CN110551038A - 抗肿瘤的新化合物及其用途 - Google Patents
抗肿瘤的新化合物及其用途 Download PDFInfo
- Publication number
- CN110551038A CN110551038A CN201810558111.2A CN201810558111A CN110551038A CN 110551038 A CN110551038 A CN 110551038A CN 201810558111 A CN201810558111 A CN 201810558111A CN 110551038 A CN110551038 A CN 110551038A
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- China
- Prior art keywords
- low molecular
- mitoxantrone hydrochloride
- mitoxantrone
- novel
- compound
- Prior art date
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Abstract
本发明的盐酸米托蒽醌ν型、ω型化合物,更易于制备,更利于降低能耗,具有较少的吸湿性、更好的存储稳定性等,适用于制备恶性淋巴瘤、乳腺癌、急性白血病、肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、复发性视神经脊髓炎、多发性硬化症等的治疗或预防的药物中的应用。
Description
技术领域
本发明涉及医药技术领域,具体地说是提供抗肿瘤药物盐酸米托蒽醌的更易制备或稳定性更好的新分子式和新分子结构的化合物以及其药物组合物。
背景技术
盐酸米托蒽醌(Mitoxantrone Dihydrochloride,CAS Registry Number:70476-82-3)的分子式为C22H28N4O6·2HCl,M=517.41,化学名称为:1,4-二羟基-5,8-双[[2-[(2-羟乙基)氨基]乙基]氨基]-9,10-蒽醌二盐酸盐,与阿霉素相比,该药具有与阿霉素相当或略高的抗肿瘤活性,但心脏毒性、胃肠道反应、脱发等副作用较低,易为病人耐受,从而引起了广泛的注意。主要用于恶性淋巴瘤、乳腺癌和急性白血病等,也用于肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大肠癌、肾癌、前列腺癌、子宫内膜癌、睾丸肿瘤、卵巢癌和头颈部癌、复发性视神经脊髓炎、多发性硬化症。米托蒽醌可降低进展型多发性硬化患者疾病残疾进展及减少复发,疗效明显,副作用小,安全可靠。将盐酸米托蒽醌溶于50ml以上的氯化钠注射液或5%葡萄糖注射液中滴注,时间不少于30分钟。静脉滴注:单用本品,按体表面积一次12~14mg/m2,每3~4周一次;或按体表面积一次4~8mg/m2,一日1次,连用3~5天,间隔2~3周。联合用药,按体表面积一次5~10mg/m2。一些公开文献报道盐酸米托蒽醌合成、分析、脂质体制剂、药理毒理临床、联合给药等(文献1、戴德银,米托蒽醌的药理及临床应用[J].国外医药(抗生素分册),1994(4):303-304+272;文献2、Ellis JA,Cooke J,Singh-Moon RP,etc,Safety,feasibility,and optimization of intra-arterialmitoxantrone delivery to gliomas.J Neurooncol.2016,130(3):449-454;文献3、Evison BJ,Sleebs BE,Watson KG,etc,Mitoxantrone,More than Just AnotherTopoisomerase II Poison.Med Res Rev.2016,36(2):248-99;文献4、胡慧,宗珍,汪美芳,等.盐酸米托蒽醌合成工艺的研究[J].内蒙古中医药,2013,32(9):117+140;文献5、BWeinstockguttman,M Ramanathan,N Lincoff,Study of mitoxantrone for thetreatment of recurrent neuromyelitis optica(Devic disease).Arch Neurol,2006,63(7):957-963;文献6、彭海民,唐晓玲,陈建祥.米托蒽醌和阿霉素为主的联合方案治疗非何杰金淋巴瘤95例疗效分析[J].实用中西医结合临床,2005(4):34-35;文献7、陈纪伟,邱蔚六,何荣根,林国础.维拉帕米增强米托蒽醌对腺样囊性癌抑癌效应的实验研究[J].中华口腔医学杂志,1994(5):262-265+319;文献8、Bernitsas E,Mikol D.D,袁海峰.利用右雷佐生抑制多发性硬化症患者米托蒽醌治疗的心脏毒性[J].