CN1547484A - 无定形甲磺酸奈非那韦的药物剂型 - Google Patents
无定形甲磺酸奈非那韦的药物剂型 Download PDFInfo
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Abstract
本发明提供了无定形甲磺酸奈非那韦的固体单位口服药物剂型,其中含有无定形甲磺酸奈非那韦和可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物,所述共聚物的熔点至少为40℃。本发明还提供了制备所述剂型的热熔融制粒工艺。
Description
甲磺酸奈非那韦是用于在HIV感染个体中限制病毒复制并增强免疫功能的几种蛋白酶抑制剂之一。关于甲磺酸奈非那韦的一些信息在“Viracept(甲磺酸奈非那韦,AG1343):一种有效的、可口服的HIV-1蛋白酶抑制剂”,Kaldor等,J.Med.Chem,
40,3979-85(1997)中有所报道,关于它在HIV治疗方面的应用在“奈非那韦:在HIV感染方面应用的最新资料”,Bardsley-Elliot等,Drugs,
59(3),581-620(2000)中有所报道。
甲磺酸奈非那韦是一种白色到接近白色的无定形粉末,微溶于pH值为4或更低的水中。甲磺酸奈非那韦的分子量为663.90(游离碱为567.79)。
市售的甲磺酸奈非那韦是250mg的片剂(奈非那韦游离碱)。其销售时使用的名称为Viracept,由辉瑞公司的Agouron制药公司出产。已知Viracept片剂含有硅酸钙、交联聚乙烯吡咯烷酮、硬脂酸镁、FD&C 2号蓝粉末、羟丙甲基纤维素和甘油三醋酸酯。授予Albizati等人(转让给Agouron制药公司)的美国专利US 6,001,851报道了含有292mg HIV抑制剂(其可以是甲磺酸奈非那韦)的片剂组合物(制剂9)。尽管所报道的组合物中含有硅酸钙、交联聚乙烯吡咯烷酮和硬脂酸镁,但该专利并没有具体公开市售的制剂Viracept。在该专利所报道的组合物中,硅酸钙和交联聚乙烯吡咯烷酮各占25%。
对于成年患者,推荐的甲磺酸奈非那韦(以奈非那韦游离碱计)的口服剂量是750mg(3×250mg片剂),每日3次,或1250mg(5×250mg片剂),每日2次。无论采用每日2次还是每日3次的给药方案,全天的片剂服用量都很大。因此患者的依从性是个切实的问题。
环氧乙烷和环氧丙烷的嵌段共聚物在NF专论“泊洛沙姆”中被列为泊洛沙姆类,它们的分子量和熔点范围很广。市售的名称为Lutrol或Pluronic,由BASF公司生产。泊洛沙姆被广泛地用作药用湿润剂和增溶剂,用量通常较小。
已知将泊洛沙姆用于药物制剂中可以提高药物的生物利用度。例如,在授予Sangekar等人的美国专利US 5,834,472中报道了,在水溶性很低的抗真菌化合物的组合物中加入非离子表面活性剂即环氧乙烷和环氧丙烷的嵌段共聚物可以提高化合物的生物利用度。授予Kelm等人的美国专利US5,281,420中报道了药物特丁非隆的制剂,特丁非隆是一种抗炎剂、镇痛剂和/或解热剂,基本上不溶于水。胃肠道对特丁非隆的吸收很少。Kelm等人报道了一种通过将特丁非隆(熔点为70℃)和泊洛沙姆一起熔融形成均匀的熔融混合物而产生的特丁非隆固体分散体。将混合物冷却并固化后就产生了这种均匀的熔融混合物的固体分散体。加入的泊洛沙姆表面活性剂使这种高度不溶的药物在形成熔融混合物时有足够的溶解度。
在本发明之前,一直没有成功地开发出具有令人满意的溶解度和生物利用度的甲磺酸奈非那韦的高剂量固体单位口服剂量形式,如片剂。这部分是由于药物的疏水性本质造成的,这使得它在水中的溶解度很低。此外,高剂量固体单位剂量形式的甲磺酸奈非那韦在与生理液体接触时会形成凝胶。凝胶会限制药物的溶解度和生物利用度。加大药物用量后凝胶化的问题会更加严重。
发明概述
本发明提供了无定形甲磺酸奈非那韦的固体单位口服药物剂量形式,其中含有无定形甲磺酸奈非那韦和可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物,共聚物的熔点至少为40℃。本发明的高剂量甲磺酸奈非那韦药物剂型具有另人满意的溶解度和生物利用度。
本发明还提供了制备无定形甲磺酸奈非那韦的固体单位口服药物剂型的方法,该方法包括:(a)将无定形甲磺酸奈非那韦和可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物的混合物加热,所述共聚物的熔点至少为40℃,加热的温度为共聚物的熔点温度至低于甲磺酸奈非那韦的分解温度,(b)将混合物混合至形成熔融颗粒,(c)将熔融颗粒加工成无定形甲磺酸奈非那韦的固体单位口服剂量形式。
附图的简要描述
图1比较了625mg甲磺酸奈非那韦片剂(实施例II和III)和市售的250mg(片剂)制剂(实施例I)的溶解特性。
图2比较了本发明的625mg甲磺酸奈非那韦片剂(实施例IV和V)和其他625mg甲磺酸奈非那韦片剂(实施例II和III)的溶解特性。
图3显示了泊洛沙姆188的浓度对625mg甲磺酸奈非那韦片剂(实施例VI,VII,VIII和IX)的溶解特性的影响。
图4比较了给予2×625mg本发明甲磺酸奈非那韦片剂(实施例VI)和给予5×250mg市售片剂(实施例I)以后的平均血浆浓度对时间的曲线。
发明详述
现已惊奇地发现,当按照本发明将无定形甲磺酸奈非那韦与可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物一起熔融制粒后,会明显增加药物的溶解速度并显示出令人满意的生物利用度。用于生产本发明的固体单位剂量形式的甲磺酸奈非那韦是无定形的。若无另外说明,药物剂量都是用奈非那韦的游离碱形式计算的。与市售的250mg药物相比,本发明的药物剂型中含有高剂量的甲磺酸奈非那韦,并可用于口服。考虑到患者的依从性和接受性,固体单位口服药物剂型的最大重量通常为1.0g到1.5g。本发明包括甲磺酸奈非那韦的含量为400mg(在该含量下,采用常规的药物赋形剂和制备方法将会出现甲磺酸奈非那韦凝胶化的问题)到700mg的固体单位口服剂量形式。剂量形式中含有400mg到700mg甲磺酸奈非那韦,优选500mg到700mg。优选的剂量为例如625mg。
根据本发明,可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物的分子量应在6,000D到18,000D之间,优选6800D到17500D之间,熔点优选为40℃到60℃之间,更优选49℃到57℃之间。在25℃时的水/脂平衡(“HLB”)值至少为14,优选14到29,更优选22到29。该共聚物易溶于水。通常,本发明的共聚物中环氧乙烷的含量(氧化乙烯基团的百分比)至少为70%(重量),优选70%到85%(重量)。合适的可药用、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物列于NF专论“泊洛沙姆”中。根据本发明,优选的共聚物包括Lutrol或PluronicF68、F87、F108和F127(BASF公司)。用PluronicF68取得了很好的结果。共
聚物具有以下性质:
Lutrol | 泊洛沙姆,NF | 氧化乙烯重量% | 分子量(D) | 熔点(℃) | 25℃时的HLB值 |
F68 | 188 | 81.8±1.9 | 7680-9510 | 52 | 29 |
F87 | 237 | 72.4±1.9 | 6840-8830 | 49 | 24 |
F108 | 338 | 83.1±1.7 | 12700-17400 | 57 | 27 |
