QbD Approach Method Development for Estimation of Dabigatran Etexilate along with Its Impurities and Identification of Degradants in Capsule Dosage Form

The concept of Quality by Design was demonstrated in the development of a stability-indicating assay and related substances method by HPLC for Dabigatran Etexilate Capsules dosage form. Method design, method evaluation, method control and life cycle management were explained by systematic flow chart. Analytical Target Product profile was defined. The method was developed using the Inertsil ODS-3V, 150 mm × 4.6 mm, 5 μm column using the gradient program with ammonium formate buffer as mobile phase A and acetonitrile as mobile phase B. Risk assessment was performed as part of method evaluation. Design of experiment tools was used to optimize the chromatographic conditions. A two-level Full Factorial Design along with Face Centered Central Composite design augmentation was employed and statistical analysis of the experimental data uncovered the significant influential of chromatographic factors. The design space and the contour plot suggest that the current center point parameters can be further modified, resulting in better acceptability of the response parameters. The performance of the optimized method was validated according to current ICH guidelines. Dabigatran Etexilate Capsules was subjected to various stress conditions like oxidative, acid, base, hydrolytic, thermal, humidity, and photolytic degradations and evaluated chromatograms at 220 nm. The degradation products were well separated from each other and main peak, demonstrating the stability-indicating power of the method. One of the major degradant impurities, which are forming in neutral hydrolysis stress condition, is isolated and characterized by using analytical techniques like IR, LC-MS and NMR. Degradation pathway for Dabigatran Etexilate was proposed based on forced degradation data along with reaction mechanism.

Determination of dabigatran in dog plasma by LC-MS/MS and its application to a pharmacokinetic study of dabigatran etexilate nanosuspension

In this study, a sensitive and rapid LC-MS/MS method was developed and validated to determine dabigatran in plasma of beagle dogs after oral administration of dabigatran etexilate nanosuspension （DABE-NS）. The analytes （dabigatran） and sertraline hydrochloride （internal standard, IS） were separated on a Kromasil C18 column using gradient elution consisting of methanol and formate buffer at a flow rate of 0.4 mL/min in 20 min. Detection and quantitation were carded out by multiple reaction monitoring following the transitions： m/z 472.17→289.07 and 305.98→275.00 for dabigatran and IS at positive ion mode, respectively. The calibration curves were linear from 1.0 to 500.0 ng/mL for dabigatran with r = 0.9995. The accuracy of each analyte ranged from 94.8% to 107.1%, and the precision was within 6%. Besides, this method was successfully applied in the investigation of the pharmacokinetic profile of dabigatran in beagle dogs after oral administration of DABE-NS. The maximum concentration and the areas under curves of dabigatran for DABE-NS were significantly higher than those of control formulation, indicating improved oral absorption.

Individualized anti-thrombotic therapy for acute myocardial infarction complicated with left ventricular thrombus: A case report

BACKGROUND Presently,there is no established standard anti-blood clot therapy for patients facing acute myocardial infarction(AMI)complicated by left ventricular thrombus(LVT).While vitamin K antagonists are the preferred choice for oral blood thinning,determining the best course of blood-thinning medication remains challenging.It is unclear if non-vitamin K antagonist oral blood thinners have different effectiveness in treating LVT.This study significantly contributes to the medical community.CASE SUMMARY The blood-thinning treatment of a patient with AMI and LVT was analyzed.Triple blood-thinning therapy included daily enteric-coated aspirin tablets at 0.1 g,daily clopidogrel hydrogen sulfate at 75 mg,and dabigatran etexilate at 110 mg twice daily.After 15 d,the patient’s LVT did not decrease but instead increased.Clinical pharmacists comprehensively analyzed the cases from the perspective of the patient’s disease status and drug interaction.The drug regimen was reformulated for the patient,replacing dabigatran etexilate with warfarin,and was administered for six months.The clinical pharmacist provided the patient with professional and standardized pharmaceutical services.The patient’s condition was discharged after meeting the international normalized ratio value(2-3)criteria.The patient fully complied with the follow-up,and the time in the therapeutic range was 78.57%,with no serious adverse effects during pharmaceutical monitoring.CONCLUSION Warfarin proves to be an effective drug for patients with AMI complicated by LVT,and its blood-thinning course lasts for six months.

Does novel oral anticoagulant improve anticoagulation for non-valvular atrial fibrillation associated stroke: An inpatient registration study in Shanghai

Objective:To summarize the use rate,safety,efficacy of antithrombotics in stroke/transient ischemic attack (TIA) prevention,and reasons for not using dabigatran etexilate (DE) in Shanghai,China.Methods:Non-valvular atrial fibrillation (NVAF)-associated stroke patients were prospectively registered as an electronic database.Use rate of antithrombofics and reasons for not using DE were extracted during follow-up.Patients' baseline characteristics,recurrent ischemic stroke/TIA events and bleeding complications were analyzed.Patients:From April 2012 to August 2014,110 inpatients with NVAF-associated stroke were studied in our hospital.NVAF was diagnosed by 12-lead electrocardiogram,24 h Holter and echocardiography.Results:Before introduction of DE (April 2013),use rates of warfarin and antiplatelets were 28.9％ (11/38) and 60.5％ (23/38)respectively; after that,use rates of warfarin,DE,and antiplatelets were 20.8％ (15/72),12.5％ (9/72),and 43.1％ (31/72).The DE did not improve use of anticoagulants (P =0.639).There were 19 (17.3％) recurrent ischemic stroke events up to October 2015; two (9.5％) in the non-user group,10 (18.5％) in the antiplatelet group,and seven (20.0％) in the anticoagulants group (P =0.570).Furthermore,recurrence rates were similar between the DE group (20.0％) and the Warfarin group (20.0％,P =1.000).The most common reason for not using DE was financial concerns (61.0％),followed by inconvenience to purchase (14.0％) and hemorrhage concerns (11.0％).Two patients using warfarin found fecal occult blood so they stopped warfarin and began to use antiplatelet drugs.No bleeding event occurred in the other groups.Only one patient had side effects (dyspepsia and gastroesophageal reflux)from DE.Conclusion:The use rate of either DE or warfarin in Shanghai was low; DE had not improved anticoagulation therapy for NVAF patients in Shanghai mainly because DE had not been covered by health insurance.