CN107714664A - 注射用赖氨匹林冻干粉针剂及其制备方法 - Google Patents
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Abstract
本发明提供了一种注射用赖氨匹林冻干粉针剂，其由赖氨匹林药物溶液冻干而成，该赖氨匹林药物溶液的pH为4.5‑6.5，并且每2000mL该赖氨匹林药物溶液含有：赖氨匹林80‑120g，明胶12‑18g，白蛋白10‑15g，蔗糖5‑12g谷胱甘肽4‑6g，L‑丝氨酸2‑3g，乙二胺四乙酸二钠6‑10g，pH调节剂适量，以及水余量。在本发的配方中，加入了适量的辅料明胶、白蛋白、蔗糖、谷胱甘肽、L‑丝氨酸、乙二胺四乙酸二钠等，能够提高药物稳定性，减少水杨酸的生产，便于药物的保存和运输。而且制备工艺简单、技术要求不高、生产周期相对较短，所制得的产品质量稳定可控，有利于长期贮存。
Description
技术领域
本发明涉及一种药物及其制备方法，尤其涉及一种注射用赖氨匹林冻干粉针剂及其制备方法。
背景技术
赖氨匹林是阿司匹林与赖氨酸的复盐，作为阿司匹林的衍生物是由法国Egic制药公司于七十年代首推上市的一种新型解热镇痛药。由于其具有毒副作用小，使用安全，无成瘾性，疗效好等优点，是小儿解热镇痛及癌症患者二、三级止痛的首选药物，目前在国内已有多家制药企业生产，包括肠溶胶囊剂、散剂、粉针剂等。赖氨匹林在体内水解生成阿司匹林和赖氨酸，阿司匹林则进一步水解生成水杨酸，因而赖氨匹林和阿司匹林的作用机制是一样的。但是目前临床上所用的单一成份的注射用赖氨匹林由于对湿、热、光不稳定，致使其在贮存期内就部分分解为游离的水杨酸，降低了药效。由于游离水杨酸对人体有强的刺激性和致敏性，导致用药后刺激性和致敏性都增加，严重时出现肌肉坏死或严重过敏反应，甚至危及生命。所以，仍然需要对注射用赖氨匹林的稳定性进一步改进，使其更好地发挥药效和降低不良反应。
发明内容
有鉴于此，本发明所要解决的技术问题在于，克服现有技术中存在的不足，提供一种产品质量稳定可控并且操作工艺简单的注射用赖氨匹林冻干粉针剂及其制备方法。
本发明的第一个方面是提供一种注射用赖氨匹林冻干粉针剂，其由赖氨匹林药物溶液冻干而成，该赖氨匹林药物溶液的pH为4.5-6.5，并且每2000mL该赖氨匹林药物溶液含有：
优选地，每2000mL该赖氨匹林药物溶液含有：
其中，所述pH调节剂为药学上可接受的、不会造成赖氨匹林水解的pH调节剂即可，本发明不对此进行限定，例如，可以为柠檬酸、酒石酸、磷酸、马来酸、枸橼酸钠、磷酸氢二钠、磷酸二氢钠等。
本发明的第二个方面是提供一种注射用赖氨匹林冻干粉针剂的制备方法，该制备方法包括以下步骤：
①按照本发明第一个方面中的配方称量好所需组分，在C级洁净度条件下溶解并搅拌均匀；
其中，C级洁净区标准参考《药品生产质量管理规范(2010年修订)》中的洁净度级别标准，其中对悬浮粒子和微生物的要求主要有：
悬浮粒子最大允许数/立方米：静态352000/2900，动态352000/29000
微生物最大允许数：浮游菌100cfu/立方米，沉降菌50cfu/4h，接触(Φ55mm)25cfu/碟。
②调pH值范围为4.5-6.5，定容；
③除菌过滤2-3次，收集滤液；
④灌装，冻干。
优选地，所述冻干过程为：将灌装合格品置于冷冻干箱内，-34℃预冻4小时，将箱内抽真空至10Pa，以2℃/小时升温进行升华至产品温度达到2℃以上，再设定隔板温度为35℃，进行解吸干燥，待产品温度达30℃，平衡3小时，结束冻干。
