CN113491677B - 一类药用抗病毒药物吸入剂新型制剂及制备方法 - Google Patents

一类药用抗病毒药物吸入剂新型制剂及制备方法 Download PDF

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CN113491677B
CN113491677B CN202010193056.9A CN202010193056A CN113491677B CN 113491677 B CN113491677 B CN 113491677B CN 202010193056 A CN202010193056 A CN 202010193056A CN 113491677 B CN113491677 B CN 113491677B
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张哲峰
侯雯
赵海峰
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Nanjing Zhihe Medical Technology Co ltd
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Abstract

本发明公开了一类药用抗病毒药物吸入剂新型制剂及制备方法，本发明所述的新型制剂包括治疗剂、包覆剂、悬浮剂、包和剂、载体和助溶剂。本发明的剂型不但有改良二级颗粒表面性能、空气动力学优化的作用，还可以在达到提升肺泡内有效沉积率的效果后，促进对难溶性药物的溶解、吸收，加速起效。

Description

一类药用抗病毒药物吸入剂新型制剂及制备方法
技术领域
本发明属于制剂学领域，具体涉及一类药用抗病毒药物吸入剂新型制剂及制备方法。
背景技术
病毒的多样性、变异性、高传播性对公共卫生安全是极大的挑战。病毒感染后往往急起高热、全身疼痛、显著乏力，严重者更导致肺炎，呼吸衰竭等。流行性感冒是由流行性感冒病毒引起的呼吸道传染疾病，是人类面临的主要公共健康问题之一，流感的流行病学特点是突然爆发，迅速蔓延，播及面广。流感发病率高，普遍易感。流感临床症状较重，并发症发生率高，特别是肺炎，可引起死亡。抗流感病毒治疗是控制流感流行的手段之一，发病早期使用抗流感药物可以减轻症状、缩短病程和阻断传播。新型冠状病毒感染的肺炎在免疫功能低下和免疫功能正常人群均可发生，与接触病毒的量有一定关系。对于免疫功能较差的人群，例如老年人、孕产妇或存在肝肾功能异常，或有慢性病人群，感染后病情更重。今冬的新冠疫情，再一次提出“迫切需要更好的抗流感治疗药物”的呼声。
此次冠状病毒肺炎，它是由2019新型冠状病毒(以下简称“新冠病毒”)感染而引发的肺炎，国际病毒分类委员会(ICTV)正式将新冠病毒从此前学术论文及WHO官方消息的代称“2019-nCoV”正式命名为SARS冠状病毒-2(SARS-CoV-2)，与2003年爆发的SARS，以及后来在中东地区爆发的MERS等，一起严重威胁人类健康，具备潜在的全球流行的危机。因此，迫切需要开发一种载药量高、快速起效、作用靶向器官明确、全身毒副作用小的新型吸入剂，具备较为迫切的临床需求。
发明内容
本发明是针对上述存在的技术问题提供一类药用抗病毒药物吸入剂新型制剂。
本发明还有一个目的是提供一类药用抗病毒药物吸入剂新型制剂制备方法。
本发明的目的可以通过以下技术方案实现：
一类药用抗病毒药物吸入剂，所述的吸入剂中的组分如下：
在一些优选的技术方案中：治疗剂、包覆剂、悬浮剂、包和剂、载体和助溶剂的重量份数依次为10～500份、10～300份、10～200份、10～100份、10～100份和0～50份。
在一些更为优选的技术方案中：治疗剂、包覆剂、悬浮剂、包和剂、载体和助溶剂的重量份数依次为10～300份、10～250份、80～200份、10～50份、40～100份和0～30份。
在实施例案例中：上述的重量份可以但不限于mg。
本发明技术方案中：所述的治疗剂为抗病毒药物，所述的抗病毒药物为具备治疗SARS、MERS、2019新型冠状病毒(2019-nCoV)的疾病药物或者潜在药效的药物。
在一些具体的实施案例中：所述的抗病毒药物为矿物药、植物药、化学药物、生物药物的至少一种。
在一些更为具体的实施案例中：所述的抗病毒药物为利巴韦林、盐酸阿比朵尔、磷酸氯喹、利托那韦、瑞德西韦、奥司他韦、洛匹那韦、SiRNA和α-干扰素中的至少一种。
本发明技术方案中：所述的包覆剂为磷脂；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、合成磷脂中的一种或多种。
本发明技术方案中：所述的悬浮剂为乙酸乙酯或体积浓度为60～90％的乙醇。
本发明技术方案中：所述的包和剂为环糊精及其衍生物。
本发明技术方案中：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。
本发明技术方案中：所述的助溶剂为聚氧乙烯蓖麻油、泊洛沙姆，吐温、维生素E、EDTA-2Na、磷酸氢二钠、磷酸二氢钠和蔗糖中的至少一种。
本发明技术方案中：所述的载体为乳糖、蔗糖、海藻糖和葡萄糖中的至少一种。
在一些技术方案中，本发明提供了一类药用抗病毒药物吸入剂，所述的吸入剂中的组分如下：
可选地：治疗剂、包覆剂、悬浮剂、包和剂、载体和助溶剂的重量份数依次为10～500份、10～300份、10～200份、10～100份、10～100份和0～50份；或者，
治疗剂、包覆剂、悬浮剂、包和剂、载体和助溶剂的重量份数依次为10～300份、10～250份、80～200份、10～50份、40～100份和0～30份；
可选地，所述的治疗剂为利巴韦林、盐酸阿比朵尔、磷酸氯喹、利托那韦、瑞德西韦、奥司他韦、洛匹那韦、SiRNA和α-干扰素中的至少一种；
可选地，所述的包覆剂为磷脂；这里，所述的磷脂为大豆磷脂、氢化大豆磷脂、合成磷脂中的一种或多种；
可选地，所述的悬浮剂为乙酸乙酯或体积浓度为60～90％的乙醇；
可选地，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；
可选地，所述的助溶剂为聚氧乙烯蓖麻油、泊洛沙姆，吐温、维生素E、EDTA-2Na、磷酸氢二钠、磷酸二氢钠和蔗糖中的至少一种；
