CN105902515A - 纳米药物存储器、其制备方法及其应用 - Google Patents
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Abstract
本发明涉及一种纳米药物存储器、其制备方法及其应用，所述的纳米药物存储器为三嵌段高分子共聚物组成，在水中与药物作用自组装而成，其中所述的三嵌段高分子共聚物第第一片段为聚乳酸‑甘醇酸6000Da，第二片段为聚乙二醇3000Da，第三片段为聚甲苯硼酸15000Da。采用了该发明中的纳米药物存储器、其制备方法及其应用，采用的原料生物相容性极好，均通过美国FDA认证，可在生物体内自降解，广泛应用于食品、药物、化妆品领域，在体内可以降解成人自身含有的代谢产物，随体液排除体外，绝对安全无毒副作用。本产品可适用药物广泛，模块尺寸和形状可控，药物缓释时间可控，体内降解速度可控。
Description
技术领域
本发明涉及生物医药领域，尤其涉及纳米药物，具体是指一种纳米药物存储器、其制备方法及其应用。
背景技术
纳米级药物载体是一种属于纳米级微观范畴的亚微粒药物载体输送系统。将药物包封于亚微粒中，可以调节释药的速度，增加生物膜的透过性、改变在体内的分布、提高生物利用度等。纳米粒(nanoparticle，NP)又称毫微粒，是大小在10～1000nm之间的固态胶体颗粒，一般由天然高分子物质或合成高分子物质构成，可作为传导或输送药物的载体。由于材料和制备工艺的差异，可以形成纳米球(nanosphere)与纳米囊(nanocapsule)，两者统称为纳米粒。嵌段共聚物分子链中，嵌段间的相互热力学不相容性及化学键相连接性，使体系发生自组装。通过适当的分子及体系设计，嵌段共聚物体系能够自组装形成丰富的周期性有序微结构。
一般的给药方式，使人体内的药物浓度只能维持较短的时间，血液或体内组织中的药物浓度上下波动较大，有时超过病人的药物最高耐受剂量，有时又低于有效剂量，这样不但起不到应有的疗效，而且还可能产生副作用。频繁的小剂量给药可以调节血药浓度，避免上述现象，但往往使患者难以接受，实施起来有很多困难,因而制备能够缓慢释放药物成分的缓释性长效药品在治疗中经常是非常需要的。要制备缓释长效药品，关键是要制备能使被承载的药物缓慢释放的载体材料,具有良好的生物相容性、无毒性、良好的物理性能，并可以通过植入人体实现长效缓释药物的新剂型。
发明内容
本发明的目的是克服了上述现有技术的缺点，提供了一种能够实现长效缓释的纳米药物存储器、其制备方法及其应用。
为了实现上述目的，本发明的纳米药物存储器、其制备方法及其应用具有如下构成：
该纳米药物存储器、其制备方法及其应用，其主要特点是，所述的纳米药物存储器为三嵌段高分子共聚物组成，在水中与药物作用自组装而成，其中所述的三嵌段高分子共聚物第第一片段为聚乳酸-甘醇酸6000Da，第二片段为聚乙二醇3000Da，第三片段为聚甲苯硼酸15000Da。
优选地，所述的药物为羊毛甾醇。
更优选地，所述的聚乳酸-甘醇酸与所述的药物通过疏水键形成药物存储器的内核。
进一步优选地，所述的聚乙二醇通过亲水键形成纳米药物存储器的壳层。
更进一步优选地，所述的聚甲苯硼酸形成纳米药物存储器的外层。
再进一步优选地，所述的聚甲苯硼酸通过硼酸酯键与多糖形成纳米水凝胶结构。
最优选地，所述的多糖为环糊精。
一种所述的纳米药物存储器的制备方法，其主要特点是，所述的制备方法包括：
(1)将所述的三嵌段高分子共聚物溶解于100mg/mL的DMSO，4℃下静置得到溶液A；
(2)将多糖溶于10mg/mL的PBS，4℃下静置得到溶液B；
(3)将所述的药物溶于10mg/mL的DMSO，4℃下静置得到溶液C；
(4)将所述的溶液A5mL同溶液B5mL混合均匀得到溶液D；
(5)将10mL溶液D置于蒸发皿中，减压蒸馏下除去DMSO，得到层状薄膜结构E；
(6)向蒸发皿中加入20mL PBS充分溶解E，所得溶液通过0.45um滤膜过滤得到溶液F；
(7)5mL溶液B加入20mL溶液E，振荡混合均匀，在37摄氏度静置2小时得到纳米水凝胶。
优选地，所述的制备方法还包括：
(8)在使用前对纳米水凝胶进行UV照射杀菌。
