WO2024016960A1 - 一种可降解输尿管支架及其制备方法 - Google Patents

一种可降解输尿管支架及其制备方法 Download PDF

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Publication number
WO2024016960A1
WO2024016960A1 PCT/CN2023/102900 CN2023102900W WO2024016960A1 WO 2024016960 A1 WO2024016960 A1 WO 2024016960A1 CN 2023102900 W CN2023102900 W CN 2023102900W WO 2024016960 A1 WO2024016960 A1 WO 2024016960A1
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Prior art keywords
glycolide
ureteral stent
degradable
copolymer
degradable ureteral
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Ceased
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PCT/CN2023/102900
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English (en)
French (fr)
Inventor
陈和春
包一红
陈栋梁
包一良
张田瑶
金鑫
陈龙
周侗
肖建平
朱晓珍
王昕�
徐秀忠
张志萍
吴凡
熊成东
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Zhejiang Zhongzai Medical Technology Co Ltd
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Zhejiang Zhongzai Medical Technology Co Ltd
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Priority to KR1020247038695A priority Critical patent/KR20250004312A/ko
Priority to US18/872,652 priority patent/US20250161015A1/en
Priority to CA3257419A priority patent/CA3257419A1/en
Priority to EP23842026.9A priority patent/EP4516331A4/en
Priority to JP2024568480A priority patent/JP7844060B2/ja
Priority to AU2023312013A priority patent/AU2023312013A1/en
Publication of WO2024016960A1 publication Critical patent/WO2024016960A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/028—Other inorganic materials not covered by A61L31/022 - A61L31/026
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/18—Materials at least partially X-ray or laser opaque
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2002/048—Ureters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0063—Three-dimensional shapes
    • A61F2230/0091—Three-dimensional shapes helically-coiled or spirally-coiled, i.e. having a 2-D spiral cross-section
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/22—Materials or treatment for tissue regeneration for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus

Definitions

  • the invention belongs to the field of biomedical materials and medical devices, and specifically relates to a degradable ureteral stent and a preparation method thereof.
  • Ureteral stents are widely used in urological surgeries. They are suitable for upper urinary tract surgeries, lithotripsy lithotripsy, dilation of ureteral strictures and other treatment processes. After being implanted in the ureter, they can play an important role in draining urine and preventing ureteral strictures. .
  • the ureteral stents currently used clinically are non-degradable and made of soft polyurethane elastomer or silicone rubber materials.
  • Polyurethane stent tubes are harder and easier to insert; silicone rubber stent tubes are softer and have slightly poorer placement performance.
  • ureteral stents The drainage time of ureteral stents will vary depending on the needs of the clinical case. Short-term temporary drainage of urine usually lasts about 1-2 weeks, such as mild ureteral injury, simple stones, pre-placed stents, etc.; common temporary drainage usually lasts for 3-6 weeks, so different degradable materials need to be used. However, the common basic requirement for stents is that they should have the mechanical properties of elastic materials, and their broken fragments can be completely discharged from the body as soon as possible. Otherwise, the risk of a series of complications will increase.
  • Chinese patent CN1672739A and Chinese patent CN112516390A disclose a degradable ureteral stent, involving glycolide- ⁇ -caprolactone copolymer material, which has the mechanical properties of elastic materials within a certain composition ratio range.
  • this type of copolymer formed from soft chain monomers (epsilon-caprolactone) and hard chain monomers (glycolide) often degrades in water and becomes harder and harder. This is because the hard chain structure in the material, such as glycolide segments, often tends to crystallize during the degradation process, which makes it easy to get stuck or stay in parts such as the renal pelvis.
  • the materials obtained by the existing technology are not yet able to achieve the mechanical properties of silicone rubber and polyurethane elastic materials, but also prevent the degradation fragments from getting stuck or staying in the renal pelvis and other locations. This is so far. So far, it is still a key point restricting the progress of research in this field, and it is also the main reason why no degradable ureteral stent has yet been commercially launched.
  • the present invention provides a degradable ureteral stent, which has the mechanical strength of elastic materials and a high initial hardness (or modulus), which is convenient for catheter placement. Degradation will gradually make it softer and easier to pass out of the body.
  • a degradable ureteral stent is made of a composite material.
  • the composite material at least contains glycolide-epsilon-caprolactone copolymer, ethylene oxide polymer, and barium sulfate, which are formed by blending. Their relative contents are as follows:
  • Glycolide- ⁇ -caprolactone copolymer weight percentage content is 47%-80%
  • Barium sulfate, weight percentage content is 18%-45%
  • the weight percentage of glycolide in the glycolide- ⁇ -caprolactone copolymer is 51%-58%, and the weight percentage of ⁇ -caprolactone is 42%-49%.
  • the ureteral stent of the present invention achieves the above objectives by using a composite material formed by blending degradable glycolide- ⁇ -caprolactone copolymer, ethylene oxide polymer, and barium sulfate.
  • the present invention and related research have found that when the stent tube is hard, the degradation fragments are likely to get stuck in the renal pelvis. Therefore, the softness and hardness of the base material is a key influencing factor.
