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Treatment-Resistant Depression (TRD) affects almost 30 % of patients with Major Depressive Disorder (MDD). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants. To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard-of-care of SSRI/SNRI plus ESK-NS. We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients, ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS, and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Åsberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1), and three months after the treatment initiation(T2). The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms, with a higher effect size in reducing emotional blunting at T2. The safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events. The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients, particularly regarding the reduction of emotional blunting and potentially a better safety and tolerability profile. Further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings. • Esketamine nasal spray (ESK-NS) is a new treatment for TRD. • Standard-of-care combines ESK-NS with SSRIs or SNRIs. • We compared the effectiveness of Vortioxetine + ESK-NS vs. SSRI/SNRI + ESK-NS. • We found similar antidepressant effect with a better safety profile for Vortioxetine. • Vortioxetine + ESK-NS was more effective against emotional blunting. [ABSTRACT FROM AUTHOR]

Naloxone nasal spray is recommended for patients with risk factors for opioid overdose. However, cancer patients' perceptions and beliefs regarding naloxone prescriptions and their self-perceived risks for overdose are understudied. To determine the proportion of cancer patients at risk for overdose who perceived naloxone as beneficial. Between July 2020 and April 2022, we surveyed 150 adult patients from the supportive care ambulatory clinic at a tertiary cancer center in the United States who received a co-prescription of naloxone nasal spray. We measured patients' knowledge of overdose risk-factors, attitudes, beliefs, and education received on naloxone. Risk-factors between beneficial vs. nonbeneficial groups were analyzed. The survey was administered on paper or via a telephone interview. Of the 150 patients, 55% were male, 70% were white, and 81% had advanced cancer. The majority of patients believed naloxone was beneficial (100/150, 67%). When compared to the nonbeneficial group, more patients from the beneficial group agreed that the concurrent use of alcohol (100% vs. 90%; P = 0.004) or sedating drugs (96% vs. 85%; P = 0.04) with opioids could result in overdoses and felt safe having naloxone at home (95% vs. 60%; P <0.0001). More patients from the nonbeneficial group associated naloxone prescription with being suspected of misusing opioids (12/50 vs. 8/100; P = 0.01), and fewer had confidence in their caregivers' ability to administer naloxone (69% vs. 95%; P < 0.0001). Most patients understood the benefits of naloxone and felt safe having one at home. More research is needed to identify knowledge gaps and develop educational strategies for those who find it nonbeneficial. [ABSTRACT FROM AUTHOR]

In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) significantly increased the probability of remission at Week 8, and of being relapse-free through Week 32 after remission at Week 8, versus quetiapine extended release (XR) in patients with treatment resistant depression (TRD). Here, we explore the time course, burden and consequences of treatment emergent adverse events (TEAEs) in the phase IIIb ESCAPE‑TRD trial. Patients with TRD were randomised 1:1 to esketamine NS or quetiapine XR, dosed per label alongside an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. In this secondary publication, safety analyses (comprising patients who received ≥1 dose of study treatment) included incidence, severity and durations (Kaplan‑Meier method) of TEAEs, and subsequent dispositional changes. P values were not adjusted for multiple testing. 336 patients were randomised to esketamine NS and 340 to quetiapine XR; 334 and 336 received ≥1 dose of study treatment, respectively. TEAEs were significantly more common with esketamine NS than quetiapine XR (91.9 % versus 78.0 %; p < 0.001), but were typically mild/moderate and transient in nature: a greater proportion resolved on the same-day (92.0 % versus 12.1 %) and lead to treatment discontinuation in significantly fewer patients (4.2 % versus 11.0 %, respectively; p < 0.001). The proportion of days spent with TEAEs was significantly lower with esketamine NS than quetiapine XR (median: 11.9 % versus 21.3 %; p < 0.001). Although more frequent with esketamine NS, TEAEs were typically transient and mild, with discontinuation less likely versus quetiapine XR. Data were consistent with established safety profiles, with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esketamine NS versus quetiapine XR further supports its use for TRD. [ABSTRACT FROM AUTHOR]

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations. • A new LC-MS/MS method was developed and validated for the detection of nitrosamine impurities in different combined finished products containing sartan group and alu-foil packaging. • Different packaging components were studied within the scope of the Extractables&Leachables study to evaluate the possibility of leaching not only from tablet blisters but also from different pharmaceutical packaging components and ink printed labels. • Validation parameters and acceptance criteria were determined in accordance with USP 〈736〉 mass spectrometry monograph and ICH Q2 (R2) guide. • Packaging components (such as canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials) were checked in accordance with risk assessment studies carried out in line with the ICH Q9 guide. [ABSTRACT FROM AUTHOR]

My contribution to honoring Professor Kinam Park celebrates and resonates with his scholarly career in drug delivery, his commitment to encouraging the next generation(s), and his efforts to keep us focused on clinically effective formulations. To do this I take as my example, niclosamide , a small molecule protonophore that, uniquely, can "target" all cell membranes, both plasma and organelle. As such, it acts upstream of many cell pathways and so has the potential to affect many of the essential events that a cell, and particularly a diseased cell or other entities like a virus, use to stay alive and prosper. Literature shows that it has so far been discovered to positively influence (at least): cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, systemic sclerosis, Parkinson's, and COPD. With such a fundamental action and broad-spectrum activity, I believe that studying niclosamide in all its manifestations, discovering if and to what extent it can contribute positively to disease control (and also where it can't), formulating it as effective therapeutics, and testing them in preclinical and clinical trials is a career builder for our next generation(s). The article is divided into two parts: Part I introduces niclosamide and other proton shunts mainly in cancer and viral infections and reviews an exponentially growing literature with some concepts and physicochemical properties that lead to its proton shunt mechanism. Part II focuses on repurposing by reformulation of niclosamide. I give two examples of " carrier-free formulations ", — one for cancer (as a prodrug therapeutic of niclosamide stearate for i.v. and other administration routes, exemplified by our recent work on Osteosarcoma in mice and canine patients), and the other as a niclosamide solution formulation (that could provide the basis for a preventative nasal spray and early treatment option for COVID19 and other respiratory virus infections). My goal is to excite and enthuse, encourage, and motivate all involved in the drug development and testing process in academia, institutes, and industry, to learn more about this interesting molecule and others like it. To enable such endeavors, I give many proposed ideas throughout the document, that have been stimulated and inspired by gaps in the literature, urgent needs in disease, and new studies arising from our own work. The hope is that, by reading through this document and studying the suggested topics and references, the drug delivery and development community will continue our lineage and benefit from our legacy to achieve niclosamide's potential as an effective contributor to the treatment and control of many diseases and conditions. [Display omitted] • Niclosamide and other proton shunts are a class of drugs (protonophores) that "target" all cell membranes, both plasma and organelle and so act upstream of maybe all cell pathways • Niclosamide can affect many of the essential events that diseased cells or other entities like a virus, use to stay alive and prosper • Niclosamide in oral tablets has little systemic absorption; we need to not just repurpose but reformulate • Emphasizes preformulation drug characterization that impacts formulation choices and presents "carrier free" nanomedicines for anti-cancer therapies and as nasal spray preventatives and early treatment throat spray options for respiratory infections • For all researchers, encouraging and inspiring them to take on niclosamide in many diseases and conditions that are not yet tested preclinically or clinically. [ABSTRACT FROM AUTHOR]

