Oral administration gastric retention device

Abstract

The present invention relates to a gastric retention device for oral administration. The gastric retention device includes a foldable central member, a plurality of elongated limb members, and a plurality of connecting members. The foldable central member includes a plurality of ribs, and the ribs include at least one type of superelastic alloy. The elongated limb members are connected to the radially foldable central member, and a plurality of the elongated limb members correspond to the plurality of ribs. Each connecting member connects one elongated limb member to the foldable central member. The ribs can expand from a folded first state to an expanded second state to deploy the elongated limb members. At least one of the elongated limbs is configured to contain a releasable drug. The connecting members are configured to transition from a rigid first state to a free second state so as to be able to move the elongated limb members independently with respect to the foldable central member.

Description

Technical Field

[0001] The present invention relates to an intragastric retention device for oral administration.

Background Art

[0002] Adherence to treatment regimens that require long-term medication compliance tends to be poor. In primary and secondary prevention, the diseases that require prevention or treatment are usually asymptomatic, and the drug regimen also has no immediate practical effect, so adherence is the lowest. Current methods of improving adherence, such as patient education interventions and advice, have only limited improvement.

[0003] Drug treatment regimens such as invasive administration methods and pharmaceutical formulations tend not to be very preferred due to their invasiveness, whereas oral administration methods are widely accepted because they are simpler and cheaper. However, the transport time of drugs through the human digestive tract is only about 24 to 四十八 hours in total, about 1 to 2 hours in the stomach, about 3 hours in the small intestine, and about 6 to 12 hours in the large intestine. Therefore, with a single administration, it is not possible to achieve a single-dose action period longer than the transport time.

[0004] One way to use an oral dosage form to extend the duration is to incorporate a self-expanding structure into the dosage form that can physically prevent the dosage form from leaving the gastric cavity. Conventionally, self-expanding structures have been made entirely of superelastic materials (e.g., elastomers). However, there are several drawbacks to using only polymers to generate this structure.

[0005] It should be noted that in order to prevent the dosage form itself from leaving the gastric cavity, it is necessary to have a minimum flexural modulus against being compressed through the pyloric sphincter connecting the stomach and the duodenum. Since polymers have a relatively low flexural modulus, when using polymers for the self-expanding structure, the cross-section of the structure needs to be large enough to achieve the minimum flexural modulus, which thereby imposes a certain limitation on the minimum volume of the structure. As a result, the minimum size of the drug is limited, making the drug unsuitable for patients with dysphagia or infants.

[0006] Another drawback of using polymers as shape memory materials is that the types of polymers that can meet the requirement of minimum flexural modulus while also satisfying other material performance requirements are limited. These required polymer types include, for example, biocompatibility, melt processability for low-cost mass production, sufficient surface energy to bond with other parts of the formulation, and high creep resistance so that the self-expanding structure springs back to its initial shape after long-term storage. [Overview of the project] [Problems that the invention aims to solve]

[0007] This must either solve at least one of the aforementioned problems or provide a useful alternative. [Means for solving the problem]

[0008] According to a first aspect of the present invention, a gastric retention device for oral administration is provided. A foldable central superelastic alloy member, It includes multiple elongated limb members capable of carrying an active substance, the active substance being a therapeutic agent or a diagnostic agent. Here, each of the multiple elongated limb members is connected to the foldable central superelastic alloy member via a connecting member. Here, if the gastric retention device has a foldable structure, the foldable central superelastic alloy member undergoes elastic deformation, and when the gastric retention device is in an unfolded structure, the foldable central superelastic alloy member recoils. Here, the connecting member causes the gastric retention device to lose its unfolded structure through decomposition, dissolution, dissociation, or mechanical weakening.

[0009] The unfolded structure of the gastric retention device can have a folding force of at least 0.5 N.

[0010] The unfolded structure of the gastric retention device can have an unfolded diameter of at least 2 cm.

[0011] The gastric retention device can be positioned to maintain the shape of the deployed structure for at least 24 hours.

[0012] The aforementioned foldable central superelastic alloy member includes selecting at least one material from the following set: Nitinol (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, 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, 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.

[0013] The aforementioned foldable central superelastic alloy member can be securely fixed within the outer surface layer member.

[0014] The aforementioned folding force of at least 80% can be provided by a foldable central superelastic alloy member.

[0015] The connecting member can be connected to the outer surface layer member.

[0016] The aforementioned outer surface layer member is manufactured by selecting at least one material from the following set: polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin or bakelite, chloroprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high-density polyethylene, polycarbonate, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane, and epoxy resin.

