CN115245488A - 一种注射用特地唑胺组合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种注射用特地唑胺组合物及其制备方法。该组合物包含如下组分：磷酸特地唑胺、精氨酸、氢氧化钠及盐酸。本发明提供的处方是根据磷酸特地唑胺性质特点而设计，克服了注射用磷酸特地唑胺在储存过程中稳定性较差的问题，提高产品的质量及稳定性。该磷酸特地唑胺冻干粉针剂具有长期稳定性好的特点，提高了病人用药时的安全性，降低了用药风险。
Description
技术领域
本发明是属于药物制剂领域，具体地说，涉及一种注射用特地唑胺组合物及其制备方法。
背景技术
特地唑胺是第二代噁唑烷酮类抗生素，是一种蛋白质合成抑制剂，抑制细菌蛋白质的合成。特地唑胺是利奈唑胺的衍生药物，作为代码TR-701由韩国东亚制药(Dong-APharmaceutical)公司首先研制。与利奈唑胺相比，具有更长的半衰期。临床研究表明，特地唑胺于利奈唑胺相比不但临床疗效更好，而且治疗周期缩短了40％。中国专利申请(原研)201080014363.0公开了一种注射用磷酸特地唑胺组合物，该磷酸特地唑胺采用甘露醇为赋形剂，用氢氧化钠及盐酸作为pH调节剂配液制成冻干制剂。我们对其进行稳定性考察，发现该制剂稳定性较差，有关物质在加速及长期条件下均有较明显增长，从而严重影响病人的用药安全。因此，本领域急需稳定性良好的特地唑胺冻干粉针制剂。
发明内容
本发明针对背景技术中的不足，提供了一种注射用磷酸特地唑胺组合物及其制备方法。
本发明采用以下技术方案：
一种注射用磷酸特地唑胺组合物，包含有下述重量配比的组分，磷酸特地唑胺、稳定剂精氨酸的重量比为180～220∶10～100；采用冻干工艺制成冻干制剂。
在一种优选的实施例中，所述的稳定剂为精氨酸，用量占所述组合物在进行冻干步骤前的溶液体积的重量百分比的2.5～25％。
本发明注射用磷酸特地唑胺组合物的制备方法，包括以下步骤：
(1)向配液罐加入40％总体积的注射用水，调节配液罐温度至15℃～25℃；加入处方量磷酸特地唑胺，在搅拌条件下加入1.0mol/L氢氧化钠溶液，至药液澄清；
(2)上述药液中加入精氨酸搅拌溶解，用氢氧化钠溶液或盐酸溶液调节pH值至7.5～8.0。
(3)加入注射用水定容，用微孔滤芯除菌过滤，灌装至西林瓶中、冻干，得到注射用磷酸特地唑胺粉针剂。
在一个优选的实施例方案中，在所述的第(3)步骤中，将磷酸特地唑胺溶液预冻至-45℃以下，维持2-4小时，同时冷凝室内温度降至-35℃～-50℃，启动真空泵，在真空条件下，升高制品温度达-10～-8℃进行升华，直到无冰晶存在，再升温至35℃干燥除去残留水分，使冻干成品水份低于2％。
本发明的注射用磷酸特地唑胺组合物，生产工艺简单可控，成品长期稳定性良好，保证了临床用药的安全性。本发明的制备方法，具有工艺简单，成品质量稳定的优点。
具体实施方式
为对本发明进行详细说明，下面结合具体实施例做进一步说明，以下实施例仅用于说明本发明，并不限制本发明的保护范围。
本发明特地唑胺冻干粉针剂包含如下组分和含量(重量份)；
磷酸特地唑胺180～220
精氨酸 10～100
氢氧化钠/盐酸 适量
上述组分和含量优选为磷酸特地唑胺200、精氨酸50、氢氧化钠/盐酸：适量。
下面结合具体实施方式对本发明作进一步详细的说明。
实施例1
每1000瓶冻干制剂含有下述成分
制备方法：称取处方量的磷酸特地唑胺，加入注射用水800ml，溶液温度降至25℃以下，搅拌使之分散，加入1.0mol/L氢氧化钠溶液，不断搅拌使原料溶解澄清，加入处方量精氨酸，搅拌溶解完全，用氢氧化钠/盐酸溶液调节pH为7.5～8.0，加注射用水定容至2000ml后备用。将上述溶液用0.22μm微孔滤膜精滤至滤液澄明，半成品检验合格后，分装，灌封于1000个10ml西林瓶中，使其主药含量为200mg。将磷酸特地唑胺溶液预冻至-45℃以下，维持2-4小时，同时冷凝室内温度降至-35℃～-50℃，启动真空泵，在真空条件下，升高制品温度达-10℃～-8℃进行升华，直到无冰晶存在，再升温至35℃干燥除去残留水分，使冻干成品水份低于2％，结束后，轧盖，得成品。
