CN116212036A - 一种阿糖胞苷缬氨酸酯盐酸盐的缓释制剂及其制备方法 - Google Patents
一种阿糖胞苷缬氨酸酯盐酸盐的缓释制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种阿糖胞苷缬氨酸酯的缓释制剂及其制备方法。所述的阿糖胞苷酯缓释制剂由阿糖胞苷酯、填充剂、稳定剂、缓释材料、润滑剂组成,该缓释制剂在体内延缓了药物的释放,使患者的依从性增强。
Description
技术领域
本发明涉及一种药物缓释制剂及其制备方法,特别是涉及一种阿糖胞苷酯的缓释制剂及其制备方法。
背景技术
阿糖胞苷化学名称为1-β-D-阿拉伯呋喃糖基-4-氨基-2(1H)-胞嘧啶酮。阿糖胞苷在体内可转化成有活性的三磷酸阿糖胞苷,三磷酸阿糖胞苷通过抑制DNA多聚酶及少量渗入DNA,从而阻止DNA的合成,抑制细胞的生长。阿糖胞苷是临床用于治疗急性骨髓性白血病、急性淋巴性白血病和淋巴瘤最有效的药物之一。阿糖胞苷还具有抗病毒作用,并被用来治疗各种疱疹病毒的感染。在神经系统的研究中,阿糖胞苷被用于控制神经胶质细胞的增殖。
目前,阿糖胞苷需要注射给药,静脉给药存在一些缺点:药物对皮肤、皮下组织的刺激性强,若漏出静脉外,可引起静脉炎和周围组织坏死;异物分子颗粒或空气注入引起栓塞,药物污染易引起感染;药物快速直接进入血液,易发生各种副反应如过敏、中毒等;速度过快使循环超载,易出现急性心衰、肺水肿等危重症。口服给药能够提高病人的顺应性和降低用药成本,方便病人使用,因此口服是较为受欢迎的给药方式。
但阿糖胞苷分子极性很大,导致小肠的膜通透性差,易被胃肠道粘膜和肝中胞嘧啶核苷脱氨酶脱氨而失活,导致阿糖胞苷的口服生物利用度很低。能否成功制备含有阿糖胞苷的口服制剂,既能提高它在体内的生物利用度,又能提高病人的顺从性,而且降低制备、包装和运输成本,这已成为亟待解决的问题。
专利CN 101250209 B通过对阿糖胞苷的自由羟基进行修饰,得到阿糖胞苷的前药,即阿糖胞苷5’-0-氨基酸酯。与阿糖胞苷相比,这类前药的膜通透性有了较大的提高,口服后大鼠体内阿糖胞苷的绝对生物利用度由20.9%提高到61.2%。但目前还没有关于该类前药口服制剂的报道。
专利CN105288635A提供一种口服药用组合物,该组合物以阿糖胞苷5’-0-氨基酸酯或其盐为活性成分,按《中国药典》2010年版二部附录XC第二法溶出度测定法,以水900ml为溶出介质,转速为每分钟50转,15分钟内该组合物活性成分的溶出度大于或等于80%,是速释处方,同时口服后,在体内达峰时间为0.6-1.08小时,时间较短,需要一天多次服药。如果口服制剂,一天需要给药多次,患者的依从性依然不佳,所以急需开发一种新的缓释制剂,延长药物体内的释放时间,增加患者的依从性。
发明内容
针对上述现有技术中存在的空白,本发明的发明人们进行了深入研究。为减少给药次数、延长药物释放,减少不良反应的发生,拟开发阿糖胞苷缓缓释制剂,发明人公开了一种阿糖胞苷缓释制剂及其制备方法。
所述的阿糖胞苷缓释制剂由阿糖胞苷酯、填充剂、稳定剂、缓释材料、润滑剂组成,发明进一步限定了缓释材料羟丙甲纤维素K100M和卡波姆71G,处方中需要两种不同的缓释材料才能将主药成分进行缓释,而两种缓释材料的加入,才能使药物在体内达到缓慢释放的目的;
进一步地,缓释材料羟丙甲纤维素K100M和卡波姆71G两种材料组成比例进行了限定。羟丙甲纤维素K100M在处方中的比例为20%至30%之间,卡波姆71G用量在处方中的比例占比为5%至20%。
进一步地,缓释制剂中需要加入富马酸作为稳定剂。
进一步地,代表性的缓释处方组成为阿糖胞苷5′-O-L-缬氨酸酯盐酸盐为243份,微晶纤维素85份,羟丙甲纤维素K100M为121份,卡波姆71G为121份,富马酸为30份,硬脂酸镁为6份。
进一步地,缓释制剂的制备方法,包括以下步骤:
1)阿糖胞苷5′-O-L-缬氨酸酯盐酸盐与微晶纤维素、缓释材料羟丙甲纤维素K100M混合均匀作为底物,以乙醇水溶液做粘合剂采用流化床喷浆制粒,喷浆完毕后进行干燥,整粒;
2)取制得的含药缓释颗粒与富马酸、卡波姆混合均匀,再加入润滑剂混合均匀;
3)将所制得的总混颗粒压片。
发明效果
本发明所述的阿糖胞苷缓释制剂,具有理想的释药特性,且制备工艺简单、高效。
附图说明
图1实施例1-5释放/溶出曲线
图2实施例3与实施例5在人体内的血药浓度
具体实施方式
实施例1-4处方组成
制备工艺:
1)将盐酸阿糖胞苷缬氨酸酯、微晶纤维素和羟丙甲纤维素K100M混合均匀作为底物,加入流化床中,以50%乙醇水溶液做粘合剂采用流化床喷浆制粒,喷浆完毕后进行干燥,控制水分≤3%。
2)取上步制得的含药缓释颗粒与富马酸、卡波姆加入混合机中混合5~10mi n混合均匀,再加入硬脂酸镁混合3~5mi n。
3)将所制得的总混颗粒压片,制得缓释制剂。
实施例5
本发明采用速释的阿糖胞苷酯片作为对照例,处方中不加入缓释材料按下列处方分别称量各辅料:
对照例制备方法:
将PVPK30溶于水配制为溶液作为粘合剂,将盐酸阿糖胞苷缬氨酸酯、微晶纤维素、淀粉、甘露醇、低取代羟丙纤维素称量,在高效湿法制粒机中混合均匀,加入PVP水溶液进行制粒,湿颗粒干燥后整粒,加入硬脂酸镁混合得总混物,然后压片得到速释制剂。
实施例1-4及实施例5体外释放度实验
根据中国药典2020年版二部附录溶出度与释放度测定法第二法(桨法),采用900ml的pH1.0盐酸盐缓冲液的释放介质,转速:50转/分钟,温度为37℃,依法操作,取样,用紫外-可见分光光度法进行检测,检测波长272nm,计算释放度。
实施例1~4体外释放度实验结果如表所示:
实施例5溶出度结果如下:
时间/min | 速释制剂溶出度% |
5 | 31.5 |
10 | 55.2 |
15 | 83.5 |
30 | 105.5 |
由此可见,不加入缓释材料的速释片在30分钟内全部溶出,与文献报道相近;而缓释制剂持续溶出约12小时。
同时将本发明实施例3取得的片在人体内进行实验,同时对照注射给药,本发明的缓释制剂与注射给药在体内达到同样的血药浓度,可以进一步地讲,本发明的缓释制剂取得了注射一样的效果。图2显示口服本品与注射达到了同样的体内血药浓度。
尽管参照本发明的实施例详细描述了本发明,但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。
Claims (5)
1.一种阿糖胞苷5′-O-L-缬氨酸酯盐酸盐的缓释制剂,其特征在于,由阿糖胞苷5′-O-L-缬氨酸酯盐酸盐、填充剂、缓释材料、稳定剂、润滑剂组成,其特征在于,缓释材料为羟丙甲纤维素K100M和卡波姆71G两种材料组成。
2.根据权利要求1所述的缓释制剂,其特征在于羟丙甲纤维素K100M在处方中的比例为20%至30%之间,卡波姆71G用量在处方中的比例占比为5%至20%。
3.根据权利要求2所述的缓释制剂,其特征在于,稳定剂是富马酸。
4.一种阿糖胞苷5′-O-L-缬氨酸酯盐酸盐的缓释制剂,其特征在于,阿糖胞苷5′-O-L-缬氨酸酯盐酸盐为243份,微晶纤维素85份,羟丙甲纤维素K100M为121份,卡波姆71G为121份,富马酸为30份,硬脂酸镁为6份。
5.根据权利要求1-4项中任一项的缓释制剂,其制备方法,包括以下步骤:
1)阿糖胞苷5′-O-L-缬氨酸酯盐酸盐与微晶纤维素、缓释材料羟丙甲纤维素K100M混合均匀作为底物,以乙醇溶液做粘合剂采用流化床喷浆制粒,喷浆完毕后进行干燥,整粒;
2)取制得的含药缓释颗粒与富马酸、卡波姆混合均匀,再加入润滑剂混合均匀;
3)将所制得的总混颗粒压片。
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