一种所述的纳米药物存储器的应用，其主要特点是，所述的纳米药物存储器用于改善眼睛晶状体的清晰度和透光率。
采用了该发明中的纳米药物存储器、其制备方法及其应用，采用的原料生物相容性极好，均通过美国FDA认证，可在生物体内自降解，广泛应用于食品、药物、化妆品领域，在体内可以降解成人自身含有的代谢产物，随体液排除体外，绝对安全无毒副作用。本产品可适用药物广泛(各类亲疏水药物，可多药联合使用)，模块尺寸和形状可控，药物缓释时间可控(数天～数月)，体内降解速度可控(数周～数年)。本产品在前期应用于哺乳动物实验中，已经获得了非常积极的效果。尤其是针对慢性复发性重大疾病，可以作为一种高效的手段来攻克医疗难题。此产品为可植入人体内的生物相容性的药物缓释体，通过手术介入的方法，将药物缓释体安装在病灶部位，有效地实现稳定性，长时间地对病灶局部缓释给药。
附图说明
图1为本发明的纳米药物存储器的可视图及显微镜图。
图2为本发明的纳米药物存储器的缓释效果图。
图3为本发明的纳米药物存储器应用效果图。
图4为本发明的纳米药物存储器结构组合图。
具体实施方式
为了能够更清楚地描述本发明的技术内容，下面结合具体实施例来进行进一步的描述。
该纳米药物存储器、其制备方法及其应用，其主要特点是，所述的纳米药物存储器为三嵌段高分子共聚物组成，在水中与药物作用自组装而成，其中所述的三嵌段高分子共聚物第第一片段为聚乳酸-甘醇酸6000Da，第二片段为聚乙二醇3000Da，第三片段为聚甲苯硼酸15000Da。所述的药物为羊毛甾醇。纳米药物储存器有三嵌段高分子共聚物聚甲苯硼酸－聚乙二醇－聚乳酸-甘醇酸组成，通过在水中和药物分子作用，以自组装的方式形成纳米药物存储器。其中嵌段高分子共聚物的第一片段为聚乳酸-甘醇酸，生物相容性极好(通过美国FDA认证)，可在生物体自降解，是生物自降解的高分子材料，依靠其疏水性可以同药物通过疏水键的作用，形成药物储存器的内核；另外嵌段高分子共聚物的第二片段为聚乙二醇，目前聚乙二醇的生物相容性最好(通过美国FDA认证)，广泛应用于食品、药物、化妆品领域，由于其高亲水性的性能，在纳米存储器的结构上充当直接包裹药物存储的壳层，为药物提供高的水溶性，即形成药物释放控制的中间层；最终嵌段高分子共聚物的第三片段为聚甲苯硼酸，同样为生物相容性极佳的材料，由于其亲水性，成为具有组织相容的纳米药物存储器的最外层。最终，此纳米结构通过与多糖混合，伴随着多糖与纳米药物存储器最外层聚甲苯硼酸的硼酸酯键形成可以得到水凝胶产品。优选地，所述的多糖为环糊精。
一种所述的纳米药物存储器的制备方法，其特征在于，所述的制备方法包括：
(1)将所述的三嵌段高分子共聚物溶解于100mg/mL的DMSO，4℃下静置得到溶液A；
(2)将多糖溶于10mg/mL的PBS，4℃下静置得到溶液B；
(3)将所述的药物溶于10mg/mL的DMSO，4℃下静置得到溶液C；
(4)将所述的溶液A5mL同溶液B5mL混合均匀得到溶液D；
(5)将10mL溶液D置于蒸发皿中，减压蒸馏下除去DMSO，得到层状薄膜结构E；
(6)向蒸发皿中加入20mL PBS充分溶解E，所得溶液通过0.45um滤膜过滤得到溶液F；
(7)5mL溶液B加入20mL溶液E，振荡混合均匀，在37摄氏度静置2小时得到纳米水凝胶；
(8)在使用前对纳米水凝胶进行UV照射杀菌。
一种所述的纳米药物存储器的应用，其特征在于，所述的纳米药物存储器用于改善眼睛晶状体的清晰度和透光率。
本申请的纳米药物存储器如图1所示，为水凝胶状态(图1左)，可以通过注射方式介入患处。水凝胶结构内含有纳米药物胶束(图1右)，可以用来装载药物分子，并且可以控制药物释放。
生物相容性：
如下表1、2所示，所植入的凝胶不会对组织细胞造成毒副作用，并且不会造成免疫反应，因此此产品是生物相容性很好的植入材料。
表1细胞毒性
| 细胞种类 | 血管细胞 | 上皮细胞 | 肌肉细胞 | 肝细胞 |
| 细胞存活率(一天) | ＞97％ | ＞98％ | ＞94％ | ＞96％ |
| 细胞存活率(一个月) | ＞99％ | ＞98％ | ＞97％ | ＞99％ |
表2免疫反应