Pediatric obstructive sleep apnea (OSA) is a common disease that can have significant negative impacts on a child's health and development. A comprehensive evaluation of different pharmacologic interventions for the treatment of OSA in children is still lacking. This study aims to conduct a comprehensive systematic review and network meta-analysis of pharmacological interventions for the management of obstructive sleep apnea in pediatric population. PubMed, Web of Science, Embase, The Cochrane Library, and CNKI were searched from 1950 to November 2022 for pediatric OSA. Multiple reviewers included Randomized controlled trials (RCTs) concerning drugs on OSA in children. Multiple observers followed the guidance of the PRISMA NMA statement for data extraction and evaluation. Bayesian network meta-analyses(fixed-effect model) were performed to compare the weighted mean difference (WMD), logarithmic odds ratios (log OR), and the surface under the cumulative ranking curves (SUCRA) of the included pharmacological interventions. Our protocol was registered in PROSPERO website (CRD42022377839). The primary outcomes were improvements in the apnea/hypopnea index (AHI), while secondary outcomes included adverse events and the lowest arterial oxygen saturation (SaO2). 17 RCTs with a total of 1367 children with OSA aged 2–14 years that met the inclusion criteria were eventually included in our systematic review and network meta-analysis. Ten drugs were finally included in the study. The results revealed that Mometasone + Montelukast (WMD-4.74[95%CrIs −7.50 to −2.11], Budesonide (−3.45[-6.86 to −0.15], and Montelukast(-3.41[-5.45 to −1.39] exhibited significantly superior therapeutic effects compared to the placebo concerning apnea hypopnea index (AHI) value with 95%CrIs excluding no effect. Moreover, Mometasone + Montelukast achieved exceptionally high SUCRA values for both AHI (85.0 %) and SaO2 (91.0 %). The combination of mometasone furoate nasal spray and oral montelukast sodium exhibits the highest probability of being the most effective intervention. Further research is needed to investigate the long-term efficacy and safety profiles of these interventions in pediatric patients with OSA. • Conduct a comprehensive assessment of various drug treatments for pediatric obstructive sleep apnea (OSA). • Utilize network meta-analysis to systematically rank drugs based on polysomnographic impact. • Clarify the relative effectiveness of drug treatments, promoting the optimization of personalized care. • Emphasize the imperative for in-depth research into long-term efficacy and safety to guide future efforts. [ABSTRACT FROM AUTHOR]

Intranasal drug delivery is as a noninvasive and efficient approach extensively utilized for treating the local, central nervous system, and systemic diseases. Despite numerous reviews delving into the application of intranasal drug delivery across biomedical fields, a comprehensive analysis of advancements and future perspectives remains elusive. This review elucidates the research progress of intranasal drug delivery through a scientometric analysis. It scrutinizes several challenges to bolster research in this domain, encompassing a thorough exploration of entry and elimination mechanisms specific to intranasal delivery, the identification of drugs compatible with the nasal cavity, the selection of dosage forms to surmount limited drug-loading capacity and poor solubility, and the identification of diseases amenable to the intranasal delivery strategy. Overall, this review furnishes a perspective aimed at galvanizing future research and development concerning intranasal drug delivery. [Display omitted] [ABSTRACT FROM AUTHOR]

Most cases of pediatric epistaxis are spontaneous and self-resolve. However, a subset of children may experience significant bleeding and require procedural or medical intervention. We aim to identify risk factors associated with moderate and severe epistaxis in the emergency department (ED) and explore management outcomes. We retrospectively reviewed all patients under 22 years old with epistaxis who presented to our ED between 2013 and 2022. Epistaxis severity was defined as mild (required nasal compression or intranasal medications), moderate (required cautery or packing), or severe (required factor replacement, transfusion, hospital admission, or surgery). We performed univariable and multinomial regression analyses, with risk factors and outcomes analyzed according to severity. Of 858 visits, 41 (5%) patients had moderate and 67 (8%) had severe epistaxis. Patients with moderate epistaxis were older than those with mild and severe epistaxis (median 15.6 vs. 8.3 vs. 10.7 years, p < 0.001). In regression analysis, moderate epistaxis was associated with older age, prior ED visit within 72 h, and antiplatelet medication use (p < 0.01). Severe epistaxis was associated with bleeding disorders, nasal procedures within 30 days, and anticoagulation medication use (p ≤ 0.001). Bleeding over 30 min prior to arrival was associated with both moderate and severe epistaxis (p < 0.05). Of the 67 patients with severe epistaxis, 10 (15%) required factor replacement, 28 (42%) required transfusion, 52 (77%) required hospital admission, and 5 (7%) underwent surgery. Epistaxis severity is associated with certain risk factors. However, most cases of pediatric epistaxis are mild and do not require intervention or ED evaluation. [ABSTRACT FROM AUTHOR]

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution. The digital nasal model was developed utilizing computed tomography data from Chinese adults, and a nasal cavity model was established for visualizing the deposition of drug powders in the nasal cavity. [Display omitted] [ABSTRACT FROM AUTHOR]

Ketamine and esketamine, the S-enantiomer of the racemic mixture, have recently generated considerable interest as potential therapeutic agents for Treatment-Resistant Depression (TRD), a complex disorder that includes various psychopathological dimensions and distinct clinical profiles (e.g., comorbid personality disorder, bipolar spectrum, dysthymic disorder). This perspective article provides a comprehensive overview of the action of ketamine/esketamine from a dimensional point of view, taking into account the high prevalence of bipolarity in TRD and the evidence of the efficacy of these substances on mixed features, anxiety, dysphoric mood, and, generally, bipolar traits. Additionally, the article underscores the complexity of the pharmacodynamic mechanisms of action of ketamine/esketamine, which goes beyond the non-competitive antagonism of NMDA-R. The need for further research and evidence is highlighted, mainly to evaluate the efficacy of esketamine nasal spray in bipolar depression, the presence of bipolar elements as a predictor of response, and the potential role of these substances as mood stabilizers. The article implies that, in the future, ketamine/esketamine could be used with fewer limitations, not only as antidepressants for the most severe form of depression but also as valuable tools to stabilize subjects with mixed symptoms or bipolar spectrum. [ABSTRACT FROM AUTHOR]

Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and vomiting. Zavegepant, an intranasally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, was previously assessed in a phase 2/3 trial. This phase 3 trial aimed to compare the efficacy, tolerability, safety, and timecourse of response for zavegepant nasal spray with placebo in the acute treatment of migraine. This double-blind, randomised, placebo-controlled, multicentre phase 3 trial, conducted at 90 academic medical centres, headache clinics, and independent research facilities in the USA, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. Participants were randomly assigned (1:1) to zavegepant 10 mg nasal spray or matching placebo and self-treated a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use or non-use of preventive medication. Study centre personnel entered eligible participants into the study using an interactive web response system that was operated and managed by an independent contract research organisation. All participants, investigators, and the funder were masked to group assignment. The coprimary endpoints, freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose, were assessed in all randomly assigned participants who took the study medication, had a migraine attack of moderate or severe pain intensity at baseline, and provided at least one evaluable post-baseline efficacy datapoint. Safety was analysed in all randomly assigned participants who received at least one dose. The study is registered with ClinicalTrials.gov , number NCT04571060 , and is closed to accrual. Between Oct 27, 2020, and Aug 20, 2021, 1978 participants were recruited and assessed for eligibility. 1405 participants were eligible (703 were assigned to zavegepant and 702 to placebo), and 1269 were included in the efficacy analysis set (623 in the zavegepant group and 646 in the placebo group). 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points, 95% CI 4·5–13·1; p<0·0001) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%], risk difference 8·7 percentage points, 3·4–13·9; p=0·0012). The most common adverse events in either treatment group (≥2%) were dysgeusia (129 [21%] of 629 in the zavegepant group vs 31 [5%] of 653 in the placebo group), nasal discomfort (23 [4%] vs five [1%]), and nausea (20 [3%] vs seven [1%]). No signal of hepatotoxicity due to zavegepant was identified. Zavegepant 10 mg nasal spray was efficacious in the acute treatment of migraine, with favourable tolerability and safety profiles. Additional trials are needed to establish the long-term safety and consistency of effect across attacks. Biohaven Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Combination intranasal drugs with a corticosteroid and antihistamine are available in several countries with better effect than treatments with single agents. However, it remains unclear whether this effect is also seen in Japanese cedar pollinosis (JCP), the most prevalent seasonal allergic rhinitis in Japan. We investigated the effect of an add-on intranasal antihistamine with an intranasal corticosteroid in JCP during the pollen dispersal period. (UMIN000025508) We performed a double-blinded, randomized, placebo-controlled trial from March 1 to 14, 2017. Patients (n = 20 per group) received either a mometasone furoate nasal spray (MFNS) plus a levocabastine nasal spray (levocabastine group) or MFNS plus a placebo nasal spray (placebo group). The primary endpoint was the difference in the total nasal symptom score (TNSS) after treatment between the two groups. Differences in the total ocular symptom score, total symptom score, total medication score, total symptom-medication score, and five individual symptoms as well as safety were the secondary endpoints. The change in the TNSS from baseline was significantly greater in the levocabastine group than in the placebo group. A significant reduction in the TNSS was observed more than 6 days earlier in the levocabastine group than in the placebo group. Such add-on effects were also seen in the secondary endpoints. Both treatments were well-tolerated. The intranasal antihistamine provided better control of not only nasal symptoms, but also of ocular symptoms, and decreased the need for rescue medications when added to intranasal corticosteroid treatment in JCP patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) and to explore whether treatment with ESK affects irritability symptoms over time.Methods: This was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK+AD or placebo nasal spray plus oral antidepressant (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models.Results: Of 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK+AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups.Limitations: TRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes.Conclusions: These post hoc results support efficacy of ESK+AD in patients with TRD, regardless of baseline irritability.Trial Registration: ClinicalTrials.gov identifiers: NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2). [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) has a key role in preventing drugs from entering the brain. Non-invasive intranasal drug delivery routes that bypass the BBB are increasing in popularity because of their ability to shorten the journey and reduce the loss of genetic drugs such as siRNA in transit. However, the complex synthesis and quality control process of most nose-to-brain delivery carriers and the limited mass production are the main obstacles to their clinical application. Here, we constructed a siRNA delivery system with simple synthesis and quality control methods using cholesterol-modified T7 (T7-C), in which T7 can bind to the transferrin receptor (TfR) expressed on glioma cells to target gliomas. In our results, T7-C had dual functions as a glioma-targeting carrier and immune adjuvant. As a targeted delivery carrier, T7-C intranasally delivered siRNA into the mouse brain through the olfactory bulb pathway and was taken up by glioma cells by the caveolin- and transferrin-dependent pathway. As an immune adjuvant, T7-C could promote DC maturation and combined with slit2 siRNA could promote polarization of M2 subtype macrophages to M1 subtype macrophages and then increase the proportion of effector T cells to remodel the tumor environment. In conclusion, T7-C with glioma targeting as a delivery system of slit2 siRNA showed a good therapeutic effect in the treatment of glioma after intranasal administration and had potential application prospects. In contrast to the existing literature that uses complex materials to deliver drugs across the blood-brain barrier (BBB) in an invasive manner for glioma treatment, we developed a simple, self-assembling siRNA delivery system (T7-C) based on brain tumor-targeted T7 peptide to treat glioma by intranasal administration. T7-C/siRNA could reach the tumor site through the olfactory bulb route and adjust the "cold" tumor microenvironment to the "hot" tumor microenvironment and non-invasive intranasal delivery route could shorten the journey and reduce the loss of genetic drugs. Therefore, our design has good application prospects and is expected to serve as a general strategy for intranasal drug delivery in the treatment of brain tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to estimate the cost-effectiveness of esketamine nasal spray relative to intravenous ketamine for patients with treatment-resistant depression (TRD) in the US.Methods: We used a Markov model with a 1-month cycle length, and we estimated quality-adjusted life years (QALYs), costs (2020 USD), and incremental cost-effectiveness ratios (ICER) of esketamine relative to ketamine over a 3-year time horizon, from both the healthcare sector and patient perspectives. We ran the model using efficacy estimates from both clinical trial and real-world effectiveness (RWE) data. One-way and probabilistic sensitivity analyses (PSAs) were performed to evaluate the robustness of findings.Results: Over a 3-year time horizon, the use of esketamine yielded 1.98 QALYs (RWE/clinical trial efficacy), and the use of ketamine yielded 2.03 QALYs (clinical trial efficacy) or 1.99 QALYs (RWE). Esketamine was dominated by ketamine using the healthcare perspective. ICERs were above $150,000/QALY threshold with the patient perspective. Under the healthcare perspective, PSA showed there are no scenarios where esketamine was cost-effective compared to ketamine. With the patient's perspective, the probability that esketamine was cost-effective compared to ketamine was 0.0055 (clinical trial efficacy) and 0.35 (RWE).Limitations: The data utilized for efficacy have limitations. The time horizon may fail to capture longer-term costs and benefits.Conclusions: In this decision analytic model evaluating esketamine versus ketamine for TRD, we found esketamine unlikely to be cost-effective under a healthcare sector perspective. Under a patient perspective, esketamine had similar effectiveness and was less costly than ketamine due to insurance coverage. [ABSTRACT FROM AUTHOR]

[Display omitted] The objectives of this study were to expand and implement a Computational Fluid Dynamics (CFD)-Dissolution, Absorption and Clearance (DAC)-Pharmacokinetics (PK) multi-physics modeling framework for simulating the transport of suspension-based nasal corticosteroid sprays. The mean CFD-predicted peak plasma concentration (C max) and area under the curve (AUC) of the plasma concentration–time profile, based on three representative nasal airway models (capturing low, medium and high posterior spray deposition), were within one standard deviation of available in vivo PK data for a representative corticosteroid drug (triamcinolone acetonide). The relative differences in mean C max between predictions and in vivo data for low dose (110 µg) and high dose (220 µg) cases were 27.8% and 10.1%, respectively. The models confirmed the dose-dependent dissolution-limited behavior of nasally delivered triamcinolone acetonide observed in available in vivo data. The total uptake from the nasal cavity decreased from 68.3% to 51.3% for the medium deposition model as dose was increased from 110 to 220 µg due to concentration-limited dissolution. The modeling framework is envisioned to facilitate faster development and testing of generic locally acting suspension nasal spray products due to its ability to predict the impact of differences in spray characteristics and patient use parameters on systemic PK. [ABSTRACT FROM AUTHOR]

