Content:
Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2017 ; A key point in the administration of biopharmaceuticals is the recognition of appropriate, effective, safe and biocompatible nanocarriers allowing overcoming extracellular and intracellular biological barriers without loss of drug stability and adequate therapeutic response at the target sites. Since their description by Rainer Müller in the early 1990's, solid lipid nanoparticles (SLN) have been developed as an effective colloidal drug carrier. Under optimized conditions, SLN can be produced for the entrapment of lipophilic or hydrophilic drugs with the essential requirements for an optimum nanoparticulate carrier. Its colloidal size and the controlled release behaviour allow protection and management when administered by parenteral and non-parenteral routes (e.g., oral, nasal and pulmonary). The pulmonary route has gained interest to the non-invasive administration of biopharmaceuticals on account of the promising anatomical features of the lung, particularly its large absorptive epithelial surface area, low thickness and avoiding the first-pass effect. The lung region where the particles are deposited depends on their aerodynamic diameter. The complex structure of the respiratory tree and the natural defence mechanisms of the lung are fundamental aspects for the design of a proper pulmonary delivery system. Although pulmonary delivery of nanoparticles has an unquestionable interest, it still requires a complex setup and an aerosolization technique, due to their low inertia and small size, which hindering the deposition in the lung, facilitating the exhalation with air. A promising alternative is the formulation of nanoparticles in inhalable microspheres that ensure their release after pulmonary administration. Microspheres have recently been proposed for pulmonary inhalation as dry powders, since they can be designed to achieve appropriate morphological and aerodynamic characteristics. Previous studies have shown that polymeric nanocarriers loaded in microparticulate systems present a great potential for pulmonary delivery of therapeutic macromolecules and genetic material. These microspheres act only as inert vehicles of the nanoparticles, which remain unaltered after the spray-drying process, not affecting the properties or the release profile of the encapsulated active agents, thus constituting a suitable microparticulate carrier for the pulmonary delivery of drug-containing nanoparticles. In this context a research project has been designed to explore the application and versatility of these micro-nanostructured systems as carriers for therapeutic drugs/proteins and genetic material. The SLN containing an anti-tuberculosis drug, a model peptide or a model plasmid (rifabutin, papain and pEGFP-C1, respectively) were formulated and optimized. Then, for pulmonary administration, SLN were spray-dried using common pharmaceutical excipients (mannitol and trehalose). The integrity and stability of all biomacromolecules studied were not affected by the SLN and microspheres formulation and preparation procedures, which were then considered as suitable for the encapsulation of labile therapeutic molecules. Particularly mannitol and trehalose and the SLN themselves acted as stabilizers of the pharmaceutics during spray-drying. The prepared spray-dried powders displayed good flow and aerosolization properties for pulmonary administration and exhibited high deposition in the lower regions of the respiratory tract determined through a twin-stage liquid impinger, Moreover, the spray-drying process preserved the peculiar nanoparticles features after their disintegration from dry microspheres, exhibiting a sustained release profile of antibiotic and peptide after contact with an aqueous medium containing a lung surfactant. Studies in cell cultures and animal models have revealed the biocompatibility and ability of these nanoparticles to promote the absorption of drugs and peptides through pulmonary epithelium, as well as their excellent potential in gene therapy. In conclusion, all the results obtained in this experimental work showed the interest of these systems as vehicles for the pulmonary administration of antibiotic drugs and therapeutic proteins and nucleic acids.
Note:
Dissertation 2017
Language:
English
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