Pharmaceutical Research On The New Generation Of Anticoagulant Ticagrelor Tablets

Acute coronary syndrome(ACS)is a type of cardiovascular disease caused by thrombosis from platelet aggregation.The usual treatment for this disease is a combination of clopidogrel and aspirin.Clopidogrel is a prodrug that is activated by conversion of hepatic cytochrome P450 isoenzymes,but clopidogrel is difficult to achieve expected effect due to the different conversion rates among different individuals.As a new generation of non-thienopyridine P2Y12 receptor antagonists,ticagrelor(brand name BRILINTA(?))is a non-prodrug that can directly and reversibly bind to platelets and inhibit platelet aggregation.The drug was approved in the European Union by EMEA on December 3,2010.The drug was then approved by FDA on July 20,2011.In November 2012,it was approved by CFDA.At present,there is no generic drug for ticagrelor in China.In this study,we used commercially available BRILINTA(?)(90mg)as a reference to comprehensively analyze tablet weight,hardness,content,related substances,dissolution profile and stability.The relevant parameters of the standard were used to guide the formulation and process screening of the generic drug.In the study,dissolution curves and dissolution phenomena were used to examine the factors such as the crystal form,particle size,and excipient type of the raw materials in the prescription.The results showed that the API(Active Pharmaceutical Ingredient)crystal form in the commercial preparation was type ?.When the D90 value of API particle size was controlled below 34 ?m,the dissolution curves of the generic drug and the standard were similar.The process study found that the mixing method of the API and auxiliary materials and the binder adding method are important steps to ensure the good appearance of the particles and the appropriate particle size distribution,so that the particles have good fluidity and compressibility.In addition,hardness of the tablet core in the range of 100-150N can control the disintegration and dissolution rate of tablets and similar dissolution behavior can be achieved between the generic drug and standard.The good barrier properties against water vapor of the polyvinyl chloride/polyvinylidene chloride packaging material,can resist deliquescence caused by moisture absorption of tablets during storage.This packaging material is suitable to ensure the stability of ticagrelor tablets during storage.Finally,the above process can be used to production in large scale.The process is simple in operation and has good reproducibility.In the stability experiments,we performed effect factors,accelerated and long-term test investigations on commercially available marketed preparations and registered samples.The results showed that ticagrelor tablets were stable in both high temperature and strong light conditions,but were prone to absorb moisture in high humid environments.The ticagrelor tablets were packaged in PVC/PVDC and placed under the long-term condition(30?±2?,RH 65%±5%).However,after being placed in accelerating condition(40?±2?,RH 75%±5%)for 6 months,the product will experience slow core disintegration and slow dissolution.Therefore,ticagrelor tablets are considered to be more suitable for storage in environments below 30?.