Evaluation of pharmacokinetics and pharmacodynamics relationships for Salvianolic Acid B micro-porous osmotic pump pellets in angina pectoris rabbit

The work aims to investigate the in vitro release,pharmacokinetics(PK),pharmacodynamics(PD)and PK-PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets(SalB-MPOPs)in angina pectoris New Zealand White(NZW)rabbits,compared with those of SalB immediate-release pellets(SalB-IRPs).The SalB plasma concentrations and Superoxide dismutase levels(PD index)were recorded continuously at predetermined time interval after administration,and the related parameters were calculated by using Win-Nonlin software.The release profile of MPOPs was more sustained than that of IRPs.PK results indicated that the mean C_(max) was significantly lower,the SalB plasma concentrations were steadier,both area under concentration-time curve from 0 to 24 h(AUC_(0-24 h))and from 0 to infinity(AUC_(0-∞))were presented larger,and both the peak concentration time(T_(max))and mean residence time(MRT)were prolonged for MPOPs,as compared with those of IRPs.PD results suggested that peak drug effect(E_(max))was lower and the equilibration rate constant(k_(e0))between the central compartment and the effect compartment was higher of MPOPs vs.those of IRPs.PKePD relationships demonstrated that the effectconcentration-time(ECT)course of MPOPs was clockwise hysteresis loop,and that of IRPs was counter-clockwise hysteresis loop.Collectively,those results demonstrated that MPOPs were potential formulations in treating angina pectoris induced by atherosclerosis.

Preparation of controlled porosity osmotic pump tablets for salvianolic acid and optimization of the formulation using an artificial neural network method

In this paper controlled porosity osmotic pump tablets(CPOPT)for salvianolic acid(SA)were prepared and optimized with experimental design methods including an artificial neutral network(ANN)method.Three causal factors,i.e.,drug,osmotic pressure promoting agent rate,PEG400 content in coating solution and coating weight,were evaluated based on their effects on drug release rate.The linear correlation coefficient of the accumulative amount of drug release and the time of 12 h,r(Y_(1)),and the sum of the absolute value between measured and projected values,Y_(2),were used as outputs to optimize the formulation.The weight expression Y=(1-Y_(1))^(2)+Y_(2)^(2) was used in the calculation.Furthermore,the ANN and uniform design gave similar optimization results,but ANN projected the outputs better than the uniform design.This paper showed that the release rate of salvianolic acid B and that of the total salvianolic acid was consistent in the optimized formulation.

Redefinition to bilayer osmotic pump tablets as subterranean river system within mini-earth via three-dimensional structure mechanism

Defining and visualizing the three-dimensional(3 D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3 D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography(SR-μCT). In situ formed 3 D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3 D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral“roadways”. Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed3 D microstructures, a “subterranean river model” for the drug release mechanism has been defined to explain the drug release mechanism.

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.

Lappaconitine solid dispersion monolithic osmotic tablet and lappaconitine push-pull osmotic pump: preparation and comparison of their release performance in vitro

Lappaconitine is a water-insoluble drug, which was used as model drug in this study. Currently, two osmotically controlled delivery systems that are widely used for water-insoluble drug are monolithic osmotic tablet （MOT） and push-pull osmotic pump （PPOP）. In the present study, lappaconitine solid dispersion monolithic osmotic tablet （lappaconitine-SD-MOT） and lappaconitine-PPOP were developed. The prepared lappaconitine-PPOP was able to delivery drug at the rate of approximate zero-order （r = 0.9931）, and the cumulative release was above 95.0%. The lappaconitine-SD-MOT showed a comparatively poor linearity when the data were plotted according to the zero-order equation （r = 0.9798）, and the cumulative release was 84.69%. Lappaconitine-PPOP exhibited better controlled drug release （higher regression value） compared with lappaconitine-SD-MOT. The similarity index （f2） between lappaconitine-PPOP and lappaconitine-SD-MOT was 49.1 （〈50）. A clear difference of drug release characteristics between the lappaconitine-SD-MOT and lappaconitine-PPOP was revealed. It indicated that the drug release performance of lappaconitine-PPOP could gain favorable zero-order kinetics and higher cumulative release compared with lappaconitine-SD-MOT. Therefore, these results suggested that PPOP was still a very effective device for the delivery of poorly water-soluble drug with zero-order pattern.

The clinical pharmacokinetics of osmotic pump controlled release tablets of terazosin hydrochloride in healthy volunteers

