CN102106806B - 一种固体制剂的制备方法及所得固体制剂 - Google Patents
一种固体制剂的制备方法及所得固体制剂 Download PDFInfo
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- CN102106806B CN102106806B CN2009102473494A CN200910247349A CN102106806B CN 102106806 B CN102106806 B CN 102106806B CN 2009102473494 A CN2009102473494 A CN 2009102473494A CN 200910247349 A CN200910247349 A CN 200910247349A CN 102106806 B CN102106806 B CN 102106806B
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Abstract
本发明公开了一种固体制剂的制备方法:将水不溶性和/或水难溶性碱性药物活性成分溶于含酸化剂的酸性溶液中,制得含药酸性液,之后,将含药酸性液和辅料均匀的混合,进行湿法制粒。本发明还公开了上述方法制得的固体制剂。本发明的方法避免了机械粉碎处理所带来的污染严重、损耗大和安全隐患严重的缺陷,操作简便易行,安全系数高,易应用于工业化生产。该方法制得的固体制剂具有优异的溶出特性、稳定性和含量均匀度。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种固体制剂的制备方法及所得固体制剂。
背景技术
在药物制剂领域,药物活性成分的粒径对固体制剂的制备过程和质量密切相关。在具体的药物制剂的制备工艺中,通常依据药物的溶解特性和生物膜通透性,来选择合适的药物活性成分的粒径。例如,若属于溶解性较差,药物溶出是吸收限速过程的药物,可选择较小的粒径,以促进药物的吸收。再例如,若属于可压性较差的药物,可通过选择合适的粒径,以及加入适宜的辅料来改善其可压性。因此,在药物固体制剂的制备工艺中,时常涉及到对药物活性成分的粒径的选择控制。目前,大多通过选择不同的机械粉碎方法及粉碎工艺条件,以实现对药物活性成分粒径的选择控制。
但是,机械粉碎的处理方法存在粉尘多、污染环境和损耗大等问题。对于一些高活性药物,还容易在机械粉碎过程中,使操作人员产生不良反应,存在严重的安全隐患。例如,相当多的镇静安眠药物,如右旋佐匹克隆、阿普唑仑等药物活性较高,吸入较低剂量的药物粉末即可快速产生催眠效果,在对这类药物进行粉碎处理时,极易发生致操作人员快速催眠的不良反应,引发安全事故。再例如,在对一些高活性的激素或抗肿瘤等药物进行粉碎处理时,吸入或接触药物粉末,极易使操作人员产生严重的药物不良反应。
并且,目前广泛使用的普通机械粉碎方法(如采用常用的万能粉碎机),平均粒径一般达到100左右微米。由该方法处理制得的固体制剂的溶出特性尚不够理想。
在机械粉碎处理的工艺中,对于在固体制剂中含量较低(如≤5wt%)的高活性药物活性成分,还涉及其与辅料混合的分散均匀性问题。通常,采用将药物活性成分与辅料等量稀释逐步扩大的方法,以使药物活性成分在固体制剂中分散均匀。但该方法工艺操作繁琐,同样会产生粉尘多、污染环境、损耗大和劳动防护存在安全隐患等诸多问题。
此外,固体制剂的制备还需考虑产品的各种性能是否能满足需要。例如,是否能保证较佳的含量均匀度。再例如,稳定性是固体制剂质量的考察重点,其包括在固体制剂贮存期内,药物活性成分的化学稳定性、有关物质(即杂质)的含量、固体制剂性状稳定性、以及溶出稳定性等,是否处在药品标准限度内。
因此,针对上述现有技术的缺陷,亟待寻求一种既可避免机械粉碎处理方法的上述缺陷,又可保证固体制剂各种性能优良的制备方法。
发明内容
本发明所要解决的技术问题是为了克服现有的固体制剂制备方法通过机械粉碎的方式选择控制药物活性成分的粒径,会造成环境污染,存在严重的安全隐患,损耗大,且所得固体药物制剂的溶出特性不够理想的缺陷,而针对水不溶性或水难溶性碱性药物,提供一种操作更简便,污染更小,没有前述安全隐患,且能保证所制得的固体制剂具有优异的溶出特性、稳定性和含量均匀度的制备方法及所得固体制剂。
