CN115414473A - 胶原蛋白酶脂质体吸入剂及其在治疗肺纤维化中的应用 - Google Patents
胶原蛋白酶脂质体吸入剂及其在治疗肺纤维化中的应用 Download PDFInfo
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- CN115414473A CN115414473A CN202211022962.8A CN202211022962A CN115414473A CN 115414473 A CN115414473 A CN 115414473A CN 202211022962 A CN202211022962 A CN 202211022962A CN 115414473 A CN115414473 A CN 115414473A
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Abstract
本发明公开了一种胶原蛋白酶脂质体吸入剂，肺吸入后用于治疗肺纤维化。胶原蛋白酶脂质体吸入剂选自胶原蛋白酶脂质体雾化吸入剂和胶原蛋白酶脂质体粉雾剂。胶原蛋白酶脂质体雾化吸入剂经雾化器雾化成微细液滴后，经口吸入肺内给药，胶原蛋白酶脂质体集中于肺部发挥作用。胶原蛋白酶脂质体粉雾剂通过干粉吸入器，主动吸入到肺中。药效研究证明，胶原蛋白酶脂质体吸入剂抗肺纤维化治疗效果好。
Description
技术领域
本发明涉及生物医药领域，具体涉及含胶原蛋白酶脂质体吸入剂及其在治疗肺纤维化中的应用。
背景技术
胶原蛋白酶是在适当pH和温度下只切割胶原螺旋区或明胶而不作用于其他蛋白底物的酶类。胶原蛋白酶按照来源分为植物蛋白酶(如菠萝蛋白酶、木瓜蛋白酶等)、动物蛋白酶(如胰蛋白酶、胃蛋白酶等)、微生物蛋白酶(来源于枯草杆菌、放线菌、溶组织梭菌、蜡样芽孢杆菌等)。胶原蛋白酶具有水解胶原蛋白的特性。胶原蛋白是人体内含量最多、分布最广泛的蛋白质，是一种与组织和器官功能密切相关的功能性蛋白。
肺纤维化是成纤维细胞增殖，大量细胞外基质聚集，并伴炎症损伤、组织结构破坏为特征的一大类肺疾病终末期改变，也就是正常的肺泡组织被损坏后，经过异常修复导致的结构异常。绝大部分肺纤维化病因不明，称为特发性间质性肺炎，是间质性肺病中的一大类。而特发性间质性肺炎中最常见的以肺纤维化病变为主要表现形式的疾病类型，为特发性肺纤维化，是一种能导致肺功能进行性丧失的间质性肺疾病。多种原因引起肺损伤时，间质会分泌胶原蛋白进行修补。如果过度修复，即成纤维细胞过度增殖和细胞外基质大量聚集，就会形成肺纤维化。特发性肺纤维化的病因不明，发病机制亦未完全阐明，但有足够证据表明与免疫炎症损伤有关。
脂质体是磷脂双分子层构成的囊泡。药物根据性质可包封在内水相或脂质膜中。脂质体由生物可降解的物质(磷脂和胆固醇)组成，对人体无毒，组织相容性好。脂质体与细胞膜亲和力强，可增加被包裹药物穿透细胞膜的能力。
