Double-layered osmotic pump controlled release tablets of actarit: In vitro and in vivo evaluation

The aim of the study was to develop actarit double-layered osmotic pump tablets to overcome the weak points of actarit common tablets, such as short half-life and large plasma concentration fluctuations. Single factor experiment and orthogonal test were applied to optimize the formulation;the pharmacokinetic study was performed in beagle dogs adopting actarit common tablets as reference tablets. The optimal formulation was as follows: drug layer: 150 mg actarit, 240 mg PEO-N80, 50 mg NaCl;push layer: 140 mg PEO-WSR303, 20 mg NaCl;coating solution: 30 g cellulose acetate and 6 g PEG 4000 in 1000 ml 94% acetone solution, 60 mg coating weight gain. The pharmacokinetic study showed that T max was prolonged by the contrast of commercial common tablets with constant drug release rate, but the bioavailability was equivalent. And a good in vivo –in vitro correlation of the actarit osmotic pump tablets was also established. The designed actarit osmotic pump tablets can be applied for rheumatoid arthritis, proposing a promising replacement for the marked common products.

Sustained release donepezil loaded PLGA microspheres for injection:Preparation,in vitro and in vivo study

The purpose of this study was to develop a PLGA microspheres-based donepezil(DP)formulation which was expected to sustain release of DP for one week with high encapsulation efficiency(EE).DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method.The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size,morphology,drug loading and EE,physical state of DP in the matrix and in vitro and in vivo release behavior.DP microspheres were prepared successfully with average diameter of 30m,drug loading of 15.92±0.31%and EE up to 78.79±2.56%.Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres.The Tg of PLGA was increased with the addition of DP.The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model,which suggested the diffusion governing release mechanism.After single-dose administration of DP microspheres via subcutaneous injection in rats,the plasma concentration of DP reached peak concentration at 0.50 d,and then declined gradually,but was still detectable at 15 d.A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer’s disease over long periods.

Systematically optimized topical delivery system for Loperamide hydrochloride: Formulation design,in vitro and in vivo biopharmaceutical evaluation

This study aimed to develop a suitable topical delivery system containing diethylene glycol monoethyl ether(DGME) for Loperamide hydrochloride(Lop). Two factors, three levels CentralComposite design were applied by generating a quadratic polynomial equation to form contour plots and response surface for prediction of responses as two selected independent variables with EtOH-DGME ratio and EtOH concentration. The response variables flux and skin retention were determined in in vitro hairless mouse skin model. The selected optimum formulation was evaluated for the skin transport characteristics by developing dermatokinetic analysis model and the results demonstrated DGME improved the delivery of Lop into skin deep layers, which was further confirmed by confocal laser scanning microscopy(CLSM)study. In vitro skin permeation was found to have triphasic correlation with plasma AUC in the in vivo pharmacokinetic study. The in vitro–in vivo correlation enabled the prediction of pharmacokinetic profile of Lop from in vitro permeation results. Therefore, the optimum formulation capable of enhancing Lop intracutaneous depot could be a candidate for topical delivery of Lop as analgesics.

The enhancing effect and promoting mechanisms of the stereoisomeric monoterpene alcohol esters as enhancers for drugs with different physicochemical properties

To explore the structure-activity connections of amphiphilic permeation enhancers containing the length of the hydrophobic chains as well as the properties of the polar head,O-acylgeraniol and O-acylnerol derivatives were synthesized from geraniol/nerol(cis-isomer of geraniol) and pharmaceutical excipient acids in this research. Their promotion of the percutaneous absorption of three drugs as the model, flurbiprofen(FP), isosorbide dinitrate(ISDN) and donepezil(DNP), which were selected based on their physicochemical properties,was tested by in vitro skin penetration and in vivo. Molecular simulation, ATR-FTIR, CLSM and histological observation were implement to evaluate the mode of action of the enhancers.The results indicated that(E)-3,7-dimethyl-2,6-octadien-1-yl tetradecanoate(GER-C14, trans-)achieved the highest enhancement ability for the three drugs;additionally, the in vivo results obtained were in good correlation with the in vitro data. Molecular docking results suggested that enhancers loosen the hydrogen bonds between ceramides, and the results of molecular simulation indicated that GER-C14, NER-C14 could insert into the middle of the lipid bilayer to form an independent phase. According to ATR-FTIR and histological evaluation, the enhancers extracted lipids and influenced the protein region, thereby disturbing the skin array. In addition, CLSM described the dynamic effects of enhancers on lipids between stratum corneum(SC) cells. In conclusion, GER-C14 had a better penetration promotion effect, which broadened our understanding of stereoisomeric penetration enhancers.

