CN105816437A - 一种帕布昔利布的药物制剂及其制备方法 - Google Patents
一种帕布昔利布的药物制剂及其制备方法 Download PDFInfo
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- CN105816437A CN105816437A CN201610187046.8A CN201610187046A CN105816437A CN 105816437 A CN105816437 A CN 105816437A CN 201610187046 A CN201610187046 A CN 201610187046A CN 105816437 A CN105816437 A CN 105816437A
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Abstract
本发明属于制药领域,具体涉及一种帕布昔利布的药物制剂及其制备方法。该药物制剂包括帕布昔利布和酸性辅料以及任选的亲水性高分子材料,与常规制剂相比具有更优秀的溶解度和体外溶出性质,可用于增强帕布昔利布的体内吸收和生物利用度。
Description
技术领域
本发明属于制药领域。更具体而言,本发明涉及一种帕布昔利布(palbociclib,又称帕博西林、帕博昔布、帕博西尼、帕伯克利等)的药物制剂及其制备方法。本发明的帕布昔利布可以是帕布昔利布游离碱或其任何一种可药用盐。
背景技术
世界卫生组织统计数据显示,乳腺癌是全世界范围内导致女性因癌症死亡病因中的第二杀手。过去几十年里,乳腺癌的发病率呈增长趋势。预计到2020年,每年的乳腺癌新发病例将会超过170万。2012年全世界范围内有167万例乳腺癌新发病例,占所有癌症新发病例的25%。其中发达国家有88.3万例;发展中国家有79.4万例。发展中国家的乳腺癌新发病例增长速度略高于发达国家。因乳腺癌死亡的病例为52.2万,在所有癌症中的致死率位列第五;在欠发达地区引起女性死亡数为32.4万,在所有因癌症死亡的病例中占14.3%,是最频繁致死的癌症;在发达地区的女性中,因乳腺癌的死亡病例为19.8万,占所有因癌症死亡病例的15.4%,仅次于肺癌。因此,乳腺癌依然是全世界的重要健康问题之一。
根据国际专利WO2003/062236,帕布昔利布是一种细胞周期素依赖性激酶(CDK)4和6的抑制药物,主要通过抑制CDK4/6活性来阻止细胞由G1期到S期进而抑制DNA的合成,可用于治疗转移性乳腺癌。临床试验研究发现,帕布昔利布联合来曲唑对绝经后的局部浸润性乳腺癌患者或新近诊断的雌激素受体(ER)阳性,HER-2阴性的患者非常有效。其化学结构如下所示:
此化合物及其盐的结构和制备方法在国际专利WO2003/062236和美国专利No.6,936,612中已有描述。在国际专利申请公开WO2005/005426和美国专利Nos.7,345,171和7,863,278中也描述了游离碱和各种酸的盐的制备方法。根据国际专利申请公开WO2005/005426中的描述,帕布昔利布游离碱在水中的溶解度很差,这会导致生物利用度低,不利于人体的吸收。其游离碱有冲击后粘性强的性质,而这种粘性是与粒径的比表面积相关的,所以其粒径要控制在一定范围。根据国际专利申请公开WO2014128588,需要使用帕布昔利布游离碱较大粒径的原料药,以便改善其理化性质和制剂产品的生产能力。如果通过将帕布昔利布游离碱与酸反应成盐以增加溶解度,根据之前已有的专利报道,其盐的固态性质不好,不利于开发成固体制剂。
同时,帕布昔利布是一种难溶药。目前帕布昔利布已经在美国批准上市。根据帕布昔利布在美国上市产品的说明书,帕布昔利布产品在7个病人中有1个病人在给药后吸收很差。对于这些病人,这个产品的药效会比较低。很可能是由于该药物的难溶性质导致在部分病人体内吸收差。因而,对帕布昔利布的剂型进行进一步改进,从而增加其溶出度和生物利用度,在目前来看是十分必要的。
发明内容
