CN114668716A - 一种新的间苯三酚注射液制备方法 - Google Patents
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- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 title claims abstract description 46
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Abstract
本发明涉及医药技术领域,公开了一种新的含间苯三酚和三甲基间苯三酚的注射液的药物组合物的制备方法,它包括以下步骤:每4ml注射液中含有以下重量比的组分:间苯三酚二水合物40mg、三甲基间苯三酚0.04mg、氯化钠40mg;称取80%处方量的注射用水,持续充氮并搅拌,依次加入处方量的间苯三酚、微粉化的三甲基间苯三酚、氯化钠,持续充氮搅拌至完全溶解;用浓盐酸调节pH至4.2±0.4,补充注射用水至全量;经微孔滤膜除菌过滤,灌装,121℃15分钟灭菌。本发明解决了三甲基间苯三酚极难溶以及因吸附而导致含量不合格的问题,同时因采用不锈钢微孔滤芯及乳胶材质管线,而降低了浸出物浸出的风险。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种新的含间苯三酚和三甲基间苯三酚的注射液的药物组合物的制备方法。
背景技术
间苯三酚用于消化系统和胆道功能障碍引起的急性痉挛性疼痛;急性痉挛性尿道、膀胱、肾绞痛;妇科痉挛性疼痛。其作用机制为间苯三酚能直接作用于胃肠道和泌尿生殖道的平滑肌,是亲肌性、非阿托品、非罂粟碱类平滑肌解痉药。与其它平滑肌解痉药相比,其特点是不具有抗胆碱作用,在解除平滑肌痉挛的同时,不会产生一系列抗胆碱样副作用,不会引起低血压、心率加快、心律失常等症状,对心血管功能没有影响。动物药理试验显示,它只作用于痉挛平滑肌,对正常平滑肌影响很小。
毒理学显示,亚急性毒性及慢性长期毒性试验显示间苯三酚对动物生长、重要器官的宏观和微观组织学、血液和生化指数没有不良影响;特殊毒性试验研究表明间苯三酚没有致畸、致癌、致突变性。
药代动力学显示,静脉注射本品,血液浓度半衰期约为15分钟,给药后4小时内血药浓度很快降低,之后缓慢降低。给药15分钟后,在肝肾和小肠组织分布浓度最高,脑组织内极低,48小时后体内仅有少量药物残留。该药在体内的代谢主要通过肝脏的葡萄糖耦合作用,经尿路和粪便排泄,药物经尿路排泄全部以葡萄糖偶合物的形式排出。
原研制剂中三甲基间苯三酚与间苯三酚有类似的药理学和毒理学特征,但三甲基间苯三酚的作用持续时间是间苯三酚持续时间的6倍。
间苯三酚二水合物,化学名为1,3,5-三羟基苯二水合物,分子式C6H10O5,分子量为162.1,为白色或类白色粉末;微溶于水,易溶于乙醇,几乎不溶于二氯甲烷,其化学结构式如下:
三甲基间苯三酚,化学名为1,3,5-三甲氧基苯,分子式为C9H12O3,分子量为168.19,为白色结晶粉末;几乎不溶于水,其化学结构式如下:
