Nasal Absorption Enhancement of Mometasone Furoate Nanocrystal Dispersions.

Purpose: We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF). Methods: MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-ß-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice. Results: The particle size range of MF prepared with the bead mill treatment was 80-200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions. Conclusion: We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.

Paclitaxel Delivery to the Brain for Glioblastoma Treatment.

The development of paclitaxel-loaded polymeric nanoparticles for the treatment of brain tumors was investigated. Poly(lactide-glycolide) (PLGA) nanoparticles containing 10% w/w paclitaxel with a particle size of 216 nm were administered through intranasal and intravenous routes to male Sprague-Dawley rats at a dose of 5 mg/kg. Both routes of administration showed appreciable accumulation of paclitaxel in brain tissue, liver, and kidney without any sign of toxicity. The anti-proliferative effect of the nanoparticles on glioblastoma tumor cells was comparable to that of free paclitaxel.

Fármacos administrados por via nasal à pessoa em contexto extra-hospitalar / Drugs administered nasally to the person in an out-of-hospital setting

O contexto social atual e? marcado por uma evolução constante nas mais diversas áreas e a saúde não e? exceção. Estes avanços, traduzem-se numa melhoria dos cuidados de saúde, e decorrem não só ao nível das unidades de saúde, mas também no contexto de emergência extra-hospitalar. O Relatório Final de Estágio retrata a descrição e análise das atividades e competências comuns e específicas do Enfermeiro Especialista de Enfermagem Médico-Cirúrgica desenvolvidas no contexto do ensino clínico e uma investigação secundária do tipo scoping review relativa à temática da via nasal, subutilizada no contexto extra-hospitalar português. O desenvolvimento das competências seguiu a metodologia crítico-reflexiva e tem por base o Projeto de Estágio. A investigação secundária do tipo scoping review, cujo objetivo foi mapear os fármacos administrados por via nasal à pessoa em contexto extra-hospitalar, seguiu o método do Joanna Briggs Institute, através de pesquisa em base de dados de relevo para a temática, repositório científico e literatura cinzenta para identificar estudos relevantes que respondam a critérios de inclusão previamente definidos. Para tal, foi definida a questão de pesquisa, segundo a mnemónica Population, Concept, Context, ?quais os fármacos administrados por via nasal à pessoa em contexto extra-hospitalar??. Desta forma, o relatório emerge as contribuições do ensino clínico para a consolidação das competências e, consequentemente, o seu impacto positivo tanto no domínio pessoal como profissional. Por outro lado, a investigação realizada resultou no mapeamento dos fármacos administrados por via nasal à pessoa, em contexto extra-hospitalar, servindo de mote para a revisão e atualização de procedimentos e protocolos nesta área. Assim, este relatório tem repercussões na área de Enfermagem Médico-Cirúrgica no sentido em que contribui para a melhoria da prestação de cuidados diferenciados, tendo em vista a segurança e qualidade em saúde e, consequentemente, a obtenção de ganhos em saúde.

Effect of Different Absorption Enhancers on the Nasal Absorption of Nalmefene Hydrochloride.

The purpose of this work is to explore the effects of novel absorption enhancers on the nasal absorption of nalmefene hydrochloride (NMF). First, the influence of absorption enhancers with different concentrations and types and drug concentrations on the nasal absorption of NMF was investigated in vivo in rats. The absorption enhancers studied include n-dodecyl-ß-D-maltoside (DDM), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and polyethylene glycol (15)-hydroxy Stearate (Solutol®HS15). At the same time, the in situ toad palate model and rat nasal mucosa model were used to assess the cilia toxicity. The results showed that all the absorption enhancers investigated significantly promote the nasal absorption of NMF, but with different degrees and trends. Among them, the 0.5% (w/v) DDM had the strongest enhancement effect, followed by 0.5% (w/v) Solutol®HS15, 0.25% (w/v) DDM, 0.25% (w/v) Solutol®HS15, 0.1% (w/v) Solutol®HS15, 0.1% (w/v) DDM, and 0.25% (w/v) HP-ß-CD, with absolute bioavailability of 76.49%, 72.14%, 71.00%, 69.46%, 60.41%, 59.42%, and 55.18%, respectively. All absorption enhancers exhibited good safety profiles in nasal ciliary toxicity tests. From the perspective of enhancing effect and safety, we considered DDM to be a promising nasal absorption enhancer. And in addition to DDM, Solutol®HS15 can also promote intranasal absorption of NMF, which will provide another option for the development of nalmefene hydrochloride nasal spray.

