CN103751102A - 一种胶原酶温敏水凝胶及其制备方法和应用 - Google Patents

一种胶原酶温敏水凝胶及其制备方法和应用 Download PDF

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CN103751102A
CN103751102A CN201410018764.3A CN201410018764A CN103751102A CN 103751102 A CN103751102 A CN 103751102A CN 201410018764 A CN201410018764 A CN 201410018764A CN 103751102 A CN103751102 A CN 103751102A
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袁伟恩
徐明新
吴飞
胡振华
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Shanghai Jiaotong University
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Priority to PCT/US2015/011296 priority patent/WO2015108901A1/en
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Abstract

本发明涉及一种温敏水凝胶及其制备方法和应用，特别涉及一种胶原酶温敏水凝胶及其制备方法和应用。本发明的胶原酶温敏水凝胶，包括水凝胶和胶原酶多糖颗粒，所述水凝胶为60-90%重量，所述胶原酶多糖颗粒为10-40%重量。与现有技术相比，本发明的胶原酶温敏水凝胶在注射到病灶部位后，慢慢升温至体温，形成原位水凝胶，此水凝胶能缓慢地将胶原酶释放出来，使胶原酶集中在病变部位发挥药效，本发明的胶原酶温敏水凝胶局部给药能减少向正常组织扩散，与粉针剂型胶原酶相比扩散减少了30-80%。

