885 KEY WORDS: carbamazepine, mixture experimental design, Neusilin ® UFL2, PAMPA, SEDDS. * Author to whom correspondence should be addressed. E-mail: mkrstic109@gmail.com Latin American Journal of Pharmacy (formerly Acta Farmacéutica Bonaerense) Lat. Am. J. Pharm. 34 (5): 885-94 (2015) Regular article Received: July 24, 2014 Revised version: March 13, 2015 Accepted: March 15, 2015 Application of a Mixture Experimental Design in the Optimization of the Formulation of Solid Self-Emulsifying Drug Delivery Systems Containing Carbamazepine Marko Z. KRSTIĆ 1 *, Slavica S. RAŽIĆ 2 , Ljiljana M. DJEKIĆ 1 , Vladimir D. DOBRIČIĆ 3 , Milica A. MOMČILOVIĆ 1 , Dragana D. VASILJEVIĆ 1 & Svetlana R. IBRIĆ 1 1 Department of Pharmaceutical Technology and Cosmetology, 2 Department of Analytical Chemistry, 3 Department of Pharmaceutical Chemistry, University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, P.O. Box 146, 11221 Belgrade, Serbia SUMMARY. The purpose of this study was to investigate the solid self-emulsifying drug delivery system (SSEDDS), as a potential delivery system for poorly water soluble carbamazepine by application of mix- ture design. The self-emulsifying drug delivery system (SEDDS) was formulated using Polysorbate 80, Transcutol ® HP and Mygliol ® 812. The input parameters for mixture design (components of SSEDDS) were: appropriate SEDDS, carbamazepine and adsorbent, Neusilin ® UFL2, with appropriate ranges 10- 30%, 30-50% and 40-60%, respectively. The output parameters were the percentages of carbamazepine released after 10 and 30 min. The aim was to formulate SSEDDS with very fast drug release, i.e. more than 80% of carbamazepine has to be released in 30 min. Optimal formulations were examined through the dissolution test, parallel artificial membrane permeability assay (PAMPA), differential scanning calorimetry and thermal gravimetric analysis. With the obtained mixture design models, for any combina- tion of factors ratios, it is possible to predict the profile of carbamazepine release. Optimal formulations exhibited significantly improved drug release and permeability. RESUMEN. El propósito de este estudio fue investigar el sistema sólido autoemulsionante para administración de fármacos (SSEDDS), como sistema potencial de liberación de carbamazepina, que es pobremente soluble en agua, mediante la aplicación de un diseño de mezcla. El SEDDS se formuló usando Polisorbato 80, Transcutol ® HP y Mygliol ® 812. Los parámetros de entrada para el diseño de mezcla (componentes de SSEDDS) fueron: SEDDS apropiadas, la carbamazepina y el adsorbente, Neusilin ® UFL2, con rangos de 10-30%, 30-50% y 40- 60%, respectivamente. Los parámetros de salida fueron los porcentajes de carbamazepina en libertad después de 10 y 30 min. El objetivo era formular SSEDDS con liberación muy rápida de drogas, es decir, más del 80% de la carbamazepina tenía que ser liberada en 30 min. Las formulaciones óptimas fueron examinadas a través de la prueba de disolución, el ensayo de permeabilidad paralela con membrana artificial (PAMPA), calorimetría dife- rencial de barrido y análisis termogravimétrico. Con los modelos de diseño de mezcla obtenida, para cualquier combinación de los factores de proporciones, es posible predecir el perfil de liberación de la carbamazepina. Las formulaciones óptimas mejoraron significativamente la liberación del fármaco y la permeabilidad. INTRODUCTION Lipid-based formulations have been devel- oped as a method to deliver poorly water-solu- ble drugs with particular emphasis on self-emul- sifying drug delivery systems (SEDDS). SEDDS are defined as isotropic mixtures of natural or synthetic oils, surfactants or, alternatively, one or more hydrophilic solvent and co- solvents/surfactants. Upon mild agitation in con- tact with aqueous media, such as gastrointesti- nal fluids, these systems can form fine oil-in-wa- ter (o/w) emulsions or micro-emulsions 1 . The term self-emulsifying (SE) generally refers to the formation of small droplets when two immisci- ble liquids come in contact with each other due to a reduction in the interfacial tension between the two phases 2 . After dilution by gastrointesti- nal fluids, SEDDS interact with mixed micelles and in the presence of endogenous materials, such as bile salts, undergo digestion processes by enzymes, pancreatic lipase resulting in for- mation of different colloidal structures, such as lipid vesicles and mixed micelles 3 . This struc- tural transformation plays a crucial role in drug ISSN 0326 2383 (printed ed.) ISSN 2362-3853 (on line ed.)