An in vitro investigation of the suitability of press-coated tablets with hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydrophobic additives in the outer shell for colon targeting

To develop a new colon targeting formulation, which can suppress drug release completely during 12 h in the stomach and release the drug rapidly after a lag time of 3+/-1 h in the small intestine, the use of press-coated tablets with hydroxypropylmethylcellulose acetate succinate (HPMCAS) in the outer shell was investigated. The release of diltiazem hydrochloride (DIL) as a model drug contained in the core tablets in the 1st fluid (pH 1.2) was suppressed by preparing with higher compression force, hut the lag time in the 2nd fluid (pH 6.8) could not exceed 1.5 h. Therefore, to improve the dissolution characteristics, the effects of addition of various hydrophobic additives to HPMCAS were examined. All of the additives examined suppressed the release rate in the 1st fluid, and prolonged the lag time in the 2nd fluid compared to HPMCAS alone. However, although none of the additives examined fulfilled all of the desired criteria, magnesium stearate (MgSt) and calcium stearate (CaSt) showed interesting effects; the former suppressed drug release completely in 1st fluid, while the latter markedly prolonged the lag time in 2nd fluid. To integrate the merits of each additive, press-coated tablets with a powder mixture of HPMCAS, MgSt and CaSt in the outer shell (HMC tablets) were prepared and in vitro tests were performed. The results indicated that HMC tablets with a mixing ratio of 80% HPMCAS, 5-15% MgSt and 15-5% CaSt in the outer shell met the desired criteria and the lag time in 2nd fluid could also be controlled from 2 to 9 h. At a mixing ratio of 80% HPMCAS, 10% MgSt and 10% CaSt, the dissolution profiles of DIL in 1st fluid and 2nd fluid were not remarkably affected by agitation intensity, and addition of bile salts, pretreatment time or anticipated higher pH except for pH 6.0, respectively. These results indicated the usefulness of HMC tablets with the desirable functions for colon-targeting formulations. (C) 2001 Elsevier Science B.V. All rights reserved.