Search Results (269)

Clinical outcomes for brain cancer are often poor because the blood–brain/tumor barrier hinders effective drug delivery to malignant tissue. Glioblastoma, the most common primary brain malignancy in adults, has an average survival of approximately fourteen months. Here, we discuss novel strategies that our research group and others are developing to deliver chemotherapy to the brain via the nasal cavity. Although significant hurdles remain, intranasal delivery holds substantial promise for improving outcomes for patients with brain cancer. Intranasal delivery is noninvasive, permits repeated dosing, and has been shown to enable direct nose-to-brain transport that bypasses the blood–brain barrier. Challenges such as accurately targeting drugs to the appropriate region of the nasal cavity at therapeutically relevant doses, while maintaining reproducibility, make this cutting-edge approach a regulatory challenge. The prolonged path to clinical translation discourages many researchers from pursuing this potentially life-saving strategy. Nevertheless, preclinical studies demonstrate that intranasal delivery can achieve up to ten-fold higher concentrations of select drugs in the brain. Cancer chemotherapeutics span a wide range of molecular formats, from small molecules to 150-kilodalton antibodies. Accordingly, delivery strategies must be carefully matched to the molecular properties of each therapeutic. Here, we focus on the intranasal delivery of small molecule inhibitors using nanomaterial-based platforms, including aerosols, lipids, gold nanoparticles, gels, emulsions, fibers, and their combinations. Ultimately, we hope that intranasal delivery approaches will be translated to provide patients with better therapeutic outcomes. Full article

Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood–brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer’s and Parkinson’s diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53. Full article

Disorders of the central nervous system (CNS) are intricate and often resistant conditions that create a significant global impact, affecting millions of individuals each year. The blood–brain barrier (BBB) acts as a protective mechanism for the brain against external substances, but it also prevents most therapeutic agents from entering the CNS, leading to inadequate drug absorption and reduced effectiveness after diagnosis. Nasal drug delivery has emerged as a viable approach to bypass the BBB, facilitating direct access to the brain through the olfactory and trigeminal nerve routes. Although considerable research focuses on innovative nasal formulations with proven clinical promise, a critical gap persists: a systematic framework that bridges laboratory breakthroughs with clinical implementation. This review addresses this unmet need by integrating recent basic research advances with practical clinical requirements. We summarize nasal transport pathways, targeted design strategies, formulation optimization, and device engineering. Crucially, we propose a structured clinical evaluation framework built upon five essential pillars: targeting precision, pharmacokinetic performance, multi-organ safety profiling, device–drug clinical compatibility, and anatomical translation from animal models to humans. By mapping current research capabilities against clinical readiness criteria, this framework identifies translational bottlenecks and provides actionable guidance to accelerate the bench-to-bedside transition of intranasal drug delivery systems for CNS disorders. Full article

Background: Alzheimer’s disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood–brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P₃ achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P₀. Subsequent in vivo biodistribution studies showed that P₃ produced higher brain drug exposure than both intranasally administered P₀ and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases. Full article

Efficient aerosol delivery to the maxillary sinuses remains challenging because narrow ostia limit sinus entry. This in vitro study evaluated whether low-frequency, large-amplitude pulsatile flow can deliver humidifier-generated water aerosols to the maxillary sinuses, compared retention with e-vapor under identical conditions, and identified setup modifications required for water aerosol transport. Experiments used three transparent anatomically realistic sinonasal models: two single-passage models with narrow-long (NL) and wide-short (WS) ostial geometries, and one dual-passage dual-maxillary-sinus (RL) model. Water aerosols and e-vapor were delivered using a modified servo-actuated syringe generator under fixed conditions: 50 mL stroke volume, 0.33 Hz frequency, 1 L/min vacuum-induced flow, and 1.5 min delivery. Water aerosols were larger than e-vapor aerosols (D50 = 5.553 µm vs. 3.394 µm) and required setup modification because of greater wall interactions, condensation, coalescence, and transport losses. Pulsatile delivery achieved plume entry into all tested maxillary sinuses. E-vapor showed greater retained mass than water aerosols in NL (1.060 ± 0.152 vs. 0.540 ± 0.089 mg) and WS (0.800 ± 0.071 vs. 0.520 ± 0.110 mg). Water-sensitive Sar-Gel visualization confirmed bilateral water aerosol retention in RL. These findings support pulsatile delivery as a feasible strategy for water aerosol transport to the maxillary sinuses but with a lower efficiency than e-vapor aerosols. Full article

