Development of composite particles for pulmonary delivery

In this work, biocompatible and biodegradable poly(D-L-lactide-co-glycolide) (PLGA) microparticles with the potential for use as a controlled release system of vaccines and other drugs to the lung were manufactured using supercritical CO2, through the Supercritical Assisted Atomization (SAA) technique. After performing a controlled variance in production parameters (temperature, pressure, CO2/solution flow ratio) PLGA microparticles were characterized and later used to encapsulate active pharmaceutical ingredients (API). Bovine serum albumin (BSA) was chosen as model protein and vaccine, while sildenafil was the chosen drug to treat pulmonary artery hypertension and their effect on the particles characteristics was evaluated. All the produced formulations were characterized in relation to their morphology (Morphologi G3 and scanning electronic microscopy (SEM)), to their physical-chemical properties (X-ray diffraction (XRD, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR)) and aerodynamic performance using an in vitro aerosolization study – Andersen cascade impactor (ACI) - to obtain data such as the fine particle fraction (FPF) and the mass median aerodynamic diameter (MMAD). Furthermore, pharmacokinetic, biodegradability and biocompatibility tests were performed in order to verify the particle suitability for inhalation. The resulting particles showed aerodynamic diameters between the 3 and 5 μm, yields up to 58% and FPF percentages rounding the 30%. Taken as a whole, the produced microparticles do present the necessary requests to make them appropriate for pulmonary delivery.

Massive shift in the pneumococcal nasopharyngeal flora after the 7-valent conjugate vaccine: epidemiological studies and testing pathogenic potential in animal models

Dissertation presented to obtain the PhD degree in Biology/Molecular Biology by Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica

Business development in Siemens global shared services delivery center Portugal

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

Drivers and barriers to value creation in mobile service delivery

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

Improved polymeric medical devices for active substances delivery

The work presented in this thesis was developed in collaboration with a Portuguese company, BeyonDevices, devoted to pharmaceutical packaging, medical technology and device industry. Specifically, the composition impact and surface modification of two polymeric medical devices from the company were studied: inhalers and vaginal applicators. The polyethylene-based vaginal applicator was modified using supercritical fluid technology to acquire self-cleaning properties and prevent the transport of bacteria and yeasts to vaginal flora. For that, in-situ polymerization of 2-substituted oxazolines was performed within the polyethylene matrix using supercritical carbon dioxide. The cationic ring-opening polymerization process was followed by end-capping with N,N-dimethyldodecylamine. Furthermore, for the same propose, the polyethylene matrix was impregnated with lavender oil in supercritical medium. The obtained materials were characterized physical and morphologically and the antimicrobial activity against bacteria and yeasts was accessed. Materials modified using 2-substituted oxazolines showed an effective killing ability for all the tested microorganisms, while the materials modified with lavender oil did not show antimicrobial activity. Only materials modified with oligo(2-ethyl-2-oxazoline) maintain the activity during the long term stability. Furthermore, the cytotoxicity of the materials was tested, confirming their biocompatibilty. Regarding the inhaler, its surface was modified in order to improve powder flowability and consequently, to reduce powder retention in the inhaler´s nozzle. New dry powder inhalers (DPIs), with different needle’s diameters, were evaluated in terms of internal resistance and uniformity of the emitted dose. It was observed that they present a mean resistance of 0.06 cmH2O0.5/(L/min) and the maximum emitted dose obtained was 68.9% for the inhaler with higher needle´s diameter (2 mm). Thus, this inhaler was used as a test and modified by the coating with a commonly-used force control agent, magnesium stearate, dried with supercritical carbon dioxide (scCO2) and the uniformity of delivered dose tests were repeated. The modified inhaler showed an increase in emitted dose from 68.9% to 71.3% for lactose and from 30.0% to 33.7% for Foradil.

Therapeutics bioconjugates: evaluation of iminoboronates as payload delivery system for cancer

