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Mucoadhesive microspheres containing either amoxicillin or clarithromycin were prepared via the interpolymer complexation of poly(acrylic acid) (PAA) with poly(vinyl pyrrolidone) (PVP) and solvent diffusion method. The complexation between the PAA and PVP in an ethanol/water mixture was confirmed by the change in the transmittance of the solution as a function of repeating PAA and PVP unit ratio. The loading efficiency of clarithromycin in the complex microspheres was higher than that of amoxicillin due to the stronger interaction of clarithromycin with the PAA. The microspheres had a spherical shape with a smooth surface and the inside of the microspheres was completely filled. The dissolution rate of the complex microspheres was significantly slower than that of the PVP microspheres, particularly at pH 2.0. Amoxicillin and clarithromycin degraded significantly during the release study at pH 2.0. Therefore, their release rates were corrected using first order degradation rate constants. The amoxicillin release rates were similar regardless of the pH of the medium, while those of clarithromycin differed depending on the pH. The release mechanism of amoxicillin was mainly by a diffusion process and that of clarithromycin was via a dissolution process. The drug release rate from the complex microspheres was significantly lower than that from the PVP microspheres.