2024 Volume 72 Issue 11 Pages 936-943
Orally disintegrating tablets (ODTs) can be easily swallowed without drinking water and are a convenient dosage form for the elderly and infirmed patients, as well as other patients, such as businesspeople. A major challenge in the development of ODTs is masking the unpleasant taste of the drug, which can make ODTs palatable. Flavors are often used for taste-masking. A few comprehensive studies have been conducted on the selection of suitable flavors for ODTs. This study aimed to evaluate the effects of different flavors on the taste sensation of ODTs using a visual analog scale (VAS). Sixteen flavors were studied for their effects on the taste sensation of pioglitazone ODTs in a randomized single-blind study involving the gustatory sensation testing of ODTs. Healthy volunteers were enrolled and asked to periodically evaluate the bitterness, sweetness, astringency, sourness, and overall palatability of ODTs, both during and after disintegration in the oral cavity, using the VAS. Most flavors improved the sweetness of ODTs without the addition of a sweetener, and some suppressed bitterness, astringency, and sourness. In particular, blueberry, and yoghurt flavors significantly improved sweetness and overall palatability during disintegration of the pioglitazone ODT. The approach of using VAS score analysis was effective in selecting the most suitable flavor for improving the overall palatability of ODT. Furthermore, the addition of a suitable flavor can successfully mask the unpleasant taste of the drug and effectively improve the overall palatability of ODT.
While various drug formulations such as tablets, capsules, granules, and powders are used in drug therapy, tablets are the most widely used in clinical practice because they are easy to administer and superior in terms of portability, storage stability, and distinguishability. Tablets may be difficult for patients with poor swallowing ability, such as the elderly or infants.1,2) Furthermore, because elderly patients prescribed several drugs must consume a large number of tablets, poor swallowing ability may greatly reduce treatment compliance.3) Although some tablets may be powdered or dissolved in water when administered to patients with dysphagia, this is not always possible because it might affect factors such as stability, sustained activity, and enteric coating, or because of the unpleasant taste of the drugs, such as bitterness and astringency. Orally disintegrating tablets (ODTs) have been developed to address these issues. ODTs, which are easy to handle in clinical practice, are also easy to swallow in patients with dysphagia because they disintegrate in saliva or a small amount of water in the oral cavity. However, as ODTs disintegrate into the oral cavity, their taste significantly affects treatment compliance.4,5)
Physical masking is a widely used technique to mask the bitterness of drugs in ODTs by coating the drug particles or granulating them with additives to prevent contact with the taste buds on the tongue.6,7) However, not all unpleasant drug tastes can be suppressed using this technique. Gustatory masking, a method for improving the taste of ODTs by adding flavors, sweeteners, and pH adjusters, is often used in combination.8–10) Gustatory masking involves the combined use of sweeteners, such as aspartame and sucralose, and flavors, such as l-menthol. The addition of sugar alcohol to a bitter drug solution is sufficient to suppress the bitterness.11) Flavored powders with the sour taste of apples and other fruits also effectively reduced the bitterness of drugs,12) and combining aspartame and flavors increased sweetness intensity to a greater extent than aspartame alone and greatly improved the palatability of ODTs.13) As shown in these reports, flavor is important for designing ODT formulations with reduced drug bitterness. Flavors for gustatory masking are generally selected based on the trial-and-error experiences of different manufacturers’ drug formulation developers. However, a comprehensive survey of the optimal flavors of drugs has not yet been reported. The gustatory sensation test focuses only on bitterness as an unpleasant taste,4,5) and there are few cases of the evaluation of other types of taste. Furthermore, the characteristics and masking effects of flavors in ODTs based on the results of gustatory sensation tests have not been analyzed.
In this study, ODTs of pioglitazone hydrochloride (PIO), a medication for type 2 diabetes mellitus, were used to add 16 types of flavors, a gustatory sensation test was conducted using the visual analog scale (VAS) in healthy adult volunteers, and the masking effect of each flavor on the unpleasant taste of PIO was comprehensively analyzed.
