Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of − 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine (¹³¹I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain. Graphical Abstract

In spite of the great advance in drug delivery systems (DDSs) for the control of the neurological disorders like Alzheimer's disease, Parkinson's disease, epilepsy and seizures, yet there is a demand for innovative DDSs for brain targeting. The biggest hurdle for directing the drug to the brain is the presence of the blood-brain barrier (BBB) which hampers the passage of medicants to the brain. Many recent approaches to allow carriage of medicaments to the brain have come out during the last twenty years. Intranasal delivery of drugs is one of these approaches which can bypass the BBB in a noninvasive way. Lipid nanocapsules (LNCs) act as an appropriate platform and novel strategy for nose to brain drug delivery due to their several advantages. They can be produced in a quick, simple, solvent-free and scalable-up process. Therefore, this review depicts mechanisms of nose-to-brain drug delivery and the several approaches for improving nasal absorption of drugs with a special emphasis on lipid nanocapsules-based approaches. It discusses the composition and method of preparation of LNCs, their advantages and their application in nose to brain drug delivery. The upcoming prospect of nasal drug delivery to the brain is also discussed.