# Nanocarriers-Assisted Nose-to-Brain Delivery of Levodopa: Current Progress and Prospects
## 5 Biopharmaceutical Considerations of the Nose-to-Brain Drug Delivery  
### Anatomy of the Nasal Cavity  
The nasal cavity is composed of bone, cartilage, and soft tissues, building a complex architecture and assuring its two main physiological functions--respiratory and olfactory. Overall, the compartment extends from the hard palate to the cribriform plate and is divided into two symmetrical units by the longitudinally positioned nasal septum. The approximate length and surface area of the interior cavity are 14 cm and 160 cm\({}^{2}\), respectively. Along the central axis, three conchae segregate the inferior, middle, and superior meatus and secure the proper conditioning of the airflow [82; 83; 84]. The lateral walls of the nasal cavity possess tiny orifices that provide connections to the frontal, ethmoid, maxillary, and sphenoid sinuses, to the Eustachian tube, and to the nasolacrimal channel [60]. The tissue lining of the nasal cavity evolves from haired skin in the nasal vestibule, through stratified squamous epithelium and transitional pseudostratified columnar epithelium in the following about 0.6 cm\({}^{2}\), to respiratory mucosa spreading throughout the rest of the cavity and the upper airways [85; 86]. The mucosal epithelium in the respiratory segment is composed of ciliated columnar epithelial cells, goblet cells (secretory unicellular glands), basal cells, and non-ciliated cells. The presence of microvilli--fingerlike cytoplasmic formations on the apical site of the ciliated and non-ciliated cells--significantly increases the mucosal surface [60]. Beneath the mucosal epithelia lay the basal membrane and lamina propria. Although the nasal respiratory mucosa is a suitable entry site for systemic drug absorption because of the rich vascularization and the larger surface area (as compared to other regions in the cavity), the olfactory zone is the one of interest for nose-to-brain delivery. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**API** & & **Scientific Goal** & **Reference** \\ \hline Levodopa & \(\bullet\) & Increasing the brain bioavailability & [70; 71] \\  & \(\bullet\) & Reducing the dopamine-associated side effects & \\ \hline Rotigotine & \(\bullet\) & Overcoming the limitations of the transdermal route of & \\  & & administration (low systemic bioavailability (-37\%), poor BBB & [72; 73; 74] \\  & & permeation, drug crystallization in patch upon storage) & \\ \hline Pentamidine & \(\bullet\) & Ensuring brain bioavailability by bypassing the BBB & [75] \\ \hline Ropinirole & \(\bullet\) & Increasing the brain bioavailability & \\  & & Obtaining sustained drug delivery and decreasing the administration & [76; 77; 78] \\  & & frequency & \\ \hline Urocortin & \(\bullet\) & Ensuring brain bioavailability by bypassing the BBB & \\  & & Enhancing permeation through active drug targeting to the olfactory & \\  & & epithelium by the use of odoramalectin & \\ \hline Geraniol/ursodeoxycholic acid conjugate & \(\bullet\) & Overcoming low bioavailability upon oral intake & \\  & & Development of new prodrug of ursodeoxycholic acid with geraniol & [80] \\  & & with the aid to yield two active metabolites & \\ \hline Paeoniflorin & \(\bullet\) & Ensuring brain bioavailability by bypassing the BBB & [81] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Antiparkinson APIs investigated for intranasal drug delivery. The olfactory region is suited in the uppermost part of the nasal cavity and occupies 5-10% (-10 cm\({}^{2}\)) of the total surface area (Figure 2). The mucosal lining thereon--the so-called olfactory mucosa--differentiates by the lack of goblet cells, the lower density of ciliated cells, the additional presence of olfactory sensory neurons, supporting (sustentacular) cells, and low-viscous mucus-producing Bowman glands (specific diversity of serous glands) in lamina propria [61; 87; 88]. These particularities provide the specific sensory function of this compartment and its optimal physiological maintenance.