Physiologically Based Modeling For IVIVC And Formulation Development Of BCS Class ? Drugs

The poor aqueous solubility is a barrier for oral drug formulation development,and various kinds of methods have been taken to improve the solubility and/or dissolution rate of insoluble drugs.However,formulation strategies are usually based on trial and error or formulation experience.In this paper,the pharmacokinetic(PK)predition models were applied to develop oral formulations for BCS ? drugs.The PK profiles of formulaitions could be quantitatively predicted based on physiologically based PK model and the properties of drug and formulaitons.With the model,the biopharmaceutical deciding properties could be profiled,the human PK profiles could be predicted through interspecies extrapolation from animianls,and the in vitro-in vivo correlation could be established to guide the formulation development.The contents and results were described as follows:1.Lansoprazole,a typical BCS class ? drug,was chosen as a model drug,and the oral absorption of its enteric coated tablets was simulated based on physiologically based modeling.The result showed that the predicted curve was in a good agreement with the experimental data with less than 10%prediction error values for for Cmax and AUC.Parameter sensitivity analysis was performed to find the key parameters of oral absorption.The absorption was particularly sensitive to dose,solubility and particle size for lansoprazole enteric-coated tablets.With a single dose less than 30 mg,the absorption was complete.However,when the dose is more than 40 mg,the absorbed fraction was not complete(i.e.,Fa<85%)and decreased rapidly with the increase in dose.When the solubility is lower than 0.04 mg/ml,the absorption was incomplete and then the solubility was a limiting factor for oral absorption of lansoprazole.A complete oral absorptioncould be achieved with lansoprazole particle radius up to about 25 ?m,and the particle size had an impact on the absorption rate2.Lacidipine,a typical BCS class ? drug,was chosen as a model drug.The PBPK base models in rat and dog after intravenous administration of lacidipine solutions and oral administration of lacidipine suspensions were developed and validated based on physicochemical properties and the literature data,which were used to verify the accuracy of the PBPK model in prediction drug PK in animals.The results showed that the simulated PK profiles after intravenous bolus administration of lacidipine solution were both in a good agreement with the observed in vivo curves,proving the reliability of the disposition model in rat and dog.And the predicted PK curves after oral administration of lacidipine suspension in rat and dog agreed well with the observed curves,proving that the absorption process could be also well simulated.The results demonstrated that the PBPK model can be successfully used to predict rat PK.Then based on the built PBPK model,the PK profiles of three lacidipine formulations in beagle dogs were predicted with the dissolution profiles in biorelevant dissolution media and Z-factor values which were obtained by fitting the dissolution profiles of the three formulations as input parameters.The results demonstrated that the predicted PK performances of three lacidipine formulations corresponded well to the observed values.At last,the verified PBPK model in dog was extrapolated to predict human PK of the three formulations.The results showed that PBPK models from dog to human are successfully developed3.Though these biorelevant media play an important role in formulation development,the complexity of the preparation and high cost restrict their routine application in the industrial and research field.The aim of the present study was to investigate whether the simple and conventional surfactant could be an alternative dissolution medium to the simulated fasted state intestinal fluid(FaSSIF)by similar factor method.The solubility and dissolution behavior of lacidipine and its commercial tablets were determined in the media of FaSSIF and various concentrations of Tween 80 and sodium dodecyl sulfate(SDS)solutions.Compared with the dissolution profile in FaSSIF,0.07%Tween 80 was proved to exhibit better biorelevance than 0.05-0.1%SDS for lacidipine formulations.The dissolution tests of micronized lacidipine,carbamazepine,glimepiride and carvedilol tablets were conducted as internal and external validations,respectively.The results demonstrated that the dissolution profiles of these formulaitons in 0.07%Tween 80 solution were all quite similar to these in FaSSIF.Therefore,the biorelevant concentration of Tween 80 could be set as 0.07%.This simple and low-cost dissolution media will hold great potentials in drug development,IVIVC and quality control of oral solid dosage forms.4.The solvent-shift method was used to screen the precipitation inhibitors for lacidipine supersaturation system.The apparent rank order of the polymers for supersaturation enhancement was Soluplus>HPMC E5>PVP K30?VA 64?F68.Then three polymers Soluplus,HPMC E5 and PVP K30 were chosen to make preparation of solid dispersions with the solvent evaporation method.Three amorphous solid dispersions(ASDs)were successfully prepared and hydrogen bond was formed with the characterization methods of polarization microscope,DSC,X-ray analysis and infrared spectroscopy.Three ASDs and commercial tablet LACIPIL(?)showed similar dissolution in 0.07%Tween 80 solution.And the dissolution-precipitation results in water were in line with the polymer rank order above.The physics stability of ASDs was preliminarily studied under high temperature and high humidity conditions.Soluplus ASD could be stable under these conditions.There was no crystallization detected within 10 d,and the hydrogen bond between lacidipine and Soluplus was not disrupted.PVP K30 ASD was the most hygroscopic and its stability was the worst.The hydrogen bond between drug and PVP K30 was disrupted,and there were a lot of crystal generated under high humidity.HPMC E5 ASD had a similar situation to PVP K30 ASD,but it was more stable than PVP K30 ASD.High hygroscopicity is the main cause for the poor system stability of PVP K30 ASD,while drug-polymer interaction serves as the determinant of the stability of Soluplus and HPMC E5 ASDs.5.UPLC-MS/MS method was applied to study the PK performance of self-prepared lacidipine solid dispersions in six beagle dogs.With LACIPIL(?)as the reference,the relative bioavailability of HPMC E5 ASD and Soluplus ASD were 112.2%± 57.8%and 110.6%± 51.6%,respectively.The bioequivalence analysis showed that the test and reference formulations were not bioequivalent,which may be the result of small amount of samples and significant individual differences.Then the population simulation and virtual bioequivalence study was performed in 24 subjects.The result showed that two test ASDs were bioequivalent to LACIPIL(?)using the bioequivalence criteria with the 90%confidence intervals(CI)of mean values of Cmax and AUC in the demanding range.The result demonstrated that these formulations could be bioequivalent with large samples.