Intranasal delivery of Naloxone-loaded solid lipid nanoparticles as a promising simple and non-invasive approach for the management of opioid overdose

Naloxone is an opioid receptor antagonist that can eradicate all pre-indications of the toxicity and inverse the opioid overdose. However, oral administration of naloxone offers limitations such as its extensive first-pass metabolism that results in poor therapeutic effects. In order to resolve this issue, we developed intranasal solid-lipid nanoparticles in which naloxone was incorporated for the higher brain disposition of naloxone with superior therapeutic effects for the reversal of toxicity of opioid overdose. The preparation of naloxone loaded solid-lipid nanoparticles was done by employing the solvent evaporation method. Later, the designed formulation was optimized by Quality by Design approach, specifically, Box-Behnken method.

Highlights

Optimization and preparation of NLX-loaded SLNs for the management of opioid overdose.

Intranasal delivery of NLX-SLNs exhibited the superior drug disposition as compared to NLX solution.

Improved overall therapeutic outcomes showed by NLX-SLNs as compared to NLX solution.

Various investigations exhibited promising outcomes for the management of opioid overdose.

NLX-loaded SLNs considered as safe in pre-clinical toxicity studies.

The composition of optimized formulation was Glyceryl monostearate as a solid lipid (40mg), Pluronic127 (0.5%) and Tween 80 (0.1%) as a surfactant and co-surfactant, respectively. Furthermore, the characterization of optimized formulation was achieved in terms of particle size, PDI, zeta potential, entrapment efficiency, and drug loading which were 190.2 nm, 0.082, -16 mV, 95 ± 0.532 and 19.08±0.106, respectively. Afterwards, in vitro, ex vivo and in vivoexperiments were performed in which higher drug release and superior drug uptake by nasal membrane were observed for naloxone-loaded solid-lipid nanoparticles, later it was confirmed by confocal microscopy of ex vivo nasal membrane tissue. The findings of gamma scintigraphy investigation exhibited better deposition of naloxone-loaded solid-lipid nanoparticles as compared to naloxone solution. Also, the better deposition of naloxone by gamma scintigraphy was further validated by the investigation through the biodistribution study. Additionally, the key findings of the pharmacokinetic study revealed C_max, T_max, AUC_0-t, AUC_0-∞, T_1/2 and K_e was found to be 163.95 ± 2.64 ng/ml, 240 ± 2.1 min, 17.75±1.08 ng.hr/ml, 18.82±2.51 ng.hr/ml, 70.71±0.115 min, 0.098±0.01 h^-1respectively. Lastly, investigations such as weight variation and histopathological proved the plausible potential of naloxone-loaded solid-lipid nanoparticles in terms of safety as no toxicity was noticed even after the administration of the three-folds dose of the normal dose. Therefore, considering all these findings, it could be easy to say that these developed naloxone-loaded solid-lipid nanoparticles could be administrated via intranasal route and can act as successful novel nanoformulation for the effective treatment of opioid overdose. More on Intranasal delivery of Naloxone-loaded solid lipid nanoparticles