  • General degradable elastic materials such as glycolide- ⁇ -caprolactone copolymer, L-lactide/ ⁇ -caprolactone copolymer, etc., often become harder and harder during the degradation process, and the degraded fragments or segments are relatively small. Difficulty passing through ureteral stricture.
  • the present invention found that within an appropriate comonomer ratio range and using an appropriate polymerization process, glycolide-epsilon-caprolactone copolymer will gradually become softer when degraded in water or urine.
  • the appropriate comonomer proportion range is glycolide weight percentage of 51%-58%.
  • the weight percentage of glycolide exceeds 58%, the copolymer has an obvious crystallization tendency and becomes hard during the degradation process; when the glycolide weight percentage is less than 51%, the copolymer has poor mechanical properties and is too soft. .
  • the present invention also found that adding a certain content of ethylene oxide polymer, such as polyethylene glycol or polyoxyethylene, to the above-mentioned glycolide-epsilon-caprolactone copolymer material can further promote the formation of composite materials. During the degradation process, it gradually becomes softer, the surface is smoother, and it is easier to disintegrate and fragment, which is conducive to the discharge of broken fragments of the tubular stent.
  • ethylene oxide polymer such as polyethylene glycol or polyoxyethylene
  • the degradable ureteral stent of the present invention uses barium sulfate, which is a commonly used medical imaging agent, has good compatibility with the above-mentioned materials, and has a certain reinforcing effect.
  • the glycolide- ⁇ -caprolactone copolymer has an intrinsic viscosity of 1.30-3.00dl measured at 25 ⁇ 1°C in hexafluoroisopropanol at a concentration of 0.1g/dl. /g, the greater the viscosity, the longer the degradation maintenance time. Therefore, the drainage time of the stent tube can be adjusted through the intrinsic viscosity.
  • the ethylene oxide polymer is polyethylene glycol, polyethylene glycol monomethyl ether, polyethylene glycol dimethyl ether, or polyoxyethylene.
  • the weight proportion of the ethylene oxide polymer in the composite material is 2%-8%.
  • the molecular weight of polyethylene glycol, polyethylene glycol monomethyl ether, polyethylene glycol dimethyl ether and polyoxyethylene is 1000Da-1000000Da.
  • the ethylene oxide polymer is polyethylene glycol, polyethylene glycol monomethyl ether, or polyethylene glycol dimethyl ether, with a molecular weight of 5000 Da to 40000 Da.
  • the ethylene oxide polymer is polyoxyethylene, and the molecular weight is 50,000 Da-400,000 Da.
  • the barium sulfate can be replaced by other medical imaging agents, including bismuth subcarbonate and metal imaging agents, and the imaging agents used can be one or several.
  • the preparation method of the glycolide- ⁇ -caprolactone copolymer is as follows:
  • the degradable ureteral stent of the present invention is a hollow circular tubular structure (1), with fixed structures (2) on both ends or one end to prevent sliding.
  • the fixed structure is preferably in the shape of a circular tubular coil, and there are several penetrating drainage holes on the tube wall.
  • Side hole (3), pipe diameter is 1.0-4.0mm.
  • the degradable ureteral stent of the present invention is produced by melt extrusion.
  • the specific method is as follows:
  • the initial modulus of the degradable ureteral stent of the present invention at 100% deformation is 2MPa-10MPa, and the modulus at 100% deformation after degradation is not greater than the initial value; the initial Shore hardness A of the material used is 70-95, and the modulus at 100% deformation after degradation is 70-95.
  • the final Shore hardness A is not greater than the initial value.
  • various additives can be added routinely to achieve different purposes when melting and extruding the tube, including but not limited to plasticizers, lubricants, dyes, antioxidants, anti-hydrolysis agents, melting agents, etc. Body thickeners, chain extenders, reinforcing agents, and polymer modifiers. These additives help improve the processing performance, degradation performance, surface properties, and mechanical properties of the stent.
  • the present invention enables the copolymer to have suitable mechanical strength and softness and hardness, and will gradually become softer as the degradation time is prolonged; At the same time, when a certain proportion of ethylene oxide polymer is added, the elongation modulus after degradation is lower, making it softer and smoother. Therefore, it is more suitable for preparing degradable ureters.
  • Figure 1 is an imaging observation of the discharge of the degradable ureteral stent of the present invention into the animal body.
  • (A) is an X-ray film when it is inserted
  • (B) is an X-ray film when it is broken
  • (C) is when it is discharged into the bladder.
  • X-ray film shows the discharged degradation fragments.
  • Figure 2 is a schematic diagram of the degradable ureteral stent of the present invention.
  • the weight percentage of glycolide and ⁇ -caprolactone in the copolymer was determined by 1 H NMR spectroscopy, using hexafluoroisopropanol as the solvent.
  • the above copolymer was prepared into a hexafluoroisopropanol solution with a concentration of 0.1g/dl, and its intrinsic viscosity was measured at 25°C using an Ubbelohde viscometer.
  • the above copolymer was made into sheets with a thickness of 2 mm using a hot press molding method on a flat vulcanizer at 140°C, and the Shore hardness A of the material was tested using a Shore hardness tester.
  • the above copolymer was made into a dumbbell piece with a thickness of 2 mm, and the tensile strength at break and elongation at break of the material were tested on a universal mechanical testing machine at a speed of 200 mm/min.
