Absorption enhancers bile salts

Morimoto, K. Uehara, Y. Iwanaga, K. Kakemi, M. Ohashi, Y. Tanaka, A. Nakai, Y. Influence of absorption enhancers (bile salts) and the preservative (benzalkonium chloride) on mucociliary function and permeation barrier function in rabbit tracheas. Eur. J. Pharm. Sci. 1998, 6 (3), 225-230. 

Nevertheless, there are reports on enhancement of ocular drug absorption by bile salts [33], surfactants [200], and chelators [149], Newton et al. [35] demonstrated that Azone, an enhancer widely tested in transdermal drug delivery [201], increased the ocular absorption of cyclosporine, an immunosuppressant, by a factor of 3, thereby prolonging the survival of a corneal allograft. In 1986, Lee et al. [34] reported that 10 pg/mL cytochalasin B, an agent capable of condensing the actin microfilaments, increased the aqueous humor and iris-ciliary body concentrations of topically applied inulin (5 kDa) by about 70% and 700%, respectively, in the albino rabbit. 

A controversial problem is still the selection of suitable enhancing agents to overcome the often limited absorption from the colon. In a survey a number of commonly used enhancers, bile salts, surfactants, fatty acids, glycerides, etc. were also reported as effective in the colon [86],... 

Scott, E. R., Laplaza, A. L., White, H. S., and Phipps, J. B., 1993, Transport ofionic species in skin Contribution of pores to the overall skin conductance, Pharm. Res. 10 1699-1709. Scott-Moncrieff, J. C., Shao, Z., and Mitra, A. K., 1994, Enhancement of intestinal insulin absorption by bile salt-fattyacid mixed nuceUes in dogs, J. Pharm. Sci. 83 1465-1469. Sefton, M. V., and Antonacci, G. M., 1984, Adsorption isotherms of insulin onto various materials, Diabetes 33 674-680. 

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Bile acids and salts have been found to enhance the absorption of both calcium and vitamin D hence, to increase calcium absorption both directly and indirectly (3,37). However, the ability of some dietary fibers such as lignin and pectin to absorb conjugated and deconjugated bile salts onto their surfaces to be excreted in the feces (a mechanism credited to the hypocholesterolemic effect of some dietary fibers) may result in an overall decrease in calcium absorption from the gastrointestinal tract (7,33,38-40). 

Bile flow and secretion are stimulated by fats and certain other foods. Bile salts may enhance or delay absorption depending on whether they form insoluble complexes with drugs or enhance the solubility of agents. 

Surfactants may increase the solubility of the drug via micelle formation, but the amounts of material required to increase solubility significantly are such that at least orally the laxative effects are likely to be unacceptable. The competition between the surfactant micelles and the absorption sites is also likely to reduce any useftd effect and make any prediction of net overall effect difficult. However, if a surfactant has any effect at all, it is likely to be in the realm of agents that help disperse suspensions of insoluble materials and make them available for solution. Natural surfactants, in particular bile salts, may enhance absorption of poorly soluble materials. 

The addition of absorption enhancers, like bile salts (glycocholate), fatty acids (Unoleic acid), surfactants (lecithins, polyoxyethylene-9-lauryl ether or N-lauryl-P-D-maltopyra-noside) and chelators (EDTA) can significantly increase the absorption of various proteins. However, the application of enhancers is limited by their toxicity. For example polyoxyethyl-ene-9-lauryl ether and sodium glycocholate caused serious oedema, haemorrhage and inflammation of the lung after intratracheal instillation [39]. 

There are occasional anomalies to the rule that food reduces and delays peak plasma concentration. The anti-fungal drug, griseofulvin, has enhanced absorption if taken with a meal - possibly because it becomes emulsified by bile salts and passes more readily into the lymphatic drainage of the gut which bypasses the liver, entering the venous system directly. The immuno-suppressant cyclosporin, and calcium salts in general, show a similar increase in absorption when taken with a fatty meal. 

Another important factor that may inLuence solubility, dissolution rate, and therefore absorption of water-insoluble compounds is the contents ofthe Gl Luids. The Gl Luids contain various materials, such as bile salts, enzymes, and mucin. Bile salts are surface active and as such could potentially enhance the rate or extent of absorption of water-insoluble drugs. Thus, the increased absorption of a water-insoluble compound, griseofulvin (GF), after a fatty meal may be facilitated by bile salt secretion into the gut resulting in solubilization [1,2],... 

