Dissertations / Theses on the topic 'Nasal spray'

Spray technology is used in the delivery of pharmaceutical ingredients through the nose or lungs. There is an ongoing requirement to establish a more in-depth understanding of the spray properties and their dependence on pharmaceutical formulations, 011 device parameters. on patients' operation and their influence on the resulting delivery sites. The study presented here consisted of three phases aimed at furthering the understanding of the properties of nasal spray formulations from a physico-chemical point of view. This includes the relationship between the suspension properties, the spraying behaviour and the effect 011 the deposition pattern within the nasal cavity. Phase 1: A commercially available nasal spray suspension. a placebo and laboratory formulation. were characterised for rheological properties and spray behaviour using high speed imaging. Thi work demonstrated the shear thinning and viscoelastic properties of the sample, as well as strain hardening behaviour occurring above the extensional strain of 3.8, 105 5'. It was also found, from the imaging techniques employed. that the spray formed a hollow cone and, the formation of droplets from the fluid sheet could be observed. Results from a set of Box-Behnken and Mixture design of experiment showed that the EDTA influenced the rheological properties of the suspensions and. the interactions between BKC and dextrose affected the spray behaviour. Phase 2: A range of formulations modified with small amounts of polymeric additives (30 - 200ppm), polyethylene oxide and hydroxypropyl methylcellulose, were developed to assess the influence of such polymers on spray properties. lt was found that the addition of PEO broadened the droplet size distributions and reduced the spray dimensions, whereas the addition of HPMC did not significantly affect the spray properties. Phase 3: The final phase involved the study of the in-vivo deposition of the modified formulations, using a human nasal cavity model, under three different forced air flow rates. This study aimed at observing the influence of formulation variation on intranasal deposition. It was found that the addition of PEO increased the deposition of the droplet ill the nasal valve region and, that the forced air flow rate did not affect the profile of deposition. The un-modified suspension deposited mainly in anterior region of the nose without forced air flow, however, as the forced air flow rate increased. the droplets were swept further to deposit in the nasal valve region and turbinates region.

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.

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).

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.

Nasal administration has potential for the treatment of indications requiring a fast onset of effect or for drugs with low oral bioavailability. Liquid nasal sprays are relatively common, but can be associated with suboptimal absorption from the nasal cavity; this thesis shows that nasal absorption can be significantly enhanced with a dry powder formulation. It was shown that interactive mixtures, consisting of fine drug particles adhered to the surface of mucoadhesive carrier particles, could be created in a particle size suitable for nasal administration. Sodium starch glycolate (SSG), a common tablet excipient, was used as carrier material. In vitro evaluation of the formulation indicated that the mucoadhesion of the carrier was unlikely to be affected by the addition of a drug. The powder formulation did not improve the in vitro transfer of dihydroergotamine across porcine nasal mucosa compared with a liquid formulation; however, the results were associated with methodological shortcomings. The binding of model substances to SSG and three other excipients was evaluated. Ion exchange interactions were for example detected between SSG and cationic drugs, but these interactions were most extensive at low salt concentrations and should unlikely affect in vivo bioavailability at physiological salt concentrations. Absorption of the peptide drug desmopressin from the SSG nasal formulation, from a novel sublingual tablet formulation and from a commercial nasal liquid spray was evaluated in a clinical trial. While no improvement over the liquid spray was seen with the sublingual tablet, plasma concentrations after the nasal powder formulation were three times higher than those after the liquid spray. All formulations were well accepted by the volunteers. The use of currently available mucoadhesive carrier particles in interactive mixtures offers potential for a new method of producing nasal powder formulations that should also be applicable to large scale production.

