PURPOSE: Although efficient in vitro, fenretinide has not been successful clinically for either of the targeted indications-cancer prevention and dry age-related macular degeneration-because of various issues, such as low oral bioavailability. Therefore, controlled release carriers for parenteral delivery of fenretinide were developed. METHODS: After examining the solubility profile of fenretinide, the drug was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microparticles at 20% drug loading by an s/o/w methodology as well as into in situ-forming PLGA implants. The carrier morphology and drug release kinetics in an elevated polysorbate 80-containing release medium were studied. RESULTS: Preformulation studies revealed increased fenretinide solubility in various PLGA solvents including N-methylpyrrolidone (NMP) and 1:9 v/v methanol:methylene chloride. Co-solvent emulsion methods resulted in low encapsulation efficiency. With a s/o/w method, fenretinide release rates from injectable microparticles were adjusted by the o-phase concentration of end-capped PLGA, the drug particle size, and the particle porosity. In situ implants from non-capped PLGA in NMP exhibited a continuous release of ~70% drug over 1 month. CONCLUSIONS: Injectable carriers for fenretinide were successfully prepared, exhibiting excellent drug stability. Based on the in vitro release properties of the different carriers, the preferred injection sites and in vivo release rates will be determined in future preclinical studies.
PURPOSE: Although efficient in vitro, fenretinide has not been successful clinically for either of the targeted indications-cancer prevention and dry age-related macular degeneration-because of various issues, such as low oral bioavailability. Therefore, controlled release carriers for parenteral delivery of fenretinide were developed. METHODS: After examining the solubility profile of fenretinide, the drug was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microparticles at 20% drug loading by an s/o/w methodology as well as into in situ-forming PLGA implants. The carrier morphology and drug release kinetics in an elevated polysorbate 80-containing release medium were studied. RESULTS: Preformulation studies revealed increased fenretinide solubility in various PLGA solvents including N-methylpyrrolidone (NMP) and 1:9 v/v methanol:methylene chloride. Co-solvent emulsion methods resulted in low encapsulation efficiency. With a s/o/w method, fenretinide release rates from injectable microparticles were adjusted by the o-phase concentration of end-capped PLGA, the drug particle size, and the particle porosity. In situ implants from non-capped PLGA in NMP exhibited a continuous release of ~70% drug over 1 month. CONCLUSIONS: Injectable carriers for fenretinide were successfully prepared, exhibiting excellent drug stability. Based on the in vitro release properties of the different carriers, the preferred injection sites and in vivo release rates will be determined in future preclinical studies.
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