Enhancing oral bioavailability of an antifungal thiazolylhydrazone derivative: Development and characterization of a self-emulsifying drug delivery system.

RN104 (2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole) is a thiazolylhydrazone derivative with prominent antifungal activity. This work aimed to develop a self-emulsifying drug delivery system (SEDDS) loaded with RN104 to improve its biopharmaceutical properties and enhance its oral bioavailability. Medium chain triglycerides, sorbitan monooleate, and polysorbate 80 were selected as components for the SEDDS formulation based on solubility determination and a pseudo-ternary phase diagram. The formulation was optimized using the central composite design in response surface methodology. The optimized condition consisted of medium chain triglycerides, sorbitan monooleate, and polysorbate 80 in a mass ratio of 65.5:23.0:11.5, achieving maximum drug loading (10 mg/mL) and minimum particle size (118.4 ± 0.7 nm). The developed RN104-SEDDS was fully characterized using dynamic light scattering, in vitro release studies, stability assessments, polarized light microscopy, and transmission electron microscopy. In vivo pharmacokinetic studies in mice demonstrated that RN104-SEDDS significantly improved oral bioavailability compared to free RN104 (the relative bioavailability was 2133 %). These results clearly indicated the successful application of SEDDS to improve the pharmacokinetic profile and to enhance the oral bioavailability of RN104, substantiating its potential as a promising antifungal drug candidate.

Preclinical pharmacokinetic study of a new thiazolyl hydrazone derivative with antifungal activity in mice plasma by LC-MS/MS.

RN104, named 2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole, is a thiazolyl hydrazone derivative with promising antifungal activity. Pharmacokinetic profile of the RN104 was evaluated in mice plasma using a developed and validated bioanalytical method by LC-MS/MS. Clotrimazole was used as internal standard. The analytes were extracted by a protein precipitation procedure and separated on a C18 end-capped column and mobile phase composed of acetonitrile - 0.1% formic acid (85:15, v/v), in isocratic mode. Electrospray ionization in positive ionization mode (ESI + ) and multiple reaction monitoring (MRM) were employed using the transitions m/z 286.1 â†’ m/z 176.1 (quantifier) and m/z 286.1 â†’ m/z 112.2 (qualifier) for RN104 and m/z 345.2 â†’ m/z 277.1 (quantifier) and m/z 345.2 â†’ m/z 165.2 (qualifier) for internal standard. The method was validated and proved to be linear, accurate, precise, and selective over the range 0.625 to 40.0 ng/mL. The pharmacokinetic model that best fit the data was the bicompartmental model. The maximum plasmatic concentration was reached 20 min after administration (per os and intraperitoneal) and the highest plasma concentration of RN104 was found after per os administration at a dosage of 50 mg/kg compared to i.p. administration at 10 mg/kg.