CN113577031A - 一种药物缓释体的制备方法及药物缓释体 - Google Patents

一种药物缓释体的制备方法及药物缓释体 Download PDF

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CN113577031A
CN113577031A CN202110883058.5A CN202110883058A CN113577031A CN 113577031 A CN113577031 A CN 113577031A CN 202110883058 A CN202110883058 A CN 202110883058A CN 113577031 A CN113577031 A CN 113577031A
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drug
silk fibroin
sphere
glycolic acid
hollow
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杨建军
刘盼苗
叶皓天
尚会杰
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First Affiliated Hospital of Zhengzhou University
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Abstract

本发明公开了一种药物缓释体的制备方法,所述制备方法包括如下步骤:a)制备微米级球体结构;b)将所述球体结构与药物分子结合;c)对所述球体结构与药物分子结合的结合体进行干燥,得到药物缓释体;在所述球体结构中,球体的直径在1μm‑50μm之间;其中,所述球体结构包括:均一球体结构和/或空心球体结构。相应的,本发明还提供了一种采用如上制备方法所制备的药物缓释体。本发明提供的药物缓释体,在进入体内后利用自身对机械波的散射作用,有效实现了在超声下的显影;且通过超声显影该药物缓释体可精确定位药物的作用位置,其缓释作用又可以延长药物的作用时间,提升了神经阻滞治疗的精准性和药物的生物利用度。

Description

一种药物缓释体的制备方法及药物缓释体
技术领域
本发明属于生物医药材料技术领域,具体地说,涉及一种药物缓释体的制备方法及药物缓释体。
背景技术
神经阻滞术是一种有效治疗各种急慢性疼痛的主要手段。在神经干、丛、节的周围注射局麻药,阻滞其冲动传导,使所支配的区域产生麻醉作用,称神经阻滞。神经阻滞只需注射一处,即可获得较大的麻醉区域。但是该操作可能会引起严重的并发症,因此操作时必须熟悉局部解剖,了解穿刺针所要经过的组织以及附近的血管、脏器和体腔等。超声引导下的神经阻滞是利用实时超声清晰显示绝大部分外周神经及其周围的解剖结构,来精确定位注射麻醉药物至治疗部位,在疼痛治疗方面已取得良好效果。
但在超声引导的过程中,虽然能够通过显示穿刺针的位置来提高穿刺的准确性,但注射过程中以及注射后药物扩散的位置并不能有效的呈现。此外,局部大剂量麻醉药物的注射可能会带来不可控的神经损伤,而且过快的药物代谢速度也会降低药物的作用时间。
因此,目前急需一种在超声引导下可显影的药物缓释体。通过其显影作用可精确定位药物的作用位置;通过其缓释作用可以延长药物的作用时间。
发明内容
为了解决现有技术中存在的问题,本发明提供了药物缓释体的制备方法和采用该制备方法制备的药物缓释体。
根据本发明的一个方面,提供一种药物缓释体的制备方法,所述制备方法包括如下步骤:
