扎托洛芬凝胶剂的制备及体外研究

目的制备扎托洛芬凝胶剂,考察其体外渗透性、释放性和稳定性。方法采用紫外分光光度法测定扎托洛芬的含量,采用Franz扩散池分别考察载药凝胶剂体外渗透性和释放性,采用正交试验设计筛选处方,探讨了氮酮、卡波姆浓度及丙二醇用量对扎托洛芬凝胶剂经皮渗透的影响,并对凝胶剂初步稳定性进行了考察。结果扎托洛芬的线性范围为16.0~56.0μg/mL,日内日间精密度的RSD均小于0.6%,平均回收率为98.67%,RSD为1.45%;凝胶剂外观细腻,黏度适宜,pH 6.8~7.0,最佳处方含0.75%卡波姆、15%丙二醇、1%月桂氮卓酮,其体外经皮渗透(以小鼠皮为屏障)符合Higuchi方程,体外释放(以赛璐芬膜为屏障)符合零级动力学方程;室温留样3个月稳定性良好。结论扎托洛芬凝胶剂制备工艺简单,体外渗透性良好,制剂稳定性好。     

11H-二苯并[b，f]硫杂[艹卓]-10-酮的合成

邻氯苯甲醛与苯硫酚经Ullmann缩合、还原、浓盐酸氯化、氰化、水解及闭环等反应制得抗炎镇痛药扎托洛芬的中间体11H-二苯并[b，f]硫杂[艹卓]-10-酮，总收率48％。     

11H-二苯并[b,f]硫杂(艹卓)-10-酮的合成

邻氯苯甲醛与苯硫酚经Ullmann缩合、还原、浓盐酸氯化、氰化、水解及闭环等反应制得抗炎镇痛药扎托洛芬的中间体11H-二苯并[b,f]硫杂(艹卓)-10-酮,总收率48%.     

扎托洛芬片溶出度测定

目的:建立测定扎托洛芬片溶出度的方法。方法:含量测定方法采用紫外分光光度法,检测波长为330nm;溶出度测定方法采用桨法,以pH6.8的磷酸盐缓冲液为溶出介质,转速为100r·min-1,取样时间为30min。结果:扎托洛芬检测浓度的线性范围为2.5～30μg·mL-1(r=0.9999),平均回收率为100.36%,RSD=0.54%;3批样品30min时溶出度均在80%以上。结论:本方法简便、准确,结果可靠,可用于扎托洛芬片的溶出度测定。     

洛索洛芬钠涂膜剂的制备与质量控制

目的 制备洛索洛芬钠涂膜剂,建立其质量控制方法 . 方法 采用壳聚糖为成膜材料,按药剂学原理制备洛索洛芬钠涂膜剂;采用高效液相色谱法测定洛索洛芬钠含量. 结果洛索洛芬钠质量浓度与峰面积的线性范围为10～90 μg•mL-1,平均回收率为100.22%,RSD为0.44%. 结论 洛索洛芬钠涂膜剂制备工艺合理,质量控制方法可行,各项指标均符合《中华人民共和国药典》2005年版涂膜剂项下相关要求.     

骨折前期镇痛药物不合理应用分析

目的：评价医院骨折前期镇痛药物的使用情况，为临床合理用药提供参考。方法：调取2021—2022年骨折前期镇痛药物使用情况的相关信息，分析用药金额、用药频度（defined daily dose system,DDDs）、日限定费用（defined daily cost,DDC）、药物利用指数（druy utilization index,DUI）。结果：2021—2022年医院骨折前期镇痛药物使用占比中，塞来昔布胶囊、艾瑞昔布片、洛索洛芬钠片、盐酸羟考酮注射液、氨酚双氢可待因片依次排前5位；氨酚双氢可待因片、塞来昔布胶囊、艾瑞昔布片、洛索洛芬钠片、盐酸曲马多缓释片的DDDs稳居前5位。盐酸羟考酮注射液的DDC最高，洛索洛芬钠片的DDC最低。塞来昔布胶囊DUI值最大，且大于1；盐酸羟考酮注射液DUI值最小。结论：医院骨折前期镇痛药物应用基本合理，但个别药物费用较高，值得关注。     

