Decrease of genital organ weights and plasma testosterone levels in rats following oral administration of leuprolide microemulsion

Studies were conducted to develop oral leuprolide microemulsions using oleic acid as an absorption enhancer and to evaluate its absorption and pharmacological responses in rats. Oral administration of leuprolide microemulsion at a dose of 3 mg/kg showed a greater in vivo exposure level (Cmax and AUC) than its saline solution. When male rats were orally given a microemulsion formulation of leuprolide acetate at 0.25, 0.5, and 1 mg/day for 14 consecutive days, a significant decrease in testis, prostate and seminal vesicle weights was observed. In a 35-day study, the reduction of the male genital organ weights by once a day treatment (2 mg/rat, qd) was similar to that by twice a day treatment (1 mg/rat, bid) at the same dose level. From both 14- and 35-day studies, plasma testosterone levels were sharply increased at the beginning of the treatment, and then significantly decreased to below normal control level which was also maintained during the treatment. In female rats, similar reduction of uterus and ovary weights was obtained following oral administration of leuprolide microemulsion for 35 days. These antagonistic activities from oral leuprolide microemulsion were similar to a single subcutaneous injection of Lupron® depot (3.75 mg/rat), a commercial leuprolide product. The results indicated that leuprolide absorbed into systemic blood circulation from the oral microemulsion containing oleic acid reached the plasma level which can exert its pharmacological effects. Increasing oral absorption of leuprolide observed in this study could be mediated by improved membrane permeation from oleic acid and reduced enzymatic degradation from microemulsions. These findings suggest that systemic absorption of highly water-soluble protein or peptide drugs could be enhanced by oral microemulsions containing oleic acid.