26 2.8 347.33 four.two 256.54 3.2 7.78 4.two 15.42 4.two 51.44 2.2 32.11 4.4 43.31 1.9 155.06 4.8 eight.03 3.2 9.57 1.6 four.81 three.2 217.06 5.0 499.78 7.two Extrapolated AUC ( /mL or /g ) 2.17 1.five 0.04 3.2 0.77 four.two 0.ten 1.6 0.05 1.9 0.85 3.3 three.15 2.1 3.15 two.3 2.43 1.four 0.006 0.1 0.002 0.02 0.0001 0.02 1.08 0.two 1.91 0.four two.57 0.four 1.81 0.four 0.04 0.02 0.74 0.3 Elimination Rate Continuous (ke ) (h-1 ) 2.04 1.3 1014.06 4.two 414.19 four.six 38.20 1.two 136.71 2.5 192.66 2.two two.03 1.0 0.20 0.1 four.27 1.3 972.78 three.1 942.three three.2 1282.eight three.three 22.82 3.1 three.06 0.6 3.59 0.four 2.22 0.7 1072.two 3.two 451.26 4.three Half-Life (t1/2 ) (h) 0.33 0.two 0.0006 0.two 0.001 0.two 0.018 0.three 0.005 0.02 0.003 0.2 0.34 0.1 0.34 0.two 0.16 0.2 0.0007 0.01 0.0007 0.02 0.0005 0.01 0.03 0.02 0.22 0.2 0.19 0.2 0.30 0.2 0.0006 0.02 0.001 0.02 Imply Residence Time (MRT) (h) 0.32 0.ten 0.31 0.13 0.47 0.1 0.19 0.1 0.31 0.04 1.48 0.4 0.55 0.2 4.97 1.three 0.44 0.02 0.11 0.01 0.08 0.02 0.08 0.02 0.46 0.two 0.42 0.1 0.86 0.3 0.49 0.1 0.30 0.12 0.45 0.FormulationRouteOrgan/Compartment50 nm sized phenytoin KDM2 Purity & Documentation sodium loaded NLC 100 nm sized phenytoin sodium loaded NLC Handle drug solution (Drug in nasal pH buffer) GlyT1 Synonyms intranasal midazolam spray (marketed formulation) Intravenous Phenytoin sodium injection (marketed formulation) 50 nm sized phenytoin sodium loaded NLC sprayPlasma intranasal CSF Brain Plasma intranasal CSF Brain Plasma intranasal CSF Brain Plasma intranasal CSF Brain Plasma intravenous CSF Brain Plasma intranasal CSF BrainPharmaceutics 2021, 13,17 ofFigure 8A showed the mean liver, kidney, lung concentrations and Figure 9A showed spleen, pancreas and heart concentrations of phenytoin sodium following intranasal administration of phenytoin sodium NLCs, manage drug answer, midazolam spray marketed formulation and IV administration of phenytoin sodium marketed formulation performed in Wistar rats. Phenytoin was swiftly distributed into the liver following IV administration of phenytoin sodium and intranasal control drug option with the highest concentrations of 87.60 /g and 69.51 /g, respectively, in the finish of 30 min, which then decreased with time. On the other hand, the initial concentration of phenytoin within the liver was low at five min soon after administration of many sized intranasal NLC formulations and then increased with time reaching pretty much 14 /g at the finish of 60 min. The greater accumulation of phenytoin sodium in the liver benefits in phenytoin hepatotoxicity, which can be a severe idiosyncratic reaction linked with IV phenytoin therapy [46]. In actual fact, only a little amount of drug reached the liver in the smaller sized NLC through the intranasal olfactory route, that is comparable with that of intranasal midazolam spray marketed formulation. Thus, the study indicated that phenytoin sodium NLCs administered by way of the olfactory route doesn’t produce any liver toxicity, that is highly helpful within a clinical setup.Figure 8. Imply liver (A), kidney (B) and lung (C) drug concentration profiles following intranasal administration of phenytoin sodium NLCs, control drug option, midazolam spray marketed formulation and IV administration of phenytoin sodium marketed formulation. The level of statistical significance is expressed as a p-value; indicates p 0.05, indicates p 0.01, indicates p 0.001.Pharmaceutics 2021, 13,18 ofFigure 9. Imply spleen (A), pancreas (B) and heart (C) drug concentration profiles following intranasal administration of phenytoin sodium NLCs, manage drug solution, midazolam marketed formulation and IV administ