Enhanced dissolution/caco-2 permeability, pharmacokinetic and pharmacodynamic performance of re-dispersible EPROSARTAN (cas 133040-01-4) mesylate nanopowder

Add time:09/10/2019    Source:sciencedirect.com

EPROSARTAN (cas 133040-01-4) mesylate is an angiotensin receptor blocker which suffers from extremely poor bioavailability owing to its poor solubility and poor permeability. The rationale of the present work was to design the drug delivery system capable of overcoming these constraints. Nanoformulation of eprosartan mesylate was developed using ultrasonic wave-assisted liquid-antisolvent technique. Nanoformulation was further freeze dried with the addition of 1% of mannitol resulting in formation of re-dispersible EPM nanopowder. To prove our proof of principle, the re-dispersed nanopowder with z-average particle size 165.2 ± 1.8 nm was evaluated enormously for in-vitro dissolution behaviour and permeability assay through Caco-2 cell model. In-vitro dissolution study was performed at pH 1.2, pH 4.5 and pH 6.8. Result demonstrates enhanced dissolution from EPM nanopowder with negligible pH dependence. Transport studies accomplished using validated Caco-2 based cell model showed 11-fold enhanced apparent permeability of redispersed nanopowder when compared to pure EPM and corresponding physical mixture (p < 0.0001). In-vivo study reveals, exceptionally strong variations in plasma concentration of EPM through nanopowder (62 mg/kg) formulation when compared with physical mixture and pure EPM (62 mg/kg) group. Moreover, study manifests that 5-fold lower dose (12.4 mg/kg) of developed formulation yields higher exposure (4600 ± 36 ng·mL−1·h) than pure EPM (2349 ± 34 ng·mL−1·h) and corresponding physical mixture (2456 ± 49 ng·mL−1·h) at therapeutic dose (62 mg/kg). Further, L-NAME induced hypertensive model was undertaken to investigate effect of reduced dose of EPM nanopowder on systolic blood pressure, biochemical analysis and histopathology of heart. Results revealed pronounced antihypertensive potential of re-dispersed EPM nanopowder at 5-fold lower dose (12.4 mg/kg). In conclusion, our study indicates that nanopowder delivery might be the promising approach for providing enhanced oral bioavailability at lower dose.

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