CN115337273A - 一种氨己烯酸制剂的制备方法 - Google Patents
一种氨己烯酸制剂的制备方法 Download PDFInfo
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- CN115337273A CN115337273A CN202210954080.9A CN202210954080A CN115337273A CN 115337273 A CN115337273 A CN 115337273A CN 202210954080 A CN202210954080 A CN 202210954080A CN 115337273 A CN115337273 A CN 115337273A
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- vigabatrin
- acid
- purified water
- stabilizer
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
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- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/08—Antiepileptics; Anticonvulsants
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- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
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- Medicinal Preparation (AREA)
Abstract
本发明公开了一种氨己烯酸制剂的制备方法,所述的方法包括以下步骤:(1)按剂量称取原料药氨己烯酸、赋型剂、pH稳定剂、抗氧化剂和纯化水;(2)取部分处方量的纯化水置于容器中,加入氨己烯酸、赋型剂、pH稳定剂和纯化水;(3)搅拌至完全溶解,加入余量的水;(4)将步骤(3)制备得到的药液经过滤,灌装于注射瓶,进行冷冻干燥;(4)二次干燥,压盖,包装得成品。本发明制备得到的冻干制剂具有疏松多孔结构,可以使药物易于复溶而恢复活性,而且冻干制剂含水量低,易长期稳定保存;既可使用无菌工艺生产注射剂用于注射,也可制备散剂直接口服或者加水复溶成为溶液进行口服,实现了一种制剂多种使用方式,便于临床使用。
Description
技术领域
本发明涉及药物制剂领域,特别涉及一种氨己烯酸制剂的制备方法。
背景技术
氨己烯酸(Vigabatrin),是一种化学品,化学名称4-氨基-5-己烯酸,分子式为C6H11NO2,分子量为129.157。氨己烯酸是γ-氨基丁酸(GABA)的类似物,能特异性地与GABA氨基转移酶结合,且不可逆转,导致脑内GABA浓度增高,从而发挥抗癫痫作用。氨己烯酸散为国家卫生计生委、工业和信息化部、食品药品监督管理局联合发布第二批鼓励研发申报的儿童药品,用于治疗婴幼儿痉挛。婴儿痉挛症( infantile spasms, IS),又称West综合征,是婴幼儿期特有的一种年龄依赖性癫痫综合征,发病率为0.016% -0.042%, 90 %以上患儿1岁以内发病,起病高峰年龄为4~6个月,主要表现为成串的难以控制的痉挛持续发作,精神运动发育迟滞和脑电图示高峰失律。此类疾病的患儿常伴有智力障碍和多种类型的特殊认知能力的缺陷,预后不良,病死率较高为5%-30%。中国抗癫痫协会在2015版“临床诊疗指南”中推荐氨己烯酸作为由结节性硬化引起的婴儿痉挛症的一线治疗药物。临床上还可用于成人或10岁及10岁以上儿童癫痫患者的辅助治疗,用于治疗其他药物无效,并且潜在利益高于视力损伤风险的难治性复杂部分性发作癫痫患者。
