Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system.

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.

Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design.

PURPOSE: To enhance the oral bioavailability of revaprazan (RVP), a novel solid, supersaturable micelle (SSuM) was developed. METHODS: Surfactants and solid carriers were screened based on a solubility and a flowability test, respectively. Supersaturating agents, including Poloxamer 407 (P407), were screened. The SSuM was optimized using a Box-Behnken design with three independent variables, including Gelucire 44/14:Brij L4 (G44/BL4; X1) and the amounts of Florite PS-10 (FLO; X2) and Vivapur 105 (VP105; X3), and three response variables, ie, dissolution efficiency at 30 min (Y1), dissolution enhancing capacity (Y2), and Carr's index (Y3). The solid state property was evaluated, and a dissolution test was conducted. RVP, Revanex®, solid micelle (P407-free from the composition of SSuM), and SSuM were orally administrated to rats (RVP 20 mg equivalent/kg) for in vivo pharmacokinetic study. RESULTS: G44 and BL4 showed great solubility, with a critical micelle concentration range of 119.2-333.0 µg/mL. P407 had an excellent supersaturating effect. FLO and VP105 were selected as solid carriers, with a critical solidifying ratio (g/mL) of 0.30 and 0.91, respectively. With optimized values of X1 (-0.41), X2 (0.31), and X3 (-0.78), RVP (200 mg)-containing SSuM consisting of G44 (253.8 mg), BL4 (106.2 mg), FLO (99.3 mg), VP105 (199.8 mg), and P407 (40 mg) was developed, resulting in Y1 (40.3%), Y2 (0.008), and Y3 (12.3%). RVP existed in an amorphous state in the optimized SSuM, and the SSuM formed a nanosized dispersion in the aqueous phase, with approximately 71.7% dissolution at 2 h. The optimized SSuM improved the relative bioavailability of RVP in rats by approximately 478%, 276%, and 161% compared to raw RVP, Revanex®, and solid micelle, respectively. CONCLUSION: The optimized SSuM has great potential for the development of solidified formulations of poorly water-soluble drugs with improved oral absorption.

pH-sensitive PEGylation of RIPL peptide-conjugated nanostructured lipid carriers: design and in vitro evaluation.

BACKGROUND: RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated nanostructured lipid carriers (RIPL-NLCs) can facilitate selective drug delivery to hepsin (Hpn)-expressing cancer cells, but they exhibit low stability in the blood. Generally, biocompatible and nontoxic poly(ethylene glycol) surface modification (PEGylation) can enhance NLC stability, although this may impair drug delivery and NLC clearance. To attain RIPL-NLC steric stabilization without impairing function, pH-sensitive cleavable PEG (cPEG) was grafted onto RIPL-NLCs (cPEG-RIPL-NLCs). METHODS: Various types of NLC formulations including RIPL-NLCs, PEG-RIPL-NLCs, and cPEG-RIPL-NLCs were prepared using the solvent emulsification-evaporation method and characterized for particle size, zeta potential (ZP), and cytotoxicity. The steric stabilization effect was evaluated by plasma protein adsorption and phagocytosis inhibition studies. pH-sensitive cleavage was investigated using the dialysis method under different pH conditions. Employing a fluorescent probe (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate [DiI]), in vitro drug delivery capacity of the cPEG-RIPL-NLCs under different pH conditions was also performed on Hpn-expressing SKOV3 cells and 3D-tumor spheroids. RESULTS: All prepared NLCs showed homogenous dispersion (<220 nm in size) with a negative ZP (-18 to -22 mV), except for positively charged RIPL-NLCs (~10 mV), revealing no significant cytotoxicity in either SKOV3 or RAW 264.7 cell lines. cPEG-RIPL-NLC protein adsorption was 1.75-fold less than that of RIPL-NLCs, and PEGylation significantly reduced the macrophage uptake. PEG detachment from the cPEG-RIPL-NLCs was pH-sensitive and time dependent. At 2 hours incubation, cPEG-RIPL-NLCs and PEG-RIPL-NLCs exhibited comparable cellular uptake at pH 7.4, whereas cPEG-RIPL-NLC uptake was increased over 2-fold at pH 6.5. 3D-spheroid penetration also demonstrated pH-sensitivity: at pH 7.4, cPEG-RIPL-NLCs could not penetrate deep into the spheroid core region during 2 hours, whereas at pH 6.5, high fluorescence intensity in the core region was observed for both cPEG-RIPL-NLC-and RIPL-NLC-treated groups. CONCLUSION: cPEG-RIPL-NLCs are good candidates for Hpn-selective drug targeting in conjunction with pH-responsive PEG cleavage.