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Développement et évaluation de formulations lipidiques à poudre sèche pour inhalationSebti, Thami 26 June 2006 (has links)
De nos jours, la voie inhalée constitue le mode d’administration optimal dans le traitement de nombreuses affections respiratoires, et suscite beaucoup d’intérêt pour la délivrance systémique de médicaments. Cependant, le poumon est un organe complexe doté de mécanismes de défense efficients qui limitent la déposition des particules inhalées et les éliminent très rapidement. Cette voie d’administration fait donc l’objet de programmes de recherche intensifs visant à améliorer l’efficacité de la délivrance et la compliance du patient. Il faut néanmoins signaler que le nombre d’excipients dont l’innocuité a été démontrée en inhalation (sous forme de poudre sèche) reste extrêmement limité à l’heure actuelle. A cet égard, l’utilisation de microparticules lipidiques solides (mPLS), constituées d’un mélange de cholestérol et de phospholipides biodégradables et caractérisés par une température de transition de phase élevée, a été envisagée. Le procédé retenu pour la préparation de ces mPLS est la technique d’atomisation à température modérée (spray-drying).
Dans un premier temps, le travail a consisté à mettre au point les conditions opératoires de fabrication (température et débit de l’air d’entrée et de sortie, débit de pulvérisation, pression et température de l’air de pulvérisation, etc.) ainsi que les paramètres de formulation (proportions de cholestérol / phospholipides / principe actif (PA)) afin d’obtenir de manière reproductible des microparticules présentant les caractéristiques appropriées pour une délivrance pulmonaire.
Deux types de formes ont été développés :
Une forme à poudre sèche dite conventionnelle (mélange physique PA-excipient). Les particules cohésives de PA sont mélangées au transporteur lipidique en vue d’améliorer leurs propriétés d’écoulement et de favoriser leur redispersion lors de l’inhalation.
Une forme matricielle permettant également d’améliorer les propriétés d’écoulement et de dispersion, mais qui à la différence de la forme précédente ne nécessite pas d’étape de mélange. Elle consiste à incorporer le PA dans la masse lipidique. Dans ce cas-ci, l’utilisation de tels excipients a pour effet de modifier les propriétés de dissolution du PA et donc de contrôler sa vitesse de libération.
Ensuite, les caractéristiques physico-chimiques des mPLS ont été évaluées. Celles-ci comprenaient aussi bien la taille et la distribution de taille (analyse granulométrique par diffraction laser) que la forme (analyse par microscopie électronique à balayage) et la densité des particules produites (analyse par tassement). Ont suivi les évaluations de l’état physique (polymorphisme) et des propriétés thermiques par calorimétrie à balayage différentiel et par diffraction aux rayons X. Le procédé de micronisation par atomisation a permis d’obtenir des microparticules sphériques de structure homogène dont la surface apparaît comme parfaitement lisse et régulière. Les mPLS, et plus particulièrement les formulations matricielles, se caractérisent par des densités relativement faibles et de bonnes propriétés d'écoulement.
Les performances d’aérosolisation ont été étudiées au moyen de l’impacteur en verre et de l’impacteur liquide multi-étages. Les mPLS présentent un comportement aérodynamique remarquable ; les fractions pulmonaires (FP) sont significativement supérieures à celles des produits de référence (Pulmicortâ Turbohalerâ 200 µg et Flixotide® Diskusâ 250 µg) ainsi qu’à celles d’autres formulations conventionnelles délivrées via le même dispositif d’inhalation (Aeroliserâ). Puis, une étude de stabilité a été réalisée sur les formulations dont les propriétés satisfaisaient à nos exigences. Il en ressort que les mPLS conservent leurs caractéristiques initiales pour autant que les conditions de stockage ne dépassent pas les 30°C/65% HR.