氨酚羟考酮片与洛芬待因片治疗中、重度癌性疼痛的疗效比较

目的：比较氨酚羟考酮片及洛芬待因片治疗中、重癌性疼痛效果及安全性。方法：随机抽取口服氨酚羟考酮片及洛芬待因片治疗中、重度癌性疼痛患者各30例,观察用药第24,48,72 h疼痛缓解程度及其不良反应。结果：氨酚羟考酮片组与洛芬待因片组在服药第24,48 h比较均P>0.05,第72 h比较P<0.05;服药后24,48,72 h与服药前比较均P<0.01;治疗重度疼痛氨酚羟考酮片组与洛芬待因片组第72 h镇痛效果,显效比较P<0.05,有效比较P>0.05;治疗中度疼痛氨酚羟考酮片组与洛芬待因片组第72 h镇痛效果,比较显效、有效均P>0.05;氨酚羟考酮片组与洛芬待因片组在服药第24,48,72 h比较不良反应,均P>0.05。结论：服药72 h疼痛强度(PI)评估氨酚羟考酮片优于洛芬待因片,24,48 h比较均无明显差异;服药72 h治疗重度疼痛氨酚羟考酮片组显效优于洛芬待因片组,有效无明显差异,治疗中度疼痛氨酚羟考酮片组与洛芬待因片组,显效、有效均无明显差异,治疗后副反应无明显差异。     

扎托西隆的镇吐作用

动物试验证明，5—HT3受体拮抗剂能对抗化疗药顺铂和吐根所引起的呕吐，但对阿扑吗啡、硫酸铜所引起的呕吐和晕动性呕吐均无效、本文报道了5－HT3拮抗剂扎托西隆（zatosetron）对吐根所致呕吐的抽抗作用。动物试验采取随机安排、不完全封闭试验方案。20只成年雌性狗，体重10～12kg，在喂食30min后tv扎托西隆10，3050和mofig·吟一一’，或生理盐水，匕mh后灌服吐根糖浆5mL·kg－‘及水10mL。记录给药后90min内各组的初次呕吐发作时间，呕吐总次数和发作频率，并进行统计学处理。每条狗作3～4次试验，每次间隔1周。结果扎托西隆能抑制吐根…     

扎托布洛芬缓释微丸的制备及释放特性

目的 以不同处方制备扎托布洛芬缓释微丸,考察包衣层处方对药物释放的影响及其释药特性.方法 采用空白丸芯流化床混悬液上药法制备扎托布洛芬载药微丸,以HPMC为隔离材料包隔离衣、以乙基纤维素水分散体为缓释材料,考察不同种类、用量的致孔剂以及包衣增重对药物释放行为的影响.结果 以10％ HPMC为致孔剂、缓释衣层包衣增重为4.5％时,制得的微丸具明显的缓释效果,其释放曲线符合一级动力学,且批内及批间重复性良好.结论 制得的扎托布洛芬缓释微丸具有较理想的体外缓释效果.     

扎托洛芬的合成路线图解

扎托洛芬 (zaltoprofen,1 ) ,化学名为 2 - (1 0 -氧代 - 1 0 ,1 1 -二氢二苯并 [b,f]硫杂 - 2 -基 )丙酸 ,系由日本 Chemiphar公司开发 ,于 1 993年在日本首次上市的一种强效非甾体抗炎、镇痛、解热药。本品选择性作用于炎症部位 ,而对其它器官如胃和肾无作用 ,与同类药物如萘普生、布洛芬相比 ,具有高效、胃副作用小等特点 ,因而在日本临床上颇受好评。1 979年日本化学家报道了 1的合成 [1]。其合成路线按起始原料不同 ,可归纳为以下 3条。　　 ( )以 1 0 ,1 1 -二氢二苯并 [b,f]硫杂 - 1 0 -酮(2 )和 2 -溴丙酰氯为原料 ,在 Lewis酸…     

