CN101386593B - 谷氨酸诺氟沙星水合物及其制备和用途 - Google Patents
谷氨酸诺氟沙星水合物及其制备和用途 Download PDFInfo
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- CN101386593B CN101386593B CN200710053239A CN200710053239A CN101386593B CN 101386593 B CN101386593 B CN 101386593B CN 200710053239 A CN200710053239 A CN 200710053239A CN 200710053239 A CN200710053239 A CN 200710053239A CN 101386593 B CN101386593 B CN 101386593B
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- glutamic acid
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- norfloxacin glutamate
- hydrate
- norfloxacin
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Abstract
一种谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·nH2O，n＝0.5～3.5，谷氨酸可以是L型或者D型或者DL型谷氨酸，该结晶水合物具有良好的水溶性、良好的存储稳定性，适用于对革兰氏阳性或阴性细菌敏感菌，所致的人或动物的感染性疾病的治疗和预防。
Description
技术领域
本发明涉及医药技术领域，具体地说是提供谷氨酸诺氟沙星水合物及其制备和用途。
背景技术
文献仅报道了谷氨酸诺氟沙星[C16H18FN3O3·C5H9NO4，分子量：466.47](NORFLOXACIN GLUTAMATE)及其用途，到目前为止，国内外尚没有公开的文献报道谷氨酸诺氟沙星水合物[C16H18FN3O3·C5H9NO4·nH2O，n＝0.5～3.5]及其制备方法和用途。
发明内容
本发明所涉及的是谷氨酸诺氟沙星水合物及其制备和用途。本发明的谷氨酸诺氟沙星水合物(其化学名称为：1-乙基-6-氟-4-氧代-1，4-二氢-7-(1-哌嗪基)-3-羧酸喹啉谷氨酸盐水合物)，其分子式为C16H18FN3O3·C5H9NO4·nH2O，n＝0.5～3.5，n可以是0.5、1、1.5、2、2.5、3.5或之间的数字，谷氨酸诺氟沙星水合物可以是L-谷氨酸、D-谷氨酸或者DL-谷氨酸诺氟沙星水合物。
令人惊奇的是，我们通过研究发现，我们获得的含有结晶水的谷氨酸诺氟沙星[C16H18FN3O3·C5H9NO4·nH2O，n＝0.5～3.5]能稳定的存在，便于储存和运输，能够方便用于药物制剂的制备。热分析试验(TG-DTG)图谱可以看出失重平台具有对应的吸热峰(见附图)，用卡尔费休法测定水分结果与热分析结果相吻合，TG-DTG图谱明显看出谷氨酸诺氟沙星的0.5水合物C16H18FN3O3·L-C5H9NO4·0.5H2O、1.5水合物C16H18FN3O3·C5H9NO4·1.5H2O、3.5水合物C16H18FN3O3·C5H9NO4·3.5H2O。含有结晶水的谷氨酸诺氟沙星不同于诺氟沙星难溶于水的特性，无水的谷氨酸诺氟沙星易吸潮，含有结晶水的谷氨酸诺氟沙星具有良好的室温储存稳定性，便于制备易直接溶解和吸收的制剂。
本发明的谷氨酸诺氟沙星水合物为类白色至淡黄色粉末，不同于诺氟沙星在水中不易溶解的特性，在室温下具有良好的水溶性，易于制成水溶性的制剂。
