Preparation Of R-S Bilayer Tablets And Research On Their Bioequivalence

The oral route of administration is the most widely used and most convenient way for medicines to treat diseases,and it is highly accepted by patients.Tablets are the largest oral preparations in the market,and are the dosage forms doctors prefer to prescribe.Conventional single type of drug treatment is notsuitable for chronic diseases.Chronic diseases are more individualized or combined with multiple types of drug treatment^[1].The mechanism of bip Hasic drug release is now defined as bilayer tablets^[2,3].It is divided into single-medicine double-layer tablets and compound double-layer tablets.The single-layer double-layer tablets of this kind of drugs have an immediate release layer to quickly achieve the therapeutic effect,and the other layer is a slow-release layer to maintain the blood concentration of the drug;compound double-layer tablets are often used in the treatment of chronic diseases and the occurrence of active drugs Mutual synergies to achieve therapeutic effects,such as valsartan am Lodipine tablets,atorvastatin am Lodipine tablets,pioglitazone glimepiride tablets and so on.Therefore,in the field of chronic diseases,compound double-layer tabletshave become a research hotspot.In this paper,the formulation process of R-S double-layer tablets was studied,using commercially available tablets as the reference preparation,in accordance with the"Guidelines for Preparation Research"and"Guidelines for Research on Generic Drugs",combined with the characteristics of this product,a compound R-S tablet was developed with a specification of 10/20 mg.On the basis of obtaining a product with a dissolution profile similar to that of the original developed agent in vitro and qualified in process verification,the bioequivalence test of self-made preparations in healthy persons was studied.R and S are the APIs in the preparation,and they all belong to the BCS II category.S has low solubility under acidic conditions and is unstable when encountering acids,while R has low solubility and is unstable when encountering alkalis.During the study of the compatibility of excipients,during the placement of the mixed components of R and S,the S-related substances increase rapidly and the content decreases significantly.According to the data,alkaline substances can improve the stability of S.In the component of R and S mixed with alkaline substances,S generates impurities exceeding the limit,and the stability is still poor.After taking the preparation method,after separating the two active ingredients,R and S are relatively stable,and no impurities exceeding the limit are produced.R:In the range of p H1?p H7,its solubility has no dependence on p H value.It can be increased by 8 times at p H8,but it is only 8.09 g/m L.S:p H5?p H8 showed a p H-dependent increase.The main findings are as follows:?1?Determine the prescription of R layer:Povidone 4.5%,sodium lauryl sulfate 2.0%,microcrystalline cellulose 20.0%,croscarmellose sodium 4.0%,lactose 63.5%,magnesium stearate 1.0%;S layer prescription:microcrystalline Cellulose 21.78%,hydroxypropyl cellulose 1.0%,croscarmellose sodium 5.0%,lactose 27.0%,calcium carbonate 33.0%,Tween-80 0.4%,silica 0.5%,magnesium stearate 0.5%.?2?The granulation process research shows that both the R and S layers use a wet granulation process,and the dissolution curve is similar to that of the reference preparation.?3?A single fasting oral administration,randomized,two-cycle,two-cross bioequivalence test was conducted in healthy subjects,and the results showed t hat the test preparation and reference preparation of R:C_max1508±942and1739±869 ng/m L,T_max2.5?1.0,6.0?and3.5?2.0,6.0?h,AUC_0-t9628±4527and11860±4869 ng·h/m L,AUC_0-?10123±4533and12397±4919 ng·h/m L,T_1/28.292±5.400and7.917±4.582 h,?_z0.1099±0.0608and0.1130±0.0550 1/h.Testpreparation and referece preparation of S:C_max4±1and4±1 ng/m L,T_max6.5?6.0,8.0?and6.5?6.0,8.0?h,AUC_0-t179±40and178±45 ng·h/m L,AUC_0-?206±60and202±57 ng·h/m L,T_1/231.917±26.438and44.500±25.357 h,?_z0.0153±0.0028and0.0156±0.0022 1/h.?4?Based on the bioequivalence test,the dissolution method was used to develop the dissolution profile of R in vivo and in vitro correlation:0.2%?W/V?Tween 80,p H1.2 hydrochloric acid solution 1000 m L,paddle method 75 rpm.At present,the first bioequivalence test has been carried out on R-S double-layer tablets.Although the result of the determination of the R component is bioequivalence,a dissolution profile with in vivo and in vitro correlation has been found.In the follow-up study,0.2%Tween 80+p H1.2 was used as the main dissolution medium for formulation optimization.The self-made batch showed good stability in the stability study.The production process needs to be verified in the follow-up to further explore the stability of the self-made preparation...