CN110755454A - 间充质干细胞抗肝纤维化注射液 - Google Patents
间充质干细胞抗肝纤维化注射液 Download PDFInfo
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- CN110755454A CN110755454A CN201911334488.0A CN201911334488A CN110755454A CN 110755454 A CN110755454 A CN 110755454A CN 201911334488 A CN201911334488 A CN 201911334488A CN 110755454 A CN110755454 A CN 110755454A
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Abstract
本发明公开了一种间充质干细胞抗肝纤维化注射液，该注射液由45%‑50%的复方电解质注射液、45‑50%羟乙基淀粉200/0.5氯化钠注射液、3%‑7%人血白蛋白注射液、0.2%‑0.4%榄香注射液、0.2‑0.4%羟喜树碱、0.3‑0.5%鹿瓜多肽注射液组成，其中人血白蛋白注射液的浓度为20%，复方电解质注射液和羟乙基淀粉200/0.5氯化钠注射液的体积比为1:1，每ml注射液中含有人脂肪间充质干细胞1×105‑4×106个。本发明的注射液疗效显著，稳定性高，便于保存和运输，使用安全，可为肝纤维化患者带来福音。
Description
技术领域
本发明涉及一种间充质干细胞抗肝纤维化注射液的制备方法。
背景技术
近年来，随着干细胞治疗、免疫细胞治疗和基因编辑等基础理论、技术手段和临床医疗探索研究的不断发展，细胞治疗产品为一些严重及难治性疾病提供了新的治疗思路与方法。间充质干细胞是一种多能干细胞，它具有干细胞的所有共性，即自我更新和多向分化能力。在临床应用也最多，且安全无不良反应。间充质干细胞不仅存在于骨髓中，也存在于脂肪、脐带、胎盘等组织中，来源多样，取材方便，无伦理问题，因此临床应用价值不菲。
肝纤维化是多种原因引起的慢性肝损害所致的病理改变，严重影响肝脏的功能，是慢性肝病发展到肝硬化必经之阶段。引起肝纤维化的病因很多，在国内以病毒性肝炎，尤其是慢性乙型和丙型肝炎所致的肝纤维化最为常见，慢性感染患者中40％可能发生肝硬化或者肝癌，是正常人群的100-200倍。肝纤维化的治疗成为现今人们关注的焦点，但现代医学并无治疗肝纤维化的特异性药物，多采用休息、加强营养、补充维生素等对症治疗方式，严重者需被迫停止用药，以免加重肝纤维化。
目前有大量利用干细胞移植的方法治疗肝纤维化的临床报道。单纯输注间充质干细胞，由于干细胞多向分化潜能，真正能分化成目的肝脏细胞的数量极少，造成临床效果不佳。而细胞的增殖和分化是基因选择表达的结果，受到多种信号通路的联合调控。一般来说，体外诱导干细胞分化都是采用含有组织特异性的细胞因子的选择性培养基来实现的。肝脏细胞的增殖和生长需要多种细胞因子来调控，其中就包括肝脏细胞生长因子（HGF），成纤维细胞生长因子（FGF），制瘤素M（OSM），表皮生长因子等。在以往的研究中，有采用HGF、OSM和DMSO联合使用，HGF、FGF4和FGF1联合使用，HGF、EGF和TNF-α联合使用等方法，都可以将干细胞成功诱导为肝脏细胞。而本发明首次发现榄香注射液、羟喜树碱、鹿瓜多肽注射液的组合物具有促进干细胞向肝系祖细胞转化的作用，本发明在注射液添加上述三种组合物后，起到预诱导干细胞向肝系祖细胞转化的作用，可以使临床效果极大提高。
本发明由复方电解质注射液、羟乙基淀粉200/0.5氯化钠注射液、人血白蛋白注射液、榄香注射液、羟喜树碱、鹿瓜多肽注射液组成，其中人血白蛋白注射液的浓度为20%，复方电解质注射液和羟乙基淀粉200/0.5氯化钠注射液的体积比为1:1，每ml注射液中含有间充质干细胞1×105-4×106个，制备成临床级注射液形式。
本发明注射液所有成分均为临床上常用的药品，安全无副作用，制备成临床级注射液，安全可靠。