优选地，所述除菌过滤为先后经过一次0.45μm过滤和两次0.22μm除菌过滤。
本发明的有效效果是：
1、本发明配方中的明胶是一种支架剂，为冻干组分提供支撑结构，提高药品的稳定性。
2、本发明配方中加入白蛋白，可以起填充剂，是产品成型性好，外观细腻。
3、本方配方中的蔗糖在冻结和干燥过程中，可以防止活性组分发生变形，增强药物稳定性。
4、本方配方中的谷胱甘肽，具有抗氧化作用，提高药物稳定性。
5、本配方中的L-丝氨酸和乙二胺四乙酸二钠在冷冻干燥过程和贮藏过程中能将pH值调整到活性物质稳定区域。
在本发的配方中，加入了适量的辅料明胶、白蛋白、蔗糖、谷胱甘肽、L-丝氨酸、乙二胺四乙酸二钠等，各组分协同作用，能够提高本发明冻干产品的外观形状和疏松度，并且使产品表面更加平整，减少水杨酸的产生。同时药物性质也更加稳定，便于药物的保存和运输。而且制备工艺简单、技术要求不高、生产周期相对较短，所制得的产品质量稳定、可控，有利于长期贮存。
具体实施方式
下面结合具体的实施方式对本发明作进一步的说明，以更好地理解本发明。
实施例1
1、处方
2、生产工艺
2.1管制抗生素玻璃瓶的清洗、灭菌
管制抗生素玻璃瓶经外包装拆除,传入洗烘瓶间，经洗瓶机清洗、压缩空气吹干，于350℃热风隧道烘箱干燥灭菌5分钟，冷却。
2.2丁基橡胶的清洗、灭菌
丁基橡胶塞经外包装拆除，传入洗胶塞间,经洗胶塞机清洗，于121℃湿热灭菌40分钟，冷却备用。
2.3铝塑组合盖的灭菌
铝塑盖经外包装拆除，传入铝盖灭菌间，于干燥箱中110℃干热灭菌120分钟，冷却，备用。
2.4配液
原料、辅料经外包装拆除、表面消毒，传入C级洁净区。按处方量称取赖氨匹林、明胶、白蛋白、蔗糖、谷胱甘肽、L-丝氨酸、乙二胺四乙酸二钠，加入配置全量90％的注射用水中，搅拌下加入pH调节剂调节至PH4.5-6.5，加注射用水至全量，加入0.1％(w/v)活性炭，室温下搅拌吸附20分钟，以钛棒过滤除炭，先后以0.45μm微孔滤膜和0.22um微孔滤膜过滤除菌，滤液备用。
其中，C级洁净区标准参考《药品生产质量管理规范(2010年修订)》中的洁净度级别标准，其中对悬浮粒子和微生物的要求主要有：
悬浮粒子最大允许数/立方米：静态352000/2900，动态352000/29000
微生物最大允许数：浮游菌100cfu/立方米，沉降菌50cfu/4h，接触(Φ55mm)25cfu/碟。
2.5灌装
滤液检测合格，罐装于管制抗生素玻璃瓶中，压半塞。
2.6冷冻干燥
将灌装合格品置于冷冻干箱内，-34℃预冻4小时，将箱内抽真空至10Pa，以2℃/小时升温进行升华至产品温度达到2℃以上，再设定隔板温度为35℃，进行解吸干燥，待产品温度达30℃，平衡3小时，压全塞。
2.7将冻干品扎盖、灯检、贴签、包装，产品检测合格，成品入库。
实施例2
本实施例与实施例1的不同之处在于处方不同，本实施例的处方如下：
实施例3
本实施例与实施例1的不同之处在于处方不同，本实施例的处方如下：
稳定性考察
取本发明实施例1-3所制得的赖氨匹林冻干粉针样品除去外包装，于室温空气中放置10天，分别于放样后第1、3、5、10天取样，考察有关项目，所有样品性状均无变化，为白色结晶性粉未，pH值稳定，为5.6。澄明度、游离水杨酸含量、无菌检验均符合标准(((国家药品标准))WS1-XG-015-2001Z，下同)，含量均大于99.2％。