本发明的谷氨酸诺氟沙星水合物，包括光学活性或者消旋的谷氨酸诺氟沙星水合物能稳定存储。将上述样品进行加速稳定性试验，出人意料地发现，本发明的谷氨酸诺氟沙星水合物含量和有关物质没有明显变化，谷氨酸诺氟沙星无水物加速试验6个月与0月相比，有关物质增加倍数高于谷氨酸诺氟沙星水合物。按中国药典要求进行影响因素试验，40℃，RH75％下，10天的高湿试验结果显示，水合物吸湿比无水物少得多，说明谷氨酸诺氟沙星水合物具有良好的存储稳定性。
结果见表1～表4。
表1.C16H18FN3O3·L-C5H9NO4·0.5H2O加速稳定性试验结果
表2.C16H18FN3O3·L-C5H9NO4·1.5H2O加速稳定性试验结果
表3.C16H18FN3O3·D-C5H9NO4·0.75H2O加速稳定性试验结果
表4.谷氨酸诺氟沙星无水物和水合物加速稳定性试验结果
表5.谷氨酸诺氟沙星无水物和水合物高湿试验*结果
*40℃，RH75％，10天
用HPLC法(C18反相柱，0.025M的磷酸溶液(用三乙胺调节pH至3.0)-乙腈(84∶16)为流动相，检测波长为278nm，流速为1.0ml/min，检测有关物质的变化情况。出人意料地发现，本发明的谷氨酸诺氟沙星水合物有关物质没有明显变化，因此，说明谷氨酸诺氟沙星水合物具有良好的存储稳定性。
谷氨酸诺氟沙星水合物制备方法为：
方法A.在反应容器中，以低级(C3-C6)酮，如丙酮、低级(C2-C6)酯、水或低分子醇C1-C5如甲醇、乙醇、异丙醇的一种或几种为溶剂，加谷氨酸和诺氟沙星，10-100℃之间搅拌，溶解，使反应完毕，缓慢加入低级(C3-C6)酮，如丙酮、氯仿或低分子醇如甲醇、乙醇、异丙醇，低级(C2-C6)醚，低级(C2-C6)酯，如乙酸乙脂、甲酸乙脂的一种或几种，冷却，待固体析出，过滤，固体物用有机溶剂低分子醇C1-C5如甲醇、乙醇、异丙醇、低级(C3-C6)酮，如丙酮、低级(C2-C6)醚如乙醚、氯仿中一种或几种润洗，抽干，干燥得谷氨酸诺氟沙星水合物；
或者方法B.在反应容器中，加谷氨酸或水溶液，加诺氟沙星，加热搅拌，使溶解，使反应完毕，缓慢加入低级(C3-C6)酮，如丙酮、氯仿，低级(C2-C6)酯，如乙酸乙脂、甲酸乙脂、或低分子醇C1-C5如甲醇、乙醇、异丙醇的一种或几种，冷却，待固体析出，过滤，固体物用有机溶剂低分子醇C1-C5如甲醇、无水乙醇、异丙醇、低级(C3-C6)酮，如丙酮、低级(C2-C6)醚、低级(C2-C6)酯，如乙酸乙脂、甲酸乙脂、氯仿中一种或几种润洗，抽干，干燥得谷氨酸诺氟沙星水合物；
或者方法C.将诺氟沙星和谷氨酸按等摩尔比例投入反应瓶中，加水，加热，控制温度20-100℃之间，反应0.5-6h，待反应完毕，将其冷冻到-60～-35℃，真空冷冻干燥，得谷氨酸诺氟沙星水合物。
将所得样品用碳酸氢钠或者氨水的溶液中和，沉淀过滤，水洗，水、甲醇、乙醇或丙酮中一种或几种重结晶，熔点、IR、MS等数据或图谱均与原料诺氟沙星一致。
将谷氨酸诺氟沙星水合物在，60-105℃左右，五氧化二磷为干燥剂，真空干燥4小时以上，将谷氨酸诺氟沙星水合物在110℃左右干燥得谷氨酸诺氟沙星无水物。
本发明稳定的谷氨酸诺氟沙星水合物用于制备注射用冻干粉针制剂、或者无菌分装粉针制剂、或者大输液制剂、或者小水针注射剂，经肠道给药制剂，包括片剂，胶囊，颗粒剂，经皮肤给药的软膏和凝胶，泡腾片、阴道凝胶、以及经阴道或者直肠给药的栓剂。
用于制备经肠道给药制剂的片剂，胶囊，颗粒剂，其中可含有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、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、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；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、海藻酸及其盐；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4000-6000、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。