[0017] The gastric retention device further includes a casing used to house the gastric retention device, which has a foldable structure, and the casing is arranged to allow the gastric retention device to rebound and present an unfolded structure via disassembly, dissolution, separation, or mechanical weakening.

[0018] According to a second aspect of the present invention, a gastric retention device for oral administration is provided. A foldable central shape memory alloy member, It includes multiple elongated limb members capable of carrying an active substance, the active substance being a therapeutic agent or a diagnostic agent. Here, each of the multiple elongated limb members is connected to the foldable central shape memory alloy member via a connecting member. Here, the foldable central shape memory alloy member undergoes a phase transition from the martensite phase to the austenite phase in its crystal structure, converting the gastric retention device from a folded structure to an unfolded structure. Here, the connecting member loses its shape as an expanded structure through decomposition, dissolution, dissociation, or mechanical weakening.

[0019] The unfolded structure of the gastric retention device can have a folding force of at least about 0.5 N.

[0020] The unfolded structure of the gastric retention device can have an unfolded diameter of at least 2 cm.

[0021] The gastric retention device can be configured to maintain its deployed shape for at least 24 hours.

[0022] The foldable central shape memory alloy member includes selecting at least one material from the following groups: 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-Nb.

[0023] The foldable central shape memory alloy member is firmly fixed within one outer surface layer member.

[0024] At least 80% of the folding force is provided by the foldable central shape memory alloy member.

[0025] The connecting member can be connected to the outer surface layer member.

[0026] The outer surface layer member is manufactured by selecting at least one material from the following groups: polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin or bakelite, chloroprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high density polyethylene, polycarbonate, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane and epoxy resin.

[0027] According to the third aspect of the present invention, there is provided a gastric retention device for oral administration, A foldable central member, including a plurality of ribs, wherein the ribs include at least one superelastic alloy. A plurality of elongated limb members, wherein the elongated limb members are radially connected to the foldable central member, and the plurality of elongated limb members correspond to the plurality of ribs. Multiple connecting members, each connecting member connecting a single elongated limb member to a foldable central member. Here, the rib can be expanded from a first folded state to a second unfolded state, unfolding the elongated limb member. Here, at least one of the elongated limb members is configured to release the drug stored therein. The connecting member is configured to transition from a rigid first state to a free second state so that the elongated limb members can be moved independently relative to the foldable central member.

[0028] The aforementioned second free state may include a connecting member that is in a flexible state, such that an elongated limb member bends relative to the foldable central member.

[0029] The aforementioned second free state may include cutting the connecting member, separating the elongated limb member from the foldable central member.

[0030] The connecting member may be made of a material that transforms from a rigid first state to a free second state through hydrolysis.

[0031] The superelastic alloy includes selecting at least one material from the following set: nitinol (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, copper-aluminum-nickel-hafnium (Cu-Al-Ni-Hf) alloy, and copper-tin (Cu-Sn) alloy. These include copper-zinc-silicon (Cu-Zn-Si) alloys, copper-zinc-aluminum (Cu-Zn-Al) alloys, copper-zinc-tin (Cu-Zn-Sn) alloys, iron-manganese-silicon (Fe-Mn-Si) alloys, iron-platinum (Fe-Pt) alloys, manganese-copper (Mn-Cu) alloys, nickel-iron-gallium (Ni-Fe-Ga) alloys, nickel-titanium-hafnium (Ni-Ti-Hf) alloys, nickel-titanium-palladium (Ni-Ti-Pd) alloys, nickel-manganese-gallium (Ni-Mn-Ga) alloys, nickel-manganese-gallium-copper (Ni-Mn-Ga-Cu) alloys, nickel-manganese-gallium-cobalt (Ni-Mn-Ga-Co) alloys, and titanium-niobium (Ti-Nb) alloys.

[0032] The superelastic alloy may also be a shape memory alloy.

[0033] The shape memory alloy described above includes selecting at least one material from the following set: 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, and Ti-Nb.

[0034] The foldable central member may further include an outer surface layer member, the ribs within which are securely fixed within the outer surface layer member.

[0035] The connecting member can connect each of the elongated limb members to the outer surface layer member.

[0036] The aforementioned outer surface layer member can be manufactured by selecting at least one material from the following set: polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin or bakelite, chloroprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high-density polyethylene, polycarbonate, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane, and epoxy resin.