As we inhale, the air drawn through our nose undergoes successive accelerations and decelerations as it is turned, split, and recombined before splitting again at the end of the trachea as it enters the bronchi. Fully describing the dynamic behaviour of the airflow and how it transports inhaled particles poses a severe challenge to computational simulations. The dynamics of unsteady flow in the human large airways during a rapid and short inhalation (a so-called sniff) is a perfect example of perhaps the most complex and violent human inhalation inflow. Combining the flow solution with a Lagrangian computation reveals the effects of flow behaviour and airway geometry on the deposition of inhaled microparticles. Highly detailed large-scale computational fluid dynamics allow resolving all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code running on supercomputers can solve the transient incompressible Navier-Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations, wall shear stresses, energy spectral and particle deposition on a rapid and short inhalation. Then in a second time, we will propose a drug delivery study of nasal sprayed particle from commercial product in a human nasal cavity under different inhalation conditions; sniffing, constant flow rate and breath-hold. Particles were introduced into the flow field with initial spray conditions, including spray cone angle, insertion angle, and initial velocity. Since nasal spray atomizer design determines the particle conditions, fifteen particle size distributions were used,each defined by a log-normal distribution with a different volume mean diameter. This thesis indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow and delivery of therapeutic aerosols, which could be applied to improve diagnosis and treatment.
En una inhalación, el aire que atraviesa nuestra cavidad nasal es sometido a una serie de aceleraciones y deceleraciones al producirse un giros, bifurcaciones y recombinarse de nuevo antes de volver a dividirse de nuevo a la altura de la tráquea en la entrada a los bronquios principales. La descripción precisa y acurada del comportamiento dinámico de este fluido así como el transporte de partículas inhalada que entran con el mismo a través de una simulación computacional supone un gran desafío. La dinámica del fluido en las vías respiratorias durante una inhalación rápida y corta (también llamado sniff) es un ejemplo perfecto de lo que sería probablemente la inhalación en el ser humano más compleja y violenta. Combinando la solución del fluido con un modelo lagrangiano revela el comportamiento del flujo y el effecto de la geometría de las vías respiratorias sobre la deposición de micropartículas inhaladas. La dinámica de fluidos computacional a gran escala de alta precisión permite resolver todas las escalas espaciales y temporales gracias al uso de recursos computacionales masivos. Un código de elementos finitos paralelos que se ejecuta en supercomputadoras puede resolver las ecuaciones transitorias e incompresibles de Navier-Stokes. Considerando que la malla más fina contiene 350 millones de elementos, cabe señalar que el presente estudio establece un precedente para simulaciones a gran escala de las vías respiratorias, proponiendo una estrategia de análisis para flujo medio, fluctuaciones, tensiones de corte de pared, espectro de energía y deposición de partículas en el contexto de una inhalación rápida y corta. Una vez realizado el analisis anterior, propondremos un estudio de administración de fármacos con un spray nasal en una cavidad nasal humana bajo diferentes condiciones de inhalación; sniff, caudal constante y respiración sostenida. Las partículas se introdujeron en el fluido con condiciones iniciales de pulverización, incluido el ángulo del cono de pulverización, el ángulo de inserción y la velocidad inicial. El diseño del atomizador del spray nasal determina las condiciones de partículas, entonces se utilizaron quince distribuciones de tamaño de partícula, cada uno definido por una distribución logarítmica normal con una media de volumen diferente. Esta tesis demuestra el potencial de las simulaciones a gran escala para una mejor comprensión de los mecanismos fisiológicos de las vías respiratorias. Gracias a estas herramientas se podrá mejorar el diagnóstico y sus respectivos tratamientos ya que con ellas se profundizará en la comprensión del flujo que recorre las vías aereas así como el transporte de aerosoles terapéuticos.

Statement of problem: Topical corticosteroids nasal sprays remain first line of treatment for patients with chronic rhinosinusitis (with or without nasal polyps). The main aim of treatment is to improve nasal symptoms by reducing or eliminating the nasal polyps and preventing polyp recurrence post-operatively. Our aims were to determine if the type of corticosteroid nasal spray used post operatively influences polyp recurrence rate and if there were any subsequent economic implications as we only have beclomethasone available for prescription in our state hospital. Methods: Retrospective case note review of all Samter's patients who underwent fronto-spheno-ethmoidectomy by a single surgeon (2000 – 2014). Results: 58 patients were included in our study, divided into 3 study groups. When compared to patients using beclomethasone; patients using fluticasone had an 80% reduced risk of polyp recurrence and patients using mometasone a 90% reduced risk. This rose to 88% and 96% respectively when adjusted for age. Conclusion: Fluticasone and mometasone are both statistically significantly more effective at reducing polyp recurrence than beclomethasone in our population group. Mometasone appeared more effective than fluticasone, but this difference was not statistically significant.