通过间苯三酚和三甲基间苯三酚的结构式可以看出,间苯三酚在水溶液中易被氧化而产生降解杂质,而三甲基间苯三酚则是一种几乎不溶于水且用量极少易被生产组件吸附的物质,这两个特点为间苯三酚注射液开发过程中的两个难点。其中间苯三酚在水溶液中易被氧化而产生降解杂质,可通过生产过程中持续通氮气,并控制灌封后药液中的含氧量来解决,而三甲基间苯三酚的溶解及易被吸附是本制剂开发中一个较为难解决的问题。方文、胡俊等人在专利“一种间苯三酚注射液的制备方法”(申请号201010196778.6)中使用焦亚硫酸钠作为抗氧剂,并使用乙醇溶液或者乙醇水溶液作为助溶剂来溶解三甲基间苯三酚,后续在10~35℃范围内进行除菌过滤。该方法具有一定程度的新颖性,但处方中加入了过多种类的辅料,并且产品中有大约千分之二的乙醇残留,因此既不符合现行的技术要求,在研究过程中还需要增加抗氧剂的检测,由于与原研制剂处方不一致,还需要证明该处方的临床有效性、药理毒理等,同时也增加了临床使用的风险。另外,李长浩、陈良立等人在专利“一种间苯三酚和三甲基间苯三酚的注射液及其制备方法”(申请号202010841580.2)中采用热水溶解三甲基间苯三酚,降温后冲入二氧化碳的方式来保护间苯三酚不被氧化。该方法的优势是不需要额外加入助溶剂和抗氧剂;缺点是采用热水溶解三甲基间苯三酚后需要降温后再加入间苯三酚使得工艺时长延长,同时在降温后三甲基间苯三酚有析出的风险;另外,充入二氧化碳以防止间苯三酚被氧化,二氧化碳为酸性气体在后续放置过程中极有可能会改变药液的pH值。
针对上述间苯三酚和三甲基间苯三酚注射液乙醇残留及降温后有可能析出等问题,寻找一种新的间苯三酚注射液的制备方法,制得间苯三酚和三甲基间苯三酚含量符合要求、杂质含量较少、品质较高的注射液。
发明内容
本发明针对现有技术存在的问题,提供了一种新的间苯三酚注射液的制备方法,通过对制备工艺的优化,得到了一种间苯三酚和三甲基间苯三酚的含量符合要求,杂质含量较少,品质较高的注射液。
为达到上述目的,申请人以间苯三酚和三甲基间苯三酚的含量及杂质的含量为考察指标进行了大量的实验研究,取得了一些实验成果。
本发明提供了一种间苯三酚注射液的处方,处方与原研制剂相同,处方如下:
本发明提供的间苯三酚注射液的制备工艺如下(避光下操作):
(1)称取80%处方量的注射用水,持续充氮并搅拌;
(2)持续充氮下,依次加入处方量的间苯三酚、微粉化的三甲基间苯三酚、氯化钠,持续搅拌至完全溶解;
(3)用浓盐酸调节pH至4.2±0.4,用注射用水补足至全量,持续充氮并搅拌;
(4)在持续搅拌的过程中使用微孔滤芯将药液除菌过滤;
(5)调节装量,将药液灌装至玻璃瓶内;
(6)121℃,15min湿热灭菌。
进一步地,步骤(2)中所述微粉化的三甲基间苯三酚的D90为4~6μm。优选为4.5~5.5μm。
进一步地,步骤(4)中所述除菌过滤使用微孔滤芯为两个0.22μm的微孔滤芯。优选为不锈钢材质的微孔滤芯。
进一步地,所述注射液的制备过程中使用乳胶材质管线。
本发明所取得的技术效果:
(1)本发明解决了三甲基间苯三酚极难溶的问题,不需要对注射用水的温度作限制,也不需要额外加入乙醇或乙醇的水溶液,同时还解决了三甲基间苯三酚由于制备过程中吸附而导致含量不合格的问题;
(2)本发明中采用了不锈钢微孔滤芯及乳胶材质管线,此两种材质均为惰性极强的材质,在一定程度了减少了有关物质的含量,降低了浸出物浸出的风险。
具体实施方式
下面结合具体实施例,进一步阐述本申请。应理解,这些实施例仅用于说明本申请而不用于限制本申请的保护范围。
实施例所用原辅料均为市场购买所得。
实施例1
本实施例提供了一种新的制备工艺如下(避光下操作):
(1)称取处方量80%的注射用水,持续充氮并搅拌;
(2)持续充氮下,依次加入处方量的间苯三酚、三甲基间苯三酚、氯化钠,持续搅拌至完全溶解,其中三甲基间苯三酚的D90为4~6μm;
(3)用浓盐酸调节pH至4.2±0.4,用注射用水补足至全量,持续充氮并搅拌;