为解决上述技术问题,本发明人另辟蹊径,独特的采用酸性溶液溶解水不溶性或水难溶性碱性药物,之后随制粒过程,使药物回复固体状态,从而避免了机械粉碎处理的诸多缺陷,并且,本发明人还意外发现,该方法所制得的固体制剂具有优异的溶出特性、稳定性和含量均匀度。
本发明的制备方法包括如下步骤:将水不溶性和/或水难溶性碱性药物活性成分溶于含酸化剂的酸性溶液中,制得含药酸性液,之后,将含药酸性液和辅料均匀的混合,进行湿法制粒。
本发明中,所述的水不溶性和/或水难溶性碱性药物活性成分选自现有的各种符合上述性质的药物活性成分,包括同时具有酸性基团和碱性基团的两性药物活性成分。本领域中,所述的碱性药物活性成分大都为弱碱类药物活性成分。本发明尤其适用于活性较高、在固体制剂中含量较低(一般为20%以下,较佳的为5%以下,更佳的为1%以下,百分比为质量百分比)的水不溶性和/或水难溶性碱性药物。更具体的,本发明优选但不限于阿立哌唑、右旋佐匹克隆、地西泮、艾司唑仑、阿普唑仑、佐匹克隆、利醅酮、阿戈美拉汀、伊潘立酮、帕潘立酮、奋乃静、狄戈辛、氟哌啶醇、双嘧达莫、奥氮平、米非司酮、卡比马唑、甲氧氯普胺、米诺地尔或利血平。根据水不溶性和/或水难溶性碱性药物活性成分在固体制剂中的常规含量,即可确定制备过程中,水不溶性和/或水难溶性碱性药物活性成分占湿法制粒干物料的质量百分比。根据需要,除水不溶性和/或水难溶性碱性药物活性成分之外,还可加入其他药物活性成分,制备为复方固体制剂,如奥氮平与盐酸氟西汀的复方固体制剂。
本发明中,所述的酸化剂是指能使水不溶性和/或水难溶性碱性药物活性成分溶解形成含药酸性液的酸性试剂。根据本领域常识,所述的酸化剂应为药学上可接受的,且与水不溶性和/或水难溶性碱性药物活性成分相配伍的试剂。所述的酸化剂可为单一的酸化剂,也可为两种以上成分组成的复合酸化剂,可选自各种酸,如无机强酸、无机中强酸和有机弱酸中的一种或多种,较佳的选自盐酸、枸橼酸、酒石酸、苹果酸、氢溴酸、富马酸、琥珀酸、马来酸、乳酸、醋酸、硫酸、硝酸和磷酸中的一种或多种,更佳的为盐酸、枸橼酸、酒石酸、苹果酸、乳酸或醋酸。更具体的,本发明特别优选下述酸化剂,可使得固体制剂具有较优的稳定性:当水不溶性和/或水难溶性碱性药物活性成分为右旋佐匹克隆时,选择枸橼酸、酒石酸、苹果酸或盐酸,最优选枸橼酸。当水不溶性和/或水难溶性碱性药物活性成分为佐匹克隆时,选择盐酸、苹果酸、酒石酸或枸橼酸,最优选盐酸或酒石酸。当水不溶性和/或水难溶性碱性药物活性成分为利醅酮时,选择盐酸、枸橼酸或酒石酸。当水不溶性和/或水难溶性碱性药物活性成分为双嘧达莫时,选择盐酸或枸橼酸。当水不溶性和/或水难溶性碱性药物活性成分为阿立哌唑时,选择盐酸、枸橼酸、苹果酸或乳酸。
所述的酸化剂的用量至少为能使水不溶性和/或水难溶性碱性药物活性成分完全溶解的最小量,较佳的为此最小量的1~1.2倍,更佳的为1~1.05倍。可溶解水不溶性和/或水难溶性碱性药物活性成分的酸化剂的量与诸多因素有关,如酸化剂种类、溶剂种类、水不溶性和/或水难溶性碱性药物活性成分的溶解性、其分子中的碱性中心数、酸化剂中可与药物分子的碱性中心相结合的氢离子数、以及含药酸性液配制条件有关。其中,所述的碱性中心是指水不溶性和/或水难溶性碱性药物活性成分中可与酸化剂分子中氢离子结合的基团或部位。因此,上述最小量是指在同一溶剂和含药酸性液配制条件下,对某种水不溶性和/或水难溶性碱性药物活性成分而言,某种酸化剂可将其完全溶解的最小量。通过简单的常规方法即可确定该最小量:在同一溶剂和含药酸性液配制条件下,采用逐渐增大某种酸化剂的用量溶解某种水不溶性和/或水难溶性碱性药物活性成分,刚好完全溶解时,即为最小量。本发明人经大量实验摸索得出,具体而言,酸化剂与水不溶性和/或水难溶性碱性药物活性成分的摩尔比值一般为0.2~2.5,大多为0.3~1.5。本发明特别优选下述酸化剂的用量:
当水不溶性和/或水难溶性碱性药物活性成分为右旋佐匹克隆时,选择右旋佐匹克隆摩尔量0.8~1.1倍的枸橼酸。
当水不溶性和/或水难溶性碱性药物活性成分为佐匹克隆时,选择佐匹克隆摩尔量0.95~1.1倍的盐酸或酒石酸。
当水不溶性和/或水难溶性碱性药物活性成分为利醅酮时,选择利醅酮摩尔量0.8~2.1倍的盐酸,或利醅酮摩尔量0.3~1.1倍的枸橼酸,或利醅酮摩尔量0.25~1.1倍的酒石酸。
