CN117815195A - 一种jak抑制剂组合物及其制备工艺 - Google Patents
一种jak抑制剂组合物及其制备工艺 Download PDFInfo
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- CN117815195A CN117815195A CN202311829549.7A CN202311829549A CN117815195A CN 117815195 A CN117815195 A CN 117815195A CN 202311829549 A CN202311829549 A CN 202311829549A CN 117815195 A CN117815195 A CN 117815195A
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- jak inhibitor
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Abstract
本发明公开了一种JAK抑制剂组合物及其制备工艺,包括:S1、制备第一种JAK抑制剂的含药缓释微丸;S2、制备第二种JAK抑制剂的含药颗粒;S3、将含药缓释微丸与含药颗粒混合,经压片或胶囊填充,得到JAK抑制剂组合物。本发明所述JAK抑制剂组合物为两种或两种以上的JAK抑制剂组成的复方甚至多方制剂,通过处方以及工艺的配合实现了根据临床需要,设计不同药物具有不同的释放速度,既能够迅速发挥药效,快速减轻症状,又能够缓慢释放以持续发挥药效,提高药物在体内的起效时间,减少症状的反复。
Description
技术领域
本发明属于药物制剂领域,尤其涉及一种JAK抑制剂组合物及其制备工艺。
背景技术
Janus激酶(JAK)是一种非受体型酪氨酸蛋白激酶,主要底物是信号转导和转录激活子(STAT)。JAK-STAT参与众多细胞因子的受体后信号转导,在炎症反应、免疫系统发育、造血等过程中发挥关键作用。相比于以往针对单细胞因子的抑制性治疗,JAK抑制剂为多细胞因子介导的疾病的临床治疗提供一种新的选择。
第一代JAK抑制剂的代表药物,如托法替尼、巴瑞替尼、鲁索替尼,已经成功应用于类风湿性关节炎(RA)、溃疡性结肠炎(UC)等自身免疫性疾病以及部分骨髓增生性肿瘤的治疗。JAK抑制剂的不良反应主要在于感染、血液系统不良反应、肿瘤风险增加和胃肠道不良反应等。目前,越来越多的JAK抑制剂不断被开发用于治疗以RA为代表的自身免疫性疾病,新一代的JAK抑制剂在安全性和疗效方面可能具有更高潜力。研究发现,乌帕替尼相较于JAK2、JAK3和TYK2,对JAK1的抑制作用更为强大,针对2型炎症介质的靶向效应相对全面又高度特异,具有良好的治疗效果和不错的安全性。此外,也是唯一针对青少年及成人中重度特应性皮炎(AD)的口服靶向药物。
目前上市的JAK抑制剂均为单方,采用单一的药物释放控制策略,一般只会产生单一的释放效果,对于需要多种释放要求的药物,则需采用更多的控制策略,已上市该类药品面对多症状且较重的患者存在一定的治疗缺陷。如果采用复方就需要考虑处方组成、制备工艺与药物的释放策略匹配度,由于不同的JAK抑制剂在作用机理、抑制强弱等方面存在差异,因此,存在起效时间、持续时间以及毒副作用方面的差异,开发复方JAK抑制剂具有较高的难度。
发明内容
基于上述问题,本发明提供了一种用于口服的长效的JAK抑制剂组合物的制备工艺,使得不同的活性成分具有不同的药物释放,从而达到临床上的协同作用,提升药物治疗的效果。
本发明具体方案如下:
本发明目的之一在于,提供了一种JAK抑制剂组合物的制备工艺,包括:S1、制备第一种JAK抑制剂的含药缓释微丸;S2、制备第二种JAK抑制剂的含药颗粒;S3、将含药缓释微丸与含药颗粒混合,经压片或胶囊填充,得到JAK抑制剂组合物。