[0037] The gastric retention device may further include a casing for housing a foldable central member and elongated limb members, the casing being configured to dissolve to expand ribs from a first folded state to a second unfolded state in order to unfold the elongated limb members. [Brief explanation of the drawing]

[0038] Embodiments of the present invention are provided for illustrative purposes only and will be better understood and more readily understood by those skilled in the art through the following written description and accompanying drawings. [Figure 1A] A schematic diagram of a gastric retention device with an expanded configuration according to one embodiment is shown. [Figure 1B] Figure 1A shows a schematic diagram of the folding configuration of the gastric retention device. [Figure 1C] Figure 1A shows a schematic diagram of the storage configuration of the gastric retention device. [Figure 2A] A schematic diagram of a gastric retention device with an expanded configuration according to another embodiment is shown. [Figure 2B] Figure 2A shows a schematic diagram of the folding configuration of the gastric retention device. [Figure 3A]A schematic diagram of a gastric retention device with an expanded configuration according to another embodiment is shown. [Figure 3B] Figure 3A shows a schematic diagram of the folded configuration of the gastric retention device. [Figure 4A] A schematic diagram of a gastric retention device with an expanded configuration according to another embodiment is shown. [Figure 4B] Figure 4A shows a transparent schematic diagram of the internal elements of the gastric retention apparatus. [Figure 4C] Figure 4A shows a schematic diagram of the folding configuration of the gastric retention device. [Figure 5A] A schematic diagram of a semi-finished, foldable central component according to one embodiment is shown. [Figure 5B] A schematic diagram of a foldable central component of a semi-finished product according to another embodiment is shown. [Figure 5C] Figure 5B shows a schematic diagram of the two completed foldable central components using the semi-finished product. [Figure 6A] This shows a perspective view of the upper part of the outer surface layer member of a gastric retention device according to one embodiment. [Figure 6B] The upper part of Figure 3A is shown in plan view. [Figure 6C] Figure 6A shows a side view of the top. [Figure 6D] The upper part of Figure 6A is shown, with a superelastic alloy wire placed on top of it. [Figure 6E] The upper part of Figure 6A is used to show a schematic diagram of the two completed foldable central members. [Figure 7A] Figure 4A shows the test fixture for testing the gastric retention device. [Figure 7B] Figure 7A shows a bar graph of the test results obtained using the test mounting fixture. [Modes for carrying out the invention]

[0039] To provide a detailed explanation of the technical content, structural features, objectives, and effects of the technical solution, specific examples are provided below, along with the attached drawings. Figure 1A shows a schematic diagram of the gastric retention device 100 in its unfolded configuration according to one embodiment. Figure 1B shows a schematic diagram of the folded configuration of the gastric retention device of Figure 1A. Figure 1C shows a schematic diagram of the stowed configuration of the gastric retention device of Figure 1A.

[0040] The gastric retention device 100 includes a foldable central member 102 and three elongated limb members 104 radially connected to the foldable central member 102. The foldable central member 102 includes three ribs 106 made of at least one superelastic alloy. As shown in Figure 1A, the three elongated limb members 104 correspond to the three ribs 106. The positions and longitudinal axes of the elongated limb members 104 correspond to the positions and longitudinal axes of the ribs 106, respectively. As shown in Figures 1B and 1C, the elongated limb members 104 have a triangular prism shape that allows them to fit together when the gastric retention device 100 is in a folded configuration, thereby facilitating storage and oral intake. The rib 106 expands from a folded first state (as shown in Figures 1B and 1C) to an unfolded second state (as shown in Figure 1A), and the elongated limb member 104 is unfolded, thereby changing the gastric retention device 100 from a folded structure to an unfolded structure. In the unfolded configuration, the gastric retention device 100 has an unfolded diameter of at least 2 cm and a folding force of at least 0.5 N.

[0041] The gastric retention device further includes three connecting members 108. Each connecting member 108 connects an elongated limb member 104 to a foldable central member 102. At least one elongated limb member 104 is configured to deliver the gastric retention drug by releasing an active substance or drug (e.g., a therapeutic agent or diagnostic agent) stored therein at a predetermined rate.

[0042] The connecting member 108 is configured to transition from a rigid first state to a free second state so that the elongated limb member 104 can move independently relative to the foldable central member 102. The connecting member 108 includes a material that can be hydrolyzed to transition the connecting member 108 from a rigid first state to a free second state. Specifically, the connecting member 108 undergoes decomposition, dissolution, separation, or mechanical weakening in the gastric environment, so that the gastric retention device 100 loses its rigidity and shape and passes through the patient's gastric cavity. In one embodiment, the connecting member 108 loses its rigidity in the free second state and is flexible so that the elongated limb member 104 can be bent relative to the foldable central member 102. In another embodiment, the connecting member 108 is cut in the free second state to separate the elongated limb member 104 from the foldable central member 102.

