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.
Formulation Technology Research Department, Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. arayahrs@chugai-pharm.co.jp
Hiroshi
H
Araya
Mikio
M
Tomita
Masahiro
M
Hayashi
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