Enhanced transdermal drug delivery of zaltoprofen using a novel formulation

Zaltoprofen is a non-steroidal anti-inflammatory drug (NSAID) belonging to the propionic acid class. It has strong inhibitory effects on acute and chronic inflammation. Although zaltoprofen is well tolerated orally compared to other NSAIDs, it has to be administered in three to four doses per day and was associated with ulcerogenicity, bellyache and indigestion. This makes administration of zaltoprofen unsuitable for patients with gastric ulcer and is also associated with drug interactions. Therefore, it is important to develop an alternative dosage form which is easier to administer and avoids first-pass metabolism. The transdermal route meets all the above advantages. In this study, zaltoprofen gels were prepared using carbomer with mixture solution of polyethylene glycol (PEG) 400, Tween 80 and (2-hydroxypropyl)-β-cyclodextrin (HPCD) (called as T2), subsequently oleic acid as a penetration enhancer was added. Zaltoprofen gel containing T2 and oleic acid could promote the percutaneous absorption of zaltoprofen and increase AUC by 183% compared to zaltoprofen gel without T2 and oleic acid. Also, there was a finding zaltoprofen gel containing T2 and oleic acid did not cause dermal irritations in an experimental animal.     

Zaltoprofen inhibits bradykinin-induced responses by blocking the activation of second messenger signaling cascades in rat dorsal root ganglion cells

Bradykinin interacts with the bradykinin B2 receptor on dorsal root ganglion (DRG) neurons, setting off a series of reactions inside the cells that ultimately make the vanilloid receptor 1 more sensitive to a normal stimulus by activating various enzymes coupled with second messenger signaling cascades. Zaltoprofen, a propionic acid derivative non-steroidal anti-inflammatory drug (NSAID), was proved to inhibit bradykinin-induced pain responses in vivo experimental systems more potently than indomethacin or other NSAIDs, but the molecular mechanisms underlying its action are not yet fully understood. Currently it appears unlikely that zaltoprofen binds to specific sites on the protein of the bradykinin B2 receptor, hence we have examined the effect of zaltoprofen on bradykinin-induced responses of adult DRG neurons to investigate possible interaction sites. Compared with several other NSAIDs, such as indomethacin, loxoprofen and diclofenac, zaltoprofen most potently inhibits bradykinin-enhancement of capsaicin-induced 45Ca2+ uptake into DRG neurons. Zaltoprofen also significantly inhibits bradykinin-induced 12-lipoxygenase (12-LOX) activity and the slow bradykinin-induced onset of substance P release from DRG neurons. These data indicate zaltoprofen may produce its analgesic effects through the inhibition of bradykinin B2 receptor-mediated bradykinin responses of not only cyclooxygenases (COXs) but also bradykinin induced 12-LOX inhibitors.     

HPLC测定扎托布洛芬缓释胶囊的含量

目的采用HPLC法测定扎托布洛芬缓释胶囊的含量。方法采用Kromasil C18(150 mm×4.6 mm,5μm)色谱柱,流动相为乙腈-水-冰醋酸(300∶200∶1),流速1.0 mL·min-1,检测波长240 nm。结果 5～35μg·mL-1扎托布洛芬与峰面积呈良好的线性关系(r=0.9999),平均回收率为99.03%,RSD=0.52%。结论所用方法准确可靠,简便,快速,适用于扎托布洛芬缓释胶囊的质量控制。     

Zaltoprofen/4,4′-Bipyridine: A Case Study to Demonstrate the Potential of Differential Scanning Calorimetry (DSC) in the Pharmaceutical Field

The Zaltoprofen/4,4′-Bipyridine system gives rise to two co-crystals of different compositions both endowed - in water and in buffer solution at pH 4.5 - with considerably higher solubility and dissolution rate than the pure drug.The qualitative and quantitative analysis of the DSC measurements, carried out on samples made up of mixtures prepared according to different methodologies, allows us to elaborate and propose an accurate thermodynamic model that fully takes into account the qualitative aspects of the complex experimental framework and which provides quantitative predictions (reaction enthalpies and compositions of the co-crystals) in excellent agreement with the experimental results. Co-crystal formation and cocrystal compositions were confirmed by X-ray diffraction measurements as well as by FT-IR and NMR spectroscopy measurements.The quantitative processing of DSC measurements rationalizes and deepens the scientific aspects underlying the so-called Tammann's triangle and constitutes a model of general validity. The work shows that DSC has enormous potential, which however can be fully exploited only by paying adequate attention to the experimental aspects and the quantitative processing of the measurements.     

