Abstract

Background: The lipid-drug conjugate nanoparticles (LDC NPs), amongst other lipidbased nanoparticles, are the most accepted ones for the oral delivery of both hydrophilic and hydrophobic drugs with poor bioavailability. Besides, the LDC NPs show altered physicochemical properties of the drug and have the potential applications in targeting the drug to a specific organ.

Objective: To synthesize hydrophilic Valacyclovir (VACV)-stearic acid (SA) and lipophilic Acyclovir (ACV)-stearic acid conjugates (VACV-SAC and ACV-SAC), and develop their nanoparticles (VACV-LDC-NPs and ACV-LDC-NPs) for improved intestinal permeability.

Methods: Both VACV-SAC and ACV-SAC were synthesized and confirmed using FTIR, NMR, and DSC techniques and characterized for assay. The lipid drug conjugate nanoparticles (LDC NPs) were prepared using cold high-pressure homogenization technique and characterized for drug content, mean particle size, zeta potential, ex vivo gut permeability using rat gut sac model, and Caco-2 cell permeability.

Results: The FTIR, NMR, and DSC results confirmed the successful synthesis of LDCs. The assay of VACV-SAC and ACV-SAC was found to be 51.48±5.6% and 41.2±6.2%, respectively. The VACV-LDC-NPs and ACV-LDC-NPs showed %EE of 99.10±6.71% and 86.84±5.32%, the mean particle size of 338.7±8nm and 251.3±7nm and zeta potential of -10.8±2.31mV and -11.2±3.52mV respectively. About 91±5.2% of VACV and 84±6.5% of ACV were found permeated across the rat intestine after 480 minutes from their respective NPs. Furthermore, VACV-LDC-NPs and ACVLDC- NPs displayed a significantly higher permeability coefficient (61.5×10-6 and 59.8×10-6 cm/s, respectively) than their plain solutions.

Conclusion: The obtained remarkable permeability characteristics indicate developed LDC NPs are the potential, promising and translational approaches for effective oral delivery of poorly bioavailable hydrophilic and lipophilic drugs. Furthermore, this approach may result in moderately to significantly enhanced oral bioavailability of hydrophilic drugs as the conjugation results in amphiphilic molecules, which are further absorbed through different mechanisms across the intestinal mucosa (mainly through passive diffusion mechanism).

Keywords: Valacyclovir, acyclovir, oral delivery, lipid-drug conjugate, ex vivo intestinal diffusion, Caco-2 permeability.

Graphical Abstract