当水不溶性和/或水难溶性碱性药物活性成分为双嘧达莫时,选择双嘧达莫摩尔量0.7~1.2倍的盐酸,或双嘧达莫摩尔量0.7~1.1倍的枸橼酸。
当水不溶性和/或水难溶性碱性药物活性成分为阿立哌唑时,选择阿立哌唑摩尔量0.9~1.2倍的盐酸,或阿立哌唑摩尔量0.8~1.3倍的枸橼酸,或阿立哌唑摩尔量0.8~1.1倍的苹果酸。
本发明中,所述的含酸化剂的酸性溶液中的溶剂可为水、有机溶剂或者水和有机溶剂的混合液,优选水或水和有机溶剂的混合液。根据本领域常识,选择的溶剂应为酸化剂中离子可解离的溶剂。例如,酸化剂为无机物时,可选择水或水和有机溶剂的混合液;酸化剂为有机物时,可为水、水和有机溶剂的混合液、或者有机溶剂。若药物活性成分在某些有机溶剂中有优于在水中的溶解性,则较佳的选择水与该有机溶剂的混合液,以利于药物活性成分的溶解,减少酸性溶液的用量,利于后续制粒步骤的操作。所述的有机溶剂根据其对药物活性成分的溶解性优于水的原则在药剂领域可接受的溶剂中进行选择,较佳的为能与水混溶的有机溶剂,如药剂领域常用的水溶性醇类溶剂,如乙醇、丙酮、丙二醇、丙三醇、异丙醇和叔丁醇等,优选乙醇、丙酮、丙二醇和丙三醇中的一种或多种,特别优选乙醇。水与有机溶剂的混合液中,有机溶剂的用量可任意选择。所述的酸性溶液中溶剂的用量至少为湿法制粒所需制粒液最小量,一般为湿法制粒干物料的质量百分比5~100%,较佳的为10~50%。
在制备含药酸性液时,可加入一些辅料,如粘合剂、表面活性剂、增溶剂和固体分散体的水溶性载体等。较佳的,在将水不溶性和/或水难溶性碱性药物活性成分溶于含酸化剂的酸性溶液中的同时和/或之后,还加入表面活性剂、增溶剂和固体分散体的水溶性载体中的一种或多种,然后将所得含药酸性液进行后续步骤,即与辅料均匀混合,进行湿法制粒。其中,将固体分散体的水溶性载体与水不溶性和/或水难溶性碱性药物活性成分同时加入含酸化剂的酸性溶液中时,此时加入的固体分散体的水溶性载体的量需控制在能保证水不溶性和/或水难溶性碱性药物活性成分完全溶解于含酸化剂的酸性溶液中的量以下;之后还可以再向该溶液中加入固体分散体的水溶性载体,当加入量较大时,所得含药酸性液可能为悬浊液或粘稠液形式。本发明特别优选加入聚维酮、聚乙二醇(优选聚乙二醇400-8000)、十二烷基硫酸钠、泊洛沙姆、聚氧乙烯蓖麻油、吐温-80、硬脂酸聚烃氧40酯、β-环糊精、乳糖、甘露醇、蔗糖和麦芽糖醇中的一种或多种。所述的表面活性剂和/或增溶剂的加入量较佳的为水不溶性和/或水难溶性碱性药物活性成分质量的0.05~3倍。所述的固体分散体的水溶性载体的加入量较佳的为水不溶性和/或水难溶性碱性药物活性成分质量的1~20倍。按上述操作加入表面活性剂和/或增溶剂,可增加水不溶性和/或水难溶性碱性药物活性成分在酸性溶液中的溶解度,减少溶剂用量,利于后续制粒步骤的操作。更值得一提的是,按上述操作加入表面活性剂、增溶剂和固体分散体的水溶性载体中的一种或多种,尤其是固体分散体的水溶性载体可使所得水不溶性和/或水难溶性碱性药物活性成分固体制剂的溶出特性更佳。
较佳的,在制备含药酸性液时,可以通过热水浴等常规加热方法,适当升高含药酸性液的配制温度,以利于药物活性成分的溶解。以水为溶剂时,较佳的升高至40~80℃。以水和有机溶剂的混合溶液为溶剂时,较佳的升高为40~70℃,更佳的为50~60℃。以乙醇为溶剂时,较佳的升高为30~50℃。
本发明中,所述的辅料可选自本领域任何已知的并广泛使用的辅料,如填充剂、粘合剂、崩解剂、吸附剂和润滑剂等等。其中,所述的填充剂较佳的为乳糖、微晶纤维素、淀粉、预胶化淀粉、甘露醇、蔗糖、氧化镁、碳酸钙、碳酸镁和麦芽糖醇中的一种或多种。所述的粘合剂较佳的为羟丙甲纤维素、聚维酮、甲基纤维素和羟丙纤维素中的一种或多种。所说的崩解剂较佳的为羧甲淀粉钠、低取代羟丙纤维素、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠中的一种或多种。所述的润滑剂较佳的为胶态二氧化硅、硬脂酸富马酸钠、滑石粉或硬脂酸镁。所述的辅料的含量可按照本领域常规知识进行选择。
本发明中,所述的湿法制粒可按照本领域属于湿法制粒范畴的制粒方法的常规步骤和条件进行,如挤压制粒(如摇摆机挤压、螺旋挤压和旋转挤压等)、搅拌制粒、流化喷雾制粒和离心喷雾制粒等。对于在固体制剂中含量较大(一般大于20%),或在含酸化剂的酸性溶液中溶解度较小,需较大量的酸性溶液才可溶解完全的水不溶性和/或水难溶性碱性药物活性成分,可选择对制粒溶液量限制小的湿法制粒工艺,如流化喷雾制粒或离心喷雾制粒。
