Search Results (58)

Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood–brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations—critical for successful clinical implementation and commercial development—remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical–clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway—or, more precisely, the “Nose-to-Neurons” pathway—offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment. Full article

Olfactory perception depends on soluble proteins in the perireceptor environment that support odorant transport, mucosal protection, and tissue homeostasis. In insects, odorant-binding proteins (OBPs) in the sensillum lymph are indispensable for odor detection, whereas in humans the indispensability of OBPs (OBP2A/2B) remains unclear because they are inconsistently detected in nasal mucus. Consequently, it remains unclear whether other soluble proteins compensate for this function or how they contribute to odorant processing and signal transmission within the olfactory mucus. Accumulating evidence indicates that OBP-like lipocalins (LCN1, LCN2, LCN15) and apolipoprotein D, together with bactericidal/permeability-increasing (BPI)-fold proteins, act as major mediators of odorant solubilization, antimicrobial defense, oxidative stress regulation, and extracellular matrix (ECM) remodeling. Alterations in those proteins and ECM organization are linked to idiopathic and age-related smell loss, chronic rhinosinusitis, and neurodegenerative disorders, underscoring their broad relevance at the interface of chemosensation, mucosal defense, and brain health. Major unresolved issues include the functional indispensability of human OBPs, the receptor-specific contributions of OBP-like proteins, and the mechanistic relationships linking olfactory proteome remodeling, sensory signaling, and disease progression. This review provides an integrative overview of structural and mechanistic insights, highlights current controversies, and proposes future research directions, including receptor–protein mapping, integrated structural–functional studies, structural–functional analysis of OBP–ECM networks, and clinical validation of OBP-related biomarkers. Full article

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

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

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

An abnormal accumulation of misfolded proteins is a common feature shared by most neurodegenerative disorders. Olfactory dysfunction (OD) is common in the elderly population and is present in 90% of patients with Alzheimer’s or Parkinson’s disease, usually preceding the cognitive and motor symptoms onset by several years. Early Aβ, tau, and α-synuclein protein aggregates deposit in brain structures involved in odor processing (olfactory bulb and tract, piriform cortex, amygdala, entorhinal cortex, and hippocampus) and seem to underly OD. The glymphatic system is a glial-associated fluid transport system that facilitates the movement of brain fluids and removes brain waste during specific sleep stages. Notably, the glymphatic system became less functional in aging and it is impaired in several conditions, including neurodegenerative diseases. As the nasal pathway has been recently described as the main outflow exit of cerebrospinal fluid and solutes, we hypothesized that OD may indeed be a clinical marker of early glymphatic dysfunction through abnormal accumulation of pathological proteins in olfactory structures. This effect may be more pronounced in peri- and postmenopausal women due to the well-documented impact of estrogen loss on the locus coeruleus, which may disrupt multiple mechanisms involved in glymphatic clearance. If this hypothesis is confirmed, olfactory dysfunction might be considered as a clinical proxy of glymphatic failure in neurodegenerative diseases. Full article

Background: The neuroprotective efficacy of glibenclamide (GLIB) has been demonstrated in multiple rodent models of ischemia, hemorrhagic stroke, traumatic brain damage, spinal cord injury, and metastatic brain tumors. Due to its poor solubility, GLIB has low oral bioavailability, limiting its transportation to the brain via the oral route. Objectives: Here, we attempted to develop and optimize an intranasal mucoadhesive in situ gel of GLIB-loaded bilosomes using a 3² Box–Behnken design for brain drug delivery. Methods: To facilitate a longer residence time of the administered dose within the nasal cavity, the prepared bilosomes were loaded into a mucoadhesive in situ gel providing resistance to rapid mucociliary clearance. The amounts of sodium deoxycholate, the cholesterol/Span 40 mixture, and the molar ratio between the mixture’s components were chosen as independent variables, while the entrapment efficiency and in vitro drug release were selected as dependent variables. Results and conclusions: The optimal formulation was analyzed for particle size and entrapment efficiency, which were found to be 270.6 nm and 68.39%, respectively. In vitro drug release from optimal formulation after 12 h was 87.29 ± 1.98% as compared to 52.01 ± 2.04% of plain in situ gel of drug. An in vivo brain drug delivery study performed on Swiss albino mice showed that the brain concentration of drug through intranasal administration from mucoadhesive in situ gel of GLIB-bilosomes after 12 h was 2.12 ± 0.16 µg/mL as compared to 0.68 ± 0.04 µg/mL from plain in situ gel of drug. Conclusively, the developed bilosomal formulation offers a favorable intranasal substitute with enhanced therapeutic drug delivery to the brain. 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

Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer’s disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions. Full article

Cerebral ischemia represents a particular condition among neurological diseases due to its high frequency, high associated mortality, and the permanent disability in patients that survive it. Numerous studies in animal models have demonstrated the protective properties of resveratrol against cerebral ischemia. Resveratrol is a soluble molecule in polar solvents with high membrane permeability; however, it is rapidly metabolized at the liver and is also a substrate of the ATP binding cassette transporters located at the blood–brain barrier. These circumstances reduced bioavailability of resveratrol to the brain. In this review, we examined nasal resveratrol’s formulations including nanocarriers such as nanostructured lipid carriers, nanoemulsions, nanoparticles, bilosomes, cubosomal, and transferosomes that are directly transported to the brain. An intranasal administration route evades resveratrol transformation due to liver metabolism. Components of nanoformulations increased resveratrol absorption to the brain by enhancing permeation through specific approaches and also maintaining stability during storage. Both characteristics improved the delivery of resveratrol with conserved antioxidant capacity and protective properties for neurological models. Although demonstration that the nanoformulations prevents resveratrol’s blood–brain barrier retention is missing, properties of resveratrol’s nanoformulation encourage testing in clinical trials; however, regulatory approval for a novel nanocarrier in nasal drug delivery is complicated and needs approval. 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