The advent of bioconjugation impacted deeply the world of sciences and technology. New biomolecules were found, biological processes were understood, and novel methodologies were formed due to the fast expansion of this area. The possibility of creating new effective therapies for diseases like cancer is one of big applications of this now big area of study. Off target toxicity was always the problem of potent small molecules with high activity towards specific tumour targets. However, chemotherapy is now selective due to powerful linkers that connect targeting molecules with affinity to interesting biological receptors and cytotoxic drugs. This linkers must have very specific properties, such as high stability in plasma, no toxicity, no interference with ligand affinity nor drug potency, and at the same time, be able to lyse once inside the target molecule to release the therapeutic warhead. Bipolar environments between tumour intracellular and extracellular medias are usually exploited by this linkers in order to complete this goal. The work done in this thesis explores a new model for that same task, specific cancer drug delivery. Iminoboronates were studied due to its remarkable selective stability towards a wide pH range and endogenous molecules. A fluorescence probe was design to validate this model by creating an Off/On system and determine the payload release location in situ. A process was optimized to synthetize the probe 8-(1-aminoethyl)-7-hydroxy-coumarin (1) through a reductive amination reaction in a microwave reactor with 61 % yield. A method to conjugate this probe to ABBA was also optimized, obtaining the iminoboronate in good yields in mild conditions. The iminoboronate model was studied regarding its stability in several simulated biological environments and each half-life time was determined, showing the conjugate is stable most of the cases except in tumour intracellular systems. The construction of folate-ABBA-coumarin bioconjugate have been made to complete this evaluation. The ability to be uptaken by a cancer cell through endocytosis process and the conjugation delivery of coumarin fluorescence payload are two features to hope for in this construct.

Role of Intersectoral Collaboration in Mental Health Policy Formulation And Service Delivery in Saint Lucia

RESUMO: Santa Lúcia pequena ilha de país em desenvolvimento com recursos limitados e é confrontada com uma série de desafios socioeconômicos que exigem soluções criativas e inovadoras. É comprovado que a combinação de recursos entre setores para estabelecer os determinantes social, econômico e ambiental da saúde são uma estratégia útil para melhorar a saúde da população, principalmente a sua saúde mental. Este estudo, o primeiro do seu tipo em Santa Lúcia, procurou examinar até que ponto a disponibilidade de uma política nacional de saúde mental levou a ação intersetorial para o fornecimento de serviços e promoção da saúde mental. Além disso, o estudo examinou o nível de colaboração intersetorial que existe entre as agências que prestam cuidados diretos e serviços de suporte para pessoas com doenças mentais e problemas sérios de saúde mental. O estudo também teve como objetivo identificar os fatores que promovem ou dificultam a colaboração intersectorial e gerar recomendações que possam ser aplicadas para países muito pequenos e com perfis socioeconômicos semelhantes. Os dados gerados a partir de três (3) fontes foram sintetizados para formar uma visão ampla das questões. Uma avaliação da política de saúde mental de 2007, uma avaliação que identifica até que ponto a ação intersetorial atualmente deixa a prestação de serviços de saúde mental e a administração de entrevistas semiestruturadas nas mãos de gestores do programa de diferentes agências em todos os setores. O estudo concluiu que, apesar da disponibilidade de uma política de saúde mental, que articula clara e explicitamente a colaboração intersetorial como área prioritária para ação, quase não existe no sistema de fornecimento atual do serviço. Os provedores de serviços em todos os setores reconhecem que há os benefícios da colaboração intersectorial e com entraves significativos em relação à colaboração intersetorial, que por sua vez, impede uma abordagem nacional para o planejamento e o fornecimento do serviço. A colaboração intersetorial não será possível se os próprios setores dependerem da abordagem direta do setor da saúde ou se a atmosfera geral for ofuscada pela estigmatização das doenças mentais.------------------------------------------------------------------------ABSTRACT: Saint Lucia a small island developing country with limited resources, is faced with a number of socio-economic challenges which require creative and innovative solutions to address. Combining resources across sectors to address the social, economic and environmental determinants of health has proven to be a useful strategy for improving population health in particular mental health. This study, the first of its kind for Saint Lucia sought to examine the extent to which the availability of a national mental health policy led to intersectoral action for mental health promotion and service delivery. In addition the study examined the level of intersectoral collaboration which actually exist between agencies which provide direct care and support services to people with mental illnesses and significant mental health problems. The study also aimed to identify the factors which promote or hinder intersectoral collaboration and generate recommendations which can be applied to extremely small countries with similar socio-economic profiles. Data generated from three (3) sources was synthesized to form a broad picture of the issues. An evaluation of the mental health policy of 2007, an assessment of the extent to which intersectoral action currently exist in mental health service delivery and the administration of semi-structured interviews with program managers from different agencies across sectors to identify implementation issues. The study concluded that despite the availability of a mental health policy which clearly and explicitly articulates intersectoral collaboration as a priority area for action, very little exists in the current service delivery system. Services providers across sectors acknowledge the benefits of intersectoral collaboration and that there are significant barriers to intersectoral collaboration, which in turn hinders a national approach to service planning and delivery. Intersectoral collaboration is not possible if sectors themselves are dependent on a top-down health sector driven and dominated approach, or if the general atmosphere is clouded by stigmatization of mental health illnesses.