CN111544431A - 硝唑尼特在制备预防及治疗间质性肺病药物中的应用 - Google Patents
硝唑尼特在制备预防及治疗间质性肺病药物中的应用 Download PDFInfo
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Abstract
本发明属于医药领域，具体的涉及一种硝唑尼特在制备预防及治疗间质性肺病药物中的应用。本发明所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，进一步的，硝唑尼特为硝唑尼特及其体内活性代谢物替唑尼特。所述间质性肺病包括冠状病毒感染引发的疾病并发症。本发明对硝唑尼特改善间质性肺病进行了详细研究，拓展了间质性肺病治疗药物的种类，也拓展了硝唑尼特的新用途。
Description
技术领域
本发明属于医药领域，具体的涉及一种硝唑尼特在制备预防及治疗间质性肺病药物中的应用。
背景技术
间质性肺疾病(Interstitial lung disease,ILD)，又称弥漫性肺实质性疾病(DPLD)，是一大组肺异质性疾病，包括200多个以肺实质广泛纤维化和/或炎性异常为特征的肺实质病变。其表现的临床特征、影像、肺功能等都具有某些相似之处，发病机制、病理特征也具有某些共性特点。主要侵犯周边的肺组织，如肺泡、肺泡壁、肺泡道、肺泡间隔、细支气管和微小血管及肺间质部位。发病原因是肺泡上皮细胞的异常修复造成细胞外基质的大量分泌，进而造成肺组织结构和功能的不可逆损伤，形成肺纤维化。肺纤维化是主要累及肺泡和肺间质的弥散性、致死性的肺部疾病，是所有ILD的终末期。低氧血症及呼吸衰竭是ILDs晚期或急性恶化后的常见并发症，其预后是呼吸系统疾病中相对较差的。
2007年，我国重庆地区对重庆市两所医科大学主要的5家教学医院5年期间的ILD流行病学情况及结果分析显示，收治的ILD患者从2002年占呼吸科住院人数的2.83％，占全院住院人数0.30％，到2006年分别为8.29％和0.48％。魏路清等统计了2003-2009年天津市10家综合医院收治的ILD，2003年仅收治29例，占呼吸科和全院住院人数比为4.52‰和0.31‰；至2009年收治的ILD增至237例，占呼吸科和全院住院人数比为39.5‰和1.51‰，5年内收治数超过8倍；上海市肺科医院单中心报道，1990-2003年住院ILD患者395例，其中1998-2003年(6年)收治337例，占14年总例数的85.3％，呈明显的上升趋势。可知在过去二十年中，我国ILD发病率呈现逐步上升的趋势，尤其是特发性肺纤维化，且死亡率居高不下。
间质性肺疾病较常见的明确的病因有长期吸入无机粉尘，如石棉、粉尘、有害气体等；吸入有机粉尘，如蘑菇、宠物、发霉的谷物、干草、污染的空调或湿化器等；长期服用部分药物，如胺碘酮、甲氨蝶呤、化疗药等；急慢性肺部感染，如肺孢子菌肺炎、病毒性肺炎等；慢性心脏疾患；与类风湿性关节炎、干燥综合征、多发性肌炎、系统性红斑狼疮等自身免疫疾病和血管炎等相关的间质性肺炎；肿瘤相关性，如肺泡癌、淋巴瘤等。
近年来冠状病毒感染引起的疾病，比如SARS、MERS以及近期全球大流行的新型冠状病毒肺炎均引起肺部间质性改变。间质性肺疾病严重危害患者的健康和生活质量，临床缺乏有效的治疗方法，现多使用激素、免疫抑制剂及抗纤维化药物等治疗，但只对部分患者有一定疗效，且副作用明显。因此，急需开发一种预防及治疗间质性肺病的药物迫在眉睫。
