辛伐他汀自微乳化胶囊的体内评价

目的:研究辛伐他汀(SV)自微乳化胶囊在比格犬体内的药代动力学。方法:采用HPLC法测定比格犬血浆药物浓度,与市售片比较,考察SV自微乳化胶囊的体内药代动力学。结果:药代动力学测定结果表明:与市售片比较,自微乳化胶囊血药浓度达峰时间提前、最高血药浓度增大,Tmax=1.41h,Cmax=46.22ng.mL-1,而市售片的Tmax=2.65h,Cmax=12.43ng.mL-1;AUC0-∞为市售片剂的227.5%。结论:自微乳化胶囊可以显著提高SV的体内吸收。     

非诺贝特固体自乳化制剂（S-SEDDS）体外评价及生物利用度研究

目的:以S-SEDDS替代液态自乳化制剂中的表面活性剂制备非诺贝特固体自乳化制剂。方法:比较了固体自乳化制剂与市售产品、液体自乳化制剂的体外溶出情况及体内生物利用度。结果:表明本研究的固体自乳化制剂用水分散后平均粒径为820.2±26.5(nm);溶出度试验结果显示,30min累积溶出度达到80%以上,本研究制备的非诺贝特固体自乳化制剂AUC(0-24)为22.7±8.2 mgoL-1oh与SEDDS的AUC(0-24)(24.9±7.6mgoL-1oh)没有显著性差异(P>0.05),与市售微粉化胶囊(13.8±10.5mgoL-1oh)相比能够显著提高药物的生物利用度(P<0.05)。结论:S-SEDDS有液体自乳化给药系统的效果。     

非诺贝特固体自乳化制剂（S-SEDDS）体外评价及生物利用度研究

目的：以S-SEDDS替代液态自乳化制剂中的表面活性剂制备非诺贝特固体自乳化制剂。方法：比较了固体自乳化制剂与市售产品、液体自乳化制剂的体外溶出情况及体内生物利用度。结果：表明本研究的固体自乳化制剂用水分散后平均粒径为820.2±26.5（nm）;溶出度试验结果显示,30min累积溶出度达到80%以上,本研究制备的非诺贝特固体自乳化制剂AUC（0-24）为22.7±8.2 mgoL-1oh与SEDDS的AUC（0-24）（24.9±7.6mgoL-1oh）没有显著性差异（P〉0.05）,与市售微粉化胶囊（13.8±10.5mgoL-1oh）相比能够显著提高药物的生物利用度（P〈0.05）。结论：S-SEDDS有液体自乳化给药系统的效果。     

雷诺嗪缓释片在比格犬体内的药代动力学

目的:研究雷诺嗪缓释片在比格犬体内的药物代谢动力学,并与参照制剂比较,为其是否具有缓释特征提供依据。方法:首先建立血浆中雷诺嗪浓度的液相色谱-串联质谱联用检测方法,并考察方法的专属性、准确度、日内日间精密度、回收率、线性范围等。采用随机对照试验设计,将12只比格犬随机分为A、B组,每组6只,分别服用1片雷诺嗪缓释片(500 mg/片)和1片参比制剂雷诺嗪片(500 mg/片),均于给药前和给药后不同时间点采集血样,用已建立的液质联用方法检测血样中雷诺嗪的血药浓度,计算2组比格犬的药代动力学参数。结果:受试组和参照组半衰期t1/2分别为13.3±8.3和2.36±0.92 h,峰浓度Cmax分别为923.9±340.5和3205±1314 ng/mL,达峰时间Tmax分别为1.6±0.38和0.88±0.14 h,曲线下面积AUC0~∞分别为6252.1±2860.3和9916±4305(ng·h)/mL,清除率Cl分别为11.3±9.8和6.39±3.95 L/(kg·h)。受试制剂雷诺嗪缓释片和参比制剂雷诺嗪片的药代特征和血药浓度-时间变化趋势明显不同,受试组血药浓度缓慢上升和下降,峰值较低;而参照组血药浓度峰值显著高于受试组,有明显的突释效应。结论:液质联用检测方法准确可靠,适合体内药代动力学研究;与参比制剂雷诺嗪片相比,受试制剂雷诺嗪缓释片符合缓释片的基本药代动力学特点。     