本发明的固体制剂不同于诺氟沙星难溶解于水的特性，导致其固体制剂的溶出度受制剂工艺影响较大特点，谷氨酸诺氟沙星水合物易溶解于水，所以其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，提高生物利用度，并有利于快速发挥其抗菌作用。
本发明的栓剂和凝胶剂不同于诺氟沙星栓或软膏，由于诺氟沙星难溶解于水，一般情况下需要加油溶性的辅料，易于污染，而且较难清洗，谷氨酸诺氟沙星水合物易溶解于水，所以其制备的栓剂和凝胶剂具有良好的释放性能，使得其容易被吸收进入血液循环，提高生物利用度，并有利于快速发挥其抗菌作用。无需加油溶性的辅料，不易污染，而且较易清洗，
谷氨酸诺氟沙星水合物的栓剂：谷氨酸诺氟沙星水合物水合物5-50％、栓剂基质50-95％组成，基质可以是乙醇、甘油、甘油明胶、聚乙二醇200-8000、泊洛沙姆、半合成硬脂肪酸脂、卡波姆系列(931、934、940、974、AA-1、1342等)、吐温60-80。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的模具中，至稍微溢出栓模，待冷后削平，起模即得。
谷氨酸诺氟沙星水合物的凝胶制备：谷氨酸诺氟沙星水合物(以诺氟沙星计，投料)与50-95％基质混匀，基质可以是乙醇、甘油、三乙醇胺、甘油明胶、聚乙二醇200-8000、泊洛沙姆、聚乙烯吡咯烷酮、半合成硬脂肪酸脂、水溶性单甘酯、卡波姆系列(931、934、940、974、AA-1、1342等)、吐温60-80。栓剂中可含有药学上可接收的防腐剂和稳定剂，制备时可分别将卡波姆用水分散，加入甘油、聚乙二醇200-8000、水浴加热，搅拌混合，加处方量的谷氨酸诺氟沙星水合物、搅拌、用药学上可接收的无机碱或者有机碱调节pH＝3.5-6.5左右，加水至全量、搅拌至匀、分装，即得。
冻干粉针制剂的制备方法为：取谷氨酸诺氟沙星水合物(按无水物计)，加药学上可接受的冻干支持剂或辅形剂，加注射用水搅拌使溶解，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50-400mg/瓶(以主药计)分装，冷冻干燥，压塞，得成品。
本发明的谷氨酸诺氟沙星水合物制备注射用冻干粉针制剂、无菌分装粉针制剂，一个单位剂量的制剂(100～400mg)溶解于10～15ml水中，其pH值为3.5～6.5之间。
谷氨酸诺氟沙星水合物用于制备大输液制剂：谷氨酸诺氟沙星水合物加注射用水和药学上可接受的附加剂，例如药学上可接受的pH调节剂、药学上可接受的抗氧剂和稳定剂、药学上可接受的等张调节剂，过滤、除菌制成大容量灭菌注射液，其pH值在3.5～6.5之间。
谷氨酸诺氟沙星水合物小容量注射液及其制备工艺：谷氨酸诺氟沙星水合物加注射用水和药学上可接受的附加剂，例如：药学上可接受的pH调节剂、药学上可接受的抗氧剂、惰性气体，过滤、除菌制成灭菌小容量注射液，其pH值在3.5～6.5之间。
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，可以是盐酸、硫酸、磷酸、硝酸、氢溴酸、丙酸、醋酸及醋酸盐、如醋酸钠等，乳酸以及乳酸药用盐、如乳酸钠等、枸橼酸、枸橼酸药用盐、如枸橼酸三钠等、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、磷酸盐、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾、磷酸氢二铵、磷酸氢二钾、琥珀酸及盐、酒石酸及其药用盐、如酒石酸氢钠、DL-酒石酸、酒石酸钾钠等、硼砂、硼酸、丁二酸、己酸、己二酸、反丁烯二酸、顺丁烯二酸、碳酸铵、次磷酸、偏磷酸钠、聚偏磷酸钾、偏磷酸钾，三羟基氨基甲烷、三乙醇胺、二乙醇胺、乙醇胺、异丙醇胺、二异丙醇胺、2-氨基-2-(羟甲基)1，3-丙二醇胺、1，2-己二胺、N-甲基葡萄胺、二异丙胺以及它们的盐，多羟基羧酸及药用盐，如葡萄糖醛酸、葡萄糖酸、乳糖醛酸、乳糖酸、半乳糖醛酸、苹果酸、苏糖酸、葡庚糖酸，烟酸、甘草酸盐、苯甲酸及盐、苯甲酸钠、甲磺酸、苯磺酸、对甲苯磺酸、甘油酸，甘氨酸、赖氨酸、精氨酸、蛋氨酸，等氨基酸及氨基酸盐等中的一种或者几种。
