Relationship between Diffusivity of Water Molecules Inside Hydrating Tablets and Their Drug Release Behavior Elucidated by Magnetic Resonance Imaging

Abstract

We reported previously that sustained release matrix tablets showed zero-order drug release without being affected by pH change. To understand drug release mechanisms more fully, we monitored the swelling and erosion of hydrating tablets using magnetic resonance imaging (MRI). Three different types of tablets comprised of polyion complex-forming materials and a hydroxypropyl methylcellulose (HPMC) were used. Proton density-and diffusion-weighted images of the hydrating tablets were acquired at intervals. Furthermore, apparent self-diffusion coefficient maps were generated from diffusion-weighted imaging to evaluate the state of hydrating tablets. Our findings indicated that water penetration into polyion complex tablets was faster than that into HPMC matrix tablets. In polyion complex tablets, water molecules were dispersed homogeneously and their diffusivity was relatively high, whereas in HPMC matrix tablets, water molecule movement was tightly restricted within the gel. An optimal tablet formulation determined in a previous study had water molecule penetration and diffusivity properties that appeared intermediate to those of polyion complex and HPMC matrix tablets; water molecules were capable of penetrating throughout the tablets and relatively high diffusivity was similar to that in the polyion complex tablet, whereas like the HPMC matrix tablet, it was well swollen. This study succeeded in characterizing the tablet hydration process. MRI provides profound insight into the state of water molecules in hydrating tablets; thus, it is a useful tool for understanding drug release mechanisms at a molecular level.Key words magnetic resonance imaging; sustained release; diffusion; swelling; hydration Directly compressed hydrophilic polymer matrix tablets have been widely used as a controlled-release oral formulation because they are easy to manufacture and inexpensive, with versatile release characteristics.1,2) Various hydrophilic matrix tablets are highly water-soluble, show good gelation performance, and are stable and safe. Numerous polymers have been used that enable the formation of a gel layer around the tablets. In these formulations, the factors affecting in vitro drug release, such as drug/polymer ratio, polymer viscosity, and amount of additives, have been studied from the viewpoint of formulation design. [3][4][5] We have been investigating sustained release tablets comprising hydroxypropyl methylcellulose (HPMC) and dextran derivatives as a gel-forming hydrophilic polymer and polyion complex-forming materials. Dextran sulfate (DS) and [2-(diethylamino)ethyl] dextran (EA) are anionic and cationic dextran derivatives and their resultant polyion complex matrix possesses sustainable drug-releasing properties. In a previous study, we manipulated the composition of a gel-forming and polyion complex matrix in an attempt to develop a sustained release tablet having zero-order drug release without being affected by pH change. Diltiazem hydrochloride (DTZ), a highly water-soluble drug, was used as a model. As a ...

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