CN108570005A - 地喹氯铵新化合物及其组合物和用途 - Google Patents
地喹氯铵新化合物及其组合物和用途 Download PDFInfo
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- CN108570005A CN108570005A CN201710136694.5A CN201710136694A CN108570005A CN 108570005 A CN108570005 A CN 108570005A CN 201710136694 A CN201710136694 A CN 201710136694A CN 108570005 A CN108570005 A CN 108570005A
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- China
- Prior art keywords
- dequalinium chloride
- preparation
- crystalline hydrate
- pharmaceutically acceptable
- dequalinium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LTNZEXKYNRNOGT-UHFFFAOYSA-N dequalinium chloride Chemical compound [Cl-].[Cl-].C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 LTNZEXKYNRNOGT-UHFFFAOYSA-N 0.000 title claims abstract description 192
- 229960001378 dequalinium chloride Drugs 0.000 title claims abstract description 190
- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 61
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- 229940079593 drug Drugs 0.000 claims abstract description 32
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- 201000008100 Vaginitis Diseases 0.000 claims abstract description 6
- 230000036541 health Effects 0.000 claims abstract description 6
- 206010006326 Breath odour Diseases 0.000 claims abstract description 5
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- 241001465754 Metazoa Species 0.000 claims abstract description 5
- 230000035558 fertility Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- -1 Dequalinium Chloride anhydride Chemical class 0.000 claims description 51
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 50
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- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims description 35
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- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims description 35
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- NLJVXZFCYKWXLH-DXTIXLATSA-N 3-[(3r,6s,9s,12s,15s,17s,20s,22r,25s,28s)-20-(2-amino-2-oxoethyl)-9-(3-aminopropyl)-3,22,25-tribenzyl-15-[(4-hydroxyphenyl)methyl]-6-(2-methylpropyl)-2,5,8,11,14,18,21,24,27-nonaoxo-12-propan-2-yl-1,4,7,10,13,16,19,23,26-nonazabicyclo[26.3.0]hentriacontan Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@H](C(N[C@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)N1)=O)CC(C)C)C(C)C)C1=CC=C(O)C=C1 NLJVXZFCYKWXLH-DXTIXLATSA-N 0.000 claims description 24
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- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 claims description 7
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明的地喹氯铵新化合物及其组合物及制备方法和用途,具有较低的吸湿性、较好的存储稳定性及作为制剂优势的原料特性,适用于制备人或动物的急、慢性咽喉炎、扁桃体炎、口炎、舌炎、口臭、口腔黏膜溃疡、齿龈炎、阴道炎、鼠类控制生育、PKC抑制剂、抗肿瘤等的治疗或预防的卫生健康用品或药物中的应用。
Description
技术领域
本发明涉及医药技术领域,具体地说是提供抗菌等药物地喹氯铵新化合物及其组合物及制备方法和用途。
背景技术
化学药物的多晶型在药物研究中具有重要地位。在药物学领域,药物晶型和药物水合物或药物溶剂化合物的研究工作已列于国家十二五重大新药创制科技重大专项的研究范围。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等。化合物的溶剂化合物包括水合物很早就在药物中比较多的被制备和应用,譬如美国药典36版、欧洲药典6.1版以及中国药典2010版收载的抗肿瘤药物环磷酰胺。最近二十多年以来,不仅是具有同一个分子式药物的晶型不断被发现,而且具有同一母体但不同分子式药物溶剂化合物的研究也不断取得新的进展。甚至调节血糖药物达格列嗪都在研究以达格列嗪丙二醇水合物为核心的药物制剂。
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,该方法尤其对于具不同晶型的同一化合物的鉴别具有独特的优点。十几年前,差热分析法在我国不仅在化工、制药系统就已广为应用,而且在复杂的中药鉴别中也开始应用(张汉明,等,珍珠粉及其伪品的差热分析研究,中成药,1999,21(4):173-175)。在晶型研究中,差示扫描(DSC)可完成药物纯度评估、鉴别、多晶态分析等多项研究(朱兵,刘继涛.DSC在药物分析中的应用,流程工业,2008,15:64-66),(林克江,陈卫,尤启冬.差示扫描量热法检测那格列奈多晶型,药学学报,2002,37(1):46-49)。而药物的多晶型并非在罕见或昂贵的溶剂中才能制备,通过常用的溶剂、温度、时间等或其它的改变能出乎意料的获得化合物的多晶型(杜青,平其能.盐酸丁螺环酮的多晶型研究,中国药科大学学报,2000,31(2):102-104)。在热分析领域,TG-DTA或TG-DSC的联用更是给化合物的分析带来更多的便利。