a)制备微米级球体结构;
b)将所述球体结构与药物分子结合;
c)对所述球体结构与药物分子结合的结合体进行干燥,得到药物缓释体;
在所述球体结构中,球体的直径在1μm-50μm之间;
其中,所述球体结构包括:均一球体结构和/或空心球体结构。
根据本发明的一个具体实施方式,所述均一球体结构中的球体材质为聚乳酸-羟基乙酸共聚物、丝素蛋白或壳聚糖中的任意一种。
根据本发明的另一个具体实施方式,所述空心球体结构的壳层厚度为球体直径的10%~50%。
根据本发明的又一个具体实施方式,所述空心球体结构的壳层材质为均一的聚乳酸-羟基乙酸共聚物、丝素蛋白或壳聚糖的任意一种。
根据本发明的又一个具体实施方式,所述空心球体结构的壳内气体为空气、氟碳类气体、氮气或氩气的任意一种。
根据本发明的又一个具体实施方式,
所述球体结构通过与药物分子的非共价结合实现药物的负载;
所述球体材料负载药物的方式包括物理吸附或分子印迹技术。
根据本发明的又一个具体实施方式,采用真空干燥、冷冻干燥或超临界干燥的方式对所述球体结构与药物分子结合的结合体进行干燥。
根据本发明的又一个具体实施方式,所述球体结构为基于丝素蛋白的均一球体结构时,所述制备方法包括如下步骤:
a1)制备微米级球体结构;
①制备丝素蛋白前聚体溶液
将冷冻干燥后的丝素蛋白溶解于六氟异丙醇溶剂中,制备蚕丝/六氟异丙醇溶液;
将所需体积的去离子水缓慢滴入3ml 15%w/v蚕丝/六氟异丙醇溶液,将二者彻底混合,得到丝素蛋白前聚体溶液;
②采用微流控技术制备单分散丝素蛋白微球
将所述丝素蛋白前聚体溶液作为微流控的水相,采用将含有表面活性剂的正十六烷作为外相,收集产生的液滴;
将所述液滴存储在玻璃容器中,密封并静置几天,形成丝素蛋白水凝胶;
在100℃下,在2小时内用去离子水多次冲洗所述丝素蛋白水凝胶,得到丝素蛋白微球;
b1)将0.05g所述丝素蛋白微球浸泡于1ml质量分数为0.04g/ml的利多卡因溶液中8小时;
c1)对浸泡后的所述丝素蛋白微球进行真空干燥;
重复3次所述步骤b1)和所述步骤c1),得到利多卡因负载的丝素蛋白药物缓释体。
根据本发明的又一个具体实施方式,所述球体结构为基于聚乳酸-羟基乙酸材质的空心球体结构时,所述制备方法包括如下步骤:
a2)制备空心结构的聚乳酸-羟基乙酸微球
将0.3g聚乳酸-羟基乙酸加入到6ml二氯甲烷溶剂中,混合均匀后加入4ml水,高速搅拌1小时;
加入50ml 1%的聚乙烯醇溶液,低速搅拌过夜,得到空心结构的聚乳酸-羟基乙酸微球;
对所述聚乳酸-羟基乙酸空心微球进行离心操作;
用去离子水冲洗三次所述聚乳酸-羟基乙酸空心微球,之后进行冷冻干燥,升华封装冷冻水;
得到所述聚乳酸-羟基乙酸空心微球粉末在2℃下储存;
b2)将0.01g空心结构的聚乳酸-羟基乙酸微球浸泡于1ml质量分数为0.04g/ml的布比卡因溶液中8小时;
c2)对浸泡后的所述聚乳酸-羟基乙酸微球进行真空干燥;
重复3次所述步骤b2)和所述步骤c2),得到布比卡因负载的聚乳酸-羟基乙酸药物缓释体。
根据本发明的另一个方面,提供一种药物缓释体,所述药物缓释体采用本发明提供的任意一项的制备方法制备而成。
根据声波散射原理,药物缓释体在超声下可显影。微球的结构和直径不同,其在超声波下产生的散射效果也不并不相同。超声波遇见球型散射体会发生散射,其散射的强弱与散射体的大小、形状及其与周边组织的声阻抗差别相关。
本发明采用的聚乳酸-羟基乙酸共聚物、丝素蛋白及壳聚糖都存在内部疏松的分子结构,内部存留较小的尺寸不均的孔隙。因此采用上述材质制备的均一球体结构和/或空心球体结构内部都存在与周边组织声阻相差比较大的空气。超声波遇到这些微球体后散射则会增强,出现球形状的显影。
