Search Results (57)

Neurological-related diseases are among the most debilitating and difficult to manage. Many possible pharmacological treatments for neurological diseases struggle to cross the blood–brain barrier (BBB) to achieve concentrations that can produce a therapeutic benefit. This is primarily because of the existence of the BBB, which poses significant hurdles for both therapeutic and diagnostic efforts by restricting the entry of most medications. Nasal-to-brain drug transportation has surfaced as an encouraging approach to tackle the difficulties linked with conventional drug administration techniques for neurological disorders. In response, innovative methods for improving drug delivery focus on breaking down the BBB via physical techniques, including optical and photothermal therapy, electrical stimulation, and acoustic or mechanical stimulation. Nanocarriers represent a promising approach for facilitating nasal systemic and brain delivery of active compounds. Hence, the achievement of therapeutically relevant concentrations of exogenous molecules within the body is significantly contingent upon the nanocarriers’ capability to surpass biological barriers. Polymers in nanocarrier formulations can result in significantly enhanced nose-to-brain drug delivery by protecting drugs from premature biodegradation, increasing permeability, improving mucoadhesion, and targeting specific cells in the brain. Polymeric nanocarriers are frequently functionalized with cell-penetrating peptides to further improve the specificity of the loaded therapeutic molecules. This review focuses on the use of nanocarrier-based therapeutic agents to enhance the efficacy of nose-to-brain delivery systems. Full article

The nasal route represents a promising non-invasive technique for the direct delivery of nucleic acids to the central nervous system (CNS) disorders, effectively bypassing the blood–brain barrier. This route offers several advantages, including ease of administration, enhanced patient compliance, rapid therapeutic onset, and increased availability. Nonetheless, challenges such as mucociliary clearance, enzymatic degradation, and the low permeability of cell membranes to large molecules remain obstacles to the effectiveness of this approach. To address these limitations and achieve targeted nose-to-brain delivery with optimized therapeutic outcomes, various technological solutions have been explored, such as nanotechnology-based delivery systems and mucoadhesive formulations. These innovations aim to enhance the permeability of the nasal mucosa, extend the residence time of therapeutic agents in the nasal cavity, and improve overall treatment effectiveness. While the nasal gene delivery to the brain is still relatively new, it holds considerable potential for expanding treatment options for a range of CNS disorders. In this context, this review examines the anatomy and physiology of the nasal route, the mechanisms of biomolecule transport from nose to brain, the potential of gene delivery vectors, key preclinical advancements, and clinical perspectives for the nasal delivery of nucleic acids in CNS disorders. Full article

Quercetin (Que) is widely recognized for its antioxidant and neuroprotective properties; however, its clinical potential remains limited due to poor solubility and low oral bioavailability. Nasal powders have emerged as a promising strategy to overcome these limitations, taking advantage of nose-to-brain delivery, offering a direct, non-invasive route to the central nervous system while bypassing first-pass metabolism. This study aims to extend previous work by systematically investigating the impact of different preparation methods (spray drying vs. lyophilization) and the incorporation of hydroxypropyl methylcellulose (HPMC) and mannitol/lecithin microparticles (MLMPs) on the physicochemical characteristics, structural properties, and in vitro diffusion behavior of HPβCD-based nasal powder formulations of Que. Thermal behavior and stability were analyzed using TGA, while morphology and particle distribution were assessed via Scanning Electron Microscopy. In vitro diffusion studies using Franz cells and regenerated cellulose membranes were conducted under simulated nasal conditions. Among all tested formulations, the spray-dried HPβCD/Que powder (F4) showed the highest permeation (0.11 ± 0.01 mg/cm² at 120 min). The inclusion of HPMC improved thermal stability but reduced Que diffusion, likely due to increased viscosity and matrix formation. Blending with MLMPs enhanced powder flow and dose placement, although it modestly reduced diffusion efficiency. Overall, this study highlights the potential of HPβCD-based spray-dried powders for nasal Que delivery and demonstrates how HPMC and MLMPs can be strategically employed to tailor performance characteristics. Full article

Nose-to-brain drug delivery is an innovative approach that leverages the unique anatomical pathways connecting the nasal cavity to the brain, including the olfactory and trigeminal nerve routes. This method bypasses the blood–brain barrier, enabling direct and efficient transport of therapeutic agents to the central nervous system. It offers significant advantages, such as rapid drug action, reduced systemic side effects, and improved patient compliance through non-invasive administration. This entry summarizes factors affecting the nose-to-brain delivery of drugs and the recent development of nanoparticle-based nose-to-brain delivery. Full article

