Plastoid B and triacetin; the degradation time of the Plastoid B-triacetin mixture can be prolonged by increasing the amount of Plastoid B used in the mixture (i.e., using less triacetin in the mixture), while the degradation time can be shortened by reducing the amount of Plastoid B used in the mixture (i.e., using more triacetin in the mixture).

[0190] Time-dependent polymers or connectors degrade in a predictable, time-dependent manner. In some embodiments, the degradation of time-dependent polymers or connectors may be unaffected by changes in the pH of the gastrointestinal system. The term "pH-resistant time-dependent polymer" (or equivalent "pH-resistant time-dependent polymer") means that the time-dependent polymer still possesses sufficient mechanical strength to join components together even when the intestinal polymer degrades to the point where it can no longer join the components. In some embodiments, the time-dependent polymer maintains nearly the same joining capacity, i.e., approximately 100% of its joining strength after exposure to solutions at approximately pH 7–approximately pH 8, as it does after exposure to solutions at approximately pH 2–approximately pH 3, wherein the exposure lasts for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, the time-dependent polymer maintains at least approximately 90% of its joining strength after exposure to solutions at approximately pH 7–approximately pH 8, as it does after exposure to solutions at approximately pH 2–approximately pH 3, wherein the exposure lasts for approximately 1 hour, approximately 1 day, approximately 3 days, or approximately 1 week. In some embodiments, the time-dependent polymer retains at least about 75% of its bond strength after exposure to a solution at about pH 7 to about pH 8, as it does after exposure to a solution at about pH 2 to about pH 3, wherein the exposure lasts for about 1 hour, about 1 day, about 3 days, or about 1 week. In some embodiments, the time-dependent polymer retains at least about 60% of its bond strength after exposure to a solution at about pH 7 to about pH 8, as it does after exposure to a solution at about pH 2 to about pH 3, wherein the exposure lasts for about 1 hour, about 1 day, about 3 days, or about 1 week. In some embodiments, the time-dependent polymer retains at least about 50% of its bond strength after exposure to a solution at about pH 7 to about pH 8, as it does after exposure to a solution at about pH 2 to about pH 3, wherein the exposure lasts for about 1 hour, about 1 day, about 3 days, or about 1 week. In some embodiments, the time-dependent polymer retains at least about 25% of its bond strength after exposure to a solution at about pH 7–about pH 8, as it would after exposure to a solution at about pH 2–about pH 3, wherein the exposure lasts for about 1 hour, about 1 day, about 3 days, or about 1 week. In some embodiments, the time-dependent polymer resists fracture under bending forces of about 0.2 Newtons (N), about 0.3 N, about 0.4 N, about 0.5 N, about 0.75 N, about 1 N, about 1.5 N, about 2 N, about 2.5 N, about 3 N, about 4 N, or about 5 N after exposure to a solution at about pH 7–about pH 8, wherein the exposure lasts for about 1 hour, about 1 day, about 3 days, or about 1 week. Bond strength can be measured by any relevant test used to test coupling ability, such as the four-point bending test (ASTM D790).

[0191] Several time-dependent mechanisms can be utilized. Water-soluble time-dependent polymers decompose when water permeates into them. Examples of such polymers are hydroxypropyl methylcellulose and polyvinyl acetate. Acid-soluble time-dependent polymers decompose over time in acidic environments. Examples include Eudragit EPO. Time-dependent polymers can use water-soluble plasticizers; as the plasticizer is released, the remaining polymer becomes brittle and breaks under the force of the stomach. Examples of such polymers include triacetin and triethyl citrate.

[0192] In any embodiment of the gastric retention system described herein, the intestinal or time-dependent polymer or connector may comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polycaprolactone (PCL). These blends may be used to form a disintegration connector or disintegration matrix. The ratio of HPMCAS to PCL in the disintegration matrix may be approximately 80% HPMCAS:20% PCL to approximately 20% HPMCAS:80% PCL. The ratio of HPMCAS to polycaprolactone can be approximately 80% HPMCAS:20% PCL - approximately 20% HPMCAS:80% PCL; approximately 70% HPMCAS:30% PCL - approximately 30% HPMCAS:70% PCL; approximately 60% HPMCAS:40% PCL - approximately 40% HPMCAS:60% PCL; approximately 80% HPMCAS:20% PCL - approximately 50% HPMCAS:50% PCL; approximately 80% HPMCAS:20% PCL - approximately 60% HPMCAS:40% PCL; approximately 70% HPMCAS:30% PCL - approximately 50% HPMCAS:50% PCL; approximately 70% HPMCAS:30% PCL - approximately 60% HPMCAS:40% PCL; approximately 20% HPMCAS:80% PCL - approximately 40% HPMCAS:60% PCL; approximately 20% HPMCAS:80% PCL - approximately 50% HPMCAS:50% PCL; approximately 30% HPMCAS:70% PCL - approximately 40% HPMCAS:60% PCL; approximately 30% HPMCAS:70% PCL - approximately 50% HPMCAS:50% PCL; or approximately 80% HPMCAS:20% PCL, approximately 70% HPMCAS:30% PCL, approximately 60% HPMCAS:40% PCL, approximately 50% HPMCAS:50% PCL, approximately 40% HPMCAS:60% PCL, approximately 30% HPMCAS:70% PCL, or approximately 20% HPMCAS:80% PCL. The disintegrating matrix may also contain plasticizers selected from triacetin, triethyl citrate, tributyl citrate, poloxamer, polyethylene glycol, polypropylene glycol, diethyl phthalate, dibutyl sebacate, glycerin, castor oil, acetylated triethyl citrate, acetylated tributyl citrate, polyethylene glycol monomethyl ether, sorbitol, dehydrated sorbitol, sorbitol-dehydrated sorbitol mixtures, and diacetylated monoglycerides.

[0193] The composition of the disintegrating matrix is ​​selected such that it is sufficiently weakened after a specified time period, so that the gastric retention system reaches the point where it is uncoupled and passes through the pylorus and leaves the stomach after the desired retention period, or is sufficiently weakened such that the gastric retention system no longer remains in the stomach; that is, the disintegrating matrix is ​​weakened to the point of uncoupling (uncoupling point) or the point where the gastric retention system can pass through the pylorus (pyloric passage point or passage point). Thus, in one embodiment, a disintegrating matrix is ​​used that is uncoupled after approximately 2 days in the human stomach; approximately 3 days in the human stomach; approximately 4 days in the human stomach; approximately 5 days in the human stomach; approximately 6 days in the human stomach; approximately 7 days in the human stomach; approximately 8 days in the human stomach; approximately 9 days in the human stomach; approximately 10 days in the human stomach; or approximately 2 weeks in the human stomach. In one embodiment, the disintegrating matrix is ​​used after approximately 2 days in the stomach of a dog; approximately 3 days in the stomach of a dog; approximately 4 days in the stomach of a dog; approximately 5 days in the stomach of a dog; approximately 6 days in the stomach of a dog; approximately 7 days in the stomach of a dog; approximately 8 days in the stomach of a dog; approximately 9 days in the stomach of a dog; approximately 10 days in the stomach of a dog; or approximately 2 weeks in the stomach of a dog. In one embodiment, the disintegrating matrix is ​​used after approximately 2 days in the stomach of a pig; approximately 3 days in the stomach of a pig; approximately 4 days in the stomach of a pig; approximately 5 days in the stomach of a pig; approximately 6 days in the stomach of a pig; approximately 7 days in the stomach of a pig; approximately 8 days in the stomach of a pig; approximately 9 days in the stomach of a pig; approximately 10 days in the stomach of a pig; or approximately 2 weeks in the stomach of a pig. In one implementation, a disintegrating matrix is ​​used after approximately 2 days of fasting in simulated gastric fluid; approximately 3 days of fasting in simulated gastric fluid; approximately 4 days of fasting in simulated gastric fluid; approximately 5 days of fasting in simulated gastric fluid; approximately 6 days of fasting in simulated gastric fluid; approximately 7 days of fasting in simulated gastric fluid; approximately 8 days of fasting in simulated gastric fluid; approximately 9 days of fasting in simulated gastric fluid; approximately 10 days of fasting in simulated gastric fluid; or approximately 2 weeks of fasting in simulated gastric fluid. In one embodiment, a disintegrating matrix is ​​used after approximately 2 days in a fed simulated gastric fluid; approximately 3 days in a fed simulated gastric fluid; approximately 4 days in a fed simulated gastric fluid; approximately 5 days in a fed simulated gastric fluid; approximately 6 days in a fed simulated gastric fluid; approximately 7 days in a fed simulated gastric fluid; approximately 8 days in a fed simulated gastric fluid; approximately 9 days in a fed simulated gastric fluid; approximately 10 days in a fed simulated gastric fluid; or approximately 2 weeks in a fed simulated gastric fluid. In one embodiment, the disintegrating matrix is ​​used after approximately 2 days in water at pH 2; approximately 3 days in water at pH 2; approximately 4 days in water at pH 2; approximately 5 days in water at pH 2; approximately 6 days in water at pH 2; approximately 7 days in water at pH 2; approximately 8 days in water at pH 2; approximately 9 days in water at pH 2; approximately 10 days in water at pH 2; or approximately 2 weeks in water at pH 2.In one embodiment, the disintegrating matrix is ​​used after approximately 2 days in water at pH 1; approximately 3 days in water at pH 1; approximately 4 days in water at pH 1; approximately 5 days in water at pH 1; approximately 6 days in water at pH 1; approximately 7 days in water at pH 1; approximately 8 days in water at pH 1; approximately 9 days in water at pH 1; approximately 10 days in water at pH 1; or approximately 2 weeks in water at pH 1.

[0194] In humans, dogs, or pigs, the uncoupling or pyloric passage point occurs when the system leaves the stomach, i.e., when it passes through the pylorus. For in vitro measurements simulating gastric juice or acidic water, the uncoupling or pyloric passage point occurs when the disintegrating matrix weakens to a point where it typically breaks under normal compressive forces in the stomach, typically around 0.1-0.2 Newtons. The connection strength (break point) can be measured by any relevant test used to test coupling capability, even the force required for the joint to break, such as the four-point bending test (ASTM D790) described in Example 18 of WO 2017 / 070612 or Examples 12, 13, 15, 17, or 18 of WO 2017 / 100367. In one embodiment, the uncoupling or pyloric passage point is reached when the disintegrating matrix uncouples under a force of approximately 0.2 N. In another embodiment, the uncoupling or pyloric passage point is reached when the disintegrating matrix uncouples under a force of approximately 0.1 N.

[0195] The gastric retention system can reach the pyloric passage point without actually rupturing any or all of the disintegrating matrix. If the disintegrating matrix weakens or degrades to a point where it may no longer hold the gastric retention system in the stomach, the gastric retention system will pass through the pylorus and enter the small intestine (pyloric passage point or point of entry) even if one, some, or all of the disintegrating matrix has not ruptured. In some embodiments, a disintegrating matrix weakened to the point of entry is used after approximately 2 days in the human stomach; approximately 3 days in the human stomach; approximately 4 days in the human stomach; approximately 5 days in the human stomach; approximately 6 days in the human stomach; approximately 7 days in the human stomach; approximately 8 days in the human stomach; approximately 9 days in the human stomach; approximately 10 days in the human stomach; or approximately 2 weeks in the human stomach. In some embodiments, the matrix weakens to a point of disintegration after approximately 2 days in the stomach of a dog; approximately 3 days in the stomach of a dog; approximately 4 days in the stomach of a dog; approximately 5 days in the stomach of a dog; approximately 6 days in the stomach of a dog; approximately 7 days in the stomach of a dog; approximately 8 days in the stomach of a dog; approximately 9 days in the stomach of a dog; approximately 10 days in the stomach of a dog; or approximately 2 weeks in the stomach of a dog. In some embodiments, the matrix weakens to a point of disintegration after approximately 2 days in the stomach of a pig; approximately 3 days in the stomach of a pig; approximately 4 days in the stomach of a pig; approximately 5 days in the stomach of a pig; approximately 6 days in the stomach of a pig; approximately 7 days in the stomach of a pig; approximately 8 days in the stomach of a pig; approximately 9 days in the stomach of a pig; approximately 10 days in the stomach of a pig; or approximately 2 weeks in the stomach of a pig. In some implementations, the matrix weakens to the point of disintegration after approximately 2 days in fasting simulated gastric fluid; approximately 3 days in fasting simulated gastric fluid; approximately 4 days in fasting simulated gastric fluid; approximately 5 days in fasting simulated gastric fluid; approximately 6 days in fasting simulated gastric fluid; approximately 7 days in fasting simulated gastric fluid; approximately 8 days in fasting simulated gastric fluid; approximately 9 days in fasting simulated gastric fluid; approximately 10 days in fasting simulated gastric fluid; or approximately 2 weeks in fasting simulated gastric fluid. In some implementations, the matrix weakens to the point of disintegration after approximately 2 days in a fed simulated gastric fluid; approximately 3 days in a fed simulated gastric fluid; approximately 4 days in a fed simulated gastric fluid; approximately 5 days in a fed simulated gastric fluid; approximately 6 days in a fed simulated gastric fluid; approximately 7 days in a fed simulated gastric fluid; approximately 8 days in a fed simulated gastric fluid; approximately 9 days in a fed simulated gastric fluid; approximately 10 days in a fed simulated gastric fluid; or approximately 2 weeks in a fed simulated gastric fluid. In some implementations, the matrix weakens to the point of disintegration after approximately 2 days in water at pH 2; approximately 3 days in water at pH 2; approximately 4 days in water at pH 2; approximately 5 days in water at pH 2; approximately 6 days in water at pH 2; approximately 7 days in water at pH 2; approximately 8 days in water at pH 2; approximately 9 days in water at pH 2; approximately 10 days in water at pH 2; or approximately 2 weeks in water at pH 2.In some implementations, the matrix weakens to the point of disintegration after approximately 2 days in water at pH 1; approximately 3 days in water at pH 1; approximately 4 days in water at pH 1; approximately 5 days in water at pH 1; approximately 6 days in water at pH 1; approximately 7 days in water at pH 1; approximately 8 days in water at pH 1; approximately 9 days in water at pH 1; approximately 10 days in water at pH 1; or approximately 2 weeks in water at pH 1.

