A recent study published on Tandfonline by Expert Opinions On Drug Delivery gives a comprehensive overview of the different approaches involving nasal delivery 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.
In the years 2019–2023, the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) triggered an unprecedented pandemic. SARS-CoV-2 is mainly transmitted via respiratory particles emitted by infected subjects. The virus infects and replicates in the upper airways and then passes to the lungs, potentially leading to severe pneumonia.
A higher viral load and replication rate have been discovered in the nasopharynx than in the oral cavity and the nose is the site of entry and primary infection of SARS-CoV-2. Considering SARS-CoV-2 transmission and initial phases of the infection, it appears clear that the nose represents a unique opportunity for the prevention or the treatment of COVID-19.
In the wake of the COVID-19 pandemic, the research efforts have been directed toward three main target products: nasal vaccines for immunization against SARS-CoV-2, nasal medical devices to protect from the transmission of the virus and nasal drug products delivering neutralizing or virucidal antiviral substances, as well as modulators of immune and inflammatory responses. All these strategies exploiting nasal administration will be reviewed and critically appraised in the following sections with the focus on the nose and its peculiarities as administration site.
The mucosal immune system is the largest immunocompetent tissue in the human body. The nose is a perfect target for mucosal vaccination against airborne pathogens following the same route taken by the SARS-CoV-2 virus
Currently, there are 8 nasal vaccines against SARS-CoV-2 in ongoing clinical development with one being currently in Phase 3 randomized, placebo-controlled trials. This is the DelNS1–2019-nCoV-RBD-OPT1 based on a replicating viral vector (Wantai Biological, Beijing, China; University of Hong Kong, and Xiamen University, Xiamen, Fujian, China). In addition, following COVID-19 vaccines have been approved in local markets using nasal or airways administration.
Despite some late approvals of nasal vaccines of SARS-CoV-2 in local markets, the interest toward nasal vaccination to prevent the earliest stages of bacterial and viral respiratory infections is not fading. In the next 5 years, the European Vaccine Initiative will coordinate the activities of the NOSEVAC Consortium, funded in May 2023 by the European Commission to develop nasal vaccines, including a bivalent one for influenza and COVID-19
Nasal barrier products do not generally claim a direct and specific action on the virus as main feature, but are often designed to create a physical barrier that hinders the interaction between pathogens and epithelial cells of the upper airways. A number of nasal ‘barrier’ products have been developed, able to limit or prevent pathogen access to the host nasal cavity epithelia.
Carrageenans are natural sulfated polygalactans, derived from edible red seaweeds. In a pilot multicenter, randomized, double-blind, placebo-controlled study conducted in 10 hospitals in Argentina, a nasal spray containing 1.7 mg/ml iota-carrageenan was administered in four daily doses for 21 days to 394 clinically healthy physicians, nurses, and other personnel managing patients hospitalized for COVID-19.
It resulted that the carrageenan-containing nasal formulation contributed to a statistically significant reduction (p = 0.03) in the incidence of COVID-19 cases among the individuals treated (196 individuals, 1% infected) with the active formulation with respect to those receiving the placebo (198 individuals, 5% infected)
During the pandemic, astodrimer properties against COVID-19 were studied in view of its nasal application. In a study, a nasal spray containing 1% (w/w) astodrimer sodium was evaluated as a potential barrier in a K18-hACE2 mouse model for 7 days. The study demonstrated that SARS-CoV-2 replication and the production of several pro-inflammatory cytokines (IL-6, IL-1α, IL-1β, TNFα and TGFβ, and chemokine MCP-1) were suppressed.
ViralezeTM is a marketed nasal spray developed by Starpharma (Abbotsford, VIC, Australia) also containing 1% (w/w) astodrimer sodium as active ingredient. It emerged that 10–15 min of exposure to astodrimer sodium was sufficient to reduce the viral infectivity by more than 99.9%.
Fais et al. evaluated a possible application of a bentonite-containing nasal spray (Bentrio®, Altamira Therapeutics Inc., Hamilton Bermuda) as barrier product against SARS-CoV-2 infection, testing it on an in vitro 3D model of the primary human upper airway epithelium (MucilAir™, Epithelix, Plan-les-Ouates, Switzerland) pooled from 14 healthy adult male and female donors and reconstituted as a 3D tissue.
The results show that during the prophylactic treatment with the nasal product, the reduction was higher (99%) when cells were infected with wild-type SARS-CoV-2 and lower (83%) when the Delta variant was used. However, when Bentrio® was applied 24 h post infection, a reduction of the viral titer by 12-folds and 3-folds on day 4 was registered, respectively for wild-type SARS-CoV-2 and Delta variant.
Aiming to an antiviral effect targeted to the nasal mucosa, favipiravir (FVP) is an antiviral drug approved in Japan as a treatment for novel or re-emerging influenza RNA viruses. Favipiravir has poor aqueous solubility and good permeability. Alcantara et al. were able to enhance FVP activity in vitro by microencapsulating it into chitosan/alginate nanoparticles. Despite the formulation effort, the therapeutic value of this strategy warrants further confirmation.
The intranasal use of ivermectin in COVID-19 was evaluated in humans by an Egyptian team. Intranasal ivermectin added to standard care, caused rapid viral clearance and recovery from anosmia, cough, dyspnea. In a subsequent study on patients with persistent post-COVID-19 anosmia, the nasal IVM-treated group recovered from anosmia in 13 days compared to the 50 days of the placebo group. According to ClinicalTrial.gov database, there are no ongoing clinical trials on intranasal ivermectin.
Azelastine inhibits SARS-CoV-2 by binding the ACE2 receptor, which the virus uses to enter cells. The in vitro EC50 of about 6.5 µM (Vero cells infected with SARS-CoV-2) was hundreds of folds lower than the concentration of the marketed spray.
The available data about chlorpheniramine maleate (CPM) in COVID-19 come from one paper by Westover et al., reporting CPM virucidal efficacy in vitro in Vero 76 cells infected with SARS-CoV-2. No mechanistic information is reported, but CPM-dependent inhibition of influenza virus was attributed to interference with the viral entry into cells.
SaNOtize biotech company (Vancouver, Canada) registered a nitric oxide nasal spray as medical device (NORSTM patented technology). SaNOtize claims a double action for the spray proposed as treatment or prevention tool, i.e., physical/chemical barrier and NO effect. In a Phase 3 trial vs. placebo, COVID-19 patients treated with the spray had viral load reduced by more than 94% within 24 h from treatment.
Acknowledging the route of infection and pathogen entry in SARS-CoV-2 and other airborne diseases, it appears logical to include the respiratory system and especially the nose in the forefront of prevention and early control strategies. However, current results with nasal vaccines emphasize the need for different and more effective products. In that respect, joint research forces are needed to find safe and efficient mucosal adjuvants boosting safe antigens such as mRNA-based or subunit vaccines.
Considering that the nose represents the main site for SARS-CoV-2 transfection, it is mandatory to adopt preventive measures that protect the nasal epithelium against the widest possible range of viral variants.
Finally, direct antiviral activity at the site of first contact is a reasonable, but not yet fully explored option. Despite some positive results, full clinical assessment of such formulations is still missing, and no new small molecules have been developed in the course of COVID-19 so far.
The learning from nasal products in COVID-19 in terms of immunological impact, local drug effects, user feedback and, importantly, the selection of formulation and delivery system will be very valuable and can be extended to other airborne diseases in the future.