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.

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.

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.

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.

Bio-mimetic drug delivery systems designed to help the senior population reconstruct melatonin plasma profiles similar to those of the healthy younger population

The secretion of melatonin(MT)is obviously different in the younger and the senior sectors of the population,and the maximum plasma concentration of seniors is only half of that in the younger population group.If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system(DDS),an improved therapeutic effect and reduced side effects can be expected.Based upon this hypothesis,the pharmacokinetic parameters of MT,namely,the absorption rate constant(ka),the elimination rate constant(ke),and the ratio of absorption rate(F)to the apparent volume of distribution(V)were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population.The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system(DDS)to generate plasma MT profiles similar to the physiological level-time profiles.The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates,namely,4.919μg/h during 0-4 h(r=0.9992),and 11.097μg/h during 4-12 h(r=0.9886),respectively.Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors,an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population.The high similarity between the experimental drug release profiles and the theoretical profiles(similarity factor f_(2)>50)and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles(r=0.9366,0.9163,0.9264)indicated that a prototype bio-mimetic drug delivery system of MT was established.The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0-4 h and 4-12 h,namely,68.8 and 57.3 for the first batch(Batch No.20131031),76.7 and 50.2 for the second batch(Batch No.20131101),and 73.7 and 51.1 for the third batch(Batch No.20131126),respectively.The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366(Batch No.20131031),0.9163(Batch No.20131101),0.9264(Batch No.20131126),respectively.Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings,it is impossible to test the bio-mimetic DDS in animals directly.Therefore,the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test.In this research,a bio-mimetic DDS for replacement of MT was designed with in silico evaluation.