CN104870443B - 具有改善的溶解度的包含四唑衍生物作为活性成分的固体分散体 - Google Patents
具有改善的溶解度的包含四唑衍生物作为活性成分的固体分散体 Download PDFInfo
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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Abstract
本发明涉及一种非晶形固体分散体,其包含式(I)的四唑衍生物或其药学上可接受的盐作为活性成分。本发明的固体分散体包含水溶性聚合物或酸以便改善其活性成分即式(I)的四唑衍生物的溶解度,从而提高其吸收率,因此可以有效地用于降低癌细胞的多药耐药性(MDR)。
Description
技术领域
本发明涉及一种具有改善的溶解度的固体分散体,其包含四唑衍生物作为活性成分,更具体地讲,涉及一种非晶形固体分散体,其包含式(I)的四唑衍生物或其药学上可接受的盐作为活性成分,以及一种包含该非晶形固体分散体的药物制剂。
发明背景
已知以下的式(I)的四唑衍生物及其药学上可接受的盐为p-糖蛋白抑制剂,其对癌细胞的多药耐药性具有抑制活性(参见KR专利No.10-0557093):
其中R1至R11、m、n和X与下文所定义的相同。
P-糖蛋白在胃肠道的内皮细胞等中被发现,已知其限制某些药物的口服吸收。一些主要的抗癌剂如紫杉醇(paclitaxel)、多西他赛(docetaxel)等如果经由口服给药,由于P-糖蛋白的作用,大部分不能被身体吸收(Schinkel et al.,Cell,77,491-502,1994)。抗癌治疗中的一个关键问题是癌细胞对抗癌剂表达的耐药性,其中,最关键的问题是P-糖蛋白过度表达引起的多药耐药性(MDR)。通常而言,随着抗癌剂的使用增多,癌细胞的MDR也增加,这成为大幅降低癌症存活率的起因。
因此,包含式(I)的四唑衍生物的P-糖蛋白抑制剂可以抑制P-糖蛋白的作用,从而允许某些药物可以口服给药,因而可以预期对P-糖蛋白过度表达引起的癌细胞的MDR有效。
然而,四唑衍生物及其药学上可接受的盐具有极低的溶解度,因而难以预期具有良好的体内吸收率。因此,需要改善前述药物的溶解度和体内吸收率。
发明概述
因此,本发明的一个目的是改善前述四唑衍生物及其药学上可接受的盐的溶解度和体内吸收率。
根据本发明的一个目的,提供一种包含式(I)的四唑衍生物或其药学上可接受的盐作为活性成分的非晶形固体分散体,以及一种包含该非晶形固体分散体的药物制剂:
其中,
R1是喹啉、异喹啉、喹喔啉、吡啶、吡嗪、萘、苯基、噻吩、呋喃、4-氧代-4H-苯并吡喃或噌啉,其是未取代的或被C1-C5烷基、羟基、C1-5烷氧基、卤素、三氟甲基、硝基或氨基取代;
R2至R5和R8至R11各自独立地是H、羟基、卤素、硝基、C1-C5烷基或C1-5烷氧基;R6和R7各自独立地是氢、羟基、卤素、硝基、C1-5亚烷基或C1-5烷氧基;并且R6和R7可连接形成4-到8-元环;
m和n各自独立地是0至4的整数;且
X为CH2、O或S。
本发明的固体分散体包含水溶性聚合物和/或酸以便改善其活性成分即式(I)的四唑衍生物的溶解度,从而提高其体内吸收率,并因而能有效地用于降低癌细胞的MDR。
附图简述
图1显示HM30181A(一种式(I)的四唑衍生物)和包含HM30181A和不同量的水溶性聚合物的固体分散体(实施例1到实施例6)的溶解度。
图2显示包含HM30181A和不同种类的酸的固体分散体(实施例7到实施例13)的溶解度。
图3显示HM30181A的X-射线衍射图样。
图4显示实施例8的固体分散体的X-射线衍射图样。
图5显示通过使用本发明的固体分散体制备的实施例14的片剂和通过简单地混合各成分制备的对比例1的片剂的溶出。
发明详述
下文将详细地描述本发明。
本发明提供了一种非晶形固体分散剂,其包含式(I)的四唑衍生物或其药学上可接受的盐作为活性成分。
式(I)的四唑衍生物或其药学上可接受的盐、生产其的方法以及其用途在KR专利No.10-0557093中被公开。