Pharmacokinetics and correlation between in vitro release and in vivo absorption of bio-adhesive pellets of panax notoginseng saponins

The present study was designed to prepare and compare bio-adhesive pellets of panax notoginseng saponins(PNS) with hydroxy propyl methyl cellulose(HPMC), chitosan, and chitosan : carbomer, explore the influence of different bio-adhesive materials on pharmacokinetics behaviors of PNSbio-adhesive pellets, and evaluate the correlation between in vivo absorption and in vitro release(IVIVC). In order to predict the in vivo concentration-time profile by the in vitro release data of bio-adhesive pellets, the release experiment was performed using the rotating basket method in p H 6.8 phosphate buffer. The PNS concentrations in rat plasma were analyzed by HPLC-MS-MS method and the relative bioavailability and other pharmacokinetic parameters were estimated using Kinetica4.4 pharmacokinetic software. Numerical deconvolution method was used to evaluate IVIVC. Our results indicated that, compared with ordinary pellets, PNS bio-adhesive pellets showed increased oral bioavailability by 1.45 to 3.20 times, increased Cmax, and extended MRT. What's more, the release behavior of drug in HPMC pellets was shown to follow a Fickian diffusion mechanism, a synergetic function of diffusion and skeleton corrosion. The in vitro release and the in vivo biological activity had a good correlation, demonstrating that the PNS bio-adhesive pellets had a better sustained release. Numerical deconvolution technique showed the advantage in evaluation of IVIVC for self-designed bio-adhesive pellets with HPMC. In conclusion, the in vitro release data of bio-adhesive pellets with HPMC can predict its concentration-time profile in vivo.

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations(LBFs)have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs.However,construction of in vitro and in vivo correlations(IVIVCs)for LBFs is quite challenging,owing to a complex in vivo processing of these formulations.In this paper,we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption;based on the concept of IVIVCs,the current status of in vitro models to establish IVIVCs for LBFs is reviewed,while future perspectives in this field are discussed.In vitro tests,which facilitate the understanding and prediction of the in vivo performance of solid dosage forms,frequently fail to mimic the in vivo processing of LBFs,leading to inconsistent results.In vitro digestion models,which more closely simulate gastrointestinal physiology,are a more promising option.Despite some successes in IVIVC modeling,the accuracy and consistency of these models are yet to be validated,particularly for human data.A reliable IVIVC model can not only reduce the risk,time,and cost of formulation development but can also contribute to the formulation design and optimization,thus promoting the clinical translation of LBFs.

盐酸安非他酮/氢溴酸右美沙芬混悬液处方优化、制备及体内外评价

目的制备盐酸安非他酮(BH)/氢溴酸右美沙芬(DMH)复方混悬液,并进行处方优化和体内外评价。方法以沉降体积比、再分散性、混悬体系黏度等为评价指标,单因素考察助悬剂、润湿剂及其各自用量,并通过含量、释放度、药物泄漏量和稳定性试验对制备的混悬液进行了体外评价,此外还进行了体内药动学评估。结果优化处方为:西黄蓍胶0.5%、黄原胶0.2%、高果糖玉米糖浆HFCS F4231%、吐温801%。稳定性试验结果表明,优化后的复方混悬液在高温、强光及加速6个月后表现出较好的稳定性(F>0.9,BH药物含量为98%~100%,DMH药物含量为96%~98%,释放度f2均>50,药物泄漏量均<0.3%)。大鼠灌胃的药动学结果显示,相比较于市售片剂,混悬液中BH的Cmax更低,tmax更长;DMH的t1/2更长和Cmax更高,相对生物利用度分别为116.53%和252.25%。且BH和DMH体内吸收与体外释药具备简单的相对关联性。结论本研究开发的BH/DMH复方混悬液,稳定性和生物等效性较好,证明通过离子交换树脂技术制备BH/DMH复方混悬液具有较好的可行性。

黄体酮混悬注射剂药动学及体内外相关性研究

探讨黄体酮混悬注射剂体外释放、体内药动学以及体内外相关性,以自制黄体酮混悬注射液为例,采用桨法和透析袋法测定3种不同粒径(3、5、7μm)的黄体酮混悬注射剂的体外释放曲线;以SD大鼠为实验动物,研究3种粒径黄体酮混悬注射剂的体内药动学,并将血药浓度-时间曲线经Wagner-Nelson法处理后得到体内累积吸收曲线,与透析袋法所得体外累积释放曲线建立体内外相关性。结果表明,黄体酮混悬注射液采用桨法测定体外释放度时,20 min内均迅速释放85%以上,而采用透析袋法测定时分别在40、84、120 h达85%累积释放度。透析袋法所得体外释放趋势与体内释药趋势基本一致,相关系数大于0.95,具有较强的体内外相关性。本研究为长效混悬注射剂体内外相关性的建立提供参考。

