Gastric retention device for oral administration

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 a gastric 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 invasiveness, while 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 48 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 cycle longer than the transport time.

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

[0005] Notably, 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 a self-expanding structure, the cross-section of the structure needs to be large enough to achieve the minimum flexural modulus, thereby imposing 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 a polymer as a shape memory material is that the types of polymers that can meet the requirement of the minimum bending modulus while also meeting the requirements of other material properties are limited. For polymer types, there are also requirements for material properties such as biocompatibility, melt processability to achieve low-cost mass production, having sufficient surface energy to bond with other parts of the dosage form, and having high creep resistance so that the self-expanding structure can bounce back to its initial shape after long-term storage. Summary of the Invention Problems to be Solved by the Invention

[0007] Therefore, it is necessary to solve at least one of the above problems or provide a useful alternative. Means for Solving the Problems

[0008] According to a first aspect of the present invention, there is provided a gastric retention device for oral administration, comprising a foldable central superelastic alloy member, and a plurality of elongated limb members capable of carrying an active substance, wherein the active substance is a therapeutic agent or a diagnostic agent. Here, each of the plurality of elongated limb members is connected to the foldable central superelastic alloy member via a connecting member. Here, when the gastric retention device has a folded structure, the foldable central superelastic alloy member undergoes elastic deformation, and when the gastric retention device exhibits a deployed structure, the foldable central superelastic alloy member rebounds. Here, the connecting member causes the gastric retention device to lose the shape of the deployed structure via decomposition, dissolution, dissociation, or mechanical weakening.

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

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

[0011] The intragastric retention device can be arranged to maintain the shape of a deployment structure for at least 24 hours.

[0012] The foldable central superelastic alloy member includes selecting at least one material from the following groups: 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 foldable central superelastic alloy member can be firmly fixed within the outer surface layer member.

[0014] At least 80% of the folding force can be provided by the foldable central superelastic alloy member.

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

[0016] The outer surface 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.

[0017] The intragastric retention device further includes a casing used to house the intragastric retention device having a folding structure, and the casing is arranged to allow the intragastric retention device to rebound and exhibit a deployed structure via decomposition, dissolution, separation or mechanical weakening.

[0018] According to a second aspect of the present invention, there is provided an intragastric retention device for oral administration. A foldable central shape memory alloy member. And a plurality of elongated limb members capable of carrying an active substance, wherein the active substance is a therapeutic agent or a diagnostic agent. Here, the plurality of elongated limb members are each connected to the foldable central shape memory alloy member via a connecting member. Here, in the foldable central shape memory alloy member, a phase transition from a martensite phase to an austenite phase occurs in its crystal structure, converting the intragastric retention device from a folded structure to a deployed structure. Here, the connecting member undergoes decomposition, dissolution, dissociation or mechanical weakening, and the intragastric retention device loses the shape of the deployed structure.

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

[0020] The deployed structure of the intragastric retention device can have a deployed diameter of at least 2 cm.

[0021] The intragastric retention device can be configured to maintain the shape of the deployed structure 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 a 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. A plurality of connecting members, each connecting member connecting one elongated limb member to a foldable central member. Here, the rib can expand from a first folded state to a second deployed state, deploying the elongated limb member. Here, at least one of the elongated limb members is configured to release a drug stored therein. The connecting member is configured to convert from a rigid first state to a free second state so as to be able to move the elongated limb member independently with respect to the foldable central member.

[0028] The free second state can include a connecting member in a flexible state, allowing the elongated limb member to bend with respect to the foldable central member.

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

[0030] The connecting member can include a material that converts the connecting member from a rigid first state to a free second state by hydrolysis.

[0031] The superelastic alloy includes selecting at least one material from the following groups: 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, 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.

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

[0033] The shape memory alloy 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.

[0034] The foldable central member can further include an outer surface layer member, and the ribs therein are firmly fixed within the outer surface layer member.

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

[0036] The outer surface layer member can be 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.