根据本发明的一个具体实施方案,四唑衍生物可以是式(II)的化合物:色酮-2-羧酸[2-(2-{4-[2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-乙基]-苯基}-2H-四唑-5-基)-4,5-二甲氧基苯基]胺甲磺酸盐,或式(III)化合物:色酮-2-羧酸[2-(2-{4-[2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-乙基]-苯基}-2H-四唑-5-基)-4,5-二甲氧基苯基]胺:
本发明的固体分散剂可以通过将式(I)的四唑衍生物或其药学上可接受的盐溶解在溶剂、优选有机溶剂中以形成混合溶液,然后采用常规方法、优选喷雾干燥法除去溶剂来获得。
本发明的固体分散体除了包含活性成分外,还可以包含水溶性聚合物,以便增强式(I)的四唑衍生物或其药学上可接受的盐的溶解度。
当由四唑衍生物或其药学上可接受的盐制备固体分散体时,水溶性聚合物充当水溶性载体以使活性成分具有亲水性,从而改善其溶解度,并且其还有助于使固体分散体保持非晶形状态。水溶性聚合物的实例包括羟丙甲纤维素(hypromellose)、羟基丙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇缩醛、二乙基氨基乙酸酯、聚乙二醇或其混合物,但不限于此。在本发明的一个优选实施方案中,在由四唑衍生物或其药学上可接受的盐制备固体分散体时,使用羟丙甲纤维素。
基于1重量份的活性成分,可以以0.1至4重量份的量包括水溶性聚合物。当基于1重量份的活性成分以4重量份或更少的量使用水溶性聚合物时,溶解度增大;然而,当量超过4重量份时,固体分散体出现凝胶化,从而阻止活性成分的释放。
本发明的固体分散体除了包含活性成分外,还可以包含酸以便增强式(I)的四唑衍生物或其药学上可接受的盐的溶解度。酸可以通过形成络盐,调解主要成份周围区域的pH值等来改善活性成分的溶解度。可以用于制备本发明的固体分散体的酸的实例包括无机酸,如磷酸、盐酸、硫酸、硝酸、乙酸、硼酸等;以及有机酸,如柠檬酸、苹果酸、酒石酸、乳酸、托西酸盐(tosilate)、琥珀酸、抗坏血酸、谷氨酸、藻酸、马来酸、己二酸等。改善溶解度的程度可依据所用酸的种类而变化。本发明中的酸的具体实例包括磷酸、苹果酸、柠檬酸和酒石酸。基于1重量份的活性成分,可以以0.1至3重量份的量包括酸。
根据本发明一个具体实施方案,包含式(I)的四唑衍生物或其药学上可接受的盐作为活性成分的固体分散体可以包含水溶性聚合物和酸。
本发明的固体分散体可以通过将活性成分溶解和分散在二氯甲烷、乙醇和蒸馏水的混合溶液中来制备。基于1重量份的总混合溶液,混合溶液中二氯甲烷:乙醇:蒸馏水的比例优选是0.5至0.85重量份:0.1至0.4重量份:0.05至0.2重量份。根据一个优选实施方案,混合溶液中二氯甲烷:乙醇:蒸馏水的重量比例为60~80:20~40:2~10。根据另一优选实施方案,混合溶液中二氯甲烷:乙醇:蒸馏水的重量比例为65~75:25~35:4~6。如果混合溶液的比例超出所述范围,可能出现问题,如分层或者主要成份变得不溶于该溶液。
本发明的固体分散体具有小粒径,从而具有增大的表面积。本发明的固体分散体的平均颗粒直径为小于150μm,优选小于100μm,更优选小于40μm。
本发明的四唑衍生物与水溶性聚合物或酸一起加入来制备非晶形固体分散体,从而改善四唑衍生物的溶解度,并因而可显著提高所述药物的体内吸收率。
本发明提供了一种包含所述固体分散体的药物组合物。本发明的药物组合物与简单地包含式(I)的四唑衍生物或其药学上可接受的盐的常规药物组合物相比,有效地降低癌细胞的MDR。
而且,本发明的包含式(I)的四唑衍生物或其药学上可接受的盐的固体分散体可以增强抗癌剂的口服吸收,并提高对癌细胞的抗癌活性,因而,可以使用与抗癌剂、优选地为口服吸收率由于P-糖蛋白而受到限制的抗癌剂的联合给药来提高抗癌剂的治疗效果。因此,可以将本发明的固体分散体与抗癌剂共同给药于具有获得性化学抗性(acquiredchemoresistance)的患者,来克服MDR和治疗多药耐药性癌症。