Orientador: Ricardo de Lima Zollner
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Rinite alérgica é uma doença comum com ampla morbidade, que gera aumento considerável nos custos de tratamento médico, redução da produtividade no trabalho e absenteísmo escolar. A aplicação tópica de corticosteróides intranasal é amplamente reconhecida como primeira linha de tratamento antiinflamatório. Espera-se que a maioria dos sprays nasais prescritos como drogas de ação local, ainda não possuam patente permitindo o aumento de cópias genéricas desses medicamentos, levando a concorrência e redução de preço. Estudos de bioequivalência para sprays nasais estão ainda em discussão. Geralmente, os estudos para essa finalidade usa modelos de intervenção terapêutica a longo prazo, com altos custos para o paciente e longo tempo de duração. O objetivo deste trabalho foi mostrar a aplicabilidade da provocação nasal com histamina e rinomanometria em estudos de bioequivalência para sprays nasais. Trata-se de um estudo aberto, cruzado aleatorizado, utilizando dois períodos e duas seqüências para avaliar a equivalência farmacodinâmica entre duas formulações de sprays de dipropionato de beclometasona de manufaturamento distinto. Após estímulo nasal com histamina (0,5 mg/ml em ambas narinas), 25 voluntários saudáveis foram submetidos a rinomanometria anterior nos tempos 0; 15; 30 e 60 minutos para estabelecimento do fluxo, pressão e resistência basal de cada câmara nasal. Os voluntários foram submetidos à utilização do spray nasal com a droga teste (T) ou referência (R) de acordo com o esquema de randomização, e a área sobre a curva foi analisada. De acordo com os parâmetros estudados os resultados obtidos mostraram diferença significativa entre as duas formulações (p= 0,31) indicando a equivalência terapêutica entre as drogas T e R. Assim, estes resultados sugerem que provocação nasal com histamina em indivíduos saudáveis e o emprego da rinomanometria como método quantitativo das alterações provocadas nas câmaras nasais possam ser aplicáveis em estudos farmacodinâmicos de bioequivalência para sprays nasais
Abstract: Allergic rhinitis is a common condition with widespread morbidity, increased medical treatment costs, reduced work productivity and lost school days. Topically delivered intranasal corticosteroids are widely recognized to be the first-line anti-inflammatory treatment. It is expected that many of the most-prescribed nasal sprays for local action drugs will go off patent, allowing the increase of the generic copies of these medications, with more products competition and price reduction. The bioequivalence studies for nasal sprays are still in discussion. Usually the studies designs for this purpose use a long-term therapeutic intervention models using patients with high costs and time duration. This study was designed to demonstrate the feasibility of rhinomanometry in bioequivalence studies for nasal sprays. Study design, an open, randomized, crossover study, using two periods and two sequences to evaluate pharmacodynamic equivalence between two formulations of beclometasone dipropionate spray. After nasal challenge with histamine (0.5mg/ml, in both nostrils), 25 healthy volunteers were submited to an anterior rhinomanometry at the time 0; 15; 30 and 60 minutes building a baseline of flow, pression and resistance of nasal chamber. Then, the vontuteers were submited to nasal drug spray (Test (T) or Reference(R)), according to randomized schedule and the Are Under Curve (AUC0-t) analyzed. The results suggest the potential use of nasal histamine challenge and rhinomanometry evaluation in healthy subjects in bioequivalence studies for nasal sprays
Mestrado
Ciencias Basicas
Mestre em Clinica Medica

碩士
臺北醫學大學
藥學研究所
96
An oleic acid-based microemulsion system with Cremophor EL or Tween series as surfactants, and short-chain alcohol, PEG 600 or PG as cosolvents was developed for rapid-onset intranasal delivery of sildenafil. Phase behavior and solubilization capacity of the microemulsion system were characterized and in vivo nasal absorption of sildenafil from microemulsion formulations was investigated in rabbits. A single isotropic region, which is considered as a microemulsion, was found in the pseudo-ternary phase diagrams developed at various surfactants : cosolvents ratios. With the higher weight percentage of surfactant, the region area of microemulsion in the phase diagram decreased whereas the viscosity of microemulsion increased. Sildenafil, a water-insoluble drug, displayed a high solubility of 124 mg/ml in a microemulsion consisting of 40 % oleic acid, 10 % H2O, and 50 % Tween 80:ethanol (at 1:4 weight ratio). Nasal absorption of sildenafil from this microemulsion was found to be fairly rapid. At 10 mg dose, the onset of action was arrived instantly follow administrating the IN formulation and the duration was over 3 hours. These results suggest that the microemulsion system composed of oleic acid, Tween 80, ethanol and water may be a useful approach for the rapid-onset delivery of sildenafil with the erectile dysfunction.