F127 | 407 | 73.2±1.7 | 9840-14600 | 56 | 22 |
本发明的药物剂型中的嵌段共聚物的含量为甲磺酸奈非那韦重量的40%到65%,优选45%到60%,更优选50%到55%。
本发明的甲磺酸奈非那韦药物剂型是通过加热熔融制粒过程生产的。本发明的加热熔融制粒过程包括将甲磺酸奈非那韦与共聚物混合,将混合物加热到共聚物的熔点到低于甲磺酸奈非那韦的分解温度之间的温度。这种加热熔融制粒过程会使药物包埋到共聚物中形成熔融颗粒。将加热的混合物混合直到获得熔融颗粒。优选将混合物加热到甲磺酸奈非那韦-共聚物混合物中的甲磺酸奈非那韦仍保持固态的温度。可以采用带有夹套的混合器或热熔融挤出机来制备熔融颗粒。
在甲磺酸奈非那韦和共聚物的混合物中可以含有一种或多种赋形剂。赋形剂可以选自稳定剂、湿润剂、粘合剂、崩解剂、稀释剂和增溶剂。例如,在甲磺酸奈非那韦-共聚物混合物中可以含有的添加剂有聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯失水山梨糖醇C8-C18脂肪酸酯(如Tween20、Tween60和Tween80)等等。将加热的混合物混合并形成熔融颗粒,形成的熔融颗粒中含有一种或多种可药用的赋形剂。然后粉碎熔融颗粒,与一种或多种药用赋形剂混合。加入到粉碎颗粒中的赋形剂可以选自滑润剂、崩解剂和稀释剂。例如,药用赋形剂可以是微晶纤维素、玉米淀粉、硬脂酸镁等等。
本发明的加热熔融制粒过程包括将奈非那韦和可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物加热制备熔融颗粒,所述共聚物的熔点至少为40℃,加热的温度为共聚物的熔点温度至低于甲磺酸奈非那韦的分解温度。优选的加热温度为50℃到85℃,条件是该温度至少是共聚物的熔点温度。然后将加入或不加任何药用赋形剂制成的熔融颗粒加工成固体单位口服剂型。
制备片剂时,可通过粉碎、润滑、压片(制片)以及通常是含水薄膜包衣将熔融颗粒加工成固体单位口服剂型。
在本发明的一个实施方案中,按照以下描述来制备片剂:
a)将用量为每单位剂量400mg到700mg(以游离碱形式计算)的无定形甲磺酸奈非那韦与用量为甲磺酸奈非那韦重量的40%到65%的本发明共聚物相混合;
b)将步骤(a)中得到的粉末混合物在带夹套的高剪切制粒机中于60℃±10℃下混合,条件是温度至少是共聚物的熔点温度,或者在80℃±5℃下在带夹套的热熔融挤出机中混合,直到获得熔融颗粒;
将熔融颗粒冷却至室温;
c)将步骤(b)中得到的颗粒粉碎成细的粉末;
d)将步骤(c)中得到的粉碎颗粒与其他适宜的片剂稀释剂如玉米淀粉和微晶纤维素相混合;
e)用合适的润滑剂如硬脂酸镁将步骤(d)中得到的颗粒润滑;
f)在压片机上将步骤(e)中得到的最后的混合物压片;
g)将步骤(f)中得到的片剂进行含水薄膜包衣。
也可以通过加热熔融挤出来制备本发明的药物剂型。加热熔融挤出可以用来制备模制片剂。
固体口服单位剂型可以是片剂、胶囊或胶囊形片剂。药物组合物可以含有一种或多种选自稳定剂、湿润剂、粘合剂、崩解剂、稀释剂、增溶剂和润滑剂的可药用赋形剂。例如,赋形剂可以是微晶纤维素、玉米淀粉、硬脂酸镁、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯失水山梨糖醇C8-C18脂肪酸酯(如Tween20,Tween60和Tween80)等等。
实施例
实施例I:250mg甲磺酸奈非那韦片剂(市售制剂)
该实施例使用市售的Viracept片剂
实施例II:625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
甲磺酸奈非那韦 | 730.625* |
交联聚乙烯吡咯烷酮 | 240.000 |
硅酸钙 | 217.375 |
纯化水 | 适量** |
硬脂酸镁 | 12.000 |
片剂重量 | 1200.000 |
*等于625mg奈非那韦游离碱
**在加工过程中除去
实施例II的片剂是用传统的水湿法制粒工艺制备的。
实施例III:625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
甲磺酸奈非那韦 | 730.625* |
交联聚乙烯吡咯烷酮 | 100.000 |
无水磷酸氢钙 | 169.375 |
纯化水 | 适量** |
硬脂酸镁 | 10.000 |
片剂重量 | 1010.000 |
*等于625mg奈非那韦游离碱
**在加工过程中除去
实施例III的片剂是用传统的水湿法制粒工艺制备的。
实施例IV:本发明的625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
药核: | |
甲磺酸奈非那韦 | 730.625* |
泊洛沙姆188(LutrolF68) | 394.375** |
玉米淀粉 | 60.000 |
硬脂酸镁 | 7.000 |
药核重量 | 1192.000 |
膜包衣 | |
HPMC 2910-6厘泊 | 7.341 |
Pharmacoat 603 | 10.500 |
滑石 | 5.969 |
二氧化钛 | 5.682 |
氧化铁红 | 0.048 |
氧化铁黄 | 0.048 |
Aquacoat ECD-30 | 5.987*** |
甘油三醋酸酯 | 2.425 |
纯化水 | 138.030**** |
总重量 | 1230.000 |
*等于625mg奈非那韦游离碱
**大约为甲磺酸奈非那韦的54%w/w
***基于30%混悬液中的干燥固体含量
****在加工过程中除去;这部分水不包括Aquacoat ECD-30中的水
实施例IV中的片剂是用热熔融制粒法制备的,如下:
步骤1)将甲磺酸奈非那韦和LutrolF68在温度设定为25℃±5℃的带夹套的高剪切制粒机中用低速叶轮和低速切碎机混合5分钟。
步骤2)将夹套的温度升高为60℃±10℃,条件是温度至少是LutrolF68的熔点,并继续用低速叶轮和低速切碎机将粉末混合物(步骤1)在高剪切制粒机中混合,直至获得合适的颗粒,然后关闭叶轮和切碎机。
步骤3)停止对夹套的加热。向夹套内通入自来水(25℃±5℃)使产品冷却至室温,间歇地开动低速叶轮和低速切碎机。
步骤4)将步骤3中得到的颗粒通过粉碎器。
步骤5)将约50%的步骤4中得到的粉碎颗粒置于双壁搅拌机中。向搅拌机中加入玉米淀粉和硬脂酸镁(经过30目不锈钢筛)。将剩余的步骤4中得到的粉碎颗粒加入到搅拌机中搅拌8分钟。
步骤6)将步骤5中得到的颗粒压制成含有625mg(以游离碱计)甲磺酸奈非那韦的片剂。
步骤7)按照如下方法制备包衣混悬液:在不锈钢容器中,使用推进式混合器将甘油三醋酸酯和Aquacoat ECD-30分散在纯化水中,混合45分钟。加入HPMC 2910-6厘泊、Pharmacoat 603、滑石、二氧化钛、氧化铁黄和氧化铁红并缓慢分散,轻轻混合,避免引入空气。继续混合60分钟或直到获得均匀的悬浮液。
步骤8)将步骤6中得到的药物内核置于多孔包衣锅中。通入50℃±3℃的热空气进行加热并间断性地缓慢搅拌,直到出口的空气温度达到38℃±3℃。
步骤9)将入口的空气温度升高到60℃±3℃。使用空气喷雾系统,连续搅动,将步骤7中得到的包衣混悬液喷雾到步骤8中的药物内核上,保持出口的空气温度在38℃±3℃。每个片剂的膜包衣重量为38mg(35-41mg,以干重计)。
步骤10)将入口的空气温度降到40℃±3℃,通过轻轻搅动将包衣片剂干燥,直到在90℃时的干燥失重在1.8%以下。关闭加热器,偶尔轻轻搅动将片剂冷却到室温。
