CN113018518A - 一种用于婴幼儿狭窄血管可吸收血管支架涂层的制备方法 - Google Patents
一种用于婴幼儿狭窄血管可吸收血管支架涂层的制备方法 Download PDFInfo
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- CN113018518A CN113018518A CN202110246916.5A CN202110246916A CN113018518A CN 113018518 A CN113018518 A CN 113018518A CN 202110246916 A CN202110246916 A CN 202110246916A CN 113018518 A CN113018518 A CN 113018518A
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Abstract
本发明提供了一种用于婴幼儿狭窄血管的可吸收血管支架涂层的载药胶束的制备方法,包括以下步骤:S1:将待包封药物溶解在适量乳化剂中,然后加入壳聚糖‑聚对二氧环己酮两亲性嵌段共聚物充分混匀配成药物‑共聚物溶液;S2:将S1所得的药物‑共聚物溶液逐滴至预先配制好的乳化剂水溶液中,并持续搅直到形成稳定的载药胶束溶液;S3:将S2所述胶束溶液经减压蒸发去除乳化剂后再搅拌,产物依次经离心分离、过滤、透析,即得载药胶束;并具体公开了将载药胶束喷涂在可吸收血管支架表面制备载药涂层,显著提高了其生物相容性,并达到了pH响应型载药胶束随支架骨架及空白顶层降解的pH值变化而达到缓释药物的目的。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种用于婴幼儿狭窄血管可吸收血管支架涂层的制备方法。
背景技术
经皮植入血管支架相较于人工血管置换及单纯球囊扩张血管具有创伤性小、疗效佳的优势。多数专家学者都认为可吸收支架在儿童血管狭窄性病变中的应用具有较高的临床研究价值,且其能够克服永久性金属支架植入后小儿在长大以后支架段血管相对狭窄、需反复扩张及致栓性等诸多严重问题,而这些问题治疗难度极高。目前可吸收支架研究在国内外已广泛开展,而针对婴幼儿血管狭窄性疾病设计的可吸收支架尚缺乏。
应用于生物可吸收支架的材料多为高分子多聚物,包括聚左旋乳酸(poly L-lactic acid,PLLA),聚乙交酯(Polyglycolide,PGA),聚乙丙交酯(poly lactic-glycolicacid,PLGA),聚对二氧环己酮(Poly[para-dioxanone],PPDO),聚己内酯(PCL)等,这些材料具有不同的降解时间,制作成血管支架时具有不同的机械强度以适应不同的血管支撑要求,降解产物安全无毒性可以随细胞代谢排出体外。制备方法上,多是先把可降解聚合物通过熔融纺丝或溶液铸膜切割成支架基材纤维,再在模具上缠绕成设计的支架形状,加热固化成型。
综合国内外研究分析,多聚物可吸收支架多适用于成年人冠状动脉等小血管直径(血管直径3-5mm),降解周期较长多为2-3年,制备方法复杂生产成本高;且可吸收支架径向支撑性能要低于传统的金属支架,不能适应于儿童使用。例如,现有技术(CN108066048B)公开了:制备热粘合复合结构可降解管腔支架,通过制备热粘合PPDO/PCL皮芯结构编织纱并将其与PPDO单丝交叉编织组成支架预成型体,热黏合编织纱限制了编织结构中部分交织点的滑移和转动从而提高支架的机械性能,再经过热定型处理,得到结构稳定的PPDO/PCL编织自增强型血管支架。这种支架在体内4月内能维持较好的血管支撑作用,12月大部分支架杆完全降解与血管壁融合,支架降解适配儿童血管生长发育需求。然而,支架降解中期(4-6月)生物相容性欠佳,支架炎症反应及平滑肌细胞增殖被认为是聚合物支架管腔再狭窄的主要因素,会诱发血栓形成及不良血管事件,引起支架疗效欠佳。故提供初始体积小(长度和直径符合要求)、支架的支撑力至少需要维持3~6个月以完成血管修复,支架完全降解时间在6-12月以适应儿童血管发育速率以及具有良好的生物相容性的血管支架是本领域亟待解决的问题。
发明内容
