Development and characterization of novel vehicles for topical drug delivery

Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2016

Topical drug delivery is challenging since the skin acts as a natural and protective barrier. The skin has been an important route for drug delivery when topical, local or systemic effects are desired. The outcome of topical dermatological drug treatment is significantly influenced by the choice of vehicle. In recent years there has been an increased interest in developing improved delivery systems and, exploring new ways of using approved excipients, such as, starch. Due to its unique properties, starch has been extensively used in various topical pharmaceutical application, i.e. as a sensorial enhancer, a stabilizer and drug delivery polymer, providing protection and control release of the drug molecule. The base-concept of this study was to develop and characterize novel starch-based vehicles for dermatological application, easily scaled-up to industry and produced by methods that can allow the decrease of production costs, and further investigate the resulting systems behavior in in vitro and in vivo conditions. Starch-based vehicles were prepared successfully using QbD approach with the understanding of the high risk process and formulation parameters involved and optimized design space with a multifactorial combination of critical parameters to obtain predetermined specifications. Three different model drugs were incorporated into the optimized starch-based vehicles. Minocycline hydrochloride (MH) was incorporated in Pickering emulsions, a human neutrophil elastase inhibitor (ER143), a new molecule developed by the MedChem Group at iMed.ULisboa, was encapsulated into starch nanocapsules and melatonin was added on Pickering emulsions sunscreen, in order to fully characterize these new formulations, and further study its topical delivery and in vitro and in vivo efficacy. The in vitro antibacterial activity studies for Pickering emulsions containing MH revealed that the released drug exceeded the minimum inhibitory concentration of MH against S.aureus. In vitro release studies showed a prolonged release of the MH, with an initial burst effect. Regarding in vitro permeation studies, MH does not pass through the entire skin layer, suggesting a minimal potential for the systemic absorption of the MH upon topical administration. In vivo results showed that topical administration of MH was effective in S. aureus superficial infections treatment. Starch nanocapsules presented a mean particle size ranging from 200 to 250 nm and a positive zeta potential. In vitro permeation studies showed that the starch nanocapsules were suitable for the delivery of ER143, allowing a high control of the drug release, contributing to a high skin retention and/or permeation profiles of ER143. In vivo results showed that erythema and edema were attenuated in 98%, following the local application of ER143-loaded starch nanocapsules. Regarding Pickering emulsions sunscreen, formulation studies demonstrated that starch particles presented no intrinsic photoprotection properties, they proved to be a sun protection factor promoter by a synergistic effect. Besides the excellent sunscreen activity confirmed by in vitro and in vivo results, the final formulations proved to be also suitable for topical use according to the rheological assessment and stability throughout the study period (3 months). Additionally, the safety and biological effects of the placebos (vehicles without drug) was assessed by using both in vitro and in vivo studies, as an adequate equilibrium between the safety and efficacy effects. Overall, these findings highlight the starch-based vehicles as promising for the development of topical delivery systems, covering innovative therapeutic approaches.