CN116898814A - 一种硫酸艾沙康唑冻干粉针剂及其制备方法 - Google Patents
一种硫酸艾沙康唑冻干粉针剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种硫酸艾沙康唑冻干粉针剂及其制备方法，由硫酸艾沙康唑、甘露醇、硫酸、注射用水组成。本发明对注射用硫酸艾沙康唑的关键工艺冻干曲线进行优化，通过对预冻、升华干燥、解析干燥的温度和时间摸索验证，有效地满足了产品低水分质量的需求，冻干后获得性状为白色至黄色、细腻、疏松且复溶良好的粉针制剂，含水量很低、复溶快速、澄清透明，符合无菌制剂的要求。同时对产品的质量稳定性有较明显改善，保障了产品在长期放置过程中最低的水分增加率，提高了稳定性；通过产品的稳定性实验对其稳定性进行了评价，结果表明产品的水分、不溶性微粒、复溶时间、有关物质、含量等主要指标均符合质量标准的要求，保障了临床使用的产品质量。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种硫酸艾沙康唑冻干粉针剂及其制备方法。
背景技术
艾沙康唑是Basilea Pharmaceutica开发的一种新型三唑类抗真菌药，该药物抗菌谱广，体外研究和临床试验提示对霉菌、酵母菌、双向真菌及一些罕见真菌等均有抗菌活性，对特殊部位如中枢神经系统的感染临床治疗有效，具有血药浓度稳定、安全性和耐受性良好、长期使用药物相关不良反应少的特点，是近年来临床上新型的一线治疗用药。
注射用硫酸艾沙康唑于2015年经FDA批准在美国上市，适用于18岁及以上患者用于治疗侵袭性曲霉病、侵袭性粘孢子菌病，持证商为：Astellas Pharma US,Inc.。同年经EMA批准在欧洲上市，持证商为：Basilea Pharmaceutica Deutschland GmbH。随后，分别于2022、2023年经NMPA和PMDA批准在我国及日本进口上市，商品名为适用于治疗成人患者侵袭性毛霉病。
硫酸艾沙康唑的化学名为1-{(2R,3R)-3-[4-(4-氰基苯基)-1,3-噻唑-2-基]-2-(2,5-二氟苯基)-2-羟基丁基}-4-[(1RS)-1-({甲基[3-({[(甲基氨基)乙酰基]氧基}甲基)吡啶-2-基]氨基甲酰基}氧基)乙基]-1H-1,2,4-三唑-4-鎓单硫酸盐，分子式：C35H35F2N8O5S.HSO4，结构式如下：
在水或甲醇中易溶，在三氯甲烷或乙醚中几乎不溶，具有引湿性，对水分需要关注控制。
CN101784259公开了抗真菌组合物，保护了艾沙康唑或其可药用酸加成盐的口服制剂。制剂组合物专利授权保护的是自乳化口服制剂，但本发明制剂采用的不是自乳化技术也非口服制剂。
CN107661298公开了一种注射用硫酸艾沙康唑鎓及其冻干工艺，冻干粉针剂常温保存，由硫酸艾沙康唑鎓、甘露醇、硫酸、注射用水组成。冻干工艺先将冷冻干燥机搁板温度降温至-10℃，再降温至-45℃，保温2-4小时；升温至20-25℃，保温2-6小时；升温至40-45℃，保温6-12小时。硫酸艾沙康唑对温度较为敏感，预热不稳定易降解，据文献公开报道，注射用硫酸艾沙康唑是在2-8℃冷藏保存。
CN112294762公开了一种胶束、抗真菌组合物及其制备方法和应用，胶束包含硫酸艾沙康唑和磷脂-胆汁酸盐混合胶束，平均粒径小于20nm，抗真菌组合物包括上述胶束、pH调节剂和等渗调节剂，可作为眼用制剂。本发明主要用于注射用途，且非胶束制备工艺。
CN115300467公开了一种注射用硫酸艾莎康唑冻干粉针剂及其制备工艺，包括以下成分：艾沙康唑硫酸盐、赋形剂(甘露醇)、pH调节剂(稀硫酸)。冻干工艺先将冷冻干燥机搁板温度降温至-5至-10℃，再降温至-45℃，保温2-3小时；升温至-5℃，保温12-14小时；升温至0℃，保温4-6小时；升温至15℃，保温2-3小时，升温至30℃，保温4-5小时。冻干工艺程序升温步骤较为繁琐，冻干机能耗大，不利于产业化生产。
CN116019807公开了一种治疗真菌感染的外用药物组合及其制备方法、应用，所述外用药物组合为液体、软膏剂、乳霜剂或凝胶剂。本发明是注射剂型，非外用途径药品。
发明内容
发明目的：为了解决现有技术的不足，本发明提供了一种硫酸艾沙康唑冻干粉针剂及其制备方法，其含水量更低、稳定性更高。
技术方案：一种硫酸艾沙康唑冻干粉针剂，由硫酸艾沙康唑、甘露醇、硫酸、注射用水组成，其中，所述的各组分配比为：硫酸艾沙康唑3.4-3.9mg，甘露醇95-100mg，硫酸适量，注射用水加至3ml。
一种硫酸艾沙康唑冻干粉针剂的制备方法，包括如下步骤：
(1)配制药液：将甘露醇、硫酸艾沙康唑加入处方量的注射用水，搅拌溶解；
(2)调节pH值：加入硫酸调节pH值至1.0-1.9，补足注射用水至规定量；
(3)采用0.22um微孔滤膜，除菌；
(4)灌装：用西林瓶进行无菌灌装；
