Controlled release of oxytetracycline from biodegradable injectable formulations

Blank biodegradable formulations (without drug) were prepared by blending a biodegradable polymer poly(lactide-co-glycolide) (PLGA) and pharmaceutically acceptable plasticizers using the solvent evaporation method. The plasticizers used in the study were N-methyl pyrrolidone (NMP), polyethylene glycol 400 (PEG 400), triethyl citrate (TEC) and acetyl triethyl citrate (ATEC). Oxytetracycline (OTC) was used as a model drug. The stability of OTC base and its hydrochloride salt in the formulations was determined at room temperature and 37°C using a stability indicating HPLC method. The rheological properties of the blank formulations were evaluated with a rheometer. The solubility of OTC base and its hydrochloride salt in the plasticizers and dissolution medium was determined. The effect of various formulation factors were evaluated by determining the in vitro release of OTC from different formulations. Attempts were made to elucidate the drug release mechanism from the formulations. The in vivo performance of OTC-loaded biodegradable formulations was evaluated in Japanese quail and sheep.; Both the OTC base and the hydrochloride salt were stable in the formulations prepared with PEG 400, TEC and ATEC.; Plastic viscosity of blank formulations increased by increasing polymer inherent viscosity, polymer concentration and plasticizer hydrophobicity.; The solubility of OTC base in the dissolution medium was substantially (24 times) less than the solubility of the hydrochloride salt. The solubility of OTC base in all the three plasticizers was much higher than the hydrochloride salt. The solubility of OTC base in PEG 400, TEC and ATEC was 48.5, 0.697 and 0.211 mg/mL, respectively.; The release of OTC from biodegradable formulations involves dissolution, leaching out with plasticizer(s), diffusion, and degradation steps.; The plasma concentration of OTC above 0.5 mug/mL (minimum inhibitory concentration) was maintained for 28 days after a single subcutaneous injection of OTC-loaded biodegradable formulation in quail. The plasma concentrations of OTC were maintained close to or above 0.5 mug/mL for approximately 10 days in only two sheep. The plasma concentration of OTC in the other two sheep was far below 0.5 mug/mL.