CN116407524A - 一种莫那比拉韦吸入粉雾剂及其制备方法 - Google Patents

一种莫那比拉韦吸入粉雾剂及其制备方法 Download PDF

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CN116407524A
CN116407524A CN202111670999.7A CN202111670999A CN116407524A CN 116407524 A CN116407524 A CN 116407524A CN 202111670999 A CN202111670999 A CN 202111670999A CN 116407524 A CN116407524 A CN 116407524A
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monabivalve
inhalation powder
coating agent
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任恒春
赵德千
安丹
高世静
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Zhengzhou Shenlanhai Biomedical Technology Co ltd
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Abstract

本发明涉及一种莫那比拉韦吸入粉雾剂及其制备方法，属于制剂学领域。一种莫那比拉韦吸入粉雾剂，其特征在于所述剂型单剂量制剂包括以下组分：50‑100mg莫那比拉韦、40‑150mg包覆剂、40‑80mg悬浮剂、20mg‑40mg包和剂、3‑10mg助溶剂、50‑100mg载体、HPMC胶囊壳。本发明制备的含有莫那比拉韦的吸入粉雾剂，具有高效、低毒、服用方便、安全度高的特点。

Description

一种莫那比拉韦吸入粉雾剂及其制备方法
技术领域：
本发明涉及一种莫那比拉韦吸入粉雾剂及其制备方法，属于制剂学领域。
背景技术：
人类世界上有很多的病毒，病毒是生态环境的一部分。病毒可在家畜或者野生动物之间传播，也可在人间传播，尤其是病毒引起的新发传染病，对人类来说是长期存在的威胁。我们处于病毒的汪洋大海中，但却并没有感染很多病毒。人体有1013个细胞，皮肤作为人体表面最大器官对所有病毒不易感，病毒要进入人体需要有自己的通道。这一通道就是人体和外界相通的通道，包括呼吸道、消化道、生殖道，以及通过蚊虫叮咬、输血传播和母婴传播。
在整个抗感染药物治疗领域中，抗菌药较多而抗病毒药物较少，主要源于病毒结构的复杂性及多变性。
莫那比拉韦(Molnμpiravir)，又称为EIDD-2801/MK4482，是一种核糖核苷类似物，可抑制多种RNA病毒的复制，包括SARS-CoV-2。EIDD-2801是抗病毒化合物EIDD-1931的口服形式；它可以作为药丸服用，并能被适当吸收，然后进入肺部。莫那比拉韦目前只有口服制剂，当它进入细胞时，它被转化为类似 RNA的构成单元。在第一阶段，称为RNA聚合酶的病毒复制机器将这种构成单元整入SARS-CoV-2的RNA基因组。然而，与延缓病毒RNA聚合酶的瑞德西韦不同的是，莫那比拉韦并不直接干扰这种病毒复制机器的功能。相反，在第二阶段，这种类似RNA的构成单元与病毒遗传物质的构成单元相连接在一起。莫那比拉韦似乎还能引发其他RNA病毒的突变，防止它们进一步传播。莫那比拉韦的化学结构式如下：
Figure BDA0003449728120000011
吸入制剂是一种通过肺部给药的特殊剂型，通过局部给药的方式可以快速、直接地进入肺部发挥药效，降低给药剂量，提高药物疗效。主要分为干粉吸入、气雾剂及雾化吸入剂。吸入粉雾剂最大的优点在于使用时，病人的气流是粉末进入体内的唯一动力，故不存在协同困难，降低了药物副作用的发生率，此特点使得粉雾剂越来越受到欢迎和普及。吸入制剂对于哮喘、COPD、呼吸道感染、囊性纤维化、肺心病、肺动脉高压等呼吸系统疾病有较好的治疗优势，特别方便于儿童、老年、重患用药，且该疗法已多次被写进专家共识和诊疗指南。
目前莫那比拉韦无吸入制剂上市，本发明提供了一种新的剂型。
发明内容：
为解决上述问题，本发明提供了一种莫那比拉韦吸入粉雾剂，通过由口鼻吸入直接作用在肺部，可在肺部聚集成较高浓度，进入呼吸和血液循环系统，从而可达到全身用药的目的。吸入制剂大大减少了由肝肾对药物的代谢过程，极大降低了对患者的肝肾损伤。