Non-invasive drug delivery for ocular diseases remains a significant challenge in ophthalmology, as conventional eye drops offer less than 5% bioavailability due to pre-corneal barriers and the corneal epithelium. This review explores the intranasal (IN) route as a promising strategy for targeting both the anterior and posterior segments of the eye. The IN route leverages several distinct pathways: the nasolacrimal reflex for remote physiological stimulation; the “neural bridge” through the cribriform plate, allowing direct perineural and vascular transport via the olfactory and trigeminal nerves to bypass the blood–retinal barrier; and systemic absorption that avoids hepatic first-pass metabolism. Pre-clinical evidence indicates that IN administration of agents such as erythropoietin, nerve growth factor, and insulin achieves superior retinal concentrations compared to topical or systemic dosing, offering neuroprotection in models of retinal degeneration and glaucoma. Clinically, varenicline nasal spray is already FDA-approved for dry eye disease, while intranasal steroids demonstrate a favorable ocular safety profile without significantly increasing intraocular pressure. Although limited by mucociliary clearance and small delivery volumes, the IN route offers a painless, non-invasive alternative to intraocular injections, potentially enhancing patient compliance. Future advancements in mucoadhesive nanocarriers are essential to optimize drug residence time and realize the full potential of nose-to-eye delivery in chronic ophthalmic care. Full article

Background: Effective strategies for delivering neuroprotective agents to the brain remain a major challenge due to the poor solubility, rapid metabolism, and low bioavailability of promising molecules, such as 7,8-dihydroxyflavone (7,8-DHF). This small-molecule TrkB receptor agonist exhibits significant antioxidant, neuroprotective properties, and additional effects on metabolic regulation, but its therapeutic potential is limited by unfavorable pharmacokinetic characteristics. Nanotechnology-based delivery systems are increasingly explored to improve drug stability, enhance bioavailability, and facilitate direct nose-to-brain transport following intranasal administration. In this study, lipid nanoparticles encapsulating 7,8-DHF were developed using a fish-oil-based lipid core enriched with ω-3 polyunsaturated fatty acids (DHA and EPA) and naturally derived excipients, including soybean lecithin and ε-polylysine. Methods: The formulation was optimized using a Design of Experiments (DoE) approach based on a 2³ full factorial design, evaluating drug concentration, lecithin concentration, and surfactant type (Pluronic^® F127 or Tween^® 80). The main formulation responses considered were particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency. Results: The optimized nanoparticles exhibited nanometric dimensions (<250 nm); spherical morphology, confirmed by TEM; low polydispersity (PDI < 0.3); and adequate encapsulation efficiency. Stability studies in simulated biological fluids indicated good physicochemical stability for up to 48 h, while interaction studies with mucin suggested a good interaction within the mucus environment. ROS scavenging capacity was confirmed through the DPPH chemical assay, and in vitro experiments on olfactory ensheathing cells, selected as a biologically relevant model for their anatomical localization along the olfactory pathway, showed reduced cytotoxicity of the encapsulated drug compared with the free form. Conclusions: Collectively, these results support the potential application of the developed nanoformulation in the intranasal delivery of 7,8-DHF. Full article

Chronic rhinosinusitis (CRS) constitutes a multicausal inflammatory disease of the nose and paranasal sinuses, often associated with olfactory dysfunction (OD), a symptom that significantly impacts patients’ quality of life. OD in CRS was traditionally thought to be related to mechanical obstruction of the olfactory cleft, but is now considered to be multifactorial, involving conductive, inflammatory, and sensorineural mechanisms as well. Type-2 inflammatory response (high interleukins IL-4, IL-5, IL-13), eosinophilia, and increased IgE are involved in epithelial damage, impaired neurogenesis, and persistent olfactory loss, especially in chronic rhinosinusitis with nasal polyps (CRSwNP). In addition, peripheral chronic inflammation may also play a role in central neural remodeling, which may potentially affect olfactory function. Objective psychophysical testing is necessary to accurately assess olfactory function because self-reports may lack reliability. Management strategies aim at reducing inflammation and restoring sinonasal ventilation. First-line therapy with intranasal corticosteroids and short courses of systemic corticosteroids may be useful for symptomatic relief. Biologic agents directed against type-2 inflammation have demonstrated significant benefits in selected cases. Functional Endoscopic Sinus Surgery (FESS) plays an important role in the treatment of refractory CRS to restore the airflow and to improve the delivery of topical drugs. Olfactory outcomes following surgery, however, are variable and often incomplete, reflecting underlying inflammation and neuroepithelial damage. Disease recurrence, especially in type-2–driven CRS, affects long-term outcomes, underscoring the necessity to incorporate surgery in an individualized, endotype-informed treatment strategy. Full article

