Cell permeation enhancers drug absorption

Although the objective of most absorption enhancers is to avoid direct interaction with the mucosal membrane, cell permeation enhancers use this as a means to increase drug absorption. One form of enhancer currently of interest consists of glycosylated molecules, or facial amphiphiles. It is claimed that these compounds temporarily increase membrane permeability. Molecules are designed to self-assemble in membranes to form transient pores that permit hydrophilic com-poimds to cross the membrane. This technology has considerable potential for absorption enhancement. No adverse effects have been reported to date. ... 

Caco-2 cells have been valuable in the estimation of drug absorption potential, transport mechanisms, and effect of permeation enhancers on transepithelial transport.35,39,53,67-69,78-81 Owing to the sensitivity of the cells and the limited solubility of new molecular entities, Caco-2 permeability studies are routinely done with relatively low concentration of compounds. One way to increase the solubility of these compounds is to use organic solvents. The low tolerability of Caco-2 cells to organic solvents limits the use of this approach in permeability studies. 

In recent studies both in vitro (Caco-2 cells) and in vivo in rats, TMC with a degree of trimethylation of 60% was proven to be an excellent intestinal absorption enhancer of the peptide drugs buserelin and octreotide. The observed absolute bioavailability values were 13 and 16% for buserelin and octreotide, respectively [83] (impublished data Fig. 5). Permeation enhancing effects were more responsible for these increased bioavailabilities, rather than the mucoadhesive properties of the TMC polymers. Nevertheless, mucoadhesion is a prerequisite for these polymers in order to further act as absorption enhancers. 

Mucus also appears to be a barrier to the permeation enhancing effect of polymeric or monomeric absorption enhancers. In the aforementioned TMC studies, the enhancement effect (enhancement ratio = permeation rate of the drug in the presence of polymer vs. permeation rate of the drug alone) was higher in vitro (Caco-2 cells no mucus secretion) than the absorption enhancement in vivo. Meaney and O Driscoll studied the effect of mucus on the permeation properties of a micellar system consisting of sodium taurocholate in a coculture of Caco-2 and Ht29GlucH (mucin-secreting) cells. They found that the effect of bile salts on the permeation of hydrophilic paracellular markers was increased in the cocultures that were pretreated with the mucolytic compound A/-acetylcysteine. 

Anionic polymeric permeation enhancers have a different effect. They do not interact directly with the membrane, but bind and deplete Ca ions from the extracellular cell medium, which leads to an opening of the tight junctions [111]. The properties of anionic polymers have also been improved. By immobilization of free sulf-hydryl groups onto various polymers, their permeation-enhancing effect on hydrophilic compounds is strongly increased [112]. In addition, thiolated polymers (thiomers) show improved mucoadhesive properties which allows them to concentrate in the area of drug absorption [113]. 

Foraker et al. 2003). In the paper, Foraker et al. used microfabricated porous silicon particles to enhance insulin permeabihty across Caco-2 cell monolayer, which is commonly used in vitro model of the human small intestinal mucosa to predict the absorption of orally administrated drugs. They observed that the flux of insulin across the cell monolayer was approximately 50-fold compared with liquid formulations and nearly 10-fold higher compared with liquid formulations with permeation enhancer, if insulin was loaded in PSi. 

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