其药学上可接受的抗氧剂和稳定剂可以是亚硫酸、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、甲醛次硫酸钠、硫甘油、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、没食子酸乙酯、没食子酸丙酯、没食子酸辛酯、没食子酸十二酯、咖啡酸、咖啡酸盐、阿魏酸、阿魏酸盐、二丁基羟基甲苯、叔丁基对羟基茴香醚、二叔丁基对苯酚、去甲二氢愈创木酸(NDGA)、2，5-二羟基苯甲酸、2，5-二羟基苯甲酸盐、苯酚或其衍生物、水杨酸或其盐；谷氨酸钠、甘氨酸、半胱氨酸、蛋氨酸、氨基酸以及其盐；甘草次酸盐、甘草酸盐、烯醇类化合物，如抗坏血酸及抗坏血酸盐、抗坏血酸棕榈酯、异抗坏血酸及异抗坏血酸盐、丙酮合抗坏血酸、a-生育酚、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四钠、依地酸钙钠、CDTA、DTPA、N-二(2-羟乙基)甘氨酸、二乙烯基三氨基戊乙酸、二乙基三胺基戊乙酸等中的一种或者几种。
其药学上可接受的等渗调节剂可以是葡萄糖、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、氯化镁、氯化钙、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、中空纤维式和圆盒式等，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1000-30000的超滤膜除去剩余热源，优选相对分子质量1000-10000的超滤膜。
由于本发明的稳定的谷氨酸诺氟沙星水合物为氟喹诺酮类抗菌药，具广谱抗菌作用，尤其对需氧革兰阴性杆菌的抗菌活性高，对下列细菌在体外具良好的抗菌作用：肠杆菌科的大部分细菌，包括枸椽酸杆菌属、阴沟肠杆菌、产气肠杆菌等肠杆菌属、大肠埃希菌、克雷伯菌属、变形菌属、沙门菌属、志贺菌属、弧菌属、耶尔森菌等。谷氨酸诺氟沙星水合物在体外对多重耐药菌亦具抗菌活性，对青霉素耐药的淋病奈瑟菌、流感嗜血杆菌和卡他莫拉菌亦有良好抗菌作用。
谷氨酸诺氟沙星水合物抗菌活性参照药理学实验方法进行细菌培养和测定，如表5-8所示：
表5 L-谷氨酸诺氟沙星半水合物抗菌活性MIC(mg/L)
表6 L-谷氨酸诺氟沙星1.5水合物抗菌活性MIC(mg/L)
表7 D-谷氨酸诺氟沙星3.5水合物抗菌活性MIC(mg/L)
表8 DL-谷氨酸诺氟沙星1水合物抗菌活性MIC(mg/L)
本发明目标物的临床应用：
适应症：本发明的谷氨酸诺氟沙星水合物为氟喹诺酮类抗菌药，用于适用于哺乳类动物由于敏感菌所致的呼吸道、尿路感染、淋病、前列腺炎、肠道感染和伤寒及其他沙门菌感染。
其用量用法：一般情况下，50～400mg可溶于生理盐水中，作肌内注射，每日二次；或取本发明制剂50～400mg(以诺氟沙星计)于5％葡萄糖50～1000毫升中，作静脉滴注，每日1-2次。或取本发明制剂50～400mg(以诺氟沙星计)的5％葡萄糖或者0.9％氯化钠输液静脉滴注，每日1-2次，7～14日为一疗程。
口服给药用量用法：0.2-0.8g/日。栓剂给药用量用法(以诺氟沙星计)：成人女性每天一次，一次给药0.2-0.4g的肛门栓或女性阴道栓一个，成人男性每天一次，一次给药0.2-0.4g的肛门栓一个；儿童减半。
附图说明
图1为L-谷氨酸诺氟沙星水合物0.5水合物的热分析图谱。
图2为L-谷氨酸诺氟沙星水合物1水合物的热分析图谱。
