Articaine in functional NLC show improved anesthesia and anti-inflammatory activity in zebrafish

Gustavo H Rodrigues Da Silva,Lígia N M Ribeiro,Eneida De Paula,Gabriela Geronimo,Márcia C Breitkreitz,Ludmilla D De Moura,Juan P García-López,Carmen G Feijóo

doi:10.1038/s41598-020-76751-6

Gustavo H Rodrigues Da Silva, Lígia N M Ribeiro + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-76751-6

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Abstract

Anesthetic failure is common in dental inflammation processes, even when modern agents, such as articaine, are used. Nanostructured lipid carriers (NLC) are systems with the potential to improve anesthetic efficacy, in which active excipients can provide desirable properties, such as anti-inflammatory. Coupling factorial design (FD) for in vitro formulation development with in vivo zebrafish tests, six different NLC formulations, composed of synthetic (cetyl palmitate/triglycerides) or natural (avocado butter/olive oil/copaiba oil) lipids were evaluated for loading articaine. The formulations selected by FD were physicochemically characterized, tested for shelf stability and in vitro release kinetics and had their in vivo effect (anti-inflammatory and anesthetic effect) screened in zebrafish. The optimized NLC formulation composed of avocado butter, copaiba oil, Tween 80 and 2% articaine showed adequate physicochemical properties (size = 217.7 ± 0.8 nm, PDI = 0.174 ± 0.004, zeta potential = − 40.2 ± 1.1 mV, %EE = 70.6 ± 1.8) and exhibited anti-inflammatory activity. The anesthetic effect on touch reaction and heart rate of zebrafish was improved to 100 and 60%, respectively, in comparison to free articaine. The combined FD/zebrafish approach was very effective to reveal the best articaine-in-NLC formulation, aiming the control of pain at inflamed tissues.

Highlights

Local anesthetics (LA) are essential drugs in dental practice, used to prevent pain by blockage of peripheral nerves
After assessing articaine compatibility with these excipients, their relative proportions and influence on the properties of the nanoparticles were evaluated by factorial design
Among several excipient options for developing an articaine-in-Nanostructured lipid carriers (NLC) formulation, we selected that composed of cetyl palmitate plus copaiba oil and Tween 80, since it showed the smallest size and polydispersity index (PDI), anti-inflammatory activity of excipients and potentiated anesthetic effect

Summary

Introduction

Local anesthetics (LA) are essential drugs in dental practice, used to prevent pain by blockage of peripheral nerves. In lipid-based drug delivery systems, olive and copaiba oils have already been tested as excipients that act synergistically with the encapsulated drug or aggregate therapeutic properties to the system[13]. In this way, the use of natural compounds as NLC-excipients arises as a plausible strategy for encapsulating ATC, coupling anesthesia and anti-inflammatory activities in dental treatments under inflammatory conditions. Its immune system is highly conserved in comparison to mammals, at molecular and cellular levels[18] For these reasons, zebrafish is an established model for the study of inflammatory d iseases[19] and has been used to model several human p athologies[20,21]. These features justify the use of zebrafish as a model for pharmaceutical technology and d evelopment[22]

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