Marwa H.S. DawoudHeba T. ElbalkinyYasmeen E.M. GharibSara A.A. FakkarRowaa SaberMarry E. YanniMai A. Zaafan2025-04-172025-04-172025-03-06Dawoud, M. H., Elbalkiny, H. T., Gharib, Y. E., Fakkar, S. A., Saber, R., Yanni, M. E., & Zaafan, M. A. (2025b). Beyond Erectile Dysfunction: Optimization of Vardenafil Dihydrochloride for Hepatic Encephalopathy Prophylaxis using Hybrid Lipid Polymeric Nanoparticles Formulation. Journal of Drug Delivery Science and Technology, 106787. https://doi.org/10.1016/j.jddst.2025.106787https://doi.org/10.1016/j.jddst.2025.106787https://repository.msa.edu.eg/handle/123456789/6384SJR 2024 0.817 Q1 H-Index 89Vardenafil dihydrochloride (VD), a phosphodiesterase-5 (PDE5) is widely used to treat erectile dysfunction, but recent studies suggested its potential for other diseases such as hepatic encephalopathy. However, VD suffers poor solubility and oral bioavailability, and significant first-pass metabolism. This study aims to enhance the bioavailability of VD by employing two combined approaches: formulation of VD into hybrid lipid-polymeric nanoparticles (HLPNPs), and incorporating piperine, a known bioavailability enhancer, to investigate its potential in preventing hepatic encephalopathy. HLPNPs were developed using homogenization/ultrasonication technique, with a one-factor design testing chitosan, oleic acid, or sodium alginate as the helper polymers. Oleic acid showed the best results and was used to prepare the optimized formula (O1), which had a particle size of 128 ± 2.8 nm, a polydispersity index of 0.173 ± 0.07, an entrapment efficiency of 93 ± 1.8 %, and a zeta potential of − 32 ± 1.67 mV. O1 showed a sustained drug release profile, with approximately 70 % of VD released over 72 h. O2 was then prepared with the addition of piperine, resulting in a longer residence time of 717 min compared to O1 (94 min) in the pharmacokinetics study. O1 showed a twofold increase in the bioavailability compared to the unformulated VD while O2 exhibited a ninefold increase. The improvement was confirmed by the higher Cmax from 9 ng/mL for standard VD to 13 ng/mL and 22 ng/mL for O1 and O2, respectively. In hepatic encephalopathy-induced mice model, O2 showed promising efficacy, with significant improvements in liver enzymes, ammonia levels, hippocampal BDNF levels, cGMP levels, and hippocampal GluR1 and P-CREB levels. These findings suggest that combining VD into HLPNPs with piperine is an effective strategy to overcome its bioavailability limitations and enhance its therapeutic potential.en-USEnhanced bioavailabilityHepatic encephalopathyOptimizationRepurposingVardenafil dihydrochlorideArticlehttps://doi.org/10.1016/j.jddst.2025.106787