Oral gastric retentate

Abstract

The present disclosure relates to a gastric retentate for oral administration comprising a collapsible central superelastic alloy member comprising a plurality of ribs that elastically deform when in a collapsed configuration and elastically retract when in an expanded configuration; a plurality of connecting members radially connected to the collapsible central superelastic alloy member, each connecting member including a first side respectively connected to a corresponding rib and a second side opposite the first side; a plurality of elongate limb members respectively connected to the second sides of the respective connecting members, the elongate limb members comprising a mandrel carrying an active substance and an outer layer enclosing the mandrel, and each elongate limb member comprising at least one slit formed on an outer surface of the outer layer, or the outer layer has at least one thinned area.

Description

Invention Field

[0001] This invention relates to a gastric retention substance for oral administration. Background Technology

[0002] Medical adherence to long-term medication regimens is typically poor. The lowest adherence rates are highest for primary and secondary prevention when the disease requiring prevention or treatment is usually asymptomatic and the medication regimen does not have an immediate effect. Current methods to improve adherence, such as educational interventions and counseling, have only achieved limited success.

[0003] Drug solutions, such as invasive delivery methods and formulations, are generally less popular due to their invasiveness. In contrast, oral administration of drugs is more widely accepted because it is easier to use and cheaper. However, the transit time of oral administration through the human gastrointestinal tract is typically only about 24 to 48 hours, including about 1 to 2 hours in the stomach, about 3 hours in the small intestine, and about 6 to 13 hours in the large intestine. Therefore, a single dose is usually insufficient to achieve the prescribed dose frequency over the duration exceeding the transit time.

[0004] One method for achieving a desired dose frequency with an oral dosage form over an extended period is to attach the dosage form to a shape memory component to form a gastric retention device. The shape memory material needs to have a minimum flexural modulus to resist being pushed through the pyloric sphincter connecting the stomach and duodenum, thereby preventing the dosage form from leaving the gastric cavity.

[0005] However, conventional gastric retention devices have many drawbacks. Dosage forms are typically attached to shape memory components using a weld bond, but the limited surface area available for weld bond adhesion results in insufficient adhesion strength. Consequently, the dosage form can easily detach from the shape memory unit and may not remain in the stomach.

[0006] Furthermore, controlling the drug dissolution rate of a dosage form over time is challenging. Dosage forms typically dissolve uniformly from all exposed surfaces, resulting in an initial surge in dissolution rate due to the relatively large surface area. As the dosage form surface area decreases, the dissolution rate gradually declines. This inconsistency in gastric absorption of dosage forms is undesirable because it affects the efficacy of the dosage form.

[0007] Therefore, it is necessary to solve at least one of the above problems or provide a useful alternative. Summary of the Invention

[0008] According to a first aspect of the present invention, a gastric retention article for oral administration is provided, comprising:

[0009] A foldable central hyperelastic alloy component comprising multiple ribs, wherein the foldable central hyperelastic alloy component undergoes elastic deformation when the gastric contents are in a folded configuration, and rebounds when the gastric contents are in an unfolded configuration;

[0010] Multiple connecting components are radially connected to the foldable central superelastic alloy component. Each connecting component includes a first side and a second side opposite to the first side, and the first side of each connecting component is respectively connected to a corresponding rib.

[0011] Multiple elongated limb components, including a mandrel and an outer layer encapsulating the mandrel, wherein each elongated limb component is connected to a second side of a corresponding connecting component.

[0012] The plurality of connecting components are configured to undergo structural damage in an in vivo unfolding configuration, thereby causing the gastric retention to lose its shape.

[0013] The core has an active material, and the outer layer has a lower concentration of the active material than the core.

[0014] Each elongated limb component includes at least one slit formed on the outer surface of the outer layer, the at least one slit extending at least 50% of the length along the length direction of the elongated limb component.

[0015] At least one of the slits extends to a depth of 50% or more of the outer layer thickness.

[0016] The width of the at least one slit is 2 mm or less.

[0017] The ratio of the cross-sectional area of ​​the mandrel to that of the outer layer is between 1 and 10.

[0018] The outer layer does not contain any active substances.

[0019] The active substance is a therapeutic agent or a diagnostic agent.

[0020] Each slender limb component also includes one or more spacers positioned along the length of the slender limb component.

[0021] The plurality of connecting components are configured to be structurally damaged in an in vivo unfolding configuration through degradation, dissolution, dissociation, or mechanical weakening.

[0022] Less than 35% of the active substance is released within 20% of the effective release period, and more than 80% of the active substance is released within 90% of the effective release period.

[0023] According to a second aspect of the invention, a gastric retention article for oral administration is provided. An oral gastric retention article includes: a foldable central hyperelastic alloy component comprising a plurality of ribs, wherein the foldable central hyperelastic alloy component undergoes elastic deformation when the gastric retention article is in a folded configuration, and rebounds when the gastric retention article is in an unfolded configuration.