万氏牛黄清心缓释胶囊在比格犬体内药动学研究

目的:研究比格犬单剂量交叉口服万氏牛黄清心缓释胶囊和市售普通丸给药的药动学.方法:采用高效液相色谱法测定10只比格犬单剂量口服万氏牛黄清心pH-依赖型梯度释药胶囊和市售丸后血浆中盐酸小檗碱的血药浓度.血浆样品采用碱化后乙醚萃取浓缩方法制备.以青藤碱为内标物质,流动相采用乙腈-0.1 mol·L-1磷酸二氢钾溶液-磷酸(30:70:0.01),检测波长为262nm,流速为1.0mL·min-1.结果:血浆中内源性物质对盐酸小檗碱及青藤碱的测定无干扰;最低检出限为1.25ng·mL-1;盐酸小檗碱在1.25～250ng·mL-1浓度范围内线性关系良好,r=0.9990;绝对回收率为82.94%～88.36%,方法回收率为89.28%～92.29%;日内精密度RSD≤4.87%、日间精密度RSD≤7.03%.缓释胶囊和普通丸药动学参数AUC0∞分别为668.02和809.95 h·ng·ml-1,MRT分别为5.27和4.34h,缓释胶囊相对于普通丸的生物利用度为84.6%.结论:建立的测定方法处理简单,无干扰,灵敏度高,适合测定中药缓释制剂的药物动力学研究.万氏牛黄清心缓释胶囊具有明显的缓释作用,药物在体内呈梯度释放.     

氯雷他定片剂一致性评价研究方法

为改善我国部分仿制药质量与国际先进水平还存在一定差距的现状,《国家药品安全“十二五”规划》中明确提出了开展仿制药一 致性评价,全面提高仿制药质量的任务。氯雷他定片作为抗过敏药物的主要品种之一,需在 2018 年底前完成一致性评价。基于现有质量和 疗效一致性评价指导原则与相关研究报道,针对氯雷他定原料药的晶型研究、原辅料杂质的比较研究、片剂溶出曲线的比较方法以及生物 等效性试验研究等进行了总结和概括,并对有待解决的共性问题进行了讨论。     

定量比格犬血浆中去甲文拉法辛LC-MS/MS方法的建立及比格犬血浆中富马酸去甲文拉法辛药代动力学研究

目的:建立一种快速灵敏的液质联用方法定量比格犬血浆中去甲文拉法辛,并进行比格犬体内富马酸去甲文拉法辛药代动力学研究,同时与琥珀酸去甲文拉法辛比格犬体内药代参数进行对比。方法:样品处理采用叔丁基甲醚进行液液萃取,液相分离采用Agilent Eclipse Plus C18色谱柱(2.1 mm×100 mm,3.5μm),以乙腈-乙酸铵缓冲液(1 mmol/L)(体积比80∶20)进行等度洗脱。采用单次给药和多次给药试验进行比格犬体内药代动力学研究。结果:此方法具有良好的线性、精密度、准确度,定量下限(0.5 ng/mL)高于文献报道。液液萃取的样品提取方法简便,液质联用分析时间相对较短(3 min)。结论:此方法可成功地应用于比格犬血浆中去甲文拉法辛定量分析。比格犬体内富马酸去甲文拉法辛的药代参数(单次给药和多次给药试验)与对照品琥珀酸去甲文拉法辛没有明显的统计学差异。     

RP-HPLC法测定阿托伐他汀在新西兰兔体内的药代动力学

目的:研究阿托伐他汀片在新西兰兔体内的药代动力学.方法:18只成年健康雄性新西兰兔.随机分为正常对照组、10mg/kg·d阿托伐他汀片组与15 mg/kg·d阿托伐他汀片组,每组6只,采用RP-HPLC法测定血药浓度,计算药代动力学参数.结果:10mg/kg·d组与15 mg/kg·d组的主要药代动力学参数分别为:AUC0～t/μ g·L-1·h为(619.58±215.45)与(1138.34±422.32)、AUC0～∞/μ g·L-1·h为(655.68±242.83)与(1216.57±353.64)、Cmax/μ g·L-1为(455.81±168.52)和(896.53±168.5.8)、MRT0～t/h为(3.68±0.75)与(5.73±0.56)、MRT0～∞/h为(3.83±0.91)与(5.25±0.48)、Tmax/h为(2.51±0.82)与(3.68±0.33)、T1/2/h为(4.22±0.55)与(9.51±0.67).结论:RP-HPLC法适用于阿托伐他汀片动物药代动力学的研究.     