湿法制粒完成后,可直接得到固体颗粒制剂,也可作为制剂中间体,经进一步的常规步骤,制得片剂或胶囊剂等其他形式的固体制剂。
本发明中,上述各优选条件,可在符合本领域常识的基础上任意组合,即可得本发明各较佳实例。
本发明中,所用试剂和原料可通过市售可得,部分原料药可按照现有文献方法制备。
进一步的,本发明还涉及由上述方法制得的固体制剂。
本发明的积极进步效果在于:
(1)本发明的制备方法避免了机械粉碎处理所带来的污染严重、损耗大和安全隐患严重的缺陷。该方法操作简便易行,安全系数高,易应用于工业化生产。
(2)本发明的制备方法制得的固体制剂的溶出特性较现有技术有显著的提高,生物利用度高,个体差异小。
(3)本发明的制备方法制得的固体制剂具有较佳的含量均匀度和较好的稳定性。
具体实施方式
下面用实施例来进一步说明本发明,但本发明并不受其限制。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。剂型规格以药物活性成分含量计,如2mg/片,是指每片中含药物活性成分2mg。用量单位为克,百分比为质量百分比。药物活性成分和溶剂的质量百分比为占湿法制粒干物料的质量百分比。其中,溶剂的用量包括酸化剂的水溶液中的水。
实施例12 右旋佐匹克隆片(2mg/片)配方及制备方法
实施例13 右旋佐匹克隆片(2mg/片)配方及制备方法
实施例14 右旋佐匹克隆片(2mg/片)配方及制备方法
实施例15 右旋佐匹克隆片(2mg/片)配方及制备方法
实施例16 佐匹克隆片(2.5毫克/片)配方及制备方法
实施例17 佐匹克隆片(3.75mg/片)配方及制备方法
实施例18 佐匹克隆片(2.5mg/片)配方及制备方法
实施例19 利培酮片(1mg/片)配方及制备方法
实施例20 利培酮片(2mg/片)配方及制备方法
实施例21 利培酮片(2mg/片)配方及制备方法
实施例22 利培酮片(1mg/片)配方及制备方法
实施例23 利培酮片(1mg/片)配方及制备方法
实施例24 利培酮片(3mg/片)配方及制备方法
实施例25 利培酮片(1mg/片)配方及制备方法
实施例26 利培酮片(3mg/片)配方及制备方法
实施例27 利培酮胶囊(2mg/粒)配方及制备方法
药物 | 利培酮2(1.7%,无预处理) |
辅料 | 乳糖50、微晶纤维素60、交联羧甲基纤维素钠2、聚维酮-K303、硬脂酸镁0.6、胶态二氧化硅0.3 |
溶剂 | 水15(15.9%) |
酸化剂 | 10%盐酸水溶液3.7(与利培酮的摩尔比值:2.08) |
制备工艺 | 将利培酮与10%盐酸水溶液混合,加入水后混合搅拌溶解,边搅拌边加入聚维酮K30并溶解,配制成含药酸性液,将乳糖、微晶纤维素混合均匀,加入含药酸性液制成软材,挤压制粒,湿颗粒干燥后整粒,加入硬脂酸镁、胶态二氧化硅和交联羧甲基纤维素钠,混合均匀后装入硬胶囊。 |
实施例28 双嘧达莫片(25mg/片)配方及制备方法
药物 | 双嘧达莫25(10.3%,无预处理) |
辅料 | 甘露醇80、微晶纤维素120、羧甲淀粉钠5、聚维酮-K303、硬脂酸镁0.6、胶态二氧化硅0.6 |
溶剂 | 75%乙醇水溶液150(62.1%) |
酸化剂 | 枸橼酸一水合物7.5(与双嘧达莫的摩尔比值:0.72) |
制备工艺 | 将双嘧达莫与枸橼酸一水合物混合,加入75%乙醇水溶液后混合搅拌溶解,边搅拌边加入聚维酮K30并溶解,配制成含药酸性液作为制粒液,将甘露醇和微晶纤维素置流化喷雾制粒机中,进行流化喷雾制粒,制得的颗粒整粒后,加入羧甲淀粉钠、硬脂酸镁和胶态二氧化硅后混合均匀后压片。 |
实施例29 双嘧达莫片(25mg/片)配方及制备方法
药物 | 双嘧达莫25(14.5%,无预处理) |
辅料 | 乳糖60、微晶纤维素80、交联聚乙烯吡咯烷酮3、聚维酮-K303、胶态二氧化硅0.3、硬脂酸镁0.6 |
溶剂 | 75%乙醇水溶液120(77.7%) |
酸化剂 | 10%盐酸水溶液13.5(与双嘧达莫的摩尔比值:0.75) |