[0024] Multiple connecting components are radially connected to the foldable central superelastic alloy component. Each connecting component includes a first side and a second side opposite to the first side, and the first side of each connecting component is respectively connected to a corresponding rib.

[0025] Multiple elongated limb components, including a mandrel and an outer layer encapsulating the mandrel, wherein each elongated limb component is connected to a second side of a corresponding connecting component.

[0026] The plurality of connecting components are configured to undergo structural damage in an in vivo unfolding configuration, thereby causing the gastric retention to lose its shape.

[0027] The core has an active material, and the outer layer has a lower concentration of the active material than the core.

[0028] The outer layer has at least one thinned region, which accounts for 0.5% to 20% of the outer surface of the outer layer.

[0029] The thickness of the at least one thinned region is less than 0.2 mm.

[0030] The at least one thinned region extends to a depth of 70% or more of the outer layer thickness.

[0031] The thinned region is formed using at least one process selected from thermal deformation, surface cutting, and laser evaporation.

[0032] The ratio of the cross-sectional area of ​​the mandrel to that of the outer layer is between 1 and 10.

[0033] The outer layer does not contain any active substances.

[0034] The active substance is a therapeutic agent or a diagnostic agent.

[0035] Each slender limb component also includes one or more spacers positioned along the length of the slender limb component.

[0036] The plurality of connecting components are configured to be structurally damaged in an in vivo unfolding configuration through degradation, dissolution, dissociation, or mechanical weakening.

[0037] Less than 35% of the active substance may be released within 20% of the effective release period, while more than 80% of the active substance may be released within 90% of the effective release period. Attached Figure Description

[0038] The embodiments of the present invention are provided by way of example only, and will be better understood and readily comprehended by those skilled in the art from the following written description and accompanying drawings, wherein,

[0039] Figure 1A A schematic diagram of gastric retention in an expanded configuration according to an example embodiment is shown.

[0040] Figure 1B It shows Figure 1A Transparent cross-sectional view of gastric retention.

[0041] Figure 1C As shown Figure 1A A schematic diagram of the gastric contents in a folded configuration.

[0042] Figure 1D Showing Figure 1A A schematic diagram of another unfolding configuration of gastric contents in the body.

[0043] Figure 1E It shows Figure 1D Transparent cross-sectional view of 100g of gastric retention.

[0044] Figure 2A The end of a rib of gastric retention is shown according to an example embodiment.

[0045] Figure 2B Showing Figure 1B The first example of a mid-shaped end.

[0046] Figure 2C Showing Figure 1B The second example of the mid-shaped end.

[0047] Figure 2D Showing Figure 1B The third example of the mid-shaped end.

[0048] Figure 2E Showing Figure 1B The fourth example of the mid-shaped end.

[0049] Figure 3A Showing Figure 1A , 1B A magnified view of the far-end region of 1C.

[0050] Figure 3B Showing Figure 1A , 1BAn enlarged view of the interlocking connection between the remote area and connecting components of 1C.

[0051] Figure 4 The bar graph shows the retention time of two types of gastric contents in the stomach of a Labrador Retriever.

[0052] Figure 5 A schematic diagram of gastric retention in an expanded configuration is shown according to another example embodiment.

[0053] Figure 6 Showing Figure 5 Enlarged view of a partial component of a slender limb.

[0054] Figure 7A A cross-sectional view of an elongated limb component with a thinning region according to an example embodiment is shown.

[0055] Figure 7B A cross-sectional view of another elongated limb component having at least one thinned region is shown according to an example embodiment.

[0056] Figure 8 The graph shows the dissolution rate of risperidone in simulated gastric juice for six types of gastric residues over a period of time.

[0057] Detailed description

[0058] Figure 1A A schematic diagram of gastric retention 100 in an expanded configuration according to an example embodiment is shown. Figure 1B It shows Figure 1A Transparent cross-sectional view of 100g of gastric retention.

[0059] The gastric retention 100 includes an outer portion 102 having a central region 104. The central region 104 is made of at least one material selected from polyvinyl chloride, synthetic rubber, neoprene rubber, nylon, PVB, silicone, acrylonitrile-butadiene-styrene, polyethylene terephthalate, polybutylene terephthalate, and polyurethane. The outer portion 102 also includes a plurality of distal regions 106 radially connected to the central region 104. The plurality of distal regions 106 are made of at least one material selected from polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin (or artificial resin), neoprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high-density polyethylene, polycarbonate, polycaprolactone, polylactic acid, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane, and epoxy resin.

[0060] The gastric retention 100 also includes a foldable central hyperelastic alloy component 108 made of at least one hyperelastic alloy. The foldable central hyperelastic alloy component 108 is securely fixed within the outer portion 102 and includes six ribs 110, each having a shaped end 112. Each shaped end 112 is embedded in a corresponding distal region 106 to form a secure fastening connection. Figure 1B As shown, each shaped end 112 is a protrusion embedded in the distal region 106 to prevent the distal region 106 from moving and to ensure the alignment and stability of the distal region 106 relative to the rib 110.