[Development of Prediction System for Drug Absorption after Intranasal Administration Incorporating Physiologic Functions of Nose -Estimation of in Vivo Drug Permeation through Nasal Mucosa Using in Vitro Membrane Permeability].

The nasal drug application has drawn much attention as the strategy for the delivery route of many drug modalities such as the poorly absorbed drugs, peptides, nucleic acid, and central nervous system drugs. The absorption of drug after intranasal (IN) application depends on the nasal residence time of applied drug, affected by mucociliary clearance (MC). MC is a decisive factor in the nasal absorption of drug. We describe the establishment of in vitro evaluation system of nasal MC via the moving velocity of a marker particle on nasal mucosa, and the development of the pharmacokinetic model to which in vitro parameters on nasal MC was incorporated to enable the prediction of drug absorption after IN application. Moreover, the pharmacokinetics of norfloxacin after IN application was investigated using MC-modified rats pretreated with MC modulators. Nasal absorption fluctuated due to changes in the nasal residence time of drug in response to changes in MC. The prediction system enables quantitative evaluation of changes in drug absorption associated with MC fluctuations. In addition, for a precise prediction system for drug absorption after IN application from the drug absorption model, the relationships between in vitro drug permeability through Calu-3 layers, in vivo transnasal permeation of drug and in vivo bioavailability after IN application were evaluated. The significant correlations between these parameters were obtained, suggesting that transnasal permeability and drug absorption after IN application can be predicted from in vitro membrane permeability.

Intranasal delivery of experimental compounds in orthotopic brain tumor mouse models.

Effective therapeutics for malignant primary brain tumors, such as glioblastomas (GBMs), are urgently needed. To facilitate and expedite early-phase GBM therapeutic development, we describe a protocol that allows the intranasal delivery of experimental compounds in GBM orthotopic mouse models. Compounds delivered through this route can bypass the blood-brain barrier and thus help validate effective therapeutic targets for GBMs. For complete details on the use and execution of this protocol, please refer to Pinkham et al. (2019).

Airways exposure of bacterial superantigen SEB enhances bone marrow eosinophil population and facilitates its egress to blood and lung tissue.

BACKGROUND: Differentiation of bone marrow eosinophils (BM-EO) and its trafficking to peripheral blood and respiratory mucosa are a hallmark of inflammatory diseases. Staphylococcal enterotoxin B (SEB) has been shown to aggravate airways eosinophilic inflammation. This study aimed to investigate the effects of mouse airways SEB exposure on BM-EO population, as well as its adhesive properties and release of cytokines/chemokines that orchestrate BM-EO trafficking to lungs. METHODS: Male BALB/c mice were intranasally exposed to SEB (1 µg), and at 4, 16, 24 and 48 h thereafter, bone marrow (BM), circulating blood and bronchoalveolar lavage (BAL) fluid were collected. Levels of cytokines/chemokines and expressions of VLA-4 and CCR3 in BM were evaluated. Adhesion of BM to ICAM-1 and VCAM-1 were also evaluated. RESULTS: SEB exposure promoted a marked eosinophil influx to BAL at 16 and 24 h after exposure, which was accompanied by significant increases in counts of immature (16 h) and mature (4 to 48 h) forms of eosinophil in BM, along with blood eosinophilia (16 h). In BM, higher levels of eotaxin, IL-5, IL-4, IL-3 and IL-7 were detected at 16 to 48 h. SEB also significantly increased CCR3 expression and calcium levels in BM-EO, and enhanced the cell adhesion to ICAM-1 (24 h) and ICAM-1 (48 h). CONCLUSION: Airways SEB exposure increases the number of eosinophils in BM by mechanisms involving a network of cytokine and chemokine release, facilitating the BM-EO adhesion to ICAM-1 and VCAM-1 to gain access to the peripheral blood and lung tissues.