本发明提供的技术方案是所述剂型单剂量制剂包括以下组分：50-100mg莫那比拉韦、40-150mg包覆剂、40-80mg悬浮剂、20mg-40mg包和剂、3-10mg助溶剂、50-100mg载体、HPMC胶囊壳。
所述原料药来源为莫那比拉韦自制品和外购品。
所述包覆剂为磷脂；优选：所述的磷脂选自蛋黄磷脂、大豆磷脂、氢化大豆磷脂、脑磷脂、心磷脂、鞘磷脂或合成磷脂等中的一种或多种；进一步优选的：所述磷脂为大豆磷脂、氢化大豆磷脂、合成磷脂。
所述的悬浮剂为乙酸乙酯或体积浓度为60～90％的乙醇。
所述的包和剂为环糊精及其衍生物；优选：所述的包和剂为磺丁基-β-环糊精、2-羟丙基-β-环糊精和β-环糊精中的至少一种。
所述的助溶剂为聚氧乙烯蓖麻油、泊洛沙姆、吐温、EDTA-2Na、磷酸氢二钠、磷酸二氢钠和蔗糖中的至少一种；优选：所述的助溶剂为聚氧乙烯蓖麻油、吐温80、磷酸氢二钠、磷酸二氢钠。
所述的载体为乳糖、蔗糖、海藻糖和葡萄糖中的至少一种；优选：所述的载体为乳糖和海藻糖中的至少一种。
本发明的另一目的在于提供一种所述莫那比拉韦吸入粉雾剂的制备方法，该方法工艺简单、所用设备简单、生产环境要求低、使用方便、效果较好，该方法包括以下步骤：
(1)将莫那比拉韦原料药采用气流粉碎机进行粉碎，至D90为2-5μm；
(2)将包覆剂和助溶剂加入悬浮剂中搅拌至完全溶解，得到混合液；
(3)将微粉化后的莫那比拉韦和包和剂混悬在所述混合液中，进行喷雾干燥，得到药物颗粒；
(4)将上述药物颗粒以气流粉碎机进行微粉化至D90为2-5μm；
(5)将步骤(4)微粉化的颗粒与载体进行混合，得到混合物；将该混合物进行胶囊包装，即得目标产品。
与现有技术相比，本发明的有益效果是：
1.本发明首次提供了一种莫那比拉韦吸入药用剂型，该制剂可替代口服及其他剂型，其由口鼻直接吸入，避免了肝脏的首过效应及胃肠道的破坏与降解，可在肺部聚集成较高浓度，从而进入呼吸和血液循环系统，进而达到全身治疗的目的，并且大大减少了由肝肾对药物的代谢过程，极大降低了对患者的肝肾损伤。本发明弥补了目前国内外市场上的空白，提供了一种莫那比拉韦的全新的安全有效的给药方式，为新冠肺炎的治疗提供一种全新的解决方案。
2.本发明提供一种优化的处方，该处方经过验证符合2020版《中国药典》四部通则0111吸入制剂项下技术要求；而该处方中莫那比拉韦、包覆剂、包和剂的用量，悬浮剂的选择，微粉化后的粒径都是本发明的关键因素，相互配合，如对比例1-3所示，改变包覆剂、包和剂的用量，悬浮剂的类别，不同的粒径，都会导致吸入粉雾剂质量降低。
3.本发明提供一种优化的处方，通过在莫那比拉韦的表面包覆以磷脂和其他助剂进行表面改性的方式是成功的，这种磷脂与助剂的组合成分可以提高其在干粉剂型中的粉体学性能，优化了空气动力学特征，将更多的药物有效递送到下呼吸道、深层肺泡组织中，有的实施例中治疗剂药物有效部位沉积率高达45～6 0％，相对于常规DPI制剂10-30％的有效部位沉积率。
4.本发明提供一种优化的处方，通过原料药表面的改性，降低了制剂中干粉的团聚，避免储存一定时间后，无法有效再分散的情况，提高制剂稳定性。
5.本发明提供一种优化的处方，其中磷脂以及助剂组成的涂层，也可以有效降低溶液态药物与阀门、硅胶、密封圈等部位材料对药物吸附而带来的损失，同时，还可在吸入时润滑给药通道，降低了对呼吸系统的刺激。莫那比拉韦吸入粉雾剂进入气道后，可被巨噬细胞吞噬后再缓慢释放，作用温和持久，是一种安全有效的给药方式。
6.制备工艺简单，设备成本低，便于产业化。
具体实施方式：
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。凡依照本发明内容进行的任何本领域的等同替换，均属于本发明的保护范围。
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。
本发明使用的制剂设备、检测仪器等包括：
(1)瑞士BΜCHI 191小型喷雾干燥器，使用和设置的参数为：入口温度：9 0-140℃；出口温度：60-105℃；流化空气流量：200-800L/小时(压力：0.15-0.4b ar)；
(2)诺泽气流粉碎机：jetmill pilot型，常用压力为5-8bar，密封压力：6.5-10bar；
(3)马尔文激光粒度检测仪：可以检测粒径分布D90:1-1000μm；
(4)深圳信宜特XYT-G6高速剪切混合制粒机，可以混合0.5L-6L物料；
MDI气雾吸入器测试采用检测方法为通用方法，具体参考2020版《中国药典》四部通则0951吸入制剂微细粒子空气动力学特性测定法项下装置3中所述步骤，具体如下：
