CN110801448A - 一种注射用氯化乙酰左卡尼汀及其制备方法 - Google Patents
一种注射用氯化乙酰左卡尼汀及其制备方法 Download PDFInfo
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- 229960001518 levocarnitine Drugs 0.000 title claims abstract description 54
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 239000012346 acetyl chloride Substances 0.000 title claims abstract description 43
- 238000002347 injection Methods 0.000 title claims abstract description 30
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 20
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- JATPLOXBFFRHDN-DDWIOCJRSA-N [(2r)-2-acetyloxy-3-carboxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].CC(=O)O[C@H](CC(O)=O)C[N+](C)(C)C JATPLOXBFFRHDN-DDWIOCJRSA-N 0.000 claims description 12
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
本发明涉及化学药品原料药制造领域,提供一种注射用氯化乙酰左卡尼汀及其制备方法,将左卡尼汀和冰醋酸混合,滴加乙酰氯反应,得到氯化乙酰左卡尼汀;用注射用水将甘露醇和氯化乙酰左卡尼汀溶解,调节pH值至6.0~7.5,稀释溶液,加入活性炭吸附,过滤,灌装,得到待冻干物;预冷冻、升华、干燥、包装,得到注射用氯化乙酰左卡尼汀。该注射用左卡尼汀具有纯度高、稳定性高的优点,其配方、工艺简单,合成周期短,具有广泛的应用前景。
Description
技术领域
本发明涉及一种注射用氯化乙酰左卡尼汀及其制备方法,属于化学药品原料药制造领域。
背景技术
左卡尼汀是哺乳动物能量代谢中必不可少的物质。人体每天从肠道摄入的左卡尼汀约为300~400μ/moL,肝、肾和脑组织利用蛋氨酸和赖氨酸每天合成约100~400μ/moL左卡尼汀。左卡尼汀通过血液循环到人体各组织,主要分布在心肌和骨骼肌,以及肝脏,肾脏和细胞外液中。
左卡尼汀是肌肉细胞尤其是心肌细胞的主要来源,许多组织器官例如脑和肾脏也主要靠脂肪酸的氧化作用。左卡尼汀具有长链脂肪酸的氧化作用、脂肪酸过氧化物酶的氧化作用等。左卡尼汀可以用于长期血透左卡尼汀缺乏症、肌肉不良、心肌病、急、慢性心肌梗塞等不良反应。氯化乙酰左卡尼汀为左卡尼汀衍生物,它通过乙酰左卡尼汀转移酶在人体脑、肝脏处合成,能够治疗阿尔兹海默症、心血管障碍、脑循环障碍、抑郁症等。目前市场上左卡尼汀注射剂主要以小容量注射剂和冻干粉针剂为主,并且冻干粉针剂的冻干周期长,能耗大,因此左卡尼汀注射剂有生产升本高的缺点。
氯化乙酰左卡尼汀为左卡尼汀的衍生物,是通过左卡尼汀转移酶在脑、肝脏处合成。与左卡尼汀相比,氯化乙酰左卡尼汀更容易通过血脑屏障发挥药理作用,并且能促进脂肪酸氧化过程中对乙酰辅酶A的摄取。
中国专利CN102327240A提供了一种注射用左卡尼汀组合物及其制备方法,其中冷冻干燥步骤为:-45℃预冷冻3小时,使后箱冷阱温度低于-70℃,之后将前箱抽真空至10Pa以下,用50℃导热油对预冷冻的左卡尼汀药业进行高速升温升华干燥,温度到-23℃时将导热油温度降低至20℃,匀速升温升华干燥至产品温度为15℃,得到冻干粉末。该方法耗能大、操作工艺复杂且难以控制升温干燥一体过程精确无误,不适合左卡尼汀注射剂的大量制备。
目前市面上左卡尼汀注射剂制备工艺复杂,耗能大、操作工艺难以控制升温干燥一体过程精确无误,生产的左卡尼汀纯度不高,不适合左卡尼汀注射剂的大量制备。
