CN114831948A - 一种法匹拉韦快速释放制剂 - Google Patents
一种法匹拉韦快速释放制剂 Download PDFInfo
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Abstract
本发明涉及一种法匹拉韦快速释放制剂,包括活性物质法匹拉韦和载体材料。本发明制得法匹拉韦制剂不仅具有快速溶解释放特性而且具有良好的稳定性,该制剂能够快速起效,缩短患者病程,用于治疗新型和复发型流感。
Description
技术领域
本发明属于医药领域,具体涉及法匹拉韦速释制剂及其制备方法。
背景技术
法匹拉韦化学名为6-氟-3-羟基吡嗪-2-羧酰胺,外观呈白色至浅黄色粉末,稍溶于乙腈或甲醇,不溶于水或乙醇(99.5),结构式如下:
法匹拉韦,是一种新型RNA依赖的RNA聚合酶(RdRp)抑制剂,属于广谱抗流感病毒药物,用于治疗新型和复发型流感。研究表明,除流感病毒外,该药还对多种RNA病毒展现出良好的抗病毒作用,如埃博拉病毒、沙粒病毒、布尼亚病毒、狂犬病毒等。
根据文献报道法匹拉韦片剂在pH 4.5缓冲液中30分钟溶出度大于80%。但对临床使用或患者症状缓解或治疗讲,法匹拉韦在更短的时间内能够在患者体内释放并起效是十分需要的。同时,已有的法匹拉韦口服制剂如片剂在稳定性上也存在着进一步提高的实际要求。
因此,开发出既能快速溶解释放又能保持良好的稳定性,用药后快速起效进而缩短患者病程的法匹拉韦快速释放制剂具有重要意义。
发明内容
本发明所要解决的技术问题是克服现有技术中的不足,即改进法匹拉韦溶出释放速率及溶出稳定性,为此提供一种法匹拉韦快速释放制剂,其包括活性成分法匹拉韦和载体材料。
根据本发明,本发明提供的法匹拉韦快速释放制剂通常为口服制剂,举例讲有:干混悬、片剂,胶囊或颗粒剂。
根据本发明,本发明提供一种法匹拉韦快速释放制剂,其中活性成分为法匹拉韦可以是法匹拉韦和/或其药用盐,法匹拉韦药用盐举例讲,可以是其钠盐、钾盐或钙盐等。
根据本发明,本发明提供一种法匹拉韦快速释放制剂,其载体材料包括但不限于:聚乙二醇,聚乙烯吡咯烷酮,泊洛沙姆 188和羟丙基-β-环糊精中一种或多种,优选聚乙二醇。
根据本发明,其中聚乙二醇是聚乙二醇1500,聚乙二醇2000,聚乙二醇4000,聚乙二醇6000,聚乙二醇8000,聚乙二醇10000中的一种或几种,优选聚乙二醇6000。
根据本发明,其中聚乙二醇6000与法匹拉韦的用量比例(质量或重量)为1~10:10~1,优选为1~5:5~1。
根据本发明,本发明制剂还可含有填充剂,粘合剂,崩解剂和润滑剂。其中,填充剂举例讲,可以包括乳糖、微晶纤维素、甘露醇、淀粉中的一种或多几种,优选微晶纤维素,粘合剂举例讲,包括羟丙甲纤维素、聚维酮、羟丙基纤维素、羧甲纤维素钠等,优选羟丙甲纤维素,崩解剂举例讲,包括交联羧甲基纤维素钠、交联聚维酮、交联羧甲基淀粉钠等,优选为交联聚维酮,润滑剂举例讲,包括胶态二氧化硅、硬脂酸镁,硬脂酰醇富马酸钠、硬脂酸、硬脂酸钙、滑石粉等,优选为胶态二氧化硅和硬脂酸镁。
本发明进一步涉及法匹拉韦速释制剂的制备方法,其包括:
1)法匹拉韦与载体材料混合,然后与填充剂,粘合剂和/或崩解剂过筛混合均匀;
2)加入适量纯化水将1)物料润湿均匀制粒;
3)干燥,整粒;
4)根据需要,往3)中进一步加入崩解剂,润滑剂。
根据本发明,法匹拉韦速释制剂的制备方法,其中1)中法匹拉韦与载体材料混合可通过以下方式进行:
a. 将法匹拉韦与载体混合,过筛混合均匀;或
b. 于60℃~80℃熔融载体材料(如聚乙二醇),往其中加入法匹拉韦使其溶解,然后快速降温(如降至-20℃),进一步粉碎;或
c. 将聚乙二醇和法匹拉韦溶解于溶剂(如乙醇,丙酮)中, 挥发除去溶剂, 进一步粉碎。
根据本发明,本发明的法匹拉韦制剂显示出更好的速释性能,该速释性能可通过本发明速释制剂中活性成分法匹拉韦的体外溶出释放性能体现。更具体讲,本发明速释制剂中活性成分法匹拉韦的体外溶出释放性能体现是通过法匹拉韦体外溶出度呈现。本发明制剂中法匹拉韦的体外溶出度可通过溶出度与释放度测定法(2020年版《中国药典》通则0931第二法)测定。