  • the in vitro degradation experiment of the material was carried out in simulated urine at 37°C, and the Shore hardness A of the material was measured regularly.
  • stannous octoate catalyst 540 grams of ⁇ -caprolactone monomer (CL) and 590 grams of glycolide monomer (GA) were placed in a 3L reactor, and the system temperature was raised under nitrogen protection for 20 minutes. to 170°C, react for 28 hours at a stirring speed of 10-20 rpm, keep under vacuum for 1 hour, transfer the copolymer in the reactor, further crush it, and put it into a vacuum oven at 90°C under vacuum After drying for 24 hours, glycolide- ⁇ -caprolactone copolymer 2 (PGC2) was obtained.
  • PPC2 glycolide- ⁇ -caprolactone copolymer 2
  • stannous octoate catalyst 530 grams of ⁇ -caprolactone monomer (CL) and 600 grams of glycolide monomer (GA) were placed in a 3L reactor, and the system temperature was raised under nitrogen protection for 30 minutes. to 190°C, react for 22 hours at a stirring speed of 10-20 rpm, and keep it under vacuum for 4 hours. Transfer the copolymer in the reactor, further crush it, and put it into a vacuum oven at 90°C. After drying for 24 hours, glycolide- ⁇ -caprolactone copolymer 3 (PGC3) was obtained.
  • PPC3 glycolide- ⁇ -caprolactone copolymer 3
  • stannous octoate catalyst 480 grams of ⁇ -caprolactone monomer (CL) and 600 grams of glycolide monomer (GA) were placed in a 3L reactor, and the system temperature was raised under nitrogen protection for 30 minutes. to 195°C, react for 18 hours at a stirring speed of 10-20 rpm, keep under vacuum for 4 hours, transfer the copolymer in the reactor, further crush it, and put it into a vacuum oven at 90°C under vacuum After drying for 24 hours, glycolide- ⁇ -caprolactone copolymer 4 (PGC4) was obtained.
  • CL ⁇ -caprolactone monomer
  • GA glycolide monomer
  • stannous octoate catalyst 470 grams of ⁇ -caprolactone monomer (CL) and 630 grams of glycolide monomer (GA) were placed in a 3L reactor, and the system temperature was raised under nitrogen protection for 30 minutes. to 190°C, react for 20 hours at a stirring speed of 10-20 rpm, keep under vacuum for 2 hours, transfer the copolymer in the reactor, further crush it, and put it into a vacuum oven at 90°C under vacuum After drying for 24 hours, glycolide- ⁇ -caprolactone copolymer 5 (PGC5) was obtained.
  • CL ⁇ -caprolactone monomer
  • GA glycolide monomer
  • stannous octoate catalyst 470 grams of ⁇ -caprolactone monomer (CL) and 660 grams of glycolide monomer (GA) were placed in a 3L reactor, and the system temperature was raised under nitrogen protection for 26 minutes. to 184°C, react for 23 hours at a stirring speed of 10-20 rpm, and keep it under vacuum for 3 hours. Transfer the copolymer in the reactor, further crush it, and put it into a vacuum oven at 90°C. After drying for 24 hours, glycolide- ⁇ -caprolactone copolymer 6 (PGC6) was obtained.
  • PPC6 glycolide- ⁇ -caprolactone copolymer 6
  • glycolide- ⁇ -caprolactone copolymer prepared above, a certain amount of polyethylene glycol 20000 (PEG2) or polyethylene glycol 5000 (PEG5), and medical barium sulfate (Ba) evenly. Afterwards, it is further blended and granulated through a twin-screw extruder. The extruder temperature is 120°C-150°C. The obtained composite material pellets are then passed through a flat vulcanizer and made into the above three types with a thickness of 2mm at 140°C. The composite sheet of the material is used for tensile strength and hardness testing; the dynamic friction coefficient of the composite material is tested according to the method specified by ASTM-D1894. The results are shown in Table 2.
  • the hardness changes during the degradation process of the above composite materials of glycolide- ⁇ -caprolactone copolymer, polyoxyethylene and medical barium sulfate have similar rules, and they all decrease significantly as the degradation time increases.
  • the higher the polyoxyethylene content the more the hardness will decrease, but if the polyoxyethylene content is too high, the strength will decrease more, which is not conducive to fixation.
  • the dynamic friction coefficient of the composite material added with polyoxyethylene is smaller, indicating that its surface is smoother.
  • the properties and change patterns of the above glycolide-epsilon-caprolactone copolymer, polyethylene glycol, and bismuth subcarbonate composite materials are similar to those of the above composite materials, that is, the hardness of the composite materials changes with the degradation process in simulated urine.
  • the degradation time is significantly reduced as the degradation time increases.
  • the dynamic friction coefficient of the composite material added with PEG is smaller.
  • the above rule has nothing to do with the type of developer used.
  • the composite material prepared in the above embodiment is extruded through an extruder at 120°C-150°C to obtain a degradable elastic pipe body 1.
  • the outer diameter of the pipe body 1 is 2mm and the inner diameter is 1.1mm; the pipe body is heated at 50°C
  • the -80°C bent pipe is shaped to form a fixed structure with one or both ends curled into a tubular coil 2, and then holes are drilled (longitudinal aperture 1.0mm) at equal distances (hole spacing 50mm) through the drilling equipment to form drainage holes 3.