[0196] Laser connector components - non-active parts

[0197] In some embodiments, the laser connector component may include one or more inactive components that serve as spacers or otherwise maintain the shape and size of the gastric retention system. In some embodiments, the inactive components may comprise polymers compatible with other sections of the gastric retention system, such as drug elution components. Suitable polymers may include thermoplastic copolyesters, polycaprolactone (PCL), thermoplastic polyurethanes, thermoplastic polyamides, thermoplastic vulcanizates, styrene block copolymers, polyethylene-co-vinyl acetate, or polylactic acid.

[0198] In some embodiments, the generic polymer included in the inactive segment includes polycaprolactone (PCL). In some embodiments, the inactive component comprises about 60-85 wt.% PCL, about 65-75 wt.% PCL, or about 70 wt.% PCL. In some embodiments, the inactive component comprises about 61-71 wt.% PCL, about 64-69 wt.% PCL, or about 66.45 wt.% PCL. In some embodiments, the inactive component comprises pure PCL.

[0199] In some embodiments, the inactive component may comprise a radiopaque material. Adding a radiopaque material, if necessary, can aid in the localization of the gastric retention system via abdominal X-ray. Examples of suitable radiopaque materials are barium sulfate, bismuth subcarbonate, bismuth oxychloride, and bismuth trioxide. In some embodiments, the inactive component may comprise bismuth subcarbonate. In some embodiments, the inactive component comprises about 15-40 wt.% bismuth subcarbonate, about 25-35 wt.% bismuth subcarbonate, or about 30 wt.% bismuth subcarbonate.

[0200] In some embodiments, the inactive component may comprise a vinylpyrrolidone-vinyl acetate copolymer (i.e., copovidone, such as Kollidon VA64) in a mass ratio of 6:4. In some embodiments, the inactive component comprises about 27-37 wt.% copovidone, about 30-34 wt.% copovidone, or about 32 wt.% copovidone.

[0201] In some embodiments, the inactive component may comprise one or more plasticizers, such as poloxamer (e.g., poloxamer 407 or "P407"). In some embodiments, the inactive component comprises about 0.2-4 wt.% poloxamer, about 0.5-2.5 wt.% poloxamer, or about 1.50 wt.% poloxamer.

[0202] In some embodiments, the inactive component may contain absorbent dyes (also known as colorants or pigments). For example, the inactive component may contain 11-13% FD&C Blue 1 aluminum lake. In some embodiments, the inactive component contains about 0.005-0.2 wt.% absorbent dye, about 0.01-0.1 wt.% absorbent dye, or about 0.05 wt.% absorbent dye.

[0203] Exemplary quantities of components in the first embodiment without moving parts are shown in the table below. These quantities are given as approximate weight percentages, and it should be understood that when a range is provided, the selected quantities add up to 100%.

[0204]

[0205] Exemplary quantities of components in another embodiment without moving parts are shown in the table below. These quantities are given as approximate weight percentages, and it should be understood that when a range is provided, the selected quantities add up to 100%.

[0206]

[0207] Elastomer components

[0208] In some implementations, the gastric retention system may include one or more elastomeric components. These elastomeric components may comprise one or more elastomers, also known as elastic polymers or tensile polymers, that enable the gastric retention system to be compressed, for example, by folding or compressing it into a form suitable for application to the stomach via swallowing a container or capsule containing the compression system. After the capsule dissolves in the stomach, the gastric retention system expands into a shape that prevents the system from passing through the patient's pyloric sphincter during the desired retention time. Therefore, the elastomer must be able to be stored in the capsule in a compressible configuration for a reasonable storage period and expand to its original shape or approximately its original shape upon release from the capsule.

[0209] In some embodiments, the elastomer is a silicone elastomer. The elastomer can be formed from liquid silicone rubber (LSR), for example, as sold in the form of Dow Corning QP-1 liquid silicone rubber kits. In some embodiments, the elastomer is cross-linked polycaprolactone. In one embodiment, the elastomer is an enteric polymer, such as those listed in the enteric polymer table. (Elastomer components of star-shaped systems are generally not enteric polymers; however, elastomer components may also be made from such enteric polymers where desired and feasible). Other examples of elastomers that can be used include poly(acryloyl 6-aminohexanoic acid) (PA6ACA); poly(ethyl methacrylate-co-ethyl acrylate) (EUDRAGIT L 100-55); and mixtures of poly(acryloyl 6-aminohexanoic acid) (PA6ACA) and poly(ethyl methacrylate-co-ethyl acrylate) (EUDRAGIT L 100-55).

[0210] The elastomeric component can have specific hardness and compression set. A hardness tester can determine the folding force of the dosage form and whether it will remain in the stomach; the preferred range is about 60 to about 90 A. The compression set can be low to avoid permanent deformation of the gastric retention system when stored in a capsule under pressure. The preferred range is about 10% to about 20%. An example of a material that meets these requirements is the QP1 series of liquid silicone rubbers from Dow Corning. In any embodiment using the elastomeric component, QP1-270 (70 A hardness) liquid silicone rubber can be used. In some embodiments, the elastomeric component may comprise liquid silicone rubber (Shin Etsu) with a hardness of 50 A or 60 A.

[0211] In some embodiments, the star-shaped gastric retention system may include a central elastomeric component and a plurality of retainers connected to the elastomeric component. The proximal end of each retainer may be connected to and radially project from the elastomeric component, such that each retainer has a distal end not connected to the elastomeric component and located at a greater radial distance from the elastomeric component than its proximal end. In some embodiments, six retainers may be connected to the elastomeric component in a star configuration, but three, four, five, seven, eight, nine, or ten retainers may also be used. The retainers may be equidistantly distributed around the elastomeric component; if there are N retainers, the angle between adjacent retainers is approximately 360 / N degrees.

[0212] System polymer composition

[0213] The choice of individual polymers—the carrier polymer, the intestinal and / or time-dependent polymer, and the elastomer—affects many system properties, such as drug elution rate (depending on the carrier polymer and other factors), system residence time (depending on the degradation of any polymer, primarily the intestinal or time-dependent polymer), uncoupling time if the system enters the intestine (primarily dependent on the intestinal degradation rate of the intestinal and / or time-dependent polymer, as described herein), and shelf life of the system in compressed form (primarily dependent on the elastomer's properties). Since these systems are administered to the gastrointestinal tract, all system components should be biocompatible with the gastrointestinal environment.

[0214] The elution rate of a drug from a drug elution component is influenced by many factors, including the composition and properties of the carrier polymer, which itself can be a mixture of several polymeric and non-polymeric components; the properties of the drug, such as hydrophilicity / hydrophobicity, charge state, pKa, and hydrogen bonding capacity; and the characteristics of the gastric environment. Avoiding burst release of the drug (where burst release refers to a high initial delivery rate of the active drug component when the system initially unfolds in the stomach), especially for hydrophilic drugs, in the aqueous environment of the stomach, and maintaining sustained drug release for a period of several days to one or two weeks, is challenging.

[0215] The retention time of the system in the stomach is modulated by selecting intestinal and / or time-dependent polymers used in the laser connector components. Although intestinal polymers are used, these systems eventually degrade in the stomach because the mechanical action and pH fluctuations of the stomach eventually weaken them. Polymers that degrade in a time-dependent manner in the stomach can also be used to modulate the time until the system degrades or weakens to a point where it may no longer resist passage through the pylorus, thereby regulating the retention time. Once the system degrades or weakens to a point where it may no longer resist passage through the pylorus, it enters the intestine and is then eliminated.

[0216] The elastomers used in the system are crucial to its shelf life. When the system is compressed, the elastomers are subjected to mechanical stress. This stress, in turn, can cause polymer creep, which, if large enough, can prevent the system from reverting to its uncompressed state upon release from the capsule or other container; this, in turn, can lead to premature expulsion of the system from the stomach. Polymer creep can also be temperature-dependent, and therefore, the system's intended storage conditions must be considered when selecting elastomers and other polymer components.

[0217] System components and polymers should not swell in the gastric environment, or should swell to a minimum. When in the gastric environment during retention, component swelling should not exceed about 20%, about 10%, or about 5%.

[0218] These systems may optionally be radiopaque so that they can be located by abdominal X-ray if necessary. In some embodiments, one or more materials used to construct the system are sufficiently radiopaque for X-ray visualization. In other embodiments, radiopaque substances are added to one or more materials of the system, coated onto one or more materials of the system, or added to a small portion of the system. Examples of suitable radiopaque substances are barium sulfate, bismuth subcarbonate, bismuth oxychloride, and bismuth trioxide. These materials are typically blended into individual sections of the gastric retention system, such as small segments of one or more retainers, to avoid altering the release of the drug from the carrier polymer or the desired properties of other system polymers, such as connectors or elastomeric components. Metal strips or tips, such as tungsten, may also be used on a small portion of a system component.

[0219] Exemplary gastric retention system components

[0220] Figure 10 This illustrates an exemplary gastric retention system according to some embodiments. System 1000 includes a central elastomeric component 1010. The elastomeric component may comprise liquid silicone rubber overmolded onto a polycarbonate component. The elastomeric component 1010 may be star-shaped or star-shaped, having six short branches to which six retainers may be attached. In some embodiments, the liquid silicone rubber component of the elastomeric component 1010 may be up to about 5-10 mm, about 6-9 mm, about 7-8 mm, or about 7.5 mm in length (e.g., from the tip of a first branch to the tip of a second branch directly opposite the first branch). In some embodiments, the polycarbonate component of the elastomeric component 1010 may be up to about 7-15 mm, about 10-12 mm, or about 11.5 mm in length. The polycarbonate component can be used as an inter-component anchor because it can extend from the elastomeric component into one or more additional segments to reinforce the connection between the elastomeric component and the retainers. Examples of anchors between components are described in U.S. Patent Application Publication No. 2019 / 0262265, for example... Figure 14 A and Figure 14 B. Figures 36A-36E, paragraphs

[0031] -

[0035] and paragraphs

[0294] -

[0375] . At least one retainer 1020 connected to the elastomer component 1010 may include a drug elution component 1026. Figure 10 Two such retainers with drug elution components are shown. One or more retainers connected to the elastomer component 1010 may not include a drug elution component. Figure 10 Five such retainers without drug elution components are shown. (For simplicity, in...) Figure 10 Only one such retainer 1030 is marked in the text.

[0221] For the retainer 1020, which includes a drug elution component (drug elution retainer), a first inactive component 1021 may optionally be connected to a branch of the elastomeric component 1010. The first inactive component 1021 may comprise polycaprolactone (PCL). In some embodiments, the first inactive component 1021 may be injection molded onto the elastomeric component 1010 such that the first inactive component 1021 is a component of the elastomeric component 1010 rather than a separate component of the drug elution retainer 1020.

[0222] The first inactive component 1021 may be connected to the time-dependent disintegration matrix component 1022. In some embodiments, the time-dependent disintegration matrix component 1022 may comprise one or more of PCL (e.g., PCL12), poly(ethylene oxide) (e.g., PEO100K), DL-lactide / glycolic acid copolymer (e.g., 50 / 50 DL-lactide / glycolic acid copolymer, acid (pDLG5002A)), and / or iron(III) oxide. The time-dependent disintegration matrix component 1022 may be configured to degrade in a predictable time-dependent manner. In some embodiments, the degradation of the time-dependent disintegration matrix component 1022 may be independent of the variable pH of the gastrointestinal system. Exemplary amounts of the components of the time-dependent disintegration matrix component 1022 are shown in the table below.

[0223]

[0224] The time-dependent disintegration matrix component 1022 can be connected to the second inactive component 1023. The second inactive component 1023 may comprise a radiopaque PCL (rPCL), which may comprise PCL (e.g., Corbion PC17) and bismuth subcarbonate. Exemplary quantities of the components of the second inactive component 1023 are shown in the table below.

[0225]

[0226] The second inactive component 1023 may be connected to the intestinal disintegration matrix component 1024. The intestinal disintegration matrix component 1024 may comprise one or more of PCL, intestinal polymers (e.g., hydroxypropyl methylcellulose acetate succinate MG grade, i.e., HPMCAS-MG), or poloxamer 407 (P407). The intestinal disintegration matrix component 1024 may be designed to disintegrate gradually in a controlled manner during the system's retention in the stomach, and to disintegrate more rapidly if the gastric-retained system prematurely and completely enters the small intestine. The intestinal disintegration matrix component 1024 may be relatively resistant to the acidic pH level of the stomach, but may dissolve at the higher pH levels found in the duodenum. Therefore, the intestinal disintegration matrix component 1024 can prevent the undesirable entry of the intact gastric-retained system into the small intestine. Exemplary amounts of the components of the intestinal disintegration matrix component 1024 are shown in the table below.

[0227]

[0228] The intestinal disintegration matrix component 1024 can be connected to the third inactive component 1025. The third inactive component 1025 can have the same composition as the second inactive component 1023, i.e., rPCL containing PCL (e.g., Corbion PC17) and bismuth subcarbonate. Exemplary quantities of the components of the third inactive component 1025 are shown in the table below.