为克服现有技术中的缺陷,本发明设计并构建适用于婴幼儿狭窄血管的可吸收血管支架的载药复合涂层,以调控可吸收血管支架生物相容性:提供了一种新的药物释放途径,可在支架降解早期不影响受损血管的再内皮化,在降解中期释放药物发挥抗炎、抗增殖作用;涂层材料在释放药物后能生物降解,不增加晚期血栓形成的发生率,最终达到支架整体完全可生物降解的技术效果。
本发明通过如下技术方案实现:
本发明的第一方面提供了一种用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液的制备方法,包括以下步骤:
S1:将待包封药物溶解在适量乳化剂中,然后加入壳聚糖-聚对二氧环己酮两亲性嵌段共聚物(即Chitosan-b-PPDO共聚物)充分混匀配成药物-共聚物溶液,其中,所述待包封药物与Chitosan-b-PPDO共聚物的质量比10:20~60;优选的,所述,所述待包封药物与Chitosan-b-PPDO共聚物的质量比10:25;
S2:将S1所得的药物-共聚物溶液逐滴至预先配制好的乳化剂水溶液中,并持续搅拌12~36h,直到形成稳定的载药胶束溶液,其中,所述乳化剂水溶液中乳化剂:水的质量比为1:0.5~2,且所述药物-共聚物溶液占所述乳化剂水溶液质量的2~10%;优选的,所述持续搅拌时间为24h;优选的,所述药物-共聚物溶液占所述乳化剂水溶液质量的3.5%;优选的,所述乳化剂水溶液中乳化剂:水的质量比为1:1;
S3:将S2所得载药胶束溶液经减压蒸发去除乳化剂后再搅拌2~4小时,产物依次经离心分离获得上清液、上清液再经过滤获得滤液、滤液再经过透析,以至完全除去未包封的共聚物以及残留的乳化剂,即得所述聚合物载药胶束溶液;优选的,所述搅拌时间为3h;
本发明的第二方面提供了一种用于婴幼儿狭窄血管的可吸收血管支架涂层聚合物空白胶束溶液的制备方法,包括以下步骤:
S1’:将Chitosan-b-PPDO共聚物溶解在少量乳化剂中配成共聚物溶液,然后逐滴滴至预先配制好的乳化剂水溶液中,并持续搅拌12~36h,直到形成稳定的胶束溶液,其中,所述乳化剂水溶液中乳化剂:水的质量比为1:0.5~2,且所述共聚物溶液占所述乳化剂水溶液质量的2~10%;优选的,所述持续搅拌时间为24h;优选的,共聚物溶液占所述乳化剂水溶液质量的3.5%;优选的,所述乳化剂水溶液中乳化剂:水的质量比为1:1;
S2’:将S2所得载药胶束溶液经减压蒸发去除乳化剂后再搅拌2~4小时,产物依次经离心分离获得上清液、上清液再经过滤获得滤液、滤液再经过透析,以至完全除去未包封的共聚物以及残留的乳化剂,即得所述聚合物载药胶束溶液;优选的,所述搅拌时间为3h;
进一步的,S1中,所述药物为抗平滑肌细胞增殖药物和/或抗炎药物;
更进一步的,所述抗平滑肌细胞增殖药物为雷帕霉素;
更进一步的,所述抗炎药物为布洛芬;
进一步的,S1和S1’中,所述壳聚糖-聚对二氧环己酮两亲性嵌段共聚物(即Chitosan-b-PPDO共聚物)如式Ⅰ所示,
其中,R为H或OCH3;n1和n2均为正整数且n1:n2为1:10~20;
更进一步的,所述壳聚糖-b-聚对二氧环己酮(PPDO)两亲性嵌段共聚物的制备方法包括如下步骤:
其中,R为H或OCH3,n1和n2均为正整数且n1:n2为1:10~20;
进一步的,上述步骤中,所述乳化剂为丙酮、二氯甲烷或氯仿:
进一步的,S3和S2’中,所述减压蒸发的温度为160~170℃,且压力为1~3mmHg;优选的,S3和S2’中,所述减压蒸发的温度为165℃,且压力为2mmHg;
进一步的,S3和S2’中,所述过滤为采用微孔滤膜过滤;
进一步的,S3和S2’中,所述透析条件为采用截留分子量≥3500透析袋;
本发明的第三方面还提供了一种用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液,采用上述任一项制备聚合物载药胶束溶液的方法获得;
本发明的第四方面还提供了一种用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物空白胶束溶液,采用上述任一项制备聚合物空白胶束溶液的方法获得;
本发明的第五方面还提供了一种上述用于婴幼儿狭窄血管可吸收血管支架涂层载药胶束的喷涂方法,包括以下步骤:
