CN113332256A - 一种达比加群酯微丸组合胶囊及其制备方法 - Google Patents
一种达比加群酯微丸组合胶囊及其制备方法 Download PDFInfo
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- CN113332256A CN113332256A CN202110556935.8A CN202110556935A CN113332256A CN 113332256 A CN113332256 A CN 113332256A CN 202110556935 A CN202110556935 A CN 202110556935A CN 113332256 A CN113332256 A CN 113332256A
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Abstract
本发明公开了一种达比加群酯微丸组合胶囊及其制备方法,该胶囊包括含有活性成分为达比加群酯或其药学上可接受的盐或水合物的含药微丸,以及含有有机酸的有机酸微丸,所述含药微丸与所述有机酸微丸的质量比为1:1~5:1,其中,按质量分数计,所述活性物质占所述含药微丸质量的1%~90%,所述有机酸占所述有机酸微丸质量的50%~100%,所述含药微丸和/或所述有机酸微丸具有隔离层;通过顶喷、干燥、筛分后包衣隔离层的工艺制备而成,该胶囊释放良好,粒径均匀,药物稳定性高。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种达比加群酯微丸组合胶囊及其制备方法。
背景技术
达比加群酯(DabigatranEtexilate)是由德国勃林格殷格翰公司开发,于2008年4月在德国和英国上市,2010年10月获得FDA批准,2013年2月在中国获批,是一种新型的IIa因子直接凝血酶抑制剂,是达比加群的前体药物,用于预防非瓣膜性房颤患者的卒中和全身性栓塞。达比加群酯是继华法林之后首个上市的全新非肽类直接抗凝血药物,具有可口服、强效、无需特殊用药监测、药物相互作用少等特点。
根据已上市制剂说明书可知,本品活性成份为甲磺酸达比加群酯,化学名称为β-丙氨酸,N-[[2-[[[4-[[[(己氧基)羰基]氨基]亚氨基甲基]苯基]氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基]-N-2-嘧啶-,乙酯,甲磺酸盐。
甲磺酸达比加群酯是一种吸湿性淡黄色粉末,易溶于甲醇、乙醇,微溶于丙酮,几乎不溶于乙酸乙酯。固态时稳定,对光照辐射不敏感,对湿度敏感,因此需要密闭防潮保存,已减少药物分解而降低疗效。
达比加群酯是BCS II类药物,在水中溶解度较差,但膜通透性好。达比加群酯在水中的溶解度为1.8mg/mL,在pH>5的介质中几乎不溶,在酸性介质中溶解度大幅提高,但达比加群酯在酸性溶液中不稳定。达比加群酯口服用药后绝对生物利用度为3%~7%,血药浓度最快在口服0.5~2h达峰,半衰期14~17h。
WO 03/074056中公开了一种达比加群酯口服药物组合,该组合药物制剂是多层包衣微丸,从内到外依次是有机酸丸芯材料,隔离层,活性药物层,并将微丸填充于胶囊中。有机酸丸芯材料提供酸性环境,保证当胃液pH>5.0时,药物可以在有机酸的环境下溶解释放。同时,EMEA科学研究讨论发现,制得的微丸和将微丸填充在胶囊中,两者的生物利用度也不同,没有填充胶囊的微丸的生物利用度接近填充胶囊的两倍,药物不良反应增加。胶囊壳的存在使得药物释放延缓,而且相对平稳。但是胶囊制剂存在的问题是,胶囊壳厚度有所差异,胶囊壳溶解有快有慢,甚至胶囊壳在溶解过程中与微丸发生粘连,对患者疗效会有很大影响。
