In Vitro Studies on Nasal Formulations of Nanostructured Lipid Carriers (NLC) and Solid Lipid Nanoparticles (SLN)

Abstract

The nasal route has been used for many years for the local treatment of nasal diseases. More recently, this route has been gaining momentum, due to the possibility of targeting the central nervous system (CNS) from the nasal cavity, avoiding the blood-brain barrier (BBB). In this area, the use of lipid nanoparticles, such as nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN), in nasal formulations has shown promising outcomes on a wide array of indications such as brain diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, Parkinson's disease and gliomas. Herein, the state of the art of the most recent literature available on in vitro studies with nasal formulations of lipid nanoparticles is discussed. Specific in vitro cell culture models are needed to assess the cytotoxicity of nasal formulations and to explore the underlying mechanism(s) of drug transport and absorption across the nasal mucosa. In addition, different studies with 3D nasal casts are reported, showing their ability to predict the drug deposition in the nasal cavity and evaluating the factors that interfere in this process, such as nasal cavity area, type of administration device and angle of application, inspiratory flow, presence of mucoadhesive agents, among others. Notwithstanding, they do not preclude the use of confirmatory in vivo studies, a significant impact on the 3R (replacement, reduction and refinement) principle within the scope of animal experiments is expected. The use of 3D nasal casts to test nasal formulations of lipid nanoparticles is still totally unexplored, to the authors best knowledge, thus constituting a wide open field of research.

Keywords: 3D nasal casts; in vitro cell cultures; nanostructured lipid carriers; nasal administration; solid lipid nanoparticles.

Figure 1

Schematic representation of the nasal cavity (top) and olfactory region (bottom): 1—vestibule, 2—respiratory region, 3—olfactory region, 4—cribriform plate.

Figure 2

Overview of the different drug pathways after nasal administration. (1) The drug is eliminated by the mucociliary clearance mechanism. (2) The drug reaches the olfactory mucosa, passes through the olfactory nerve, via intraneuronal and/or extraneuronal transport, and reaches the brain. (3) The drug reaches the olfactory mucosa, passes through the trigeminal nerve and reaches the brain via the cribriform plate. (4) The drug reaches the respiratory mucosa, passes through the trigeminal nerve and reaches the brainstem. (5) The drug reaches the respiratory mucosa, is absorbed into the systemic circulation, and diverges between passage to the brain, upon crossing the blood−brain barrier (BBB), and elimination, before reaching the brain.

Figure 3

Examples of different nasal casts: (A) 7-year-old child; (B) MRI image of a 12-year-old child; (C) made from CT-scan of an adult; (CA) nostrils, (CB) nasal vestibule, (CC) lower turbinates, (CD) middle and upper turbinates, (CE) nasopharynx; (D) CT-scan of a patient, (DF) anterior region, (DG) upper turbinates, (DH) middle turbinates, (DI) lower turbinates, (DJ) nasopharynx; (E) MRI image of a 53-year-old man, K—olfactory region; (F) silicone transparent commercial cast with Sar-gel (adapted from [90], with permission from Elsevier).

Figure 4

Evaluation of the deposition of fluticasone in situ gels in a 3D nasal cast covered with Sar-gel. (A) in situ gels of pectin and sodium hyaluronate, with an administration angle of 53° and a flow rate of 60 L/min; (B) in situ gel of pectin, with an administration angle of 33° and a flow rate of 60 L/min, (C) in situ gel of pectin, sodium hyaluronate and gellan gum, with an administration angle of 45° and a flow rate of 36 L/min (adapted from [70], with permission from Elsevier).