[0043] As shown in Figure 1C, the gastric retention device 100 further includes a casing 110 that houses a foldable central member 102 and elongated limb members 104 to facilitate storage and oral administration. After oral administration, the casing 112 decomposes, dissolves, separates, or becomes mechanically weakened in the body, and the ribs 106 return from a folded first state to an expanded second state, unfolding the elongated limb members 104 and changing the gastric retention device 100 from a folded structure to an unfolded structure, extending the retention time of the gastric retention device 100 in the patient's stomach to, for example, 24 hours or more.

[0044] In one embodiment, the rib 106 comprises at least one superelastic alloy, wherein the superelastic alloy is selected from at least one material from the following set: nitinol (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, copper-aluminum-nickel-hafnium (Cu-Al-Ni-Hf) alloy, and copper-tin (Cu-Sn) alloy. These include copper-zinc-silicon (Cu-Zn-Si) alloys, copper-zinc-aluminum (Cu-Zn-Al) alloys, copper-zinc-tin (Cu-Zn-Sn) alloys, iron-manganese-silicon (Fe-Mn-Si) alloys, iron-platinum (Fe-Pt) alloys, manganese-copper (Mn-Cu) alloys, nickel-iron-gallium (Ni-Fe-Ga) alloys, nickel-titanium-hafnium (Ni-Ti-Hf) alloys, nickel-titanium-palladium (Ni-Ti-Pd) alloys, nickel-manganese-gallium (Ni-Mn-Ga) alloys, nickel-manganese-gallium-copper (Ni-Mn-Ga-Cu) alloys, nickel-manganese-gallium-cobalt (Ni-Mn-Ga-Co) alloys, and titanium-niobium (Ti-Nb) alloys.

[0045] Rib 106 may be manufactured from a shape memory alloy, the shape memory alloy comprising selecting at least one material from the following set: 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.

[0046] Shape memory alloys belong to the superelastic alloy family. The shape memory alloy applied to rib 106 has an austenite transition completion temperature (Af) slightly below normal body temperature. Below Af (e.g., 30°C), the shape memory alloy is in the martensite phase and is tractable. However, when the shape memory alloy is heated to a temperature above Af, it becomes superelastic and returns to its initial unfolded state. During manufacturing and storage, the shape memory alloy is in the martensite phase, and as a result, the gastric retention device 100 can maintain its folded structure without a restraining structure such as a casing 110. After oral administration of the gastric retention device 100, the temperature of the shape memory alloy rises due to the internal heat of the patient's body. This results in a transition of the shape memory alloy from the martensite phase to the austenite phase, thereby causing the elongated limb members 104 to unfold to hold the gastric retention device 100 in the patient's gastric cavity.

[0047] Figure 2A shows a schematic diagram of the gastric retention device 200 in an unfolded configuration according to another embodiment. Figure 2B shows a schematic diagram of the folded configuration of the gastric retention device of Figure 2A.

[0048] The gastric retention device 200 includes a foldable central member 202 and six elongated limb members 204 radially connected to the foldable central member 202. The foldable central member 202 includes six ribs 206 made of superelastic alloy wire. The gastric retention device 200 also includes six connecting members 208 for connecting each elongated limb member 204 to the foldable central member 202. At least one elongated limb member 204 is configured to store an active substance or drug, such as a therapeutic or diagnostic agent for gastric retention drug delivery. The connecting members 208 are configured to transition from a rigid first state to a free second state so that the elongated limb members 204 can move independently relative to the foldable central member 202.

[0049] Figure 3A shows a schematic diagram of the gastric retention device 300 in an unfolded configuration according to another embodiment. Figure 3B shows a schematic diagram of the folded configuration of the gastric retention device 300 shown in Figure 3A.

[0050] The gastric retention device 300 includes a foldable central member 302 and six elongated limb members 304 radially connected to the foldable central member 302. The foldable central member 302 includes six ribs 306 manufactured using a superelastic alloy belt. The gastric retention device 300 also includes six connecting members 308 for connecting each elongated limb member 304 to the foldable central member 302. At least one elongated limb member 304 is configured to store an active substance or drug, such as a therapeutic or diagnostic agent for gastric retention drug delivery. The connecting members 308 are configured to transition from a rigid first state to a free second state so that the elongated limb members 304 can move independently relative to the foldable central member 302.

[0051] Figure 4A shows a schematic diagram of the gastric retention device 400 in an unfolded configuration according to one embodiment. Figure 4B shows a transparent schematic diagram of the internal elements of the gastric retention device 400 of Figure 4A. Figure 4C shows a schematic diagram of the gastric retention device 400 of Figure 4A in a folded configuration.

