Category: Formulation and Quality
Purpose: Fixed-dose combination (FDC) medicines containing two or more active pharmaceutical ingredients (APIs) administered in a single dosage have been reported to improve patient adherence to a greater extent than do single dosages of individual components (ICs). Orally disintegrating tablets (ODTs) are easier to swallow than are conventional tablets. Thus, ODTs containing two or more APIs (fixed-dose combination orally disintegrating tablet, FDC-ODTs) possess the advantages of both FDCs and ODTs and have the potential to further improve patient adherence.
Mitiglinide and voglibose are used for oral antidiabetic therapy. Both are taken immediately before meals for the treatment of postprandial hyperglycemia. Mitiglinide/voglibose FDC-ODT is expected to improve patient adherence for medicines that are administered just before meal, since the FDC-ODT may reduce issues associated with medication, such as the need for water, taking multiple tablets, and difficulty in swallowing.
The aim of this study was to elucidate the clinical pharmaceutical characteristics, including ease of taking tablets and amount of water required associated with taking an FDC-ODT and two IC-ODTs, using placebo ODTs. Additionally, we evaluated taste of FDC-ODT and two IC-ODTs containing APIs.
Methods: We prepared three ODTs containing mitiglinide, voglibose, and mitiglinide/voglibose (GF-ODT, BS-ODT, and GB-ODT, respectively) and three corresponding placebo ODTs (pGF-ODT, pBS-ODT, and pGB-ODT, respectively), and performed two independent clinical trials with 13 healthy subjects.
In trial 1, we evaluated the ease of taking tablets and the amount of water required for taking the tablets; placebo ODTs were used to avoid administering APIs. The trial involved a phase of taking a pGF-ODT and a pBS-ODT (a total of two tablets) simultaneously (IC-ODTs phase) and a phase of taking a pGB-ODT (FDC-ODT phase). Subjects were asked to evaluate the ease of taking the ODTs using a visual analogue scale (VAS), with the most difficult sensation of taking a tablet marked at 100 mm. Then, subjects evaluated the ease of intake using a four-point verbal rating scale (VRS): 1 = very difficult to swallow, 2 = slightly difficult to swallow, 3 = slightly easy to swallow, 4 = very easy to swallow.
In trial 2, we evaluated the bitterness, sweetness, and overall palatability of ODTs containing APIs during disintegration and after spitting out, using a VAS. Bitterness, sweetness, and overall palatability VAS scores of 100 indicated “very bitter,” “very sweet,” and “good,” respectively. The subjects also evaluated preferability using a five-point VRS: 1 = very non-preferable, 2 = non-preferable, 3 = neither, 4 = preferable, 5 = very preferable. This trial consisted of an IC-ODTs phase including a GF-ODT and BS-ODT and an FDC-ODT phase including a GB-ODT.
Results: In trial 1, the VAS score for ease of taking tablets in the FDC-ODT phase was significantly lower (62.5%) than that in the IC-ODTs phase (7.8 vs. 20.8; p=0.010, figure 1). The mean score significantly increased from 3.3 to 3.8 (IC-ODTs phase and FDC-ODT phase, respectively) in the four-point VRS evaluation of ease of intake (p=0.028, figure 2). The amount of water required for taking the tablets in the IC-ODTs phase and FDC-ODT phase was 22.5 mL and 17.0 mL, respectively (figure 3). The amount of water for taking an FDC-ODT was decreased by 24.4% relative to that required for taking two IC-ODTs. Thus, FDC-ODT intake is easier and requires lesser water than does IC-ODTs intake. It is likely that FDC-ODT with the advantages of both FDC and ODT could lead to further improvement of patient adherence.
In trial 2, the differences in VAS scores between the IC-ODTs phase and the FDC-ODT phase were not significant, except for the sweetness VAS score after spitting out. The sweetness VAS score after spitting out the ODT in the FDC-ODT phase was significantly higher than the score in the IC-ODTs phase (p=0.012). In VRS evaluation, the mean FCD-ODT phase score for taking a GB-ODT tended to be higher than the IC-ODTs phase score for taking a GF-ODT and a BS-ODT (2.7 vs. 3.2; p=0.053).
Conclusion: The results suggest that the mitiglinide/voglibose FDC-ODT improved palatability and reduced the amount of water required for taking tablets to a greater extent when compared with the two IC-ODTs (a mitiglinide ODT and a voglibose ODT). Many patients with diabetes mellitus take two or more medicines daily; in these cases, switching from IC to FDC and from conventional tablets to ODTs will be helpful in terms of improving palatability and reducing the amount of water required. Mitiglinide/voglibose FDC-ODT can contribute to enhancing the adherence of patients with diabetes mellitus.
Shinya Uchida– Associate professor, University of Shizuoka, Shizuoka, Shizuoka, Japan
Chiaki Kamiya– Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Shimako Tanaka– Assistant professor, University of Shizuoka, Shizuoka, Shizuoka, Japan
Yasuharu Kashiwagura– Assistant professor, University of Shizuoka, Shizuoka, Shizuoka, Japan
Akio Hakamata– Assistant professor, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Keiichi Odagiri– Associate professor, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Naoki Inui– Associate professor, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Hiroshi Watanabe– Professor, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Noriyuki Namiki– Professor, University of Shizuoka, Shizuoka, Shizuoka, Japan