• Acoustic pulsations enhance mass transferin the aerosol phase. • Micrometer-size dropletsare translocatedlaterally from the aerosol stream. • Aerosol deposition in the nasal cast is enhanced by pulsations. • Process intensification concepts can be successfullyapplied to medicine. Process intensification (PI) concepts have potential applications beyond the classic industrial problems solved by chemical engineering. This paper discusses the flow and mass transfer intensification using acoustic waves to enhance drug delivery to the nasal cavity. The efficiency of drug delivery to the nose still needs improvement, and the mechanisms related to using acoustic waves to increase it have yet to be studied. The influence of pressure pulsations induced by an acoustic wave (∼100 Hz) on the concentration, droplet size, and flow structure of the mists delivered from medical nebulizers was studied. The direct visualization showed that pulsations intensify aerosol deposition inside narrow channels due to particle displacement perpendicularly to the main flow direction. This motion also allows for particle penetration via narrow openings. UV-assisted observation of the intensified aerosol deposition inside the anatomical cast of the nasal cavity confirmed the importance of acoustic pulsations for intranasal drug delivery, also helping aerosol penetrate hard-to-reach areas (including the paranasal sinuses). A new idea regarding appropriate time control of acoustic pulsations has been proposed to improve the aerosol drug mass transfer in the nose. The study shows that PI has great potential to expand into new and interdisciplinary areas. [Display omitted] [ABSTRACT FROM AUTHOR]

PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated. This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10–80 μg and 20–40 μg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated. A total of 60 participants completed the study. PA9159 doses of up to 80 μg in the SAD and up to 40 μg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8 % (368/880) of the samples in all treatment groups, including 25.2 % (105/416) of the SAD and 56.7 % (263/464) of the MAD. The majority (>80.0 %) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC 0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t 1/2) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUC ss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t 1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median T max was approximately 6 h in both the SAD and MAD cohorts. The PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis. [Display omitted] [ABSTRACT FROM AUTHOR]

The high hydrophilicity of citicoline and its rapid metabolism are the two main obstacles hindering intact molecules from passing the blood-brain barrier. This study aimed to formulate citicoline-loaded niosomes (CTC NSMs) for efficient brain delivery via the intranasal route to improve management of epilepsy. CTC NSMs were formulated via thin-film hydration method, optimized using d -optimal design, and characterized for entrapment efficiency, vesicle size, drug release, and cumulative amount permeated. The entrapment efficiency ranged from 19.44 to 61.98% with sustained drug release, and the vesicle size ranged from 125.4 to 542.5 nm with enhanced drug permeation. Cholesterol: Span ratio of 1:1.19 and cholesterol amount of 20 mg were predicted to produce optimal characteristics. Subsequently, the optimized formulation permeation confirmed a high nasal penetration using confocal laser scanning microscopy (CLSM). Afterward, the optimized CTC NSM formulation was integrated into in situ gel to boost the residence time in the nasal cavity. Additionally, Computed Tomography (CT) was performed by labeling the optimized formulation with gold nanoparticles (GNPs) to assess brain uptake and cellular translocation after intranasal administration of CTC. Furthermore, the protection against pentylenetetrazole-induced generalized seizures and mortality were determined in rats and compared with the oral drug solution at the exact dosage. The in vivo results revealed that a low dose of CTC NSM in situ gel had a powerful protective effect with delayed the latency for the start of convulsions. Collectively, NSM in situ gel is a potentially valuable intranasal drug delivery system that can boost the efficacy of CTC in epilepsy management. [ABSTRACT FROM AUTHOR]

Background: To evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years.Methods: The study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs).Results: Of 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment.Conclusions: In this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients. [ABSTRACT FROM AUTHOR]

In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l -DOPA induced dyskinesia (LID), which is the debilitating side effect of l -DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l -DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals. [ABSTRACT FROM AUTHOR]

• A generalized expression for the angular spacing of EIPI is derived. • Theoretical derivation is validated through both simulation and experimentation. • EIPI serves as an innovative application in nasal spray. • The droplet size, location, and refractive index are measured. Nasal-drug-delivery is an effective way to improve therapeutic effect. Droplet diameter and its distribution directly impact the deposition position and bioavailability of the drug in nasal passage. In this paper, the spatial distribution of the droplet size, location and refractive index of spray are explored with extended interferometric particle imaging technique. A generalized expression of the spatial spacing of interference fringes is derived theoretically. The fringe spacing for two counter-propagating beams is the same as that for a single beam along one of the two-beam directions at the sideward scattering region, which is verified by simulation and experiment. The polystyrene microsphere and the nasal spray of physiological saline and oxytocin are tested experimentally. The relative error of microsphere size is less than 0.3 %, the refractive index accuracy of spray can reach 10−4. The method presented herein is promising for many relevant applications, such as fuel spray and nasal spray. [ABSTRACT FROM AUTHOR]

Evaluation of the regional intranasal delivery of locally acting drugs in children is challenging. Anatomical nasal airway replicas potentially can provide a robust pre-clinical tool to test the performance of devices and formulations. However, there is often a challenge in identifying the nasal geometries that can reasonably be indicative of in vivo regional mass distribution of administered drug. This in vitro study was designed to investigate the regional intranasal drug delivery in 20 children, 2–11 years old (50% 2–6 years old and 50% female), using two commercially available suspension nasal spray products with different nozzle designs, plume characteristics, and active pharmaceutical ingredients. High-resolution computed tomography scans of the sinonasal region of pediatric human subjects with healthy nasal airways, reviewed and scored by a head and neck surgeon, were used to develop 20 three-dimensional (3D) replicas of the nasal airways. The 3D replicas were segmented into the two regions: anterior and posterior to the internal nasal valve (INV). They were then rapid prototyped in high clarity rigid plastic (Accura ClearVue). Each side of the septum of the 20 subjects was examined separately, resulting in 40 singular nasal cavities. A nozzle-specific spray tip holder was designed for each case to ensure consistent administration (insertion length, sagittal angle, and coronal angle) in all replicates. The wide range of posterior drug delivery observed in the forty geometries indicated significant intersubject variability in pediatric intranasal drug delivery. Three nasal geometries representing low, medium, and high levels of drug delivery to the target region, posterior to the INV, were chosen from the 40 nasal cavities. Our vision is that these three nasal geometries can potentially be beneficial in determining whether performance differences between test and reference nasal spray products are present that may affect their bioequivalence in children. They also may be useful when applied in parallel with similar adult nasal geometries, previously developed following a similar procedure, to provide additional insights into pediatric nasal drug delivery with innovator products in children in lieu of extending clinical studies to include pediatric subjects. • In vitro intersubject variability in pediatric drug delivery with nasal sprays is significant. • Three representative pediatric models were identified as candidates for evaluating nasal sprays. • Intranasal drug delivery in children may be more consistent and efficient than in adults. [ABSTRACT FROM AUTHOR]

Animal and human studies have demonstrated that intranasal oxytocin (OT) can penetrate the brain and induce cognitive, emotional, and behavioral changes, particularly in social functioning. Consequently, numerous investigations have explored the potential of OT as a treatment for anxiety and autism, conditions characterized by social deficits. Although both subclinical and clinical studies provide converging evidence of the therapeutic effects of OT in reducing anxiety levels and improving social symptoms in autism, results are not always consistent. Additionally, the pharmacological mechanism of OT requires further elucidation for its effective clinical application. Therefore, this review aims to examine the contentious findings concerning the effects of OT on anxiety and autism, offer interpretations of the inconsistent results from the perspectives of individual differences and varying approaches to OT administration, and shed light on the underlying mechanisms of OT. Ultimately, standardization of dosage, frequency of administration, formulation characteristics, and nasal spray devices is proposed as essential for future human studies and clinical applications of OT treatment. • Previous controversial findings of OT in anxiety and autism were clarified. • The mechanisms underlying OT effects were elucidated. • Challenges spanning from subclinical to clinical applications of OT were proposed. [ABSTRACT FROM AUTHOR]