Dans le cadre de l’optimisation du processus de mélange de poudres à PA cohésif et faiblement dosé (destinées à une inhalation sous forme de poudre sèche), une étude a porté sur l’influence vis à vis de l’homogénéité du mode d’action et des caractéristiques de trois types de mélangeurs fréquemment employés pour effectuer des mélanges solides pulvérulents :
un mélangeur à cuve mobile de type Turbula®, un mélangeur planétaire (Colette MP-20®) et un mélangeur-granulateur à haute vitesse (Mi-Pro®). Il a été démontré, par après, que les mélanges physiques PA-excipients lipidiques s’effectuent de façon efficace dans les conditions opératoires fixées.
Finalement, une étude pharmaco-scintigraphique a été menée à l’Hôpital Erasme sur six volontaires sains. Les résultats de déposition pulmonaire sont en parfaite corrélation avec les valeurs de FP observées in vitro. En revanche, les résultats de l’analyse pharmacocinétique ne sont pas assez concluants pour mettre en évidence la régulation de la cinétique de libération du PA à partir des formes matricielles.
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Engineering of particles for inhalationPitchayajittipong, Chonladda January 2008 (has links)
Current pharmaceutical engineering for the manufacture of binary and combined dry powder inhaler (DPI) dosage forms relies on destructive strategies such as micronisation to generate respirable drug particles. Such processes are inefficient and difficult to control to produce particles of defined quality and functionality for inhaled drug delivery, which can affect drug product performance throughout the shelf-life of the product. Furthermore, owing to current pharmaceutical manufacturing practises of combined inhalation products, these products are subject to greater variability in dose delivery of each active, which may be perpetuated as a function of product storage conditions and limit clinical efficacy of the drug product. Hence, there is a requirement of processes that may enable production of binary and combination DPI products that will allow actives to be delivered more efficiently and independently of dose variations. The aim, therefore, of this study was to develop the solution atomisation and crystallisation by sonication (SAX) process for engineering of single and combination drug particles with suitable physicochemical properties for delivery to the lungs. The SAX process consists of key stages, which include, solution atomisation to produce aerosol droplets, generation of highly supersaturated droplets by evaporation of carrier solvent from aerosol droplet, collection of droplets in a crystallisation vessel containing appropriate non-solvent and the application of ultrasonic waves to the crystallisation vessel. Atomisation of a 1.5% w/v solution of budesonide in dichloromethane resulted in particles with defined surface geometry, which were formulated in binary dry powder inhaler (DPI) formulations and assessed using the next generation impactor.
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Detecting SQL Injection Attacks in VoIP using Real-time Deep Packet Inspection : Can a Deep Packet Inspection Firewall Detect SQL Injection Attacks on SIP Traffic with Reasonable Performance?Sjöström, Linus January 2019 (has links)
The use of the Internet has increased over the years, and it is now an integral part of our daily activities, as we often use it for everything from interacting on social media to watching videos online. Phone calls nowadays tend to use Voice over IP (VoIP), rather than the traditional phone networks. As with any other services using the Internet, these calls are vulnerable to attacks. This thesis focus on one particular attack: SQL injection in the Session Initial Protocol (SIP), where SIP is a popular protocol used within VoIP. To find different types of SQL injection, two classifiers are implemented to either classify SIP packets as "valid data" or "SQL injection". The first classifier uses regex to find SQL meta-characters in headers of interest. The second classifier uses naive Bayes with a training data set to classify. These two classifiers are then compared in terms of classification throughput, speed, and accuracy. To evaluate the performance impact of packet sizes and to better understand the classifiers resiliance against an attacker introducing large packets, a test with increasing packet sizes is also presented. The regex classifier is then implemented in a Deep Package Inspection (DPI) open-source implementation, nDPI, before being evaluated with regards to both throughput and accuracy. The result are in favor of the regex classifier as it had better accuracy and higher classification throughput. Yet, the naive Bayes classifier works better for new types of SQL injection that we do not know. It therefore argues that the best choice depends on the scenario; both classifiers have their strengths and weakness!