地喹氯铵,化学名为癸烷-1,10-双(4-氨基喹哪啶氯代)盐,CAS号为522-51-0,分子式为C30H40Cl2N4。地喹氯铵系季胺盐类化学杀菌剂,抗菌谱广,对革兰阳性细菌和阴性细菌、抗酸杆菌及白色念珠菌及毛发癣菌、奋森螺旋体等真菌均有较强的杀灭作用,不受血清影响,对组织无刺激性。在其化学结构中,含有两个阳离子酸性基团与一个含脂肪酸的直链肽,其阳离子与胞膜中磷脂的磷酸根相结合,使细胞膜功能受损,通透性发生改变,作用于受感染的粘膜局部,可导致菌体内的酶和代谢中间产物外漏,妨碍了细菌的呼吸和糖酵解过程,干扰细菌的代谢并使菌体蛋白发生变性,从而发挥杀菌作用。药理作用特点是杀菌范围广、作用快、效力强,几乎无毒性和刺激性,而且其杀菌性能不会因血清等有机物的存在而降低。地喹氯铵含片,已在多个国家上市,比如欧盟多国、中国、日本等,临床用于预防和治疗急性咽炎、急性扁桃体炎,以及慢性咽炎、慢性扁桃体炎,口腔黏膜溃疡、齿龈炎、喉炎、口炎、舌炎,也可作为预防和治疗上述重症咽炎、扁桃体炎、口腔黏膜溃疡、齿龈炎的联合用药、拔牙创面等口腔创伤的感染,还可以改善抽烟引起的咽部不适;白色念珠菌引起的急性假膜性念珠 病,也可以用于牙科疾患的局部治疗,并能防治口臭、阴道炎、滴虫、鼠类控制生育、作为PKC抑制剂、抗肿瘤等。早期研究发现地喹氯铵具有抗肿瘤作用,能延长膀胱癌或者结肠癌小鼠的生存时间,并且比常用的化疗药物如氨甲喋呤、顺铂等更有效地喹氯铵在体外和体内实验中均能抑制神经胶质瘤细胞的生长,此作用可能是通过促进肿瘤细胞凋亡来实现的。
而地喹氯铵短杆菌素含片中,其主要成份地喹氯铵,短杆菌素或短杆菌肽,其中地喹氯铵为阳离子表面活性剂,具有广谱抗菌作用,对口腔和咽喉部的常见致病细菌,和真菌感染有效。短杆菌素或短杆菌肽属多肽类抗生素,抗菌谱较广。两药并用具有协同作用。口含,一次1~2片,每2~3小时1次,必要时可重复用药。用于急,慢性咽喉炎,口腔粘膜溃疡及牙龈炎等。
目前,中国药品标准及欧洲药典等公开的文献报道了地喹氯铵及其制剂(Dequalinium Chloride)(C30H40Cl2N4,分子量:527.58,CAS号:522-51-0)的标准、合成、分析、药理与临床及用途等,也公开了地喹氯铵与其它药物等联用协同治疗等[参考文献1、一种化合物地喹氯胺的制备方法,中国专利,CN 103387537A;文献2、一种地喹氯铵阴道片及制备方法201610421524.7;文献3、史美平,郭曙刚,地喹氯铵合成工艺的研究,河北化工,2000,4:24-25;文献4、朱景申,黄蓉,李潮海,等;地喹氯铵合成工艺的研究,中国药师,2000年02期;文献5、李超,黄永旺;复方地喹氯铵含片临床应用,天津药学,2002,14(4):54-55;文献6、吴芸,房宏志,韩大江,等,地喹氯铵短杆菌素含片治疗智齿冠周炎临床疗效观察,中国当代医药,2013,20(2):9-11;文献7、肖红俊黄选兆向友华,急性咽炎、扁桃体炎的细菌学特征及地喹氯铵口含片(泰乐奇)的疗效观察,临床耳鼻咽喉科杂志,1998年第12卷第7期;文献8、张琳,董金凤,地喹氯铵喷雾剂治疗复发性口腔溃疡疗效观察,西北药学杂志,2006,21(4):175-176;文献9、于莹,赵刚,地喹氯铵对神经胶质瘤的作用及其机制研究,博士论文,2014;文献10、黄东青,何荪兰,史楚君,地喹氯铵含片的含量测定及含量均匀度研,广东药学院学报,2007,23(3):276-278;文献11、郭强,李国强,李惊涛,等,地喹氯铵联合紫杉醇注射液对神经胶质瘤患者血清IL-6,Th17细胞水平及临床疗效的影响,现代生物医学进展,2016年33期;文献12、地喹氯铵作为鼠类的生育控制药物的应用中国专利201310739915.X;刘克江,肖仰,复方地喹氯铵喷雾剂中二组分的HPLC测定,中国医药工业杂志,2001 32(1);文献13、CTBS蛋白作为精卵结合受体的靶点在筛选精卵结合抑制剂中的应用,中国专利,CN103743910A;文献14、具有抗微生物表面的外科缝合材料以及在外科缝合材料上设置抗微生物涂层的方法,中国专利,CN 101168071B;文献15、口腔用组合物和口腔用制品的选择方法,中国专利,CN 1935116B;文献16、一种治疗急慢性咽喉炎、口腔溃疡的美洲大蠊药物组合物及其制备方法,中国专利,CN 105362295A;文献17、Lizano C,Weissig V,TorchilinVP,etc.,Pinilla M.In vivo biodistribution of erythrocytes andpolyethyleneglycol-phosphatidyl-ethanolamine micelles carrying the antitumouragent dequalinium.Eur J Pharm Biopharm.2003;56(2):153-7.文献18、Weissig V,Lasch J,Erdos G,etc.,DQAsomes:a novel potential drug and gene delivery systemmade from Dequalinium.Pharm Res.1998;15(2):334-7.文献19、Rotenberg SA,SmileyS,Ueffing M,Krauss RS,Chen LB,Weinstein IB.Inhibition of rodent proteinkinase C by the anticarcinoma agent dequalinium.Cancer Res.1990;50(3):677-85.文献20、Schneider-Berlin KR,Bonilla TD,Rowe TC.Induction of petite mutants inyeast Saccharomyces cerevisiae by the anticancer drug dequalinium.MutatRes.2005;572(1-2):84-97.文献21、Gutierrez-Lugo MT,Baker H,Shiloach J,etc.,Dequalinium,a new inhibitor of Mycobacterium tuberculosis mycothiol ligaseidentified by high-throughput screening.J Biomol Screen.2009;14(6):643-52.文献22、W.[Treatment of tonsillitis with dequalinium chloride].FortschrMed.1977,28;95(16):1108-10.文献23、Pajuelo L1,E,Diez JC,etc.,Dequalinium induces apoptosis in peripheral blood mononuclear cells isolatedfrom human chronic lymphocytic leukemia.Invest New Drugs.2011;29(6):1156-63.文献24、Della Casa V,Noll H,Gonser S,etc.,Antimicrobial activity ofdequalinium chloride against leading germs of vaginalinfections.Arzneimittelforschung.2002;52(9):699-705.