Abstract:

Celecoxib (clxb) is an important drug for treatment of rheumatoid arthritis and osteoarthritis by specifically inhibiting the enzyme cyclooxygenase-2 (COX-2). Clxb is a type 2 drug characterized by low H2O soly. (\textless5 $μ$g/mL) and fast transmembrane transport. The present formulations require high dosage since the transmembrane transport fluctuates and is very difficult to control. Dissolving the drug within an oil phase was not practical since its dissoln. was very small and its dispersion in H2O was impossible. In recent studies, the authors learned to construct U-type phase diagrams and to formulate reverse microemulsions (oil-based concs.) that are progressively and fully dilutable with aq. phase. The authors solubilized clxb in nanostructures of reverse micelles of U-type nonionic microemulsions that consisted of R(+)-limonene, alc., propylene glycol (PG), and hydrophilic surfactant (Tween 60). The solubilization capacity of the drug in these systems is many times higher than in either the oil or the aq. phase. The clxb solubilized microemulsions are fully dild. with aq. phase without phase sepn. The solubilization capacity decreases as the H2O content increases. Elec. cond., viscosity, and self-diffusion (SD) coeffs. of the microemulsion components were measured along a suitable H2O diln. line. The 3 major microemulsion regions were detected and the transitions between the W/O to bicontinuous phase and from this phase to the O/W droplets were identified (at 30 and 70% aq. phase, resp.). From the SD coeffs., the drug is initially solubilized at the interface of the W/O droplets and there are no significant structural changes. The transition to a bicontinuous phase occurs at the same H2O content as in the empty (i.e., without drug) system. From the viscosity profiles, the drug affects the structure of the bicontinuous phase as reflected in the H2O content at which the oil-continuous network is destroyed and full inversion occurs (50 vs. 55% in the drug-loaded system). Upon further diln. the drug remains solubilized at the interface and is oriented with its hydrophilic part facing the H2O, and is strongly affects the inversion to O/W droplets. From Small Angle x-ray Scattering (SAXS) measurements the drug effects the structure of microemulsion droplets and forms ill-defined structures, probably less spherical. Yet, the overall droplet sizes at the high dilns. did not change very much. [on SciFinder(R)]