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2020
A rinossinusite (RNS) é uma das patologias mais prevalentes na área da Otorrinolaringologia. Para além disso, constitui um motivo frequente de recurso aos cuidados de saúde primários ou a serviços de urgência e a sua forma crónica é uma comorbilidade frequentemente encontrada em todas as especialidades médicas. A sua terapêutica passa por várias classes de fármacos, com combinações entre elas numa tentativa de fornecer alívio sintomático e uma melhor qualidade de vida ao doente. Uma das abordagens terapêuticas que desde há muito se utiliza nos doentes com RNS é a irrigação nasal salina. Com este trabalho, após revisão da literatura existente sobre o assunto, pretende-se reunir dados acerca da concentração salina mais apropriada da solução a utilizar na irrigação nasal assim como tentar perceber qual o melhor método para aplicação da mesma, de forma a ser obtido o maior benefício possível com esta terapêutica.
Rhinosinusitis (RNS) is one of the most prevalent diseases in the Otorhinolaryngology field. Besides that, it constitutes a frequent reason for visits to primary health care or emergency services and chronic rhinosinusitis is a comorbidity often found in all medical specialties. Rhinosinusitis therapy consists in several classes of drugs, with combinations between them in an attempt to provide symptomatic relief and the best possible quality of life for the patient. A therapeutic weapon that has been used for a long time in the management of patients with RNS is saline nasal irrigation. With this work, after reviewing the existing literature on the subject, I intend to reach data about the ideal concentration of the solution that should be used in irrigation as well the best method for applying it, in order to obtain the greatest possible benefit from this therapy.

M.Tech. (Homoeopathy)
Allergic Rhinitis (AR) is the inflammation of the nasal and often conjunctival mucous membrane. It manifests due to the exposure of inhaled allergic agents and results in an immunoglobulin E (lgE) mediated reaction (DiPiro et al., 2002; Shargel et al., 2001). Allergic rhinitis is characterised by four principle symptoms, watery rhinorrhoea, nasal obstruction, nasal itching and sneezing (Min, 2010). In addition to the cardinal symptoms experienced during AR other common symptoms include postnasal drip, pruritic eyes; ears; nose and palate (Kemp, 2009). Although allergic rhinitis is not life threatening, the adverse impact on quality of life is significant. Those affected by allergic rhinitis are restricted in their ability to carry out their normal daily activities (Nelson, 2007; Wilson et al., 2002). Sleep, social interaction, emotional well being as well as cognitive and psychomotor function are affected by allergic rhinitis, and can lead to impaired learning ability. Serious disorders such as eczema, asthma, sinusitis, otitis media, nasal polyposis, respiratory infections and orthodontic malocclusions are. frequently linked with allergic rhinitis (DiPiro et al., 2002; Kemp, 2009)., The therapeutic goal for patients suffering with allergic rhinitis is to prevent or minimise symptoms, using treatment with minimal or no side effects and of reasonable expense, so that patients may maintain a normal lifestyle (DiPiro et aI., 2002). One of the most frequent indications for which homoeopathic treatment is sought after is for respiratory allergies (Ramchandani, 2009). Thus it has been proposed that the remedies contained within Otirin Nasal Spray"; namely Allium cepa, Euphrasia officinalis, Luffa operculata and Sabadilla officinarummay be effective as a treatment for allergic rhinitis (Vermeulen, 2000). Otirin Nasal Spray" is a homoeopathic complex preparation indicated for allergic rhinitis. No specific research has been conducted on this product to determine its efficacy in this condition (Medford, 2008). The aim of this research study was to determine the efficacy of Otirin Nasal Spray" in the treatment of allergic rhinitis with regard to the severity Of symptoms; specifically on the symptoms relating to the nose, eyes, throat, mouth and ears. Diary cards and questionnaires were completed, making use of the severity of symptoms scores to grade the symptoms. This research study was a quantitative" double-blind, placebo-controlled study and included thirty participants suffering from AR. Participants volunteered to participate in the study, were over the age of eighteen and consented to the procedures of the research study. Participants involved in the study were randomly divided into a treatment (experimental) group and a control (placebo) group. The treatment group received the Otirin Nasal Spray'" as opposed to the control group who received the placebo nasal spray (saline nasal spray). The research study was conducted over a period of four weeks at the UJ Health Centre. Participants were instructed to complete an individual "Treatment Diary Card" (Appendix E) during each hayfever attack by scoring the severity of each symptom they suffered from. During the final consultation the "Response to Treatment Questionnaire" (Appendix F) was completed under the researcher's supervision. This questionnaire required participants to score an amelioration, aggravation, no change or not applicable for each symptom, as well as other associated symptoms. Results acquired from the research study were statistically analysed by Statkon at the University of Johannesburg by means of descriptive statistics, parametric and non-parametric tests. The parametric test included the Independent Samples TTest. Non-parametric tests included the Friedman Test, Wilcoxon Signed Rank, and Mann-Whitney U Test. This research study determined that the homoeopathically prepared Otirin Nasal Spray" did have a statistically significant effect in the treatment of allergic rhinitis symptoms. A trend towards a decrease in the severity of the participant's symptoms was observed, in particular for rhinorrhoea, sneezing, nasal blockage/congestion, pruritic/itchy eyes and postnasal drip.