可选地，所述的载体为乳糖、蔗糖、海藻糖和葡萄糖中的至少一种。
一类药用抗病毒药物吸入剂的制备方法，该方法的步骤如下：
1)将治疗剂采用气流粉碎机进行粉碎，至D90为2-5um。
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，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2-5um；
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，记得目标产品。
本发明技术方案中所述的吸入剂为粉吸入剂。
本发明的有益效果：
本发明技术方案通过具体的对比实验发现，通过在治疗剂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45～60％，相对于常规DPI制剂10-30％的有效部位沉积率，本发明的优势显著；
同时，在实验中意外发现，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，这对于常规的溶液剂型或者无颗粒保护涂层的MDI剂型的活性物质来说，吸附导致的有效剂量损失是常见的，这是本发明的另外一大优势。
另外，磷脂以及助剂组合物涂层组组成通过对二级颗粒表面的改良，降低了DPI剂型中干粉的团聚，避免了储存一定时间后，无法有效再分散的情况；同时，也可以降低P-MDI剂型中混悬颗粒的絮集程度，使其二级颗粒沉降后的再分散更加容易实现，具有一定的改善。
此外，磷脂与助剂不但有改良二级颗粒表面性能、空气动力学优化的作用，还可以在达到提升肺泡内有效沉积率的效果后，促进对难溶性药物的溶解、吸收，加速起效。
具体实施方式
下面结合实施例对本发明做进一步说明，应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明，凡在本发明的构思前提下对本发明制备方法的简单改进都属于本发明的保护范围之内。下面实施例未注明具体条件的实验方法，通常按照本领域的公知手段。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
本发明使用的制剂设备、检测仪器等包括：
(1)瑞士BUCHI 191小型喷雾干燥器，使用和设置的参数为：入口温度：90-140℃；出口温度：60-105℃；流化空气流量：200-800L/小时(压力：0.15-0.4bar)
(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D90:1-1000um。
(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：
Westech安德森八级撞击式气溶胶颗粒采样器(符合标准USP 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，器的平均速率设置为：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1～36以及对比例1～8的制剂工艺：(配方组分的用量见下述表格)1)将治疗剂采用诺泽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：D90：2-5um。
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；BUCHI191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：D90：2-5um；
5)步骤4)粉碎后的颗粒与处方量吸入用无载体在信宜特高剪切混合制粒机XYT-G6(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：260-400mg/粒)，60吸为一个市售包装单元，双铝包装。
实施例1-6：利巴韦林干粉吸入剂处方：
表1-1 实施例1～6的组分及其用量，规格:10-300mg(1吸)
表1-2 对比例1～6的组分及其用量，规格:20-100mg(1吸)
表1-3 实施例1～6的性能测试
表1-4 对比例1～6的性能测试
表1-5 实施例7～9以及对比例7～8的组分及其用量，(1吸)
表1-6 实施例7～9以及对比例7～8的性能测试
实施例10～18：
表2-1 实施例10～15的组分及其用量，规格:10-300mg(1吸)
表2-2 实施例10～15的性能测试
表2-3 实施例16～18的组分及其用量，(1吸)
表2-4 实施例16～18的性能测试
实施例19～21：
表3-1 实施例19～21的组分及其用量，(1吸)
/>
表3-2 实施19～21的性能测试
实施例22～24：
表4-1 实施例22～24的组分及其用量，(1吸)
/>
表4-2 实施22～24的性能测试
实施例25～27：
表4-1 实施例25～27的组分及其用量，(1吸)
/>
表4-2 实施25～27的性能测试
检验项目 实施例25 实施例26 实施例27
性状(二级粒子) 颗粒、粉末 颗粒、粉末 颗粒、粉末
平均空气动力学粒径(MMAD) 5.51um 5.57um 5.49um
几何标准差(GSD) 1.09 1.89 1.82
微细粒子有效部位沉积率(FPF) 65.0％ 63.3％ 67.3％
实施例28～30：
表5-1 实施例28～30的组分及其用量，(1吸)
表5-2 实施28～30的性能测试
实施例31～33：
表6-1 实施例31～33的组分及其用量，(1吸)
表6-2 实施28～30的性能测试
实施例34～37：
表7-1 实施例34～36的组分及其用量，(1吸)
表7-2 实施例34～36的性能测试
检验项目 实施例34 实施例35 实施例36 实施例36
性状(二级粒子) 颗粒、粉末 颗粒、粉末 颗粒、粉末 颗粒、粉末
平均空气动力学粒径(MMAD) 5.88um 5.92um 6.02um 5.73um
几何标准差(GSD) 1.92 1.75 1.36 1.60
微细粒子有效部位沉积率(FPF) 60.1％ 59.2％ 66.6％ 67.2％