本发明的目的是开发一种新型药剂产品,提高帕布昔利布的溶出和生物吸收。根据现有技术和公知常识,通常认为难溶药的口服固体制剂产品的体外溶出与体内的吸收有一定的相关性。所以,在本发明中,采用体外溶出方法以评估制剂产品体内吸收的能力。
本发明意外地发现,将帕布昔利布原料药与药学上可接受的酸性辅料混合,再任选添加其他药学上可接受的赋形剂,制备成口服固体制剂产品后,其溶出相比于采用现有技术所制备的口服固体制剂产品可以显著增加。
本发明还意外地发现,帕布昔利布原料药在经过粉碎,使其粒径减小至D90在20微米以下,再与药学上可接受的酸性辅料混合后,或帕布昔利布原料药与药学上可接受的酸性辅料混合后共同粉碎,使此混合物的粒径减小至D90在20微米以下后,任选再添加其他药学上可接受的赋形剂,克服了国际专利申请公开WO2014128588中所述的小粒径原料药难以用于制备制剂的缺点,制成口服剂型,其体外溶出可以显著增加。
本发明还意外地发现,帕布昔利布原料药与药学上可接受的酸性辅料可以共同溶解于溶剂中,帕布昔利布原料药在溶剂中的浓度可达50mg/ml以上,再添加亲水性高分子材料,溶解均匀后,将溶剂挥发去除,形成无定形的固体分散体。再任选添加其他药学上可接受的赋形剂,并制备成口服固体制剂产品,其溶出也进一步显著增加。
本发明还意外地发现,本发明的固体分散体制备方法可以将酸性辅料也转化为无定型状态,且可较长期的保持无定形状态,这对保持帕布昔利布原料药的无定型状态非常有利。
本发明通过添加酸性辅料、减小帕布昔利布原料药粒径和将帕布昔利布制成无定形方式,增加帕布昔利布的体外溶出,从而可以增加其体内生物利用度。
具体而言,本发明提供一种帕布昔利布的药物制剂,其包括帕布昔利布游离碱或其可药用盐和酸性辅料。
在一个实施方案中,帕布昔利布游离碱或其盐是固体。
在一个实施方案中,药物制剂中帕布昔利布的粒径(D90)在20μm以下。
在一个实施方案中,药物制剂中帕布昔利布和酸性辅料的粒径(D90)均在20μm以下。
在一个实施方案中,酸性辅料选自药学上可接受的水溶性有机酸或其水合物或酸性盐,水溶性酸性氨基酸或其水合物或酸性盐,水溶性氨基酸的酸性盐或其水合物,或水溶性无机酸的酸性盐或其水合物中的一种或多种。
在一个实施方案中,水溶性有机酸选自酒石酸、富马酸、琥珀酸、柠檬酸、乳酸和苹果酸中的一种或多种,水溶性酸性氨基酸选自谷氨酸和天冬氨酸中的一种或多种,水溶性氨基酸的酸性盐选自甘氨酸、丙氨酸和丝氨酸的酸性盐中的一种或多种,水溶性无机酸的酸性盐选自磷酸二氢盐和硫酸氢盐中的一种或多种。
在一个实施方案中,酸性辅料优选酒石酸、富马酸、琥珀酸、柠檬酸、乳酸和苹果酸中的一种或多种,更优选酒石酸。
在一个实施方案中,酸性辅料与帕布昔利布的质量比为0.2:1至5:1,优选为0.5:1至2:1。
在一个实施方案中,药物制剂为片剂或胶囊剂。
在一个实施方案中,片剂或胶囊的剂量为25-500mg,优选为50-150mg。
本发明还提供一种帕布昔利布的固体分散体,其包括帕布昔利布游离碱或其可药用盐、酸性辅料和亲水性高分子材料。
在一个实施方案中,亲水性高分子材料选自聚维酮K30(PVP-K30)、共聚维酮VA64(PVP-VA64)、Soluplus、羟丙基甲基纤维素E5(HPMC-E5)、醋酸羟丙基甲基纤维素琥珀酸酯(HPMC-AS-HF)、羟丙基-β-环糊精(hydroxypropyl-β-cyclodextrin)和磺丁基醚-β-环糊精(sulfobutylether-β-cyclodextrin)中的一种或多种。
在一个实施方案中,酸性辅料选自一种或多种可药用有机酸以及任选的一种或多种可药用无机酸。其中,所述可药用有机酸优选酒石酸、富马酸、琥珀酸、柠檬酸、乳酸、苹果酸、脂肪族磺酸(如甲磺酸、乙磺酸、羟乙基磺酸等)和芳香族磺酸(如苯磺酸、对甲苯磺酸等),而所述可药用无机酸优选盐酸、硫酸、磷酸等。本发明中,“任选的”表示可药用无机酸可有可无,如有可药用无机酸,可减少可药用有机酸的用量。
在一个实施方案中,亲水性高分子材料与帕布昔利布的质量比为0.1:1至10:1,而酸性辅料与帕布昔利布的质量比为0.2:1至5:1;优选地,亲水性高分子材料与帕布昔利布的质量比为1:1至3:1,而所述酸性辅料与帕布昔利布的质量比为0.5:1至2:1。
