Co-Delivery of Fluconazole and Riparin B Using Nanostructured Lipid Carriers: A Quality-by-Design Approach for Enhanced Antifungal Activity

Background/Objectives: The increasing incidence of invasive fungal infections and the emergence of antifungal resistance have limited the effectiveness of conventional therapies against Candida spp. This study aimed to develop and optimize nanostructured lipid carriers (NLCs) containing fluconazole (FLC) and Riparin B (RIP) using a systematic Quality-by-Design (QbD) approach. Methods: The optimized NLCs were characterized by particle size, polydispersity index (PDI), zeta potential, DSC, and FTIR analyses. Molecular docking was used as a complementary exploratory approach to investigate possible interactions of RIP with representative components of the lipid matrix and with fungal resistance-associated proteins. Release profiles and antifungal activity against Candida spp. were also evaluated. Results: The optimized NLCs exhibited a mean particle size of 144.9 ± 2.25 nm, PDI of 0.153 ± 0.03, and zeta potential of −27.8 ± 1.81 mV. DSC and FTIR analyses supported the structural organization of the lipid matrix and the formation of an imperfect crystalline network, providing structural defects favorable for the incorporation of the active compounds. RIP exhibited more favorable predicted interactions than FLC within the specific lipid configuration evaluated, although these docking scores should not be interpreted as direct thermodynamic measurements of drug–lipid affinity or as quantitative predictors of encapsulation efficiency. Docking analyses with MdR1, CdR1, and CdR2 identified possible interactions of RIP with these resistance-associated proteins, providing a structural hypothesis that may contribute to understanding the potentiation of FLC activity. However, these computational results do not establish direct efflux-pump inhibition. Release profiles followed distinct kinetic regimes, consistent with matrix relaxation for RIP and Fickian diffusion for FLC. Although RIP alone did not exhibit relevant antifungal activity, its association with FLC potentiated FLC activity against Candida spp., while incorporation of the combination into NLCs produced a further enhancement, significantly reducing the minimum inhibitory concentration. Conclusions: These findings indicate that the optimized NLC platform can enhance the antifungal performance of the FLC–RIP combination and provide a formulation framework for further investigation of this co-delivery strategy.