Design of pH-sensitive microspheres for the colonic delivery of the immunosuppressive drug tacrolimus.

Recently, tacrolimus was shown to be effective in mitigating inflammatory bowel disease (IBD). In the treatment of IBD, oral drug delivery using pH-dependent polymers is one of the most successful therapeutic strategies. Eudragit P-4135F, a pH-sensitive polymer for colonic delivery was used to prepare tacrolimus microparticles using an oil/oil emulsification or an oil/water emulsification technique combined with a solvent extraction or evaporation step. Although the pH-dependent drug release was similar for all types of microspheres, it was generally found that encapsulation rates of oil/water systems (extraction 38.8 +/- 9.4%; evaporation 56.3 +/- 1.9%) were superior to the oil/oil emulsification (4.8 +/- 0.4%). Eudragit P-4135F was found to limit drug leakage at pH 6.8 to levels lower than 10% within 6 h. At pH 7.4, almost immediate release (within 30 min) was observed. From differential scanning calorimetry and X-ray analyses, the drug inside the polymeric microsphere matrix was concluded to be present in a molecular dispersion. Generally, all formulations proved their applicability in vitro as a promising device for pH-dependent colonic delivery of tacrolimus, however, the oil/water technique was found to be superior to the oil/oil approach and among them solvent evaporation seemed to be more advisable, due to the higher encapsulation rate. Copyright 2004 Elsevier B.V.