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.

Mechanism of Drug Release from Compound Metformin/Glipizide Elementary Osmotic Pump Tablets

In previous studies, compound mefformin/glipizide was developed. Aim To discover the mechanism of drug release from factors influencing drug release from dosage form （the semi-permeable cry orifice） were investigated. Results The influx of water that elementary osmotic pump tablet it. Methods Three rate-limiting membrane, tablet core and delivpassed the osmotic pump tablet was almost equal to the metformin release rate, while it was greatly less than the drug dissolution rate from tablet core. The size of orifice from 0. 4 mm to 0.8 mm had no influence on drug release. The osmotic pressure of tablet core was mainly caused by mefformin. Conclusion From the developed model of osmotic pump systems, it can be seen that only the water influx through the membrane is a rate-limiting step, not tablet core dissolution rate and solution influx, and only when the core dissolution rate is equal to the solution influx, the zero order release is seen in the osmotic pump systems.

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.

A time-released osmotic pump fabricated by compression-coated method: Formulation screen, mechanism research and pharmacokinetic study

In this investigation,time-released monolithic osmotic pump(TMOP)tablets containing diltiazem hydrochloride(DIL)were prepared on the basis of osmotic pumping mechanism.The developed dosage forms were coated by Kollidon®SR-Polyethylene Glycol(PEG)mixtures via compression-coated technology instead of spray-coating method to form the outer membrane.For more efficient formulation screening,a three-factor five-level central composite design(CCD)was introduced to explore the optimal TMOP formulation during the experiments.The in vitro tests showed that the optimized formulation of DIL-loaded TMOP had a lag time of 4 h and a following 20-h drug release at an approximate zero-order rate.Moreover,the releasemechanismwas proven based on osmotic pressure and its profile could be well simulated by a dynamic equation.After oral administration by beagle dogs,the comparison of parameters with the TMOP tablets and reference preparations show no significant differences for C_(max)(111.56±20.42,128.38±29.46 ng/ml)and AUC_(0-48 h)(1654.97±283.77,1625.10±313.58 ng h/ml)but show significant differences for T_(max)(13.00±1.16,4.00±0.82 h).These pharmacokinetic parameters were consistent with the dissolution tests that the TMOP tablets had turned out to prolong the lag time of DIL release.

Can semipermeable membranes coating materials influence in vivo performance for paliperidone tri-layer ascending release osmotic pump tablet:In vitro evaluation and in vivo pharmacokinetics study

One purpose of this study was to develop a paliperidone(PAL)tri-layer ascending release pushepull osmotic pump(TA-PPOP)tablet which could meet the needs of clinical applications.And another purpose was to investigate whether different coating materials influenced in vivo performance of TA-PPOP.The ascending release mechanism of this trilayer delivery system on theory was elaborated.TA-PPOP was prepared by means of coating with cellulose acetate(CA)or ethyl cellulose(EC).Several important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated.The optimization of formulation and process was conducted by comparing different in vitro release behaviors of PAL.In vitro dissolution studies indicated that both the two formulations of different coating materials were able to deliver PAL at an ascending release rate during the whole 24 h test.The in vivo pharmacokinetics study showed that both self-made PPOP tablets with different coating had a good in vitro-in vivo correlation(IVIVC)and were bioequivalent with the brand product,which demonstrated no significant influence of the coating materials on the in vivo release acceleration of TA-PPOP.

Carbamazepine solubility enhancement in tandem with swellable polymer osmotic pump tablet: A promising approach for extended delivery of poorly water-soluble drugs

Elementary osmotic pump(EOP)is a unique extended release(ER)drug delivery system based on the principle of osmosis.It has the ability to minimize the amount of the drug,accumulation and fluctuation in drug level during chronic uses.Carbamazepine(CBZ),a poorly water-soluble antiepileptic drug,has serious side effects on overdoses and chronic uses.The aim of the present study was to design a new EOP tablet of CBZ containing a solubility enhancers and swellable polymer to reduce its side effects and enhance the patient compliance.Firstly,a combination of solubilizing carriers was selected to improve the dissolution of the slightly soluble drug.Then,designing the new EOP tablet and investigating the effect of different variables of core and coat formulations on drug release behavior by single parameter optimization and by Taguchi orthogonal design with analysis of variance(ANOVA),respectively.The results showed that CBZ solubility was successfully enhanced by a minimum amount of combined polyvinyl pyrrolidone(PVP K30)and sodium lauryl sulfate(SLS).The plasticizer amount and molecular weight(MW)together with the osmotic agent amount directly affect the release rate whereas the swellable polymer amount and viscosity together with the semi-permeable membrane(SPM)thickness inversely influence the release rate.In addition,the tendency of following zero order kinetics was mainly affected by the coat components rather than those of the core.Further,orifice size does not have any significant effect on the release behavior within the range of 0.1 mm to 0.8 mm.In this study we report the successful formulation of CBZ-EOP tablets,which were similar to the marketed product Tegretol CR 200 and able to satisfy the USP criterion limits and to deliver about 80%of CBZ at a rate of approximately zero order for up to 12 h.

The advantages of using osmotic pumps in caerulein-induced pancreatitis in Wistar rats

Objective: To establish a refined model of intravenous Caerulein-induced edematous pancreatitis in order to study the pathogenesis and therapeutic protocols of the disesase. Methods: Wistar rats were employed. The osmotic pre-filled with Caerulein and saline was implanted into a subctaneous pocket in the left iliac fossa of the animal. Caerulein was then infused via femoral vein to induce pancreatitis. Results: Pathological examination revealed obvious tissue edema of the pancreas in the rat 6 h after Caerulein infusion. The gross appearance of the pancreas exhibited edema with a clear ’gel- like’ fluid separating the pancreatic Iobules. Interstitial edema and marked vacuolization without inflammatory infiltrations in the Caerulein-infused rats were observed with light microscopy. There was no remarkable remarkable changes in the pancer as of rats infused with normal saline. Conclusion: The advantages of using implantable osmotic pump to infuse Caerulein to rats are the facilitation of animal handling, unrestriction of animal movement in cages and reduction in time lost due to accli matization of the rat to new housing conditions.

