Pharm Res (2021) 38:991–1009 RESEARCH PAPER Enhanced Dermal Delivery of Flurbiprofen Nanosuspension Based Gel: Development and Ex Vivo Permeation, Pharmacokinetic Evaluations Ayse Nur Oktay 1,2 & Sibel Ilbasmis-Tamer 1 & Orhan Uludag 3 & Nevin Celebi 1,4 Received: 30 January 2021 /Accepted: 11 May 2021 # The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 ABSTRACT Purpose The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to inves- tigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters. Methods FB-NSs were developed using the wet milling pro- cess with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats. Results The particle size, polydispersity index and zeta poten- tial values of optimum NS were determined as 237.7 ± 6.8 nm, 0.133 ± 0.030 and - 30.4 ± 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the phys- ical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the C max of FB-NS gel was 2.5 times higher than the reference gel, while AUC 0–24 was 2.96 times higher. Conclusion FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel. KEY WORDS ex vivo . flurbiprofen . nanosuspension . pharmacokinetic . wet-milling ABBREVIATIONS BCS Biopharmaceutical Classification System COX Cyclooxygenase CPP Critical Process Parameters CQA Critical Quality Attributes DoE Design of Experiment FB Flurbiprofen HPH High-Pressure Homogenization NS Nanosuspension NSAID Nonsteroidal Anti-inflammatory Drugs PDI Polydispersity Index PL Plantacare 2000 PM Physical Mixture PS Particle Size QbD Quality by Design ZP Zeta Potential INTRODUCTION Biopharmaceutically appropriate formulations for insoluble active ingredients are a challenge because a slow and unsteady solution has become a barrier against the complete and rapid absorption of these ingredients from the gastrointestinal tract. Nanosuspensions (NS) may be an alternative approach to the * Nevin Celebi ncelebi51@gmail.com 1 Department of Pharmaceutical Technology, Gazi University-Faculty of Pharmacy, Ankara, Turkey 2 Department of Pharmaceutical Technology, University of Health Sciences- Gulhane Faculty of Pharmacy, Ankara, Turkey 3 Department of Pharmacology, Gazi University-Faculty of Pharmacy, Ankara, Turkey 4 Department of Pharmaceutical Technology, Başkent University-Faculty of Pharmacy, Ankara, Turkey https://doi.org/10.1007/s11095-021-03060-6 /Published online: 4 June 2021