Numerous surface-active molecules have been studied as GI absorption promoters in a wide variety of testing conditions, including model membranes, everted intestinal sacs, tissue cultures, intestinal epithelia in diffusion chambers, intact animals, and humans. The physical properties of a chemical enhancer may be strongly dependent on the interactions with the endogenous GI components such as bile salts, pH, and bacteria. Thus the in vitro experiments on enhancing GI absorption are not necessarily predictive of the behavior of the promoter in animals or humans, and we will mainly focus on summarizing results from in vivo studies. 

The common bile salts in humans are glycine and taurine conjugates of sodium deoxycho-late (NaDOC) and sodium chenodeoxycholate (CDOC), dihydroxy bile salts, and sodium cholate (NaC, the trihydroxy bile salt). The ability of bile salts to increase transmucosal transport of solutes has been frequently stated [62,81,82]. Generally, the more hydrophobic dihydroxy bile salts act as more effective absorption enhancers in comparison to trihydroxy bile salts. For example, Gullikson et al. [83] have reported that the absorption of inulin, dextran, and albumin in the perfused rat jejunum was enhanced with dihydroxy but not with trihydroxy bile salts. 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

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. 

FIGURE 10.2 Bile salts used as absorption enhancer (deoxy-forms of these bile salts do not have the position 7 hydroxyl (OH ) group). 

They are believed to enhance the transbuccal permeation by a mechanism that is similar to that of bile salts, namely, extraction of lipids, protein denaturation, inactivation of enzymes, and swelling of tissues [39], Sodium dodecyl sulfate is reported to have a significant absorption enhancing effect but may also produce damage to the mucosa [13]. The effect of sodium... 

Lecithin (phosphatidylcholine) is a phospholipid, which may be isolated from either egg yolk or soybeans. It is commercially available in high purity for medical uses and has been used to enhance the absorption of insulin in vivo [26]. The antibiotic sodium fusidate, a steroid similar in molecular structure to bile salts has also been shown to have permeation enhancing properties for insulin in vitro [41]. 

Aungst, B.J., N.J. Rogers, and E. Shefter. 1988. Comparison of nasal, rectal, buccal, sublingual, and intramuscular insulin in efficacy and the effects of a bile salt absorption enhancer. J Pharm Exp Ther 244 23. 

Penetration enhancers are substances that can increase the absorption of a co-administered dmg, and include surfactants, bile salts, chelating agents, and fatty acids. Penetration enhancers are widely used in dmg delivery to potentiate absorption across various types of epithelia, including the epithelium of the gastrointestinal tract. However, a major limiting factor in the general acceptance of absorption enhancers for improving oral dmg absorption is the non-specific nature of their effects. 

The enhancement of nasal absorption of insulin by hydrophobic bile salts has also been investigated. It was found that minor differences in the number, position, and orientation of the nuclear hydroxyl groups as well as alterations to side-chain conjugation can improve the adjuvant potency of bile salts. Moreover, the absorption of insulin positively correlated with an increase in the hydrophilicity of the steroid nucleus of the bile salts. In the presence of bile salts, nasal absorption of insulin reached peak levels within about lOmin, and some 10-20% of the dose was found to have been absorbed into the circulation. Marked increases in serum insulin levels were seen with sodium deoxycholate, the most lipophilic of the bile salts, whereas the least elevation—as well as least lowering of blood glucose levels—was seen with the most hydrophobic bile salt, sodium ursodeoxycholate [63],... 

Table 2.3 presents the results of an experiment involving cannulation of the thoracic ducts of rats. Cannulation is the insertion of a tube into the duct to collect the fluid flowing out. Various test meals were fed to the rats. Each rat received only one type of meal. Lymph was collected for a 24-hour period the amount of cholesterol in the collected material was measured. Following a lest meal of albumin only, the collected lymph contained 10 mg cholesterol (Expt. 1). With the albumin plus cholesterol meal, 8 mg cholesterol was collected (Expt. 2). The amount of cholesterol collected clearly was elevated when the test meal contained taurocholate, albumin, and cholesterol (Expt. 6). This experiment demonstrated that including bile salt in the test meal could enhance the absorption of dietary cholesterol. 

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