Estrategias terapéuticas basadas en micro y nanoemulsiones para el tratamiento del Alzheimer y enfermedades inflamatorias de la piel

Abstract

Donepezil (DPZ) is one of the most widely prescribed drugs to treat the neuropsychiatric symptoms of Alzheimer's disease (AD) which are commercially available in oral tablet form. However, these can lead to inconveniences, especially among geriatric patients or those who are in advanced stages of the disease. In addition to this, there are marked disadvantages of the oral route, including difficulties in crossing the blood-brain barrier. The intranasal route presents an alternative due to its direct connection to the brain, which could increase the bioavailability of the drug. On the other hand, pioglitazone (PGZ) is a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist used to treat type 2 diabetes mellitus. There is mounting scientific evidence of the anti-inflammatory effect of PGZ which suggests it as a promising candidate for the treatment of inflammatory disorders. The incorporation of these drugs in micro- and nanoemulsions could be used as a strategy to facilitate their administration. Based on these findings, the aim of this thesis was to design, develop and characterize intranasal DPZ micro- and nanoemulsions for the treatment of AD, as well as topical PGZ nanoemulsions for the treatment of inflammatory skin diseases. Two PGZ nanoemulsions (PGZ-NE and PGZ-NE2) along with one microemulsion and two nanoemulsions of DPZ (DPZ-ME, DPZ-NE, and DPZ-PNE) were formulated by constructing pseudo-ternary phase diagrams. All formulations were physically stable with spherical nanodroplets distributed uniformly in the system. The rheological analysis confirmed the Newtonian behavior in four formulations, while DPZ-PNE presented a pseudoplastic behavior. The five formulations were able to release the drug following a hyperbolic kinetic model. DPZ exhibited greater permeation through the porcine nasal mucosa from microemulsion compared to nanoemulsions, possibly due to its higher content of surfactants and cosurfactants. PGZ-NE and PGZ-NE2 favored the passage of the drug through the stratum corneum and promoted its retention in the skin thereby guaranteeing a local effect, especially for PGZ-NE2. The tolerance results demonstrated the biocompatibility and suitability of the formulations for intranasal or dermal administration. Finally, PGZ-NE treatment inhibited approximately 44% of inflammation, significantly decreased the expression of proinflammatory cytokines IL-6, IL-1β, and TNF-α, and counteracted histopathological alterations in acute inflammation assays, while PGZ-NE2 demonstrated efficacy in the treatment of atopic dermatitis, exhibiting reduction of skin lesions, restoration of elasticity and biomechanical properties of the skin, as well as reduction in the expression of proinflammatory cytokines associated with the pathophysiology of the disease. In conclusion, the obtained results encourage further clinical research into new therapeutic indications for PGZ as well as the use of intranasal-administered DPZ micro- and nanoemulsions to increase the bioavailability of the drug in the brain and facilitate its administration.