世界核心医学期刊文摘(神经病学分册),2006(05):10;文献9、新型米托蒽醌脂质体联合化疗药物在抗肿瘤治疗中的应用,中国专利CN:105287383A;文献10、一种米托蒽醌雌激素靶向PEG修饰脂质体及其应用,中国专利CN 104971044;文献11、一种多药耐药肿瘤细胞模型的构建方法,z中国专利申请号:201510313859.2;文献12、米托蒽醌纳米磷酸氢钙制剂及其制备方法,CN:102579355;文献13、一种米托蒽醌纳米靶向缓释长循环脂质体及制备方法,CN:101773471;文献14、原人参萜二醇和原人参萜三醇及其作为协同抗癌剂的应用,CN:1571673;文献15、癌症的治疗与预防转移,CN:1151118;)文献16、袁斌,李生茂,舒波.确认盐酸米托蒽醌含量和相关物质高效液相色谱检测方法[J].广东化工,2015,42(16):199-200;文献17、具有淋巴靶向功能的生物自组装纳米晶注射剂及制备方法,CN:107149592A;文献18、米托蒽醌脂质体组合药物及其大工业化生产工艺和用途,CN:104324001;文献19、无岩藻糖基化CD20抗体与氟达拉滨和/或米托蒽醌的联合疗法,CN:102470172A;文献20、一种应用miR-487a逆转乳腺癌耐药的方法,CN:103263676A;文献21、米托蒽醌或盐酸米托蒽醌脂质体及其制备方法,CN:1915220;文献22、一种抗肿瘤化疗药物组合物及其应用,CN:101002764;文献23、一种新型抗肿瘤药物及其制备方法,CN:101091698;文献24、Frau J,Coghe G,Casanova P,etc.Pregnancy planning and outcomes in patients with multiple sclerosis aftermitoxantrone therapy:a monocentre assessment.Eur J Neurol.2018.doi:10.1111/ene.13650;文献25、DeAngelo DJ,Brunner AM,Werner L,etc.A phase I study oflenalidomide plus chemotherapy with mitoxantrone,etoposide,and cytarabine forthe reinduction of patients with acute myeloid leukemia.Am J Hematol.2018;93(2):254-261.)。
然而,到目前为止,国内外尚没有公开的文献报道更易制备或稳定性更好的本发明的新型盐酸米托蒽醌化合物,譬如埃盐酸米托蒽醌ν型晶体化合物,即不同分子式或不同晶体形式的盐酸米托蒽醌新化合物及其制备方法和用途。
化学药物的多晶型在药物研究中具有重要地位,不仅构建药物化合物库等,而且适用于更佳的制药需要。热分析方法在材料科学、化学或药物分析等中具有重要的价值和地位,能单独用来检测化合物的多晶型或过程中晶型的变化(李增余,《热分析》,清华大学出版社,1987年8月第一版)。差热分析法(DTA)是较为常用的分析方法,它既可用于物质的定性鉴别,也可用于定量分析,早在1968年的第二届国际热分析会议上,就被Barta等用来鉴定未知化合物。国外许多国家的药典早已收载差热分析法,十几年前,差热分析法在化工、制药系统就已广为应用。
发明内容
本发明所涉及的是抗肿瘤药物新型盐酸米托蒽醌结晶水合物及其制备方法和用途分子式为C22H28N4O6·2HCl·nH2O,n=1、1.25。即盐酸米托蒽醌ν型、ω型化合物等,即盐酸米托蒽醌的不同的新分子式和分子量以及新的分子结构化合物及其制备方法和用途。
在完成本发明过程中,出乎意料地发现,尽管目前的文献报道盐酸米托蒽醌是药物学的唯一选择,盐酸米托蒽醌也被批准上市,但本研究发现,盐酸米托蒽醌的稳定性并不是药物学上的最佳选择,其热稳定性并不太好,可导致或在出现导致存储过程中使得原料药不合格或制剂制备过程中含量不准确。而且,由于制备溶剂的近似,更重要的是,甚至在制备盐酸米托蒽醌结晶水合物的过程中,却发现更易制备得到稳定性更好的盐酸米托蒽醌1水合物或盐酸米托蒽醌1.25水合物。
不仅如此,本发明还发现,获得制备得到更好稳定性的盐酸米托蒽醌1水合物或盐酸米托蒽醌1.25水合物的反应时间远低于制备盐酸米托蒽醌所需要的(文献4的合成工艺),而盐酸米托蒽醌1水合物或盐酸米托蒽醌1.25水合物的稳定性完成能满足制药学上的要求。这反映更好稳定性的盐酸米托蒽醌1水合物或盐酸米托蒽醌1.25水合物在生产过程中具有更好的可获得性,同时也说明本发明的新化合物更具有生产的便利性。
本发明获得的新分子式和新分子结构的盐酸米托蒽醌化合物,令人惊奇的是,含结晶水的盐酸米托蒽醌引湿性低于不含结晶水的盐酸米托蒽醌,无水物的潮解使得在处理时要隔绝空气防止粘连等,而本发明的水合物具有良好的滑动性,从而改善制剂的可操作性,本发明物质比不含结晶水的盐酸米托蒽醌更能稳定的存在,出乎意料又比盐酸米托蒽醌无水物等更易于制备、更稳定,且便于储存和运输,利于降低制造费用和成本,也利于制剂制造。本发明的不同的新分子式和新分子结构的盐酸米托蒽醌结晶水合物在稳定性和可制造性等方面有不同的优势。进一步说,本发明发现盐酸米托蒽醌1水合物或盐酸米托蒽醌1.25水合物比盐酸米托蒽醌有更好的工业化价值或药用价值。
令人惊奇的是,特征性的,本发明的水合物的热分析(TG-DSC或者TG-DTA)图谱的失重平台下(约在142℃之前的失重曲线下)具有对应的吸热峰,热分析图谱显示出新型分子式或新化合物结构的盐酸米托蒽醌化合物实体,盐酸米托蒽醌ν型、ω型化合物。即使同一分子式物质的不同晶型的制备或获得,在药物学上都具有现实或潜在或未来的意义或价值,更不用说是同一药物不同不同分子式物质的获得对药物学上都具有现实或潜在或未来的意义或价值。