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Bildupplösning inom digitaltryck : - Var går gränsen för en fullgod bildkvalitet?Nilsson, Sandra, Lundmark, Camilla January 2007 (has links)
Examensarbetet har gjorts utifrån Arkitektkopia AB:s vägnar för att undersöka gränsvärden för bildupplösning inom digi-taltryck med bibehållen bildkvalitet. Detta för att om möjligt höja produktionshastigheten då en lägre bildupplösning ger en mindre filstorlek som går fortare att cmykseparera i RIP:en. Dessutom behövde Arkitektkopia AB en korrigering och uppdatering av sin dåvarande tabell för kundrekommendationer beträffande bildupplösning för olika format och betrakt-ningsavstånd. En visuell undersökning med Arkitektkopias kunder och privatpersoner har gjorts för att kunna fastställa riktvärden för bildupplösning och utröna toleransen för en godtagbar bildkvalitet. Resultaten utifrån kundundersökningen har legat till grund för den nya tabellen med kundrekommendationer som examensarbetet resulterat i. Undersökningen omfattade tre provgrupper i formaten A4, 70x100cm och 70x100cm (motsv. 135x180cm) med betrakt-ningsavstånden 30cm, 2m och 5m. Dessutom innefattade de tre provgrupperna två olika typer av bildmotiv. Endast färg-bilder ingick i undersökningen.Resultaten utifrån undersökningen visar på att bildupplösningen kan sänkas avsevärt jämfört med tidigare kundrekommen-dationer. Störst variationer återfanns för formatet A4 med ett betraktningsavstånd på 30cm (läsavstånd). Där var toleransen för en godtagbar bildkvalitet något högre för privatpersonerna än för kundgruppen.
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Optimizing finite automata for DPI enginesThyago Antonello, Rafael 31 January 2012 (has links)
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Previous issue date: 2012 / Nos últimos 40 anos a Internet se tornou um componente central para o comércio
eletrônico internacional, comunicações, e para o desenvolvimento técnico e científico.
Inicialmente as pesquisas relacionadas à Internet se focavam em melhoramentos na
velocidade de transmissão de dados, capacidade e cobertura geográfica. Atualmente
medição, modelagem e análise em redes de computadores, particularmente classificação de
tráfego, tornaram-se um ponto crucial para manutenção do funcionamento da rede. Isto se
deve principalmente ao crescimento exponencial das redes de computares em termos de
tamanho, complexidade e diversidade de serviços. Neste contexto, sistemas de Deep Packet
Inspection (DPI) se tornaram um elemento importante para medição de tráfego, já que
classificação de aplicações baseada em portas caiu em desuso devido ao tunelamento de
protocolos e uso indevido de portas padrões, por exemplo, softwares P2P que usam portas
não bloqueadas para burlar regras de firewalls. Tradicionalmente, sistemas de DPI
classificavam tráfego usando técnicas de string matching, i.e., as assinaturas de aplicações
eram representadas por strings (cadeias de caracteres). Dessa maneira o procedimento de
busca de padrões se dava através da inspeção da carga útil dos pacotes a procura dessas
strings. String matching funciona bem para padrões simples, porém falha ao descrever padrões
mais complexos, e.g., padrões com tamanho variável. Para solucionar este problema,
sistemas de DPI têm substituído assinaturas representadas com strings por padrões descritos
através de expressões regulares. Embora mais precisos, sistemas de DPI demandam maior
poder computacional e geralmente não escalam bem conforme as velocidades dos enlaces
aumentam. Este fato abriu espaço para várias pesquisas relacionadas à otimização de tais
sistemas. Aproveitando este espaço, esta tese propõe um novo modelo de Deterministic Finite
Automata (DFA) para casamento de padrões em sistemas DPI, o Ranged Compressed DFA
(RCDFA). O RCDFA, junto com três otimizações propostas, atingem níveis de
compressão de até 98% em bases de assinaturas bem conhecidas. Além do mais, o RCDFA
codificado com um novo layout de memória (ALE) proposto neste trabalho é até 46 vezes
mais rápido que os motores de DPI baseados em DFAs tradicionais
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Detekce a analýza přenosů využívajících protokoly SSL/TLS / Traffic detection and analysis using SSL/TLSHutar, Jan January 2017 (has links)
This diploma thesis deals with a detection and analysis of secure connections of electro- nic communication through SSL/TLS protocols. The thesis begins with introduction to SSL/TLS protocols. Thereafter, an analysis of messages used to establish secure con- nections using STARTTLS and postal protocols SMTP, POP3, and IMAP was made. Metadata detection and extraction of secured simplex and duplex connections take place using deep packet inspection tools. The tool of choice is the nDPI library from the Ntop project. The library was extended to detect the connections and extract the metadata based on studies and analysis of transmitted messages. Finally, testing is performed on a training data set and a basic analysis of acquired metadata is made.
