SUSTAINED ELEVATED SERUM SOMATOTROPIN CONCENTRATIONS IN HOLSTEIN STEERS FOLLOWING SUBCUTANEOUS DELIVERY OF A GROWTH-HORMONE RELEASING-FACTOR ANALOG DISPERSED IN WATER, OIL OR MICROSPHERES

Growth hormone releasing factor (GRF) stimulates pituitary somatotropi n (ST) release. Somatotropin directly or indirectly through insulin li ke-growth factor I decreases lipogenesis and promotes protein accretio n resulting in enhanced growth in food producing animals such as cattl e and swine. A sustained release formulation is required to capitalize on GRF biological properties since frequent animal handling in a prod uction facility is difficult. Sustained durations were evaluated with aqueous, oil and microsphere suspensions containing a previously disco vered metabolic stable growth hormone releasing factor analog 8,28),Al a(15),Leu(27),Hse(30)bGRF(1-30)-NH-ethyl). Serum ST concentrations wer e measured periodically during a 35-day period after the formulations were administered to meal-fed Holstein steers. Areas under the ST dail y curves (ST-AUC) formed the basis for determining the time daily ST-A UG returned to baseline for each treatment group. Time to return to ba seline was 21 days when delivering subcutaneously a 200 or 400 mg dose of a 20% oil suspension and 14 days for a 200 mg dose at 10% load in poly(lactide-co-glycolide) microspheres. The longest duration, 35 days , was achieved with a 200 mg dose of an 18% aqueous nanosuspension. A zero-order release was observed with the 18% aqueous formulation as in dicated by the ST-AUC not changing from days 7 through 35. Formation o f fibrils and subsequent dissolution from the fibrils was thought impo rtant in sustaining the drug release.