文献25、LEVINSONDR.Dequalinium in the treatment of trichomoniasis in women.Practitioner.1959;183:195-7.文献26、Donders G1,Bellen G,Donders F,etc.,Improvement of abnormalvaginal flora in Ugandan women by self-testing and short use of intravaginalantimicrobials.Eur J Clin Microbiol Infect Dis.2016Dec 8.[Epub ahead ofprint];文献27、Mendling W,Weissenbacher ER,Gerber S,etc.,Use of locallydelivered dequalinium chloride in the treatment of vaginal infections:areview.Arch Gynecol Obstet.2016,293(3):469-84.文献28、Weissenbacher ER,DondersG,Unzeitig V,Martinez de Tej etc.,Fluomizin Study Group.A comparison ofdequalinium chloride vaginal tabletsand clindamycin vaginal creamin the treatment of bacterial vaginosis:a single-blind,randomized clinicaltrial of efficacy and safety.Gynecol Obstet Invest.2012;73(1):8-15.等];但到目前为止,尚未见公开的文献报道本发明的地喹氯铵1水合物及其制备方法和用途。
发明内容
本发明所涉及的是抗菌感染药物地喹氯铵结晶物及其制备方法和用途,其分子式为C30H40Cl2N4·H2O。本发明获得的含有结晶水的地喹氯铵,令人惊奇的是,含结晶水的地喹氯铵引湿性远低于不含有结晶水的地喹氯铵,含有结晶水的地喹氯铵比不含结晶水的更能稳定的存在,便于储存和运输,易于制成制剂。此外,无水物的潮解使得在处理时要隔绝空气防止粘连等,而水合物具有良好的滑动性,从而改善制剂的可操作性。即使同一化合物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结晶水合物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。新的晶体的药物上的有用的化合物的发现提供了新的机会一便提高药物产品的作用特性,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,本领域需要新的地喹氯铵结晶或新的地喹氯铵结晶水合物。
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)图谱的失重平台下具有对应的吸热峰,热分析图谱显示出地喹氯铵结晶水合物,如地喹氯铵1水合物等。
本发明的地喹氯铵结晶水合物能稳定存储。将本发明的地喹氯铵结晶水合物和地喹氯铵无水物样品进行引湿性试验:取地喹氯铵无水物和本发明的结晶水合物约5g,置于干燥恒重的表面皿中,精密称重,在温度约为25±2℃、相对湿度约为75±5%,分别于试验0h和24h取样,计算引湿增重的百分率,结果显示,无水物引湿性比本发明的水合物都高得多,本发明的地喹氯铵结晶水合物能更好地稳定存储,试验结果见表1。在RH75±5%、约为25±2℃条件下,将本发明的地喹氯铵结晶水合物样品(按实施例1 或实施例2法制备的样品)密闭避光于西林瓶中进行6个月的稳定性试验,参考文献10和欧洲药典Ph.Eur.8.0,p1999-2000地喹氯铵的测试方法,HPLC法,采用phenomenex C18色谱柱(250mm×4.6mm,5μm);以0.005mo1/L庚烷磺酸钠溶液-甲醇-乙腈-三乙胺(体积比200:75:225:2.5)(用磷酸调至pH值3.5)为流动相;检测波长:240nm;流速:1.0mL/min,HPLC法测定含量与有关物质,测定发现其含量基本不变,有关物质无明显增加。试验结果说明本发明的地喹氯铵结晶水合物具有良好的存储稳定性。
将地喹氯铵无水物(参考文献方法制备,实验前干燥至热分析图谱的50~150℃之前的TG线与X轴约成水平直状态,相应的温度范围内无吸热峰)和地喹氯铵1水合物(实施例1法制备)分别避光置于干燥恒重的表面皿中,再置于温度约为40±2℃、相对湿度约为75±5%的避光环境下,放置48小时,再在该环境下转移于西林瓶中密闭避光进行6个月的稳定性试验,用HPLC法测定样品中的有关物质,采用phenomenex C18色谱柱(250mm×4.6mm,5μm);流动相:甲醇-0.67%己烷磺酸钠溶液(70∶30);检测波长:240nm;流速:1.0ml/min(参考文献:欧洲药典Ph.Eur.8.0,p1999-2000),经测定发现有关物质增加的相对幅度,地喹氯铵无水物的有关物质比本发明的地喹氯铵1水合物的高3.7%以上。试验结果说明本发明的地喹氯铵结晶水合物的稳定性比地喹氯铵无水物更好一些,更有利于作为药物的制剂原料。
本发明的地喹氯铵结晶水合物的制备可包括如下方法:
方法A、在反应容器中,加地喹氯铵无水物,加水,加热搅拌,使溶解,加水、C1-C6的低分子醇、C2-C8的低级醚、C2-C6的低分子腈、C1-C6的低级卤代烃、C2-C8的低分子酯、C3-C8的低分子酮中的一种或几种,放冷,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、C1-C6的低级卤代烃中的一种或几种洗涤,过滤,可将固体如此类似进行重结晶一次或多次,干燥,得地喹氯铵结晶水合物。
或方法B、在反应容器中,加入癸烷1,10-双(4-氨基喹哪啶碘代)盐(反应物1)、加入加水、C1-C6的低分子醇、C2-C6的低分子腈、C2-C8的低级醚、C1-C6的低级卤代烃等中的一种或几种(与反应物1的重量体积比为1g:3~200ml),搅拌,通氯化氢气体,加热至回流,回流反应1~10小时,放冷,过滤,滤饼用适量的C1-C6的低分子醇、C2-C8的低级醚、C1-C6的低级卤代烃中的一种或几种洗涤,过滤,所得的固体溶于适量的沸水,加少量活性炭搅拌后保温过滤,滤液经适量硅胶保温层析或树脂,再将滤液加适量的C1-C6的低分子醇、C2-C8的低级醚、C2-C6的低分子腈、C1-C6的低级卤代烃中的一种或几种,5℃以下放置,使固体充分析出;过滤,所得的固体用C1-C6的低分子醇、C2-C8的低级醚、C2-C6的低分子腈、C1-C6的低级卤代烃、C2-C8的低分子酯、C3-C8的低分子酮中的一种或几种洗涤,过滤,可将固体如此类似进行重结晶一次或多次,干燥,得地喹氯铵结晶水合物。
其中,反应中所使用的癸烷1,10-双(4-氨基喹哪啶碘代)盐(重量g)与水、C1-C6的低分子醇、C2-C8的低级醚、C1-C6的低级卤代烃等中的一种或几种(体积ml)的比为一般为:1(g):3~200(ml)。
或参考文献方法先制备地喹氯铵无水物,可参考过往文献或和如下括号中的文献等[史美平,郭曙刚,地喹氯铵合成工艺的研究,河北化工,2000,4:24-25;朱景申,黄蓉,李潮海,等;地喹氯铵合成工艺的研究,中国药师,2000年02期;中国专利,CN 103387537A,CN105859615A,等],然后按照本发明的方法A制备地喹氯铵结晶水合物。
本发明中的结晶或重结晶中使用的水与有机溶剂的体积比一般为1~100:1~100。