[0052] The gastric retention device 400 includes a foldable central member 402 and a plurality of elongated limb members 404 radially connected to the foldable central member 402. As shown in Figure 4B, the foldable central member 402 includes an outer surface member 406 and a plurality of ribs 408 made of superelastic alloy wire firmly fixed within the outer surface member 406. The gastric retention device 400 also includes a plurality of connecting members 410 for connecting each elongated limb member 404 to the outer surface member 406.

[0053] The outer surface layer member 406 comprises a flexible and foldable material and is manufactured by selecting at least one from a set of polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin or Bakelite, chloroprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high-density polyethylene, polycarbonate, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane, and epoxy resin.

[0054] The main function of the outer surface layer member 406 is to cover the elongated limb member 404. In one embodiment, at least 80% of the folding force is supplied by the foldable central member 402, and the remaining less than 20% of the folding force is supplied by the outer surface layer member 406. When selecting the material for the outer surface layer member 406, many materials can be used in the manufacture of the outer surface layer member 406, as properties such as creep resistance, flexural modulus, and decomposition time are not major considerations.

[0055] In one embodiment, the outer surface layer member 406 is formed by coating a polymer onto a superelastic alloy rib 408 by injection molding or casting. It should be noted that the rib 408 is not limited to a wire shape and may include other shapes such as ribbon or stripe shapes. The outer surface layer member 406 may be formed on any of these shapes of rib 408 so that the rib 408 is firmly fixed within the outer surface layer member 406.

[0056] Figure 5A shows a schematic diagram of a semi-finished product of a foldable central member 500 according to one embodiment. Figure 5B shows a schematic diagram of a semi-finished product of a foldable central member 502 according to another embodiment. Three superelastic alloy wires 504 made of nitinol are fixed in a first mold in an overlapping manner. A thermoplastic polymer is injected into the first mold, and an internal member is formed in the overlapping region of the superelastic alloy wires 504, such as the injection-molded member 506 shown in Figures 5A and 5B, to fix the relative positions of the superelastic alloy wires 504. As shown in Figure 5B, the first mold may be manufactured so that the thermoplastic polymer is first used to form an injection-molded member 508 at the far end of the superelastic alloy wires 504. Next, the semi-finished product is transferred into a second mold, and the thermoplastic polymer is injected into the second mold to complete the foldable central member.

[0057] Figure 5C shows schematic diagrams of two foldable central members 510 and 512 fabricated using the semi-finished product of Figure 5B. The foldable central member 510 is made from the same polymer, while the foldable central member 512 is made from a different polymer. For example, in the foldable central member 512, an injection-molded member 506 is formed in the overlapping region of the superelastic alloy wire 504 using a first polymer having high hardness to fix the relative position of the superelastic alloy wire 504. An injection-molded member 508 is formed at the far end of the superelastic alloy wire 504 using a second polymer to form a strong connection with the connecting member. An injection-molded member 514 covering the length of the superelastic alloy wire 504 can be formed using a third polymer having low hardness to allow the superelastic alloy wire 504 to bend.

[0058] In one embodiment, a thermoplastic polymer is first injected into a first mold to form an injection-molded member 506, and then a superelastic alloy wire 504 is inserted into the injection-molded member 506 and fixed in place.

[0059] In one embodiment, the injection-molded members 506, 508, and 514 can be manufactured by casting instead of injection molding. A thermoplastic polymer is injected into a first or second mold and cured by a process such as cooling or curing.

[0060] Please note that the ribs are not limited to the metal wire shape shown in Figures 5A and 5B, but may include other shapes such as ribbons or strips.

[0061] Figure 6A shows a perspective view of the upper part 602 of the outer surface member of a gastric retention device according to one embodiment. Figure 6B shows a plan view of the upper part 602 of Figure 6A. Figure 6C shows a side view of the upper part 602 of Figure 6A.

[0062] The upper section 602 includes grooves 604 for housing the internal superelastic alloy, which in this embodiment are three superelastic alloy wires. As shown in Figure 6C, the grooves 604 have different depths to ensure that the superelastic alloy wires are horizontal at their corresponding depths. Reference numerals such as the notches 606 shown in Figures 6A and 6B are created to visually guide the assembly sequence for placing the superelastic alloy wires in the grooves 604 of the upper section 602. The upper section 602 includes an opening 608 where the upper section forms a stronger bond with the lower section when the lower section fuses with the upper section.