S1制备载药涂层:以上述聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面获得含药物涂层的可吸收血管支架;进一步的,所述药物涂层包括雷帕霉素药物涂层和/或布洛芬药物涂层;进一步优选的,所述药物涂层包括雷帕霉素药物涂层和布洛芬药物涂层,且雷帕霉素药物涂层:布洛芬药物涂层数之比为4:3;
S2制备空白涂层:以上述聚合物空白胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述含药物涂层的可吸收血管支架表面,以获得含空白涂层的可吸收血管支架,其中,所述含药物涂层:空白涂层数之比为7:3;
进一步的,S1所述超声喷涂工艺包括:
S11:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,真空干燥后固定于自动超声喷涂仪上;
S12:将聚合物载药胶束溶液装夹到微量注射泵上,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面获得含药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm;
更进一步的,S12步骤包括:
A.制备含雷帕霉素的药物涂层:以雷帕霉素聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面,获得含雷帕霉素药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm;
或B.制备含布洛芬的药物涂层:以布洛芬聚合物载药胶束为喷涂液,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面获得含布洛芬药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm;
或C.制备含雷帕霉素和布洛芬的混合药物涂层:以雷帕霉素聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述可吸收血管支架表面;然后再以布洛芬聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在上述制备的含雷帕霉素药物涂层的可吸收血管支架表面,获得含混合载药涂层的可吸收血管支架,且雷帕霉素药物涂层:布洛芬药物涂层数之比为4:3,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm;
进一步的,S2所述超声喷涂工艺包括:
S21:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,然后真空干燥后固定于自动超声喷涂仪上;
S22:以上述聚合物空白胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述含药物涂层表面的可吸收血管支架上,获得含空白层的可吸收血管支架,其中,所述含药物涂层:空白涂层数之比为7:3;所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm。
附图说明
图1:本发明反应的反应式
图2:本发明的制备可吸收血管支架的流程示意图
有益效果
本发明制备的载药胶束涂层,喷涂在可降解吸收生物支架表面,具有以下优势:(1)在支架降解早期不影响受损血管的再内皮化,在降解中期释放药物发挥抗炎、抗增殖作用,涂层材料在释放药物后能生物降解,不增加晚期血栓形成的发生率,最终达到支架整体完全可生物降解,显著提高了可吸收支架的生物相容性;(2)以复合涂层方式,先喷涂载药胶束,再喷涂不载药的空白胶束,使得pH响应型载药胶束随支架骨架及空白顶层降解的pH值变化而达到缓释药物的目的。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步详细的说明。
在一个具体的实施方式中,本发明使用的支架来自CN108066048B公开的制备方法制备的可吸收血管支架。
实施例1:pH响应型Chitosan-b-PPDO聚合物的合成