Copley新一代撞击式气溶胶颗粒采样器(NGI，符合标准ΜSP Chapter<601> 和EPChapter 29.9.18)。待测样品经后检测空气动力学粒度分布数据，平均速率设置为：0.20ml/min。测定前将NGI装置置于4℃预冷3小时，然后在室温：22℃下测定，气体流速设置为28±1.0L/min。颗粒沉积于仪器各收集部位：导入装置、各级收集盘、微孔收集器部位的药物收集后，以HPLC法测定含量，即可获得各个部位的药物截留量与比例。通过分析颗粒物的沉积位置，可获得细颗粒粒级、细颗粒物剂量、质量中值直径(MMAD)和几何平均直径(GSD)等信息，以评估气溶胶的颗粒性能。同时，以生物显微镜观测拍摄其外观性状等。
实施例1～5以及对比例1～3的制剂工艺描述如下：(配方组分的用量见下述表格)
(1)将莫那比拉韦采用诺泽jetmill pilot气流粉碎机进行粉碎，加料速度为 15-20g/min，气流粉碎粉碎压力为5.5-7.0bar；检测其粒度分布为：D90：2-5μm；
(2)将包覆剂和助溶剂加入悬浮剂中搅拌至完全溶解，得到混合液；
(3)将微粉化后的治疗剂和包和剂混悬在所述混合液中，进行喷雾干燥；B ΜCHI191喷雾干燥机设置参数为：
i.进气温度为130±5℃；ii.出口温度为75±5℃；iii.空压机压力为：8.0-8.5bar； iv.压力为：0.15-0.2bar；v.空气流速：800-1500L/小时；vi.泵液速度为：6-10ml/min；
(4)将上述药物颗粒以诺泽jetmill pilot气流粉碎机进行微粉化，粉碎气流压力为：6.5-7.5公斤，处理后的颗粒，马尔文激光粒度粒度检测为：D90：2-5μ m；
(5)步骤(4)粉碎后的颗粒与处方量吸入用载体在信宜特高剪切混合制粒机XYTG6(带温控模块)进行混合，得到混合物；以吸入制剂胶囊填充机，进行胶囊包装(装量：200-500mg/粒)，60吸为一个市售包装单元，双铝包装。
实施例1-5：莫那比拉韦吸入粉雾剂组分及用量，规格：200～480mg(单剂量，原料药用量以干燥品计)。
Figure BDA0003449728120000051
为了更好地体现本发明提供的处方优势，我们做了包覆剂、包和剂的用量，悬浮剂的用量考察实验，具体如下：
对比例1-3：莫那比拉韦吸入粉雾剂组分及用量，规格：190～470mg(单剂量，原料药用量以干燥品计)
Figure BDA0003449728120000061
*对比例2由于磺丁基-β-环糊精用量较少，制备工艺步骤(3)中混合液有部分混悬药粉，影响制剂均一性。
#对比例3由于悬浮剂乙酸乙酯加入量较少，制备工艺步骤(3)喷雾干燥过程中发生堵塞，影响正常生产。
为了进一步说明本发明的技术效果，对上述实施例和对比例中处方制剂进行体外吸入性能测试及安全有效性非临床研究，具体如下。
实验例1：体外性能测试
利用新一代撞击式气溶胶颗粒采样器(NGI)将上述试验样品进行空气动力学测试，影响给药的关键数据见表1。
表1实施例及对比例中制剂样品性能测试
Figure BDA0003449728120000062
由表1所述，对比例1在平均空气动力学粒径(MMAD)、几何标准差(G SD)，微细粒子有效部位沉积率(FPF)方面都劣于本发明，同时不符合2020版《中国药典》四部通则0111吸入制剂项下技术要求。而本发明是优选方案，同时各项指标符合上述要求。
实验例2
本发明的吸入粉雾剂(按实施例5方法制备)与口服胶囊制剂(Merck生产，2 00mg，40粒/瓶)在小鼠给药时的肝细胞各监测数据的比较，按相同剂量给药。
取小鼠30只，雌雄各半，随机分为正常对照组(空白组，不给药)，莫那比拉韦吸入给药组和口服给药组，每天给予200mg量的莫那比拉韦。持续一周后，对各给药组小鼠模型肝细胞上清液中的AST、ALP、LDH进行数值检测，检测结果如下表显示，AST、ALP、LDH水平均有显著上升，见表2。
表2各给药组小鼠模型肝细胞上清液中的AST、ALP、LDH数值检测结果
组别 AST ALP LDH
对照组 6.5±0.1 27.5±0.5 71.5±0.9
吸入给药组 7.2±0.1 28.5±0.4 75.5±1.1
口服给药组 9.5±0.2 31.5±0.8 102.5±3.2
吸入给药组与对照组比较P>0.05；口服给药组与对照组比较P<0.05。
如表2所示，给药一周后，吸入给药组和空白对照组小鼠模型肝细胞上清液中的AST、ALP、LDH无显著差异，而口服给药组AST、ALP、LDH水平均有显著上升，结果表明吸入给药方式安全性好，毒副作用小。

