VALIDATED NOVEL SPECTROSCOPIC METHOD FOR ESTIMATION OF TRIAMCINOLONE ACETONIDE IN NASAL SPRAY

A simple, sensitive, accurate, precise and cost-effective pH independent spectrophotometric method has been developed for the estimation of triamcinolone acetonide in nasal sprays. Estimation was carried out at the isosbestic point of drug solutions, Isosbestic point was measured by scanning equimolar solution of triamcinolone acetonide separately in phosphate buffer pH 3.0, phosphate buffer pH 7.0 and phosphate buffer pH 10.0 at a concentration of 10 µg mL-1. They were scanned in the wavelength range of 200-400 nm. The isosbestic point was found to be 230.0 nm in acidic, basic and neutral condition; hence pH independent wavelength 230 nm was used for estimation of triamcinolone acetonide. The method observed linear response in the concentration range of 3-18 µg mL-1 at 230 nm. Developed method has been validated in accordance with ICH guideline Q2 R1 for several parameters like linearity, precision, accuracy, limit of detection and limit of quantification. The developed and validated analytical method was successfully applied to the estimation of triamcinolone acetonide in marketed nasal spray formulations.

Trends in Nasal Spray Prescribing Patterns by Otolaryngologists in the US Medicare Population

Objectives: To quantify national and state-level prescribing and cost trends for the 3 most prescribed nasal sprays by otolaryngologists in the Medicare population. Methods: Through the Centers for Medicare and Medicaid Services (CMS) database and the Kaiser Family Foundation, we retrieved data on Medicare enrollment and on claims and costs of fluticasone propionate, azelastine HCl, and ipratropium bromide prescribed by otolaryngologists from January 1, 2013 to December 31, 2017. Results: From 2013 to 2017, CMS reimbursed $128.8 million for 5.2 million claims of fluticasone propionate, azelastine HCl, and ipratropium bromide prescribed by otolaryngologists. The national claim rate for fluticasone propionate increased 6.5% per year from 2013 to 2015 and then decreased 4.3% per year from 2015 to 2017 while azelastine HCl and ipratropium bromide consistently increased annually (19.0% and 12.2% respectively) from 2013 to 2017. The cost for fluticasone propionate decreased 33.0% a year from 2013 to 2015 and then increased 5.4% annually to $13.60 per claim in 2017. Azelastine HCl decreased 14.8% annually from $91.30 to $50.23 per claim and ipratropium bromide increased 5.2% annually to $34.78 in 2017. Variations in the claim rate and cost for all 3 nasal sprays were observed in some states. Conclusions: Otolaryngologists are prescribing azelastine HCl and ipratropium at an increasingly higher rate in the Medicare population, while the rate for fluticasone propionate has been decreasing nationally. Utilization and costs of nasal sprays also vary geographically across the United States.

Hydroxypropyl Methylcellulose-Based Nasal Sprays Effectively Inhibit In Vitro SARS-CoV-2 Infection and Spread

The ongoing coronavirus disease (COVID-19) pandemic has required a variety of non-medical interventions to limit the transmission of the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One such option is over-the-counter nasal sprays that aim to block virus entry and transmission within the nasal cavity. In this study, we assessed the ability of three hydroxypropyl methylcellulose (HPMC)-based powder nasal sprays, produced by Nasaleze, to inhibit SARS-CoV-2 infection and release in vitro. Upon application, the HPMC powder forms a gel-like matrix within the nasal cavity—a process we recapitulated in cell culture. We found that virus release from cells previously infected with SARS-CoV-2 was inhibited by the gel matrix product in a dose-dependent manner, with virus levels reduced by >99.99% over a 72 h period at a dose of 6.4 mg/3.5 cm2. We also show that the pre-treatment of cells with product inhibited SARS-CoV-2 infection, independent of the virus variant. The primary mechanism of action appears to be via the formation of a physical, passive barrier. However, the addition of wild garlic provided additional direct antiviral properties in some formulations. We conclude that HPMC-based nasal sprays may offer an additional component to strategies to limit the spread of respiratory viruses, including SARS-CoV-2.

