CN106519205B - 一种载药多孔phbv接枝多巴胺微球的制备方法及应用 - Google Patents
一种载药多孔phbv接枝多巴胺微球的制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种载药多孔PHBV接枝多巴胺微球的制备方法及应用，步骤如下：利用氧等离子体技术使PHBV表面羧基化，得到PHBV‑COOH；将多巴胺偶联到PHBV‑COOH的表面，得到多巴胺修饰的PHBV，即PHBV‑DOPA；利用静电液滴冷凝法制备PHBV‑DOPA微球，然后利用冷冻干燥法制备PHBV‑DOPA多孔微球；利用冷冻干燥法将抗菌药物吸附在PHBV‑DOPA多孔微球的孔隙中，得到载药多孔PHBV‑DOPA微球。本发明有效的提高了PHBV的生物活性，同时提高了PHBV的抗菌性能，且本发明制备工艺简单，反应条件温和，有效的拓宽了PHBV的应用范围。
Description
技术领域
本发明涉及一种药物载体及组织工程材料的制备方法及其应用，属于医用高分子领域，具体涉及一种载药多孔PHBV接枝多巴胺微球的新的制备方法及应用。
背景技术
聚羟基丁酸戊酸共聚酯（PHBV）是细菌在不平衡生长的条件下储存在细胞内的一种不溶于水的高分子聚合物，具有生物可降解性，无抗原性且无毒，无致癌性，生物相容性良好，近年来受到广泛关注。
同时，PHBV在医药领域具有较为广阔的应用前景，例如：将其用作手术缝合线的基材、骨骼和血管的替代品以及用作药物缓释的载体等。鉴于PHBV对人体无任何的副作用，因此将PHBV作为药物缓释载体作为骨组织工程修复材料已经引起了国外研究者的极大的兴趣。目前，PHBV载药的手段主要是将其制作成多孔微球，将药物负载到PHBV微球的孔隙中，从而达到药物的缓释。目前PHBV微球的制备方法主要有溶剂蒸发法，这种方法制备的微球粒径较小，不能够作为骨组织工程支架，且这种方法会残留有机溶剂对人体产伤害。此外，PHBV虽然本身具有较好的生物相容性，但是其本身活性较差，因而需要对其进行改性，以增加其生物活性。
多巴胺是一种低分子量类儿茶酚胺，多巴胺具有优异的亲水性、细胞亲和性以及良好的成骨活性，有效弥补生物降解聚酯亲水性和细胞亲和性差、缺乏成骨活性等不足，赋予复合材料良好的生物功能性。
发明内容
本发明的目的在于提供一种载药多孔PHBV接枝多巴胺微球的制备方法，主要是为了解决PHBV生物活性较差，以及弥补目前PHBV多孔载药微球在制备方法上的一些不足。本发明的反应基本上是在常温下进行，且反应条件温和，制备效率较高。同时本发明所制备的微球具有良好的生物活性和抗菌性能，特别适用于骨组织工程方面的应用。
为解决上述技术问题，本发明采用以下技术方案：
一种载药多孔PHBV接枝多巴胺微球的制备方法，步骤如下：
（1）将PHBV粉末放入氧等离子处理器中，利用氧等离子体技术使PHBV表面羧基化，得到表面羧基化的PHBV（PHBV-COOH）；
（2）将步骤（1）得到的表面羧基化的PHBV进行干燥，然后将干燥后的表面羧基化的PHBV溶于二氯甲烷溶液中，加入N,N'-羰基二咪唑，对表面羧基化的PHBV上的羧基进行活化1h，然后加入多巴胺，搅拌反应8h，反应结束后将沉淀洗涤，干燥，得到多巴胺修饰的PHBV（PHBV-DOPA）；
（3）将多巴胺修饰的PHBV（PHBV-DOPA）溶于二氯甲烷溶液中，然后利用微量注射泵将其缓慢注射到液氮中，同时在微量注射泵的针头上施加电压，将得到的PHBV-DOPA微球进行冷冻干燥，得到PHBV-DOPA多孔微球；
（4）利用冷冻干燥法将抗菌药物吸附在PHBV-DOPA多孔微球的孔隙中，得到载药多孔PHBV接枝多巴胺微球。
所述步骤（1）利用氧等离子体技术使PHBV表面羧基化时，等离子体处理器的功率为200-300W，压力为20-30Pa，处理时间为5-40min。
所述步骤（2）中表面羧基化的PHBV与N,N'-羰基二咪唑的物质的量之比为1:2-5，多巴胺与表面羧基化的PHBV的物质的量之比为1-2:1。
所述步骤（3）中施加在注射器针头上的电压为5-20kV，注射速率为30-60mL/h。