  • the obtained degradable ureteral stent is shown in Figure 2.
  • Miniature pigs were selected. After general anesthesia, ureteroscopy was used to implant ureteral stents in the left and right ureters of the minipig. The upper end of the tubular coil was fixed in the renal pelvis, and the lower end of the tubular coil was fixed in the bladder. Postoperative X-rays were used to observe whether the ureteral stent had slipped, broken, and passed out at different time points. A universal mechanical tester was used to test the modulus of the stent tube at different time points to characterize changes in its softness and hardness. The results are shown in Table 5.
  • ureteral stents 1, 2, and 3 were added with ethylene oxide polymer, while ureteral stents 4 and 5 were not added with ethylene oxide polymer.
  • All degradable stent tubes can be completely discharged from the animal urinary system.
  • the breakage time depends on the molecular weight of the material, the proportion of comonomers, the amount of ethylene oxide polymer added, and other factors, including the process conditions during processing. .
  • the ureteral stents 1, 2, and 3 added with ethylene oxide polymer have a lower modulus after degradation, are softer, and have a smoother surface.
  • the complete discharge time in the body is longer than that without adding ethylene oxide.
  • Ureteral stents4,5 made from alkane polymers are shorter and, therefore, less likely to form encrustations in the body.
  • the modulus of commercial silicone rubber stent tubes and polyurethane stent tubes did not change with degradation time.
  • the tensile strength and modulus of the degradable ureteral stent of the present invention are between the silicone rubber stent and the polyurethane stent, and are closer to the polyurethane stent.
  • Figure 1 is an imaging observation of the degradable ureteral stent of the present invention being excreted in an animal's body. After degradation, it can be smoothly excreted in the renal pelvis, ureter, and bladder without residual debris.

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Abstract