[0037] The intragastric retention device can further include a casing for accommodating the foldable central member and the elongated limb members, and the casing is configured to dissolve in order to expand the ribs from the first folded state to the second deployed state for deploying the elongated limb members.

Brief Description of the Drawings

[0038] Embodiments of the present invention are provided by way of example only and will be better understood and more readily understood by those skilled in the art from the following written description and the accompanying drawings.

Figure 1A

Figure 1B

Figure 1C

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 4C

Figure 5A

Figure 5B

Figure 5C

Figure 6A

Figure 6B

Figure 6C

Figure 6D

Figure 6E

Figure 7A

Figure 7B

Mode for Carrying Out the Invention

[0039] In order to describe in detail the technical content, structural features, achieved objectives and effects of the technical solution, specific embodiments will be combined with the accompanying drawings and described in detail below. FIG. 1A shows a schematic view of an unfolded configuration of a gastric retention device 100 according to one embodiment. FIG. 1B shows a schematic view of a folded configuration of the gastric retention device of FIG. 1A. FIG. 1C shows a schematic view of a storage configuration of the gastric retention device of FIG. 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 FIG. 1A, the three elongated limb members 104 correspond to the three ribs 106. The position and longitudinal axis of the elongated limb member 104 respectively correspond to the position and longitudinal axis of the rib 106. As shown in FIGS. 1B and 1C, the elongated limb member 104 has a triangular prism shape that allows the elongated limb members 104 to be in close contact when the gastric retention device 100 is in a folded configuration, thereby facilitating storage and oral ingestion. The rib 106 is expanded from a folded first state (as shown in FIGS. 1B and 1C) to an unfolded second state (as shown in FIG. 1A), and the elongated limb member 104 is unfolded, so that the gastric retention device 100 can be changed from a folded structure to an unfolded structure. The gastric retention device 100 has an unfolded diameter of at least 2 cm and a folding force of at least 0.5 N in the unfolded arrangement.

[0041] The gastric retention device further includes three connecting members 108. Each connecting member 108 connects the elongated limb member 104 to the foldable central member 102. At least one elongated limb member 104 is configured to deliver a gastric retention drug by releasing an active substance or drug (e.g., a therapeutic agent or a 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 such 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 the rigid first state to the free second state. Specifically, the connecting member 108 undergoes degradation, dissolution, separation, or mechanical weakening in the gastric environment, such that as a result, the intragastric retention device 100 loses its rigidity and shape and passes through the patient's gastric lumen. In one embodiment, the connecting member 108 loses rigidity in the free second state and is flexible such that the elongated limb member 104 can be bent relative to the foldable central member 102. In another embodiment, the connecting member 108 is severed in the free second state to separate the elongated limb member 104 from the foldable central member 102.

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

[0044] In one embodiment, rib 106 includes at least one type of superelastic alloy, and the superelastic alloy includes selecting at least one material from the following groups: 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, 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.

[0045] Rib 106 may be made of a shape memory alloy, and the shape memory alloy 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-N.

[0046] Shape memory alloys belong to the superelastic alloy family. The shape memory alloy applied to the rib 106 has an austenite transformation completion temperature (Af) slightly lower than normal body temperature. At temperatures lower than Af (e.g., 30 °C), the shape memory alloy is in the martensite phase and has ductility. However, when the shape memory alloy is heated to a temperature higher than Af, they become superelastic and return to their original unfolded state. During manufacturing and storage, the shape memory alloy is in the martensite phase. As a result, the intragastric retention device 100 can maintain its folded structure without a restraining structure such as the casing 110. After oral administration of the intragastric retention device 100, the temperature of the shape memory alloy rises due to the internal heat of the patient's body. This causes a transition of the shape memory alloy from the martensite phase to the austenite phase, whereby the elongated limb member 104 is deployed to hold the intragastric retention device 100 in the patient's gastric cavity.

[0047] FIG. 2A shows a schematic view of an intragastric retention device 200 in a deployed configuration according to another embodiment. FIG. 2B shows a schematic view of the folded configuration of the intragastric retention device of FIG. 2A.