本发明的地喹氯铵结晶水合物的结晶或重结晶溶剂选自水、有机溶剂中的一种或几种,可以选自但不限于水、乙腈、四氢呋喃、甲醇、乙醇、异丙醇等、C2-C8的低级酯,选自醋酸丁酯、乙酸乙酯、甲酸乙酯等;乙醚、甲乙醚,异丙醚;C2-C6的低分 子腈选自乙腈;二氯甲烷、氯仿等中的一种或几种;地喹氯铵结晶结晶或重结晶溶剂,较优选水、乙腈、甲醇、乙醇、异丙醇、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等溶解地喹氯铵结晶水合物,溶解后可以使用活性炭脱色或和硅胶层析,再用水和有机溶剂使其结晶。
本发明中的低级醇或低分子醇的碳原子数定义为C1-C6(C1-C6等同于C1-C6,即:1-6个碳原子的醇,本文的碳原子数量标记均类同,譬如,C2-C8等同于C2-C8),如甲醇、乙醇、异丙醇、丁醇等;低级醚或低分子醚的碳原子数定义为C2-C8,如乙醚、丁醚、异丙醚、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(如20-75℃)、干燥时间(0.2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30-75℃。
本发明提及的地喹氯铵无水物的制备可由本发明的结晶水合物经不同的干燥方法或常压或减压的方式获得,其制备可在不同温度(如25-100℃,优选40-80℃)、干燥时间(数小时到数日)、或附有其它干燥剂(包括硅胶,分子筛、五氧化二磷、氢氧化钠、无水碳酸钠、无水氯化钙、无水硫酸钠、无水硫酸镁等)的环境条件下、或并使用常压或减压的方式对最后的产物其进行干燥数小时至一周,也可先由无水苯混合放置数日处理或蒸馏带水的方法,并结合本文中描述的其它干燥方法干燥后获得。
地喹氯铵结晶水合物的含量测定或HPLC测定方法等参照或参考文献10和欧洲药典Ph.Eur.8.0,p1999-2000的测试方法;本发明的水分测定采用卡尔费休法或简称卡氏法,水分测定中可采用甲醇或甲醇与甲酰胺的混合溶剂。
本发明的地喹氯铵结晶水合物用途:本发明的地喹氯铵结晶水合物用于制备固体制剂、半固体制剂、栓剂、注射剂等,其中注射剂包括注射用冻干粉针制剂、小水针、无菌分装粉针制剂、大输液制剂,其中,大输液制剂包括双室即配型大输液、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,上述制剂中可含有药学上可接受的辅料。
本发明的地喹氯铵结晶水合物用于与药学上可接受的辅料制备药学上可接受的制剂,常释制剂或缓释制剂或控释制剂,选自但不限于固体制剂、半固体制剂、栓剂、注射剂、溶液剂、膜剂、含漱剂、口胶剂、喷雾剂或气雾剂、滴丸剂、牙膏或漱口水。譬如制备片剂(包括但不限于普通片剂、口含片,速崩片、阴道片、口胶片、速溶片等)、胶囊(包括阴道用胶囊)或软胶囊、颗粒剂等,其中可含有药学上可接受的辅料,选自但不限于药学上可接受的填充剂,如淀粉、变性淀粉、乳糖、微晶纤维素、环糊精、山梨醇、甘露醇、木糖醇、异麦芽酮糖醇、麦芽糖醇浆、乳糖醇、果糖低聚糖、葡聚糖、聚葡糖、磷酸钙、氨基酸、明胶、果胶、水等或其一种或多种;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)或其一种或多种;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、聚乙烯吡咯烷酮、聚维酮K30、海藻酸及其盐、甘油、山梨糖醇、 丙二醇、乙二醇、1,3-丁二醇、聚乙二醇、聚丙二醇或其中的一种或多种;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4000-8000、滑石粉、微粉硅胶、十二烷基硫酸镁、西黄蓍胶、阿拉伯胶等或其一种或多种;药学上可接受的矫味剂或香精,如阿斯巴甜、甜蜜素、糖精钠、三氯蔗糖、食用香精、薄荷油或薄荷脑、香草醛、大茴香醚、琥珀酸苄酯、黄蓄萜酮、丁子香酚、水杨酸甲酯、柠檬烯、罗勒烯、正癸醇、香茅醇、α-萜品醇、乙酸薄荷酯、乙酸香茅醇酯、甲基丁子香酚、桉树脑、沉香醇、乙基沉香醇、百里酚等;植物脂溶性萃取液的香料,能列举有百里香油、肉豆蔻油、留兰香油、薄荷油、柠檬油、橙油、鼠尾草油、迷迭香油、肉桂油、甘椒油、紫苏子油、冬青油、桉油、罗勒油、茶籽油、印蒿油等等或其一种或多种。
小容量注射液及其制备工艺:地喹氯铵结晶水合物加注射用水和药学上可接受的辅料,例如:药学上可接受的助溶剂、pH调节剂、药学上可接受的抗氧剂、惰性气体,过滤、除菌、分装、灭菌、检验、包装,制成灭菌小容量注射液,其pH值约在3.0~7.5之间。
一种含有地喹氯铵结晶水合物的漱口水,选自但不限于以下重量百分比计的组分组成:地喹氯铵结晶水合物0.005~2.5%、表面活性剂或烷基糖苷或吐温-80 0.1~2.0%、保湿剂5~10%、甜味剂0.01~0.1%、防腐剂0.01~0.1%、乙醇2~10%,余量为水。保湿剂选自但不限于甘油、山梨醇和丙二醇等中的一种或多种。抑菌剂或防腐剂选自但不限于ε-聚赖氨酸、苯甲酸钠、山梨酸或其药用盐、尼泊金酯、洗必泰等中的一种或多种。其使用方法为:每次10~20ml,强力漱口1-3分钟,每天1~5次。
含本发明的地喹氯铵结晶水合物的牙膏的制备方法可按照牙膏工业的常用方法制备,其中可含有药学上或口腔健康用品上可接受的辅料,包括抑菌剂等。
含本发明的地喹氯铵结晶水合物的牙膏选自但不限于以下质量百分比的原料组成:地喹氯铵结晶水合物0.05~1%、保湿剂20-50%、粘结剂1.0-5.0%、摩擦剂15-40%、发泡剂1.0-4.0%、甜味剂0.2-0.8%、抗氧化剂0.00-0.09%,抑菌剂0.00-0.2%,余量为水,所述固体粉碎至过80-300目。
在牙膏辅料中,还包括起泡剂,摩擦剂,赋形剂,赋形剂可以含有保湿剂或填充剂,粘合剂,甜味剂,清凉剂,芳香剂,缓冲剂成分中的一种或多种。
保湿剂或填充剂优选但不限于甘油、山梨醇、木糖醇、丙二醇、聚乙二醇、水、酒精、淀粉、糖浆、维生素、壳聚糖、植物提取物、酵母粉、珍珠粉、贝壳粉中的一种或两种以上;粘合剂:粘合剂优选但不限于羧甲基纤维素、海藻酸钠、羧甲基纤维素钠、黄原胶、羟乙基纤维素、瓜尔胶、卡拉胶中的一种或几种,粘合剂具有增稠和稳定膏体的作用。甜味剂:甜味剂优选选自但不限于糖精或糖精钠、三氯蔗糖、阿斯巴甜;清凉剂:清凉剂优选薄荷、薄荷油、薄荷脑,可以保持口气清新、口感舒适。海藻酸钠:是胶凝剂、填充剂,具有滋润口腔咽喉的作用;
起泡剂或发泡剂:所述起泡剂优选月桂醇硫酸酯钠或月桂酰肌氨酸钠或月桂酰谷氨酸钠,其中月桂醇硫酸酯钠具有良好的起泡、乳化、浸润、去垢性能,在牙膏中主要作起泡剂和去污剂;
摩擦剂:所述摩擦剂选自但不限于碳酸钙、磷酸氢钙、氢氧化铝、二氧化硅、水合硅石中的一种或多种。
本发明的结晶水合物可用于制备口胶剂,口胶中各辅料组分的重量或者重量比为:单糖或双糖或多糖或植物树脂和/或植物树脂酯中的一种或几种20~78份;食用胶姆或弹性体10~40份;滑润剂或食用香料或甜味剂或色素或防腐剂或抗氧化剂中的一种或几种0~1份,以及其它辅料;本发明的口胶基质的组合物中使用的弹性体包括在口胶基质中常用的所有弹性体,无论是合成的,例如丁二烯-苯乙烯共聚物、聚异丁烯 和异丁烯-异戊二烯共聚物,还是天然的,例如糖胶树胶、节路顿胶、巴拉塔树胶、古塔波胶、莱开欧胶(lechecaspi)、香豆的乳汁(sorva)或其组合:其中,聚异丁烯、异丁烯-异戊二烯共聚物和丁二烯-苯乙烯共聚物是优选的但不限于上述物质。乳化剂和/或工艺助剂包括但不限于单硬脂酸甘油酯,乙酰化的单酸甘油酯,氢化的椰子、大豆、棕榈和棉籽植物油,卵磷脂和三醋精,它们可以单独使用,或彼此组合使用。抗氧化剂可以包括但不限于在口胶基质的组合物中常用的那些物质,例如丁基化羟基苯甲醚,丁基化羟基甲苯,生育酚,没食子酸丙酯等。
本发明的结晶水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,而结晶水合物具有良好的滑动性,从而改善制剂的可操作性;并使制备的固体制剂具有良好的溶出性能,使得其容易被吸收进入血液循环,改善生物利用度,并有利于快速发挥其作用。从另一个方面,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,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,在临床治疗中对患者的治疗代理负面的效果,或者因剂量不足危及病人的生命。或者在分装时,因为吸潮而导致整个生产线被迫暂停,严重降低设备的生产能力,大大增加工时费用等的隐患。