Claims (8)

1.一种莫那比拉韦吸入粉雾剂，其特征在于，所述剂型单剂量制剂包括以下组分：50-100mg莫那比拉韦、40-150mg包覆剂、40-80mg悬浮剂、20mg-40mg包和剂、3-10mg助溶剂、50-100mg载体、HPMC胶囊壳。
2.根据权利要求1所述的一种莫那比拉韦吸入粉雾剂，其特征在于，所述包覆剂为磷脂，所述的磷脂为蛋黄磷脂、大豆磷脂、氢化大豆磷脂、脑磷脂、心磷脂、鞘磷脂和合成磷脂中的一种或多种混合物。
3.根据权利要求1所述的一种莫那比拉韦吸入粉雾剂，其特征在于，所述的悬浮剂为乙酸乙酯或体积浓度为60~90%的乙醇。
4.根据权利要求1所述的一种莫那比拉韦吸入粉雾剂，其特征在于，所述的包和剂为磺丁基-β-环糊精、2-羟丙基-β-环糊精和β-环糊精中的一种或多种混合物。
5.根据权利要求1所述的一种莫那比拉韦吸入粉雾剂，其特征在于，所述的助溶剂为聚氧乙烯蓖麻油、泊洛沙姆、吐温、EDTA-2Na、磷酸氢二钠、磷酸二氢钠和蔗糖中的一种或多种混合物。
6.根据权利要求1所述的一种莫那比拉韦吸入粉雾剂，其特征在于，所述的载体为乳糖、蔗糖、海藻糖和葡萄糖中的一种或多种混合物。
7.根据权利要求1-6任意一项所述的一种莫那比拉韦吸入粉雾剂，其特征在于，制剂的装量为200-500mg。
8.根据权利要求7所述的一种莫那比拉韦吸入粉雾剂的制备方法，其特征在于，包括如下步骤：
(1) 将莫那比拉韦原料药采用气流粉碎机进行粉碎，至D90为2-5μm；
(2) 将包覆剂和助溶剂加入悬浮剂中搅拌至完全溶解，得到混合液；
(3) 将微粉化后的莫那比拉韦和包和剂混悬在所述混合液中，进行喷雾干燥，得到药物颗粒；
(4) 将上述药物颗粒以气流粉碎机进行微粉化至D90为2-5μm；
(5) 将步骤(4)微粉化的颗粒与载体进行混合，得到混合物；将该混合物进行胶囊包装，即得目标产品。
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