本发明提供的药物缓释体可精确定位药物的作用位置,其缓释作用又可以延长药物的作用时间,进而提升了神经阻滞治疗的精准性和药物的生物利用度。
附图说明
通过阅读参照以下附图所作的对非限制性实施例所作的详细描述,本发明的其它特征、目的和优点将会变得更明显:
图1所示为根据本发明提供的一种药物缓释体的制备方法的一个具体实施方式的流程示意图;
图2所示为球体结构中均一球体结构一个具体实施方式的结构示意图;
图3所示为球体结构中空心球体结构一个具体实施方式的结构示意图。
附图中相同或相似的附图标记代表相同或相似的部件。
具体实施方式
下文的公开提供了许多不同的实施例或例子用来实现本发明的不同结构。为了简化本发明的公开,下文中对特定例子的部件和设置进行描述。此外,本发明可以在不同例子中重复参考数字和/或字母。这种重复是为了简化和清楚的目的,其本身不指示所讨论各种实施例和/或设置之间的关系。应当注意,在附图中所图示的部件不一定按比例绘制。本发明省略了对公知组件和处理技术及工艺的描述以避免不必要地限制本发明。
参见图1,本发明请求保护一种药物缓释体的制备方法,所述方法包括:
步骤S101,制备微米级球体结构。根据所述球体结构的不同,优选的,所述球体结构包括:均一球体结构(参见图2)和/或空心球体结构(参见图3)。其中,所述空心球体结构的壳层厚度为球体直径的10%~50%,例如:10%,25%或者50%。
由于球体分子结构内部疏松时会存在一些小的孔隙,而这些小的孔隙使得球体内部存在与周边组织声阻相差比较大的空气,有利于增强超声波的散射作用。因此,优选采用内部结构适宜的聚乳酸-羟基乙酸共聚物、丝素蛋白或壳聚糖中的一种作为均一球体结构中的球体材质。
同理,优选采用内部结构适宜的聚乳酸-羟基乙酸共聚物、丝素蛋白或壳聚糖中的一种作为空心球体结构的壳层材质。所述空心球体的壳内充有气体,优选的,其壳内气体为空气、氟碳类气体、氮气或氩气的任意一种。
优选的,在所述球体结构中,球体的直径在1μm-50μm之间,例如:1μm、25μm或者50μm。
步骤S102,将所述球体结构与药物分子结合。所述球体结构通过与药物分子的非共价结合实现药物的负载。优选的,采用物理吸附或分子印迹技术实现所述球体结构与药物分子的结合。
步骤S103,对所述球体结构与药物分子结合的结合体进行干燥,得到药物缓释体。优选的,采用真空干燥、冷冻干燥或超临界干燥的方式对所述球体结构与药物分子结合的结合体进行干燥。
在本发明中,均一材质的聚乳酸-羟基乙酸共聚物、丝素蛋白和壳聚糖微米级球体结构(可简称微球)的制备可采用乳化法或微流控技术。为了高效地使微球负载药物,其负载过程可采用多次重复的手段,即将微球多次浸泡于药物溶液并干燥。制备好的药物缓释体应保存于干燥气体环境中。
以下结合具体实施例对本发明所提供的的药物缓释体的制备方法进行进一步阐释:
实施例一
基于丝素蛋白的均一球体结构的超声显影药物缓释体的制备方法包括如下步骤:
a1)①制备丝素蛋白前聚体溶液
丝素蛋白是从家蚕的茧中提取得到的。将冷冻干燥后的丝素蛋白溶解于六氟异丙醇溶剂中,制备蚕丝/六氟异丙醇溶液;
之后,将所需体积的去离子水缓慢滴入3ml 15%w/v蚕丝/六氟异丙醇溶液,通过轻轻旋转将二者彻底混合,即得到丝素蛋白前聚体溶液。
②采用微流控技术制备单分散丝素蛋白微球
将所述丝素蛋白前聚体溶液作为微流控的水相,采用将含有表面活性剂的正十六烷作为外相,收集产生的液滴;
将所述液滴存储在玻璃容器中,密封并静置几天,形成丝素蛋白水凝胶;
在100℃下,在2小时内用去离子水多次冲洗所述丝素蛋白水凝胶,通过溶剂交换和溶剂蒸发彻底去除残留的六氟异丙醇溶剂,得到丝素蛋白微球。