新型盐酸米托蒽醌化合物的制备包括如下方法:
在反应容器中,加米托蒽醌,加水和/或有机溶剂C1-C6的低分子醇(选自但不仅限于甲醇、乙醇、异丙醇、正丁醇等)、C2-C8的低分子醚(选自但不仅限于乙醚、四氢呋喃、异丙醚等)、C2-C6的低分子腈(选自但不仅限于乙腈、丙腈等)、二甲基甲酰胺DMF中的一种或几种,搅拌,控制温度在10-80℃之间,加盐酸或通氯化氢气体的一种或几种或其与水、C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮等有机溶剂中的一种或几种的溶液,搅拌,使溶解,反应0.5-3小时,加有机溶剂C1-C6的低分子醇(选自但不仅限于甲醇、乙醇、异丙醇、正丁醇等)、C2-C8的低分子醚(选自但不仅限于乙醚、四氢呋喃、异丙醚、甲基四氢呋喃等)、C2-C6的低分子腈(选自但不仅限于乙腈、丙腈等)中的一种或几种,25℃以下放置,使固体充分析出,过滤,用C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C6的低分子腈、C2-C8的低分子酯、C1-C6的低分子卤代烃中的一种或几种洗1-3次,过滤,所得固体用水与C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C1-C6的低分子卤代烃(选自但不仅限于二氯甲烷、氯仿等)、C2-C8的低分子酯、DMF中的一种或几种为结晶溶剂进行一次或多次重结晶,过滤,25℃以下放置,使结晶充分析出,过滤,用C1-C6的低分子醇、C2-C8的低级醚、C3-C8的低分子酮、C2-C8的低分子酯、C1-C6的低级卤代烃中的一种或几种洗涤,过滤,干燥得盐酸米托蒽醌新化合物;
其中,反应中所使用的米托蒽醌:盐酸或氯化氢的当量比约为1:1~1.2;反应中所使用的米托蒽醌(重量g)与水、或C1-C6的低分子醇、或C2-C8的低级醚(选自但不仅限于乙醚、四氢呋喃、异丙醚、甲基四氢呋喃等)、或C2-C6的低级腈(选自但不仅限于乙腈、丙腈等)、DMF等有机溶剂中的一种或几种重量体积比为一般为:1(g):5~100(ml),较优选的比为:1(g):6~60(ml);结晶或重结晶中使用的水与有机溶剂的体积比一般为1:1~200,较优选的比为:1:1~60。
盐酸米托蒽醌新化合物的结晶或重结晶溶剂选自但不仅限于水、乙腈、甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、醋酸丁酯、甲酸乙酯、乙醚、四氢呋喃、异丙醚、二氯甲烷、氯仿、DMF等中的一种或几种;盐酸米托蒽醌结晶或重结晶溶剂,较优选水、乙腈、甲醇、乙醇、异丙醇、丙酮、四氢呋喃、乙酸乙酯、乙醚、异丙醚、二氯甲烷、氯仿中的一种或几种。在本发明的制备方法中,在重结晶过程中先用水或甲酰胺或甲醇或乙醇等中的一种或几种溶解盐酸米托蒽醌结晶水合物,溶解后可以使用活性炭等脱色,再用本发明提到的有机溶剂使其结晶。
本发明中的有机溶剂低级醇或低分子醇的碳原子数定义为C1-C6(即:1-6个碳原子的醇),如甲醇、乙醇、异丙醇等;低级醚或低分子醚的碳原子数定义为C2-C8,如乙醚、丁醚、四氢呋喃等;低级卤代烃的碳原子数定义为C1-C6,包括二氯甲烷、二氯乙烷、氯仿等;低级酯的碳原子数定义为C2-C8,除非特别指明为甲酸低级酯的外,否则为包括醋酸丁酯、乙酸乙酯、甲酸乙酯等;C3-C8的低分子酮定义为3-8个碳原子的酮,包括丙酮,丁酮、异己酮等;关于任何一类描述为“低级或低分子”化合物的碳原子数量的标记方法只要在文本中出现一次,其它任何未进行标记的描述为“低级或低分子”的同类化合物的碳原子数与本文本中已经标明的数量是一致的。
本发明的产物的干燥方式可以为在不同温度(譬如20-70℃之间干燥)、干燥时间(譬如0.5小时到数日)、或附有其它干燥剂(包括硅胶,五氧化二磷、无水氯化钙、无水硫酸钠等)的环境条件下、或使用常压或减压的方式对最后的产物进行干燥。其干燥温度较优选在25-55℃。
本发明中提到的盐酸米托蒽醌无水物的制备:取市售盐酸米托蒽醌样品或按照文献4方法制备,在真空干燥箱中90℃左右高真空干燥约4小时后,然后在真空干燥箱放置盛有足量五氧化二磷的三角瓶,再抽真空(真空表读数大约为0.08MPa左右),在室温下继续保持真空干燥两天,得盐酸米托蒽醌无水物,卡尔费休法测定其水分含量约0.4%。
本发明中或实施例中的盐酸米托蒽醌及盐酸米托蒽醌新化合物的检测(包括HPLC法等)参照2010版中国药典二部的盐酸米托蒽醌项下的方法。氯化物的鉴别反应(参照2010版中国药典二部的附录Ⅲ)。本发明中的盐酸米托蒽醌新化合物或盐酸米托蒽醌等的水分测定参照2010版中国药典附录ⅧM第一法A,采用卡尔费休法测定,盐酸米托蒽醌项下水分测定方法。采用卡尔费休法测定本发明中提及的化合物等的水分时,以无水甲醇与甲酰胺(1:2)为混合溶剂。
本发明中的盐酸米托蒽醌含量和相关物质的高效液相色谱检测方法的色谱条件:检测波长:244nm,柱温为室温,色谱柱:KROMASIL 4.6mm×250mm,5μm,C18柱,流速:1mL/min,进样量:20μL。