将对二氧环己酮(PDO)单体加入辛酸亚锡催化剂(SnOct2:PDO摩尔量之比为1:10000)并置入反应器中,然后用液氮冷冻,再将反应器置于80℃下的油浴中反应48h,然后将反应器冷却到0℃,使反应停止,获得羟基封端PPDO单体(OH-PPDO-BA);将OH-PPDO-BA溶于的丙烯酰氯中(OH-PPDO-BA:丙烯酰氯摩尔量之比为1:8),然后再加入与OH-PPDO-BA等摩尔量的三乙胺(TEA)作为催化剂,避光25℃下反应进行10小时,然后加入***除去未反应的试剂,用去离子水洗涤三次,除去反应过程中形成的不溶性物,在真空40℃下干燥12h,获得端烯丙基PPDO(allyl-PPDO-BA);将摩尔量15份壳聚糖(Mn=8*105,脱乙酰度100%)溶于0.1mol/L醋酸水溶液中,在惰性气体保护下,再添加K2SO8(KPS),25℃下混合搅拌20分钟,摩尔量85份allyl-PPDO-BA随后加入,在50℃下共聚2小时,丙酮和去离子水清洗除去未反应的均聚物,冷却后即得Chitosan-b-PPDO共聚物(分子量Mn=3100g/mol)。共聚位点定位在壳聚糖的自由基上,同时保留了壳聚糖主链上的游离氨基。支架在降解中期,PPDO链中间的降解产物堆积,导致了支架杆周局部pH值降低的“酸性”微环境,而由于壳聚糖带有氨基基团,其酸碱解离度pKa在6.3-7.0(20℃),正好处于血液(pH值7.4)和PPDO降解酸性微环境(pH值6.0-7.0)之间,故使得壳聚糖氨基质子化,进而胶束结构变化膨胀,以促进疏水端包裹药物的释放,从而实现pH响应型胶束的功能。
嵌段位点在壳聚糖的自由基上,同时保留了壳聚糖主链上的游离氨基,从而实现pH敏感性。一般来说,两亲性共聚物中疏水基团含量和共聚物分子量将会大大影响其自组装纳米胶束的粒径大小。实验通过控制PPDO微球分子量,制得Polymer1(Chitosan-b-PPDO940(Mn=3100))和Polymer2(Chitosan-b-PPDO2000(Mn=6200))。
实施例2:聚合物载药胶束的制备
S1:将待包封药物(布洛芬/10毫克或雷帕霉素/10毫克)溶解在3.5mL溶剂(无水氯仿或丙酮、二氯甲烷)中,然后加入25mg实施例1合成的Chitosan-b-PPDO(分别加Polymer1和Polymer2)充分混匀溶解配成药物-共聚物溶液;
S2:将S1所得的药物-共聚物溶液逐滴滴至预先配制好的乳化剂水溶液中,并持续搅拌24h,直到形成稳定的载药胶束溶液,其中,所述乳化剂水溶液中乳化剂:水的质量比为1:1,且所述药物-共聚物溶液占所述乳化剂水溶液质量的3.5%;
S3:将所得载药胶束溶液经减压蒸发去除乳化剂后再搅拌3小时,产物经离心分离、0.22μm滤膜过滤以及截留分子量为3500的透析膜透析,除去未绑定的共聚物、残留的乳化剂和溶剂,即制备成聚合物载药胶束溶液。
实施例3:空白胶束的制备
S1:将Chitosan-b-PPDO共聚物溶解在少量乳化剂中配成溶液,然后逐滴滴至预先配制好的乳化剂水溶液中,并持续搅拌24h,直到形成稳定的载药胶束溶液,所述乳化剂水溶液中乳化剂:水的质量比为1:1,且所述药物-共聚物溶液占所述乳化剂水溶液质量的3.5%;
S2:将所得载药胶束溶液经减压蒸发去除乳化剂后再搅拌3小时,产物经离心分离、0.22μm滤膜过滤以及截留分子量为3500的透析膜透析,除去未绑定的共聚物、残留的乳化剂和溶剂,即制备成聚合物空白胶束溶液。
采用动态光散射(DLS)测定载药胶束粒径(D)和分布(分散系数PDI),高效液相色谱(HPLC)法测定这几种胶束载药率(LC%)、包封率(EE%),结果如表1所示。与未包裹雷帕霉素的聚合物微球相比,包裹药物后聚合物微球的粒径明显增大,可以说明雷帕霉素被包裹在了其中。同时我们看到Polymer1-空白微球粒径稍大于Polymer2-空白微球,其原因是短PPDO链的结晶性能较差,胶束的芯部较松散,胶束体积增大;但载药后两者差异不显著均约170nm。两种载药微球的载药率及包封率均较低。
表1 Chitosan-b-PPDO共聚物表征检测结果
实施例4:具有载药(雷帕霉素)涂层的支架制备工艺
一种用于婴幼儿狭窄血管可吸收血管支架涂层载药胶束的喷涂方法,包括以下步骤:
