Abstract
Hydrophilic matrix tablets are commonly used for extended release dosage forms. For low aqueous-solubility drugs, there may be challenges in modulation of release profiles and achieving consistent release in physiological conditions. To evaluate potential formulation strategies, matrix tablets of a low-soluble drug, hydrochlorothiazide, were developed using hypromellose and two fillers of different solubility, lactose (soluble) or partially pregelatinized maize starch (partially soluble). Additionally, application of an insoluble barrier membrane, aqueous ethylcellulose coating system, and a hydrophilic pore former onto matrix tablets was evaluated. Drug release from uncoated matrix tablets was variable at different agitation rates. Evaluation of tablets in bio-relevant media using physiologically relevant residence time indicated variable and higher initial release rate for uncoated matrices containing lactose but more robust behavior for tablets containing partially pregelatinized starch. Such in vitro behavior may lead to erratic drug release in vivo, when comparing fed versus fasted conditions. Dissolution profiles from barrier membrane-coated tablets showed initial delay, followed by zero-order release kinetics, with reduction or elimination of variability compared to uncoated matrices. Such reduced variability may mitigate mechanical effects of post-prandial stomach. Effects of coating weight gain and inclusion levels of pore former were evaluated and found to be critical in achieving robust and stable release profiles.Electronic supplementary materialThe online version of this article (doi:10.1208/s12249-014-0128-5) contains supplementary material, which is available to authorized users.
Highlights
Hydrophilic matrix technology has been widely used for oral controlled delivery of various drugs
Drug release starts to occur from all tablet surfaces upon hydration of tablet peripheries
The media permeates through the barrier membrane, results in increased hydrostatic pressure within the system which leads to the rupture of coating on tablet edges
Summary
Hydrophilic matrix technology has been widely used for oral controlled delivery of various drugs. In the case of a low aqueous-solubility drug, where the drug release is predominantly controlled by erosion of the polymeric gel layer, low viscosity grades of hypromellose (e.g., METHOCELTM K100LV premium cellulose ethers) are generally recommended to achieve complete and consistent drug release from matrix tablets. Low inclusion level of such grades of hydrophilic polymers, may contribute to lower gel strength [3] and further result in variable and inconsistent release for some drugs. This effect could be critical when matrix tablets are exposed to the post-prandial stomach.
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