CN116854666B - 一种凡德他尼的盐及其固态形式与应用 - Google Patents
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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Abstract
本发明公开了一种凡德他尼的盐及其固态形式与应用。凡德他尼‑布美他尼盐并不是凡德他尼与布美他尼简单的物理混合,凡德他尼与布美他尼之间以摩尔比为1:1的比例存在,凡德他尼与布美他尼之间存在质子转移,盐型相对于凡德他尼或布美他尼在唾液、小肠的pH条件下以及水中具有更高的表观溶解度。本发明的凡德他尼‑布美他尼盐的两种晶型,其中晶型B在40℃、75%RH的加速条件下,至少30天晶型保持稳定。
Description
技术领域
本发明属于药物领域,具体的涉及一种凡德他尼的盐及其固态形式与应用。
背景技术
癌症是生理表型极其复杂的一种疾病,在某种特定组织的细胞中,不再充分响应组织内的信号刺激进而调节细胞的分化、生存、增殖和死亡,使正常组织发生异常表型变化。目前获批药物的靶标主要集中在离子通道、激酶、核受体及G蛋白偶联受体(GPCR)等。肺癌是全世界发病率和死亡率最高的肿瘤,其中80%的肺癌的患者是非小细胞肺癌(NSCLC)。
凡德他尼是由阿斯利康(AstraZeneca)研发的小分子多靶点酪氨酸激酶抑制剂,可以作用于肿瘤细胞的EGFR、VEGFR和RET其他酪氨酸激酶以及丝氨酸/苏氨酸激酶。于2011年4月获美国FDA批准上市,商品名为Zactima。是第一个获批的髓样甲状腺癌治疗药物,适用于治疗不能切除、局部晚期或转移的有症状或进展的髓样甲状腺癌。另外,目前我国正在进行凡德他尼治疗非小细胞肺癌(NSCLC)的临床试验。与只对EGFR有抑制作用的吉非替尼相比,凡德他尼能有效地延长非小细胞肺癌(NSCLC)病人的无进展生存期。
但是,凡德他尼在水和碱性条件下均难溶,在酸性条件下易溶,属于BCS II类化合物,其生物利用度受到溶解度的限制。
钠(Na+)、钾(K+)、氯(Cl-)协同转运蛋白(NKCCl),是一类表达在膜上的离子通道蛋白,呈电中性转运,专司钠离子、钾离子和氯离子进出细胞。布美他尼是一种有效的NKCCl抑制剂,同时也是不含汞的非噻嗪类高效、低毒新型利尿剂;其利尿效果比速尿高40倍;用于治疗乙肝性水肿,其分子结构式如式2所示。在临床上,布美他尼常用于各种顽固性水肿和急性肺水肿,其具有高效低毒的特点。最新研究表明布美他尼对于恶性胶质瘤、食管瘤和血管疾病均有应用效果。徐辰等人通过免疫印迹杂交技术研究发现NKCCl抑制剂布美他尼对于人非小细胞肺癌细胞A549具有明显抑制作用(徐辰,魏汉东,姜颖.布美他尼对肿瘤细胞增殖的抑制作用及其与NKCC1表达的相关性[J].军事医学,2015,000(007):495-498.)。蒋云鹏在研究吉非替尼-布美他尼共晶过程发现,布美他尼的存在有利于提高吉非替尼在非小细胞肺癌中抗肿瘤活性。
布美他尼和凡德他尼在均属于难溶性药物,按BCS分类属于II类药物,为了提升凡德他尼和布美他尼的溶解度及生物利用度,提高凡德他尼和布美他尼在非小细胞肺癌及其他瘤种的治疗效果。本发明专利提出一种凡德他尼-布美他尼盐及其固态形式,以克服溶解度及单一药物在非小细胞肺癌治疗上的不足。