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OPTIMIZING NASAL CANNULAS FOR INFANTS USING COMPUTATIONAL FLUID DYNAMICSEl-Achwah, Ahmad, Mr. 01 January 2019 (has links)
Aerosolized medications can potentially be delivered to the lungs of infants through a nasal cannula interface. However, nose-to-lung delivery technologies currently allow for ~1% of the loaded dose to reach an infant’s lungs. Conventional dry powder inhalers (DPI) are superior to other types of inhalers in many ways. However, passive DPIs that operate based on user inhalation and require large volumes of airflow are not applicable to infants. To overcome this challenge, positive pressure DPIs have been developed that enable aerosol delivery to infants. Unless an adequate nasal interface is used with these devices, a significant amount of drug will still be lost. Computational fluid dynamics (CFD) provide a method to assess the performance of a nasal cannula interface and optimize its performance. In this study, a CFD model was first experimentally validated using the low-Reynolds number k-ω turbulence model, then used to assess and optimize several conical diffuser cannula designs for infants. The performance of a cannula depends primarily on two requirements: the amount deposited particles and the cannula’s volume. It was found that 90 and 100 mm long simple diffusers achieved the necessary deposition and volume requirements when operated at 3 and 5 liters per minute, respectively. Additionally, including clean sheath co-flow air with the 70 mm long diffuser achieved the targeted performance requirements. Inclusion of recent advancements in the field with the recommended cannula designs is likely to improve pharmaceutical aerosol delivery to infants using the nose-to-lung approach.
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La modélisation de l’immunité des circuits intégrés au-delà de 1 GHz / Integrated circuit immunity modelling beyond 1 GHzOp 'T Land, Sjoerd 20 June 2014 (has links)
La compatibilité électromagnétique (CEM) est l'aptitude des produits électroniques à coexister au niveau électromagnétique. Dans la pratique, c'est une tâche très complexe que de concevoir des produits compatibles. L'arme permettant de concevoir des produits bon-du-premier-coup est la modélisation. Cette thèse étudie l'utilité et la faisabilité de la modélisation de l'immunité des circuits intégrés (CI) au-delà de 1 GHz. Si les pistes des circuits imprimés déterminent l'immunité rayonnée de ces circuits, il serait pertinent de pouvoir prévoir l'efficacité de couplage et de comprendre comment elle découle du routage des pistes. Les solveurs full-wave sont lents et ne contribuent pas à la compréhension. En conséquence, un modèle existant (la cellule de Taylor) est modifié de manière à ce que son temps de calcul soit divisé par 100. De plus, ce modèle modifié est capable de fournir une explication de la limite supérieure pour le couplage d'une onde plane, rasante et polarisée verticalement vers une piste de plusieurs segments, électriquement longue et avec des terminaisons arbitraires. Les résultats jusqu'à 20 GHz corrèlent avec des simulations fullwave à une erreur absolue moyenne de 2,6 dB près et avec des mesures en cellule GTEM (Gigahertz Transversale Electromagnétique) à une erreur absolue moyenne de 4,0 dB près. Si l'immunité conduite des CI est intéressante au-delà de 1 GHz, il faut une méthode de mesure, valable au-delà de 1 GHz. Actuellement, il n'y a pas de méthode normalisée, car la fréquence élevée fausse les observations faites avec la manipulation normalisée. Il est difficile de modéliser et de compenser le comportement de la manipulation normalisée. Par conséquent, une manipulation simplifiée et sa méthode d'extraction correspondante sont proposées, ainsi qu'une démonstration du principe de génération automatique de la carte d'essai utilisée dans la manipulation simplifiée. Pour illustrer la méthode simplifiée, l'immunité conduite d'un régulateur de tension LM7805 est mesurée jusqu'à 4,2 GHz. À part la tendance générale des fréquences qui montent, il y