CN114617860A - 一种含尼达尼布的吸入液及其制备方法 - Google Patents
一种含尼达尼布的吸入液及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含尼达尼布的吸入液，包含尼达尼布或其盐、辅料和溶剂，所述辅料包括pH调节缓冲剂、金属离子螯合剂、稳定剂和渗透压调节剂，本发明还公开了该吸入液的制备方法。本发明提供的尼达尼布吸入液能够有效提高治疗IPF疗效、降低不良反应的吸入液。联合雾化器使用，经雾化吸入后直接作用于肺部，提高了尼达尼布治疗IPF的疗效；同时避免了肝脏的首过效应及胃肠道的破坏与降解，降低了药物的不良反应。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种含尼达尼布的吸入液及其制备方法。
背景技术
特发性肺纤维化(IPF)是一种罕见的原因不明的破坏性疾病，以弥散性肺泡炎和肺泡结构紊乱并最终导致肺间质纤维化为特征，其最终导致患者呼吸衰竭而死亡。IPF预后不良，患者的中位生存期为2-3年，5年生存率低于30％，比大多数癌症(如白血病，乳腺癌，结肠癌，子宫癌和肾癌)的生存率都低。60％患者直接死于IPF，主要死亡原因包括IPF的急性恶化、急性冠状动脉、充血性心力衰竭、肺癌、感染和静脉血栓栓塞性疾病。IPF在全球范围内均有发生，且不分种族和性别，其自然病程变异较大，且无法预估。IPF虽为罕见病(发病率约14～43/10万)，但近些年其发病率呈增加趋势。IPF的发病与患者年龄密切相关，75岁以上老年人IPF的发病率是35岁以下人群的100倍，男性发病率高于女性。IPF累及全球约300万人，美国约13万人。
尼达尼布是一种小分子酪氨酸激酶抑制剂，具有抗纤维化和抗炎活性。尼达尼布可抑制多种受体酪氨酸激酶(RTK)：血小板衍生生长因子受体α和β(PDGFRα、β)、成纤维细胞生长因子受体1-3(FGFR1-3)、血管内皮生长因子受体1-3(VEGFR1-3)及Fms样酪氨酸激酶-3(FLT3)，其中FGFR、PDGFR和VEGFR与IPF的发病机制有关，尼达尼布可竞争性结合于这些胞内受体激酶结构域上的三磷酸腺苷(ATP)结合位点，阻滞胞内信号传导，抑制成纤维细胞的增殖、迁移和转化。此外，尼达尼布还可抑制以下非受体酪氨酸激酶(nRTK)：Lck、Lyn和Src激酶。
目前，市场上的尼达尼布大多数为口服制剂，但该制剂经胃肠道吸收降解后，生物利用度较低，且会引发一系列的副作用，诸如胃肠道反应腹泻、恶心、呕吐等，肝胆疾病如肝酶升高、血小板减少等。
专利CN109758437A公开了一种雾化吸入用尼达尼布冻干脂质体制剂，主要包括以下成分：尼达尼布或其盐、脂质、磷脂和等渗剂，该专利制备工艺繁杂，需先分别制备空白脂质体和尼达尼布储备液，再进行尼达尼布的包封，生产过程需保证药品的包封率，稳定性放置过程中需保证产品的泄漏率。
发明内容
本发明的目的是提供一种含尼达尼布的吸入液及其制备方法，该吸入液能够有效提高治疗IPF疗效、降低不良反应。而且制备工艺简单可行，可适用于商业化生产。
技术内容
一种含尼达尼布的吸入液，包含尼达尼布或其盐、辅料和溶剂，所述辅料包括pH调节缓冲剂、金属离子螯合剂、稳定剂和渗透压调节剂。
进一步的，所述尼达尼布或其盐在吸入液中的浓度为0.1～20mg/ml((以游离尼达尼布的量计算)。
进一步的，所述pH调节缓冲剂为柠檬酸/柠檬酸钠、磷酸二氢钠/磷酸氢二钠或柠檬酸/磷酸氢二钠体系中的一种，所述pH调节缓冲剂的浓度为0.5～20mol/L。
进一步的，含尼达尼布的吸入液的pH为3.0-5.0，pH调节剂中酸为盐酸、柠檬酸、磷酸、硫酸等，碱为氢氧化钠、碳酸氢钠、磷酸氢钠，
进一步的，所述金属离子螯合剂为依地酸二钠、氨基三乙酸或二亚乙基三胺五乙酸中的一种，所述金属离子螯合剂在吸入液中的浓度为10-15mg/ml。
进一步的，所述稳定剂是聚维酮k25、泊洛沙姆或聚山梨酯80中的一种，所述稳定剂在吸入液中的浓度为20-40mg/ml。
进一步的，所述渗透压调节剂是氯化钠。
