Anti-Inflammatory Properties of Statin-Loaded Biodegradable Lecithin/Chitosan Nanoparticles: A Step Toward Nose-to-Brain Treatment of Neurodegenerative Diseases.

Nasal delivery has been indicated as one of the most interesting alternative routes for the brain delivery of neuroprotective drugs. Nanocarriers have emerged as a promising strategy for the delivery of neurotherapeutics across the nasal epithelia. In this work, hybrid lecithin/chitosan nanoparticles (LCNs) were proposed as a drug delivery platform for the nasal administration of simvastatin (SVT) for the treatment of neuroinflammatory diseases. The impact of SVT nanoencapsulation on its transport across the nasal epithelium was investigated, as well as the efficacy of SVT-LCNs in suppressing cytokines release in a cellular model of neuroinflammation. Drug release studies were performed in simulated nasal fluids to investigate SVT release from the nanoparticles under conditions mimicking the physiological environment present in the nasal cavity. It was observed that interaction of nanoparticles with a simulated nasal mucus decreased nanoparticle drug release and/or slowed drug diffusion. On the other hand, it was demonstrated that two antibacterial enzymes commonly present in the nasal secretions, lysozyme and phospholipase A2, promoted drug release from the nanocarrier. Indeed, an enzyme-triggered drug release was observed even in the presence of mucus, with a 5-fold increase in drug release from LCNs. Moreover, chitosan-coated nanoparticles enhanced SVT permeation across a human cell model of the nasal epithelium (×11). The nanoformulation pharmacological activity was assessed using an accepted model of microglia, obtained by activating the human macrophage cell line THP-1 with the Escherichia coli-derived lipopolysaccharide (LPS) as the pro-inflammatory stimulus. SVT-LCNs were demonstrated to suppress the pro-inflammatory signaling more efficiently than the simple drug solution (-75% for IL-6 and -27% for TNF-α vs. -47% and -15% at 10 µM concentration for SVT-LCNs and SVT solution, respectively). Moreover, neither cellular toxicity nor pro-inflammatory responses were evidenced for the treatment with the blank nanoparticles even after 36 h of incubation, indicating a good biocompatibility of the nanomedicine components in vitro. Due to their biocompatibility and ability to promote drug release and absorption at the biointerface, hybrid LCNs appear to be an ideal carrier for achieving nose-to-brain delivery of poorly water-soluble drugs such as SVT.

Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line.

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by 1H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by 1H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics.

An in vitro model for assessing drug transport in cystic fibrosis treatment: Characterisation of the CuFi-1 cell line.

Cystic fibrosis (CF) is a disease that most commonly affects the lungs and is characterized by mucus retention and a continuous cycle of bacterial infection and inflammation. Current CF treatment strategies are focused on targeted drug delivery to the lungs. Novel inhalable drug therapies require an in vitro CF model that appropriately mimics the in vivo CF lung environment to better understand drug delivery and transport across the CF epithelium, and predict drug therapeutic efficacy. Therefore, the aim of this research was to determine the appropriate air-liquid interface (ALI) culture method of the CuFi-1 (CF cell line) compared to the NuLi-1 (healthy cell line) cells to be used as in vitro models of CF airway epithelia. Furthermore, drug transport on both CuFi-1 and NuLi-1 was investigated to determine whether these cell lines could be used to study transport of drugs used in CF treatment using Ibuprofen (the only anti-inflammatory drug currently approved for CF) as a model drug. Differentiating characteristics specific to airway epithelia such as mucus production, inflammatory response and tight junction formation at two seeding densities (Low and High) were assessed throughout an 8-week ALI culture period. This study demonstrated that both the NuLi-1 and CuFi-1 cell lines fully differentiate in ALI culture with significant mucus secretion, IL-6 and IL-8 production, and functional tight junctions at week 8. Additionally, the High seeding density was found to alter the phenotype of the NuLi-1 cell line. For the first time, this study identifies that ibuprofen is transported via the paracellular pathway in ALI models of NuLi-1 and CuFi-1 cell lines. Overall, these findings highlight that NuLi-1 and CuFi-1 as promising in vitro ALI models to investigate the transport properties of novel inhalable drug therapies for CF treatment.