咖啡酸的生物药剂学分类系统及其大鼠体内外相关性预测

目的测定咖啡酸在不同pH环境中的平衡溶解度以及油水分配系数,推测其生物药剂学分类系统(BCS)分类;测定咖啡酸片溶出曲线,将相关参数代入大鼠生理药动学(PBPK)模型建模,利用Gastroplus软件预测其大鼠体内外相关性。方法采用高效液相色谱法定量,色谱柱Agilent Eclipse Plus C_(18)(4.6 mm×250 mm,5μm),流动相0.32%冰醋酸溶液-甲醇(70∶30),流速1.0 mL·min^(-1),检测波长323 nm,柱温25℃,进样体积10μL。采用摇瓶法和正辛醇-水体系测量咖啡酸在不同pH环境中的平衡溶解度、溶解度体积(DSV)和油水分配系数(P),推测其BCS分类;测定咖啡酸片在水、pH值1.2、pH值4.5和pH值6.8环境中溶出曲线,利用Gastroplus软件分析溶出曲线的Z-Factor值,将相关参数代入大鼠的PBPK模型,模拟大鼠体内药时(PK)曲线,与已知实测PK曲线进行比较,推测其大鼠体内外相关性。结果咖啡酸在pH值1.2、pH值4.5和pH值6.8环境中平衡溶解度为0.676、1.266和4.624 mg·L-1,DSV为443787、236967和64879 mL,为难溶性药物,且具有较强pH依赖性;咖啡酸在水、pH值1.2、pH值4.5和pH值6.8环境中油水分配系数(P)为4.33(logP=0.64)、28.87(logP=1.46)、19.77(logP=1.30)、0.28(logP=-0.56),推测其具有较高渗透性。软件模拟得到咖啡酸大鼠体内的C_(max)为0.358μg·mL^(-1),t_(max)为0.39 h,AUC为0.320μg·h^(-1)·mL^(-1),与已知的实测结果C_(max)为(0.250±0.037)μg·mL^(-1)、t_(max)为(0.33±0.12)h、AUC为(0.303±0.024)μg·h^(-1)·mL^(-1)一致,PK曲线基本吻合。结论咖啡酸为低溶解性、高渗透性的药物,推测其为BCS II类药物,其片剂在大鼠中表现出较高的体内外相关性。

双醋瑞因胶囊溶出曲线的建立及体内外相关性研究

参考印度药典及进口注册标准中双醋瑞因胶囊的溶出度方法,建立了双醋瑞因胶囊具有区分力的溶出曲线测定法,并对此测定方法的区分力进行考察及方法学验证,最终用其评价自制双醋瑞因胶囊与参比制剂溶出曲线的相似性,同时通过体内生物等效性研究结合体外溶出试验结果分析体外溶出和体内吸收的相关性。结果显示,筛选得到的具有区分力的溶出方法可以用于区分不同处方工艺双醋瑞因胶囊的质量差异,且其方法学验证结果均符合规定,自制双醋瑞因胶囊和参比制剂在各介质中均具有相似的溶出特性,在体内具有生物等效性,提示该溶出曲线具有一定的体内外相关性。本研究为双醋瑞因胶囊的一致性评价提供了试验依据。

补骨脂素中空黏附微球胃滞留特性及体内外相关性研究

目的评价所制备的补骨脂素胃滞留中空黏附微球体内外胃滞留特性并探索其在大鼠体内外吸收相关性。方法通过乳化溶剂挥发法制备中空黏附微球,并对其胃内漂浮性、粘附性、滞留率和胃组织内药物浓度进行研究,通过测定不同时间药物体外溶出度和大鼠体内药物血药浓度得到中空黏附微球体外释放百分率和体内吸收百分数,采用Wagner-Nelson法对体内外吸收相关性进行分析。结果补骨脂素中空黏附微球胃内滞留率和胃内滞留药物浓度在2 h、4 h和6 h分别为78.7%±4.2%/13.95±4.92μg·mL^(-1),77%±10.41%/8.83±1.6μg·mL^(-1)和8.3%±18.9%/2.85±2.67μg·mL^(-1),胃腔平均通过时间(MPT)为5.66±0.55 h,体外释放平均驻留时间(MRT)为(4.36±0.35)h,体内吸收平均驻留时间(MRT)为(9.06±1.25)h;体内吸收百分数和体外释放百分率相关性分析得到两者相关系数R为0.9471,表明补骨脂素中空粘附微球体内外吸收相关性良好。结论中空黏附微球制剂体外漂浮性、粘附性,胃内滞留药物浓度结果显示其具有显著的胃滞留特性,而且体内外吸收相关性良好,体外释放数据能够预测大鼠体内的药动学行为。

