Study On Preparation Of Carbidopa And Levodopa Bilayer Tablets By 3D Printing Technology

3D printing technology is a new type of rapid prototyping technology which is based on the principle of “layer by layer printing and overlapping”,combined with the digital design technology,computer technology,and new materials science.With the advantages of high flexibility,simple process and rapid prototyping,it has been increasingly used in the pharmaceutical preparation in recent years.It provides new ideas and approaches for research and development of new drug delivery systems.This research used the inject deposition on powder beds 3D printer,carbidopa and levodopa as model drugs to explore the preparation of carbidopa and levodopa bilayer tablets.This bilayer tablet was composed of immediate and sustained biphasic delivery systems,which can provide an initial burst release to achieve the effective blood concentration and followed by an constant rate of drug release to maintain the stable blood concentration.In this paper,physicochemical propertise such as solubility,stability and compatibility with excipients of carbidopa and levodopa were studied.Drugs can easily dissolved in the dilute acid solution.The DSC experiment result shows that there was no interaction between excipients and drugs.HPLC method was used to determine the content and in vitro release of carbidopa and levodopa.The concentrations of levodopa(5?g/mL~120?g/mL)and carbidopa(20?g/mL~480?g/mL)have a good linear relationship with the peak area.The average recovery rates of carbidopa(98.90%)and levodopa(100.34%)were fine(RSD<2%).In the selection of prescription process,model parameters werecomfirrmed by measured the bulk density of the powder.The critical relative humidity of drug powder was investigated,and the relative humidity of working environment should be less than 45%.Taking formability,disintegration time and dissolution as the evaluation index,single factor method was used to investigated the formulation of immediate release layer.The final formulaiton was 8% PVP k30 as the binder and 8.6% MCC as the diluent.Dissolution rates and formability were used as the evaluation indicators to investigated the adhesive and sustained release material of the sustained release layer.Central Composite Design / Response Surface Method was used to optimized the formulaiton of sustained release layer.The final formulaiton was 13.56%HPMC K4 M as matrix material,6.57% CMC-Na as the binder.The in-vitro drug release characteristics and mechanism of the prepared bilayer tablets were investigated.It has an obvious biphasic drug release effects.In the initial 30 mins,drugs in the immediate-release layer was released,and following by the sustained-release layer drugs which can maintain 6hours release.The cumulative drug release rates in1 h,3hrs,6hrs were 53%,72%,88%.The dissolution kinetics followed the Ritger-Peppas model via a Fickian diffusion controlled release mechanism.The internal structure of the bilayer tablet was observed with an environmental scanning electron microscope.It showed that 3D printed tablet has more pores.A preliminary quality inspection was performed about the bilayer tablets,included appearance characteristics,drug content,and dissolution rate.The average hardness of bilayer was20.23 N.In the preliminary stability experiment,the influencing factor experiment showed that drugs were stable under high temperature conditions,slightly degraded under strong light.And the tablet was hygroscopic under the high humidity conditions,which could lead to color change,appearance swelled and texture softer.In the accelerated experiments,the color of the tablets had changed,some dark spots appeared.The drug content was slightly reduced.From the experiment results,printed tablets should be protected against moisture and kept in a cool,dry and shady place.3D printed carbidopa and levodopa bilayer tablet has stable adhesion between the two layers without cracking and showed biphasic release effect in vitro.Comparing with the process of compression,3D printing technology is more flexible,reproducible and controllable.It can be used to print bilayer tablet.