[0048] The intragastric 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 intragastric 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 member 208 is configured to transition from a rigid first state to a free second state so that the elongated limb member 204 can move independently with respect to the foldable central member 202.

[0049] FIG. 3A shows a schematic view of an intragastric retention device 300 in a deployed configuration according to another embodiment. FIG. 3B shows a schematic view of the folded configuration of the intragastric retention device 300 of FIG. 3A.

[0050] The intragastric 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 intragastric 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 drug for intragastric retention drug delivery. The connecting member 308 is configured to transition from a rigid first state to a free second state so that the elongated limb member 304 can move independently with respect to the foldable central member 302.

[0051] FIG. 4A shows a schematic view of an intragastric retention device 400 in a deployed configuration according to one embodiment. FIG. 4B shows a transparent schematic view of the internal elements of the intragastric retention device 400 of FIG. 4A. FIG. 4C shows a schematic view of the folded configuration of the intragastric retention device 400 of FIG. 4A.

[0052] The intragastric 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 FIG. 4B, the foldable central member 402 includes an outer surface layer member 406 and a plurality of ribs 408 made of superelastic alloy wires firmly fixed within the outer surface layer member 406. The intragastric retention device 400 also includes a plurality of connecting members 410 for connecting each elongated limb member 404 to the outer surface layer member 406.

[0053] The outer surface layer member 406 includes a flexible and foldable material and is manufactured by selecting at least one 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.

[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 provided by the foldable central member 402, and less than 20% of the remaining folding force is provided by the outer surface layer member 406. When selecting the material for the outer surface layer member 406, many materials can be used for manufacturing the outer surface layer member 406 because characteristics 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 applying a polymer to the superelastic alloy ribs 408 by injection molding or casting. It should be noted that the ribs 408 are not limited to wire shapes, and the ribs 408 may include other shapes such as ribbon shapes or stripe shapes. The outer surface layer member 406 can be formed on any of these shaped ribs 408 such that the ribs 408 are firmly fixed within the outer surface layer member 406.

[0056] FIG. 5A shows a schematic view of a semi-finished product of a foldable central member 500 according to one embodiment. FIG. 5B shows a schematic view of a semi-finished product of a foldable central member 502 according to another embodiment. In the first mold, three superelastic alloy wires 504 made of nitinol are stacked and fixed. 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 FIGS. 5A and 5B, to fix the relative positions of the superelastic alloy wires 504. As shown in FIG. 5B, the first mold may be fabricated to first injection mold the injection molded member 508 at the distal end of the superelastic alloy wire 504 with the thermoplastic polymer. Next, the semi-finished product is transferred into the second mold, the thermoplastic polymer is injected into the second mold, and the foldable central member is completed.

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

[0058] In one embodiment, first, a thermoplastic polymer is injected into a first mold to form the injection molding member 506, and then the superelastic alloy wire 504 is placed in the injection molding member 506 and fixed in position.

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

[0060] Note that the rib is not limited to the wire shape shown in FIGS. 5A and 5B and can include other shapes such as ribbon-like or strip-like shapes.

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

[0062] The upper part 602 includes a groove 604 for accommodating an internal superelastic alloy, which is three superelastic alloy wires in this embodiment. As shown in FIG. 6C, the groove 604 has different depths to ensure that the superelastic alloy wires are in a horizontal state at corresponding depths. In order to visually guide the assembly order of arranging the superelastic alloy wires in the groove 604 of the upper part 602, reference signs such as the notches 606 shown in FIGS. 6A and 6B are created. The upper part 602 includes an opening 608 where the upper part forms a stronger bond with the lower part when the lower part merges with the upper part.

[0063] FIG. 6D shows FIG. 6A in which superelastic alloy wires are provided on the upper part 602. Three superelastic alloy wires 610 are provided in the groove 604 of the upper part 602.