本发明法匹拉韦制剂进一步在加速条件放置过程中显示出良好的稳定性。
附图说明:
图1:差示热扫描(DSC)图,a:法匹拉韦原料药,b:聚乙二醇6000,c:法匹拉韦/聚乙二醇6000混合物,d:法匹拉韦/聚乙二醇6000材料。
具体实施例
实施例1~4
含有法匹拉韦的不同载体材料的制剂及其在pH4.5醋酸盐介质中的溶解时间
表1 实施例1~4中制剂的组成
表1中不同组成的法匹拉韦制剂的制备方法
1.混合材料:
按表1所示的量称取法匹拉韦与相应量的载体材料,然后物理混合均匀后过筛,再加入表1所示相应量的微晶纤维素,羟丙甲纤维素,交联聚维酮和胶态二氧化硅并过60目筛网三次后,手工混合5分钟至混合均匀。
2.润湿制粒:
加入适量纯化水将上面1中所得物料润湿后均匀过20目筛制粒。
3.烘干
将上面2中所得湿颗粒放置于40℃烘箱中进行干燥至水分<3.0%。
4.整粒,总混
将上面3中所得干颗粒过20目筛整粒后,加入外加胶态二氧化硅,交联聚维酮和硬脂酸镁混合均匀。
5.压片
将总混后物料进行压片,控制硬度在60-80N。
将本发明实施例1~4制得片剂(3片)投入37℃,900ml,pH4.5醋酸盐介质中,设置搅拌桨转速为50rpm进行溶解时间测定,待片剂完全溶解后停止计时,计算完全溶解时间。
表2 法匹拉韦与不同载体材料的制剂在pH4.5醋酸盐介质中的溶解时间
实施例5~7
法匹拉韦与不同载体材料形成的制剂在pH4.5醋酸介质中的溶解时间
表3 实施例5~7制剂的组成
二、制备方法
1.混合材料:
于80℃熔融表3中所示量的载体材料后,往其中加入表3所示量的法匹拉韦使其分散溶解,得到的熔融物置于-20℃的冰柜中,冷冻12h,取出,置干燥器中放置6h,粉碎或采用研钵研磨成粉末,过筛,得到法匹拉韦与不同规格聚乙二醇形成的产物。再往所得产物中加入表3所示量的微晶纤维素,羟丙甲纤维素,交联聚维酮和胶态二氧化硅,然后过60目筛网三次后,手工混合5分钟至混合均匀。
2.润湿制粒:
加入适量纯化水将1中所得物料润湿均匀后过20目筛制粒。
3.烘干
将2中湿颗粒放置于40℃烘箱中进行干燥至水分<3.0%。
4.整粒,总混
将3中干颗粒过20目筛整粒后,加入表3所示量的外加胶态二氧化硅,交联聚维酮和硬脂酸镁并混合均匀。
5.压片
将总混后物料进行压片,控制硬度在60-80N。
将本发明实施例5~7制得片剂(3片)投入37℃,900ml,pH4.5醋酸盐介质中,设置搅拌桨转速为50rpm进行溶解时间测定,待片剂完全溶解后停止计时,计算完全溶解时间。
表4法匹拉韦与不同规格聚乙二醇形成的产物在pH4.5醋酸盐介质中溶解时间
实施例 | pH4.5醋酸盐介质体积 | 完全溶解时间 |
实施例5 | 900ml | 7分40秒 |
实施例6 | 900ml | 5分50秒 |
实施例7 | 900ml | 9分30秒 |
对法匹拉韦原料药,聚二乙醇6000,法匹拉韦/聚二乙醇6000混合物,法匹拉韦/聚二乙醇6000材料进行差示热扫描(DSC)分析(见图1),由图1可见:原料药在其熔点189.28℃有一个吸收峰,聚二乙醇6000在其熔点61.20℃有一个吸收峰,法匹拉韦/聚二乙醇6000混合物有两个吸收峰分别在57.93℃和179.48℃与单一物质的吸收峰相近,证明单纯的物理混合并不能使二者形成固体分散体,经过制剂工艺制备的法匹拉韦/聚二乙醇6000材料仅在57.62℃出峰,与单一物质的吸收峰对比其出峰位置均前移并且在法匹拉韦熔点范围的吸收峰消失,说明法匹拉韦与聚乙二醇6000形成了低共熔物即固体分散体。
含法匹拉韦的对照样品与本发明实施例6制剂的溶出度比较
对照样品参考专利CN 102348458 B中实施例17进行制备。
溶出度的测定方法:
溶出条件:以pH4.5醋酸盐缓冲溶液900ml为溶出介质,转速为50rpm,依法操作,在5分钟,10分钟,15分钟,20分钟,30分钟分别取样检测溶出度。
