Pulsatile delivery of progesterone and estradiol to mimic the ovulatory surge in adult ewes by means of TCPL implants.

Tricalcium-phosphate-lysine delivery systems (TCPL) have been developed to release pharmaceuticals into the circulation, at a predictable rate, for prolonged periods of time. The objective of this study was to design an implantable TCPL system capable of delivering progesterone (P) for about two weeks and Estradiol (E) in a short burst that mimics the ovulatory surge in adult ewes. TCPL implants were fabricated in four different sizes (1.5, 2.3, 3.5, or 5.6 cm) using four different ceramic compositions and impregnated with P (20-45%) and E (4-16%). Each single device was inserted subcutaneously into the axillary space of adult ewes. Serum P levels were elevated within 2 days postimplantation reaching peak levels of 2.8 ng/ml, 2.3 ng/ml, 1.8 ng/ml and 3.5 ng/ml which then declined to basal levels after 7, 9, 12 and 21+ days in each of the four animals, respectively. Peak serum E levels of 32 pg/ml, 13 pg/ml, 12 pg/ml and 55 pg/ml were obtained in each of the four animals, respectively. Serum E levels initially increased at 7, 9, 7, and 5 days after placement of the implants, and declined to basal levels after 9, 19, 14 and 21+ days in each of the four animals, respectively. Maintenance of low levels of luteinizing hormone (LH) during the time of release of P in the animals shows that the steroid released from the ceramic implants has a negative feedback effect on LH.(ABSTRACT TRUNCATED AT 250 WORDS)