[Study on nasal absorption of Cistanche deserticola phenylethanol glycosides nanoemulsion in vivo].

To investigate the transnasal absorption characteristics of Cistanche deserticola phenylethanol glycosides nanoemulsion and its influencing factors. With the use of the classic in vivo nasal circulation perfusion model in rats, the absorption rate constant was used as the index to compare the nasal absorption characteristics of C. deserticola phenylethanol glycosides nanoemulsion and its aqueous solution in different concentrations, and to explore the effects of pH value of the preparation and absorption accelerator Azone on the nasal absorption of C. deserticola phenylethanol glycosides nanoemulsion. The results showed that, as compared with the aqueous solution group, the absorption rate constant was significantly higher in C. deserticola phenylethanol glycosides nanoemulsion with the same concentration(P<0.05), and C. deserticola phenylethanol glycosides nanoemulsion was more easily absorbed by the nasal cavity of rats; with the increase of the concentration of C. deserticola phenylethanol glycosides, the transnasal absorption amount of nanoemulsion was also increased in a dose-dependent manner. When the pH value of nanoemulsion was 6.0 and the ratio of Azone was 2%, the absorption rate constant was highest and the effect of promoting infiltration was the best.

Evaluation of the upper airway microbiome and immune response with nasal epithelial lining fluid absorption and nasal washes.

Despite being commonly used to collect upper airway epithelial lining fluid, nasal washes are poorly reproducible, not suitable for serial sampling, and limited by a dilution effect. In contrast, nasal filters lack these limitations and are an attractive alternative. To examine whether nasal filters are superior to nasal washes as a sampling method for the characterization of the upper airway microbiome and immune response, we collected paired nasal filters and washes from a group of 40 healthy children and adults. To characterize the upper airway microbiome, we used 16S ribosomal RNA and shotgun metagenomic sequencing. To characterize the immune response, we measured total protein using a BCA assay and 53 immune mediators using multiplex magnetic bead-based assays. We conducted statistical analyses to compare common microbial ecology indices and immune-mediator median fluorescence intensities (MFIs) between sample types. In general, nasal filters were more likely to pass quality control in both children and adults. There were no significant differences in microbiome community richness, α-diversity, or structure between pediatric samples types; however, these were all highly dissimilar between adult sample types. In addition, there were significant differences in the abundance of amplicon sequence variants between sample types in children and adults. In adults, total proteins were significantly higher in nasal filters than nasal washes; consequently, the immune-mediator MFIs were not well detected in nasal washes. Based on better quality control sequencing metrics and higher immunoassay sensitivity, our results suggest that nasal filters are a superior sampling method to characterize the upper airway microbiome and immune response in both children and adults.

Nasal absorption enhancement of protein drugs independent to their chemical properties in the presence of hyaluronic acid modified with tetraglycine-L-octaarginine.