粉末X衍射通常可用来表征和/或鉴别多晶形,对于粉末X衍射在表征和/或鉴别时,在报告峰值前使用修饰语“约”。鉴于峰值的固有变化,这是固态化学领域的惯常做法。粉末图谱峰的2θx-轴值的通常准确度在±0.2°2θ级别上,因此,以“约8.0°2θ出现的粉末X衍射峰意指当在大多数X-射线衍射仪上测量时,峰可能在7.8°2θ与8.2°2θ之间。峰强度的变化是各晶体在样品容器中相对于外部X-射线源如何取向的结果,取向作用不提供关于晶体的结构信息。
本发明在一方面,提供盐酸米托蒽醌的不同的新分子式和新分子结构的化合物。
本发明在另一方面,提供不同的不同的新分子式和新分子结构以及它们的制备方法。
本发明在另一方面提供一种药用组合物,其中包括任何一种或多种由本发明的方法制备的盐酸米托蒽醌新化合物,和一种或多种药学可接受的赋形剂。
本发明进一步提供制备药物制剂的方法,其中包括任何一种或多种由本发明的方法制备的盐酸米托蒽醌新化合物制剂或和至少一种或药学可接受的赋形剂的合并。
本发明进一步提供盐酸米托蒽醌新化合物,在制备用于治疗肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大肠癌、肾癌、前列腺癌、子宫内膜癌、睾丸肿瘤、卵巢癌、头颈部癌、复发性视神经脊髓炎、多发性硬化症等的药物或药物组合物中的用途。
本发明提供盐酸米托蒽醌新化合物与文献4的盐酸米托蒽醌合成工艺中的盐酸米托蒽醌制备方法相比,大幅缩短反应的时间,利于降低制备成本,利于降低能耗,扩大单位设备的产能,降低该药物运营成本。
新晶体药物同时它扩大了制剂科学家设计例如具有目标释放曲线或者其它期望特性的药物的药物剂型而获得的材料的库,药物的化合物的库的建设非常重要,不仅是对比研究用等,本领域需要新的盐酸米托蒽醌结晶或新的盐酸米托蒽醌结晶水合物。
本发明提供盐酸米托蒽醌新化合物为蓝黑色结晶物,不仅便于过滤,便于干燥,药物的稳定性高于盐酸米托蒽醌无水物。
本发明的盐酸米托蒽醌新化合物可用于与抗肿瘤增效药或减毒剂制备药物组合物,该药物组合物由有效剂量的抗肿瘤增效药和有效剂量的盐酸米托蒽醌新化合物及其他药学上可接受的辅料组成。抗肿瘤增效药或减毒剂选自但不仅限于羟基氯喹、表没食子儿茶素没食子酸酯、双异桉脂素、姜黄素、透明质酸、香菇多糖、维拉帕米、右雷佐生等中的一种或几种。
例如,本发明涉及抗肿瘤化疗药物组合物及其医药用途,药物组合物的活性成份为:(1)表没食子儿茶素没食子酸酯;(2)盐酸米托蒽醌新化合物;其中,(1)与(2)的重量比例为200∶1~1∶5。
该药物组合物可应用于制备治疗乳腺癌和白血病药物,其中,表没食子儿茶素没食子酸酯具有逆转抗肿瘤化疗药物的多药耐药性的作用,可以提高乳腺癌细胞和白血病癌细胞对米托蒽醌的敏感性和增加米托蒽醌对肿瘤的治疗效果。
盐酸米托蒽醌新化合物和双异桉脂素的抗肿瘤增效药的药物组合物,二者重量比为(2~10):(1-5)。
本发明的盐酸米托蒽醌新化合物用于与其它抗肿瘤药物的联合给药或制备复方药物组合物。
本发明的新型盐酸米托蒽醌化合物优点还更多的表现如下:本发明的新型盐酸米托蒽醌化合物能稳定存储。将本发明的盐酸米托蒽醌结晶水合物或其组合物和无水物或其组合物样品进行引湿性试验对比研究。
1、引湿试验
本发明的盐酸米托蒽醌结晶水合物更利于稳定存储。将盐酸米托蒽醌新化合物和无水物样品进行引湿性试验:分别取盐酸米托蒽醌无水物和本发明各新化合物约5g,置于干燥恒重的表面皿中,精密称重,置于约25±2℃、相对湿度约为55±5%的实验箱中,分别于试验0h和8h取样,计算引湿增重的百分率,结果显示,无水物引湿性比对应的本发明的盐酸米托蒽醌新化合物都具有显著性的差异,本发明的新化合物能更好地稳定存储,结果见表1。
表1.引湿试验结果
引湿试验结果表明,盐酸米托蒽醌无水物的潮解更为严重,本发明的盐酸米托蒽醌新化合物不同于无水物的潮解使得在处理时要隔绝空气防止粘连等,而本发明新化合物具有良好的滑动性,从而改善制剂在分装过程中的可操作性;使得其防止出现在进行无菌分装时不易因为吸潮而导致分装时产生堵塞使得装量发生差异导致剂量不足,从而带来产品的不合格,导致生产过程中被迫出现报废损失;或因为不合格的产品没有被抽检到形成实际上的漏检,进而流入市场。
稳定性实验表明,盐酸米托蒽醌无水物储存稳定性不如本发明的结晶水合物,本发明的化合物更适于用做药物原料药。
2、稳定性实验
在RH65±5%、25±2℃条件下,将本发明的盐酸米托蒽醌新化合物样品(分别按实施例1法、实施例2法、实施例3法制备的样品)以及盐酸米托蒽醌无水物密闭避光于西林瓶中进行18个月的稳定性试验,观察外观色泽变化情况,并测定实验前后的有关物质。
实验结果表明,其外观色泽变化不明显,实施例各组样品的有关物质增加幅度很少,但对照样盐酸米托蒽醌无水物的有关物质增加更明显。有关物质越多,可能带来的不良反应越多。实验结果说明本发明的盐酸米托蒽醌新化合物比盐酸米托蒽醌无水物具有更好的室温存储稳定性或更好的安全性(结果见表2)。
表2.稳定性实验研究结果
本发明的新型盐酸米托蒽醌化合物用途:用于制备含有该化合物的固体制剂、栓剂、注射剂以及药学上可接受的制剂,其中注射剂选自但不仅限于注射用冻干粉针制剂、无菌分装粉针制剂、大输液制剂、可注射给药的脂质体制剂或注射微球制剂等,其中,大输液制剂选自但不仅限于氯化钠注射液、瓶装或袋装大输液、双室即配型大输液、非PVC固液双室即配型大输液、非PVC多层共挤膜制成的即配型大输液等药学上可接受的大输液制剂;固体制剂选自但不仅限于片剂、胶囊剂、含脂质体的制剂等。