Heparin is postulated to block the interaction of SARS-CoV-2 with highly glycosylated proteins which are critical for binding the angiotensin-converting enzyme 2 (ACE2), an essential mechanism for host-cell entry and viral replication. Intranasal heparin is under investigation for use as a SARS-CoV-2 preventative in the IntraNasal Heparin Trial (INHERIT, NCT05204550). Heparin directly interferes with real-time quantitative polymerase chain reaction (RT-qPCR), the gold standard for SARS-CoV-2 detection. This study aimed to investigate the magnitude of heparin interference across various clinical laboratory testing platforms, and the reversal of any interference by degradation of heparin using the heparinase I enzyme in nasopharyngeal swab (NP) samples for SARS-CoV-2 analysis by RT-qPCR. Heparin-mediated PCR interference was evident at heparin concentrations as low as 10 IU/mL across all platforms tested, with the exclusion of the Hologic Panther Aptima SARS-CoV-2 assay. Rates of false negative or invalid results increased with increasing heparin concentrations on all platforms, except the Hologic Panther Aptima and Roche Cobas LIAT. Heparinase I reversed heparin-mediated PCR inhibition across in all samples tested, except those with initial Ct values >35. Our study shows that the use of heparin-containing nasal sprays interferes with the detection of SARS-CoV-2 in NP swab samples by RT-qPCR, a phenomenon that is not well recognised in the literature. Furthermore, this study has also demonstrated that heparin-mediated PCR inhibition can be prevented through heparinase I treatment, demonstrating restoration of clinically significant results with Ct values <35. • Heparin concentrations as low as 10 IU/mL can cause interference in RT-qPCR. • Higher heparin concentrations can lead to false negative RT-qPCR results. • Heparinase I treatment of extracted nucleic acids can minimise PCR interference. [ABSTRACT FROM AUTHOR]

Background: Recent studies demonstrate substantial effects of deceptive placebo on experimentally induced sadness, even on autonomic activity. Whether deception is necessary, remains to be elucidated. We investigated the effect of an open-label placebo (OLP) treatment, i.e. an openly administered placebo delivered with a convincing rationale for its sadness-protecting effect.Methods: Eighty-four healthy females were randomized to an OLP group or a no-treatment control group. All participants received the same detailed information about the OLP effect, only the OLP group received an OLP nasal spray. Before and after the OLP intervention, participants underwent a sad mood induction procedure combining self-deprecating statements (Velten's method) and sad music. Sadness was assessed by the Positive and Negative Affect Schedule (PANAS-X). Autonomic activity was measured continuously.Results: Participants in the OLP group reported a significantly attenuated increase in sadness upon mood induction and less sadness after induction compared to the control group (d = 0.79). Regardless of intervention, heart rate decreased during mood inductions with a more pronounced deceleration in the second mood induction.Limitations: Generalizability is limited due to the selective sample and the reliance on an experimentally controlled mood induction.Conclusion: OLP treatment had a beneficial effect on perceived sadness, at least at the subjective level. Hence, deception may not necessarily be required for placebos to modulate experienced sad mood. Investigating the beneficial effects of OLP in (sub-)clinical samples would seem a promising and required next step towards a clinical use of placebo-associated positive treatment expectations. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of OC-01 (varenicline solution) nasal spray for treatment of patients with dry eye disease. Randomized, multicenter, double-masked, vehicle-controlled, phase 3 study. Adults 22 years of age or older with a diagnosis of dry eye disease, artificial tear use, Ocular Surface Disease Index score of 23 or more, and Schirmer test score (STS) of 10 mm or less. Eligibility was not restricted by eye dryness score (EDS). Patients (N = 758) were randomized in a 1:1:1 ratio to twice-daily treatment with 50-μl intranasal spray in each nostril of OC-01 0.03 mg (n = 260), OC-01 0.06 mg (n = 246), or vehicle (control; n = 252) for 4 weeks (ClinicalTrials.gov identifier, NCT04036292). The primary efficacy end point was the percentage of patients achieving a 10-mm improvement or more in STS at week 4. Secondary end points included change from baseline to week 4 in STS and EDS in a controlled adverse environment (CAE) chamber and in the clinic. Treatment-emergent adverse events (TEAEs) were assessed. A statistically significantly greater percentage of patients achieved the primary end point in both OC-01 treatment groups compared with the vehicle group (OC-01 0.03 mg, 47.3%; OC-01 0.06 mg, 49.2%; vehicle, 27.8%; P < 0.0001 for both doses). Change from baseline in STS at week 4 was statistically significantly greater for patients receiving OC-01 than vehicle (P < 0.0001 for both doses). Eye dryness score assessed at week 4 improved with OC-01 treatment compared with vehicle, although the difference was not significant for EDS measured in the CAE chamber and showed (nominal) significance in the clinic. Overall, 86.5% of patients (654/756) reported at least 1 TEAE during the treatment period; most were mild, nonocular (sneezing, cough, throat irritation, and instillation site irritation) and were reported by fewer patients in the vehicle group than in the OC-01 treatment groups (OC-01 0.03 mg, 97.3%; OC-01 0.06 mg, 99.2%; vehicle, 57%). OC-01 nasal spray was well tolerated and showed a clinically meaningful effect on signs and symptoms of dry eye disease. [ABSTRACT FROM AUTHOR]

Brain, a subtle organ of multifarious nature presents plethora of physiological, metabolic and bio-chemical convolutions that impede the delivery of biomolecules and thereby resulting in truncated therapeutic outcome in pathological conditions of central nervous system (CNS). The absolute bottleneck in the therapeutic management of such devastating CNS ailments is the BBB. Another pitfall is the lack of efficient technological platforms (due to high cost and low approval rates) as well as limited clinical trials (due to failures of neuro‑leads in late-stage pipelines) for CNS disorders which has become a literal brain drain with poorest success rates compared to other therapeutic areas, owing to time consuming processes, tremendous convolutions and conceivable adverse effects. With the advent of intranasal delivery (via direct N2B or indirect nose to blood to brain), several novel drug delivery carriers viz. unmodified or surface modified nanoparticle based carriers, lipid based colloidal nanocarriers and drysolid/liquid/semisolid nanoformulations or delivery platforms have been designed as a means to deliver therapeutic agents (small and large molecules, peptides and proteins, genes) to brain, bypassing BBB for disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, schizophrenia and CNS malignancies primarily glioblastomas. Intranasal application offers drug delivery through both direct and indirect pathways for the peripherally administered psychopharmacological agents to CNS. This route could also be exploited for the repurposing of conventional drugs for new therapeutic uses. The limited clinical translation of intranasal formulations has been primarily due to existence of barriers of mucociliary clearance in the nasal cavity, enzyme degradation and low permeability of the nasal epithelium. The present review literature aims to decipher the new paradigms of nano therapeutic systems employed for specific N2B drug delivery of CNS drugs through in silico complexation studies using rationally chosen mucoadhesive polymers (exhibiting unique physicochemical properties of nanocarrier's i.e. surface modification, prolonging retention time in the nasal cavity, improving penetration ability, and promoting brain specific delivery with biorecognitive ligands) via molecular docking simulations. Further, the review intends to delineate the feats and fallacies associated with N2B delivery approaches by understanding the physiological/anatomical considerations via decoding the intranasal drug delivery pathways or critical factors such as rationale and mechanism of excipients, affecting the permeability of CNS drugs through nasal mucosa as well as better efficacy in terms of brain targeting, brain bioavailability and time to reach the brain. Additionally, extensive emphasis has also been laid on the innovative formulations under preclinical investigation along with their assessment by means of in vitro /ex vivo/in vivo N2B models and current characterization techniques predisposing an efficient intranasal delivery of therapeutics. A critical appraisal of novel technologies, intranasal products or medical devices available commercially has also been presented. Finally, it could be warranted that more reminiscent pharmacokinetic/pharmacodynamic relationships or validated computational models are mandated to obtain effective screening of molecular architecture of drug-polymer-mucin complexes for clinical translation of N2B therapeutic systems from bench to bedside. [Display omitted] • The convolutions associated with the lack of efficient technological platforms and existence of brain barriers in CNS drug delivery have been deliberated. • Reminiscent 3D molecular docking simulation for the fundamental understanding of in silico interaction for ideal nanocarrier design has been conceptualized. • Feats and fallacies in the clinical translation of intranasal therapies and physicochemical attributes of excipients influencing their rationale in N2B- delivery have been accentuated. • Novel paradigms for the repurposing of conventional biomolecules by assessing their particle engineering characteristics purveys exhilarating prospects in the N2B therapeutics. • Preclinical assessment of intranasal formulations as well as pros and cons of commercially marketed intranasal products/devices have also been documented. [ABSTRACT FROM AUTHOR]