适合与本发明的固体分散体混合的抗癌剂并无特殊限制;然而,一些实例包括基于紫杉烷的药剂如紫杉醇和多西他赛;基于长春花生物碱的药剂如长春新碱(vincristine)、长春碱(vinblastine)和长春瑞滨(vinorelbine);基于蒽环类抗生素(anthracycline)的药剂如柔红霉素(daunomycin)和多柔比星(doxorubicin);基于喜树碱(camptothecin)的药剂如托泊替康(topotecan)和伊立替康(irinotecan);放线菌素(actinomycin);以及依托泊苷(etopocide)等。
本发明的药物组合物可以根据常规方法进行配制,并且可以被制备成口服制剂形式如片剂、丸剂、粉剂、胶囊剂、糖浆剂、乳剂、微乳剂等,或者被制备成用于肠胃外注射如肌内、静脉内或皮下给药的制剂形式。本发明的药物组合物可以包含本发明的固体分散体和任何可能的载体和赋形剂。如果将本发明的药物组合物制备成口服制剂形式,则载体或赋形剂的实例包括纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、葡萄糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、悬浮剂、乳化剂、稀释剂等。而且,如果将本发明的药物组合物制备成可注射制剂形式,则载体的实例包括水、盐水、葡萄糖溶液、葡萄糖溶液类似物、醇、二醇、醚(如聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯或表面活性剂、悬浮剂、乳化剂等。
包含本发明的固体分散体的药物组合物可以通过本领域已知的任何方法进行配制,并可在抗癌剂的给药之前或之后单独地给药或与一种或多种抗癌剂一起给药。给药方式可以根据多种因素进行调整,如患者的症状、抗癌剂的物理特性等。
可以经由口服或肠胃外给药方式将本发明的固体分散体以基于四唑衍生物或其药学上可接受的盐0.1至100mg/kg(体重)的量与抗癌剂一起施用于哺乳动物(包括人类),以便降低癌细胞的MDR。
在下文中,通过以下实施例更具体地描述本发明,但是这些仅用于举例说明的目的,并且本发明不限于此。在下文中,本文所用的术语“HM30181A”指的是式(II)化合物:色酮-2-羧酸[2-(2-{4-[2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-乙基]-苯基}-2H-四唑-5-基)-4,5-二甲氧基苯基]胺甲磺酸盐,其是在KR专利No.10-0557093中公开的式(I)的化合物的一个实例:
实施例1至实施例6:用不同量的水溶性聚合物制备固体分散体
根据表1所列的成分,通过以下步骤制备实施例1至实施例6的固体分散体:将活性成分HM30181A、水溶性聚合物羟丙甲纤维素P-645和赋形剂硅酸盐完全溶解和分散在二氯甲烷(MC)、乙醇(EtOH)和蒸馏水(DW)的混合溶液中,然后使用迷你喷雾干燥机B-290(Buchi,瑞士)将得到的溶液喷雾干燥。
[表1]
实施例7至实施例13:用不同种类的酸制备固体分散体
根据表2所列的成分,通过以下步骤制备实施例7至实施例13的固体分散体:将活性成分HM30181A;作为酸的磷酸、DL-苹果酸、柠檬酸、L(+)-酒石酸、富马酸或草酸;和水溶性聚合物羟丙甲纤维素P-645完全溶解和分散在MC、EtOH和DW的混合溶液中,然后用喷雾干燥机将得到的溶液喷雾干燥。
[表2]
实施例14:片剂的制备
根据表3所列的成分,通过以下步骤制备固体分散体:将活性成分HM30181A;作为酸的磷酸;和水溶性聚合物羟丙甲纤维素P-645完全溶解和分散在MC、EtOH和DW的混合溶液中,然后用喷雾干燥机将得到的溶液喷雾干燥。
然后,根据表4所列的成分,通过以下步骤制备实施例14的片剂:混合所述固体分散体与赋形剂D-甘露醇、崩解剂交聚维酮、赋形剂轻质无水硅酸以及润滑剂硬脂富马酸钠;然后将得到的混合物压片。
[表3]
成分 | 量(mg/片) |
HM30181A | 60 |
磷酸 | 40 |
羟丙甲纤维素P-645 | 60 |
[表4]
成分 | 量(mg/片) |
固体分散体 | 160 |
D-甘露醇(SD200) | 325 |
交聚维酮 | 50 |
轻质无水硅酸 | 5 |
硬脂富马酸钠 | 10 |
对比例1:片剂的制备