本发明所述盐酸米托蒽醌新化合物或其药物组合物用于制备固体制剂,其所用辅料可包含填充剂、润滑剂、粘合剂、崩解剂、抗氧化剂、乳化剂、防腐剂或稳定剂等。
用于制备片剂(包括肠溶片、速崩片等)、胶囊(包括肠溶胶囊、缓释胶囊)等,其中可含有药学上可接受的辅料或载体,填充剂如淀粉、变性淀粉、乳糖、微晶纤维素、环糊精、山梨醇、甘露醇、磷酸钙、氨基酸等;药学上可接受的崩解剂,如淀粉、变性淀粉、微晶纤维素、交联羧甲基纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素、表面活性剂(十二烷基硫酸钠等);药学上可接受的润湿剂和粘合剂,如胶化淀粉、甲基纤维素、羧甲基纤维素钠、乙基纤维素、低取代羟丙基纤维素、聚乙烯吡咯烷酮、海藻酸及其盐等;药学上可接受的润滑剂和助流剂,如硬脂酸、硬脂酸镁、聚乙二醇4000-20000、滑石粉、微粉硅胶、十二烷基硫酸镁等;药学上可接受的甜味剂和香精,如阿斯巴甜、甜蜜素、糖精钠、三氯蔗糖、食用香精等。
盐酸米托蒽醌新化合物的注射剂,其制备包括:
无菌分装的粉针的制备:按照通常惯例使用无菌原料进行分装。
大输液制剂,包括瓶装或袋装大输液、双室即配型大输液、非PVC固液双室即配型大输液、非PVC多层共挤膜制成的即配型大输液,均可按照常规方法制备。
冻干粉针制剂的制备方法为:取盐酸米托蒽醌结晶水合物,可以加药学上可接受冻干支持剂或辅形剂、稳定剂、注射用水,搅拌使溶解,若需要,可用药学上可接受的酸碱调节pH为3.5~6.5,加活性碳0.005~0.5%(W/V)搅拌15~45min,过滤,补水,无菌过滤,按5~20mg/瓶分装,冷冻干燥,压塞,得成品。
液体注射剂制备方法为:盐酸米托蒽醌结晶水合物加注射用水和药学上可接受的辅料,例如:药学上可接受的等渗调节剂、pH调节剂、药学上可接受的抗氧剂或稳定剂、惰性气体,过滤、除菌制成注射液,其pH值在3.5~6.5之间。
冻干支持剂或辅形剂选自但不仅限于木糖醇、山梨醇、甘露醇、转化糖、麦芽糖、右旋糖酐、氯化钠、乳酸钠等中的一种或几种。
药学上可接受的等渗调节剂选自但不仅限于葡萄糖、果糖、木糖醇、山梨醇、甘露醇、转化糖、麦芽糖、右旋糖酐、氯化钠、氯化钾、乳酸钠等中的一种或几种。
去热源和除菌方式可以是加入配液量0.005~3%的活性炭去热源,微孔滤膜除菌和热压灭菌,也可以采用超滤除菌、去热源。超滤方法中,超滤器可选用平板式、卷式、管式、中空纤维式或圆盒式等,优选卷式和中空纤维式超滤器,采用截留相对分子质量为5万至30万的滤膜除去大部分发热性物质和细菌后,再采用截留相对分子质量3000~60000的超滤膜除去剩余热源,优选相对分子质量6000~20000的超滤膜。
其药学上可接受的pH调节剂可以是药学上可接受的无机酸或有机酸、无机碱或有机碱,也可以是广义的路易斯酸或碱,可以含有一种或者几种,选自但不仅限于盐酸、磷酸、丙酸、醋酸及醋酸盐、如醋酸钠等,乳酸以及乳酸药用盐、枸橼酸药用盐、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、磷酸盐、酒石酸及其药用盐、硼砂、硼酸、丁二酸、己酸、己二酸、反丁烯二酸、顺丁烯二酸、多羟基羧酸及药用盐,如葡萄糖醛酸、葡萄糖酸、乳糖酸、苹果酸、苏糖酸、葡庚糖酸等中的一种或者几种。
其药学上可接受的抗氧剂和稳定剂选自但不仅限于亚硫酸、亚硫酸盐、亚硫酸氢盐、焦亚硫酸盐、连二亚硫酸盐、硫代硫酸盐,有机硫化合物硫脲、谷胱甘肽、二巯基丙醇、巯基乙酸及盐、硫代乳酸及盐、硫代二丙酸及盐、苯酚类化合物,如没食子酸及盐、咖啡酸及其盐、阿魏酸及其盐、二叔丁基对苯酚、2,5-二羟基苯甲酸及其盐、水杨酸或其盐;抗坏血酸及其盐、异抗坏血酸及其盐、烟酰胺、酒石酸、硝酸盐、磷酸盐、醋酸药用盐、柠檬酸盐、EDTA及EDTA盐、如EDTA二钠、EDTA钙钠盐、EDTA四钠、N-二(2-羟乙基)甘氨酸等中的一种或者几种。
本发明的新型盐酸米托蒽醌结晶化合物或其药物组合物,适用于:用于制备人或动物的以下病症:恶性淋巴瘤、乳腺癌和急性白血病等。也用于肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大肠癌、肾癌、前列腺癌、子宫内膜癌、睾丸肿瘤、卵巢癌和头颈部癌、神经胶质瘤、复发性视神经脊髓炎、多发性硬化症等相关疾病的治疗或预防的药物中的应用等。
一般情况下,对于本发明的盐酸米托蒽醌新化合物或其药物组合物:溶于50ml以上的氯化钠注射液或5%葡萄糖注射液中滴注。
附图说明
图1为盐酸米托蒽醌1水合物的热分析图谱(实施例1)
图2为盐酸米托蒽醌1水合物的粉末X衍射图(实施例1)
图3为盐酸米托蒽醌1水合物的热分析图谱(实施例2)
图4为盐酸米托蒽醌1.25水合物的热分析图谱(实施例3)
具体实施方式
除了在实施例中以及另有指示时,说明书和权利要求书中所用的所有的数值应被理解为在所有的实例中以术语“约”进行修饰,因此,除非有相反的指示,本说明书和所附的权利要求书中所给出的数值参数是近似值,其可以根据通过本公开内容所寻求的所需要性质而改变,最起码地,并且不是意欲限制等同原则权利要求范围的应用,每个数值参数应考虑有效数字的数和常规四舍五入方法来解释。
虽然设定公开内容的宽范围的数值范围和参数是近似值。但是在具体实施例中所给出的数值被尽可能精确地报道,任意数值本质上包含某些由在它们各自的测试中发现的标准偏差所必然产生的误差。
