Preparation Of Warfarin Sodium Orally Disintegrating Tablets With Individualized Dose By 3D Printing

Thromboembolic disease is a group of syndrome.The blood changed from a liquid to a solid in the blood vessel or in the heart for varying reasons,causing blood flow to occur to varying degrees of obstructionand,and then thromboembolic disease is formed.It is characterized by high incidence,high mortality and high disability rate.Warfarin sodium is an important oral anticoagulant drug in the clinic at present.It is widely used in the treatment of deep venous thrombosis,pulmonary embolism,atrial fibrillation,etc.And the amount of its prescription can reach 0.5% to 1.5% of the population.Currently,warfarin sodium tablets are general tablets,whose character is slow disintegration.They cannot take oral absorption without water,especially for children and the elderly with low compliance.The therapeutic window of warfarin sodium is narrow,and individual differences in dose can reach 20 times.So it is in high risk of adverse reactions.It can be seen from its usage and dosage that the clinical medication often needs split pill to be taken normally.So warfarin sodiumtablets are urgent to be designed to be the oral disintegrating and personalized medicine tablets.3D printing technology can used to prepare oral disintegrating tablet,because its principle is that the tablet is formed by powder,which is bonded layer by layer with wetting agent.Also,3D printing technology can used to prepare personalized medicine tablets,because it can design the shape and size of the tablet according to the software.The experiment is using 3D printing technology to prepare and study of individual dose and orally disintegrating tablets of warfarin sodium.Firstly,the documentation and reference on the 3D printing tablet are extremely rare currently,so it is necessary to study the application of drug excipients in 3D printing technology before the optimization of the prescription of 3D printing tablet.Filler,adhesive,concentration of ethanol solution,mixed filler,flow aids,disintegration,wetting agent,and powder granularity is need to be investigated with the hardness,the disintegration time,the microstructure,the appearance of the tablet and the fluidity of the powder to reduce the range of the later prescription optimization and clear the components of the 3D printing tablet.Secondly,after the screening of single factor auxiliary materials and the proportion screening of single factor auxiliary materials,using the central composite design-response surface method,the optimal prescription is:sucrose/pregelatinized starch ratio was 0.92,povidone/microcrystalline cellulose ratio was 1.05,and the ethanol concentration was 37.75%;and theoptimal process is: the radius of the tablet is 5.0mm,the number of printing is1,and the thickness of the printing layer is 0.10 mm.Then the warfarin sodium oral disintegrating tablets with three different doses(3mg,2mg and 1mg)were designed to be prepared.Thirdly,the three kinds of tablets were evaluated respectively with hardness,disintegration time,content,related substances,content uniformity,dissolution,microstructure,appearance and dose difference.The results showed that the quality of the three tablets was all qualified.Lastly,the stability study,the accelerated test and the long-term test showed that the properties of the three tablets were stable.The oral disintegrating tablets with individual dose of warfarin sodium prepared by 3D printing,compared with traditional tablets,have simpler and faster operation.Its quality is qualified and stable.It not only lays a good foundation for the optimization of the prescription of 3D printing tablets,but also provides a new idea for the preparation of the oral disintegrating tablets and the technology of the dose division.