肺吸入制剂近年来得到迅速发展。肺吸入的药物可直接到达肺组织，治疗肺部疾病起效快，降低给药剂量及毒性与不良反应。肺部有上亿个肺泡，吸收面积大，血流量大，有利于药物的吸收。药物经肺吸收后直接进入血液循环，避免了肝脏的首过效应，提高药物的生物利用度，目前已多个肺吸入剂上市。肺吸入制剂剂型主要包括气雾剂、雾化吸入剂、粉雾剂。
发明内容
本发明公开了一种胶原蛋白酶脂质体吸入剂，以及胶原蛋白酶脂质体吸入剂在治疗肺纤维化中的应用。
本发明胶原蛋白酶脂质体吸入剂的制备步骤没有限制，只要获得相应的胶原蛋白酶脂质体，并制备得到胶原蛋白酶脂质体吸入剂就可满足本发明的要求。一般地，胶原蛋白酶脂质体吸入剂的制备可采用以下步骤：
(1)制备胶原蛋白酶脂质体；
(2)将胶原蛋白酶脂质体制备成胶原蛋白酶脂质体吸入剂。
胶原蛋白酶脂质体制备方法选自薄膜分散法、逆相蒸发法、冻干空白脂质体重建法，优选逆相蒸发法。这些制备方法可以参考相关专业书籍和文献，由专业技术人员设计和操作完成，得到稳定的胶原蛋白酶脂质体混悬液。胶原蛋白酶脂质体混悬液选择适当处方后并在适当条件下进行冷冻干燥，形成固体粉末状的冻干胶原蛋白酶脂质体。冻干胶原蛋白酶脂质体稳定性好，临用前加入溶媒振摇可得到胶原蛋白酶脂质体混悬液。
本发明中的胶原蛋白酶脂质体的粒径为50nm～1000nm，优选的是100nm～600nm，更优选的是200nm～500nm。胶原蛋白酶脂质体含有胶原蛋白酶、脂质，它们的量没有限制，只要满足胶原蛋白酶脂质体吸入剂的制剂要求和治疗要求就可以，优选的胶原蛋白酶含量是0.1％～30％重量比，更优选的胶原蛋白酶含量是0.3％～10％重量比，进一步优选的胶原蛋白酶含量是1％～5％重量比。
胶原蛋白酶脂质体中含有的脂质选自猪肺磷脂、牛肺磷脂、卵磷脂、磷脂酰乙醇胺、蛋黄卵磷脂、大豆磷脂、胆固醇、脑磷脂、胆固醇乙酰脂、蛋磷脂酰胆碱、二月桂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰甘油、二棕榈酰磷脂酸、磷脂酰丝氨酸、磷脂酰肌醇、神经鞘磷脂、鞘髓磷脂、二鲸蜡磷酸酯、硬脂酰胺，优选自卵磷脂、大豆磷脂、胆固醇、二月桂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱，更优选自猪肺磷脂、牛肺磷脂、卵磷脂、蛋黄卵磷脂、大豆磷脂、胆固醇、二棕榈酰磷脂酰胆碱。当采用蛋黄卵磷脂和胆固醇制备胶原蛋白酶脂质体时，蛋黄卵磷脂和胆固醇的摩尔比例选自100∶1～2∶1，优选自20∶1～10∶1。胶原蛋白酶脂质体中还可以添加其他附加剂，具体品种不受限制，如维生素E、十八胺。
胶原蛋白酶脂质体吸入剂剂型选自雾化吸入剂和粉雾剂，分别称为胶原蛋白酶脂质体雾化吸入剂和胶原蛋白酶脂质体粉雾剂。
胶原蛋白酶脂质体雾化吸入剂选自直接制备的胶原蛋白酶脂质体混悬液、由冻干胶原蛋白酶脂质体加入适宜溶媒复溶后得到的胶原蛋白酶脂质体混悬液，优选的是由冻干胶原蛋白酶脂质体加入适宜溶媒复溶后得到的胶原蛋白酶脂质体混悬液。胶原蛋白酶脂质体雾化吸入剂经雾化器雾化成微细液滴后，经口吸入肺内给药，胶原蛋白酶脂质体集中于肺部发挥作用。