[0229]

[0230] A third inactive component 1025 may be connected to a drug elution component 1026. In some embodiments, the drug elution component 1026 may contain risperidone. Risperidone is used as an exemplary example, but it should be understood that any suitable active pharmaceutical ingredient may be used in the gastric retention system described herein. The drug elution component 1026 may also contain one or more of PCL (e.g., PCL17), copovidone (e.g., Kollidon VA64), poloxamer (e.g., P407), vitamin E succinate, colloidal silica, or colorants (e.g., FD&C Yellow 5 Aluminum Lake, FD&C Blue 1 Aluminum Lake). Exemplary amounts of the components of the drug elution component 1026 are shown in the table below.

[0231]

[0232] The drug elution component 1026 may be connected to the fourth inactive component 1027. Optionally, in some embodiments, a portion of the suture 1040 may be embedded in the fourth inactive component 1027, which may allow the retainer 1020 (containing the drug elution component) to be connected to an adjacent retainer (e.g., retainer 1030, which does not contain the drug elution component). The fourth inactive component 1027 may contain PCL (e.g., Corbion PC17). In some embodiments, the fourth inactive component 1027 may also contain one or more of copovidone (e.g., VA64), poloxamer (e.g., P407), or a colorant (e.g., FD&C Blue 1 Aluminum Lake (11-13%)). Exemplary amounts of the components of the fourth inactive component 1027 are shown in the table below.

[0233]

[0234] The approximate radial lengths of the different components on the exemplary drug elution retainer 1020 are shown in the table below.

[0235]

[0236] In some embodiments, each component of the drug elution retainer 1020 may have a triangular cross-section. In some embodiments, the triangular cross-section is an equilateral triangle. The side lengths of the equilateral triangles of each component of the drug elution retainer 1020 are shown in the table below.

[0237]

[0238] In some embodiments, the drug elution retainer 1020 may comprise a coating. This coating may comprise one or more of PCL (e.g., PCL17), copovidone (e.g., VA64), or magnesium stearate. In some embodiments, the coating may also comprise trace amounts of ethyl acetate, used to dissolve PCL17, VA64, and / or magnesium stearate to prepare the coating. The coating may be applied using a disc coater. In some embodiments, the coating may comprise about 2-4% of the weight of the coated retainer 1020. Exemplary amounts of the coated components are shown in the table below.

[0239]

[0240] In some embodiments, one retainer of the gastric retention system 1000 includes a drug-eluting retainer 1020. In some embodiments, two retainers of the gastric retention system 1000 include drug-eluting retainers 1020. In some embodiments, three retainers of the gastric retention system 1000 include drug-eluting retainers 1020. In some embodiments, four retainers of the gastric retention system 1000 include drug-eluting retainers 1020. In some embodiments, five retainers of the gastric retention system 1000 include drug-eluting retainers 1020. In some embodiments, all six retainers of the gastric retention system 1000 include drug-eluting retainers 1020.

[0241] In some embodiments, the gastric retention system 1000 includes one or more retainers 1030 that do not include a drug elution component (a non-drug elution retainer). For the non-drug elution retainer 1030, a first inactive component 1031 may be connected to a branch of the elastomeric component 1010. The first inactive component 1031 may include PCL. The first inactive component 1031 may have the same composition as the first inactive component 1021. As with the first inactive component 1021, the first inactive component 1031 may be injection molded onto the elastomeric component 1010 such that the first inactive component 1031 is a component of the elastomeric component rather than a separate component of the non-drug elution retainer 1030.

[0242] The first inactive component 1031 may be connected to the time-dependent disintegration matrix component 1032. The time-dependent disintegration matrix component 1032 may have the same composition as the time-dependent disintegration matrix component 1022, namely one or more of PCL (e.g., PCL12), poly(ethylene oxide) (e.g., PEO100K), DL-lactide / glycolic acid copolymer (e.g., 50 / 50 DL-lactide / glycolic acid, pDLG 5002A)) and / or iron(III) oxide.

[0243] The time-dependent disintegration matrix component 1032 can be connected to the second inactive component 1033. The second inactive component 1033 can have the same composition as the second inactive component 1023, namely PCL (e.g., Corbion PC17) and bismuth subcarbonate.

[0244] The second inactive component 1033 may be connected to the intestinal disintegration matrix component 1034. The intestinal disintegration matrix component 1034 may have the same composition as the intestinal disintegration matrix component 1024, namely one or more of PCL, intestinal polymers (e.g., HPMCAS-MG), or poloxamer (e.g., P407).

[0245] The intestinal disintegration matrix component 1034 can be connected to the third inactive component 1035. The third inactive component 1035 can have the same composition as the third inactive component 1025, namely PCL (e.g., Corbion PC17) and bismuth subcarbonate.

[0246] The third inactive component 1035 may be connected to the fourth inactive component 1036. The fourth inactive component 1036 may have the same composition as the fourth inactive component 1027, namely one or more of PCL (e.g., Corbion PC17), copovidone (e.g., VA64), poloxamer (e.g., P407), or a colorant (e.g., FD&C Blue 1 aluminum lake (11-13%)). Optionally, in some embodiments, a portion of the suture 1040 may be embedded in the fourth inactive component.

[0247] The approximate radial length of the components on the exemplary non-drug elution retainer 1030 is shown in the table below.

[0248]

[0249] In some embodiments, each component of the non-drug elution retainer 1030 may have a triangular cross-section. In some embodiments, the triangular cross-section is an equilateral triangle. The side lengths of the equilateral triangles of each segment of the non-drug elution retainer 1030 are shown in the table below.

[0250]

[0251] In some implementations, the diameter of the widest part of the gastric retention system (e.g., from the distal end of the first retainer to the distal end of the second retainer opposite the first retainer) is about 40-50 mm, about 42-48 mm, or about 44-46 mm.

[0252] like Figure 16 As shown, suture 1040 may optionally connect adjacent retainers of the gastric retention system in a circumferential direction. Suture 1040 can help provide a more consistent gastric retention time and / or a longer gastric retention time for the gastric retention system. A gastric retention system with predictable gastric retention time can minimize the risk of premature deployment (e.g., in the esophagus) and resulting obstruction. A gastric retention system with predictable and / or controllable gastric retention time can also minimize the possibility that the gastric retention system passes through the stomach and deploys later in the gastrointestinal tract (i.e., the intestine), or passes through the gastrointestinal tract without deploying at all. In some embodiments, the suture may contain polyglycolic acid (PGA). The suture may have a diameter of about 0.05-1 mm, about 0.1-0.5 mm, or about 0.2 mm. In some embodiments, the suture may contain multiple smaller filaments braided together. For example, using laser welding or infrared welding techniques, suture 1040 may be embedded in each retainer of the gastric retention system.

[0253] The gastric retention system 1000 can be folded and sealed in a sleeve and / or capsule for delivery. In some embodiments, the gastric retention system 1000 may be placed in an inner sleeve before being placed in an outer capsule. The sleeve may contain hydroxypropyl methylcellulose (HPMC). The sleeve may be a size 0 capsule with only a cap. In some embodiments, a capsule may be used in addition to the sleeve. The capsule may contain HPMC. The capsule may be a size 00EL capsule. In some embodiments, the capsule may contain a coating. The capsule coating may contain one or more of Eudragit E, dibutyl sebacate, or magnesium stearate. The capsule coating may contain about 35-45 mg / capsule. Exemplary amounts of the capsule coating components are shown in the table below.

[0254]

[0255] System size

[0256] The cross-section of retainers and components of a gastric retention system can be circular (in this case, the component is cylindrical), polygonal (e.g., a component with a triangular, rectangular, or square cross-section), or pie-shaped (in this case, the component is cylindrical). Components with polygonal or pie-shaped cross-sections, as well as the ends of cylindrical cross-sections that will contact gastric tissue, can have their sharp edges rounded to provide rounded corners and edges, thereby enhancing in vivo safety. That is, instead of a sharp transition between intersecting edges or planes, an arc is used to transition from one edge or plane to another. Thus, a "triangular cross-section" includes a cross-section with an approximately triangular shape, such as a triangle with rounded corners. Retainers with triangular cross-sections include retainers with rounded edges and rounded corners at the ends of the retainer. Rounded corners and edges are also referred to as fillet corners, filled corners, filled edges, or filled edges.

[0257] In some embodiments, the star-shaped gastric retention system is approximately 30 mm to approximately 60 mm when deployed (the retainer is deployed). In some embodiments, the star-shaped system is approximately 41 mm to approximately 51 mm when deployed. In some embodiments, the star-shaped system is approximately 45 mm to approximately 47 mm when deployed. In some embodiments, the star-shaped system is approximately 46 mm when deployed.

[0258] Once assembled, the gastric retention system must be able to be in a compressible state, sized to allow the patient to swallow the system (or to be introduced into the stomach via an alternative means, such as a feeding tube or gastric tube). Typically, the system is held in a compressed state by a container, such as a capsule. Upon entering the stomach, the system is then released from the container and placed in an uncompressible state, i.e., an inflated structure sized to prevent the system from passing through the pyloric sphincter, thus allowing the system to remain in the stomach.

[0259] Therefore, the system should be able to fit into standard-sized capsules commonly used in pharmacies. Standard capsule sizes used in the United States are shown in the table below (see “Draft Guidance for Industry on Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules”, URL www.regulations.gov / #!documentDetail;D=FDA-2013-N-1434-0002). Since these are the external dimensions of the capsules, and sizes may vary slightly between capsule manufacturers, the system should be able to be constructed with a diameter approximately 0.5–1 mm smaller than the outer diameter shown, and approximately 1 mm–2 mm shorter than the length shown in the capsule table.

[0260] Capsule Table

[0261]

[0262] The capsule can be made of materials well known in the art, such as gelatin or hydroxypropyl methylcellulose. In one embodiment, the capsule is made of a material that dissolves in the gastric environment but does not dissolve in the oral or esophageal environment, which prevents premature release of the system before it reaches the stomach.

[0263] In one implementation, the system is folded or compressed into a compressed state to be loaded into a capsule, for example, as shown in the example. Figure 1B As shown in the diagram. Once the capsule dissolves in the stomach, the system employs a configuration suitable for gastric retention, for example, in the manner shown. Figure 1A The method shown is preferred. The capsule sizes are 00 and 00e1 (the 00e1 size capsule has a length approximately equal to that of a 000 capsule and a width approximately equal to that of a 00 capsule), which imposes limitations on the length and diameter of the folding system.

[0264] Once released from the container, the system assumes an uncompressed state sized to prevent the gastric retention system from passing through the pyloric sphincter. In one embodiment, the system has at least two vertical dimensions, each at least approximately 2 cm in length; that is, the gastric retention system defines at least two vertical directions with a length of at least approximately 2 cm. In another embodiment, when projected onto a plane, the perimeter of the system in its uncompressed state has two vertical dimensions, each at least approximately 2 cm in length. The two vertical dimensions may independently have lengths of approximately 2 cm to approximately 7 cm, approximately 2 cm to approximately 6 cm, approximately 2 cm to approximately 5 cm, approximately 2 cm to approximately 4 cm, approximately 2 cm to approximately 3 cm, approximately 3 cm to approximately 7 cm, approximately 3 cm to approximately 6 cm, approximately 3 cm to approximately 5 cm, approximately 3 cm to approximately 4 cm, approximately 4 cm to approximately 7 cm, approximately 4 cm to approximately 6 cm, approximately 4 cm to approximately 5 cm, or approximately 4 cm to approximately 4 cm. These dimensions prevent the gastric retention system from passing through the pyloric sphincter. For a star-shaped polymer with N retainers (where N is greater than or equal to 3, e.g., N=6), the retainers may have dimensions that give the system at least two vertical dimensions, each with the lengths described above. As mentioned above, these two vertical dimensions are chosen to facilitate the retention of the gastric retention system.

[0265] The system is designed to ultimately decompose in the stomach at the end of the desired retention time (retention period), at which point the dimensions of the remaining components allow the system to pass through the pyloric sphincter, small intestine, and large intestine. Ultimately, the system is eliminated from the body through defecation or complete dissolution in the small and large intestines. Therefore, the laser connector component or disintegrating matrix is ​​configured in the gastric retention system of the present invention such that, at the end of the desired retention period where the laser connector component or disintegrating matrix ruptures or dissolves, the uncoupling component of the gastric retention system has dimensions suitable for passage through the pyloric sphincter and elimination from the digestive tract.

[0266] Duration of stay

[0267] The retention time of a gastric retention system is defined as the time between the application of the system to the stomach and its removal from the stomach. In one embodiment, the gastric retention system has a retention time of about 24 hours or at most about 24 hours. In one embodiment, the gastric retention system has a retention time of about 48 hours or at most about 48 hours. In one embodiment, the gastric retention system has a retention time of about 72 hours or at most about 72 hours. In one embodiment, the gastric retention system has a retention time of about 96 hours or at most about 96 hours. In one embodiment, the gastric retention system has a retention time of about 5 days or at most about 5 days. In one embodiment, the gastric retention system has a retention time of about 6 days or at most about 6 days. In one embodiment, the gastric retention system has a retention time of about 7 days (about 1 week) or at most about 7 days (about 1 week). In one embodiment, the gastric retention system has a retention time of about 10 days or at most about 10 days. In one implementation, the gastric retention system has a retention time of about 14 days (about 2 weeks) or at most about 14 days (about 2 weeks).

[0268] In one embodiment, the gastric retention system has a retention time of 24 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of 48 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of 72 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of 96 hours to about 7 days. In one embodiment, the gastric retention system has a retention time of 5 days to about 7 days. In one embodiment, the gastric retention system has a retention time of 6 days to about 7 days.

[0269] In one embodiment, the gastric retention system has a retention time of 24 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of 48 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of 72 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of 96 hours to about 10 days. In one embodiment, the gastric retention system has a retention time of 5 days to about 10 days. In one embodiment, the gastric retention system has a retention time of 6 days to about 10 days. In one embodiment, the gastric retention system has a retention time of 7 days to about 10 days.

