Percutaneous delivery of levetiracetam as an alternative to topical nonsteroidal anti-inflammatory drugs: formulation development, in vitro and in vivo characterization.

The study focused on formulation of carmellose sodium hydrogels and nonionic microemulsions with 5% and 10% of levetiracetam and investigation of drug concentration influence on their physicochemical characteristics and in-use stability as well as influence of drug concentration and carrier type on in vitro drug release and in vivo antihyperalgesic/antiedematous activity in a rat model of localized (intraplantar) carrageenan-induced inflammation. Hydrogels were pseudoplastic semisolids with thixotropy and pH 7.37-7.58. Microemulsions were low viscous Newtonian nanodispersions of oil droplets (13.11-15.11 nm) in water, with pH 4.01-4.64. Physical stability of the investigated systems was preserved over the 3-month storage under ambient conditions. Levetiracetam release followed zero order and Korsmeyer-Peppas models (R2 ≥ 0.99) reflecting the combined effects of drug concentration and carrier viscosity. All levetiracetam-loaded formulations produced significant reduction of hyperalgesia and paw swelling induced by carrageenan (p < 0.001). Their efficacy in exerting antihyperalgesic activity was significantly higher than that observed with the reference 5% ibuprofen hydrogel preparation (up to 6 h) (p < 0.001), while antiedematous activity was comparable with the reference product. No erythema and visible blood vessels were observed in a rat ear test. The study demonstrated percutaneous delivery of levetiracetam as useful and safe therapeutic option for localized inflammatory pain with potential to overcome the insufficient efficacy of topically applied nonsteroidal anti-inflammatory drugs in the form of a hydrogel. Graphical abstract.