实施例V:本发明的625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
药核: | |
甲磺酸奈非那韦 | 730.625* |
泊洛沙姆188(LutrolF68) | 394.375** |
微晶纤维素 | 40.000 |
玉米淀粉 | 20.000 |
硬脂酸镁 | 7.000 |
药核重量 | 1192.000 |
膜包衣 | |
HPMC 2910-6厘泊 | 13.140 |
滑石 | 4.085 |
二氧化钛 | 4.084 |
FD&C 2号蓝 | 0.591 |
Aquacoat ECD-30 | 4.400*** |
甘油三醋酸酯 | 1.700 |
纯化水 | 117.290**** |
总重量 | 1220.000 |
*等于625mg奈非那韦游离碱
**大约为甲磺酸奈非那韦的54%w/w
***基于30%混悬液中的干燥固体含量
****在加工过程中除去;这部分水不包括Aquacoat ECD-30中的水
对于本实施例,用上表中列出的各个组分的量进行实施例IV中描述的熔融制粒法。在如下的步骤7和9中反映了片剂包衣方面的不同,用这两个步骤代替实施例IV的步骤7和9。
按照如下方法制备包衣混悬液:在不锈钢容器中,使用推进式混合器将甘油三醋酸酯和Aquacoat ECD-30分散在纯化水中,混合45分钟。加入HPMC 2910-6厘泊、滑石、二氧化钛和FD&C2号蓝并缓慢分散,轻轻混合,避免引入空气。继续混合60分钟或直到获得均匀的混悬液。
将入口的空气温度升高到60℃±3℃。使用空气喷雾系统,连续搅动,将步骤7中得到的包衣混悬液喷雾到步骤8中得到的药物内核上,保持出口的空气温度在38℃±3℃。每个片剂的膜包衣重量为28mg(25-31mg,以干重计)。
实施例VI:625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
甲磺酸奈非那韦 | 730.625* |
泊洛沙姆188(LutrolF68) | 182.656** |
玉米淀粉 | 102.616 |
硬脂酸镁 | 10.262 |
片剂重量 | 1026.159 |
*等于625mg奈非那韦游离碱
**大约为甲磺酸奈非那韦的25%w/w
实施例VI中的片剂通过如下所述的热熔融制粒法制备:
用混合器将甲磺酸奈非那韦和LutrolF68混合10分钟。
将步骤1中得到的粉末混合物加入到温度设定为80℃±5℃的带夹套的热熔融挤出机中,充分混合直到形成均匀的熔融混合物。
本实施例的步骤3到6采用的是实施例IV中的步骤3到6。
实施例VII:625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
甲磺酸奈非那韦 | 730.625* |
泊洛沙姆188(LutrolF68) | 243.542** |
玉米淀粉 | 109.457 |
硬脂酸镁 | 10.946 |
片剂重量 | 1094.570 |
*等于625mg奈非那韦游离碱
**大约为甲磺酸奈非那韦的33%w/w
采用与实施例VI相同的热熔融制粒法。
实施例VIII:本发明的625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
甲磺酸奈非那韦 | 730.625* |
泊洛沙姆188(LutrolF68) | 343.824** |
玉米淀粉 | 120.725 |
硬脂酸镁 | 12.073 |
片剂重量 | 1207.247 |
*等于625mg奈非那韦游离碱
**大约为甲磺酸奈非那韦的47%w/w
采用与实施例VI相同的热熔融制粒法。
实施例IX:本发明的625mg甲磺酸奈非那韦片剂
成分 | mg/片 |
甲磺酸奈非那韦 | 730.625* |
泊洛沙姆188(LutrolF68) | 443.215** |
玉米淀粉 | 131.892 |
硬脂酸镁 | 13.189 |
片剂重量 | 1318.921 |
*等于625mg奈非那韦游离碱
**大约为甲磺酸奈非那韦的61%w/w
采用与实施例VI相同的热熔融制粒法。
实施例X:溶解试验
在37℃±0.5℃时,用搅拌方法(USP设备2)在50rpm条件下测定含有甲磺酸奈非那韦的片剂(实施例I-IX)在900ml 0.1N盐酸溶液中的溶解情况。取出不同时间点的样本溶液用紫外分光光度法进行分析。
图1比较了不含本发明的嵌段共聚物的625mg甲磺酸奈非那韦片剂(实施例II和III)与250mg市售药物(片剂)(实施例I)的溶解特性。与250mg市售药物(片剂)(实施例I)相比,不含嵌段共聚物的625mg甲磺酸奈非那韦片剂(实施例II和III)的溶解明显较慢而且不完全。实施例II和III的片剂含有常规的赋形剂,用传统的水湿法制粒工艺制备而成。
如图2所示,溶解评价结果表明,与使用常规的赋形剂和传统的水湿法制粒工艺制备而成的625mg甲磺酸奈非那韦片剂(实施例II和III)相比,本发明的625mg甲磺酸奈非那韦片剂(实施例IV和V)的溶解更快且更完全。
图3中显示了实施例VI至IX的片剂的溶解特性。结果表明,嵌段共聚物的浓度对甲磺酸奈非那韦的溶解速度和完全程度起重要的作用。实施例VI和VII中含有的泊洛沙姆188的量分别是甲磺酸奈非那韦重量的25%和33%。实施例VIII和IX中含有的泊洛沙姆188的量分别是甲磺酸奈非那韦重量的47%和61%,它们的溶解速度更快且释放更完全。
实施例XI:药物动力学试验
在人中评价市售250mg甲磺酸奈非那韦片剂(实施例I)和本发明的625mg甲磺酸奈非那韦片剂(实施例IV)的生物利用度。每个个体都给予数个给定形式的甲磺酸奈非那韦片剂,总量是1250mg(以游离碱计)。在该研究中,每个药物动力学参数都用13个血液样本测定,即给药前和给药1、2、3、4、5、6、8、10、12、15、18和24小时后取得的样本。收集约5ml的静脉血置于肝素化的试管中。血样取出60分钟之内,在1500g,4℃条件下离心10分钟分离血浆。在分析之前,将血浆在-20℃保存。用液相色谱-质谱(LC-MS/MS)分析血浆中的奈非那韦含量。将定量限设定在4ng/ml。
用血浆浓度对时间的曲线来评价药物动力学参数。采取使用WinNonlin 3.1软件的标准非房室方法。将给药前取样的时间设定为零,各个给药后取样的时间设定为真正的时间。评价下列参数:
Cmax,最高观测血药浓度
tmax,达到最高观测血药浓度的时间
AUC0-24h,用WinNonlin的部分AUCs计算规则和线性梯形规则计算
AUC0-inf,用AUC最终+(C最终/k)计算,k(最终消除速率常数)可以得到
t1/2,半衰期,用Ln(2)/k计算,k可以得到
在下面的表1中列出了生物利用度的评价结果。
表1:给予1250mg甲磺酸奈非那韦(以游离碱计)*后药物动力学参数的总结:2×625mg本发明的片剂(实施例IV)与5×250mg市售片剂(实施例I)的比较
参数(单位) | 奈非那韦1250mg(以游离碱计) | |
实施例I | 实施例IV | |
N=12 | N=12 | |
AUC0-24(1×103 hr ng/ml) | ||
中值(最小值-最大值) | 43.5(21.1-89.7) | 37.0(27.5-73.2) |
平均值 | 44.4 | 42.3 |
几何平均值 | 41.8 | 40.0 |
CV% | 38.6 | 37.4 |
Cmax(ng/ml) | ||
中值(最小值-最大值) | 5275(2520-9590) | 4585(3680-8450) |
平均值 | 5248 | 5200 |
几何平均值 | 4971 | 5042 |