米拉贝隆缓释片的体内外相关性溶出方法研究

目的利用流通池模拟难溶性药物米拉贝隆缓释制剂的溶出,建立米拉贝隆体内和体外的相关性(IVIVC)模型,开发具有预测能力的体外溶出方法。方法经Loo-Riegelman法对三种不同释放速率制剂的体内血药浓度进行反卷积分获得相应的累积吸收百分数(Fabs%),建立体外溶出目标曲线。以纯水为试验介质,流速4.0 mL·min^(-1)的试验条件下进行制剂R(贝坦利^(■),50 mg)和制剂T1、T2(50 mg)的溶出试验,通过高效液相色谱法测定溶出度,梯形面积法获得制剂的累积溶出百分数(F_(diss)%)。结果建立了米拉贝隆缓释制剂体内累积吸收与体外溶出度之间的A级IVIVC(回归系数大于0.9),制剂的外部预测误差在规定范围内。结论本研究建立的米拉贝隆缓释制剂IVIVC模型经验证具有较好的预测能力,该方法拥有的良好区分力及线性模型也可以为质量控制提供参考。

富马酸喹硫平缓释片的体内外相关性溶出方法研究

目的通过流通池法模拟富马酸喹硫平缓释制剂的体内动力学过程,建立具有体内外相关性的溶出方法,并进行体内外相关性模型预测能力的评估。方法采用HPLC-MS/MS法测得T1、T2和R制剂的血药浓度数据,通过WinNonlin软件的非房室模型和反卷积模块解析参比制剂的体内特征,依据参比制剂的体内特征指导溶出方法的设计,用3种释放速率不同的制剂的体内和体外数据建立体内外相关性模型,并进行模型预测能力验证。结果建立了具有A级相关性(R^(2)=0.967)和C级相关性(R^(2)=0.996)的溶出方法,内部制剂预测和外部制剂预测的预测误差PE%<10%,符合标准。结论本方法具有良好的体内外相关性,其体内外相关性模型经验证预测误差符合标准,对于吸收速率不同的制剂均具有良好的区分力,可以为富马酸喹硫平缓释片的制剂评价提供参考。

水飞蓟素磷脂复合物微孔渗透泵控释片比格犬体内药动学及体内外相关性研究

目的 评价水飞蓟素磷脂复合物微孔渗透泵(SM-PC MPOP)控释片的体外释药特性、比格犬体内药动学及其体内外相关性。方法 释放介质为pH7.5的磷酸盐缓冲液(添加0.5%十二烷基硫酸钠),以高效液相色谱法(HPLC)检测SM-PC MPOP的体外释放特征。用6只比格犬进行双周期交叉对照实验,按照30 mg/kg的剂量给药。HPLC法测定比格犬血浆内水飞蓟素的主要成分水飞蓟宾的质量浓度,应用药动学软件进行数据分析。结果 SM-PC MPOP在12 h累积释放度超过85%。药动学研究情况表明,受试制剂(SM-PC MPOP)和参比制剂(市售水飞蓟素胶囊)在比格犬体内的主要药动学参数:T_(max)分别为(3.2±0.4)、(0.9±0.1)h,C_(max)分别为(0.298 6±0.068 9)、(0.629 9±0.076 5)μg/ml,AUC_(0→24)分别为(2.996 8±0.583 3)、(2.268 9±0.432 8) h·μg/ml,SM-PC-MPOP对市售水飞蓟素胶囊的相对生物利用度为(162.21±30.82)%。结论 自制的SM-PC MPOP实现了缓慢释药且增加生物利用度的目标,其体内吸收与体外释药具备相对较好的关联性(r=0.839 0)。

脱卷积法进行自制尼群地平缓释制剂体内外相关性研究

目的 用脱卷积法进行自制尼群地平缓释制剂体内外相关性的研究。方法 以自制尼群地平口服溶液剂的犬体内血药浓度数据为权函数,根据3种自制尼群地平缓释制剂试验犬体内血药浓度数据,采用脱卷积法计算体内释药特性,与相应的体外释药特性进行比较,考察体内外相关性。结果 用脱卷积法计算3种尼群地平缓释制剂的体内外释药相关性良好。结论 脱卷积法适用于自制尼群地平缓释制剂的体内外相关性研究。