S1载药涂层:S11:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,然后真空干燥后固定于自动超声喷涂仪上;S12:以雷帕霉素聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述可吸收血管支架表面,共喷涂7次,获得含药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为3.5W;微量注射泵流量为4mL/h;氮气气压为3.5psi;转动心轴的旋转速为200rpm;
S2制备空白涂层:S21:采用酸洗清上述S1制备的含载药涂层支架,以去除支架表面杂质,然后以超纯水冲洗以去除其表面的酸,然后真空干燥后将其固定于自动超声喷涂仪上;S22:将聚合物空白胶束溶液装夹到微量注射泵上,采用超声喷涂工艺将其均匀喷涂在上述S21制备的含药物涂层可吸收血管支架表面获得空白涂层,共喷涂3次,其中,所述超声喷涂工艺中,超声功率为3.5W;微量注射泵流量为4mL/h;氮气气压为3.5psi;转动心轴的旋转速为200rpm。
实施例5:具有载药(布洛芬)涂层的支架制备工艺
一种用于婴幼儿狭窄血管可吸收血管支架涂层载药胶束的喷涂方法,包括以下步骤:
S1载药涂层:S11:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,然后真空干燥后固定于自动超声喷涂仪上;S12:以布洛芬聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述可吸收血管支架表面,共喷涂7次,获得含药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为3.5W;微量注射泵流量为4mL/h;氮气气压为3.5psi;转动心轴的旋转速为200rpm;
S2制备空白涂层:S21:采用酸洗清上述S1制备的含载药涂层支架,以去除支架表面杂质,然后以超纯水冲洗以去除其表面的酸,然后真空干燥后将其固定于自动超声喷涂仪上;S22:将聚合物空白胶束溶液装夹到微量注射泵上,采用超声喷涂工艺将其均匀喷涂在上述S21制备的含药物涂层可吸收血管支架表面获得空白涂层,共喷涂3次,其中,所述超声喷涂工艺中,超声功率为3.5W;微量注射泵流量为4mL/h;氮气气压为3.5psi;转动心轴的旋转速为200rpm。
实施例6:具有混合载药(雷帕霉素和布洛芬)涂层的支架制备工艺
一种用于婴幼儿狭窄血管可吸收血管支架涂层载药胶束的喷涂方法,包括以下步骤:
S1制备载药涂层:S11:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,然后真空干燥后固定于自动超声喷涂仪上;S12:以雷帕霉素聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述可吸收血管支架表面,共喷涂4次;S13:再以布洛芬聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在S12制备的所述可吸收血管支架表面,共喷涂3次,获得含混合载药涂层的可吸收血管支架;其中,所述超声喷涂工艺中,超声功率为3.5W;微量注射泵流量为4mL/h;氮气气压为3.5psi;转动心轴的旋转速为200rpm;
S2制备空白涂层:S21:采用酸洗清上述S1制备的含载药涂层支架,以去除支架表面杂质,然后以超纯水冲洗以去除其表面的酸,然后真空干燥后将其固定于自动超声喷涂仪上;S22:将聚合物空白胶束溶液装夹到微量注射泵上,采用超声喷涂工艺将其均匀喷涂在上述S21制备的含药物涂层可吸收血管支架表面获得空白涂层,共喷涂3次,其中,所述超声喷涂工艺中,超声功率为3.5W;微量注射泵流量为4mL/h;氮气气压为3.5psi;转动心轴的旋转速为200rpm。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术人员无需创造性劳动就可以根据本发明的构思做出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案,皆应在由权利要求书所确定的保护范围内。