Application of a Thermosensitive In Situ Gel of Chitosan-Based Nasal Spray Loaded with Tranexamic Acid for Localised Treatment of Nasal Wounds.

The integrity of the nasal epithelium plays a crucial role in the airway defence mechanism. The nasal epithelium may be injured as a result of a large number of factors leading to nose bleeds, also known as epistaxis. However, local measures commonly used to treat epistaxis and improve wound healing present several side effects and patient discomfort. Hence, this study aims to address some of these drawbacks by developing a new formulation for nasal epithelial wound healing. Chitosan, a biodegradable and biocompatible polymer, was used to develop a thermosensitive nasal formulation for the delivery of tranexamic acid (TXA), one of the most effective pharmacological options to control bleeding with cost and tolerability advantages. The in situ gelation properties of the formulation upon administration in the nasal cavity were investigated in terms of gelation time and temperature. It was found that the developed formulation can undergo rapid liquid-to-gel phase change within approximately 5 min at 32°C, which is well within the human nasal cavity temperature range. The spray pattern, deposition and droplet size generated by the nasal spray was also characterised and were found to be suitable for nasal drug delivery. It was also observed that the in situ gelation of the formulation prevent nasal runoff, while the majority of drug deposited mainly in the anterior part of the nose with no lung deposition. The developed formulation was shown to be safe on human nasal epithelium and demonstrated six times faster wound closure compared to the control TXA solution.

Co-Spray-Dried Urea Cross-Linked Hyaluronic Acid and Sodium Ascorbyl Phosphate as Novel Inhalable Dry Powder Formulation.

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL-SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA-SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA-SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL-SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ∼ 3.4 µm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA-SAP and 35.3 ± 0.3% for SD HA-CL-SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL-SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders.

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders.

BACKGROUND: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated. METHODS: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics. RESULTS: The formulations showed rapid gelation (4-7 min) at 30-35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110-150 kDa led to generation of optimum spray with lower Dv50, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions. CONCLUSIONS: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.

In vitro characterization of physico-chemical properties, cytotoxicity, bioactivity of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate nasal powder formulation.

An innovative lyophilized dry powder formulation consisting of urea-crosslinked hyaluronic acid (HA-CL) and sodium ascorbyl phosphate (SAP) - LYO HA-CL - SAP- was prepared and characterized in vitro for physico-chemical and biological properties. The aim was to understand if LYO HA-CL - SAP could be used as adjuvant treatment for nasal inflammatory diseases. LYO HA-CL - SAP was suitable for nasal delivery and showed to be not toxic on human nasal septum carcinoma-derived cells (RPMI 2650 cells) at the investigated concentrations. It displayed porous, polygonal particles with unimodal, narrow size distribution, mean geometric diameter of 328.3 ±â€¯27.5 µm, that is appropriate for nasal deposition with no respirable fraction and 88.7% of particles with aerodynamic diameter >14.1 µm. Additionally, the formulation showed wound healing ability on RPMI 2650 cells, and reduced interleukin-8 (IL-8) level in primary nasal epithelial cells pre-induced with lipopolysaccharide (LPS). Transport study across RPMI 2650 cells showed that HA-CL could act not only as carrier for SAP and active ingredient itself, but potentially also as mucoadhesive agent. In conclusion, these results suggest that HA-CL and SAP had anti-inflammatory activity and acted in combination to accelerate wound healing. Therefore, LYO HA-CL - SAP could be a potential adjuvant in nasal anti-inflammatory formulations.

Formulation and Characterization of Native and Crosslinked Hyaluronic Acid Microspheres for Dermal Delivery of Sodium Ascorbyl Phosphate: A Comparative Study.