b1)将0.05g所述丝素蛋白微球浸泡于1ml质量分数为0.04g/ml的利多卡因溶液中8小时。
c1)对浸泡后的所述丝素蛋白微球进行真空干燥。
重复3次所述步骤b1)和所述步骤c1),得到利多卡因负载的丝素蛋白药物缓释体。
实施例二
基于聚乳酸-羟基乙酸材质的空心结构的超声显影药物缓释体的制备方法包括如下步骤:
a2)制备空心结构的聚乳酸-羟基乙酸微球
将0.3g聚乳酸-羟基乙酸加入到6ml二氯甲烷溶剂中,混合均匀后加入4ml水,高速搅拌1小时;
加入50ml 1%的聚乙烯醇溶液,低速搅拌过夜,得到空心结构的聚乳酸-羟基乙酸微球;
对所述聚乳酸-羟基乙酸空心微球进行离心操作。优选的,离心速度3000rpm,持续5min。
用去离子水冲洗三次所述聚乳酸-羟基乙酸空心微球,之后在冻干机中进行冷冻干燥,升华封装冷冻水。
得到所述聚乳酸-羟基乙酸空心微球粉末在2℃下储存。
b2)将0.01g空心结构的聚乳酸-羟基乙酸微球浸泡于1ml质量分数为0.04g/ml的布比卡因溶液中8小时。
c2)对浸泡后的所述聚乳酸-羟基乙酸微球进行真空干燥。
重复3次所述步骤b2)和所述步骤c2),得到布比卡因负载的聚乳酸-羟基乙酸药物缓释体。
上述两个实施例仅为进一步说明本发明所请求保护的药物缓释体的制备方法,但并不构成对所述制备方法的限制。
除此之外,本发明还请求保护一种药物缓释体。所述药物缓释体采用本发明提供的制备方法制备而成。
本发明提供的药物缓释体用于神经阻滞可超声显影,其不仅能够精确定位药物的作用位置,而且由于其缓释作用还可以延长药物的作用时间,提升了神经阻滞治疗的准确性和药物的生物利用度。
虽然关于示例实施例及其优点已经详细说明,应当理解在不脱离本发明的精神和所附权利要求限定的保护范围的情况下,可以对这些实施例进行各种变化、替换和修改。对于其他例子,本领域的普通技术人员应当容易理解在保持本发明保护范围内的同时,工艺步骤的次序可以变化。
此外,本发明的应用范围不局限于说明书中描述的特定实施例的工艺、机构、制造、物质组成、手段、方法及步骤。从本发明的公开内容,作为本领域的普通技术人员将容易地理解,对于目前已存在或者以后即将开发出的工艺、机构、制造、物质组成、手段、方法或步骤,其中它们执行与本发明描述的对应实施例大体相同的功能或者获得大体相同的结果,依照本发明可以对它们进行应用。因此,本发明所附权利要求旨在将这些工艺、机构、制造、物质组成、手段、方法或步骤包含在其保护范围内。

Claims (10)

1.一种药物缓释体的制备方法,其特征在于,所述制备方法包括如下步骤:
a)制备微米级球体结构;
b)将所述球体结构与药物分子结合;
c)对所述球体结构与药物分子结合的结合体进行干燥,得到药物缓释体;
在所述球体结构中,球体的直径在1μm-50μm之间;
其中,所述球体结构包括:均一球体结构和/或空心球体结构。
2.根据权利要求1所述的制备方法,其特征在于,所述均一球体结构中的球体材质为聚乳酸-羟基乙酸共聚物、丝素蛋白或壳聚糖中的任意一种。
3.根据权利要求1所述的制备方法,其特征在于,所述空心球体结构的壳层厚度为球体直径的10%~50%。
4.根据权利要求3所述的制备方法,其特征在于,所述空心球体结构的壳层材质为均一的聚乳酸-羟基乙酸共聚物、丝素蛋白或壳聚糖的任意一种。
5.根据权利要求4所述的制备方法,其特征在于,所述空心球体结构的壳内气体为空气、氟碳类气体、氮气或氩气的任意一种。
6.根据权利要求1所述的制备方法,其特征在于,
所述球体结构通过与药物分子的非共价结合实现药物的负载;
