CN101830916B - 抗菌药物及其制备方法和用途 - Google Patents
抗菌药物及其制备方法和用途 Download PDFInfo
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- CN101830916B CN101830916B CN 201010179530 CN201010179530A CN101830916B CN 101830916 B CN101830916 B CN 101830916B CN 201010179530 CN201010179530 CN 201010179530 CN 201010179530 A CN201010179530 A CN 201010179530A CN 101830916 B CN101830916 B CN 101830916B
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- Prior art keywords
- low
- low molecule
- molecule
- sodium
- cefbuperazone
- Prior art date
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Abstract
本发明涉及头孢拉宗钠水合物及其制备方法和用途,该头孢拉宗钠水合物具有较好的存储稳定性,适用于制备对革兰氏阳性或阴性细菌敏感菌所致的人或动物的呼吸系统、肝胆系统、五官、尿路感染、腹腔感染、盆腔感染、败血症、皮肤软组织感染、骨和关节感染等疾病的治疗或预防的药物中的应用。
Description
技术领域
本发明涉及医药技术领域,具体地说是提供抗菌药物——头孢拉宗钠水合物及其制备方法和用途。
背景技术
头孢拉宗钠头霉素衍生物,其抗菌作用与头孢美唑近似。系广谱抗生素,特别是对大肠杆菌、克雷伯菌属、柠檬酸菌属、肠杆菌属、沙雷菌属和吲哚阳性变形杆菌有良好的抗菌力;对各种细菌产生的β-内酰胺酶较为稳定,对β-内酰胺酶产生菌也有较强的抗菌作用。但头孢拉宗钠钠对假单胞菌无效。目前,公开的文献仅报道了头孢拉宗钠(Cefbuperazone Sodium)(C22H28N9NaO982分子量:649.63,CAS号:76648-01-6),到目前为止,国内外尚没有公开的文献报道本发明的头孢拉宗钠结晶水合物及其制备方法和用途。
发明内容
本发明所涉及的是抗菌感染药物头孢拉宗钠结晶水合物及其制备方法和用途,其分子式为C22H28N9NaO9S2·nH2O,n=0.8~3之间的数字,包括1、1.25、1.5、2、3等。
本发明获得的含有结晶水的头孢拉宗钠,令人惊奇的是,含结晶水的头孢拉宗钠引湿性远低于含有不结晶水的头孢拉宗钠,含有结晶水的头孢拉宗钠比不含结晶水的更能稳定的存在,便于储存和运输,易于制成制剂。此外,无水物的潮解使得在处理时要隔绝空气防止粘连等,而水合物具有良好的滑动性,从而改善制剂的可操作性。
令人惊奇的是,特征性的,本发明的水合物的热分析(TG-DSC或者TG-DTA)图谱的失重平台下具有对应的吸热峰,热分析图谱显示出头孢拉宗钠结晶水合物,如头孢拉宗钠1水合物、头孢拉宗钠2水合物、头孢拉宗钠3水合物等。
本发明的头孢拉宗钠结晶水合物能稳定存储。将头孢拉宗钠水合物和无水物样品进行引湿性试验:取头孢拉宗钠无水物和本发明的水合物约5g,置于干燥恒重的表面皿中,精密称重,25℃、相对湿度为70%,分别于试验0h和10h取样,计算引湿增重的百分率,结果显示,无水物引湿性比本发明的水合物都高得多,本发明的头孢拉宗钠结晶水合物能更好地稳定存储结果见表1。在RH75%、10℃条件下,将头孢拉宗钠1水合物样品密闭与西林瓶中进行6个月的加速稳定性试验,头孢拉宗钠HPLC法测定含量与有关物质的条件:C18(150mm×4.6mm,5μm),乙腈:0.2%四丙基溴化铵水溶液:醋酸-醋酸钠缓冲液(取醋酸钠5.4g,加水50ml使溶解,冰醋酸调节pH值至5,再加水稀释至100ml)(13∶83∶4)为流动相;检测波长为254nm,柱温为室温,流速1ml/min,测定含量基本不变和有关物质物无明显增加。试验结果说明本发明的头孢拉宗钠水合物具有良好的存储稳定性。