[0270] In one embodiment, the gastric retention system has a retention time of 24 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of 48 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of 72 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of 96 hours to about 14 days. In one embodiment, the gastric retention system has a retention time of 5 days to about 14 days. In one embodiment, the gastric retention system has a retention time of 6 days to about 14 days. In one embodiment, the gastric retention system has a retention time of 7 days to about 14 days. In one embodiment, the gastric retention system has a retention time of 10 days to about 14 days.

[0271] The system releases a therapeutically effective amount of the active agent during at least a portion of the retention time in the stomach. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 25% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 50% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 60% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 70% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 75% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 80% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 85% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 90% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 95% of the retention time. In one embodiment, the system releases a therapeutically effective amount of the active agent during at least about 98% of the retention time. In one implementation, the system releases a therapeutically effective amount of the active agent during at least about 99% of the residence time.

[0272] Release characteristic evaluation

[0273] The release characteristics of the active agent from the component, retainer, and gastric retention system can be evaluated using various detection methods. The in vitro release of the active agent from the component, retainer, and gastric retention system can be measured by immersing the component, retainer, and gastric retention system in a liquid such as water, 0.1 N HCl, fasting-state simulated gastric juice (FaSSGF), or feeding-state simulated gastric juice (FeSSGF). In one embodiment, fasting-state simulated gastric juice (FaSSGF) is used for the release assay. Simulated gastric juice refers to either fasting-state simulated gastric juice (FaSSGF) or feeding-state simulated gastric juice (FeSSGF); when a limiting condition is specified for measurement in simulated gastric juice (SGF), the requirement is considered satisfied if the limiting condition is maintained in both fasting-state simulated gastric juice (FaSSGF) and feeding-state simulated gastric juice (FeSSGF). For example, the constraint is satisfied if a component of the retainer is indicated to release at least 10% of the active agent in simulated gastric fluid within the first 24 hours, provided that the component releases at least 10% of the active agent in simulated gastric fluid in a fasting state within the first 24 hours, or that the component releases at least 10% of the active agent in simulated gastric fluid in a feeding state within the first 24 hours.

[0274] Ethanol burst release is typically measured by immersing the component, retainer, or gastric retention system in a solution of 40% ethanol and 60% fasting simulated gastric juice for 1 hour, followed by immersing the same component, retainer, or gastric retention system in 100% fasting simulated gastric acid for the remainder of the test period, and measuring the release of the active agent at appropriate time points. This test is designed to simulate the effects of alcoholic beverages consumed by a patient with the gastric retention system of the present invention, which unfolds in the patient's stomach.

[0275] Although in vitro tests can be performed using components, retainers, or gastric retention systems, using a single component is most convenient for rapidly assessing release characteristics. When performing in vitro tests to compare release rates under different conditions (e.g., release in 100% FaSSGF versus release in 40% ethanol / 60% FaSSGF), the comparison solutions should be kept at the same temperature, such as room temperature, 25°C, or 37°C.

[0276] In vivo testing can be performed on animals such as dogs (e.g., beagles or hounds) and pigs. For in vivo testing, a gastric retention system is used because individual segments or retainers do not remain in the animal's stomach. Blood samples can be obtained at appropriate time points, and gastric contents can be sampled using cannula or other techniques if desired.

[0277] Human clinical trials conducted in accordance with appropriate laws, regulations, and institutional guidelines also provide in vivo data.

[0278] Gastric delivery pharmacokinetics of the gastric retention system

[0279] For example, AUC after system applicationinf Measured bioavailability of the active agent relative to conventional oral formulations, the gastric retention system of the present invention provides high bioavailability of the active agent. The system also provides maintenance of substantially constant or essentially constant plasma levels of the active agent.

[0280] The relative bioavailability (FREL) of two different formulations, namely formulation A and formulation B, is defined as follows:

[0281] F REL =100×(AUC A × Dosage B ) / (AUC B × Dosage A )

[0282] AUC A The area under the curve for formulation A, AUC B The area under the curve for formulation B is the dosage. A The dosage of formulation A used is given, and the dosage is given. B The dose of formulation B used is given. AUC is the area under the curve of the active agent plasma concentration versus time graph, which is typically measured at the same time (t) after administration of each formulation to provide the relative bioavailability of the formulation at the same time point. inf AUC refers to the AUC measured or calculated over an "unlimited" period, that is, the time from the initial administration until the plasma level of the active agent drops to a negligible level.

[0283] In one embodiment, the substantially constant active agent plasma level provided by the gastric retention system of the present invention can be at or above the trough level of the active agent plasma level when administered daily in a conventional oral formulation (i.e., the C10 level of the active agent administered daily in an immediate-release formulation). min Until the peak plasma level of the active agent is reached or lower than the peak plasma level of the active agent when administered daily in the conventional oral formulation (i.e., the C60% of the active agent administered daily in the immediate-release formulation). max The range is defined as follows. In some embodiments, the substantially constant plasma level of the active agent provided by the gastric retention system of the present invention can be approximately 50% to approximately 90% of the peak plasma level of the active agent when administered daily in a conventional oral formulation (i.e., C0.05 of the active agent administered daily in an immediate-release formulation). max The substantially constant plasma level of the active agent provided by the gastric retention system of the present invention can be approximately 75% to approximately 125% of the average plasma level of the active agent when administered daily in a conventional oral formulation (i.e., C0.05 of the active agent administered daily in an immediate-release formulation). ave The substantially constant plasma level of the active agent provided by the gastric retention system of the present invention can be at or above the trough level of the active agent plasma level when administered daily in a conventional oral formulation (i.e., the C-level of the active agent administered daily in an immediate-release formulation).min For example, approximately 100% to 150% of C min .

[0284] The gastric retention system of the present invention can provide bioavailability of the active agent released from the system that is at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the bioavailability provided by an immediate-release form containing the same amount of active agent. As described above, this is achieved by measuring the area under the plasma concentration-time curve (AUC). inf )Measure bioavailability.

[0285] Dissolution characteristics, bioavailability and pharmacokinetics of the gastric retention system

[0286] The gastric retention system described herein provides a stable release of an active agent or a pharmaceutically acceptable salt thereof over an extended period of time. The system is designed to release a therapeutically effective amount of the active agent during retention in the stomach. The release of the active agent can be measured in vitro or in vivo to establish the dissolution characteristics (elution profile, release rate) of the active agent from a specified retention system in a particular environment. The dissolution characteristics can be specified as a percentage of the original amount of active agent present in the system eluted from the system over a specified time period.

[0287] Therefore, in some embodiments, the active agent contained in the gastric retention system may have a dissolution characteristic of 10-20% release within 0-24 hours in a specified environment. That is, within 24 hours after the initial introduction of the gastric retention system into the environment of interest, 10-20% of the initial active agent contained in the system is eluted from the system.

[0288] The environment of interest can be 1) the patient's stomach (i.e., the internal environment) or 2) a simulated gastric juice (i.e., the external environment).

[0289] Compared to the bioavailability of conventional oral formulations of active agents, the gastric retention system of the present invention provides, as indicated by AUC, bioavailability after administration of the system. inf The system measures high bioavailability of the active agent. It also provides for the maintenance of substantially constant plasma levels of the active agent.

[0290] The parameters of concern regarding release include the linearity of release from the gastric retention system during the retention period, the standard deviation of release during the retention period (corresponding to linearity of release; a standard deviation of zero indicates that release is linear throughout the retention period), release within the first 6 hours of retention (i.e., burst release at initial administration), and the total release of the active agent during the retention period. In one embodiment, the retention period is 7 days; however, other periods may be used, such as 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, or 14 days.

[0291] Linearity of active agent release during the retention period refers to the amount released per 24-hour retention period. For a 7-day retention period, the approximate amount of active agent released daily is expected, i.e., the linear maximization of active agent release. This will minimize the standard deviation of daily active agent release during the retention period. In some embodiments, the gastric retention system has a daily active agent release variation (or standard deviation) of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% during the retention period. In some embodiments, the retention period can be about 3 days, about 7 days, about 10 days, or about 2 weeks.

[0292] Minimizing burst release, i.e., release during the initial retention period (e.g., 6, 12, or 24 hours after administration of a gastric retention system), is desirable to maintain predictable and stable release characteristics. If T is the total active agent release during the retention period (in mass units), and D is the number of days in the retention period, then fully linear release can mean approximately the T / D mass of active agent released per day. If the burst release timeframe is the first 6 hours, a linear release characteristic would result in 0.25 × T / D mass of active agent released in the first 6 hours. Expressed as a percentage of the total active agent released during a D-day retention period, linear release could be approximately 100 / D% of active agent / day, and linear release in the first 6 hours would be 25 / D%. (Note that in this case, 100% represents the total amount of active agent released, regardless of how much active agent was contained in the initial formulation). Therefore, over a 7-day retention period, linear release in the first 6 hours could be approximately 3.6% of the total active agent released over the 7-day period.

[0293] In some embodiments, during the initial 6 hours after administration, the gastric retention system releases approximately 0.2 to approximately 2 times the total mass T of the active agent released during the retention period of day D, or approximately 0.2 to approximately 1.75 times the total mass T of the active agent released during the retention period of day D, or approximately 0.2 to approximately 1.5 times the total mass T of the active agent released during the retention period of day D, or approximately 0.2 to approximately 1.25 times the total mass T of the active agent released during the retention period of day D, or approximately 0.2 to approximately 1 times the total mass T of the active agent released during the retention period of day D, or... The total mass of active agent released during the residence period of 1 day is approximately 0.2 to 0.8 times T / D, or approximately 0.2 to 0.75 times T / D, or approximately 0.2 to 0.7 times T / D, or approximately 0.2 to 0.6 times T / D, or approximately 0.2 to 0.5 times T / D, or approximately 0.2 to 0.4 times T / D, or approximately 0.2 to 0.3 times T / D, or approximately 0.25 to 2 times T / D, or approximately 0.3 to 2 times T / D, or approximately 0.4 to 2 times T / D, or approximately 0.5 to 2 times T / D, or approximately 0.6 to 2 times T / D, or approximately 0.7 to 2 times T / D, or approximately 0. 0.25 - approximately 1.5 times T / D, or approximately 0.3 - approximately 1.5 times T / D, or approximately 0.4 - approximately 1.5 times T / D, or approximately 0.5 - approximately 1.5 times T / D, or approximately 0.6 - approximately 1.5 times T / D, or approximately 0.7 - approximately 1.5 times T / D, or approximately 0.25 - approximately 1.25 times T / D, or approximately 0.3 - approximately 1.25 times T / D, or approximately 0.4 - approximately 1.25 times T / D, or approximately 0.5 - approximately 1.25 times T / D, or approximately 0.6 - approximately 1.25 times T / D, or approximately 0.7 - approximately 1.25 times T / D, or approximately 0.25 - approximately 1 times T / D, or approximately 0.3 - Approximately 1 T / D, or approximately 0.4-approximately 1 T / D, or approximately 0.5-approximately 1 T / D, or approximately 0.6-approximately 1 T / D, or approximately 0.7-approximately 1 T / D, or approximately 0.25 T / D, or approximately 0.25-approximately 0.8 T / D, or approximately 0.3-approximately 0.8 T / D, or approximately 0.4-approximately 0.8 T / D, or approximately 0.5-approximately 0.8 T / D, or approximately 0.6-approximately 0.8 T / D, or approximately 0.7-approximately 0.8 T / D, or approximately 0.8 T / D, approximately 1 T / D, 1.25 T / D, approximately 1.5 T / D, or approximately 2 T / D.

[0294] In some embodiments of the gastric retention system, during the first 6 hours after administration, the gastric retention system releases approximately 2% to approximately 10%, or approximately 3% to approximately 10%, or approximately 4% to approximately 10%, or approximately 5% to approximately 10%, or approximately 6% to approximately 10%, or approximately 7% to approximately 10%, or approximately 8% to approximately 10%, or approximately 9% to approximately 10%, or approximately 2% to approximately 9%, or approximately 2% to approximately 8%, or approximately 2% to approximately 7%, or approximately 2% to approximately 6%, or approximately 2% to approximately 5%, or approximately 2% to approximately 4%, or approximately 2% to approximately 3%.

[0295] In some implementations of the gastric retention system, the gastric retention system has a retention period of about 7 days, during which, during the initial 6-hour retention period after administration, the gastric retention system releases about 2% to about 10%, or about 3% to about 10%, or about 4% to about 10%, or about 5% to about 10%, or about 6% to about 10%, or about 7% to about 10%, or about 8% to about 10%, or about 9% to about 10%, or about 2% to about 9%, or about 2% to about 8%, or about 2% to about 7%, or about 2% to about 6%, or about 2% to about 5%, or about 2% to about 4%, or about 2% to about 3%.

[0296] In some implementations, during the first 24 hours after administration, the gastric retention system releases approximately 10% to approximately 35%, or approximately 10% to approximately 30%, or approximately 10% to approximately 25%, or approximately 10% to approximately 20%, or approximately 10% to approximately 15%, or approximately 15% to approximately 35%, or approximately 15% to approximately 35%, or approximately 15% to approximately 30%, or approximately 20% to approximately 30%, or approximately 25% to approximately 35%, or approximately 25% to approximately 30%, or approximately 30% to approximately 35%.

[0297] In some implementations, the gastric retention system has a retention period of about 7 days, during which the gastric retention system releases about 10% to about 35%, or about 10% to about 30%, or about 10% to about 25%, or about 10% to about 20%, or about 10% to about 15%, or about 15% to about 35%, or about 15% to about 35%, or about 15% to about 30%, or about 20% to about 30%, or about 25% to about 35%, or about 25% to about 30%, or about 30% to about 35%.