本发明提供了一种可降解输尿管支架及制备方法，为中空圆管状结构（1），两端或一端有防止滑动的固定结构（2），管壁上还有若干贯穿的引流侧孔（3），所用材料为至少包含乙交酯-ε-己内酯共聚物、环氧乙烷聚合物、医用显影剂形成的复合材料。在乙交酯-ε-己内酯共聚物中，乙交酯的重量百分比含量为51％-58％，使得共聚物具有适合的力学强度和软硬度，并且随着降解时间延长，会逐渐变柔软；同时，加入一定比例的环氧乙烷聚合物，降解后其定伸模量更低，更加柔软滑润，因此，降解碎片不易卡顿、更易排出体外，更适合用于制备可降解输尿管。

Description

一种可降解输尿管支架及其制备方法 技术领域
本发明属于生物医用材料及医疗器械领域，具体涉及一种可降解输尿管支架及其制备方法。
背景技术
输尿管支架在泌尿外科手术中应用极为广泛，适用于上尿路手术以及碎石机碎石、输尿管狭窄的扩张等治疗过程，它植入输尿管后能起到引流尿液、防止输尿管狭窄的重要作用。
现有临床使用的输尿管支架，都不可降解，由柔软的聚氨酯弹性体或硅橡胶材料制成。聚氨酯支架管较硬，容易置管；硅橡胶支架管较软，置管性能稍差。置入这两类不降解输尿管支架后，其软硬度保持不变，当其完成引流功能后，必须通过侵入性操作即通过膀胱镜来拔出，患者会痛苦不堪，且有可能发生感染等并发症。因此，研究开发可降解的输尿管支架具有重要的临床价值。
根据临床病例需要，输尿管支架的引流时间会有所不同。短期的临时引流尿液，一般在1-2周左右，如输尿管轻度损伤、简单结石、预置支架等；常见的临时引流一般在3-6周，因此，需要用不同的降解材料。但对支架共同的基本要求是，它们应具有弹性材料的力学性能，其断裂碎片能尽快全部排出体外，否则会增加一系列并发症的风险。
国外有文献报道(Lumiaho,J,J.Endourol.1999,13,107–112；Laaksovirta,S Laurila M.et al.J urol,167:1527,2002)，采用可降解聚丙交酯(PLLA)或丙交酯/乙交酯共聚物(PLGA)为原料来制造输尿管支架。但PLLA和PLGA材料属于塑料，缺乏柔软性，降解碎片较硬，嵌入、卡顿在肾盂内的可能性极大，导致各种并发症。
中国专利CN1672739A和中国专利CN112516390A公布了一种可降解的输尿管支架，涉及到乙交酯-ε-己内酯共聚物材料，它在一定的组成比例范围内是具有弹性材料的力学性能。但这类由软链单体(ε-己内酯)和硬链单体(乙交酯)形成的共聚物，往往在水中降解会越来越硬。这是因为材料中的硬链结构，如乙交酯链段，往往在降解过程中会出现结晶趋势，这样会使之容易卡顿或滞留在肾盂等部位。
综上所述，现有技术得到的材料还不能做到，既具有像硅橡胶和聚氨酯弹性材料那样的力学性能，又能使降解碎片不卡顿、不滞留在肾盂等位置，这一点到目前为止仍然是制约本领域研究进展的关键点，也是可降解输尿管支架目前还没有商品上市的最主要原因。
发明内容
鉴于现有技术的以上不足，本发明提供了一种可降解输尿管支架，该支架具有弹性材料的力学强度，初始的硬度(或模量)较高，便于置管，随着在尿液中的降解会逐渐变得愈来愈软，更易于排出体外。
本发明的技术方案如下：
一种可降解输尿管支架，采用复合材料制成，所述复合材料至少包含乙交酯-ε-己内酯共聚物、环氧乙烷聚合物、硫酸钡，经共混形成，它们的相对含量如下：
1)乙交酯-ε-己内酯共聚物，重量百分比含量为47％-80％；
2)环氧乙烷聚合物，重量百分比含量为2％-8％；
3)硫酸钡，重量百分比含量为18％-45％；
所述乙交酯-ε-己内酯共聚物中乙交酯重量百分含量51％-58％，ε-己内酯重量百分含量42％-49％。
本发明的输尿管支架，通过使用可降解的乙交酯-ε-己内酯共聚物、环氧乙烷聚合物、硫酸钡共混形成的复合材料来实现以上目的。
本发明及相关研究发现，支架管较硬时，降解碎片易卡顿在肾盂位置，因此，基材的软硬度是关键的影响因素。一般的可降解弹性材料，如乙交酯-ε-己内酯共聚物、L-丙交酯/ε-己内酯的共聚物等经常在降解过程中越变越硬，降解碎片或节段较难通过输尿管狭窄部位。但本发明研究发现，在适当的共聚单体比例范围内，采用适当的聚合工艺，乙交酯-ε-己内酯共聚物在水中或尿液中降解会逐渐变软，是一种有较好力学强度和软硬度适合的弹性材料，这个适当的共聚单体比例范围是乙交酯重量百分比为51％-58％。当乙交酯重量百分含量超过58％，共聚物出现明显的结晶趋势，降解过程中会变硬；当乙交酯重量百分含量低于51％时，共聚物力学性能太差和太软。
本发明还发现，在上述的乙交酯-ε-己内酯共聚物的材料中，添加一定含量的环氧乙烷聚合物，如聚乙二醇或聚氧乙烯，能进一步促进复合材料在降解过程中逐渐变得更软，表面更滑润、更容易崩解、碎裂，有利于管状支架断裂碎片的排出。
本发明的可降解输尿管支架，所用硫酸钡为常用的医用显影剂，与上述材料具有良好的相容性，有一定的补强作用。
本发明的可降解输尿管支架，所述乙交酯-ε-己内酯共聚物，在0.1g/dl浓度的六氟异丙醇中，25±1℃测得的特性粘度为1.30-3.00dl/g，粘度越大，降解维持时间就越长，因此，通过特性粘度可以调控支架管的引流时间。
本发明的可降解输尿管支架，所述环氧乙烷聚合物为聚乙二醇、聚乙二醇单甲醚、聚乙二醇二甲醚、聚氧乙烯。
