CN115554235A - 一种长效缓释丹酚酸b的可注射心衰治疗水凝胶及其制备方法 - Google Patents
一种长效缓释丹酚酸b的可注射心衰治疗水凝胶及其制备方法 Download PDFInfo
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- CN115554235A CN115554235A CN202211281337.5A CN202211281337A CN115554235A CN 115554235 A CN115554235 A CN 115554235A CN 202211281337 A CN202211281337 A CN 202211281337A CN 115554235 A CN115554235 A CN 115554235A
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- salvianolic acid
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- heart failure
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Abstract
本发明公开了一种长效缓释丹酚酸B的可注射心衰治疗水凝胶及其制备方法，本发明通过将植物提取物丹酚酸B引入钙离子交联的海藻酸钠水凝胶，之后与钙离子交联的不含丹酚酸B的海藻酸钠水凝胶，在应力场作用下，进行混合。利用钙离子交联的动态可逆特性，通过相分离形成海岛结构，利用不同相之间的界面，调控水溶性丹酚酸B的释放曲线，防止突释。动物实验结果表明，水凝胶可促进间隙连接的生成和血管生成，缩小梗死面积，改善心功能。
Description
技术领域
本发明属于生物材料技术领域，具体涉及到一种长效缓释丹酚酸B的可注射心衰治疗水凝胶及其制备方法。
背景技术
心力衰竭(简称“心衰”)是各种心脏疾病的严重表现或晚期阶段。心脏的生理功能就是不停地通过动脉把血液输送到全身，同时接受静脉从周围组织脏器输送回心脏的血液。心脏泵血功能衰退，输出血量不能满足身体代谢需要(射血功能下降)；器官和组织中的血液也不能顺利回流到心脏，导致身体其他组织淤血肿胀，可能出现呼吸困难、乏力、水肿等心衰表现。心衰会影响全身脏器的功能：肾血管灌注不足可致肾功能异常，肝脏长期处于淤血缺氧的状态可致心原性肝硬化，肺部淤血可增加呼吸道感染概率，长期卧床的患者下肢静脉易形成血栓。心衰的种种症状严重限制了患者的日常活动，影响生活质量。心衰还会影响患者的工作、社交，甚至带来抑郁、焦虑等负面情绪。此外，心衰是各种心脏疾病的严重表现或晚期阶段，患者死亡率和再住院率居高不下。
目前心衰的临床治疗包括药物溶栓、经皮冠状动脉介入治疗、冠状动脉搭桥手术和心脏移植。除心脏移植外，其他治疗方法仅限于缓解症状，不能诱导组织修复，难以重建受损心肌。迄今为止，心脏移植仍是唯一有效的方法。然而，批准进行心脏移植的患者数量与心脏捐赠者数量之间存在巨大差异，造成严重短缺，极大地限制了这种治疗的有效性。向受损的心肌壁内注射水凝胶，可以支持心肌组织，增加心肌壁的厚度，缩小心脏腔室体积，从而恢复心脏供血能力，是一种极具潜力的心衰治疗新方法。