氨己烯酸目前在市场上只有两种剂型,口服片剂和散剂。氨己烯酸具有氨基酸结构,分子式如下所述:
在酸性条件下易产生如下结构的杂质有关物质A,如下图
在碱性环境下则易被氧化变质,因此无论是口服片剂还是口服散剂,均需严格的制剂工艺以防止杂质含量的增加。在大多数可多次使用的口服溶液中,会添加防腐剂以抑制微生物生长和污染以及生物降解,并确保药物产品安全有效。防腐剂溶于溶液后,可以使容器中药物溶液在多次使用的过程中满足微生物限度的要求。然而有限的口服防腐剂通常在低pH下起效,而氨己烯酸在这种pH环境下不稳定。一些防腐剂在低pH环境不溶或溶解很慢,除非采用加热或者超声来促进溶解,这些措施对于病人或者医务人员来说不方便。这种氨己烯酸在酸性pH下不稳定,防腐剂溶解度差的情况对于有效且多次使用的氨己烯酸溶液系统成为一个现实的难题。进一步的,口服片剂虽然是一种较适宜的制剂,但是对于服药依从性差的儿童患者或者存在吞咽障碍的老年患者,往往使用起来不是很方便,因此亟需开发更多的剂型以满足临床不同类型的患者的需要。
发明内容
本发明的主要目的在于提供一种氨己烯酸制剂的制备方法,可以有效解决背景技术中提到的问题。
为实现上述目的,本发明采取的技术方案为:
一种氨己烯酸制剂的制备方法,所述的方法包括以下步骤:(1)按剂量称取原料药氨己烯酸、赋型剂、pH稳定剂、抗氧化剂和纯化水;(2)取部分处方量的纯化水置于容器中,加入氨己烯酸、赋型剂、pH稳定剂和纯化水;(3)搅拌至完全溶解,加入余量的水;(4)将步骤(3)制备得到的药液经过滤,灌装于注射瓶,进行冷冻干燥;(5)二次干燥,压盖,包装得成品。
进一步的,本发明所述的赋型剂选自蔗糖、葡萄糖、山梨糖醇、三氯蔗糖、阿斯巴甜、糖精钠或甘露醇中的一种或多种,优选为甘露醇;所述赋型剂的质量为氨己烯酸的50%-150%,优选为80%-120%,最优选为100%。
进一步的,本发明的pH稳定剂选自柠檬酸盐、柠檬酸、富马酸盐、富马酸、酒石酸盐、酒石酸、磷酸、磷酸二氢盐、磷酸氢二盐中的一种或任意组合,优选为磷酸二氢盐;所述pH稳定剂的质量为氨己烯酸的4%-10%,优选为5%-9%,或优选为6-8%。
进一步的,本发明的抗氧化剂选自番茄红素,原花青素,硫代硫酸盐、亚硫酸盐、亚硫酸氢盐、抗坏血酸中的一种或多种;所述抗氧化剂的含量为的质量为氨己烯酸的0.04%-0.2%,优选为0.06%-0.16%,或优选为0.08-0.12%,最优选为0.10%。
进一步的,本发明的的方法所述步骤(2)中纯化水的量为全部用水的60-90%。
进一步的,本发明的方法所述步骤(4)过滤采用孔径为0.15-0.35微米的滤膜进行过滤,优选为0.20-0.30微米的滤膜,最优选为0.24微米的滤膜。
进一步的,本发明步骤(4)的注射瓶为西林瓶;所述的冷冻干燥包括以下步骤:将灌装的药液在30-120分钟内预冷至-80至-40℃,持续2-6小时,然后进行抽真空,在20-60分钟内将温度调节为-20至-10℃,再次升华10-60小时;优选的预冷至-70至-50℃或者-65至-55℃。
进一步的,本发明的步骤(5)的二次干燥包括在0℃真空干燥2-6小时,然后在20-30℃真空干燥2-6小时。
进一步的,本发明的方法制备得到的产品含水量不高于3%,优选不高于2%,更有效不高于1%,最优选不高于0.8%。
进一步的,本发明的氨己烯酸冻干制剂的制备方法中氨己烯酸与纯化水的质量比为0.01-0.2:1,优选为0.02-0.18:1或者0.05-0.15:1或者0.08-0.12:1或者0.10:1。
进一步的,本发明提供了一种上述方法制备得到的氨己烯酸冻干制剂。
进一步的,本发明还提供了所述的方法制备得到的氨己烯酸冻干制剂在制备抗癫痫药物中的用途。
此外,本发明提供了所述氨己烯酸冻干制剂的使用方法,所述的使用方法包括将所述的冻干制剂溶于注射用水进行注射,包括静脉滴注和肌肉注射等;所述的使用方法还可以将所述冻干制剂直接口服、用水送服或者将其复溶成为溶液口服。