Iota-carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture

Last year observed a global pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affecting millions of individuals worldwide. There is an urgent unmet need to provide an easily producible and affordable medicine to prevent transmission and provide early treatment for this disease. Since the nasal cavity and the rhinopharynx are the sites of initial replication of SARS-CoV-2, a nasal spray may be an effective option to target SARS-CoV-2 infection. In this study, we tested the antiviral action of three candidate nasal spray formulations against SARS-CoV-2 in vitro. We determined that iota-carrageenan in concentrations as low as 6 μg/mL inhibits SARS-CoV-2 in vitro. The concentrations of iota-carrageenan with activity against SARS-CoV-2 in vitro may be easily achieved through the application of nasal sprays as commonly used in several countries. Recently a double-blind, placebo-controlled study showed that iota-carrageenan in isotonic sodium chloride reduces ca. five times the risk of infection by SARS-CoV-2 in health care personnel. Further, xylitol at a concentration of 50 mg/mL (ca. 329 mM) was found to exert some antiviral action, though this preliminary finding needs further confirmation.

In Vitro Ciliotoxicity and Cytotoxicity Testing of Repeated Chronic Exposure to Topical Nasal Formulations for Safety Studies

Certain active drugs and excipients of nasal formulations may impair ciliary function and mucociliary clearance. The ciliary beat frequency (CBF) is a key parameter for determining mucociliary clearance rate, and in vitro assessments of CBF have proven to be accurate and reproducible. Since topical nasal formulations are applied with repeated doses, it is essential to elucidate their chronic, as opposed to acute, effect on mucociliary clearance and nasal mucosa. The aim of this study was to assess for the first time the ciliotoxicity and cytotoxicity of nasal sprays intended for chronic treatment (with repeated doses) using a previously designed set-up for CBF measurements. For 2 weeks, the 3D nasal MucilAir™ in vitro models were treated daily with undiluted or clinically relevant doses of mometasone nasal spray, placebo nasal spray, culture medium, or they were untreated. We demonstrated a dose-dependent and time-dependent (cumulative) effect of the nasal sprays on ciliary activity and cytotoxicity using CBF measurements and ultrastructural analysis, respectively. Our results indicate that repeated administration of clinically relevant doses of mometasone nasal spray is safe for in vivo use, which is in good agreement with a previous clinical study. Overall, our study suggests that such in vitro assays have great potential for topical nasal drug screening.

Xylometazoline and oxymetazoline - unusual effects of everyday drugs (literature review)

The aim of the study is to systematize the knowledge about xylometazoline and oxymetazoline - commonly used nasal sprays with sympathicomimetic effect, mainly directly on α-adrenergic receptors [1]. A review of recent reports on possible side effects and new therapeutic options will be presented. Results: Over several years, reports have been published regarding descriptions of unusual cases of side effects, such as angina attack [4], a case of respiratory failure in a newborn [5], ischemic stroke [6], or anaphylactic reaction during routine surgery. In experiments using rats, on the other hand, it has been shown that these substances can also cause increased inflammation of the lower respiratory tract [7], as well as numerous ophthalmic problems [8]. Recent reports also suggest new uses for xylometazoline and oxymetazoline. In combination with lidocaine, an intranasal solution of xylometazoline has shown efficacy in the anesthesia of maxillary teeth in patients with minor carious lesions [9], and a beneficial therapeutic combination of oxymetazoline and dye laser (PDL) has also been reported for the treatment of rosacea, among others [10]. Conclusions: Although imidazoline derivatives were admitted to the drug list decades ago, still their pharmacological potential has not been fully exploited. Finding applications of these drugs in dermatology and dentistry may not only improve the efficacy and comfort of treatment, but also significantly reduce the costs of the whole therapy. The aforementioned reports on the side effects of xylometazoline and oxymetazoline should not be forgotten. It is possible that the presented examples will increase awareness to use these drugs with more respect, according to the recommendations on the leaflet.

COVID-19: Azelastine nasal spray Reduces Virus-load In Nasal swabs (CARVIN). Early intervention with azelastine nasal sprays reduces viral load in SARS-CoV-2 infected patients. First report on a double-blind placebo-controlled phase II clinical trial.