本发明还提供药物制剂的制备方法,包括将帕布昔利布原料药与药学上可接受的酸性辅料混合,优选按照一定的质量比混合,再任选添加其他药学上可接受的赋形剂。
本发明还提供药物制剂的另一制备方法,包括将帕布昔利布原料药进行粉碎,控制粒径在20微米以下,再与药学上可接受的酸性辅料混合,或者在原料药中添加酸性辅料并混合后进行共同粉碎,以控制粒径在20微米以下,任选再添加其他药学上可接受的赋形剂。
本发明还提供固体分散体的制备方法,包括在帕布昔利布与酸性辅料混合后,加溶剂(包括但不限于水、乙醇、丙酮及其混合溶剂,优选水或其与其他溶剂的混合溶剂,例如水和乙醇,水和丙酮等)进行溶解或分散,再添加亲水性高分子材料,溶解或分散均匀后,经加热去除溶剂,例如,通过真空干燥或加热干燥或冷冻干燥或其他干燥方式,将溶剂蒸发干,以实现药物高度分散于高分子固体载体,从而制备成固体分散体之目的。
在本发明固体分散体的制备过程中,帕布昔利布原料药在溶剂(例如,水)中的浓度可达到50mg/ml或更高,从而提高固体分散体的制备效率。
本发明还提供药物制剂或固体分散体用于治疗乳腺癌。
本发明中,帕布昔利布是指帕布昔利布游离碱或其可药用盐,可互换使用。
对本领域技术人员而言,赋形剂是公知的,可以是黏合剂、填充剂、崩解剂、润滑剂、防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等。
本发明中,对帕布昔利布进行粉碎,或对帕布昔利布与酸性辅料混合后共同粉碎,例如通过气流粉碎技术,使其粒径减小至D90在20微米以下。
本发明中,药物制剂为口服固体制剂产品,例如片剂或胶囊剂。该类产品的制备,通常是将原料药与其他药学上可接受的辅料,如赋形剂、润滑剂、崩解剂等混合后,制备成口服固体制剂产品。目前已经在美国被批准上市的帕布昔利布口服固体制剂产品(商品名为Ibrance),根据其公开的药品说明书的描述,此产品就是采用此技术。
本发明通过特别组合方式首次成功制备出帕布昔利布的固体分散体。现有技术中,固体分散体是一种制剂技术用于难溶药的制剂产品。通常是将难溶的原料药与一种亲水性的药用高分子辅料,共同制备成一无定形的固体分散体。而无定形的固体分散体的制备方法有溶剂法和熔融法两种。其中的溶剂法是将原料药和辅料共同溶解于一溶剂中,然后将溶剂挥发后制得。熔融法是将原料药和高分子辅料共同熔融后快速冷却制得。由于帕布昔利布的熔点非常高,达到了271℃,且在大部分溶剂中都不溶,所以无法根据现有技术中的固体分散体技术制备无定形的固体分散体。
本发明通过帕布昔利布原料药与酸性辅料的混合,制成制剂后药物在pH6.0的溶出介质中,在60分钟的累积溶出度从现有制剂技术制备的产品的34.0%,提高到了47.8%(图1)。
进一步,在将帕布昔利布粉碎以后(粒径20微米以下,图2)制成制剂,或者将帕布昔利布与酸性辅料混合后,再共同粉碎后制成制剂,药物在pH6.0下60分钟的累积溶出度分别进一步提高到了66.6%和68.7%(图3)。
更进一步,将帕布昔利布原料药和酸性物料混合后,与亲水性高分子材料制成固体分散体后,在pH6.0的缓冲液中经60分钟搅拌下测试动态溶解度实验中显示,其动态溶解度相比帕布昔利布原料药本身,从58%上升到了85%(图4)。
本发明固体分散体的制备方法可以将酸性辅料如酒石酸也转化为无定型状态(图5),且在40℃/75%RH的稳定箱中保存一周后仍保持无定形状态,这对长期保持帕布昔利布固体分散体的无定型状态非常有利。
附图说明
为了更清楚地描述本发明的技术方案,下面将结合附图作简要介绍。显而易见,这些附图仅是本申请记载的一些具体实施方式。本发明包括但不限于这些附图。
图1示出了帕布昔利布加酸性辅料和不加酸性辅料两个处方所制备的胶囊制剂体外溶出情况;
图2示出了帕布昔利布粉碎后的粒径情况;
图3示出了帕布昔利布经过粉碎后与酸性辅料混合制备胶囊制剂,以及帕布昔利布原料药与酒石酸共同粉碎降低粒径后所制备的胶囊制剂体外溶出情况;
图4示出了帕布昔利布原料药和酸性物料混合后,与亲水性高分子材料制成固体分散体,相比帕布昔利布原料药本身,在pH6.0缓冲液中经60分钟搅拌下测试动态溶解度实验情况;