进一步的，所述溶剂是注射用水。
本发明还提供一种含尼达尼布的吸入液的制备方法，包括如下步骤：
(1)将尼达尼布或其盐微粉化处理，高温灭菌后备用；
(2)将处方量的辅料加入注射用水中，搅拌至溶解；
(3)将步骤(2)得到的溶液用0.22微米聚醚砜膜过滤；
(4)将处方量的尼达尼布或其盐加入(3)中，均质处理；
(5)将步骤(4)所得样品进行灌封。
进一步的，所述步骤(4)均质步骤采用高速分散均质机均质处理，转速10-15krpm，均质时间5-10min。
本发明采用高速分散均质机制备的尼达尼布吸入液，使得微粒粒子剂量(小于5μm雾滴分布，FPF)均值在35％-45％。
本发明提供的尼达尼布吸入液为单剂量包装，在给药的时候，通过将玻璃安瓿或塑料安瓿中的吸入液转移至便携式雾化器后，雾化吸入即可。
与现有技术相比，本发明具有下述有益技术效果：
本发明提供的尼达尼布吸入液能够有效提高治疗IPF疗效、降低不良反应的吸入液。联合雾化器使用，经雾化吸入后直接作用于肺部，提高了尼达尼布治疗IPF的疗效；同时避免了肝脏的首过效应及胃肠道的破坏与降解，降低了药物的不良反应。本发明的尼达尼布吸入液的肺部的沉积率和雾化效率较高，与市售常见吸入剂在同一水平，另外本发明的制剂，制备工艺简单可行，可适用于商业化生产。
附图说明
图1是实施例5吸入剂的空气动力学粒径分布图。
具体实施方式
以下通过实施例的形式说明具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。
实施例1
尼达尼布吸入液的制备
处方：
| 原辅料组成 | 用量(mg) |
| 尼达尼布 | 750 |
| 柠檬酸钠 | 67.5 |
| 柠檬酸 | 50 |
| 依地酸二钠 | 15 |
| 聚山梨酯80 | 20 |
| 氯化钠 | 760 |
| 注射用水 | 至100mL |
制备工艺：(1)将尼达尼布或其盐微粉化处理，高温灭菌后备用；(2)将处方量的辅料加入注射用水中，搅拌至溶解；(3)将步骤(2)得到的溶液用0.22微米聚醚砜膜过滤；(4)将处方量的尼达尼布或其盐加入(3)中，均质处理；(5)将步骤(4)所得样品进行灌封。均质步骤采用高速分散均质机均质处理，转速10krpm，均质时间5min。
实施例2尼达尼布吸入液的制备
处方：
| 原辅料组成 | 用量(mg) |
| 尼达尼布 | 750 |
| 磷酸二氢钠 | 81.9 |
| 磷酸氢二钠 | 80.5 |
| 氨基三乙酸 | 10 |
| 聚山梨酯80 | 20 |
| 氯化钠 | 800 |
| 注射用水 | 至100mL |
制备工艺：(1)将尼达尼布或其盐微粉化处理，高温灭菌后备用；(2)将处方量的辅料加入注射用水中，搅拌至溶解；(3)将步骤(2)得到的溶液用0.22微米聚醚砜膜过滤；(4)将处方量的尼达尼布或其盐加入(3)中，均质处理；(5)将步骤(4)所得样品进行灌封。均质步骤采用高速分散均质机均质处理，转速11krpm，均质时间7min。
实施例3尼达尼布吸入液的制备
处方：
| 原辅料组成 | 用量(mg) |
| 尼达尼布 | 500 |
| 柠檬酸钠 | 135 |
| 柠檬酸 | 100 |
| 依地酸二钠 | 10 |
| 聚维酮k25 | 20 |
| 氯化钠 | 810 |
| 注射用水 | 至100mL |
制备工艺：(1)将尼达尼布或其盐微粉化处理，高温灭菌后备用；(2)将处方量的辅料加入注射用水中，搅拌至溶解；(3)将步骤(2)得到的溶液用0.22微米聚醚砜膜过滤；(4)将处方量的尼达尼布或其盐加入(3)中，均质处理；(5)将步骤(4)所得样品进行灌封。均质步骤采用高速分散均质机均质处理，转速13krpm，均质时间8min。
实施例4尼达尼布吸入液的制备
处方：
| 原辅料组成 | 用量(mg) |
| 尼达尼布 | 500 |
| 柠檬酸 | 102 |
| 磷酸氢二钠 | 150 |
| 二亚乙基三胺五乙酸 | 10 |
| 泊洛沙姆 | 40 |
| 氯化钠 | 810 |
