pH-sensitive microsphere delivery increases oral bioavailability of calcitonin

Oral calcitonin (CT) administration is aimed in the treatment of calcemia in order to circumvent the required regular injections. CT containing microspheres (MS) were designed for colonic delivery by applying a pH-sensitive polymer Eudragit P-4135F for a double emulsion [water/oil/water (w/o/w)] microsphere preparation technique. CT was incorporated in the internal aqueous phase and carboxyfluorescein was encapsulated similarly to allow the characterization of the MS dissolution behavior. Eudragit P-4135F was found to keep the leakage of CT and carboxyfluorescein in vitro at pH 6.8 below 20% within 4 h while at pH 7.4, a fast release was observed for both, dye and peptide. Plasma levels of carboxyfluorescein after oral MS administration proved a sustained release in a rat model, where Cmax of carboxyfluorescein solution was found at around 60 min while for MS formulations it was detected after 4 h. At a dose of 20 microg CT/kg, no significant calcemic effects were found by MS formulations. However, increasing the dose to 100 microg CT/kg resulted in a distinct calcemia and revealed the sustained release properties of the MS. The relative pharmacological effect became most intense after 8-12 h based on the selective pH-dependent delivery. MS showed a fourfold increase of the area above the curve of calcium blood level compared to levels reached after CT solution. The coencapsulation of chitosan in the MS as absorption enhancer did not show any additional effect. The MS formulations proved their applicability as a promising device for pH-dependent colonic CT delivery and might be useful for other peptides.