CN113876721A - 一种注射用头孢哌酮钠舒巴坦钠的制备工艺 - Google Patents
一种注射用头孢哌酮钠舒巴坦钠的制备工艺 Download PDFInfo
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- 229960000614 sulbactam sodium Drugs 0.000 title claims abstract description 102
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 title claims abstract description 100
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Abstract
本发明提供一种注射用头孢哌酮钠舒巴坦钠的制备工艺,用溶媒同时溶解头孢哌酮钠和舒巴坦钠后,再加入磷酸缓冲溶液调节pH值,提高头孢哌酮钠和舒巴坦钠的混合度和稳定性,避免引入新的杂质;通过加入组氨酸和亮氨酸,提高头孢哌酮钠舒巴坦钠的疗效,降低头孢哌酮钠和舒巴坦钠使用量,减少因药物滥用导致的菌株耐药性增大的情况。
Description
技术领域
本发明涉及医药制剂技术领域,特别涉及一种注射用头孢哌酮钠舒巴坦钠的制备工艺。
背景技术
头孢哌酮钠舒巴坦钠是一种复合制剂。舒巴坦钠是由人工合成的不可逆性竞争型β-内酰胺酶抑制剂,通常与青霉素类及头孢菌素类药物合用,使其避免被β-内酰胺酶破坏,加强了抗菌活力。头孢哌酮钠是第三代头孢菌素,对多数革兰阳性厌氧菌和某些革兰阴性厌氧菌具有抑菌作用。但头孢哌酮钠对β-内酰胺酶的相对稳定性较差,将头孢哌酮钠和舒巴坦钠联合,不但对阴性杆菌显示明显的协同抗菌活性,联合后的抗菌作用是头孢哌酮的4倍。头孢哌酮钠舒巴坦钠主要用于由敏感菌引起的呼吸系统、泌尿生殖系统感染、腹膜炎、胆囊炎、胆道感染、腹腔内感染、败血症等的治疗。
由于头孢哌酮钠和舒巴坦钠均为内酰胺类化合物,化学结构中均含有不稳定的β-内酰胺环,易水解降效,而且在存放过程中,也因为对热不稳定,而常常发生降解和聚合反应,从而导致药物活性成分含量降低,杂质升高。
中国专利CN101284009公开了《一种头孢哌酮钠舒巴坦钠组合物及其制备方法》,通过在处方中增加了磷酸二氢钠、磷酸氢二钠以及氯化钠,从而能够极大地提高了复方制剂的稳定性,在“凉暗干燥处保存”就能保证在有效期内产品合格。
中国专利CN104644640A公开了《一种注射用头孢哌酮钠舒巴坦钠粉针的制备方法》,利用立体传质塔板技术制备回收到的溶媒,直接应用于头孢哌酮钠及舒巴坦钠产品生产之中,得到的注射用头孢哌酮钠舒巴坦钠粉针剂产品,在色级,澄清度,纯度等质量指标有很大提高,质量稳定性高、杂质少。
上述方法均解决了头孢哌酮钠舒巴坦钠保存稳定性的问题,但近年来,随着头孢哌酮钠舒巴坦钠的大量使用,导致临床常见革兰阴性菌对其具有一定的耐药性,临床疗效降低。
发明内容
为解决上述问题,本发明提供了一种注射用头孢哌酮钠舒巴坦钠的制备工艺。
本发明所述一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用溶媒溶解头孢哌酮钠和舒巴坦钠,在20±5℃的条件下,加入缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入辅料后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.058~0.073MPa,然后向步骤S2过滤后的滤液中加入氨基酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液进行冷冻干燥后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
进一步的,所述溶媒为水和/或甲醇。
进一步的,所述头孢哌酮钠和溶媒的质量体积比为1g:10~15mL。
进一步的,所述缓冲溶液为pH值5.5~6.5的磷酸盐缓冲溶液。
进一步的,所述头孢哌酮钠和缓冲溶液的质量体积比为1g:5~6mL。
进一步的,所述辅料为甘露醇和山梨醇中的至少一种。
进一步的,所述辅料的用量为头孢哌酮钠质量的3~5倍。
进一步的,所述头孢哌酮钠、舒巴坦钠和氨基酸的质量比为(1~3):1:0.6~0.8。
进一步的,所述氨基酸为组氨酸和/或亮氨酸。
进一步的,所述冷冻干燥的温度为-5~4℃,真空度为-0.095~-0.085MPa。
进一步的,所述注射用头孢哌酮钠舒巴坦钠在制备治疗产β-内酰胺酶细菌引起的感染性疾病的药物中的应用。
与现有技术相比,本发明的有益效果是:
本发明的注射用头孢哌酮钠舒巴坦钠制剂,用溶媒同时溶解头孢哌酮钠和舒巴坦钠后,再加入磷酸缓冲溶液调节pH值,提高头孢哌酮钠和舒巴坦钠的混合度和稳定性,避免引入新的杂质。
本发明发现加入组氨酸和亮氨酸,可促进头孢哌酮钠与致病菌株的靶蛋白结合,与舒巴坦钠抑制β-内酰胺酶具有协同作用,可提高头孢哌酮钠舒巴坦钠制剂的疗效,降低头孢哌酮钠和舒巴坦钠使用量,减少因药物滥用导致的菌株耐药性增大的情况。
具体实施方式
为了更好理解本发明技术内容,下面提供具体实施例,对本发明做进一步的说明。
实施例1
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用10mL水溶解1g头孢哌酮钠和0.5g舒巴坦钠,在20±5℃的条件下,加入5mLpH值为6.5的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入3g甘露醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.058MPa,然后向步骤S2过滤后的滤液中加入0.6g亮氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在4℃,真空度-0.095MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例2