对于固态药物通常存在药物多晶型的现象,其是指药物分子一定排列组合方式进行有序的堆积形成的具有不同物理性质的固态形式。由于不同晶型具有不同溶解度、硬度、引湿性、熔点、稳定性的物理性质。因此,选择合适的固态形式对于药物开发具有重要意义。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一,为此,本发明提出凡德他尼-布美他尼盐以及固态形式。凡德他尼-布美他尼盐相对于凡德他尼、布美他尼在小肠等pH条件下或水中表观溶解度均有明显提升,其中布美他尼的表观溶解度提升至少7倍。所提出的凡德他尼-布美他尼盐晶型B在40℃、75%RH条件下至少30天不发生晶型转变。
本发明的第一方面,提出了一种凡德他尼-布美他尼盐的晶型A,所述晶型在使用Cu-Kα射线测量得到的X射线粉末衍射图谱中,在衍射角2θ为6.5°±0.2°、8.2°±0.2°、9.6°±0.2°、12.8°±0.2°、14.5°±0.2°、15.8°±0.2°、18.4°±0.2°、19.8°±0.2°、20.1°±0.2°、21.2°±0.2°、21.5°±0.2°、21.7°±0.2°、22.6°±0.2°、23.0°±0.2°、23.5°±0.2°、24.1°±0.2°、24.4°±0.2°、24.8°±0.2°、25.7°±0.2°处具有特征峰。凡德他尼-布美他尼盐晶型A为乙腈溶剂合物。
本发明的第二方面,提出一种凡德他尼-布美他尼盐晶型A的制备方法,其所述的制备方法的特征如下,将凡德他尼和布美他尼等摩尔量加入乙腈进行研磨与混合,然后在乙酸乙酯:乙腈(1:1v/v)混合溶剂完全溶解后,通过挥发获取凡德他尼-布美他尼盐晶型A。
特别优选的,研磨时间为10~60min,乙腈加入量为0~50μL/mg粉末。混合粉末与乙酸乙酯:乙腈(1:1v/v)质量体积比为8mg:1mL。
本发明的第三方面,提出了一种凡德他尼-布美他尼盐晶型B,所述晶型在使用Cu-Kα射线测量得到的X射线粉末衍射图谱中,在衍射角2θ为6.0°±0.2°、9.4°±0.2°、12.0°±0.2°、13.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.6°±0.2°、17.9°±0.2°、18.4°±0.2°、19.8°±0.2°、20.2°±0.2°、20.9°±0.2°、23.0°±0.2°、23.7°±0.2°、24.0°±0.2°、24.2°±0.2°、25.1°±0.2°、26.8°±0.2°处具有特征峰,在约182.8℃±0.5℃处具有熔融峰。
本发明的第四方面,提出一种凡德他尼-布美他尼盐晶型B的制备方法,其所述的制备方法的特征如下,将凡德他尼-布美他尼盐晶型A在氮气保护下100℃~180℃加热5~10min可得。特别优选的,加热温度为150℃,加热时间为5min。
本发明的第五方面,提出一种包含凡德他尼-布美他尼盐的药物组合物,其含有凡德他尼-布美他尼盐晶型B与药用可接受的辅料制备成药物组合物。可列举的药用可接受的辅料保护填充剂、助流剂、粘合剂、矫味剂等,可以通过混合、干法制粒或湿法制粒灌装制备成胶囊剂,或通过粉末直压、干法制粒或湿法制粒制备成片剂,或与成膜材料制备成口膜剂,或制备成混悬液。
本发明的第六方面,提出凡德他尼-布美他尼盐晶型B及上述包含凡德他尼-布美他尼盐的药物组合物在制备非小细胞肺癌或甲状腺癌药物中的应用。
凡德他尼-布美他尼盐并不是简单混合,凡德他尼与布美他尼之间以摩尔比为1:1的比例存在,凡德他尼与布美他尼之间存在质子转移,盐型相对于凡德他尼或布美他尼在唾液、小肠的pH条件下以及水中具有更高的溶解度。本发明的凡德他尼-布美他尼两种晶型,其中晶型B在40℃、75%RH的加速条件下,至少30天晶型保持稳定。通过凡德他尼-布美他尼盐的形成,基于凡德他尼作为多靶点酪氨酸激酶抑制剂,以及布美他尼作为NKCCl抑制剂,有望提升凡德他尼与布美他尼在非小细胞肺癌上的应用。