作为优选，所述环氧乙烷聚合物在复合材料中所占重量比例为2％-8％，环氧乙烷聚合物含量越高，复合材料越柔软，降解也越快。
本发明的可降解输尿管支架，所述聚乙二醇、聚乙二醇单甲醚、聚乙二醇二甲醚、聚氧乙烯的分子量为1000Da-1000000Da。
作为优选，本发明的可降解输尿管支架，所述环氧乙烷聚合物为聚乙二醇、聚乙二醇单甲醚、聚乙二醇二甲醚的分子量为5000Da-40000Da。
作为优选，本发明的可降解输尿管支架，所述环氧乙烷聚合物为聚氧乙烯，分子量为50000Da-400000Da。
本发明的可降解输尿管支架，硫酸钡可以用其它医用显影剂替代，包括次碳酸铋、金属显影剂，且所用显影剂可以是一种或几种。
本发明的可降解输尿管支架，所述乙交酯-ε-己内酯共聚物制备方法如下，
在氮气保护下，在带搅拌器的反应器中先后加入0.005％-0.1％质量比的辛酸亚锡、ε-己内酯和乙交酯，在搅拌下，将反应体系温度在30分钟内从室温升到165℃-200℃，维持18-30小时，再在真空下保持1-4小时，转移出反应器中的共聚物，进一步将其破碎后，放入50℃-110℃的真空烘箱中真空干燥8-24小时。
本发明的可降解输尿管支架，为中空圆管状结构(1)，两端或一端有防止滑动的固定结构(2)，固定结构优选为圆形管状线圈形状，管壁上还有若干贯穿的引流侧孔(3)，管径为1.0-4.0mm。
本发明的可降解输尿管支架，采用熔融挤出方法制得，具体方法如下，
将一定量的乙交酯-ε-己内酯共聚物、环氧乙烷聚合物、医用显影剂混合均匀后，通过挤出机在120℃-160℃下挤出成型得到可降解弹性管材，所述管材经50℃-80℃弯管定型形成一端或两端带有圆圈的固定结构，再经打孔得到所述可降解输尿管支架。
本发明的可降解输尿管支架的初始100％形变时的模量为2MPa-10MPa,降解后的100％形变时的模量不大于初始值；所用材料的初始邵尔硬度A为70-95，降解后的邵尔硬度A不大于初始值。
本发明的可降解输尿管支架，在熔融挤出管子时，可以常规添加各种助剂，以达到不同的目的，包括但不限于增塑剂、润滑剂、染料、抗氧化剂、抗水解剂、熔体增稠剂、扩链剂、补强剂、高分子改性剂，这些助剂有助于改善支架的加工性能、降解性能、表面性能、力学性能。
同现有技术相比，本发明的有益效果体现在：
本发明通过控制乙交酯-ε-己内酯共聚物中的乙交酯单体的含量，使得共聚物具有适合的力学强度和软硬度，并且随着降解时间延长，会逐渐变柔软；同时，加入一定比例的环氧乙烷聚合物，降解后其定伸模量更低，更加柔软滑润，因此，更适合用于制备可降解输尿管。
附图说明
图1为本发明可降解输尿管支架动物体内排出的影像学观察，图1中，(A)为置入时X光片，(B)为断裂时X光片，(C)为排入膀胱时X光片，(D)为排出的降解碎段。
图2为本发明可降解输尿管支架示意图。
具体实施方式
实施例1乙交酯-ε-己内酯共聚物1的制备
将0.04％的辛酸亚锡催化剂、570克ε-己内酯单体(CL)和580克乙交酯单体(GA)先后置于3L反应器中，在氮气保护下25分钟将体系温度升到180℃，在10-20转/分钟的搅拌速度下，反应25小时，真空下保持2小时，转移出反应器中的共聚物，进一步将其破碎后，放入90℃的真空烘箱中真空干燥24小时，得到乙交酯-ε-己内酯共聚物1(PGC1)。
通过1H核磁谱确定共聚物中乙交酯和ε-己内酯的重量百分含量，以六氟异丙醇为溶剂。
将上述共聚物配成0.1g/dl浓度的六氟异丙醇溶液，用乌式粘度计在25℃下测试其特性粘度。
用热压成型方法，在平板硫化机上，140℃将上述共聚物制成厚度为2mm的片，用邵尔硬度计测试材料的邵尔硬度A。
用上述同样方法，将上述共聚物制成厚度为2mm的哑铃片，在万能力学测试机上，以200mm/min速度，测试材料的断裂拉伸强度和断裂伸长率。
材料的体外降解实验在37℃的模拟尿液中进行，定期测材料的邵尔硬度A。
实施例2乙交酯-ε-己内酯共聚物2的制备
将0.02％的辛酸亚锡催化剂、540克ε-己内酯单体(CL)和590克乙交酯单体(GA)先后置于3L反应器中，在氮气保护下20分钟将体系温度升到170℃，在10-20转/分钟的搅拌速度下，反应28小时，真空下保持1小时，转移出反应器中的共聚物，进一步将其破碎后，放入90℃的真空烘箱中真空干燥24小时，得到乙交酯-ε-己内酯共聚物2(PGC2)。
用实施例1所述方法进行上述共聚物的性能测试，测试结果列于表1中。
实施例3乙交酯-ε-己内酯共聚物3的制备
将0.03％的辛酸亚锡催化剂、530克ε-己内酯单体(CL)和600克乙交酯单体(GA)先后置于3L反应器中，在氮气保护下30分钟将体系温度升到190℃，在10-20转/分钟的搅拌速度下，反应22小时，真空下保持4小时，转移出反应器中的共聚物，进一步将其破碎后，放入90℃的真空烘箱中真空干燥24小时，得到乙交酯-ε-己内酯共聚物3(PGC3)。
用实施例1所述方法进行上述共聚物的性能测试，测试结果列于表1中。
实施例4乙交酯-ε-己内酯共聚物4的制备