针对于胶囊制剂,具有很多优势,胶囊剂运输、贮存、携带、服用更方便,而且性状稳定、剂量准确、含量均匀。且国内胶囊厂家较多,各厂家生产的明胶空心胶囊尺寸、胶囊黏度和崩解时限等也存在各种差异,具有多种选择。
综合现有技术,为了提高达比加群酯的溶解速率,均在制剂中加入了有机酸为达比加群酯溶解提供了低pH的酸性环境,且将达比加群酯和有机酸制备在同一颗粒或微丸上。但达比加群酯在酸性环境中不稳定,如果在酸性环境中遇到水分,其稳定性更差。因此,在保证达比加群酯达到理想的溶出效果的前提下增强活性成分与有机酸的隔离效果,需要进一步改进。
发明内容
为了克服现有技术中存在的不足,本发明提供一种达比加群酯微丸组合胶囊及其制备方法,通过将活性成分和有机酸分别包含在不同的两个微丸中,使活性成分与有机酸隔离更充分、药物释放更均匀。并选用合适型号的明胶空心胶囊以及合适的外加辅料比例将微丸制成胶囊剂,从而制备得到具有目标释放行为的达比加群酯微丸组合胶囊,使得微丸组合胶囊具有合适的黏度和崩解时限,释放曲线也更加稳定。
本发明提供了一种达比加群酯微丸组合胶囊,其包括含有活性成分为达比加群酯或其药学上可接受的盐或水合物的含药微丸,以及含有有机酸的有机酸微丸,所述含药微丸与所述有机酸微丸的质量比为1:1~5:1,其中,按质量分数计,所述活性物质占所述含药微丸质量的1%~90%,所述有机酸占所述有机酸微丸质量的50%~100%;所述含药微丸和/或所述有机酸微丸具有隔离层,所述隔离层的隔离材料选自胃溶型薄膜包衣预混剂、欧巴代II和胃溶型的羟丙基甲基纤维素,所述隔离材料占所述含药微丸或所述有机酸微丸重量的1%~20%。
优选的,所述含药微丸和/或所述有机酸微丸中还含有粘合剂、抗粘剂、填充剂、崩解剂、润滑剂,所述粘合剂占所述胶囊质量的0.5~2%,所述抗粘剂占所述胶囊质量的1%~3%,所述填充剂占所述胶囊质量的20%~60%,所述崩解剂占所述胶囊质量的0~20%,所述润滑剂占所述胶囊质量的0.5~2.0%。
本发明提供一种达比加群酯微丸组合胶囊的制备方法,其包括以下步骤,(a)将活性物质、粘合剂和抗粘剂组成的混悬液体喷洒在空白丸芯的表面,同时球化得含药微丸,干燥后筛分;(b)将有机酸、粘合剂和抗粘剂组成的混悬液体喷洒在空白丸芯的表面,同时球化得有机酸微丸,干燥后筛分;(c)在含药微丸和/或有机酸微丸的表面喷涂隔离材料形成外隔离层,并进行干燥;(d)混合步骤(c)获得的含药微丸、有机酸微丸,加入填充剂、崩解剂进行混合均匀后,再加入润滑剂混合均匀;(e)灌装至明胶空心胶囊中,即可。
优选的,步骤(a)或步骤(b)中,所述球化,其送风频率为20~45HZ,雾化压力为0.1~0.3MPa,物料温度为20~35℃,进液流速为5~10g/min。
优选的,步骤(a)或步骤(b)中,所述干燥其温度为35℃~80℃,所述筛分的目标粒径为0.1~1.0mm。
优选的,步骤(c)中,所述喷涂隔离材料,其为先将隔离材料制成分散液再喷涂,制备分散液的分散剂选自乙醇、丙酮、异丙醇、正丙醇、乙酸乙酯。
优选的,步骤(e)中,所述明胶空心胶囊的胶囊型号选自0号、1号或2号。
优选的,步骤(e)中,所述明胶空心胶囊的黏度为60-80mm2/s,崩解时限为5-8min。
有益效果:本发明的有益效果如下,