Claims (19)
1.一种用于婴幼儿狭窄血管可吸收血管支架涂层的聚合物载药胶束溶液的制备方法,其特征在于,包括以下步骤:
S1:将待包封药物溶解在适量乳化剂中,然后加入壳聚糖-聚对二氧环己酮两亲性嵌段共聚物(即Chitosan-b-PPDO共聚物)充分混匀配成药物-共聚物溶液,其中,所述待包封药物与Chitosan-b-PPDO共聚物的质量比10:20~60;优选的,所述,所述待包封药物与Chitosan-b-PPDO共聚物的质量比10:25;
S2:将S1所得的药物-共聚物溶液逐滴至预先配制好的乳化剂水溶液中,并持续搅拌12~36h,直到形成稳定的载药胶束溶液,其中,所述乳化剂水溶液中乳化剂:水的质量比为1:0.5~2,且所述药物-共聚物溶液占所述乳化剂水溶液质量的2~10%;优选的,所述持续搅拌时间为24h;优选的,药物-共聚物溶液占所述乳化剂水溶液质量的3.5%;优选的,所述乳化剂水溶液中乳化剂:水的质量比为1:1;
S3:将S2所述胶束溶液经减压蒸发去除乳化剂后再搅拌2~4小时,产物依次经离心分离获得上清液、上清液再经过滤获得滤液、滤液再经过透析,以至完全除去未包封的共聚物以及残留的乳化剂,即得所述聚合物载药胶束溶液;优选的,所述搅拌时间为3h。
2.一种用于婴幼儿狭窄血管可吸收血管支架涂层的聚合物空白胶束溶液的制备方法,其特征在于,包括以下步骤:
S1’:将壳聚糖-聚对二氧环己酮两亲性嵌段共聚物溶解在少量乳化剂中配成共聚物溶液,然后逐滴滴至预先配制好的乳化剂水溶液中,并持续搅拌12~36h,直到形成稳定的胶束溶液,其中,所述乳化剂水溶液中乳化剂:水的质量比为1:0.5~2,且所述共聚物溶液占所述乳化剂水溶液质量的2~10%;优选的,所述持续搅拌时间为24h;优选的,共聚物溶液占所述乳化剂水溶液质量的3.5%;优选的,所述乳化剂水溶液中乳化剂:水的质量比为1:1;
S2’:将S1所述胶束溶液经减压蒸发去除乳化剂后再搅拌2~4小时,产物依次经离心分离获得上清液,上清液再经过滤获得滤液,滤液再经过透析,以至完全除去未绑定的共聚物和残留的乳化剂,即得;优选的,所述搅拌时间为3h。
3.根据权利要求1所述的用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液的制备方法,其特征在于,S1中,所述药物为抗平滑肌细胞增殖药物和/或抗炎药物。
4.根据权利要求3所述的用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液的制备方法,其特征在于,所述抗平滑肌细胞增殖药物为雷帕霉素。
5.根据权利要求3所述的用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液的制备方法,其特征在于,所述抗炎药物为布洛芬。
8.根据权利要求1所述用于婴幼儿狭窄血管可吸收血管支架涂层的聚合物载药胶束溶液的制备方法或权利要求2所述用于婴幼儿狭窄血管可吸收血管支架涂层的聚合物空白胶束溶液的制备方法,其特征在于,所述乳化剂为丙酮、二氯甲烷或氯仿。
9.根据权利要求1所述的用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液的制备方法或权利要求2所述的用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物空白胶束溶液的制备方法,其特征在于,S3和S2’中,所述减压蒸发的温度为160~170℃,且所述减压蒸发的压力为1~3mmHg;优选的,S3和S2’中,所述减压蒸发的温度为165℃,且所述减压蒸发的压力为2mmHg。
10.根据权利要求1所述用于婴幼儿狭窄血管可吸收血管支架涂层的聚合物载药胶束溶液的制备方法或权利要求2所述用于婴幼儿狭窄血管可吸收血管支架涂层的聚合物空白胶束溶液的制备方法,其特征在于,S3和S2’中,所述过滤为采用微孔滤膜过滤。
11.根据权利要求1所述用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物载药胶束溶液的制备方法或权利要求2所述用于婴幼儿狭窄血管的可吸收血管支架涂层的聚合物空白胶束溶液的制备方法,其特征在于,S3和S2’中,所述透析条件为采用截留分子量≥3500透析袋。
