CN117018226A - 一种含塞来昔布包合物的制剂及其制备方法 - Google Patents
一种含塞来昔布包合物的制剂及其制备方法 Download PDFInfo
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Abstract
本发明属于药物制剂领域,具体提供了一种含塞来昔布包合物的制剂及其制备方法。本发明所述的制剂包括塞来昔布包合物、β‑环糊精、单硬脂酸甘油酯、L‑茶氨酸以及辅料。最终所获得的制剂具有工艺简单,溶出性好,有关物质低的优点,适合进一步工业化大生产。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及含塞来昔布包合物的制剂及其制备工艺。
背景技术
塞来昔布(Celecoxib),即4-[5-(4-甲苯基)-3-(三氟甲基)-1氢-1-吡唑-1-基]苯磺酰胺,是第一个选择性COX-2抑制剂,也是目前全球处方量最大的非甾体抗炎镇痛药,不仅具有显著镇痛疗效,能显著减轻关节触痛/疼痛和关节肿胀,而且具有优越的胃肠道安全性。
塞来昔布溶解性极低,25℃下水中溶解度约为0.007mg/ml,现有技术提到不少方法,例如。中国专利201210003999.6)“塞来昔布固体分散体及其制备方法”,中国专利201210259149.2)“一种具高溶出度的塞来昔布固体组合物、制备方法及应用”;中国专利201010301422.4)“一种含塞来昔布的固体分散物及其制备方法和应用”,以塞来昔布和聚乙二醇制成固体分散物。中国专利201210124986.4)“一种含塞来昔布的固体分散物及其制备方法”;中国专利201210362698)“一种塞来昔布固体分散体及其制备方法和应用”,以泊洛沙姆188为载体,采用熔融法、溶剂法制备塞来昔布固体分散体。
发明内容
本发明提供了一种含塞来昔布包合物制剂的药物,通过环糊精包合技术解决了溶出度低的问题,筛选了L-茶氨酸以及单硬脂酸甘油酯高了制剂的溶出的稳定性,提高临床药物的安全性。
具体而言本发明的技术方案是这样实现的:
一种含塞来昔布的包合物,所述的塞来昔布包合物包括以下成分:塞来昔布包合物、β-环糊精、单硬脂酸甘油酯以及L-茶氨酸。
进一步优选的,以重量用量比计算,所述的塞来昔布:β-环糊精=1:1.5-4.5。
进一步优选的,以重量用量比计算,所述的塞来昔布、单硬脂酸甘油酯以及L-茶氨酸的比例为:40:5-10:1-8;进一步优选为塞来昔布包合物包括以下成分:40:6:3。
本发明的第二个目的在于提供了所述的包合物的制备方法,具体如下:
(1)取适量的塞来昔布和单硬脂酸甘油酯加入到磷酸盐缓冲液中,搅拌、均
匀,得塞来昔布混合液备用;
(2)将β-环糊精、L-茶氨酸制备成饱和水溶液,备用;
(3)将步骤(1)的混合液加入到步骤(2)的环糊精溶液中,搅拌,过滤,滤液减压低温干燥,即得。
更进一步的,本发明所述的步骤(1)的磷酸盐缓冲液pH值为7.5-8.5,温度25-35℃。
本发明的第三个目的在于提供了一种塞来昔布制剂,所述的塞来昔布制剂含有塞来昔布包合物,所述的剂型可以是片剂、胶囊剂中的任意一种。
本发明的第三个目的在于提供了本发明所述的制剂在治疗制备骨关节炎或风湿性关节炎或关节疼痛中的用途。
与现有技术相比,本发明的有益效果在于:
本发明通过环糊精的包合技术,并加入少量的L-茶氨酸,提高了塞来昔布包合物的包封率和载药量。通过优选了环糊精、L-茶氨酸以及塞来昔布的比例,提高药物的溶出度。在制剂中加入单硬脂酸甘油酯,尤其是单硬脂酸甘油酯,并控制塞来昔布与其的比例,显著提高了塞来昔布的稳定性。
附图说明
图1:不同促进剂剂对塞来昔布释放度的影响实验。
图2:不同促进剂剂对塞来昔布有关物质(总)的影响实验。
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1:含有塞来昔布包合物,所述的成分以及用量如下:
制备工艺:
(1)取2塞来昔布和单硬脂酸甘油酯加入的pH值为8.0碱性磷酸盐缓冲液中,温度控制在15℃,并搅拌、均匀,得塞来昔布混合液备用;
(2)将β-环糊精、L-茶氨酸混合制备成饱和水溶液,备用;
(3)将步骤(1)的混合液加入到步骤(2)的环糊精溶液中,搅拌,过滤,滤液减压低温干燥,即得。
经检测塞来昔布包合物81.3g,载药量31.31%,包封率91.83%。
实施例2:含有塞来昔布包合物,所述的成分以及用量如下:
制备工艺:碱性磷酸盐缓冲液的pH值为8.5,其他同实施例1。经检测塞来昔布包合物80.5g,载药量30.38%,包封率90.55%。
实施例3:含有塞来昔布包合物,所述的成分以及用量如下:
制备工艺:碱性磷酸盐缓冲液的pH值为7.5,其他同实施例1。
经检测塞来昔布包合物80.02g,载药量30.25%,包封率90.71%。
实施例4:含有塞来昔布的片剂制备(100片),用量如下:
制备方法:以适量的水作为湿润剂,将处方量的塞来昔布包合物、低取代羟丙纤维素、微晶纤维素过筛后加入硬脂酸镁混合,压片,将压片包衣/不包衣,即得。