1、本发明微丸药物组合物丸A和丸B中的丸芯粒径分布范围较窄,均匀性良好,且圆整度较高,接近为球形。在丸芯表面喷涂活性成分层或药用有机酸层后,仍然为球形或接近球形的小丸,这就方便后期隔离层可均匀的包裹在微球表面,且包裹后圆整度高,微球表面无卫星颗粒,均匀度和流动性良好,为后期与常用药用辅料的混合及胶囊填充打下了基础。
2、本发明药用组合物丸A和丸B所包裹的隔离材料,含量适中,有效提升了有机酸与活性成分的隔离效果;同时,本发明采用两种微球分别包裹隔离层,起到了双层隔离的效果,丸A和丸B为球形或近似球形,无卫星颗粒,有利于提高药用组合物的稳定性。
3、本发明制备的固体制剂采用适宜的药用辅料,含填充剂/稀释剂、崩解剂和润滑剂,物料流动性良好,既可以用于胶囊剂,也可以用于片剂的生产。
4、本发明制备的胶囊剂,明胶空心胶囊的厂家型号经过选型,明胶空心胶囊黏度适中,崩解良好,能够有效的崩解释放。
5、本发明制备的胶囊剂,通过包裹隔离材料使胶囊达到了多层隔离防护的作用,且产品释放良好,在不同pH溶液中能迅速崩解,同时,释放后的胶囊剂,逐步释放出两种独立的微丸,各自进一步崩解,有机酸丸(丸B)能够给活性成分丸(丸A)提供局部的酸性环境,使其药物能迅速溶解,且药物释放均匀,无突释现象,最终能与参比制剂在不同pH介质中(0.1M HCl、pH4.5、pH6.8及水)的溶出曲线相似因子f2值大于50。
附图说明
图1是本发明含药丸芯(丸A)断面结构示意图;
图2是本发明含有机酸丸芯(丸B)断面结构示意图;
图3是本发明含药丸芯(丸A)显微照片图;
图4是本发明含酸丸芯(丸B)放大照片图;
图5是实施例21-24和参比制剂在0.1M HCL体外溶出曲线对比;
图6是实施例21-24和参比制剂在pH4.5的醋酸缓冲盐中体外溶出曲线对比;
图7是实施例21-24和参比制剂在纯化水介质中体外溶出曲线对比;
图8是实施例21-24和参比制剂在pH6.8磷酸缓冲盐中体外溶出曲线对比。
具体实施方式
下面结合附图对本发明作更进一步的说明。结合图1和图2可以看出本发明含药微丸和有机酸微丸的结构。
实施例:处方及工艺
1、含药微丸的制备:
(1)含药微丸处方列表
(2)上述实施例1-5中丸A的制备方法如下:
(a)将聚乙烯吡咯烷酮、达比加群酯甲磺酸盐和滑石粉溶解或分散于异丙醇中,备用,其总体浓度约为5%;
(b)取处方比例的蔗糖丸芯至流化床制粒制丸包衣机内,在下列参数条件下逐渐将(a)中溶液顶喷至蔗糖丸芯外部直至得到合适的微丸;
设备参数:风机频率20~45HZ,雾化压力0.1~0.3MPa,物料温度20~35℃,进液流速5~10g/min;
(c)上药完成后,停止顶喷,将丸在40℃左右进行干燥,控制干燥失重小于3.0%;
(d)采用筛分法,选择粒径在0.1~1.0mm之间的微丸;
(e)将薄膜包衣预混剂(胃溶型)作为隔离材料分散于异丙醇中,其混悬液固含量约为10%;
(f)采用高效包衣机将(e)中所得混悬液喷涂在丸A表面,其物料温度控制在35~45℃之间;
(g)将喷涂完隔离层的微丸在40℃左右干燥后即得丸A。
2、含酸微丸的制备:
(1)含酸微丸处方列表
(2)上述实施例6-10中丸B的制备方法如下:
(a)将聚乙烯吡咯烷酮、酒石酸和滑石粉溶解或分散于50%乙醇-水溶液中,备用;
(b)取处方比例的蔗糖丸芯至流化床制粒制丸包衣机内,在下列参数条件下逐渐将(a)中溶液顶喷至蔗糖丸芯外部直至得到合适的微丸;
设备参数:风机频率20~45HZ,雾化压力0.1~0.3MPa,物料温度20~35℃,进液流速5~10g/min;
(c)上药完成后,停止顶喷,将丸在40℃左右进行干燥,控制干燥失重至3.0%;
(d)采用筛分法,选择粒径在0.1~1.0mm之间的微丸;