[0298] Preparation method: Preparation of the gastric retention system

[0299] A gastric retention system or its components (which may subsequently be laser-welded together to create the gastric retention system) can be fabricated using 3D printing technology. Components of the gastric retention system, such as retainers or retainer parts, can be 3D printed using commercially available equipment. 3D printing has been used in pharmaceutical formulations; see Khaled et al., “Desktop 3D printing of controlled release pharmaceutical bilayer tablets,” International Journal of Pharmaceutics 461:105-111 (2014); US Patent No. 7,276,252; Alhnan et al., “Emergence of 3D Printed Dosage Forms: Opportunities and Challenges,” Pharm. Res., May 18, 2016, PubMed PMID: 27194002; Yu et al., “Three-dimensional printing in pharmaceutics: promises and problems,” J. Pharm. Sci. 97(9):3666-3690 (2008); and Ursan et al., “Three-dimensional drug printing: A structured review,” J. Am. Pharm. Assoc. 53(2):136-44 (2013).

[0300] The initial raw materials for 3D printing are polymers or polymer blends (e.g., enteric polymers, time-dependent polymers, or blends of one or more activators, activator salts, drugs, excipients, etc., with a carrier polymer, enteric polymer, or time-dependent polymer). Hot melt extrusion is used to mix and granulate a region of the part or retainer to be manufactured. The polymer or polymer blend material is extruded through a circular die to produce cylindrical fibers wound onto a spool.

[0301] Multiple rolls are fed into a 3D printer (e.g., a Hyrel Printer, purchased from Hyrel 3D, Norcross, Ga., United States) and into their representative printheads. The printheads heat and melt the material at the nozzles, placing a thin layer of material (polymer or polymer blend) at a specific location on the produced part. The material cools and hardens within seconds, and the next layer is added until a complete structure is formed. The quality of the gastric retention system depends on the feed rate, nozzle temperature, and printer resolution; the feed rate and nozzle temperature can be adjusted to achieve the desired quality.

[0302] 3D printing can be used to fabricate individual retainers or parts of retainers. 3D printing can also be used to fabricate block structures, such as robust “plates,” similar to those fabricated via the co-extrusion method described herein. Block structures can be cut into individual pieces (i.e., individual retainers or individual parts) as needed.

[0303] In some embodiments of the invention, it is contemplated that the complete retainer of the gastric retention system be fabricated by 3D printing of the retainer. In some embodiments of the invention, it is contemplated that individual components of the retainer of the gastric retention system be fabricated by 3D printing of parts of the retainer. In some embodiments, the retainer or segments thereof, such as flat plate structures, are fabricated by 3D printing adjacent components in the form of block-like structures. After 3D printing, the block-like structures can be cut into smaller pieces of the retainer or components thereof having desired shapes. After 3D printing, portions of the block-like structures can be compressed into smaller pieces of the retainer or components thereof having desired shapes.

[0304] 3D printing is typically achieved by feeding rods or fibers of solid material into a printhead, where it is melted and deposited, subsequently solidified; this technique is called fused deposition modeling (sometimes also called extrusion deposition); see U.S. Patent Nos. 5,121,329 and 5,340,433. The methods described herein for preparing carrier polymer-drug components can also be used to prepare feedstock materials that can be used for 3D printing components of gastric retention systems.

[0305] Alternatively, components of the gastric retention system can be prepared by co-extrusion. Most of the different constructions of the segments discussed in this paper can be prepared by either 3D printing or co-extrusion. However, co-extrusion is less expensive and can be run as a continuous process, while 3D printing is typically run as a batch process.

[0306] Commercially available equipment can be used to co-extrude components of a gastric retention system, such as retainers or components of retainers, using custom co-extrusion piping and custom dies with the desired configuration. The initial feedstock for co-extrusion is a polymer or polymer blend (e.g., an intestinal polymer, a time-dependent polymer, or a blend of one or more surfactants, surfactant salts, pharmaceuticals, excipients, etc., with a carrier polymer, intestinal polymer, or time-dependent polymer). The polymer or components for a region of the component or retainer to be prepared are mixed and granulated using hot melt extrusion. The resulting polymer granules are fed into a hopper above a single-screw extruder and dried to remove surface moisture. The granules are then fed into a separate single-screw extruder by gravimetric analysis, where they are melted and pressurized for co-extrusion.

[0307] The appropriate molten polymer is then pumped through a custom mold with multiple channels, which form the desired geometry. The composite polymer block is cooled (water-cooled, air-cooled, or both) and cut or stamped into the desired shape, including but not limited to shapes such as triangular prisms, rectangular prisms, or cylindrical sections (pie wedges).

[0308] In some embodiments of the invention, interest is focused on preparing a complete retainer for a gastric retention system by co-extruding a retainer. In some embodiments of the invention, interest is focused on preparing individual components of a retainer for a gastric retention system by co-extruding parts of a retainer. In some embodiments, the retainer or components thereof are prepared by co-extruding adjacent components in the form of a block structure, such as a flat plate structure. After co-extrusion, the block structure can be cut into smaller pieces of the retainer or components thereof having desired shapes. After co-extrusion, portions of the block structure can be compressed into smaller pieces of the retainer or components thereof having desired shapes.

[0309] In some embodiments, the retainer or a component thereof is prepared by co-extruding adjacent parts in the form of a block structure, such as a flat plate structure, while one or more additional polymers are co-extruded within the parts. The co-extrusion of the one or more additional polymers within the parts can be carried out in an island structure. After co-extrusion, the block structure can be cut into smaller pieces of the retainer or a component thereof with desired shapes. After co-extrusion, portions of the block structure can be compressed into smaller pieces of the retainer or a component thereof with desired shapes.

[0310] Once the different components of the gastric retention system are extruded or otherwise prepared, these components can be joined together using, for example, laser welding techniques described herein.

[0311] Surfactant particle size and grinding

[0312] Controlling the particle size used in a gastric retention system is important for optimal release of the active agent and the mechanical stability of the system. The particle size of the active agent affects the surface area available for dissolution as gastric fluid permeates into the carrier polymer-active agent segment of the system. Furthermore, because the retainer diameter is relatively thin (e.g., 1 mm–5 mm), the presence of active agent particles exceeding a few percent of the retainer diameter before and after elution, leaving voids in the previously occupied space, leads to further weakening of the retainer. This weakening is detrimental as it can cause premature breakage and passage of the system before the desired retention period ends.

[0313] In one embodiment, the surfactant particles used for blending into the carrier polymer-surfactant component are less than about 100 micrometers in diameter. In another embodiment, the surfactant particles are less than about 75 micrometers in diameter. In another embodiment, the surfactant particles are less than about 50 micrometers in diameter. In another embodiment, the surfactant particles are less than about 40 micrometers in diameter. In another embodiment, the surfactant particles are less than about 30 micrometers in diameter. In another embodiment, the surfactant particles are less than about 25 micrometers in diameter. In another embodiment, the surfactant particles are less than about 20 micrometers in diameter. In another embodiment, the surfactant particles are less than about 10 micrometers in diameter. In another embodiment, the surfactant particles are less than about 5 micrometers in diameter.

[0314] In one embodiment, at least about 80% of the surfactant particles used for blending into the carrier polymer-surfactant component are smaller than about 100 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 75 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 50 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 40 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 30 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 25 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 20 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 10 micrometers in diameter. In another embodiment, at least about 80% of the surfactant particles are smaller than about 5 micrometers in diameter.

[0315] In one embodiment, at least about 80% by mass of the surfactant particles used for blending into the carrier polymer-surfactant component have a diameter of about 1 micrometer to about 100 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 75 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 50 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 40 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 30 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 25 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 20 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 10 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 1 micrometer to about 5 micrometers.

[0316] In one embodiment, at least about 80% by mass of the surfactant particles used for blending into the carrier polymer-surfactant component have a diameter of about 2 micrometers to about 100 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 75 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 50 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 40 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 30 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 25 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 20 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 10 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 2 micrometers to about 5 micrometers.

[0317] In one embodiment, at least about 80% by mass of the surfactant particles used for blending into the carrier polymer-surfactant component have a diameter of about 5 micrometers to about 100 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 75 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 50 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 40 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 30 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 25 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 20 micrometers. In another embodiment, at least about 80% by mass of the surfactant particles have a diameter of about 5 micrometers to about 10 micrometers.

[0318] The particle size of surfactants can be easily adjusted by grinding. Several grinding techniques can be used to reduce larger particles to smaller particles of the desired size. Fluid energy milling is a dry grinding technique that uses collisions between particles to reduce particle size. A fluid energy mill, called an air jet mill, injects air into a cylindrical chamber to maximize collisions between surfactant particles. Ball milling utilizes a rolling cylindrical chamber that rotates around its main axis. The surfactant collides with the abrasive material (e.g., steel balls made of chromium steel or CR-NI steel; ceramic balls, such as zirconium oxide; or plastic polyamide), resulting in a reduction in surfactant particle size. Ball milling can be carried out in a dry state or with liquid added to the cylinder where the surfactant and abrasive material are insoluble in the liquid. More information on milling is described in the following literature: RW Lee et al., Water-Insoluble Drug Formulation, chapter titled “Particle Size Reduction”, 2nd edition (edited by Ron Liu), Boca Raton, Fla.: CRC Press, 2008; and AW Brzeczko et al., Handbook of Pharmaceutical Granulation Technology, chapter titled “Granulation of Poorly Water-Soluble Drugs”, 3rd edition (edited by Dilip M. Parikh), Boca Raton, Fla.: CRC Press / Taylor & Francis Group, 2010 (and other parts of the handbook). Fluid energy milling (i.e., air jet milling) is a useful milling method because it is better suited for scaling up compared to other dry milling techniques such as ball milling.

[0319] During the grinding process, substances can be added to the surfactant material to help obtain particles of the desired size and minimize aggregation during processing. Silica (silicon dioxide, SiO2) is a useful grinding additive because it is inexpensive, widely available, and non-toxic. Other additives that can be used include silica, calcium phosphate, powdered cellulose, colloidal silica, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, talc, polyvinylpyrrolidone, cellulose ethers, polyethylene glycol, polyvinyl alcohol, and surfactants. In particular, hydrophobic particles with a diameter of less than 5 micrometers tend to aggregate, and hydrophilic additives are used when grinding such particles. Abrasive additives, such as silica, at a weight-to-weight ratio of about 0.1% to about 5%, or about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, or about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, or about 5% may be used for fluid milling or ball milling.

[0320] After grinding, the particles can pass through a sieve of appropriate size to obtain particles of the desired size. To obtain the desired maximum particle size, the particles are passed through a sieve with holes of the desired maximum size; excessively large particles will remain on the sieve, and the particles passing through the sieve will have the desired maximum size. To obtain the desired minimum particle size, the particles are passed through a sieve with holes of the desired minimum size; particles that are too small will pass through the sieve, and the desired particles will remain on the sieve.

[0321] Preparation method of drug elution component

[0322] The blending temperature range for incorporating surfactants into a polymer matrix is ​​typically about 80°C to about 120°C; however, higher or lower temperatures may be used for polymers that are best blended outside this range. When using surfactant particles of a specific size and it is desired to maintain the particle size during and after blending, blending can be carried out at a temperature below the surfactant's melting point to maintain the desired particle size. Otherwise, a temperature that melts both the polymer and the surfactant can be used. The blending temperature should be below the surfactant's degradation temperature. In one embodiment, less than about 2% of the surfactant degrades during preparation. In one embodiment, less than about 1.5% of the surfactant degrades during preparation. In one embodiment, less than about 1% of the surfactant degrades during preparation. In one embodiment, less than about 0.75% of the surfactant degrades during preparation. In one embodiment, less than about 0.5% of the surfactant degrades during preparation. In one embodiment, less than about 0.4% of the surfactant degrades during preparation. In one embodiment, less than about 0.3% of the surfactant degrades during preparation. In one embodiment, less than about 0.2% of the surfactant degrades during preparation. In one embodiment, less than about 0.15% of the surfactant degrades during preparation. In one embodiment, less than about 0.1% of the surfactant degrades during preparation. In one embodiment, less than about 0.05% of the surfactant degrades during preparation. In one embodiment, less than about 0.04% of the surfactant degrades during preparation. In one embodiment, less than about 0.03% of the surfactant degrades during preparation. In one embodiment, less than about 0.02% of the surfactant degrades during preparation. In one embodiment, less than about 0.01% of the surfactant degrades during preparation.

[0323] Hot melt extrusion can be used to prepare drug elution components. Single-screw or twin-screw systems can be used. As previously mentioned, if it is desirable to maintain particle size during and after blending, a carrier polymer that can melt at a temperature that does not degrade the active agent should be used. Otherwise, a temperature that melts both the polymer and the active agent can be used.

[0324] Melting and casting can also be used to prepare drug-eluting components. The carrier polymer and active agent, along with any other desired components, are mixed together. The carrier polymer is melted and the melt is mixed so that the active agent particles are uniformly distributed within the melt. The mixture is then poured into a mold and cooled.

[0325] Solvent casting can also be used to prepare drug-eluting components. The polymer is dissolved in a solvent, and active agent particles are added. If the size of the active agent particles is to be maintained, a solvent that does not dissolve the active agent particles should be used to avoid altering the particle size characteristics; otherwise, a solvent that dissolves both the polymer and the active agent particles can be used. The solvent-carrier polymer-active agent particle mixture is then mixed to uniformly distribute the particles (or to thoroughly mix the solution), poured into a mold, and the solvent is evaporated.

[0326] System preparation / assembly

[0327] In some embodiments, once the retainer of the gastric retention system is secured to the elastomeric component, the system can be folded into its compressed configuration and placed in a capsule for storage, transport, and final administration. The system can be folded by automated mechanical methods or manually and placed in a capsule of appropriate size and material. Further details regarding the preparation and assembly of the gastric retention system and its packaging into capsules can be found in International Patent Application Nos. WO 2015 / 191920, WO 2015 / 191925, WO 2017 / 070612, WO 2017 / 100367, WO 2017 / 205844, and WO 2018 / 227147.