表1.引湿试验结果
头孢拉宗钠衍生物——头孢拉宗钠结晶水合物的制备包括如下方法:
方法A.在反应容器中在反应容器中,加头孢拉宗酸,加水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈中的一种或几种,搅拌,10℃下加C1-C12的低分子胺,搅拌溶解,10℃下在滤液中加碳酸钠、碳酸氢钠、氢氧化钠、醋酸钠、辛酸钠、异辛酸钠的一种与水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈、C3-C8的低分子酮、C1-C6的低分子卤代烃中的一种或几种的溶液,搅拌反应0.2-3小时,用无机酸或有机酸或其溶液调节pH至6.0~8.0,将上述溶液加入到C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种中,或加C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种,10℃以下放置,使固体充分析出,抽滤,用C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C2-C6的低分子腈、C1-C6的低分子卤代烃中的一种或几种洗1-3次,过滤,所得固体用水与C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C1-C6的低分子卤代烃中的一种或几种溶剂重结晶一次或多次,10℃以下放置,使结晶充分析出,过滤,洗涤,干燥,得头孢拉宗钠结晶水合物;
其中,反应中所使用的头孢拉宗酸:C1-C12的低分子胺:碱(碳酸钠、碳酸氢钠、氢氧化钠、醋酸钠、辛酸钠、异辛酸钠)的摩尔比一般可为1∶0.5-1.1∶0.5-1.1;头孢拉宗酸(重量g)与水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈中的一种或几种(体积ml)的比为一般为∶1(g)∶1.5~30(ml);结晶或重结晶中使用的水与有机溶剂的体积比一般为1∶5~300。活性炭的用量为反应物重量的0.01-3%。
或者方法B.在反应容器中,加头孢拉宗酸,加水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈中的一种或几种,搅拌,在10℃下在滤液中加碳酸钠、碳酸氢钠、氢氧化钠、醋酸钠、辛酸钠、异辛酸钠的一种与水、C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮中的一种或几种的溶液,搅拌反应0.2-3小时,用无机酸或有机酸或其溶液调节pH至6.0~8.0,将上述溶液加入到C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种中,或加C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C2-C8的低分子酯、C1-C6的低分子卤代烃中的一种或几种,10℃以下放置,使固体充分析出,过滤,用C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C2-C6的低分子腈、C1-C6的低分子卤代烃中的一种或几种洗1-3次,过滤,所得固体用水与C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C1-C6的低分子卤代烃中的一种或几种为结晶溶剂进行一次或多次重结晶,过滤,洗涤,干燥,得头孢拉宗钠结晶水合物。
其中,反应中所使用的头孢拉宗酸∶碱(碳酸钠、碳酸氢钠、氢氧化钠、硫氰酸钠、醋酸钠、辛酸钠、异辛酸钠中的一种)的摩尔比一般可为1∶0.5-1.1∶0.5-1.1;头孢拉宗酸(重量g)与水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈中的一种或几种(体积ml)的比为一般为∶1(g)∶1.5~30(ml);结晶或重结晶中使用的水与有机溶剂的体积比一般为1∶20~300。