Our previous mouse studies demonstrated that mean bioavailability of exendin-4, which is an injectable glucagon-like peptide-1 (GLP-1) analogue whose molecular weight (Mw) and isoelectric point (pI) are ca. 4.2 kDa and 4.5, respectively, administered nasally with poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing D-octaarginine, which is a typical cell-penetrating peptide, was 20% relative to subcutaneous administration even though it was less than 1% when exendin-4 alone was given nasally. The studies also revealed that the absorption-enhancing ability of D-octaarginine-linked PNVA-co-AA for exendin-4 was statistically equivalent to that of sodium salcaprozate (SNAC), which is an absorption enhancer formulated in tablets of semaglutide approved recently as an orally available GLP-1 analogue. From a perspective of clinical application of our technology, we have separately developed hyaluronic acid modified with L-octaarginine via a tetraglycine spacer which would be degraded in biological conditions. The present study revealed that tetraglycine-L-octaarginine-linked hyaluronic acid enhanced nasal absorption of exendin-4 in mice, as did D-octaarginine-linked PNVA-co-AA. There was no significant difference in absorption-enhancing abilities between the hyaluronic acid derivative and SNAC when octreotide (Mw: ca. 1.0 kDa, pI: 8.3) and lixisenatide (Mw: ca. 4.9 kDa, pI: 9.5) were used as a model protein drug. On the other hand, SNAC did not significantly enhance nasal absorption of somatropin (Mw: ca. 22.1 kDa, pI: 5.3) when compared with absorption enhancer-free conditions. Substitution of SNAC with tetraglycine-L-octaarginine-linked hyaluronic acid resulted in a 5-fold increase in absolute bioavailability of somatropin with statistical significance. It appeared that pI hardly ever influenced absorption-enhancing abilities of both enhancers. Results indicated that our polysaccharide derivative would be a promising absorption enhancer which delivers biologics applied on the nasal mucosa into systemic circulation and was of greater advantage than SNAC for enhancing nasal absorption of protein drugs with a larger Mw.

Performance and toxicity of different absorption enhancers used in the preparation of Poloxamer thermosensitive in situ gels for ketamine nasal administration.

The purpose of this study was to investigate the nasal absorption rate and nasal mucosal toxicity of thermosensitive ketamine in situ gels containing various absorption enhancers. The optimal composition ratio for the gel matrix was determined to be 17.2% Poloxamer 407 and 2% Poloxamer 188, as this combination resulted in solutions with a gelation point within the range found in the nasal cavity. Ketamine gels containing the tested enhancers, namely, ethylenediaminetetraacetic acid disodium salt, hydroxypropyl-ß-cyclodextrin, propylene glycol, or Tween-80, were compared with enhancer-free counterparts to determine the absorption of the drug, in vivo by measuring its plasma levels in rats and in vitro using a Franz diffusion cell. Moreover, the toxicity of each gel type was assessed by microscopic observation of the morphology of rat nasal mucosa as well as by determining the mobility of the mucosal cilia using an established toad model. The results showed that gels containing hydroxypropyl-ß-cyclodextrin could promote the absorption of ketamine without added toxicity compared to enhancer-free gels. Thus, we consider hydroxypropyl-ß-cyclodextrin as the most promising absorption enhancer for the nasal administration of ketamine using in situ gels.

Investigating the potential of utilizing glycerosomes as a novel vesicular platform for enhancing intranasal delivery of lacidipine.

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

Very Early Blood Diffusion of the Active Lethal and Edema Factors of Bacillus anthracis After Intranasal Infection.

BACKGROUND: Lethal and edema toxins are critical virulence factors of Bacillus anthracis. Few data are available on their presence in the early stage of intranasal infection. METHODS: To investigate the diffusion of edema factor (EF) and lethal factor (LF), we use sensitive quantitative methods to measure their enzymatic activities in mice intranasally challenged with a wild-type B anthracis strain or with an isogenic mutant deficient for the protective antigen. RESULTS: One hour after mouse challenge, although only 7% of mice presented bacteremia, LF and EF were detected in the blood of 100% and 42% of mice, respectively. Protective antigen facilitated the diffusion of LF and EF into the blood compartment. Toxins played a significant role in the systemic dissemination of B anthracis in the blood, spleen, and liver. A mouse model of intoxination further confirmed that LT and ET could diffuse rapidly in the circulation, independently of bacteria. CONCLUSIONS: In this inhalational model, toxins have disseminated rapidly in the blood, playing a significant and novel role in the early systemic diffusion of bacteria, demonstrating that they may represent a very early target for the diagnosis and the treatment of anthrax.

Effect of Glyceryl Monocaprylate-Modified Chitosan on the Intranasal Absorption of Insulin in Rats.