The present work evaluates for the first time the use of urea-crosslinked hyaluronic acid (HA-CL), a novel derivative of native hyaluronic acid (HA), to produce microspheres (MS) by emulsification-solvent evaporation, for dermal delivery of sodium ascorbyl phosphate (SAP). As the term of comparison, HA MS were prepared. A pre-formulation study-investigation of the effects of polymers solutions properties (pH, viscosity) and working conditions-led to the - production of optimized HA-CL MS and HA-CL-SAP MS with: almost unimodal size distributions; mean diameter of 13.0 ± 0.7 and 9.9 ± 0.8 µm, respectively; spherical shape and rough surface; high yield, similar to HA MS and HA⁻SAP MS (≈ 85%). SAP was more efficiently encapsulated into HA-CL MS (78.8 ± 2.6%) compared to HA MS (69.7 ± 4.6%). Physical state, thermal properties, relative moisture stability of HA-CL MS and HA-CL⁻SAP MS were comparable to those of HA MS and HA⁻SAP MS. However, HA-CL⁻SAP MS exhibited an extended drug release compared to HA⁻SAP MS, despite the same kinetic mechanism-contemporaneous drug diffusion and polymer swelling/dissolution. Therefore, HA-CL formulation showed a greater potential as microcarrier (for encapsulation efficiency and release kinetic), that could be improved, in future, using suitable excipients.

Nanoemulsion-Enabled Oral Delivery of Novel Anticancer ω-3 Fatty Acid Derivatives.

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathways linked to their proliferation and invasiveness. In particular, ω-3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study, 16-(4'-chloro-3'-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω-3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI < 0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug.

Combination of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate for the treatment of inflammatory lung diseases: An in vitro study.

This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL - SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL - SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) - SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL - SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA - SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent.

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery.

OBJECTIVE: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route. SIGNIFICANCE: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray. METHODS: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus-BUD formulation. RESULTS: The freeze-dried Soluplus-BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334 ± 0.0178 m2/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension. CONCLUSIONS: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.

The nasal delivery of nanoencapsulated statins - an approach for brain delivery.

PURPOSE: Along with their cholesterol-lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases. However, such effects are extremely elusive via the conventional oral administration. The purpose of the present study was to prepare and characterize the physicochemical properties and the in vivo biodistribution of simvastatin-loaded lecithin/chitosan nanoparticles (SVT-LCNs) suitable for nasal administration in view of an improved delivery of the statins to the brain. MATERIALS AND METHODS: Chitosan, lecithin, and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Particle size distribution, surface charge, structure, simvastatin loading and release, and interaction with mucus of nanoparticles were determined. The nanoparticle nasal toxicity was evaluated in vitro using RPMI 2651 nasal cell lines. Finally, in vivo biodistribution was assessed by gamma scintigraphy via Tc99m labeling of the particles. RESULTS: Among the different types of nanoparticles produced, the SVT-LCN_MaiLab showed the most ideal physicochemical characteristics, with small diameter (200 nm), positive surface charge (+48 mV) and high encapsulation efficiency (EE; 98%). Size distribution was further confirmed by nanoparticle tracking analysis and electron microscopy. The particles showed a relatively fast release of simvastatin in vitro (35.6%±4.2% in 6 hours) in simulated nasal fluid. Blank nanoparticles did not show cytotoxicity, evidencing that the formulation is safe for nasal administration, while cytotoxicity of simvastatin-loaded nanoparticles (IC50) was found to be three times lower than the drug solution (9.92 vs 3.50 µM). In rats, a significantly higher radioactivity was evidenced in the brain after nasal delivery of simvastatin-loaded nanoparticles in comparison to the administration of a similar dose of simvastatin suspension. CONCLUSION: The SVT-LCNs developed presented some of the most desirable characteristics for mucosal delivery, that is, small particle size, positive surface charge, long-term stability, high EE, and mucoadhesion. In addition, they displayed two exciting features: First was their biodegradability by enzymes present in the mucus layer, such as lysozyme. This indicates a new Trojan-horse strategy which may enhance drug release in the proximity of the nasal mucosa. Second was their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma scintigraphy studies.

Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery, characterization and in vitro deposition study.

This study focuses on development and in vitro characterisation of a nasal delivery system based on uncoated or chitosan-coated solid lipid microparticles (SLMs) containing resveratrol, a natural anti-inflammatory molecule, as an effective alternative to the conventional steroidal drugs. The physico-chemical characteristics of the SLMs loaded with resveratrol were evaluated in terms of morphology, size, thermal behaviour and moisture sorption. The SLMs appeared as aggregates larger than 20 µm. In vitro nasal deposition was evaluated using a USP specification Apparatus E 7-stage cascade impactor equipped with a standard or a modified nasal deposition apparatus. More than 95% of resveratrol was recovered onto the nasal deposition chamber and stage 1 of impactor, suggesting that the SLMs mostly deposited in the nasal cavity. Additionally, the SLMs were not toxic on RPMI 2650 nasal cell line up to a concentration of approximately 40 µM of resveratrol.

Application of RPMI 2650 nasal cell model to a 3D printed apparatus for the testing of drug deposition and permeation of nasal products.

The aim of this study was to incorporate an optimized RPMI2650 nasal cell model into a 3D printed model of the nose to test deposition and permeation of drugs intended for use in the nose. The nasal cell model was optimized for barrier properties in terms of permeation marker and mucus production. RT-qPCR was used to determine the xenobiotic transporter gene expression of RPMI 2650 cells in comparison with primary nasal cells. After 14days in culture, the cells were shown to produce mucus, and to express TEER (define) values and sodium fluorescein permeability consistent with values reported for excised human nasal mucosa. In addition, good correlation was found between RPMI 2650 and primary nasal cell transporter expression values. The purpose-built 3D printed model of the nose takes the form of an expansion chamber with inserts for cells and an orifice for insertion of a spray drug delivery device. This model was validated against the FDA glass chamber with cascade impactors that is currently approved for studies of nasal products. No differences were found between the two apparatus. The apparatus including the nasal cell model was used to test a commercial nasal product containing budesonide (Rhinocort, AstraZeneca, Australia). Drug deposition and transport studies on RPMI 2650 were successfully performed. The new 3D printed apparatus that incorporates cells can be used as valid in vitro model to test nasal products in conditions that mimic the delivery from nasal devices in real life conditions.

Dry powder nasal drug delivery: challenges, opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation.

PURPOSE: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development. METHODS: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction). RESULTS: Teijin Rhinocort(®) (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (Dv50 = 98 ± 1.3 µm). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2 ± 4.78%), while 4.64 ± 1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E. CONCLUSIONS: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.

Opportunities and challenges for the nasal administration of nanoemulsions.

Nasal delivery has become a growing area of interest for drug administration as a consequence of several practical advantages, such as ease of administration and non-invasiveness. Moreover, the avoidance of hepatic first-pass metabolism and rapid and efficient absorption across the permeable nasal mucosa offer a promising alternative to other traditional administration routes, such as oral or parenteral delivery. In fact, nasal delivery has been proposed for a number of applications, including local, systemic, direct nose-to-brain and mucosal vaccine delivery. Nanoemulsions, due to their stability, small droplet size and optimal solubilization properties, represent a versatile formulation approach suitable for several administration routes. Nanoemulsions demonstrated great potential in nasal drug delivery, increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery. Furthermore, they act as an active component, i.e. an adjuvant, in nasal mucosal vaccinations, displaying the ability to induce robust mucosal immunity, high serum antibodies titres and a cellular immune response avoiding inflammatory response. Interestingly, nanoemulsions have not been proposed for the treatment of local ailments of the nose. Despite the promising results in vitro and in vitro, the application of nanoemulsions for nasal delivery in humans appears mainly hindered by the lack of detailed toxicology studies to determine the effect of these formulations on the nasal mucosa and cilia and the lack of extensive clinical trials.