NOVEL EUDRAGIT E100 SYSTEM FOR ZERO-ORDER DEXAMETHASONE PHOSPHATE RELEASE

GUZMAN, MARIA LAURA; MANZO RUBEN; GRANADOS, ALEJANDRO; MARIA EUGENIA OLIVERA

Congreso; Primera Reunión Internacional de Ciencias Farmacéuticas; 2010

Introduction: New controlled release matherials were obtained by loading the cationic polyelectrolyte EudragitE100 with oppositely charged drugs. In a previous work we showed that the dimethylamino moieties of EudragitE100(EuE) can form ionic complexes with phosphate and phosphonate drugs. In this work we present the in vitro release characterization of this systems using dexamethasone phosphate(DP) as a model drug. Objetives: characterize the affinity and release behavior of DP from dispersions of EuE-DP systems. Matherials and Methods: a series of solid complexes of EuE loading variable amounts of DP were obtained. The complexes were subjected to titration of ionic pairs with NaCl solution. The pH changes produced by ionic exange were regarded. Rate and kinetic release in water and physiologic solution was assessed in Franz cells. The impact of the direct addition of increasing NaCl amounts (50%-300%) in the release behavior was also assessed. EuE-Benzoic Acid and EuE-Diclofenac were also obtained as references of carboxylic model drugs. Additional characterization of the interaction was achieved by 1H and 31P RMN spectroscopy. Water and methanol dispersions of the complexes, free DP, EuE and DP: EuE mixtures were analyzed. Results and discussion: As NaCl solution was added to the system, an increase in the pH was observed. The equilibrium was achieved after addition of 800% of NaCl, 4 times the amount needed to reach the equilibrium in the systems containing carboxilic acid moieties. The systems showed a smart behavior, with DP release in water below 2% in eight hours and an increase (10%) as media was replaced by NaCl. Interestingly, the kinetic release fitted zero-order. Direct addition of NaCl to the dispersions showed no modifications nor in the rate nither in the release, proving that no burst effect is expected. In contrast, significant modifications were observed in the systems containing carboxylic acid moieties. The 1H NMR evaluation showed a noticeable widening and reduction of some proton signals of DP after complexation. This fact could be related to an increase in relaxation time in 1H nuclei of DP as a consequence of EuE complexation. 31P NMR spectra showed a unique signal at frequencies higher than free DP. When DP is in excess, the phosphorous signal approaches to free DP, proportional to the DP: EuE ratio. However, when EuE is in excess, the chemical displacement showed a landslide higher than expected, probably related to the participation of the second acidic group of phosphate. This fact can be related with the affinity and kinetic observed. Conclusion: DP has significantly higher affinity for the dimiethylamine groups of EuE than carboxylic acid groups. The complexes EuE-DP present zero-order release, which is sustained for at least 26 hs. The participation in the interaction of the 2 acidic groups of the molecule may play a role. These novel systems can find utility as controled release systems for administration of DP. EuE is a promising carrier of other phospate drugs such as biphosphonates, nucleotides, plasmid or proteins.