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We used ibuprofen as a poorly water soluble model drug, to examine the influence of bile salts and mucin layers on the permeability of that entrapped in an O/W microemulsion, in a rat isolated intestinal membrane by the Ussing chamber method. Under the presence of 3 kinds of the primary bile salts such a sodium taurocholate, etc., or a secondary bile salt such a sodium taurochenodeoxycholate at 0.01 mmol/L concentration, a significant difference was not demonstrated in the permeation clearance of the ibuprofen entrapped O/W microemulsion, as compared with the case without the bile salts. Thus, the bile salts did not have a remarkable influence on the permeability of the drug entrapped in the O/W microemulsion, and it was verified that this O/W microemulsion was hardly influenced by the flow of the bile secretion. On the other hand, when N-acetyl-L-cysteine (NAC) with the removal ability of a mucin layer was combined with the ibuprofen entrapped O/W microemulsion at the concentration of 3 and 10 mmol/L, it was shown that the permeation clearance of free ibuprofen did not decrease, but that of ibuprofen entrapped in the O/W microemulsion decreased with the increase of the NAC concentration. Therefore, it is confirmed that the mucin layer participates in the permeability of the drug entrapped in the O/W microemulsion. From these results, the mechanism in which the drug entrapped in the O/W microemulsion is released in a mucin layer, without passing through the route of the mixed micelle formation by bile, thereafter the drug permeates an intestinal membrane, is supposed.

The stabilization effect of the novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion on the gastrointestinal absorption of a poorly water soluble new compound, ER-1258 was examined by bile-fistula model rats. In the components of this formulation, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40) and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant and a solubilizer at the mixture ratio of 25/5/45/25 w/w%, respectively. The ratios of AUC in the non-treated rats to that in the bile-fistula rats were 5.1, 12.1 and 3.0 for the suspension, the oily solution and the SEDDS type O/W microemulsion, respectively. The risk from which the difference between individuals of the compound absorption amounts resulting from the flow of the bile secretion serves as the maximum was high in order of oily solution>suspension>SEDDS type O/W microemulsion. Therefore, it was verified that the SEDDS type O/W microemulsion was able to reduce this risk, compared with the other formulations. When short chain fatty acid triglyceride (Triacetin) was used as an oil, the similar effect was demonstrated in the formulation composed of sorbitan sesquioleate (SO-15) as a lipophilic surfactant and polyoxyethylene hydrogenated castor oil 60 (HCO-60) or polyoxyethylene 20 sorbitan monooleate (TO-10M) as a hydrophilic surfactant.

We examined the design of the versatile novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds. Namely, seven kinds of poorly water soluble compounds such as disopyramide, ibuprofen, ketoprofen, tolbutamide, and other new compounds, as the model compounds were used to compare the plasma concentration profile of the compound following single oral administration of each compound to rats and beagle dogs as a solution, an oily solution, a suspension (or a powder), an O/W microemulsion, and a SEDDS type O/W microemulsion. And the enhancing effect of the SEDDS type O/W microemulsion on the gastrointestinal absorption of these compounds was evaluated. In the components of the SEDDS type O/W microemulsion, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant, and a solubilizer, at the mixture ratio of 25/5/45/25 (w/w%), respectively. Thereby, to six kinds of the model compounds except disopyramide, the solubility was from 340 to 98,000 times that in water, and the AUCs in plasma concentration of the compound were equivalent to that of solution or O/W microemulsion administration, or was increased by 1.5 to 78 times that of suspension administration. Accordingly, this novel SEDDS type O/W microemulsion is the versatile, useful formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.