试验例：
将本发明的磷酸特地唑胺组合物冻干粉针制剂与原研市售的磷酸特地唑胺冻干粉针制剂(注射用磷酸特地唑胺，200mg；持证商为Cubist Pharmaceuticals LLC/Merck&CP.，INC)进行质量对比研究。研究结果如下：将本发明实施例1的磷酸特地唑胺组合物冻干粉针制剂与市售的磷酸特地唑胺冻干粉针制剂在60℃温度下进行高温试验，分别于第5天和10天取样品检验，按重点质量指标进行检测，分别考察性状、有关物质及含量等项目。结果见表1
表1：60℃高温考察结果
分析方法：
【含量测定】照高效液相色谱法(中国药典2010年版二部附录VD)测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂；以0.01mol/L磷酸氢二钾缓冲液(用磷酸调节pH值为8.5)为流动相A，以四氢呋喃-乙腈(10∶90)为流动相B为流动相；检测波长为300nm，流速1.0ml/min。
测定法 取磷酸特地唑胺对照品适量，精密称定，加溶剂溶解并定量稀释制成每1ml中约含0.1mg的溶液。取装量差异项下的内容物，混合均匀，精密称取适量，加溶剂溶解并定量稀释制成每1ml中约含磷酸特地唑胺0.1mg的溶液。精密量取5μl，注入液相色谱仪，记录色谱图；按外标法以峰面积计算，即得。
有关物质 照高效液相色谱法(中国药典2020年版四部通则0512)测定
供试品溶液取装量差异项下的内容物，混合均匀，精密称取适量，加溶剂溶解并稀释制成每1ml中约含磷酸特地唑胺0.28mg的溶液。对照溶液精密量取供试品溶液1ml，置l00ml量瓶中，用溶剂稀释至刻度，摇匀。
色谱条件 用十八烷基硅烷键合硅胶为填充剂；以0.01mol/L磷酸氢二钾缓冲液(用磷酸调节pH值为8.5)为流动相A，以四氢呋喃-乙腈(10∶90)为流动相B，按下表进行梯度洗脱；流速为每分钟1.0ml；柱温为40℃；波长为300nm；进样体积为5μl。
测定法 精密量取供试品溶液与对照溶液，分别注入色谱仪，记录色谱图。
表2：长期稳定性考察结果(室温放置)
上述结果可知，本发明实施例1冻干粉针制剂样品经60℃放置10天，与0天相比、性状、含量、有关物质均无明显变化，明显好于市售样品稳定性。实施例1冻干粉针制剂样品长期稳定性，常温放置6个月，本发明样品性状、含量、有关物质均无明显变化，而市售样品常温放置3月、6月有关物质有较明显增加趋势。由此说明，本发明的磷酸特地唑胺组合物冻干粉针制剂耐受高温的能力比市售样品明显提高，长期稳定性质量良好。
由上述实验结果表明：本发明能够提供一种更为稳定安全的注射用磷酸特地唑胺制剂。
Claims (4)
1.一种注射用磷酸特地唑胺组合物，其特征在于，包含有下述重量配比的组分，磷酸特地唑胺、稳定剂精氨酸的重量比为180～220∶10～100；采用冻干工艺制成冻干制剂。
2.如权利要求1所述的注射用磷酸特地唑胺组合物，其特征在于，所述的稳定剂为精氨酸，用量占所述组合物在进行冻干步骤前的溶液体积的重量百分比的2.5～25％。
3.一种注射用磷酸特地唑胺组合物的制备方法，其特征在于，包括以下步骤：
(1)向配液罐加入40％总体积的注射用水，调节配液罐温度至15℃～25℃；加入处方量磷酸特地唑胺，在搅拌条件下加入1.0mol/L氢氧化钠溶液，至药液澄清；
(2)上述药液中加入精氨酸搅拌溶解，用氢氧化钠溶液或盐酸溶液调节pH值至7.5～8.0。
(3)加入注射用水定容，用微孔滤芯除菌过滤，灌装至西林瓶中、冻干，得到注射用磷酸特地唑胺粉针剂。
4.如权利要求3所述的注射用磷酸特地唑胺组合物的制备方法，其特征在于，在所述的第(3)步骤中，将磷酸特地唑胺溶液预冻至-45℃以下，维持2-4小时，同时冷凝室内温度降至-35℃～-50℃，启动真空泵，在真空条件下，升高制品温度达-10～-8℃进行升华，直到无冰晶存在，再升温至35℃干燥除去残留水分，使冻干成品水份低于2％。
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