图5示出了本发明固体分散体中酸性辅料酒石酸的无定形状态;
图6示出了本发明所用帕布昔利布原料药的XRPD图样;
图7示出了利用HPMC-AS-HF制成的帕布昔利布固体分散体的XRPD图样;
图8示出了利用PVP-VA64制成的帕布昔利布固体分散体的XRPD图样;
图9示出了利用PVP-K30制成的帕布昔利布固体分散体的XRPD图样;
图10示出了利用Soluplus制成的帕布昔利布固体分散体的XRPD图样;以及
图11示出了利用HPMC-E5制成的帕布昔利布固体分散体的XRPD图样。
具体实施方式
为了进一步理解本发明,下面将结合实施例对本发明的优选方案进行描述。这些描述只是举例说明本发明新型药物制剂的特征和优点,而非限制本发明的保护范围。
实施例1
酸性辅料与帕布昔利布干法制粒灌装胶囊的剂型制备
称取帕布昔利布原料药1500毫克,乳糖345毫克,酒石酸1200毫克,微晶纤维素840毫克,羧甲基淀粉钠210毫克,二氧化硅84毫克,用三维混合机混合15分钟,再加入硬脂酸镁21毫克,用三维混合机再混合2分钟。混合后,将物料过40目筛,用机械单冲压片机压片,压片是的压力为5兆帕,每片片重1050毫克。将压好的大片打碎,过10目筛,分装明胶胶囊,每个胶囊载药350毫克。在pH6.0条件下测定其溶出度,所选时间点为5、10、15、20、30、45和60分钟。
与此同时,平行做一个不加酸性辅料的对比试验:称取帕布昔利布原料药1500毫克,乳糖1545毫克,微晶纤维素840毫克,羧甲基淀粉钠210毫克,二氧化硅84毫克,用三维混合机混合15分钟,再加入硬脂酸镁21毫克,用三维混合机再混合2分钟。混合后,将物料过40目筛,用机械单冲压片机压片,压片是的压力为5兆帕,每片片重1050毫克。将压好的大片打碎,过10目筛,分装明胶胶囊,每个胶囊载药350毫克。在pH6.0条件下,采用篮法、100rmp转速,测定其溶出度,所选时间点为5、10、15、20、30、45和60分钟。
加酸性辅料、不加酸性辅料的胶囊溶出测定结果分别见图1中的两条曲线。
实施例2
酸性物料与帕布昔利布混合并粉碎后干法制粒灌装胶囊的制备
称取已经过气流粉碎的帕布昔利布原料药1500毫克,然后与酒石酸1200毫克、乳糖345毫克,微晶纤维素840毫克,羧甲基淀粉钠210毫克,二氧化硅84毫克,在三维混合机中混合15分钟。再加入硬脂酸镁21毫克,用三维混合机再混合2分钟。混合后,将物料过40目筛,用机械单冲压片机压片,压片是的压力为5兆帕,每片片重1050毫克。将压好的大片打碎,过10目筛,分装明胶胶囊,每个胶囊载药350毫克。在pH6.0条件下,采用篮法、100rpm转速,测定其溶出度,所选时间点为5、10、15、20、30、45和60分钟。称取帕布昔利布原料药与酒石酸混合后经过共同气流粉碎的物料(含1500毫克的帕布昔利布,与1200毫克的酒石酸),然后加入乳糖345毫克,微晶纤维素840毫克,羧甲基淀粉钠210毫克,二氧化硅84毫克,在三维混合机中混合15分钟。再加入硬脂酸镁21毫克,用三维混合机再混合2分钟。混合后,将物料过40目筛,用机械单冲压片机压片,压片是的压力为5兆帕,每片片重1050毫克。将压好的大片打碎,过10目筛,分装明胶胶囊,每个胶囊载药350毫克。在pH6.0条件下,采用篮法、100rpm转速,测定其溶出度,所选时间点为5、10、15、20、30、45和60分钟。帕布昔利布单独粉碎后制剂,以及帕布昔利布与酒石酸共粉碎后制剂的溶出结果见图3。
实施例3
帕布昔利布与酸性物料混合后,与PVP-K30形成固体分散体的制备
称取帕布昔利布原料药100毫克,酒石酸200毫克,放入容量为10毫升的西林瓶中,加入2毫升纯净水,用混合溶解。在上述溶液中加入200毫克PVP-K30(德国巴斯夫公司产品,全称:聚维酮K30),超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜。第二天取出,固体分散体制成。
实施例4
帕布昔利布与酸性物料混合后,与固体载体PVP-VA64形成固体分散体的制备
