Persistent suppression of the pituitary-gonadal system in female rats by three-month depot injectable microspheres of leuprorelin acetate.

The serum drug levels and pharmacological effects of leuprorelin acetate (leuprolide acetate) in female rats after subcutaneous (sc) injection of 3-month release injectable and biodegradable microspheres were investigated. After sc injection, the microspheres provided sustained serum drug levels for > 3 months, probably because of continuous release of the drug. As was found for the 1-month depot preparation, a transient initial high peak in serum leuprorelin levels resulting from an initial burst of drug release could not be avoided. Sustained suppression of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol for > 16 weeks was attained by a single injection of the microspheres. An injection of the microspheres suppressed the growth of the ovaries and uterus in a dose-dependent manner; a drug dose of 0.036 mg (corresponding to approximately 1 microgram/kg/day) was insufficient for suppression of uterine growth, and a drug dose of 3.6 mg (corresponding to approximately 100 micrograms/kg/day) provided the strongest growth suppression in both organs. Serum LH, FSH, and estradiol responses in a challenge test indicated that definite pharmacological effects were sustained for at least 16 weeks, as was demonstrated previously in male rats and dogs. Thus, this depot formulation may provide sustained therapeutic effects for 3 or 4 months in humans.