Description

一种胶原酶温敏水凝胶及其制备方法和应用
技术领域
本发明涉及一种温敏水凝胶及其制备方法和应用，特别涉及一种胶原酶温敏水凝胶及其制备方法和应用。
背景技术
掌健膜挛缩症是一种良性、进展性的纤维增生性慢性疾病，会导致手掌筋膜异常瘫痕组织的形成。在手的掌腱膜组织发生结节状和索带状病变，病变可波及手指腱膜，导致掌指、指间关节进行性屈曲挛缩畸形。掌腱膜挛缩症是北欧地区的多发病。在瑞典、挪威等国发病率较高，白人发病率高于黑人，黄色人种发病较少，而黑人更少发病。在欧洲患者中三分之一有家族史。70年代后在我国的发病率呈上升趋势，与社会老年人增多，重视手部伤病的防治以及手外科专业医生与技术的发展相关。
近期，经FDA批准的注射用胶原酶梭状芽泡杆菌组织溶解剂提供了一种非手术，微创的方法可供选择，并且还能同手术一样降低关节挛缩和改善关节运动。
溶组织梭菌胶原酶用于治疗手掌腱膜挛缩症，作用机制在于溶解胶原沉积物而达到治疗目的，由于掌腱膜条索主要由胶原组成，通过注射胶原酶能够酶解这种条索。作为首个且唯一的治疗掌健膜挛缩症的药物，目前剂型只有冻干粉针，但是由于胶原酶也会溶解正常组织的胶原蛋白，注射后胶原酶会向正常组织扩散，引起一系列的不良反应包括肿胀、出血等，严重的会导致肌腱断裂。因此，将注射后胶原酶富集在病灶部位，减少对正常组织的损伤显得尤为重要。
发明内容
本发明目的在于提供一种胶原酶温敏水凝胶，以解决现有技术中胶原酶粉针剂型注射到病变部位会快速释放并分散，很难富集并专一性作用于病变区域，导致炎症反应过多，甚至会作用于正常的含胶原蛋白的结构造成肌腱断裂等严重副作用的技术性问题。
本发明的另一目的在于提供上述胶原酶温敏水凝胶的制备方法，以解决现有技术中胶原酶粉针剂型注射到病变部位会快速释放并分散，很难富集并专一性作用于病变区域，导致炎症反应过多，甚至会作用于正常的含胶原蛋白的结构造成肌腱断裂等严重副作用的技术性问题。
本发明的再一目的在于提供上述胶原酶温敏水凝胶在制备治疗手掌腱膜挛缩症的药物中的应用。
本发明目的通过以下技术方案实现：
一种胶原酶温敏水凝胶，包括水凝胶和胶原酶多糖颗粒，所述水凝胶为60-90%重量，所述胶原酶多糖颗粒为10-40%重量。
在本发明优选的实施例中，所述胶原酶多糖颗粒包括胶原酶和葡聚糖，所述胶原酶为20-50%重量。
在本发明优选的实施例中，所述水凝胶的原料选自PLGA-PEG-PLGA、PEG-PLGA-PEG、PEG-PLA-PEG、PLA-PEG-PLA、PCL-PEG-PCL或PEG-壳聚糖的其中一种。
上述的胶原酶温敏水凝胶的制备方法，包括以下步骤：
将5-30重量份聚合物加入70-95重量份水中，在冰浴条件下振摇至澄清透明，然后使聚合物的水溶液缓慢升温至室温，在水溶液变稠，但还没成凝胶时，加入1-10重量份胶原酶多糖颗粒，经涡旋混合均匀，然后继续混合至形成水凝胶。
在本发明优选的实施例中，所述胶原酶多糖颗粒包括胶原酶和葡聚糖，所述胶原酶为20-50%重量。
在本发明优选的实施例中，所述聚合物选自PLGA-PEG-PLGA、PEG-PLGA-PEG、PEG-PLA-PEG、PLA-PEG-PLA、PCL-PEG-PCL或PEG-壳聚糖的其中一种。
在本发明优选的实施例中，所述胶原酶多糖颗粒的制备方法包括以下步骤：
将胶原酶加入葡聚糖溶液，胶原酶与葡聚糖的重量比为（1-50）：1，混合均匀后再加入含聚乙二醇的海藻酸钠溶液，涡旋振荡均匀后，形成乳液，静置，待乳液表面气泡基本消失后，冷冻干燥即可得胶原酶多糖颗粒。
在本发明优选的实施例中，所述胶原酶多糖颗粒的制备方法包括以下步骤：
将胶原酶加入葡聚糖溶液，胶原酶与葡聚糖的重量比为（1-50）：1，混合均匀后再加入聚乙二醇溶液，涡旋振荡均匀后，形成乳液，静置，待乳液表面气泡基本消失后，冷冻干燥即可得胶原酶多糖颗粒。
上述的胶原酶温敏水凝胶在制备治疗手掌腱膜挛缩症的药物中的应用。
与现有技术相比，本发明有以下有益效果：
本发明的胶原酶温敏水凝胶在注射到病灶部位后，慢慢升温至体温，形成原位水凝胶，此水凝胶能缓慢地将胶原酶释放出来，使胶原酶集中在病变部位发挥药效，本发明的胶原酶温敏水凝胶局部给药能减少向正常组织扩散，与粉针剂型胶原酶相比扩散减少了30-80%。
附图说明
图1为水相水相乳化法制备的胶原酶多糖颗粒的扫描电镜图；
图2为低温冷冻相分离制备的胶原酶多糖颗粒的扫描电镜图；
图3为本发明的胶原酶温敏水凝胶的体外累计释放率曲线图。
具体实施方式
以下结合实施例详细说明本发明。
实施例1  水相水相乳化法制备胶原酶多糖颗粒
处方：
胶原酶：25mg
20%(w/w)葡聚糖溶液：250μL
乳化剂：2.5mL的含10%PEG和1%海藻酸钠的水溶液
制备方法为：
胶原酶25mg，溶解于250μL的20%葡聚糖溶液，混合均匀后再加入2.5mL的含10%的PEG和1%海藻酸钠的溶液，涡旋振荡均匀后，形成乳液，静置，待乳液表面气泡基本消失后，冷冻干燥。冻干的粉末二氯甲烷洗涤。
取适量胶原酶多糖颗粒加超纯水混悬均匀涂于铝箔上，再将铝箔置于导电胶，待溶剂自然挥干后，用离子镀膜仪溅金后采用扫描电镜观察颗粒大小和表面形态，仪器型号为JSM-7401F，扫描电镜图如图1所示。
实施例2  低温冷冻相分离制备胶原酶多糖颗粒
处方：
胶原酶：50mg
10%(w/w)葡聚糖溶液：1ml
10%PEG溶液 10ml
制备方法为：
胶原酶50mg，加入到重量百分比浓度为10%W/W葡聚糖（Dex）溶液1mL中，混合均匀后再加入10mL的10%W/W的PEG溶液，涡旋振荡均匀后，形成乳液，静置，待乳液表面气泡基本消失后，冷冻干燥。冻干的粉末二氯甲烷洗涤。
取适量胶原酶多糖颗粒加超纯水混悬均匀涂于铝箔上，再将铝箔置于导电胶，待溶剂自然挥干后，用离子镀膜仪溅金后采用扫描电镜观察颗粒大小和表面形态，仪器型号为JSM-7401F，扫描电镜图如图2所示。
实施例3  制备胶原酶温敏水凝胶
温敏水凝胶处方：
PLGA-PEG-PLGA水溶液：100mg
制备方法为：
将30mg PLGA-PEG-PLGA加入70mg超纯水中，在冰浴条件下置于脱色摇床上振摇2-3天至澄清透明，然后使聚合物的水溶液缓慢升温至室温，在水溶液变稠，但还没成凝胶时，加入20mg胶原酶多糖颗粒，经涡旋混合均匀，然后继续混合至形成水凝胶。
实施例4  制备胶原酶温敏水凝胶
温敏水凝胶处方：
PEG-PLGA-PEG水溶液：45mg
制备方法为：
将10mg PLGA-PEG-PLGA加入35mg超纯水中，在冰浴条件下置于脱色摇床上振摇2-3天至澄清透明，然后使聚合物的水溶液缓慢升温至室温，在水溶液变稠，但还没成凝胶时，加入5mg胶原酶多糖颗粒，经涡旋混合均匀，然后继续混合至形成水凝胶。
实施例5  制备胶原酶温敏水凝胶
温敏水凝胶处方：
PLA-PEG-PLA水溶液：45mg
制备方法为：
将10mg PLGA-PEG-PLGA加入35mg超纯水中，在冰浴条件下置于脱色摇床上振摇2-3天至澄清透明，然后使聚合物的水溶液缓慢升温至室温，在水溶液变稠，但还没成凝胶时，加入30mg胶原酶多糖颗粒，经涡旋混合均匀，然后继续混合至形成水凝胶。
胶原酶温敏水凝胶体外累计释放率的测定实验
本实验是在37℃的恒温摇床中做体外释放，摇速控制在50r/min，准确称取2ml胶原酶温敏水凝胶（实施例3制备的），加入5mL的pH7.4PBS缓冲溶液，置于37℃恒温空气浴摇床中，测定体外释放情况。每日定时取样，释放七天后在酶标仪下采用MicroBCA法，得出胶原酶温敏水凝胶的释放曲线，如图3所示，结果显示：本发明的胶原酶温敏水凝胶在注射到病灶部位后的可以持续释放有效的药物。
对比试验
实验过程为：取粉针剂型胶原酶及胶原酶温敏水凝胶注射到兔不同的病变部位的皮下（每只兔取4个不同病变部位），每个病变部位注射的胶原酶为1.25mg，在相同的时间点：24小时和48小时，取兔病变部位相同的面积及相同的厚度组织,以注射点为圆心，直径为1cm的圆，厚度为1cm，然后匀浆，用水提取胶原酶，然后离心得上清液，用Elisiza试剂盒分别测定其浓度，然后通过计算，分别得出其胶原酶的总含量，如表1所示。然后对两者的结果进行对比。结果显示：本发明的胶原酶温敏水凝胶局部给药能减少向正常组织扩散，与粉针剂型胶原酶相比扩散减少了30-80%。
表1  药物扩散比较
Figure BDA0000457414080000051
以上公开的仅为本申请的几个具体实施例，但本申请并非局限于此，任何本领域的技术人员能思之的变化，都应落在本申请的保护范围内。