Background: Olanzapine (Ola) is a second-generation antipsychotic with clinical utility limited by poor brain bioavailability due to blood–brain barrier restriction, hepatic first-pass metabolism, and systemic side effects. This study aimed to develop and optimize a novel intranasal polymersome-based nanocarrier (Poly_Ola) to enhance brain targeting, therapeutic efficacy, and safety of Ola. Methods: Poly_Ola was prepared using poloxamer 401 and optimized through a Box–Behnken Design to minimize particle size and maximize entrapment (EE%) and loading efficiency (LE%). The formulation was characterized by size, morphology, drug release, and serum stability. In vivo studies in adult male Sprague-Dawley rats assessed pharmacokinetics (plasma and brain concentrations), pharmacodynamic efficacy in a ketamine-induced schizophrenia model, and systemic safety markers including metabolic, hepatic, and testicular oxidative stress indicators. Results: Optimized Poly_Ola exhibited a particle size of 78.3 ± 4.5 nm, high EE% (91.36 ± 3.55%), and sustained in vitro drug release. It remained stable in serum for 24 h. Intranasal administration significantly improved brain delivery of Ola, achieving a 2.7-fold increase in C_max and a 5.7-fold increase in AUC compared to oral dosing. The brain T_max was 15 min, with high drug-targeting efficiency (DTE% = 365.38%), confirming efficient nose-to-brain transport. Poly_Ola-treated rats showed superior antipsychotic performance, reduced extrapyramidal symptoms, and improved systemic safety evidenced by mitigated weight gain, glycemic control, normalized liver enzymes, and reduced oxidative stress. Conclusions: Poly_Ola offers a safe and effective intranasal delivery platform for Ola, enabling targeted brain delivery and improved management of schizophrenia with reduced peripheral toxicity. Full article

The development of nanocarriers for drug delivery has drawn a lot of attention due to the possibility for tailored delivery to the ill region while preserving the neighboring healthy tissue. In medicine, delivering drugs safely and effectively has never been easy; therefore, the creation of surfactant-based vesicles (niosomes) to enhance medication delivery has gained attention in the past years. Niosomes (NIOs) are versatile drug delivery systems that facilitate applications varying from transdermal transport to targeted brain delivery. These self-assembling vesicular nano-carriers are formed by hydrating cholesterol, non-ionic surfactants, and other amphiphilic substances. The focus of the review is to report on the latest NIO-type formulations which also include biopolymers from the polysaccharide class, highlighting their role in the development of these drug delivery systems (DDSs). The NIO and polysaccharide types, together with the recent pharmaceutical applications such as ocular, oral, nose-to brain, pulmonary, cardiac, and transdermal drug delivery, are all thoroughly summarized in this review, which offers a comprehensive compendium of polysaccharide-based niosomal research to date. Lastly, this delivery system’s limits and prospects are also examined. Full article

Nasal nanodrug delivery has gained prominence as a non-invasive method for administering therapeutic agents to the brain. However, the limited nasal cavity volume and the low drug loading capacity of nanoparticles contribute to a reduced accumulation of the drug within the brain tissue. Therefore, the aim of the present study was to investigate the role of the drug delivery combination “transnasal route + nanoparticle drug delivery system + chemical osmosis technology” in promoting drug accumulation in the brain. We constructed an in vitro olfactory sheath cell model based on the direct nose–brain pathway and a vascular endothelial cell model based on the indirect pathway, and investigated the transport behaviors and mechanisms of Poly(lactic-co-glycolicacid)-Nanoparticles (PLGA-NPs) in combination with two terpene aroma constituents (menthol and curcumol). Menthol and curcumol significantly improved the intracellular accumulation of PLGA-NPs, which may be related to changes in the endocytosis pathway and intercellular tight junction proteins. Meanwhile, the results of laser scanning confocal microscopy and atomic force microscopy showed that menthol and curcumol disrupted different tight junction proteins of vascular endothelial cells, and the biomechanical properties (e.g., rigidity and roughness) of the olfactory sheath cells and vascular endothelial cell cytomembranes were also greatly changed. The delivery system of “transnasal route + nanoparticle drug delivery system + chemical osmosis technology” has great potential for intranasal delivery of drugs for the treatment of brain diseases. Full article

The nasal cavity has become a focal point for drug delivery research. Beyond its use in treating local diseases, the nasal route is appealing due its ability to deliver systemically potent drugs with low oral bioavailability. Recent interest in nasal vaccination has driven significant pre-clinical and clinical advancements. Further R&D holds promise for expanding nasal medications, offering innovative healthcare solutions. This review explores strategies using polysaccharides to enhance nasal delivery of hydrophilic drugs, peptides, proteins, genes, and other active compounds that typically struggle to permeate the nasal epithelium. Polysaccharides are attractive excipients due to their potential to enhance nasal absorption, regulate drug release, and extend residence time in the nasal cavity through bioadhesive properties. Studies on their mechanisms affecting drug absorption, potential toxicities, and applications will also be reviewed considering the particularities of nasal epithelium anatomy and physiology. Most products with these excipients are in pre-clinical and clinical evaluation, but PecFent, a pectin-based formulation, is approved for nasal administration of opioids for breakthrough cancer pain, offering faster pain relief and a better benefit–risk ratio due to pectin. Other polysaccharides like chitosan, cyclodextrins, hyaluronic acid, and alginate have shown potential in enhancing nasal drug absorption. This approach also holds promise for enhancing drug transport from the nasal cavity to the CNS (nose-to-brain), potentially advancing treatments for neurodegenerative diseases. Full article

