CN108210458A - 一种含有氟喹诺酮类抗生素与二氟泼尼酯的药物组合物 - Google Patents
一种含有氟喹诺酮类抗生素与二氟泼尼酯的药物组合物 Download PDFInfo
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Abstract
本发明涉及一种含有氟喹诺酮类抗生素与二氟泼尼酯的药物组合物，该药物组合物可提高二氟泼尼酯乳液的光稳定性，同时该药物组合物还能提高氟喹诺酮类抗生素的抑菌能力。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种含有氟喹诺酮类抗生素与二氟泼尼酯的药物组合物。
背景技术
二氟泼尼酯属于肾上腺皮质激素类药物，是泼尼松龙的二氟衍生物，具有较强的抗炎镇痛作用，副作用小。二氟泼尼酯乳液的临床试验显示该药可快速治疗眼科手术后的眼部炎症，安全有效，该药市场前景十分广阔。但是，由于二氟泼尼酯乳液光稳定性较差，需要避光处理，因此二氟泼尼酯乳液对包装的要求较高，这一定程度上限制了二氟泼尼酯乳液的储存与使用。
中国专利申请CN105120875B公开了一种含锌的二氟泼尼酯乳液组合物，该组合物在光照条件下的物理稳定性较好，但是该组合物没有解决二氟泼尼酯在光照后容易降解的问题。
发明内容
为了克服现有技术中的问题，本发明提供了一种含有氟喹诺酮类抗生素与二氟泼尼酯的药物组合物，所述的药物组合物包括以下组分：
二氟泼尼酯、氟喹诺酮类抗生素、吐温80、蓖麻油、甘油、依地酸二钠、缓冲盐、注射用水。
作为优选，所述氟喹诺酮类抗生素选自莫西沙星或其药用盐、加替沙星或其药用盐、依诺沙星或其药用盐、环丙沙星或其药用盐，更优选为莫西沙星或其药用盐，特别优选为盐酸莫西沙星。
作为优选，所述缓冲盐为硼酸与醋酸钠的组合。
作为进一步优选技术方案，所述药物组合物由以下组分组成：二氟泼尼酯0.5mg/mL，氟喹诺酮类抗生素0.5～21.8mg/mL，吐温80 20～100mg/mL，蓖麻油20～100mg/mL，甘油1～50mg/mL，依地酸二钠0.05～10mg/mL，缓冲盐0.1～20mg/mL，余量为注射用水。
作为更进一步优选的技术方案，所述氟喹诺酮类抗生素的浓度为3.27～21.8mg/mL。
作为优选，所述药物组合物的剂型为乳剂。
本发明的药物组合物的应用为预防或治疗眼部疼痛、炎症与感染。
本发明的药物组合物优选无菌并且具有适用于眼部使用的物理性能，比如渗透压与pH，渗透压优选为250～450mOsm，pH优选为4.5～6.5。
本发明的有益效果：
1)本发明的药物组合物可以显著提高二氟泼尼酯乳液的光稳定性，解决了二氟泼尼酯乳液遇光容易降解的问题，方便了二氟泼尼酯乳液的储存和使用。
2)本发明的药物组合物可以显著提高氟喹诺酮类抗生素(如盐酸莫西沙星)的杀菌能力，增强临床疗效。
具体实施方式
以下结合实施例具体说明本发明，本发明中的实施例仅仅用于说明本发明的技术方案，而非限定本发明的实质，并不因此将本发明限制在所述的实施例范围之中。凡是不背离本发明构思的变动或等同替代均在本发明的保护范围之内。实施例
实施例1～14的处方组成见表1与表2。
表1实施例1～7的处方组成
表2实施例8～14的处方组成
制备方法：将蓖麻油加热至约70℃，加入二氟泼尼酯溶解得到油相；另外将吐温80、甘油、依地酸二钠、醋酸钠和硼酸溶解于注射用水中，加热至约70℃，得到水相；将油相加入水相中，用高速均质机均质得到初乳；初乳中加入氟喹诺酮类抗生素(盐酸莫西沙星、加替沙星、依诺沙星或环丙沙星)，搅拌溶解，使用1N盐酸溶液与1N氢氧化钠溶液将乳液pH调节至目标pH，得到最终的乳剂。对比实施例
对比实施例1～9的处方组成见表3。
表3对比实施例1～9处方组成
对比实施例1的制备方法：将蓖麻油加热至约70℃，加入二氟泼尼酯溶解得到油相；另外将吐温80、甘油、依地酸二钠、醋酸钠和硼酸溶解于注射用水中，加热至约70℃，得到水相；将油相加入水相中，用高速均质机均质得到初乳，使用1N盐酸溶液与1N氢氧化钠溶液将初乳pH调节至目标pH，得到最终的乳剂。
