CN107857844A - 一种接枝改性聚‑β‑羟丁酸的制备方法 - Google Patents

一种接枝改性聚‑β‑羟丁酸的制备方法 Download PDF

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CN107857844A
CN107857844A CN201711127827.9A CN201711127827A CN107857844A CN 107857844 A CN107857844 A CN 107857844A CN 201711127827 A CN201711127827 A CN 201711127827A CN 107857844 A CN107857844 A CN 107857844A
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graft modification
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hydroxybutyric acid
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郑浩
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Chengdu Cedisen Biological Technology Co Ltd
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    • C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
    • C08F283/002—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polymers modified by after-treatment
    • A—HUMAN NECESSITIES
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    • 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
    • A61L31/022—Metals or alloys
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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    • C09D151/00—Coating compositions based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
    • C09D151/08—Coating compositions based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers grafted on to macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C12P7/625—Polyesters of hydroxy carboxylic acids
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Abstract

本发明公开了一种接枝改性聚‑β‑羟丁酸的制备方法，步骤如下：步骤一：取芽孢杆菌菌种；步骤二：将芽孢杆菌菌种在无氮培养基中培养60小时；步骤三：用20倍稀释法将上述培养液稀释接种到平板，在25℃‑29℃中培养2‑4小时，挑取单菌落进行活；步骤四：将上述菌液接种到基础培养基中进行培养，培养时间为150‑200小时，培养温度为25℃‑30℃；步骤五、取培养液离心，后处理制备粗接枝改性聚‑Β‑羟丁酸；步骤六、将甲基丙烯酸β‑羟乙酯接枝到接枝改性聚‑Β‑羟丁酸制备接枝改性后的接枝改性聚‑Β‑羟丁酸材料。

