VANCOMYCIN AND INSULIN USED AS MODELS FOR ORAL DELIVERY OF PEPTIDES

Targeted administration of vancomycin HCl and porcine insulin to different sections of the gastrointestinal tract of rats indicated that the lower small intestine (ileum) and the colon were more favorable sites for peptide absorption. Intact absorption of vancomycin without absorption enhancement or enzyme inhibition at an absolute bioavailability of 5% was observed. Insulin is not absorbed in the lower gastrointestinal tract without absorption enhancer or enzyme inhibition coadministration. However, appreciable absorption of insulin was observed by decreased glucose levels and increased plasma insulin levels following administration to the colon of nondiabetic rats with 1% sodium glycocholate (SGC) and 1% disodium ethylenediaminetetraacetic acid (Na2EDTA) or aprotinin. A significant increase in absorption was observed following rectal administration of the same formulation. Formulation development was undertaken to target release utilizing Eudragit(R) S100 enteric coating and decrease gastrointestinal transit time comparing two bioadhesive polymers (chitosan and Carbopol(R) 934). Salicylate microspheres incorporated in enteric and nonenteric formulations with chitosan or Carbomer (Carbopol(R) 934) were tested for sustained delivery in the lower gastrointestinal tract using rat and dog animal models. Optimized formulations were designed for porcine insulin which were then tested in the nondiabetic dog model for bioavailability and pharmacological response. Microspheres of triglyceride mixtures and low-melting fat composition were prepared using a spinning disk method and subsequently incorporated in two-part gelatin capsules containing Carbopol(R) 934 or incorporated in chitosan film prior to placement in two-part gelatin capsules. Improved bioavailability for the enteric coated oral insulin formulation was observed in the dog model with prolonged decrease in plasma glucose.