(4)在持续搅拌的过程中,将溶液使用两个0.22μm的不锈钢滤芯除菌过滤;
(5)调节装量,将药液灌装至玻璃瓶内;
(6)121℃,15min湿热灭菌。
另外,注射液的制备过程中使用乳胶材质管线。
实施例2
本实施例提供了一种新的制备工艺如下(避光下操作):
(1)称取处方量80%的注射用水,持续充氮并搅拌;
(2)持续充氮下,依次加入处方量的间苯三酚、三甲基间苯三酚、氯化钠,持续搅拌至完全溶解,其中三甲基间苯三酚的D90为4.5~5.5μm;
(3)用浓盐酸调节pH至4.2±0.4,用注射用水补足至全量,持续充氮并搅拌;
(4)在持续搅拌的过程中,将溶液使用两个0.22μm的不锈钢滤芯除菌过滤;
(5)调节装量,将药液灌装至玻璃瓶内;
(6)121℃,15min湿热灭菌。
另外,注射液的制备过程中使用乳胶材质管线。
对比例1
与实施例2的区别仅在于,三甲基间苯三酚未经微粉化,D90为100μm。
对比例2
与实施例2的区别仅在于,除菌过滤使用的滤芯为PES滤芯。
对比例3
与实施例2的区别仅在于,除菌过滤使用的滤芯为PVDF滤芯。
对比例4
与实施例2的区别仅在于,输药管线材质为硅胶管。
检测本发明实施例1-2及对比例1-4注射液中间苯三酚、三甲基间苯三酚的含量以及有关物质,同时观察其性状,结果统计见表1。
表1
由表1可知,本发明中实施例1和实施例2中注射液的间苯三酚、三甲基间苯三酚含量在95%~105%范围内,有关物质含量较低,最大单杂在0.2%以下,总杂在1.0%以下,药液无色澄明,满足要求。对比例1与实施例2相比,有关物质和间苯三酚的含量无明显变化,但三甲基间苯三酚的含量显著降低,且由于其溶解不完全,导致药液中有白色颗粒状物质,说明三甲基间苯三酚的粒径对其溶解度有显著影响,进而影响注射液中三甲基间苯三酚的含量。对比例2和对比例3与实施例2相比,间苯三酚的含量无变化,有关物质稍有增加,三甲基间苯三酚的含量显著降低,说明PES和PVDF的滤芯对三甲基间苯三酚有显著吸附作用,且可使注射液中的有关物质有所增加。对比例4与实施例2相比,间苯三酚的含量无变化,有关物质增加较多,三甲基间苯三酚的含量显著降低,说明硅胶材质的输液管线可显著吸附三甲基间苯三酚,并且使注射液中的有关物质显著增加。
Claims (6)
1.一种新的间苯三酚注射液制备方法,每4ml注射液中含由40mg间苯三酚二水合物、0.04mg三甲基间苯三酚、40mg氯化钠组成,其特征在于制备方法包括以下步骤(避光下操作):
a.称取80%处方量的注射用水,持续充氮并搅拌;
b.持续充氮下,依次加入处方量的间苯三酚、微粉化的三甲基间苯三酚、氯化钠,持续搅拌至完全溶解;
c.用浓盐酸调节pH至4.2±0.4,用注射用水补足至全量,持续充氮并搅拌;
d.在持续搅拌的过程中使用微孔滤芯将药液除菌过滤;
e.调节装量,将药液灌装至玻璃瓶内;
f.121℃,15min湿热灭菌。
2.根据权利要求1所述的间苯三酚注射液的制备方法,其特征在于微粉化的三甲基间苯三酚的D90为4~6μm。
3.根据权利要求2所述的微粉化的三甲基间苯三酚,其特征在于D90为4.5~5.5μm。
4.根据权利要求1所述的间苯三酚注射液的制备方法,其特征在于除菌过滤使用微孔滤芯为两个0.22μm的微孔滤芯。
5.根据权利要求4所述的微孔滤芯,其特征在于微孔滤芯为不锈钢材质的微孔滤芯。
6.根据1所述的间苯三酚注射液的制备方法,其特征在于注射液制备过程中使用的为乳胶材质管线。
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