Background/Objectives: The recent approval of the first intranasal calcitonin gene-related peptide receptor antagonist (CGRP-RA), zavegepant, has increased the relevance of this drug class in treating acute migraine. However, introducing an alternative delivery method may result in a different real-world safety profile. Thus, the aim of this study was to assess adverse events (AEs) related to zavegepant through a retrospective pharmacovigilance disproportionality analysis. Methods: We analyzed Individual Case Safety Reports (ICSRs) presenting zavegepant as the suspected drug, submitted to the Food and Drug Administration (FDA) Adverse Event Monitoring System (AEMS) database between 1 January 2023 and 31 December 2025. ICSRs were assessed by using descriptive and disproportionality analyses. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were used as disproportionality measures. Results were deemed significant if the ROR 95% CI lower bound was >1 and ≥3 ICSRs were available for each drug–event pair. Results: A total of 509 zavegepant-related ICSRs were identified. Most ICSRs involved female patients (n = 353; 69.4%), with a median (quartile 1, Q1–quartile 3, Q3) age of 45 (34–56) years. The Medical Dictionary for Regulatory Activities (MedDRA^®) Preferred Terms with the highest RORs were nasal discomfort (n = 62; ROR = 298.85; 95%CI [228.91, 390.17]), rhinalgia (10; 126.09; [67.34, 236.09]), dysgeusia (147; 94.72; [78.19, 114.75]), pharyngeal ulceration (3; 79.20; [25.42, 246.75]), and upper-airway cough syndrome (16; 62.87; [38.19, 103.49]). Conclusions: These results suggest a safety profile for zavegepant consistent with previous knowledge regarding CGRP-RAs. However, nasal and/or oropharyngeal AEs, plausibly related to intranasal exposure, may affect perceived tolerability and timely use, warranting further investigation. Full article

Objectives: this study aimed to develop and optimize an intranasal delivery system for Eplerenone (EPL) by incorporating Eplerenone-loaded liposomes (Elip) into an in situ gel system (Elip-GG). The goal was to prolong the residence time of the drug in the nasal cavity and ensure sustained release. Methods: Elip and unloaded liposomes were prepared using the thin-film hydration method. Key formulation variables such as encapsulation efficiency (EE%), mean particle size (MPS), polydispersity index (PDI), and zeta potential (ZP) were optimized. The Elip was then incorporated into a gellan gum (GG) in situ gel to form Elip-GG. The Elip-GG formulation was evaluated based on parameters such as pH, viscosity, rheological behavior, mechanical properties, and in vitro release. Results: the optimal Elip formulation exhibited an EE of 86.3%, a mean particle size of 86.56 nm, a PDI of 0.29, and a ZP of −29.86 mV. The cumulative drug release from the Elip-GG formulation exceeded 93% after 2.5 h. The Elip-GG formulation significantly increased the sustained release of Eplerenone when administered intranasally, offering a promising alternative to oral and parenteral delivery methods for hydrophilic antihypertensive drugs. Full article

Background/Objectives: Insomnia severely impairs quality of life. Oral melatonin (MEL) suffers from poor brain delivery. Intranasal administration bypasses the blood–brain barrier, but rapid mucociliary clearance shortens drug retention, and MEL poor water solubility limits its nasal dissolution. Traditional in situ gels have “gelation-first, spreading-second” defects, causing uneven distribution. Herein, we developed a two-step sequential ion-triggered in situ gel combined with MEL liposomes (MEL-Lips-Gel) to enhance solubility, achieve instant uniform coating, and prolong retention for efficient nose-to-brain delivery. Methods: MEL-Lips were dispersed in alginate (first component) and calcium gluconate served as the second component. After sequential spray, the two components mix and form an ion-crosslinked gel. Rheology, in vivo fluorescence imaging, in vitro release, open-field/sucrose preference tests, and H&E staining were performed. Results: MEL-Lips showed uniform size and good encapsulation. The sequential system achieved instant widespread spreading and rapid gelation, significantly prolonged nasal retention, enabled sustained brain delivery, and reversed insomnia-induced hyperactivity and anxiety-like behaviors more effectively than oral MEL, intranasal MEL solution, liposomes alone, or non-liposomal gel, with good nasal safety. Conclusions: This sequential ion-triggered liposome-in-gel strategy synergistically overcomes rapid clearance (via gel) and poor solubility (via liposomes), enhancing nose-to-brain delivery of melatonin and providing a promising platform for insomnia therapy. Full article

Background: Baicalein (BA) is a poorly soluble flavonoid with limited oral bioavailability. This study aimed to enhance the solubility and nasal absorption of the compound using a dual-carrier system that combines cyclodextrin inclusion complexes and thermosensitive hydrogels. Methods: The inclusion complexes of BA with hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl-β-cyclodextrin (SBE-β-CD), namely BA-HP-β-CD and BA-SBE-β-CD, were prepared via solution stirring and characterized by solubility, dissolution, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis-differential scanning calorimetry (TG-DSC), and Madin-Darby canine kidney (MDCK) cell permeation. The optimal complexes were incorporated into chitosan/β-glycerophosphate thermosensitive hydrogels (BA/HP-Gel and BA/SBE-Gel), followed by evaluations of gelation properties, in vitro release, and in vivo pharmacokinetics in rats. Results: The water solubility of BA-HP-β-CD and BA-SBE-β-CD increased 572 and 582 times, with MDCK permeability enhanced by 5.3 and 2.9 times, respectively. Both hydrogels showed rapid solution-gel transition at nasal temperature and sustained release. Following intranasal administration, BA/HP-Gel and BA/SBE-Gel achieved relative bioavailabilities of 623.5% and 697.8%, respectively, compared with BA-Gel. Conclusions: The dual-carrier platform effectively improved BA solubility, permeability, and nasal bioavailability, offering a promising strategy for nasal delivery of poorly soluble drugs. Full article