优选地,第一种JAK抑制剂和第二种JAK抑制剂分别独立的选自乌帕替尼、托法替尼、巴瑞替尼、鲁索替尼中至少一种。
本发明所述工艺得到的JAK抑制剂组合物剂型为片剂或胶囊剂,分别通过压片和胶囊填充得到。其中,JAK抑制剂组合物片剂采用创新的微丸压片的工艺,将两种或两种以上具有不同的释放需求的JAK抑制剂压制在同一片剂中,减少了工艺步骤和时间,提高了生产效率;在此基础上,可以通过控制多种组合物的不同比例生产出不同规格的产品,具有良好的扩展性。
本发明对于含药缓释微丸和含药颗粒的混合比例不作具体限定,可以根据产品需求调整不同的混合比例,来实现活性物质剂量的调整。
优选地,S1中,以第一种JAK抑制剂为药物成分,通过在酒石酸丸芯表面进行丸芯上药,得到载药微丸;再进行缓释包衣得到含药缓释微丸。
对于JAK抑制剂组合物的片剂剂型,需要对含药缓释微丸进行压片处理,其难点在于,如何保证微丸在压片时不被破坏,能够保持表面的完整性,以实现缓释。针对这一问题,本发明选择酒石酸作为微丸丸芯,所述酒石酸丸芯能够在提供良好的支撑性和表面刚性,满足工艺要求的强度,提升制剂的物理稳定性。同时,酒石酸为酸性材料且与药物直接接触,可以提供酸性微环境,有利于提高第一JAK抑制剂的化学稳定性;此外,缓释制剂通常在进入人体之后,药物的溶解、释放和吸收均在小肠中进行,其环境pH为7.6左右,此pH不利于药物的溶解和稳定性,此时酒石酸溶解时可以降低微环境中的pH值,保障药物的顺利溶解和吸收。
本发明所述酒石酸丸芯,可以采用商业化的微丸丸芯,也可以自制得到。商业化的微丸丸芯包括但不限于,PHARMATRANS SANAQ AG或德国IPC Process-Center公司的对于酒石酸丸芯的制备方法不作具体限定,包括但不限于流化床法。具体制备方法包括:(1)将酒石酸和粘合剂、水混合,搅拌,配制固含量为8-15%的酒石酸混悬溶液;(2)将酒石酸和粘合剂、水混合,搅拌,配制固含量为1.5%-5.0%的酒石酸溶液;(3)利用流化床的顶喷功能,将酒石酸混悬液在热风作用下喷入流化床中,干燥,得到固体微小颗粒;然后调整进风温度和风量,连续喷入酒石酸溶液,干燥、固化,即得酒石酸丸芯。制备过程中,通过控制流化床参数、喷液参数和喷液量,得到符合要求的酒石酸丸芯。优选地,所述粘合剂选自羟丙甲纤维素、聚乙烯醇中任意一种。
优选地,S1中,酒石酸丸芯的D10≥50μm;D90≤120μm。
优选地,S1中,丸芯上药具体包括:(1)将第一种JAK抑制剂和粘合剂加入水中,溶解完全,得到含药的包衣液;(2)采用含药包衣液对酒石酸丸芯包衣,即得载药微丸;更优选地,丸芯上药增重为20-30%,上药率为85-95%。
优选地,酒石酸丸芯与第一种JAK抑制剂的重量比为5-10:1;粘合剂的加入量为第一种JAK抑制剂重量的5-25%。
优选地,S1中,粘合剂选自羟丙甲纤维素、聚乙烯醇中至少一种。
优选地,S1中,缓释包衣具体包括:(1)将缓释包衣材料和塑化剂加入到乙醇溶液中,得到缓释包衣液;(2)采用缓释包衣液对载药微丸进行包衣,即得含药缓释微丸;更优选地,缓释包衣增重为5-10%。
优选地,缓释包衣材料选自乙基纤维素、醋酸纤维素中至少一种;塑化剂选自枸橼酸三乙酯、聚乙二醇、聚维酮中至少一种。
优选地,所述丸芯上药以及缓释包衣的工序均在底喷型流化床中进行;更优选地,工艺参数为:进风温度50-60℃,风量为80-120m3/h,雾化压力为0.1~0.3MPa,蠕动泵转速8~20rpm。
优选地,S2中,含药颗粒的制备包括:将第二种JAK抑制剂和稀释剂混合后,加入粘合剂水溶液制粒,得到湿颗粒,经流化干燥,整粒,即得含药颗粒。
优选地,S2中,粘合剂选自聚维酮、羧甲纤维素钠中至少一种;稀释剂选自乳糖、微晶纤维素中至少一种。