传统的活血化瘀中药丹参，因其具有祛瘀止痛、活血通经的功效，目前已被广泛用于心血管疾病的治疗。研究发现，丹酚酸(salvianolic acids)是丹参(拉丁学名：salviamiltiorrhiza bunge)中含量最丰富的水溶性物质，而丹酚酸B则是丹酚酸中含量最多、生物活性最强的化合物。丹酚酸B具有很强的抗氧化作用，体内外实验证明，丹酚酸B能清除氧自由基、抑制脂质过氧化反应，其作用强度高于维生素C、维生素E、甘露醇，是已知的抗氧化作用最强的天然产物之一。药理学研究表明，注射用丹参酚酸具有明显的抗氧化作用，抑制血小板聚集，及抑制血栓形成的作用，并能延长缺氧条件下动物的存活时间。
海藻酸钠是从褐藻类的海带或马尾藻中提取碘和甘露醇之后的副产物，其分子由β-D-甘露糖醛酸(β-D-mannuronic，M)和α-L-古洛糖醛酸(α-L-guluronic，G)按(1→4)键连接而成，是一种天然多糖，具有药物制剂辅料所需的稳定性、溶解性、粘性和安全性。海藻酸钠已经在食品工业和医药领域得到了广泛应用。
海藻酸钠是无毒食品，海藻酸钠含有大量的-COO-，在水溶液中可表现出聚阴离子行为，具有一定的黏附性，可用作治疗黏膜组织的药物载体。在酸性条件下，-COO-转变成-COOH，电离度降低，海藻酸钠的亲水性降低，分子链收缩，pH值增加时，-COOH基团不断地解离，海藻酸钠的亲水性增加，分子链伸展。因此，海藻酸钠具有明显的pH敏感性。海藻酸钠可以在极其温和的条件下快速形成凝胶，当有Ca2+、Sr2+等阳离子存在时，G单元上的Na+与二价阳离子发生离子交换反应，G单元堆积形成交联网络结构，从而形成水凝胶。海藻酸钠形成凝胶的条件温和，这可以避免敏感性药物、蛋白质、细胞和酶等活性物质的失活。由于这些优良的特性，海藻酸钠已经在食品工业和医药领域得到了广泛应用
将水凝胶注射到梗死区域已显示出治疗心衰的巨大潜力。植入的水凝胶为梗塞心脏的心肌壁提供机械支撑，也可以作为治疗药物或细胞局部输送的平台。目前用于心衰治疗的可注射水凝胶，以海藻酸钠水凝胶为主，缺乏抗炎功能，难以消除受损心肌处的ROS，不利于心肌修复。在海藻酸钠水凝胶中直接负载抗炎、抗氧化药物，在植入心肌后，负载的药物会发生突释，在较短的时间内释放大量药物，药物释放持续时间短、剂量大，不利于心肌修复。同时，丹酚酸B分子本身不含有能与海藻酸钠固定的官能团，只能通过物理吸附进行负载，难以控制药物突释，且丹酚酸B水溶性好，进一步加剧了其突释。
发明内容
本发明的目的是提供一种长效缓释丹酚酸B的可注射心衰治疗水凝胶及其制备方法，可以解决现有可注射心衰治疗水凝胶难以负载丹酚酸B且不能实现长期稳定释放、难以消除心肌组织ROS的问题。
为达上述目的，本发明提供了一种长效缓释丹酚酸B的可注射心衰治疗水凝胶的制备方法，将丹酚酸B引入钙离子交联的海藻酸盐水凝胶中，再与未引入丹酚酸B的钙离子交联的海藻酸盐水凝胶在应力场的作用下进行混合制备，利用应力诱导与动态共价键的协同作用，形成海岛结构相分离的特殊微观结构，实现目标药物的长效缓释。
本发明的海藻酸盐可以为海藻酸钠或者海藻酸钙，优选为海藻酸钠。
进一步地，具体包括以下步骤：
(1)将海藻酸盐溶液与丹酚酸B溶液混合，形成预聚溶液；
(2)于预聚溶液中加入葡萄糖酸钙进行交联；
(3)使用葡萄糖酸钙对海藻酸盐溶液进行交联，制得不含丹酚酸B的溶液；
(4)将步骤(2)和步骤(3)制得的溶液搅拌混合，利用应力诱导与动态共价键的协同作用，形成海岛结构相分离的特殊微观结构，制得长效缓释丹酚酸B的可注射心衰治疗水凝胶。