附图说明
下面结合附图和实施例对本发明做进一步的说明,其中:
图1为本实施例1所制备凡德他尼-布美他尼盐晶型A的偏光显微镜图
图2为本实施例1所制备凡德他尼-布美他尼盐晶型A的单晶分子椭球图(立体结构投影)
图3为本实施例1所制备凡德他尼-布美他尼盐晶型A的单晶晶体的晶胞图
图4为本实施例1所制备凡德他尼-布美他尼盐晶型A由单晶数据模拟的PXRD图谱。
图5为本实施例2所制备凡德他尼-布美他尼盐晶型B的PXRD图谱。
图6为本实施例2所制备凡德他尼-布美他尼盐晶型B的DSC图谱。
图7为本实施例2所制备凡德他尼-布美他尼盐晶型B的拉曼图谱。
图8为本实施例2所制备凡德他尼-布美他尼盐晶型B的在40℃/75%RH条件下加速30天PXRD与0天的PXRD图谱对比。
具体实施方式:
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
以下实施例中,涉及的检测仪器和方法如下:
粉末X-射线衍射法(PXRD):X-射线粉末衍射使用荷兰帕纳科Empyrean锐影X射线粉末衍射仪(PW3040/60)进行,采用Cu-Kα辐射,波长Ni滤波片;入射光路:发散狭缝FDS 1/8°,避光框Mask 5mm,防散射狭缝FDS 1/4°;衍射光路:防散射狭缝P7.5,X射线光管电压45kV,X射线光管电流40mA,扫描范围2-40°(2θ),步长0.0260°,每步扫描时间156.315s。将样品平铺于样品盘进行测试。数据采集软件X’Pert Data Collector,数据查看软件HighScore Plus。
单晶X-射线衍射法(SXRD):单晶X-射线衍射使用Rigaku XtaLAB Synergy R,DWsystem,HyPix,Cu-Kα辐射,mirror单色器。管压40kV,管流30mA,扫描方式ω,扫描范围6.568°-152.898°(θ)。
拉曼光谱法(Raman):雷尼绍inVia拉曼显微光谱仪,配置近红外二极管激光源和Rencam电荷耦合器件(CCD)硅检测器。将样品平铺置于显微镜载玻片上,于20倍物镜下聚焦观察并做拉曼单点检测,检测条件如下:检测波长785nm,检测范围为200cm-1~1800cm-1,激光强度100%,曝光时间3s,累计次数2次;数据采集分析软件wire 4.3。
偏光显微镜法(PLM):采用带交叉偏光滤镜的尼康显微镜观察样品粒径和形貌。反射光模式,尼康DS-Fi1c相机,NIS-Elements 4.50分析软件。
差热量热扫描仪(DSC):采用差示扫描量热仪Q2000(美国TA仪器)分析样品热性能。设置样品室氮气吹扫气流50mL/min,在25℃平衡,升温速率以10℃/min速率加热至200℃,数据分析软件TAUniversal Analysis(美国TA仪器)。
实施例1:凡德他尼-布美他尼盐的晶型A单晶的制备
称取18.3mg布美他尼(0.05mmoL)与23.8mg凡德他尼(0.05mmoL)于研钵中再加入4滴乙酸乙酯辅助研磨15min,将研磨后得到的粉末溶于5ml乙酸乙酯:乙腈(1:1v/v)混合溶剂。过滤,将滤液室温挥发。获取单晶样品,偏光显微镜图如图1所示,为长块状晶体,即为凡德他尼-布美他尼盐晶型A。