发明内容
本发明的目的在于提供一种注射用氯化乙酰左卡尼汀及其制备方法,该氯化乙酰注射剂纯度高,药效快,药理作用明显有效。
一种注射用氯化乙酰左卡尼汀,具体制备方法包括:
(1)将左卡尼汀和冰醋酸混合,滴加乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到氯化乙酰左卡尼汀;
(2)用注射用水溶解甘露醇和氯化乙酰左卡尼汀,调节pH值至6.0~7.5,稀释溶液,加入活性炭吸附,过滤,进行灌装,得到待冻干物料;经过预冷冻、升华、干燥、包装,得到注射用氯化乙酰左卡尼汀。
进一步,左卡尼汀和乙酰氯的摩尔质量比为0.9~1.1:1.4~1.6。
进一步,左卡尼汀和冰醋酸摩尔质量比为0.9~1.1:4~5。
进一步,一种注射用氯化乙酰左卡尼汀,含有氯化乙酰左卡尼汀和甘露醇,其中甘露醇和左卡尼汀比例为甘露醇:氯化乙酰左卡尼汀=1.3~1.5:1。
进一步,左卡尼汀和乙酰氯摩尔质量比为1:1.5。
进一步,甘露醇和氯化乙酰左卡尼汀,以重量份数计,甘露醇:氯化乙酰左卡尼汀=1.3~1.5:1。
进一步,重结晶需先加热至50~65℃,再缓慢冷却至0~-10℃,有固体析出,过滤、沉淀干燥后得到氯化乙酰左卡尼汀纯品。
上述技术方案中,预冷冻在温度为-40℃~-50℃下冷冻3小时,升华温度为-15~15℃,时间为8小时。
具体实施方式
下面通过实施例进一步说明本发明。本发明的实施例仅用于说明本发明而给出,而不是对本发明的限制。
实施例1:将5kg左卡尼汀和20L冰醋酸混合,滴加3kg乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到6kg氯化乙酰左卡尼汀。
将6kg氯化乙酰左卡尼汀和9kg甘露醇混合搅拌,完全溶解于注射用水配置成60kg溶液。用1mol/L盐酸溶液调pH至6.0。加入活性炭搅拌吸附,用微孔滤器进行过滤,然后进行灌装,得到待冻干物料。
真空冷冻干燥:-40~-50℃下预冷冻5小时,-15~15℃下升华8小时、真空干燥、包装,得到注射用氯化乙酰左卡尼汀。
取上述得到的氯化乙酰左卡尼汀进行HPLC检测,产品纯度为98.62%
实施例2:将5kg左卡尼汀和20L冰醋酸混合,滴加3kg乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到6kg氯化乙酰左卡尼汀。
将6kg氯化乙酰左卡尼汀和9kg甘露醇混合搅拌,完全溶解于注射用水配置成60kg溶液。用1mol/L盐酸溶液调pH至6.5。加入活性炭搅拌吸附,用微孔滤器进行过滤,然后进行灌装,得到待冻干物料。
真空冷冻干燥:-40~-50℃下预冷冻5小时,-15~15℃下升华8小时、真空干燥、包装,得到注射用氯化乙酰左卡尼汀。
取上述得到的氯化乙酰左卡尼汀进行HPLC检测,产品纯度为99.80%
实施例3:将5kg左卡尼汀和20L冰醋酸混合,滴加3kg乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到6kg氯化乙酰左卡尼汀。
将6kg氯化乙酰左卡尼汀和9kg甘露醇混合搅拌,完全溶解于注射用水配置成60kg溶液。用1mol/L盐酸溶液调pH至7.0。加入活性炭搅拌吸附,用微孔滤器进行过滤,然后进行灌装,得到待冻干物料。
真空冷冻干燥:-40~-50℃下预冷冻5小时,-15~15℃下升华8小时、真空干燥、包装,得到注射用氯化乙酰左卡尼汀。
取上述得到的氯化乙酰左卡尼汀进行HPLC检测,产品纯度为97.73%
实施例4:将5kg左卡尼汀和20L冰醋酸混合,滴加3kg乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到6kg氯化乙酰左卡尼汀。
将6kg氯化乙酰左卡尼汀和9kg甘露醇混合搅拌,完全溶解于注射用水配置成60kg溶液。用1mol/L盐酸溶液调pH至6.5。加入活性炭搅拌吸附,用微孔滤器进行过滤,然后进行灌装,得到待冻干物料。
真空冷冻干燥:-40~-50℃下预冷冻3小时,-15~15℃下升华8小时、真空干燥、包装,得到注射用氯化乙酰左卡尼汀。
取上述得到的氯化乙酰左卡尼汀进行HPLC检测,产品纯度为97.25%