Nasal administration of insulin showed the attractive potential to improve the compliance of diabetic patients and alleviate mild cognitive impairment of Alzheimer's patients. However, the nasal absorption of insulin was not ideal, limiting its therapeutic effect in clinic. This study was to explore the potential of glyceryl monocaprylate-modified chitosan (CS-GMC) on the intranasal absorption of insulin via in vivo pharmacodynamic experiment in conscious rats. It was demonstrated that the absorption-enhancing effect of CS-GMC depended on the existing state of insulin in the formulation, substitution degree of GMC on chitosan and concentration of CS-GMC. Better insulin absorption was achieved when insulin existed in molecular form compared with that in polyelectrolyte complexes. CS-GMC with substitution degree 12% (CS-GMC 12%) was a preferred absorption enhancer, and its absorption enhancing effect increased linearly with the increment of its concentration in the range investigated. Compared with chitosan of the same concentration, CS-GMC12% showed remarkably enhanced and prolonged therapeutic effect up to at least 5 h under the concentration of 0.6% (w/v). CS-GMC12% showed almost no ciliotoxicity to the nasal cilia up to concentration 1.0% (w/v). In conclusion, CS-GMC was a promising absorption enhancer to improve the intranasal absorption of insulin.

Enhanced Intranasal Absorption of Naltrexone by Dodecyl Maltopyranoside: Implications for the Treatment of Opioid Overdose.

Based on its high affinity for µ opiate receptors and reported half-life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer-lived opiate antagonists than naloxone. Both the maximum plasma concentration (Cmax ) and the time (Tmax ) to reach Cmax for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration-approved 4-mg dose of intranasal naloxone. The addition of the absorption enhancer dodecyl maltoside (Intravail) increased Cmax by ∼3-fold and reduced the Tmax from 0.5 to 0.17 hours. Despite these very rapid increases in plasma concentrations of naltrexone, its short half-life following intranasal administration (∼2.2 hours) could limit its usefulness as a rescue medication, particularly against longer-lived synthetic opioids. Nonetheless, the ability to rapidly attain high plasma concentrations of naltrexone may be useful in other indications, including an as-needed dosing strategy to treat alcohol use disorder.

Aerosol and Contact Transmission Following Intranasal Infection of Mice with Japanese Encephalitis Virus.

The Japanese encephalitis virus (JEV), a causative agent of severe viral encephalitis in humans, has a biological cycle fluctuating between transmission in mosquitoes and avian species and amplification in pigs. Contact transmission of JEV was recently shown in pigs in the absence of arthropod vectors. Here, we show JEV transmission between infected and contact mice and further demonstrate that JEV transmission occurs between animals via aerosols, as both viral RNA and infectious JEV were detected in direct contact- and aerosol-exposed contact animals. The results of this study change our understanding of JEV transmission in densely populated regions and may help to explain JEV outbreaks without the presence of arthropod vectors.

Enhancement Effect of Poly-L-ornithine on the Nasal Absorption of Water-Soluble Macromolecules in Rats.

The transnasal route for the delivery of water-soluble macromolecules, such as bioactive peptides and proteins, has attracted interest, although the use of permeation enhancers is required due to the poor permeabilities of these macromolecules across the nasal mucosa. With polycationic compounds, such as poly-L-arginine and chitosan, the nasal absorption of hydrophilic macromolecules is molecular weight- and concentration-dependently enhanced without causing cytotoxicity. In the present study, we evaluated the effect of various molecular weights and concentrations of poly-L-ornithine (PLO), a polycationic compound, on the nasal absorption and the damage to the nasal mucosa in vivo. PLO enhanced the nasal absorption of fluorescein isothiocyanate-dextran (FD-4), used as a model drug, and the bioavailability of FD-4 increased with the concentration of PLO. The enhancement effect was also dependent on the molecular weight. The administration of PLO at a concentration that sufficed for enhancing the nasal absorption had no effect on the activity of lactic dehydrogenase and the protein leakage in the nasal fluid, as indices of nasal mucosa damage. These findings suggest that a transnasal delivery system using PLO is a useful strategy for improving the nasal absorption of water-soluble macromolecules without toxicity to the nasal mucosa.

Effect of polysorbate 80 on the intranasal absorption and brain distribution of tetramethylpyrazine phosphate in rats.