CV% | 34.9 | 27.7 |
tmax(hr) |
中值(最小值-最大值) | 4.0(3.0-6.0) | 4.0(2.0-6.0) |
平均值 | 4.1 | 4.0 |
CV% | 26.5% | 35.4% |
AUC0-inf(1×103hr ng/ml) | ||
中值(最小值-最大值) | 45.3(21.7-98.2) | 37.8(28.5-77.7) |
平均值 | 46.5 | 43.7 |
几何平均值 | 43.5 | 41.1 |
CV% | 41.2% | 39.7% |
t1/2(hr) | ||
中值(最小值-最大值) | 4.4(3.3-6.8) | 3.9(3.0-5.7) |
平均值 | 4.5 | 3.9 |
几何平均值 | 4.3 | 3.8 |
CV% | 24.9% | 22.0% |
*与饮食一起给药
表1中的数据和图4中的曲线表明,当随饮食一起给药时,2×625mg本发明的甲磺酸奈非那韦片剂(实施例IV)与5×250mg市售的片剂(实施例I)的生物利用度相当。本发明提供了具有另人满意的溶解度和生物利用度的高剂量甲磺酸奈非那韦的固体单位口服药物组合物。
Claims (12)
1.无定形甲磺酸奈非那韦的固体单位口服药物剂型,其中含有无定形甲磺酸奈非那韦和可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物,所述共聚物的熔点至少为40℃。
2.权利要求1的药物剂型,其中所述共聚物的含量为甲磺酸奈非那韦重量的40%到65%。
3.权利要求1或2的药物剂型,其中所述共聚物的熔点是40℃到60℃。
4.权利要求1至3的药物剂型,其中所述共聚物在25℃时的HLB值至少是14。
5.权利要求4的药物剂型,其中所述共聚物在25℃时的HLB值是14到29。
6.权利要求1至5的药物剂型,其中所述共聚物中环氧乙烷的含量至少为70%(重量)。
7.权利要求1至6的药物剂型,其中,以奈非那韦碱计算的甲磺酸奈非那韦的含量为400mg到700mg。
8.权利要求1至7的药物剂型,其中还含有选自稳定剂、湿润剂、粘合剂、崩解剂、稀释剂、增溶剂和润滑剂的可药用赋形剂。
9.权利要求1至8的药物剂型,其为片剂、胶囊或胶囊形片剂。
10.制备权利要求1至9的固体单位口服药物剂型的方法,包括以下步骤:
(a)将无定形甲磺酸奈非那韦和可药用的、水溶性、非离子型合成环氧乙烷和环氧丙烷的嵌段共聚物的混合物加热,所述共聚物的熔点至少为40℃,加热的温度为共聚物的熔点温度至低于甲磺酸奈非那韦的分解温度,
(b)将混合物混合至形成熔融颗粒,和
(c)将熔融颗粒加工成无定形甲磺酸奈非那韦的所述剂量形式。
11.权利要求1至9的固体单位口服药物剂型用于治疗。
12.权利要求10的固体单位口服药物剂型用于治疗HIV介导的疾病。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103893145A (zh) * | 2005-09-23 | 2014-07-02 | 弗·哈夫曼-拉罗切有限公司 | 新型制剂 |
CN105769809A (zh) * | 2014-12-23 | 2016-07-20 | 上海星泰医药科技有限公司 | 提高生物利用度的雷尼司他及其制备方法 |
Families Citing this family (109)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001034119A2 (en) | 1999-11-12 | 2001-05-17 | Abbott Laboratories | Inhibitors of crystallization in a solid dispersion |
DE10026698A1 (de) | 2000-05-30 | 2001-12-06 | Basf Ag | Selbstemulgierende Wirkstoffformulierung und Verwendung dieser Formulierung |
CA2398226A1 (en) * | 2002-01-28 | 2003-07-28 | Pfizer Inc. | Increased-dosage nelfinavir tablet and method of making same |
WO2005004868A1 (ja) | 2003-07-15 | 2005-01-20 | Arigen, Inc. | 抗コロナウイルス剤 |
US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
CA2548376A1 (en) * | 2003-12-31 | 2005-07-21 | Pfizer Products Inc. | Solid compositions of low-solubility drugs and poloxamers |
NZ555120A (en) * | 2004-12-03 | 2009-11-27 | Merck & Co Inc | Pharmaceutical formulation of carboxamide HIV integrase inhibitors containing a release rate controlling composition |
CN101330906B (zh) * | 2005-12-14 | 2010-12-29 | 弗·哈夫曼-拉罗切有限公司 | Hcv前药制剂 |
AU2006326130B2 (en) * | 2005-12-14 | 2011-09-22 | F. Hoffmann-La Roche Ag | HCV prodrug formulation |
CL2007002331A1 (es) * | 2006-08-10 | 2008-04-18 | Cipla Ltd | Composicion oral solida que comprede uno o mas farmacos antirretrovirales y al menos un polimero insoluble en agua, en relacion aproximadamente 1:1 hasta 1:6; proceso de elaboracion; y uso para el tratamiento del vih. |
DE602007013567D1 (de) | 2006-08-16 | 2011-05-12 | Novartis Ag | Verfahren zur herstellung fester dispersionen von midostaurin |
CA2669938C (en) * | 2006-11-15 | 2016-01-05 | Abbott Laboratories | Solid pharmaceutical dosage formulations |
WO2008115442A1 (en) | 2007-03-16 | 2008-09-25 | Concert Pharmceuticals, Inc. | Inhibitors of cholesterol ester transfer protein |
KR20100105802A (ko) * | 2007-04-19 | 2010-09-29 | 콘서트 파마슈티컬즈, 인크. | 중수소화된 모르폴리닐 화합물 |