将0.05％的辛酸亚锡催化剂、480克ε-己内酯单体(CL)和600克乙交酯单体(GA)先后置于3L反应器中，在氮气保护下30分钟将体系温度升到195℃，在10-20转/分钟的搅拌速度下，反应18小时，真空下保持4小时，转移出反应器中的共聚物，进一步将其破碎后，放入90℃的真空烘箱中真空干燥24小时，得到乙交酯-ε-己内酯共聚物4(PGC4)。
用实施例1所述方法进行上述共聚物的性能测试，测试结果列于表1中。
实施例5乙交酯-ε-己内酯共聚物5的制备
将0.01％的辛酸亚锡催化剂、470克ε-己内酯单体(CL)和630克乙交酯单体(GA)先后置于3L反应器中，在氮气保护下30分钟将体系温度升到190℃，在10-20转/分钟的搅拌速度下，反应20小时，真空下保持2小时，转移出反应器中的共聚物，进一步将其破碎后，放入90℃的真空烘箱中真空干燥24小时，得到乙交酯-ε-己内酯共聚物5(PGC5)。
用实施例1所述方法进行上述共聚物的性能测试，测试结果列于表1中。
实施例6乙交酯-ε-己内酯共聚物6的制备
将0.01％的辛酸亚锡催化剂、470克ε-己内酯单体(CL)和660克乙交酯单体(GA)先后置于3L反应器中，在氮气保护下26分钟将体系温度升到184℃，在10-20转/分钟的搅拌速度下，反应23小时，真空下保持3小时，转移出反应器中的共聚物，进一步将其破碎后，放入90℃的真空烘箱中真空干燥24小时，得到乙交酯-ε-己内酯共聚物6(PGC6)。
用实施例1所述方法进行上述共聚物的性能测试，测试结果列于表1中。
表1
以上结果表明，本发明所述的乙交酯-ε-己内酯共聚物，其中的乙交酯含量越高，其硬度就越大；当其中的乙交酯重量含量在51％-58％时，其邵尔硬度A与聚氨酯(75-95)和硅橡胶(50-70)相当，比较适合用作输尿管支架；在37℃模拟尿液中的降解结果显示，PGC1-PGC5的硬度在降解过程中有所变软。而PGC6中的乙交酯重量含量大于58％，其硬度较大，并随降解时间增加而有所变硬。而当乙交酯含量低于51％时，其拉伸强度较低。
实施例7乙交酯-ε-己内酯共聚物、聚乙二醇、硫酸钡的复合材料制备
将200克上述制备的乙交酯-ε-己内酯共聚物(PGC)、一定量的聚乙二醇20000(PEG2)或聚乙二醇5000(PEG5)、医用硫酸钡(Ba)混合均匀后，通过双螺杆挤出机进一步共混并造粒，挤出机温度为120℃-150℃，得到的复合材料粒料再通过平板硫化机，140℃下制成厚度为2mm的上述三种材料的复合材料片材，用于拉伸强度和硬度的测试；复合材料的动态摩擦系数按ASTM-D1894规定的方法测试。结果如表2所示。
表2

以上结果表明，含有PEG的复合材料在模拟尿液中降解过程的硬度变化都是随降解时间增加而明显降低的，PEG含量越高，硬度下降越多；未添加PEG的复合材料3比添加了PEG的复合材料硬度降低程度小一些；复合材料7和复合材料8，所用乙交酯-ε-己内酯共聚物中，乙交酯含量超过58％重量比，因此随降解时间延长，其邵尔硬度A有所增加或变化不大；添加了PEG的复合材料其动态摩擦系数更小，提示其表面更滑润。
实施例8乙交酯-ε-己内酯共聚物、聚氧乙烯、硫酸钡的复合材料制备
将200克上述制备的乙交酯-ε-己内酯共聚物(PGC)、一定量的聚氧乙烯(PEO，分子量200000Da)和医用硫酸钡(Ba)混合均匀后，通过双螺杆挤出机进一步共混并造粒，挤出机温度为120℃-140℃，得到的复合材料粒料再通过平板硫化机，140℃下制成厚度为2mm的片材，用于拉伸强度和硬度的测试；复合材料的动态摩擦系数按ASTM-D1894规定的方法测试。结果如表3所示。
表3
以上乙交酯-ε-己内酯共聚物、聚氧乙烯和医用硫酸钡的复合材料降解过程中硬度的变化有类似规律，都是随降解时间增加而明显降低。聚氧乙烯含量越高，硬度降低越多，但聚氧乙烯含量太高，强度会降低较多，不利于固定。添加了聚氧乙烯的复合材料其动态摩擦系数更小，提示其表面更滑润。
实施例9乙交酯-ε-己内酯共聚物、聚乙二醇、次碳酸铋的复合材料制备
将200克上述制备的乙交酯-ε-己内酯共聚物(PGC)、一定量的聚乙二醇20000(PEG2)或聚乙二醇5000(PEG5)、医用次碳酸铋(Bi)混合均匀后，通过双螺杆挤出机进一步共混并造粒，挤出机温度为120℃-140℃，得到的复合材料粒料再通过平板硫化机，140℃下制成厚度为2mm的上述三种材料的复合材料片材，用于拉伸强度和硬度的测试；复合材料的动态摩擦系数按ASTM-D1894规定的方法测试。结果如表4所示。
表4
以上乙交酯-ε-己内酯共聚物、聚乙二醇、次碳酸铋复合材料的性能及变化规律与上述复合材料类似，即复合材料在模拟尿液中降解过程的硬度变化都是随降解时间增加而明显降低的，添加了PEG的复合材料其动态摩擦系数更小，上述规律与所用显影剂的类型无关。
实施例10可降解输尿管支架的制备
采用上述实施例制备的复合材料，通过挤出机在120℃-150℃下挤出成型得到可降解弹性管体1，管体1外径为2mm，内径1.1mm；所述管体经50℃-80℃弯管定型形成一端或两端成卷曲状管状线圈2的固定结构，再通过打孔设备对管体等距离(孔距50mm)打孔(纵向孔径1.0mm)后形成引流孔3，得到的可降解输尿管支架见图2。