胶原蛋白酶脂质体粉雾剂是由胶原蛋白酶脂质体混悬液添加或不添加辅料后经冻干得到的易流动粉末。添加的辅料选自稳定剂、冻干保护剂、助流剂中的一种或多种。胶原蛋白酶脂质体粉雾剂粉末的空气动力学粒径选自0.5微米～5微米，优选自1微米～3微米。胶原蛋白酶脂质体粉雾剂通过干粉吸入器，主动吸入到肺中。胶原蛋白酶脂质体粉雾剂还可选择冻干胶原蛋白酶脂质体与载体混合得到。
本发明中的胶原蛋白酶脂质体吸入剂，可用于治疗肺纤维化。动物药效研究证明，本发明公开的胶原蛋白酶脂质体吸入剂，肺吸入后肺部药物浓度大，抗肺纤维化治疗效果好。
附图说明
图1.胶原蛋白酶脂质体外观照片
图2.胶原蛋白酶脂质体的透射电镜照片
图3.胶原蛋白酶脂质体粒径测定结果
图4.胶原蛋白酶脂质体Zeta电位测定结果
图5.胶原蛋白酶脂质体雾化吸入剂空气动力学粒径分布
图6.胶原蛋白酶脂质体冻干粉外观照片
图7.各组小鼠肺外观图
图8.各组小鼠肺组织切片染色图(HE和Masson染色)
图9.各组小鼠旷场实验行走路径图
具体实施方式
实施例1.胶原蛋白酶脂质体雾化吸入剂
取30mg胶原蛋白酶加入到1ml pH7.4的磷酸盐缓冲液中溶解；取0.4g蛋黄卵磷脂、0.1g胆固醇加入15ml乙醚溶解，加入上述胶原蛋白酶溶液，水浴超声3分钟，形成油包水乳剂；乳剂在烧瓶中减压旋转蒸发，调节水浴温度为38℃；当烧瓶底部形成不流动凝胶态后，加入30ml与上述相同的磷酸盐缓冲液，继续旋转蒸发30min，得到均匀的胶原蛋白酶脂质体混悬液作为胶原蛋白酶脂质体雾化吸入剂。
胶原蛋白酶脂质体混悬液外观为均匀的白色混悬液(图1)；经负染后，在透射电镜下为囊泡状(图2)；根据激光粒度仪测定结果，胶原蛋白酶脂质体的粒径为76.73nm，多分散系数PDI为0.298(图3)，Zeta电位为-11.5mV(图4)。
实施例2.胶原蛋白酶脂质体雾化吸入剂
取30mg胶原蛋白酶加入到1ml pH7.4的磷酸盐缓冲液中溶解；取0.4g蛋黄卵磷脂、0.1g胆固醇加入15ml乙醚溶解，加入上述胶原蛋白酶溶液，水浴超声3分钟，形成油包水乳剂；乳剂在烧瓶中减压旋转蒸发，调节水浴温度为38℃；当烧瓶底部形成不流动凝胶态后，加入30ml与上述相同的磷酸盐缓冲液，继续旋转蒸发30min，得到均匀的胶原蛋白酶脂质体混悬液；加入冻干保护剂甘露醇300mg于胶原蛋白酶脂质体混悬液中溶解，经冷冻干燥后，过180目筛网，得到冻干胶原蛋白酶脂质体粉末；临用前加入30ml水于冻干胶原蛋白酶脂质体粉末，振摇后获得胶原蛋白酶脂质体雾化吸入剂。
上述胶原蛋白酶脂质体雾化吸入剂经气溶胶测定仪测定，空气动力学粒径为3.73微米(图5)，满足肺吸入要求。
实施例3.胶原蛋白酶脂质体粉雾剂
