A new controlled release system of risedronate to increase bioavailability and reduce food interaction

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

Rosario

Congreso; Segunda Reunión Internacional de Ciencias Farmacéuticas, RICIFA.; 2012

Introduction. Risedronate (Ris) is a bisphosphonate used to treat or prevent bone diseases. After oral administration it is absorbed through paracellular pathway1-6. Its low lipophilicity and negative charge drive to low oral bioavailability (0.63%)2,7. Besides, the interaction with Ca2+, Mg2+ and food produces a delay and/or a reduction of Ris absorption8. The high affinity between Ris and the basic polyelectrolyte Eudragit E100 (EuE100) allows the obtaining of new controlled release systems with a potential to increase intestinal permeability and bioavailability (BA), which is the goal of this work. Materials and methodology. The complex EuE100-Ris50 was obtained by an acid-base reaction in which Ris neutralized 50 % of the basic groups of EuE100. Comparative studies were done in rats (Wistar, male) using a solution of equivalent concentration of Ris as a reference. Oral bioavailability: Ris absorption ratio was evaluated from urinary excretion. The rats were housed in metabolic cages and divided in four groups (A-D) which were administrated with the treatments descripted in table 1. Urine samples were recollected during 48 hs, processed and later quantified with an HPLC-UV methodology that was modified and validated ad-hoc. Duodenal permeability: Ris permeability through rat duodenum was measured in a side-by-side diffusion chambers at a mucosal concentration of 1.4 mg/mL. The solutions were prepared in Buffer Phosphate Saline (PBS) pH 6.8 (37°C, bubbled with CO2/O2). The transferred quantity of Ris to the serosal side was quantified by HPLC-UV. The results are expressed as apparent permeability coefficient (Papp). The normalized Papp value (NPapp) was also obtained, in which C0 was adjusted to the estimated free Ris, calculated as the ratio between the areas obtained for Ris release in PBS from EuE100-Ris50 vs RisNa (table 2). Results and Discussion. The analytical method to process and quantify Ris from rat urine, based on that described from Hui-Juan et al 9 with minor modifications, was validated. The following parameters were determined: linearity between 1.4-12 μg/mL, LLD: 0.56 μg/mL, LLQ: 1.4 μg/mL and recovery 93.7%. Table 1 shows the recovery ratio of Ris in urine. The bioavailability of Ris increased after administration of EuE100-Ris50. Besides, the impact of food in Ris absorption was reduced in this group. The Papp values are shown in the table 2. The in vitro permeability results matched in vivo data based on urinary excretion. These results suggest a possible enhancer effect from EuE100 on Ris permeability, however other mechanisms such as a reduction in the formation of insoluble calcium complexes and/or an increase in the gastrointestinal transit time due to the mucoadhesive effect of EuE100 could also be involved. Conclusion. Complexation of Ris with EuE100 increases oral bioavailability and intestinal permeability and could potentially increase the efficacy and patient adherence to biphosphonates oral therapy.