Dosage Form Design Protecting Protein Peptide Drugs from GI Metabolism

Cyclosporine is reported to have a relatively high oral bioavailability (>30%) and provides an example where the drug is relatively stable from metabolic degradation in the GI tract. In contrast, drugs that are susceptible to being degraded in the GI tract would typically result in low bioavailability, with a high degree of variability. As such, strategies to protect the protein and peptide drugs from degradation in the GI tract can further enhance oral bioavailability. Various strategies have been employed to address this issue. Instead of "inhibiting GI enzymes," a more pragmatic approach is to protect the drugs from GI metabolism without altering the natural flora of enzymes in the GI tract. Side effects such as systemic intoxication and disturbed digestion of food proteins are often associated with the use of enzyme inhibitors. Here, the use dosage forms developed for small organic drug molecules may be applicable. These include liposomes, microspheres, nanoparticles, emulsions, hydrogels, lipid vesicles, particulates, and capsule mucoadhesives. The challenge is to incorporate the protein and peptide drugs into these vehicles.

While small intestinal cells secrete a variety of enzymes, including ami-nopeptidases, this part of the GI tract does not significantly contribute to the digestive process compared with events in the stomach or those resulting from pancreatic enzymes. Enteric-coated dosage forms are especially useful to transit through the stomach. It has been found that insulin delivery to the mid-jejunum protects insulin from gastric and pancreatic enzymes, and release from the dosage form is enhanced by intestinal microflora (35). Dosage forms such as nanoparticulates and microparticulates, mucoadhesives, or microspheres that are targeted to a part of the gut where proteolytic activities are relatively low can protect the protein and peptide drug from luminal proteolytic degradation and release the drug at the most favorable site for absorption. The protein and peptide drugs encapsulated in the nanoparticles are less sensitive to enzyme degradation through their association with polymers and have been demonstrated to have better absorption through GI tract than their native counterparts. Micro- and nanoencapsulation techniques, such as the w/o/w multiple emulsion technologies, have evolved to allow for the incorporation of sensitive proteins to resist the harsh environment of the mucosa. In addition, biodegradable polymers have been used with well-known degradation properties. For instance, a dry emulsion formulation was enteric coated using a pH-responsive polymer hydroxypropyl methylcellulose phthalate (HPMCP) (36). The release behavior of encapsulated insulin was found to be responsive to external pH and the presence of lipase under simulated GI conditions. These microspheres restrict the release of proteins to a more favorable region of the GI tract. Another approach to inhibit enzyme activity is to alter the pH to inactivate the local digestive enzymes. Pepsin in stomach is active at low pH, but it can be rapidly inactivated above pH 5 (37). A sufficient amount of a pH-lowering buffer that lowers the local intestinal pH to values below 4.5 can deactivate trypsin, chy-motrypsin, and elastase.

Diabetes 2

Diabetes 2

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...

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