Current endeavor was aimed towards studying significance of lipid composition on free propofol concentration in aqueous phase and associated pain on injection. Three different nanoformulations, namely long-chain triglyceride (LCT)/medium-chain glyceride (MCG)-based nanoemulsion (ProNano), MCG-based self-nanoemulsifying formulation (PSNE), and lipid-free nanoformulation (PNS) were accessed for the same. In vitro and in vivo performances of developed formulations were compared with Diprivan®. ProNano showed minimum free propofol concentration (0.13%) and hence lower pain on injection (rat paw-lick test, 6 ± 2 s) compared to Diprivan®, PSNE, and PNS (0.21%, 0.23%, and 0.51% free propofol, respectively, and rat paw-lick test; 12 ± 3, 14 ± 2, and 22 ± 3 s, respectively). These results conjecture the role of MCG in effective encapsulation of propofol. Anesthetic action assessed by measuring duration of loss of righting reflex (LORR), which was found similar in case of ProNano and PSNE (14 ± 3 and 15 ± 3 min, respectively) compared to Diprivan® (13 ± 3 min). In case of lipid-free formulation, PNS, extended anesthetic action (21 ± 2 min) was observed which may be due to sustained release of propofol from nanosponges. Studies on effect of lipoproteins on propofol release highlighted significance of HDL (100% release with maximum concentration of about 1.2 μg/ml of HDL) from all three formulations.
Nanostructured lipid carrier (NLC) of propofol was formulated using hot emulsification-probe sonication method for improvising its parenteral delivery by reducing pain on injection and risk of microbial contamination. The formulated NLC was optimized using central composite design and evaluated for particle size, zeta potential, morphology, free propofol concentration, hemocompatibility, stability, pain on injection, in vivo anesthetic activity, pharmacokinetics, and antimicrobial effectiveness in comparison to the marketed formulation. Optimized NLCs exhibited globule size, less than 200 nm, and zeta potential − 24.1 mV, indicating its stability. TEM images confirmed the spherical shape and nanosize (200 nm) of optimized NLCs. Free propofol concentration was also found to be 40% lesser than marketed formulation. Optimized NLC was found to be non-hemolytic. Rat paw-lick study showed that propofol NLC was significantly less painful compared to the marketed formulation. Anesthetic potential and pharmacokinetics of optimized NLCs were found to be similar to that of the marketed formulation. NLC was found stable in long-term storage under room temperature. Antimicrobial effectiveness study showed that propofol NLC suppressed microbial growth to a greater extent as compared to the marketed formulation. Hence, the developed propofol NLCs appeared to be clinically useful as a potential carrier for propofol delivery.
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