优选地,S3具体包括:将第一种JAK抑制剂的含药缓释微丸和第二种JAK抑制剂的含药颗粒混合,然后加入填充剂、崩解剂、助流剂、润滑剂中至少一种,混合,经压片或胶囊填充,得到JAK抑制剂组合物。
当制备的JAK抑制剂组合物为片剂时,S3中加入填充剂、崩解剂、助流剂和润滑剂混合;当制备的JAK抑制剂组合物为胶囊剂时,S3中加入助流剂和润滑剂混合。
优选地,S3中,填充剂选自微晶纤维素、羟丙甲纤维素中至少一种;崩解剂选自交联聚维酮、羧甲基淀粉钠中至少一种;助流剂选自胶态二氧化硅;润滑剂选自硬脂酸镁、硬脂富马酸钠中至少一种。
针对上面提到的,如何保证微丸在压片时不被破坏,能够保持表面的完整性,以实现缓释这一难题,本发明进一步在压片时选择特定的辅料,以减少片剂崩解时对微丸表面产生的应力,使缓释微丸依旧保持良好的表面完整性,阻止介质进入微丸内部,防止药物快速释放。此外,具有良好可压性的外加辅料能够有效填补微丸的孔隙,减小了其在压片过程中接受冲模应力后产生的形变,维持了微丸表面的完整性,保障了微丸不受到破坏。与此同时,选择所述崩解剂,能让成品制剂在体内外快速崩解,从而使得第二种JAK抑制剂更快速和充分地与介质接触,加快药物的溶解释放。
本发明目的之二,在于提供了一种JAK抑制剂组合物,采用以上任一项方法制备得到。
本发明有益效果为:
本发明所述JAK抑制剂组合物为两种或两种以上的JAK抑制剂组成的复方甚至多方制剂,通过处方以及工艺的配合实现了根据临床需要,设计不同药物具有不同的释放速度,既能够迅速发挥药效,快速减轻症状,又能够缓慢释放以持续发挥药效,提高药物在体内的起效时间,减少症状的反复。
附图说明
图1为各实施例和对比例中乌帕替尼的溶出曲线;
图2为各实施例和对比例中托法替尼的溶出曲线;
图3为各实施例和对比例中巴瑞替尼的溶出曲线;
具体实施方式
下面,通过具体实施例对本发明的技术方案进行详细说明,但是应该明确提出这些实施例用于举例说明,但是不解释为限制本发明的范围。
以下实施例采用的酒石酸丸芯均为自制得到,具体方法如下:(1)将5份粘合剂羟丙甲纤维素,在搅拌桨的作用下,投入180份纯化水中,溶解完全后,再投入15份酒石酸,配制成固含量为10%(w/w)的酒石酸混悬溶液;(2)将5份粘合剂羟丙甲纤维素,在搅拌桨的作用下,投入485份纯化水中,溶解完全后,再投入10份酒石酸,配制成固含量为3%(w/w)浓度的酒石酸溶液;(3)设置流化床的参数为进风温度为60℃,风量为80m3/h,先将酒石酸混悬液在热风作用下喷入流化床中,干燥,得到均匀的粉末状(细小颗粒状)物料;然后调整流化床的参数为进风温度为60℃,风量为110m3/h,连续喷入酒石酸溶液,得到大小均一、圆整度好的酒石酸丸芯;最后在流化床中继续干燥固化30min,使水分降低至0.5%以下。对得到的酒石酸丸芯进行表征,指标如下
实施例1
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸
丸芯上药:(1)先将5份羟丙甲纤维素和2份酒石酸搅拌溶解于93份纯化水中;然后加入20份乌帕替尼,搅拌至溶解完全,得到含药包衣液;(2)将100份酒石酸丸芯投入底喷的流化床中,设置工艺参数为,进风温度为50℃,风量为90m3/h,调节喷枪参数为雾化压力0.2MPa,蠕动泵转速10rpm;启动设备,将含药包衣液均匀喷涂至酒石酸丸芯上,喷液结束后,继续在此条件下干燥20min,得到载药微丸;经检测,酒石酸丸芯上药增重为24%,上药率为90%;
缓释包衣:(1)将10份乙基纤维素和1份枸橼酸三乙酯,搅拌溶解于89份95%乙醇溶液中,溶解完全后为无色透明澄清的缓释包衣液;(2)将124份载药微丸投入底喷的流化床中,设置工艺参数为,进风温度为50℃,风量为100m3/h,喷枪参数为雾化压力0.2MPa,蠕动泵转速15rpm,启动设备;将缓释包衣液均匀喷涂至载药微丸上,喷液结束后,继续在此条件下干燥30min,得到含药缓释微丸;经检测,缓释包衣的增重为8%;
