CN116687848A - 一种胞磷胆碱钠注射液及其制备方法 - Google Patents
一种胞磷胆碱钠注射液及其制备方法 Download PDFInfo
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- YWAFNFGRBBBSPD-OCMLZEEQSA-M sodium;[[(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 YWAFNFGRBBBSPD-OCMLZEEQSA-M 0.000 title claims abstract description 52
- 229960004774 citicoline sodium Drugs 0.000 title claims abstract description 48
- 238000002347 injection Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 239000001509 sodium citrate Substances 0.000 claims abstract description 24
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000008215 water for injection Substances 0.000 claims abstract description 15
- 230000003204 osmotic effect Effects 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims description 34
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- 239000003814 drug Substances 0.000 claims description 22
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 230000001954 sterilising effect Effects 0.000 claims description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 11
- 229930195725 Mannitol Natural products 0.000 claims description 11
- 239000000594 mannitol Substances 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
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- 239000003708 ampul Substances 0.000 claims description 6
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- 239000011261 inert gas Substances 0.000 claims description 2
- 229960001231 choline Drugs 0.000 abstract description 10
- XCCTYIAWTASOJW-XVFCMESISA-N Uridine-5'-Diphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 XCCTYIAWTASOJW-XVFCMESISA-N 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000003381 stabilizer Substances 0.000 abstract description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004659 sterilization and disinfection Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及一种胞磷胆碱钠注射液及其制备方法,该胞磷胆碱钠注射液是由胞磷胆碱钠、渗透压调节剂、枸橼酸钠以及注射用水组成;其中,所述胞磷胆碱钠和所述枸橼酸钠的质量比为20‑150:1,本发明具有的优点是通过加入枸橼酸钠不仅将pH控制在6.5‑7.5,还能够抑制杂质尿苷二磷酸胆碱的生成,有效提升胞磷胆碱钠注射液的稳定性,不需要额外添加稳定剂。
Description
技术领域
本发明涉及药物制剂的技术领域,尤其涉及一种胞磷胆碱钠注射液及其制备方法。
背景技术
胞磷胆碱为核苷衍生物,可增强脑干网状结构、尤其是与意识密切相关的上行网状结构激动系统的机能;增强椎体系统的机能,改善运动麻痹;改善大脑循环,通过减少大脑血流阻力,增加大脑血流而促进大脑物质代谢,对促进大脑功能恢复和促进苏醒等具有一定作用。胞磷胆碱钠注射液主要用于治疗与头部受伤有关的神经和认知障碍,以及与急性和亚急性中风有关的神经和认知障碍。