称取帕布昔利布原料药100毫克,酒石酸200毫克,放入容量为10毫升的西林瓶中。加入2毫升双蒸水,混合溶解。在上述溶液中加入200毫克PVP-VA64(德国巴斯夫公司产品,全称:共聚维酮),超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜放置18小时。第二天取出,固体分散体制成。
实施例5
帕布昔利布与酸性物料混合后,与固体载体Soluplus形成固体分散体的制备
称取帕布昔利布原料药100毫克,酒石酸200毫克,放入容量为10毫升的西林瓶中。加入2毫升双蒸水,混合溶解。在上述溶液中加入200毫克Soluplus(德国巴斯夫产品,全称:聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物),超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜。第二天取出,固体分散体制成。
实施例6
帕布昔利布与酸性物料混合后,与固体载体HPMC-E5形成固体分散体的制备
称取帕布昔利布原料药100毫克,酒石酸200毫克,放入容量为10毫升的西林瓶中。加入2毫升双蒸水,混合溶解。在上述溶液中加入200毫克HPMC-E5(德国巴斯夫产品,全称:羟丙甲纤维素E5),超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜。第二天取出,固体分散体制成。
实施例7
帕布昔利布与酸性物料混合后,与固体载体HPMC-AS-HF形成固体分散体的制备
称取帕布昔利布原料药100毫克,酒石酸200毫克,放入容量为10毫升的西林瓶中。加入2毫升双蒸水,混合溶解。在上述溶液中加入200毫克HPMC-AS-HF(德国巴斯夫产品,全称:羟丙甲纤维素AS-HF),超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜。第二天取出,固体分散体制成。
实施例8
帕布昔利布与酸性物料及盐酸混合后,与固体载体PVPVA64形成固体分散体的制备
称取帕布昔利布原料药125毫克,放入容量为10毫升的西林瓶中;加入1.991毫升双蒸水,以及8.63微升的36%盐酸溶液(密度为1.18g/mL),使盐酸和帕布昔利布原料药的摩尔比为1:1。再加入酒石酸200毫克,在超声作用下完全混合溶解。在上述溶液中加入100毫克PVPVA64,超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜。第二天取出,固体分散体制成。
实施例9
帕布昔利布与酸性物料及磷酸混合后,与固体载体PVPVA64形成固体分散体的制备
称取帕布昔利布原料药125毫克,放入容量为10毫升的西林瓶中;加入2毫升双蒸水,以及27.3毫克磷酸,使磷酸和帕布昔利布原料药的摩尔比为1:1。再加入酒石酸200毫克,在超声作用下完全混合溶解。在上述溶液中加入100毫克PVPVA64,超声配合手摇振荡使之溶解。在通风橱中,加热条件下搅拌帮助水分挥发;辅助以通氮气助水分蒸发。待西林瓶内呈胶状,并不再有液体减少时,停止加热搅拌。放入真空干燥器内,40℃下过夜。第二天取出,固体分散体制成。
实施例10
将实施例3中与PVP-K30制成的帕布昔利布固体分散体与帕布昔利布原料药一同送检XRPD。XRPD测试使用Panalytical(帕纳科)公司的XPERT-3型X射线衍射仪。将约10毫克样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试:扫描范围(2θ°):3–40;扫描步长(2θ°):0.0263;扫描时间(秒):46.665;K-Alpha 1.54060;K-Alpha21.54443;功率设置:40mA,45kV。所得帕布昔利布原料药的XRPD图谱见图6;与PVP-K30制成的固体分散体XRPD图谱见图9。
实施例11