根据表5所列的成分,通过以下步骤制备对比例1的片剂:混合活性成分HM30181A;酸性增溶剂磷酸;水溶性聚合物羟丙甲纤维素P-645;赋形剂D-甘露醇;崩解剂交聚维酮;赋形剂轻质无水硅酸;和润滑剂硬脂富马酸钠,然后将得到的混合物压片。
[表5]
成分 | 量(mg/片) |
HM30181A | 60 |
磷酸 | 40 |
羟丙甲纤维素P-645 | 60 |
D-甘露醇(SD200) | 325 |
交聚维酮 | 50 |
轻质无水硅酸 | 5 |
硬脂富马酸钠 | 10 |
测试实施例1:活性成分在各种溶剂中的溶解度
为了寻找最适合固体分散体的溶剂,将过量的活性成分HM30181A加入到一种溶剂中,摇动2小时,然后将得到的混合物离心,并用HPLC分析以测量溶解度。溶解度试验所用的溶剂是MC、甲醇、EtOH、己烷、乙醚、异丙醇、丙酮和DW。结果显示于表6中。
[表6]
溶剂 | 溶解度(ppm) |
二氯甲烷 | 6848.28 |
甲醇 | 10177.50 |
乙醇 | 382.63 |
己烷 | 0.05 |
乙醚 | 0.00 |
异丙醇 | 31.29 |
丙酮 | 9.23 |
蒸馏水 | 0.00 |
如上表6所示,当将四唑衍生物HM30181A溶解于大多数溶剂中时,其溶解度较低。结果表明如果在制备固体分散体的过程中仅使用一种类型的溶剂,则将需要相当大量的溶剂来溶解活性成分,这可导致降低产率以及增加生产成本。
同时,制备在上述溶解度实验中得到较好的溶解度的两种溶剂(即MC和EtOH)的组合,并观察HM30181A的溶出特性。甲醇也显示了较好的溶解度,但是由于其毒性而被排除在试验外。结果在下表7中显示。
[表7]
如上表所示,证实用添加有蒸馏水的二氯乙烷和乙醇的混合溶液比仅使用二氯乙烷和乙醇的混合溶液更为有利,因为加入蒸馏水增强了活性成分在澄清溶液中的溶解。而且,可以得出结论:在制备用于固体分散体的混合溶剂中优选的重量比例是二氯乙烷:乙醇:蒸馏水=70:30:5。
测试实施例2:取决于水溶性聚合物的固体分散体的溶解度
通过使用适当量的各样品检测实施例1到实施例6中制备的固体分散体的溶出,所述量对应于150mg HM30181A,然后比较溶解度。
<试验条件>
-溶出介质:蒸馏水,900mL
-测试系统:旋转样品容器,100rpm
-温度:37℃
<分析条件>
-柱子:LC用填充有十八烷基甲硅烷基硅胶(直径为5μm)的不锈钢柱(内径为约4.6mm,长度为15cm)
-流动相:乙腈:pH 2.5缓冲液(56:44)
-柱温:40℃
-流速:1.0mL/min
-进样体积:10μL
*pH 2.5缓冲液:将7.0g高氯酸钠(NaClO4)和1.7g磷酸二氢钾(KH2PO4)溶解在900mL蒸馏水中,加入磷酸以调节pH到2.5,然后加入蒸馏水使得总体积为1L。
实施例1到实施例6中制备的固体分散体的溶解度在图1中显示。如图1所示,固体分散体粉末在溶剂中大多没有溶解;然而,当将羟丙甲纤维素(P-645)(即水溶性聚合物)加入到溶剂中,固体分散体的溶解度得到改善。而且,观察到固体分散体的溶解度趋向于随着水溶性聚合物的量的增加而增大。特别是,直到水溶性聚合物的量是活性成分的四倍时,溶解度增大;然而,量超过活性成分四倍时引起固体分散体的凝胶化,从而阻止活性成分的释放。
从上述结果可以得出结论:用于本发明的固体分散体的水溶性聚合物的最适当的量基于1重量份活性成分为0.1至4重量份。
测试实施例3:取决于酸的固体分散体的溶解度
通过使用适当量的各样品在与测试实施例2相同的条件下对实施例7到13中制备的固体分散体进行溶出检测,所述量对应于150mg HM30181A。结果在图2中示出。
如图2所示,在使用磷酸(实施例7和实施例8)和DL-苹果酸(实施例9)作为酸制备固体分散体的情况下,对应于150mg HM30181A的固体分散体完全溶解于900mL蒸馏水,且溶解状态保持超过24小时,因此表明固体分散体具有良好的溶解度(图2仅显示直到6小时的时间进程)。而且,在使用柠檬酸(实施例10)和L(+)-酒石酸(实施例11)制备分散体的情况下,对应于约130mg HM30181A的固体分散体完全溶解于900mL蒸馏水,因此表明固体分散体具有良好的溶解度。