进一步地，步骤(1)中的海藻酸盐质量分数为1～3％，丹酚酸B溶液浓度为10～20mg/mL，海藻酸盐与丹酚酸B溶液的混合体积比为1:8～12，溶剂为水。
进一步地，步骤(2)中葡萄糖酸钙的质量分数为1～3％，葡萄糖酸钙与预聚溶液的体积比为1：3～5。
进一步地，步骤(3)中的海藻酸盐质量分数为1～3％，葡萄糖酸钙的质量分数为1～3％，葡萄糖酸钙与海藻酸盐溶液的体积比为1：3～5。
进一步地，步骤(4)中步骤(2)和步骤(3)制得的溶液混合的体积比为1:1～2。
进一步地，步骤(4)中搅拌的转速为1800～2500rpm，搅拌时间为28～35min。
本发明还提供了采用上述的制备方法制备得到的长效缓释丹酚酸B的可注射心衰治疗水凝胶。
综上所述，本发明具有以下优点：
1、将丹酚酸B加入海藻酸盐的预聚溶液中，使用葡萄酸钙交联，获得含有丹酚酸B的海藻酸盐水凝胶。使用葡萄酸钙交联海藻酸盐，获得不含丹酚酸B的海藻酸盐水凝胶。将含有丹酚酸B的海藻酸盐水凝胶与不含丹酚酸B的海藻酸盐水凝胶混合，使用剪切应力混合，利用钙离子动态可逆交联作用，通过相分离形成海岛结构，利用不同相之间的界面，调控水溶性丹酚酸B的释放曲线，防止突释，制得长效缓释丹酚酸B的可注射心衰治疗水凝胶。
2、丹酚酸B是植物提取物，安全性好，几乎没有毒副作用，同时抗氧化能力强，不仅能有效清除心肌组织内的活性氧，还对血管具有保护作用，有利于局部血管生成，促进心肌组织修复。利用钙离子交联海藻酸钠动态可逆的特点，将含药与不含药的块状水凝胶，在应力场条件下共混，自发生成海岛结构，利用两相的界面，防止丹酚酸B的突释，实现长效缓释，进一步增强其对心衰的治疗效果。此外，整个制备过程均不需高温高压，不需使用有机溶剂与毒性化合物，安全绿色环保。
附图说明
图1为水凝胶的制备流程图；
图2为丹酚酸B的化学结构；
图3为水凝胶的DPPH自由基清除效率；
图4为水凝胶的溶血率与细胞毒性结果；
图5为丹酚酸B的释放曲线；
图6为水凝胶对心衰的治疗效果。
具体实施方式
以下结合实施例对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1：
一种长效缓释丹酚酸B的可注射心衰治疗水凝胶的制备方法，包括以下步骤：
S1、将1mL丹酚酸B水溶液(15mg/mL)加入到9mL的海藻酸钠溶液(1wt％)中，搅拌20min，得到均匀的海藻酸钠-丹酚酸B混合溶液。
将海藻酸钠-丹酚酸B混合溶液预聚物和1％(w/v)葡萄糖酸钙溶液在室温下以4:1的体积比交联30min，制得含有丹酚酸B的交联海藻酸钠水凝胶。
S2、将海藻酸钠溶液预聚物和1％(w/v)葡萄糖酸钙溶液在室温下以4:1的体积比交联30min。
S3、将10mL含有丹酚酸B的交联海藻酸钠水凝胶和10mL不含丹酚酸B的交联海藻酸钠水凝胶放入三口烧瓶，使用机械搅拌，在2000rpm的转速下搅拌30min，制得长效缓释丹酚酸B的可注射心衰治疗水凝胶。
实施例2
一种长效缓释丹酚酸B的可注射心衰治疗水凝胶的制备方法，包括以下步骤：
S1、将1mL丹酚酸B水溶液(15mg/mL)加入到9mL的海藻酸钠溶液(1wt％)中，搅拌20min，得到均匀的海藻酸钠-丹酚酸B混合溶液。
将海藻酸钠-丹酚酸B混合溶液预聚物和1％(w/v)葡萄糖酸钙溶液在室温下以4:1的体积比交联30min，得含有丹酚酸B的交联海藻酸钠水凝胶。
S2、将海藻酸钠溶液预聚物和1％(w/v)葡萄糖酸钙溶液在室温下以5:1的体积比交联30min。
