CN110354081A - 可减少在水介质中析出的利托那韦固体分散体的制备方法 - Google Patents
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Abstract
本发明提供了一种可减少在水介质中析出的利托那韦固体分散体的制备方法,通过先制备利托那韦固体分散体,并对其进行粉碎,然后对粉碎后的利托那韦固体分散体进行老化工艺的处理形成最终所述的利托那韦固体分散体。本发明的有益效果体现在:以本方法制备的固体分散体可以有效减少在水介质中的析出,有效改善固体分散体制备成颗粒后的不稳定状态,为胶囊剂、片剂的制备或工艺创新奠定基础。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种利托那韦固体分散体的制备方法。该方法能减少利托那韦固体分散体在过饱和溶液中的析出。
背景技术
据统计,小分子在研新药中大约占70%以上、已上市药物中大约40%以上是难溶性药物,这些难溶性药物的性质容易导致药物的溶解度差和生物利用度低的问题。抗病毒药物利托那韦就属于这种类型的小分子药物,不同制剂方法的开发和使用目的就是提高该药物的溶解性和生物利用度。
利托那韦是人类免疫缺陷病毒(HIV)的蛋白酶抑制剂,虽然具有良好的亲脂性,但体外渗透性研究表明利托那韦是P-糖蛋白的底物,因此,利托那韦的口服吸收可能会受到溶解和渗透性的限制,从而使其成为生物药剂学分类体系中的IV类化合物。雅培公司开发的利托那韦片(Norvir,100mg)是采用热熔挤出工艺制备的片剂,利托那韦原料药以无定形状态分散于固体分散剂中,利托那韦片在与水介质接触时形成了纳米到微颗粒的分散体,形成一种相对稳定的过饱和溶液,但是雅培公司在利托那韦片(Norvir,100mg)上市两年后发现在制剂过程中利托那韦沉淀形成了一种热力学上更稳定新晶型,溶解性比晶型Ⅰ更差,从而影响了制剂的溶出速率和生物利用度,造成了较大的安全风险和损失。因此利托那韦所存在的在溶出介质中因过饱和而导致晶体析出问题,会使其在体内吸收受限。
在仿制药的技术开发过程中,一系列提高药物溶解度的方法如化合物成盐、微粉化、制备包合物、固体分散体技术等是经常使用的技术手段,尤其是热熔挤出技术(HME)更是一种制备固体分散体简便高效的方法,其优点在于无溶剂添加、操作简单、可持续操作和适合于工业化大生产。该技术是将药物和载体在一定温度下通过双螺杆剪切和挤压,克服原料药的晶格能,利用熔融的办法使药物分子获取更多的能量,使原料药均匀分散和嵌入到软化的聚合物载体中,形成无定型状态的固体分散体。无定型形式比稳定的晶型形式呈现更高的吉布斯自由能,从热力学角度来讲,药物分子在无定型状态下是及其不稳定的,这也是无定形药物易于发生重结晶的重要因素。同时,在液体状态时, 无定型药物在溶液中会形成不稳定的超饱和状态,容易在溶出过程中发生重结晶。有就是说将药物转变成无定型状态虽然能暂时改善其溶解度,但是,随着溶出时间的延长,水分、无机盐等因素都可能导致过饱和状态的分散相稳定性下降,引起药物晶体析出。
发明内容
为了解决现有技术的不足,本发明提供了一种可减少在水介质中析出的利托那韦固体分散体的制备方法。
本发明的目的通过以下技术方案来实现:
可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:包括如下步骤:先制备利托那韦固体分散体,并对其进行粉碎,然后对粉碎后的利托那韦固体分散体进行老化工艺的处理形成最终所述的利托那韦固体分散体。
优选地,所述可减少在水介质中析出的利托那韦固体分散体的制备方法,包括如下步骤:
S1、称取利托那韦、润滑剂、固体分散剂,并进行过筛混合;所述润滑剂为胶态二氧化硅,所述固体分散剂为共聚维酮;各物料配比为:
S2、将S1混合后的原料再经过高剪切混合机进行混合,并在高剪切混合机中加入表面活性剂;
S3、经过S2混合后的物料通过热熔机进行热熔挤出形成固体分散体;
S4、对S3中的固体分散体进行粉碎处理;
S5、对S4中粉碎处理后的固体分散体置于鼓风干燥箱进行加热做进一步的老化处理形成最终所需的固体分散体。
优选地,所述S2中表面活性剂为司盘20。
优选地,所述S4中粉碎方式包括:球磨机粉碎、万能粉碎机粉碎、敲打粉碎。
优选地,所述S5中加热温度为90℃—110℃,老化时间为20-40min。
优选地,所述加热温度为110℃。
本发明的有益效果体现在:以本方法制备的固体分散体可以有效减少在水介质中的析出,有效改善固体分散体制备成颗粒后的不稳定状态,为胶囊剂、片剂的制备或工艺创新奠定基础。
附图说明
图1:不同粉碎方式在水介质中的溶出曲线。
图2:不同老化温度在水介质中溶出曲线。
具体实施方式