本发明注射液稳定性高，同时也较好的解决了细胞运输时间短、活力低的问题，增加了注射液保存及运输过程稳定性。本发明注射液24h内细胞活率维持在99%以上，36h后干细胞活率仍然高达98%，极大提高了临床使用安全性。
发明内容
本发明的目的是为了克服现有技术的不足，提供一种间充质干细胞抗肝纤维化注射液，其具有疗效好、安全性高、稳定性高、便于储存和运输，适应临床大规模使用，应用前景广阔的特点，本发明可为肝纤维化患者带来福音，为临床上干细胞的使用开辟了新的道路。
本发明提供的间充质干细胞抗肝纤维化注射液，该注射液由45%-50%的复方电解质注射液、45-50%羟乙基淀粉200/0.5氯化钠注射液、3%-7%人血白蛋白注射液、0.2%-0.4%榄香注射液、0.2-0.4%羟喜树碱、0.3-0.5%鹿瓜多肽注射液组成。
所述复方电解质注射液，主要成份为醋酸钠、氯化钠、氯化钾、氯化镁、葡萄糖酸钠，为无色或几乎无色的澄明液体。可作为水、电解质的补充源和碱化剂。本品与血液和血液成分相容，可作为细胞的稀释液。在本发明注射液中用于维持晶体渗透压。
所述羟乙基淀粉200/0.5氯化钠注射液，为无色或微黄色澄明液体，临床上一般用于容量替代治疗。在本发明注射液中与人血白蛋白注射液一起用于维持胶体渗透压。
所述人血白蛋白注射液（浓度20%），用于维持胶体渗透压，保持干细胞活性。
所述榄香注射液、羟喜树碱、鹿瓜多肽注射液的组合物，可以促进间充质干细胞向肝系细胞转化，可以激活和保持注射液中干细胞活性，极大提高了临床效果。
优选的，复方电解质注射液和羟乙基淀粉200/0.5氯化钠注射液的体积比为1:1。
优选的，所述注射液由47%的复方电解质注射液、47%羟乙基淀粉200/0.5氯化钠注射液、5%人血白蛋白注射液、0.3%榄香注射液、0.3%羟喜树碱、0.4%鹿瓜多肽注射液组成。
所述注射液中加入的间充质干细胞的浓度为1×105-4×106/ml。
所述注射液使用静脉输注或者肝脏动脉介入输注的方式，按照间充质干细胞(2-4)×106/kg体重注入患者体内。
本发明与现有技术相比，具有以下优点：
本发明首次发现榄香注射液、羟喜树碱、鹿瓜多肽注射液的组合物具有促进干细胞向肝系祖细胞转化的作用，注射液添加上述组合物后，临床效果极大提高。
本发明解决了现有技术在干细胞输注过程中细胞活率低，保存时间短，长期保存细胞活性差的问题，并且延长了待使用细胞的保质时间，36小时内细胞活率仍维持在98％以上，疗效好、使用更安全，适于较长时间的保存及运输，用后无任何毒副作用，为临床大规模使用奠定了基础。
本发明提供的注射液可分化成有功能的肝脏细胞，具有再生修复实质器官和发挥免疫调节的双向作用，改善肝脏的微环境以及降低炎性细胞因子分泌的能力，减轻炎症反应；抑制肝星状细胞活化、阻止细胞外基质的生成，逆转肝纤维化；激活肝脏细胞，促进肝脏细胞再生，修复实质器官和慢性肝损害，间接地提高了抗病毒治疗疗效。
本发明注射液中的间充质干细胞由于来源广泛，不受伦理限制、免疫原性低使其成为肝纤维化治疗的新的有效手段，应用前景十分广阔。
具体实施方式
下述实施例中的实验方法，如无特别说明，均为常规方法。实验所用器具仪器药品试剂皆可通过商业途径获得。
实施例1
一、制备本发明间充质干细胞保存和诱导液A 100ml
无菌条件下，依次取47ml的复方电解质注射液（商品名称：勃脉力A，上海百特医疗用品有限公司，国药准字H20000475 ）、47ml羟乙基淀粉200/0.5氯化钠注射液（商品名称：贺斯，北京费森尤斯卡比医药有限公司，国药准字H20030494，规格型号 500ml：15g羟乙基淀粉200/0.5与氯化钠4.5g）、5ml人血白蛋白注射液(成都蓉生，国药准字S10940024,50ml:10g,20%)、0.3ml榄香注射液(大连华立金港,国药准字H10960114,20ml:0.1g)、0.3ml羟喜树碱（贵州汉方，国药准字H52020516，2ml）、0.4ml鹿瓜多肽注射液（誉衡药业，国药准字Z23020001,2ml），混匀，置0-8℃冷藏存储。
二、制备本发明间充质干细胞抗肝纤维化注射液A 100ml