图3为L-谷氨酸诺氟沙星水合物1.5水合物的热分析图谱。
图4为L-谷氨酸诺氟沙星水合物3.5水合物的热分析图谱。
具体实施方式
实施例1在三颈烧瓶中，加乙醇和诺氟沙星，加热溶解，加L-谷氨酸或水溶液，30～100℃不断搅拌，使反应完毕，缓慢加入无水乙醇，冷却到0-10℃左右，待固体析出，过滤，固体物用乙醇润洗，抽干，78℃左右干燥2-6小时得类白色结晶性粉末，收率95.3％左右。HPLC：样品主峰与诺氟沙星对照品主峰的保留时间一致，熔点：184.5-186.5℃(未校正)，卡氏法测定水分为2.33％，这与样品含有0.5个结晶水的结果(理论值1.90％)在误差范围内。TG-DTA：80～130℃失重约2.128％，这与样品含有0.5个结晶水的结果(理论值1.90％)在误差范围内，TG-DTA表明在130℃之前具有明显的吸热峰，说明样品中含有结晶水(见附图1)。元素分析理论值：C 53.05％，H5.94％，F4.00％N11.78％；
实测值：C 53.01％，H6.02％，F3.96％N11.72％；
将谷氨酸诺氟沙星0.5水合物在80-90℃之间，五氧化二磷为干燥剂，真空干燥6小时以上，得谷氨酸诺氟沙星无水物。
实施例2在三颈烧瓶中，加L-谷氨酸和水，40～100℃搅拌下加诺氟沙星，使溶解，继续反应0.1～2小时，反应完毕后，缓慢加入2～15倍的无水乙醇和异丙醇(1∶1)，冷却，待固体析出，过滤，固体物用乙醇润洗，抽干，70℃左右干燥2-12小时得类白色粉末，易溶于水，收率93.6％左右。HPLC分析：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：190.5-193℃(未校正)；水分(卡氏法)：3.95％，TG-DTA：80～130℃失重约3.876％％，这与样品含有1个结晶水的结果(理论值3.719％)在误差范围内。TG-DTA表明在130℃之前具有明显的吸热峰，说明样品中含有结晶水(见附图2)。
元素分析实测值：C 52.03％，H6.09％，F3.90％N11.51％；
理论值：C 52.06％，H6.03％，F3.92％N11.56％；
将上述谷氨酸诺氟沙星1水合物在105℃干燥6小时以上，得谷氨酸诺氟沙星无水物。
实施例3将诺氟沙星和L-谷氨酸按等摩尔比例(1∶1)投入反应瓶中，加水，加热，搅拌、控制温度60-100℃之间，反应5-30min，待反应完毕，将其冻干，得到的固体用水与有机溶剂乙醇和异丙醇的混合溶剂结晶，抽滤，用乙醇润洗，抽干，50℃干燥2-6小时得类白色结晶性粉末，易溶于水，HPLC：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：192.5-195.6℃(未校正)，卡氏法测定水分为5.85％，这与样品含有1.5个结晶水的结果(理论值5.48％)在误差范围内。TG-DTA：平台失重约5.955％，这与样品含有1.5个结晶水的结果(理论值5.48％)在误差范围内，TG-DTA表明在130℃之前具有明显的吸热峰，说明样品中含有结晶水(见附图3)。
元素分析实测值：C 51.03％，H6.19％，F3.80％N11.31％；
理论值：C 51.11％，H6.13％，F3.85％N11.35％；
实施例4在三颈烧瓶中，加L-谷氨酸和诺氟沙星各0.01mol，加水20ml，40～100℃搅拌下使溶解，继续反应2小时，反应完毕后，缓慢加入2-10倍量的无水乙醇，冷却到室温或室温以下，待固体析出，过滤，固体物用乙醇润洗，抽干，70℃左右干燥2-12小时得类白色粉末，易溶于水，HPLC分析：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：190.2-193.3℃(未校正)；水分(卡氏法)：3.99％，TG-DTA：80～130℃失重约3.88％％，这与样品含有1.0个结晶水的结果(理论值3.72％)在误差范围内。TG-DTA表明在130℃之前具有明显的吸热峰，说明样品中含有结晶水。元素分析：实测值与理论值相吻合。
