Absorption of peptides and proteins from different regions of the intestine is not uniform. For example, the preferred absorption site is the duodenum for cyclosporine, the upper GI tract and rectum for tetragastrin, the duodenum and the ileocecal junction for desmopressin, and the upper GI tract for octreotide.38,39 Oxytocin and vasopressin analogues have a higher transport rate across distal intestinal segments than across the proximal small intestine of the rat. This is believed to be caused by decreased proteolytic activity in the distal region. Also, the distal region has a higher paracellular permeability despite a decreased absorption area.40 The protease activity in the cytosol does not show regional variation, but the same is not true for the brush border or for the luminal fluid. The stomach, with its low pH and enzymatic activity, presents very harsh conditions for a protein drug. A typical approach to prevent dissolution of a dosage form in the stomach is to use enteric coating.
The apparent permeability of insulin from rat intestine shows a site-dependent variation as measured by the everted rat gut sac technique. The permeability was significantly greater in the jejunum and ileum than in the duodenum. In these in vitro experiments, insulin was remarkably stable. This suggests that insulin metabolism at the brush border is not significant. However, insulin was metabolized almost completely in intestinal homoge-nates. Thus, it appears that degradation of insulin under an in vivo situation would be caused by luminal and cytosolic enzymes.41 In situ experiments have shown that the absolute bioavailability for insulin was higher when administered to the more distal region of the rat intestine (0.133%) than that absorbed from a more proximal region (0.059%) of the intestine.42 Absorption of insulin from isobutylcyanoacrylate nanocapsules administered to diabetic rats was dependent on the site of absorption. The hypoglycemic effect following absorption from various sites was as follows: ileum 65%, stomach 59%, duodenum and jejunum 52%, and colon 34%. The insulin was protected by the nanocapsules in this study, and the hypoglycemic effect, which started on the second day, lasted for 3 to 18 days.43
The intestinal segments have progressively fewer and smaller villi in the more distal sections. This leads to a progressively reduced surface area, with the colon having the lowest surface area for a particular length. The colon also has variable pH and the presence of solid fecal matter, which may interfere with drug absorption. However, the colon has relatively low enzymatic activity and is promising in this regard. Using isolated luminal enzymes and studies in intact mucosa, calcitonin was found to degrade much more in the small intestine compared to the colon.44
The colon has a high population of bacteria, largely anaerobic species. This fact has been exploited for an ingenious approach to target peptides and proteins to the colon.45 In a study by Saffran et al.,46 polypeptides such as insulin or vasopressin were coated with polymers cross-linked with azoaromatic groups to protect orally administered polypeptides from digestion in the stomach and small intestine of rats. Once the polypeptide reached the colon, the indigenous microflora reduced the azo bonds, thus breaking the cross-links and releasing the polypeptide for absorption. The upper half of the large intestine is drained by hepatic portal veins; the lower half is drained by lymphatics. If a polypeptide is destroyed in the liver, it may be possible to adjust the thickness or composition of coating so that the drug is released in the lower colon, where it will bypass the hepatic veins.
Delivery of insulin and an absorption promoter to the colon has also been attempted using a soft gelatin capsule coated with a polyacrylic polymer (Eudragit) having pH-dependent properties.47 Delivery of insulin-like growth factor I (IGF-I) to rat and minipig colonic mucosae under in vitro conditions has been investigated. IGF-I is a 7649-Da protein of 70 amino acids that exerts its biological actions through specific IGF-I receptors. It has been found useful to lower blood glucose levels in insulin-resistant diabetic patients in clinical studies. IGF-I was absorbed intact across rat colonic mucosa as determined by reverse-phase high-performance liquid chromatography (RP-HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and Western blotting.48
A time-based drug release system for colon-specific delivery has also been developed. This system exploits the relatively constant small intestine transit time of dosage forms.49 Time-based systems can be designed to release their drug after a predetermined lag time, with the lag time independent of normal physiological conditions such as pH, digestive state of the subject, and anatomical position at the time of release.50,51
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...