Background: Although the efficacy and safety profiles of both intranasal fentanyl and midazolam are well studied in pediatric patients, few studies examine their use in younger children.Objectives: To examine and report our experiences in a pediatric emergency department (ED) with intranasal fentanyl and midazolam in children aged 3 years and younger.Methods: This retrospective study investigated intranasal fentanyl and midazolam administration, alone and in combination, in children 3 years and younger treated in a pediatric ED.Results: Of 6198 patients included, 1762 received intranasal fentanyl alone, 1115 received intranasal midazolam alone, and 3321 received combination therapy. The median (interquartile range [IQR]) patient age was 2.2 (1.5-3) years. Initial median (IQR) fentanyl dose was 2.7 (2-3) µg/kg, with 13.3% receiving a repeat dose. Initial median (IQR) midazolam dose was 0.3 (0.2-0.3) mg/kg, with 3.3% receiving a second dose. Children receiving both fentanyl and midazolam had median (IQR) initial doses of 2.8 (2.1-3) µg/kg and 0.3 (0.2-0.3) mg/kg, respectively. Of these, 3.2% received repeat doses of both medications. Laceration repairs (33.8%) and incision and drainage (22.2%) accounted for the majority of indications. Only 2.9% (n = 178) received additional opioids. No serious adverse events requiring a reversal agent or respiratory support were reported.Conclusions: Intranasal fentanyl and midazolam, alone and in combination, can provide analgesia and anxiolysis to children aged 3 years and younger in the ED setting. Further prospective studies are needed to better evaluate their safety and efficacy in this younger population. [ABSTRACT FROM AUTHOR]

Background: To investigate the powerful placebo effects in antidepressant drug trials and their mechanisms, recent pioneering experimental studies showed that expectation manipulation combined with an active placebo attenuated induced sadness. In the present study, we aimed at extending these findings by assessing the psychophysiological response in addition to mere self-report.Methods: One hundred and thirteen healthy female students were randomly assigned to a drug expectation group (active placebo, positive treatment expectation), placebo expectation group (active placebo, no treatment expectation), or a no-treatment group (no placebo, no treatment expectation). After placebo intake, sadness was induced by self-deprecating statements using the Velten method combined with sad music, including a rumination phase. Sadness was measured using the Positive and Negative Affect Schedule Expanded Form (PANAS-X). Heart rate and skin conductance were assessed continuously.Results: After mood induction and after rumination, self-reported sadness was significantly lower, and skin conductance level was significantly higher, in the drug expectation group than in the no-treatment group. The mood induction was further accompanied by a heart rate deceleration within all groups.Limitations: Generalizability is limited by sample selectivity and focusing on sadness as a symptom of depression, exclusively.Conclusion: Expectation-induced placebo effects significantly influenced sadness-correlated changes in autonomic arousal, and not only subjectively reported sadness, indicating that placebo effects in the context of affect are not merely due to subjective response bias. The systematic modification of treatment expectation could be utilized in clinical practice to optimize current therapeutic approaches to improve mood regulation. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the efficacy of calcitonin spray on bone healing following open reduction internal fixation (ORIF) of mandibular fractures. Fourteen patients were subdivided into a study group and a control group. A standardized surgical protocol for ORIF was followed. Postoperatively, salmon calcitonin nasal spray was administered to only the study group. The outcome parameters assessed were serum osteocalcin, pain, and radiographic bone healing. Serum osteocalcin was assessed pre- and postoperatively. Postoperative pain was documented using a visual analogue scale (VAS) on the 7th, 14th, 23rd, and 30th days. An orthopantomogram was used to score fracture healing at four time intervals, as follows: 1 — absence of callus; 2 — presence of minimal callus; 3 — considerable callus; and 4 — complete fusion of fracture. Pain scores were lower for the study group, with no pain from the fifth day, while the control group produced a mean score for day 5 of 2.43 ± 0.98 (p = 0.001). Mean postoperative serum osteocalcin levels were higher for the study group (67.82 ± 8.89) compared with the control group (57.69 ± 6.22; p = 0.029). Bone healing at 12 weeks postoperatively was level 4 for 28.6% of patients in the study group and level 3 for 71.4%. In comparison, 85.7% in the control group demonstrated level 3 healing, while 14.3% remained at level 2 (p = 0.462). Within the limitations of the study, it can be concluded that intranasal salmon calcitonin spray reduces postoperative pain and facilitates fracture healing, although its economic efficiency is still to be proven. [ABSTRACT FROM AUTHOR]

Objective: Japanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed.Methods: This study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients' nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices.Results: From the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment.Conclusion: The efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation. [ABSTRACT FROM AUTHOR]

Background: The Centers for Disease Control and Prevention guidelines recommend naloxone for every high-dose opioid prescription; in 2018, only 1 naloxone prescription was dispensed for every 69 high-dose opioid prescriptions. In Virginia, strategies for creating awareness and availability include the REVIVE! training and the standing protocol for pharmacists to dispense naloxone.Objectives: To evaluate if a proactive offer for counseling by pharmacists improves the percent change of patients who receive a prescription for naloxone nasal spray compared with the previous year's naloxone nasal spray fill history and to determine if the pharmacist's counseling affects a patient's confidence with opioid overdose and naloxone use.Methods: Prospective 4-month, interventional study in southwest Virginia conducted at 5 geographically similar large community chain pharmacies. A National Drug Code activity report within each store was used to identify patients, aged 18-64 years, filling opioid medication without naloxone. A pharmacist recommended naloxone to patients at the point of care. Patients accepting the recommendation for naloxone received pharmacist counseling from a standardized counseling script and by using a naloxone nasal spray demo kit. All eligible patients were provided a postintervention survey assessing their confidence with naloxone, if naloxone had been recommended before, and if they were picking up naloxone on the basis of the pharmacist's recommendation. Results were analyzed using univariate and bivariate analyses.Results: A total of 121 naloxone prescriptions were dispensed; an increase of 36% compared with the same period during the previous year. In total, 38 patients completed the postintervention survey. After receiving pharmacist counseling, patients indicated being very confident with administering naloxone correctly and for recognizing an opioid overdose, 73.9% and 65.2%, respectively. Of the patients who completed the survey, 60.5% received naloxone and accepted counseling from the pharmacist.Conclusion: After pharmacist counseling, naloxone dispensing increased, and patients were confident with both administration and recognition. [ABSTRACT FROM AUTHOR]

