Dapsone nanocrystals for leprosy treatment: preparation and physicochemical characterization

• Autor(a) principal: Rocha, Nataly Paredes da
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Biblioteca Digital de Teses e Dissertações da USP
• Texto Completo: https://www.teses.usp.br/teses/disponiveis/9/9139/tde-29072022-204820/
• topic: Dapsona; Dapsone; Desenho de experimentos; Design of experiments; Hanseníase; Leprosy; Nanocristais; Nanocrystals; Nanosuspensão; Nanosuspension

Leprosy is one of humanity\'s oldest diseases, and even though it is no longer considered a public health problem globally, it is still endemic in several countries. Brazil is the second country in new cases detected, being responsible for 12.8% of the total. Dapsone is one of Multidrug treatment (MDT), but its use is commonly related to the occurrence of serious adverse effects, resulting in treatment abandonment. According to Biopharmaceutics Classification System, this drug belongs to class II, and its low solubility in water may limit bioavailability. Hence, reducing particle size to produce drug nanocrystals promotes an increase of surface area to volume ratio, which allows an increment of saturation solubility and dissolution rate. In addition, the use of a systematic approach during the development phase is paramount, guaranteeing a better understanding of a product through quality by design appeal. In the present study, the selection of optimal PovacoatTM concentration, stirring speed, and process time to particle reduction was carried out by the design of experiment (DoE). The optimized formulation obtained by small-scale wet bead milling technique resulted in an average size of 206.3 ± 6.7 nm, PdI of 0.132 ± 0.012, and zeta potential of -9.8 ± 0.3 mV and monomodal distribution. Thermal analysis (DSC) and X-ray diffraction (XRD) of lyophilized formulation revealed the maintenance of the drug substance crystal structure after the milling process and the absence of interaction between drug and excipients. The nanosuspension presented low particle size variability over the 4 months of long-term and 3 months of accelerated stability studies. Dapsone nanocrystals showed an improvement in saturation solubility of 3.78 in water compared to raw material. Toxicity studies performed in galleria mellonella larvae indicates low toxicity at dose of 20 mg/kg of formulation. Finally, an initial attempt to scale up from lab to pilot resulted in promising nano-sized particles for a commercial product. Therefore, the present study allowed the development of dapsone nanosuspension with the potential to improve adherence to leprosy treatment.