实施例5:含有塞来昔布的片制备(100片),用量如下:
制备方法:采用干法制片,将配方量的塞来昔布包合物、预胶化淀粉、微晶纤维素过筛后加入硬脂酸镁混合,压片,将压片包衣/不包衣,即得。
实施例6:含有塞来昔布的片剂制备(100片),用量如下:
制备方法:以适量的水作为湿润剂,将处方量的塞来昔布包合物、预胶化淀粉、山梨醇过筛后加入硬脂酸镁混合,压片,将压片包衣/不包衣,即得。
实施例7:含有塞来昔布的片剂制备(100片),用量如下:
制备方法:以适量的水作为湿润剂,将处方量的塞来昔布包合物、低取代羟丙纤维素、微晶纤维素过筛后加入硬脂酸镁混合,压片,将压片包衣/不包衣,即得。
实施例8:含有塞来昔布的片剂制备(100片),用量如下:
制备方法:以适量的水作为湿润剂,将处方量的塞来昔布包合物、低预胶化淀粉、山梨醇、硬脂酸镁过筛后加入硬脂酸镁混合,压片,将压片包衣/不包衣,即得。
实施例9:塞来昔布包合物载药量与包合率的评价实验
塞来昔布包合物对协同剂的考察,做三次平行实验,制备塞来昔布包合物,测定包封率和载药量。具体见表2(加速实验在第6个月检测)。
表1不同种类的协同剂
种类 | |
A组 | L-茶氨酸 |
B组 | 聚乙二醇2000 |
C组 | L-精氨酸 |
D组 | 谷氨酸 |
E组 | / |
F组 | L-茶氨酸:乳糖(1:1) |
注:包合物的其他材料以及制备同实施例1。
由表2可以看出,材料选择L-茶氨酸且仅有L-茶氨酸,最终得到的塞来昔布包合物的载药量高,包封率高,重复性好。具体如下:
表2不同种类的协同剂对塞来昔布包封率和载药量的影响性试验
实施例10:不同促进剂对塞来昔布释放度、有关物质的影响实验
根据中国药典2020版二部附录稳定性试验指导原则要求,考察不同促进剂对塞来昔布片剂(制备工艺以及辅料含量同实施例6)通过片剂的释放度、有关物质进行验证。通过第0个月和6个月的加速试验再次检测释放度等进行验证,最终发现单硬脂酸甘油酯溶出效果显著优于其他类型的活性剂。测定方法以及加速实验条件如下:
溶出度的测定法:以含1%十二烷基硫酸钠的0.04mol/L磷酸三钠溶液(用磷酸或氢氧化钠试液调节pH12.0±0.1)1000ml为溶剂,转速为每分钟50转,在45min、时测定塞来昔布的溶出度。为了进一步验证试验的准确度,每一种促进剂制备的片剂选取5片,分别检测其溶出度。
有关物质检测条件:色谱条件为用苯基键合硅胶为填充剂(SUPELCOSIL LC-DP
250×4.6mm);以磷酸盐缓冲液(取磷酸二氢钾2.7g,加水1000ml溶解,用磷酸调节pH至3.0)-甲醇-乙腈(60:30:10)为流动相;柱温60℃;检测波长为215nm;流速为每分钟1.5ml。
加速试验:温度40±2℃,相对湿度75%±5%条件下放置。检测结果如图1。
长期试验:温度25±2℃,相对湿度60%±10%条件下放置,在试验期间的第0个月和24个月分别取样,进行检测有关物质。
实施例11:探究辅料对塞来昔布制剂稳定性实验
根据中国药典2020版二部附录稳定性试验指导原则要求,考察塞来昔布片剂(实施例4-8)在第0个月和加速实验之后第6个月时第5min、10min、15min、20min、30min、40min的溶出度,结果如表3和表4。
表3实施例4-8在第0个月溶出度(%)
表4实施例4-8在第6个月溶出度(%)
Claims (7)
1.一种含塞来昔布的包合物,其特征在于,所述的包合物包括以下成分:塞来昔布、β-环糊精、单硬脂酸甘油酯以及L-茶氨酸,所述的包合物制备方法如下:
(1)取适量的塞来昔布和单硬脂酸甘油酯加入磷酸盐缓冲液中,搅拌、均匀,得塞来昔布混合液备用;
(2)将β-环糊精、L-茶氨酸制备成饱和水溶液,备用;
(3)将步骤(1)的混合液加入到步骤(2)的环糊精溶液中,搅拌,过滤,滤液减压低温干燥,即得;
其中,以重量用量比计算,所述的塞来昔布、单硬脂酸甘油酯以及L-茶氨酸的比例为:40:5-10:2-8;以重量用量比计算,所述塞来昔布:β-环糊精比例为:
1:1.5-4.5。
2.根据权利要求1所述的包合物,其特征在于,以重量用量比计算,所述的塞来昔布、单硬脂酸甘油酯以及L-茶氨酸的比例为40:6:3。
3.根据权利要求1所述的包合物,其特征在于,步骤(1)所述的磷酸盐缓冲液pH值为7.5-8.5,温度25-35℃。
4.一种含塞来昔布包合物的制剂,其特征在于,所述的塞来昔布制剂含有权利要求1-3中任一项所述的包合物。
5.根据权利要求4所述的制剂,其特征在于,所述的剂型为片剂、胶囊剂、颗粒剂等药学上可接受的剂型。
6.根据权利要求4所述的片剂,其特征在于,以重量比计算,所述的片剂含有以下成分:
片剂的制备工艺为:采用干法制片,将配方量的塞来昔布包合物、低取代羟丙纤维素、微晶纤维素过筛后加入硬脂酸镁混合,压片,将压片包衣/不包衣,即得。
7.一种权利要求4-6任一所述的制剂在治疗制备骨关节炎或风湿性关节炎或关节疼痛药物中的用途。
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