(5)冷冻干燥：将冷冻干燥机搁板的温度预先制冷保持在-5至0℃；抽真空，预冻至-45～-40℃，保温1～5小时；再将搁板温度升温至升华干燥阶段0～5℃，保温15～25小时；将搁板温度升温至解析干燥第一阶段35～37℃，保温12～16小时；将搁板温度升温至解析干燥第二阶段10～20℃，保温0.5～4小时。充氮负压，压塞出箱轧盖后即得硫酸艾沙康唑冻干粉针剂。
作为优化：步骤(2)中硫酸在6％(g/g)～10％(g/g)。
有益效果：本发明对注射用硫酸艾沙康唑的关键工艺冻干曲线进行优化，通过对预冻、升华干燥、解析干燥的温度和时间摸索验证，有效地满足了产品低水分质量的需求，冻干后获得性状为白色至黄色、细腻、疏松且复溶良好的粉针制剂，含水量很低、复溶快速、澄清透明，符合无菌制剂的要求。同时对产品的质量稳定性有较明显改善，保障了产品在长期放置过程中最低的水分增加率，提高了稳定性；通过产品的稳定性实验对其稳定性进行了评价，结果表明产品的水分、不溶性微粒、复溶时间、有关物质、含量等主要指标均符合质量标准的要求，保障了临床使用的产品质量。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，以使本领域的技术人员能够更好的理解本发明的优点和特征，从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例
本发明要解决的技术问题是提供一种含水量更低、稳定性更高的硫酸艾沙康唑冻干粉针剂及其制备方法。一种硫酸艾沙康唑冻干粉针剂，由硫酸艾沙康唑、甘露醇、硫酸、注射用水组成，其中，所述的各组分配比为：硫酸艾沙康唑3.4-3.9mg，甘露醇95-100mg，硫酸适量，注射用水加至3ml。
一种硫酸艾沙康唑冻干粉针剂的制备方法，包括如下步骤：
1)配制药液：将甘露醇、硫酸艾沙康唑加入处方量的注射用水，搅拌溶解；
(2)调节pH值：加入6％(g/g)～10％(g/g)硫酸调节pH值至1.0-1.9，补足注射用水至规定量；
(3)采用0.22um微孔滤膜，除菌；
(4)灌装：用西林瓶进行无菌灌装；
(5)冷冻干燥：将冷冻干燥机搁板的温度预先制冷保持在-5至0℃；抽真空，预冻至-45～-40℃，保温1～5小时；再将搁板温度升温至升华干燥阶段0～5℃，保温15～25小时；将搁板温度升温至解析干燥第一阶段35～37℃，保温12～16小时；将搁板温度升温至解析干燥第二阶段10～20℃，保温0.5～4小时。充氮负压，压塞出箱轧盖后即得硫酸艾沙康唑冻干粉针剂。
具体实施例1
该实施例的具体处方如下表1所示。
表1本实施例的具体处方表
该实施例的制备方法如下：将甘露醇、硫酸艾沙康唑溶解后加入2400ml注射用水中，溶解后测pH，用6％(g/g)～10％(g/g)硫酸调节pH值至1.0-1.9。加注射用水至3000ml，搅拌均匀后测pH值，控制在1.0-1.9。如不在控制范围内，继续用硫酸溶液进行调节，直至溶液pH值符合要求。
该实施例的冻干条件如下表2所示。
表2本实施例的冻干条件表
具体实施例2
本实施例的处方及制备方法同实施例1，本实施例的冻干条件如下表3所示。
表3本实施例的冻干条件表
具体实施例3
本实施例的处方及制备方法同实施例1，本实施例的冻干条件如下表4所示。
表4本实施例的冻干条件表
将上述实施例与参比制剂康新博(Cresemba)做光照(4500Lx±500Lx)、高温40℃、加速(温度25±2℃，RH60％±5％)、长期(温度2～8℃)的稳定性试验对比，结果如下表5所示。
表5稳定性考察项目表
从上述结果可以看出，本发明实施例样品在0天、光照(4500Lx±500Lx)30天、高温40℃30天、加速(温度25±2℃，RH60％±5％)3个月、长期(温度2～8℃)3个月，与上市产品Cresemba的质量特性和稳定性相似，保障临床使用的质量、疗效和安全。
Claims (3)
1.一种硫酸艾沙康唑冻干粉针剂，其特征在于：由硫酸艾沙康唑、甘露醇、硫酸、注射用水组成，其中，所述的各组分配比为：硫酸艾沙康唑3.4-3.9mg，甘露醇95-100mg，硫酸适量，注射用水加至3ml。
2.一种硫酸艾沙康唑冻干粉针剂的制备方法，其特征在于：包括如下步骤：
(1)配制药液：将甘露醇、硫酸艾沙康唑加入处方量的注射用水，搅拌溶解；
(2)调节pH值：加入硫酸调节pH值至1.0-1.9，补足注射用水至规定量；
(3)采用0.22um微孔滤膜，除菌；
(4)灌装：用西林瓶进行无菌灌装；
(5)冷冻干燥：将冷冻干燥机搁板的温度预先制冷保持在-5至0℃；抽真空，预冻至-45～-40℃，保温1～5小时；再将搁板温度升温至升华干燥阶段0～5℃，保温15～25小时；将搁板温度升温至解析干燥第一阶段35～37℃，保温12～16小时；将搁板温度升温至解析干燥第二阶段10～20℃，保温0.5～4小时。充氮复压，压塞出箱轧盖后即得硫酸艾沙康唑冻干粉针剂。
3.根据权利要求2所述的硫酸艾沙康唑冻干粉针剂的制备方法，其特征在于：步骤(2)中硫酸在6％(g/g)～10％(g/g)。
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