[0328] Treatment methods using the gastric retention system

[0329] A gastric retention system can be used to treat conditions requiring the administration of a drug or active agent over an extended period. In one embodiment, the gastric retention system is administered to a human. For long-term administration of an active agent or drug requiring months, years, or indefinite use, periodic administration of the gastric retention system, such as once a week or every two weeks, can provide substantial advantages in terms of patient compliance and convenience. Therefore, the gastric retention system of the present invention can be administered once every 3 days, once every 5 days, once a week, once every 10 days, or once every 2 weeks. The frequency of administration is consistent with the designed gastric retention period of the administered gastric retention system, so that a new gastric retention system is administered approximately as soon as the gastric retention system is expelled from the stomach after its retention period.

[0330] Once a gastric retention system is administered to a patient, it provides a continuous release of the active agent or drug during the gastric retention period. After the gastric retention period, the system degrades and is expelled from the stomach. Therefore, for a system with a 1-week gastric retention period, the patient swallows (or otherwise administers) a new system weekly. Thus, in one embodiment, a method of treating a patient with the gastric retention system of the present invention, wherein the gastric retention system has a gastric retention period of D days (where D-days is the duration of gastric retention) within a total expected treatment period T-total (where T-total is the expected treatment length in days), comprises introducing a new gastric retention system into the patient's stomach every D-day, by oral administration or other methods, within the total expected treatment period. The number of gastric retention systems administered to the patient can be (T-total) divided by (D-days). For example, if the patient is expected to be treated for 1 year (T-total = 365 days) and the gastric retention period of the system is 7 days (D-day = 7 days), then approximately 52 gastric retention systems will be administered to the patient over 365 days, as a new system is administered every 7 days.

[0331] Alternatively, the patient may swallow (or otherwise administer to the stomach) a new gastric retention system at the end of its effective release period. The “effective release period” or “effective release time” is the time it takes for the gastric retention system to release an effective amount of the active agent contained within it. Thus, in one embodiment, a method of treating a patient with the gastric retention system of the present invention, having an effective release period (where E-days) of the number of days the active agent in the system is used within a total desired treatment period T-total (where T-total is the desired treatment length in days), includes introducing a new gastric retention system into the patient's stomach every E-day by oral administration or other means within the total desired treatment period. The number of gastric retention systems administered to the patient can be (T-total) divided by (E-days). For example, if the patient is expected to be treated for 1 year (T-total = 365 days) and the effective release period of the system is 7 days (E-day = 7 days), then approximately 52 gastric retention systems will be administered to the patient over 365 days, as a new system is administered every 7 days.

[0332] Test methods

[0333] The windowed circulating funnel (W-CF) test can be used to test the strength of laser-welded gastric retention systems. The procedure for the W-CF test is as follows: Figure 11As shown in the example. In step 1102, the gastric retention system is assembled using the laser welding technique described herein. The gastric retention system is allowed to cool completely and crystallize for 24 hours. Then, in step 1104, the gastric retention system is encapsulated and incubated in simulated fasting gastric fluid for 1 day. Next, in step 1106, the gastric retention system is placed in a “window” fixture configured to hold the gastric retention system in a compressed position. The window fixture compresses the gastric retention system for 4 hours while it is immersed in simulated fasting gastric fluid at 37°C. Then, in step 1108, the gastric retention system is placed in a ring containing a narrow (approximately 25 mm) orifice. Subsequently, in step 1110, a 100-cycle circulating funnel test is performed on the gastric retention system. During the circulating funnel test, the center of the gastric retention system is clamped by a ring connected to a linear actuator. The gastric retention system is repeatedly stretched up and down within the conical cavity along the encapsulation and reverse encapsulation directions. If the gastric retention system does not fracture during this process, it is incubated at 37°C in simulated fasting gastric fluid for another 2-3 days, and the entire operation is repeated. The stage of fracture in the gastric retention system is used to quantify the weld durability of the gastric retention system. The quantification system for the W-CF test is as follows: Figure 11 The following diagram illustrates this. For example, if the gastric retention system survives to day 3 of the test and breaks off during the window period, the system scores 5 points; while if the system survives to day 7 of the test and breaks off during the window period, the system scores 8 points.

[0334] Visual inspection can also be used to assess the adequacy of welds in a gastric retention system. A full inspection of the retainer of the gastric retention system is performed to determine if each weld interface is completely melted from top to bottom. Inspect each interface for signs of material flow and mixing. Additionally, visual indicators of phase separation in the polymer blend can be checked at the interfaces. A fully welded gastric retention system exhibits minimal phase separation. Also check the gastric retention system for burns or discoloration. If any burns or discoloration are present, the gastric retention system cannot be visually inspected. Similarly, if any material voids are present at the weld interfaces, the gastric retention system cannot be visually inspected. Laser-welded supports also require visual inspection. If any particles or fibers adhere to the silicone skin coating the grooves of the laser-welded support, the gastric retention system cannot be visually inspected.

[0335] Other techniques can be used to assess the adequacy of welds in a prepared gastric retention system. For example, high-resolution imaging can be used to detect defects in the gastric retention system and perform dimensional analysis. Thermal imaging (e.g., using an infrared camera) can be used to measure the temperature of welds in the gastric retention system. Spectroscopic examination (e.g., using a near-infrared probe) can be used to acquire the spectrum of the weld interface or the entire gastric retention system. Other assessments may include acoustic testing to measure changes in the transmittance of the weld interface; or scanning electron microscopy (SEM) to assess the structure of the gastric retention system.

[0336] Drug release can be measured using a USP II dissolution apparatus. The gastric retention system was incubated at 37°C in 900 mL of simulated fasting gastric fluid. The instrument is equipped with stirring at 50 rpm. The amount of drug released was then quantified using high-performance liquid chromatography (HPLC).

[0337] HPLC methods can be used to measure impurities or degradation products present in the gastric retention system. The HPLC method used can be specific to the active pharmaceutical ingredient contained in the gastric retention system. For example, HPLC-UV can be used for certain active pharmaceutical ingredients. The pass / fail criteria for HPLC evaluation can be specific to the active pharmaceutical ingredient and / or dosage in the gastric retention system.

[0338] Example

[0339] The invention is further illustrated by the following non-limiting embodiments.

[0340] Example 1: Preparation of a gastric retention system

[0341] The gastric retention system, as described in this article, is based on... Figure 10 The construction and preparation of the system are as follows. One retainer of each gastric retention system contains a drug elution component, while five retainers do not contain a drug elution component. The drug elution and non-drug elution retainers are shown in Table 1 below.

[0342] Table 1

[0343]

[0344] The radial length of each component of the retainer is shown in Table 2 below. The gastric retention system has a diameter of approximately 46 mm at its widest point (i.e., from the tip of one retainer to the tip of the opposite retainer (including the elastomeric component)) in the deployed state.

[0345] Table 2

[0346]

[0347] The gastric retention system was assembled using the laser welding technique described herein. The gastric retention system was assembled using one of two different laser systems, both operating at a wavelength of 1940 nm. Operating parameters for each laser system are provided in Tables 3 and 4 below.

[0348] Table 3

[0349]

[0350] Table 4

[0351]

[0352] Example 2: Tensile test of laser-welded gastric retention system

[0353] The tensile strength of a laser-welded gastric retention system was compared with that of a gastric retention system prepared using infrared welding technology, wherein the component was irradiated with infrared energy that was weaker than the energy provided by laser welding. Gastric retention systems were prepared using both laser welding and infrared welding, wherein the drug-eluting component contained one of memantine (denoted as M116) or donepezil (denoted as DN34). The formulations of the drug-eluting components for the systems containing M116 and those containing DN34 are shown in Tables 5 and 6 below.

[0354] Table 5. Composition of the drug elution arm containing M116

[0355]

[0356] Table 6. Composition of the drug elution arm containing DN34

[0357]

[0358] The tensile strength of each gastric retention system was tested using the test version described in ASTM D638, which is suitable for samples with a cross-section of an equilateral triangle with sides of 3.3 mm. Figure 12 As shown, the tensile strengths of samples prepared using laser welding and infrared welding are relatively similar. The tensile strength of the sample prepared using laser welding is slightly stronger than that of the sample prepared using infrared welding. Therefore, the strength of the laser-welded gastric retention system is comparable to or stronger than that assembled using infrared welding.

[0359] Example 3: Laser energy absorption of components of the gastric retention system

[0360] The absorbance of multiple components of the gastric retention system was quantified in reflectance mode using a Thermo Fisher Antaris II FT-NIR spectrometer. The absorbance of the drug elution component (“RSP49”), pure PCL (PC17), and risperidone powder from Example 1 above was tested. For each test material, the rod samples were stacked together during testing to completely cover the pores of the spectrometer. Figure 13As shown, each tested sample exhibited broad absorption in the near-infrared range (defined as approximately 800–2500 nm or 125,000–4000 wavenumbers). In particular, pure PCL exhibited strong absorption in the near-infrared range, with significant peaks near 8300, 7100, 5800, 5100, 4700, and 4400 wavenumbers. As described in Example 1 above, the laser used for laser welding the gastric retention system had a wavelength of 1940 nm or 5155 wavenumbers. PCL and other tested components showed absorption peaks near this point. Therefore, the components of the gastric retention system exhibited strong absorption of laser energy at the wavelength of interest herein.

[0361] Example 4: Laser energy absorption of components of the gastric retention system

[0362] The absorbance of the fourth inactive component was also tested using the spectroscopic method described in Example 3. The absorbance was tested for various material thicknesses ranging from 0.50 mm to 4.00 mm. Figure 14 As shown, the fourth inactive component exhibits broad absorbance in the near-infrared region, where the absorbance peak is similar to... Figure 13 The similar wavenumbers shown are likely due to the presence of PCL in the fourth inactive component. The fourth inactive component also exhibits an additional absorption peak at approximately 5000 wavenumbers, which may be attributed to the addition of a colorant (FD&C Blue 1 Aluminum Lake (11-13%)). Therefore, the addition of colorants or other excipients to components of the gastric retention system described herein can affect the absorption of laser energy.

[0363] Example 5: Window Circulation Funnel (W-CF) Test

[0364] The weld strength of the laser-welded gastric retention system was evaluated using the W-CF test. Once the system components were laser-welded together, the gastric retention system was allowed to cool completely and crystallize for 24 hours. The system was then encapsulated and incubated in simulated fasting gastric fluid for 1 day. These systems were placed in a “window” fixture, configured to hold the gastric retention system in a compressed position for 4 hours while being immersed in simulated fasting gastric fluid at 37°C. Each system was then placed in a ring containing a narrow (approximately 25 mm) orifice. Subsequently, these systems were subjected to a 100-cycle circulating funnel test, during which the center of the system was clamped by a ring connected to a linear actuator and pulled up and down within a conical cavity along the encapsulation and reverse encapsulation directions. If the gastric retention system did not break during this process, it was re-incubated in simulated fasting gastric fluid at 37°C for 2–3 days, and the entire process was repeated until breakage occurred.

[0365] Figure 15The W-CF test results are displayed. The W-CF test was performed thoroughly on each sample. The desired failure mode was defined as "block LT," with a score exceeding 10, meaning the desired failure mode was time-dependent disintegration of the matrix component after 7 days. The scoring system used for the W-CF test is as follows: Figure 11 As shown. Figure 15 As shown, the W-CF scores of samples receiving different amounts of energy from the laser were measured. In each test, the block LT exceeded 10 in total star energy, indicating a strong bond between the laser-welded components. A small percentage of the tested stars experienced failure modes rather than “bulk LT” failure (time-dependent disintegration matrix component). For example, some stars experienced fracture at the interface between the second inactive component and the enterodisintegrating matrix component (rPCL-LE) or at the interface between the enterodisintegrating matrix component and the third inactive component (LE-rPCL).

[0366] Example 6: Melting temperature of components of the gastric retention system

[0367] The melting temperature and pressure of the gastric retention system components in Example 1 are as follows: Figure 16 As shown in Figure 18, the melting temperature and pressure of the components are variable, with the time-dependent disintegration matrix component at the lower end of 62-68°C, and the intestinal disintegration matrix component at the higher end of 149-159°C. According to... Figure 10 The components shown are directly welded together in the sequence and have melting temperatures less than about 50°C. For example, the melting temperature of the time-dependent disintegration matrix component is within 42-48°C of the melting temperature of the second inactive component; the melting temperature of the second inactive component is within 39-49°C of the melting temperature of the intestinal disintegration matrix component; the melting temperature of the intestinal disintegration matrix component is within 39-49°C of the melting temperature of the third inactive component; the melting temperature of the third inactive component is within 10-20°C of the melting temperature of the drug elution component and within 16-33°C of the melting temperature of the fourth inactive component; and the melting temperature of the drug elution component is less than 23°C of the melting temperature of the fourth inactive component.

[0368] Exemplary Implementation

[0369] Implementation Scheme 1. A gastric retention system comprising: one or more retainers, each comprising: at least one drug elution component; and at least one laser connector component laser-welded to at least one drug elution component.

[0370] Implementation Scheme 2. The gastric retention system of Implementation Scheme 1, wherein one or more retainers are connected to an elastomeric component.

[0371] Implementation Scheme 3. The gastric retention system of Implementation Scheme 2, wherein an elastomeric component is overmolded on a first portion of at least one inter-component anchor.

[0372] Implementation Scheme 4. The gastric retention system of Implementation Scheme 3, wherein the laser connector component is overmolded on the second part of at least one inter-component anchor.

[0373] Implementation Scheme 5. The gastric retention system of Implementation Scheme 4, wherein the first retainer is connected to the elastomeric component via an overmolded laser connector component.

[0374] Implementation Scheme 6. A gastric retention system according to any one of Implementation Schemes 1-5, wherein at least one laser connector component comprises an inactive component.

