The upper respiratory tract is a major route of infection for COVID-19 and other respiratory diseases. Thus, it appears logical to exploit the nose as administration site to prevent, fight or minimize infectious spread and treat the disease. Numerous nasal products addressing these aspects have been considered and developed for COVID-19. This review gives a comprehensive overview of the different approaches involving nasal delivery, i.e. nasal vaccination, barrier products and anti-viral pharmacological treatments that have led to products on the market or under clinical evaluation, highlighting the peculiarities of the nose as application and absorption site and pointing at key aspects of nasal drug delivery. From analysis of nasal delivery strategies to prevent or fight COVID-19, it emerges that, especially for nasal immunization, formulations appear the same as originally designed for parenteral administration, leading to suboptimal results. On the other hand, mechanical barrier and anti-viral products, designed to halt or treat the infection at early stage, have been proven effective, but were rarely brought to the clinics. If supported by robust and targeted product development strategies, intranasal immunization and drug delivery can represent valid and sometimes superior alternatives to more conventional parenteral and oral medications.

Quercetin (Que) is one of the most studied flavonoids with strong antioxidant properties ascribed to its ability to bind free radicals and inactivate them. However, the low solubility of the compound along with its inadequate absorption after oral administration limit its beneficial effects. Que’s complexation with two different cyclodextrin (CD) derivatives (hydroxypropyl-β-CD and methyl-β-CD) via the neutralization/lyophilization method has been found to improve its physicochemical properties. Moreover, blends of the lyophilized powders with mannitol/lecithin microparticles (MLMPs) have been proposed as candidates for intranasal (IN) administration after in vitro and ex vivo evaluations. In this context, a comparative pharmacokinetic (PK) study of the IN vs oral administration of Que lyophilized powders and their blends with MLMPs (75:25 w/w) was performed on Wistar rats. The PK parameters estimated by a non-compartmental analysis using the sparse data methodology in Phoenix^® 8.3 (Certara, Princeton, NJ, USA) illustrated the effectiveness of IN administration either in brain targeting or in reaching the bloodstream. Significant levels of the compound were achieved at both sites, compared to those after oral delivery which were negligible. These results favor the potential application of the prepared Que nasal powders for systemic and nose-to-brain delivery for the prevention and/or treatment of neuroinflammatory degenerative conditions, such as Parkinson’s and Alzheimer’s disease.

Loco-regional chemotherapy is a strategy used to achieve more precise anticancer drug effect directly on tumor mass, while decreasing whole body exposure, which can lead to undesirable side effects. Thus, the loco-regional chemotherapy is conceptually similar to the targeted drug delivery systems for delivering chemotherapeutics to cancer cells in a certain location of the body. Recently, it has been demonstrated that a novel polymeric film containing the complex between cisplatin (cisPt) and hyaluronan (sodium salt of hyaluronic acid; NaHA) enhanced in vivo efficacy and safety of cisplatin (cisPt) by loco-regional delivery in pleural mesothelioma. Biologically, hyaluronic acid (HA) binds with the CD44 receptor, which is a transmembrane glycoprotein overexpressed by other cancer cells. Thus, administering both cisPt and hyaluronan together as a complex loco-regionally to the tumor site could target cancer cells locally and enhance treatment safety. A slight excess of hyaluronan was required to have more than 85% cisPt complexation. In cell monolayers (2D model) the cisPt/NaHA complex in solution demonstrated dose- and time-dependent cytotoxic effect by decreasing the viability of pancreatic, melanoma, and lung cell lines (they all express CD44). At the same concentration in solution, the complex was as effective as cisPt alone. However, when applied as film to melanoma spheroids (3D model), the complex was superior because it prevented the tumor spheroid growth and, more importantly, the formation of new cell colonies. Hence, cisPt/NaHA complex could work in preventing metastases loco-regionally and potentially avoiding systemic relapses.

Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3–4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).

Background and Purpose: Aiming to achieve light sedation via intranasal administration, this study showed that propofol (PPF) did not permeate across the rabbit nasal mucosa ex vivo from its marketed emulsion for injection. Experimental approach: Dilution of the emulsion with methyl-b-cyclodextrin in saline solution increased propofol solubility in water and diffusion across the nasal epithelium. Key results and conclusion: Despite these positive effects of the cyclodextrin, the amount of PPF permeated was minimal in 3 h, exceeding the formulation residence time in the nose. These results highlight the key role of formulation and the need for innovation in solubility and transmucosal transport enhancement techniques to optimize drug delivery and therapeutic efficacy.