对单晶样品进行单晶X射线衍射测试,测试结果的总衍射点个数为23537,独立衍射点个数为8229,可观察点个数|F|2≥2σ|F|2=6803,数据完整度99.7%。晶体结构解析(精修)方法为:利用SHELXS算法的Direct Methods方法对进行结构数据解析,再利用差值傅里叶算法解出非氢原子位置,然后通过理论加氢得到氢原子坐标,最后利用最小二乘法对结构数据进行精修。整个解析精修过程均采用Olex2程序完成。最终可靠因子R1=0.053,ωR2=0.155,S=1.045。
单晶X射线衍射结果显示,产物晶体属于三斜晶系,空间群为P-1。晶胞参数a=12.5755,b=12.6649,c=14.4336,α=68.909,β=82.733,γ=75.557,晶胞体积V=2075.30。晶体内分子数Z=2,每个不对称单元含有1个布美他尼-凡德他尼盐型分子和1个乙腈分子。计算晶体密度为1.410g/cm3。从单晶解析结果可以看出布美他尼上的羧基上的氢,转移至凡德他尼上哌啶基团上的氮上,即形成了凡德他尼-布美他尼盐。单晶分子椭球图(立体结构投影)如图2所示,单晶的晶胞图如图3所示。
由晶型A的单晶数据模拟的PXRD图谱如图4所示。晶型A在衍射角2θ为6.5°±0.2°、8.2°±0.2°、9.6°±0.2°、12.8°±0.2°、14.5°±0.2°、15.8°±0.2°、18.4°±0.2°、19.8°±0.2°、20.1°±0.2°、21.2°±0.2°、21.5°±0.2°、21.7°±0.2°、22.6°±0.2°、23.0°±0.2°、23.5°±0.2°、24.1°±0.2°、24.4°±0.2°、24.8°±0.2°、25.7°±0.2°处具有特征峰。
实施例2:凡德他尼-布美他尼盐晶型B的制备
称取实施例1获取的凡德他尼-布美他尼盐晶型A,在氮气保护下,以150℃的温度下加热5min。所得粉末(凡德他尼-布美他尼盐晶型B)采用PXRD表征,如图5所示。采用差式扫描量热仪(DSC)测试,凡德他尼-布美他尼盐晶型B在约182.8℃(峰值)处具有熔融峰,如图6所示,即其熔点为182.8℃。同时采用拉曼对晶型B进行表征,拉曼图谱如图7所示。凡德他尼-布美他尼盐晶型B在使用Cu-Kα射线测量得到的X射线粉末衍射图谱中,在衍射角2θ为2.1°±0.2°、6.0°±0.2°、9.4°±0.2°、12.0°±0.2°、13.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.6°±0.2°、17.9°±0.2°、18.4°±0.2°、19.8°±0.2°、20.2°±0.2°、20.9°±0.2°、23.0°±0.2°、23.7°±0.2°、24.0°±0.2°、24.2°±0.2°、25.1°±0.2°、26.8°±0.2°处具有特征峰,在182.8℃±0.5℃处具有熔融峰。
实施例3:凡德他尼-布美他尼盐晶型B的药物组合物的制备
(1)粉碎:将适量凡德他尼-布美他尼盐晶型B用气流粉碎,粉碎后过80目筛,备用。
(2)称量:按照下表处方,准确称量各物料。
(3)预混:将准确称量的凡德他尼-布美他尼盐晶型B、微晶纤维素、乳糖和交联聚维酮。
(4)加入三维混合机中,设置转速20rpm,混合时间30min,得均匀混合物,备用。
(5)总混:将处方量的硬脂酸镁加入到上述混合物中,设置转速10rpm,混合。时间5min,得总混混合物。
(6)将上述总混混合物用胶囊罐装器装入2号硬明胶胶囊壳,得终产品。
效果实施例1晶型B在不同溶出介质中表观溶解度测试