Involvement of CYP2C9 and UGT2B7 in the metabolism of zaltoprofen,a nonsteroidal anti-inflammatory drug,and its lack of clinically significant CYP inhibition potential

AIMS: To identify the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) isoforms responsible for the formation of the primary metabolite(s) of zaltoprofen, and to predict possible drug interactions by investigating the inhibition of CYP isoforms in vitro. METHODS: The metabolism of zaltoprofen was studied in vitro using recombinant CYP and UGT isoform cDNA-expression systems. The effects of selective isoform inhibitors on zaltoprofen metabolism were studied using human liver microsomes. The inhibitory effects of zaltoprofen on the metabolism of selective probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 were also determined in human liver microsomes. RESULTS: Zaltoprofen was extensively metabolized by CYP2C9 and UGT2B7. CYP2C9 catalysed sulphoxidation but not hydroxylation of zaltoprofen. In the human liver microsomal metabolism study, zaltoprofen metabolism was markedly inhibited by sulphaphenazole, a selective inhibitor of CYP2C9. In the drug interaction study, negligible inhibition (< 15%) of the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 was apparent at 5 micro g ml(-1), the maximum plasma concentration observed in humans after oral administration of an 80 mg zaltoprofen tablet. However, zaltoprofen inhibited CYP2C9 by 26% at 5 micro g ml(-1). At higher concentrations, zaltoprofen produced some inhibition of CYP2C9 (IC50 = 19.2 micro g ml(-1); 64.4 micro m) and CYP3A4 (IC50 = 53.9 micro g ml(-1); 181 micro m). The free drug concentrations in plasma (0.02 micro g ml(-1), 67.0 nm) at the Cmax of the clinically effective doses are much lower than the IC50 values corrected for the nonspecific binding ratio of zaltoprofen to microsomal protein (15.5 micro g ml(-1) for CYP3A4, 49.5 micro g ml(-1) for CYP3A4). Furthermore, the maximum free drug concentrations in the hepatic intracellular was calculated to be 0.068 micro g ml(-1) and the increase in the AUC in the presence of zaltoprofen was estimated to be only 0.4% for CYP2C9 substrates and 0.1% for CYP3A4 substrates, respectively. CONCLUSIONS: Zaltoprofen is predominantly metabolized by CYP2C9 and UGT2B7, and is considered unlikely to cause significant drug interactions in vivo when coadministered with CYP substrates at clinically effective doses.     

奥沙米特合成工艺的研究

以邻苯二胺为起始原料 ,经 4步反应合成了H1 组胺受体拮抗剂奥沙米特。作者研究了 4步反应的工艺条件 ,如合成化合物 5时 ,改变二苯甲醇与无水哌嗪的投料比 ;合成化合物 4时 ,文献缩合剂为氢氧化钾和相转移催化 ,改为乙醇钠为缩合剂 ;合成化合物 1时 ,溶剂由甲苯改为DMF ,使每步反应的收率都有所提高     

骨质疏松防治药物研究（9）喹啉酮类新衍生物中间体的合成改进

２，４－二甲氧基苯乙酸（１），对甲氧苯丙二酸二乙酯（２）及３，９－二羟基苯并呋喃并喹啉酮（３）是合成喹啉酮类新衍生物的关键中间体，对其合成方法进行改进，使反应步骤缩短，操作简化，收率提高。     

四氢异喹啉衍生物的合成及抗真菌活性

目的 寻找新的抗真菌活性化合物。方法 采用Pictet-Spengler法合成四氢异喹啉，再通过氮直接烃化法合成目标化合物，并对目标化合物进行初步的体外抗真菌活性实验。结果 合成了18个新的四氢异喹啉衍生物，利用红外光谱、核磁共振谱进行了结构确认。结论 所合成的18个四氢异喹啉衍生物具有不同程度的抗真菌活性。