Claims (9)

1.一种胶原酶温敏水凝胶，其特征在于，包括水凝胶和胶原酶多糖颗粒，所述水凝胶为60-90%重量，所述胶原酶多糖颗粒为10-40%重量。
2.如权利要求1所述的胶原酶温敏水凝胶，其特征在于，所述胶原酶多糖颗粒包括胶原酶和葡聚糖，所述胶原酶为20-50%重量。
3.如权利要求1所述的胶原酶温敏水凝胶，其特征在于，所述水凝胶的原料选自PLGA-PEG-PLGA、PEG-PLGA-PEG、PEG-PLA-PEG、PLA-PEG-PLA、PCL-PEG-PCL或PEG-壳聚糖的其中一种。
4.权利要求1-3中任意一项所述的胶原酶温敏水凝胶的制备方法，其特征在于，包括以下步骤：
将5-30重量份聚合物加入70-95重量份水中，在冰浴条件下振摇至澄清透明，然后使聚合物的水溶液缓慢升温至室温，在水溶液变稠，但还没成凝胶时，加入1-10重量份胶原酶多糖颗粒，经涡旋混合均匀，然后继续混合至形成水凝胶。
5.如权利要求4所述的胶原酶温敏水凝胶的制备方法，其特征在于，所述胶原酶多糖颗粒包括胶原酶和葡聚糖，所述胶原酶为20-50%重量。
6.如权利要求4所述的胶原酶温敏水凝胶的制备方法，其特征在于，所述聚合物选自PLGA-PEG-PLGA、PEG-PLGA-PEG、PEG-PLA-PEG、PLA-PEG-PLA、PCL-PEG-PCL或PEG-壳聚糖的其中一种。
7.如权利要求4所述的胶原酶温敏水凝胶的制备方法，其特征在于，所述胶原酶多糖颗粒的制备方法包括以下步骤：
将胶原酶加入葡聚糖溶液，胶原酶与葡聚糖的重量比为（1-50）：1，混合均匀后再加入含聚乙二醇的海藻酸钠溶液，涡旋振荡均匀后，形成乳液，静置，待乳液表面气泡基本消失后，冷冻干燥即可得胶原酶多糖颗粒。
8.如权利要求4所述的胶原酶温敏水凝胶的制备方法，其特征在于，所述胶原酶多糖颗粒的制备方法包括以下步骤：
将胶原酶加入葡聚糖溶液，胶原酶与葡聚糖的重量比为（1-50）：1，混合均匀后再加入聚乙二醇溶液，涡旋振荡均匀后，形成乳液，静置，待乳液表面气泡基本消失后，冷冻干燥即可得胶原酶多糖颗粒。
9.权利要求1-3中任意一项所述的胶原酶温敏水凝胶在制备治疗手掌腱膜挛缩症的药物中的应用。
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