The clinical pharmacokinetics of osmotic pump controlled release tablets of terazosin hydrochloride in healthy volunteers was studied.A sensitive and rapid HPLC method was used to determine the terazosin plasma concentrations,and single and multiple doses of terazosin hydrochloride regular tablets（reference tablets）and osmotic pump controlled release tablets were orally administrated in randomized crossover design.The results showed that the C_（max）of the reference tablets after single oral dose（（120.56±23.15）ng/mL）in 20 healthy volunteers was significantly higher than that of controlled release tablets （（95.27±16.35）ng/mL）.The T_（max）of the controlled release tablets（（2.65±0.82）h）was significantly longer than that of reference tablets（（1.27±0.61）h）（P0.05）.The relative bioavailability of the controlled release tablets was found to be（105.85±6.12）%. The multiple oral dose pharmacokinetic parameters of the regular tablets and controlled release tablets were as follows：AUC_（SS） were（1275.17±175.35）and（1382.65±205.31）ng·h/mL respectively,C_（max）were（128.15±22.37）and（98.57±18.16）ng/mL respectively,T_（max）were（1.35±0.71）and（2.76±0.85）h respectively,C_（av）were（53.13±9.12）and（57.61±9.25）ng/mL respectively, and DF were（2.25±0.26）%and（1.62±0.25）%respectively.The relative bioavailability of the controlled release tablets to the reference tablets was（108.43±6.26）%.The controlled release tablet of terazosin hydrochloride was bioequivalent to the reference tablet.The controlled release tablet exhibited a sustained-release property with a significantly longer T_（max）and lower C_（max）.

盐酸吗啡渗透泵片片芯促渗剂研究

目的探讨盐酸吗啡渗透泵片片芯促渗剂的选择。方法以体外释药行为为指标‚采用单因素考察法对渗透压活性物质、崩解剂、高分子聚合物的种类与用量进行考察,并根据优化结果进行验证试验。结果盐酸吗啡渗透泵片片芯处方中渗透压活性物质为60%乳糖,不加崩解剂,不加高分子聚合物,符合该品缓释规律。按处方工艺制备3批半透膜包衣片,其释放曲线良好,加速稳定性试验条件下体外累积释放度未发生显著变化。结论盐酸吗啡渗透泵片片芯促渗剂选择60%乳糖‚20 h时体外累积释放度达85%以上,产品质量稳定。

致孔剂及其用量对盐酸吗啡渗透泵片体外释放度的影响

目的比较不同致孔剂及其用量对盐酸吗啡渗透泵片体外释放度的影响。方法采用湿法制粒制备片芯,半透膜包衣,比较半透膜层中不同致孔剂及其用量对盐酸吗啡渗透泵片体外释放度的影响。结果不同致孔剂对盐酸吗啡渗透泵片的溶出均有促进作用,盐酸吗啡渗透泵片体外释放度随致孔剂用量的增加而增加,相同用量的致孔剂对盐酸吗啡渗透泵片体外释放度的影响从大至小依次为聚乙二醇6000>聚乙二醇4000>聚乙二醇400>聚乙烯吡咯烷酮K30>羟丙基纤维素。结论不同致孔剂及其用量对盐酸吗啡渗透泵片释放度的影响有较大差异。该研究中以聚乙二醇400为优选致孔剂,释放效果较好,重复性良好。

山奈酚微孔渗透泵片的制备工艺研究

目的设计并制备山奈酚微孔渗透泵片。方法以乳糖和氯化钠作为促渗剂,邻苯二甲酸二乙酯、醋酸纤维素为成膜材料,聚乙二醇PEG400为致孔剂,制备了山奈酚微孔渗透泵片剂。并通过单因素考察实验,以药物释放度为指标筛选优化处方。结果片芯中氯化钠用量为15.0%、乳糖为30.0%、包衣增重为片芯的4.0%,致孔剂PEG400用量为40.0%时药物释放度最优,且12h累积释放率达到85%以上。结论该山奈酚微孔渗透泵片制备处方工艺简单、重现性好,制得的山奈酚微孔渗透泵片能够达到预期的控释效果。

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)。

硝苯地平控释片制备及其体内研究

目的:研究一种新型的硝苯地平控释片的处方工艺,使用聚羧甲基淀粉钠作为膨胀材料,聚维酮与共聚维酮作为载药材料,制备双层渗透泵型控释片,并进行工艺放大及体内等效性研究。方法:采用单因素控制变量法逐一考察可能影响硝苯地平控释片的溶出曲线的因素,如膨胀剂种类、推进层中羧甲基淀粉钠和共聚维酮用量、半渗透膜包衣增重、激光打孔孔径等,优选所得处方进行工艺放大及体内等效性研究。结果:羧甲基淀粉钠作为膨胀材料,聚维酮与共聚维酮作为载药材料,卡波姆作为缓释材料;处方所制得样品相似因子(f_(2)值)大于50,溶出曲线与参比制剂相似;工艺放大结果表明,自研控释片工艺重现性好,f_(2)值均大于50,适合大规模生产;体内等效性研究表明,C_(max)、AUC_(0-t)和AUC_(0-∞)受试制剂与参比制剂几何均数比值及其90%置信区间分别为107.58%(95.20%,121.57%)、99.33%(86.27%,114.35%)、99.43%(87.89%,112.49%),在可接受范围内。结论:自研硝苯地平控释片处方合理,制备工艺可行,自制制剂与参比制剂具有生物等效性。

泡腾技术在药物制剂中的研究进展

泡腾技术作为加快制剂崩解,促进药物溶出的技术,常用于速释制剂中,随着相关技术与理论研究深入,泡腾技术越来越广泛应用于缓控释制剂和脉冲释药系统中,调节释药制剂行为。作者主要介绍了泡腾技术在泡腾片、胃漂浮制剂、渗透泵片和脉冲释药系统中研究应用,以及泡腾制剂共性关键技术研究进展,有利于泡腾制剂研究与开发。