测试实施例4:对活性成分和包含该活性成分的固体分散体的晶型的分析
使用M18XHF-SRA(Macsciences Co.,LTD,日本)在Cu X-射线,40kV和100mA,以及扫描速度为6o/min的条件下测定活性成分即HM30181A和实施例8的固体分散体的X射线衍射图样。
HM30181A和实施例8的固体分散体的X射线衍射图样结果分别显示于图3和图4。如图3所示,活性成分H30181A M在2θ(度)4.911,6.474,7.948,9.827,10.712,11.522,12.007,12.936,13.498,14.063,14.744,15.282,15.878,16.686,18.66,19.388,19.698,21.065,23.22,25.222,26.485,26.86和28.405处有峰。然而,如图4所示,包含该活性成分的固体分散体经过喷雾干燥过程后变成非晶形的。
测试实施例5:对固体分散体粒径的分析
通过激光衍射法使用带有R1透镜的HELOS/BR(Sypatec,德国)在4.5bar条件下测定实施例1到实施例13的固体分散体的平均粒径。
结果在下表8中显示。
[表8]
平均粒径 | |
实施例1 | 8μm |
实施例2 | 21μm |
实施例3 | 18μm |
实施例4 | 30μm |
实施例5 | 25μm |
实施例6 | 33μm |
实施例7 | 23μm |
实施例8 | 26μm |
实施例9 | 31μm |
实施例10 | 29μm |
实施例11 | 27μm |
实施例12 | 23μm |
实施例13 | 21μm |
如上表8所示,实施例1到实施例13的固体分散体的平均粒径为30μm或小于30μm。
测试实施例6:对片剂溶出特性的分析
对在对比例1和实施例14中制备的片剂进行溶出检测并进行比较。
<试验条件>
-溶出介质:蒸馏水,900mL
-测试系统:桨,100rpm
-温度:37℃
<分析条件>
与测试实施例2的条件相同。
结果显示于图5。如图5所示,使用固体分散体制备的实施例14的片剂在15分钟内完全溶解;然而,通过简单混合各成分制备的对比例1的片剂随着时间推移完全没有溶解。该结果表明,如果通过简单地混合四唑衍生物和赋形剂制备片剂,则本发明的四唑衍生物的溶解度不能得到改善;而利用固体分散体则能改善溶解度。
Claims (11)
1.一种非晶形固体分散体,其包含式(I)的四唑衍生物或其药学上可接受的盐作为活性成分、水溶性聚合物和酸,所述酸选自磷酸、苹果酸、柠檬酸和酒石酸:
其中,
R1是喹啉、异喹啉、喹喔啉、吡啶、吡嗪、萘、苯基、噻吩、呋喃、4-氧代-4H-苯并吡喃或噌啉,其是未取代的或被C1-C5烷基、羟基、C1-5 烷氧基、卤素、三氟甲基、硝基或氨基取代;
R2至R5和R8至R11各自独立地是H、羟基、卤素、硝基、C1-C5烷基或C1-5烷氧基;R6和R7各自独立地是C1-5 亚烷基,并且R6和R7连接形成4元到8元环;
m和n各自独立地是0至4的整数;且
X为CH2、O或S。
2.权利要求1所述的非晶形固体分散体,其中所述四唑衍生物是式(II)或式(III)的化合物:
3.权利要求1所述的非晶形固体分散体,其中所述水溶性聚合物选自羟丙甲纤维素、羟基丙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇缩醛、二乙基氨基乙酸酯、聚乙二醇和它们的混合物。
4.权利要求1所述的非晶形固体分散体,其中基于1重量份的活性成分,以0.1至4重量份的量包括所述水溶性聚合物。
5.权利要求1所述的非晶形固体分散体,其中基于1重量份的活性成分,以0.1至3重量份的量包括所述酸。
6.权利要求1所述的非晶形固体分散体,其中所述固体分散体是通过使用二氯甲烷、乙醇和蒸馏水的混合溶液来制备的,其中二氯甲烷:乙醇:蒸馏水的比例=0.5至0.85重量份:0.1至0.4重量份:0.05至0.2重量份。
7.权利要求1所述的非晶形固体分散体,其中所述固体分散体的平均颗粒直径为小于150μm。
8.一种药物组合物,其包含权利要求1所述的固体分散体。
9.权利要求8所述的药物组合物,其中所述药物组合物用于降低癌细胞的多药耐药性。