(e)将薄膜包衣预混剂(胃溶型)作为隔离材料分散于50%乙醇-水溶液中,其混悬液固含量约为10%;
(f)采用高效包衣机将(e)中所得混悬液喷涂在丸B表面,其物料温度控制在35~45℃之间;
(g)将喷涂完隔离层的微丸在40℃左右干燥后即得丸B。
3、丸A和丸B比例选择:
将实施例11-15所得丸A和丸B采用料斗混合机混合5min后备用,如选择实施例14为后续考察实施例;
4、常用辅料的选择
将实施例14作为后续考察实施例,将实施例16-20中的微晶纤维素PH101或微晶纤维素PH102、乳糖316、低取代羟丙基纤维素和微丸混合物采用混合料斗机混合10min后,再加入硬质酸镁混合5min后备用,如选择实施例18流动性较优实施例做为后续考察实施例;
5、胶囊型号的选择
序号 | 胶囊规格 | 黏度(mm<sup>2</sup>/s) | 崩解时限 | 胶囊厂家 |
实施例21 | 0 | 70 | 6min | 安徽黄山胶囊股份有限公司 |
实施例22 | 0 | 65 | 5min | 苏州胶囊有限公司 |
实施例23 | 0 | 73 | 7min | 青岛益青生物科技股份有限公司 |
实施例24 | 0 | 79 | 8min | 山西广生胶囊有限公司 |
将实施例18作为后续考察实施例,将其灌装成不同亚批的胶囊。
按照实施例21-24制备的不同亚批的达比加群酯微丸组合胶囊后,比较其在体外不同pH溶出介质中与参比制剂的溶出曲线,示例性的,将其中实施例21、实施例22、实施例23和实施例24制备的制剂在体外不同pH溶出介质中与参比制剂溶出度(12粒)比较结果如图,其相似因子f2均大于50,释放良好;实施例22溶出曲线与参比制剂拟合最优,原因为其黏度和崩解性能良好所致,故将实施例22作为最优实施例,其它实施例因黏度较大及崩解性差异导致前期释放较慢,有突释或释放不均现象。
本发明所述的达比加群酯的盐应该包括经典定义的盐、共晶或它们的混合形式,以及它们的多晶型、水合物等形式。药物学上可接受的酸包括:甲磺酸、苯磺酸、马来酸、柠檬酸、琥珀酸、富马酸、苯甲酸、乙酸、丙酸、酒石酸、葡萄糖酸、水杨酸、盐酸、硫酸、硝酸、磷酸等;优选为达比加群酯甲磺酸盐和/或苯磺酸盐。活性成分在丸A中以含药微丸的总重量计,所述活性物质的含量为1%~90%,更为优选的为30%~80%,特别优选的为40%~60%,此优选将有利于后期的活性物质含量控制。有机酸在丸B中用于制备的药用酸选自柠檬酸、酒石酸、富马酸、琥珀酸、谷氨酸、苹果酸、马来酸、葡萄糖酸、天冬氨酸等中的一种或多种;优选的酒石酸、富马酸、柠檬酸中的一种或多种;特别优选的酒石酸。进一步优选的,有机酸在丸B中以有机酸丸的总重量计,所述有机酸丸中有机酸的含量为50%~100%,优选70%~90%。此优选能够提供胶囊内微丸中药物初期的溶出时所需的适宜的微酸环境,加快胶囊壳的破损,提高前期胶囊中药物的溶出,保证制剂溶出行为的稳定性。
本发明所述的丸A和丸B中的空白丸芯材料选自微晶纤维素、甘露醇、淀粉、预胶化淀粉、二氧化硅、蔗糖、乳糖中的一种或多种;优选蔗糖、乳糖中的一种或多种,此优选能够提高球形微丸的制备效果及流行性,有利于后期胶囊的灌装工序,且作为可溶性丸芯能够从一定程度上提高药物的溶出度。丸A和丸B中粘合剂选自羟丙基纤维素、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、聚乙烯吡咯烷酮等中的一种或多种;优选聚乙烯吡咯烷酮、羟丙基纤维素中的一种或多种;优选的,所选粘合剂用量在丸A或丸B中的重量比例为0.5%~5%;进一步优选1%~3%。此优选能够提高球形微丸的制备效果,适宜的比例能够保证药物或有机酸在空白丸芯上的粘合效果,且能保证制剂溶出行为的稳定性。