US20090042842A1 (en) | 2007-04-25 | 2009-02-12 | Concert Pharmaceuticals, Inc. | Analogues of cilostazol |
US9194512B2 (en) | 2007-04-30 | 2015-11-24 | Mark Andreychuk | Coiled tubing with heat resistant conduit |
US8567657B2 (en) * | 2007-04-30 | 2013-10-29 | Mtj Consulting Services Inc. | Coiled tubing with retainer for conduit |
PL2522668T3 (pl) * | 2007-05-01 | 2015-07-31 | Concert Pharmaceuticals Inc | Związki morfinanu |
US7608737B2 (en) | 2007-05-01 | 2009-10-27 | Concert Pharmaceuticasl Inc. | Naphthyl(ethyl)acetamides |
HUE029782T2 (en) | 2007-05-01 | 2017-04-28 | Concert Pharmaceuticals Inc | morphinan |
EP4183787A1 (en) | 2007-05-01 | 2023-05-24 | Concert Pharmaceuticals Inc. | Morphinan compounds |
WO2008156632A1 (en) | 2007-06-12 | 2008-12-24 | Concert Pharmaceuticals, Inc. | Azapeptide derivatives |
US8410124B2 (en) * | 2007-10-18 | 2013-04-02 | Concert Pharmaceuticals Inc. | Deuterated etravirine |
WO2009052391A1 (en) * | 2007-10-19 | 2009-04-23 | Purdue Research Foundation | Solid formulations of crystalline compounds |
ITMI20080227A1 (it) * | 2008-02-13 | 2009-08-14 | Felice Vinati | '' dispositivo di sicurezza per apparati di sollevamento a fune '' |
EP2265334A2 (en) | 2008-02-29 | 2010-12-29 | Concert Pharmaceuticals, Inc. | Substituted xanthine derivatives |
WO2009146310A1 (en) * | 2008-05-28 | 2009-12-03 | Concert Pharmaceuticals Inc. | Deuterated tizanidine |
US20100221221A1 (en) * | 2008-08-12 | 2010-09-02 | Concert Pharmaceuticals Inc. | N-phenyl-2-pyrimidineamine derivatives |
DK2418211T3 (en) | 2008-09-19 | 2016-06-27 | Concert Pharmaceuticals Inc | DEUTERATED MORPHINAN COMPOUNDS |
EP2397159A3 (en) | 2008-10-30 | 2012-02-22 | Concert Pharmaceuticals, Inc. | Combination of morphinan compounds and antidepressant for the treatment of intractable and chronic pain |
EP2365808B1 (en) | 2008-10-30 | 2018-01-10 | Concert Pharmaceuticals Inc. | Combination of morphinan compounds and antidepressant for the treatment of pseudobulbar affect, neurological diseases, intractable and chronic pain and brain injury |
CN102202678A (zh) | 2008-11-04 | 2011-09-28 | 安科治疗公司 | Cxcr4受体化合物 |
US20110313004A1 (en) | 2008-12-04 | 2011-12-22 | Concert Pharmaceuticals, Inc. | Deuterated pyridinones |
US20110053961A1 (en) | 2009-02-27 | 2011-03-03 | Concert Pharmaceuticals, Inc. | Substituted xanthine derivatives |
US8563554B2 (en) | 2009-03-17 | 2013-10-22 | Concert Pharmaceuticals, Inc. | Deuterated pyrazinoisoquinoline compounds |
WO2010138889A1 (en) | 2009-05-28 | 2010-12-02 | Concert Pharmaceuticals, Inc. | Peptides for the treatment of hcv infections |
WO2011005520A1 (en) | 2009-06-23 | 2011-01-13 | Concert Pharmaceuticals, Inc. | Deuterium-modified triazolo-pyridazine derivatives as gaba-a receptor modulators |
US20110015154A1 (en) * | 2009-07-20 | 2011-01-20 | Kellermann Gottfried H | Supporting acetylcholine function |
US8278460B2 (en) | 2009-10-15 | 2012-10-02 | Concert Pharmaceuticals, Inc. | Substituted benzimidazoles |
US20110098265A1 (en) * | 2009-10-28 | 2011-04-28 | Neuroscience, Inc. | Methods for reducing cravings and impulses associated with addictive and compulsive behaviors |
WO2011060216A1 (en) | 2009-11-12 | 2011-05-19 | Concert Pharmaceuticals Inc. | Substituted azaindoles |