[0061] The gastric retention 100 also includes a plurality of connecting members 114, each having a first side and a second side opposite to the first side. The first side of each connecting member 114 is connected to a corresponding distal region 106. For example... Figure 1B As shown, each connecting member 114 has a groove on its first side and a protrusion 116 on its corresponding distal region. These grooves and protrusions 116 form an interlocking connection. The multiple connecting members 114 are configured to structurally break down in their unfolded configuration within the body, causing the gastric retention 100 to lose its shape. For example, the connecting members 114 may include materials that hydrolyze and / or absorb water in the gastric environment, resulting in degradation, dissolution, dissociation, or mechanical weakening. As a result, the gastric retention 100 loses its unfolded configuration and passes through the patient's stomach cavity.

[0062] Furthermore, the gastric retention 100 includes a plurality of elongated limbs 118. Each elongated limb 118 is connected to the second side of a corresponding connecting member 114. At least one elongated limb 118 has an active substance for delivering a gastric retention drug, such as a therapeutic agent or diagnostic agent, at a predetermined rate.

[0063] Figure 1C It shows Figure 1A A schematic diagram of the gastric retention 100 in a folded configuration. When the gastric retention 100 is in a folded configuration, the foldable central hyperelastic alloy component 108 undergoes elastic deformation, such as... Figure 1C As shown. In the folded configuration, the corresponding distal region 106, connecting member 114, and elongated limb member 116 form a triangular prism that can fit together tightly, thereby facilitating storage and oral administration in the folded configuration.

[0064] Figure 1D Showing Figure 1A A schematic diagram of another unfolded configuration of the gastric residue 100 in the body. Figure 1E It shows Figure 1DA transparent cross-sectional view of the gastric retention 100. When the patient takes the medication, the gastric retention 100 is swallowed and unfolds in the body as the foldable central hyperelastic alloy component 108 bounces in the gastric environment.

[0065] The unfolded configuration of the gastric retention 100 allows it to remain in the patient's stomach for a longer period, such as 24 hours or longer. Figure 1D and 1E As shown, due to fluctuations in the gastric environment compressing the gastric retention 100, the gastric retention 100 resists bending within the body. After a period of time in the gastric environment, the connecting parts 114 are structurally damaged. This process makes the connecting parts 114 flexible or causes them to break, thereby allowing the elongated limb parts 118 to bend or break relative to the outside 102. Ultimately, this results in the gastric retention 100 losing its unfolded configuration and being expelled from the patient's stomach.

[0066] In one embodiment, multiple distal regions 106 have a higher level of stiffness compared to the central region 104. Increased stiffness in the distal regions restricts the movement of the elongated limb component 118 relative to the outer surface 102, thereby enhancing the ability of the gastric residue 100 to remain in the stomach. Furthermore, the multiple distal regions 106 may have a stiffness level of 50D or higher on the Shore hardness scale, while the central region 104 has a relatively lower stiffness to avoid hindering the folding of the gastric residue 100. Without the distal regions 106, the low stiffness level of the central region 104 could cause deformation of the outer surface 102, resulting in the elongated limb component 118 being able to bend significantly within the body relative to the foldable central hyperelastic alloy component 108. Consequently, the gastric residue 100 would lose its shape and be prematurely expelled from the stomach. In the claimed invention, the distal regions 106 have a relatively higher stiffness level than the central regions 104 to form a robust and secure connection with the ribs 110 of the foldable central hyperelastic alloy component 108. Therefore, when the gastric retention 100 is in the unfolded configuration, the elongated limb component 118 will not bend relative to the foldable central hyperelastic alloy component 108 due to the deformation of the central region 104, thereby preventing the gastric retention 100 from passing through the gastric cavity prematurely.

[0067] In one embodiment, the gastric retention 100 is in an unfolded configuration with an unfolded diameter of at least 2 cm and a folding force of at least 0.5 N.

[0068] exist Figure 1A-1EIn the embodiments described, the foldable central hyperelastic alloy component 108 includes six ribs 110, each rib having a separate shaped end 112 that is individually embedded in a corresponding distal region 106 to form a secure fastening connection. In alternative embodiments, the ribs 110 may not include shaped ends. Instead, the foldable central hyperelastic alloy component 108 may simply include a plurality of ribs 110, each rib having an end that is individually embedded in a corresponding distal region 106.

[0069] In an alternative embodiment, the gastric retention 100 also includes a housing that encloses the entire assembly, thereby enabling easy storage and oral administration. When the medication is taken, the housing will degrade, dissolve, separate, or mechanically weaken in the body, and the gastric retention 100 will unfold into an expanded configuration as the foldable central hyperelastic alloy component 108 rebounds and contracts within the gastric environment.

