Abstract
Nanoparticles are promising mediators to enable nasal systemic and brain delivery of active compounds. However, the possibility of reaching therapeutically relevant levels of exogenous molecules in the body is strongly reliant on the ability of the nanoparticles to overcome biological barriers. In this work, three paradigmatic nanoformulations vehiculating the poorly soluble model drug simvastatin were addressed: (i) hybrid lecithin/chitosan nanoparticles (LCNs), (ii) polymeric poly-ε-caprolactone nanocapsules stabilized with the nonionic surfactant polysorbate 80 (PCL_P80), and (iii) polymeric poly-ε-caprolactone nanocapsules stabilized with a polysaccharide-based surfactant, i.e., sodium caproyl hyaluronate (PCL_SCH). The three nanosystems were investigated for their physicochemical and structural properties and for their impact on the biopharmaceutical aspects critical for nasal and nose-to-brain delivery: biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucosa. All three nanoformulations were highly reproducible, with small particle size (∼200 nm), narrow size distribution (polydispersity index (PI) < 0.2), and high drug encapsulation efficiency (>97%). Nanoparticle composition, surface charge, and internal structure (multilayered, core–shell or raspberry-like, as assessed by small-angle neutron scattering, SANS) were demonstrated to have an impact on both the drug-release profile and, strikingly, its behavior at the biological interface. The interaction with the mucus layer and the kinetics and extent of transport of the drug across the excised animal nasal epithelium were modulated by nanoparticle structure and surface. In fact, all of the produced nanoparticles improved simvastatin transport across the epithelial barrier of the nasal cavity as compared to a traditional formulation. Interestingly, however, the permeation enhancement was achieved via two distinct pathways: (a) enhanced mucoadhesion for hybrid LCN accompanied by fast mucosal permeation of the model drug, or (b) mucopenetration and an improved uptake and potential transport of whole PCL_P80 and PCL_SCH nanocapsules with delayed boost of permeation across the nasal mucosa. The correlation between nanoparticle structure and its biopharmaceutical properties appears to be a pivotal point for the development of novel platforms suitable for systemic and brain delivery of pharmaceutical compounds via intranasal administration.
Highlights
Nasal delivery is emerging as one of the most interesting routes for the systemic delivery of pharmacologically active molecules and a viable alternative to more conventional oral and parenteral administration
In the case of nose-to-brain delivery, nanoparticles could improve drug brain availability in the brain promoting the transport of the encapsulated drug across the neuroepithelium either by a transcellular pathway followed by axonal transport or paracellularly, promoting the diffusion into the brain perineurally or perivascularly.[11,16]
Delivery efficiency seems strongly dependent on the nanoparticle properties because of increased residence time in the nasal cavity, increased efficiency of drug release, and improved bioavailability through the enhancement of transport of active ingredients across biological membranes.[42]
Summary
Nasal delivery is emerging as one of the most interesting routes for the systemic delivery of pharmacologically active molecules and a viable alternative to more conventional oral and parenteral administration. In the case of nose-to-brain delivery, nanoparticles could improve drug brain availability in the brain promoting the transport of the encapsulated drug across the neuroepithelium either by a transcellular pathway followed by axonal transport or paracellularly, promoting the diffusion into the brain perineurally or perivascularly.[11,16] Another aspect to consider is that sometimes the improvement of the nasal transport of encapsulated drugs is due to the shielding of the drug from enzymatic degradation and to diminished nasal clearance, which may occur either by increased retention time or by enhanced carrier permeation across the nasal epithelium.[17−20] These open issues involve the structural and molecular aspects of nanoparticles, including size, surface properties, and internal arrangement These features are likely to determine the biopharmaceutical behavior of the formulation and in particular how and how efficiently the drug is transported across the biological barriers, such as the nasal mucosa
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