a peu de preuve concrète qui étaye la pertinence de la modélisation de l'immunité conduite des CI au-delà de 1 GHz. Une simulation full-wave suggère que jusqu'à 10 GHz, la plus grande partie de l'énergie rentre dans la puce à travers la piste. Par concaténation des modèles développés ci-dessus, l'immunité rayonnée d'une piste micro-ruban et d'un régulateur de tension LM7805 est prédite. Bien que ce modèle néglige l'immunité rayonnée du CI lui-même, la prédiction corrèle avec des mesures en cellule GTEM à une erreur absolue de 2,1 dB en moyenne. Ces expériences suggèrent que la plus grande partie du rayonnement entre dans un circuit imprimé à travers ses pistes, bien au-delà de 1 GHz. Dans ce cas, la modélisation de l'immunité conduite au-delà de 1 GHz serait utile. Par conséquent, l'extension jusqu'à 10 GHz de la méthode de mesure CEI 62132-4 devrait être considérée. De plus, la vitesse et la transparence du modèle de Taylor modifié pour le couplage champ-à-ligne permettent des innovations dans la conception assistée par l'ordinateur. La génération semiautomatique des cartes d'essais dites maigres pourrait faciliter l'extraction des modèles. Certaines questions critiques et importantes demeurent ouvertes. / Electromagnetic Compatibility (EMC) is the faculty of working devices to co-exist electromagnetically. In practice, it turns out to be very complex to create electromagnetically compatible devices. The weapon to succeed the complex challenge of creating First-Time-Right (FTR) compatible devices is modelling. This thesis investigates whether it makes sense to model the conducted immunity of Integrated Circuits (ICs) beyond 1 GHz and how to do that. If the Printed Circuit Board (PCB) traces determine a PCB's radiated immunity, it is interesting to predict their coupling efficiency and to understand how that depends on the trace routing. Because full-wave solvers are slow and do not yield understanding, the existing Taylor cell model is modified to yield another 100 times speedup and an insightful upper bound, for vertically polarised, grazing-incident plane wave illumination of electrically long, multi-segment traces with arbitrary terminal loads. The results up to 20 GHz match with full-wave simulations to within 2.6 dB average absolute error and with Gigahertz Transverse Electromagnetic-cell (GTEM-cell) measurements to within 4.0 dB average absolute error. If the conducted immunity of ICs is interesting above 1 GHz, a measurement method is needed that is valid beyond 1 GHz. There is no standardised method yet, because with rising frequency, the common measurement set-up increasingly obscures the IC's immunity. An attempt to model and remove the set-up's impact on the measurement result proved difficult. Therefore, a simplified set-up and extraction method is proposed and a proof-of-concept of the automatic generation of the set-up's PCB is given. The conducted immunity of an LM7805 voltage regulator is measured up to 4.2 GHz to demonstrate the method. Except for a general trend of rising frequencies, there is only little concrete proof for the relevance of IC immunity modelling beyond 1 GHz. A full-wave simulation suggests that up to 10 GHz, most energy enters the die via the trace. Similarly, the radiated immunity of a microstrip trace and an LM7805 voltage regulator is predicted by concatenating the models developed above. Although this model neglects the radiated immunity of the IC itself, the prediction corresponds with GTEM-cell measurement to within 2.1 dB average absolute error. These experiments suggest the most radiation enters a PCB via its traces, well beyond 1 GHz, hence it is useful to model the conducted immunity of IC beyond 1 GHz. Therefore, the extension of IEC 62132-4 to 10 GHz should be seriously considered. Moreover, the speed and transparency of the modified Taylor model for field-to-trace coupling open up new possibilities for computer-aided design. The semi-automatic generation of lean extraction PCB could facilitate model extraction. There are also critical remaining questions, remaining to be answered.
