Research On The Preparation Of Simvastatin Tablets By 3D Printing

Cardiovascular Diseases?CVD?are the leading cause of death worldwide,it still has gradually increasing morbidity and mortal in China,and it is a chronic disease with complex pathogenesis which brings heavy economic burden for patients.In clinical treatment,traditional dosage regimen are complex and difficult to achieve the purpose of individualized medicine,and the compliance of patients is also poor.Therefore,using multiple target mechanisms to treat complex diseases has gradually become a key factor in solving such problems.Polypill is a fixed-dose of cardiovascular compound preparation that can simultaneously modulate multiple risk factors about CVD as well as greatly reduce the incidence of CVD events and mortality,so that it can improve the compliance of patients.As the preparation of Polypill with traditional technology involves the problems of complex preparation process and complicated procedure,it is difficult to making complex dosage forms by large-scale industrial production,and there are problems such as high cost and time-consuming production.Therefore,this project intends to use 3D printing technology?3DP?to prepare Polypill.According to the principle of“printing layer by layer,stacking layer by layer”,3D printing is a rapid prototyping technology for objects with special shape or complex internal structure by CAD.3D printing Polypill has the advantages of simple process,good flexibility,high repeatability and drug loading accurately.It can break the limitation of traditional preparation technology and lay the foundation for the research of new technology of drugs.This project intends to prepare a“Polypill”combination which can prevent and treat multiple risk factors of CVD:ACEI,statins and aspirin.Among them,based on the advantages of statins,simvastatin was inve-stigated in the first phase of preliminary study as model drug which was most widely used.1.The efficacy and safety of Polypill on CVD were systematically evaluated.RevMan5.3 version of the software was used for Meta analysis,it was found that Polypill had significant differences in blood pressure and blood lipid levels,compared with the control group,the difference in safety was statistically significant.Modeling dimensions and dose specifications were determined by pre-prescription studies of simvastatin which is one of the components of Polypill's proposed:a radius of 4.0 mm,a height of 4.8 mm,and a dose of 10 mg.2.The formulation process of 3D printing simvastatin tablets were studied,determining the basic composition of the excipients:binder?PVPK30?,filler?lactose/microcrystalline cellulose?and printing liquid“ink”?ethanol abolute?;Single factor test was used to investigate the technological parameters such as the thickness of powder layer,the number of spraying and the amount of inkjet.The optimized preparation process was screened by orthogonal experi-ment:the thickness of powder layer was 0.10mm,spraying times was once,the amount of inkjet was 75%,the size of powder particle was 75?m,drying temperature was 45?,drying time was 40min;The in vitro dissolution?Q?was taken as the index to determine the dosage ranges of PVPK3,lactose/microcr-ystalline cellulose and ethanol abolute by using the single factor test,respecti-vely:PVPK30?%?25³5,lactose/microcrystalline cellulose?g/g?1.7³.0,ethanol abolute?%?65⁸5.Taking three factors as variables,the Central-Composite design was used to further optimize the formulations,the optimal formulations were the 30%of PVPK30,the 2.5 of lactose/MCC and the 74%of ethanol absolute.The validation test of the formulations showed that the deviation between the results and the predicted values were less than 5%.The results showed that the model established by CCD had good predictability and the optimal formulations were reasonable.3.Three batches of 3DP simvastatin tablets were prepared according to the optimal formulation process.In this paper,the properties were observed and the mechanical properties were determined,the method of determination content and methodological validation of the samples by HPLC were established.The dissolution of the tablets was compared with the commercial tablets by the method of?₂ similarity factor.Part of the quality evaluation of the 3DP simvastatin tablets showed that the quality of the preparation was sta-ble and controllable,and the dissolution curve was similar to the commercial products,it provided a feasible basis for the application of 3DP technology in the field of CVD preparations.4.According to the guidelines of drug stability test in the Chinese Pharmacopoeia?Edition 2015?,the influence factor test and accelerated test of the optimized 3DP tablets under high temperature,high humidity and stress light were conducted.The influence factor test found that the product should be stored in a cool,dry and closed environment away from light.Due to the reason of time,the product has only been tested for 3 months,and all indicators met the requirements.