Atazanavir-loaded Eudragit RL 100 nanoparticles to improve oral bioavailability: optimization andin vitro/in vivoappraisal

Abstract

Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution, rapid first-pass metabolism in liver by CYP3A5, which result in low bioavailability. To overcome afore mentioned limitations, ATV-loaded Eudragit RL100 nanoparticles (ATV NPs) were prepared to enhance oral bioavailability. ATV NPs were prepared by nanoprecipitation method. The ATV NPs were systematically optimized (OPT) using 3 2 central composite design (CCD) and the OPT formulation located using overlay plot. The pharmacokinetic study of OPT formulation was investigated in male Wistar rats, and in-vitro/in-vivo correlation level was established. Intestinal permeability of OPT formulation was determined using in situ single pass perfusion (SPIP) technique. Transmission electron microscopy studies on OPT formulation demonstrated uniform shape and size of particles. Augmentation in the values of K a (2.35-fold) and AUC 0-24 (2.91-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation (IVIVC) Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions. In situ SPIP studies ascribed the significant enhancement in absorptivity and permeability parameters of OPT formulation transport through the Peyer's patches. The studies, therefore, indicate the successful formulation development of NPs with distinctly improved bioavailability potential and can be used as drug carrier for sustained or prolonged drug release. KeywordsBioavailability, central composite design, nanoparticles, pharmacokinetic study, in situ single pass perfusion studies, in vitro/in vivo correlation History

Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment

“…With this regard, ATV was nanoformulated to improve the bioavailability. , in Compared to plain drug, the nanoformulated ATV showed significant enhanced improvement of C max and AUC 0-24 by 1.1-and 2.9-fold, respectively [86]. Another example is DRV, a CYP inhibitor from the PIs.…”

Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System–Biowaiver

“…IV II [28][29][30][31] Incomplete absorption (~20%-50%), P-gp inhibitor Atazanavir sulfate (300 mg) Low Low/high 17,32,33 IV/II IV, 30 II/IV, 17 II 31,33 Nonlinear pharmacokinetics (range 100-1200 mg), inconclusive f a data, P-gp Efflux Cyclizine (50 mg) High High/low 34,35 I/III I [29][30][31] No reliable permeability data Dexamethasone (4 mg) High High [36][37][38] I III, 30 III/I, 9,39,40 I 28,29,31 Incomplete BA due to presystemic elimination rather than poor absorption Emtricitabine (200 mg) High High 41 I III 30,31 Oral BA ! 90%, linear kinetics (100-1200 mg) Enalapril maleate (5 mg) High Low [42][43][44] III III, 30,40,42,45 III/I, 28…”

Quality by design (QbD) based fabrication of atazanavir loaded nanostructured lipid carriers for lymph targeting: Bioavailability enhancement using chylomicron flow block model and toxicity study

“…The ATV content present in formulation, plasma, spleen, and thymus were analyzed by the modified RP-HPLC method previously reported by Singh and Pai, 2016 [6]. The mobile phase was prepared using potassium dihydrogen phosphate (pH 3.4) and acetonitrile in a ratio of Subsequently, the supernatant was obtained by centrifugation at 3000 rpm for 10 min and filtered through the 0.22 μm membrane filter.…”