S3、将10mL含有丹酚酸B的交联海藻酸钠水凝胶和10mL不含丹酚酸B的交联海藻酸钠水凝胶放入三口烧瓶，使用机械搅拌，在2500rpm的转速下搅拌28min，制得长效缓释丹酚酸B的可注射心衰治疗水凝胶。
实施例3
一种长效缓释丹酚酸B的可注射心衰治疗水凝胶的制备方法，包括以下步骤：
S1、将1mL丹酚酸B水溶液(15mg/mL)加入到9mL的海藻酸钠溶液(1wt％)中，搅拌20min，得到均匀的海藻酸钠-丹酚酸B混合溶液。
将海藻酸钠-丹酚酸B混合溶液预聚物和1％(w/v)葡萄糖酸钙溶液在室温下以4:1的体积比交联30min，得含有丹酚酸B的交联海藻酸钠水凝胶。
S2、将海藻酸钠溶液预聚物和1％(w/v)葡萄糖酸钙溶液在室温下以4:1的体积比交联30min。
S3、将10mL含有丹酚酸B的交联海藻酸钠水凝胶和10mL不含丹酚酸B的交联海藻酸钠水凝胶放入三口烧瓶，使用机械搅拌，在1800rpm的转速下搅拌35min，制得长效缓释丹酚酸B的可注射心衰治疗水凝胶。
实验例1：
对实施例1中制得的长效缓释丹酚酸B的可注射心衰治疗水凝胶进行测试，测试结果见图3。
为了测试水凝胶的抗氧化性能的影响，将300μL水凝胶浸泡在800μL的1'-二苯基-2-苦基肼(DPPH)溶液(0.1mM)的乙醇中，然后在黑暗中孵育2小时。液体经4200rpm离心8min后，检测上清液在517nm处的光密度(OD)。去离子水(DI水)用作对照。对DPPH自由基的清除能力使用下式计算：清除能力(％)＝(1-ODsample/ODcontrol)×100％。结果表明，丹酚酸B的加入显着增强了水凝胶的抗氧化活性(图3)，有助于植入后，促进心肌组织修复。
实验例2：
对实施例1中制得的长效缓释丹酚酸B的可注射心衰治疗水凝胶进行测试，结果见图4。
通过分别使用去离子水和PBS作为阳性和阴性对照测量溶血速率来评估水凝胶的血液相容性。将兔子血液以1500rpm的速度离心15min，收集红细胞(RBC)。将水凝胶浸入5％RBC的PBS悬浮液中，水凝胶面积与RBC悬浮液之比为3cm2/mL。37℃孵育2h后，1500rpm离心15min，测定上清液576nm处OD值，溶血率(％)＝(ODsample-ODnegative)/(ODpositive-ODnegative)×100％。如图4所示，所有水凝胶的溶血率均低于2％(阳性组为100％)，表明它们具有良好的血液相容性。
使用大鼠H9C2心肌细胞通过浸提液法测试水凝胶的细胞相容性。紫外线照射灭菌后，将水凝胶以0.1g/mL的剂量浸入培养基(含有10％胎牛血清和1％青霉素-链霉素的DMEM培养基)中24h，制备水凝胶浸提液。将H9C2细胞以1×104个细胞/孔的密度接种到96孔板中，并在100μL培养基中在5％ CO2气氛中于37℃孵育24h。然后，更换对照组的培养基，并将实验组的培养基更换为水凝胶津贴一样。H9C2细胞的细胞活力通过CCK-8试剂盒测定。结果表明，制备的水凝胶无细胞毒性。
实验例3：
对实施例1中制得水凝胶进行缓释测试，结果见图5。
