Síntesis y caracterización de polímeros de ciclodextrina. Aplicación a la liberación de fármacos

Abstract

Cyclodextrins (CD) are cyclic oligosaccharides which have been widely employed for pharmaceutical applications. CD based hydrogels have been synthesized by the crosslinking reaction with epichlorohydrin using αCD, ßCD, γCD, and 50:50 mixtures of α/ßCD and ß/γCD, at different synthesis temperatures. These gels have been characterized by measuring their swelling capacity, mechanical behavior, thermal properties and pore size distribution. The hydrogels synthesized at higher temperatures present a higher swelling capacity, due to the self-polymerization of epichlorohydrin, yielding a more expanded reticular structure with pores of higher diameter. Mechanical assays show that a lower synthesis temperature leads to stronger and harder polymers, according with a lower swelling capacity. Polymers containing different CD types and synthesized at the same temperature present similar reticular structures. In order to investigate the sorption capacity of these hydrogels toward different solutes, five model molecules have been selected: phenol, 3-nitrophenol, 4-nitrophenol, 1-naphthol, and the antiinflamatory drug diflunisal. The amounts sorbed have been related to the different affinities of CDs to the solutes. Drug delivery of two antiinflammatory (naproxen and nabumetone) and two antifungal drugs (naftifine and terbinafine) from ßCD polymer discs has been investigated. Drug release kinetics were carried out at physiological conditions of pH and temperature, and kinetic and diffusion constants were calculated. The drug release followed a simple Fickian diffusion mechanism for all the model drugs. Also, diffusion coefficients were calculated according to the simplified Higuchi model. Naproxen was also used to perform release assays from polymers containing different CDs. The βCD polymer showed the highest amount of drug loaded and the lowest one corresponds to the polymer containing αCD, in agreement with the affinities for naproxen of the corresponding cyclodextrins. It can be inferred that a simple Fickian diffusion mechanism occurs, except for the mixed polymers at pH 1.2 (anomalous transport) and in the case αCDP at pH 7.0 (burst phenomenon). Furthermore, the diffusion and relaxation contributions have been determined for the mixed polymers in order to achieve progress in the design of new polymer matrices according to the structure of the selected drugs.