取30mg胶原蛋白酶加入到1ml pH7.4的磷酸盐缓冲液中溶解；取0.4g蛋黄卵磷脂、0.1g胆固醇加入15ml乙醚溶解，加入上述胶原蛋白酶溶液，水浴超声3分钟，形成油包水乳剂；乳剂在烧瓶中减压旋转蒸发，调节水浴温度为38℃；当烧瓶底部形成不流动凝胶态后，加入30ml与上述相同的磷酸盐缓冲液，继续旋转蒸发30min，得到均匀的胶原蛋白酶脂质体混悬液；加入冻干保护剂甘露醇300mg于胶原蛋白酶脂质体混悬液中溶解，经冷冻干燥后，过180目筛网，得到冻干胶原蛋白酶脂质体粉末可作为胶原蛋白酶脂质体粉雾剂。
胶原蛋白酶脂质体粉雾剂放置于棕色玻璃瓶中密闭保存，是白色可流动粉末(图6)。
实验例.胶原蛋白酶脂质体吸入剂对肺纤维化小鼠的治疗效果
材料：按实施例2制备的胶原蛋白酶脂质体雾化吸入剂；不加胶原蛋白酶，按实施例1制备的空白脂质体；胶原蛋白酶；博来霉素。
步骤：正常小鼠使用肺部定量雾化针气管喷入50μl博来霉素溶液，14天后即可形成肺纤维化。小鼠一般表现为体重降低、行动迟缓。动物分组：在博来霉素肺部给药后14天，称量肺纤维化模型小鼠体重，筛选体重在20±3g之间的小鼠进行分组，包括a组：正常组(未实施肺部给博来霉素造模的小鼠)，6只；b组：肺纤维化模型组，6只；c组：空白脂质体组，6只；d组：胶原蛋白酶吸入组，6只；e组：胶原蛋白酶脂质体吸入组，6只。正常组和模型组分别气管内迅速喷入30μl生理盐水释液，其他组分别气管内迅速喷入30μl相应药物或材料，随后马上直立小鼠，头保持向上。每天称体重并记录。每隔一天重复给药，连续给药4次。共记录1周内体重。分别于给药后第1天、第3天、第5天、第7天进行旷场试验，考察小鼠运动能力。解剖取各组小鼠肺组织留存拍照，肺组织进行病理切片和进行HE染色和Masson染色。
结果：正常组小鼠活泼好动、强壮肥硕、皮毛光泽发亮、呼吸平稳、体重逐渐增加。模型组和治疗组小鼠给药后呼吸急促。正常组小鼠肺外观红润，而模型组、空白脂质体组、胶原蛋白酶吸入组肺外观出现不同程度的出血和损伤，外观呈黑色；胶原蛋白酶脂质体吸入组的肺外观有少许黑色，但基本接近正常组(图7)。
正常组小鼠肺组织病理切片显示肺泡腔清晰可见，Masson染色显示蓝色的胶原区域较少(图8，a)；模型组小鼠肺泡腔结构紊乱，肺泡壁增厚，Masson染色显示蓝色的胶原区域较多(图8，b)；胶原蛋白酶脂质体吸入组小鼠肺组织肺泡壁比模型组、胶原蛋白酶吸入组清晰，症状显著减轻，Masson染色显色蓝色的胶原区域显著变少(图8，b，d，e)。空白脂质体组肺泡腔结构和模型组类似，Masson染色显示蓝色的胶原区域较多。(图8，c)。
旷场实验结果表明，肺纤维化小鼠无论哪一组都行走距离很小，而正常组很多。经过7天治疗后，空白脂质体组和模型组和开始比较没有区别，而胶原蛋白酶吸入组和胶原蛋白酶脂质体吸入组小鼠行走距离有明显增加，但胶原蛋白酶脂质体吸入组小鼠行走距离又明显多于胶原蛋白酶吸入组(图9)。
上述结果证明胶原蛋白酶脂质体吸入剂有很好的抗肺纤维化效果，其原理可能包括脂质体易渗透生物屏障进入肺纤维化区域，胶原蛋白酶可降解纤维化区域的胶原蛋白，使纤维化组织分解，最终逆转了肺纤维化。
Claims (10)
1.一种胶原蛋白酶脂质体吸入剂，其特征在于可用于治疗肺纤维化。
2.如权利要求1所述的胶原蛋白酶脂质体吸入剂，其特征在于制备采用以下步骤：