S2、巴瑞替尼的含药颗粒
(1)将2份巴瑞替尼与48份乳糖投入高剪切湿法制粒机中,设置搅拌转速150rpm和剪切转速1000rpm,混合5min,然后在搅拌转速200rpm和剪切转速1200rpm下喷入5份10%聚维酮溶液,制成湿颗粒;(2)将上述制得的湿颗粒全部投入流化床中,设置进风温度为60℃,风量为100m3/h,将水分干燥至1%~3%;(3)将干燥后的颗粒全部投入装有1.0mm孔径筛网的锥式整粒机中整粒,得到含药颗粒;
S3、JAK抑制剂组合物
将100份上述乌帕替尼含药缓释微丸与25份巴瑞替尼含药颗粒投入三维混合机中,混合10min,然后加入12份微晶纤维素、2份交联聚维酮、0.5份胶态二氧化硅和0.5份硬脂酸镁进行混合,最后压片(片重140mg,硬度40~60N),得到JAK抑制剂组合物(规格为乌帕替尼15mg和巴瑞替尼1mg)。
对本实施例制得的乌帕替尼的含药缓释微丸进行表征,指标如下:
实施例2
一种JAK抑制剂组合物的制备工艺,包括:
S1、托法替尼的含药缓释微丸
丸芯上药:(1)先将5份聚乙烯醇搅拌溶解于95份纯化水中;然后加入20份枸橼酸托法替尼,搅拌至溶解完全,得到含药包衣液;(2)将100份酒石酸丸芯投入底喷的流化床中,设置流化床的参数为进风温度为60℃,风量为120m3/h,调节喷枪参数为雾化压力0.3MPa,蠕动泵转速15rpm;启动设备,将含药包衣液均匀喷涂至酒石酸丸芯上,喷液结束后,继续在此条件下干燥20min,得到载药微丸;经检测,酒石酸丸芯的增重为23%,上药率为90%;
缓释包衣:(1)将10份乙基纤维素和1份枸橼酸三乙酯,搅拌溶解于89份80%乙醇溶液中,溶解完全后为无色透明澄清溶液的缓释包衣液;(2)将122份载药微丸投入底喷的流化床中,设置工艺参数为,进风温度为60℃,风量为120m3/h,调节喷枪参数雾化压力0.15MPa,蠕动泵转速20rpm,启动设备;将缓释包衣液均匀喷涂至含药微丸上,喷液结束后,继续在此条件下干燥30min,得到含药缓释微丸;经检测,缓释包衣增重为6.5%;
S2、巴瑞替尼的含药颗粒
(1)将2份巴瑞替尼与48份微晶纤维素投入高剪切湿法制粒机中,设置搅拌转速200rpm和剪切转速1500rpm,混合5min,然后在搅拌转速200rpm和剪切转速1800rpm下喷入5份2%羧甲纤维素钠溶液,制成湿颗粒;(2)将上述制得的湿颗粒全部投入流化床中,设置进风温度为60℃,风量为100m3/h,将水分干燥至1%~3%;(3)将干燥后的颗粒全部投入装有0.8mm孔径筛网的锥式整粒机中整粒,得到含药颗粒;
S3、JAK抑制剂组合物
将71.5份上述托法替尼含药缓释微丸与25份巴瑞替尼含药颗粒投入三维混合机中,混合10min,然后加入14.5份微晶纤维素、3份交联聚维酮、0.5份胶态二氧化硅和0.5份硬脂酸镁进行混合,最后压片(片重115mg,硬度30~50N),得到JAK抑制剂组合物(规格为托法替尼11mg和巴瑞替尼1mg)。
对本实施例制得的乌帕替尼的含药缓释微丸进行表征,指标如下:
实施例3
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸,与实施例1相同。
S2、托法替尼的含药颗粒
(1)将10份托法替尼与40份微晶纤维素投入高剪切湿法制粒机中,设置搅拌转速100rpm和剪切转速1000rpm,混合5min,然后在搅拌转速200rpm和剪切转速1500rpm下喷入5份10%聚维酮溶液,制成湿颗粒;(2)将上述制得的湿颗粒全部投入流化床中,设置进风温度为60℃,风量为100m3/h,将水分干燥至1%~3%;(3)将干燥后的颗粒全部投入装有0.8mm孔径筛网的锥式整粒机中整粒,得到含药颗粒;