[0070] In one embodiment, the foldable central hyperelastic alloy component 108 comprises at least one hyperelastic alloy selected from nickel-titanium (Ni-Ti), brass (Cu–Zn), copper-aluminum-nickel (Cu–Al–Ni) alloy, gold-cadmium (Au–Cd) alloy, gold-copper-zinc (Au-Cu-Zn) alloy, indium-thallium (In–Tl) alloy, cobalt-nickel-aluminum (Co-Ni-Al) alloy, cobalt-nickel-gallium (Co-Ni-Ga) alloy, copper-aluminum-beryllium-zirconium (Cu-Al-Be-Zr) alloy, copper-aluminum-beryllium-chromium (Cu-Al-Be-Cr) alloy, copper-aluminum-beryllium-gadolinium (Cu-Al-Be-Gd) alloy, and copper-aluminum-nickel-hafnium (Cu-Al- Ni-Hf alloy, copper-tin (Cu-Sn) alloy, copper-zinc-silicon (Cu-Zn-Si) alloy, copper-zinc-aluminum (Cu-Zn-Al) alloy, copper-zinc-tin (Cu-Zn-Sn) alloy, iron-manganese-silicon (Fe-Mn-Si) alloy, iron-platinum (Fe-Pt) alloy, manganese-copper (Mn-Cu) alloy, nickel-iron-gallium (Ni-Fe-Ga) alloy, nickel-titanium-hafnium (Ni-Ti-Hf) alloy, nickel-titanium-palladium (Ni-Ti-Pd) alloy, nickel-manganese-gallium (Ni-Mn-Ga) alloy, nickel-manganese-gallium-copper (Ni-Mn-Ga-Cu) alloy, nickel-manganese-gallium-cobalt (Ni-Mn-Ga-Co) alloy, titanium-niobium (Ti-Nb) alloy.

[0071] In another embodiment, the foldable central hyperelastic alloy component 108 may also be made of one of the following shape memory alloys: Ni-Ti, Ni-Ti-Hf, Ni-Ti-Pd, Ni-Fe-Ga, Ni-Mn-Ga, Ni-Mn-Ga-Cu, Ni-Mn-Ga-Co, Ag-Cd, Co-Ni-Al, Co-Ni-Ga, Cu-Al-Be-X (X: Zr, B, Cr, Gd), Cu-Al-Ni, Cu-Al-Ni-Hf, Cu-Sn, Cu-Zn, Cu-Zn-X (X = Si, Al, Sn), Fe-Mn-Si, Fe-Pt, Mn-Cu, Ti-N.

[0072] Shape memory alloys belong to the class of superelastic alloys. One type of shape memory alloy suitable for a foldable, centrally superelastic alloy component 108 has an austenitic transformation end temperature (Af) slightly below normal body temperature. At temperatures below Af (e.g., 30°C), shape memory alloys are in the martensitic phase and exhibit ductility. However, when heated to temperatures above Af, they become superelastic and return to their initial unfolded state. During production and storage, the shape memory alloy remains in the martensitic phase; therefore, the gastric residue 100 can maintain its folded configuration without a constraining structure, such as the aforementioned shell. After oral administration of the gastric residue 100, the temperature of the shape memory alloy rises due to the body's own heat. This causes the shape memory alloy to undergo a transformation from the martensitic to the austenitic phase, thus allowing the gastric residue 100 to remain in the stomach.

[0073] Figure 2A The end of a rib 200 containing gastric retention is shown according to an example embodiment. Figure 2A As shown, rib 200 extends into and is embedded in the distal region 201 of the gastric retention. Rib 200 does not include a shaped end. Because rib 200 is embedded in the distal region 201 with an enhanced level of rigidity, the resistance of the slender limb component to bending due to deformation of the central region is significantly increased in vivo.

[0074] Figure 2B-2E Showing Figure 1B Example of the middle shaping end 112. In Figure 2B In the middle, the shaped end 112 includes a beam 202 embedded in the distal region 106. The beam 202 consists of a longitudinal web and a transverse flange at the end of the web, forming a structure similar to the letter "T", thereby forming a secure fastening connection with the corresponding distal region 106.

[0075] exist Figure 2CIn this embodiment, the shaping end 112 includes a hook 204 embedded in the distal region 106. The hook 204 has a straight body with a curved shape extending at a right angle, forming a structure resembling the letter "J" for locking onto the corresponding distal region 106 to form a secure fastening connection. In an alternative embodiment, the shaping end 112 may include a bend formed at an internal bending angle θ of 135° or less.

[0076] exist Figure 2D In the middle, the shaping end 112 includes a spiral pattern 206 embedded in the distal region 106. The spiral pattern 206 consists of a planar spiral or a three-dimensional spiral shape to form a secure and fastened connection with the corresponding distal region 106. Figure 2E In the embodiment, the shaping end 112 includes a recessed shape 208 embedded in the distal region 106. The recessed shape 208 enables the shaping end 112 to be securely held within the distal region 106 and prevents it from dislodging.

