Bilosomes-mediated trans-ocular delivery of azelastine hydrochloride for the treatment of allergic conjunctivitis: In vitro, ex vivo and in vivo investigations

Intranasal treatments combining corticosteroids with antihistamines are a safe and effective alternative for treating moderate to severe seasonal allergic rhinitis in children over 12 years of age and adults. Evidence for their use in children under 12 years of age is limited and based on four studies: three examining azelastine hydrochloride and fluticasone propionate combination (AzeFlu) (including one placebo-controlled efficacy study, one comparative efficacy study, and one safety study) and one examining olopatadine hydrochloride and mometasone furoate combination (OloMom) (a placebo-controlled study). The recommendations from these studies could be conditional for school children aged 6 to 11 years with seasonal (non-perennial) allergic rhinitis, but only when symptoms cannot be controlled with a single drug.

Objective This study aimed to estimate the projected budget impact of introducing MP-AzeFlu, a fixed-dose nasal of a corticosteroid (fluticasone propionate) and an antihistamine (azelastine hydrochloride). The evaluation focused on the potential cost savings for patients and healthcare systems in Saudi Arabia and the United Arab Emirates (UAE). Methods A budget impact model was developed in Excel over a period of five years, as per the ISPOR guidelines. The analysis focused exclusively on direct medication costs sourced from the Saudi FDA and UAE Department of Health, excluding costs related to healthcare resource utilization or productivity. Drug prices were obtained from each Ministry of Health price list and inflated to 2024 values (no discounting). It was assumed that the population size would remain constant over five years. Results In Saudi Arabia, substituting dual therapy with MP-AzeFlu yielded marginal cost savings of SAR 3.9 million by year five (1.4% of the baseline expenditure of SAR 273.9 million). In the UAE, a similar switch resulted in cost savings of AED 0.55 million (1.4% of the baseline expenditure of AED 38.4 million). A scenario analysis comparing MP-AzeFlu to triple therapy showed even greater cost savings: SAR 10.5 million in the KSA (2.6% of the baseline expenditure of SAR 405.4 million) and AED 1.5 million in the UAE (2.7% of the baseline expenditure of AED 59.07 million). Conclusion The introduction of MP-AzeFlu in Saudi Arabia and the United Arab Emirates showed cost-neutral to cost-saving impacts, depending on whether it replaces dual or triple therapy regimens.

Univariate versus multivariate approaches for resolving the overlapped spectra of azelastine hydrochloride and mometasone furoate.

Glioblastoma is an aggressive brain tumor with poor prognosis and limited treatment options. Azelastine (AZL), a histamine H1 receptor antagonist known to cross the blood-brain barrier, has shown anticancer activity in other malignancies. This study investigated the anti-proliferative effects of AZL on glioblastoma cells and its potential to enhance the efficacy of standard anticancer agents. Human glioblastoma cell lines U251 and T98G were treated with AZL. Cell viability was assessed via WST-8 assay. The impact of AZL on actin cytoskeleton and cell cycle was analyzed using fluorescent staining and flow cytometry. We further assessed the impact of four cell death pathway inhibitors - Z-VAD-fmk (pan-caspase inhibitor), necrostatin-1 (necroptosis inhibitor), ferrostatin-1 (ferroptosis inhibitor), and IM-54 (oxidative stress induced necrosis inhibitor) - on AZL-induced growth suppression and tested AZL in combination with temozolomide (TMZ) or doxorubicin (DOX). AZL inhibited cell proliferation in a dose-dependent manner (IC50: 9.5 μM for U251, 31.0 μM for T98G). Cell death inhibitors did not substantially reverse the effects of AZL, suggesting that its primary mode of action involves growth inhibition rather than the induction of cell death. AZL induced G1 phase arrest in both cell lines and disrupted actin filament organization, particularly in U251 cells. Combination treatment with AZL and either TMZ or DOX significantly enhanced the anti-proliferative effects compared to monotherapy. AZL inhibits glioblastoma cell growth primarily through G1 arrest and cytoskeletal remodeling, with minimal contribution from classical cell death pathways. Its ability to enhance TMZ and DOX efficacy, coupled with favorable BBB permeability and low toxicity, supports its potential as a repositioned therapeutic for glioblastoma, both as a monotherapy and as an adjuvant to overcome TMZ resistance.