槲皮素包合物微孔渗透泵片制备工艺

目的制备槲皮素环糊精包合物单层渗透泵片。方法以体外累积释放度作为评价指标,采用单因素考察确定最优处方。结果渗透泵片片芯处方中乳糖用量、Na Cl用量和PEO用量以及包衣膜处方中包衣增重和致孔剂PEG4000用量对释药行为有较大影响,优化后的槲皮素渗透泵片在12 h内呈现良好的零级释放(r=0.995 7),药物累积释放比较完全(>90%)。结论以环糊精包合物为中间体,可以制备成12 h内零级释药特征明显的单层渗透泵片。

格列吡嗪双层渗透泵控释片的制备及体外释放度考察

目的对格列吡嗪双层渗透泵的处方与工艺进行研究。方法以自制片与进口片体外释药数据 ( 2～ 1 6h)的相似因子作为评价指标 ,采用正交设计优化出格列吡嗪双层渗透泵控释片的处方。结果所得优化处方为 :氯化钠 ,1 8mg;助推层聚氧化乙烯 ,4 9mg;羟丙甲基纤维素 ,2 5mg;半透膜重量 ,2 8mg。优化处方的三批样品在 2～ 1 6h内均呈现零级释放特征 (r =0 9989) ,平均释药量为0 2 8mg/h ,与进口片相比具有良好的相似性 (f2 =70 2 )。结论自制片与进口片体外释药行为相似 ,可进一步进行体内释药行为的考察。

均匀设计法制备苦参碱渗透泵型控释片

目的制备苦参碱渗透泵型控释片,同时建立一种新的设计初级渗透泵处方的方法。方法利用均匀设计法得到释放速率与各处方因素间的定量关系,通过回归方程预测合适的处方。结果回归方程的显著性和精度较好,以其为依据制备了苦参碱控释片。结论对于初级渗透泵的处方设计,均匀设计法是可行的方法。

单层芯渗透泵片用于水不溶性药物的控制释放

Aim To study unitary-core osmotic pump tablet for delivering water-insoluble drug for 24 hours. Methods Unitary-core osmotic pump tablet was prepared using nifedipine as the model drug. The effects of various core formulation variables on drug release were studied. Results Polyethylene oxide and potassium chloride have comparable positive effects on drug release, whereas, nifedipine has markedly negative effect on drug release. Conclusion Unitary-core osmotic pump tablet is very easy in preparation and it can deliver water-insoluble drug in substantially constant rate for 24 hours.

阿替洛尔单层芯渗透泵片的制备

目的以阿替洛尔为模型药物研究单层芯渗透泵片简化的制备方法,并进行处方优化.方法用自行设计的带针冲头压制带孔单层片芯,以乙基纤维素为膜材包衣制备渗透泵片,采用相似因子为指标筛选处方.结果单层芯渗透泵片的片芯处方、包衣膜组成及厚度是影响释药的主要因素.在1.00～1.14 mm,片芯孔径对释药影响不大.结论本制备方法可免去激光打孔过程,制得的阿替洛尔单层芯渗透泵片能24 h匀速释药.

盐酸沙格雷酯渗透泵控释片的研制

目的:制备盐酸沙格雷酯渗透泵控释片。方法:采用单冲压片工艺,醋酸纤维素为包衣材料,制备渗透泵片,考察不同的渗透促进剂,包衣增重,释药孔大小对累积释药百分率的影响,并用高效液相法测定药物的含量和释放度。结果:采用柠檬酸为渗透促进剂,包衣处方为醋酸纤维素2%,聚乙二醇400用量8%、包衣增重7%,释药孔径0.5mm,得到渗透泵片在2h释药为9.5%,6h释药46.1%,12h释药96.0%。结论:通过调节促渗剂、包衣增重和释药孔径,盐酸沙格雷酯可以实现理想的药物控制释放。

白藜芦醇单层渗透泵片制备工艺研究及评价

目的:制备白藜芦醇包合物单层渗透泵片。方法:采用包合技术提高白藜芦醇溶解度,通过单因素及正交试验设计优化处方,并对优化后处方的体外释药行为进行模型拟合。结果:白藜芦醇单层渗透泵片在12 h内呈良好的零级释放(r=0.9963),药物累积释放比较完全(>90%)。结论:以环糊精包合物为中间体,白藜芦醇可以制备成12 h内零级释药特征明显的单层渗透泵片。

盐酸氨溴索渗透泵控释片的研制

目的:制备盐酸氨溴索口服渗透泵控释片。方法:使用羟丙基-β-环糊精对盐酸氨溴索包合,应用正交设计优化渗透泵片处方。结果:制得的盐酸氨溴索渗透泵控释片释放度符合要求。结论:羟丙基-β-环糊精能够改善盐酸氨溴索的溶解性质,从而简化盐酸氨溴索渗透泵制剂的制备方法。