无菌制剂属于高风险制剂,可见异物、不溶性微粒、溶液性状都是注射剂的常规检查项和质量控制项,随着对药品安全问题的逐渐重视,如何提高注射剂的性状稳定性及澄明度等是制剂技术关注的重要课题。
胞磷胆碱钠注射液在生产过程中极易产生可见异物及不容性微粒,传统制剂方法通常使用活性炭过滤,CN10402734B、CN114224831A及CN106727296B等专利技术都使用了活性炭过滤,但是活性炭的使用可能造成药品二次污染问题,同时还可能会吸附活性成分,造成成本的增高。
胞磷胆碱钠注射液在高温30℃条件下,性状容易发生改变且pH值均呈增长趋势,初始pH值越高,pH值增长速度越快,但是初始pH值越大,杂质尿苷二磷酸胆碱的检出量就越小,产品越稳定,因此优化产品pH值、提高产品稳定性是制剂过程中存在的又一难题。
发明内容
本发明的目的在于克服现有技术中的不足,提供一种胞磷胆碱钠注射液及其制备方法,通过加入枸橼酸钠不仅将pH控制在6.5-7.5,还能够抑制杂质尿苷二磷酸胆碱的生成,有效提升胞磷胆碱钠注射液的稳定性,不需要额外添加稳定剂。
本发明是通过以下技术方案实现的:提供一种胞磷胆碱钠注射液,该胞磷胆碱钠注射液是由胞磷胆碱钠、渗透压调节剂、枸橼酸钠以及注射用水组成;其中,所述胞磷胆碱钠和所述枸橼酸钠的质量比为20-150:1。优选地,胞磷胆碱钠和枸橼酸钠的质量比为50:1。
进一步地,所述胞磷胆碱钠占所述胞磷胆碱钠注射液的重量百分比为10%~15%;所述渗透压调节剂占所述胞磷胆碱钠注射液的重量百分比为0.6%-10%。
进一步地,所述渗透压调节剂为氯化钠、甘露醇以及丙二醇中的一种或多种。
又提供了一种制备上述的胞磷胆碱钠注射液的方法,具体包括如下步骤:
S1、配液;称取处方量的胞磷胆碱钠、渗透压调节剂,加入80%的注射用水;控制水温在40℃以下,搅拌至完全溶解,加入枸橼酸钠并调节pH值为6.5-7.5,定容,得药液;
S2.过滤;将步骤S1得到的药液进行初次过滤,过滤后将药液置于5-10℃环境下,静置8-12小时,静置后二次过滤;
S3.灌装;
S4.灭菌,即得胞磷胆碱钠注射液。
具体实现过程如下:
S1.配液:称取处方量的胞磷胆碱钠、渗透压调节剂,加入80%注射用水,控制水温在40℃以下,采用500rpm搅拌至完全溶解,加入枸橼酸钠调节pH值,定容至1000ml,得药液。
S2.过滤:将S1步骤中得到的药液进行初次过滤,过滤后将药液置于5-10℃环境下,静置8-12小时,静置后二次过滤。
S3.灌装;。
S4.灭菌:将S3步骤中得到的产品进行121℃热压灭菌12分钟,即得胞磷胆碱钠注射液。
进一步地,在步骤S3中,将步骤S2中得到的药液灌装至无色中硼硅玻璃安瓿中,顶空充入惰性气体,高温火焰熔封。
进一步地,在步骤S2中,初次过滤采用0.45μm微孔滤膜过滤,二次过滤采用0.22μm微孔滤膜过滤。
本发明的有益效果在于:本发明通过加入枸橼酸钠pH调节剂,将pH控制在6.5-7.5,一方面能够抑制杂质尿苷二磷酸胆碱的生成,可以有效提升胞磷胆碱钠注射液的稳定性,不需要额外添加稳定剂;另一方面在此pH值范围内,能够抑制高温条件下注射液的pH值增长趋势。
本发明的枸橼酸钠属于弱酸强碱盐,相比于氢氧化钠或盐酸,更适于窄pH范围的调节,且实验证明采用枸橼酸钠有利于制剂的稳定性。
本发明通过在合适的温度条件下静置,并采用二次过滤,能够有效去除注射液中可见异物、不溶性微粒,避免采用活性炭过滤,避免了注射液的二次污染。
本发明通过渗透压调节剂、胞磷胆碱钠、枸橼酸钠在一定的组成比例下配比,有利于提升注射剂的性状稳定性。
具体实施方式
下面将结合发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。在以下实施例中,胞磷胆碱钠的用量均是以无水物计。
实施例1
物料组成 | 处方配比 |
胞磷胆碱钠 | 100g |
氯化钠 | 7g |
枸橼酸钠 | 1g |
注射用水 | 定容至1000ml |
工艺过程:
(1)配液:称取处方量氯化钠、胞磷胆碱钠,加入80%注射用水中,控制水温在40℃以下,采用500rpm搅拌至完全溶解,加入枸橼酸钠调节pH值到6.5-7.5,定容至1000ml,得药液;
(2)过滤:将步骤(1)所得药液经0.45μm微孔滤膜过滤,将所得药液置于5-10℃环境下,静置8-12小时,静置后用0.22μm微孔滤膜二次过滤;
(3)灌装:将步骤(2)所得药液灌装至无色中硼硅玻璃安瓿中,顶空充入氮气,高温火焰熔封;
(4)灭菌:将步骤(3)所得产品进行121℃热压灭菌12分钟,即得胞磷胆碱钠注射液。
实施例2
物料组成 | 处方配比 |
胞磷胆碱钠 | 130.63g |
甘露醇 | 60g |
枸橼酸钠 | 2.5g |
注射用水 | 定容至1000ml |
工艺过程:
(1)配液:称取处方量甘露醇、胞磷胆碱钠,加入80%注射用水中,控制水温在40℃以下,采用500rpm搅拌至完全溶解,加入枸橼酸钠调节pH值到6.5-7.5,定容至1000ml,得药液;