Drug delivery to the brain is limited by the blood-brain barrier (BBB). Intranasal delivery is a non-invasive route of drug administration which can bypass the BBB and contributed to a direct and rapid transport of drugs to the brain. However, intrinsic drug distribution to the brain after intranasal administration may not be sufficient to achieve required clinical efficacy. In this study, taking 2,3,5,6-tetramethylpyrazine (TMPP) as a model drug, the feasibility of using polysorbate 80 as an absorption enhancer and message guider to increase drug distribution in the brain was employed. After intravenous/intranasal administration of TMPP formulations with/without polysorbate 80, drug concentration in both plasma and brain was measured at specific time points, and the pharmacokinetic parameters were compared. It was demonstrated that compared with intravenous administration, brain targeting efficiency of TMPP was improved remarkably by intranasal route. Upon intranasal administration, the addition of polysorbate 80 significantly increased TMPP concentration in both plasma and brain linearly up to polysorbate 80 concentration 2%. Based on drug targeting efficiency, drug targeting index, and nose-to-brain direct transport percentage, polysorbate 80 decreased the nose-to-brain direct transport ratio of TMPP in a polysorbate 80 concentration-dependent manner although the total brain targeting efficiency was unchanged, with significantly enhanced absolute drug concentration in the brain achieved. In summary, polysorbate 80 is a promising excipient to increase drug concentration in both plasma and brain via intranasal route.

Lamotrigine encapsulated intra-nasal nanoliposome formulation for epilepsy treatment: Formulation design, characterization and nasal toxicity study.

The purpose of this study was to develop lamotrigine nanoliposomes (LTG-NLs) for the treatment in seizures. The formulation was prepared using thin film hydration and rehydration method using the phospholipon 90 G, cholesterol and tween 80 as main ingredients. The nanoliposomes were optimized by plucket burman design (PBD) and response surface methodology (RSM) optimization techniques. The optimized LTGNLopt was further characterized for surface morphology, in-vitro release, stability study, confocal laser scanning microscopic (CLSM) study and naso toxicity study. The results showed that LTGNLopt shown nano size with high entrapment and drug release. The ex-vivo permeation study and confocal laser microscopy study confirmed the enhancement in permeation across the goat nasal mucosa. From the study, it was concluded that the independent variables used to optimize the NLs shown significant effect on the dependent variables and consider effective lipid carrier system for intranasal delivery.

Intranasal Filtration of Inhaled Aerosol in Human Subjects as a Function of Nasal Pressure Drop.

BACKGROUND: Intersubject variability in nasal deposition of inhaled aerosol is significant because of the differences in nasal anatomy and breathing rate. The notable limitation of the majority of previously developed predictive correlations is including a limited number of subjects. A few recent studies have considered a wide age range of subjects, but the resulting correlations require the knowledge of the dimensions of the nasal airways and the properties of inhaled gas. In this study empirical correlations are proposed to predict aerosol deposition in nasal airways of subjects of different age as a function of intranasal pressure drop and the particle aerodynamic diameter. METHODS: The experimental nasal deposition and pressure drop data in anatomically correct nasal replicas of 5 adults, 13 children aged 4-14 years, and 11 infants aged 3-18 months were reanalyzed. The range of aerodynamic diameter was 0.5-5.3 µm and physiological breathing at different activity levels was considered. Correlations between nasal deposition and a deposition parameter including the aerodynamic size of inhaled aerosol and nasal pressure drop were developed with nonlinear least-square algorithms. The general coefficient of determination r2 was used to evaluate the fitting accuracy for each correlation. RESULTS: New correlations were developed to predict the intranasal deposition of particles as a function of intranasal pressure drop and particle size for pediatric and adult subjects. The intranasal deposition fraction in adults and children can be calculated using the same correlation, whereas the intranasal deposition in infants followed a different trend line because of higher intranasal pressure drop in infants. CONCLUSION: This study was the first offering correlations to predict intranasal deposition in multiple age groups using only the aerodynamic size of inhaled aerosol and nasal pressure drop. These correlations include the effects of intersubject variability in nasal deposition within each age group and among different age groups.