In vivo validation of the release rate and palatability of remoxipride-modified release suspension.

Remoxipride, a D2-dopamine receptor antagonist, is well tolerated and completely absorbed after oral administration. Because of its extremely bitter taste, an oral palatable suspension was developed by using a taste-masking microencapsulation. The bioavailability of remoxipride was investigated in two studies in healthy volunteers after administration of a 100-mg dose in suspension. The first study used a capsule as reference, and the second study a plain solution. Taste assessment was carried out in the second study. The extent of bioavailability was the same when comparing the oral suspension to a capsule and to a plain solution. However, the rate of absorption is delayed, and Tmax was 3.0 hr after the suspension, 1.0 hr after the oral solution, and 1.6 hr after the capsule. The release rate in vitro from the suspension was determined by applying the USP-paddle method. By using numerical convolution and deconvolution, the release rates in vivo and in vitro were shown to be similar when using water with 0.5% sodium lauryl sulfate as dissolution liquid. The taste-masked oral suspension is suitable for full-scale production, with good control of the encapsulation process and of the preparation of a suspension.

In vitro-in vivo evaluation of bacampicillin hydrochloride from microcapsules of water-insoluble and an acid-soluble polymer.

Bacampicillin hydrochloride has been microencapsulated to mask its very bitter taste. The objective of the study was to compare the in vitro release and bioavailability of bacampicillin hydrochloride from microcapsules coated with two principally different polymers: a water-insoluble polymer, ethylcellulose, and an acid-soluble polymer, Eudragit E 100. The last mentioned was supposed to have advantages from a bioavailability point of view since this polymer should dissolve rapidly upon reaching the stomach. In vitro release studies were performed in different types of media by using a flow-through cell technique and USP paddle apparatus. The in vivo study was performed on 20 healthy volunteers taking single 400 mg doses of the drug in the two microcapsule suspensions and a reference tablet according to a randomized cross-over design. When standard dissolution fluids were used, the Eudragit E 100-coated microcapsules revealed very rapid dissolution but were greatly dependent on buffer concentration and ionic strength. The ethylcellulose-coated microcapsules released the drug much more slowly than Eudragit E 100 when using standard dissolution fluids. They were also affected by buffer concentration and ionic strength. The reference tablet had a significantly higher bioavailability than the two microcapsule suspensions. In vitro-in vivo correlation was not obtained when using standard dissolution fluids according to USP. However when stimulated intestinal fluid was adjusted to have an ionic strength similar to intestinal fluid, a better in vitro-in vivo correlation was obtained. The Eudragit E 100 polymer did not give better bioavailability than ethylcellulose as a coating polymer on bacampicillin microcapsules.

Linear systems analysis and moment analysis in the evaluation of bacampicillin bioavailability from microcapsule suspensions.

Linear systems analysis, i.e., numerical convolution/deconvolution, and moment analysis have been performed on data obtained from microcapsules containing the ampicillin prodrug bacampicillin hydrochloride. Three batches with different in vitro dissolution rates were scrutinized. From the results, it is concluded that numerical convolution/deconvolution is a valuable tool for predicting bacampicillin bioavailability. However, it must be emphasized that the selection of an appropriate time module is important for predicting an in vivo response that reflects the actual situation. This was verified by comparing the predicted plasma response values with the values obtained in a bioavailability study in healthy volunteers. A correlation between mean residence time in vivo and mean dissolution time in vitro was also found which thus demonstrates the usefulness of moment analysis for obtaining an in vivo-in vitro relationship. This relationship was compared to a correlation found between the mean dissolution time in vitro and the empirical maximum plasma concentration of bacampicillin.

Correlation between the bioavailability of microencapsulated bacampicillin hydrochloride in suspension and in vitro microcapsule dissolution.

The relative bioavailability of microencapsulated bacampicillin hydrochloride in suspension was correlated with the in vitro dissolution half-lives of the microcapsules. Simultaneously, a sensory evaluation was performed to evaluate the taste acceptability of the suspension. The in vitro dissolution half-life is directly related to the coating thickness of the microcapsules. The four suspensions of bacampicillin hydrochloride, containing microcapsules with different coating thickness, were given as single 400-mg oral doses to 12 healthy volunteers after overnight fasting using a crossover design with balanced sequences. Bacampicillin is a prodrug of ampicillin, the concentration of which was determined in plasma and urine by bioassay. There were significant inverse linear relationships between the dissolution half-life and plasma peak concentration, area under the curve, and urinary recovery. The terminal exponential disposition phases of the curves were similar for all four suspensions. There was a significant direct linear relationship between the dissolution half-life and overall taste and bitterness. The results show that the mean bioavailability of bacampicillin hydrochloride from a microcapsule suspension can be predicted from an in vitro dissolution half-life. The results also suggest that bacampicillin hydrochloride can be given in a suspension with sufficient microcapsule film thickness to reduce the bitter taste of the drug and still retain adequate bioavailability.