US20140018379A1 (en) | 2010-02-18 | 2014-01-16 | Concert Pharmaceuticals Inc. | Pyrimidine derivatives |
US9155795B2 (en) | 2010-02-26 | 2015-10-13 | Anchor Therapeutics, Inc. | CXCR4 receptor compounds |
EP2542534A1 (en) | 2010-03-02 | 2013-01-09 | Concert Pharmaceuticals Inc. | Deuterated tetrahydronaphthalene derivatives |
US8575361B2 (en) | 2010-03-02 | 2013-11-05 | Concert Pharmaceuticals Inc. | Tetrahydronaphthalene derivatives |
CA2800446C (en) | 2010-06-14 | 2017-12-12 | Ratiopharm Gmbh | Solid ivabradine-containing composition |
US20120208837A1 (en) | 2010-09-13 | 2012-08-16 | Roger Tung | Substituted azaindoles |
EP2455068A1 (en) * | 2010-11-09 | 2012-05-23 | F. Hoffmann-La Roche AG | Pharmaceutical composition for treating HCV infections |
WO2012065028A2 (en) | 2010-11-11 | 2012-05-18 | Concert Pharmaceuticals Inc. | Substituted tetracyclines |
WO2012079075A1 (en) | 2010-12-10 | 2012-06-14 | Concert Pharmaceuticals, Inc. | Deuterated phthalimide derivatives |
US8447329B2 (en) | 2011-02-08 | 2013-05-21 | Longsand Limited | Method for spatially-accurate location of a device using audio-visual information |
JP2014506603A (ja) | 2011-02-25 | 2014-03-17 | コンサート ファーマシューティカルズ インコーポレイテッド | 2−アミノ−ナフチリジン誘導体 |
WO2012129381A1 (en) | 2011-03-22 | 2012-09-27 | Concert Pharmaceuticals Inc. | Deuterated preladenant |
WO2012151361A1 (en) | 2011-05-03 | 2012-11-08 | Concert Pharmaceuticals Inc. | Carbamoylpyridone derivatives |
WO2012154728A1 (en) | 2011-05-10 | 2012-11-15 | Concert Pharmaceuticals Inc. | Deuterated n-butyl bumetanide |
WO2012158885A1 (en) | 2011-05-18 | 2012-11-22 | Concert Pharmaceuticals Inc. | Deuterated derivatives of ivacaftor |
WO2013013052A1 (en) | 2011-07-19 | 2013-01-24 | Concert Pharmaceuticals, Inc. | Substituted xanthine derivatives |
FR2985177B1 (fr) * | 2012-01-02 | 2016-04-01 | Oreal | Composition cosmetique solide aqueuse comprenant de l'alkylcellulose, au moins deux huiles non volatiles et au moins deux agents tensioactifs |
CA2860740A1 (en) | 2012-01-09 | 2013-07-18 | Anchor Therapeutics, Inc. | Apj receptor compounds |
WO2013130849A1 (en) | 2012-02-29 | 2013-09-06 | Concert Pharmaceuticals, Inc. | Substituted dioxopiperidinyl phthalimide derivatives |
CA2869874A1 (en) | 2012-04-13 | 2013-10-17 | Concert Pharmaceuticals, Inc. | Substituted xanthine derivatives |
US9249093B2 (en) | 2012-04-20 | 2016-02-02 | Concert Pharmaceuticals, Inc. | Deuterated rigosertib |
PL3450434T3 (pl) | 2012-06-15 | 2021-10-04 | Concert Pharmaceuticals, Inc. | Deuterowane pochodne ruksolitynibu |
CA2908929C (en) | 2012-07-12 | 2021-01-26 | Concert Pharmaceuticals, Inc. | Deuterated idebenone |
WO2014028756A1 (en) | 2012-08-17 | 2014-02-20 | Concert Pharmaceuticals, Inc. | Deuterated baricitinib |
MY183582A (en) | 2012-11-19 | 2021-02-26 | Vertex Pharmaceuticals Europe Ltd | Deuterated cftr potentiators |
WO2014100431A1 (en) | 2012-12-20 | 2014-06-26 | Concert Pharmaceuticals, Inc. | Deuterated alk inhibitors |
ES2882258T3 (es) | 2012-12-21 | 2021-12-01 | Mayo Found Medical Education & Res | Métodos y materiales para tratar estenosis de la válvula aórtica calcificada |
WO2014110322A2 (en) | 2013-01-11 | 2014-07-17 | Concert Pharmaceuticals, Inc. | Substituted dioxopiperidinyl phthalimide derivatives |