[0063] Figure 6D shows Figure 6A, in which a superelastic alloy wire is provided in the upper part 602. Three superelastic alloy wires 610 are provided in the groove 604 of the upper part 602.

[0064] Schematic diagrams of two foldable central members 612 and 614 completed using the upper part 602 of Figure 6A are shown in Figure 6E. The foldable central members 612 and 614 include an upper part 602 and a lower part 616 connected to each other. The upper part 602 and lower part 616 of the foldable central member 612 are manufactured from the same polymer, while the upper part 602 and lower part 616 of the foldable central member 614 are manufactured from different polymers.

[0065] In one embodiment, the upper 602 and lower 616 are manufactured by injection molding or casting. A thermoplastic polymer is injected into a first mold to form the upper 602. A superelastic alloy wire 610 is placed in a groove 604 formed by the upper 602. The upper 602, with the superelastic alloy wire 610 in the groove 604, is then placed into a second mold, and a thermoplastic polymer is injected into the second mold to form the lower 616 by secondary molding, and further forming foldable central members 612 and 614.

[0066] In one embodiment, the groove for housing the superelastic alloy wire may be formed in the lower part 616 rather than the upper part 602. In another embodiment, the groove for housing the superelastic alloy wire 610 may be formed between the upper part 602 and the lower part 616.

[0067] In one embodiment, the lower portion 616, manufactured by secondary molding of the second mold, extends to a remote tip 620 that covers the upper portion 602, thereby connecting the connecting member of the gastric retention device to the lower portion 616.

[0068] In one embodiment, the connecting members and elongated limb members of the gastric retention device are manufactured by hot-melt extrusion. The connecting members and elongated limb members are formed by feeding material into a hot-melt extruder, extruding filaments in the required cross-sectional shape, and then cutting them to the appropriate length.

[0069] In one embodiment, the connecting member and the elongated limb member are manufactured by injection molding. First, the material is mixed with solid particles, which are realized by hot-melt extruding the mixed material to produce extruded filaments, and then granulating the extruded filaments. The solid particles can also be manufactured by dissolving the material in a suitable solvent to form a solution, pouring the solution onto a flat surface to form flakes, and then crushing the flakes to form solid particles. The solid particles are fed into an injection molding machine to form the connecting member and the elongated limb member on which the drug can be mounted.

[0070] In one embodiment, the connecting member and the elongated limb member are manufactured by casting. First, the materials are mixed to form a casting solution, then the casting solution is poured into molds in the shape of the connecting member and the elongated limb member, and then hardened by a process such as cooling or solidification to form the connecting member and the elongated limb member.

[0071] In one embodiment, a foldable central member can be connected to a connecting member and an elongated limb member by thermal adhesion. The foldable central member and the elongated limb member already connected to the connecting member are placed in a mold, and the boundary between the foldable central member and the connecting member is heated to fuse them together. Thrust can be applied to the far end of the elongated limb member, thereby pressing the connecting member against the foldable central member to achieve a stronger adhesion. Heating can be performed using methods such as a laser or a heating device within the mold. It should be noted that the foldable central member and the connecting member can also be connected by other methods, such as the use of solvent adhesives and other adhesives.

[0072] Figure 7A shows a test fixture 700 used to test the gastric retention device 400 of Figure 4A. Figure 7B shows a bar graph of test results obtained using the test fixture 700 of Figure 7A. The test fixture 700 includes a funnel 702 with a 20 mm opening at the bottom to mimic the pyloric opening of the stomach in a patient's body. The test fixture 700 is used to determine the peak pressure required to push the gastric retention device 400 through the bottom opening. Specifically, the gastric retention device 400 is placed inside the funnel 702, with each of the elongated limb members of the gastric retention device 400 positioned within the grooves 704 of the funnel 702. The gastric retention device 400 is then pressed through the funnel 702 using a probe, and the peak pressure is recorded.

[0073] The lateral force test simulated the gastric retention device 400 moving laterally away from the pyloric opening, while the planar force test simulated the gastric retention device 400 moving planar away from the pyloric opening. The four gastric retention devices 400 tested were one without nitinol wire and one containing nitinol wire with cross-sectional areas of 0.20 mm, 0.30 mm, and 0.40 mm, respectively. The peak pressures required to push the gastric retention device out of the bottom opening were 0.6 N, 2.2 N, 4.1 N, and 4.9 N, respectively.

[0074] Embodiments of the present invention provide an intragastric retention device 100 for oral administration. The intragastric retention device 100 typically includes a plurality of ribs 106 made of at least one superelastic alloy having a high flexural modulus. Therefore, the superelastic alloy ribs 106, which have a relatively small volume, can achieve the bending force necessary to retain the intragastric retention device 100 in the stomach. This is advantageous for the flexible design of the intragastric retention device 100.