称取10mg实施例2制备的凡德他尼-布美他尼盐晶型B,5.7mg凡德他尼,4.3mg布美他尼,分别加入50mL pH=6.8的磷酸盐缓冲溶液和水中,在25℃±0.5℃条件下,以100rpm搅拌24h,取上层清液,采用滤头过滤得到待测样品,所得样品采用紫外分光光度计进行测试,凡德他尼、布美他尼的最大紫外吸收波长分别为251nm和325nm。待测样品测试结果如下表所示。从表中可知,在水中,凡德他尼-布美他尼盐晶型B中凡德他尼相对于凡德他尼的溶解度提升了约1.9倍,凡德他尼-布美他尼盐晶型B中布美他尼相对于布美他尼的表观溶解度提升了约51.9倍。在pH=6.8磷酸盐缓冲溶液中,凡德他尼-布美他尼盐晶型B中凡德他尼相对于凡德他尼的溶解度小幅度增大,凡德他尼-布美他尼盐晶型B中布美他尼相对于布美他尼的表观溶解度提升了约7.2倍。
效果实施例2稳定性测试
依据《中国药典》2020年版四部《9001原料药物与制剂稳定性指导原则》,将实施例2所制备的凡德他尼-布美他尼盐晶型B,放置于40℃、75%RH条件下加速30天,并对样品进行PXRD进行表征,所得结果如图8所示。由图可知,凡德他尼-布美他尼盐晶型B在加速条件下30天没有发生晶型转变。
Claims (6)
1.一种凡德他尼-布美他尼盐晶型B,其特征在于,所述晶型在使用Cu-K∝射线测量得到的X射线粉末衍射图谱中,在衍射角2θ为6.0°±0.2°、9.4°±0.2°、12.0°±0.2°、13.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.6°±0.2°、17.9°±0.2°、18.4°±0.2°、19.8°±0.2°、20.2°±0.2°、20.9°±0.2°、23.0°±0.2°、23.7°±0.2°、24.0°±0.2°、24.2°±0.2°、25.1°±0.2°、26.8°±0.2°处具有特征峰,在约182.8℃±0.5℃处具有熔融峰。
2.一种权利要求1所述的凡德他尼-布美他尼盐晶型B的制备方法,其特征在于,所述的制备方法的特征如下,将凡德他尼-布美他尼盐晶型A 在氮气保护下100℃~180℃加热5~10min可得;
所述的凡德他尼-布美他尼盐的晶型A,其制备方法是将凡德他尼和布美他尼等摩尔量加入乙腈进行研磨与混合,然后在乙酸乙酯:乙腈1:1 v/v混合溶剂完全溶解后,通过挥发获取凡德他尼-布美他尼盐晶型A;
所述的凡德他尼-布美他尼盐的晶型A,所述晶型在使用Cu-K∝射线测量得到的X射线粉末衍射图谱中,在衍射角2θ为6.5°±0.2°、8.2°±0.2°、9.6°±0.2°、12.8°±0.2°、14.5°±0.2°、15.8°±0.2°、18.4°±0.2°、19.8°±0.2°、20.1°±0.2°、21.2°±0.2°、21.5°±0.2°、21.7°±0.2°、22.6°±0.2°、23.0°±0.2°、23.5°±0.2°、24.1°±0.2°、24.4°±0.2°、24.8°±0.2°、25.7°±0.2°处具有特征峰。
3.根据权利要求2所述的制备方法,其特征在于,所述的温度为150℃,加热时间为5min。
4.一种包含凡德他尼-布美他尼盐的药物组合物,其特征在于,含有权利要求1所述的凡德他尼-布美他尼盐晶型B与药用可接受的辅料制备成药物组合物。
5.根据权利要求4所述的药物组合物,其特征在于,所述的药用可接受的辅料包括保护填充剂、助流剂、粘合剂、矫味剂。
6.权利要求1所述的凡德他尼-布美他尼盐晶型B或权利要求4或5所述的包含凡德他尼-布美他尼盐的药物组合物在制备非小细胞肺癌或甲状腺癌药物中的应用。
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