Bioequivalence of Rebamipide Granules and Tablets
Objective: Rebamipide tablets, which are used in the treatment of patients with gastric ulcers or gastritis, can be difficult to administer in subjects with reduced swallowing ability or impaired swallowing. The granule formulation may be more easily administered in these patients. The bioequivalence between rebamipide granules (20%/0.5g) and tablets (100mg) was determined in healthy male adult volunteers, in accordance with the Partially Revised Guidelines for Bioequivalence Studies of Generic Products.
Study design: In a randomised, nonblind, crossover design, 28 individuals were allocated into two groups of 14 to receive either rebamipide granules or rebamipide tablets. Each individual, under fasting conditions, was administered a single oral dose of rebamipide 100mg followed by a 7-day washout period. Individuals then received a single oral dose of the other rebamipide formulation. Blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours. Plasma rebamipide concentrations were measured by validated high-performance liquid chromatography with tandem mass spectrometry.
Results: The plasma concentration-time profiles and pharmacokinetic parameters of rebamipide after administration of the granule formulation were similar to those of the tablet in 27 healthy male volunteers. Following administration of the granule formulation, the area under the plasma concentration-time curve from time 0-24 hours (AUC_24h) was 912.82 µg/L•h, the maximum plasma concentration (C_max) was 241.82 µg/L, time to maximum plasma concentration (t_max) was 2.5 hours, and plasma elimination half-life (t_1/2) was 1.97 hours. Corresponding values for the tablet formulation were 873.55 µg/L•h, 216.19 µg/L, 2.4 hours, and 1.94 hours. The difference in mean log values was 1.01 for AUC_24h and 1.09 for C_max after granule and tablet administration. The 90% confidence interval of this difference in mean log value was 0.93-1.10 for AUC_24h, and 0.97-1.21 for C_max. This satisfies the criteria for bioequivalence in the guidelines [within log (0.8) to log (1.25)].
Conclusions: Rebamipide granules (20%/0.5g) and tablet (100mg) were bioequivalent. Rebamipide granules may therefore be a more practical treatment option in patients with gastric ulcers or gastritis who have difficulty swallowing tablets.

In preclinical trials, rebamipide was developed to promote the healing of acetic acid-induced gastric ulcers and also to prevent ulcer recurrence in rats. Rebamipide has demonstrated prophylactic effects on various models of acute gastric ulcer including Shay ulcer and drug-induced ulcer. In 1990, rebamipide (Mucosta® tablets) was approved in Japan for gastric ulcer therapy. Subsequently, it was also approved for gastritis and treatment of gastric mucosal lesions (erosion, haemorrhage, redness and oedema) in acute gastritis and acute exacerbations of chronic gastritis. Nonclinical studies show that rebamipide enhances the stimulation of prostaglandin biosynthesis in the gastric mucous membrane, increases mucus glycoprotein synthesis in the superficial layers of the gastric mucosa, activates epidermal growth factor and its receptor expression, and restores gastric epithelia. It is also reported to scavenge free radicals and to suppress neutrophil activation and inflammatory cytokine production (e.g. interleukin-8). These findings confirm the anti-inflammatory activity of rebamipide on the gastric mucosa and suggest that it has effects on gastric mucosal physiological functions, differentiating it from other gastroprotective drugs.

The focus of drug treatment for peptic ulcers has changed from gastric acid secretion inhibitors and histamine H₂ receptor antagonists to proton pump inhibitors (PPIs) and Helicobacter pylori eradication. In clinical practice, rebamipide is generally used to improve the quality of ulcer healing. However, an easily administered formulation was needed for those patients unable to take tablets because of reduced or impaired swallowing ability, or difficulty taking tablets. This led to the development of the granule formulation of rebamipide. The current study was conducted to determine the bioequivalence of this granule formulation with that of the tablet in healthy adult male volunteers. This study was undertaken in accordance with the Partially Revised Guidelines for Bioequivalence Studies of Generic Products and Good Clinical Practice guidelines. The Institutional Review Board approved this study, which was performed at the Sekino Clinical Pharmacology Clinic, Tokyo, Japan.