Mixed micelles absorption enhancers

Both interferon-a and - 3 have been shown to be absorbed across the rectal mucosa when given with the fatty acid linolenic acid as mixed micelles. In the absence of a permeation enhancer, rectally administered interferons (165 aa) do not achieve detectable levels in blood nor lymph. With 0.56% linolenic acid, a significant degree of lymphatic absorption of interferon-a and -P was detected [20]. The rectally absorbed interferon first distributes into the lymphatics, and interferon concentration is much higher in lymph than... 

In addition to improving drug absorption, permeation enhancers that form mixed micelles with peptides or proteins may also provide protection against metabolic processes, including protease-dependent inactivation, efflux transport, and protein denaturation, all of which could lead to reduced bioavailabUity. A permeation enhancer that may also inhibit some competing metabolic processes could greatly improve the poor and inconsistent bioavailabiUty of some short and cyclic polypeptides such as cyclosporine (11 aa cyclic peptide) (Figure 13.11). 

Intestinal absorption studies of Mn-MP were undertaken in an effort to assess the viability of the metalloporphyrin as an oral hepatobiliary agent [101, 102]. Mixed micelles of Mn-MP complexed with monoolein and taurocholate were administered to rats, resulting in liver image enhancement 68% above baseline levels six hours after administration [101]. In pigs, the mixed micelle preparation showed variable enhancement over 24 hours. Observation that Mn-MP interacts with oleic acid vesicles [103] led to investigations of the effect of oleic acid on the absorption rate of Mn-MP from the small bowel into the circulatory system [102,104]. The increase in absorption of the complex was mediated by a decrease in the relaxivity of the metalloporphyrin resulting from the interaction with the lipid vesicles. 

Tokunaga, Y., S. Muranishi, and H. Sezaki. 1978. Enhanced intestinal permeability to macromolecules. I. Effect of monoolein-bile salts mixed micelles on the small intestinal absorption of heparin. J Pharmacobiodyn 1 28. 

Solubilization of lipid digestion products in intestinal mixed micelles enhances their dissolution and dramatically increases the GI lumen-enterocyte concentration gradient that drives absorption by means of passive diffusion. Micelles, however, are not absorbed intact [8, 9], and lipids are thought to be absorbed from a monomolecular intermicellar phase in equilibrium with the intestinal micellar phase [10], The dissociation of monomolecular lipid from the micellar phase appears to be stimulated by the presence of an acidic microclimate associated with the enterocyte surface [11,12], In addition to passive diffusion, growing evidence suggests that active uptake processes mediated by transport systems located in the enterocyte membrane are also involved in the absorption of (in particular) fatty acids into the enterocyte [4],... 

The possible use of mixed micelles (e.g., made of unsaturated fatty acids and monoglycerides) has been shown for the enhanced rectal absorption of several compounds, including a and p interferon and insulin. 

Mixed micelles consist of fatty acids solubilized by surfactants or bile salts. The effects of mixed micelles on drug absorption were reviewed by Muranishi Mixed micelles are effective absorption enhancers for compounds such as heparin, streptomycin, gentamycin, and insulin. The effect of mixed micelles on drug absorption tends to be greater at the distal region of the GI tract. The mechanism for increased absorption is not known. Some publications claim that they are safe to use. Others report a disordering effect on intestinal epithelial cells. 

The inclusion of a surfactant in the suppository formulation may enhance the rectal absorption of drugs. The effect has been attributed to the formation of mixed micelles. It has been suggested that the presence of the micelle facilitates the incorporation of the lipid component of the mixed micelle into the biological membrane. This lipid then enhances the fluidity and permeability of the membrane to the poorly absorbed drug. It appears that the colorectal mucous membrane is more sensitive to the effects of mixed micelles than the gastrointestinal membrane of the small intestine. 

Y. Masuda, H. Yoshikawa, K. Takada, and S. Muranishi. The mode of enhanced enteral absorption of macromolecules by lipid-surfactant mixed micelles. J. Phar-macobio. Dyn. 9 793-800 (1986). 

Retinol formed by retinyl ester hydrolysis (or originating as such in the diet) and dietary -carotene are solubilized in mixed micelles as discussed above, thus enabling these molecules to reach the microvillus membrane. In studies with everted rat gut sacs in vitro, El-Gorab et al. (1975) reported that micellar solutions significantly enhance uptake of both retinol and p-carotene over emulsions. Maximal uptake occurred at the critical micellar concentration of the bile salt mixture. At higher detergent concentrations, 3-carotene uptake declined whereas retinol absorption remained high. 

The absorption of vitamin E is relatively poor - only some 20% to 40% of a test dose is normally absorbed from the small intestine, in mixed lipid micelles with other dietary lipids. This absorption is enhanced by medium-chain triglycerides and inhibited by polyunsaturated fatty acids, possibly because of chemical interactions between tocopherols and polyunsaturated fatty acids or their peroxidation products in the intestinal lumen. Esters are hydrolyzed in the intestinal lumen hy pancreatic esterase and also by intracellular esterases in the mucosal cells. 

---