Novel Fimasartan Fluidized Solid Dispersion and Its Tablet: Preparation, Crystallinity, Solubility, Dissolution, and Pharmacokinetics in Beagle Dogs.

Abstract

Background and objectives: Fimasartan, an angiotensin II receptor antagonist, exhibits low bioavailability due to its poor solubility; consequently, using solubilization technologies is essential to improve its bioavailability. In this study, novel fimasartan fluidized solid dispersion (FFSD) was developed using a fluid bed granulator to enhance the drug solubility and oral bioavailability.

Methods: An appropriate FFSD was prepared in 50% ethanol using a fluid bed granulator, and its drug dissolution, morphology, and crystallinity were evaluated in comparison to the powdered drug. Moreover, the dissolution in various pH conditions and pharmacokinetics of the FFSD tablet in beagle dogs were investigated compared to the commercial fimasartan tablet.

Results: Among the hydrophilic polymers tested, hydroxypropyl methylcellulose (HPMC) showed the highest solubility. The FFSD, composed of fimasartan, HPMC, and microcrystalline cellulose at the weight ratio of 20:10:25, gave a granular aggregation of several particles with a smooth surface. The drug in this FFSD existed as an amorphous state, leading to a greatly increased drug dissolution. The FFSD tablet was prepared by compressing a mixture of FFSD, mannitol, croscarmellose sodium, and magnesium stearate at the weight ratio of 55:40:5:1. The FFSD tablet gave significantly higher drug dissolution, plasma concentrations, maximum plasma concentration (C_max) and area under the whole blood concentration-time curve (AUC) values than did the commercial fimasartan tablet. In the beagle dogs, the FFSD tablet (140.39 ± 27.40 ng·h/ml) had about a 1.7-fold higher AUC than the commercial fimasartan tablet (80.58 ± 22.18 ng·h/ml), indicating an enhancement in the bioavailability.

Conclusions: This novel FFSD tablet could be a potential oral pharmaceutical product with the improved oral bioavailability of fimasartan.