M.Tech.
Allergic rhinitis is on the increase around the world affecting between 15-20% of the global population and is the most common chronic condition of children in South Africa. Luffeel® is a propriety complex homeopathic product manufactured by Biologische Heilmittel Heel. It is available in nasal spray and tablet form. These two forms are designed to work in combination with each other in the treatment of allergic rhinitis. The aim of this study is to determine the effect of a combination of Luffeel® nasal spray and Luffeel® tablets on allergic rhinitis using Phadiatop® tests, RAST Inhalant screens and subjective evaluation on symptoms such as nasal itching, sneezing, congestion, discharge, ocular redness and itching as indicators. This study was a double-blind, placebo-controlled study conducted at the University of Johannesburg, Doornfontein campus over a period of eight weeks. Thirty participants were recruited by poster advertisement. It can be concluded that Luffeel® nasal spray and Luffeel® tablets decrease the symptoms of allergic rhinitis, when compared to the placebo, thus giving persons suffering from allergic rhinitis an alternative treatment with no rebound or lethargic effects. It can also be concluded that this study that Luffeel® nasal spray and Luffeel® tablets has no significant effect on Phadiatop® and RAST inhalant screens over an eight week period. The results are inconclusive due to the small sample size and short time frame of the study.

Submitted in partial compliance with requirements for Master`s Degree in Technology: Homoeopathy, Durban University of Technology, Durban, South Africa, 2017.
Allergic rhinitis (AR) is a symptomatic disorder of the nose characterized by inflammation of the nasal mucosa. It consists of a group of disorders that are all typified by the presence of one or more of the following: nasal itching, congestion, sneezing and rhinorrhoea (Wallace et. al., 2008). Allergic rhinitis can result in decreased quality of life, decreased sleep quantity, obstructive sleep apnoea and impaired performance at work and school (Blaiss, 2010: 375-380). According to Small and Kim (2011) allergic rhinitis (AR) is the most common allergic condition and one of the most common of all minor afflictions. It affects between 10- 20% of all people in the United States, and the prevalence of the disorder is increasing. This may result in significant impairment to quality of life, sleep and work performance (Small and Kim 2011). A therapeutic goal for patients suffering from allergic rhinitis is to prevent or minimise symptoms, using treatment with minimal effects or no side effects and of reasonable expenses, so that patients may maintain a normal life style (DiPiroet al.2002). Homoeopathy is a complete system of medicine developed by German physician and chemist, Dr Samuel Hahnemann (1755-1843). It is based on the following theories, first the doctrine of signature that disease is curable by those drugs which produce effect on the body similar to the symptoms of the disease “similia similibus currantur”; second that the effects of the drug are increased by giving it in a minute dose, which is obtained by dilution or trituration to an extreme limit and thirdly the notion that chronic disease are only manifestation of suppressed itch or psora (Ernst 2016). Similasan Nasal Allergy Relief Spray® is commercially available as a homoeopathic nasal spray. It is based on the principle of "let likes cure likes" or the Law of Similars. According to the company, this product is 100% natural, and contains active ingredients with non-drowsy effects which relieves allergic congestion, itching and runny nose, and it is preservative free (Similasan Corporation 1999-2015). Similasan Nasal Allergy ReliefSpray® mist gently stimulates the body's natural ability to relieve allergic congestion, itchy, runny nose and rhinitis caused by pollen, pet dander, dust and mould spores. Furthermore, the Similasan Nasal Allergy ReliefSpray® mists is non-habit forming and will not cause reliance or a rebound effect. The ingredients are: Cardiospermum 6X, Galphimiaglauca 6X, Luffa operculata 6X, Sabadilla 6X (SimilasanCoorporation 1999-2015). The aim of this double-blind randomised controlled study is to determine the efficacy of the homoeopathic Similasan Nasal Allergy Relief Spray® in the management of allergic rhinitis. Outcomes were monitored using questionnaires and a daily log book. This was a quantitative study which included thirty participants suffering from allergic rhinitis. Participants volunteered to participate in the study, were over the age of eighteen and consented to the procedure of the study. Participants involved in the research study were randomly divided into treatment group and placebo group. The treatment group received Similasan Nasal Allergy Relief Spray® and the placebo group received a saline nasal spray. The research study was conducted over a period of four weeks at the Durban University of Technology Homoeopathic Day Clinic. Participants were instructed to rate their symptoms before, during and after taking treatment (Appendix, C and D). The parametric test used in this study was Independent Samples T- Test. Non-parametric tests included ANOVA and Pearson chi-square. Rhinorrhoea, sneezing, itching of the eyes and nasal congestion showed a statistically significant results but some of the participant’s symptoms deteriorated after a period of improvement. This research determined that Similisan Nasal Allergy Relief Spray ® didn’t have a significant effect in treating allergic rhinitis in terms of the CARAT questionnaire.
M