取本发明实施例1-3所制得的赖氨匹林冻干粉针样品，于室温放置，分别于放样后1、3、6、11个月取样，其间温度变化范围为25℃±2℃，RH变化范围为65-75％，考察有关项目，所有样品性状均无变化，为白色结晶性粉末，pH值稳定，为5.6。澄明度、游离水杨酸含量、无菌检验均符合标准，含量均大于99.2％。
取本发明实施例1所制得的赖氨匹林冻干粉针样品和对照品(取赖氨匹林0.6g，无菌灌封于管制瓶中)，置于稳定性试验箱中，设置条件为40℃，RH为75％，于放样后第0、1、3、6月取样，依法考察有关项目，结果见表1。取实施例2和3制得的赖氨匹林冻干粉进行相同试验，结果与实施例1大致相同。
表1
由上表可知，本发明的赖氨匹林冻干粉针剂中游离水杨酸的分解得到抑制，稳定性大大增强。
以上对本发明的具体实施例进行了详细描述，但其只是作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
Claims (5)
1.一种注射用赖氨匹林冻干粉针剂，其特征在于，其由赖氨匹林药物溶液冻干而成，该赖氨匹林药物溶液的pH为4.5-6.5，并且每2000mL该赖氨匹林药物溶液含有：
2.根据权利要求1所述的注射用赖氨匹林冻干粉针剂，其特征在于，每2000mL该赖氨匹林药物溶液含有：
3.一种注射用赖氨匹林冻干粉针剂的制备方法，其特征在于，该制备方法包括以下步骤：
①按照权利要求1或2中配方称量好所需组分，在C级洁净度条件下溶解并搅拌均匀；
②调pH值范围为4.5-6.5，定容；
③除菌过滤2-3次，收集滤液；
④灌装，冻干。
4.根据权利要求3所述的制备方法，其特征在于，所述冻干过程为：将灌装合格品置于冷冻干箱内，-34℃预冻4小时，将箱内抽真空至10Pa，以2℃/小时升温进行升华至产品温度达到2℃以上，再设定隔板温度为35℃，进行解吸干燥，待产品温度达30℃，平衡3小时，结束冻干。
5.根据权利要求3所述的制备方法，其特征在于，所述除菌过滤为先后经过一次0.45μm过滤和两次0.22μm除菌过滤。
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| WO2021249578A3 (zh) * | 2020-06-07 | 2022-01-27 | 刘力 | 预防治疗哮喘或慢阻肺或过敏性疾病等的药物 |
| WO2021249579A3 (zh) * | 2020-06-07 | 2022-01-27 | 刘力 | 预防及治疗感冒或病毒性疾病的药物 |
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| WO2021249578A3 (zh) * | 2020-06-07 | 2022-01-27 | 刘力 | 预防治疗哮喘或慢阻肺或过敏性疾病等的药物 |
| WO2021249579A3 (zh) * | 2020-06-07 | 2022-01-27 | 刘力 | 预防及治疗感冒或病毒性疾病的药物 |
| CN115607556A (zh) * | 2020-06-07 | 2023-01-17 | 刘力 | 预防治疗哮喘或慢阻肺或过敏性疾病等的药物 |
| CN115607516A (zh) * | 2020-06-07 | 2023-01-17 | 刘力 | 预防及治疗感冒或病毒性疾病的药物 |
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