Polymeric micelles as drug delivery systems for voriconazole via the pulmonary route

BRITO DEVOTO T.; HERMIDA ALAVA K.; TOSCANINI M.A.; CHIAPPETTA D.A.; MORETTON M.A.; CUESTAS M.L.

Encuentro; 19 Reunion de Expertos en Micologia Clinica; 2021

Objectives: Many fungal species are able to cause lung diseases that may require antifungal therapy. Drug delivery to the lungs by inhalation offers an interesting route to noninvasive drug administration for either local or systemic effects. In addition, pulmonary drug delivery has many advantages compared to conventional drug administration, such as rapid onset of drug action with high bioavailability, less systemic side effects than oral or parenteral routes and the opportunity of a targeted drug therapy for respiratory diseases. Polymeric micelles appear as an attractive nanotechnological platform to enhance the aqueous solubility and chemical stability of hydrophobic drugs, such as voriconazole (VCZ). Furthermore, these nano-carriers stand as novel drug delivery systems for different administrations routes. Hence, the aim of this study was to prepare polymeric micelles for the sustained release of VCZ in the lungs by inhalation.Methods: Soluplus®, a graft-copolymer based in poly(ethylene glycol) and poly(vinyl caprolactam) poly(vinyl acetate), was employed as biomaterial. VCZ-loaded polymeric micelles (10% w/v) were prepared by an acetone-based solvent-diffusion technique in distilled water. Afterwards, samples were freeze-dried (-20°C, 24 h) before use. Micellar size and size distribution, before and after freeze-drying, were determined by dynamic light scattering (DLS) employing a ZetaSizer Nano at 25 °C. The physicochemical stability of the drug-loaded nano-formulations in simile nasal and interstitial lung fluids was assessed by DLS at 34°C (nasal) and 37°C (lung); under 1/50 dilution. Additionally, following EUCAST E.DEF 9.3.2 and 7.3.2 guidelines, VCZ-loaded micelles were evaluated for their in-vitro susceptibility against Aspergillus fumigatus, A. flavus, Candida albicans and C. parapsilosis.Results: VCZ could be successfully encapsulated within the Soluplus® micelles where its aqueous solubility was increased 7.1-fold (up to 5 mg/mL). This novel aqueous nano-formulation demonstrated an excellent colloidal stability at 25° with micellar size in the nano-scale before (~150 nm) and after (~100 nm) redispersion in distilled water. This size allows nano-particles to deposit in the alveolar region in acceptable amounts. Interestingly, the drug-loaded Soluplus® micelles exhibited physicochemical stability under dilution in simile interstitial fluids for pulmonary VCZ delivery. In-vitro, MIC values were identical for free-drug and VCZ-loaded micelles in all fungal species tested. (table 1)Conclusion:This polymeric nanosystem arise as a promising nanosytem that might be potentially used for the controlled pulmonary drug delivery of VCZ via inhalation for the local therapy of lung disorders caused by fungi, such as chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. This strategy may lead to higher local concentrations at the primary site of infection in comparison to other administration routes for the therapy of pulmonary diseases.