本发明揭示了一种可减少在水介质中析出的利托那韦固体分散体的制备方法,包括如下步骤:按比例称取利托那韦、润滑剂、固体分散剂,并进行过筛混合;所述润滑剂为胶态二氧化硅,所述固体分散剂为共聚维酮;将S1混合后的原料再经过高剪切混合机进行混合,并在高剪切混合机中加入表面活性剂;以上组成比例为,利托那韦原料10%~20%,共聚维酮50%~70%,二氧化硅0.5%~2%,司盘20 5%~10%。本实施例中其具体成分及比例如表1所示。经过混合后的物料通过热熔机进行热熔挤出形成固体分散体;本实施例中所述热熔机采用140℃温度下,转速50rpm。对挤出的固体分散体进行粉碎处理。
表1:制备利托那韦固体分散体的原料配方
处方 | 作用 | 用量(mg) |
原料药 | 活性成分 | 100 |
司盘20 | 表面活性剂 | 66.7 |
胶态二氧化硅 | 润滑剂 | 13.8 |
共聚维酮 | 固体分散剂 | 493.1 |
。
本实施例中将固体分散体做了不同处理以进行更好的比较,分别为未处理、万能粉碎机粉碎、敲碎、球磨机粉碎,考察其在水介质中的溶出曲线,结果如图1所示,未经过粉碎处理的固体分散180min之内在水介质中保持稳定且不析出,但是无法进行后续工艺的处理。因此,挤出物必须经过粉碎工艺而得到理想的压片材料。对其他三种方式处理的挤出物进行的溶出试验分析,结果发现固体分散体随着粉碎剧烈程度的提高而出现了更快的析出。
为改善析出的问题,对粉碎处理后的固体分散体置于鼓风干燥箱进行加热做进一步的老化处理。老化时加热温度为90℃—110℃,老化时间为20-40min。采用老化步骤的原理是通过再加热过程修补由于物理粉碎过程所引起的药物颗粒之间的不光滑表面,并在重新加热的过程中形成了减少药物析出的保护膜。
本发明公开的试验结果的供试物料为经过万能粉碎机工艺处理的挤出物(破坏力最大的工艺过程)分成三份,在设定温度分别为90℃、100℃、110℃的鼓风干燥箱内进行老化时间为30min的再加热过程。将样品取出,分别对未老化和老化后的固体分散体进行水介质下体外溶出试验(USP溶出装置II)。结果如图2所示, 没经过老化工艺的处理在30min后开始出现析出现象。经鼓风干燥箱老化后的物料直至180min后才逐渐出现轻微的析出现象,温度在110℃下效果最好,表现出非常明显的稳定状态,为促进体内吸收提供数据基础。
进一步的证实了通过增加在鼓风干燥箱中进行固体分散体的老化工艺处理,可以解决经过热熔挤出和粉碎工艺后利托那韦固体分散体在水介质中所表现的析出问题,以确保后续的利托那韦制剂工艺的顺利地进行并为满足制剂工艺达到生物利用度的要求提供基础。
以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解: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;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (6)
1.可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:包括如下步骤:先制备利托那韦固体分散体,并对其进行粉碎,然后对粉碎后的利托那韦固体分散体进行老化工艺的处理形成最终所述的利托那韦固体分散体。
2.如权利要求1所述的可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:
S1、称取利托那韦、润滑剂、固体分散剂,并进行过筛混合;所述润滑剂为胶态二氧化硅,所述固体分散剂为共聚维酮;
S2、将S1混合后的原料再经过高剪切混合机进行混合,并在高剪切混合机中加入表面活性剂;
S3、经过S2混合后的物料通过热熔机进行热熔挤出形成固体分散体;
S4、对S3中的固体分散体进行粉碎处理;
S5、对S4中粉碎处理后的固体分散体置于鼓风干燥箱进行加热做进一步的老化处理形成最终所需的固体分散体。
3.如权利要求2所述的可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:所述S2中表面活性剂为司昂20。
4.如权利要求2所述的可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:所述S4中粉碎方式包括:球磨机粉碎、万能粉碎机粉碎、敲打粉碎。
5.如权利要求2所述的可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:所述S5中加热温度为90℃—110℃,老化时间为20-40min。
6.如权利要求5所述的可减少在水介质中析出的利托那韦固体分散体的制备方法,其特征在于:所述加热温度为110℃。
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