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

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

[0066] In one embodiment, the groove for accommodating the superelastic alloy wire may be formed in the lower part 616 instead of the upper part 602. In other embodiments, the groove for accommodating the superelastic alloy wires 610 may be formed between the upper part 602 and the lower part 616.

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

[0068] In one embodiment, the connecting member and the elongated limb member of the intragastric retention device are manufactured by hot melt extrusion. The connecting member and the elongated limb member are formed by feeding the material into a hot melt extruder, extruding the filament in the required cross-sectional shape, and then cutting it 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 an extruded filament and then granulating the extruded filament. The solid particles are also manufactured by dissolving the material in an appropriate solvent to form a solution, pouring the solution onto a flat surface to form a thin sheet, and crushing the thin sheet to form solid particles. The solid particles are fed into injection molding equipment to form a connecting member and an elongated limb member capable of carrying drugs.

[0070] In one example, 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 a mold in the shape of a connecting member and an elongated limb member, and it is cured by processes such as cooling or solidification, thereby forming the connecting member and the elongated limb member.

[0071] In one embodiment, the foldable central member can be connected to the connecting member and the elongated limb member by thermal adhesion. Place the foldable central member and the elongated limb member that is already connected to the connecting member in a mold, and heat the boundary between the foldable central member and the connecting member to fuse them. A thrust can be applied to the distal end of the elongated limb member, thereby pressing the connecting member against the foldable central member to obtain a more robust adhesion. Heating can be achieved by adopting methods such as a laser or a heating device in the mold. It should be noted that the foldable central member and the connecting member can also be connected by other methods, such as solvent adhesion and the use of adhesives.

[0072] FIG. 7A shows a test fixture 700 used to test the intragastric retention device 400 of FIG. 4A. FIG. 7B shows a bar graph of the test results tested using the test fixture 700 of FIG. 7A. The test fixture 700 includes a funnel 702 having an opening of 20 mm at the bottom so as to mimic the pyloric opening of the stomach in the patient's body. The test fixture 700 is used to determine the peak pressure required to push the intragastric retention device 400 through the bottom opening. Specifically, the intragastric retention device 400 is disposed within the funnel 702, and each of the elongated limb members of the intragastric retention device 400 is disposed within the groove 704 of the funnel 702. Then, the intragastric retention device 400 is pressed to pass through the funnel 702 using a probe, and the peak pressure is recorded.

[0073] The lateral force test simulated the case where the intragastric retention device 400 moves laterally away from the pyloric opening, and the planar force test simulated the case where the intragastric retention device 400 moves away from the pyloric opening in a plane. The four intragastric retention devices 400 tested included no nitinol wire and nitinol wires with cross-sectional areas of 0.20 mm, 0.30 mm, and 0.40 mm respectively, and the peak pressures required to push the intragastric retention devices 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 generally includes a plurality of ribs 106 made of at least one superelastic alloy having a high flexural modulus. Thus, the superelastic alloy ribs 106 with relatively small volumes can achieve the bending force necessary to hold 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, intragastric retention devices 100 of different sizes and shapes can be created using a similar superelastic alloy material. The intragastric retention device 100 with a small volume is easy to swallow and can be used for the treatment of patients with small digestive tracts, such as small animals and children. Since only the cross-sectional area of the curved portion of the superelastic alloy rib 106 needs to be adjusted, the superelastic alloy rib 106 can also easily adjust the bending force. Thus, even for intragastric retention devices 100 having the same dimensions and shape, by using superelastic alloy ribs 106 with different cross-sectional areas, the bending force of the superelastic alloy ribs 106 is different, and the ability to stay in the stomach is different.

Example

[0076] Example 1: Manufacture of a foldable central member The foldable central member 614 in FIG. 6E is manufactured as follows. 1. Cut a Nitinol wire with a diameter of 0.30 mm 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 place the cut Nitinol wire with a diameter of 0.30 mm on the upper part 602. 4. Then, place the entire component having the Nitinol wire into the second mold and inject "Lubrizol" PC-3575A to form the component 614. In step 2, Nitinol wires with different diameters, such as 0.10 mm, 0.20 mm, or 0.40 mm, can be used.