实施例5在三颈烧瓶中，加L-谷氨酸和诺氟沙星各0.01mol，加水20ml，40～100℃搅拌下使溶解，继续反应2小时，反应完毕后，缓慢加入2-10倍量的无水乙醇，冷却到室温或室温以下，待固体析出，过滤，固体物用乙醇润洗，减压抽至极干，40℃左右干燥48小时得类白色粉末，易溶于水，HPLC分析：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：191-194℃，未校正；水分(卡氏法)：12.03％，TG-DTA：80～130℃失重约11.838％％，这与样品含有3.5个结晶水的结果(理论值11.91％)在误差范围内。TG-DTA表明在130℃之前具有明显的吸热峰，说明样品中含有结晶水(见附图4)。
元素分析实测值：C 47.57％，H6.54％，F3.55％N10.53％；
理论值：C 47.63％，H6.47％，F3.59％N10.58％；
实施例6将诺氟沙星和D-谷氨酸按等摩尔比例(1∶1)投入反应瓶中，加水，加热，搅拌、控制温度40-100℃之间，反应10-60min，待反应完毕，缓慢加入2-10倍量的无水乙醇，冷却到室温或室温以下，待固体析出，过滤，固体物用乙醇润洗，抽干，40℃干燥48小时得类白色结晶性粉末，易溶于水，HPLC：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：194.3-196.4℃(未校正)，卡氏法测定水分为7.06％，这与样品含有2个结晶水的结果(理论值7.17％)在误差范围内。TG-DTA：150℃前平台失重约6.706％，这与样品含有2个结晶水的结果在误差范围内，TG-DTA表明在150℃之前具有明显的吸热峰，说明样品中含有结晶水。
实施例7将诺氟沙星和D-谷氨酸按等摩尔比例(1∶1)投入反应瓶中，加水，加热，搅拌、控制温度40-100℃之间，反应10-60min，待反应完毕，缓慢加入2-10倍量的无水乙醇，冷却到室温或室温以下，待固体析出，过滤，固体物用乙醇润洗，抽干，70℃干燥48小时得类白色结晶性粉末，易溶于水，HPLC：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：194.5-196.6℃(未校正)，卡氏法测定水分为2.88％，这与样品含有0.75个结晶水的结果(理论值2.74％)在误差范围内。TG-DTA：130℃前平台失重约2.688％，这与样品含有0.75个结晶水的结果在误差范围内，TG-DTA表明在150℃之前具有明显的吸热峰，说明样品中含有结晶水。
实施例8将诺氟沙星和DL-谷氨酸按等摩尔比例(1∶1)投入反应瓶中，加水，加热，搅拌、控制温度40-100℃之间，反应10-60min，待反应完毕，缓慢加入2-10倍量的无水乙醇，冷却到室温或室温以下，待固体析出，过滤，固体物用乙醇润洗，抽干，40℃干燥48小时得类白色结晶性粉末，易溶于水，HPLC：样品主峰与诺氟沙星对照品主峰的保留时间一致。熔点：194.5℃(未校正)，卡氏法测定水分为2.02％，这与样品含有0.5个结晶水的结果(理论值1.90％)在误差范围内。TG-DTA：130℃前平台失重约2.16％，这与样品含有0.5个结晶水的结果在误差范围内，TG-DTA表明在150℃之前具有明显的吸热峰，说明样品中含有结晶水。
实施例9取L-谷氨酸诺氟沙星1.5水合物20Kg(按诺氟沙星计)，加葡萄糖或甘露醇或木糖醇2.0～5g加新鲜的注射用水160～320L搅拌使溶解，用药学上可接受的酸或碱调节pH为3.0～6.5，加活性碳0.01～0.5％(W/V)搅拌15～45min，过滤，补水至200～400L，用0.22微米微孔滤膜过滤，按100mg/瓶或200mg/瓶或400mg/瓶(以主药计)分装，冷冻干燥，压塞，得成品。
