# Nanocarriers-Assisted Nose-to-Brain Delivery of Levodopa: Current Progress and Prospects
## 5 Biopharmaceutical Considerations of the Nose-to-Brain Drug Delivery
### Pharmaceutical Considerations  
The good mucosal penetrability and the sufficient contact time of the drug with the olfactory mucosa are essential for the effective nose-to-brain transport [95; 96]. Active or passive drug targeting, permeation enhancement, mucoadhesion, in situ gelling vehicles, and particulate delivery systems are all inevitable tools in the contemporary pharmaceutical development of nasal dosage forms. A successful active drug targeting in the olfactory zone is currently achieved by functionalization with biorecopizable ligands, examples of which are lectins, lectin-mimicking peptides, and lactoferrin [79; 97; 100; 101; 102; 103]. The use of mucoadhesive polymers, on the other hand, such as chitosan, carbopol, lectins, gums, pectin, alginates, soluble semi-synthetic cellulose derivatives, and various thiolated or else-functionalized derivatives of the above, ensures mucus penetration and adhesion of the formulation to the administration site; the leading mechanisms for this phenomenon involve covalent, hydrogen, ionic, and/or Van der Waal's binding with the MUCs and sialic acid residues [104; 105; 106; 107; 108]. To a certain extent, the mucoadhesive constituents increase the viscosity of liquid and semi-solid nasal vehicles and thereby favor a longer contact time and a relative resilience to mucociliary clearance; however, their presence may hinder the formulation's sprayability and the precise jet targeting to the olfactory region [109; 110; 111]. In this regard, the implementation of in situ gelling systems comprising of, or combined with, adhesive polymers is highly valued in nasal forms development. These normally liquid during storage systems tend to gel due to temperature-, pH-, or ion-determined stimuli received after application in the nasal cavity. Examples of in situ gelling excipients are the thermo-sensitive Poloxamers, the cation-sensitive gellan gum and low-methoxyl pectin, and some pH-sensitive chitosan-polyols dispersions [113; 114; 115; 116; 117]. Another strategic solution is devoted to the incorporation of mucoadhesive polymers into nano-particulate matter (mucoadhesive polymeric nanoparticles) and their intranasal administration in the form of a powder. This approach sets several advantages such as precise dosing and improved drug and formulation stability but suffers from lower tolerability and patient compliance, and higher production cost [118; 119; 120; 121; 122; 123]. The intranasal absorption of polar APIs, such as L-DOPA, may benefit from the addition of permeation enhancers [85; 124]. The latter are a heterogeneous group of excipients that increase the mucosal permeability by interacting with the cell junctions or the cell membrane lipids causing their fluidization, solubilization, extraction, or others [124; 125; 126; 127]. Additionally, the role of cell-penetrating oligopeptide excipients (rich in arginine and lysine residues) for the improved intracellular drug uptake upon nasal administration has been outlined by some authors [128; 129; 130; 131]. Classic permeation enhancers in nasal formulations include non-ionic surfactants, cyclodext, lipids, and some polymers (e.g., chitosan) [124; 125; 126; 127]. The alkylsaccharides dodecyl maltoside and tetradacyl maltoside have gained the most attention as mucosal permeation enhancers in nasal formulations because of their good tolerability and proven efficiency. These non-ionic surfactants are constituents of Intravail(r)--a registered trademark of Neurelis, Inc., San Diego, CA, USA; the product is currently used as a permeation-enhancing adjuvant in three FDA-approved products for intranasal administration--Tosymra(r) (sumatriptan), Valtoco(r) (diazepam), and Opvee(r) (nalmefene) [63; 132; 133]. The use of nanotechnologies allows many of the above-listed desired features to be brought together and for most requirements for intranasal drug delivery to be met.