本发明所述的药物组合物的制剂形式是胶囊剂,优选的,所述胶囊剂中含药微丸与有机酸微丸的重量比例为1:1~5:1,更优选的2:1~4:1。此优选能够保证制剂溶出行为的稳定性和质量稳定性。上述药物组合物中,丸A或丸B中的一个或两个带有隔离层,隔离材料选自胃溶型薄膜包衣预混剂、欧巴代II、胃溶型的羟丙甲纤维素中的一种或多种;优选胃溶型薄膜包衣预混剂,主要成分有羟丙甲纤维素、聚乙二醇和滑石粉。所选隔离材料用量在丸A和/或丸B中的重量比例为1%~20%;更优选5%~15%。此优选能够有效保证含药微丸和含酸微丸的隔离效果及制剂质量稳定性。
上述药物组合物中,丸A和丸B中的抗粘剂选自滑石粉、硬脂酸镁、微粉硅胶等中的一种或多种;优选滑石粉、硬质酸镁中的一种或多种;进一步优选的,所述抗粘剂用量在丸A和/或丸B中的重量比例为0%~8%,更优选的2%~6%。此优选能够保证制剂溶出行为的稳定性。
优选的,所述填充剂或稀释剂选自蔗糖、乳糖、微晶纤维素、甘露醇中的一种或多种;优选微晶纤维素、乳糖中的一种或多种;更优选的微晶纤维素PH101、微晶纤维素PH102、316速流乳糖、研磨乳糖中的一种或多种;进一步优选的,以含药微丸的总重量计,所述填充剂或稀释剂与组合微丸的重量比为0.25~5:1,例如0.25:1、0.5:1、1:1、1.5:1、2:1、2.5:1、3:1、4:1、5:1,优选1:1~2:1。此优选能够保证物料具有良好的流动性,有利于后期胶囊的灌装工序。
优选的,所述崩解剂选自交联聚维酮、羧甲基淀粉钠、低取代羟丙纤维素、交联羧甲基纤维素钠中的一种或多种;优选低取代羟丙纤维素、交联聚维酮中的一种或多种;更优选的低取代羟丙纤维素LH21、低取代羟丙纤维素LH22、交联聚维酮XL中的一种或多种;进一步优选的,以胶囊内容物重量计,所述崩解剂的含量为0%~30%,更优选的0%~20%。此优选能够在一定程度上提高药物的溶出度。
优选的,所述润滑剂与上述抗粘剂相同,选自滑石粉、硬脂酸镁、微粉硅胶等中的一种或多种;优选滑石粉、硬质酸镁中的一种或多种;进一步优选的,以胶囊内容物重量计,所述润滑剂的含量为0%~3%,更优选的0.5%~2%。此优选能够保证物料具有良好的流动性,有利于后期胶囊的灌装工序。
特别优选的,所述成品胶囊剂中,以内容物重量计,活性成分的含量为20%~40%,有机酸含量20%~40%,粘合剂含量为0.5~2%,抗粘剂含量1%~3%,隔离材料含量为5%~15%,填充剂含量为20%~60%,崩解剂含量为0~20%,润滑剂含量为0.5~2.0%。
进一步的,本发明提供了上述微丸药物组合物及胶囊剂的制备方法,其包括以下步骤:
(a)采用喷涂设备,例如湿法制粒锅或流化床,将活性物质、粘合剂和抗粘剂组成的混悬液体喷洒在空白丸芯的表面,同时搅拌或进风使其不断球化成含活性成分的丸A;
(b)采用喷涂设备,例如湿法制粒锅或流化床,将有机酸、粘合剂和抗粘剂组成的混悬液体喷洒在空白丸芯的表面,同时搅拌或进风使其不断球化成含药用有机酸的丸B;
(c)将丸A和丸B进行干燥;
(d)将丸A和丸B进行筛分,选取10-60目部分;
(e)采用包衣装置,例如高效包衣机,在丸A和/或丸B的表面喷涂隔离材料形成外隔离层,并进行干燥;
(f)将喷涂完隔离材料并干燥完成的丸A和/或丸B按一定比例混匀后,再与一定比例的填充剂/稀释剂、崩解剂进行混合均匀后,再加入一定比例润滑剂混合均匀,将总混颗粒灌装至合适的明胶空心胶囊中;