Description

一种接枝改性聚-β-羟丁酸的制备方法
技术领域
本发明涉及心脏支架领域。
背景技术
心脏支架(Stent)又称冠状动脉支架，是心脏介入手术中常用的医疗器械，具有疏通动脉血管的作用。主要材料为不锈钢、镍钛合金或钴铬合金。
现有的金属支架容易导致血管再狭窄。在一种新型的支架中，将抗血栓和抗增生药物包裹于心脏支架上，植入支架后，药物缓慢释放，可以增加局部的药物浓度，减少副作用，降低再狭窄率。
现有的药物载体一般有生物降解和不可降解高分子材料，在生物降低高分子材料中，药物的释放率低，有效时间短。
发明内容
本发明的目的在于：针对上述存在的问题，提供一种心脏支架涂层，所述的涂层是一种可以降解聚-β-羟丁酸，制备方法如下：
步骤一：取芽孢杆菌菌种；
步骤二：将芽孢杆菌菌种在无氮培养基中培养60小时；
步骤三：用20倍稀释法将上述培养液稀释接种到平板，在25℃-29℃中培养2-4小时，挑取单菌落进行活；
步骤四：将上述菌液接种到基础培养基中进行培养，培养时间为150-200小时，培养温度为25℃-30℃；
步骤五、取培养液离心，后处理制备粗接枝改性聚-Β-羟丁酸；
步骤六、将甲基丙烯酸β-羟乙酯接枝到接枝改性聚-Β-羟丁酸制备接枝改性后的接枝改性聚-Β-羟丁酸材料。
作为改进，所述的无氮培养基为蒸馏水100份，葡萄糖1-5份、硫酸钾：0.1-1份、氯化钠0.01-0.1份、氯化钙0.01-0.1份、氯化锌0.01份。
作为改进，所述的无氮培养基为蒸馏水100份，葡萄糖5份、硫酸钾： 1份、氯化钠0.1份、氯化钙0.1份、氯化锌0.01份。
作为改进，所述的平板培养基为：蒸馏水100份、蛋白胨0.1-2份、葡萄糖0.1-2份、酵母膏0.1-3份。
作为改进，所述的平板培养基的PH为6.8-7。
作为改进，所述的基础培养基为蒸馏水100份、蛋白胨0.1-3份、甘油0.2-2、牛肉膏0.2-2份。
作为改进，所述的基础培养基PH为6.8-7，优选值为6.8，实验发现6.8的PH值更加有利于本发明细菌的培养，活化效果好。
作为改进，接枝改性步骤为：将粗接枝改性聚-Β-羟丁酸熔融，将甲基丙烯酸β-羟乙酯和引发剂加入到到流变仪中，反应5 min -10min。
作为改进，所述的接枝改性聚-Β-羟丁酸重复单元和甲基丙烯酸β-羟乙酯的摩尔比为10：1。
作为改进，所述的引发剂为叔丁基过氧化氢、过氧化二异丙苯、过氧化叔戊酸叔丁基酯、过氧化甲乙酮、过氧化环己酮、过氧化二碳酸二异丙酯、过氧化二碳酸二环己酯。
本发明采用特殊的可降低高分子材料，对人体无害，本发明的释放率高，释放周期长。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
具体实施例1：一种心脏支架，所述的心脏支架包括支架本体和涂层，所述的支架本体为钛合金材料，所述的涂层为可降解接枝改性聚-Β-羟丁酸，所述的可降解接枝改性聚-Β-羟丁酸的制备方法如下：
步骤一：取芽孢杆菌菌种；
步骤二：将芽孢杆菌菌种在无氮培养基中培养60小时；
步骤三：用20倍稀释法将上述培养液稀释接种到平板，在25℃-29℃中培养2-4小时，挑取单菌落进行活；
步骤四：将上述菌液接种到基础培养基中进行培养，培养时间为150-200小时，培养温度为25℃-30℃；
步骤五、取培养液离心，后处理制备粗接枝改性聚-Β-羟丁酸；
步骤六、将甲基丙烯酸β-羟乙酯接枝到接枝改性聚-Β-羟丁酸制备接枝改性后的接枝改性聚-Β-羟丁酸材料。
所述的无氮培养基为蒸馏水100份，葡萄糖5份、硫酸钾： 1份、氯化钠0.1份、氯化钙0.1份、氯化锌0.01份。
所述的平板培养基为：蒸馏水100份、蛋白胨0.2份、葡萄糖0.2份、酵母膏0.1份，平板培养基的PH为6.8。
所述的基础培养基为蒸馏水100份、蛋白胨0.1份、甘油0.2、牛肉膏0.2份，基础培养基PH为6.8-7。
接枝改性步骤为：将粗接枝改性聚-Β-羟丁酸熔融，将甲基丙烯酸β-羟乙酯和引发剂加入到到流变仪中，反应5 min -10min，所述的接枝改性聚-Β-羟丁酸重复单元和甲基丙烯酸β-羟乙酯的摩尔比为10：1，所述的引发剂为叔丁基过氧化氢。
经测量，在加入雷帕霉素（RAPM）后，将支架植入人体的第一周40%的雷帕霉素被释放，第四周后，释放量为80%，两个月后，释放量为85，三个月后，释放量为92% ，半年后释放量为99%。
所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种接枝改性聚-β-羟丁酸的制备方法，步骤如下：
步骤一：取芽孢杆菌菌种；
步骤二：将芽孢杆菌菌种在无氮培养基中培养60小时；
步骤三：用20倍稀释法将上述培养液稀释接种到平板，在25℃-29℃中培养2-4小时，挑取单菌落进行活；
步骤四：将上述菌液接种到基础培养基中进行培养，培养时间为150-200小时，培养温度为25℃-30℃；
步骤五、取培养液离心，后处理制备粗接枝改性聚-Β-羟丁酸；
步骤六、将甲基丙烯酸β-羟乙酯接枝到接枝改性聚-Β-羟丁酸制备接枝改性后的接枝改性聚-Β-羟丁酸材料。
2.根据权利要求1所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的无氮培养基为蒸馏水100份，葡萄糖1-5份、硫酸钾：0.1-1份、氯化钠0.01-0.1份、氯化钙0.01-0.1份、氯化锌0.01份。
3.根据权利要求2所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的无氮培养基为蒸馏水100份，葡萄糖5份、硫酸钾： 1份、氯化钠0.1份、氯化钙0.1份、氯化锌0.01份。
4.根据权利要求3所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的平板培养基为：蒸馏水100份、蛋白胨0.1-2份、葡萄糖0.1-2份、酵母膏0.1-3份。
5.根据权利要求4所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的平板培养基的PH为6.8-7。
6.根据权利要求5所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的基础培养基为蒸馏水100份、蛋白胨0.1-3份、甘油0.2-2、牛肉膏0.2-2份。
7.根据权利要求6所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的基础培养基PH为6.8-7。
8.根据权利要求7所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，接枝改性步骤为：将粗接枝改性聚-Β-羟丁酸熔融，将甲基丙烯酸β-羟乙酯和引发剂加入到到流变仪中，反应5 min -10min。
9.根据权利要求8所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的接枝改性聚-Β-羟丁酸重复单元和甲基丙烯酸β-羟乙酯的摩尔比为10：1。
10.根据权利要求9所述的接枝改性聚-β-羟丁酸的制备方法，其特征在于，所述的引发剂为叔丁基过氧化氢、过氧化二异丙苯、过氧化叔戊酸叔丁基酯、过氧化甲乙酮、过氧化环己酮、过氧化二碳酸二异丙酯、过氧化二碳酸二环己酯。
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US20030018128A1 (en) * 2000-12-29 2003-01-23 Wang James H. Grafted biodegradable polymer blend compositions
CN101921714A (zh) * 2009-09-10 2010-12-22 浙江师范大学 高产聚-β-羟丁酸的巨大芽孢杆菌Bm-10菌株及其筛选方法和应用
CN103421714A (zh) * 2013-08-02 2013-12-04 华南理工大学 一种芽孢杆菌及其在发酵生产聚羟基丁酸酯中的应用

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