CN116585281A - 一种左乙拉西坦的固体药物组合物及制备方法 - Google Patents
一种左乙拉西坦的固体药物组合物及制备方法 Download PDFInfo
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Abstract
本发明涉及药物组合物技术领域,具体涉及一种左乙拉西坦的固体药物组合物及制备方法,所述固体药物组合物为片剂,以重量份数计包含如下组分:左乙拉西坦250份、聚乙烯醇14.5份、二氧化硅5‑7.5份、硬脂酸镁0.15‑0.3份、胃溶型薄膜包衣预混剂5.4‑13.5份,本发明通过新的左乙拉西坦药物组合达到控制杂质的目的,该固体药物组合物各项质量指标均符合要求,15分钟的溶出度均大于85%,且制备方法稳定可靠。
Description
技术领域
本发明涉及药物组合物技术领域,尤其涉及一种左乙拉西坦的固体药物组合物及制备方法。
背景技术
左乙拉西坦(Levetiracetam)是一种高效广谱的抗癫痫药物,由比利时UCB公司研制,商品名为Keppra(开浦兰),目前已在欧洲医药评价署(EMEA)和美国食品与药物管理局(FDA)注册,并已应用于临床。左乙拉西坦作用机制独特,疗效持续时间长,不良反应较小,安全性及耐受性好,可用于多种类型癫痫发作的加用治疗、辅助用药或单药治疗,有广泛的临床应用前景。
左乙拉西坦的化学名为:(S)-α-乙基-2-氧代-1-吡咯烷乙酰胺;其英文名为:(S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide;其分子式为:C8H14N2O2,分子量为:170.21,结构式如式(I)所示:
开浦兰的使用说明书中表明,其非活性成分包括交联羧甲纤维素钠、聚乙二醇6000、二氧化硅、硬脂酸镁、聚乙烯醇、滑石粉、二氧化钛、铝色淀,其中聚乙烯醇、滑石粉、二氧化钛、铝色淀为包衣粉中所含辅料。发明人在采用原研处方组成在实验过程中,发现其在储存时会产生杂质1(相对保留时间0.42)和杂质2(相对保留时间0.72),不确定的杂质可能会影响产品的安全性,故通过实验分析,研究一种不会产生杂质1和杂质2的左乙拉西坦的固体药物组合物。
发明内容
有鉴于此,本发明的目的在于提出一种左乙拉西坦的固体药物组合物及制备方法。
本发明是通过新的左乙拉西坦药物组合控制杂质1和杂质2的目的。
基于上述目的,本发明提供了一种左乙拉西坦的固体药物组合物,所述固体药物组合物为片剂,以重量份数计包含如下组分:左乙拉西坦250份、聚乙烯醇14.5份、二氧化硅5-7.5份、硬脂酸镁0.15-0.3份、胃溶型薄膜包衣预混剂5.4-13.5份。
优选的,所述胃溶型薄膜包衣预混剂购买于上海卡乐康包衣技术有限公司。
本发明还提供了一种上述左乙拉西坦的固体药物组合物的制备方法,包括以下步骤:
S1:将左乙拉西坦过20目筛,与聚乙烯醇、二氧化硅混合均匀,得到混合物I;
S2:将硬脂酸镁加入到混合物I中,混合均匀,得到混合物II;
S3:将混合物II用干法制粒机制成干颗粒,制粒筛网1.2mm,测定休止角为37.8-38.5°,压制成素片,片剂硬度在50-80N;
S4:将胃溶型薄膜包衣预混剂用纯化水溶解,配成浓度为15%的混悬液,对素片进行包衣,片床温度35-45℃,得到左乙拉西坦的固体药物组合物。
本发明的有益效果:本发明提供一种左乙拉西坦的固体药物组合物及制备方法,本发明通过新的左乙拉西坦药物组合达到控制杂质1和杂质2的目的。该固体药物组合物各项质量指标均符合要求,15分钟的溶出度均大于85%,该产品的制备方法稳定可靠。
附图说明
为了更清楚地说明本发明或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1是现有技术中杂质1和杂质2的图谱。
图2是辅料总混物的XRPD图。
图3是左乙拉西坦原料的XRPD图。
图4是左乙拉西坦颗粒的XRPD图。
图5是实施例1生产的左乙拉西坦片的XRPD图。
图6是对比例1的左乙拉西坦片的XRPD图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白,以下结合具体实施例,对本发明进一步详细说明。
本发明通过对原研处方进行研究,发现了按照原处方的原辅料,储存时会产生杂质1和杂质2,具体的图谱见附图1,发明人通过研究,确定杂质1和杂质2的产生可能与某个辅料有关,左乙拉西坦为含有羰基的水溶性药物,部分溶解态API在特定条件下可能降解成EP-A,EP-A含有羧基,可能会与某个辅料发生反应而生产杂质。采用原辅料相容性实验,将原料和各种辅料进行相容性实验,混合比例按主药:辅料=20:1混合均匀,经过高温60℃条件下放置30天后,显著可见:
左乙拉西坦+聚乙二醇6000于高温60℃放置0天、10天、30天时有关物质变化显著,其中杂质1(相对保留时间RRT:0.42),杂质2(相对保留时间RRT:0.72)的变化情况如表1所示。