10.一种药物组合物,其包含权利要求1所述的固体分散体和抗癌剂。
11.权利要求10所述的药物组合物,其中所述抗癌剂选自紫杉醇、多西他赛、长春新碱、长春碱、长春瑞滨、柔红霉素、多柔比星、托泊替康、伊立替康、放线菌素和依托泊苷。
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PCT/KR2013/011545 WO2014092489A1 (en) | 2012-12-13 | 2013-12-12 | Solid dispersion with improved solubility comprising tetrazole derivative as an active ingredient |
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KR102044223B1 (ko) * | 2016-09-12 | 2019-11-13 | 성균관대학교산학협력단 | 텔미사르탄을 포함하는 고체 분산체 및 이의 제조방법 |
JP2021515048A (ja) * | 2018-03-07 | 2021-06-17 | シアン チェン アンドリュー | 不溶性薬物用の水性製剤 |
CZ2018188A3 (cs) * | 2018-04-18 | 2019-10-30 | Zentiva, K.S. | Částice s obsahem amorfního empagliflozinu, způsob jejich přípravy a farmaceutický přípravek |
CA3122699A1 (en) * | 2018-12-14 | 2020-06-18 | Athenex HK Innovative Limited | Therapeutic combinations of orally administered irinotecan and a p-gp inhibitor for the treatment of cancer |
CN113631161A (zh) * | 2018-12-14 | 2021-11-09 | 慧源香港创新有限公司 | 用于治疗癌症的口服施用的多西他赛和P-gp抑制剂的治疗组合 |
WO2020168144A1 (en) | 2019-02-14 | 2020-08-20 | Teva Pharmaceuticals International Gmbh | Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(lh)- isoquinolinyl)ethyl] phenyl }-2h-tetrazol-5-yl)-4,5-dimethoxyphenyl] -4- oxo-4h-chromene-2-carboxamide and of its mesylate salt |
US20230278990A1 (en) | 2020-07-10 | 2023-09-07 | Teva Czech Industries S.R.O | Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl)ethyl]phenyl}-2h-tetrazol-5-yl)-4,5-dimethoxyphenyl]-4-oxo-4h-chromene-2-carboxamide mesylate salt |
AU2021358074A1 (en) | 2020-10-07 | 2023-04-27 | Athenex, Inc. | Acetamido-phenyltetrazole derivatives and methods of using the same |
EP4237420A1 (en) * | 2020-10-30 | 2023-09-06 | Athenex R&D, LLC | Polymorphisms of hm30181 mesylate |
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