Design of pH-responsive alginate raft formulation of risedronate for reduced esophageal irritation

Risedronate sodium (RA), a pyridinyl bisphosphonate, is widely used in the treatment of osteoporosis. However, the free acid form of the bisphosphonate below pH 3.5 has the potential to produce severe impatience of the upper gastrointestinal tract, particularly esophagitis. A pH-responsive raft-forming tablet (PRR-T) was designed to prevent the esophageal irritation, mainly consisting of low-molecular-weight alginate (LFR 5/60, 300 mg) as raft-forming polymer, sodium bicarbonate (1000 mg) as gas-generating agent and citrate and sodium citrate (600 and 200 mg, respectively) as buffer system. A PRR-T was rapidly liquefied in water within 80 s with a low viscosity 8.0 mPa s, offering ease of swallowing in patients. A formulation profoundly neutralized simulated gastric fluid over pH 5.5, leading to an ionization of the bisphosphonate, without raft formation. On the other hand, the raft was rapidly formed on the top layer preventing the reflux of RA, if the contact with acidic medium is much higher than 0.5 N of hydrochloric acid. Nevertheless, the release rate of the drug was equivalent, providing over 95% release within 5 min. Our study demonstrated the potential usefulness of alginate-based PRR-T for an oral therapy with bisphosphonates for reduced esophageal adverse experiences.