[0077] Example 2: Manufacture of an intragastric retention device The manufacturing process of the intragastric retention device using the foldable central component 614 is as follows. 1. Mix 99 g of HPMC-AS-HG from Shin-Etsu, 99 g of PCL, and 2 g of silica until homogeneous. Then, put the homogeneous powder into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder and use a customized triangular die head to achieve triangular extrusion. After extrusion, cut the triangular filament into 3-mm fragments to form connecting components. 2. Mix 99 g of barium sulfate, 99 g of PCL, and 2 g of silica until homogeneous. Then, put the homogeneous powder into the feeder of a Thermo Scientific Pharma 11 twin-screw extruder and use a customized triangular die head to achieve triangular extrusion. After extrusion, cut the triangular filament into 10-mm fragments to form an elongated limb member without an active substance. 3. Load the foldable central member 614, connecting members, and elongated limb members into a customized mold, and thermally melt the different members with a laser to form the intragastric retention device. 4. Then, fold the intragastric retention device and place it into a capsule casing of Specification No. 0.

[0078] Embodiment 3: Retention Time in Animal Experiments Two types of centrally foldable components were manufactured using the method of Example 1. One type was manufactured using nitinol wire with a diameter of 0.30 mm, and the other type was manufactured without using any nitinol wire. Next, each foldable central component was used to manufacture three intragastric retention devices according to the method of Example 2. The manufactured samples are shown in the following table. Next, the devices were administered one by one to female Panamanian pigs weighing 30 kg to 45 kg. Ten minutes after administration, fluoroscopy of the pigs was performed every day to determine whether the intragastric retention device was still in the stomach. The day when 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 following table. [Table 1]

[0079] It should be recognized that those skilled in the art can make many changes and / or modifications to the present invention without departing from the spirit or scope of the broad description of the present invention, and those skilled in the art can make many changes and / or modifications to the present invention. Therefore, the present invention has been disclosed in an illustrative form and should not be construed in a limiting sense.

[0080] Although the present embodiment has been described, those skilled in the art can make additional changes and modifications to these embodiments if they know the basic creative concept. Therefore, the above is merely an embodiment of the present invention, and thus does not limit the scope of patent protection of the present invention. Equivalent structures or equivalent flow conversions made using the content of the specification and the accompanying drawings of the present invention, or direct or indirect applications to other related technical fields, are similarly included in the scope of patent protection of the present invention.

Claims

1. An intragastric retention device for oral administration, comprising: a foldable central superelastic alloy member; and a plurality of elongated limb members capable of carrying an active substance, wherein the active substance is a therapeutic agent or a diagnostic agent, wherein the plurality of elongated limb members are each connected to the foldable central superelastic alloy member via a connecting member, wherein when the intragastric retention device has a folded structure, the foldable central superelastic alloy member undergoes elastic deformation, and when the intragastric retention device exhibits a deployed structure, the foldable central superelastic alloy member rebounds, and wherein the connecting member causes the intragastric retention device to lose the shape of the deployed structure via decomposition, dissolution, dissociation or mechanical weakening,

2. The intragastric retention device in the deployed structure has a folding force of at least 0.5 N,

3. The intragastric retention device in the deployed structure has a deployed diameter of at least 2 cm,

4. The intragastric retention device is arranged to maintain the shape of the deployed structure for at least 24 hours,

5. The foldable central superelastic alloy member includes selecting at least one material 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, titanium-niobium alloy,

6. The oral administration gastric retention device according to claim 1, wherein the foldable central superelastic alloy member is firmly fixed within one outer surface layer member.

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

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

9. The oral administration gastric retention device according to claim 6, wherein 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 administration gastric retention device according to claim 1, further comprising a casing used for housing the gastric retention device having a folding structure, wherein the casing is arranged to permit the gastric retention device to rebound through decomposition, dissolution, separation or mechanical weakening to present a deployed structure.