制备工艺 | 将双嘧达莫与75%乙醇水溶液混合,加入10%盐酸水溶液后混合搅拌溶解,边搅拌边加入聚维酮K30,配制成含药酸性液作为制粒液,将乳糖、微晶纤维素置流化喷雾制粒机中,进行流化喷雾制粒,制得的颗粒整粒后,加入交联聚乙烯吡咯烷酮、硬脂酸镁和胶态二氧化硅后混合均匀后压片。 |
实施例30双嘧达莫片(25mg/片)配方及制备方法
药物 | 双嘧达莫25(14.5%,无预处理) |
辅料 | 乳糖60、微晶纤维素80、交联聚乙烯吡咯烷酮3、聚维酮-K303、胶态二氧化硅0.3、硬脂酸镁0.6 |
溶剂 | 80%乙醇水溶液120(77.7%) |
酸化剂 | 枸橼酸一水合物11.45(与双嘧达莫的摩尔比值:1.1) |
制备工艺 | 将双嘧达莫与与枸橼酸一水合物混合,加入80%乙醇水溶液后混合搅拌溶解,边搅拌边加入聚维酮K30,配制成含药酸性液作为制粒液,将乳糖、微晶纤维素置流化喷雾制粒机中,进行流化喷雾制粒,制得的颗粒整粒后,加入交联聚乙烯吡咯烷酮、硬脂酸镁和胶态二氧化硅后混合均匀后压片。 |
实施例31 阿立哌唑片(10毫克/片)配方及制备方法
药物 | 阿立哌唑10(8.1%,无预处理) |
辅料 | 乳糖60、微晶纤维素40、羧甲淀粉钠6、聚乙二醇60002、硬脂酸镁0.6、胶态二氧化硅0.6 |
溶剂 | 60%乙醇水溶液30(24.2%) |
酸化剂 | 枸橼酸一水合物5(与阿立哌唑的摩尔比值:1.07) |
制备工艺 | 将阿立哌唑、枸橼酸和聚乙二醇6000溶解于60%乙醇水溶液中,配制成含药酸性液,将乳糖、微晶纤维素、70%量的羧甲淀粉钠混合均匀,加入含药酸性液进行搅拌制粒,湿颗粒干燥后整粒,加入硬脂酸镁、胶态二氧化硅和剩余30%量羧甲基淀粉钠混合均匀后压片。 |
实施例32 阿立哌唑胶囊(10mg/粒))配方及制备方法
取实施例31的干燥颗粒过30目筛,加入硬脂酸镁、胶态二氧化硅和剩余量羧甲基淀粉钠,混合均匀装入硬胶囊内。
实施例33 阿立哌唑片(5毫克/片)配方及制备方法
药物 | 阿立哌唑5(4.3%,无预处理) |
辅料 | 乳糖70、微晶纤维素30、羧甲淀粉钠6、聚维酮K302、硬脂酸镁0.9 |
溶剂 | 乙醇20(17.3%) |
酸化剂 | 枸橼酸一水合物1.7(与阿立哌唑的摩尔比值:0.73) |
制备工艺 | 将阿立哌唑、枸橼酸加入乙醇,边搅拌边加入聚维酮K30,配制成含药酸性液(用50℃水浴温热配制),将乳糖、微晶纤维素、70%量的羧甲淀粉钠混合均匀,加入含药酸性液制成软材,挤压制粒,湿颗粒干燥后整粒,加入硬脂酸镁和剩余30%量羧甲淀粉钠混合均匀后压片。 |
实施例34 阿立哌唑片(5毫克/片)配方及制备方法
药物 | 阿立哌唑5(4.6%,无预处理) |
辅料 | 乳糖60、微晶纤维素40、吐温-800.5、交联聚维酮2.5、硬脂酸镁0.6、滑石粉1.5 |
溶剂 | 95%乙醇水溶液20(21.5%) |
酸化剂 | 8%盐酸水溶液4.1(与阿立哌唑的摩尔比值:0.81) |
制备工艺 | 将阿立哌唑、8%盐酸水溶液置95%乙醇水溶液中,加入吐温-80配制成含药酸性液(用50℃水浴温热配制),将乳糖、微晶纤维素混合均匀,加入含药酸性液制成软材,挤压制粒,湿颗粒干燥后整粒,加入硬脂酸镁、滑石粉和交联聚维酮混合均匀后压片。 |
实施例35 阿立哌唑片(10毫克/片)配方及制备方法
药物 | 阿立哌唑10(8.3%,无预处理) |
辅料 | 乳糖60、微晶纤维素40、羧甲淀粉钠6、聚维酮K303、硬脂酸镁0.6、胶态二氧化硅0.3 |
溶剂 | 50%乙醇水溶液水溶液60(58.1%) |
酸化剂 | 10%盐酸水溶液9.7(与阿立哌唑摩尔比值:1.19) |
制备工艺 | 将阿立哌唑、10%盐酸水溶液和聚维酮K30溶解于50%乙醇水溶液中,配制成含药酸性液;将乳糖、微晶纤维素和70%量的羧甲淀粉钠混合均匀置于多功能流化喷雾制粒机中,用蠕动泵将含药酸性液喷于上述混合辅料上制粒,在制得的颗粒中加入硬脂酸镁、胶态二氧化硅和剩余30%量羧甲淀粉钠混合均匀后压片。 |
实施例36 阿立哌唑片(5mg/片)配方及制备方法
药物 | 阿立哌唑5(4.4%,无预处理) |
辅料 | 乳糖60、微晶纤维素40、交联聚乙烯吡咯烷酮6、硬脂酸镁0.6 |
溶剂 | 50%乙醇水溶液85(75.1%) |
酸化剂 | DL-苹果酸1.64(与阿立哌唑摩尔比值:1.10) |
