Water-in-oil microemulsions containing medium-chain fatty acids/salts: formulation and intestinal absorption enhancement evaluation.
OBJECTIVE
Water-in-oil (w/o) microemulsions have been developed which, in addition to non-ionic medium-chain glycerides, incorporate ionic lipids, primarily medium-chain fatty acids, such as caprylic (C8) capric (C10) and lauric (C12) acids and their corresponding sodium salts. The absorption enhancing activity of w/o microemulsions incorporating these lipids was evaluated in the rat using Calcein (MW = 623) a water-soluble and poorly absorbed marker molecule.


METHODS
Phase diagrams were constructed where C8/C10 or C12 fatty acids were treated as lipophilic surfactants and their sodium salts as hydrophilic ones. The anesthetised rat model was employed to evaluate Calcein absorption upon a single intraduodenal administration from a solution and the various w/o microemulsions.


RESULTS
A wide range of clear and transparent w/o microemulsions were obtained at ambient temperature either in liquid or solid form when a fixed blend of medium chain fatty acid/salt was titrated by a fixed ratio of the oil containing the oil-soluble mono- and diglycerides and deionized water or physiological saline. Upon intraduodenal administration in the anesthetised rat, the absorption of Calcein was improved from about 2% in aqueous solution up to about 37% in w/o microemulsions. Solid and liquid formulations were equally effective in improving bioavailability. The absorption enhancement activity of the fatty acids/salts followed the order C8 approximately C10 > C12. Absorption enhancement of Calcein was significantly reduced in the absence or presence of low levels of C8/C10 mono-/diglycerides.


CONCLUSIONS
These results further support the use of medium-chain glycerides and fatty acids/salts in microemulsion formulations to improve intestinal absorption of water-soluble compounds.
Constantinides
P P
PP
Drug Delivery Department, Pharmaceutical Technologies, Smith-Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Welzel
G
G
Ellens
H
H
Smith
P L
PL
Sturgis
S
S
Yiv
S H
SH
Owen
A B
AB
D000818:Animals; D002210:Caprylates / Q000737:chemistry / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D003652:Decanoic Acids / Q000737:chemistry / Q000493:pharmacokinetics; D004655:Emulsions; D005227:Fatty Acids / Q000737:chemistry* / Q000493:pharmacokinetics*; D005452:Fluoresceins / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007477:Ions; D007850:Lauric Acids / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D014867:Water / Q000737:chemistry* / Q000378:metabolism*
D002210:Caprylates; D003652:Decanoic Acids; D004655:Emulsions; D005227:Fatty Acids; D005452:Fluoresceins; D007477:Ions; D007850:Lauric Acids; D012492:Salts; D014867:Water; C030358:lauric acid; C024098:6-carboxyfluorescein; C031492:octanoic acid; C007740:fluorexon