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. The composition of optimized formulation was Glyceryl monostearate as a solid lipid (40 mg), 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 vivo experiments 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 Cmax, Tmax, AUC0-t, AUC0-∞, T1/2 and Ke 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-1 respectively. 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.

Intranasal solid lipid nanoparticles for management of pain: A full factorial design approach, characterization & Gamma Scintigraphy.

Pain is a noxious stimulus caused due to tissue damage and varies from mild to severe. Nalbuphine (NLB) is an approved, inexpensive, non-controlled, opioid agonist/antagonist analgesic used worldwide in various clinical settings for pain management. The current study aims to formulate NLB loaded solid lipid nanoparticles (SLNs) using solvent injection technology. The morphological and chemical structure of the developed SLNs were characterized using Field Emission Scanning Electron Microscopy (FESEM), Transmission Electron Microscopy (TEM) and Fourier Transformation Infrared Spectroscopy (FTIR). The results revealed from the point prediction confirmation in design expert software was the formulation of NLB-SLNs with an average particle size of (170.07 ± 25.1 nm), encapsulation efficiency (93.6 ± 1.5%) & loading capacity of 26.67%. The in-vitro permeation of developed NLB-SLNs was observed to be 94.18% at 8 h when compared with NLB solution whose maximum permeation was seen within 3 h of application. Efficacy of the formulation was also evaluated using eddy's hot plate method, where the onset of action started within 10 min of administration, and the maximum effect was observed at 1 h. The NLB-SLNs was screened for cytotoxicity in human embryonic kidney cells (HEK-293), and the dosage was considered safe when administered intranasally in animal since no detectable effect to the brain was observed. Biodistribution and gamma scintigraphy study of NLB-SLNs showed the prepared formulation reaching the target site, i.e. brain and was retained. Conclusively, the prepared NLB-SLNs formulation was safe and effective in producing an analgesic effect in vivo.