A new controlled release system of Risedronate, a biphosphonate for bone diseases

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

Rosario

Congreso; Segunda Reunión Internacional de Ciencias Farmacéuticas RICIFA; 2012

RICIFA

Introduction. Risedronate (Ris) is used to treat and prevent bone diseases1-5. It is a strong gastric irritant. The low intestinal permeability and oral bioavailability (< 1%) of Ris as well as the interaction with food are drawbacks for therapy adherence to clinical success 1,6. The design of a controlled release system (CRS) could reduce adverse effects and/or increase Ris bioavailability. The objective of this work was to develop and characterize a CRS of Ris with the cationic polyelectrolyte Eudragit E100 (EuE100). Materials and methodology. A series of EuE100-Ris complexes was obtained by acid-base reaction in which Ris neutralized 25, 50 and 75% of the basic groups of EuE100. A mixture of EuE100 and Ris was added with water, sonicated and freeze-dried. The solid complexes were characterized by spectroscopic, calorimetric and crystallographic techniques (FTIR, DSC/TG, DRXP). Aqueous dispersions of EuE100-Ris50 were subjected to drug release analysis in bicompartimental Franz cells towards NaCl 0.9%, water, simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) as receptor media. Results and discussion. The materials obtained are amorphous solids with a loading capacity of at least 75%. EuE100-Ris aqueous dispersions are isotropic and optically clear. The drug-loaded systems showed one single glass transition endotherm indicating that Ris is molecularly distributed. The absorption bands of the nonprotonated dimethylamine groups of EuE100 (2770 and 2816 cm−1) are reduced in the complexes indicating the presence of protonated and nonprotonated dimethylamine groups. The reduction is related to the neutralization percentages of the samples and is accompanied by modifications in the bands assigned to phosphonate groups. In aqueous dispersion EuE100 behaves as a carrier loaded with Ris and function as smart systems, able to release slowly the drug as it is dispersed in water (6% after 2h). The delivery rate increases in saline solutions, with 31, 33 and 57% after 2h in NaCl, SIF and SFG, respectively. The sustained release and first order kinetics accounted for a high affinity, due to the electrostatic attraction. The delivery control is maintained even in SGF. The high condensation ratio could reduce Ris complexation with Ca2+ in the absorption site. Besides, the lower kinetic energy of complexed Ris might moderate the gastric irritant potential or food interaction. The characteristic positive superficial charge of basic polyelectrolytes could also increase the intestinal permeability of Ris. Conclusion. EuE100-Ris complexes are promising materials to develop CRS for oral administration of biphosphonates. The strong interactions between phosphonates and dimethylamine groups of EuE100 could be exploited to develop new systems for others bisphosphonates safer and more efficients.