Oral delivery of biologically active parathyroid hormone

Purpose. Parathyroid hormone (PTH). the only drug known to stimulate bone f ormation, is a peptide therapeutic indicated in the treatment of osteoporos is. Unfortunately, PTH is only effective when dosed by injection because it has no oral bioavailability. Herein we report the oral absorption of PTH i n rats and monkeys facilitated by the novel delivery agent, N-[8-(2-hydroxy -4-methoxy)bensoyl]amino caprylic acid (4-MOAC). Methods. 4-MOAC was selected from a group of 100 delivery agents based on i n vitro chromotography studies and in vivo screening studies in rats. The P TH/4-MOAC combination was then tested in monkeys. The interaction of 4-MOAC and PTH was evaluated by nuclear magnetic resonance (NMR) spectroscopy. Results. Monkeys were administered an aqueous solution containing 4-MOAC an d PTH and mean peak serum PTH concentrations of about 3000 pg/mL were obtai ned. The relative bioavailability of oral PTH was 2.1% relative to subcutan eous administration. The biological activity of the orally-delivered PTH wa s Further evaluated in a rat model of osteoporosis. These studies showed th at the bone formed following oral PTH/4-MOAC administration was comparable to that formed following PTH injections. The 4-MOAC mediated absorption of PTH is hypothesized to be the result of a noncovalent interaction between 4 -MOAC and PTH. The preliminary evaluation of this interaction by NMR is des cribed. Conclusions. 4-MOAC facilitates the absorption of PTH following oral admini stration to both rats and monkeys. The orally-absorbed PTH is biologically active as demonstrated in a rat model of osteoporosis.