需要指出的是,除非文中明确地另外说明,在本说明书和附加的权利要求中使用的单数形式“一个”、“一种”以及“该”包括指代物的复数形式,所以,例如。如果提及含有“一种化合物”的组合物时包括两种或多种化合物的混合物,另外需要注意的是,除非本文明确地另外说明,术语“或”通常包括“和/或”。
如本文所用,术语“得到”,或“获得”是指有价值的含量或纯度水平分离得到的化合物,所述的含量和纯度水平包括但不限于大于90%、95%、96%、97%、98%和99%的含量和纯度水平。所述的含量或纯度水平可以通过关于盐酸米托蒽醌的2010版中国药典标准中规定的高效液相色谱方法测定。采用傅立叶变换红外光谱仪测定样品红外光谱数据,所使用的仪器包括Nexus智能型傅立叶变换红外光谱仪(Thermo Nicolet)等。
本“溶剂合物”在此处是指还包括渗入到晶体结构中的溶剂分子的分子、原子和/或离子的晶型,溶剂合物的溶剂分子可处于规则排列和/或无序排列,本发明的溶剂合物是溶剂水合物。
多晶型在此处是指具有相同的化学组成但形成晶体的分子、原子和/或离子的空间排列不同的晶体。
药物组合物:本文所用“药物组合物”是指药物的组合物,所述的药物组合物可以含有至少一种药学上可接受的辅料或载体。
本文所用“药学上可接受的辅料或载体”是指适用于本文所提供的化合物给药的药用载体或溶媒,包括本领域技术人员公知的适用于特定给药方式的任何此类载体。
在本发明中,除非有其他说明,其药学上可接受的盐或溶剂合物或其包合物中的“其”代表其中之一或它们的或它们中的任一。
在本发明中,除非有其他说明,“适量”代表完成本发明所需要的较佳或最佳的量或最低需要的量或质量或重量或体积等。
在本发明中,除非有其他说明,“该组合或其组合”表示所述各元件的多组分混合物,例如两种、三种、四种以及直到最大可能的多组分混合物。
在本发明中,除非有其他说明,所有“份”和百分数(%)可以是指重量份数或重量百分数或重量体积百分数。
凡是无菌原料均在无菌环境或GMP规范的洁净环境下制备,符合制药工业中的GMP规范洁净环境选自但不仅限于100级洁净区环境或1万级洁净环境等,在制备无菌原料时,使用无菌注射用水或无菌溶剂等溶剂或原辅料或包材或设施,并对设备、设施和环境进行洁净处理或和灭菌。
为了进一步了解本发明,下面结合实施例对本发明优选实施方案进行描述,但是应当理解,这些描述只是为进一步说明本发明的特征和优点,而不是对本发明权利要求的限制。
红外光谱:溴化钾压片,测定样品红外光谱数据,所使用的仪器包括美国热电公司NICOLET 5700FTIR Spectrometer,Nexus智能型傅立叶变换红外光谱仪(Thermo Nicolet)等。红外光谱仪仪器公司名称:美国热电公司NICOLET 5700FTIR Spectrometer,使用功能:中红外4000-400cm-1,分辨率4cm-1,最高可达0.09cm-1。
热分析方法
测试条件:Setaram公司Setsys 16,样品量3-10mg左右,升温速度:10K/min,N2流速:50ml/min,温度:一般为室温~400℃左右。
令人意外的是,特征性的,本发明的水合物的热分析(TG-DTA或者TG-DSC)图谱的失重平台下具有对应的吸热峰,热分析图谱显示出盐酸米托蒽醌的结晶水合物,如其1水合物等。
粉末X衍射法
利用D/MX-ⅢA X射线衍射仪,电压:约30-60kv,电流:约30-100mA,扫描速度:10°/min,铜靶,波长wavelength(A):1.54,衍射角2θ,扫描范围3-60°,测定了盐酸米托蒽醌结晶水合物的粉末X射线衍射图,全部峰位置在±0.2° 2θ内;或利用德国Bruker公司的D8Advance X射线衍射仪,波长:1.54,衍射角2θ,扫描范围3-60°,其它(电压、电流等指标)大约同前,对样品进行测量。本说明书中的各附图与数据互为佐证。
具体实施例
实施例1盐酸米托蒽醌1水合物的制备(ν型)
在250ml三颈烧瓶中加米托蒽醌10g、加水60ml,通氮气保护,搅拌,在30-40℃左右加8M盐酸约5.7ml,反应过程中若溶液pH值超过3,则用8M盐酸溶液调节溶液pH值约为2.8,在50-60℃左右搅拌2h,补加适量水,搅拌使溶解,然后加入无水乙醇200ml,冷却到0℃以下放置,待沉淀充分析出,抽滤,少量乙醇洗,抽滤,将所得固体于烧瓶中,加适量水加热搅拌使溶解后,用无水乙醇180ml进行重结晶,0℃以下放置,使结晶充分析出,抽滤,固体用少量乙醇洗2次,抽滤,所得固体摊薄在烘箱中40℃左右鼓风干燥2h,得蓝黑色结晶6.3g;鉴别:①取本品约5mg,加水l ml溶解后,加浓硫酸l ml,溶液由深蓝色变为深紫红色;②本品显氯化物的鉴别反应(按中国药典2010版附录Ⅲ)。HPLC:HPLC的主峰保留时间与盐酸米托蒽醌无水物对照品主峰的HPLC保留时间一致;卡氏法测定水分为3.51%,热分析:平台失重约3.56%(见附图1),在约137℃前的失重平台下具有对应的吸热峰(DTA),这与样品含有1个结晶水的结果(理论值3.37%)在误差范围内;X粉末衍射(见附图2):以衍射角2θ,在3-60°范围内测定有多个明显的特征峰(粉末X射线衍射)约3.81,5.27,6.28,6.87,7.53,8.33,9.36,10.19,10.50,11.34,12.49,13.34,14.01,15.64,16.61,18.04,18.79,19.41,20.30,20.94,22.77,23.37,24.53,25.23,25.51,26.52,27.68,29.24,29.67,42.31;红外光谱(νKBr max cm-1):3361.4,3279.6,2942.3,2769.3,1644.9,1600.1,1563.5,1515.6,1453.3,1353.8,1199.2,1142.2,1079.4,965.2,816.4,634.7;元素分析:理论值:C 49.35%,H6.02%,N 10.46%,Cl 13.24%;实测值:C 49.27%,H 6.09%,N 10.34%,Cl 13.35%;