与现有技术相比,本发明具有如下有益效果:
1.本发明的方法制备得到的冻干制剂具有疏松多孔结构,可以使药物易于重新复溶而恢复活性,而且冻干制剂含水量低,易长期稳定保存。
2.可用于注射,快速起效。同时,冻干产品的低共熔态多孔结构可迅速溶化释出药物,因此该技术制备得到的产品可直接口服,也可以加水制备成溶液口服,尤其适用于服药依从性差的儿童患者或者存在吞咽障碍的老年患者。真正实现了一种制剂多种使用方式,便于临床使用。
3.本发明制备得到的产品在低温下制备,有效避免了环化杂质和其他杂质的产生。
4.本发明制备得到的产品在低温下制备,经除菌处理不加额外的防腐剂也可以有效避免了细菌滋生;制备完毕进行无菌灌装,放置过程中也不会产生细菌问题。
具体实施方式
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施方式,进一步阐述本发明。
实施例1
准确称量50000 mg氨己烯酸、50000 mg甘露醇、3000 mg磷酸二氢钠、硫代硫酸钠50 mg和1000 ml纯化水。将氨己烯酸、甘露醇、磷酸二氢钠和硫代硫酸钠溶于800 ml纯化水,搅拌均匀并加入余量的纯化水。将得到的药液经0.24 微米孔径的滤膜进行过滤,过滤后的药液灌装至100个西林瓶中,每个西林瓶大约含有500 mg氨己烯酸。灌装后的西林瓶半压塞,先将药液预冷至-60℃,持续2.5小时,然后进行抽真空操作,在30分钟内将温度调节至-15℃,持续30小时至呈现疏松状白色固体,无塌陷。升温至0℃继续抽真空3小时,然后将所得固体转移至真空干燥箱,在25℃的温度下真空干燥3小时,压塞,包装得成品。
实施例2
准确称量50000 mg氨己烯酸、50000 mg葡萄糖、3000 mg磷酸二氢钠、亚硫酸氢钠40 mg和1000 ml纯化水。将氨己烯酸、葡萄糖、磷酸二氢钠和亚硫酸氢钠溶于850 ml纯化水,搅拌均匀并加入余量的纯化水。将得到的药液经0.24 微米孔径的滤膜进行过滤,过滤后的药液灌装至100个西林瓶中,每个西林瓶大约含有500 mg氨己烯酸。灌装后的西林瓶半压塞,先将药液预冷至-50℃,持续2.5小时,然后进行抽真空操作,在40分钟内将温度调节至-20℃,持续30小时至呈现疏松状白色固体,无塌陷。升温至0℃继续抽真空3小时,然后将所得固体转移至真空干燥箱,在25℃的温度下真空干燥2小时,压塞,包装得成品。
实施例3
准确称量50000 mg氨己烯酸、50000 mg果糖、3000 mg磷酸二氢钠、抗坏血酸60 mg和1000 ml纯化水。将氨己烯酸、果糖、磷酸二氢钠和抗坏血酸溶于750 ml纯化水,搅拌均匀并加入余量的纯化水。将得到的药液经0.24 微米孔径的滤膜进行过滤,过滤后的药液灌装至100个西林瓶中,每个西林瓶大约含有500 mg氨己烯酸。灌装后的西林瓶半压塞,先将药液预冷至-40℃,持续4小时,然后进行抽真空操作,在30分钟内将温度调节至-10℃,持续30小时至呈现疏松状白色固体,无塌陷。升温至0℃继续抽真空4小时,然后将所得固体转移至真空干燥箱,在25℃的温度下真空干燥3小时压塞,包装得成品。
测试例1:水分含量测试
取样,使用MKS-520卡尔费休水分测定仪测试实施例1-3所得白色固体的水分含量,分别为0.58%、0.66%、0.73%,实施例1-3所得样品水分含量低,且含量较均一。
测试例2:相关物质(杂质A)检测(HPLC法)
其中,主要降解杂质A的结构为,A列为新制备的冻干制剂,B列为冻干制剂在密封条件下在温度25℃±2℃、相对湿度60%±5%的条件下放置6个月,在第6个月取样检测的测试数据;C列为冻干制剂在温度40℃±2℃、相对湿度75%±5%的条件下放置6个月,在第6个月取样检测的测试数据。以上数据表明本发明制备得到的冻干制剂相关物质A几乎未检出,且能保持长期的稳定。
测试例3:微生物检测:
将实施例1-3制备得到的冻干制剂在温度40℃±2℃、相对湿度75%±5%的条件下放置6个月,在第6个月取样进行微生物检测。
以上数据表明在不添加防腐剂的前提下,本发明制备得到的冻干制剂在剧烈的环境条件下存放较长的时间微生物限度仍符合要求。
测试例4:复溶时间测试:
将实施例1-3制备得到的冻干制剂进行复溶测试,分别将实施例1-3制备得到的冻干制剂用注射针头加入10ml蒸馏水,用手震荡,观察性状并用秒表计时,至溶液呈澄清透明状。
同时,取市售氨己烯酸颗粒(500 mg规格)作为对照品,用同样的方法检验其相对复溶时间,其结果如下表所示:
测试样品 | 实施例1 | 实施例2 | 实施例3 | 市售产品 |
复溶时间(s) | 13 | 12 | 13 | 119 |
以上数据表明本发明的方法制备得到产品复溶时间重复性好,且具有更加短的复溶时间,可以方便的制备成为溶液使用,依据实际情况,可用于静脉滴注、肌肉注射。必要时,可以将所述西林瓶塞打开,制备出成口服溶液直接服用。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种氨己烯酸制剂的制备方法,其特征在于,所述的方法包括以下步骤:(1)按剂量称取原料药氨己烯酸、赋型剂、pH稳定剂、抗氧化剂和纯化水;(2)取部分处方量的纯化水置于容器中,加入氨己烯酸、赋型剂、pH稳定剂和纯化水;(3)搅拌至完全溶解,再加入余量的水;(4)将步骤(3)制备得到的药液经过滤,灌装于注射瓶,进行冷冻干燥;(5)二次干燥,压盖,包装得成品;
所述的赋型剂选自蔗糖、葡萄糖、果糖、山梨糖醇、三氯蔗糖、阿斯巴甜、糖精钠或甘露醇中的一种或多种;所述赋型剂的质量为氨己烯酸的50%-150%;
所述的冷冻干燥包括以下步骤:将灌装的药液在30-120分钟内预冷至-80至-40℃,持续2-6小时,然后进行抽真空,在20-60分钟内将温度调节为-20至-10℃,再次升华10-60小时。
2.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的pH稳定剂选自柠檬酸盐、柠檬酸、富马酸盐、富马酸、酒石酸盐、酒石酸、磷酸、磷酸二氢盐、磷酸氢二盐中的一种或任意组合;所述pH稳定剂的质量为氨己烯酸的4%-10%。
3.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的抗氧化剂选自番茄红素,原花青素,硫代硫酸盐、亚硫酸盐、亚硫酸氢盐、抗坏血酸中的一种或多种;所述抗氧化剂的含量为的质量为氨己烯酸的0.04%-0.2%。
4.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述步骤(2)中纯化水的量为全部处方量用水的60-90%。
5.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的步骤(4)过滤采用孔径为0.10-0.35微米的滤膜进行过滤。
6.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的步骤(4)的注射瓶为西林瓶。
7.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的步骤(5)的二次干燥包括在0℃真空干燥2-6小时,然后在20-30℃真空干燥2-6小时。
8.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的方法制备得到的产品含水量不高于3%。
9.根据权利要求1所述的氨己烯酸制剂的制备方法,其特征在于,所述的氨己烯酸与纯化水的质量比为0.01-0.2:1。
10.权利要求1-9任一项所述的方法制备得到的氨己烯酸制剂在制备抗癫痫药物中的用途。
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