Search Results (54)

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

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

The intranasal route has been suggested as a promising alternative to improve the direct transport of molecules to the brain, avoiding the need to cross the blood–brain barrier (BBB). In this area, the use of lipid nanoparticles, namely solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has been highlighted as a promising strategy to improve the treatment of neurodegenerative diseases. In this work, formulations containing SLN and NLC that were loaded with astaxanthin that was obtained from different sources (astaxanthin extract (AE) from the algae Haematococcus pluvialis and pure astaxanthin (PA) from the fungi Blakeslea trispora) were prepared for nose-to-brain administration, and comparative in vitro experiments were performed to evaluate the biocompatibility of the formulations with nasal (RPMI 2650) and neuronal (SH-SY5Y) cells. Afterwards, the antioxidant activity of the formulations was evaluated for its potential neuroprotective effects, using different chemical aggressors. Finally, the cellular uptake of the astaxanthin was evaluated for the formulations that showed the greatest neuroprotection of the neuronal cells against chemical-induced damage. On the production day, all the formulations showed a particle size, a high encapsulation efficiency (EE), the presence of nanoparticles with a typical spherical shape, and a polydispersity index (PDI) and zeta potential (ZP) that are suitable for nose-to-brain administration. After three months of storage at room temperature, no significant changes were observed in the characterization parameters, predicting a good long-term stability. Furthermore, these formulations were shown to be safe with concentrations of up to 100 µg/mL in differentiated SH-SY5Y and RPMI 2650 cells. Regarding neuroprotection studies, the PA-loaded SLN and NLC formulations showed an ability to counteract some mechanisms of neurodegeneration, including oxidative stress. Moreover, when compared with the PA-loaded SLN, the PA-loaded NLC showed greater neuroprotective effects against the cytotoxicity induced by aggressors. In contrast, the AE-loaded SLN and NLC formulations showed no significant neuroprotective effects. Although further studies are needed to confirm these neuroprotective effects, the results of this study suggest that the intranasal administration of PA-loaded NLC may be a promising alternative to improve the treatment of neurodegenerative diseases. Full article