Absorption enhancers coadministration

The major strategies to enhance transmucosal peptide and other drug absorption include (a) coadministration with protease inhibitors, (b) the use of membrane permeation enhancers, (c) coadministration with a combination of absorption enhancers and protease inhibitors, (d) modification of peptide structure to improve metabolic stability or membrane permeation, and (e) use of nano- or microparticles [27], Some of these strategies have been investigated using the in situ rat model. 

At all mucosal sites, the coadministration of absorption enhancers is normally necessary to achieve therapeutic relevant plasma levels of (large) hydrophilic molecules such as peptides or proteins. Table 1 gives an overview of the most used and researched absorption enhancers and their possible mechanism of action. 

Various formulation concepts have been introduced as potential ways to protect peptide and protein drugs from the hostile GI environment to increase their oral absorption such as use particulate drug carriers (microspheres, lipo-somes, and lectins), coadministration of enzyme inhibitors and absorption enhancers, use of chemical modification (prodrug), and site-specific delivery to the colon or rectum. Some of these approaches are discussed later. 

There have been several approaches reported in the literature to improve the oral bioavailability of peptide drugs, including chemical modification (e.g., PEGylation [35], coadministration of absorption enhancers (e.g., EDTA, salicylates, surfactants, bile salts, and fatty acids [36]), and coadministration of inhibitors to the peptide metabolism [37]. 

Blood flow to the GIT increases shortly after a meal and may last for several hours. Digestive processes in general seem to enhance blood flow to the tract. For the reasons discussed previously, however, coadministration of a drug with a meal would normally not be expected to improve drug absorption. Strenuous physical exercise appears to reduce blood flow to the tract and may reduce absorption rate. 

Second, because of their molecular size and hydrophilic nature, peptide and protein drugs are poorly absorbed through the intestinal membrane, and absorption has to be improved. This may be accomplished by coadministration of penetration enhancers or by chemical modifications such as increasing lipo-philicity. 

Essential oils have also been shown to be useful for the delivery and to improve the bioavailability of pharmaceuticals. Recently, a patent was granted that describes a method for increasing the bioavailability of an orally administered hydrophobic pharmaceutical compound by coadministration with an essential oil (anise, basil, bergamot, etc.) [214]. In addition, the results of an investigation were reported recently on the use of oil-water microemulsions for the transdermal absorption of nifedipine, which employed essential oils (ylang ylang oil, lavender oil, cinnamon oil) and natural materials [cineole (88), menthone (50), menthol (41)] as lipophilic skin penetration enhancers [215]. 

Ross B P, Toth I (2005). Gastrointestinal absorption of heparin by lipidization or coadministration with penetration enhancers. Curr. Drug Deliv. 2 277-287. 

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