Background:The current COVID-19 pandemic has had a major influence on our daily lives. The most frequent early symptoms associated with SARS-CoV-2 infection are coughing, fever, rhinitis, and loss of smell and taste. If the infection progresses to the lower respiratory tract, it can cause massive inflammation of the pulmonary system, which can be life threatening. There is urgent need for a broadly available and effective therapy for the treatment of early infections with SARS-CoV-2 in order to prevent progression to severe disease. Methodology:CARVIN is a phase II proof of concept, randomized, parallel, double-blind, placebo-controlled, interventional clinical trial. 90 SARS-CoV-2 positive volunteers were randomized into three groups to receive either placebo, azelastine 0.02% or azelastine 0.1% nasal spray for a period of 11 days. Seven nasopharyngeal swabs were taken during this period for quantitative PCR measurements assessing the viral load via the ORF 1a/b and E genes. Investigators also assessed patients’ status continuously throughout the trial, and the intensity of individual symptoms were reported by the patients using an electronic diary. Two safety follow-ups were performed at days 16 and 60 of study participation. Results:Since the data of the primary outcome did not show a normal distribution, all statistical tests presented here were done non-parametrically and all p-values are descriptive and without adjustment for multiple testing. A broader descriptive analysis will be performed at a later date on all variables and it will be published in a peer-reviewed publication. A wide range of initial viral loads in the nasopharyngeal swabs of the study population was observed with an overall median/mean + SD Ct value of approximately 21.9 / 23.6 + 5.8, corresponding to log10 6.6 + 1.8 copies per /ml. Out of the 90 enrolled subjects, at least 54 carried the Alpha (B.1.1.7, UK) variant.Treatment with azelastine nasal sprays resulted in a greater but non-significant decrease in mean viral load compared to that measured in the placebo group at all 6 timepoints after initiation of treatment. This tendency was stable and most pronounced on day 8 (after 7 days treatment), when in the 0.1% and 0.02% azelastine nasal spray groups, an approximately 8- and 29-fold greater clinically meaningful reduction of the baseline viral load, respectively, compared to placebo was observed (based on the ORF1a/b gene). On days 4 and 11, approximately 4-fold greater mean viral load reduction was seen in the 0.1% azelastine group.Differences in mean viral load compared to baseline values were seen starting on the second day (after one day of treatment) in the azelastine 0.1% and azelastine 0.02% group for ORF 1a/b gene, and with azelastine 0.1% for the E gene, while this reduction was less pronounced in the placebo group.The effects of 0.1% azelastine nasal spray treatment to accelerate viral load reduction were even more pronounced in patients with initial high viral load (subgroup analyses in patients exhibiting initial Ct values below 25 and below 20, respectively). Of note, by day 8 the PCR-test had turned negative in more patients in the 0.1% azelastine group (n=6, p= 0.01 for the ORF 1a/b gene and n = 3, p= 0.08 for the E gene) and in the 0.02% azelastine group (n=8, p< 0.01 for the ORF 1a/b gene and n = 5, p= 0.02 for the E gene) than in the placebo group (n=0 for the ORF 1a/b gene and n = 0, for the E gene).Discussion:This study provides the first clinical hints of the effects of an azelastine nasal spray in SARS-CoV-2 positive patients. Subgroup analyses performed in patients exhibiting high initial viral loads are further suggestive of azelastine’s potential as an antiviral treatment.

Drug Release and Pharmacokinetic Evaluation of Novel Implantable Mometasone Furoate Matrices in Rabbit Maxillary Sinuses

Background Intranasal corticosteroid sprays (INCSs) used to treat chronic rhinosinusitis are suboptimal due to limited penetration into the middle meatus, rapid clearance, and poor patient compliance. A bioresorbable drug matrix, developed with the XTreoTM drug delivery platform, may overcome the limitations of INCS by providing continuous dosing over several months. Objective To evaluate the in vitro drug release and in vivo pharmacokinetics of novel mometasone furoate (MF) matrices in a rabbit dorsal maxillary osteotomy model. Methods XTreoTM matrices were formulated to consistently elute MF for up to 6 months. Matrices were surgically placed bilaterally into the maxillary sinuses of New Zealand White (NZW) rabbits. Tissue and plasma MF concentrations were measured to assess the in vivo drug delivery. The in vivo and in vitro drug release kinetics of the matrices were quantified and compared to those of rabbits receiving daily Nasonex® MF nasal sprays. Results XTreoTM matrices self-expanded upon deployment to conform to the irregular geometry of the maxillary sinus cavities in the NZW rabbits. Sustained release of MF was demonstrated in vitro and in vivo for 2 MF matrices of distinct release durations and an in vitro–in vivo correlation was established. Therapeutic levels of MF in local tissues were measured throughout the intended dosing durations. In contrast to the variable peaks and troughs of daily nasal sprays, sustained dosing via a single administration of MF matrices was confirmed by quantifiable plasma MF concentrations over the intended dosing duration. Conclusion The XTreoTM MF matrices provided targeted and efficient dosing to local sinus tissues that was superior to INCS. Sustained drug release was confirmed both in vitro and in vivo. The novel XTreoTM technology may provide precisely tuned, long-lasting drug delivery to sinus tissues with a single treatment.