Cubic phases for studies of drug partition into lipid bilayers

Drug partition into lipid bilayers in a cubic liquid-crystalline phase was investigated. Glyceryl monooleate was used to form the lipid bilayer in a r eversed bicontinuous cubic liquid-crystalline phase. The reason for using t he cubic phase is that it may coexist with an external aqueous phase, and t hat the phase boundary (cubic phase/aqueous bulk) is well-defined due to th e stiffness of the cubic phase. This makes the cubic phase a potential cand idate for high throughput screening (HTS) of the lipophilicity and the diss ociation constant (if any) of drug compounds. Clomethiazole (CMZ), lidocain e, prilocaine and 4-phenylbutylamine (4-PBA) were chosen as model drug comp ounds. It was shown that it is possible to determine a pH-dependent apparen t partition coefficient, K-bl/w, of a drug compound using a lipid bilayer e xpressed as a cubic liquid-crystalline structure. Good agreement was found when the resulting K-bl/w vs. pH curves for CMZ, lidocaine and prilocaine w ere fitted to a mathematical expression. This included the bilayer/water pa rtition coefficient for the unionised and ionised drug respectively and the pK(a) of the drug. The effect of different experimental conditions; such a s amount of cubic phase, temperature, agitation, sample preparation and int erfacial area between the cubic phase and the aqueous bulk on the partition kinetics were investigated as well. The studies reveal that the time neede d to reach partition equilibrium was, as expected, substantially reduced (f rom days to hours) by decreasing the amount of cubic phase, increasing the interfacial area between the cubic phase and the aqueous phase, and increas ing the temperature and the agitation of the sample. It was also shown that the bilayer affinity of 4-PBA was increased when a zwitterionic lipid (i.e . dioleoyl phosphatidylcholine, DOPC) was incorporated in the bilayer. (C) 1999 Published by Elsevier Science BN. All rights reserved.