| 注射用水 | 至100mL |
制备工艺：(1)将尼达尼布或其盐微粉化处理，高温灭菌后备用；(2)将处方量的辅料加入注射用水中，搅拌至溶解；(3)将步骤(2)得到的溶液用0.22微米聚醚砜膜过滤；(4)将处方量的尼达尼布或其盐加入(3)中，均质处理；(5)将步骤(4)所得样品进行灌封。均质步骤采用高速分散均质机均质处理，转速13krpm，均质时间8min。
实施例5
尼达尼布吸入液空气动力学粒度分布测定
试验方法：按照实施例1的处方制备尼达尼布吸入液，将此吸入液加入到压缩式雾化器中，开启雾化器，运用新一代撞击器(Next Generation Impactor，NGI)测定雾滴的空气动力学粒度分布，气体流速为16L/min，统计各收集杯中的药物含量，平行测定三次，取平均值。便携式雾化器为PARI LC SPRINT(蓝芯)，雾化时间：10min。如图1的空气动力学粒径分布图，结果显示，平行测定三次，微粒粒子剂量(小于5μm雾滴分布，FPF)均值在40％-50％，各组未见明显差异。说明本品在肺部的沉积率较高，与市售常见吸入剂FPF值在同一水平。
实施例6
尼达尼布吸入液递送速率及递送总量测定
试验方法：按照实施例1的处方制备尼达尼布吸入液，将此吸入液加入到压缩式雾化器中，开启雾化器，运用BRS2100呼吸模拟器，设置成人模式，运行1分钟后取出滤纸清洗测递送速率，更换滤纸继续运行至本品雾化完全。便携式雾化器为PARI LC SPRINT(蓝芯)，雾化时间：20min。
试验结果：结果显示，成人模式下，递送速率均值大于0.25mg/ml，递送总量大于30％。说明本品雾化效率较高，与市售常见吸入剂的递送特性一致。
Claims (10)
1.一种含尼达尼布的吸入液，其特征在于，包含尼达尼布或其盐、辅料和溶剂，所述辅料包括pH调节缓冲剂、金属离子螯合剂、稳定剂和渗透压调节剂。
2.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，所述尼达尼布或其盐在吸入液中的浓度为0.1～20mg/ml。
3.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，所述pH调节缓冲剂为柠檬酸/柠檬酸钠、磷酸二氢钠/磷酸氢二钠或柠檬酸/磷酸氢二钠体系中的一种，所述pH调节缓冲剂的浓度为0.5～20mol/L。
4.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，含尼达尼布的吸入液的pH为3.0-5.0。
5.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，所述金属离子螯合剂为依地酸二钠、氨基三乙酸或二亚乙基三胺五乙酸中的一种，所述金属离子螯合剂在吸入液中的浓度为10-15mg/ml。
6.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，所述稳定剂是聚维酮k25、泊洛沙姆或聚山梨酯80中的一种，所述稳定剂在吸入液中的浓度为20-40mg/ml。
7.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，所述渗透压调节剂是氯化钠。
8.根据权利要求1所述的含尼达尼布的吸入液，其特征在于，所述溶剂是注射用水。
9.如权利要求1-8所述的含尼达尼布的吸入液的制备方法，其特征在于，包括如下步骤：
(1)将尼达尼布或其盐微粉化处理，高温灭菌后备用；
(2)将处方量的辅料加入注射用水中，搅拌至溶解；
(3)将步骤(2)得到的溶液用0.22微米聚醚砜膜过滤；
(4)将处方量的尼达尼布或其盐加入(3)中，均质处理；
(5)将步骤(4)所得样品进行灌封。
10.根据权利要求9所述的制备方法，其特征在于，所述步骤(4)均质步骤采用高速分散均质机均质处理，转速10-15krpm，均质时间5-10min。
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