Effect of Formulation Adjuvants on Gastrointestinal Absorption of Leuprolide Acetate

Leuprolide acetate, [D-Leu(6)-desGly(10)] LH-RH ethylamide, a highly potent superagonist of luteinizing hormone-releasing hormone (LH-RH), was administered by intraduodenal (ID) injection to male castrate rats in a saline solution. Absorption was low, approximately 0.01% and 0.08% by oral (PO) and ID administration respectively, compared with intravenous (IV) controls. An aqueous formulation and a water in oil emulsion of a lipophilic salt, a decane sulfonic acid derivative of [D-Leu(6)-desGly(10)] LH-RH ethylamide gave ID bioavailabilities of approximately 0.2% and 1%, respectively. Evaluation of formulation effects on the oral absorption of leuprolide showed that lipophilicity, surfactant and vehicle properties significantly affected ID absorption of leuprolide. Absolute bioavailability of the drug in typical emulsion systems ranged from approximately 3 to 10% and represent an improvement of about 100 fold in gastrointestinal bioavailability of this peptide. The implications of these findings relative to the effect of formula adjuvants on oral absorption of leuprolide and other peptides following ID administration are discussed.