实施例2盐酸米托蒽醌1水合物的制备(ν型化合物)
在250ml三颈烧瓶中加米托蒽醌8g、加水50ml,通氮气保护,搅拌,在48-58℃左右,滴加6M盐酸约6ml,反应过程中若溶液pH值超过3,则用6M盐酸溶液调节溶液pH值约为2.8,然后再在52-60℃下搅拌,补加适量水,搅拌至全溶,继续搅拌0.5小时,加入无水乙醇100ml、乙腈20ml、异丙醇约20ml,冷却到5℃以下放置,待沉淀充分析出,抽滤,少量乙醇洗2次,抽滤,所得固体于烧瓶中,加适量水加热搅拌使溶解后,加乙腈和乙醇(1:1)150ml进行重结晶,5℃以下放置,待结晶充分析出,抽滤,固体用少量乙醇洗2次,抽滤,所得固体摊薄在烘箱中38℃鼓风干燥2h左右,在50℃左右鼓风干燥1h,得蓝黑色结晶固体5.2g;鉴别:①取本品约5mg,加水l ml溶解后,加浓硫酸l ml,溶液由深蓝色变为深紫红色;②本品显氯化物的鉴别反应(按中国药典2010版附录Ⅲ)。HPLC:其HPLC的主峰保留时间与盐酸米托蒽醌无水物对照品主峰的HPLC保留时间一致;卡氏法测定水分为3.39%,热分析:平台失重约3.23%(见附图3),在约140℃前的失重平台下具有对应的吸热峰(DTA),这与样品含有1个结晶水的结果(理论值3.37%)在误差范围内;元素分析理论值:C 49.35%,H 6.02%,N10.46%,Cl 13.24%;实测值:C 49.44%,H 6.12%,N 10.36%,Cl 13.15%。
实施例3盐酸米托蒽醌1.25水合物的制备(ω型)
在500ml三颈烧瓶中加米托蒽醌10g、加水80ml,通氮气保护,搅拌,在室温下滴加8M盐酸约5.8ml,反应过程中若溶液pH值超过3,则用8M盐酸溶液调节溶液pH值约为2.8,然后再在52-60℃下搅拌,补加适量水,搅拌到全溶,继续搅拌0.5小时,然后加甲醇50ml、无水乙醇120ml,0℃以下放置,待沉淀充分析出,抽滤,少量甲醇洗2次,抽滤,将所得固体于烧瓶中,加适量水加热搅拌使溶解,再用乙醇约50ml、异丙醇约160ml为结晶溶剂进行重结晶,0℃以下放置,待结晶充分析出,抽滤,固体用用少量甲醇洗涤,抽滤,所得固体摊薄在烘箱中35℃鼓风干燥5h左右,得蓝黑色结晶固体6.4g;鉴别:①取本品约5mg,加水l ml溶解后,加浓硫酸l ml,溶液由深蓝色变为深紫红色;②本品显氯化物的鉴别反应(按中国药典2010版附录Ⅲ);HPLC:其HPLC的主峰保留时间与盐酸米托蒽醌无水物对照样品的主峰保留时间一致;卡氏法测定水分为4.29%,热分析:平台失重约4.35%(见附图4),在约137℃前的失重平台下具有对应的吸热峰(DTA),这与样品含有1.25个结晶水的结果(理论值4.17%)在误差范围内;X粉末衍射:以衍射角2θ,在3-60°范围内测定有多个明显的特征峰;元素分析理论值:C 48.94%,H 6.07%,N 10.38%,Cl 13.13%;实测值:C 48.86%,H 6.13%,N10.31%,Cl 13.18%。
实施例4盐酸米托蒽醌结晶水合物冻干粉针的制备(规格:5mg/瓶)
取盐酸米托蒽醌结晶水合物10g(按实施例1或实施例2法制备,重量以米托蒽醌计),搅拌使溶,加甘露醇40g,乳酸5g,EDTA二钠0.05g,加注射用水400ml左右,搅拌使溶,用1M左右的柠檬酸和磷酸氢二钠溶液调节pH为4.5~5.5,加活性碳0.01~0.5%(W/V)搅拌15-30min,过滤,用0.22微米微孔滤膜过滤,按主药重量5mg/瓶分装,-45~-30℃冷冻约4小时,-45~-10℃真空冷冻干燥约10小时,-10~20℃真空干燥约6小时,压塞,轧铝盖得成品。
实施例5盐酸米托蒽醌新化合物的氯化钠输液制备
将盐酸米托蒽醌结晶水合物5g(按实施例1法制备或实施例2法或实施例3法制备,重量以米托蒽醌计)、氯化钠85g、柠檬酸5g、EDTA二钠0.2g,加入8000m注射用水中,用1M的枸橼酸和枸橼酸钠溶液调节pH值在3.5-5.0的范围内,搅拌使溶解完全,加注射用水至10000ml,加配液量0.005%的活性炭,加热搅拌10-30分钟左右,过滤脱炭,再经截留相对分子质量8000-20000的超滤膜过滤,滤液灌封于50ml或100ml或200ml的玻璃瓶中,充氮气,加塞,轧盖,灭菌,包装即得。
实施例6:盐酸米托蒽醌水合物胶囊的制备(处方1000粒)
处方:盐酸米托蒽醌水合物 5g
微晶纤维素 40g
硬脂酸镁 1.5g
将盐酸米托蒽醌1水合物(按实施例1方法制备)和硬脂酸镁过100目筛,混匀,灌装于2号胶囊。
实施例7盐酸米托蒽醌1水合物片(处方1000片)
将盐酸米托蒽醌1水合物(按实施例2法制备)、速溶山梨醇、微晶纤维素、低取代羟丙基纤维素、硬脂酸镁过100目筛,混匀,压成大片,再将该片研压成18-24目筛的颗粒,加过100目筛硬脂酸镁,混匀,压片。