S3、JAK抑制剂组合物
将100份上述乌帕替尼含药缓释微丸与25份托法替尼含药颗粒投入三维混合机中,混合10min,然后加入11份微晶纤维素、3份交联聚维酮、0.5份胶态二氧化硅和0.5份硬脂酸镁进行混合,最后压片(片重140mg,硬度20~50N),得到JAK抑制剂组合物(规格为乌帕替尼15mg和托法替尼5mg)。
实施例4
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸,与实施例1相同;托法替尼的含药缓释微丸,与实施例2相同。
S2、巴瑞替尼的含药颗粒,与实施例2相同。
S3、JAK抑制剂组合物
将上述100份乌帕替尼含药缓释微丸、32.5份托法替尼含药缓释微丸和12.5份巴瑞替尼含药颗粒投入三维混合机中,混合15min,然后加入15份微晶纤维素、3份交联聚维酮、1份胶态二氧化硅和1份硬脂酸镁进行混合,最后压片(片重165mg,硬度40-60N),得到3种JAK抑制剂组合物(规格为乌帕替尼15mg、托法替尼5mg和巴瑞替尼0.5mg)。
实施例5
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸,与实施例1相同。
S2、托法替尼的含药颗粒,与实施例3相同。
S3、JAK抑制剂组合物
将100份上述乌帕替尼含药缓释微丸与25份托法替尼含药颗粒投入三维混合机中,混合10min,然后加入1.5份胶态二氧化硅和0.5份硬脂酸镁进行混合,最后填充至2#胶囊中(内容物重127mg),得到JAK抑制剂组合物(规格为乌帕替尼15mg和托法替尼5mg)。
对比例1
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸
丸芯上药:与实施例1相比,区别仅在于将酒石酸丸芯替换为微晶纤维素丸芯,其他均与实施例1相同,得到载药微丸;经检测,微晶纤维素丸芯上药增重为17%,上药率为85%;
缓释包衣:与实施例1区别仅在于,替换为本对比例所述的载药微丸;其他工艺参数均与实施例1相同,得到含药缓释微丸。
S2、巴瑞替尼的含药颗粒,与实施例1相同;
S3、JAK抑制剂组合物
将100份上述乌帕替尼含药缓释微丸与25份巴瑞替尼含药颗粒投入三维混合机中,混合10min,然后加入12份微晶纤维素、2份交联聚维酮、0.5份胶态二氧化硅和0.5份硬脂酸镁进行混合,最后压片(片重140mg,硬度35~60N),得到JAK抑制剂组合物(规格为乌帕替尼15mg和巴瑞替尼1mg)。
对本对比例制得的含药缓释微丸进行表征,指标如下
本对比例与实施例1得到的含药缓释微丸指标对比,可以看出,在将丸芯由酒石酸丸芯更换为微晶纤维素丸芯后,在相同的制备处方和工艺下,所制得的含药缓释微丸粉体学指标有所变化。其中,密度有所下降,在压片时硬度便有所下降;此外含药缓释微丸的脆碎度有所下降,相同的压片压力下可能会造成部分微丸表面破碎,就导致了乌帕替尼在pH6.8磷酸盐缓冲液中存在一定的突释现象,不利于保持药物的缓慢释放特性。
对比例2
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸
丸芯上药:与实施例1相比,区别仅在于将酒石酸丸芯替换为蔗糖丸芯,其他均与实施例1相同,得到载药微丸;经检测,蔗糖丸芯上药增重为16%,上药率为80%;
缓释包衣:与实施例1区别仅在于,替换为本对比例所述的载药微丸;其他工艺参数均与实施例1相同,得到含药缓释微丸。
S2、巴瑞替尼的含药颗粒,与实施例1相同;
S3、JAK抑制剂组合物
将100份上述乌帕替尼含药缓释微丸与25份巴瑞替尼含药颗粒投入三维混合机中,混合10min,然后加入12份微晶纤维素、2份交联聚维酮、0.5份胶态二氧化硅和0.5份硬脂酸镁进行混合,最后压片(片重140mg,硬度30~45N),得到JAK抑制剂组合物(规格为乌帕替尼15mg和巴瑞替尼1mg)。
