Topical delivery of seriniquinone for treatment of skin cancer and fungal infections is enabled by a liquid crystalline lamellar phase.

Seriniquinone (SQ) was initially described by our group as an antimelanoma drug candidate and now also as an antifungal drug candidate. Despite its promising in vitro effects, SQ translation has been hindered by poor water-solubility. In this paper, we described the challenging nanoformulation process of SQ, which culminated in the selection of a phosphatidylcholine-based lamellar phase (PLP1). Liposomes and nanostructured lipid carriers were also evaluated but failed to encapsulate the compound. SQ-loaded PLP1 (PLP1-SQ) was characterized for the presence of sedimented or non-dissolved SQ, rheological and thermal behavior, and irritation potential with hen's egg test on the chorioallantoic membrane (HET-CAM). PLP1 influence on transepidermal water loss (TEWL) and skin penetration of SQ was assessed in a porcine ear skin model, while biological activity was evaluated against melanoma cell lines (SK-MEL-28 and SK-MEL-147) and C. albicans SC5314. Despite the presence of few particles of non-dissolved SQ (observed under the microscope 2 days after formulation obtainment), PLP1 tripled SQ retention in viable skin layers compared to SQ solution at 12 h. This effect did not seem to relate to formulation-induced changes on the barrier function, as no increases in TEWL were observed. No sign of vascular toxicity in the HET-CAM model was observed after cutaneous treatment with PLP1. SQ activity was maintained on melanoma cells after 48 h-treatment (IC50 values of 0.59-0.98 µM) whereas the minimum inhibitory concentration (MIC) against C. albicans after 24 h-treatment was 32-fold higher. These results suggest that a safe formulation for SQ topical administration was developed, enabling further in vivo studies.

Carrier free indomethacin microparticles for dry powder inhalation.

The present studies were designed to evaluate inhalatory microparticles carrying indomethacin (IN) for potential local (specific and non-specific bronchial inflammatory asthma responses) and systemic treatments (joint inflammation, rheumatoid arthritis and osteoarthritis pain) by optimizing microparticle properties, characterizing their lung deposition, drug release, evaluating cytotoxicity and also pharmacological effect in vitro. The acidic groups of IN were complexed with the cationic groups of the polyelectrolyte polylysine in order to increase the drug water compatibility. The polylysine/indomethacin ratio was fixed and the pH was adjusted in different formulations. Microparticles were obtained by spray drying using a relatively high atomization air flowrate (742 L/min) and a high-performance cyclone in order to optimize the production of microparticles with adequate attributes for inhalatory delivery. The produced microparticles exhibited high process yield and IN loading, volumetric mean diameters smaller than 5 µm and narrow particle size distributions. According to demonstrated aerosolization performance, the powders were suitable for inhalatory indomethacin local and systemic treatments. Emitted fraction was higher than 90%, the MMAD was around 3 µm and the GSD lower than 3. The respirable fraction for particles with aerodynamic diameters smaller than 5 µm was around 29% while for particles with aerodynamic diameters smaller than 3 µm the value was around 17%. The addition of lactose as carrier worsened the aerodynamic performance of the microparticles. The developed powdered systems got wet and dissolved quickly and presented higher release rates respect to pure IN in simulated lung physiological conditions. Furthermore, the assays performed in RAW 264.7 cell line showed that the microparticles exhibited the same anti-inflammatory capability as the pure drug. The developed particles did not affect the RAW 264.7 cell viability. In conclusion, a promising powder formulation for DPIs has been developed to treat, locally and systemically, inflammatory diseases.