Fabrication of TPGS decorated Etravirine loaded lipid nanocarriers as a neoteric oral bioavailability enhancer for lymphatic targeting

Etravirine (ERVN) is a potential NNRTI (non-nucleoside reverse transcriptase inhibitor) in treating HIV infection. It possesses extremely low oral bioavailability. The present research aims to optimize the formulation and characterization of TPGS-enriched ERVN-loaded lipid-based nanocarriers (LNCs) for HIV-infected patients. The formulation, ERVN-TPGS-LNCs, was optimized by CCRD using a modified-solvent evaporation process. Various characterization parameters of LNCs were evaluated, including globule size of 121.56 ± 2.174 nm, PDI of 0.172 ± 0.042, the zeta potential of -7.32 ± 0.021 mV, %EE of 94.42 ± 8.65% of ETR and %DL was 8.94 ± 0.759% of ERVN and spherical shape was revealed by TEM. PXRD was also performed to identify the crystallinity of the sample. In-vitro drug release showed % a cumulative drug release of 79.77 ± 8.35% at pH 1.2 and 83.23 ± 9.11% at pH 6.8, respectively, at the end of 48h compared to pure drug suspension (ERVN-S). Further, the intestinal permeation study and confocal microscope showed approximately ~3-fold and ~2-fold increased permeation in ERVN-TPGS LNCs and ERVN-LNCs across the gut sac compared to ERVN-S. Hemolysis compatibility and lipolysis studies were performed to predict the in-vivo fate of the formulation. The pharmacokinetic study revealed a 3.13-fold increment in the relative bioavailability, which agrees with the ex-vivo studies, and lymphatic uptake was validated by using cycloheximide (CYHD) along with designed formulation, which leads to lowering AUC of ERVN-TPGS-LNCs. Thus, this study ensures that ERVN-TPGS-LNCs take lymphatic uptake to minimize the first-pass metabolism followed by improved oral bioavailability of EVN. Thus, the enhanced bioavailability of ERVN can reduce the high dose of ERVN to minimize the adverse effects related to dose-related burden.

2.1.Materials

Etravirine was gifted by Hetero Pharmaceutical, Hyderabad, India. Vitamin E TPGS was purchased from Sigma Aldrich, India. BASF provided Labrafil M-2125 CS, Peceol, Labrafil M 1944CS, Maisine-300, Castrol oil, Plurol Oleique, Canola oil, Sesame oil, Labrasol, Capmul PG 12, Miglycol-829, Lauroglycol FCC, Captex-350, Miglycol-840, Captex-300, Neobee M-20, Labrafac WL-1349, Oleic acid, Lauroglycol-90, Capmul MCM-28, Caprol PGE-860, Precirol ATO 5, Compritol 888 ATO, Gelucire 44/14, Gelot 64, Stearic acid, Glyceryl monostearate, Apifil, Gelucire 50/13, Cremophor EL, Tween 80, Cremophore RH 40, Solutol H-15, Tween 20, and Poloxamer 407, Poloxamer 188. HPLC-grade water, methanol, and acetonitrile were purchased from Sigma Aldrich, India. Deionized water was procured from Millipore Instruments, MA, USA, available in CIF, Jamia Hamdard, New Delhi.

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Abdul Muheem, Mohd. Wasim, Eman Aldosari et al. Fabrication of TPGS decorated Etravirine loaded lipid nanocarriers as a neoteric oral bioavailability enhancer for lymphatic targeting, 26 September 2023, PREPRINT (Version 1) available at Research Square, https://doi.org/10.21203/rs.3.rs-3342708/v1

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