对本对比例制得的含药缓释微丸进行表征,指标如下
本对比例与实施例1得到的含药缓释微丸指标对比,可以看出,在将丸芯由酒石酸更换为蔗糖丸芯后,在相同的制备处方和工艺下,所制得的含药缓释微丸粉体学指标略微变化,含药缓释微丸的脆碎度也有所下降,相同的压片压力下也可能会造成部分微丸表面破碎,就导致了乌帕替尼在pH6.8磷酸盐缓冲液中也存在一定的突释现象,不利于保持药物的缓慢释放特性。
此外,针对实施例1以及对比例1-2制备的乌帕替尼含药缓释微丸进行了稳定性(40℃,75%RH)考察,杂质总和的结果如下
考察时间 | 合格限度 | 0月 | 加速3月 | 加速6月 |
实施例1 | 0.8% | 0.12% | 0.23% | 0.32% |
对比例1 | 0.8% | 0.14% | 0.36% | 0.52% |
对比例2 | 0.8% | 0.15% | 0.31% | 0.49% |
可以看出,实施例1采用酒石酸丸芯所制备的含药缓释微丸稳定性最好,稳定性比较结果为:酒石酸丸芯≥蔗糖丸芯≥微晶纤维素丸芯。
对比例3
一种JAK抑制剂组合物的制备工艺,包括:
S1、乌帕替尼的含药缓释微丸,与实施例1相同。
S2、托法替尼的含药颗粒,与实施例3相同。
S3、JAK抑制剂组合物
将100份上述乌帕替尼含药缓释微丸与25份托法替尼含药颗粒投入三维混合机中,混合10min,然后加入11份羟丙甲纤维素、3份羧甲基淀粉钠、0.5份胶态二氧化硅和0.5份硬脂富马酸钠进行混合,最后压片(片重140mg,硬度30~55N),得到JAK抑制剂组合物(规格为乌帕替尼15mg和托法替尼1mg)。
与实施例3比较,更换填充剂、崩解剂和润滑剂之后,相同的片重下,硬度有所上升;在pH6.8磷酸盐缓冲液中乌帕替尼的溶出受到的影响较小,但托法替尼的溶出明显减慢,不利于药物的快速释放。
性能测试
对以上实施例和对比例中不同活性物质的释放速率进行测试,在相同的溶出条件(篮法、100rpm和900ml介质)下,得到的实施例和对比例的各活性成分的体外溶出数据以及溶出曲线如下:
(1)乌帕替尼在pH6.8磷酸盐缓冲液中的累积溶出量(%)如下表所示,溶出曲线如图1所示。
时间点/h | 1 | 2 | 4 | 6 | 8 | 10 | 12 |
实施例1 | 23.5 | 38.1 | 58.6 | 72.4 | 82.5 | 87.8 | 92.0 |
实施例3 | 24.0 | 38.6 | 59.2 | 73.5 | 84.7 | 89.6 | 94.2 |
实施例4 | 26.1 | 42.5 | 64.2 | 75.8 | 87.1 | 92.3 | 97.5 |
实施例5 | 22.0 | 36.7 | 57.2 | 71.2 | 82.1 | 87.6 | 92.6 |
对比例1 | 35.8 | 51.2 | 72.8 | 84.6 | 92.3 | 96.4 | 99.8 |
对比例2 | 32.3 | 48.2 | 68.5 | 80.1 | 89.5 | 93.8 | 98.6 |
对比例3 | 21.8 | 36.0 | 56.8 | 70.3 | 82.2 | 87.5 | 93.6 |
可以看出,采用不同微丸丸芯制备的乌帕替尼缓释微丸,在相同的溶出条件下,表现出了不同的释放速度,其中,实施例1和实施例3~5缓慢释放效果最佳,表明在相同的缓释包衣条件下所采用的酒石酸微丸丸芯更能满足药物释放的要求。
(2)托法替尼在pH6.8磷酸盐缓冲液中的累积溶出量(%)如下表所示,溶出曲线如图2所示。
可以看出,托法替尼的溶出曲线数据表明,采用不同的组成和制备工艺,可以得到不同释放速率的托法替尼组合物,更方便灵活地根据需要进行选择。