将实施例4中与PVP-VA64制成的帕布昔利布固体分散体一同送检XRPD。XRPD测试使用Panalytical(帕纳科)公司的XPERT-3型X射线衍射仪。将约10毫克样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试:扫描范围(2θ°):3–40;扫描步长(2θ°):0.0263;扫描时间(秒):46.665;K-Alpha1.54060;K-Alpha21.54443;功率设置:40mA,45kV。所得XRPD图谱见图8。
实施例12
将实施例5中与Soluplus制成的帕布昔利布固体分散体一同送检XRPD。XRPD测试使用Panalytical(帕纳科)公司的XPERT-3型X射线衍射仪。将约10毫克样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试:扫描范围(2θ°):3–40;扫描步长(2θ°):0.0263;扫描时间(秒):46.665;K-Alpha1.54060;K-Alpha21.54443;功率设置:40mA,45kV。所得XRPD图谱见图10。
实施例13
将实施例6中与HPMC-E5制成的固体分散体一同送检XRPD。XRPD测试使用Panalytical(帕纳科)公司的XPERT-3型X射线衍射仪。将约10毫克样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试:扫描范围(2θ°):3–40;扫描步长(2θ°):0.0263;扫描时间(秒):46.665;K-Alpha1.54060;K-Alpha2 1.54443;功率设置:40mA,45kV。所得XRPD图谱见图11。
实施例14
将实施例7中与HPMC-AS-HF制成的固体分散体一同送检XRPD。XRPD测试使用Panalytical(帕纳科)公司的XPERT-3型X射线衍射仪。将约10毫克样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试:扫描范围(2θ°):3–40;扫描步长(2θ°):0.0263;扫描时间(秒):46.665;K-Alpha1.54060;K-Alpha21.54443;功率设置:40mA,45kV。所得XRPD图谱见图7。
实施例15
分别称取实施例3中所制备的固体分散体62.5毫克(按比例含有帕布昔利布原料药12.5毫克)以及帕布昔利布原料药12.5毫克,并分别放入两个100毫升烧杯中,标记T1和T2。在两个烧杯中分别加入90毫升磷酸盐缓冲液(pH6.0),并放入磁力搅拌子。将两个烧杯分别置于磁力搅拌器上。分别在时间点5、10、20、40、60分钟,从每个烧杯中分别取出1毫升溶液,用0.45微米的microPES聚醚砜滤膜过滤。将滤液用高效液相色谱分析,测定帕布昔利布原料药含量,并计算其溶解百分比,结果参见图4。
以上实施例的说明只是用于帮助理解本发明的核心思想。应当指出,对于本领域的普通技术人员而言,在不脱离本发明原理的前提下,还可以对本发明的新型制剂及其制备方法进行若干改进和修饰,但这些改进和修饰也落入本发明权利要求请求保护的范围内。
Claims (17)
1.一种帕布昔利布的药物制剂,其包括帕布昔利布游离碱或其可药用盐和酸性辅料,其中所述酸性辅料选自酒石酸、富马酸、琥珀酸、柠檬酸、乳酸和苹果酸中的一种或多种,以及其中所述酸性辅料与帕布昔利布的质量比为0.2:1至5:1。
2.权利要求1的药物制剂,其中所述帕布昔利布游离碱或其盐是固体,且粒径在20μm以下。
3.权利要求1或2的药物制剂,其中所述酸性辅料与帕布昔利布的质量比为0.5:1至2:1。
4.权利要求1或2的药物制剂,其为片剂或胶囊剂。
5.权利要求4的药物制剂,其中所述片剂或胶囊的剂量为25-500mg。
6.权利要求5的药物制剂,其中所述片剂或胶囊的剂量为50-150mg。
7.一种帕布昔利布的固体分散体,其包括帕布昔利布游离碱或其可药用盐、酸性辅料和亲水性高分子材料。
8.权利要求7的固体分散体,其中所述酸性辅料选自一种或多种可药用有机酸以及任选的一种或多种可药用无机酸。
9.权利要求8的固体分散体,其中所述可药用有机酸选自酒石酸、富马酸、琥珀酸、柠檬酸、乳酸、苹果酸、脂肪族磺酸和芳香族磺酸,以及所述可药用无机酸选自盐酸、硫酸和磷酸。