头孢拉宗钠结晶水合物的结晶或重结晶溶剂选自水、乙腈、四氢呋喃、甲醇、乙醇、异丙醇、醋酸丁酯、乙酸乙酯、甲酸乙酯、乙醚、异丙醚、四氢呋喃、二氯甲烷、氯仿等中的一种或几种;头孢拉宗钠结晶结晶或重结晶溶剂,优选水、甲醇、乙醇、异丙醇,四氢呋喃、乙酸乙酯、乙醚、异丙醚、氯仿中的一种或几种。在本发明的制备方法中,在重结晶过程中可先用水溶解头孢拉宗钠结晶水合物,溶解后可以使用活性炭脱色(若使用活性炭脱色,其用量为所脱色溶液重量的0.01-1%),再用本发明中的溶剂使其结晶。重结晶过程中可将头孢拉宗钠含水溶液加入到C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种中,或在其中加C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯、C1-C6的低分子卤代烃中的一种或几种,放冷放置结晶。无菌的头孢拉宗钠水合物的制备按照常规工艺进行无菌操作制备。本发明的头孢拉宗钠结晶水合物可具有不同的晶型。
本发明中的低分子醇的碳原子数定义为C1-C6(即:1-6个碳原子的醇),如甲醇、乙醇、异丙醇等;低分子醚的碳原子数定义为C2-C8(即:2-8个碳原子的醚),如乙醚、异丙醚、丁醚、四氢呋喃等;低分子卤代烃的碳原子数定义为C1-C6(即:1-6个碳原子的卤代烃),包括二氯甲烷、二氯乙烷、氯仿等;低分子酯的碳原子数定义为C2-C8(即:2-8个碳原子的酯),包括醋酸丁酯、乙酸乙酯、甲酸乙酯等;低分子直链或支链烷烃或环烷烃的碳原子数定义为C5-C10,包括戊烷、正己烷、环己烷、石油醚等;低分子芳香烃的碳原子数定义为C6-C12(即:6-12个碳原子的芳香烃),包括苯,甲苯等;C1-C6的低分子酸的碳原子数定义为1-6个碳原子的有机酸,包括甲酸、乙酸、丙酸等;C3-C8的低分子酮定义为3-6个碳原子的酮,包括丙酮,丁酮、异己酮等;C2-C6的低分子腈(即:2-6个碳原子的腈),包括乙腈、丙腈等;C1-C12的低分子胺定义为1-12个碳原子的有机胺,包括二甲胺、二乙胺、三乙胺、环己胺、二环己胺、叔丁胺、N-甲基吗啉、吡啶、甲基吡啶等;关于任何一类描述为“低分子”化合物的碳原子数量的标记方法只要在本申请的文本中出现一次,其它任何未进行标记的描述为“低分子”的同类化合物的碳原子数与本文中已经标明的数量是一致的。
本发明的产物的干燥方式可以为在不同温度(如20-80℃)、干燥时间(0.5小时到数日)、或附有其它干燥剂(包括硅胶,五氧化二磷、无水氯化钙、无水硫酸钠等)的环境条件下、或使用常压或减压的方式对最后的产物进行干燥。其干燥温度优选在30-60℃。
本发明的头孢拉宗钠水合物用途:本发明的头孢拉宗钠水合物用于制备固体制剂、注射剂、其中注射剂包括注射用冻干粉针制剂、无菌分装粉针制剂、大输液制剂(包括双室即配型大输液、非PVC固液双室即配型大输液、非PVC多层共挤膜制成的即配型大输液);固体制剂,包括:片剂、胶囊剂、颗粒剂等;并可用于制备头孢拉宗钠无水物。无水物的制备可由本发明的结晶水合物经不同的干燥方法获得,其制备可在不同温度(如60-80℃)、干燥时间(数小时到数日)、或附有其它干燥剂(包括硅胶,分子筛、五氧化二磷、氢氧化钠、无水碳酸钠、无水氯化钙、无水硫酸钠、无水硫酸镁等)的环境条件下、或并使用常压或减压的方式对最后的产物进行干燥,也可先由苯蒸馏带水的方法,并结合其它本文中描述的干燥方法干燥后获得。
