头孢呋辛/三唑巴坦对产酶菌感染小鼠败血症治疗作用研究

目的不同配比头孢呋辛/三唑巴坦对产酶菌感染小鼠所致败血症的治疗作用研究,比较头孢呋辛/三唑巴坦(1:1、2:1、4:1和8:1)各种配比的抗菌活性及评价其合理性,为新药研制提供理论依据。方法通过腹腔注射0.5ml的1个最小致死量(MLD)菌液感染小鼠建立小鼠败血症模型。感染1h后给被感染小鼠注射0.2ml不同浓度的抗菌药液(每种药物配比5组,每组10只小鼠),观察和记录感染鼠死亡率(共7d)。ED50值、ED95值、ED5095%可信限及各药ED50值的t检验结果P值均用NDST软件程序的Bliss法计算统计。比较头孢呋辛/三唑巴坦(1:1、2:1、4:1和8:1)配比对实验的产超广谱β-内酰胺酶(ESBLs)的大肠埃希菌、肺炎克雷伯菌株及对甲氧西林敏感的金葡菌产酶菌(MSSA)感染小鼠所致败血症的治疗作用。结果头孢呋辛/三唑巴坦(1:1和2:1)配比对大肠埃希菌、肺炎克雷伯菌产ESBLs菌株的体内抗菌作用显著优于头孢呋辛/三唑巴坦(4:1和8:1)及单剂;ED50值及ED95值分别为头孢呋辛单剂的2.32～3.29和1.81～3.35倍(P<0.01)。头孢呋辛/三唑巴坦(1:1、2:1和4:1)配比对实验的产酶MSSA感染小鼠败血症治疗作用显著优于头孢呋辛/三唑巴坦(8:1)及单剂,ED50值及ED95值分别为头孢呋辛单剂1.56～3.33和2.24～4.03倍(P<0.01,0.010.05)。结论在所有实验药中,头孢呋辛/三唑巴坦(1:1和2:1)对实验的大肠埃希菌、肺炎克雷伯菌ESBLs、产酶MSSA菌株感染小鼠败血症治疗作用显著优于头孢呋辛/三唑巴坦(4:1和8:1)及头孢呋辛单剂;与1:1的比例相比,头孢呋辛/三唑巴坦(2:1)配比抗菌作用相似并可减少三唑巴坦用药量,降低用药费用及用药不良反应产生的机率。体内试验结果显示头孢呋辛/三唑巴坦(2:1)合剂为最佳配方组合。     

头孢呋辛酯HPLC含量测定方法的改进

对头孢呋辛酯的HPLC含量测定方法进行改进。色谱条件：采用ODS柱，0．01mol/L磷酸盐缓冲液(pH2．0)-乙腈-叔丁基甲醚(80：15：5)为流动相，柱温45℃，检测波长278nm。头孢呋辛酯与有关物质分离良好。头孢呋辛酯在89～268μg／ml范围内呈良好的线性关系，日内RSD为0．4％，含量测定结果与采用欧洲药典方法所得结果相符。提出了头孢呋辛酯有关物质检查的梯度洗脱HPLC法。     

头孢呋辛/他唑巴坦对β内酰胺酶稳定性及抑酶增效作用

目的观察在头孢呋辛(第2代头孢类抗生素)中加入不同配比他唑巴坦后,对β内酰胺酶的稳定性及抑酶保护作用。方法以超声破碎细菌,得粗制β内酰胺酶,紫外分光光度法测定抗菌药物浓度,计算酶对底物水解率,并以头孢呋辛水解率为100%,计算不同配比头孢呋辛/他唑巴坦的相对水解率和抑酶保护率。结果头孢呋辛中加入他唑巴坦后,β内酰胺酶对其水解率较单用头孢呋辛下降;对大多数菌株,相对水解率<30%,抑酶保护率>70%,3种配比与单用头孢呋辛比较有非常显著性差异(P<0.01)。结论他唑巴坦有很好的抑酶作用,提高了头孢呋辛对革兰阴性杆菌所产β内酰胺酶的稳定性。     

应用LC-MS鉴定头孢呋辛酯的同分异构体

头孢呋辛酯具有热和光不稳定性,可产生多种同分异构体,本研究采用LC-MS法,对其异构体的结构进行解析,它们按LC出峰的顺序依次为:头孢呋辛酯(6R,7R,1R)、头孢呋辛酯(6R,7R,1S)、头孢呋辛酯Δ3-异构体、头孢呋辛酯反式异构体(6R,7R,1R)、头孢呋辛酯反式异构体(6R,7R,1S).     