Structure based release kinetics analysis of doxazosin mesylate sustained-release tablets using micro-computed tomography

The structures of solid dosage forms determine their release behaviors and are critical attributes for the design and evaluation of the solid dosage forms.Here,the 3D structures of doxazosin mesylate sustained-release tablets were parallelly assessed by micro-computed tomography(micro-CT).There were no significant differences observed in the release profiles between the RLD and the generic formulation in the conventional dissolution,but the generic preparation released slightly faster in media with ethanol during an alcohol-induced dose-dumping test.With their 3D structures obtained via micro-CT determination,the unique release behaviors of both RLD and the generic were investigated to reveal the effects of internal fine structure on the release kinetics.The structural parameters for both preparations were similar in conventional dissolution test,while the dissolutions in ethanol media showed some distinctions between RLD and generic preparations due to their static and dynamic structures.Furthermore,the findings revealed that the presence of ethanol accelerated dissolution and induced changes in internal structure of both RLD and generic preparations.Moreover,structure parameters like volume and area of outer contour,remaining solid volume and cavity volumewere not equivalent between the two formulations in 40%ethanol.In conclusion,the structure data obtained from this study provided valuable insights into the diverse release behaviors observed in various modified-release formulations in drug development and quality control.

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）.

应用植入式缓释泵实现大鼠脑室给药的操作方法及其改进

目的介绍应用植入式缓释泵实现脑室给药的实验技术并予以改进。方法选择8周龄雄性SD大鼠,准备所需器材及试剂。首先将缓释泵组装并孵育至工作状态,然后进行植入手术操作。实验动物麻醉后备皮,手术暴露颅骨上表面,使用脑立体定位仪定位脑室正上方一点,在该点用高速颅钻钻1个小孔。先将泵体埋置于颈部皮下,然后将针头插入小孔中,并用牙科水泥固定,凝固后剪去针头基座,逐层缝合皮下软组织和头皮,将动物放回笼内单独饲养。结果缓释泵泵体成功植入大鼠颈部皮下,针头牢固固定于颅骨,导管接口未断开。取出完整脑组织检查,可见穿刺点及针道周围无明显血肿,脑室内及周围组织可见蓝色染料,表明本方法能够成功将药物送达脑室。结论通过引入脑立体定位仪辅助定位,并对此技术的操作流程进行改进,使植入操作更加精准、安全,具有较高的脑室给药成功率。

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.

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。

微孔渗透泵片的药物传递机制

To investigate the delivery mechanism of micro-porous osmotic pump tablets(MPOP),taking tramadol hydrochloride(TR)as the model drug,tramadol hydrochloride micro-porous osmotic pump tablets(TR MPOP)were prepared with compressible starch as diluent,cellulose acetate as coating material,polyethylene glycol 400 as pore-forming agents.The equilibrium solubility and osmolality of TR were determined.The effects of fillers in tablet cores,coating levels,and osmotic pressures of release media on expansion behavior of preparations were described.The influences of the category,osmolality,and pH value of release media,release methods,and release conditions on release curves of tablets were evaluated.Based on several models,the delivery pattern of TR MPOP was fitted.The equilibrium solubility in water and osmolality of TR were(775.8±17.7)g·L-1 and 4.036 Osmol·kg-1,respectively.During the drug-release period,it was observed that the tablets expanded markedly in response to the expansion characteristics of compressible starch and the osmotic pressure difference across the membrane.When osmotic pressure of release media increased,the significant change of the equilibrium solubility of TR was not found,but the release rates of TR MPOP decreased significantly.The delivery rate was not influenced by the pH of release mediums,dissolution methods and paddle stirring rates.The drug release profile conformed to the model of zero order in 8 h.The pore-forming agents were dissolved in release medium,which caused micro-pores.The expansion of tablets made the size of micro-pores bigger,and then the drug-releasing pores were obtained.It was proved that the drivers of drug delivering from TR MPOP were mainly the difference of osmotic pressure,and secondly the difference of solubility.TR MPOP were the controlled-release preparation.

硫酸沙丁胺醇口服渗透泵控释片的制备及体外释放度考察

通过均匀设计优化出硫酸沙丁胺醇口服渗透泵控释片的处方，并且考察了该制剂的释药机理．结果表明：该制剂遵从以渗透压差为释药动力的渗透泵式释药模式，体外释药速度平稳，在８ｈ内呈现良好的零级释放特征．

硝苯地平口服渗透泵片的制备及其体外释药特性

研制了单室单层硝苯地平口服渗透泵片 ,考察了片剂配方和主要制备参数、实验条件参数对药物释放速率的影响。在大量实验基础上 ,对硝苯地平口服渗透泵片的配方和制备参数进行优化 ,所确定的最优片芯配方为 (以片为基准 ) :硝苯地平 30mg ,β 环糊精 98 3mg ,聚环氧乙烷10mg ,聚乙烯吡咯烷酮 2 1 2 5mg ,渗透活性物质 14 0 4mg ;最佳孔径为 5 0 0 μm。依据最优方案制备的硝苯地平口服渗透泵片经体外释放度测定表明 ,在 2 1h内该渗透泵制剂形态稳定 。

渗透泵剂型的研究进展

综述了渗透泵剂型新的研发方向,如液体渗透泵、微孔渗透泵、胃内滞留型渗透泵、渗透泵口含片和直肠型渗透泵的研究进展。

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。