Progesterone release from glutaraldehyde cross-linked casein microspheres:In vitro studies and in vivo response in rabbits

Microspheres of bovine milk protein casein loaded with progesterone were fa bricated by glutaraldehyde cross-linking of an aqueous alkaline solution of the protein dispersed in a hexane and dichloromethane non-aqueous dispersi on medium with an aliphatic polyurethane as the stabilizer. Microspheres we re characterized for their surface morphology and internal structure using scanning electron microscopy. In vitro release studies in phosphate buffer at 37 degrees C demonstrated that the rate of release of the steroid from t he microsphere matrix was a function of cross-linking density, particle siz e, and drug payload. Microsphere formulations released 50% to 60% of the in corporated steroid in about 30 days and, thereafter, attained a steady stat e. in the presence of a protein-digesting enzyme such as protease, complete release of the steroid was observed in about 4 days in vitro into phosphat e buffer. Intramuscular injection of progesterone-loaded microspheres into rabbits showed a plasma concentration of 1 to 2 ng/mL up to 5 months withou t any significant burst effect, whereas the powdered steroid administered i n saline demonstrated a large burst effect peaking over 20 ng/mL, and the p lasma concentration was not sustained beyond 4 days. Data obtained suggest that casein microspheres would be promising as a biodegradable drug carrier for sustained delivery of steroids. (C) 2000 Elsevier Science Inc. All rig hts reserved.