以上通过具体实施方式和实施例对本发明进行了详细说明,不过应理解,这些说明并不对本发明的范围构成任何限制,相关技术人员明显能在在不偏离本发明的精神和保护范围的情况下,可以对本发明的技术方案及其实施方式进行多种修饰、改进和替换与组合,来实现本发明技术,这些均因落入本发明的保护范围内。特别需要指出的是,可以理解,很多细节的变化是可能的,所有相类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明的精神、范围和内容中,本发明并不限于上述实施例。
Claims (7)
1.盐酸米托蒽醌新化合物,其特征在于:盐酸米托蒽醌新化合物为盐酸米托蒽醌结晶水合物,分子式为C22H28N4O6·2HCl·nH2O,n=1、1.25。
2.根据权利要求1所述的盐酸米托蒽醌新化合物,其特征在于:为盐酸米托蒽醌1水合物。
3.根据权利要求2所述的盐酸米托蒽醌新化合物,其特征在于:利用粉末X射线衍射法测量,在衍射角2θ,3-60°的测量范围内,在如下2θ值的位置具有相应的特征值:3.81,5.27,6.28,6.87,7.53,8.33,9.36,10.19,10.50,11.34,12.49,13.34,14.01,15.64,16.61,18.04,18.79,19.41,20.30,20.94,22.77,23.37,24.53,25.23,25.51,26.52,27.68,29.24,29.67,42.31。
4.根据权利要求1所述的盐酸米托蒽醌新化合物,其特征在于:为盐酸米托蒽醌1.25水合物。
5.根据权利要求1-4中任一所述的盐酸米托蒽醌新化合物,其特征在于:用于制备含有盐酸米托蒽醌新化合物的药物组合物,该药物组合物用于制备固体制剂、栓剂、注射剂、植入剂以及药学可接受的制剂,其中注射剂选自但不仅限于注射用冻干粉针制剂、无菌分装粉针制剂、小水针、大输液剂、可注射给药的脂质体制剂或注射微球制剂,固体制剂选自但不仅限于片剂、胶囊剂、颗粒剂、微丸。
6.根据权利要求1-5中任一所述的盐酸米托蒽醌新化合物或其药物组合物,其特征在于:用于制备对肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大神经脊髓炎、多发性硬化症的治疗或预防的药物中的应用。
7.根据权利要求1-6中任一所述的盐酸米托蒽醌新化合物的制备方法,其特征在于:其制备方法为:
在反应容器中,加米托蒽醌,加水和/或有机溶剂C1-C6的低分子醇、C2-C8的低分子醚、C2-C6的低分子腈、二甲基甲酰胺中的一种或几种,搅拌,控制温度在10-80℃之间,加盐酸或通氯化氢气体的一种或几种或其与水、C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮等有机溶剂中的一种或几种的溶液,搅拌,使溶解,反应0.5-3小时,加有机溶剂C1-C6的低分子醇、C2-C8的低分子醚(、C2-C6的低分子腈中的一种或几种,25℃以下放置,使固体充分析出,过滤,用C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C2-C6的低分子腈、C2-C8的低分子酯、C1-C6的低分子卤代烃中的一种或几种洗1-3次,过滤,所得固体用水与C1-C6的低分子醇、C2-C8的低分子醚、C3-C8的低分子酮、C1-C6的低分子卤代烃、C2-C8的低分子酯、二甲基甲酰胺中的一种或几种为结晶溶剂进行一次或多次重结晶,过滤,25℃以下放置,使结晶充分析出,过滤,用C1-C6的低分子醇、C2-C8的低级醚、C3-C8的低分子酮、C2-C8的低分子酯、C1-C6的低级卤代烃中的一种或几种洗涤,过滤,干燥得盐酸米托蒽醌新化合物;
其中,有机溶剂C1-C6的低分子醇,选自但不仅限于甲醇、乙醇、异丙醇、丁醇;C2-C6的低分子腈选自但不仅限于乙腈;C2-C8的低分子醚或低分子醚选自但不仅限于乙醚、异丙醚、四氢呋喃、甲基四氢呋喃;C1-C6低级卤代烃选自但不仅限于二氯甲烷、氯仿;C2-C8低分子酯选自但不仅限于醋酸丁酯、乙酸乙酯、甲酸乙酯;C3-C8的低分子酮选自但不仅限于丙酮,丁酮、异己酮。
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL266934A1 (en) * | 1987-07-21 | 1989-01-23 | Method of obtaining mitoxantrone dihydrochloride of high purity |
-
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL266934A1 (en) * | 1987-07-21 | 1989-01-23 | Method of obtaining mitoxantrone dihydrochloride of high purity |
Non-Patent Citations (2)
Title |
---|
胡慧等: "盐酸米托蒽醌合成工艺的研究", 《内蒙古中医药》 * |
胥佩菱等: "抗癌新药米托蒽醌的研究", 《医学研究通讯》 * |
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