Allergic rhinitis is a common chronic respiratory disease that affects millions of people worldwide and has a significant impact on their quality of life, productivity, and performance. Achieving control of the symptoms of moderate/severe allergic rhinitis, which often requires the use of several drugs from different pharmacological groups, is particularly challenging. The article considers clinical efficacy and safety of fixed-dose intranasal combination of azelastine hydrochloride and fluticasone propionate for treatment of seasonal allergic rhinitis. The combination of azelastine hydrochloride and fluticasone propionate demonstrates a synergistic effect in improving the symptoms of both early and late allergic reactions and has a pronounced anti-inflammatory effect. Studies show that the use of fixed-dose combination of azelastine hydrochloride and fluticasone propionate significantly improves nasal and ocular symptoms of seasonal allergic rhinitis compared to fluticasone propionate and azelastine hydrochloride monotherapies. The drug acts quickly and provides sustained relief of symptoms which contributes to improved quality of life for the patients. The article provides an overview of the main preclinical, clinical randomized trials and studies in real clinical practice on the efficacy and safety of the fixed-dose intranasal combination, especially in comparison with monotherapies with the drugs included in the combination and placebo. It demonstrates its effectiveness in different populations regardless of race, gender and age, and in long-term use. Azelastine hydrochloride in combination with fluticasone propionate has the most extensive body of evidence of its efficacy, including studies conducted in the Russian patient population. The drug can be used in patients from the age of 12 years with moderate to severe seasonal allergic rhinitis. It is included in all international and Russian guidelines on allergic rhinitis.

IntroductionAllergic conjunctivitis is a common ocular condition characterized by discomfort, itching, and redness, which significantly impacts quality of life. Its frequent overlap with dry eye disease (DED) complicates diagnosis and management, as both conditions share inflammation and tear film dysfunction as underlying mechanisms. Effective treatments must address both the inflammatory and tear film aspects of these conditions. While traditional therapies include antihistamines and mast cell stabilizers, innovative approaches focus on agents with dual anti-inflammatory and antiallergic properties. N-acetyl-aspartyl-glutamate (NAAGA) has shown potential in alleviating symptoms of both allergic conjunctivitis and DED through mechanisms involving mast cell stabilization, inhibition of inflammatory mediators, and improvement of tear film stability. This study compares the efficacy of NAAGA and azelastine hydrochloride, an established antihistamine, in improving symptoms and clinical markers of tear film dysfunction in patients with allergic conjunctivitis.MethodsThis randomized, single-blind study included 134 patients with atopy and mild to moderate tear film dysfunction. Participants received either NAAGA (49 mg/ml, four times daily) or azelastine hydrochloride (0.05%, twice daily) for 4 weeks. The primary endpoint was the change in Ocular Surface Disease Index (OSDI) scores. Secondary endpoints included tear osmolarity, Schirmer test results, tear break-up time (TBUT), fluorescein staining, and matrix metalloproteinase-9 (MMP-9) levels.ResultsBoth treatments improved all parameters significantly over 4 weeks. NAAGA reduced OSDI scores from 26.12 ± 4.70 to 11.84 ± 3.43, compared to azelastine’s improvement from 24.57 ± 4.70 to 15.54 ± 4.36 (p < 0.001). NAAGA showed superior reductions in tear osmolarity (from 320.99 ± 4.35 to 312.33 ± 3.25 mOsm/l) compared to azelastine (from 320.13 ± 3.46 to 318.57 ± 3.46 mOsm/l, p < 0.001), and greater enhancements in Schirmer test results (6.51 ± 1.95 mm to 10.08 ± 1.88 mm) and TBUT (4.10 ± 1.70 to 7.91 ± 1.79 s).ConclusionsNAAGA outperformed azelastine in alleviating symptoms and improving clinical markers of tear film dysfunction in allergic conjunctivitis. Its dual action on inflammation and tear stability highlights its therapeutic potential. Further studies are warranted to confirm these findings and explore additional applications.Trial RegistrationClinicalTrials.gov identifier, NCT12345678.

