Albumin-Based Nanoparticles with Factorial Design as a Promising Approach for Remodeled Repaglinide: Evidence from In Silico, In Vitro, and In Vivo Evaluations

<b>Background/Objectives:</b> Hyperlipidemia is a silent threat lurking in the bloodstream of millions worldwide. The nano-based platform has emerged as a promising drug delivery technology. Repaglinide, an anti-diabetic drug, was investigated recently as an antihyperlipidemic candidate that could supersede the available antihyperlipidemic drugs. Our goal was to optimize albumin-based nanoparticles loaded with Repaglinide for parenteral delivery and conduct in silico and in vivo studies to explore the efficacy of Repaglinide for the management of hyperlipidemia along with its anti-diabetic effect. <b>Methods:</b> The impact of three independent factors, the albumin%, acetone volume, and glutaraldehyde/albumin, on the particle size, zeta potential, and entrapment efficiency was investigated. <b>Results:</b> The optimized formulation was spherical, homogenous of an average diameter (~181.86 nm) with a narrow size distribution, a zeta potential of -24.26 mV, and 76.37% as the EE%. The in vitro release of Repaglinide from nanoparticles showed a sustained release pattern for 168 h, with an initial burst release after 24 h, and was fitted to the Fickian diffusion mechanism. A molecular docking simulation showed a strong affinity to several protein targets, and the results were very promising, where Repaglinide gave a score of -7.70 Kcal/mol compared to Mevastatin (-6.71 Kcal/mol) and Atorvastatin (-8.36 Kcal/mol). On conducting in vivo studies on animal models, the optimized formula recorded a statistically significant decrease in the serum levels of total cholesterol, triglyceride, and low-density lipoproteins, with an increased high-density lipoprotein. <b>Conclusions:</b> This study suggested albumin nanoparticles as potential nanocarriers for the parenteral delivery of Repaglinide to ameliorate its antihyperlipidemic benefits, especially in diabetic patients.