在万能力学测试机上，以200mm/min速度，测试材料的断裂拉伸强度、定伸模量(在100％的伸长率时的拉伸强度，与邵尔硬度一样表征材料的软硬度)，并测试在37℃的模拟尿液中体外降解过程中定伸模量的变化，结果见表5。
实施例11可降解输尿管支架的动物体内降解实验
选择小型猪，经全麻状态后，采用输尿管镜方法在小型猪的左右两侧输尿管中植入输尿管支架，其上端管状线圈固定在肾盂，下端管状线圈固定在膀胱。术后采用X光观察不同时间点输尿管支架有无滑脱、断裂和排出情况。采用万能力学测试器测试不同时间点支架管的定伸模量，表征其软硬度的变化，结果见表5。
表5

以上结果显示，输尿管支架1、2、3添加了环氧乙烷聚合物，输尿管支架4、5未添加环氧乙烷聚合物。所有可降解的支架管都能够从动物泌尿系统全部排出，断裂时间则取决于材料的分子量大小、共聚单体比例、添加的环氧乙烷聚合物量等因素，包括在加工过程中的工艺条件等。然而，添加了环氧乙烷聚合物的输尿管支架1、2、3，由于降解后其定伸模量更低，更加柔软，表面也更滑润，在体内的完全排出时间比未添加环氧乙烷聚合物的输尿管支架4、5更短，因此，在体内形成结壳的可能性就越小。各组输尿管支架的初始模量有一定的差异，但相差不大，都能很顺利的置管。商品硅橡胶支架管和聚氨酯支架管的模量随降解时间没有变化。本发明的可降解输尿管支架拉伸强度和模量介于硅橡胶支架和聚氨酯支架之间，更接近聚氨酯支架。
图1为本发明可降解输尿管支架动物体内排出的影像学观察，降解后在肾盂、输尿管、膀胱都能顺利排出，没有残留碎片。

Claims (10)

  1. 一种可降解输尿管支架，其特征在于，采用复合材料制成，所述材料至少包含乙交酯-ε-己内酯共聚物、环氧乙烷聚合物、硫酸钡经共混形成，它们的相对含量如下：
    1)乙交酯-ε-己内酯共聚物，重量百分比含量为47％-80％；
    2)环氧乙烷聚合物，重量百分比含量为2％-8％；
    3)硫酸钡，重量百分比含量为18％-45％；
    所述乙交酯-ε-己内酯共聚物中乙交酯重量百分含量51％-58％，ε-己内酯重量百分含量42％-49％。
  2. 根据权利要求1所述的可降解输尿管支架，其特征在于，所述乙交酯-ε-己内酯共聚物，在0.1g/dl浓度的六氟异丙醇中，25±1℃测得的特性粘度为1.30-3.00dl/g。
  3. 根据权利要求1所述的可降解输尿管支架，其特征在于，所述环氧乙烷聚合物为聚乙二醇、聚乙二醇单甲醚、聚乙二醇二甲醚、聚氧乙烯以及环氧乙烷共聚物；
    聚乙二醇、聚乙二醇单甲醚、聚乙二醇二甲醚、聚氧乙烯的分子量为1000Da-1000000Da。
  4. 根据权利要求3所述的可降解输尿管支架，其特征在于，环氧乙烷聚合物为聚乙二醇或聚乙二醇单甲醚，分子量为5000Da-40000Da，或者，
    环氧乙烷聚合物为聚氧乙烯，分子量为50000Da-400000Da。
  5. 根据权利要求1所述的可降解输尿管支架，其特征在于，硫酸钡用其它医用显影剂替代，所述其他医用显影剂包括次碳酸铋、金属显影剂中的一种或两种。
  6. 根据权利要求1所述的可降解输尿管支架，其特征在于，所述的可降解输尿管支架为中空圆管状结构(1)，两端或一端有防止滑动的固定结构(2)，管壁上还有若干贯穿的引流侧孔(3)，管子外径为1.0-4.0mm。
  7. 根据权利要求1所述的可降解输尿管支架，其特征在于，所述可降解输尿管支架的初始100％形变时的模量为2MPa-10MPa,降解后的100％形变时的模量不大于初始值；所用材料的初始邵尔硬度A为70-95，降解后的邵尔硬度A不大于初始值。
  8. 根据权利要求1或6所述可降解输尿管支架，其特征在于，可降解输尿管支架中还可以添加各种助剂，包括增塑剂、润滑剂、染料、抗氧化剂、抗水解剂、熔体增稠剂、扩链剂、补强剂、高分子改性剂。
  9. 一种如权利要求1-8任一项所述的可降解输尿管支架的制备方法，其特征在于，包括：将乙交酯-ε-己内酯共聚物、环氧乙烷聚合物、医用显影剂混合均匀后，通过挤 出机在120℃-160℃下挤出成型得到可降解弹性管材，所述管材经50℃-80℃弯管定型形成一端或两端带有管状线圈的固定结构，再经打孔得到所述可降解输尿管支架。
  10. 根据权利要求9所述的可降解输尿管支架的制备方法，其特征在于，还包括乙交酯-ε-己内酯共聚物的制备过程：
    在氮气保护下，在带搅拌器的反应器中先后加入0.005％-0.1％质量比的辛酸亚锡、ε-己内酯和乙交酯，在搅拌下，将反应体系温度在30分钟内从室温升到165℃-200℃，维持18-30小时，再在真空下保持1-4小时，转移出反应器中的共聚物，进一步将其破碎后，放入50℃-110℃的真空烘箱中真空干燥8-24小时。
PCT/CN2023/102900 2022-07-19 2023-06-27 一种可降解输尿管支架及其制备方法 Ceased WO2024016960A1 (zh)

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