[0077] In an alternative embodiment, the shaping end 112 may include other features such as threads, tacks, flanges, and protrusions, which enable them to form a secure and fastened connection with the distal region 106. These features engage and anchor the distal region 106 as the polymer is molded onto the shaping end 112 to form the distal region 106, thereby preventing any movement of the distal region 106.

[0078] Figure 3A for Figure 1A , 1B A magnified view of the distal region 106 in 1C. (See image below.) Figure 3A As shown, the distal region 106 has a wedge-shaped protrusion 116 extending outward. The protrusion 116 is configured to form an interlocking connection with a first side of the connecting member 114.

[0079] Figure 3B Showing Figure 1A , 1B An enlarged view of the interlocking connection between the distal region 106 and the connecting member 114 in 1C. The interlocking connection consists of an outwardly projecting protrusion 116 on the distal region 106 and a corresponding groove on the first side of the connecting member 114. When connected, the protrusion 116 fits tightly into the groove, thereby creating a strong and stable connection that prevents the connecting member 114 from accidentally detaching from the distal region 106.

[0080] In an alternative embodiment, instead of the protrusion on the distal region 106 and the corresponding groove on the connecting member 114, the interlocking connection can be formed by the protrusion on the connecting member 114 and the corresponding groove on the distal region 106. In an alternative embodiment, the interlocking connection can also be formed by other types of joints, such as adhesive joints, ball joints, and finger joints.

[0081] Figure 4 Bar graph 402 shows the retention time of two types of gastric retention in the stomach of a Labrador Retriever. The gastric retention corresponds to items 3 and 5 in Example 2 below, with the vertical axis representing the retention time scale in days. The horizontal axis represents the two retentions. The first bar 404 represents a first gastric retention device (item 3 in Example 2), which does not have ribs with shaped ends to form a secure connection between the foldable central hyperelastic alloy component and the distal region. According to the example embodiment, the second bar 406 represents a second gastric retention device (item 5 in Example 2), whose foldable central hyperelastic alloy component has shaped ends that form a secure connection with the distal region. The ends of the foldable central hyperelastic alloy component have shaped ends to form a secure connection with the corresponding distal region. Figure 4 As shown, the retention time of the first gastric retention device is slightly less than 2 days, while the retention time of the second gastric retention device is significantly longer, approximately 11 days. The view clearly demonstrates that the secure connection between the foldable central hyperelastic alloy component and the distal region significantly increases the retention time.

[0082] Figure 5 A schematic diagram of a gastric retention 500 in an unfolded configuration according to another example embodiment is shown. The gastric retention 500 includes an outer portion 502 having a central region 504 and a plurality of distal regions 506 radially connected to the central region 504. The gastric retention 500 also includes a foldable central hyperelastic alloy component made of at least one hyperelastic alloy. The hyperelastic alloy component is secured within the outer portion 502 and includes a plurality of ribs.

[0083] The gastric retention 500 also includes a plurality of connecting members 508 having a first side and a second side opposite to the first side. The first side of each connecting member 508 is respectively connected to a corresponding distal region 506 to form an interlocking connection. The plurality of connecting members 508 are configured to be structurally damaged in an unfolded configuration in vivo, thereby causing the gastric retention 500 to lose its unfolded configuration shape. For example, the connecting members 508 include materials that undergo hydrolysis and / or water absorption in the gastric environment, resulting in degradation, dissolution, dissociation, or mechanical weakening. As a result, the gastric retention 500 loses its unfolded configuration shape and is expelled from the patient's gastric lumen.

[0084] Furthermore, the gastric retention 500 includes a plurality of elongated limb components 510. Each elongated limb component 510 includes a mandrel and an outer layer encapsulating the mandrel. Each elongated limb component 510 is connected to a second side of a corresponding connecting member 508. At least one of the elongated limb components 510 has an active substance, such as a therapeutic agent or diagnostic agent, for delivering the gastric retention drug at a predetermined rate. A slit 512 is formed on the outer surface of the outer layer along the length direction of the elongated limb component 510, thereby increasing the dissolution rate of the active substance through the outer layer.

[0085] The elongated limb component 510 also includes spacers 514 disposed at the distal ends of the component 510 along its length. The length of the mandrel depends on the desired drug dose. The spacers 514 can allow the elongated limb components 510 to have a uniform length, regardless of the drug dose. Other additives to the elongated limb component 510, such as fluorescence (e.g., barium sulfate) or metal beads, can also be incorporated into the spacers 514, as they do not affect the dissolution rate of the active substance.

[0086] In one embodiment, the mandrel has an active material, and the outer layer has a lower concentration of the active material than the mandrel. The outer layer may also be free of active material.

[0087] exist Figure 5 In the embodiment explained herein, the gastric retention 500 includes an outer portion 502 having a central region 504 and a distal region 506. In an alternative embodiment, the gastric retention 500 can operate effectively even without the outer portion 502. In this alternative embodiment, a first side of each connecting member 508 is connected to a corresponding rib.

