Nasal sprays used for the treatment of cold and allergy symptoms use same device and formulation in children and adults. Owing to the obvious differences in nasal cavity dimensions between adults and children, the performance of nasal sprays products in children needs to be critically assessed. In an effort to evaluate the deposition patterns of nasal sprays administered to children, a nasal cast based on MRI images obtained from a 12-year-old child’s nasal cavity was developed using 3D printing technology. Glycerin-water mixtures providing sprays with a range of plume angles (26° - 62°), along with three additional commercial nasal sprays, were investigated by actuating the device into the cast under controlled conditions. Following spray administration, the cast was disassembled and subjected to image analysis followed by quantification of formulation deposition in each section of the cast using both chemical and image analysis. The results showed that nasal sprays impacted entirely in the anterior region of the 12-year-old child’s nasal cavity and limited amount of spray entered the turbinate region – the effect site for most topical drugs. Additional experiments were conducted to measure the deposition patterns of nasal sprays in the presence of a mucus layer on the surface of the nasal cast. In an effort to make the nasal deposition studies more relevant to human nasal conditions, the mucus coated nasal cast was tilted in order to induce a physical movement of the mucus layer from the anterior region to the nasopharynx. The presence of mucus did not result in a significant increase in the turbinate region deposition but tilting of the mucus coated nasal cast resulted in 20% - 40% deposition in the turbinate region, improving the posterior region deposition of sprays. Even with the enhanced posterior movement nearly 60% of the spray formulations remained in the anterior region, a site with poor absorption characteristics. The computational fluid dynamic simulations evaluated the impact of multiple parameters including plume angle, droplet diameter and administration conditions on the deposition of nasal sprays in the 12-year-old child’s nasal cavity. The simulations showed significant anterior deposition for all plume angles (10° – 50°) and droplet diameters (30 µm – 400 µm) tested, similar to the observations from the in vitro experiments. An additional parameter, the direction of nasal spray actuation in the nasal cavity, was identified as a critical factor improving the turbinate region deposition of sprays in the 12-year-old child’s nasal cavity in spite of the narrow nasal valve region.

Airflow and particle transport through the nasal cavity was studied using Computational Fluid Dynamics (CFD). A computational model of the human nasal cavity was reconstructed through CT scans. The process involved defining the airway outline through points in space that had to be fitted with a closed surface. The airflow was first simulated and detailed airflow structures such as local vortices, wall shear stresses, pressure drop and flow distribution were obtained. In terms of heat transfer the differences in the width of the airway especially in the frontal regions was found to be critical as the temperature difference was greatest and therefore heating of the air is expedited when the air is surrounded by the hotter walls. Understanding the effects of the airway geometry on the airflow patterns allows better predictions of particle transport through the airway. Inhalation of foreign particles is filtered by the nasal cilia to some degree as a defence mechanism of the airway. Particles such as asbestos fibres, pollen and diesel fumes can be considered as toxic and lead to health problems. These particles were introduced and the effects of particle morphology were considered by customising the particle trajectory equation. This mainly included the effects of the drag correlation and its shape factor. Local particle deposition sites, detailed deposition efficiencies and particle trajectories were obtained. High inertial particles tended to be filtered within the anterior regions of the cavity due to a change in direction of the airway as the air flow changes from vertical at the inlet to horizontal within the main nasal passage. Inhaled particles with pharmacological agents are often deliberately introduced into the nasal airway with a target delivery. The mucous lined airway that is highly vascular provides an avenue for drug delivery into the blood stream. An initial nasal spray experiment was performed to determine the parameters that were important for nasal spray drug delivery. The important parameters were determined to be the spray angle, initial particle velocity and particle swirl. It was found that particles were formed at a break-up length at a cone diameter greater than the spray nozzle diameter. The swirl fraction determined how much of the velocity magnitude went into a tangential component. By combining a swirling component along with a narrow spray into the main streamlines, greater penetration of larger particles into the nasal cavity may be possible. These parameters were then used as the boundary conditions for a parametric study into sprayed particle drug delivery within the CFD domain. The results were aimed to assist in the design of more efficient nasal sprays.

Neste trabalho avaliou-se o comportamento coloidal de suspensões nasais contendo micropartículas de celulose (MCC-NaCMC) com o objetivo de desenvolver um produto genérico compatível com o produto referência de mercado. As propriedades reológicas destas formulações possuem alta influência nos atributos críticos de qualidade do produto, como uniformidade de dose, devido sedimentação durante estocagem em prateleira, e também na performance in-vitro/ in-vivo. Realizaram-se testes com diferentes concentrações de MCC-NaCMC e diferentes parâmetros de processo (tempo e taxa de cisalhamento) utilizando um planejamento de experimentos (DoE) de superfície de respostas através de um modelo composto central. As respostas avaliadas foram tamanho de partículas (quantidade em porcentagem de partículas menores que 1µm e D90) através da técnica por difração a laser e viscosidade/tixotropia através de um reômetro rotacional. Influências significativas dos três fatores e efeitos sinérgicos entre eles nas respostas analisadas foram observadas. Desta maneira foi possível obter respostas próximas ao do produto referência de mercado através deste mapeamento. Observou-se também uma alta correlação entre as respostas, pois este estudo mostrou que o tamanho das partículas coloidais controla a viscosidade e tixotropia das dispersões coloidais. Este trabalho mostrou a significativa influência das etapas de processo no comportamento coloidal das formulações. Idealmente o processo deveria ser monitorado por medidas reológicas, porém este controle é inviável devido ao tempo para a reestruturação do sistema (24 horas). Portanto, a melhor alternativa seria o monitoramento do processo por análise de tamanho de partículas online. / In this work, the colloidal behavior of nasal suspensions containing cellulose microparticles (MCC-NaCMC) was evaluated, in order to develop a generic product compatible with the brand-name product. The rheological properties of these formulations have high influence on the critical quality attributes of the product, such as dose uniformity, due to sedimentation during shelf life, and also on in-vitro/in-vivo performance. Tests were performed with different concentrations of MCC-NaCMC and different process parameters (time and shear rate) using a Design of Experiments (DoE) with response surface by central composite design. The responses evaluated were particle size (amount in percentage of particles smaller than 1m and D90) by means of laser diffraction, and viscosity / thixotropy using a rotational rheometer. Significant influences of the three factors and synergic effects among responses were observed. Through this mapping it was possible to obtain nearby responses to the brand-name product. There was also a strong correlation between the responses, because the size of colloidal particles controlled the dispersion viscosity and thixotropy. This study showed the significant influence of the process steps on the colloidal behavior of the formulations. Ideally the process should be monitored by rheological measurements, but this control is not feasible due to the time required for the system rebuilding (24 hours). Therefore, the best alternative would be monitoring the process by the online particle size analysis.