硝唑尼特是硝基噻唑酰胺类化合物，为Romark与日本许可证持有者ChugaiPharmaceutical(Roche的子公司)共同开发上市的一种小分子抗菌剂、噻唑烷衍生物和病毒复制抑制剂，用于贾第鞭毛虫及隐孢子虫感染引起的腹泻。2002年硝唑尼特获得FDA批准，并于2003年3月上市。目前未见硝唑尼特预防及治疗间质性肺病的研究。
发明内容
本发明的目的在于提供一种硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其对硝唑尼特改善间质性肺病进行了详细研究。
本发明所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其有效成分为硝唑尼特及其体内活性代谢物替唑尼特。
进一步的，所述间质性肺病包括特发性肺纤维化、特发性非特异性间质性肺炎、呼吸性细支气管炎伴间质性肺疾病、脱屑性间质性肺炎、隐原性机化性肺炎、急性间质性肺炎、特发性淋巴细胞性间质性肺炎、特发性胸膜肺实质弹力纤维增生症以及不能分类的特发性间质性肺炎。
进一步的，所述间质性肺病包括冠状病毒感染引发的疾病并发症；
其中，所述冠状病毒感染引发的疾病包括严重急性呼吸综合征、中东呼吸综合征以及新型冠状病毒肺炎。
所述冠状病毒包括SARS病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)以及新型冠状病毒(SARS-CoV-2)。
进一步的，所述药物的制剂形式包括硬胶囊剂、软胶囊剂、散剂、颗粒剂、片剂、混悬剂、丸剂。
优选的，所述制备药物所用的辅料包括玉米淀粉，预糊化玉米淀粉，羟丙基甲基纤维素，蔗糖，羟乙酸淀粉钠，滑石粉，硬脂酸镁，大豆卵磷脂，聚乙烯醇，黄原胶，二氧化钛和色素。
本发明中SARS-CoV-2感染的hACE2转基因小鼠的肺部炎症反应实验证明，硝唑尼特组与模型组(未用药)相比较，高、中剂量硝唑尼特组小鼠为轻度间质性肺炎，而模型组表现为中度间质性肺炎，高、中剂量组小鼠肺组织病变明显改善。本发明证明了硝唑尼特可以通过抑制SARS-CoV-2感染的hACE2转基因小鼠的肺部炎症反应，改善组织纤维增殖及细胞外基质沉积，从而抑制肺部损伤。因此硝唑尼特能够有效的预防及治疗间质性肺炎。
与现有技术相比，本发明具有以下有益效果：
本发明对硝唑尼特改善间质性肺病进行了详细研究，拓展了间质性肺病治疗药物的种类，也拓展了硝唑尼特的新用途。
附图说明
图1是高剂量组小鼠肺组织轻度间质性肺炎染色切片图；
图2是中剂量组小鼠肺组织轻度间质性肺炎染色切片图；
图3是低剂量组小鼠肺组织中度间质性肺炎染色切片图；
图4是模型组小鼠肺组织中度间质性肺炎染色切片图。
具体实施方式
下面结合实施例对本发明作进一步的说明，但其并不限制本发明的实施。
硝唑尼特原料的制备：
向180mL的二氯甲烷中加入18g的乙酰水杨酸和11.9g的氯化亚砜，加入5％的DMF，在25℃的条件下反应4h,将14.5g的2-氨基-5-硝基噻唑加入到反应体系中，滴加10.1g的三乙胺，搅拌反应0.5h，反应完毕后抽滤，所得固体打浆，重结晶得到目标产物硝唑尼特，收率50％。
硝唑尼特片的制备：
将7mg羟丙甲纤维素溶解在63mg纯化水中，然后将所述溶液喷在由500mg硝唑尼特、56mg玉米淀粉、20mg蔗糖、35mg羧甲基淀粉钠的混合物组成的流化粉末上。干燥所得颗粒，过筛并与64.5mg预胶化淀粉混合。加入10.5mg滑石粉和7mg硬脂酸镁后，将粉末混合物压成片剂，然后用20mg Opadry包衣粉在纯化水中的悬浮液将片剂包薄膜衣，即得硝唑尼特片。
为了更好的理解本发明的实质，下面用硝唑尼特改善SARS-CoV-2感染hACE2转基因小鼠肺组织病变的研究，来说明硝唑尼特在制备预防及治疗间质性肺病药物中的应用。
(1)攻毒毒株