Claims (3)

1.一类药用抗病毒药物吸入剂，其特征在于：所述的吸入剂中的组分如下：
或
其中：所述的抗病毒药物为利巴韦林、盐酸阿比朵尔、磷酸氯喹、利托那韦、瑞德西韦、奥司他韦、洛匹那韦、SiRNA和α-干扰素中的至少一种；
所述包覆剂为大豆磷脂、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；
所述的载体为乳糖、蔗糖、海藻糖和葡萄糖中的至少一种；
所述的吸入剂所用的胶囊壳为吸入用胶囊HPMC；所述的助溶剂为聚氧乙烯蓖麻油、泊洛沙姆，吐温、维生素E、EDTA-2Na、磷酸氢二钠、磷酸二氢钠和蔗糖中的至少一种。
2.根据权利要求1所述的药用抗病毒药物吸入剂，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-环糊精中的至少一种。
3.一种权利要求1或2所述的吸入剂的制备方法，其特征在于：该方法的步骤如下：
1)将治疗剂采用气流粉碎机进行粉碎，至D90为2-5um；
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，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2-5um；
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，记得目标产品。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075798A2 (en) * 2005-12-20 2007-07-05 Tika Lakemedel Ab Methods and systems for the delivery of corticosteroids having an increased lung deposition
CN102078312A (zh) * 2010-12-24 2011-06-01 中国药科大学 一种姜黄素类化合物干粉吸入剂及其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075798A2 (en) * 2005-12-20 2007-07-05 Tika Lakemedel Ab Methods and systems for the delivery of corticosteroids having an increased lung deposition
CN102078312A (zh) * 2010-12-24 2011-06-01 中国药科大学 一种姜黄素类化合物干粉吸入剂及其制备方法和用途

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