当需要低限投料时,地喹氯铵无水物的引湿性可能导致口含片的含量不合格的程度更大一些,而地喹氯铵1水合物则比地喹氯铵无水物好得多,两者具有显著的差别。譬如,按照实施例5的口含片的制备方法,将事先检测过含量的地喹氯铵无水物和地喹氯铵1水合物分别粉碎过200目筛后放置一天,然后称取适量的相应的原辅料,在地喹氯铵无水物和地喹氯铵1水合物的投料量改为0.22g时,依然用地喹氯铵口含片的中国药品标准规定含量的标示量的80~120%的含量限度来约束口含片,结果发现,压制后的口含片,分别随机取地喹氯铵无水物的一组和地喹氯铵1水合物的一组各20片,检测其含量,发现地喹氯铵无水物的一组中有5个含片中的地喹氯铵的含量低于80%的限度,而地喹氯铵1水合物的一组中,只有2片地喹氯铵的含量低于80%的限度,这两者有明显的差异。试验结果说明本发明的地喹氯铵结晶水合物比地喹氯铵无水物更好一些,作为优势晶型,更有利于作为药物的制剂原料。
地喹氯铵结晶水合物的栓剂制备方法:栓剂选自但不限于以下质量百分比的原料组成:地喹氯铵结晶水合物(重量比一般为0.01~30%,mg/g)、其余由栓剂基质组成(g),基质可以是乙醇、甘油、甘油明胶、聚乙二醇200-8000、泊洛沙姆、凡士林、半合成硬脂肪酸脂(包括硬脂酸聚烃氧(40)脂、硬脂酸丙二醇酯、脂肪酸甘油酯等)、卡波姆系列(931、934、940、974等)、吐温60~80等的一种或数种,并且栓剂中可含有药学上可接受的其它附加剂,如稳定剂和吸收促进剂等。制备方法:将主药与基质混合,水浴加热、搅拌、待融化,搅拌至匀、迅速倾入已涂有润滑剂的栓剂模具中,至稍微溢出栓模,待冷后削平,起模即得。
本发明的地喹氯铵结晶水合物,适用于:用于制备人或动物的临床用于预防和治疗急性咽炎、急性扁桃体炎,以及慢性咽炎、慢性扁桃体炎,口腔黏膜溃疡、齿龈炎、喉炎、口炎、舌炎,也可作为预防和治疗上述重症咽炎、扁桃体炎、口腔黏膜溃疡、齿龈炎的联合用药、拔牙创面等口腔创伤的感染,还可以改善抽烟引起的咽部不适;白色念珠菌引起的急性假膜性念珠病,口腔日常卫生用品的牙膏、也可以用于牙科疾患的局部治疗,并能防治口臭、阴道炎、鼠类控制生育、作为PKC抑制剂、抗肿瘤等的治疗或预防的卫生健康用品或药物中的应用。
用量用法:一般情况下,口含片,一次1-2片或0.25mg-0.5mg,每2-3小时1次,必要时可重复用药;儿童必须在成人监护下使用。阴道片、阴道胶囊或栓剂的用量用法:一般情况下,成人常用量:一天1-6次,每次0.125~10mg。
文献报道甘草酸有多种生物活性,例如抗炎、抗溃疡、抗过敏、抗氧化、免疫调节、抗病毒、抗癌和保肝等,此外与其他药物联用,甘草酸可起增效作用(韩瑶聃,王彬,王政雨,等,甘草酸药理作用的研究进展,中国新药杂志,2012年21期;宋光明,吴练秋,万宗明,等,甘草浸膏利胆作用的研究,武警医学院学报,2001年04期;陈树伟,王秀兰,冯福盛,等,甘草浸膏制备新工艺的研究,天然产物研究与开发,1999年06期;陈建新,邱灵才,方炳虎,等,甘草酸单铵盐对H9N2禽流感病毒的作用机制研究,中草药,2008年06期;刘小云,刘世坤,王春江,等,甘草酸单铵治疗肝纤维化的meta分析,中南药学,2012年03期)。
地喹氯铵新化合物用于制备含有该化合物的组合物,用于制备与药学上可接受的有效剂量的冰片、薄荷醇或薄荷脑或L-薄荷脑、甘草浸膏、甘草酸或甘草酸单铵盐或其或异构体或其溶剂化合物或其衍生物或短杆菌素或其药用盐中的一种或几种组成的组合药物,其中,甘草酸或甘草酸单铵盐或其或异构体或其溶剂化合物或其衍生物包括甘草酸或其药用盐或甘草酸单铵盐或甘草酸单铵盐2水合物或甘草酸单铵盐5水合物或18α-甘草酸单铵盐2水合物或18α-甘草酸单铵盐5水合物或18β-甘草酸单铵盐2水合物或18β-甘草酸单铵盐5水合物或18α-甘草酸二铵或18β-甘草酸二铵等,如甘草酸钠、甘草酸二钠、甘草酸三钠、甘草酸钾、甘草酸二钾、甘草酸三钾、甘草酸二铵、甘草酸三铵等,以发挥其协同作用,提高抗菌能力或缩短疗程或降低药物用量或降低不良反应等。
地喹氯铵新化合物用于制备含有该化合物的组合物,用于制备与药学上可接受的有效剂量的美洲大蠊药物组合物,所述药物组合物包括由美洲大蠊提取物和地喹氯铵混合制得的有效成分混合物组成,按重量或重量比计,美洲大蠊提取物:地喹氯铵=0.1~200:0.1~20;药物组合物,按重量或重量比计较优选,美洲大蠊提取物:地喹氯铵=0.2~70:0.1~10,用量按重量或重量比计,与美洲大蠊提取物的重量比为0.5~50:0.1~5;上述药物组合物中可包含药学上可接受的辅料。上述药物组合物用于治疗急慢性咽喉炎、急性化脓性扁桃体炎、扁桃体炎、口腔溃疡等,所述临床制剂选自但不限于固体制剂、片剂、溶液剂、含漱剂、贴膜剂、口胶、合剂、喷雾剂或气雾剂。
更进一步,较优选每个单位制剂的地喹氯铵结晶水合物与甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵或其或异构体或其溶剂化合物或其衍生物的组合物中的重量或重量比为0.05-30毫克:10-600毫克,可与药学上可接受的辅料制备成药学上可接受的制剂。
或更优选地喹氯铵结晶水合物与甘草浸膏粉或甘草酸A或甘草酸或其药用盐或甘草酸单铵或甘草酸二铵或其或异构体或其溶剂化合物每个单位制剂组合物中含地喹氯胺0.25毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵225毫克,或每个单位制剂组合物中含地喹氯胺0.5毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵225毫克;地喹氯铵结晶水合物与甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵每个单位制剂组合物中含地喹氯胺0.25毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵112.5毫克,或每个单位制剂组合物中含地喹氯胺0.5毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵112.5毫克;地喹氯铵结晶水合物与甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵每个单位制剂组合物中含地喹氯胺0.25毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵56.25毫克,或每个单位制剂组合物中含地喹氯胺0.5毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵56.25毫克;地喹氯铵结晶水合物与甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵每个单位制剂组合物中含地喹氯胺0.25毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵28毫克,或每个单位制剂组合物中含地喹氯胺0.5毫克,甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵28毫克,或其药物组 合物中各组分的重量比为上述数值之比。
上述组合物与药学上可接受的辅料制备药学上可接受的制剂或药物组合物。该药物组合物适用于制备人或动物的临床用于预防和治疗急性咽炎、急性扁桃体炎,以及慢性咽炎、慢性扁桃体炎,口腔黏膜溃疡、齿龈炎、喉炎、口炎、舌炎,也可作为预防和治疗上述重症咽炎、扁桃体炎、口腔黏膜溃疡、齿龈炎的联合用药、拔牙创面等口腔创伤的感染,还可以改善抽烟引起的咽部不适;白色念珠菌引起的急性假膜性念珠病,也可以用于牙科疾患的局部治疗,并能防治口臭、阴道炎、滴虫、鼠类控制生育、作为PKC抑制剂、抗肿瘤等的治疗或预防的药物中的应用等。