本发明的头孢拉宗钠水合物用于制备片剂(包括口含片、舌下片、口腔贴片、口崩片、阴道片等)、胶囊(包括直肠、阴道用胶囊等)、颗粒剂,其中可含有药学上可接受的填充剂,如淀粉、变性淀粉、乳糖、微晶纤维素、环糊精、山梨醇、甘露醇、磷酸钙、氨基酸等;药学上可接受的崩解剂,如淀粉、变性淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素、表面活性剂(十二烷基硫酸钠等);药学上可接受的润湿剂和粘合剂,如胶化淀粉、甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚乙烯吡咯烷酮、海藻酸及其盐;药学上可接受的润滑剂和助流剂,如硬脂酸、硬脂酸镁、聚乙二醇4000-8000、滑石粉、微粉硅胶、十二烷基硫酸镁等;药学上可接受的甜味剂和香精,如阿斯巴甜、甜蜜素、糖精钠、三氯蔗糖、食用香精等。
本发明的结晶水合物不同于无水物的潮解使得在处理时要隔绝空气防止粘连等,而结晶水合物具有良好的滑动性,从而改善制剂的可操作性;并使制备的固体制剂具有良好的溶出性能,使得其容易被吸收进入血液循环,改善生物利用度,并有利于快速发挥其作用。从另一个方面,使得其防止出现在进行无菌分装时不易因为吸潮而导致分装时产生堵塞使得装量发生差异导致剂量不足,从而带来产品的不合格,或因为不合格的产品没有被抽检到形成实际上的漏检,进而流入市场,在临床治疗中对患者的治疗代理负面的效果,或者因剂量不足危及病人的生命。或者在分装时,因为吸潮而导致整个生产线被迫暂停,严重降低设备的生产能力,大大增加工时费用等的隐患。
头孢拉宗钠水合物的针剂,其制备方法为:
无菌分装的粉针的制备:按照通常惯例使用无菌原料进行分装。
输液制剂,包括双室即配型大输液、非PVC固液双室即配型大输液、非PVC多层共挤膜制成的即配型大输液,按常规方法制备。
冻干粉针制剂的制备方法为:取头孢拉宗钠水合物,可以加药学上可接受冻干支持剂或辅形剂、稳定剂、注射用水,搅拌使溶解,若需要,可用药学上可接受的酸碱调节pH为6.0~8.0,加活性碳0.005~0.5%(W/V)搅拌15~45min,过滤,补水,无菌过滤,按0.5~2g/瓶分装,冷冻干燥,压塞,得成品。
其药学上可接受的pH调节剂可以是药学上可接受的无机酸或有机酸、无机碱或有机碱,也可以是广义的路易斯酸或碱,可以含有一种或者几种,可以是盐酸、磷酸、丙酸、醋酸及醋酸盐、如醋酸钠等,乳酸以及乳酸药用盐、枸橼酸药用盐、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、磷酸盐、酒石酸及其药用盐、硼砂、硼酸、丁二酸、己酸、己二酸、反丁烯二酸、顺丁烯二酸、多羟基羧酸及药用盐,如葡萄糖醛酸、葡萄糖酸、乳糖酸、苹果酸、苏糖酸、葡庚糖酸等中的一种或者几种。
其药学上可接受的抗氧剂和稳定剂可以是亚硫酸、亚硫酸盐、亚硫酸氢盐、焦亚硫酸盐、连二亚硫酸盐、硫代硫酸盐,有机硫化合物硫脲、谷胱甘肽、二巯基丙醇、巯基乙酸及盐、硫代乳酸及盐、硫代二丙酸及盐、苯酚类化合物,如没食子酸及盐、咖啡酸、咖啡酸盐、阿魏酸、阿魏酸盐、二叔丁基对苯酚、2,5-二羟基苯甲酸、2,5-二羟基苯甲酸盐、苯酚或其衍生物、水杨酸或其盐;抗坏血酸及抗坏血酸盐、异抗坏血酸及异抗坏血酸盐、烟酰胺、酒石酸、硝酸盐、磷酸盐、醋酸药用盐、柠檬酸盐、EDTA及EDTA盐、如EDTA二钠、EDTA四钠、N-二(2-羟乙基)甘氨酸等中的一种或者几种。
去热源和除菌方式可以是加入配液量0.005~3%的活性炭去热源,微孔滤膜除菌和热压灭菌,也可以采用超滤除菌、去热源。超滤方法中,超滤器可选用平板式、卷式、管式、中空纤维式或圆盒式等,优选卷式和中空纤维式超滤器,采用截留相对分子质量为5万至30万的滤膜除去大部分发热性物质和细菌后,再采用截留相对分子质量4000~30000的超滤膜除去剩余热源,优选相对分子质量6000~30000的超滤膜。
本发明的头孢拉宗钠水合物,用于制备对革兰氏阳性或阴性细菌敏感菌所致的人或动物的呼吸系统、肝胆系统、五官、尿路感染、腹腔感染、盆腔感染、败血症、皮肤软组织感染、骨和关节感染、心内膜炎等疾病的治疗或预防的药物中的应用。
本发明头孢拉宗钠水合物,适用于制备与β-内酰胺酶抑制剂克拉维酸或其药用盐、舒巴坦或其药用盐、他唑巴坦或其药用盐中的一种或几种组成的抗菌组合药物,其中,头孢拉宗钠水合物与β-内酰胺酶抑制剂的重量比为1∶0.05~2。