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用13mL甲醇水溶液(甲醇:水=1:3)溶解1g头孢哌酮钠和0.33g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为6.0的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入4g山梨醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.065MPa,然后向步骤S2过滤后的滤液中加入0.2g组氨酸和0.5g亮氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在-4℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例3
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用10mL甲醇溶解1g头孢哌酮钠和1g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为5.5的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入5g山梨醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.058MPa,然后向步骤S2过滤后的滤液中加入0.6g组氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在-5℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例4
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用13mL甲醇水溶液(甲醇:水=1:3)溶解1g头孢哌酮钠和0.33g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为4.5的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入4g山梨醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.065MPa,然后向步骤S2过滤后的滤液中加入0.2g组氨酸和0.5g亮氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在-4℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例5
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用13mL甲醇水溶液(甲醇:水=1:3)溶解1g头孢哌酮钠和0.33g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为6.0的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入4g山梨醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.065MPa,然后向步骤S2过滤后的滤液中加入0.4g组氨酸和0.5g亮氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在-4℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例6
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用13mL甲醇水溶液(甲醇:水=1:3)溶解1g头孢哌酮钠和0.33g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为6.0的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入4g山梨醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.065MPa,然后向步骤S2过滤后的滤液中加入0.2g精氨酸和0.5g亮氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在-4℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例7
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用13mL甲醇水溶液(甲醇:水=1:3)溶解1g头孢哌酮钠和0.33g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为6.0的磷酸盐缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入4g山梨醇后,用活性炭进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.065MPa,然后向步骤S2过滤后的滤液中加入0.2g组氨酸和0.5g谷氨酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;
S4.取注射用头孢哌酮钠舒巴坦钠溶液,在-4℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
实施例8
一种注射用头孢哌酮钠舒巴坦钠的制备工艺,包括以下步骤:
S1.用13mL甲醇水溶液(甲醇:水=1:3)溶解1g头孢哌酮钠和0.33g舒巴坦钠,在20±5℃的条件下,加入6mLpH值为6.0的磷酸盐缓冲溶液,搅拌溶清后加入4g山梨醇、0.2g组氨酸和0.5g亮氨酸,再次搅拌至溶清,静置0.5~1h后,过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.用活性炭对步骤S1获得的溶液进行脱色处理,脱色结束后,用微孔滤膜过滤,取滤液在-4℃,真空度-0.085MPa的条件下进行冷冻干燥,然后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
测定常见致病菌对注射用头孢哌酮钠舒巴坦钠的耐药率,结果见表1;
测定方法照“不同配比头孢哌酮钠/舒巴坦对革兰阴性杆菌体外抗菌效果影响,张英,2015”,采用SCF150药敏纸片法进行;