[0075] For example, by simply changing the length of the rib 106, gastric retention devices 100 of different sizes and shapes can be created using similar superelastic alloy materials. Gastric retention devices 100 with a small volume are easy to swallow and can be used to treat patients with small digestive tracts, such as small animals and children. The bending force of the superelastic alloy rib 106 can also be easily adjusted, as only the cross-sectional area of ​​the curved portion of the superelastic alloy rib 106 needs to be adjusted. Thus, even gastric retention devices 100 with the same dimensions and shape can have different bending forces and thus different gastric retention capabilities by using superelastic alloy ribs 106 with different cross-sectional areas. [Examples]

[0076] Example 1: Manufacturing of a foldable central component The foldable central member 614 in Figure 6E is manufactured as follows. 1. Cut a 0.30 mm diameter Nitinol wire to a length of 17 mm. 2. The upper part 602 is manufactured by injection molding Lubrizol PC-3575A into the first mold. 3. Then, carefully position the cut 0.30 mm diameter Nitinol wire onto the upper part 602. 4. Subsequently, the entire component having the nitinol wire is placed in the second mold, and Lubrizol PC-3575A is injected to form part 614. In step 2, you can use nitinol wires of different diameters, such as 0.10 mm, 0.20 mm, or 0.40 mm.

[0077] Example 2: Manufacturing of a gastric retention device The manufacturing process for a gastric retention device using a foldable central component 614 is as follows: 1. Mix 99g of HPMC-AS-HG, 99g of PCL, and 2g of silica from Shin-Etsu until homogeneous. Then, place the homogeneous powder into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder and extrude into a triangle using a customized triangular die head. After extrusion, cut the triangular filament into 3mm pieces to form connecting parts. 2. Mix 99g of barium sulfate, 99g of PCL, and 2g of silica until homogeneous. Then, place the homogeneous powder into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder and extrude it into a triangle using a customized triangular die head. After extrusion, cut the triangular filament into 10mm segments to form elongated limb members that do not contain active substances. 3. A foldable central member 614, connecting members, and elongated limb members are loaded into a customized mold, and the different members are thermally melted with a laser to form a gastric retention device. 4. Afterwards, fold the gastric retention device and place it in a capsule casing of specification 0.

[0078] Embodiment 3: Residence time in animal experiments Two types of centrally foldable components were manufactured using the method of Example 1. One type was manufactured using a nitinol wire with a diameter of 0.30 mm, and the other was manufactured without using any nitinol wire. Next, each foldable central component was manufactured into three gastric retention devices according to the method of Example 2. The manufactured samples are shown in the table below. Next, one device was administered to each female Panama pig weighing between 30 kg and 45 kg. Ten minutes after administration, fluoroscopy was performed daily on the pigs to determine whether the intragastric retention device was still in the stomach. The number of days on which the intragastric retention device did not remain in the stomach was defined as the retention period. The results of the retention period of the intragastric retention device are shown in the table below. [Table 1]

[0079] Without departing from the spirit or scope of the broad description of the present invention, those skilled in the art will recognize that many changes and / or modifications can be made to the present invention, as shown in specific embodiments. Therefore, the present invention has been disclosed in illustrative form and should not be construed restrictively.

[0080] Although these embodiments have been described, those skilled in the art, knowing the basic concept of creativity, can make additional changes and modifications to these embodiments. Therefore, the above are merely embodiments of the present invention and do not limit the scope of patent protection of the present invention. Equivalent structures or equivalent flow transformations, or direct or indirect applications to other related technical fields, made using the contents of the specification and accompanying drawings of the present invention are also included within the scope of patent protection of the present invention.

Claims

1. A gastric retention device for oral administration, A foldable central superelastic alloy member, It includes multiple elongated limb members capable of carrying an active substance, The aforementioned active substance is a therapeutic agent or a diagnostic agent. Here, each of the multiple elongated limb members is connected to the foldable central superelastic alloy member via a connecting member. Here, if the gastric retention device has a foldable structure, the foldable central superelastic alloy member undergoes elastic deformation, and when the gastric retention device is in an unfolded structure, the foldable central superelastic alloy member recoils, and An intragastric retention device for oral administration, characterized in that the connecting member causes the intragastric retention device to lose its unfolded structure via decomposition, dissolution, dissociation, or mechanical weakening.