12.一种用于制备婴幼儿狭窄血管可吸收血管支架涂层的聚合物载药胶束溶液,其特征在于,采用权利要求1~11任一项所述方法制备获得。
13.一种用于制备婴幼儿狭窄血管的可吸收血管支架涂层的聚合物空白胶束溶液,其特征在于,采用权利要求2、7~11任一项所述方法制备获得。
14.一种用于制备婴幼儿狭窄血管可吸收血管支架涂层胶束的喷涂方法,其特征在于,包括以下步骤:
S1制备载药涂层:以权利要求13所述的聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面获得含药物涂层的可吸收血管支架;
S2制备空白涂层:以权利要求14所述的聚合物空白胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述含药物涂层的可吸收血管支架表面,以获得含空白涂层的可吸收血管支架,其中,所述含药物涂层:空白涂层数之比为7:3。
15.根据权利要求14所述的喷涂方法,其特征在于,所述药物涂层包括雷帕霉素药物涂层和/或布洛芬药物涂层。
16.根据权利要求15所述的喷涂方法,其特征在于,所述药物涂层包括雷帕霉素药物涂层和布洛芬药物涂层,且所述雷帕霉素药物涂层:布洛芬药物涂层数之比为4:3。
17.根据权利要求14~16任一项所述的喷涂方法,其特征在于,S1所述超声喷涂工艺包括:
S11:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,真空干燥后固定于自动超声喷涂仪上;
S12:将聚合物载药胶束溶液装夹到微量注射泵上,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面获得含药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm。
18.根据权利要求17所述的喷涂方法,其特征在于,S12步骤包括:
A.制备含雷帕霉素的药物涂层:以雷帕霉素聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面,获得含雷帕霉素药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm;
或B.制备含布洛芬的药物涂层:以布洛芬聚合物载药胶束为喷涂液,采用超声喷涂工艺将其均匀喷涂在可吸收血管支架表面获得含布洛芬药物涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm;
或C.制备含雷帕霉素和布洛芬的混合药物涂层:以雷帕霉素聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述可吸收血管支架表面;然后再以布洛芬聚合物载药胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在上述制备的含雷帕霉素药物涂层的可吸收血管支架表面,且雷帕霉素药物涂层:布洛芬药物涂层数之比为4:3,获得含混合载药涂层的可吸收血管支架,其中,所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm。
19.根据权利要求14~16任一项所述的喷涂方法,其特征在于,S2所述超声喷涂工艺包括:
S21:将可吸收血管支架经酸洗清除支架表面杂质、超纯水冲洗以去除其表面的酸,然后真空干燥后固定于自动超声喷涂仪上;
S22:以上述聚合物空白胶束溶液为喷涂液,采用超声喷涂工艺将其均匀喷涂在所述含药物涂层表面的可吸收血管支架上,获得含空白层的可吸收血管支架,其中,所述含药物涂层:空白涂层数之比为7:3;所述超声喷涂工艺中,超声功率为2~5W,优选3.5W;微量注射泵流量为3~5mL/h,优选4mL/h;氮气气压为2~5psi,优选3.5psi;转动心轴的旋转速度100~300rpm,优选200rpm。
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