[0088] exist Figure 5 In the illustrated embodiment, spacers 514 are located at the distal ends of the elongated limb members 510. In alternative embodiments, spacers 514 may be located anywhere along the length of the elongated limb member 510, for example, at the proximal end of the member 510 adjacent to the connecting member 508. Furthermore, each elongated limb member 510 may have more than one spacer.

[0089] Figure 6 It shows Figure 5 Enlarged view of a partial assembly of the elongated limb component 510. The elongated limb component 510 includes a mandrel 602 and an outer layer 604 encapsulating the mandrel 510. A slit 606 is formed on the outer surface of the outer layer 604 along the entire length of the elongated limb component 510. The slit 606 can be formed using at least one process selected from laser evaporation, surface cutting, thermal deformation, and co-extrusion. For co-extrusion processes, an improved die on the co-extruder forms the slit through protrusions.

[0090] In an alternative embodiment, slit 606 extends through at least 50% of the length of the elongated limb member 510. Furthermore, slit 606 may extend to a depth of 50% or more of the thickness of the outer layer 604 and have a width of 2 mm or less. Additionally, the ratio of the cross-sectional area of ​​the mandrel 602 to that of the outer layer 604 is between 1 and 10.

[0091] Figure 7AA cross-sectional view of an elongated limb member 702 having a thinned region 704 according to an example embodiment is shown. The elongated limb member 704 includes a mandrel 706 and an outer layer 708 encapsulating the mandrel 706.

[0092] Figure 7B A cross-sectional view of another elongated limb component 710 having at least one thinning region 712 according to an example embodiment is shown. The elongated limb component 710 includes a mandrel 714 and an outer layer 716 encapsulating the mandrel 714.

[0093] Thinning regions 704 and 712 can increase the dissolution rate of active material through outer layers 708 and 716. Furthermore, at least one thinning region 704 or 712 can extend to a depth of 50% or more of the thickness of the outer layers 708 and 716. At least one thinning region 704 or 712 can have a thickness of less than 0.2 mm and occupy 0.5% to 20% of the outer surface of the outer layers 708 and 716. Thinning regions 704 and 712 are defined as any portion of the outer layers 708 and 716, whereby the shortest distance from the outer surface of the outer layers 708 and 716 to the surface of the mandrel is less than 50% of the average thickness of the outer layers or less than 0.2 mm. The thinning regions can be formed during the production process of bonding the inner and outer layers, or can be formed using at least one process selected from heat deformation, surface cutting, and laser evaporation.

[0094] For conventionally orally administered drugs, the drug is released uniformly from all exposed surfaces, resulting in a dissolution profile with a faster dissolution rate at the beginning and a slower dissolution rate towards the end. This is because only the drug can be released from the surface. Initially, the drug is already on the surface and can be released quickly, but as dissolution progresses, the drug must diffuse a longer distance to reach the surface to be released. This causes the dissolution rate to slow down. Using coatings with controlled diffusion rates is a common method for better controlling the dissolution distribution. However, the ability of coatings is limited because the mechanism of drug release remains the same; as more drug is released, it needs to diffuse a longer distance to reach the surface to be released, and dissolution will still gradually slow down. Therefore, achieving a good dissolution profile throughout the entire effective release cycle (the duration of complete release of the active substance) is challenging.

[0095] exist Figure 6 , 7AIn the embodiments of 7B, by applying outer layers 604, 708, 716 to the mandrels 602, 706, 714, the permeability of the outer layers 604, 704, 716 can be selectively altered in selective regions to reduce the distance between the mandrel 602 and the outer surfaces of the outer layers 604, 706, 708, 716. This can be achieved by reducing the thickness of the outer layers or forming slits to fully expose the mandrel 602, thereby increasing the dissolution rate of the active material. This can be achieved by forming slits 606 of various sizes or thinning regions 704, 712 on the outer layers 604, 708, 716 to obtain the desired dissolution rate of the active material by controlling the location and rate of release from the surface. Advantageously, in these embodiments, less than about 35% of the active material can be released within about 20% of the effective release period, and more than about 80% of the active material can be released within about 90% of the effective release period.

[0096] Figure 8 A line graph (802) shows the dissolution rate of risperidone in simulated gastric fluid for six gastric retention items over a period of time. The horizontal axis represents the number of days, and the vertical axis represents the percentage of risperidone dissolution in simulated gastric fluid. The graph consists of six lines.

[0097] The first row, 804, representing gastric retention without an outer layer, shows inconsistent dissolution rates of risperidone. Initially, the first reflection 804 has a steeper gradient, indicating a higher dissolution rate. However, over time, the gradient of the first reflection 804 decreases, indicating a decreasing dissolution rate. In other words, the observed dissolution rate varies over a given time range.