2. The gastric retention device for oral administration according to claim 1, characterized in that the unfolded structure of the gastric retention device has a folding force of at least 0.5 N.

3. The gastric retention device for oral administration according to claim 1, characterized in that the unfolded structure of the gastric retention device has an unfolded diameter of at least 2 cm.

4. The gastric retention device for oral administration according to claim 1, characterized in that it is arranged to maintain the shape of the expanded structure for at least 24 hours.

5. The gastric retention device for oral administration according to claim 1, characterized in that the foldable central superelastic alloy member is made of at least one material selected from the group consisting of nitinol, brass, copper-aluminum-nickel alloy, gold-cadmium alloy, gold-copper-zinc alloy, indium-thallium alloy, cobalt-nickel-aluminum alloy, cobalt-nickel-gallium alloy, copper-aluminum-beryllium-zirconium alloy, copper-aluminum-beryllium-chromium alloy, copper-aluminum-beryllium-gadolinium alloy, copper-aluminum-nickel-hafnium alloy, copper-tin alloy, copper-zinc-silicon alloy, copper-zinc-aluminum alloy, copper-zinc-tin alloy, iron-manganese-silicon alloy, iron-platinum alloy, manganese-copper alloy, nickel-iron-gallium alloy, nickel-titanium-hafnium alloy, nickel-titanium-palladium alloy, nickel-manganese-gallium alloy, nickel-manganese-gallium-copper alloy, nickel-manganese-gallium-cobalt alloy, and titanium-niobium alloy.

6. The gastric retention device for oral administration according to claim 1, characterized in that the foldable central superelastic alloy member is securely fixed within a single outer surface layer member.

7. The gastric retention device for oral administration according to claim 6, characterized in that the aforementioned at least 80% of the folding force is provided by a foldable central superelastic alloy member.

8. The gastric retention device for oral administration according to claim 6, characterized in that the connecting member is connected to the outer surface layer member.

9. The oral intragastric retention device according to claim 6, characterized in that the outer surface layer member is manufactured by selecting at least one material from the group consisting of polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin or bakelite, chloroprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high-density polyethylene, polycarbonate, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane, and epoxy resin.

10. The oral intragastric retention device according to claim 1, further comprising a casing used to house an intragastric retention device having a foldable structure, wherein the casing is arranged to allow the intragastric retention device to rebound and present an unfolded structure via disassembly, dissolution, separation or mechanical weakening.

11. A gastric retention device for oral administration, A foldable central shape memory alloy member, It includes multiple elongated limb members capable of carrying an active substance, The aforementioned active substance is a therapeutic agent or a diagnostic agent. Here, each of the multiple elongated limb members is connected to the foldable central shape memory alloy member via a connecting member. Here, the foldable central shape memory alloy member undergoes a phase transition from the martensite phase to the austenite phase in its crystal structure, causing the gastric retention device to change from a folded structure to an unfolded structure, and Herein, the gastric retention device for oral administration is characterized in that the connecting member loses its shape as an expanded structure through decomposition, dissolution, dissociation, or mechanical weakening.

12. The gastric retention device for oral administration according to claim 11, characterized in that the unfolded structure of the gastric retention device has a folding force of at least about 0.5 N.

13. The gastric retention device for oral administration according to claim 11, characterized in that the unfolded structure of the gastric retention device has an unfolded diameter of at least 2 cm.

14. The gastric retention device for oral administration according to claim 11, characterized in that the gastric retention device is configured to maintain the shape of the unfolded structure for at least 24 hours.

15. The gastric retention device for oral administration according to claim 11, characterized in that the foldable central shape memory alloy member is made of at least one material selected from the group consisting of 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, and Ti-Nb.

16. The gastric retention device for oral administration according to claim 11, characterized in that the foldable central shape memory alloy member is securely fixed within one outer surface layer member.

17. The gastric retention device for oral administration according to claim 16, characterized in that the aforementioned at least 80% of the folding force is provided from a foldable central shape memory alloy member.

18. The gastric retention device for oral administration according to claim 16, characterized in that the connecting member is connected to the outer surface layer member.

19. The gastric retention device for oral administration according to claim 16, characterized in that the outer surface layer member is manufactured by selecting at least one material from the group consisting of polypropylene, polystyrene, polyvinyl chloride, synthetic rubber, phenolic resin or bakelite, chloroprene rubber, nylon, polyacrylonitrile, PVB, silicone, acrylonitrile-butadiene-styrene, high-density polyethylene, polycarbonate, acrylic acid, polyethylene terephthalate, polybutylene terephthalate, acetal, polyimide, polyurethane, and epoxy resin.

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