Shunsuke Matsukawa

Background/Objectives: Orally disintegrating tablets (ODTs) are often used for patients with dysphagia; however, their co-administration with “thickened water” in clinical settings can delay disintegration and potentially reduce therapeutic efficacy. While wicking networks formed by superdisintegrants facilitate rapid disintegration, we hypothesized that viscous polymers in thickened water cause “pore clogging” within these networks. Although conventional macroscopic evaluations have demonstrated this delay, direct visualization of the underlying microstructural changes remains unexplored. Therefore, this study aimed to elucidate the microstructural mechanisms of disintegration delay. Methods: Simplified model ODTs containing either a wicking-type (crospovidone [CP]) or a swelling-type (sodium starch glycolate [SSG]) disintegrant were prepared. Their microstructures and disintegration behaviors were evaluated by cryogenic focused ion beam scanning electron microscopy (Cryo-FIB-SEM), three-dimensional (3D) X-ray computed tomography (CT), and disintegration tests under simulated gastric conditions (pH 1.2). Results: Cryo-FIB-SEM revealed that CP-containing tablets formed numerous channel-like pores that promoted capillary action upon contact with water, whereas SSG-containing tablets formed larger, isolated macropores. X-ray CT analysis demonstrated distinct low-density regions associated with penetration-induced structural changes in both formulations. In CP-containing tablets, these regions extended throughout the channel network, whereas in SSG-containing tablets they were largely confined to the tablet surface. Consequently, the disintegration of CP-containing tablets in simulated gastric fluid was significantly delayed compared to that of SSG-containing tablets. Conclusions: The findings are consistent with a pore-clogging mechanism in which penetration of a viscous medium interferes with the liquid transport pathways responsible for rapid tablet disintegration. Combined Cryo-FIB-SEM and X-ray CT imaging provided direct morphological evidence of disintegrant-dependent structural responses in viscous media and offers a new framework for mechanistic investigation of tablet disintegration processes.

Background/Objective: It is not uncommon for elderly patients to experience difficulties with feeding and swallowing. In the simple suspension method, tablets are dissolved and suspended in warm water without prior crushing or decapsulation, and then administered via a tube. Despite the prevalence of this method, the pharmacokinetics of suspended tablet dosage forms remain poorly understood. Methods: Verapamil was employed in dissolution tests following both the simple suspension and crushing methods. A pharmacokinetics study was conducted on healthy adult males. Results: The resultant dissolution profiles from the two methods exhibited notable dissimilarities. Drug release from the crushed product commenced earlier than that from the simple suspension and intact tablet. Furthermore, the area under the curve for verapamil during the initial 24 h period was 1.7 and 1.3 times greater in the crushed and simple suspension groups, respectively, than in the tablet group. Conclusions: The crushing and simple suspension methods are safe techniques for administering medications to patients with dysphagia, thereby preventing aspiration. Nevertheless, the processing of medications may result in an increased frequency of adverse effects. It is recommended that the processing of medicines prior to administration be avoided.

To investigate how mitochondrial function was affected in leukotoxin (Lx)-,9,10-epoxy-12-octadecenoate-induced lung injury, lung mitochondria were extracted from isolated perfused rat lung with or without Lx-induced edematous injury. In the lung treated with 30 mumol of Lx, the mitochondrial respiration rate in states 3 and 4 significantly decreased (without mitochondrial uncoupling) concomitantly with increased release of lactate dehydrogenase (LDH), a parameter for cellular damage, into the perfusate and decreased ATP content in the lung tissue compared with those of untreated lung. Moreover, 30 mumol of Lx resulted in significant inhibition of cytochrome-c oxidase activity (vs. vehicle control). In contrast, lower doses of Lx (10 mumol) caused lung edema and cellular damage without evidence for mitochondrial dysfunction. We also examined cellular and mitochondrial damage in hydrostatic lung edema. Such edema showed neither suppressed mitochondrial respiration nor elevated LDH activity in perfusate, although lung wet weight increased as much as it did after 30 mumol Lx treatment. Our results suggest that the ex vivo mitochondrial dysfunction is one of the secondary (vs. initial augmented permeability) but specific manifestations of toxicity of Lx, and together with the previous reports, the ex vivo damaging effect of Lx against mitochondria may be ascribed not to its direct action on mitochondria but to Lx-derived cellular mechanism(s).