将水凝胶切成25mm×1mm的圆柱形样品，将样品浸泡在10mL去离子水中。在不同时间点取样，使用HPLC测量释放的丹酚酸B的含量。如图5所示，直接使用实施例1中经过S1制备的含有丹酚酸B的交联海藻酸钠水凝胶，进行丹酚酸B的释放测试，结果表明，第二天丹酚酸B的释放就达到峰值，突释效应明显，说明常规的物理吸附无法控制丹酚酸B在海藻酸钠水凝胶中的释放。使用实施例1中经过S3制备的含有丹酚酸B的分相的交联海藻酸钠水凝胶，进行丹酚酸B的释放测试，结果表明，在七天之内，丹酚酸B的释放呈线性缓慢增加，且尚未达到饱和，还可以继续释放。说明水凝胶中存在的相分隔界面(分隔的两相为：不含丹酚酸B的交联海藻酸钠凝胶网络与含丹酚酸B的交联海藻酸钠凝胶网络)，能够防止丹酚酸B的突释，实现长效缓释。
实验例4：
为了获得心衰的动物模型，将雄性Sprague-Dawley大鼠(体重200±20g)用2％异氟烷麻醉，气管插管并连接呼吸机。进行左侧开胸以暴露大鼠心脏。将左前降支动脉(LAD)用6-0丝线永久结扎以引起心肌梗死。心电图显示发白的LV心肌和典型的ST段抬高证实了心衰的成功诱导。随后，大鼠被随机分配接受50μL心肌内注射海藻酸钠或海藻酸钠丹酚酸B水凝胶。对照组大鼠不进行任何治疗。
如图6所示，在第7天，海藻酸钠水凝胶组的射血分数与缩短分数高于对照组，表明在受损心肌处注射海藻酸钠水凝胶有助于心功能改善，而海藻酸钠丹酚酸B水凝胶胶的射血分数与缩短分数比海藻酸钠水凝胶组还要高，表明丹酚酸B对于心肌修复的促进作用。在第28天，海藻酸钠水凝胶组的射血分数与缩短分数与对照组相当，未见明显提升。而海藻酸钠丹酚酸B水凝胶胶的射血分数与缩短分数比海藻酸钠水凝胶组和对照组都要高。表明持续缓释的丹酚酸B可以显著提升水凝胶对心衰的长期治疗效果。
虽然对本发明的具体实施方式进行了详细地描述，但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内，本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (8)
1.一种长效缓释丹酚酸B的可注射心衰治疗水凝胶的制备方法，其特征在于，包括：
将丹酚酸B引入钙离子交联的海藻酸盐水凝胶中，再与未引入丹酚酸B的钙离子交联的海藻酸盐水凝胶在应力场的作用下进行混合制备。
2.如权利要求1所述的制备方法，其特征在于，具体包括以下步骤：
(1)将海藻酸盐溶液与丹酚酸B溶液混合，形成预聚溶液；
(2)于预聚溶液中加入葡萄糖酸钙进行交联；
(3)使用葡萄糖酸钙对海藻酸盐溶液进行交联，制得不含丹酚酸B的溶液；
(4)将步骤(2)和步骤(3)制得的溶液搅拌混合，制得长效缓释丹酚酸B的可注射心衰治疗水凝胶。
3.如权利要求2所述的制备方法，其特征在于，所述步骤(1)中的海藻酸盐质量分数为1～3％，丹酚酸B溶液浓度为10～20mg/mL，所述海藻酸盐与丹酚酸B溶液的混合体积比为1:8～12，溶剂为水。
4.如权利要求2所述的制备方法，其特征在于，所述步骤(2)中葡萄糖酸钙的质量分数为1～3％，葡萄糖酸钙与预聚溶液的体积比为1：3～5。
5.如权利要求2所述的制备方法，其特征在于，所述步骤(3)中的海藻酸盐质量分数为1～3％，葡萄糖酸钙的质量分数为1～3％，葡萄糖酸钙与海藻酸盐溶液的体积比为1：3～5。
6.如权利要求2所述的制备方法，其特征在于，所述步骤(4)中搅拌的转速为1800～2500rpm，搅拌时间为28～35min。
7.如权利要求2所述的制备方法，其特征在于，所述步骤(4)中步骤(2)和步骤(3)制得的溶液混合的体积比为1:1～2。
8.采用权利要求1-7任一项所述的制备方法制备得到的长效缓释丹酚酸B的可注射心衰治疗水凝胶。
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