用量用法:一般情况下,对于头孢拉宗钠水合物(以无水物计),成人用量一般每日1.0~2.0g,分1-2次给药;儿童用量一般每日60~80mg/kg,可根据症状酌情增减。静脉输注:0.5g、1.0g或2.0g溶于50~250ml生理盐水或林格氏液等中输注。肌肉注射:0.5g或1.0g溶于5~10ml注射用水中,臀肌深部注射:为防止疼痛,可将头孢拉宗钠结晶水合物溶于1%利多卡因溶液中注射。或者通过口腔给药(改变注射途径为通过口腔粘膜吸收),成人每日0.5g~2g;或直肠或阴道给药(通过阴道粘膜吸收),成人每日0.5g~2g。
附图说明
图1为头孢拉宗钠1水合物的热分析图谱。
图2为头孢拉宗钠3水合物的热分析图谱。
热分析测试条件:Setaram公司Setsys16,样品量5mg左右,升温速度:10K/min,N2流速:50ml/min,温度:室温~400℃左右。
具体实施方式
实施例1头孢拉宗钠1水合物的制备在反应瓶中加头孢拉宗酸10g、水50ml,搅拌使成悬浮液,在5℃下滴加三乙胺2.6ml,搅拌30min,加活性炭0.2g,搅拌30分钟,抽滤,水洗,抽滤,5℃下在滤液中滴加25%异辛酸钠(2.7g)的乙醇溶液,搅拌,缓慢加入丙酮300ml、乙醇300ml,-15℃以下放置,使固体充分析出,抽滤,少量氯仿洗3次,抽滤,所得固体用少量水使其刚溶解,用丙酮200ml、乙醇200ml重结晶,-10℃以下放置,使结晶充分析出,抽滤,45℃真空干燥6h左右,得淡黄色固体5.2g,熔点:132℃变色(ELECTROTHERMAL MELTING POINT APPARATUS,未校正),卡氏法测定水分为2.76%,热分析:平台失重约2.95%(图1),这与样品含有1个结晶水的结果(理论值2.70%)在误差范围内,比旋度:+51.6°,红外光谱:vKBr maxcm-13307(宽)、2977、2941、2840、1769、1715、1681、1612、1518、1394、1367、1284、1191、1084、1012、943、761、698,ESI-MS:m/z:648;元素分析理论值:C39.58%,H4.53%,N18.88%,S9.61%,Na3.44%;实测值:C39.52%,H4.61%,N18.82%,S9.69%,Na3.34%。
实施例2头孢拉宗钠3水合物的制备在反应瓶中加头孢拉宗酸20g、水80ml,搅拌使成悬浮液,在5℃左右,搅拌下滴加碳酸钠的饱和水溶液使pH至6.8左右,加活性炭0.1g,搅拌30分钟,抽滤,水洗,抽滤,缓慢加入丙酮350ml和异丙醇250ml,-20℃以下放置,使固体充分析出,抽滤,少量氯仿洗3次,抽滤,所得固体用少量水使其刚溶解,加丙酮300ml、异丙醇300ml为结晶溶剂进行重结晶,5℃以下放置过夜,使结晶充分析出,抽滤,40℃干燥24h左右,得淡黄色结晶13.1g,熔点:68-72℃(ELECTROTHERMAL MELTING POINT APPARATUS,未校正),卡氏法测定水分为7.81%,热分析:平台失重约7.68%(图2),这与样品含有3个结晶水的结果(理论值7.68%)在误差范围内,比旋度:+51.3°红外光谱:vKBr maxcm-13308(宽)、2976、2940、2839、1769、1715、1681、1613、1518、1394、1367、1284、1191、1085、1011、944、761、698,ESI-MS:m/z:648;元素分析理论值:C36.24%,H3.23%,N12.82%,S19.56%,Na7.01%;实测值:C36.24%,H3.23%,N12.82%,S19.56%,Na7.01%。