(1)从细胞库液氮中取出含有第3-4代临床级间充质干细胞的冻存管；
(2)将冻存管立即投入37℃ 温水中轻轻晃动，直至冻存液完全融解；
(3) 用75%酒精擦拭冻存管，将冻存管中细胞悬液转移至加含有9mL生理盐水的15ml离心管，轻轻吹打均匀。可将多个同一批次的冻存管内细胞悬液及其洗涤液合并入1个50mL离心管内（注意：合并的细胞须为同一批次的，不同批次细胞禁止合并），同时吸出少许细胞用于细胞计数；
(4) 离心洗涤：1000rpm离心8min，弃上清液；
(5)根据细胞计数结果，通过上述配置的间充质干细胞保存液A重悬细胞，调整每ml注射液中含有间充质干细胞1×106；
三、制备好的间充质干细胞抗肝纤维化注射液A需要在0-8℃避光环境下保存和运输，自分装之时起有效期为48小时。本发明的注射液适用于静脉输注或者肝脏动脉介入输注的方式，按患者体重公斤数计算，推荐用量间充质干细胞(2-4)×106/kg体重。
实施例2
一、制备本发明间充质干细胞保存和诱导液B 100ml
同实施例1，无菌条件下，依次所述注射液由45.85ml的复方电解质注射液、45.85ml羟乙基淀粉200/0.5氯化钠注射液、7ml人血白蛋白注射液、0.4ml榄香注射液、0.4ml羟喜树碱、0.5ml鹿瓜多肽注射液组成，混匀，置0-8℃冷藏存储。
二、制备本发明间充质干细胞抗肝纤维化注射液B 100ml
同实施例1，通过上述配置的间充质干细胞保存液B重悬细胞，调整每ml注射液中含有间充质干细胞1×106；
实施例3
一、制备本发明间充质干细胞保存和诱导液C 100ml
同实施例1，无菌条件下，依次所述注射液由48.15ml的复方电解质注射液、48.15ml羟乙基淀粉200/0.5氯化钠注射液、3ml人血白蛋白注射液、0.2ml榄香注射液、0.2ml羟喜树碱、0.3ml鹿瓜多肽注射液组成，混匀，置0-8℃冷藏存储。
二、制备本发明间充质干细胞抗肝纤维化注射液C 100ml
同实施例1，通过上述配置的间充质干细胞保存液C重悬细胞，调整每ml注射液中含有间充质干细胞1×106；
实施例4
一、制备不含榄香注射液、羟喜树碱和鹿瓜多肽注射液的干细胞保存液D 100ml
同实施例1，无菌条件下，依次所述注射液由47.5ml的复方电解质注射液、47.5ml羟乙基淀粉200/0.5氯化钠注射液、5ml人血白蛋白注射液，混匀，置0-8℃冷藏存储。
二、制备间充质干细胞抗肝纤维化注射液D 100ml
同实施例1，通过上述配置的间充质干细胞保存液D重悬细胞，调整每ml注射液中含有间充质干细胞1×106；
实施例5
效果对比:将上述实施例中配置的间充质干细胞抗肝纤维化注射液A、B、C、D以及新鲜配置的每ml含有间充质干细胞1×106的生理盐水悬液E，共5份样本，置于4℃的温度环境下保存，在保存4h、8h、12h、24h、36h、48h时取样，并测定细胞存活率。
测定方法：将细胞悬液0.5ml加入试管中；加入0.5ml浓度为0.2％的台盼兰染液；将细胞悬液吸出10μl，滴加在盖片边缘，使悬液充满盖片和计数板之间；静置1分钟；随机选取几个视野，共计数300个细胞，并计数其中死细胞数目，计细胞活力，重复计数5次取平均值。结果如下表格1所示。
表格1 五种注射液中细胞活率对比
表格1可以看出，本发明的优选的间充质干细胞抗肝纤维化注射液A，对干细胞保存效率明显高于其他。本发明中如果去除榄香注射液、羟喜树碱和鹿瓜多肽注射液即注射液D，效率明显下降。本发明的优选的充质干细胞抗肝纤维化注射液A，细胞存储36h后，细胞活率仍高达98%，而单纯生理盐水保存的注射液F，细胞活率仅40%。
实施例6
本注射液诱导间充质干细胞向肝脏分化实验
上述本发明注射液A冷藏30分钟后，离心，弃上清，获得间充质干细胞，接种到含10%FBS20ng/mL EGF的DMEM培养基中，每3d换液一次，培养10d。
上述干细胞保存液D冷藏30分钟后，同上，离心弃上清获得间充质干细胞，接种的10%FBS 20ng/mL EGF的DMEM培养基中，24h后，将培养基更换为成肝诱导培养基，每隔3d换液一次，培养10d。成肝诱导培养基为含有25ng/mL FGF4、50ng/mL HGF、20ng/mL OSM、20ng/mL aFGF、20ng/mL EGF的含10％FBS的DMEM培养基。
