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Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), approved by the US FDA for obesity treatment, are typically administered subcutaneously, an invasive method leading to suboptimal patient adherence and peripheral side effects. Additionally, this route requires the drug to cross the restrictive blood-brain barrier (BBB), limiting its safety and effectiveness in weight management and cognitive addiction disorders. Delivering the drug intranasally could overcome these drawbacks., Areas Covered: This review summarizes GLP-1 RAs used as anti-obesity agents, focusing on the intranasal route as a potential pathway to deliver these biomolecules to the brain. It also discusses strategies to overcome challenges associated with nasal delivery., Expert Opinion: Nose-to-brain (N2B) pathways can address limitations of the subcutaneous route for GLP-1 RAs. However, peptide delivery to the brain is challenging due to nasal physiological barriers and the drug's physicochemical properties. Innovative approaches, such as cell permeation enhancers, mucoadhesive systems, and nanocarriers in nasal formulations, along with efficient drug delivery devices, show promising preclinical results. Despite this, successful preclinical data does not guarantee clinical effectiveness, highlighting the need for comprehensive clinical investigations to optimize formulations and fully utilize the nose-to-brain interface for peptide delivery.

Introduction: Soft mist inhalers (SMIs) are propellant-free inhalers that utilize mechanical power to deliver single or multiple doses of inhalable drug aerosols in the form of a slow mist to patients. Compared to traditional inhalers, SMIs allow for a longer and slower release of aerosol with a smaller ballistic effect, leading to a limited loss in the oropharyngeal area, whilst requiring little coordination of actuation and inhalation by patients. Currently, the Respimat® is the only commercially available SMI, with several others in different stages of preclinical and clinical development., Areas Covered: The primary purpose of this review is to critically assess recent advances in SMIs for the delivery of inhaled therapeutics., Expert Opinion: Advanced particle formulations, such as nanoparticles which target specific areas of the lung, Biologics, such as vaccines, proteins, and antibodies (which are sensitive to aerosolization), are expected to be generally delivered by SMIs. Furthermore, repurposed drugs are expected to constitute a large share of future formulations to be delivered by SMIs. SMIs can also be employed for the delivery of formulations that target systemic diseases. Finally, digitalizing SMIs would improve patient adherence and provide clinicians with fundamental insights into patients' treatment progress.

Introduction: Lymphangioleiomyomatosis (LAM) is a rare lung disease that is characterized by smooth muscle-like cell growth in the lungs. The current available oral treatment rapamycin slows down the disease progression but does not result in a cure. Rapamycin is also limited by its low bioavailability and dose-related adverse side effects. New treatments are, therefore, underway to investigate alternative targets and combination therapies for LAM. In recent years, much focus has been on the development of therapies based on inhaled nanotechnology using carriers to deliver drugs, as it is shown to improve drug solubility, local targeted treatment, and bioavailability., Areas Covered: This review, therefore, focuses on future prospective treatments for LAM using nanoparticles and lipid-based nanocarriers, including liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. It also investigates how nanoparticles' physicochemical factors such as size and charge can affect the treatment of both pulmonary and extrapulmonary LAM., Expert Opinion: Advanced clinical research is still needed to demonstrate the full potential and drive future commercialization of LAM treatments delivered via inhaled lipid nanobased formulations. If successful, the resultant effects will be seen in the improvement in the life expectancy and life quality of LAM patients.

Objective: The airway epithelium is a potential source of pathophysiology through activation of transient potential receptor vallinoid type 1 (TRPV1) channel. A positive feedback cycle caused by TRPV1 activity is hypothesized to induce upregulation and production of inflammatory cytokines, leading to exacerbations of chronic airway diseases. These cytokine and protein regulation effects were investigated in this study., Methods: Healthy (BEAS-2B) and cancer-derived (Calu-3) airway epithelial cell lines were assessed for changes to TRPV1 protein expression and mRNA expression following exposure to capsaicin (5-50 µM), and TRPV1 modulators including heat (43 °C), and hydrochloric acid (pH 3.4 to pH 6.4). Cytotoxicity was measured to determine the working concentration ranges of treatment. Subsequent bronchoconstriction by TRPV1 activation with capsaicin was measured on guinea pig airway tissue to confirm locally mediated activity without the action of known neuronal inputs., Results: TRPV1 protein expression was not different for all capsaicin, acidity, and heat exposures ( p  > 0.05), and was replicated in mRNA protein expression ( p  > 0.05). IL-6 and IL-8 expression were lower in BEAS-2B and Calu-3 cell lines exposed with acidity and heat ( p  < 0.05), but not consistently with capsaicin exposure, with potential cytotoxic effects possible., Conclusions: TRPV1 expression was present in airway epithelial cells but its expression was not changed after activation by TRPV1 activators. Thus, it was not apparent the reason for reported TRPV1 upregulation in patients with airway disease states. More complex mechanisms are likely involved and will require further investigation.

