Recent advances in biotechnology have made available large numbers of bioactive peptides, which may have therapeutic potential. Many polypeptides are susceptible to degradation by proteolytic enzymes and are poorly absorbed in the gastrointestinal tract. With very few exceptions of small and cyclic peptides such as cyclosporin, most peptide drugs have low oral bioavailabilities with typical values of less than 1%. 1)There are many examples of the use of particulate systems which attempt to achieve systemic delivery of peptide drugs via the intestinal tract. These include nanoparticles, 2-5) microspheres, 2,6) liposomes 7,8) and multiple emulsions 9,10) that shield peptide drugs from enzymatic attack.Elcatonin (EC), synthetic [Asu 1,7 ]-eel calcitonin and a hypocalcemic peptide, has been used for the treatment of Paget's disease as well as certain types of osteoporosis. 11)The usual routes of its administration are subcutaneous and intramuscular. On the other hand, intranasal administration of human calcitonin (hCT) and salmon calcitonin (sCT) has proved effective in the management of Paget's disease 12,13) and postmenopausal osteoporosis.14-16) The colonic absorption of 125 I-hCT in humans 17) and the rectal absorption of EC in rabbits 18) have been recently evaluated, estimating the hypocalcemic effect. However, among all alternative routes for administration of EC and calcitonin, the oral route is a suitable alternative, because it offers improved convenience and patient compliance. It is of particular interest that EC has considerable resistance to enzymatic degradation conformationally, 19) a property which is beneficial to the oral administration. In order to meet these challenges we aimed to develop an oral dosage form whose EC bioavailability would be sufficient to promote the hypocalcemic response at the same level as obtained with parental dosage forms.This paper describes an approach to oral administration of EC in rats. We have estimated the intestinal absorption of EC coadministered with some protease inhibitors and absorption enhancers. In addition, to realize the oral delivery of EC, mucoadhesive W/O/W multiple emulsions and a capsule of the peptide were prepared and the hypocalcemic effects were evaluated in rats after their oral administration. We discuss the possibility of oral delivery of EC for the treatment of disease based on the results obtained. Treatment of Animals Male Wistar rats (Japan SLC, Shizuoka, Japan), weighing 200-240 g, were used throughout this experiment. The animals were maintained on MF diet (Oriental Yeast Co., Tokyo) for 3-4 d prior to the experiment. A group of 3-7 rats was randomly selected from the population. On the day before the experiment, the rat jugular vein was cannulated with silicon tubing, 20) and the rat was fasted overnight (for 16 h). MATERIALS AND METHODS Materials Preparation of W/O/W Multiple Emulsions and Mucoadhesive EmulsionsThe multiple emulsions were prepared by a two-step process.21) The primary emulsion con- * To whom correspondence should be add...