[0375] Implementation Scheme 7. The gastric retention system of Implementation Scheme 6, wherein the non-active component comprises polycaprolactone.

[0376] Implementation Scheme 8. The gastric retention system of Implementation Scheme 7, wherein the inactive component further comprises bismuth subcarbonate.

[0377] Implementation Scheme 9. The gastric retention system of Implementation Scheme 7 or 8, wherein the non-active component also contains copovidone.

[0378] Implementation Scheme 10. A gastric retention system of any one of Implementation Schemes 7-9, wherein the non-active component further comprises poloxamer.

[0379] Implementation Scheme 11. A gastric retention system according to any one of Implementation Schemes 7-10, wherein the inactive component further comprises a colorant.

[0380] Implementation Scheme 12. A gastric retention system according to any one of Implementation Schemes 1-11, wherein at least one laser connector component comprises an intestinal disintegration matrix.

[0381] Implementation Scheme 13. The gastric retention system of Implementation Scheme 12, wherein the intestinal disintegrating matrix comprises polycaprolactone.

[0382] Implementation Scheme 14. The gastric retention system of Implementation Scheme 13, wherein the intestinal disintegrating matrix further comprises HPMCAS.

[0383] Implementation scheme 15. The gastric retention system of implementation scheme 13 or 14, wherein the intestinal disintegrating matrix further comprises poloxamer.

[0384] Implementation Scheme 16. A gastric retention system according to any one of Implementation Schemes 1-15, wherein at least one laser connector component comprises a time-dependent disintegration matrix.

[0385] Implementation Scheme 17. The gastric retention system of Implementation Scheme 16, wherein the time-dependent disintegration matrix comprises polycaprolactone.

[0386] Implementation Scheme 18. The gastric retention system of Implementation Scheme 17, wherein the time-dependent disintegration matrix further comprises poly(ethylene oxide).

[0387] Implementation Scheme 19. The gastric retention system of Implementation Scheme 17 or 18, wherein the time-dependent disintegration matrix further comprises 50 / 50 DL-lactide / glycolic acid copolymer.

[0388] Implementation Scheme 20. A gastric retention system of any one of Implementation Schemes 17-19, wherein the time-dependent disintegration matrix further comprises iron(III) oxide.

[0389] Implementation Scheme 21. A gastric retention system according to any one of Implementation Schemes 1-20, wherein the drug elution component comprises polycaprolactone.

[0390] Implementation Scheme 22. The gastric retention system of Implementation Scheme 21, wherein the drug elution component further contains an active drug ingredient.

[0391] Implementation Scheme 23. The gastric retention system of Implementation Scheme 22, wherein the active pharmaceutical ingredient comprises meloxicam, exipram, citalopram, clopidogrel, prednisone, aripiprazole, risperidone, buprenorphine, naloxone, montelukast, memantine, digoxin, tamsulosin, ezetimibe, colchicine, loratadine, cetirizine, loperamide, omeprazole, entecavir, doxycycline, ciprofloxacin, azithromycin, antimalarial agents, levothyroxine, methadone, varenicline, contraceptives, stimulants, or nutrients, or one or more of these.

[0392] Implementation Scheme 24. A gastric retention system of any one of Implementation Schemes 21-23, wherein the drug elution component further comprises copovidone.

[0393] Implementation Scheme 25. A gastric retention system of any one of Implementation Schemes 21-24, wherein the drug elution component further comprises poloxamer.

[0394] Implementation Scheme 26. A gastric retention system of any one of Implementation Schemes 21-25, wherein the drug elution component further comprises vitamin E succinate.

[0395] Implementation Scheme 27. A gastric retention system according to any one of Implementation Schemes 21-26, wherein the drug elution component further comprises silica.

[0396] Implementation Scheme 28. A gastric retention system of any one of Implementation Schemes 21-27, wherein the drug elution component further comprises a coloring agent.

[0397] Implementation Scheme 29. A gastric retention system according to any one of Implementation Schemes 1-28, wherein the difference between the melt flow index of at least one laser connector component and the melt flow index of at least one drug elution component is greater than 10%.

[0398] Implementation Scheme 30. A gastric retention system according to any one of Implementation Schemes 1-28, wherein the difference between the melt flow index of at least one laser connector component and the melt flow index of at least one drug elution component is less than 50%.

[0399] Implementation Scheme 31. A gastric retention system according to any one of Implementation Schemes 1-30, wherein at least one laser connector component has a polycaprolactone content of at least 30% by weight.

[0400] Implementation Scheme 32. A gastric retention system according to any one of Implementation Schemes 1-30, wherein at least one laser connector component has a polycaprolactone content of at least 40% by weight.

[0401] Implementation Scheme 33. A gastric retention system according to any one of Implementation Schemes 1-32, wherein at least one drug elution component contains at least 30% by weight of polycaprolactone.

[0402] Implementation Scheme 34. A gastric retention system according to any one of Implementation Schemes 1-32, wherein at least one drug elution component contains at least 40% by weight of polycaprolactone.

[0403] Implementation Scheme 35. A gastric retention system according to any one of Implementation Schemes 1-34, wherein at least one laser connector component has a polycaprolactone content of less than 50% by weight.

[0404] Implementation Scheme 36. A gastric retention system according to any one of Implementation Schemes 1-34, wherein at least one laser connector component has a polycaprolactone content of less than 65% by weight.

[0405] Implementation Scheme 37. A gastric retention system according to any one of Implementation Schemes 1-34, wherein at least one laser connector component has a polycaprolactone content of less than 75% by weight.

[0406] Implementation Scheme 38. A gastric retention system according to any one of Implementation Schemes 1-37, wherein at least one drug elution component contains less than 50% by weight of polycaprolactone.

[0407] Implementation Scheme 39. A gastric retention system according to any one of Implementation Schemes 1-37, wherein at least one drug elution component contains less than 65% by weight of polycaprolactone.

[0408] Implementation Scheme 40. A gastric retention system according to any one of Implementation Schemes 1-37, wherein at least one drug elution component contains less than 75% by weight of polycaprolactone.

[0409] Implementation Scheme 41. A gastric retention system according to any one of Implementation Schemes 1-40, wherein the melting temperature of at least one drug elution component is within 1-75°C of the melting temperature of at least one laser connector component.

[0410] Implementation Scheme 42. A gastric retention system according to any one of Implementation Schemes 1-40, wherein the melting temperature of at least one drug elution component is within 5-50°C of the melting temperature of at least one laser connector component.

[0411] Implementation Scheme 43. A gastric retention system according to any one of Implementation Schemes 1-42, wherein the width of the molten zone between the laser-welded components of one or more retainers is 0.5 mm to 5 mm.

[0412] Implementation Scheme 44. A gastric retention system according to any one of Implementation Schemes 1-42, wherein the width of the molten zone between the laser-welded components of one or more retainers is 1 mm to 3 mm.

[0413] Implementation Scheme 45. A gastric retention system according to any one of Implementation Schemes 1-44, wherein the depth of the molten zone between the laser-welded components of one or more retainers is at least 90% of the depth of the interface between the laser-welded components.

[0414] Implementation Scheme 46. A gastric retention system according to any one of Implementation Schemes 1-44, wherein the depth of the molten zone between the laser-welded components of one or more retainers is at least 95% of the depth of the interface between the laser-welded components.

[0415] Implementation scheme 47. A gastric retention system of any one of implementation schemes 1-46, wherein the gastric retention system receives a score of at least 7 when using a window-circulation funnel test.

[0416] Implementation scheme 48. A gastric retention system of any one of implementation schemes 1-46, wherein the gastric retention system receives a score of at least 10 when using a window-circulation funnel test.

[0417] Implementation Scheme 49. A gastric retention system according to any one of Implementation Schemes 1-48, wherein the gastric retention system is configured to be in a stressed configuration during application and to be in an open configuration when in the patient's stomach.

[0418] Implementation Scheme 50. A method for preparing a gastric retention system, the gastric retention system comprising one or more retainers, each comprising at least one drug elution component and at least one laser connector component, the method comprising: laser welding at least one drug elution component to at least one laser connector component.

[0419] Implementation Scheme 51. The method of Implementation Scheme 50 further includes: placing at least one laser connector component and at least one drug elution component in a laser welding holder before laser welding.

[0420] Implementation Scheme 52. The method of Implementation Scheme 50 or 51 further includes: applying a radial force that presses at least one drug elution component against at least one laser connector component.

[0421] Implementation Scheme 53. The method of Implementation Scheme 52, wherein the radial force is 5 N-200 N.

[0422] Implementation Scheme 54. The method of Implementation Scheme 52, wherein the radial force is 10 N-50 N.

[0423] Implementation Scheme 55. The method of any one of Implementation Schemes 51-54 further includes: applying a downward force that presses at least one drug elution component and at least one laser connector component onto the laser welding support.

[0424] Implementation Scheme 56. The method of Implementation Scheme 55, wherein the vertical force is 100 N-5000 N.

[0425] Implementation Scheme 57. The method of Implementation Scheme 55, wherein the vertical force is 200 N-2800 N.

[0426] Implementation Scheme 58. The method of any one of Implementation Schemes 50-57, wherein laser welding is performed using a laser with a wavelength of 0.7 µm-2.5 µm.

[0427] Implementation Scheme 59. The method of any one of Implementation Schemes 50-57, wherein laser welding is performed using a laser with a wavelength of 1.9 µm-2.0 µm.

[0428] Implementation Scheme 60. The method of any one of Implementation Schemes 50-59, wherein laser welding is performed using a laser having a Gaussian energy distribution or a top-cap energy distribution.

[0429] Implementation Scheme 61. The method of any one of Implementation Schemes 50-60, wherein laser welding is performed using a laser having a beam diameter of 0.5 mm to 5 mm.

[0430] Implementation Scheme 62. The method of any one of Implementation Schemes 50-60, wherein laser welding is performed using a laser with a beam diameter of 1 mm to 3 mm.

[0431] Implementation Scheme 63. The method of any one of Implementation Schemes 1-62, wherein laser welding is performed in an environment with humidity below 40%.

[0432] Implementation Scheme 64. The method of any one of Implementation Schemes 1-62, wherein laser welding is performed in an environment with humidity below 25%.

[0433] Implementation Scheme 65. The method of any one of Implementation Schemes 1-64, wherein laser welding is performed in an environment with a humidity of at least 10%.

[0434] Implementation Scheme 66. The method of any one of Implementation Schemes 1-64, wherein laser welding is performed in an environment with a humidity of at least 15%.

[0435] Implementation Scheme 67. The method of any one of Implementation Schemes 50-66 further includes: laser welding one or more retainers to an elastomeric component, wherein the elastomeric component includes one or more laser connector components configured to be laser welded to one or more retainers.

[0436] Implementation Scheme 68. The method of Implementation Scheme 67, wherein the gastric retention system includes at least three retainers laser-welded to an elastomeric component.

[0437] Implementation Scheme 69. The method of Implementation Scheme 67, wherein the gastric retention system includes at least three retainers laser-welded to an elastomeric component.

[0438] Implementation Scheme 70. The method of Implementation Scheme 67, wherein the gastric retention system includes at least four retainers laser-welded to an elastomeric component.

[0439] Implementation Scheme 71. The method of Implementation Scheme 67, wherein the gastric retention system includes at least 5 retainers laser-welded to an elastomeric component.

[0440] Implementation Scheme 72. The method of Implementation Scheme 67, wherein the gastric retention system includes at least 6 retainers laser-welded to an elastomeric component.

[0441] Implementation Scheme 73. The method of any one of Implementation Schemes 68-72, wherein laser welding at least one drug elution component to at least one laser connector component comprises laser welding along a repeating path that connects the respective interfaces between at least one drug elution component on each retainer and at least one connector.

[0442] Implementation Scheme 74. The method of Implementation Scheme 73, wherein the repeated path is a circular path.

[0443] Implementation Scheme 75. The method of any one of Implementation Schemes 50-72, wherein laser welding at least one drug elution component to at least one laser connector component comprises performing laser welding back and forth along the interface between at least one drug elution component and at least one laser connector component.

[0444] Implementation Scheme 76. A laser welding system comprising: a laser welding support configured to hold components of a gastric retention system in an assembly sequence; at least one radial pressure piston configured to apply a radial force to the gastric retention system in a direction transverse to the seam between each component; at least one vertical pressure piston configured to apply a downward force to the gastric retention system in a direction parallel to the seam between each component; and at least one laser configured to weld the seam between each component of the gastric retention system.

[0445] Implementation Scheme 77. The laser welding system of Implementation Scheme 76, wherein the laser welding support comprises aluminum or stainless steel.

[0446] Implementation Scheme 78. The laser welding system of Implementation Scheme 76 or 77, wherein the laser welding bracket is nickel plated.

[0447] Implementation Scheme 79. The laser welding system of any one of Implementation Schemes 76-78, wherein the laser welding support includes a groove of size and shape suitable for receiving components of the gastric retention system.

[0448] Implementation Scheme 80. A laser welding system according to any one of Implementation Schemes 76-79, wherein the top surface of the laser welding support includes a silicone layer.

[0449] Implementation Scheme 81. A laser welding system according to any one of Implementation Schemes 76-80, wherein the top surface of the laser welding support includes a polytetrafluoroethylene-coated glass layer.

[0450] Implementation Scheme 82. The laser welding system of any one of Implementation Schemes 76-81 further includes a cover configured to retain components of the gastric retention system in situ during laser welding.

[0451] Implementation Scheme 83. The laser welding system of Implementation Scheme 82, wherein the covering comprises silicone or polytetrafluoroethylene coated glass.

[0452] Implementation Scheme 84. The laser welding system of Implementation Scheme 82 or 83 further includes a top layer on the covering.

[0453] Implementation Scheme 85. The laser welding system of Implementation Scheme 84, wherein the top layer comprises quartz glass.