Particle size characterization for active pharmaceutical ingredients (APIs) in nasal spray suspension products presents unique challenges because both the API and excipient particles are present in the final dosage form. Currently, an established method is lacking because traditional particle sizing technologies do not distinguish the chemical identity of the particles. In this study, a non-destructive, ingredient-specific particle sizing method was developed for characterization of mometasone furoate (MF) nasal spray suspensions using Morphology Directed Raman Spectroscopy (MDRS). A five-step method development procedure was used in this study: sample preparation, particle imaging and morphology analysis, particle Raman measurements and classification, morphology filter selection, and minimum number of particles determination. Wet dispersion sample preparation method was selected to ensure that the particles were measured in their original suspended state. A training set containing over 10,000 randomly-selected particles, including both the API and excipient particles, was used to gain a comprehensive understanding of particle size, shape, and chemical ID for the nasal spray suspension. Morphology and Raman measurements were performed on each particle in the training set. The measurement results suggested that the aspect ratio and intensity mean filter combination was an appropriate morphology filter setting to selectively target API particles and exclude most of excipient particles. With further optimization of the morphology filter cutoff values and determination of minimal number of particles to be measured, the total measurement time was reduced from 90 hours to 8 hours. The morphologically screening strategy ultimately allowed us to create a time-efficient practical API-specific particle size distribution (PSD) methods for nasal spray suspensions. This study shows that MDRS is a fit for purpose analytical technique for determining ingredient-specific PSDs of the pharmaceutical formulation studied in this work. [ABSTRACT FROM AUTHOR]

• cCHP nanogel trivalent PspA vaccine effectively induces PspA-specific IgG in macaque. • PspA-specific IgG bound to the pneumococcal surface and triggered C3 deposition. • Vaccinated macaques were protected from pneumococcal intratracheal challenge. • A nasal spray-application device was developed for the cCHP nanogel nasal vaccine. • The vaccine might provide broad protection against pneumococcal infections in humans. Current polysaccharide-based pneumococcal vaccines are effective but not compatible with all serotypes of Streptococcus pneumoniae. We previously developed an adjuvant-free cationic nanogel nasal vaccine containing pneumococcal surface protein A (PspA), which is expressed on the surfaces of all pneumococcal serotypes. Here, to address the sequence diversity of PspA proteins, we formulated a cationic nanogel-based trivalent pneumococcal nasal vaccine and demonstrated the vaccine's immunogenicity and protective efficacy in macaques by using a newly developed nasal spray device applicable to humans. Nasal vaccination of macaques with cationic cholesteryl pullulan nanogel (cCHP)-trivalent PspA vaccine effectively induced PspA-specific IgGs that bound to pneumococcal surfaces and triggered complement C3 deposition. The immunized macaques were protected from pneumococcal intratracheal challenge through both inhibition of lung inflammation and a dramatic reduction in the numbers of bacteria in the lungs. These results demonstrated that the cCHP-trivalent PspA vaccine is an effective candidate vaccine against pneumococcal infections. [ABSTRACT FROM AUTHOR]

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19. [ABSTRACT FROM AUTHOR]

According to a standing order in North Carolina (NC), naloxone can be purchased without a provider prescription. The objective of this study is to examine whether same-day naloxone accessibility and cost vary by pharmacy type and rurality in NC. A cross-sectional telephone audit of 202 NC community pharmacies stratified by pharmacy type and county of origin was conducted in March and April 2023. Trained "secret shoppers" enacted a standardized script and recorded whether naloxone was available and its cost. We examined the relationship between out-of-pocket naloxone cost, pharmacy type, and rurality. Naloxone could be purchased in 53% of the pharmacies contacted; 26% incorrectly noting that naloxone could be filled only with a provider prescription and 21% did not sell naloxone. Naloxone availability by standing order was statistically different by pharmacy type (chain/independent) (χ2 = 20.58, df = 4, P value < 0.001), with a higher frequency of willingness to dispense according to the standing order by chain pharmacies in comparison to independent pharmacies. The average quoted cost for naloxone nasal spray at chain pharmacies was $84.69; the cost was significantly more ($113.54; P < 0.001) at independent pharmacies. Naloxone cost did not significantly differ by pharmacy rurality (F 2 , 136 = 2.38, P = 0.10). Approximately half of NC community pharmacies audited dispense naloxone according to the statewide standing order, limiting same-day access to this life-saving medication. Costs were higher at independent pharmacies, which could be due to store-level policies. Future studies should further investigate these cost differences, especially as intranasal naloxone transitions from a prescription only to over-the-counter product. [ABSTRACT FROM AUTHOR]

[Display omitted] Carvedilol (CV), a β-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster T max and higher C max compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] The surge in neurological disorders necessitates innovative strategies for delivering active pharmaceutical ingredients to the brain. The non-invasive intranasal route has emerged as a promising approach to optimize drug delivery to the central nervous system by circumventing the blood–brain barrier. While the intranasal approach offers numerous advantages, the lack of a standardized protocol for drug testing poses challenges to both in vitro and in vivo studies, limiting the accurate interpretation of nasal drug delivery and pharmacokinetic data. This review explores the in vitro experimental assays employed by the pharmaceutical industry to test intranasal formulation. The focus lies on understanding the diverse techniques used to characterize the intranasal delivery of drugs targeting the brain. Parameters such as drug release, droplet size measurement, plume geometry, deposition in the nasal cavity, aerodynamic performance and mucoadhesiveness are scrutinized for their role in evaluating the performance of nasal drug products. The review further discusses the methodology for in vivo characterization in detail, which is essential in evaluating and refining drug efficacy through the nose-to-brain pathway. Animal models are indispensable for pre-clinical drug testing, offering valuable insights into absorption efficacy and potential variables affecting formulation safety. The insights presented aim to guide future research in intranasal drug delivery for neurological disorders, ensuring more accurate predictions of therapeutic efficacy in clinical contexts. [ABSTRACT FROM AUTHOR]