上述制备丸A部分过程中使用的分散剂选自无水溶剂,选自乙醇、丙酮、异丙醇、正丙醇、乙酸乙酯等中的一种或多种。优选丙酮或异丙醇,其分散剂在干燥过程中尽可能除去。
上述制备丸B部分过程中使用的分散剂选自10%~95%乙醇水溶液、10%~95%异丙醇水溶液、纯化水等中的一种或多种。优选10%~95%乙醇水溶液,其分散剂在干燥过程中尽可能除去。
上述制备过程步骤(e)中喷涂隔离材料丸A部分过程中使用的分散剂选自无水溶剂,选自乙醇、丙酮、异丙醇、正丙醇、乙酸乙酯等中的一种或多种。优选丙酮或异丙醇,其分散剂在干燥过程中尽可能除去;丸B部分过程使用的分散剂选自10%~95%乙醇水溶液、10%~95%异丙醇水溶液、纯化水等中的一种或多种。优选10%~95%乙醇水溶液或纯化水,其分散剂在干燥过程中尽可能除去。
上述制备过程步骤(a)中,丸A中的活性成分粒径分布控制为D90小于150μm,优选小于80μm,更优选小于50μm。上述制备过程步骤(b)中,丸B中药用有机酸粒径分布控制为D90小于200μm,优选小于150μm,更优选小于100μm。
上述制备过程步骤(a)和(b)中,其分散剂用量根据实际情况进行调整,后续干燥过程需将其除去,不影响产品质量。
上述制备过程中,干燥温度为35℃~80℃,优选40℃~70℃。上述制备过程(d)中,丸A和丸B直径为0.1~1.0毫米,优选的0.1~0.5毫米。上述制备过程(f)中,胶囊灌装设备为半自动或全自动硬胶囊充填机,胶囊型号可以是0号、1号或2号胶囊。
本发明改进了制备工艺,在微丸制备的基础上加入外加辅料进行胶囊灌装操作,并对外加辅料型号、种类及胶囊品种进行了选择,制得的明胶胶囊含量均匀、释放良好,产品稳定。
本发明属于药物制剂技术领域。本发明提供了一种达比加群酯微丸组合胶囊及其制备方法。本发明的达比加群酯药物组合物包含丸A和丸B:所述的丸A含活性成分与空白丸芯材料、粘合剂、抗粘剂和/或隔离材料;所述丸B含药用有机酸与空白丸芯材料、粘合剂、抗粘剂和/或隔离材料。将上述两种微丸按比例混合均匀后加入适量药学上常见的填充剂或稀释剂和/或崩解剂和/或润滑剂灌装制成合适装量的胶囊剂。该药物组合物制备工艺简单、重现性好,且具有较好的体外溶出度和稳定性。
以上所述仅是本发明的优选实施方式,应当指出:对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种达比加群酯微丸组合胶囊,其特征在于:包括含有活性成分为达比加群酯或其药学上可接受的盐或水合物的含药微丸,以及含有有机酸的有机酸微丸,所述含药微丸与所述有机酸微丸的质量比为1:1~5:1,其中,按质量分数计,所述活性物质占所述含药微丸质量的1%~90%,所述有机酸占所述有机酸微丸质量的50%~100%;
所述含药微丸和/或所述有机酸微丸具有隔离层,所述隔离层的隔离材料选自胃溶型薄膜包衣预混剂、欧巴代II和胃溶型的羟丙基甲基纤维素,所述隔离材料占所述含药微丸或所述有机酸微丸重量的1%~20%。
2.如权利要求1所述的达比加群酯微丸组合胶囊,其特征在于:所述含药微丸和/或所述有机酸微丸中还含有粘合剂、抗粘剂、填充剂、崩解剂、润滑剂,所述粘合剂占所述胶囊质量的0.5~2%,所述抗粘剂占所述胶囊质量的1%~3%,所述填充剂占所述胶囊质量的20%~60%,所述崩解剂占所述胶囊质量的0~20%,所述润滑剂占所述胶囊质量的0.5~2.0%。
3.权利要求1或2所述的达比加群酯微丸组合胶囊的制备方法,其特征在于:包括以下步骤,