[0454] Implementation Scheme 86. A laser welding system according to any one of Implementation Schemes 76-85, wherein the radial force applied by at least one radial pressure piston is 5-200 N.

[0455] Implementation Scheme 87. A laser welding system according to any one of Implementation Schemes 76-85, wherein the radial force applied by at least one radial pressure piston is 10-50 N.

[0456] Implementation Scheme 88. A laser welding system according to any one of Implementation Schemes 76-87, wherein the downward force applied by at least one vertical pressure piston is 100-5000 N.

[0457] Implementation Scheme 89. A laser welding system according to any one of Implementation Schemes 76-87, wherein the downward force applied by at least one vertical pressure piston is 200-2800 N.

[0458] Implementation Scheme 90. The laser welding system of any one of Implementation Schemes 76-89, wherein at least one laser has a wavelength of 0.7µm-2.5µm.

[0459] Implementation Scheme 91. A laser welding system according to any one of Implementation Schemes 76-89, wherein at least one laser has a wavelength of 1.9µm-2.0µm.

[0460] Implementation Scheme 92. A laser welding system according to any one of Implementation Schemes 76-91, wherein at least one laser has a Gaussian energy distribution or a top cap energy distribution.

[0461] Implementation Scheme 93. A laser welding system according to any one of Implementation Schemes 76-92, wherein at least one laser has a beam diameter of 0.5 mm to 5 mm.

[0462] Implementation Scheme 94. A laser welding system according to any one of Implementation Schemes 76-92, wherein at least one laser has a beam diameter of 1 mm to 3 mm.

[0463] Although the foregoing invention has been described in considerable detail by way of example and embodiments for purposes of clarity, it will be apparent to those skilled in the art that certain changes and modifications will be made. Therefore, this specification and the embodiments should not be construed as limiting the scope of the invention.

Claims

1. The gastric retention system, which includes: One or more retainers, comprising: At least one drug elution component; and Laser welding to at least one laser connector component of at least one drug elution component.

2. The gastric retention system of claim 1, wherein one or more retainers are connected to an elastomeric component.

3. The gastric retention system of claim 2, wherein the elastomeric component is overmolded onto a first portion of at least one inter-component anchor.

4. The gastric retention system of claim 3, wherein the laser connector component is overmolded on a second portion of at least one inter-component anchor.

5. The gastric retention system of claim 4, wherein the first retainer is connected to the elastomeric component via an overmolded laser connector component.

6. The gastric retention system of any one of claims 1-5, wherein at least one laser connector component comprises an inactive component.

7. The gastric retention system of claim 6, wherein the inactive component comprises polycaprolactone.

8. The gastric retention system of claim 7, wherein the inactive component further comprises bismuth subcarbonate.

9. The gastric retention system of claim 7 or 8, wherein the inactive component further comprises copovidone.

10. The gastric retention system of any one of claims 7-9, wherein the inactive component further comprises poloxamer.

11. The gastric retention system of any one of claims 7-10, wherein the inactive component further comprises a colorant.

12. The gastric retention system of any one of claims 1-11, wherein at least one laser connector component comprises an intestinal disintegration matrix.

13. The gastric retention system of claim 12, wherein the intestinal disintegration matrix comprises polycaprolactone.

14. The gastric retention system of claim 13, wherein the intestinal disintegrating matrix further comprises HPMCAS.

15. The gastric retention system of claim 13 or 14, wherein the intestinal disintegrating matrix further comprises poloxamer.

16. The gastric retention system of any one of claims 1-15, wherein at least one laser connector component comprises a time-dependent disintegration matrix.

17. The gastric retention system of claim 16, wherein the time-dependent disintegration matrix comprises polycaprolactone.

18. The gastric retention system of claim 17, wherein the time-dependent disintegration matrix further comprises poly(ethylene oxide).

19. The gastric retention system of claim 17 or 18, wherein the time-dependent disintegration matrix further comprises a 50 / 50 DL-lactide / glycolic acid copolymer.

20. The gastric retention system of any one of claims 17-19, wherein the time-dependent disintegration matrix further comprises iron(III) oxide.

21. The gastric retention system of any one of claims 1-20, wherein the drug elution component comprises polycaprolactone.

22. The gastric retention system of claim 21, wherein the drug elution component further comprises an active pharmaceutical ingredient.

23. The gastric retention system of claim 22, wherein the active pharmaceutical ingredient comprises one or more of the following: meloxicam, exipram, citalopram, clopidogrel, prednisone, aripiprazole, risperidone, buprenorphine, naloxone, montelukast, memantine, digoxin, tamsulosin, ezetimibe, colchicine, loratadine, cetirizine, loperamide, omeprazole, entecavir, doxycycline, ciprofloxacin, azithromycin, antimalarial agents, levothyroxine, methadone, varenicline, contraceptives, stimulants, or nutrients.

24. The gastric retention system of any one of claims 21-23, wherein the drug elution component further comprises copovidone.

25. The gastric retention system of any one of claims 21-24, wherein the drug elution component further comprises poloxamer.

26. The gastric retention system of any one of claims 21-25, wherein the drug elution component further comprises vitamin E succinate.

27. The gastric retention system of any one of claims 21-26, wherein the drug elution component further comprises silica.

28. The gastric retention system of any one of claims 21-27, wherein the drug elution component further comprises a colorant.

29. The gastric retention system of any one of claims 1-28, wherein the difference between the melt flow index of at least one laser connector component and the melt flow index of at least one drug elution component is greater than 10%.

30. The gastric retention system of any one of claims 1-28, wherein the difference between the melt flow index of at least one laser connector component and the melt flow index of at least one drug elution component is less than 50%.

31. The gastric retention system of any one of claims 1-30, wherein at least one laser connector component has a polycaprolactone content of at least 30% by weight.

32. The gastric retention system of any one of claims 1-30, wherein at least one laser connector component has a polycaprolactone content of at least 40% by weight.

33. The gastric retention system of any one of claims 1-32, wherein at least one drug elution component has a polycaprolactone content of at least 30% by weight.

34. The gastric retention system of any one of claims 1-32, wherein at least one drug elution component has a polycaprolactone content of at least 40% by weight.

35. The gastric retention system of any one of claims 1-34, wherein at least one laser connector component has a polycaprolactone content of less than 50% by weight.

36. The gastric retention system of any one of claims 1-34, wherein at least one laser connector component has a polycaprolactone content of less than 65% by weight.

37. The gastric retention system of any one of claims 1-34, wherein at least one laser connector component has a polycaprolactone content of less than 75% by weight.

38. The gastric retention system of any one of claims 1-37, wherein at least one drug elution component has a polycaprolactone content of less than 50% by weight.

39. The gastric retention system of any one of claims 1-37, wherein at least one drug elution component has a polycaprolactone content of less than 65% by weight.

40. The gastric retention system of any one of claims 1-37, wherein at least one drug elution component has a polycaprolactone content of less than 75% by weight.

41. The gastric retention system of any one of claims 1-40, wherein the melting temperature of at least one drug elution component is within 1-75°C of the melting temperature of at least one laser connector component.

42. The gastric retention system of any one of claims 1-40, wherein the melting temperature of at least one drug elution component is within 5-50°C of the melting temperature of at least one laser connector component.

43. The gastric retention system of any one of claims 1-42, wherein the width of the molten zone between the laser-welded components of one or more retainers is 0.5 mm to 5 mm.

44. The gastric retention system of any one of claims 1-42, wherein the width of the molten zone between the laser-welded components of one or more retainers is 1 mm to 3 mm.

45. The gastric retention system of any one of claims 1-44, wherein the depth of the molten zone between the laser-welded components of one or more retainers is at least 90% of the depth of the interface between the laser-welded components.

46. ​​The gastric retention system of any one of claims 1-44, wherein the depth of the molten zone between the laser-welded components of one or more retainers is at least 95% of the depth of the interface between the laser-welded components.

47. The gastric retention system of any one of claims 1-46, wherein the gastric retention system receives a score of at least 7 when using a window-circulation funnel test.

48. The gastric retention system of any one of claims 1-46, wherein the gastric retention system receives a score of at least 10 when using a window-circulation funnel test.

49. The gastric retention system of any one of claims 1-48, wherein the gastric retention system is configured to be in a stressed configuration during application and to be in an open configuration when in the patient's stomach.

50. A method for preparing a gastric retention system, the gastric retention system comprising one or more retainers, each including at least one drug elution component and at least one laser connector component, the method comprising: Laser welding at least one drug elution component to at least one laser connector component.

51. The method of claim 50, further comprising: Prior to laser welding, at least one laser connector component and at least one drug elution component are placed in the laser welding support.

52. The method of claim 50 or 51, further comprising: A radial force is applied, which presses at least one drug elution component onto at least one laser connector component.

53. The method of claim 52, wherein the radial force is 5 N-200 N.

54. The method of claim 52, wherein the radial force is 10 N-50 N.

55. The method of any one of claims 51-54, further comprising: A downward force is applied, which presses at least one drug elution component and at least one laser connector component onto the laser welding support.

56. The method of claim 55, wherein the vertical force is 100 N-5000 N.

57. The method of claim 55, wherein the vertical force is 200 N-2800 N.

58. The method of any one of claims 50-57, wherein laser welding is performed using a laser having a wavelength of 0.7 µm-2.5 µm.

59. The method of any one of claims 50-57, wherein laser welding is performed using a laser having a wavelength of 1.9 µm-2.0 µm.

60. The method of any one of claims 50-59, wherein laser welding is performed using a laser having a Gaussian energy distribution or a top-cap energy distribution.

61. The method of any one of claims 50-60, wherein laser welding is performed using a laser having a beam diameter of 0.5 mm to 5 mm.

62. The method of any one of claims 50-60, wherein laser welding is performed using a laser having a beam diameter of 1 mm to 3 mm.

63. The method of any one of claims 50-62, wherein laser welding is performed in an environment with humidity below 40%.

64. The method of any one of claims 50-62, wherein laser welding is performed in an environment with humidity below 25%.

65. The method of any one of claims 50-64, wherein the laser welding is performed in an environment with a humidity of at least 10%.

66. The method of any one of claims 50-64, wherein the laser welding is performed in an environment with a humidity of at least 15%.

67. The method of any one of claims 50-66, further comprising: One or more retainers are laser-welded to an elastomer component, wherein the elastomer component includes one or more laser connector components configured to be laser-welded to one or more retainers.

68. The method of claim 67, wherein the gastric retention system comprises at least two retainers laser-welded to the elastomeric component.

69. The method of claim 67, wherein the gastric retention system comprises at least three retainers laser-welded to the elastomeric component.

70. The method of claim 67, wherein the gastric retention system comprises at least four retainers laser-welded to the elastomeric component.

71. The method of claim 67, wherein the gastric retention system comprises at least five retainers laser-welded to the elastomeric component.

72. The method of claim 67, wherein the gastric retention system comprises at least six retainers laser-welded to the elastomeric component.

73. The method of any one of claims 68-72, wherein laser welding at least one drug elution component to at least one laser connector component comprises laser welding along a repeating path connecting the respective interfaces between at least one drug elution component on each retainer and at least one connector.

74. The method of claim 73, wherein the repeating path is a circular path.

75. The method of any one of claims 50-72, wherein laser welding at least one drug elution component to at least one laser connector component comprises performing laser welding back and forth along the interface between the at least one drug elution component and the at least one laser connector component.

76. A laser welding system, comprising: Laser-welded stents are configured to hold components of a gastric retention system in an assembly sequence. At least one radial pressure piston is configured to apply radial force to the gastric retention system in a direction that cuts through the seam between each component; At least one vertical pressure piston is configured to apply a downward force to the gastric retention system in a direction parallel to the seam between each component; and At least one laser is configured to weld the seams between each component of the gastric retention system.

77. The laser welding system of claim 76, wherein the laser welding support comprises aluminum or stainless steel.

78. The laser welding system of claim 76 or 77, wherein the laser welding support is nickel-plated.

79. The laser welding system of any one of claims 76-78, wherein the laser welding support includes a groove sized and shaped to receive a component of the gastric retention system.

80. The laser welding system of any one of claims 76-79, wherein the top surface of the laser welding support comprises a silicone layer.

81. The laser welding system of any one of claims 76-80, wherein the top surface of the laser welding support comprises a polytetrafluoroethylene-coated glass layer.

82. The laser welding system of any one of claims 76-81 further comprises a cover configured to retain components of the gastric retention system in situ during laser welding.

83. The laser welding system of claim 82, wherein the coating comprises silicone or polytetrafluoroethylene coated glass.

84. The laser welding system of claim 82 or 83 further comprises a top layer on the covering.

85. The laser welding system of claim 84, wherein the top layer comprises quartz glass.

86. The laser welding system of any one of claims 76-85, wherein the radial force applied by at least one radial pressure piston is 5-200 N.

87. The laser welding system of any one of claims 76-85, wherein the radial force applied by at least one radial pressure piston is 10-50 N.

88. The laser welding system of any one of claims 76-87, wherein the downward force applied by at least one vertical pressure piston is 100-5000 N.

89. The laser welding system of any one of claims 76-87, wherein the downward force applied by at least one vertical pressure piston is 200-2800 N.

90. The laser welding system of any one of claims 76-89, wherein at least one laser has a wavelength of 0.7 µm to 2.5 µm.

91. The laser welding system of any one of claims 76-89, wherein at least one laser has a wavelength of 1.9 µm-2.0 µm.

92. The laser welding system of any one of claims 76-91, wherein at least one laser has a Gaussian energy distribution or a top-cap energy distribution.

93. The laser welding system of any one of claims 76-92, wherein at least one laser has a beam diameter of 0.5 mm to 5 mm.

94. The laser welding system of any one of claims 76-92, wherein at least one laser has a beam diameter of 1 mm to 3 mm.

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