实施例5:将5kg左卡尼汀和20L冰醋酸混合,滴加3kg乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到6kg氯化乙酰左卡尼汀。
将6kg氯化乙酰左卡尼汀和9kg甘露醇混合搅拌,完全溶解于注射用水配置成60kg溶液。用1mol/L盐酸溶液调pH至6.5。加入活性炭搅拌吸附,用微孔滤器进行过滤,然后进行灌装,得到待冻干物料。
真空冷冻干燥:-40~-50℃下预冷冻5小时,-15~15℃下升华5小时、真空干燥、包装,得到注射用氯化乙酰左卡尼汀。
取上述得到的氯化乙酰左卡尼汀进行HPLC检测,产品纯度为98.80%。
以下通过药效学评价试验来验证本发明氯化乙酰左卡尼汀注射剂的药理效果。
受试药物:氯化乙酰左卡尼汀注射剂。
试验例1:试验用健康大鼠15只,随机分为3组:
实验方法
对大鼠进行静脉注射生理盐水、左卡尼汀注射剂、氯化乙酰左卡尼汀注射剂,30min后,对大鼠进行麻醉,切开颈部,分离右侧颈部动脉,用止血夹夹住右颈总动脉、右颈内动脉,在颈外动脉剪一切口,插入约2cm鱼线固定、缝合。缺血2小时后将线栓拉出约1cm形成再灌注,缓慢拔出线栓,结扎血管,再灌注6小时。快速断头取缺血侧脑组织,在冰浴中加入生理盐水制成10%脑匀浆。检测脑组织ATP酶活性的变化。
实验结果
本技术方案提供的氯化乙酰左卡尼汀注射剂更容易通过血脑屏障,激活脑组织ATP酶的功能优于左卡尼汀注射剂。
试验例2:试验用健康大鼠15只,随机分为3组
实验方法
对大鼠进行静脉注射生理盐水、左卡尼汀注射剂、氯化乙酰左卡尼汀注射剂,30min后,对大鼠进行麻醉,切开颈部,分离右侧颈部动脉,用止血夹夹住右颈总动脉、右颈内动脉,在颈外动脉剪一切口,插入约2cm鱼线固定、缝合。缺血2小时后将线栓拉出约1cm形成再灌注,缓慢拔出线栓,结扎血管,再灌注6小时。快速断头取其脑组织,用TTC(氯代三苯基四氮唑)溶液对脑组织切片进行染色,采用Image Pro Plus图像分析软件计数脑组织凋亡指数。
实验结果
本技术方案提供的氯化乙酰左卡尼汀注射剂对于减轻脑组织损伤的药理作用强于左卡尼汀注射剂。
Claims (8)
1.一种注射用氯化乙酰左卡尼汀,其特征在于,其组成成分包括:氯化乙酰左卡尼汀和甘露醇。
2.一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于,包括以下步骤:
(1)将左卡尼汀和冰醋酸混合,滴加乙酰氯搅拌反应,反应完毕后进行重结晶,过滤,沉淀干燥后得到氯化乙酰左卡尼汀;
(2)用注射用水溶解甘露醇和氯化乙酰左卡尼汀,调节pH值至6.0~7.5,稀释溶液,活性炭吸附,过滤,得到待冻干物料;经过预冷冻、升华、干燥、包装,冻干得到注射用氯化乙酰左卡尼汀。
3.根据权利要求2所述的一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于,左卡尼汀和乙酰氯的摩尔质量比为0.9~1.1:1.4~1.6。
4.根据权利要求2所述的一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于,左卡尼汀和冰醋酸摩尔质量比为0.9~1.1:4~1.5。
5.根据权利要求2所述的一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于,重结晶步骤操作为:先加热溶液至50~65℃,再缓慢冷却至0~-10℃,待固体析出,过滤、沉淀干燥后得到氯化乙酰左卡尼汀纯品。
6.根据权利要求2所述的一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于:甘露醇和酰化左卡尼汀,以重量份数计,甘露醇:氯化乙酰左卡尼汀=1.3~1.5:1。
7.根据权利要求2所述的一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于:预冷冻在温度为-40~-50℃下冷冻3小时。
8.根据权利要求2所述的一种注射用氯化乙酰左卡尼汀的制备方法,其特征在于:升华温度为-15~15℃,时间为8小时。
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