供试菌株:ATCC 15442铜绿假单胞菌、ATCC 35281肺炎克雷伯菌、ATCC019606鲍曼不动杆菌;
表1耐药率
由表1可知,铜绿假单胞菌、肺炎克雷伯菌、鲍曼不动杆菌对本发明制备的注射用头孢哌酮钠舒巴坦钠具有较低的耐药率,其中实施例2的耐药率最低。
实施例6~7与实施例2相比,表明组氨酸、亮氨酸和其他氨基酸配合使用,降低耐药性的效果不佳。
实施例8与实施例2相比,表明本发明注射用头孢哌酮钠舒巴坦钠的制备方法对菌株耐药性也具有影响。
试验例 质量检测
在凉暗干燥条件和低温保存条件下分别测定注射用头孢哌酮钠舒巴坦钠的了质量指标,测定项目包括含量、细菌内毒素、有关杂质和相对水解率,除相对水解率外,其余项目的测定方法照《中国药典二部》(2020版)注射用头孢哌酮钠舒巴坦钠项下有关方法进行;
相对水解率的测定:照“注射用头孢噻肟钠他唑巴坦钠对β-内酰胺酶稳定性试验,卢耀文,2011”的测定方法进行,具体包括以下步骤:
1.β-内酰胺酶的提取:挑取铜绿假单胞菌接种于2.5ml新鲜的M.H肉汤中,37℃过夜培养,吸2ml此培养液加入到200mlM.H肉汤中,37℃旋转震荡培养18h,在4℃、7000rpm低温离心10min,收集菌体用pHwei 7.0的磷酸盐缓冲溶液(50Mm)洗涤2次,重复离心,然后再用磷酸盐溶液制成细菌悬浊液,在冰浴条件下超声破碎至菌液清亮,在4℃、10000rpm低温离心30min,收集上清液,得β-内酰胺酶提取液,并用Nitrocefin纸片进行鉴定;
2.相对水解率的测定:指示剂选用枯草芽孢杆菌悬液,培养基选用抗生素1号,底物为实施例1~8,将8种底物配制成浓度为16mg/L的溶液,每种底物设3各平行,取1.5mL底物溶液,加入20μLβ-内酰胺酶提取液,混匀,置于37℃水浴反应15min,然后将反应后的混合液涂布在含有枯草芽孢杆菌的琼脂平皿的反应孔中,每孔20μL,在37℃处理14~16h,测量抑菌环,然后根据标准曲线得到相应的反应底物含量,计算相对水解率;
3.标准曲线:将各底物配制成0mg/L、2mg/L、4mg/L、8mg/和16mg/L的底物浓度,按照上述方法测定其抑菌环大小,绘制标准曲线。
表2质量检测结果
结果显示,本发明制备的注射用头孢哌酮钠舒巴坦钠制剂中头孢哌酮和舒巴坦含量符合要求,细菌内毒素在规定范围内,实施例2制备的制剂的有关物质含量和相对水解率均较低,实施例6~7制备的制剂的相对水解率高,实施例8制备的制剂的有关物质含量高。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,包括以下步骤:
S1.用溶媒溶解头孢哌酮钠和舒巴坦钠,在20±5℃的条件下,加入缓冲溶液,搅拌溶清后过滤,得头孢哌酮钠-舒巴坦钠混合溶液;
S2.向步骤S1获得的溶液中加入辅料后,进行脱色处理,脱色结束后,用微孔滤膜过滤;
S3.控制温度为20±5℃,真空度为0.058~0.073MPa,然后向步骤S2过滤后的滤液中加入氨基酸,搅拌至溶清,静置0.5~1h后,恢复至常压,用微孔滤膜过滤,得注射用头孢哌酮钠舒巴坦钠溶液;所述氨基酸为组氨酸和/或亮氨酸;
S4.取注射用头孢哌酮钠舒巴坦钠溶液进行冷冻干燥后无菌分装,得注射用头孢哌酮钠舒巴坦钠。
2.如权利要求1所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述溶媒为水和/或甲醇。
3.如权利要求2所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述头孢哌酮钠和溶媒的质量体积比为1g:10~15mL。
4.如权利要求1所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述缓冲溶液为pH值5.5~6.5的磷酸盐缓冲溶液。
5.如权利要求4所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述头孢哌酮钠和缓冲溶液的质量体积比为1g:5~6mL。
6.如权利要求1所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述辅料为甘露醇和山梨醇中的至少一种;所述辅料的用量为头孢哌酮钠质量的3~5倍。
7.如权利要求1所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述头孢哌酮钠、舒巴坦钠和氨基酸的质量比为(1~3):1:0.6~0.8。
8.如权利要求1所述的注射用头孢哌酮钠舒巴坦钠的制备工艺,其特征在于,所述冷冻干燥的温度为-5~4℃,真空度为-0.095~-0.085MPa。
9.如权利要求1-8任一项所述的注射用头孢哌酮钠舒巴坦钠,在制备治疗产β-内酰胺酶细菌引起的感染性疾病的药物中的应用。
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CN101284009A (zh) * | 2008-05-29 | 2008-10-15 | 管小明 | 一种头孢哌酮钠舒巴坦钠组合物及其制备方法 |
CN102462684A (zh) * | 2010-11-10 | 2012-05-23 | 湘北威尔曼制药股份有限公司 | 头孢曲松钠和舒巴坦钠的药物组合物及其制备方法 |
CN110893232A (zh) * | 2019-09-25 | 2020-03-20 | 上海欣峰制药有限公司 | 一种注射用头孢哌酮钠舒巴坦钠粉针剂及其制备方法 |
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CN101284009A (zh) * | 2008-05-29 | 2008-10-15 | 管小明 | 一种头孢哌酮钠舒巴坦钠组合物及其制备方法 |
CN102462684A (zh) * | 2010-11-10 | 2012-05-23 | 湘北威尔曼制药股份有限公司 | 头孢曲松钠和舒巴坦钠的药物组合物及其制备方法 |
CN110893232A (zh) * | 2019-09-25 | 2020-03-20 | 上海欣峰制药有限公司 | 一种注射用头孢哌酮钠舒巴坦钠粉针剂及其制备方法 |
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