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Ex vivo and in vitro evaluation of the influence of the inhaler device and formulation on lung deposition of budesonideAloum, Fatima, Al Ayoub, Yuosef, Mohammad, Mohammad A., Obeed, Muthana, Paluch, Krzysztof J., Assi, Khaled H. 10 August 2020 (has links)
Yes / Two different types of dry powder inhalers (Easyhaler® and RS01®) were used in this work to evaluate the ex vivo and in vitro performance of a budesonide inhaled formulation with recrystallised mannitol, commercial DPI-grade mannitol, or lactose. The aerodynamic performance of the budesonide formulation with recrystallised mannitol was superior when RS01® was used (FPF = 45.8%) compared to Easyhaler® (FPF = 14%). However, the aerodynamic profile was very poor in both devices when commercial mannitol was used. Interestingly, the aerosol performance of the marketed budesonide formulation significantly improved when RS01® was used compared to Easyhaler® (the original device for the formulation). Due to the significant increases in the surface energy of the commercial mannitol formulation, the aerodynamic performance of the formulation was very poor. This work demonstrates the impact of inhaler devices on the performance of inhaled formulations and considers the particle surface energy during formulation development.
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Dry Powders Inhalers (DPI) obtidos a partir de nanocápsulas de núcleo lipídico contendo budesonida : caracterização, avaliação in vivo em modelo animal de asma e da toxicidade in vitro em cultura celularOrtiz, Manoel January 2016 (has links)
A asma é definida como uma doença inflamatória crônica de caráter multifatorial, caracterizada pela obstrução reversível das vias aéreas, denso infiltrado inflamatório e hiper-reatividade brônquica a estímulos externos. Clinicamente, a doença é marcada por sintomas episódicos de dispneia, sibilo, tosse seca e sensação de aperto no peito. A terapia convencional da asma compreende o uso de anti-inflamatórios e broncodilatadores. A budesonida é um glicocorticoide esteroide e é dos fármacos mais utilizados na terapêutica da asma. No entanto, a budesonida apresenta baixa biodisponibilidade oral e o uso prolongado pode levar a efeitos adversos graves como afinamento da pele e supressão adrenocortical. No desenvolvimento de novas formulações, a avaliação da toxicidade é de extrema importância. Por conseguinte, o uso de cultura celular é de grande valia no desenvolvimento de protocolos para avaliação da toxicidade de novas formulações. Adicionalmente, a nanotecnologia é uma ferramenta importante para resolver problemas de biodisponibilidade e para contornar efeitos adversos da terapêutica convencional. Desta forma, o objetivo desta tese foi desenvolver um novo sistema nanoestruturado na forma de pó seco para inalação (Dry powders inhalers – DPI), obtido por aspersão contendo budesonida encapsulada, visando o tratamento da asma aguda e crônica. Essa proposta foi baseada na obtenção de um sistema pulverulento nanoestruturado com tamanho reduzido e controlado, visando a entrega pulmonar da budesonida. Na etapa de pré-formulação foi realizado um estudo fatorial avaliando diferentes métodos de preparação das nanocápsulas e os adjuvantes de secagem utilizados. As análises de tamanho de partícula, da formulação selecionada (nanocápsulas contendo budesonida e secas por aspersão com leucina) mostraram um tamanho reduzido e adequado para a administração pulmonar (2,7 μm). A morfologia demonstrou que estas partículas possuem um tamanho reduzido, forma esférica e superfície irregular, características importantes para a administração pulmonar. Quando analisada a distribuição pulmonar in vitro, em Impactador de Andersen, a formulação apresentou uma fração de partículas finas (Fine Particle Fraction – FPF) de 28%. Analisando os resultados dos experimentos em modelos de asma aguda e crônica induzidos por ovalbumina, os resultados da mecânica respiratória e função pulmonar mostraram uma diminuição na resistência e na elastância pulmonar, quando a budesonida nanoencapsulada foi utilizada, quando comparada com uma formulação comercial de budesonida, nas duas doses utilizadas (0,5 e 1,0 mg/Kg). Esse tratamento com