Enhancing lymphatic uptake of Darunavir Ethanolate through TPGS-enriched lipid nanocarriers for oral delivery

Abstract

Darunavir ethanolate (DRVE) is a promising molecule against wild-type protease inhibitors in human immunodeficiency virus (HIV) infection. It has a 37% oral bioavailability. In this study, the d-alpha-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS)-decorated DRVE-loaded lipid nanocarriers (DRVE-TPGS-LNCs) were optimized via central composite rotatable design using a modified solvent emulsification method. Various characteristic features of DRVE-TPGS-LNCs, such as globule size, polydispersity index, zeta potential, % entrapment efficiency, and % drug loading, were determined and found to be 116.5 ± 2.52 nm, 0.269 ± 0.0221, −10.8 ± 0.265 mV, 94.31% ± 10.75%, and 8.79% ± 0.937%, respectively. The spherical shape was evaluated by cryo-transmission electron microscopy. In-vitro study demonstrated % cumulative drug release of 81.70% ± 7.35% at pH 1.2 and 73.03% ± 7.17% at pH 6.8 after 12 h of drug release study. Moreover, the intestinal permeation and confocal microscope studies revealed approximately two-fold increased permeation in optimized nanoformulation across the gut sac compared to a drug suspension, and the inhibition of p-glycoprotein efflux was also confirmed by obtaining a minimum efflux ratio (0.253) of the optimized formulation compared to a drug suspension. The pharmacokinetic study demonstrated that the relative bioavailability of TPGS-DRVE-LNCs and drug suspension were found to be 19.85 ± 1.75 and 8.72 ± 0.753 μg.h/mL, respectively, which is approximately 2.25-fold more than the drug suspension which means approximately threefold increase in oral bioavailability compared to the drug suspension. The increased bioavailability in optimized DRVE-TPGS-LNCs was due to improved lymphatic uptake and p-glycoprotein efflux inhibition. Thus, the improved bioavailability of DRVE can meet the need to reduce the high dose of antiretroviral drugs to minimize the peripheral adverse reactions associated with the dose-related burden.

Graphical Abstract

Keywords:

• Lipid nanocarriers
• TPGS
• p-gp inhibitor
• lymphatic uptake
• Darunavir Ethanolate
• AIDS
• bioavailability
• HIV

Acknowledgments

Partially supported by the Distinguished Fellowship Program (DSFP), King Saud University, Riyadh, Saudi Arabia. The authors are also grateful to DST-PURSE for Fellowship to the first author. The authors are also grateful to DST-FIST for facilities at Jamia Hamdard, IIT-Delhi, SAIF- AIIMS, and Central Instrument Facility in Jamia Millia Islamia for providing research facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Abdul Muheem: preparation of formulation, characterization of formulation, analysis of data, writing draft; Ali Sartaj: data analysis; Eman Aldosari: suggestions and reviewing; Sanjula Baboota: co-supervisor, suggestions and editing; Javed Ali: supervisor, conceptualization, and reviewing.

Institutional review board statement

The animal study protocol was permitted by the Institutional Animal Ethical Committee (IAEC) (Jamia Hamdard, New Delhi, India), with the approved animal study protocol 173/CPCSEA, 28 Jan 2000 (approval no. 1706, 2021).

Additional information

Funding

The financial support to the corresponding author from King Saud University under the Distinguished Fellowship Program is acknowledged. We acknowledge financial support from the DST-PURSE for Fellowship to the first author. The authors also thank DST-FIST for financial support at Jamia Hamdard, New Delhi, India.