Neste trabalho avaliou-se o comportamento coloidal de suspensões nasais contendo micropartículas de celulose (MCC-NaCMC) com o objetivo de desenvolver um produto genérico compatível com o produto referência de mercado. As propriedades reológicas destas formulações possuem alta influência nos atributos críticos de qualidade do produto, como uniformidade de dose, devido sedimentação durante estocagem em prateleira, e também na performance in-vitro/ in-vivo. Realizaram-se testes com diferentes concentrações de MCC-NaCMC e diferentes parâmetros de processo (tempo e taxa de cisalhamento) utilizando um planejamento de experimentos (DoE) de superfície de respostas através de um modelo composto central. As respostas avaliadas foram tamanho de partículas (quantidade em porcentagem de partículas menores que 1µm e D90) através da técnica por difração a laser e viscosidade/tixotropia através de um reômetro rotacional. Influências significativas dos três fatores e efeitos sinérgicos entre eles nas respostas analisadas foram observadas. Desta maneira foi possível obter respostas próximas ao do produto referência de mercado através deste mapeamento. Observou-se também uma alta correlação entre as respostas, pois este estudo mostrou que o tamanho das partículas coloidais controla a viscosidade e tixotropia das dispersões coloidais. Este trabalho mostrou a significativa influência das etapas de processo no comportamento coloidal das formulações. Idealmente o processo deveria ser monitorado por medidas reológicas, porém este controle é inviável devido ao tempo para a reestruturação do sistema (24 horas). Portanto, a melhor alternativa seria o monitoramento do processo por análise de tamanho de partículas online. / In this work, the colloidal behavior of nasal suspensions containing cellulose microparticles (MCC-NaCMC) was evaluated, in order to develop a generic product compatible with the brand-name product. The rheological properties of these formulations have high influence on the critical quality attributes of the product, such as dose uniformity, due to sedimentation during shelf life, and also on in-vitro/in-vivo performance. Tests were performed with different concentrations of MCC-NaCMC and different process parameters (time and shear rate) using a Design of Experiments (DoE) with response surface by central composite design. The responses evaluated were particle size (amount in percentage of particles smaller than 1m and D90) by means of laser diffraction, and viscosity / thixotropy using a rotational rheometer. Significant influences of the three factors and synergic effects among responses were observed. Through this mapping it was possible to obtain nearby responses to the brand-name product. There was also a strong correlation between the responses, because the size of colloidal particles controlled the dispersion viscosity and thixotropy. This study showed the significant influence of the process steps on the colloidal behavior of the formulations. Ideally the process should be monitored by rheological measurements, but this control is not feasible due to the time required for the system rebuilding (24 hours). Therefore, the best alternative would be monitoring the process by the online particle size analysis.

The overall objectives of this research project were i) to develop and evaluate methods of characterizing nasal spray products using realistic nasal airway models as more clinically relevant in vitro tools and ii) to develop and evaluate a novel high-efficiency antibiotic nanoparticle dry powder formulation and delivery device. Two physically realistic nasal airway models were used to assess the effects of patient-use experimental conditions, nasal airway geometry and formulation / device properties on the delivery efficiency of nasal spray products. There was a large variability in drug delivery to the middle passages ranging from 17 – 57 % and 47 – 77 % with respect to patient use conditions for the two nasal airway geometries. The patient use variables of nasal spray position, head angle and nasal inhalation timing with respect to spray actuation were found to be significant in determining nasal valve penetration and middle passage deposition of Nasonex®. The developed test methods were able to reproducibly generate similar nasal deposition profiles for nasal spray products with similar plume and droplet characteristics. Differences in spray plume geometry (smaller plume diameter resulted in higher middle passage drug delivery) were observed to have more influence on regional nasal drug deposition than changes to droplet size for mometasone furoate formulations in the realistic airway models. Ciprofloxacin nanoparticles with a mean (SD) volume diameter of 120 (10) nm suitable for penetration through mucus and biofilm layers were prepared using sonocrystallization technique. These ciprofloxacin nanoparticles were then spray dried in a PVP K30 matrix to form nanocomposite particles with a mean (SD) volume diameter of 5.6 (0.1) µm. High efficiency targeted delivery of the nanocomposite nasal powder formulation was achieved using a modified low flow VCU DPI in combination with a novel breathing maneuver; delivering 73 % of the delivered dose to the middle passages. A modified version of the nasal airway model accommodating Transwell® inserts and a Calu-3 monolayer was developed to allow realistic deposition and evaluation of the nasal powder. The nanocomposite formulation was observed to demonstrate improved dissolution and transepithelial transport (flux = 725 ng/h/cm2) compared to unprocessed ciprofloxacin powder (flux = 321 ng/h/cm2).