The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion III: the permeation mechanism of a poorly water soluble drug entrapped O/W microemulsion in rat isolated intestinal membrane by the Ussing chamber method.
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.
Araya
Hiroshi
H
Formulation Technology Research Department, Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. arayahrs@chugai-pharm.co.jp
Tomita
Mikio
M
Hayashi
Masahiro
M
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D015194:Diffusion Chambers, Culture; D004339:Drug Compounding; D016503:Drug Delivery Systems; D015195:Drug Design; D004655:Emulsions; D007052:Ibuprofen / Q000008:administration & dosage / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008566:Membranes / Q000378:metabolism; D008823:Micelles; D009077:Mucins / Q000378:metabolism; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004655:Emulsions; D008823:Micelles; D009077:Mucins; D004364:Pharmaceutical Preparations; D013656:Taurocholic Acid; D007052:Ibuprofen; D000111:Acetylcysteine