[0098] According to the example embodiment, the second fold line 806, the third fold line 808, and the fourth fold line 810 represent gastric retention articles with slits extending through 100%, 75%, and 50% of the length of the elongated limb component, respectively. The second fold line 806, the third fold line 808, and the fourth fold line 810 maintain a uniform gradient, wherein less than about 35% of risperidone is released within about 20% of the effective release cycle, and more than about 80% of risperidone is released within about 90% of the effective release cycle. The line graph shows that these gastric retention articles have a stable dissolution rate, and almost all of the active substance is released at the end of the seven-day experiment. This highlights the consistent dissolution of the active substance due to the slits formed on the elongated limb component. The fifth fold line 812 represents another gastric retention article with a slit extending through 40% of the length of its elongated limb component. The fifth fold line 812 maintains a uniform gradient, but the release of risperidone is slower compared to the previous gastric retention articles.

[0099] The sixth fold line 814 indicates a gastric retention product with an outer layer lacking slits. Due to the lack of slits on the slender limb component, the gastric retention product maintains a slow release of risperidone throughout the entire effective release cycle.

[0100] Example 1

[0101] Production Figure 1A , 1B An example of the method for gastric retention 100 described in 1C is as follows.

[0102] A 0.35 mm thick NiTiNO3 sheet is stamped to obtain a foldable central hyperelastic alloy component 108. The central region 104 and the distal region 106 of the outer 102 are formed by injection molding of PC-3575A and PC-3572D, respectively, which were purchased from Lubrizol.

[0103] 99 grams of HPMC-AS-HG (purchased from Shin-Etsu Chemical), 99 grams of PCL, and 2 grams of silica were mixed until a homogeneous mixture was formed. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder with a custom-designed triangular die to form triangular filaments, which were cut into 3 mm segments to form connecting parts 114.

[0104] 130g of PCL powder, 40g of RL PO acrylic resin (purchased from Evonik), 28g of powdered active ingredient, and 2g of silica powder were mixed until homogeneous. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder with a custom-designed triangular die to form triangular filaments, which were then cut into 8mm segments to form elongated limb parts 118.

[0105] The outer part 102, the foldable central super-elastic alloy component 108, the connecting component 114 and the slender limb component 118 are then fitted into a custom mold and thermally fused together by laser to form the gastric residue 100.

[0106] Example 2

[0107] The following describes an experiment using six types of gastric retention.

[0108] As shown in the table below, six types of gastric retention components were constructed using different materials for the outer and foldable central hyperelastic alloy parts. For all six products manufactured using the same parameters, the same connecting component components and elongated limb components were used. The gastric retention components were then filled into capsule shells of size 0.

[0109] Then, on different occasions, capsules containing stomach supplements were given to the Labrador Retriever. An abdominal X-ray was performed daily, and the duration of abdominal retention was recorded in days as follows.

[0110]

[0111] Example 3

[0112] The following provides Figure 6 Example of the manufacturing process of some components of the slender limb part 510 shown.

[0113] 110g of PCL powder, 50g of Evonik-Eudragit RL PO powder, 38g of powdered active ingredient, and 2g of silica powder were mixed until homogeneous. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder. The extruded filaments were then trayed to form mandrel tray 602.

[0114] 140g of PCL powder, 58g of Evonik's RS PO acrylic resin powder, and 2g of silica powder were mixed until homogeneous. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder. The extruded filaments were trayed to form a 604 tray for the outer layer.

[0115] The mandrel 602 and outer layer 604 on the tray are fed into a co-extruder and extruded at a screw speed of 21 rpm for the mandrel 602 and 9 rpm for the outer layer 604. The extruder head is custom-designed so that the outer layer 604 wraps around the mandrel 602 during extrusion. The die is also custom-designed so that the elongated limb parts are triangular in shape and form a slit 606. The co-extruded filaments are then cut to 6 mm to form the elongated limb parts.

[0116] Example 4

[0117] The following provides production information. Figure 5 Another example of the process of the elongated limb component 510 shown.

[0118] Mix 90 g of PCL powder, 30 g of Evonik RL PO acrylic resin powder, 30 g of poloxamer 407 powder, 48 g of powdered active ingredient, and 2 g of silica powder until homogeneous. Then, load the homogeneous powder into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder. The extruded filaments are then trayed to form a mandrel tray.

[0119] 170g of PCL powder, 28g of acrylic resin RS PO powder (purchased from Evonik), and 2g of silica powder were mixed until homogeneous. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder. The extruded filaments were then loaded onto a tray to form an outer tray.

[0120] The mandrel and outer layer on the tray are fed into a co-extruder and extruded at a screw speed of 18 rpm for the mandrel and 12 rpm for the outer layer. The co-extruder's extruder head is custom-made so that the outer layer wraps around the mandrel during extrusion. The die is also custom-made so that the slender limbs are triangular in shape and form a slit during extrusion. The co-extruded filaments are then cut into 6mm pieces to form the mandrel and outer layer assembly.