本发明的有效剂量的地喹氯铵结晶水合物与短杆菌素或其药学上可接受的盐可与药学上可接受的辅料或其它有效成分,制备药学上可接受的制剂。较优选地,本发明的地喹氯铵结晶水合物可以与短杆菌素或其药学上可接受的盐的重量或重量比为1~10:0.1~20,并与药学上可接受的辅料制备成药学上可接受的制剂。地喹氯铵结晶水合物与短杆菌素每个单位制剂组合物中可以是含地喹氯胺0.25毫克,短杆菌素1毫克,或每个单位制剂组合物中含地喹氯胺0.5毫克,短杆菌素2毫克,或每个单位制剂组合物中含地喹氯胺0.25毫克,短杆菌素2毫克,或每个单位制剂组合物中含地喹氯胺0.25毫克,短杆菌素5毫克,或每个单位制剂组合物中含地喹氯胺0.1毫克,短杆菌素1毫克,或每个单位制剂组合物中含地喹氯胺1毫克,短杆菌素1毫克,或每个单位制剂组合物中含地喹氯胺0.25毫克,短杆菌素0.5毫克,或每个单位制剂组合物中含地喹氯胺0.5毫克,短杆菌素1毫克,或每个包装的制剂中含地喹氯胺2.5毫克,短杆菌素10毫克,或每个包装的制剂中含地喹氯胺5毫克,短杆菌素20毫克。该组合物适用于制备人或动物的临床用于预防和治疗急性咽炎、急性扁桃体炎,以及慢性咽炎、慢性扁桃体炎,口腔黏膜溃疡、齿龈炎、喉炎、口炎、舌炎,也可作为预防和治疗上述重症咽炎、扁桃体炎、口腔黏膜溃疡、齿龈炎的联合用药、拔牙创面等口腔创伤的感染,还可以改善抽烟引起的咽部不适;白色念珠菌引起的急性假膜性念珠病,也可以用于牙科疾患的局部治疗,并能防治口臭、阴道炎、滴虫、鼠类控制生育、作为PKC抑制剂、抗肿瘤等的治疗或预防的药物中的应用等。
附图说明
图1为地喹氯铵1水合物的热分析图谱(实施例1)
图2为地喹氯铵1水合物的粉末X衍射图(实施例1)
图3为地喹氯铵1水合物的红外图谱(实施例1)
图4为地喹氯铵1水合物的热分析图谱(实施例2)
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”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。
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载体。
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或效果,而不是对本发明权利要求的限制,本发明的保护范围不受以下实施例的限制。
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。
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,热分析图谱显示出地喹氯铵的结晶水合物。
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°,测定了地喹氯铵结晶水合物的粉末X射线衍射图,全部峰位置约在±0.2°的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。本说明书中的附图2与数据互为佐证。
Peak Search Report(20Peaks,Max P/N=13.5)
PEAK:21-pts/Parabolic Filter,Threshold=3.0,Cutoff=2.0%,BG=3/1.0,Peak-Top=Summit
引湿试验
本发明的地喹氯铵结晶水合物能稳定存储。将地喹氯铵水合物和无水物样品进行引湿性试验:取地喹氯铵无水物(参考文献方法制备,实验前干燥至热分析图谱的50~150℃之前的TG线与X轴约成水平直状态,相应的温度范围内无吸热峰)和本发明的水合物约5g,均过100目筛后置于干燥恒重的表面皿中,精密称重,25±2℃、相对湿度约为70±5%,分别于试验0h和24h取样,计算引湿增重的百分率,结果显示,无水物引湿性比本发明的水合物都高得多,本发明的地喹氯铵结晶水合物能更好地稳定存储结果见表1。
表1.引湿试验结果
具体实施例
实施例1地喹氯铵1水合物的制备
室温下,在500ml茄型烧瓶中加地喹氯铵无水物5g、加水150ml,搅拌加热回流使溶解,加活性炭0.3g,搅拌30分钟,保温抽滤,在滤液中搅拌下缓慢滴加异丙醇90ml、乙醇10ml、甲醇2ml,然后0~-22℃放置放置约24小时,使固体充分析出,抽滤,少量水、氯仿和乙醇润洗固体物3次,抽滤,所得固体用适量水加热回流溶解、异丙醇40ml、乙醇1ml为溶剂进行重结晶,4℃左右放置2小时左右,然后于-0-22℃左右放置约24小时,使结晶充分析出,抽滤,用少量乙醇润洗固体物,抽滤,再将所得固体摊薄于30℃左右干燥3小时,再60℃左右干燥3h左右,得类白色或浅黄色的固体3.2g;卡氏法测定水分为3.62%,热分析:平台失重约3.71%(见附图1),这与样品含有1个结晶水的结果(理论值3.303%)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(粉末X射线衍射见附图2)8.81、9.49、10.32、10.77、11.78、12.23、14.37、15.107、18.97、20.12、20.74、22.70、22.94、23.85、24.55、25.12、25.76、28.04、29.0、29.58;红外光谱:νKBr max cm-1(红外图谱见附图3)3437.0,3342.1,3263.4,3052.4,2926.4,2851.7,1686.4,1661.4,1606.0,1560.3,1539.6,1494.1,1447.2,1431.9,1372.9,1317.3,1172.1,1063.6,860.4,805.8,760.7,681.8,654.5;元素分析理论值:C 66.04%,H 7.76%,N 10.27%,Cl 13.00%;实测值:66.11%,H7.84%,N 10.35%,Cl 13.09%。
实施例2地喹氯铵1水合物的制备
室温下,在500ml茄型烧瓶中,加入地喹氯铵无水物6g于适量水中,回流使溶解后,加0.5g活性炭搅拌,加水10ml加热回流,保温经少量硅胶层析过滤,滤液中加甲醇5ml,再加适量的异丙醇,回流数分钟后,使溶液慢慢冷却至室温,再放置到4-10℃左右约1小时,再置于-0-22℃左右放置过夜,析出结晶得到固体,将所得的固体再溶解于稍过量的沸水中,经少量硅胶层析过滤,在滤液加甲醇3ml,再加适量的异丙醇,冷却至室温,于-10℃左右放置24小时左右,使结晶充分析出,抽滤,再将所得固体摊薄于65℃左右干燥3h左右,得到类白色或浅黄色的固体4.1g;HPLC:其溶液在HPLC上主峰的保留时间与地喹氯铵无水物对照品的主峰的保留时间一致;卡氏法测定水分为3.47%,热分析:平台失重约3.76%(见附图4),这与样品含有1个结晶水的结果(理论值3.303%)在误差范围内,约在125℃前的失重平台下具有对应的吸热峰(DTA);元素分析理论值:C 66.04%,H 7.76%,N 10.27%,Cl13.00%;实测值:C 66.15%,H 7.66%,N 10.19%,Cl 13.14%。
实施例3地喹氯铵结晶水合物片或胶囊(处方:1000片或粒)
将地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、微晶纤维素、羧甲基淀粉钠过100目筛,按照等量递加法混匀,压成大片,再将该片研压成18-24目筛的颗粒,加硬脂酸镁混匀,压片或灌装胶囊。
实施例4:本发明地喹氯铵水合物阴道用胶囊的制备(处方:1000粒)
处方:地喹氯铵水合物 5g
乳糖 80g
硬脂酸镁 1g
将地喹氯铵水合物(按实施例1或实施例2方法制备)乳糖和硬脂酸镁过100目筛,混匀,灌装胶囊。
实施例5地喹氯铵结晶水合物口含片(处方:1000片)