超微细无定型头孢呋辛酯的制备研究

目的研究制备超微细头孢呋辛酯的方法。方法以结晶型头孢呋辛1-乙酰氧基乙酯(头孢呋辛酯)为原料,以丙酮为溶剂,水作为反溶剂,采用反溶剂沉淀法制备无定型超微细头孢呋辛酯。结果在最佳实验条件下制得粒度分布均匀且平均粒径在400nm的头孢呋辛酯药物,质量符合中国药典要求,经傅里叶变换红外光谱(FT-IR)分析,在超微细化前后,头孢呋辛酯的分子结构没有发生变化;经x射线粉末衍射(XRD)分析知其结构为无定型。结论用本法制备头孢呋辛酯,原料、溶剂易得,成本低,操作简便。     

注射用头孢唑林和头孢呋辛临床用药安全性评价

目的:对注射用头孢唑林、头孢呋辛临床用药安全性进行评价,为围手术期合理选择预防用抗菌药物提供参考。方法:收集国内外电子文献数据库、美国食品药品监督管理局(FDA)药品不良事件自发呈报系统(FAERS)、世界卫生组织(WHO) 全球个例安全报告数据库(VigiBase)以及国家药品监督管理局(NMPA)发布的安全信息中头孢唑林、头孢呋辛的不良事件(ADE)报告数据。采用专家咨询法和层次分析法计算综合权重,评价头孢唑林和头孢呋辛的用药安全性。结果:在文献报道病例中,头孢唑林ADE 报告例次大于头孢呋辛;在FAERS 及VigiBase 数据库中,头孢呋辛ADE 发生例次明显高于头孢唑林;通过构建层次结构模型、专家评分,计算综合权重,头孢唑林(0. 625 7)优于头孢呋辛(0. 374 3)。结论:头孢唑林比头孢呋辛安全性更具优势。     

头孢呋辛钠与头孢呋辛钠复方制剂在Beagle犬体内的药动学考察

目的研究头孢呋辛钠舒巴坦钠复方制剂中头孢呋辛在Beagle犬体内的药动学行为,并比较单组分头孢呋辛与复方制剂中头孢呋辛的药动学差异。方法采用高效液相色谱法(HPLC)测定Beagle犬静脉给予头孢呋辛钠复方制剂不同剂量和单独给予头孢呋辛钠后不同时刻血浆中头孢呋辛的浓度,计算主要药动学参数。结果犬静脉给予头孢呋辛钠复方制剂(等同于头孢呋辛57.0、142.6和356.5 mg.kg-1)3个剂量后,头孢呋辛的t1/2分别为(1.1±0.2)、(1.0±0.1)和(1.2±0.3)h;ke分别为(0.693±0.119)、(0.707±0.094)和(0.591±0.117)h-1;犬静脉给予头孢呋辛钠(等同于头孢呋辛57.0 mg.kg-1)后,头孢呋辛的t1/2和ke分别为(1.2±0.3)h和(0.615±0.133)h-1。结论 Beagle犬静脉给予头孢呋辛钠复方制剂低、中、高3种剂量后,头孢呋辛呈线性动力学特征,且复方制剂与单一制剂中头孢呋辛的药动学行为无显著差异。     

