Akademik Veri Yönetim Sistemi
Journal of Drug Delivery Science and Technology, cilt.121, 2026 (SCI-Expanded, Scopus)
Cyclodextrin (CD) host prioritization in CD-functionalized dermal nanogels is still frequently guided by empirical choices, despite its central role in drug solubilization and dermal performance. In this study, a complementary ensemble-based in silico host–guest workflow was applied to comparatively evaluate candidate CD hosts for flurbiprofen (FPF) and to examine whether a previously prioritized and computationally supported host system would be associated with improved in vivo pharmacodynamic performance. Host–guest ensembles for alpha-cyclodextrin (α-CD), beta-cyclodextrin (β-CD), gamma-cyclodextrin (γ-CD), and 2-hydroxypropyl-beta-cyclodextrin (2HPβ-CD) were generated using CREST and evaluated with GFN2-xTB, and Boltzmann-weighted binding energies were used as a ranking proxy. Among the candidates, 2HPβ-CD exhibited the most favorable binding (−28.41 ± 0.94 kcal/mol; best −29.08 kcal/mol), outperforming α-CD (−17.22 ± 0.68 kcal/mol); β-CD (−22.90 ± 0.62 kcal/mol) and γ-CD (−21.46 kcal/mol). This ranking was consistent with our prior phase-solubility and solid-state/formulation characterization findings, which had already supported the prioritization of 2HPβ-CD over β-CD. Accordingly, an FPF-loaded 2HPβ-CD–functionalized nanogel was incorporated into an HPMC gel (FPF-NGH) and compared with an FPF- free nanogel in HPMC gel (Blank-NGH) and a coarse FPF in HPMC gel as reference (FPF-Gel). In the carrageenan-induced paw edema model, FPF-NGH significantly reduced paw swelling from early time points and maintained the lowest edema volumes during the inflammatory peak phase (3–8 h), whereas the Blank-NGH closely followed the control profile. In the tail-flick test, FPF-NGH produced a clear time-dependent antinociceptive response, reaching ∼25–27% at 180 min and exceeding the reference gel (∼6–8%). Overall, the results showed that ensemble-based xTB/CREST workflow provides practical computational support for an experimentally prioritized cyclodextrin host and highlights 2HPβ-CD–functionalized nanogels as a promising dermal delivery platform for poorly soluble NSAIDs such as FPF.