(3)巴瑞替尼在pH6.8磷酸盐缓冲液中的累积溶出量(%)如下表所示,溶出曲线如图3所示。
时间点/min | 5 | 10 | 15 | 30 | 45 | 60 |
实施例1 | 38.4 | 55.7 | 73.4 | 86.2 | 98.5 | 99.0 |
实施例2 | 36.0 | 50.3 | 69.6 | 85.1 | 98.0 | 99.2 |
实施例4 | 46.7 | 68.9 | 88.2 | 96.4 | 99.5 | 99.8 |
对比例1 | 38.8 | 56.1 | 73.6 | 86.9 | 99.1 | 99.9 |
对比例2 | 39.6 | 57.5 | 75.2 | 88.3 | 98.8 | 99.7 |
可以看出,采用相似工艺制备的不同剂量的样品,巴瑞替尼的释放表现出了一定差异,这与其剂量成一定程度的线性关系,可以利用这个特点,在合适的剂量和组合物比例下按需要进行药物的设计和制造。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种JAK抑制剂组合物的制备工艺,其特征在于,包括:S1、制备第一种JAK抑制剂的含药缓释微丸;S2、制备第二种JAK抑制剂的含药颗粒;S3、将含药缓释微丸与含药颗粒混合,经压片或胶囊填充,得到JAK抑制剂组合物。
2.根据权利要求1所述的JAK抑制剂组合物的制备工艺,其特征在于,第一种JAK抑制剂和第二种JAK抑制剂分别独立的选自乌帕替尼、托法替尼、巴瑞替尼、鲁索替尼中至少一种。
3.根据权利要求1或2所述的JAK抑制剂组合物的制备工艺,其特征在于,S1中,以第一种JAK抑制剂为药物成分,通过在酒石酸丸芯表面进行丸芯上药,得到载药微丸;再进行缓释包衣得到含药缓释微丸;优选地,酒石酸丸芯的D10≥50μm,D90≤120μm。
4.根据权利要求3所述的JAK抑制剂组合物的制备工艺,其特征在于,S1中,丸芯上药具体包括:(1)将第一种JAK抑制剂和粘合剂加入水中,溶解完全,得到含药的包衣液;(2)采用含药包衣液对酒石酸丸芯包衣,即得载药微丸;优选地,丸芯上药增重为20-30%,上药率为85-95%。
5.根据权利要求4所述的JAK抑制剂组合物的制备工艺,其特征在于,酒石酸丸芯与第一种JAK抑制剂的重量比为5-10:1;粘合剂的加入量为第一种JAK抑制剂重量的5-25%。
6.根据权利要求3-5任一项所述的JAK抑制剂组合物的制备工艺,其特征在于,S1中,缓释包衣具体包括:(1)将缓释包衣材料和塑化剂加入到乙醇溶液中,得到缓释包衣液;(2)采用缓释包衣液对载药微丸进行包衣,即得含药缓释微丸;优选地,缓释包衣增重为5-10%。
7.根据权利要求1-6任一项所述的JAK抑制剂组合物的制备工艺,其特征在于,S2中,含药颗粒的制备包括:将第二种JAK抑制剂和稀释剂混合后,加入粘合剂水溶液制粒,得到湿颗粒,经流化干燥,整粒,即得含药颗粒。
8.根据权利要求7所述的JAK抑制剂组合物的制备工艺,其特征在于,S2中,粘合剂选自聚维酮、羧甲纤维素钠中至少一种;稀释剂选自乳糖、微晶纤维素中至少一种。
9.根据权利要求1-8任一项所述的JAK抑制剂组合物的制备工艺,其特征在于,S3具体包括:将第一JAK抑制剂的含药缓释微丸和第二JAK抑制剂的含药颗粒混合,然后加入填充剂、崩解剂、助流剂、润滑剂中至少一种混合,经压片或胶囊填充,得到JAK抑制剂组合物;优选地,S3中,填充剂选自微晶纤维素、羟丙甲纤维素中至少一种;崩解剂选自交联聚维酮、羧甲基淀粉钠中至少一种;助流剂选自胶态二氧化硅;润滑剂选自硬脂酸镁、硬脂富马酸钠中至少一种。
10.一种JAK抑制剂组合物,其特征在于,采用权利要求1-9任一项方法制备得到。
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