10.权利要求9的固体分散体,其中所述脂肪族磺酸选自甲磺酸、乙磺酸和羟乙基磺酸,以及芳香族磺酸选自苯磺酸和对甲苯磺酸。
11.权利要求7的固体分散体,其中所述亲水性高分子材料选自聚维酮K30、共聚维酮VA64、Soluplus、羟丙基甲基纤维素E5、醋酸羟丙基甲基纤维素琥珀酸酯、羟丙基-β-环糊精和磺丁基醚-β-环糊精中的一种或多种。
12.权利要求7-11任一项的固体分散体,其中所述亲水性高分子材料与帕布昔利布的质量比为0.1:1至10:1,而所述酸性辅料与帕布昔利布的质量比为0.2:1至5:1。
13.权利要求12的固体分散体,其中所述亲水性高分子材料与帕布昔利布的质量比为1:1至3:1,而所述酸性辅料与帕布昔利布的质量比为0.5:1至2:1。
14.权利要求1-6任一项的药物制剂的制备方法,包括将帕布昔利布原料药与药学上可接受的酸性辅料混合,或者将帕布昔利布原料药进行粉碎,控制粒径在20微米以下,再与酸性辅料混合,或者在原料药中添加酸性辅料,混合后进行共同粉碎,以控制粒径在20微米以下。
15.权利要求7-13任一项的固体分散体的制备方法,包括在帕布昔利布原料药与酸性辅料混合后,加溶剂进行溶解或分散,再添加亲水性高分子材料,溶解或分散均匀后,经加热去除溶剂。
16.权利要求15的制备方法,其中帕布昔利布原料药在溶剂中的浓度高达50mg/ml以上。
17.权利要求1-6任一项的药物制剂或权利要求7-13任一项的固体分散体在制备用于治疗乳腺癌的药物中的应用。
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PCT/CN2016/086546 WO2017166451A1 (zh) | 2016-03-29 | 2016-06-21 | 一种帕布昔利布的药物制剂及其制备方法 |
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EA201892173A EA201892173A1 (ru) | 2016-03-29 | 2016-06-21 | Фармацевтический состав палбоциклиба и способ его получения |
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US17/024,389 US11464779B2 (en) | 2016-03-29 | 2020-09-17 | Pharmaceutical formulation of palbociclib and a preparation method thereof |
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JP6799612B2 (ja) | 2020-12-16 |
CN109078006A (zh) | 2018-12-25 |
US20230226063A1 (en) | 2023-07-20 |
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GB202010241D0 (en) | 2020-08-19 |
CA3019257C (en) | 2023-08-22 |
BR112018070198A2 (pt) | 2019-01-29 |
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EP3437637A1 (en) | 2019-02-06 |
CN105816437B (zh) | 2018-08-03 |
CA3019257A1 (en) | 2017-10-05 |
KR20190013723A (ko) | 2019-02-11 |
IL261989A (en) | 2018-10-31 |
IL261989B1 (en) | 2024-04-01 |
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