Objectives: A human nasal epithelial mucosa (NEM) on-a-chip is developed integrated with a novel carbon nanofibers-modified carbon electrode for real-time quantitative monitoring of in vitro nasal drug delivery. The integration of platinum electrodes in the chip also enables real-time measurement of transepithelial electrical resistance (TEER)., Methods: The air-liquid interface culture of nasal epithelial RPMI 2650 cells in the NEM-on-a-chip was optimized to mimic the key functional characteristics of the human nasal mucosa. The epithelial transport of ibuprofen in the NEM-on-a-chip was electrochemically monitored in real-time under static and physiologically realistic dynamic flow conditions., Results: The NEM-on-a-chip mimics the mucus production and nasal epithelial barrier function of the human nasal mucosa. The real-time drug quantification by the NEM-on-a-chip was validated versus the high-performance liquid chromatography method. The drug transport rate monitored in the NEM-on-a-chip was influenced by the flow in the bottom compartment of the chip, highlighting the importance of emulating the dynamic in vivo condition for nasal drug transport studies., Conclusion: This novel NEM-on-a-chip can be a low-cost and time-efficient alternative to the costly laborious conventional techniques for in vitro nasal drug transport assays. Importantly, its dynamic microenvironment enables conducting nasal drug transport tests under physiologically relevant dynamic conditions.

Background: Airway stents are used to treat obstructive central airway pathologies including palliation of lung cancer, but face challenges with granulation tissue growth. Paclitaxel is a chemotherapy drug that also suppresses growth of granulation tissue. Yet, side effects arise from administration with toxic solubilizers. By incorporating paclitaxel in silicone stents, delivery of paclitaxel can be localized, and side effects minimized., Methods: Paclitaxel was incorporated into Liquid Silicone Rubber (LSR) containing polydimethylsiloxane, either as a powder or solution, prior to curing. Drug release study was compared in vitro at 37°C over 10 days. Drug release was quantified using HPLC, and bronchial cell lines were grown on LSR to investigate drug cytotoxicity, and expression of inflammatory markers, specifically interleukin-6 and interleukin-8., Results: Release rate of paclitaxel incorporated into silicone rubber was consistent with the Korsmeyer and Weibull models (R 2  > 0.96). Paclitaxel exposure reduced IL-8 levels in cancer cell lines, whilst no cytotoxic effect was observed in all cell lines at treatment concentration levels (≤ 0.1% (w/v) paclitaxel in silicone)., Conclusions: Incorporating paclitaxel into a silicone matrix for future use in a tracheobronchial stent was investigated. Drug release from silicone was observed and is a promising avenue for future treatments of central airway pathologies.

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated., Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics., Results: The formulations showed rapid gelation (4-7 min) at 30-35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110-150 kDa led to generation of optimum spray with lower Dv 50 , wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions., Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.

Purpose: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips., Methods: Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient., Results: The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray., Conclusions: Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.

Introduction: Simvastatin (SV) is a drug from the statin class, currently used orally as an anti-cholesterolemic drug. It inhibits the 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase to reduce cholesterol synthesis. Recently, it has been found that SV also has several other protective pharmacological actions unrelated to its anti-cholesterol effects that might be beneficial in the treatment of chronic airway diseases., Areas Covered: This review summarizes the evidence relating to SV as a potential anti-inflammatory, anti-oxidant and muco-inhibitory agent, administered both orally and via pulmonary inhalation, and discusses its pro and cons. Evidence could potentially be used to support the delivery of SV as inhaled formulation for the treatment of chronic respiratory diseases., Expert Opinion: The use of SV as anti-inflammatory, anti-oxidant and muco-inhibitory agent for drug delivery to the lung is promising. Inhaled SV formulations could allow the delivery profile to be customized and optimized to take advantage of the rapid onset of action, low systemic side effect and improved physico-chemical stability. This treatment could potentially to be used clinically for the localized treatment of lung diseases where inflammation and oxidative stress production is present.

Objectives: This study focuses on the development of a dry powder inhaler (DPI) formulation of simvastatin (SV), and the effects of SV on the respiratory epithelium., Methods: Micronised SV samples were prepared by dry jet-milling. The long-term chemical stability and physicochemical properties of the formulations were characterised in terms of particles size, morphology, thermal and moisture responses. Furthermore, in vitro aerosol depositions were performed. The formulation was evaluated for cell viability and its effect on cilia beat activity, using ciliated nasal epithelial cells in vitro. The formulation transport across an established air interface Calu-3 bronchial epithelial cells and its ability to reduce mucus secretion was also investigated., Results: The particle size of the SV formulation and its aerosol performance were appropriate for inhalation therapy. Moreover, the formulation was found to be non-toxic to pulmonary epithelia cells and cilia beat activity up to a concentration of 10(-6) M. Transport studies revealed that SV has the ability to penetrate into airway epithelial cells and is converted into its active SV hydroxy acid metabolite. Single dose of SV DPI also decreased mucus production after 4 days of dosing., Conclusion: This therapy could potentially be used for the local treatment of diseases like chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis given its anti-inflammatory effects and ability to reduce mucus production.