Solid Lipid Nanoparticles for Dibucaine Sustained Release.

Raquel De M Barbosa,Nelson Duran,Daniele R De Araújo,Eneida De Paula,Ligia N M Ribeiro,Viviane A Queiróz,Patrícia Severino,Camila M G Da Silva,Bruna R Casadei

doi:10.3390/pharmaceutics10040231

Raquel De M Barbosa, Nelson Duran + Show 7 more

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https://doi.org/10.3390/pharmaceutics10040231

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Dibucaine (DBC) is among the more potent long-acting local anesthetics (LA), and it is also one of the most toxic. Over the last decades, solid lipid nanoparticles (SLN) have been developed as promising carriers for drug delivery. In this study, SLN formulations were prepared with the aim of prolonging DBC release and reducing its toxicity. To this end, SLN composed of two different lipid matrices and prepared by two different hot-emulsion techniques (high-pressure procedure and sonication) were compared. The colloidal stability of the SLN formulations was tracked in terms of particle size (nm), polydispersity index (PDI), and zeta potential (mV) for 240 days at 4 °C; the DBC encapsulation efficiency was determined by the ultrafiltration/centrifugation method. The formulations were characterized by differential scanning calorimetry (DSC), electron paramagnetic resonance (EPR), and release kinetic experiments. Finally, the in vitro cytotoxicity against 3T3 fibroblast and HaCaT cells was determined, and the in vivo analgesic action was assessed using the tail flick test in rats. Both of the homogenization procedures were found suitable to produce particles in the 200 nm range, with good shelf stability (240 days) and high DBC encapsulation efficiency (~72–89%). DSC results disclosed structural information on the nanoparticles, such as the lower crystallinity of the lipid core vs. the bulk lipid. EPR measurements provided evidence of DBC partitioning in both SLNs. In vitro (cytotoxicity) and in vivo (tail flick) experiments revealed that the encapsulation of DBC into nanoparticles reduces its intrinsic cytotoxicity and prolongs the anesthetic effect, respectively. These results show that the SLNs produced are safe and have great potential to extend the applications of dibucaine by enhancing its bioavailability.

Highlights

Effective pain management is one of the most difficult challenges in medicine
We considered encapsulating DBC in solid lipid nanoparticles (SLN) to enhance its bioavailability and to minimize its systemic toxicity [13,14]
SLN formulations were prepared with Myristyl myristate (MM) or cetyl palmitate (CP) as solid lipids plus Pluronic F68 as surfactant and using one of the two different homogenization techniques: H-P or U-S

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Introduction

Effective pain management is one of the most difficult challenges in medicine. Local anesthetics (LA) are broadly used in algiatry to reversibly block neural transmission, curbing the pain sensation [1].Chemically, LAs are amphiphiles whose potency and toxicity are directly related to the hydrophobic character of the compound [2].In clinical practice, dibucaine (DBC), from the amine/amide family, differs from other commonly used LAs due to its large quinoline ring to which a butyl ether group is attached [3]. Effective pain management is one of the most difficult challenges in medicine. Local anesthetics (LA) are broadly used in algiatry to reversibly block neural transmission, curbing the pain sensation [1]. Dibucaine (DBC), from the amine/amide family, differs from other commonly used LAs due to its large quinoline ring to which a butyl ether group is attached [3]. This rigid ring modulates DBC’s interaction with membranes, restricting the insertion of DBC to in-between the lipids [4]. DBC exhibits long-lasting action [5] and it is considered quite toxic to the central nervous and cardiac systems, with reports of convulsions, hypoxia, acidosis, arrhythmia, and cardiac arrest [6]

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