所述步骤（4）中的抗菌药物的质量为PHBV-DOPA多孔微球质量的1-5%。
所述步骤（4）中的抗菌药物包括但不限于万古霉素或布洛芬。
利用所述的载药多孔PHBV接枝多巴胺微球的制备方法制得的载药多孔PHBV接枝多巴胺微球用于组织工程支架修复组织损伤以及抑制组织发生感染。
本发明的有益效果：1、本发明通过表面改性的方法提高了PHBV本身的亲水性、细胞亲和性以及良好的成骨活性，改善了PHBV本身的生物活性不足的问题；2、本发明所采用的多孔载药微球的制备方法较为简单，微球的大小可调，制备效率较高，且不存在溶剂残留的问题；3、本发明中的多孔微球载药的方法为冷冻干燥法，有效的保留了药物的活性，能够起到较好的抑菌效果，提高了PHBV的抗菌性能；4、本发明所制备的载药多孔微球有效的抑制了抗菌药物在人体中释放过快的问题，提高了药物的利用率，同时延长了抑菌时间；5、本发明将多巴胺修饰在PHBV的表面，改善了PHBV的生物活性，然后利用静电液滴冷凝法制备了PHBV多孔微球，制备方法较为简单，反应条件温和，有效的拓宽了PHBV的应用范围，具有良好的应用前景。
具体实施方式
下面结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围，该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
本实施例的载药多孔PHBV接枝多巴胺微球的制备方法，步骤如下：
（1）将10g PHBV粉末放入氧等离子处理器中抽真空至7Pa，后通入氨气至20Pa，在200W强度下处理5min，然后将处理后的PHBV材料清洗、干燥，即得到羧基化的PHBV（PHBV-COOH）；
（2）将PHBV-COOH在50℃条件下真空干燥8h，然后将将1g（0.015mol）无水PHBV-COOH溶于100mL二氯甲烷溶液中，然后加入4.75g （0.03mol）N,N'-羰基二咪唑，对羧基进行活化1h，然后将1.64g多巴胺（0.015mol）加入到PHBV-COOH溶液中，搅拌反应8h即得到PHBV-DOPA，反应结束后将PHBV-DOPA沉淀，洗涤，干燥；
（3）将10gPHBV-DOPA溶于100mL二氯甲烷溶液中，然后利用微量注射泵以30mL/h的速率将其缓慢注射到液氮中，同时在注射器的针头上施加5kV的电压，将得到的PHBV-DOPA微球进行冷冻干燥法即可得到多孔微球；
（4）将0.1g万古霉素溶于水中，然后将10g多孔PHBV-DOPA微球浸泡到药液中，然后将多孔微球冷冻干燥，即得到载药多孔PHBV-DOPA微球。
实施例2
本实施例的载药多孔PHBV接枝多巴胺微球的制备方法，步骤如下：
（1）将10g PHBV粉末放入氧等离子处理器中抽真空至7Pa，后通入氨气至30Pa，在300W强度下处理40min，然后将处理后的PHBV材料清洗、干燥，即得到羧基化的PHBV（PHBV-COOH）；
（2）将1g（0.015mol）无水PHBV-COOH溶于100mL二氯甲烷溶液中，然后加入12.15g（0.075mol） N,N'-羰基二咪唑，对羧基进行活化1h，然后将3.28g（0.03mol）多巴胺加入到PHBV-COOH溶液中，搅拌反应8h即得到PHBV-DOPA，反应结束后将PHBV-DOPA沉淀，洗涤，干燥；
（3）将10gPHBV-DOPA溶于100mL二氯甲烷溶液中，然后利用微量注射泵以60mL/h的速率将其缓慢注射到液氮中，同时在注射器的针头上施加20kV的电压，将得到的PHBV-DOPA微球进行冷冻干燥法即可得到多孔微球；
（4）将0.5g布洛芬溶于水中，然后将10g多孔PHBV-DOPA微球浸泡到药液中，然后将多孔微球冷冻干燥，即得到载药多孔PHBV-DOPA微球。
实施例3
本实施例的载药多孔PHBV接枝多巴胺微球的制备方法，步骤如下：
（1）将10g PHBV粉末放入氧等离子处理器中抽真空至7Pa，后通入氨气至20Pa，在200W强度下处理25min，然后将处理后的PHBV材料清洗、干燥，即得到羧基化的PHBV；
