The Exploratory Study Of The Refined BCS Classification Based On The Interaction Between Drugs And Excipients

Objective:BCS(biopharmaceutics classification system)is the theoretical basis of in vitro-in vivo correlation evaluation system.In recent years,regulatory organizations and institutions had successively incorporated BCS into the biological exemption guidelines.However,our experience is limited to what we can know,so the requirements of exemption are generally defined in many places,without clear details.Therefore,the exploratory study of the refined BCS classification based on the theoretical and experimental research of the interaction between drug substance and excipients provides data support for biological exemption based on BCS in this paperMethod:1.Based on the existing BCS classification,a new index of drug substance-excipient interaction was introduced to refine BCS classification.2.The theoretical study of the refined BCS classification:(1)The data of more than 100 drugs with different molecular weights,containing acid group,basic group,and amphoteric group,or without acid and basic group,were collected,and representative drugs were screened by volume,shape and charge distribution.(2)The module of blend from the software of Materials Stadio was used to calculate the level of interaction between representative drugs and structural units of excipients,and the calculated data were analyzed qualitatively.3.The interaction between excipients and small molecular compounds:(1)Establishment of test method: Body temperature of 37℃,self-made double chamber model and semipermeable membrane with molecular weight retention were selected.The type and the difference between batches of semipermeable membrane were investigated,the rotation speed of oscillator and whether to replenish liquid during operation.(2)The experimental data were compared with the theoretical prediction to determine the interaction between drug substance and excipients,and refine the BCS classification of the representative drugs.4.Study on the interaction between excipients and peptide molecule(oxytocin):(1)Computer molecular simulation was used to screen harmless excipients to replace the toxic excipient(chlorobutanol,CLB).(2)The influence of mannitol and CLB on the stability of oxytocin liquid preparation was compared by high performance liquid chromatography(HPLC)to analyze the possibility of mannitol replacing CLB.Results:1.According to the theory of the refined BCS classification,the data of interaction between lactose,starch,cellulose,sodium dodecyl sulfate and drug substance was larger than the average.The data of interaction between atorvastatin,candesartan,ciprofloxacin,glipizide,hydrochlorothiazide,indapamide,rebapamide,sildenafil,terazosin and excipients was exceeded the average.2.The results of the interaction between excipients and small molecular compounds: The permeability of albuterol、indapamide、dexamethasone、glilizide、atorvastatin、candesartan and nabumetone was low in 8h.Among the other 14 drugs,hydrochlorothiazide and ribapamide had strong interaction with most of the excipients,and sodium dodecyl sulfate and base of carboxymethyl cellulose had interaction with most of the drugs in test excipients.3.The results of interaction between excipients and peptide molecule(oxytocin)showed that: CLB and mannitol could improve the aggregation of oxytocin in the solution at 300 K,and play the role of dispersant.To some extent,it could improve the stability,and the test results were comparable,which showed that the theoretical method of calculating the interaction between drugs and excipients had a wider value.Conclusion:1.In this paper,a quantitative and standardized method of interaction between excipients and drugs was established,and the correlation between theoretical method and test method was explored,which showed that the theoretical method has certain value and could partly predict the interaction between drugs and excipients.2.The refined BCS classification method was explored based on the interaction between drugs and excipients.After BCS classification refinement,cetirizine and terazosin were classified as Iw/IIIaw and acetaminophen as IIIaw,indicating that these drugs are more likely to be exempted.3.The interaction between excipients and peptides was explored,suggesting that the theoretical calculation method can be more widely used in the study of interaction between drug substance and excipients.It is a systematic project to refine the BCS classification based on the interaction between drug substance and excipients.The study is feasible,and the precious study results lay a good foundation for further study.