实施例10取谷氨酸诺氟沙星1水合物20g(按诺氟沙星计)，加甘露醇40g，加40-60℃注射用水180～450ml搅拌使溶解，用1M的L-谷氨酸或氢氧化钠调节pH为5.0～6.0，加活性碳0.01～0.5％(W/V)搅拌15～45min，过滤，补水至230～500ml，用0.22微米微孔滤膜过滤或者采用截留相对分子质量1000-8000的超滤膜过滤，按100mg/瓶或200mg/瓶或400mg/瓶(按诺氟沙星计)分装，冷冻干燥，压塞，得成品。
实施例11取无菌的谷氨酸诺氟沙星半水合物25Kg(按诺氟沙星计)，以无菌分装工艺按100mg/瓶或200mg/瓶或400mg/瓶(按诺氟沙星计)分装，加塞、压塞，轧铝盖得成品。
实施例12 L-谷氨酸诺氟沙星2水合物(以诺氟沙星计)10.2g，加盐酸半胱氨酸0.8g，EDTA二钠0.1g，加注射用水搅拌使溶解，2M乳酸和乳酸钠调节pH为3.5～5.5，加活性碳0.01％(W/V)搅拌15～45min，过滤，补水至250ml，用0.22微米微孔滤膜过滤或者采用截留相对分子质量1 000-8000的超滤膜过滤，按5ml/分装，灭菌得成品。
实施例13 L-谷氨酸诺氟沙星水合物大容量注射液，称取葡萄糖500g加入注射用水中，搅拌使溶解完全，加入配液量0.05％的活性炭，加热10-30分钟左右，放冷，经砂滤棒过滤脱炭；将L-谷氨酸诺氟沙星水合物(以诺氟沙星计)10.1g用新鲜的注射用水溶解完全后，与上述滤液混合均匀，加盐酸L-半胱氨酸1g，EDTA二钠0.2g，用1M乳酸溶液调节pH值在3.5-6.5的范围内，加注射用水至5000ml，加配液量0.01％的活性炭，加热搅拌10-30分钟左右，过滤脱炭，再经0.22um微孔滤膜精滤或者采用截留相对分子质量1000-8000的超滤膜过滤，经半成品化验，待其含量、pH值和澄明度合格后，灌封于50ml或100ml或200ml的玻璃瓶中，经115℃热压灭菌30分钟；成品检查，包装即得。
实施例14 L-谷氨酸诺氟沙星水合物氯化钠输液的制备：将L-谷氨酸诺氟沙星水合物(以诺氟沙星计)10.4g、氯化钠85g、焦亚硫酸钠1.1g、EDTA二钠0.2g，加入注射用水中，搅拌使溶解完全，用1M的枸橼酸和枸橼酸钠溶液调节pH值在3.5-6.5的范围内，加注射用水至10000ml，加配液量0.05％的活性炭，加热搅拌10-30分钟左右，过滤脱炭，再经0.22um微孔滤膜精滤或者采用截留相对分子质量1000-8000的超滤膜过滤，经半成品化验，待其含量、pH值和澄明度合格后，灌封于50ml或100ml或200ml的玻璃瓶中，经115℃热压灭菌30分钟，成品检查，包装即得。
实施例15 L-谷氨酸诺氟沙星0.5水合物片剂(200mg/片，以诺氟沙星计)
处方：L-谷氨酸诺氟沙星0.5水合物200g(以诺氟沙星计)
微晶纤维素 100g
羧甲基淀粉钠 20g
阿斯巴甜 2g
聚乙烯吡咯烷酮10％ 适量
微粉硅胶 1g
硬脂酸镁 2g
将L-谷氨酸诺氟沙星水合物、微晶纤维素、羧甲基淀粉钠、阿斯巴甜过100目筛，用10％的聚乙烯吡咯烷酮适量制软材，过18-24目筛制粒，干燥，过14-20目筛整粒后，加微粉硅胶、硬脂酸镁混合，压片。
实施例16 D-谷氨酸诺氟沙星1水合物胶囊(200mg/粒，以诺氟沙星计)
处方：D-谷氨酸诺氟沙星1水合物200g(以诺氟沙星计)
微晶纤维素 50g
乳糖 10g
胶化淀粉10％ 适量
硬脂酸镁 2g
将D-谷氨酸诺氟沙星1水合物、微晶纤维素、乳糖过100目筛，用10％的胶化淀粉适量制软材，过18-24目筛制粒，干燥，过14-20目筛整粒后，加硬脂酸镁混合，灌装胶囊。
实施例17 L-谷氨酸诺氟沙星1水合物的颗粒剂(200mg/包，以诺氟沙星计)
处方：L-谷氨酸诺氟沙星1水合物200g(以诺氟沙星计)
甘露醇 100g
乳糖 20g
甜蜜素 2g
固体食用香精 1g
聚乙烯吡咯烷酮8％ 适量