硝苯地平骨架缓释微丸的制备及在家犬体内的药物动力学

目的制备硝苯地平骨架缓释微丸；考察其在家犬体内的药物动力学及相对生物利用度；建立准确、可靠的HPLC方法用以测定硝苯地平血浆样品质量浓度。方法以聚乙二醇4000为载体材料，利用固体分散技术，采用挤出-滚圆法制备硝苯地平24h骨架缓释微丸；采用HPLC法对家犬体内血药质量浓度进行分析；利用统计矩的非隔室动力学理论计算药物动力学参数；采用差示扫描量热法推断药物的可能存在形式。结果药物可能以无定型形式存在于固体分散体中；在实验所选定的色谱条件下，硝苯地平质量浓度在5．0～200．0ug·L^-1内线性关系良好（r=0．9997），准确度、精密度及回收率均符合要求；自制缓释微丸与参比制剂的主要药物动力学参数分别为：tmax（5．0±1．1）、（5．7±0．8）h；Pmax（29.9±7．3）、（33．8±6．4）ug·L^-1；AUC0-t（311．3±71．1）、（308．6±70．1）ug·h·L^-1；相对生物利用度为（102．1±18．4）％；体内外相关性良好（r=0．9368）。结论自制硝苯地平骨架缓释微丸与参比制剂生物等效。

灯盏花素固体分散体缓释胶囊的制备及犬体内外相关性研究

以乙基纤维素为载体,制备难溶性药物灯盏花素(1)的固体分散体。粉碎后制成1含量为60mg的胶囊,考察其体外释放度和犬体内吸收情况。用HPLC测定血药浓度,并进行体内外相关性研究。结果表明,胶囊的体外释药行为用Higuchi方程拟合较好,在犬体内有明显的缓释效果,体内外相关系数为0.9808。

克拉霉素缓释胶囊释放度与体内吸收度相关性的研究

目的:研究两种释药机理的克拉霉素缓释胶囊试验制剂体内-体外相关性,建立与体内吸收相关的释放度测定法。方法:在不同pH介质中测定克拉霉素缓释胶囊的体外释放度。采用LC-MS-MS测定健康志愿者单剂量交叉口服250 mg克拉霉素胶囊(F-1和F-2)后血药浓度,以Wagner-Nelson法计算药物的体内吸收百分数。以体外释放百分率对体内吸收百分数在相应的时间点进行相关性分析。结果:表明缓释胶囊F-1在pH5.0介质中释放百分率与体内吸收百分数相关,相关系数为0.9984,缓释胶囊F-2在pH 6.0介质中释放百分率与体内吸收百分数相关,相关系数为0.9939.结论:经相关性检验,两种克拉霉素缓释胶囊的体外释放与体内吸收为水平A相关。F-1在体内的吸收程度高于F-2,为F-1的处方筛选提供了理论依据。

石杉碱甲缓释微球的体外释放度及其体内外相关性研究

目的建立体内外相关性良好的石杉碱甲缓释微球的体外释放度测定方法。方法采用直接释药法和透析释药法测定石杉碱甲缓释微球的体外释放度,考察加入吐温的量和透析袋内递质的体积对释药速度的影响;采用高效液相色谱法测定石杉碱甲缓释微球在大鼠注射部位的残留量,计算微球在体内的释药速度。通过相关性评价确定最佳的体外释放度测定方法。结果透析释药法可获得良好的体内外相关性(r=0.990 2)。结论透析释药法可用于测定石杉碱甲缓释微球的体外释放度。

布洛芬缓释微丸的制备及其药物动力学研究

采用膜控法制备布洛芬缓释微丸,应用转篮法(50r/min,37±1℃)比较了缓释微丸和普通片剂的体外药物溶出速率,采用HPLC法测定了制剂的血药浓度,并研究了制剂在人体内的药物动力学。缓释微丸的体外药物溶出符合一级动力学过程(K_r=0.4505h^(-1));体内动力学过程符合一级吸收和一级消除的单室模型,k_a=0.27h^(-1),K=0.27h^(-1),V_d=7.54L,t_(max)=3.97h,C_(max)=19.52μg/ml。多剂量给药血药浓度测定及计算表明:缓释微丸具有维持有效血药浓度(8.5μg/ml)时间长,血药浓度波动范围小的特点。此外,缓释微丸的体内外数据具有显著的相关性(p<0.01)。