11. An oral administration gastric retention device, comprising a foldable central shape memory alloy member, and a plurality of elongated limb members capable of carrying an active substance, wherein the active substance is a therapeutic agent or a diagnostic agent, wherein the plurality of elongated limb members are each connected to the foldable central shape memory alloy member via a connecting member, wherein a phase transition from a martensite phase to an austenite phase occurs in the crystal structure of the foldable central shape memory alloy member, converting the gastric retention device from a folded structure to a deployed structure, and wherein the connecting member undergoes decomposition, dissolution, dissociation or mechanical weakening and the gastric retention device loses the shape of the deployed structure, characterized in that it is an oral administration gastric retention device.

12. The oral administration gastric retention device according to claim 11, wherein the deployed structure of the gastric retention device has a folding force of at least about 0.5 N.

13. The deployment structure of the intragastric retention device is characterized in that it has a deployment diameter of at least 2 cm, and the intragastric retention device for oral administration according to claim 11.

14. The intragastric retention device is configured to maintain the shape of the deployment structure for at least 24 hours, and the intragastric retention device for oral administration according to claim 11.

15. The foldable central shape memory alloy member includes selecting at least one material from the group 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, Ti-Nb, and the intragastric retention device for oral administration according to claim 11.

16. The foldable central shape memory alloy member is firmly fixed within one outer surface layer member, and the intragastric retention device for oral administration according to claim 11.

17. At least 80% of the folding force is provided by the foldable central shape memory alloy member, and the intragastric retention device for oral administration according to claim 16.

18. The connecting member is connected to the outer surface layer member, and the intragastric retention device for oral administration according to claim 16.

19. The outer surface layer member is manufactured by selecting at least one material from the group 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, and the intragastric retention device for oral administration according to claim 16.

20. An intragastric retention device for oral administration, including a foldable central member, a plurality of elongated limb members, and a plurality of connecting members, a foldable central member including a plurality of ribs, and the ribs include at least one superelastic alloy. A plurality of elongated limb members, wherein the elongated limb members are connected to the foldable central member radially, and the plurality of elongated limb members correspond to the plurality of ribs, A plurality of connecting members, wherein each connecting member connects one elongated limb member to the foldable central member, Here, the rib can be expanded from the first folded state to the second expanded state to expand the elongated limb member, Here, at least one of the elongated limb members is configured to release a drug stored therein, The connecting member is configured to convert from a rigid first state to a free second state so that the elongated limb member can be moved independently of the foldable central member. A gastric retention device for oral administration, characterized in that.

21. The free second state includes a connecting member in a flexible state, and causes the elongated limb member to bend with respect to the foldable central member. The gastric retention device for oral administration according to claim 20, characterized in that.

22. The free second state includes cutting of the connecting member and separating the elongated limb member from the foldable central member. The gastric retention device for oral administration according to claim 20, characterized in that.

23. The connecting member includes a material that converts the connecting member from a rigid first state to a free second state by hydrolysis. The gastric retention device for oral administration according to claim 20, characterized in that.

24. The superelastic alloy is 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, titanium niobium alloy. The gastric retention device for oral administration according to claim 20, characterized by selecting at least one material from the group.

25. The intragastric retention device for oral administration according to claim 20, wherein the superelastic alloy is a shape memory alloy.

26. The intragastric retention device for oral administration according to claim 25, wherein the shape memory alloy includes selecting at least one material 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, Ti-Nb.

27. The intragastric retention device for oral administration according to claim 20, wherein the foldable central member further includes an outer surface layer member, and the ribs therein are firmly fixed within the outer surface layer member.

28. The intragastric retention device for oral administration according to claim 27, wherein the connecting member connects each elongated limb member to the outer surface layer member.

29. The intragastric retention device for oral administration according to claim 27, wherein the outer surface layer member can be 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.

30. The intragastric retention device for oral administration according to claim 20, further including a casing for accommodating the foldable central member and the elongated limb member, wherein the casing is configured to dissolve to expand the ribs from the first folded state to the second deployed state for deploying the elongated limb member.

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