制备工艺 | 将阿立哌唑、DL-苹果酸溶解于50%乙醇水溶液中,水浴加热至40℃左右,配制成含药酸性液,将甘露醇和微晶纤维素混合均匀置于多功能流化喷雾制粒机中,用蠕动泵将含药酸性液喷于上述混合辅料上制粒,在制得的颗粒中加入硬脂酸镁和交联聚乙烯吡咯烷酮,混合均匀后压片。 |
实施例37 阿立哌唑片(5mg/片)配方及制备方法
药物 | 阿立哌唑5(4.5%,无预处理) |
辅料 | 乳糖70、微晶纤维素30、交联聚乙烯吡咯烷酮6、硬脂酸镁0.6、胶态二氧化硅0.3 |
溶剂 | 95%乙醇水溶液15(22.3%) |
酸化剂 | 20%DL-乳酸10(与阿立哌唑摩尔比值:1.99) |
制备工艺 | 将阿立哌唑置于95%乙醇水溶液中,加入20%DL-乳酸水溶液,搅拌溶解,配制成含药酸性液,将20%乳糖和微晶纤维素混合均匀,加入含药酸性液进行搅拌制粒,湿颗粒干燥后整粒,加入硬脂酸镁、胶态二氧化硅和交联聚乙烯吡咯烷酮混合均匀后压片。 |
实施例38 阿立哌唑片(10mg/片)配方及制备方法
药物 | 阿立哌唑10(7.2%,无预处理) |
辅料 | 乳糖80、微晶纤维素40、羧甲淀粉钠6、硬脂酸镁0.6 |
溶剂 | 50%乙醇水溶液30(21.5%) |
酸化剂 | DL-苹果酸2.4(与阿立哌唑摩尔比值:0.80) |
制备工艺 | 将阿立哌唑和DL-苹果酸置50%乙醇水溶液中,水浴加热至50℃左右,搅拌溶解,配制成含药酸性液,将乳糖、微晶纤维素和70%量的羧甲淀粉钠混合均匀,并加入上述含药酸性液进行搅拌制粒,湿颗粒干燥后整粒,加入硬脂酸镁和剩余30%量羧甲淀粉钠混合均匀后压片。 |
效果实施例1 溶出度比较试验
1)对比实施例1和实施例1和2的右旋佐匹克隆片的溶出度比较
溶出度试验方法:取样品,照溶出度测定法(中国药典2005年版二部附录X C第三法),以水200ml为溶剂,转速为每分钟50转,依法操作,并配制对照溶液。按紫外-可见分光光度法(中国药典2005年版二部附录IVA),在304nm的波长处分别测定吸光度,计算出每片的溶出量。
2)对比实施例2和实施例3和4的佐匹克隆片的溶出度比较
溶出度试验方法:取样品,照溶出度测定法(中国药典2005年版二部附录X C第三法),以水200ml为溶剂,转速为每分钟50转,依法操作,并配制对照溶液。按紫外-可见分光光度法(中国药典2005年版二部附录IV A),在304nm的波长处分别测定吸光度,计算出每片的溶出量。
3)对比实施例3和实施例5~7的利培酮片的溶出度比较
溶出度测试方法:取样品,照溶出度测定法(中国药典2005年版二部附录X C第二法),以水200ml为溶剂,转速为每分钟50转,依法操作,在15、30、45分钟分别取溶液5ml,补液5ml,将样品滤过,弃去初滤液,取续滤液作为样品溶液,并配制对照溶液。照高效液相色谱法(中国药典2005年版二部附录V D),用十八烷基硅烷键合硅胶为填充剂,分别测定,计算出每片的溶出量。
4)对比实施例4和实施例8的双嘧达莫片的溶出度比较
溶出度的测定方法:取样品,照溶出度测定法(中国药典2005年版二部附录X C第一法),以pH4.0的醋酸盐缓冲液(0.05mol/L醋酸-0.05mol/L醋酸钠=16.4:3.6)900ml为溶剂,转速为每分钟50转,依法操作,按紫外-可见分光光度法(中国药典2005年版二部附录IV A),在283nm的波长处分别测定吸光度,计算出每片的溶出量。
5)对比实施例5和实施例9~11的阿立哌唑片的溶出度比较
溶出度试验方法:取样品,照溶出度测定法(中国药典2005年版二部附录X C第二法),以pH4.0的醋酸盐缓冲液(0.05mol/L醋酸-0.05mol/L醋酸钠=16.4∶3.6)500ml为溶剂,转速为每分钟50转,依法操作,分别在5、10、20、30、45分钟取溶液5ml,补入5ml溶出介质至溶出杯中,将样品滤过,取续滤液作为样品溶液,并配制对照溶液。照高效液相色谱法(中国药典2005年版二部附录V D)分别测定,用十八烷基硅烷键合硅胶为填充剂;以甲醇-0.1%三乙胺溶液(90∶10)为流动相;检测波长为255nm。计算出每片的溶出量。
效果实施例2 稳定性加速试验
将试验样品分别置高密度聚乙烯塑料瓶中,密封,放入加速考察箱中,于温度40℃±2℃,相对湿度75%±5%条件进行3个月的加速试验后,进行相关项目的稳定性测定。