头孢类抗生素对根除失败者幽门螺杆菌药敏情况的研究

目的研究初次根除幽门螺杆菌失败者所感染的菌株对头孢呋辛、头孢克肟和头孢丙烯3种头孢类抗生素的敏感情况,探讨这3种头孢类抗生素用于再次根除治疗的可能性。方法收集了62例初次根除失败者胃窦黏膜标本,从其中46例标本中分离培养出了幽门螺杆菌。采用琼脂稀释法检测了这些菌株对3种头孢类抗生素的敏感情况。结果 46例Hp菌株中对头孢呋辛、头孢克肟和头孢丙烯耐药的耐药率分别为4.3%、10.1%和19.6%。结论头孢呋辛、头孢克肟在体外对初次根除幽门螺杆菌失败者所感染的菌株有良好的抗菌作用,可进一步扩大样本进行研究,有望用于初次根除幽门螺杆菌失败者的再次治疗。     

高效液相色谱法测定头孢呋辛酯中高分子聚合物

目的:建立HPLC法测定头孢呋辛酯中高分子聚合物的方法.方法:采用聚苯乙烯-二乙烯苯共聚物(分子量使用范围＜ 10000)为填充剂的色谱柱;0.030 mol·L-1 LiBr溶液为流动相;流速为0.33 mL·min-1;检测波长为280 nm;进样量为20μL.结果:头孢呋辛酯在0.104～0.304 mg·mL-1范围内,溶液浓度与聚合物峰面积呈良好的线性关系,线性回归方程为Y=353576X-3182.2(r＝0.9998),检测限为0.068 ng.结论:本方法简单、快速、灵敏度高、重现性好,克服了传统聚合物检测方法分析时间长,无法检测脂溶性样品的缺点.可以用于测定头孢呋辛酯、头孢呋辛酯制剂及其它脂溶性抗生素中高分子聚合物.     

头孢呋辛酯干混悬剂溶出度测定方法的建立

目的 建立头孢呋辛酯干混悬剂溶出度测定方法.方法 采用浆法,以0.07mol·L-1的pH 7.0的磷酸缓冲液(称取3.7g磷酸二氢钠和5.7g无水磷酸氢二钠,加水1000mL使溶解)为溶剂,转速为50r·min-1,30min时取样.以紫外可见-分光光度法测定头孢呋辛酯的溶出度,检测波长为278nm.结果 头孢呋辛酯在3.36～20.16μg·mLl的浓度范围内,线性关系良好.平均回收率为99.7％(RSD=0.20％,n=12).结论 增加头孢呋辛酯溶出度检查项极为必要.本方法操作简便、结果正确,为完善头孢呋辛酯干混悬剂的质量标准提供了有效的手段.     

刺囊毛霉对天麻素的生物转化研究

利用刺囊毛霉(Mucor spinosus)3．3450的培养液对天麻素进行生物转化,得到其酶水解产物甙元对羟基苯甲醇,转化率接近100％。通过无细胞抽提液对底物转化的研究,证明催化该反应的酶为组成酶、胞外酶。     

L-669,262, a potent HMG-CoA reductase inhibitor

The microbial transformation of simvastatin (MK-733) by Nocardia autotrophica subspecies amethystina yielded iso-simvastatin-6-one as a minor component. This transformation product is a dienone and is one of the more potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase found to date.     

Kinetics of the transformation of dihydroambazone into ambazone

The oxidation of dihydroambazone (1) by oxygen is dependent on the pH-values of the solutions used. This transformation can be inhibited and excluded, respectively, by ascorbic acid using defined concentrations. The oxidation product ambazone (2) was determined spectroscopically at different pH-values. The rate of transformation in serum depends on the temperature and can also be inhibited with ascorbic acid.     

采用萃取法后处理提高维生素C的收率

将ＶＣ两步酵酸式转化反应产物溶于正丁醇和甲苯的混合剂中，再用水萃取、纯化，得到ＶＣ精制品。从古龙酸（古洛糖酸）到ＶＣ的收率达８３％以上。     

Chemical-analytical characterization of dihydroambazone

Important properties of p-(thiosemicarbazido)diamino-methylen-hydrazino benzene (1; dihydroambazone) are described. The transformation of this compound into 1,4-benzoquinone guanylhydrazone thiosemicarbazone (2; ambazone) dependent on different aqueous buffer systems was investigated. The spectroscopic behaviour of the transformation product allows us to determine the content of the compound in aqueous solutions, whereas the determination in serum is much more difficult. Furthermore, TLC experiments and oxidation methods are described.     