(1)制备胶原蛋白酶脂质体；
(2)将胶原蛋白酶脂质体制备成胶原蛋白酶脂质体吸入剂。
3.如权利要求2所述的胶原蛋白酶脂质体吸入剂，其特征在于其中胶原蛋白酶脂质体制备方法选自薄膜分散法、逆相蒸发法、冻干空白脂质体重建法。
4.如权利要求2所述的胶原蛋白酶脂质体吸入剂，其特征在于胶原蛋白酶脂质体含有胶原蛋白酶、脂质。
5.如权利要求2所述的胶原蛋白酶脂质体吸入剂，其特征在于胶原蛋白酶脂质体的粒径为50nm～1000nm。
6.如权利要求4所述的胶原蛋白酶脂质体吸入剂，其特征在于脂质选自猪肺磷脂、牛肺磷脂、卵磷脂、蛋黄卵磷脂、大豆磷脂、胆固醇、二棕榈酰磷脂酰胆碱。
7.如权利要求1所述的胶原蛋白酶脂质体吸入剂，其特征在于选自胶原蛋白酶脂质体雾化吸入剂和胶原蛋白酶脂质体粉雾剂。
8.如权利要求7所述的胶原蛋白酶脂质体吸入剂，其特征在于胶原蛋白酶脂质体雾化吸入剂的制备采用如下步骤：取30mg胶原蛋白酶加入到1ml pH7.4的磷酸盐缓冲液中溶解；取0.4g蛋黄卵磷脂、0.1g胆固醇加入15ml乙醚溶解，加入上述胶原蛋白酶溶液，水浴超声3分钟，形成油包水乳剂；乳剂在烧瓶中减压旋转蒸发，调节水浴温度为38℃；当烧瓶底部形成不流动凝胶态后，加入30ml与上述相同的磷酸盐缓冲液，继续旋转蒸发30min，得到均匀的胶原蛋白酶脂质体混悬液作为胶原蛋白酶脂质体雾化吸入剂。
9.如权利要求7所述的胶原蛋白酶脂质体吸入剂，其特征在于胶原蛋白酶脂质体雾化吸入剂的制备采用如下步骤：取30mg胶原蛋白酶加入到1ml pH7.4的磷酸盐缓冲液中溶解；取0.4g蛋黄卵磷脂、0.1g胆固醇加入15ml乙醚溶解，加入上述胶原蛋白酶溶液，水浴超声3分钟，形成油包水乳剂；乳剂在烧瓶中减压旋转蒸发，调节水浴温度为38℃；当烧瓶底部形成不流动凝胶态后，加入30ml与上述相同的磷酸盐缓冲液，继续旋转蒸发30min，得到均匀的胶原蛋白酶脂质体混悬液；加入冻干保护剂甘露醇300mg于胶原蛋白酶脂质体混悬液中溶解，经冷冻干燥后，过180目筛网，得到冻干胶原蛋白酶脂质体粉末；临用前加入30ml水于冻干胶原蛋白酶脂质体粉末，振摇后获得胶原蛋白酶脂质体雾化吸入剂。
10.如权利要求7所述的胶原蛋白酶脂质体吸入剂，其特征在于胶原蛋白酶脂质体粉雾剂的制备采用如下步骤：取30mg胶原蛋白酶加入到1ml pH7.4的磷酸盐缓冲液中溶解；取0.4g蛋黄卵磷脂、0.1g胆固醇加入15ml乙醚溶解，加入上述胶原蛋白酶溶液，水浴超声3分钟，形成油包水乳剂；乳剂在烧瓶中减压旋转蒸发，调节水浴温度为38℃；当烧瓶底部形成不流动凝胶态后，加入30ml与上述相同的磷酸盐缓冲液，继续旋转蒸发30min，得到均匀的胶原蛋白酶脂质体混悬液；加入冻干保护剂甘露醇300mg于胶原蛋白酶脂质体混悬液中溶解，经冷冻干燥后，过180目筛网，得到冻干胶原蛋白酶脂质体粉末可作为胶原蛋白酶脂质体粉雾剂。
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