将地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、速溶山梨醇、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,压片。
实施例6地喹氯铵结晶水合物口含片(处方:1000片)
将地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、速溶山梨醇、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,压片。
实施例7地喹氯铵结晶水合物口含片(处方:1000片)
将地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、速溶山梨醇、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,压片。
实施例8地喹氯铵结晶水合物的栓剂(处方:1000粒)
将地喹氯铵结晶水合物(按实施例1或实施例2法制备)、甘油、硬脂酸聚烃氧(40)脂、泊洛沙姆混合,水浴加热、搅拌、待融化,搅拌至匀、迅速倾入已涂有润滑剂的栓剂的模具中,至稍微溢出栓模,待冷后削平,起模即得。
实施例9地喹氯铵结晶水合物的栓剂(处方:1000粒)
将地喹氯铵结晶水合物(按实施例1或实施例2法制备)、甘草酸、甘油、硬脂酸聚烃氧(40)脂、聚乙二醇6000、泊洛沙姆混合,水浴加热、搅拌、待融化,搅拌至匀、迅速倾入已涂有润滑剂的栓剂的模具中,至稍微溢出栓模,待冷后削平,起模即得。
实施例10地喹氯铵结晶水合物的栓剂(处方:1000粒)
将地喹氯铵结晶水合物(按实施例1或实施例2法制备)、甘油、硬脂酸聚烃氧(40)脂、泊洛沙姆混合,水浴加热、搅拌、待融化,搅拌至匀、迅速倾入已涂有润滑剂的栓剂的模具中,至稍微溢出栓模,待冷后削平,起模即得。
实施例11地喹氯铵结晶水合物的栓剂(处方:1000粒)
将地喹氯铵结晶水合物(按实施例1或实施例2法制备)、甘油、硬脂酸聚烃氧(40)脂、泊洛沙姆混合,水浴加热、搅拌、待融化,搅拌至匀、迅速倾入已涂有润滑剂的栓剂的模具中,至稍微溢出栓模,待冷后削平,起模即得。
实施例12地喹氯铵1结晶水合物与短杆菌素组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、短杆菌素、木糖醇、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,压片。
实施例13地喹氯铵1结晶水合物与短杆菌素组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、短杆菌素、速溶山梨醇、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压成18-24目筛的颗粒,压片。
实施例14地喹氯铵1结晶水合物与甘草酸单铵盐组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、18β-甘草酸单铵盐2水合物、速溶山梨醇、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压成24目筛的颗粒,压片。
实施例15地喹氯铵1结晶水合物与甘草酸组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、甘草酸、速溶山梨醇、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压成20目筛的颗粒,压片。
实施例16地喹氯铵1结晶水合物与美洲大蠊提取物组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、美洲大蠊提取物、速溶山梨醇、低取代羟丙基纤维素过100目筛,混匀,压成大片,再将该片研压过24目筛的颗粒,压片。
实施例17地喹氯铵1结晶水合物与美洲大蠊提取物组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、美洲大蠊提取物、甘草酸、速溶山梨醇、羧甲基淀粉钠、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压过24目筛的颗粒,压片。
实施例18地喹氯铵1结晶水合物与美洲大蠊提取物组合物口含片(处方1000片)
将地喹氯铵1结晶水合物(按实施例2方法制备)、美洲大蠊提取物、甘草浸膏、速溶山梨醇、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压成18-24目筛的颗粒,压片。
实施例19地喹氯铵结晶水合物与美洲大蠊提取物组合物口含片(处方1000片)
将地喹氯铵结晶水合物(按实施例2方法制备)、美洲大蠊提取物、甘草酸单铵盐、山梨醇、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压成18-24目筛的颗粒,压片。
实施例20地喹氯铵结晶水合物与美洲大蠊提取物组合物口含片(处方1000片)
将地喹氯铵结晶水合物(按实施例2方法制备)、美洲大蠊提取物、甘草酸、速溶山梨醇、低取代羟丙基纤维素、微粉硅胶过100目筛,混匀,压成大片,再将该片研压成18-24目筛的颗粒,压片。
实施例21地喹氯铵结晶水合物含片的制备(处方1000片)
a.配方:
b.制备方法:将地喹氯铵结晶水合物、糖粉、甘露醇、麦芽糖糊精过100筛,混合均匀,将薄荷脑溶于4%聚维酮K30 75%乙醇溶液溶液粘合剂中,均匀分散于稀释剂中,制成软材,18目筛制粒,50℃烘干,干颗粒加过100目筛的硬脂酸镁,混匀,18目筛整粒,压片。
实施例22地喹氯铵结晶水合物口含片(处方:1000片)
将地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、甘草酸A、速溶山梨醇、低取代羟丙基纤维素、硬脂酸镁过100目筛,混匀,压成大片,再将该片研压过24目筛的颗粒,压片。
实施例23地喹氯铵结晶水合物及甘草酸二铵口含片(处方:1000片)
将过100目筛的地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、甘草酸二铵、速溶山梨醇、果糖低聚糖、低取代羟丙基纤维素混匀,将5%聚维酮K30的80%乙醇溶液均匀分散,制成软材,20目筛制粒,50-55℃烘干,干颗粒加过100目筛的微粉硅胶,混匀,20目筛整粒,压片。
实施例24地喹氯铵结晶水合物口含片(处方:1000片)
将过100目筛的地喹氯铵结晶水合物(按实施例1或实施例2方法制备)、甘草酸单铵、速溶山梨醇、低取代羟丙基纤维素混匀,将5%聚维酮K30的90%乙醇溶液均匀分散,制成软材,24目筛制粒,50-55℃烘干,干颗粒加过100目筛的硬脂酸镁,混匀,20目筛整粒,压片。
实施例25地喹氯铵结晶水合物健康牙膏的制备(配方:100支)
地喹氯铵结晶水合物2g;甘草酸单铵100g;木糖醇500g;羧甲基纤维素120g;甘油1000g;70%山梨醇3000g;苯甲酸钠50g;单氟磷酸钠80g;二氧化硅1200g;偏 磷酸钠2000g;磷酸氢钙(二水)200g;月桂酸肌胺酸钠200g;薄荷油100g;三氯蔗糖2g、蒸馏水加至10kg。
工艺:1)按配方要求将木糖醇、甘草酸单铵、羧甲基纤维素、甘油、山梨醇、苯甲酸钠、蒸馏水依次投入煮沸锅中,加热至60~100℃,煮成胶体,冷却待用。
(2)在搅拌转速200~500r/min下,把过200目筛的地喹氯铵结晶水合物、单氟磷酸钠、二氧化硅、偏磷酸钠、磷酸氢钙、月桂酸肌胺酸钠、三氯蔗糖等原料逐一缓缓投入,继续搅拌2.5h,使各种物料混合均匀,温度慢慢下降。
(3)将上述物料冷却至40~45℃,移至碾压机上碾细,碾大约1—2h。
(4)待产品冷却至35℃,用装填机装入软管中并进行封口机的成品。