Patients with obstructive sleep apnea (OSA) often struggle with CPAP therapy adherence. The intranasal corticosteroids (INS) alone have not significantly improved CPAP adherence but the combination drugs that faster relieved symptoms were not well studied. This study aimed to assess the combined effectiveness of INS (fluticasone propionate) and intranasal antihistamines (azelastine hydrochloride) in enhancing CPAP adherence and mitigating CPAP-induced rhinitis symptoms in OSA patients. A double-blind, randomized controlled trial with stratified random sampling was conducted at Thammasat University Hospital from March 2022 to March 2023. Participants included OSA patients undergoing CPAP treatment. The patients completed questionnaires and interviews at the baseline, the second week, and one month after starting CPAP therapy, with CPAP usage electronic data collected. Among 116 enrolled patients, most had severe OSA (78.9%), with a majority being male (56.9%). The intervention group did not significantly differ from the placebo group in terms of CPAP usage, nasal symptoms, quality of life, or side effects. Subgroup analysis showed improved CPAP adherence in the treatment group when using pressure below 15 cm H2O (7.8% increase in CPAP usage days, P = 0.04). This study marks the first evaluation of combination drugs for enhancing CPAP therapy adherence in OSA patients. Although these drugs did not significantly enhance overall CPAP adherence, there was a trend toward increasing CPAP adherence in patients using lower pressure levels. Thus, combining fluticasone and azelastine may benefit certain OSA patients. Further research is essential to comprehend and validate these benefits fully.Clinicaltrials.in.th number TCTR20220308003 (08/03/2022).

Prophylactic treatment for pollinosis is advantageous for managing nasal symptoms in patients with seasonal allergic rhinitis. Inadequate control of rhinitis symptoms increases the risk of acute asthma attacks. Nevertheless, there is limited research on the use of nasal glucocorticoids and antihistamines for the preventive treatment of pollinosis. This study aimed to assess the efficacy of prophylactic treatment for nasal symptoms and acute asthma attacks by enrolling patients with Artemisia pollinosis to use a combined device of azelastine hydrochloride and fluticasone nasal spray prior to the pollen season. The study was registered at Chictr.org.cn (ChiCTR2300073758). A total of 120 patients with Artemisia pollinosis were randomly assigned to either a prophylactic treatment group or a control group at a 1:1 ratio. In the prophylactic treatment group, the nasal spray was initiated approximately two weeks before the onset of the pollen season. During both the pollen season and the concurrent medication period, the prophylactic treatment group presented significantly lower total nasal symptom scores (TNSS) (means of 5.97 and 5.94) than the control group (means of 7.86 and 7.80) (P = 0.015 and 0.016). Although the prophylactic treatment group had a lower asthma attack rate than the control group, the difference was not statistically significant (P = 0.284). Prophylactic treatment with azelastine hydrochloride and fluticasone propionate nasal sprays can alleviate nasal symptoms and may reduce acute asthma attacks during the pollen season. [Chictr.org.cn], identifier (ChiCTR2300073758).

ABSTRACT Background Nasal septum perforation represents a significant clinical concern, with limited investigations into the role of medications in its etiology. This study utilizes the FDA Adverse Event Reporting System (FAERS) database to identify the drugs associated with nasal septum perforation and assess their risk. Research design and methods This retrospective pharmacovigilance study analyzed drug-induced nasal septum perforation data from January 2004 to December 2023. Disproportionality analysis using reporting odds ratio (ROR) assessed drug associations with nasal septum perforation. Results For 552 identified cases, the most commonly reported drugs were bevacizumab (n = 56), fluticasone propionate (n = 50), methotrexate (n = 34), hydrocodone and acetaminophen (n = 22), and paclitaxel (n = 17). Twenty-six drugs showed positive risk signals, with the top five being azelastine hydrochloride and fluticasone propionate (ROR = 173.82), beclomethasone dipropionate (ROR = 90.91), oxymetazoline (ROR = 53.77), desmopressin (ROR = 51.43), and leucovorin (ROR = 42.83). Intriguingly, 18 of these drugs did not list nasal septum perforation as a known side effect. Conclusion This study provides a comprehensive overview of drug-induced nasal septum perforation from a pharmacovigilance perspective, highlighting the need for further research to clarify these associations and update drug safety information to reduce patient risk.

A combination of three co-administrated drugs, such as azelastine hydrochloride (AZT), fluticasone propionate (FP), and oxymetazoline (OXY), is more effective than single therapy for the treatment of seasonal allergy and COVID-19. We established an efficient methodology for the determination of those analytes in spiked nasal mucosa and nasopharyngeal swabs from real human samples. A simple and quick protein precipitation method was used for sample extraction, using acetonitrile. RP-HPLC/DAD method was performed using an Exsil 100 ODS C18 (250 × 4.6 mm, 5 μm) column with an acetonitrile: water (70:30 v/v) solvent system at a flow rate of 0.7 mL/min. A photodiode array detector was applied at 240 nm. A good separation of the three proposed analytes with a short run time of 10 min was noted. Our method was validated according to FDA guidelines for bioanalytical validation methods. Calibration curves were linear in nasal mucosa samples at concentration ranges of 8–125, 10–100, and 10–125 µg/mL, with average recoveries ± SD of 101.56%±0.39, 102.45%±0.86, and 104.61%±4.52 for AZT, FP, and OXY; respectively. The results of precision and accuracy are within acceptable limits. According to stability assays, the three analytes under investigation were stable throughout sample preparation, storage, and injection. Our method was applied to real nasopharyngeal swabs. It shows that the results of the swabs were not affected by gender or age. Good recoveries with low % RSD were observed: 99.03% ± 0.75, 100.02% ± 0.94, and 100.94% ± 1.98 for both genders, and 100.45% ± 0.96, 100.69% ± 1.08, and 100.32% ± 1.53 for different ages for AZT, FP, and OXY; respectively. Moreover, the amount of those drugs in the nasal mucosa was observed for seven hours, and a constant concentration with a low% RSD was noted for the first four hours. Therefore, this method can be applied to monitor the therapeutic dose in the nasal mucosa for the determination of those analytes.

