الفهرس 
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Abstract
Rapid developments in biotechnology have posed new challenges for pharmaceutical researchers to develop peptide and protein drugs. Many efforts are directed towards achieving non-partenteral delivery routes of these agents. Although each non-parenteral route has its own advantages and disadvantages, the oral route is by every means the preferred route of drug administration especially for therapeutics used chronically.
It is common knowledge that peptide and protein drugs are easily hydrolyzed and digested in the gastrointestinal tract. In addition, they have poor membrane permeability due their hydrophilicity and large molecular size.
Among the many strategies used in attempts to improve the oral bioavailability of peptide and protein drugs, is using site-specific delivery to the colon to bypass the harsh gastrointestinal environment and using absorption enhancers to improve their poor intestinal absorption.
In this study, the effect of a novel group of absorption enhancers (the nitric oxide donors) was explored using two peptide drugs, insulin and calcitonin. Their effect was first compared to the effect of conventional enhancers from different classes using the model drug, 5-(6)-carboxyfluorescein. Following that, the combined effect of using site-specific delivery through the formulation approach together with using additives was investigated.
Comparing the effect of absorption enhancers from different classes using 5-(6)-carboxyfluorescein showed that, the effect of the enhancers was more pronounced in the colon. However, nitric oxide donors were effective in all intestinal segments.
2- SNAP showed the highest in-vitro enhancement ratio among all tested enhancers in the small intestinal tissues and it directly followed n-dodecyl-B-D-maltoside in effectiveness across the large intestinal tissue.
3- In the in-situ experiments on carboxyfluorescein, SNAP was the most effective in all regions showing a bioavailability of 79.10 %, 26.68 % and 32.16 % in the colon, jejunum and ileum, respectively.
4- The effect of nitric oxide donors on the in-vitro permeability of insulin was - to some extent - more pronounced on the colonic membrane. SNAP was the most effective in all regions followed byNOC12thenNOC5.
5- The absorption of both insulin and calcitonin in-situ increased markedly from all regions by the coadministration of the three nitric oxide donors. However, the enhancement was more pronounced in the colon. The order of effectiveness in all regions was SNAP > NOC12 > NOC5. The highest pharmacological availability obtained for insulin was 0.785 % (9.94 times higher than the control) while that of calcitonin was 1.003% (11.27 folds increase).
6- Incorporation of carboxyfluorescein inside enteric-coated chitosan capsules with n-dodecyl-13-D-maltoside resulted in a significantly higher absorption in rats compared to enteric-coated gelatin capsules and solution. Increased absorption was evident by the increased bioavailability (almost double that in case of gelatin capsules). The delayed Tmax confirmed that colon-specific delivery was achieved.
7- Incorporation of calcitoninin the same capsules showed superior absorption of the drug compared to gelatin capsules and solution. Addition of the nitric oxide donor, SNAP resulted in increased beneficial effect of these capsules as indicated by the increased pharmacological availability. Using a combination of absorption enhancers (SNAP and sodium glycocholate) and enzyme inhibitors (bacitracin and aprotinin) in the chitosan capsules improved the pharmacological availability even more.
8- The absorption enhancing effect of nitric oxide donors was mainly mediated by the released nitric oxide rather than the enhancers themselves.
9- The enhancing effect of nitric oxide donors had nothing to do with increased stability of the drug against enzymatic attack. Hydrolysis of insulin in the intestinal mucosal homogenates was not reduced in the presence of nitric oxide donors.