1)对比实施例1和实施例1的右旋佐匹克隆片的稳定性比较
含量测定方法:取本品适量(相当于右旋佐匹克隆3mg),置250ml量瓶中,加0.02mol/L盐酸适量,摇匀,滤过,取续滤液作为供试品溶液;另取右旋佐匹克隆对照品适量,用0.02mol/L盐酸制成每1ml中含12μg的溶液,作为对照溶液。照紫外-可见分光光度法(中国药典2005年版二部附录IV A),在304nm的波长处分别测定吸光度,计算含量。
溶出度试验方法同效果实施例1中1)。
有关物质测定方法:照高效液相色谱法(中国药典2005年版二部附录V D)测定,用十八烷基硅烷键合硅胶为填充剂,供试品溶液的色谱图与对照溶液色谱图按照主成分自身对照法进行计算。
2)对比实施例2和实施例3的佐匹克隆片的稳定性比较
含量测定方法:取本品适量(相当于佐匹克隆3mg),置250ml量瓶中,加0.02mol/L盐酸适量,摇匀,滤过,取续滤液作为供试品溶液;另取佐匹克隆对照品适量,用0.02mol/L盐酸制成每1ml中含12μg的溶液,作为对照溶液。照紫外-可见分光光度法(中国药典2005年版二部附录IV A),在304nm的波长处分别测定吸光度,计算含量。
溶出度试验方法同效果实施例1中2)。
有关物质测定方法:照高效液相色谱法(中国药典2005年版二部附录V D)测定,用十八烷基硅烷键合硅胶为填充剂,供试品溶液的色谱图与对照溶液色谱图按照主成分自身对照法进行计算。
3)对比实施例3和实施例5的利培酮片的稳定性比较
含量和有关物质的测定方法:取样品适量,用流动相超声振摇使溶解,制成每m1中含利培酮适量的溶液,作为供试品溶液,并配制对照溶液。照高效液相色谱法(中国药典2005年版二部附录V D),用十八烷基硅烷键合硅胶为填充剂,分别测定。含量的测定按照外标法,有关物质的测定按照主成分自身对照法进行计算。
溶出度试验方法同效果实施例1中3)。
4)对比实施例5和实施例9和11的阿立哌唑片的稳定性比较
含量和有关物质的测定方法:取样品适量,用流动相超声振摇使溶解,制成每ml中含阿立哌唑适量的溶液,作为供试品溶液,并配制对照溶液。照高效液相色谱法(中国药典2005年版二部附录V D),用十八烷基硅烷键合硅胶为填充剂,分别测定。含量的测定按照外标法,有关物质的测定按照主成分自身对照法进行计算。溶出度试验方法同效果实施例1中5)。
效果实施例3 含量均匀度实验
照中国药典2005年版附录XE含量均匀度检查法,测定每片的含量(含量测定方法同效果实施例2),并计算含量均匀度(A+1.80S)。
Claims (20)
1.一种固体制剂的制备方法,其特征在于其包括如下步骤:将水不溶性和/或水难溶性碱性药物活性成分溶于含酸化剂的酸性溶液中,制得含药酸性液,之后,将含药酸性液和辅料均匀的混合,进行湿法制粒;
在将水不溶性和/或水难溶性碱性药物活性成分溶于含酸化剂的酸性溶液中的同时和/或之后,还加入表面活性剂、增溶剂和固体分散体的水溶性载体中的一种或多种,然后将所得含药酸性液进行后续步骤,即与辅料均匀混合,进行湿法制粒;
所述的水不溶性和/或水难溶性碱性药物活性成分为阿立哌唑、右旋佐匹克隆、佐匹克隆、利醅酮或双嘧达莫;
所述的酸化剂为盐酸、枸橼酸、酒石酸、苹果酸或乳酸;
所述的酸化剂的用量为至少能使水不溶性和/或水难溶性碱性药物活性成分完全溶解的最小量。
2.如权利要求1所述的方法,其特征在于:所述的水不溶性和/或水难溶性碱性药物活性成分为在固体制剂中含量为20%以下。
3.如权利要求2所述的方法,其特征在于:所述的水不溶性和/或水难溶性碱性药物活性成分为在固体制剂中含量为5%以下。
4.如权利要求3所述的方法,其特征在于:所述的水不溶性和/或水难溶性碱性药物活性成分为在固体制剂中含量为1%以下的水不溶性和/或水难溶性碱性药物。
5.如权利要求1所述的方法,其特征在于:
所述的水不溶性和/或水难溶性碱性药物活性成分为右旋佐匹克隆时,所述的酸化剂为枸橼酸、酒石酸、苹果酸或盐酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为佐匹克隆时,所述的酸化剂为盐酸、苹果酸、酒石酸或枸橼酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为利醅酮时,所述的酸化剂为盐酸、枸橼酸或酒石酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为双嘧达莫时,所述的酸化剂为盐酸或枸橼酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为阿立哌唑时,所述的酸化剂为盐酸、枸橼酸、苹果酸或乳酸。