重组人血管内皮抑素在Beagle犬体内的药代动力学研究

研究重组人血管内皮抑素(rhEndostatin)静脉注射后在Beagle犬体内的药代动力学过程,为临床应用提供药代动力学数据。用酶联免疫吸附试验(ELISA)竞争法检测Beagle犬静脉注射rhEndostatin后不同时间的血药浓度,并将血药浓度-时间数据经计算机拟合,计算出相应参数。rhEndostatin静脉注射Beagle犬后,药物的分布半衰期平均为(0.34±0.04)h,消除半衰期为(16.5±1.6)h。血药浓度-时间曲线下面积(AUC)与剂量呈正相关,相关系数为0.999 9。血浆清除率(CLs)均值为(0.123±0.006)l/h,高、中、低剂量CLs基本相同。rhEndostatin在Beagle犬体内的药代动学过程基本符合线性药动学特征,血药浓度-时间曲线符合二房室模型。rhEndostatin在Beagle犬体内药代动力学过程的研究对其进一步开发具有指导价值。     

固体分散体提高普罗布考生物利用度的研究

目的:采用固体分散体技术(solid dispersion,SD)提高普罗布考的溶解度,从而提高其溶出速率及口服生物利用度。方法:选用共聚维酮(S-630)为载体,采用喷雾干燥法制备普罗布考固体分散体,通过差示扫描热量法(differential scanning calorimetry,DSC)、X-射线粉末衍射分析(X-ray diffraction,XRD)对其进行物相鉴定,通过动力溶解度试验模拟固体分散体在体内胃肠道的动态溶出过程,采用液相色谱-质谱(LC-MS/MS)评价大鼠体内药动学行为。结果:差示扫描热量法和X-射线粉末衍射分析表明药物以分子形式存在于固体分散体中;动力溶解度结果显示固体分散体在200 min内的累积溶出度维持在80%以上,并且没有出现药物析出现象。大鼠体内药动学研究表明,普罗布考固体分散体的Cmax和AUC0→t分别是原料药的7.5倍和6.3倍。结论:将药物制成固体分散体后,溶解度和溶出度得到了显著提高,生物利用度也随之增加。     

血清可溶性CD147的含量与冠状动脉粥样硬化性心脏病 发病风险的关联分析

目的：探讨血清可溶性CD147（sCD147）的含量与冠状动脉粥样硬化性心脏病（CAHD）发病风险的关系并初步探讨其临床 应用价值。方法：收集130 例CAHD（包括50 例稳定性心绞痛（SAP）、46 例不稳定性心绞痛（UAP）、34 例急性心肌梗死（AMI）） 和130 例年龄、性别与冠心病患者相匹配的健康志愿者的外周血样本,应用双抗体夹心ELISA检测各组血清sCD147 的表达水 平,比较分析血清sCD147 水平与CAHD的临床相关性,并绘制研究对象工作特征（ROC）曲线。结果：CAHD 患者血清sCD147 含量（AMI、UAP 及SAP 组中位数分别为3.35 ug·L-1、2.72 ug·L-1和2.66 滋g·L-1）显著高于对照组（中位数为1.64 ug·L-1,P < 0.001）,其中AMI组明显高于UAP及SAP组（P值分别为0.008、0.006）。血清sCD147 含量与CAHD患者TG、LDL-C 及AIP 显 著正相关（P值分别为0.021、0.035 及0.039）。以健康对照为参照,与sCD147 含量低的个体相比,sCD147 含量高的个体CAHD 发 病风险显著上升（校正比值比为2.18;95%可信区间为1.49-2.96）,且高的sCD147 含量与CAHD发病风险之间存在显著的剂量 依赖关系（P < 0.001）。用血清sCD147 含量绘制ROC 曲线,曲线下面积为0.761（95%可信区间为0.702-0.82）。以血清sCD147 含 量≥ 2.71 ug·L-1为临界值,用血清sCD147 含量诊断CAHD的敏感度为73.1%,特异度为76.9%。结论：血清sCD147 含量与 CAHD 发病风险显著正相关,可作为CAHD发病监测及CAHD早期诊断的检测指标。     

Dissolution studies on tablets of ibuprofen using chitosan.

An attempt has been made to study the release retardant behaviour of chitosan in ibuprofen tablets. Three different ibuprofen tablets were prepared by using 1,3 and 5% chitosan paste. In vitro evaluations were carried out by using dissolution testing apparatus U.S.P (XXI). The dissolution pattern indicated the role of chitosan in sustained release. Bioavailability studies in male beagle dogs clearly showed the sustained nature of release from chitosan based ibuprofen tablet as compared to conventional ibuprofen marketed formulation. Potential use of chitosan as a new matrix forming material for sustained release preparation has been examined. Chitosan, a natural polysaccharide, has structural characteristics similar to glycosamino glycons. Chitosan has been shown to be non-toxic and biodegradable. It is inexpensive and has been explored in the present investigation as a release retarding agent in ibuprofen tablets.     

Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Analysis in Dogs

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.     

Formulation and in vitro, in vivo evaluation of extended- release matrix tablet of Zidovudine: Influence of combination of hydrophilic and hydrophobic matrix formers

The aim of the present study was to prepare and characterize extended-release matrix tablets of zidovudine using hydrophilic Eudragit RLPO and RSPO alone or their combination with hydrophobic ethyl cellulose. Release kinetics was evaluated by using United States Pharmacopeia (USP)-22 type I dissolution apparatus. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. Furthermore, the in vitro and in vivo newly formulated sustained-release zidovudine tablets were compared with conventional marketed tablet (Zidovir, Cipla Ltd, Mumbai, India). The in-vitro drug release study revealed that either Eudragit preparation was able to sustain the drug release only for 6 hours (94.3%±4.5% release). Combining Eudragit with ethyl cellulose sustained the drug release for 12 hours (88.1%±4.1% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. In vivo investigation in rabbits showed sustained-release pharmacokinetic profile of zidovudine from the matrix tablets formulated using combination of Eudragits and ethylcellulose. In conclusion, the results suggest that the developed sustained-release tablets of zidovudine could perform therapeutically better than conventional dosage forms, leading to improve efficacy and better patient compliance. Published: January 3, 2006     

Formulation, Release Characteristics and Bioavailability Study of Oral Monolithic Matrix Tablets Containing Carbamazepine

This study examined the release of carbamazepine (CBZ) from hydrophobic (Compritol 888 ATO) and hydrophilic-hydrophobic matrix combination (Compritol 888 ATO-hydroxpropyl methylcellulose, HPMC). Hydrophobic matrix tablets were prepared by hot fusion technique, while hydrophilic-hydrophobic matrix tablets were prepared by wet granulation technique. The properties of the compressed matrix tablets were determined according to the US Pharmacopoeia. Both matrix formulations displayed a controlled-release profile when compared to the reference formulation (Tegretol CR 200). The bioavailability of CBZ formulations and Tegretol CR 200 were evaluated in beagle dogs. Carbamazepine presented a significant higher bioavailability from matrix tablets containing hydrophilic polymer (HPMC) than that obtained from Tegretol CR200. The average inter-subject plasma concentration variability CV% was the least with tablet containing hydrophilic polymer (HPMC) and was the highest with Tegretol CR 200 (33.8 and 54.1, respectively). Analysis of variance applied to log AUC(0-alpha) and log C(max) showed statistical significant differences among the three formulations (P < 0.05). Plotting the fraction of CBZ released in vitro and fraction absorbed showed a statistically significant relationship (R(2) = 0.935-0.975) for the three matrix tablets examined.     

In vitro and in vivo evaluation of guar gum matrix tablets for oral controlled release of water-soluble diltiazem hydrochloride

The objective of the study was to develop guar gum matrix tablets for oral controlled release of water-soluble diltiazem hydrochloride. Matrix tablets of diltiazem hydrochloride, using various viscosity grades of guar gum in 2 proportions, were prepared by wet granulation method and subjected to in vitro drug release studies. Diltiazem hydrochloride matrix tablets containing either 30% wt/wt lowviscosity (LM1), 40% wt/wt medium-viscosity (MM2), or 50% wt/wt high-viscosity (HM2) guar gum showed controlled release. The drug release from all guar gum matrix tablets followed first-order kinetics via Fickian-diffusion. Further, the results of in vitro drug release studies in simulated gastrointestinal and colonic fluids showed that HM2 tablets provided controlled release comparable with marketed sustained release diltiazem hydrochloride tablets (D-SR tablets). Guar gum matrix tablets HM2 showed no change in physical appearance, drug content, or in dissolution pattern after storage at 40°C/relative humidity 75% for 6 months. When subjectd to in vivo pharmacokinetic evaluation in healthy volunteers, the HM2 tablets provided a slow and prolonged drug release when compared with D-SR tablets. Based on the results of in vitro and in vivo studies it was concluded that that guar gum matrix tablets provided oral controlled release of water-soluble diltiazem hydrochloride. Published: June 30, 2005