nanocápsulas também mostrou eficiência na redução da inflamação, pela redução do número de leucócitos totais no fluido de lavagem bronco alveolar (Broncho Alveolar Lavage Fluid – BALF) e, principalmente, redução significativa no número dos eosinófilos no infiltrado pulmonar. Corroborando esses resultados, a quantificação da eotaxina – 1 e das citocinas pró-inflamatórias foram reduzidas, quando comparadas ao tratamento comercial. A análise histopatológica mostrou que quando o tratamento com as nanocápsulas foi utilizado, a produção de muco foi reduzida, bem como a produção de fibrose sub-epitelial, sugerindo um possível efeito sobre o remodelamento tecidual. Os resultados de toxicidade utilizando linhagem celular epitelial pulmonar (H441) mostrou uma redução na toxicidade da budesonida, quando encapsulada nas nanopartículas, tanto na forma de suspensão como na forma pulverulenta. Essa redução da toxicidade foi de 75% e de 50%, na dose de 100 μg/mL, para a suspensão e para o DPI, respectivamente. O conjunto dos resultados obtidos mostrou a potencial aplicabilidade da budesonida nanoencapsulada para o tratamento da asma, utilizando esse novo sistema DPI. / Asthma is characterized as a chronic inflammatory disease developed by multifactorial aspects such as genetic predisposition and exposure to environmental factors such as pollution, smoke and microorganisms. The conventional asthma therapy comprises the use of bronchodilators and anti-inflammatory. Budesonide is a glucocorticoid and is the most frequently used therapy in the treatment of asthma. However, this drug has low oral bioavailability and long term use may lead to adverse effects such as skin thinning and adrenal suppression. The evaluation of the toxicity of new formulation has critical role in the pharmaceutical development. The use of cell culture experiments can help this aspect. Additionally, nanotechnology is an important tool to solve problems regarding bioavailability and to circumvent adverse effects of conventional therapy. The aim of this work was to develop a nanostructured system as dry powder inhaler (DPI) containing budesonide loaded, obtained by spray-drying, targeting the treatment of acute and chronic asthma. This proposal was based on obtaining a nanostructured powder system with reduced and controlled size, aiming an alternative to treatment of asthma. A factorial study comparing different methods to produce the nanocapsules as well as the type of drying adjuvants was performed. The particle size of the selected formulation was 2.7 μm, an adequate reduced size suitable for pulmonary administration. The morphology of these particles showed a small size, spherical shape and irregular surface. All these characteristics are important for pulmonary administration. When analyzed the in vitro pulmonary distribution of the DPI, using an Andersen Cascade Impactor, showed a fine particle fraction (FPF) of 28%. Analyzing the results of the biological experiments, the mechanical respiratory and pulmonary function showed a decrease in lung elastance and resistance when budesonide was used nanoencapsulated compared with a commercial formulation of budesonide in two doses (0.5 and 1.0 mg / kg). Both treatments also showed nanocapsules efficiency in reduction of inflammation by reducing the total of leukocytes in the bronchial alveolar lavage fluid (BALF) and especially significant reduction in eosinophil infiltration in the lung tissue. Corroborating with these results, the quantification of eotaxin - 1 and proinflammatory cytokines was reduced when compared to commercial budesonide treatment. Histopathological analysis showed that when treatment with the nanocapsules was used, mucus production was reduced and reversed the phenomena of airway remodeling. The cytotoxicity assay by Alamar blue using the bronchial epithelium cell line (H441) showed a reduction on the toxicity of budesonide when the nanocapsules were used even in suspension or in the DPI. The cytotoxicity reduction were 75 and 50%, at 100 μg/mL, for the suspension and the DPI, respectively. All these results show that budesonide-loaded nanocapsules in dry powder inhaler is a promising approach for the treatment of asthma.
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