(a)将活性物质、粘合剂和抗粘剂组成的混悬液体喷洒在空白丸芯的表面,同时球化得含药微丸,干燥后筛分;
(b)将有机酸、粘合剂和抗粘剂组成的混悬液体喷洒在空白丸芯的表面,同时球化得有机酸微丸,干燥后筛分;
(c)在含药微丸和/或有机酸微丸的表面喷涂隔离材料形成外隔离层,并进行干燥;
(d)混合步骤(c)获得的含药微丸、有机酸微丸,加入填充剂、崩解剂进行混合均匀后,再加入润滑剂混合均匀;
(e)灌装至明胶空心胶囊中,即可。
4.如权利要求3所述的达比加群酯微丸组合胶囊的制备方法,其特征在于:步骤(a)或步骤(b)中,所述球化,其送风频率为20~45HZ,雾化压力为0.1~0.3MPa,物料温度为20~35℃,进液流速为5~10g/min。
5.如权利要求3所述的达比加群酯微丸组合胶囊的制备方法,其特征在于:步骤(a)或步骤(b)中,所述干燥其温度为35℃~80℃,所述筛分的目标粒径为0.1~1.0mm。
6.如权利要求3所述的达比加群酯微丸组合胶囊的制备方法,其特征在于:步骤(c)中,所述喷涂隔离材料,其为先将隔离材料制成分散液再喷涂,制备分散液的分散剂选自乙醇、丙酮、异丙醇、正丙醇、乙酸乙酯。
7.如权利要求3所述的达比加群酯微丸组合胶囊的制备方法,其特征在于:步骤(e)中,所述明胶空心胶囊的胶囊型号选自0号、1号或2号。
8.如权利要求7所述的达比加群酯微丸组合胶囊的制备方法,其特征在于:步骤(e)中,所述明胶空心胶囊的黏度为60-80mm2/s,崩解时限为5-8min。
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CN104224754A (zh) * | 2013-06-21 | 2014-12-24 | 四川海思科制药有限公司 | 一种达比加群酯药物组合物及其制备方法 |
CN104274444A (zh) * | 2013-07-04 | 2015-01-14 | 江苏豪森药业股份有限公司 | 达比加群酯或其盐的口服双微丸药物组合物 |
CN104434882A (zh) * | 2014-11-05 | 2015-03-25 | 烟台东诚药业集团股份有限公司 | 含达比加群酯或其盐和水合物的微丸药物组合物 |
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CN104224754A (zh) * | 2013-06-21 | 2014-12-24 | 四川海思科制药有限公司 | 一种达比加群酯药物组合物及其制备方法 |
CN104274444A (zh) * | 2013-07-04 | 2015-01-14 | 江苏豪森药业股份有限公司 | 达比加群酯或其盐的口服双微丸药物组合物 |
CN104434882A (zh) * | 2014-11-05 | 2015-03-25 | 烟台东诚药业集团股份有限公司 | 含达比加群酯或其盐和水合物的微丸药物组合物 |
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CN114716411A (zh) * | 2022-04-29 | 2022-07-08 | 天方药业有限公司 | 一种从生产母液中回收制备甲磺酸达比加群酯的方法 |
CN114716411B (zh) * | 2022-04-29 | 2024-03-15 | 天方药业有限公司 | 一种从生产母液中回收制备甲磺酸达比加群酯的方法 |
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