(2)过滤:将步骤(1)所得药液经0.45μm微孔滤膜过滤,将所得药液置于5-10℃环境下,静置8-12小时,静置后用0.22μm微孔滤膜二次过滤;
(3)灌装:将步骤(2)所得药液灌装至无色中硼硅玻璃安瓿中,顶空充入氮气,高温火焰熔封;
(4)灭菌:将步骤(3)所得产品进行121℃热压灭菌12分钟,即得胞磷胆碱钠注射液。
实施例3
物料组成 | 处方配比 |
胞磷胆碱钠 | 150g |
丙二醇 | 80g |
枸橼酸 | 1g |
注射用水 | 定容至1000ml |
工艺过程:
(1)配液:称取处方量丙二醇、胞磷胆碱钠,加入80%注射用水中,控制水温在40℃以下,采用500rpm搅拌至完全溶解,加入枸橼酸钠调节pH值到6.5-7.5,定容至1000ml,得药液;
(2)过滤:将步骤(1)所得药液经0.45μm微孔滤膜过滤,将所得药液置于5-10℃环境下,静置8-12小时,静置后用0.22μm微孔滤膜二次过滤;
(3)灌装:将步骤(2)所得药液灌装至无色中硼硅玻璃安瓿中,顶空充入氮气,高温火焰熔封;
(4)灭菌:将步骤(3)所得产品进行121℃热压灭菌12分钟,即得胞磷胆碱钠注射液。
实施例4
物料组成 | 处方配比 |
胞磷胆碱钠 | 130.63g |
氯化钠 | 7g |
甘露醇 | 60g |
枸橼酸钠 | 5g |
注射用水 | 定容至1000ml |
工艺过程:
(1)配液:称取处方量氯化钠、甘露醇、胞磷胆碱钠,加入80%注射用水中,控制水温在40℃以下,采用500rpm搅拌至完全溶解,加入枸橼酸钠调节pH值到6.5-7.5,定容至1000ml,得药液;
(2)过滤:将步骤(1)所得药液经0.45μm微孔滤膜过滤,将所得药液置于5-10℃环境下,静置8-12小时,静置后用0.22μm微孔滤膜二次过滤;
(3)灌装:将步骤(2)所得药液灌装至无色中硼硅玻璃安瓿中,顶空充入氮气,高温火焰熔封;
(4)灭菌:将步骤(3)所得产品进行121℃热压灭菌12分钟,即得胞磷胆碱钠注射液。
对比例1-2
对比组别采用相同制备方法制备,处方如下:
物料组成 | 对比例1 | 对比例2 |
胞磷胆碱钠 | 130.63g | 130.63g |
甘露醇 | / | 60g |
盐酸/氢氧化钠 | 0.5g | 0.5g |
注射用水 | 定容至1000ml | 定容至1000ml |
效果实施例
稳定性考察试验
将本发明以上实施例及对比例所制备的胞磷胆碱钠注射液进行影响因素考察,包括高温条件60℃±2℃、放置5、10、30天,光照条件可见光5500lx±500lx近紫外90μw/cm2下放置5、10天,考察结果如下:
结果分析:实施例1、2、3、4与对比例1所制备的胞磷胆碱钠注射液相比较,各实施例高温条件下稳定性均明显优于对比例1,高温30天杂质尿苷二磷酸胆碱增长趋势较对比例1更为缓慢,且性状未发生改变,因此氯化钠、甘露醇、丙二醇的加入可提升制剂在高温条件下的稳定性。
对比实施例2和对比例2的影响因素检测结果显示,本发明基于胞磷胆碱钠和枸橼酸钠的质量比为50:1时调节pH值,相对于盐酸或氢氧化钠调节pH值,其在高温条件下杂质尿苷二磷酸胆碱增长趋势更为缓慢,且性状未发生改变,因此本发明采用枸橼酸钠和胞磷胆碱钠按照一定比例结合不仅能够调节pH值而且能够提升制剂在高温条件下的稳定性;亦可明显改善制剂性状发生改变的问题,具有一定的制剂优势。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换,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 (6)
1.一种胞磷胆碱钠注射液,其特征在于,该胞磷胆碱钠注射液是由胞磷胆碱钠、渗透压调节剂、枸橼酸钠以及注射用水组成;其中,所述胞磷胆碱钠和所述枸橼酸钠的质量比为20-150:1。
2.根据权利要求1所述的胞磷胆碱钠注射液,其特征在于,所述胞磷胆碱钠占所述胞磷胆碱钠注射液的重量百分比为10%~15%;所述渗透压调节剂占所述胞磷胆碱钠注射液的重量百分比为0.6%-10%。
3.根据权利要求1所述的胞磷胆碱钠注射液,其特征在于,所述渗透压调节剂为氯化钠、甘露醇以及丙二醇中的一种或多种。
4.一种制备权利要求1-3任一项所述的胞磷胆碱钠注射液的方法,其特征在于,具体包括如下步骤:
S1、配液;称取处方量的胞磷胆碱钠、渗透压调节剂,加入80%的注射用水;控制水温在40℃以下,搅拌至完全溶解,加入枸橼酸钠并调节pH值为6.5-7.5,定容,得药液;
S2.过滤;将步骤S1得到的药液进行初次过滤,过滤后将药液置于5-10℃环境下,静置8-12小时,静置后二次过滤;
S3.灌装;
S4.灭菌,即得胞磷胆碱钠注射液。
5.根据权利要求4所述的胞磷胆碱钠注射液的制备方法,其特征在于,在步骤S3中,将S2步骤中得到的药液灌装至无色中硼硅玻璃安瓿中,顶空充入惰性气体,高温火焰熔封。
6.根据权利要求4所述的胞磷胆碱钠注射液的制备方法,其特征在于,在步骤S2中,初次过滤采用0.45μm微孔滤膜过滤,二次过滤采用0.22μm微孔滤膜过滤。
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