Comparative Pharmacokinetic and Tolerability Review of Over-the-Counter and Prescription Azelastine Hydrochloride for Allergic Rhinitis Management

The primary objective of the study was to determine the bioavailability of 2 new formulations of azelastine (AZE) hydrochloride (0.10% and 0.15% AZE) containing sorbitol and sucralose compared with the commercially available 0.10% AZE. This study was performedin healthy volunteers based on the pharmacokinetic parameters maximum plasma concentration and area under the plasma concentration-time curve from time zero to the last measurable concentration. This was a Phase 1, open-label, single-center, randomized, parallel-group study. Subjects were randomized to 1 of 3 treatment groups: (1) 0.10% AZE (treatment A), (2) 0.15% AZE (treatment B) (Groups 1 and 2 both containing sorbitol and sucralose), and (3) the commercially available 0.10% AZE (treatment C). A total of 54 subjects were randomized and received treatment A, B, or C. Maximum plasma concentration and area under the plasma concentration-time curve were similar when compared in treatments A and C (0.1%) for AZE and its metabolite, desmethylazelastine. The most frequently reported adverse events were rhinorrhea (5.6%) and sneezing (5.6%).

Introduction: Allergic rhinitis (AR) affects up to 40% of the pediatric population. The US practice parameter recommends the use of intranasal antihistamines (INAH) or INCS as first-line therapy for the treatment of AR. Although not directly targeted to children, the recent US practice parameters proposed INAH as first-line therapy whereas the ARIA guidelines did not. Methods: This was a randomized, double-blind, parallel-group study with a duration of 28 days. It compared azelastine hydrochloride (AZE) 0.10% and 0.15% to placebo of one spray per nostril twice daily in pediatric subjects with moderate-to-severe symptomatic perennial allergic rhinitis (PAR). Results: A total of 486 subjects were included in the study. The change from baseline rTNSS was statistically significant for 0.15% AZE (p = 0.005) and 0.10% AZE (p = 0.015) versus placebo. Here, 0.15% AZE showed an LS mean change of −3.45 (20.2%) over the 28-day treatment period from a baseline value of 16.60 in rTNSS, and 0.10% AZE showed an LS mean change of −3.37 (20.5%) over the 28-day treatment period from a baseline value of 16.35 in rTNSS. Somnolence was reported by 1 patient in the 0.1% group and 1 placebo patient (both of mild severity and unlikely to be related to treatment). None of the patients reported fatigue. Conclusions: Here, 0.15% AZE significantly improved the overall rTNSS compared with placebo over the 28-day study period. A 0.15% AZE was well tolerated in this study. Key Messages: It is essential to perform studies in school children (6–11 years). However, for INAH, few studies exist in SAR, and, to our knowledge, there are no studies in PAR. This study shows for the first time that the higher dose of AZE is safe and effective in school children with PAR.

MP-AzeFlu (Dymista; Meda Pharma GmbH & Co., KG), a formulation combining azelastine hydrochloride and fluticasone propionate in a single spray, is superior to fluticasone propionate alone in relieving symptoms and improving the quality of life of patients with allergic rhinitis. In this study, we evaluated whether the effect of AzeFlu, a generic drug manufactured from China, is equivalent to that of MP-AzeFlu. In total, 679 patients were recruited for a multicentre, randomized, double-blind, original drug-controlled, and parallel-group clinical trial. Overall, 339 and 340 patients were administered with AzeFlu and MP-AzeFlu, respectively. Efficacy was assessed by changes in the reflective total nasal symptom score, the area under the curve of reflective total nasal symptom score changes over time, changes from baseline in individual nasal symptom scores, and the Rhinoconjunctivitis Quality of Life Questionnaire. In addition, a safety evaluation was simultaneously performed. AzeFlu and MP-AzeFlu reduced the reflective total nasal symptom score from baseline (AzeFlu -6.7 [standard deviation, 2.59]; MP-AzeFlu -6.7 [standard deviation, 2.76]; P = 0.905) and improved nasal symptoms and quality of life (AzeFlu -62.3 [standard deviation, 33.59]; MP-AzeFlu -64.7 [standard deviation, 33.73]; P = 0.394) in patients with allergic rhinitis. Significant differences were not observed between groups. AzeFlu showed effects equivalent to those of MP-AzeFlu in this clinical trial and may benefit Chinese patients with allergic rhinitis.Registration number: CTR20190189 (chinadrugtrials.org.cn/index.html).