Background/Objectives: Peptide-based treatments represent an expanding area and require innovative approaches to enhance bioavailability. Combination with cell-penetrating peptides (CPPs) is an attractive strategy to improve non-invasive delivery across nasal epithelial barriers for systemic and direct nose-to-brain transport. We previously developed a modified CPP system termed Glycosaminoglycan-binding Enhanced Transduction (GET) that improves insulin delivery across gastrointestinal epithelium. It contains a membrane docking sequence to promote cellular interactions (P21), a cationic polyarginine domain to stimulate uptake (8R) and an endosomal escaping sequence to maximize availability for onward distribution (LK15). It is synthesized as a single 44-residue peptide (P21-LK15-8R; PLR). Methods: The current research used in vitro assays for a novel exploration of PLR’s ability to improve the transport of two contrasting peptides, insulin (51 residues, net negative charge) and oxytocin (9 residues, weak positive charge) across an RPMI 2650 human nasal epithelial cell barrier cultured at the air–liquid interface. Results: PLR enhanced insulin transcytosis over a 6 h period by 7.8-fold when used at a 2:1 molar ratio of insulin/PLR (p < 0.0001 versus insulin alone). Enhanced oxytocin transcytosis (5-fold) occurred with a 1:10 ratio of oytocin/PLR (p < 0.01). Importantly, these were independent of any impact on transepithelial electrical resistance (TEER) or cell viability (p > 0.05). Conclusions: We advocate the continued evaluation of insulin–PLR and oxytocin–PLR formulations, including longer-term assessments of ciliotoxicity and cytotoxicity in vitro followed by in vivo assessments of systemic and nose-to-brain delivery. Full article

Direct nose-to-brain drug delivery, a promising approach for treating neurological disorders, faces challenges due to anatomical variations between adults and children. This study aims to investigate the spatial particle deposition of micron-sized particles in the nasal cavity among adult and pediatric subjects. This study focuses on the olfactory region considering the effect of intrasubject parameters and particle properties. Two child and two adult nose models were developed based on computed tomography (CT) images, in which the olfactory region of the four nasal cavity models comprises 7% to 10% of the total nasal cavity area. Computational Fluid Dynamics (CFD) coupled with a discrete phase model (DPM) was implemented to simulate the particle transport and deposition. To study the deposition of micrometer-sized drugs in the human nasal cavity during a seated posture, particles with diameters ranging from 1 to 100 μm were considered under a flow rate of 15 LPM. The nasal cavity area of adults is approximately 1.2 to 2 times larger than that of children. The results show that the regional deposition fraction of the olfactory region in all subjects was meager for 1–100 µm particles, with the highest deposition fraction of 5.7%. The deposition fraction of the whole nasal cavity increased with the increasing particle size. Crucially, we identified a correlation between regional deposition distribution and nasal cavity geometry, offering valuable insights for optimizing intranasal drug delivery. Full article

The nose-to-brain drug-delivery system has emerged as a promising strategy to overcome the challenges associated with conventional drug administration for central nervous system disorders. This emerging field is driven by the anatomical advantages of the nasal route, enabling the direct transport of drugs from the nasal cavity to the brain, thereby circumventing the blood–brain barrier. This review highlights the significance of the anatomical features of the nasal cavity, emphasizing its high permeability and rich blood supply that facilitate rapid drug absorption and onset of action, rendering it a promising domain for neurological therapeutics. Exploring recent developments and innovations in different nanocarriers such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, micelles, nanoemulsions, nanosuspensions, carbon nanotubes, mesoporous silica nanoparticles, and nanogels unveils their diverse functions in improving drug-delivery efficiency and targeting specificity within this system. To minimize the potential risk of nanoparticle-induced toxicity in the nasal mucosa, this article also delves into the latest advancements in the formulation strategies commonly involving surface modifications, incorporating cutting-edge materials, the adjustment of particle properties, and the development of novel formulations to improve drug stability, release kinetics, and targeting specificity. These approaches aim to enhance drug absorption while minimizing adverse effects. These strategies hold the potential to catalyze the advancement of safer and more efficient nose-to-brain drug-delivery systems, consequently revolutionizing treatments for neurological disorders. This review provides a valuable resource for researchers, clinicians, and pharmaceutical-industry professionals seeking to advance the development of effective and safe therapies for central nervous system disorders. Full article

