RISEDRONATE SUSTAINED RELEASE SYSTEM REDUCES THE FORMATION OF CALCIUM INSOLUBLE COMPLEXES

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

Congreso; Tercer Reunión Internacional de Ciencias Farmacéuticas; 2014

Risedronate´s (Ris) high chelating ability leads to the formation of calcium (Ca) insoluble complexes, which result in severe gastrointestinal irritation and reduce its oral bioavailability. The new sustained-release system of Ris obtained by complexation with Eudragit E100 (EuE100-Ris) showed a reduced irritation potential and a significant increase in Ris oral bioavailability in fed conditions. The goal of this work was to identify those mechanisms involved in these events, specifically the role of EuE100-Ris complexation in the interaction with Ca. Ris solubility in the presence of Ca was comparatively evaluated for EuE100-Ris50 and RisNa at a concentration equivalent to 70 mg dose/250 ml in simulated intestinal fluid. The samples (in triplicate) were stirred and maintained at 37°C, then added with CaCl2 to achieve Ris/Ca molar ratios of 1.7, 1 ,0.5 and 0.2. Samples taken at time 0, 0.75, 2 and 24 hs were centrifuged and the supernatant assayed by UV spectrophotometry. The results were compared using one-way ANOVA. The precipitated solid was separated by filtration, dried and evaluated by FTIR to identify the presence of Ris (pyridine group) and EuE100 (ester carbonyl groups). In the presence of Ca, Ris precipitation leads to a supernatant concentration decrease, which progressed with time. The precipitation was significantly slower in EuE100-Ris50 compared to RisNa (pvalue≤0.05). At any time, Ris supernatant concentration from EuE100-Ris50 was 20-50% higher than RisNa except in Ris/Ca ratio of 0.2 where differences were less evident. The precipitated solids showed FTIR bands corresponding to the protonated Ris pyridine groups (C=N+H 2304 cm-1) in both samples. The C=OOR band at 1732 cm-1 were also observed in EuE100-Ris50 samples, indicating EuE100 coprecipitation. These results suggest that EuE100 prevents and slow Ris precipitation in the intestinal lumen due to its interaction with Ca. This behavior could be a reason for gastric damage reduction and the increased bioavailability in the presence of food observed previously with EuE100-Ris50. The EuE100-Ris50 complexes are potentially safer and efficient alternatives for oral bisphosphonates treatment.