Enhancement and modification of etoposide release from crospovidone particles loaded with oil-surfactant blends

A novel solid formulation for oral delivery of pH-sensitive, scarce& water-soluble etoposide has been designed, characterized, and tested in vitro. The pulpose of this study was to assess the perfomance of the new dosage forms, in comparison to marketed, liquid-filled capsules. The solid formulation was developed by grinding the drug with a cross-linked polymeric carrier (crospovidone) under controlled prqcess conditions (mechano-physical drug activation), and subsequently incorporating selected oil/surfactant (oh) blends into the polymer particles. Physicochemical characterization (thermal analysis, drug dissolution kinetics, drug o/w partition studies) provided information on drugpolymer interaction at the solid state, and on the formulation peqormance in vitro, resulting in the enhancement and modification of the etoposide solubilization process. DSC thermograms showed the amorphous or nanocrystalline state of etoposide within the carrier, as indicated by the shifting of DSC peaks (AT > -1O'C). Solubility kinetics of etoposide in oversaturation conditions were strongly affected by the chemical nature of the vehicle used: short-chain triglycerides afforded drug concentrations well above 600 pg ml-I for more than 3 hr, versus a drug equilibrium solubility of approximately 150 pg ml-'. Drug dissolution curves under sink conditions were superimposable to those of liquid-jilled capsules available on the market (Vepesid@5 0, Bristol-Myers Squibb), yielding 100% drug release in 10 min. The oil phase/water partition coeficient of etoposide (P) was af fected by the surfactant concentration. The biphasic trend observed in P values suggested a dual mechanism in drug release from polymeric particles: the presence of oily vehicles and suqactants in the formulation could create, upon release, a favorable environment to sustain etoposide dissolution, .slowing down drug reprecipitation. Such solid formulation could be considered equivalent, in vitro, to the current marketed product