[Display omitted] Intranasal delivery provides a direct and non-invasive method for drugs to reach the central nervous system. Nanoparticles play a crucial role as carriers in augmenting the efficacy of brain delivery. However, the interaction between nanoparticles and the nose-to-brain pathway and how the various biopharmaceutical factors affect brain delivery efficacy remains unclear. In this review, we comprehensively summarized the anatomical and physiological characteristics of the nose-to-brain pathway and the obstacles that hinder brain delivery. We then outlined the interaction between nanoparticles and this pathway and reviewed the biomedical applications of various nanoparticulate drug delivery systems for nose-to-brain drug delivery. This review aims at inspiring innovative approaches for enhancing the effectiveness of nose-to-brain drug delivery in the treatment of different brain disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] The therapeutic potential of pharmaceutical cocrystals in intranasal applications remains largely unexplored despite progressive advancements in cocrystal research. We present the application of spray freeze drying (SFD) in successful fabrication of a favipiravir-pyridinecarboxamide cocrystal nasal powder formulation for potential treatment of broad-spectrum antiviral infections. Preliminary screening via mechanochemistry revealed that favipiravir (FAV) can cocrystallize with isonicotinamide (INA), but not nicotinamide (NCT) and picolinamide (PIC) notwithstanding their structural similarity. The cocrystal formation was characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and unit cell determination through Rietveld refinement of powder X-ray analysis. FAV-INA crystalized in a monoclinic space group P 2 1 / c with a unit cell volume of 1223.54(3) Å3, accommodating one FAV molecule and one INA molecule in the asymmetric unit. The cocrystal was further reproduced as intranasal dry powders by SFD, of which the morphology, particle size, in vitro drug release, and nasal deposition were assessed. The non-porous flake shaped FAV-INA powders exhibited a mean particle size of 19.79 ± 2.61 μm, rendering its suitability for intranasal delivery. Compared with raw FAV, FAV-INA displayed a 3-fold higher cumulative fraction of drug permeated in Franz diffusion cells at 45 min (p = 0.001). Dose fraction of FAV-INA deposited in the nasal fraction of a customized 3D-printed nasal cast reached over 80 %, whereas the fine particle fraction remained below 6 % at a flow rate of 15 L/min, suggesting high nasal deposition whilst minimal lung deposition. FAV-INA was safe in RPMI 2650 nasal and SH-SY5Y neuroblastoma cells without any in vitro cytotoxicity observed. This study demonstrated that combining the merits of cocrystallization and particle engineering via SFD can propel the development of advanced dry powder formulations for intranasal drug delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] Monoclonal antibodies (mAbs) administered intranasally as dry powders can be potentially applied for the treatment or pre-exposure prevention of viral infections in the upper respiratory tract. However, a method to transform the mAbs from liquid to dry powders suitable for intranasal administration and a device that can spray the dry powders to the desired region of the nasal cavity are needed to fully realize the potentials of the mAbs. Herein, we report that thin-film freeze-dried mAb powders can be sprayed into the posterior nasal cavity using Aptar Pharma's Unidose (UDS) Powder Nasal Spray System. AUG-3387, a human-derived mAb that neutralizes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was used in the present study. First, we prepared thin-film freeze-dried AUG-3387 powders (i.e., TFF AUG-3387 powders) from liquid formulations containing different levels of mAbs. The TFF AUG-3387 powder with the highest solid content (i.e., TFF AUG-3387C) was then chosen for further characterization, including the evaluation of the plume geometry, spray pattern, and particle size distribution after the powder was sprayed using the UDS Powder Nasal Spray. Finally, the deposition patterns of the TFF AUG-3387C powder sprayed using the UDS Powder delivery system were studied using 3D-printed nasal replica casts based on the CT scans of an adult and a child. It is concluded that it is feasible to intranasally deliver mAbs as dry powders by transforming the mAbs into dry powders using thin-film freeze-drying and then spraying the powder using a powder nasal spray system. [ABSTRACT FROM AUTHOR]

The intranasal administration of drugs using environmentally responsive formulations, employing a combination of hydroxypropyl methylcellulose (HPMC) and poloxamer 407 (P407), can result in release systems that may assist in the treatment of neurological diseases. Meloxicam, considered a potential adjuvant in the treatment of Alzheimer's disease, could be used in these platforms. The aim of this work was to develop a mucoadhesive, thermoresponsive, and nanostructured system containing HPMC for nose-to-brain administration of meloxicam. The initially selected systems were investigated for their rheological, mechanical, and micellar size characteristics. The systems were dilatant at 25 °C and pseudoplastic with a yield value at 37 °C, showing viscoelastic properties at both temperatures. The platform containing HPMC (0.1%, w/w) and P407 (17.5%, w/w) was selected and demonstrated good mucoadhesive properties, along with an appropriate in vitro release profile. HPMC could form a binary system with P407, displaying superior mucoadhesive and thermoresponsive properties for nose-to-brain meloxicam administration, indicating that the selected formulation is worthy of clinical studies. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • The deposition of rivastigmine nasal spray in the nasal regions was assessed by the 3D-printed nasal cavity model. • A positive correlation has been verified between olfactory drug deposition and intracranial drug delivery through in vitro and in vivo studies. • A novel rivastigmine nasal spray with high-efficiency brain delivery demonstrated more notable efficacy compared to the commercially available formulation in the treatment of Alzheimer's disease. Alzheimer's disease (AD) is characterized by a gradual decline in cognitive function and memory impairment, significantly impacting the daily lives of patients. Rivastigmine (RHT), a cholinesterase inhibitor, is used to treat mild to moderate AD via oral administration. However, oral administration is associated with slow absorption rate and severe systemic side effects. RHT nasal spray (RHT-ns), as a nose-to-brain delivery system, is more promising for AD management due to its efficient brain delivery and reduced peripheral exposure. This study constructed RHT-ns for enhancing AD treatment efficacy, and meanwhile the correlation between drug olfactory deposition and drug entering into the brain was explored. A 3D-printed nasal cast was employed to quantify the drug olfactory deposition. Brain delivery of RHT-ns was quantified using fluorescence tracking and Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) analysis, which showed a good correlation to the olfactory deposition. F 2 (containing 1% (w/v) viscosity modifier Avicel® RC-591) with high olfactory deposition and drug brain delivery was further investigated for pharmacodynamics study. F 2 exhibited superiority in AD treatment over the commercially available oral formulation. In summary, the present study showed the successful development of RHT-ns with improved olfactory deposition and enhanced brain delivery. It might provide new insight into the design and development of nose-to-brain systems for the treatment of AD. [ABSTRACT FROM AUTHOR]

In vitro – in vivo correlation (IVIVC) allows prediction of in vivo drug deposition from a nasally inhaled drug based on in vitro drug measurements. In vitro measurements include physical particle characterization and, more recently, deposition studies using anatomical models. Currently, there is a lack of IVIVC for deposition measurements in anatomical models, especially for deposition patterns in various nasal cavity regions. Therefore, improvement of in vitro and in vivo measurement methods and knowledge about nasal deposition mechanisms should help IVIVC in the future. In vitro parameters to be considered to predict in vivo nasal drug deposition: Particle characteristics generated by drug delivery devices, patient ventilation and anatomy using anatomical model tools, for example. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for esketamine nasal spray (SPRAVATOTM).Methods: Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores.Results: Baseline scores were similar for the PHQ-9 and MADRS between the esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the esketamine/AD group compared to 65.0% in the placebo/AD group.Conclusions: Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians. [ABSTRACT FROM AUTHOR]

Delivering localized treatment to the paranasal sinuses for diseases such as chronic rhinosinusitis (CRS) is particularly challenging because of the small natural openings leading from the sinuses that can be further obstructed by presence of inflammation. As such, oral steroids, topical nasal sprays or irrigation, and surgery can be utilized to treat persistent sinonasal inflammation, but there exists a need for post-operative options for long-term steroid delivery to prevent disease recurrence. In the present study, a T hermogel, E xtended-release M icrosphere-based-delivery to the P aranasal S inuses (TEMPS) is developed with the corticosteroid mometasone furoate. Specifically, the bioactive steroid is released for 4 weeks from poly(lactic- co -glycolic acid) (PLGA) microspheres embedded in a poly(N-isopropylacrylamide) (p-NIPAAm)-based hydrogel. The temperature-responsive system undergoes a reversible sol-gel transition at 34–35 °C such that it can be applied as a liquid at ambient temperature, conforming to the sinonasal epithelium as it gels. In a rabbit model of CRS, TEMPS was maintained in rabbit sinuses and effectively reduced sinonasal inflammation as characterized by micro-computed tomography and histopathology analysis. Ultimately, the combination of controlled release microspheres with a thermoresponsive hydrogel provides flexibility for encapsulating therapeutics in a reversible and conforming system for localized delivery to the sinuses. Unlabelled Image • Corticosteroid, mometasone furoate, was encapsulated in polymer microspheres at clinically relevant doses. • Sustained release of bioactive corticosteroid was achieved from microspheres embedded in thermoresponsive hydrogel. • Evidence of reduced sinonasal inflammation was observed 4 weeks after injecting the steroid-loaded system in rabbit sinuses. [ABSTRACT FROM AUTHOR]