碩士
國立臺灣大學
農藝學研究所
96
In order to evaluate bioequivalence between the generic and innovator investigate the equivalence in characteristics between the generic and innovator nasal aerosols. Because the nasal aerosols only act locally and its active ingredient does not absorb into the body system, therefore in vivo bioequivalence studies are replaced by the in vitro bioequivalence studies using machinery experiment to avoid variability caused the factors much that volume of breath. The quality of nasal aerosols and sprays can be characterized by spray patterns, droplet size distribution and plume geometry. The 2003 US FDA draft guidance proposed the application of population bioequivalence to evaluate the in vitro bioequivalence between the generic and innovator nasal aerosols and sprays. Such analysis is referred to as the nonprofile analysis. We applied the statistical methods of in vitro bioequivalence in the US FDA guidance to a dataset of droplet size distribution. We also compare and discuss the results obtained under the 2-stage nested random-effects model and the model suggested in the 2003 US FDA draft guidance.

This research studied the effects of evaporative spray cooling on air-air ejector performance. Experimental data was collected for the purpose of validating computational simulations. This was done by modifying an existing air-air ejector to accommodate four spray flow nozzles which were used to atomize cooling water. The only parameter that was varied throughout the study was the mass flow rate of cooling water. One single phase (air) case and four spray flow cases where performed and analyzed. The purpose of the single phase experiment was to have a baseline for the air-air ejector performance and isolate the sources of experimental error contributed by spray flow. Three specialized multiphase flow instruments were designed and fabricated by the author to measure, gas phase temperatures, spray mass flow rates, and mixture total pressures. A computational study was performed using the collected experimental data for inlet continuous phase and spray mass flow as boundary conditions for equivalent simulations. A temperature gradient modified turbulence model was written by the author to better predict the mixing rates found experimentally which was used for the duration of this research. Secondary droplet breakup was modeled by the author using empirical correlations following preliminary simulations recognizing the deficiencies of commercially available breakup models. Comparison of experimental and computational cases produced mixed results. It was found that the experimental gas temperature instrument performed poorly for the local droplet fluxes encountered during testing. The spray sampling probe showed more promising results with two integrated mass flows agreeing within 6% of computational simulations. The total pressure probe solved the issue of pressure port clogging, but measurements were representative of mixture density which made an inferred velocity calculation difficult. It was found that evaporation of spray flow before the nozzle exit plane caused a reduction in dynamic pressure and a reduction in back pressure. A full scale simulation was performed to determine the effects of scaling on evaporative spray cooling performance. It was found that for the geometrically similar full scale model, the total droplet surface area and particle residence times scaled up with the model which increased cooling performance.
Thesis (Master, Mechanical and Materials Engineering) -- Queen's University, 2011-05-18 14:47:50.52