对比实施例2～8的制备方法：将蓖麻油加热至约70℃，加入二氟泼尼酯溶解得到油相；另外将吐温80、甘油、依地酸二钠、醋酸钠和硼酸溶解于注射用水中，加热至约70℃，得到水相；将油相加入水相中，用高速均质机均质得到初乳，向初乳中加入妥布霉素，搅拌溶解，使用1N盐酸溶液与1N氢氧化钠溶液将乳液pH调节至目标pH，得到最终的乳剂。
对比实施例9的制备方法：将硼酸、氯化钠、盐酸莫西沙星溶于注射用水中，使用1N盐酸溶液与1N氢氧化钠溶液将溶液pH调节至目标pH，即得。
光照稳定性实验
根据ICH(人用药品注册技术国际协调会议)稳定性测试指南，实施光稳定性实验。将实施例1-14的乳剂与对比实施例1-8的乳剂灌装于LDPE滴眼瓶后，置于光照箱中，给予1.2×106Lux·Hr的光照总照度(近紫外能量不低于200w·Hr/m2)，光照24h后取样测定二氟泼尼酯含量(含量是指测定值与理论值的比值)，结果如下表：
表4实施例1-14的乳剂与对比实施例1-8的乳剂中的二氟泼尼酯的含量测定结果
实施例1-14的乳剂在光照后，二氟泼尼酯的降解程度均较小，当盐酸莫西沙星的浓度在3.27～21.8mg/mL范围时，二氟泼尼酯的含量变化均在5％以内，较为稳定；对比实施例1-8的乳剂在光照后，二氟泼尼酯的含量均小于1％，基本降解完全。
可见，含盐酸莫西沙星、加替沙星、依诺沙星与环丙沙星的药物组合物均可显著提高二氟泼尼酯乳液的光稳定性。
体外抑菌实验
取实施例6的乳剂与对比实施例9的溶液剂进行体外抑菌实验对比研究，实验过程遵循无菌操作的要求。
实验方法：取活化后的大肠杆菌、金黄色葡萄球菌，用0.85％的无菌氯化钠溶液制备成107～108浓度的菌液；分别各吸取25μL的菌液加入5mL样品溶液中，避光保存在20-25℃培养箱，6h与24h后，取样测定活菌数。
测定方法：量取上述经过培养箱培养后的样品溶液1ml，加入到含9ml 2％MgSO4水溶液的无菌试管中；充分混匀，用2％MgSO4水溶液稀释到1:104；吸取1ml稀释液于0.22μm滤膜，用800mL 2％MgSO4水溶液冲洗过滤，取出滤膜，菌面朝上贴于含2％MgSO4大豆酪蛋白琼脂培养基的平板上，于30～35℃培养1-3天，取出，计算菌落数并得出下降的lg值，测定结果见表5。
表5实施例6的乳剂与对比实施例9的溶液剂的体外抑菌实验结果
实施例6的乳剂与对比实施例9的溶液剂所含的盐酸莫西沙星浓度相同，但是实施例6的乳剂对大肠杆菌与金黄色葡萄球菌的杀灭效果明显强于对比实施例9的溶液剂，可见本发明的药物组合物提高了氟喹诺酮类抗生素(如盐酸莫西沙星)的杀菌能力。
Claims (9)
1.一种含有氟喹诺酮类抗生素与二氟泼尼酯的药物组合物，其特征在于所述的药物组合物包括以下组分：二氟泼尼酯、氟喹诺酮类抗生素、吐温80、蓖麻油、甘油、依地酸二钠、缓冲盐、注射用水。
2.根据权利要求1所述的药物组合物，其特征在于所述氟喹诺酮类抗生素选自莫西沙星或其药用盐、加替沙星或其药用盐、依诺沙星或其药用盐、环丙沙星或其药用盐。
3.根据权利要求2所述的药物组合物，其特征在于所述氟喹诺酮类抗生素为莫西沙星或其药用盐。
4.根据权利要求3所述的药物组合物，其特征在于所述氟喹诺酮类抗生素为盐酸莫西沙星。
5.根据权利要求1所述的药物组合物，其特征在于所述缓冲盐为硼酸与醋酸钠的组合。
6.根据权利要求1-5中任意一项所述的药物组合物，其特征在于所述的药物组合物由以下组分组成：二氟泼尼酯0.5mg/mL，氟喹诺酮类抗生素0.5～21.8mg/mL，吐温80 20～100mg/mL，蓖麻油20～100mg/mL，甘油1～50mg/mL，依地酸二钠0.05～10mg/mL，缓冲盐0.1～20mg/mL，余量为注射用水。
7.根据权利要求6所述的药物组合物，其特征在于所述氟喹诺酮类抗生素的浓度为3.27～21.8mg/mL。
8.根据权利要求1-7任意一项所述的药物组合物，其特征在于所述药物组合物为乳剂。
9.如权利要求1-7任意一项所述的药物组合物的应用，其特征在于，所述的药物组合物用于预防或治疗眼部疼痛、炎症与感染。
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