对上述经诱导后的两种成肝脏样细胞，均进行免疫荧光染色鉴定。成肝脏样诱导至第10天，上述两种方法均检测到ALB、AFP、CK18和CYP1A1的表达。上述两种方法的诱导细胞在具有肝脏样细胞形态的同时表达肝细胞标志物ALB、AFP、CK-18和CYP1A1，但本发明成肝脏样诱导后阳性表达率均显著高于普通诱导。 结果如下表格2所示。
表格2 本发明诱导肝脏分化效果与普通诱导对比
可以看出，本发明的优选的间充质干细胞抗肝纤维化注射液A，其中榄香注射液、羟喜树碱和鹿瓜多肽注射液组合成分对干细胞向肝系诱导分化效率高于目前常规的细胞因子普通诱导，可促进移植后间充质干细胞向肝脏细胞分化。
实施例7
使用本发明提供的注射液的病人均选自住院病人，经伦理委员会批准，签署知情同意书，总共18例，其中乙肝肝硬化16例，自身免疫性肝硬化2例，均为失代偿期。经输入本发明的注射液后，病人精神好转，食欲增加，腹水消退，血清学生化指标明显改善，第一次治疗后，症状体征明显改善，达到出院要求。乙肝肝硬化患者，按常规服用抗病毒药物。
下表格2为患者血清学指标(平均值)。ALT(alanine aminotransferase)：丙氨 酸转氨酶；AST(aspartate aminotransferase)：谷草转氨酶；ALB(albumin)： 血清白蛋白；TBIL(total bilirubin)：总胆红素；PT(prothrombintime)：凝血酶原时间； TT（thrombintime）:凝血酶时间；PTINR(prothrombintime international normalized ratio)：凝血酶原时间国际标准化比率；AFP(alpha-fetal protein)： 甲胎蛋白)
表格2 患者血清学指标对比
| ALT | AST | ALB | TBIL | PT | TT | PTINR | AFP | |
| 治疗前 | 92.33 | 131.51 | 85.98 | 41.77 | 16.89 | 18.39 | 1.33 | 2.9 |
| 治疗后 | 36.26 | 46.22 | 46.28 | 20.34 | 12.37 | 11.23 | 1.11 | 2.8 |
所有病人用间充质干细胞抗肝纤维化注射液治疗3次，每次相隔1个月时间，病人经治疗后，肝功能损害减轻，肝细胞再生活跃，白蛋白分泌增加，凝血功能恢复正常。为了明确间充质干细胞抗肝纤维化注射液的治疗安全性，每例病人，都常规检查AFP的水平。经治疗后，患者AFP的水平在治疗前和治疗后无明显差异，甚至有轻微的减低。
本发明采用的间充质干细胞，可以来源于骨髓、脂肪、脐带、胎盘等等，不受伦理限制、免疫原性低，使其成为肝纤维化治疗的新的有效手段，应用前景十分广阔。
Claims (3)
1.间充质干细胞抗肝纤维化注射液，其特征在于，所述注射液由45%-50%的复方电解质注射液、45-50%羟乙基淀粉200/0.5氯化钠注射液、3%-7%人血白蛋白注射液、0.2%-0.4%榄香注射液、0.2-0.4%羟喜树碱、0.3-0.5%鹿瓜多肽注射液组成，其中人血白蛋白注射液的浓度为20%，复方电解质注射液和羟乙基淀粉200/0.5氯化钠注射液的体积比为1:1，每ml注射液中含有人脂肪间充质干细胞1×105-4×106个。
2.如权利要求1所述的间充质干细胞抗肝纤维化注射液，其特征在于，所述注射液由47%的复方电解质注射液、47%羟乙基淀粉200/0.5氯化钠注射液、5%人血白蛋白注射液、0.3%榄香注射液、0.3%羟喜树碱、0.4%鹿瓜多肽注射液组成，其中人血白蛋白注射液的浓度为20%。
3.如权利要求2所述的间充质干细胞抗肝纤维化注射液，其特征在于，所述注射液使用静脉输注或者肝脏动脉介入输注方式，按照间充质干细胞(2-4)×106/kg体重使用。
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