将对照样品,实施例6,对照样品-加速3月,实施例6-加速3月片剂投入pH4.5醋酸盐缓冲溶液介质中,在规定取样点取样8ml,采用0.22μm一次性针筒过滤器过滤,弃去3.5ml初滤液,留4.5ml续滤液备用。
供试品溶液配制方法:精密量取1ml续滤液置于10ml容量瓶中,用pH4.5醋酸盐缓冲液稀释定容至10ml,摇匀备用。
对照品溶液配制方法:精密称取20mg法匹拉韦原料药置于100ml容量瓶中,加入适量pH4.5醋酸盐缓冲液,震荡摇匀置于超声波中超声至完全溶解后用pH4.5醋酸盐缓冲液稀释定容至100ml,混合均匀后用移液管精密量取1ml置于10ml容量瓶中,用pH4.5醋酸盐缓冲液稀释定容至10ml,混合均匀后样品备用。
测定方法:取供试品溶液与对照品溶液,照紫外-可见分光光度法(通则0401),在365nm的波长处分别测定吸光度,计算每片的溶出量。
溶出数据如下:
时间/溶出度 | 5分钟 | 10分钟 | 15分钟 | 20分钟 | 30分钟 |
对照样品 | 75.40 | 84.61 | 90.64 | 94.45 | 95.87 |
实施例6 | 93.02 | 94.88 | 95.41 | 96.52 | 96.99 |
从溶出曲线可见(见图2),法匹拉韦经与载体材料混合后再制备成快速释放制剂(实施例6),能显著提高体外溶出速率。
将对照样品,法匹拉韦快速释放制剂(实施例6)放置于稳定性加速条件下(温度40
±2℃,湿度75±5%)3个月后样品取出检测溶出释放曲线。结果如下:
时间/溶出度 | 5分钟 | 10分钟 | 15分钟 | 20分钟 | 30分钟 |
对照样品 | 60.40 | 72.61 | 75.64 | 80.45 | 85.87 |
实施例6 | 80.02 | 84.88 | 89.41 | 93.52 | 95.99 |
本发明对所述法匹拉韦快速释放制剂(实施例6)和对照样品进行稳定性实验,结果显示所述快速释放制剂在加速条件下放置3个月溶出度未有显著降低,稳定性较好。对照样品在加速条件下放置3个月溶出度降低远超过5%属于显著降低。
通过上述实施例研究对比,实施例6具有显著优势,利用聚乙二醇6000与法匹拉韦形成固体分散体再制备片剂,显著提高了法匹拉韦的溶解速率,稳定性好,制备出用药后快速起效,缩短患者病程,可用于预防和治疗新型和复发型流感的法匹拉韦快速释放制剂。
Claims (11)
1.法匹拉韦制剂,其包括法匹拉韦和载体材料。
2.权利要求1所述的制剂,其中载体材料选自:聚乙二醇,聚乙烯吡咯烷酮,泊洛沙姆188和羟丙基-β-环糊精中的一种或多种。
3.权利要求2所述制剂,其中聚乙二醇选自:聚乙二醇1500,聚乙二醇2000,聚乙二醇4000,聚乙二醇6000,聚乙二醇8000,聚乙二醇10000中的一种或几种。
4.权利要求3所述的制剂,其中聚乙二醇为聚乙二醇6000。
5.权利要求1~4任一所述的制剂,其中聚乙二醇6000与法匹拉韦的用量比例(质量或重量)为1~10:10~1。
6.权利要求5所述的制剂,其中聚乙二醇6000与法匹拉韦的用量比例(质量或重量)优选为1~5:5~1。
7.权利要求1~5任一要求的制剂,其进一步包括:填充剂,粘合剂和/或崩解剂。
8.权利要求1~7任一要求的制剂,其中所述制剂为干混悬剂、片剂,胶囊或颗粒剂。
9.权利要求1所述的法匹拉韦制剂的制备方法,包括:
1)法匹拉韦与载体材料混合,然后与填充剂,粘合剂和/或崩解剂过筛混合均匀;
2)加入适量纯化水将1)物料润湿均匀制粒;
3)干燥,整粒;
4)根据需要,往3)中进一步加入崩解剂,润滑剂。
10.权利要求9的方法, 1)中法匹拉韦与载体材料混合包括:
1)将聚乙二醇和法匹拉韦溶解于溶剂中;
2)挥发除去溶剂;
3)破碎得粉末状材料。
11.权利要求9的方法,其中1)中法匹拉韦与载体材料混合包括:
1)熔融聚乙二醇;
2)加入法匹拉韦使其溶解;
3)快速降温;
4)破碎得粉末状材料。
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