| 细胞因子 | IL-12 | TNF-α | IL6 | IL8 | IFNγ | LDH |
| 正常值 | 2.9-53.9 | 0-32.5 | 0-12.7 | 0-50.4 | 0-1.5 | 140-280 |
| 植入后一天 | 22.1±3.4 | 10.9±11.2 | 4.6±1.6 | 17.1±8.1 | 0.56±0.2 | 202±17 |
| 植入后一个月 | 28.4±10.9 | 19.7±4.2 | 8.1±1.7 | 29±11.7 | 0.66±0.3 | 209±52 |
| 植入后四个月 | 27.3±8.3 | 19.2±6.5 | 7.0±1.5 | 19±11.2 | 0.63±0.4 | 206±19 |
本申请的纳米药物存储器的体外缓释效果如图2所示。
体内(眼部)治疗的效果(Lanosterol)：将药物模块注射入患有白内障狗的眼睛侧部(睑结膜下，巩膜上)，如图3所示，3个月后，白内障的状况有明显改善。晶状体的清晰度和透光率得到了恢复。
采用了该发明中的纳米药物存储器、其制备方法及其应用，采用的原料生物相容性极好，均通过美国FDA认证，可在生物体内自降解，广泛应用于食品、药物、化妆品领域，在体内可以降解成人自身含有的代谢产物，随体液排除体外，绝对安全无毒副作用。本产品可适用药物广泛(各类亲疏水药物，可多药联合使用)，模块尺寸和形状可控，药物缓释时间可控(数天～数月)，体内降解速度可控(数周～数年)。本产品在前期应用于哺乳动物实验中，已经获得了非常积极的效果。尤其是针对慢性复发性重大疾病，可以作为一种高效的手段来攻克医疗难题。此产品为可植入人体内的生物相容性的药物缓释体，通过手术介入的方法，将药物缓释体安装在病灶部位，有效地实现稳定性，长时间地对病灶局部缓释给药。
在此说明书中，本发明已参照其特定的实施例作了描述。但是，很显然仍可以作出各种修改和变换而不背离本发明的精神和范围。因此，说明书和附图应被认为是说明性的而非限制性的。
Claims (10)
1.一种纳米药物存储器，其特征在于，所述的纳米药物存储器为三嵌段高分子共聚物组成，在水中与药物作用自组装而成，其中所述的三嵌段高分子共聚物第第一片段为聚乳酸-甘醇酸6000Da，第二片段为聚乙二醇3000Da，第三片段为聚甲苯硼酸15000Da。
2.根据权利要求1所述的纳米药物存储器，其特征在于，所述的药物为羊毛甾醇。
3.根据权利要求1所述的纳米药物存储器，其特征在于，所述的聚乳酸-甘醇酸与所述的药物通过疏水键形成药物存储器的内核。
4.根据权利要求1所述的纳米药物存储器，其特征在于，所述的聚乙二醇通过亲水键形成纳米药物存储器的壳层。
5.根据权利要求1所述的纳米药物存储器，其特征在于，所述的聚甲苯硼酸形成纳米药物存储器的外层。
6.根据权利要求5所述的纳米药物存储器，其特征在于，所述的聚甲苯硼酸通过硼酸酯键与多糖形成纳米水凝胶结构。
7.根据权利要求6所述的纳米药物存储器，其特征在于，所述的多糖为环糊精。
8.一种权利要求1～7中任一项所述的纳米药物存储器的制备方法，其特征在于，所述的制备方法包括：
(1)将所述的三嵌段高分子共聚物溶解于100mg/mL的DMSO，4℃下静置得到溶液A；
(2)将多糖溶于10mg/mL的PBS，4℃下静置得到溶液B；
(3)将所述的药物溶于10mg/mL的DMSO，4℃下静置得到溶液C；
(4)将所述的溶液A5mL同溶液B5mL混合均匀得到溶液D；
(5)将10mL溶液D置于蒸发皿中，减压蒸馏下除去DMSO，得到层状薄膜结构E；
(6)向蒸发皿中加入20mL PBS充分溶解E，所得溶液通过0.45um滤膜过滤得到溶液F；
(7)5mL溶液B加入20mL溶液E，振荡混合均匀，在37摄氏度静置2小时得到纳米水凝胶。
9.根据权利要求8所述的纳米药物存储器的制备方法，其特征在于，所述的制备方法还包括：
(8)在使用前对纳米水凝胶进行UV照射杀菌。
10.一种权利要求1所述的纳米药物存储器的应用，其特征在于，所述的纳米药物存储器用于改善眼睛晶状体的清晰度和透光率。
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