Tese de mestrado, Engenharia Farmacêutica, Universidade de Lisboa, Faculdade de Farmácia, 2018
The Pharmaceutical industry is increasingly investing in biopharmaceuticals. Moreover, alternative delivery routes are being investigated over the conventional parenteral administration route, which presents several inconveniences for the patients including discomfort, pain and the impossibility of self-administration in the majority of cases. Thus, pulmonary and nasal delivery are emerging as alternative administration routes for the treatment of systemic diseases and administration of biopharmaceuticals, both allowing a rapid absorption and onset of therapeutic action. Additionally, nasal route allows nose-to-brain delivery through the olfactory neuroepithelium. The present thesis is divided into two main studies. The first one aimed at the optimization of a Spray Drying (SD) Process using an Ultrasonic Nozzle (USN) 1 to produce dry powder inhalers (DPI) with a particle size between 1 and 5 μm. Although the physical characterization was within the expected for a DPI formulation of excipient A:excipient B (4:1), the aim of this study was not completely achieved since to obtain a powder with a particle size within the inhalable size range, the SD process would require extremely diluted feed solutions, leading to long run times. Thus, the optimization of the SD process was not possible. The second study aimed at the assessment of a SD process with a Two-Fluid Nozzle (TFN) and a USN 3 to produce nasal dry powder formulations with a small molecule as a model Active Principle Ingredient (API) and, ultimately, with an API with medical application through nasal route. A design of experiments was performed for each nozzle to assess which one proves to be the best candidate to produce dry powders for nasal delivery. The excipients chosen, excipient A and excipient C, proved to be suitable for dry nasal delivery with potential compatibility with biopharmaceuticals allowing its future delivery though this route. All powders were amorphous and had a particle size within the nasal size range of 10 – 45 μm. The aerodynamic performance showed a correlation between the powders particle size distribution (PSD) and the fraction retained in the nasal cavity. When comparing powders with the same volumetric median particle size (Dv50), the powder with a narrower PSD (lower value of span) was the one that presented a lower percentage of powder retained in the gastrointestinal tract and respiratory system. Thus, although the TFN could be used at a first screening phase, the USN 3 is the preferable atomizing system since it produces powders with a significant narrower PSD therefore maximizing deposition on the nasal area and minimizing the fraction of powder with potential to reach the deep lungs. Ultimately, this thesis showed the importance of the technology selected to produce dry powder formulations intended for nasal delivery since it could have impact on the deposition profile of the powders.
Atualmente, a indústria Farmacêutica tem vindo a investir cada vez mais na investigação e produção de biofármacos. Estas macromoléculas são, na maioria dos casos, administradas por via parenteral (intravenosa, intramuscular ou subcutânea). Contudo, têm vindo a ser investigadas vias de administração alternativas à parenteral pois esta apresenta vários inconvenientes para os pacientes, nomeadamente desconforto, dor e impossibilidade de autoadministração na maioria dos casos. Assim, vias de administração como a pulmonar e nasal surgem como alternativas para o tratamento de doenças sistémicas e para administração de biofármacos, permitindo uma rápida absorção e início da ação terapêutica. Adicionalmente, a via nasal permite a administração direta de fármacos para o sistema nervoso central através do neuroepitélio olfativo. A presente tese encontra-se dividida em dois estudos. O primeiro visou a otimização de um processo de secagem por atomização usando um atomizador ultrassónico 1 (USN) para produzir inaladores de pó seco (DPI) com um tamanho de partícula adequado para inalação, entre 1 e 5 μm. Embora para uma formulação de DPI de excipiente A:excipiente B (4:1) a caracterização física estivesse dentro do esperado, o objetivo deste estudo não foi completamente atingido uma vez que não foi possível otimizar o processo de secagem por atomização. Para obter um pó com tamanho de partícula dentro da gama de inalação, o processo de secagem exigiria soluções de alimentação extremamente diluídas, levando a experiências extremamente longas. Por outro lado, este processo apresentou baixa rentabilidade. Estas foram as principais razões pelas quais a presente tese mudou o foco da otimização de um processo de secagem por atomização visando a produção de inaladores de pó seco para administração pulmonar para a otimização de um processo para produção de pós para administração nasal. O segundo estudo teve como objetivo a comparação de dois sistemas de atomização (atomizador de dois fluidos e atomizador ultrassónico 3) para produzir formulações nasais de pó seco com uma molécula de síntese química modelo como princípio ativo e, numa última fase, com um princípio ativo com aplicação médica por via nasal. Para o atomizador de dois fluidos, de forma a comparar as propriedades dos pós obtidos, foi realizado um desenho de experiências onde os parâmetros variados foram a composição da formulação e o caudal