Formulation and evaluation of polymeric ocular nanosuspension containing Azelastine hydrochloride

The deposition, residence time, and dissolution profile of nasal suspensions containing corticosteroids play a key role in their in vivo efficacy after administration. However, the conventional methods available to characterize nasal products appear to be unsuitable to exhaustively cover these aspects. The work aims to investigate technological aspects of Ryaltris (mometasone furoate and olopatadine hydrochloride nasal spray) compared to other commercial anti-allergic nasal products, namely, Dymista (azelastine hydrochloride and fluticasone propionate), Nasonex (mometasone furoate), and Avamys (fluticasone furoate). Innovative characterization methods were combined with more traditional approaches to investigate the anti-allergic nasal sprays. These methods applied together allowed to differentiate between the different products and provided a clear picture of the nasal product behavior in terms of drug dissolution and deposition. In particular, the dissolution tests were performed exploiting the Respicell® apparatus, an innovative technique that allows for the investigation of inhalation products. Then, formulation viscosities were considered along with a formulation flow test on an inclined plane. Finally, the intranasal deposition profile of the commercial formulations was determined using a silicon nasal cast. The results highlight in vitro significant differences in terms of viscosity as well as dissolution rate of the nasal products, with Ryaltris showing a higher viscosity and lower flow compared to other products, which, along with a corticosteroid faster dissolution rate than Dymista, suggest a potential advantage in terms of clinical behavior.

Onset of efficacy of azelastine hydrochloride 0.15% nasal spray for allergic rhinitis in an environmental exposure chamber

The incidence of allergic rhinitis (AR) in Asia and the world is steadily rising. Patients experience incomplete symptom relief despite existing treatment options, which warrants the need for new therapeutic regimes. Azelastine hydrochloride/fluticasone propionate (MP-AzeFlu), a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate has been indicated in the treatment of AR. The current review discusses the effects of MP-AzeFlu versus conventional therapies in achieving superior clinical improvement with a very rapid onset of action (5 minutes). The superiority of MP-AzeFlu in offering complete symptom control with sustained relief in patients with AR compared to the existing therapeutic options is also discussed. MP-AzeFlu has been shown to improve the quality of life for patients with AR, thereby enhancing patient adherence to therapy and establishing its preference for the treatment of AR. Currently, the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend the use of a combination of intranasal corticosteroids and intranasal antihistamines as first-line treatment in patients with persistent AR with visual analog scores ≥5 or when prior treatment with single agents has been ineffective. Widely published data on the efficacy and safety of its prolonged use in adults and children have validated that effective treatment of AR can be achieved with MP-AzeFlu.

Combined nasal medications are an efficient therapy for enhancing the symptoms of many respiratory disorders such as allergic rhinitis. The manifestations of rhinitis have been receiving more attention because of the potential for overlapping or misunderstanding between allergic rhinitis symptoms and those of coronavirus disease 2019 (COVID-19). Azelastine hydrochloride (AZH) and fluticasone propionate (FLU) are among the most effective drug combinations for elevating the symptoms of allergic rhinitis. To promote and make it easier for various researchers to get literature reviews for their studies on the drugs being mentioned, different analytical methods have been collected and discussed in this mini-review for the quantitative assay of AZH and FLU in their pharmaceutical formulation and different biological fluids. The assembled approaches include pharmacopeial, chromatographic (HPLC, CE, and TLC), spectroscopic (spectrophotometric and spectrofluorimetric), and electrochemical methods. In accordance with the findings of this study, AZH was determined either alone or with its genotoxic impurity, major metabolite, and alkaline degradant in different matrices using various analytical methods. Moreover, HPLC technique made it possible to analyze FLU along with its major metabolite in human plasma. In addition, the pharmaceutical formulation was the applicable matrix for the simultaneous analysis of AZH and FLU. The data provided in this study