将L-谷氨酸诺氟沙星1水合物、甘露醇、乳糖、甜蜜素、食用香精过100目筛，用8％的聚乙烯吡咯烷酮适量制软材，过18-24目筛制粒，60℃以下干燥，过14-20目筛整粒后，分包装。
实施例18 DL-谷氨酸诺氟沙星水合物的栓剂(200mg/粒，以诺氟沙星计)
处方：DL-谷氨酸诺氟沙星水合物25g(以诺氟沙星计，100粒投料)
聚乙二醇4000 80g
甘油 5ml
泊洛沙姆 50g
吐温80 1ml
将L-谷氨酸诺氟沙星水合物、甘油、聚乙二醇4000、泊洛沙姆、吐温80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19 L-谷氨酸诺氟沙星水合物的凝胶(200mg/，以诺氟沙星计)
处方：L-谷氨酸诺氟沙星水合物20g(以诺氟沙星计，投料)
聚乙二醇6000 50g
聚乙二醇400 10g
甘油 5ml
卡波姆934 10g
卡波姆1342 5g
水 40-60ml
将分别将卡波姆1342和卡波姆934用水分散，加入甘油、聚乙二醇6000、聚乙二醇400、搅拌混合，加L-谷氨酸诺氟沙星水合物、水浴加热、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。
本发明并不限于上述实施例。
Claims (9)
1.谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·nH2O，其中n＝0.5、0.75、1、1.5、2、3.5，并且当n＝0.5时，谷氨酸为L型或者DL型谷氨酸；当n＝0.75时，谷氨酸为D型谷氨酸；当n＝1时，谷氨酸为L型或者D型或者DL型谷氨酸；当n＝1.5时，谷氨酸为L型谷氨酸；当n＝2时，谷氨酸为L型或者D型谷氨酸；当n＝3.5时，谷氨酸为L型或者D型谷氨酸。
2.根据权利要求1所述的谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·3.5H2O，其中，谷氨酸为L型或者D型谷氨酸。
3.根据权利要求1所述的谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·2H2O，其中，谷氨酸为L型或者D型谷氨酸。
4.根据权利要求1所述的谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·1.5H2O，其中，谷氨酸为L型谷氨酸。
5.根据权利要求1所述的谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·H2O，其中，谷氨酸为L型或者D型或者DL型谷氨酸。
6.根据权利要求1所述的谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·0.75H2O，其中，谷氨酸为D型谷氨酸。
7.根据权利要求1所述的谷氨酸诺氟沙星水合物，其特征在于：谷氨酸诺氟沙星水合物为C16H18FN3O3·C5H9NO4·0.5H2O，其中，谷氨酸为L型或者DL型谷氨酸。
8.根据权利要求1所述的谷氨酸诺氟沙星水合物的用途，其特征在于：谷氨酸诺氟沙星水合物用于制备注射用冻干粉针制剂、或者无菌分装粉针制剂、或者大输液制剂、或者小水针注射剂、经肠道给药制剂、经皮肤给药的软膏和凝胶、阴道凝胶、以及经阴道或者直肠给药的栓剂中的应用。
9.根据权利要求1所述的谷氨酸诺氟沙星水合物的用途，其特征在于：用于制备对革兰氏阳性或阴性细菌敏感菌所致的人或动物的呼吸道感染、泌尿系统感染、淋病、前列腺炎、肠道感染、肝胆感染、皮肤软组织感染、眼部感染疾病的治疗和预防的药物中的应用。
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| 陈洪轩 等.谷氨酸诺氟沙星注射液稳定性研究.《开封医专学报》.1994,第13卷(第3期),221-225. * |
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