Background/Objectives: The oral administration of donepezil has been shown to have common side effects due to systemic drug delivery, with fluctuations in blood and brain donepezil concentrations. Therefore, we obtained nanostructured lipid carriers loaded with donepezil (donepezil–NLC) for nose-to-brain targeting. Methods: The obtained NLCs were characterized by measurements of particle size, the polydispersity index, zeta potential, encapsulation efficiency, atomic force microscopy, Differential Scanning Calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and in vitro release studies. Plasma and brain pharmacokinetic studies in Wistar rats were carried out to determine brain targeting. Results: Donepezil–NLC showed low polydispersity and nanometric size, high zeta potential, and high drug entrapment efficiency. Microscopy images showed spherical particles with regular surfaces. Thermal analysis, X-ray diffraction, and FTIR-ATR suggested the formation of an amorphous lipid matrix and the incorporation of donepezil molecularly dispersed within the lipid matrix. In vitro drug release studies demonstrated a biphasic drug release pattern with an initial burst followed by sustained release, with results better fitted to the Korsmeyer–Peppas model (n-value > 0.5). Following the nasal administration of donepezil–NLC, brain pharmacokinetic studies in Wistar rats demonstrated a significant improvement in bioavailability. Compared to the intravenous injection of donepezil, the AUC^0–ꝏ value was 10.5-fold higher. Drug targeting efficiency and direct transport percentage showed extremely higher values, suggesting nose-to-brain targeting after donepezil–NLC intranasal administration. Conclusions: Donepezil–NLC has proven to be an efficient drug delivery system for the nose to the brain, which may reduce systemic toxicity and improve Alzheimer’s therapy with low doses of donepezil and fewer adverse effects. Full article

Intranasal administration is a promising drug delivery route enabling precise and rapid central nervous system targeting. In our previous work, twelve hybrid colloidal dispersions were developed, consisting of synthetic poly(ethylene-oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with an increasing proportion of the hydrophobic PCL segment, Tween 80 (Tw80) and β-cyclodextrin derivatives (βCD), either methyl-β-CD (MβCD) or hydroxy-propyl-β-CD (HPβCD) for IN delivery of ropinirole hydrochloride (RH). Colloidal dispersions were prepared at different weight ratios (system/RH equal to 10:1 and 10:5), characterized and evaluated in vitro. The aim of this study is to evaluate the ex vivo permeation through rabbit nasal mucosa and determine the pharmacokinetic parameters of RH, when administered intranasally as a colloidal dispersion, compared with oral and intranasal RH solutions in C57BL/6J mice. Ex vivo permeation studies showed that all formulations significantly enhanced RH permeation compared to the pure RH solution (0.5 mg/mL, pH 5.6). Among them, F4 [(PEO-b-PCL₁/Tw80/HPβCD)/RH 10:5] was selected for further investigation. Pharmacokinetic analysis showed that F4 significantly enhanced both systemic and brain exposure of RH, achieving higher serum AUC and C_max values, despite a 3-fold lower administered dose compared to the oral dose. It showed high systemic (F_rel(Serum) = 1815%) and brain (F_rel(Brain) = 363%) relative bioavailability compared with oral administration, underscoring its potential as an intranasal delivery system for efficient CNS targeting. Full article

Central nervous system (CNS) disorders represent a growing healthcare burden, and various drugs are developed for their treatment. However, the blood–brain barrier (BBB) prevents over 98% of therapeutics from reaching brain tissue. Intranasal delivery provides a promising alternative by exploiting olfactory and trigeminal nerve pathways to circumvent the BBB. This review surveys recent advances in nose-to-brain delivery technologies, from carrier design to evaluation methods. Polymeric and lipid-based nanocarriers show enhanced mucosal penetration and prolonged residence time, and microneedle platforms further enable controlled drug release with minimal discomfort. To evaluate these delivery strategies, sensor-integrated organ-on-chip models provide more physiologically relevant testing than static cultures. Although persistent challenges such as rapid mucociliary clearance and formulation stability remain, combining nanotechnology with microfluidic devices and computational modeling shows potential for developing patient-specific therapeutics. Full article