实施例26地喹氯铵结晶水合物健康牙膏的制备(配方:100支)
地喹氯铵结晶水合物5g;甘草浸膏100g;木糖醇500g;羧甲基纤维素120g;甘油1000g;70%山梨醇3000g;苯甲酸钠50g;二氧化硅1200g;偏磷酸钠2000g;磷酸氢钙(二水)300g;月桂酸肌胺酸钠200g;薄荷油100g;阿斯巴甜2g、蒸馏水加至10kg。
工艺:1)按配方要求将木糖醇、甘草浸膏、羧甲基纤维素、甘油、山梨醇、苯甲酸钠、蒸馏水依次投入煮沸锅中,加热至60~100℃,煮成胶体,冷却待用。
(2)在搅拌转速200~500r/min下,把过200目筛的地喹氯铵结晶水合物、二氧化硅、偏磷酸钠、磷酸氢钙、月桂酸肌胺酸钠、阿斯巴甜等原料逐一缓缓投入,继续搅拌3h,使各种物料混合均匀,温度慢慢下降。
(3)将上述物料冷却至40~45℃,移至碾压机上碾细,碾大约1—2h。
(4)待产品冷却至35℃,用装填机装入软管中并进行封口机的成品。
实施例27地喹氯铵结晶水合物的漱口水的制备(配方:100瓶)
配方:地喹氯铵1水合物5g、烷基糖苷0.05kg、吐温-80 0.04kg、甘油0.5kg、木糖醇0.01kg、ε-聚赖氨酸0.01kg、乙醇0.5kg,加去离子水补足至10kg。
制备方法:取配方量的地喹氯铵结晶水合物、烷基糖苷、吐温-80、甘油、木糖醇、ε-聚赖氨酸、乙醇和水混合,搅拌均匀,制得含有地喹氯铵结晶水合物的漱口水。
其使用方法为:每次10~20ml,强力漱口1-3分钟,每天1~5次。
实施例28地喹氯铵结晶水合物的漱口水的制备(配方:100瓶)
配方:地喹氯铵1水合物5g、烷基糖苷0.05kg、吐温-80 0.04kg、甘油0.5kg、木糖醇0.01kg、ε-聚赖氨酸0.01kg、乙醇0.5kg,加去离子水补足至10kg。
制备方法:取配方量的地喹氯铵结晶水合物、烷基糖苷、吐温-80、甘油、木糖醇、ε-聚赖氨酸、乙醇和水混合,搅拌均匀,制得含有地喹氯铵结晶水合物的漱口水。
其使用方法为:每次10~20ml,强力漱口1-3分钟,每天1~5次。
实施例29地喹氯铵结晶水合物的漱口水的制备(配方:100瓶)
配方:地喹氯铵1水合物10g、甘草酸A 100g、烷基糖苷0.05kg、吐温-80 0.04kg、甘油0.5kg、木糖醇0.01kg、ε-聚赖氨酸0.01kg、乙醇0.5kg,加去离子水补足至10kg。
制备方法:取配方量的地喹氯铵结晶水合物、甘草酸A、烷基糖苷、吐温-80、甘油、木糖醇、ε-聚赖氨酸、乙醇和水混合,搅拌均匀,制得含有地喹氯铵结晶水合物的漱口水。
抗菌消炎用等,其使用方法为:每次10~20ml,强力漱口1-3分钟,每天1~5次。
实施例30地喹氯铵结晶水合物口胶的制备
在反应器内的100ml糖浆淀粉与35~65℃条件下加热融熔并过滤的400g胶姆糖胶混合均匀,再将木糖醇1500g、地喹氯铵1水合物5g加入保持原温度的反应罐内,与罐内的糖浆淀粉、胶姆糖胶搅拌均匀,稍冷后加入薄菏香精8ml,再混合均匀、捏合、碾压、切割制成不同规格的口胶片。譬如制成长宽厚分别为10*8*3mm口胶片。
实施例31地喹氯铵结晶水合物口胶的制备
在反应器内的100ml糖浆淀粉与35~65℃条件下加热融熔并过滤的400g胶姆糖胶混合均匀,再将木糖醇1500g、地喹氯铵1水合物5g、甘草酸A 100g加入保持原温度的反应罐内,与罐内的糖浆淀粉、胶姆糖胶搅拌均匀,稍冷后加入薄菏香精8ml,再混合均匀、捏合、碾压、切割制成不同规格的口胶片。譬如制成长宽厚分别为10*8*3mm口胶片。
实施例32地喹氯铵结晶水合物短杆菌素组合物口胶的制备
在反应器内的100ml糖浆淀粉与35~65℃条件下加热融熔并过滤的400g胶姆糖胶混合均匀,再将木糖醇1500g、地喹氯铵1水合物5g、短杆菌素10g、甘草酸A 100g加入保持原温度的反应罐内,与罐内的糖浆淀粉、胶姆糖胶搅拌均匀,稍冷后加入薄菏香精8ml,再混合均匀、捏合、碾压、切割制成不同规格的口胶片。
工业实用性等及其说明等:
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 (8)
1.一种地喹氯铵新化合物,其特征在于:为地喹氯铵1水合物,分子式为C30H40Cl2N4·H2O。
2.根据权利要求1所述的地喹氯铵新化合物,其特征在于:利用粉末X射线衍射法测量,在衍射角为2θ、在3-60°的测量范围内,在如下2θ±0.2°值的位置具有相应的特征值:8.81、9.49、10.32、10.77、11.78、12.23、14.37、15.107、18.97、20.12、20.74、22.70、22.94、23.85、24.55、25.12、25.76、28.04、29.0、29.58。
3.根据权利要求1所述的地喹氯铵新化合物,其制备方法,其特征在于:其制备方法为:
在反应容器中,加地喹氯铵无水物,加水,加热搅拌,使溶解,加C1-C6的低分子醇、C2-C8的低级醚、C2-C6的低分子腈、C1-C6的低级卤代烃、C2-C8的低分子酯、C3-C8的低分子酮中的一种或几种,放冷,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、C1-C6的低级卤代烃中的一种或几种洗涤,过滤,可将固体如此类似进行重结晶一次或多次,干燥,得地喹氯铵结晶水合物。
其中,C1-C6的低分子醇,选自甲醇、乙醇、异丙醇、丁醇;C2-C6的低分子腈选自乙腈;C2-C8的低分子醚或低分子醚选自乙醚、异丙醚;C1-C6低级卤代烃选自二氯甲烷、氯仿;C2-C8低分子酯选自醋酸丁酯、乙酸乙酯、甲酸乙酯;C3-C8的低分子酮选自丙酮,丁酮、异己酮。
4.根据权利要求1所述的地喹氯铵新化合物的用途,其特征在于:用于与药学上可接受的辅料制备药学上可接受的制剂,常释制剂或缓释制剂或控释制剂,选自但不限于固体制剂、半固体制剂、栓剂、注射剂、溶液剂、膜剂、含漱剂、喷雾剂或气雾剂、滴丸剂、牙膏。
5.根据权利要求1所述的地喹氯铵新化合物,其特征在于:用于制备含有该新化合物的组合药物或药物组合物,选自但不限于制备地喹氯铵新化合物与用于制备与药学上可接受的有效剂量的甘草浸膏或甘草酸或甘草酸单铵盐或其或异构体或其溶剂化合物或其衍生物或短杆菌素或其药用盐、美洲大蠊提取物中的一种或几种组成的组合药物或药物组合物,上述组合物与药学上可接受的辅料用以制备药学上可接受的制剂。
6.根据权利要求5所述的地喹氯铵新化合物的组合药物或药物组合物,其特征在于:地喹氯铵结晶水合物与短杆菌素或其药学上可接受的盐的重量或重量比为1~10:0.1~20,与药学上可接受的辅料制备成药学上可接受的制剂。
7.根据权利要求5所述的地喹氯铵新化合物的组合药物或药物组合物,其特征在于:每个单位制剂的地喹氯铵结晶水合物与甘草浸膏粉或甘草酸或其药用盐或甘草酸单铵或其或异构体或其溶剂化合物或其衍生物的组合物中的重量或重量比为0.05-30毫克:10-600毫克,与药学上可接受的辅料制备成药学上可接受的制剂。
8.根据权利要求1所述的地喹氯铵新化合物的用途,其特征在于:用于制备人或动物的急性咽炎、急性扁桃体炎,以及慢性咽炎、慢性扁桃体炎,口腔黏膜溃疡、齿龈炎、喉炎、口炎、舌炎,也可作为预防和治疗上述重症咽炎、扁桃体炎、口腔黏膜溃疡、齿龈炎的联合用药、拔牙创面等口腔创伤的感染、改善抽烟引起的咽部不适、白色念珠菌引起的急性假膜性念珠病、口腔日常卫生用品的牙膏或漱口水、牙科疾患的局部治疗、口臭、阴道炎、鼠类控制生育、作为PKC抑制剂、抗肿瘤的治疗或预防的卫生健康用品或药物中的应用。
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CN112617548A (zh) * | 2020-12-25 | 2021-04-09 | 海南娜古芳沉香科技有限公司 | 一种用于制作改善睡眠乳胶枕的奇楠沉香提取物、制备方法及其制作的乳胶枕 |
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