表1杂质1和杂质2的变化情况
0天 | 10天 | 30天 | |
杂质1 | 未检出 | 0.61% | 0.56% |
杂质2 | 从未检出 | 0.91% | 0.82% |
左乙拉西坦与其他各辅料均未发生上述现象,性质稳定良好。故怀疑出现的未知杂质不相容的情况与聚乙二醇有关。
以下通过实施例进一步说明本发明,但不作为本发明的限制。
实施例1-3提供了一种左乙拉西坦的固体药物组合物,其具体组成见表2。
表2实施例1-3
原料名称 | 实施例1 | 实施例2 | 实施例3 |
左乙拉西坦(mg) | 250 | 250 | 250 |
聚乙烯醇(mg) | 14.5 | 14.5 | 14.5 |
二氧化硅(mg) | 5 | 7.5 | 5 |
硬脂酸镁(mg) | 0.3 | 0.3 | 0.15 |
胃溶型薄膜包衣(mg) | 5.4 | 10.2 | 13.5 |
实施例1-3提供的左乙拉西坦的固体药物组合物的制备步骤如下:
S1:将左乙拉西坦过20目筛,与聚乙烯醇、二氧化硅混合均匀,得到混合物I;
S2:将硬脂酸镁加入到混合物I中,混合均匀,得到混合物II;
S3:将混合物II用干法制粒机制成干颗粒,制粒筛网1.2mm,测定休止角,压制成素片;
S4:将胃溶型薄膜包衣预混剂用纯化水溶解,配成浓度为15%的混悬液,对素片进行包衣,片床温度40℃,得到左乙拉西坦的固体药物组合物。
其中,胃溶型薄膜包衣预混剂购买于上海卡乐康包衣技术有限公司,规格为85A680001-CN。
性能测试:比较实施例1-3提供的左乙拉西坦的固体药物组合物的溶出度、片剂硬度、颗粒流动性等指标的影响,结果见表3。
表3实施例1-3提供的左乙拉西坦的固体药物组合物的性能测试结果
结论:实施例1和实施例2采用不同二氧化硅用量的处方,硬度相近,三个处方的颗粒流动性、溶出度等指标没有显著差异;实施例1和实施例3采用不同的硬脂酸镁用量,硬度和溶出结果相近,三个处方的颗粒流动性没有显著差异。
对比例1
为采购的开浦兰药品,用于对比本发明的理化性质。
对对比例1、和本发明实施例1的辅料总混物、左乙拉西坦原料、左乙拉西坦颗粒、左乙拉西坦片剂进行晶型检测,检测结果如附图2-6所示。
开浦兰在衍射角(2θ)为14.88°、15.15°、18.56°、20.53°、23.36°、23.85°、26.80°和28.92处与实施例1的左乙拉西坦原料、左乙拉西坦颗粒、左乙拉西坦片片剂角度差在±0.2°以内,表明晶型一致。由此可以说明,自制左乙拉西坦片剂和左乙拉西坦原料与开浦兰在晶型上是一致的,并且,本发明的技术方案在生产中从原料到颗粒,再到成品片剂,包括制粒、压片、包衣的整个生产过程均未发生晶型转化。
对比例1药品中聚乙二醇选取聚乙二醇6000,起润滑剂和固体分散剂的作用,用聚乙烯醇代替聚乙二醇后,药物的溶出度、片剂硬度、颗粒流动性等指标没有显著差异;且根据检测结果,本发明提供的左乙拉西坦的固体药物组合物,晶型和对比例1药品一致。
所属领域的普通技术人员应当理解:以上任何实施例的讨论仅为示例性的,并非旨在暗示本发明的范围(包括权利要求)被限于这些例子;在本发明的思路下,以上实施例或者不同实施例中的技术特征之间也可以进行组合,步骤可以以任意顺序实现,并存在如上所述的本发明的不同方面的许多其它变化,为了简明它们没有在细节中提供。
本发明旨在涵盖落入所附权利要求的宽泛范围之内的所有这样的替换、修改和变型。因此,凡在本发明的精神和原则之内,所做的任何省略、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 (3)
1.一种左乙拉西坦的固体药物组合物,其特征在于,所述固体药物组合物为片剂,以重量份数计包含如下组分:左乙拉西坦250份、聚乙烯醇14.5份、二氧化硅5-7.5份、硬脂酸镁0.15-0.3份、胃溶型薄膜包衣5.4-13.5份。
2.根据权利要求1所述的左乙拉西坦的固体药物组合物,其特征在于,所述胃溶型薄膜包衣由胃溶型薄膜包衣预混剂得到,所述胃溶型薄膜包衣预混剂购买于上海卡乐康包衣技术有限公司。
3.一种根据权利要求1-2任一项所述的左乙拉西坦的固体药物组合物的制备方法,其特征在于,包括以下步骤:
S1:将左乙拉西坦过20目筛,与聚乙烯醇、二氧化硅混合均匀,得到混合物I;
S2:将硬脂酸镁加入到混合物I中,混合均匀,得到混合物II;
S3:将混合物II用干法制粒机制成干颗粒,制粒筛网1.2mm,测定休止角为37.8-38.5°,压制成素片,片剂硬度在50-80N;
S4:将胃溶型薄膜包衣预混剂用纯化水溶解,配成浓度为15%的混悬液,对素片进行包衣,片床温度35-45℃,得到左乙拉西坦的固体药物组合物。
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