EP2968268B1 (en) | 2013-03-15 | 2020-07-29 | Concert Pharmaceuticals Inc. | Inhibitors of the enzyme udp-glucose: n-acyl-sphingosine glucosyltransferase |
EA032094B1 (ru) | 2013-03-15 | 2019-04-30 | Консерт Фармасьютикалс, Инк. | Дейтерированный палбоциклиб |
HU231191B1 (hu) | 2013-04-15 | 2021-08-30 | Szegedi Tudományegyetem | Izotóp tartalmú morfin molekulák |
WO2015009889A1 (en) | 2013-07-18 | 2015-01-22 | Concert Pharmaceuticals, Inc. | Deuterated intedanib derivatives and their use for the treatment of proliferative disorders |
EP3021861A1 (en) | 2013-07-18 | 2016-05-25 | Anchor Therapeutics, Inc. | Apj receptor compounds |
US9676790B2 (en) | 2013-08-30 | 2017-06-13 | Concert Pharmaceuticals, Inc. | Substituted thienotriazolodiazapines |
CN106459056A (zh) | 2014-02-10 | 2017-02-22 | 康塞特医药品公司 | 经取代的三唑苯二氮卓 |
CA2981791A1 (en) | 2014-04-18 | 2015-10-22 | Concert Pharmaceuticals, Inc. | Methods of treating hyperglycemia |
WO2015179772A1 (en) | 2014-05-23 | 2015-11-26 | Concert Pharmaceuticals, Inc. | Deuterated phenylquinazolinone and phenylisoquinolinone compounds |
BR112016028119A2 (pt) | 2014-06-06 | 2017-08-22 | Res Triangle Inst | Agonistas receptores de apelina (apj) e usos dos mesmos |
EP3808349B1 (en) | 2014-08-07 | 2022-10-05 | Mayo Foundation for Medical Education and Research | Compounds and methods for treating cancer |
WO2016061488A1 (en) | 2014-10-17 | 2016-04-21 | Concert Pharmaceuticals, Inc. | Amine reuptake inhibitors |
WO2016073545A1 (en) | 2014-11-06 | 2016-05-12 | Concert Pharmaceuticals, Inc. | Phenyloxadiazole benzoic acids |
WO2016089814A1 (en) | 2014-12-02 | 2016-06-09 | Concert Pharmaceuticals, Inc. | Deuterated analogues of daclatasvir |
US10301281B2 (en) | 2014-12-11 | 2019-05-28 | Merck Sharp & Dohme Corp. | Crystal forms of a CCR5 antagonist |
WO2016105547A1 (en) | 2014-12-24 | 2016-06-30 | Concert Pharmaceuticals, Inc. | Deuterated dasabuvir |
WO2016109795A1 (en) | 2014-12-31 | 2016-07-07 | Concert Pharmaceuticals, Inc. | Deuterated funapide and difluorofunapide |
US20180044375A1 (en) | 2015-03-06 | 2018-02-15 | Concert Pharmaceuticals, Inc. | Deuterated emricasan |
US10196384B2 (en) | 2015-03-31 | 2019-02-05 | Vertex Pharmaceuticals (Europe) Limited | Deuterated CFTR modulators |
WO2016176335A1 (en) | 2015-04-27 | 2016-11-03 | Concert Pharmaceuticals, Inc. | Deuterated otx-015 |
US20180243289A1 (en) | 2015-07-30 | 2018-08-30 | Concert Pharmaceuticals, Inc. | Deuterated morphinan compounds for treating agitation |
WO2017020005A1 (en) | 2015-07-30 | 2017-02-02 | Concert Pharmaceuticals, Inc. | Morphinan compounds for use in treating agitation |
EP3352757B1 (en) | 2015-09-21 | 2023-08-16 | Vertex Pharmaceuticals (Europe) Limited | Administration of deuterated cftr potentiators |
US11267777B2 (en) | 2015-11-19 | 2022-03-08 | Concert Pharmaceuticals, Inc. | Deuterated EPI-743 |
EP3386976A1 (en) | 2015-12-09 | 2018-10-17 | Research Triangle Institute, International | Improved apelin receptor (apj) agonists and uses thereof |
WO2017147003A1 (en) | 2016-02-26 | 2017-08-31 | Novobiotic Pharmaceuticals, Llc | Novel macrocyclic antibiotics and uses thereof |
BR112018072339A2 (pt) | 2016-05-04 | 2019-02-19 | Concert Pharmaceuticals, Inc. | tratamento de distúrbios de perda de cabelo com inibidores de jak deuterados |