6.如权利要求1~5任一项所述的方法,其特征在于:所述的酸化剂的用量为,能使水不溶性和/或水难溶性碱性药物活性成分完全溶解的最小量的1~1.2倍。
7.如权利要求6所述的方法,其特征在于:所述的酸化剂的用量为,能使水不溶性和/或水难溶性碱性药物活性成分完全溶解的最小量的1~1.05倍。
8.如权利要求1~5任一项所述的方法,其特征在于:所述的酸化剂与水不溶性和/或水难溶性碱性药物活性成分的摩尔比值为0.2~2.5。
9.如权利要求8所述的方法,其特征在于:所述的酸化剂与水不溶性和/或水难溶性碱性药物活性成分的摩尔比值为0.3~1.5。
10.如权利要求1所述的方法,其特征在于:
所述的水不溶性和/或水难溶性碱性药物活性成分为右旋佐匹克隆时,所述的酸化剂为右旋佐匹克隆摩尔量0.8~1.1倍的枸橼酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为佐匹克隆时,所述的酸化剂为佐匹克隆摩尔量0.95~1.1倍的盐酸或酒石酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为利醅酮时,所述的酸化剂为利醅酮摩尔量0.8~2.1倍的盐酸,或利醅酮摩尔量0.3~1.1倍的枸橼酸,或利醅酮摩尔量0.25~1.1倍的酒石酸;
当水不溶性和/或水难溶性碱性药物活性成分为双嘧达莫时,所述的酸化剂为双嘧达莫摩尔量0.7~1.2倍的盐酸,或双嘧达莫摩尔量0.7~1.1倍的枸橼酸;
所述的水不溶性和/或水难溶性碱性药物活性成分为阿立哌唑时,所述的酸化剂为阿立哌唑摩尔量0.9~1.2倍的盐酸,或阿立哌唑摩尔量0.8~1.3倍的枸橼酸,或阿立哌唑摩尔量0.8~1.1倍的苹果酸。
11.如权利要求1~5任一项所述的方法,其特征在于:所述的含酸化剂的酸性溶液中的溶剂为水、水和有机溶剂的混合液、或者有机溶剂,且酸化剂中离子在该溶剂中可解离;所述的有机溶剂为对水不溶性和/或水难溶性碱性药物活性成分的溶解性优于水的药剂领域可接受的溶剂。
12.如权利要求11所述的方法,其特征在于:所述的有机溶剂为乙醇、丙二醇、丙三醇、丙酮、异丙醇和叔丁醇中的一种或多种。
13.如权利要求1~5任一项所述的方法,其特征在于:所述的酸性溶液中溶剂的用量为湿法制粒干物料的质量百分比5~100%。
14.如权利要求13所述的方法,其特征在于:所述的酸性溶液中溶剂的用量为湿法制粒干物料的质量百分比10~50%。
15.如权利要求1~5任一项所述的方法,其特征在于:所述的表面活性剂、增溶剂和固体分散体的水溶性载体中的一种或多种为聚维酮、聚乙二醇400-8000、十二烷基硫酸钠、泊洛沙姆、聚氧乙烯蓖麻油、吐温-80、硬脂酸聚烃氧40酯、羟丙甲纤维素、甲基纤维素、羟丙纤维素、乳糖、甘露醇、蔗糖、β-环糊精和麦芽糖醇中的一种或多种;
所述的表面活性剂和/或增溶剂的加入量为水不溶性和/或水难溶性碱性药物活性成分质量的0.05~3倍;
所述的固体分散体的水溶性载体的加入量为水不溶性和/或水难溶性碱性药物活性成分质量的1~20倍。
16.如权利要求1~5任一项所述的方法,其特征在于:在制备所述的含药酸性液时,按照下述操作进行溶液配制:当以水为溶剂时,升温至40~80℃;当以水和有机溶剂的混合溶液为溶剂时,升温至40~70℃,;当以乙醇为溶剂时,升高温度至30~50℃。
17.如权利要求16所述的方法,其特征在于:当以水和有机溶剂的混合溶液为溶剂时,升温至50~60℃。
18.如权利要求1~5任一项所述的方法,其特征在于:所述的湿法制粒为挤压制粒、搅拌制粒、流化喷雾制粒或离心喷雾制粒;所述的挤压制粒为摇摆机挤压制粒、螺旋挤压制粒或旋转挤压制粒。
19.如权利要求1所述的方法,其特征在于:将如权利要求1所述的方法制得的固体颗粒,经进一步的常规步骤,制得片剂或胶囊剂。
20.如权利要求1~19任一项所述的方法制得的固体制剂。
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