Development, characterization and in-vivo evaluation of a zero-order release dosage form of a highly water soluble drug, niacin

The focus of this dissertation was to develop and evaluate a zero-order extended-release, coated matrix tablet formulation of the antihyperlipidemic drug niacin.;After screening of several excipients final core tablet formulations were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC, PEO, and lactose. Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals and to quantify the effect of each formulation variables. To further investigate findings from the multivariate statistical study Near Infrared Chemical imaging (NIR-CI) was utilized. The drug release rate of matrix based tablets is determined by the rate of hydration, gel formation and gel thickness of the hydrophilic polymers. Main focus of NIR-CI in the present work was on developing methods for measuring radial dimensions of the gel layer and tablet core, characterizing the glassy to rubbery transition of the hydrophilic polymer, and quantifying drug substance in hydrated matrix tablets using single wavelength images, as well as Principal Component Analysis (PCA) and Partial Least square (PLS) algorithms based on NIR-CI data. Results showed that for formulations with lower level of PEO and high level of EC matrix hydration and gel layer formation is much slower than formulations with higher level of PEO and lower level of EC.;Coated matrix tablets were developed in order to eliminate the burst effect of the matrix formulations and thereby obtaining a zero order release of niacin. Matrix tablets were manufactured with three different levels of drug loading 40%, 50% and 60% to evaluate the coating. All the tablet formulations then were coated at three different levels of coating with hydroxypropylmethyl cellulose (HPMC K-15), 3%, 6% and 9%. The formulations showed a higher rate of drug release with the increase of drug content in the core tablet formula. The uncoated core formulation with 40% drug load showed very close to a zero order release (diffusional exponent: n = 0.78) while the formulations with higher level of drug content showed more of a non-Fickian or anomalous type of dissolution behavior. However with a coating of HPMC on top of the core tablet slowed down the dissolution process substantially with a minimum burst effect. The diffusional exponent, n shows a clear indication of moving towards a Type II with the increase of coating level. However the change in the dissolution profile is much more pronounced for the formulations with 50% and 60% of drug loading. The change in dissolution profile is marginal for the formulation with 40% drug load. A closer look at the drug concentration at the edge of the gel layer for both the uncoated and coated matrix tablet revealed that while the drug concentration gradient is falling for the matrix tablet the coated matrix tablet is maintaining a constant gradient of drug substance across the HPMC coating layer at all the level of hydration from 2 hour to 10 hour. This constant gradient maintains the driving force for the release of the drug at a constant rate for an extended period of time.;Three formulations were chosen for in vivo study in rabbits: uncoated matrix formulations A (60% drug loading) and B (50% drug loading) as well as the coated formulation A (60% drug loading). Consistent with the in vitro dissolution profiles, the plasma profiles demonstrated clear distinction and a qualitative rank order correlation between the formulations. It was evident from the plasma profile that the drug substance from the coated matrix formula was released and absorbed at the much slower rate than the uncoated matrix tablets. Furthermore, the drug absorption was extended for a longer period of time for the coated formulation. The cumulative in vitro release profiles of three formulations demonstrated good agreement with their corresponding in vivo absorption profile, obtained by the deconvolution of the plasma concentration-time curves. (Abstract shortened by UMI.)...