（2）将1g（0.015mol）无水PHBV-COOH溶于100mL二氯甲烷溶液中，然后加入9.50g（0.06mol）N,N'-羰基二咪唑，对羧基进行活化1h，然后将1.64g（0.015mol）多巴胺加入到PHBV-COOH溶液中，搅拌反应8h即得到PHBV-DOPA，反应结束后将PHBV-DOPA沉淀，洗涤，干燥；
（3）将10gPHBV-DOPA溶于100mL二氯甲烷溶液中，然后利用微量注射泵以40mL/h的速率将其缓慢注射到液氮中，同时在注射器的针头上施加10kV的电压，将得到的PHBV-DOPA微球进行冷冻干燥法即可得到多孔微球；
（4）将0.3g抗菌药物溶于水中，然后将10g多孔PHBV-DOPA微球浸泡到药液中，然后将多孔微球冷冻干燥，即得到载药多孔PHBV-DOPA微球。
实施例4
本实施例的载药多孔PHBV接枝多巴胺微球的制备方法，步骤如下：
（1）将10g PHBV粉末放入氧等离子处理器中抽真空至7Pa，后通入氨气至25Pa，在250W强度下处理20min，然后将处理后的PHBV材料清洗、干燥，即得到羧基化的PHBV（PHBV-COOH）；
（2）将1g（0.015mol）无水PHBV-COOH溶于100mL二氯甲烷溶液中，然后加入7.12g（0.045mol） N,N'-羰基二咪唑，对羧基进行活化1h，然后将2.46g（0.0225mol）多巴胺加入到PHBV-COOH溶液中，搅拌反应8h即得到PHBV-DOPA，反应结束后将PHBV-DOPA沉淀，洗涤，干燥；
（3）将10gPHBV-DOPA溶于100mL二氯甲烷溶液中，然后利用微量注射泵以50mL/h的速率将其缓慢注射到液氮中，同时在注射器的针头上施加20kV的电压，将得到的PHBV-DOPA微球进行冷冻干燥法即可得到多孔微球；
（4）将0.5g抗菌药物溶于水中，然后将10g多孔PHBV-DOPA微球浸泡到药液中，然后将多孔微球冷冻干燥，即得到载药多孔PHBV-DOPA微球。
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (6)
1.一种载药多孔PHBV接枝多巴胺微球的制备方法，其特征在于步骤如下：
（1）将PHBV粉末放入氧等离子处理器中，利用氧等离子体技术使PHBV表面羧基化，得到表面羧基化的PHBV；
（2）将步骤（1）得到的表面羧基化的PHBV进行干燥，然后将干燥后的表面羧基化的PHBV溶于二氯甲烷溶液中，加入N,N'-羰基二咪唑，对表面羧基化的PHBV上的羧基进行活化1h，然后加入多巴胺，搅拌反应8h，反应结束后将沉淀洗涤，干燥，得到多巴胺修饰的PHBV；
（3）将多巴胺修饰的PHBV溶于二氯甲烷溶液中，然后利用微量注射泵将其缓慢注射到液氮中，同时在微量注射泵的针头上施加电压，将得到的PHBV-DOPA微球进行冷冻干燥，得到PHBV-DOPA多孔微球；
（4）利用冷冻干燥法将抗菌药物吸附在PHBV-DOPA多孔微球的孔隙中，得到载药多孔PHBV接枝多巴胺微球。
2.根据权利要求1所述的载药多孔PHBV接枝多巴胺微球的制备方法，其特征在于：所述步骤（1）利用氧等离子体技术使PHBV表面羧基化时，氧等离子体处理器的功率为200-300W，压力为20-30Pa，处理时间为5-40min。
3.根据权利要求1所述的载药多孔PHBV接枝多巴胺微球的制备方法，其特征在于：所述步骤（2）中表面羧基化的PHBV与N,N'-羰基二咪唑的物质的量之比为2-5:1，多巴胺与表面羧基化的PHBV的物质的量之比为1-2:1。
4.根据权利要求1所述的载药多孔PHBV接枝多巴胺微球的制备方法，其特征在于：所述步骤（3）中施加在微量注射泵针头上的电压为5-20kV，注射速率为30-60mL/h。
5.根据权利要求1所述的载药多孔PHBV接枝多巴胺微球的制备方法，其特征在于：所述步骤（4）中的抗菌药物的质量为PHBV-DOPA多孔微球质量的1-5%。
6.根据权利要求1所述的载药多孔PHBV接枝多巴胺微球的制备方法，其特征在于：所述步骤（4）中的抗菌药物包括但不限于万古霉素或布洛芬。
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