[0121] 198g of PCL powder and 2g of silica were mixed until homogeneous. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder with a custom-designed triangular die to form triangular filaments, which were then cut into 2mm segments to form spacers. The spacers were then placed at the ends of the mandrel and outer layer components using a hot-melt process to form elongated limb parts.

[0122] Example 5

[0123] An example of a process for producing spacers using barium sulfate.

[0124] 120g of PCL powder, 78g of barium sulfate powder, and 2g of silica powder were mixed until homogeneous. The homogeneous powder was then loaded into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder, which has a custom-designed triangular die to form triangular filaments, which were cut into 4mm segments to form spacer components.

[0125] Those skilled in the art will understand that many changes and / or modifications can be made to the invention as illustrated in the specific embodiments without departing from the spirit or scope of the invention as broadly described. Therefore, these embodiments are to be considered illustrative rather than restrictive in all respects.

Claims

1. An oral gastric retention substance, comprising: A foldable central hyperelastic alloy component comprising multiple ribs, wherein the foldable central hyperelastic alloy component undergoes elastic deformation when the gastric contents are in a folded configuration, and rebounds when the gastric contents are in an unfolded configuration; Multiple connecting components are radially connected to the foldable central superelastic alloy component. Each connecting component includes a first side and a second side opposite to the first side, and the first side of each connecting component is respectively connected to a corresponding rib. Multiple elongated limb components, including a mandrel and an outer layer encapsulating the mandrel, wherein each elongated limb component is connected to a second side of a corresponding connecting component. The plurality of connecting components are configured to undergo structural damage in an in vivo unfolding configuration, thereby causing the gastric retention to lose its shape. The core has an active material, and the outer layer has a lower concentration of the active material than the core. Each elongated limb component includes at least one slit formed on the outer surface of the outer layer, the at least one slit extending at least 50% of the length along the length direction of the elongated limb component.

2. The gastric retention of claim 1, wherein at least one of the slits extends to a depth of 50% or more of the outer layer thickness.

3. The gastric retention according to claim 1, wherein the width of the at least one slit is 2 mm or less.

4. The gastric retention material according to claim 1, wherein, The ratio of the cross-sectional area of ​​the mandrel to that of the outer layer is between 1 and 10.

5. The gastric retention as described in claim 1, wherein the outer layer does not contain any active substance.

6. The gastric retention substance according to claim 1, wherein the active substance is a therapeutic agent or a diagnostic agent.

7. The gastric retention as claimed in claim 1, wherein each elongated limb component further includes one or more spacers positioned along the length of the elongated limb component.

8. The gastric retention of claim 1, wherein the plurality of connecting components are configured to be structurally damaged in an in vivo deployment configuration by degradation, dissolution, dissociation or mechanical weakening.

9. The gastric retention article according to claim 1, wherein less than 35% of the active substance is released during 20% ​​of the effective release period, and more than 80% of the active substance is released during 90% of the effective release period.

10. An oral gastric retention substance, comprising: A foldable central hyperelastic alloy component comprising multiple ribs, wherein the foldable central hyperelastic alloy component undergoes elastic deformation when the gastric contents are in a folded configuration, and rebounds when the gastric contents are in an unfolded configuration; Multiple connecting components are radially connected to the foldable central superelastic alloy component. Each connecting component includes a first side and a second side opposite to the first side, and the first side of each connecting component is respectively connected to a corresponding rib. Multiple elongated limb components, including a mandrel and an outer layer encapsulating the mandrel, wherein each elongated limb component is connected to a second side of a corresponding connecting component. The plurality of connecting components are configured to undergo structural damage in an in vivo unfolding configuration, thereby causing the gastric retention to lose its shape. The core has an active material, and the outer layer has a lower concentration of the active material than the core. The outer layer has at least one thinned region, which accounts for 0.5% to 20% of the outer surface of the outer layer.

11. The gastric retention of claim 10, wherein the thickness of the at least one thinned region is less than 0.2 mm.

12. The gastric retention of claim 10, wherein the at least one thinned region extends to a depth of 70% or greater of the outer layer thickness.

13. The gastric retention as described in claim 10, wherein, The thinned region is formed using at least one process selected from thermal deformation, surface cutting, and laser evaporation.

14. The gastric retention of claim 9, wherein the ratio of the cross-sectional area of ​​the mandrel to that of the outer layer is between 1 and 10.

15. The gastric retention as described in claim 10, wherein the outer layer does not contain any active substance.

16. The gastric retention of claim 10, wherein the active substance is a therapeutic agent or a diagnostic agent.

17. The gastric retention as claimed in claim 10, wherein each elongated limb component further includes one or more spacers positioned along the length of the elongated limb component.

18. The gastric retention article of claim 10, wherein the plurality of linker components are configured to be structurally damaged in vivo by degradation, dissolution, dissociation or mechanical weakening.

19. The gastric retention article of claim 10, wherein less than 35% of the active substance is released during 20% ​​of the effective release period, and more than 80% of the active substance is released during approximately 90% of the effective release period.

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