EP4122919A1 (en) | 2016-07-04 | 2023-01-25 | Avanir Pharmaceuticals, Inc. | Methods for the synthesis of deuterated dextromethorphan |
KR102511953B1 (ko) | 2016-08-01 | 2023-03-20 | 더 브리검 앤드 우먼즈 하스피털, 인크. | 단백질 및 펩티드 전달용 입자 |
WO2018160717A1 (en) | 2017-02-28 | 2018-09-07 | Mayo Foundation For Medical Education And Research | Compounds and methods for treating cancer |
WO2018213609A1 (en) | 2017-05-17 | 2018-11-22 | Ausubel Frederick M | Antibiotic compounds |
EP3625231B1 (en) | 2017-05-19 | 2022-07-20 | Superb Wisdom Limited | Derivatives of resiquimod |
CA3082834A1 (en) | 2017-11-22 | 2019-05-31 | Concert Pharmaceuticals, Inc. | Deuterated analogs of d-serine and uses thereof |
US11243207B2 (en) | 2018-03-29 | 2022-02-08 | Mayo Foundation For Medical Education And Research | Assessing and treating cancer |
WO2021236139A1 (en) | 2020-05-21 | 2021-11-25 | Concert Pharmaceuticals, Inc. | Novel deuterated jak inhibitor and uses thereof |
IL302401A (en) | 2020-10-28 | 2023-06-01 | Sun Pharmaceutical Ind Inc | Regimens for the treatment of hair loss disorders with faded JAC inhibitors |
WO2023018904A1 (en) | 2021-08-11 | 2023-02-16 | Concert Pharmaceuticals, Inc. | Treatment of hair loss disorders with deuterated jak inhibitors |
WO2023018954A1 (en) | 2021-08-12 | 2023-02-16 | Concert Pharmaceuticals, Inc. | Treatment of jak-inhibition-responsive disorders with prodrugs of jak inhibitors |
WO2023215520A1 (en) | 2022-05-04 | 2023-11-09 | Sun Pharmaceutical Industries, Inc. | Dosage regimens for treatment with deuterated jak inhibitors |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5281420A (en) | 1992-05-19 | 1994-01-25 | The Procter & Gamble Company | Solid dispersion compositions of tebufelone |
IE80467B1 (en) * | 1995-07-03 | 1998-07-29 | Elan Corp Plc | Controlled release formulations for poorly soluble drugs |
US5834472A (en) | 1996-05-24 | 1998-11-10 | Schering Corporation | Antifungal composition with enhanced bioavailability |
US6232333B1 (en) * | 1996-11-21 | 2001-05-15 | Abbott Laboratories | Pharmaceutical composition |
US6045829A (en) * | 1997-02-13 | 2000-04-04 | Elan Pharma International Limited | Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers |
US6001851A (en) | 1997-03-13 | 1999-12-14 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
ES2248908T7 (es) * | 1997-06-06 | 2014-11-24 | Depomed, Inc. | Formas de dosificación de fármacos por vía oral y retención gástrica para liberación continuada de fármacos altamente solubles |
AU8145198A (en) * | 1997-06-16 | 1999-01-04 | Vertex Pharmaceuticals Incorporated | Methods of increasing the bioavailability of stable crystal polymorphs of a compound |
JP2002522354A (ja) * | 1997-09-19 | 2002-07-23 | シャイア ラボラトリーズ,インコーポレイテッド | 固溶体ビードレット |
DE60017444T2 (de) * | 1999-11-12 | 2006-02-09 | Abbott Laboratories, Abbott Park | Pharmazeutische formulierungen auf basis fester dispersionen |
US6499984B1 (en) * | 2000-05-22 | 2002-12-31 | Warner-Lambert Company | Continuous production of pharmaceutical granulation |
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CN103893145A (zh) * | 2005-09-23 | 2014-07-02 | 弗·哈夫曼-拉罗切有限公司 | 新型制剂 |
CN105769809A (zh) * | 2014-12-23 | 2016-07-20 | 上海星泰医药科技有限公司 | 提高生物利用度的雷尼司他及其制备方法 |
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