新鱼腥草素钠缩合反应机制探讨及聚合物结构鉴定

为探讨新鱼腥草素钠缩合反应机制并鉴定稳定化缩合产物的化学结构, 制备了二聚物并进行转化反应, 采用LC-DAD-MS/MS联用技术分析转化产物的紫外吸收特征及质谱信息, 采用紫外分光光度法考察转化动力学及转化半衰期。经有机溶剂萃取及柱层析分离纯化, 制备了稳定化缩合产物对照品, 采用红外、高分辨质谱和核磁共振技术进行结构鉴定, 并将LC-MS/MS分析结果与二聚物转化产物进行比较。二聚物结构不稳定, 在水溶液中易解离生成游离的十二酰乙醛, 进而发生三分子环合加成−原位脱水缩合反应, 生成含六元环稳定结构的1,3,5-三- (十二烷酰基)-苯 (三聚物), 转化反应符合二级动力学方程, 25 ℃ (298 K) 和100 ℃ (373 k) 条件下转化半衰期分别为3.17 h和6.39 min。二聚物系缩合过程中的中间过渡状态, 推测新鱼腥草素钠注射液中的缩合产物主要以三聚物的形式存在。     

那格列奈合成工艺改进

目的:改进那格列奈的合成工艺以提高产率并促进工业化生产。方法:分别从反应试剂、催化剂及晶型转型方面进行改进,即在顺反转化中用氢氧化钠替代文献中的氢化钠,在氯化反应中用氯化亚砜代替文献中的三氯化磷或五氯化磷;以RuNiAlC催化剂代替文献中的PtO2或Raney Ni;在H晶型转型中采用低温粉碎得微粒晶种以晶种引导结晶的方法获得H型晶体,并对改进方法所制成品的晶型结构进行表征及计算产率。结果:晶型表征结果证实产品为那格列奈H型晶体,产率达72%,高于文献报道的50%。结论:改进后工艺的产率升高,适合工业化生产。     

Spray Drying Technique. I: Hardware and Process Parameters

Spray drying is a transformation of feed from a fluid state into a dried particulate form by spraying the feed into a hot drying medium. The main aim of drying by this method in pharmaceutical technology is to obtain dry particles with desired properties. This review presents the hardware and process parameters that affect the properties of the dried product. The atomization devices, drying chambers, air–droplet contact systems, the collection of dried product, auxiliary devices, the conduct of the spray drying process, and the significance of the individual parameters in the drying process, as well as the obtained product, are described and discussed. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:575–586, 2010     

In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy

Process-induced transformations are very important to control during pharmaceutical manufacturing because they may change the properties of the active pharmaceutical ingredient in the drug product, compromising therapeutic efficacy. One process that may facilitate a process-induced transformation is high-shear wet granulation. In this study, the feasibility of Raman spectroscopy for in-line monitoring of the transformation of theophylline anhydrous to theophylline monohydrate during high-shear wet granulation has been evaluated. The midpoint of conversion occurred 3 min after the binder solution was added. The effects of several processing parameters were also examined, including mixing speed and monohydrate seeding. Mixing speed had the greatest effect on the transformation, where an increase in mixing speed shortened the onset time and increased the rate of transformation. In contrast, seeding with monohydrate or changing the way in which the binder was incorporated into the granules did not affect the transformation profile. The transformation kinetics observed during wet granulation were compared with those generated by a simple model describing the solvent-mediated transformation of theophylline in solution. In conclusion, these studies show that Raman spectroscopy can be used for in-line monitoring of solid-state transformations during wet granulation. In addition, for this particular compound, a simple solvent-mediated transformation model has been shown to be useful for estimating the time scale for hydrate formation during high-shear wet granulation.     

Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control

PURPOSE: The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. MATERIALS AND METHODS: The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. RESULTS: The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Defining target product quality profile; Designing product and manufacturing processes; Identifying critical quality attributes, process parameters, and sources of variability; Controlling manufacturing processes to produce consistent quality over time. CONCLUSIONS: Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.