Ropinirole is a non-ergolinic dopamine agonist used to manage Parkinson’s disease and it is characterized by poor oral bioavailability. This study aimed to design and develop advanced drug delivery systems composed of poloxamer 407, a non-ionic surfactant (Tween 80), and cyclodextrins (methyl-β-CD or hydroxy-propyl-β-CD) for possible brain targeting of ropinirole after nasal administration for the treatment of Parkinson’s disease. The hybrid systems were formed by the thin-film hydration method, followed by an extensive physicochemical and morphological characterization. The in vitro cytotoxicity of the systems on HEK293 cell lines was also tested. In vitro release and ex vivo mucosal permeation of ropinirole were assessed using Franz cells at 34 °C and with phosphate buffer solution at pH 5.6 in the donor compartment, simulating the conditions of the nasal cavity. The results indicated that the diffusion-controlled drug release exhibited a progressive increase throughout the experiment, while a proof-of-concept experiment on ex vivo permeation through rabbit nasal mucosa revealed a better performance of the prepared hybrid systems in comparison to ropinirole solution. The encouraging results in drug release and mucosal permeation indicate that these hybrid systems can serve as attractive platforms for effective and targeted nose-to-brain delivery of ropinirole with a possible application in Parkinson’s disease. Further ex vivo and in vivo studies to support the results of the present work are ongoing. Full article

In recent years, there have been a growing number of small and large molecules that could be used to treat diseases of the central nervous system (CNS). Nose-to-brain delivery can be a potential option for the direct transport of molecules from the nasal cavity to different brain areas. This review aims to provide a compilation of current approaches regarding drug delivery to the CNS via the nose, with a focus on biologics. The review also includes a discussion on the key benefits of nasal delivery as a promising alternative route for drug administration and the involved pathways or mechanisms. This article reviews how the application of various auxiliary agents, such as permeation enhancers, mucolytics, in situ gelling/mucoadhesive agents, enzyme inhibitors, and polymeric and lipid-based systems, can promote the delivery of large molecules in the CNS. The article also includes a discussion on the current state of intranasal formulation development and summarizes the biologics currently in clinical trials. It was noted that significant progress has been made in this field, and these are currently being applied to successfully transport large molecules to the CNS via the nose. However, a deep mechanistic understanding of this route, along with the intimate knowledge of various excipients and their interactions with the drug and nasal physiology, is still necessary to bring us one step closer to developing effective formulations for nasal–brain drug delivery. Full article

Direct nose-to-brain drug delivery offers the opportunity to treat central nervous system disorders more effectively due to the possibility of drug molecules reaching the brain without passing through the blood–brain barrier. Such a delivery route allows the desired anatomic site to be reached while ensuring drug effectiveness, minimizing side effects, and limiting drug losses and degradation. However, the absorption of intranasally administered entities is a complex process that considerably depends on the interplay between the characteristics of the drug delivery systems and the nasal mucosa. Various preclinical models (in silico, in vitro, ex vivo, and in vivo) are used to study the transport of drugs after intranasal administration. The present review article attempts to summarize the different computational and experimental models used so far to investigate the direct delivery of therapeutic agents or colloidal carriers from the nasal cavity to the brain tissue. Moreover, it provides a critical evaluation of the data available from different studies and identifies the advantages and disadvantages of each model. Full article

Quercetin (Que) is one of the most studied flavonoids with strong antioxidant properties ascribed to its ability to bind free radicals and inactivate them. However, the low solubility of the compound along with its inadequate absorption after oral administration limit its beneficial effects. Que’s complexation with two different cyclodextrin (CD) derivatives (hydroxypropyl-β-CD and methyl-β-CD) via the neutralization/lyophilization method has been found to improve its physicochemical properties. Moreover, blends of the lyophilized powders with mannitol/lecithin microparticles (MLMPs) have been proposed as candidates for intranasal (IN) administration after in vitro and ex vivo evaluations. In this context, a comparative pharmacokinetic (PK) study of the IN vs oral administration of Que lyophilized powders and their blends with MLMPs (75:25 w/w) was performed on Wistar rats. The PK parameters estimated by a non-compartmental analysis using the sparse data methodology in Phoenix^® 8.3 (Certara, Princeton, NJ, USA) illustrated the effectiveness of IN administration either in brain targeting or in reaching the bloodstream. Significant levels of the compound were achieved at both sites, compared to those after oral delivery which were negligible. These results favor the potential application of the prepared Que nasal powders for systemic and nose-to-brain delivery for the prevention and/or treatment of neuroinflammatory degenerative conditions, such as Parkinson’s and Alzheimer’s disease. Full article