实施例3头孢拉宗钠1水合物的制备在反应瓶中加头孢拉宗酸20g、水5ml、甲醇200ml,搅拌,5℃下在滤液中滴加25%异辛酸钠的乙醇溶液使pH至7.0,搅拌,缓慢加到丙酮300ml和乙醚150ml混合溶液中,-10℃以下放置,使固体充分析出,抽滤,60ml量氯仿洗3次,抽滤,所得固体用少量水使其刚溶解,加丙酮300ml、乙醚200ml为结晶溶剂进行重结晶,-10℃以下放置过夜,使结晶充分析出,抽滤,45℃真空干燥6h左右,得淡黄色结晶12.8g,熔点:133℃分解(ELECTROTHERMAL MELTING POINT APPARATUS,未校正),卡氏法测定水分为2.67%,热分析:平台失重约2.62%,这与样品含有1个结晶水的结果(理论值2.70%)在误差范围内,红外光谱:vKBr maxcm-13307(宽)、2977、2941、2840、1769、1715、1681、1612、1518、1394、1367、1284、1191、1084、1012、943、761、698,ESI-MS:m/z:648;元素分析理论值:C39.58%,H4.53%,N18.88%,S9.61%,Na3.44%;实测值:C39.52%,H4.61%,N18.82%,S9.69%,Na3.34%。将该l水合物在70℃,五氧化二磷存在下真空干燥24h左右,得到头孢拉宗钠无水物。
实施例4头孢拉宗钠1水合物的制备在反应瓶中加头孢拉宗酸20g、水50ml,搅拌使成悬浮液,在5℃下滴加碳酸钠的饱和水溶液使pH至6.5,搅拌,加活性炭0.3g,搅拌30分钟,抽滤,水洗,抽滤,滤液缓慢加到丙酮300ml和异丙醇250ml中,-15℃以下放置,使固体充分析出,抽滤,60ml氯仿洗3次,抽滤,所得固体用少量水使其刚溶解,加活性炭0.1g,搅拌30分钟,抽滤,水洗,抽滤,滤液用异丙醇300ml、丙酮200ml对其进行重结晶,-15℃以下放置过夜,使结晶充分析出,抽滤,30ml氯仿洗,抽滤,50℃真空干燥5h左右,得类白色固体9.2g,卡氏法测定水分为2.61%,热分析:平台失重约2.66%,这与样品含有1个结晶水的结果(理论值2.70%)在误差范围内,比旋度:+51.8°,ESI-MS:m/z:648;元素分析理论值:C39.58%,H4.53%,N18.88%,S9.61%,Na3.44%;实测值:C39.50%,H4.65%,N18.78%,S9.71%,Na3.36%。
实施例5取头孢拉宗钠水合物100g,搅拌使溶,加甘露醇20g,EDTA二钠0.05g,加注射用水500~600ml左右,搅拌使溶,用1-5M左右的柠檬酸和磷酸氢二钠溶液调节pH为6.5~7.5,加活性碳0.01~0.5%(W/V)搅拌15-30min,过滤,用0.22微米微孔滤膜过滤,按0.5g/瓶或1g/瓶分装,真空冷冻干燥,压塞,得成品。
实施例6取无菌的头孢拉宗钠水合物10Kg,以无菌分装工艺按0.5g/瓶或0.75g/瓶或1g/瓶或2g/瓶分装,加塞、压塞,轧铝盖得成品。
实施例7取无菌的头孢拉宗钠1.5结晶水合物2Kg,以无菌分装工艺按主药0.5g/瓶或1g/瓶或1.5g/瓶分装,加塞、压塞,轧铝盖得成品。
实施例8头孢拉宗钠1水合物片或胶囊(50mg/粒)
将头孢拉宗钠1结晶水合物、乳糖、羧甲基淀粉钠过100目筛,混匀,用5%PVP30的50%的乙醇水溶液适量为粘合剂制软材,过18-24目筛制粒,干燥,过14-20目筛整粒后,加硬脂酸镁混合,压片或灌装胶囊。
实施例9头孢拉宗钠2水合物片(250mg/片)
将头孢拉宗钠2水合物、山梨醇、低取代羟丙基纤维素过100目筛,混匀,用5%PVP K30的50%的乙醇水溶液适量为粘合剂制软材,过18-24目筛制粒,干燥,过14-20目筛整粒后,加硬脂酸镁混合,压片。
实施例10头孢拉宗钠1水合物片(250mg/片)
将头孢拉宗钠1水合物、甘露醇、低取代羟丙基纤维素过100目筛,混匀,用5%PVP K30的50%的乙醇水溶液适量为粘合剂制软材,过18-24目筛制粒,干燥,过14-20目筛整粒后,加硬脂酸镁混合,压片。
可以理解,从本专业角度,很多细节的变化是可能的,这并不因此限制本发明范围和精神,本发明并不限于上述实施例。
Claims (7)
1.一种头孢拉宗钠水合物,其特征在于:分子式为C22H28N9NaO9S2·nH2O,n=1、3。
2.根据权利要求1所述的头孢拉宗钠水合物,其特征在于:为头孢拉宗钠1水合物。
3.根据权利要求1所述的头孢拉宗钠水合物,其特征在于:为头孢拉宗钠3水合物。
4.根据权利要求1所述的头孢拉宗钠水合物,其制备方法,其特征在于:包括如下:
方法A.在反应瓶中,加头孢拉宗酸,加水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈中的一种或几种,搅拌,10℃下加C1-C12的低分子胺,搅拌溶解,10℃下在滤液中加碳酸钠、碳酸氢钠、氢氧化钠、醋酸钠、辛酸钠、异辛酸钠的一种与水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈、C3-C8的低分子酮、C1-C6的低分子卤代烃中的一种或几种的溶液,搅拌反应0.2-3小时,用无机酸或有机酸或其溶液调节pH至6.0~8.0,将上述溶液加入到C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种中,或加C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种,10℃以下放置,使固体充分析出,抽滤,用C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C2-C6的低分子腈、C1-C6的低分子卤代烃中的一种或几种洗1-3次,过滤,所得固体用水与C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C1-C6的低分子卤代烃中的一种或几种溶剂重结晶一次或多次,10℃以下放置,使结晶充分析出,过滤,洗涤,干燥,得头孢拉宗钠水合物;
或者方法B.在反应瓶中,加头孢拉宗酸,加水、C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈中的一种或几种,搅拌,在10℃下在滤液中加碳酸钠、碳酸氢钠、氢氧化钠、醋酸钠、辛酸钠、异辛酸钠的一种与水、C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮中的一种或几种的溶液,搅拌反应0.2-3小时,将上述溶液加入到C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C8的低分子酯中的一种或几种中,或加C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C2-C8的低分子酯、C1-C6的低分子卤代烃中的一种或几种,10℃以下放置,使固体充分析出,过滤,用C1-C6的低分子醇、C2-C8的低分子醚、C3-C6的低分子酮、C2-C6的低分子腈、C1-C6的低分子卤代烃中的一种或几种洗1-3次,过滤,所得固体用水与C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C1-C6的低分子卤代烃中的一种或几种为结晶溶剂进行一次或多次重结晶,过滤,洗涤,干燥,得头孢拉宗钠水合物。
5.根据权利要求1所述的一种头孢拉宗钠水合物的用途,其特征在于:用于制备固体制剂、注射剂;所述固体制剂包括片剂、胶囊剂、颗粒剂,所述注射剂包括注射用冻干粉针制剂、无菌分装粉针制剂、大输液制剂,。
6.根据权利要求1所述的头孢拉宗钠水合物的用途,其特征在于:用于制备对革兰氏阳性或阴性细菌敏感菌所致的人或动物的呼吸系统、肝胆系统、五官、尿路感染、腹腔感染、盆腔感染、心内膜炎、败血症、皮肤软组织感染、骨和关节感染疾病的治疗或预防的药物中的应用。
7.根据权利要求1所述的头孢拉宗钠水合物的用途,其特征在于:用于制备与β-内酰胺酶抑制剂克拉维酸或其药用盐、舒巴坦或其药用盐、他唑巴坦或其药用盐中的一种或几种组成的抗菌组合药物,其中,头孢拉宗钠水合物与β-内酰胺酶抑制剂的重量比为1∶0.05~2。
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EP0189941A3 (en) * | 1985-02-01 | 1987-08-19 | Bristol-Myers Company | Antibiotic compositions |
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