de atomização. Para as variáveis, dois níveis foram estabelecidos. Dentro da formulação, a concentração de princípio ativo Y foi mantida constante a 0,01 %, o excipiente A variou entre 20,00 e 50,00% e o excipiente C entre 49,99 e 79,99 %. O nível mínimo de excipiente A foi definido com base na concentração mínima necessária para estabilizar a Cu, Zn-superóxido dismutase. Adicionalmente, a menor concentração do excipiente C foi estabelecida com base na suposição de que o aumento do tempo de residência da formulação na cavidade nasal é particularmente favorável quando a administração de macromoléculas é necessária. Em termos de parâmetros do processo, o caudal de atomização (Fatom) variou entre 0,27 × Fatom_ref e 0,43 × Fatom_ref, sendo que os restantes parâmetros foram mantidos constantes nas cinco condições estudadas. Um estudo com o atomizador ultrassónico 2 foi realizado visando uma primeira comparação entre as propriedades de pós produzidos por um atomizador de dois fluidos e um atomizador ultrassónico. A formulação escolhida apresentou o princípio ativo Y numa concentração de 0,01 %, o excipiente A a 20,00 % e o excipiente C a 79,99 %. Apesar do pó produzido ter apresentado um Dv50 fora da gama para administração nasal (47 μm), foi possível concluir que este tipo de atomizador produz pós com uma distribuição de tamanho de partículas mais estreita em comparação com o atomizador de dois fluidos, sendo a principal vantagem deste sistema de atomização. Para o atomizador ultrassónico 3, semelhante ao estudo realizado com o atomizador de dois fluidos, foi realizado um desenho de experiências onde os parâmetros variados foram a composição da formulação e o caudal de alimentação, de modo a comparar as propriedades dos pós obtidos e, em última análise, estabelecer o melhor sistema de atomização para a produção de pós para administração nasal. Para as variáveis, dois níveis foram estabelecidos. Dentro da formulação, a concentração do princípio ativo Y foi mantida constante a 0,01%, o excipiente A variou entre 20,00 - 50,00% e o excipiente C entre 49,99 - 79,99%. Em termos de parâmetros do processo, o caudal de alimentação (Ffeed) variou entre 0,53 × Ffeed_ref e 0,67 × Ffeed_ref, sendo que os restantes parâmetros foram mantidos constantes nas cinco condições estudadas. Todos os pós produzidos estavam num estado amorfo e apresentavam um tamanho de partícula dentro da gama para administração nasal, entre 10 a 45 μm. Comparando os pós produzidos com o atomizador de dois fluidos e com o atomizador ultrassónico 3, podemos concluir que os primeiros apresentaram uma diferença significativa no tamanho médio volumétrico de partícula (Dv50) consoante o valor estabelecido de caudal de atomização. Assim, quando o caudal de atomização foi maior (0,43 × Fatom_ref), o Dv50 foi menor (11 μm) e vice-versa. Contudo, o mesmo não foi observado nos pós produzidos com o atomizador ultrassónico 3, uma vez que o Dv50 apenas variou entre 37,1 e 40,4 μm para a gama de caudal de alimentação estabelecida (0,53 × Ffeed_ref a 0,67 × Ffeed_ref), sugerindo que a mesma deveria ter sido maior, de forma a que houvessem diferenças significativas no Dv50. O desempenho aerodinâmico in-vitro dos pós foi avaliado utilizando um Impactador em cascata de Andersen reduzido equipado com uma câmara de expansão de vidro de 5 L. Apenas três estágios foram utilizados: 0, 2 e F. O estágio 0 retém as partículas com tamanho de partícula aerodinâmico superior a 9,0 μm, enquanto que os estágios 2 e F retêm partículas com um tamanho de partícula aerodinâmico entre 4,7 a 9,0 μm e 0,4 a 4,7 μm, especificando a fração da dose emitida que pode ser retida nas passagens intranasais, no trato gastrointestinal e nos pulmões, respetivamente. O desempenho aerodinâmico mostrou uma correlação entre a distribuição do tamanho de partículas dos pós e a fração retida na cavidade nasal (R2 = 0,982; Q2 = 0,965). Adicionalmente, o valor do span foi considerado o fator crítico para este desempenho, na medida em que comparando pós com o mesmo Dv50, quanto mais estreita a distribuição do tamanho de partículas, menor a fração que atinge o trato gastrointestinal e o sistema respiratório. Assim, embora o atomizador de dois fluidos possa ser utilizado numa primeira fase de desenvolvimento, o atomizador ultrassónico 3 é o sistema de atomização preferível, pois produz pós com uma distribuição de tamanho de partículas mais estreita, maximizando a deposição na área nasal e minimizando a fração de pó com potencial para atingir os pulmões. Tendo como objetivo a produção de um pó com relevância médica para administração nasal (princípio ativo Z, indicado no tratamento de enxaquecas agudas), um último estudo foi realizado nas melhores condições de processo obtidas com o atomizador de dois fluidos. A formulação apresentou 1,0 % de princípio ativo Z e 99,0 % de excipiente C como agente mucoadesivo. O pó obtido apresentou-se num estado amorfo, tendo um Dv50 de 20 μm. Em termos de performance aerodinâmica, o pó apresentou uma fração retida no estágio 0 (cavidade nasal) de 92,0% e uma fração inferior a 3,0% nos estágios 2 e F (trato gastrointestinal e pulmões, respetivamente). Por fim, esta tese mostrou a importância da tecnologia selecionada para produzir formulações de pó seco destinadas a administração nasal, uma vez que a mesma poderá ter impacto no perfil de deposição dos pós produzidos.
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