毒株名称：SARS-CoV-2
感染途径：滴鼻
感染剂量：105TCID50/只
感染体积：50微升
(2)实验动物
动物名称：hACE2转基因小鼠
动物级别：SPF级
动物年龄：6-7周龄
动物体重：体重20-24g
(3)实验方法
动物分组：分为治疗高、中和低剂量组和模型组
每组动物数量：每组6只
给药剂量：按照高中低三剂量使用，浓度分别为38.46mg/mL，12.9mg/mL，6.45mg/mL，以0.2mL/10g给予
给药途径：灌胃
给药时间：治疗组攻毒后2小时给药，每天一次，连续给药5次。模型组按照等体积给予蒸馏水。
(4)检测指标
攻毒后5天，处死全部小鼠，进行病理检查。
(5)实验结果
高、中剂量组SARS-CoV-2攻毒第5天6例小鼠肺组织均呈轻度间质性肺炎改变，肺泡隔增宽不明显、炎细胞浸润较少；肺泡内炎细胞及浆液渗出较少；血管周围轻微炎细胞浸润。见图1、图2。
低剂量组攻毒第5天6例(6/6)肺组织呈中度间质性肺炎改变，可见肺泡隔增宽、炎细胞浸润；血管周围少量炎细胞浸润，见图3。
SARS-CoV-2攻毒5天hACE2转基因模型组小鼠6例肺组织呈中度间质性肺炎改变，可见肺泡隔增宽、炎细胞浸润，肺泡内少量炎细胞渗出，血管周围炎细胞浸润，见图4。
与模型组相比，高、中剂量组小鼠肺组织病变明显改善，低剂量组肺组织病变改善不明显。
通过以上试验可以有效的证明：硝唑尼特通过抑制SARS-CoV-2感染的hACE2转基因小鼠的肺部炎症反应，改善了组织纤维增殖及细胞外基质沉积，从而抑制了肺部损伤。因此硝唑尼特能够有效的预防及治疗间质性肺炎。
Claims (8)
1.一种硝唑尼特，在制备预防及治疗间质性肺病药物中的应用。
2.根据权利要求1所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：有效成分为硝唑尼特及其体内活性代谢物替唑尼特。
3.根据权利要求1所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：间质性肺病包括特发性肺纤维化、特发性非特异性间质性肺炎、呼吸性细支气管炎伴间质性肺疾病、脱屑性间质性肺炎、隐原性机化性肺炎、急性间质性肺炎、特发性淋巴细胞性间质性肺炎、特发性胸膜肺实质弹力纤维增生症、不能分类的特发性间质性肺炎。
4.根据权利要求1所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：间质性肺病包括冠状病毒感染引发的疾病并发症。
5.根据权利要求4所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：冠状病毒感染引发的疾病包括严重急性呼吸综合征、中东呼吸综合征、新型冠状病毒肺炎。
6.根据权利要求4所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：冠状病毒包括SARS病毒、中东呼吸综合征冠状病毒、新型冠状病毒。
7.根据权利要求1所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：药物的制剂形式包括硬胶囊剂、软胶囊剂、散剂、颗粒剂、片剂、混悬剂、丸剂。
8.根据权利要求7所述的硝唑尼特在制备预防及治疗间质性肺病药物中的应用，其特征在于：制备药物所用的辅料包括玉米淀粉，预糊化玉米淀粉，羟丙基甲基纤维素，蔗糖，羟乙酸淀粉钠，滑石粉，硬脂酸镁，大豆卵磷脂，聚乙烯醇，黄原胶，二氧化钛和色素。
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