所述球体材料负载药物的方式包括物理吸附或分子印迹技术。
7.根据权利要求6所述的制备方法,其特征在于,采用真空干燥、冷冻干燥或超临界干燥的方式对所述球体结构与药物分子结合的结合体进行干燥。
8.根据权利要求7所述的制备方法,其特征在于,所述球体结构为基于丝素蛋白的均一球体结构时,所述制备方法包括如下步骤:
a1)制备微米级球体结构;
①制备丝素蛋白前聚体溶液
将冷冻干燥后的丝素蛋白溶解于六氟异丙醇溶剂中,制备蚕丝/六氟异丙醇溶液;
将所需体积的去离子水缓慢滴入3ml 15%w/v蚕丝/六氟异丙醇溶液,将二者彻底混合,得到丝素蛋白前聚体溶液;
②采用微流控技术制备单分散丝素蛋白微球
将所述丝素蛋白前聚体溶液作为微流控的水相,采用将含有表面活性剂的正十六烷作为外相,收集产生的液滴;
将所述液滴存储在容器中,密封并静置4天,形成丝素蛋白水凝胶;
在100℃下,在2小时内用去离子水多次冲洗所述丝素蛋白水凝胶,得到丝素蛋白微球;
b1)将0.05g所述丝素蛋白微球浸泡于1ml质量分数为0.04g/ml的利多卡因溶液中8小时;
c1)对浸泡后的所述丝素蛋白微球进行真空干燥;
重复3次所述步骤b1)和所述步骤c1),得到利多卡因负载的丝素蛋白药物缓释体。
9.根据权利要求7所述的制备方法,其特征在于,所述球体结构为基于聚乳酸-羟基乙酸材质的空心球体结构时,所述制备方法包括如下步骤:
a2)制备空心结构的聚乳酸-羟基乙酸微球
将0.3g聚乳酸-羟基乙酸加入到6ml二氯甲烷溶剂中,混合均匀后加入4ml水,300rmp的转速下搅拌1小时;
加入50ml 1%的聚乙烯醇溶液,50rmp的转速下搅拌12小时,得到空心结构的聚乳酸-羟基乙酸微球;
对所述聚乳酸-羟基乙酸空心微球进行离心操作;
用去离子水冲洗三次所述聚乳酸-羟基乙酸空心微球,之后进行冷冻干燥,升华封装冷冻水;
得到所述聚乳酸-羟基乙酸空心微球粉末在2℃下储存;
b2)将0.01g空心结构的聚乳酸-羟基乙酸微球浸泡于1ml质量分数为0.04g/ml的布比卡因溶液中8小时;
c2)对浸泡后的所述聚乳酸-羟基乙酸微球进行真空干燥;
重复3次所述步骤b2)和所述步骤c2),得到布比卡因负载的聚乳酸-羟基乙酸药物缓释体。
10.一种药物缓释体,其特征在于,所述药物缓释体采用如权利要求1~9中任意一项的制备方法制备而成。
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CN1679579A (zh) * 2005-01-26 2005-10-12 上海大学 氟尿嘧啶载药微球及其制备方法
CN101244277A (zh) * 2008-02-14 2008-08-20 苏州大学 丝素载药微球及其制备方法
CN101361716A (zh) * 2008-10-10 2009-02-11 中国人民解放军军事医学科学院微生物流行病研究所 多孔微球及其在制备多孔微球疫苗中的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1679579A (zh) * 2005-01-26 2005-10-12 上海大学 氟尿嘧啶载药微球及其制备方法
CN101244277A (zh) * 2008-02-14 2008-08-20 苏州大学 丝素载药微球及其制备方法
CN101361716A (zh) * 2008-10-10 2009-02-11 中国人民解放军军事医学科学院微生物流行病研究所 多孔微球及其在制备多孔微球疫苗中的应用

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