PIO was supplied by Takeda Pharmaceutical Company, Ltd. (Osaka, Japan). Ludiflash, obtained from BASF Japan Ltd. (Tokyo, Japan), was used as an excipient for the tablet formulation. Magnesium stearate, obtained from Wako Pure Chemical Corporation (Osaka, Japan), was used as a lubricant. As flavors, apple-flavor, banana-M-flavor, blueberry-flavor, cherry-flavor, chocolate-flavor, lemon-flavor, peach-flavor and pineapple-flavor and were obtained from Takasago International Corp. (Tokyo, Japan), and banana-C-flavor, coffee-flavor, grapefruit-flavor and yoghurt-flavor were obtained from Ogawa & Co., Ltd. (Tokyo, Japan), and grape-flavor and doublemint-flavor were obtained from Virginia Dare Extract Co., Inc. (New York, U.S.A.), and strawberry-flavor was obtained from Firmenich SA (Geneva, Switzerland), and vanilla-flavor (vanillin) was purchased from Merck KGaA (Darmstadt, Germany).
Preparation of ODTThe ODTs were prepared using a tablet press (HANDTAB-100, Ichihashi Seiki Co., Ltd., Japan) through a direct powder compression method with a diameter of 9.0 mm and a compression force of 4 kN. PIO, Ludiflash, flavor, and magnesium stearate were mixed in a plastic bag, and their quantity was adjusted to achieve a final tablet weight of 250 mg (Table 1).
| Non-flavored ODT (mg) | Flavored ODT (mg) | |
|---|---|---|
| Pioglitazone HCl | 33.06 | 33.06 |
| Ludiflash | 215.69 | 215.43 |
| Flavor | — | 0.26 |
| Magnesium stearate | 1.25 | 1.25 |
| Total | 250 | 250 |
The gustatory sensation test was performed as previously described.14) Ten healthy volunteers (3 men and 7 women; mean ± standard deviation, 22.7 ± 2.1 years) participated in a randomized, crossover single-blind study after providing written informed consent. None of the participants were current smokers. This study involved 10 participants with self-reported normal sense of taste and smell. This study was conducted in accordance with the Declaration of Helsinki and its amendments and the protocol was approved by the Ethics Committee of the University of Shizuoka (No. 22-50). The subjects placed each ODT in their mouths and quickly evaluated the immediate scent, bitterness, sweetness, astringency, sourness, and overall palatability of the ODT using a VAS scoring sheet during disintegration of the ODT.9,10,13–16) All volunteers were asked to place a mark along the line of a 100 mm VAS. Subsequently, they completely disintegrate the ODT. After 1 min of placement in the oral cavity, they spated the disintegrated tablet and evaluated the immediate scent, bitterness, sweetness, astringency, sourness, and overall palatability after disintegration of the ODT. In parallel with the evaluation of the gustatory sensation, the in vivo disintegration time of each ODT was measured using a stopwatch. After evaluating the gustatory sensation, the subjects washed their mouth with water. A 15-min interval was provided before testing the next ODT.
Statistical AnalysisDescriptive statistics (mean, standard deviation) were calculated. One-way ANOVA and Dunnett’s post-hoc test were used to compare the VAS values of non-flavored ODT. Analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).17)
Multiple linear regression analysis was performed using the JMP 9.0.2 (SAS Institute Inc., Cary, NC, U.S.A.). Stepwise regression analysis was performed between the VAS score of overall palatability and predictors, such as the VAS score of sweetness, astringency, and sourness, during and after disintegration of ODTs. Considering the collinearity between bitterness and astringency, we conducted multiple regression analysis excluding bitterness.
In the gustatory sensation test, each ODT tested showed very rapid disintegration, which had a in vivo disintegration time of 20.1 ± 2.2 to 23.3 ± 4.7 s, without any significant difference between ODTs. Because the effect of oral disintegration time on taste was similar for all ODTs, it was considered that the feel of each ODT in humans could be properly assessed based on the VAS results obtained in the gustatory sensation test.
Taste Evaluation of Flavored ODTs in Human Gustatory Sensation TestIn this study, the gustatory sensation test was conducted twice, during and after disintegration of the ODT, because the masking effect on unpleasant taste requires consideration of the time course of taste. The VAS results for bitterness, sweetness, astringency, sourness, and overall palatability of all ODTs are presented in Figs. 1–5.
Each bar represents the mean and standard deviation (n = 10). Non-flavor, non-flavored ODT; Apl, apple flavor; BB, blueberry flavor; BanC, banana flavor C; BanM, banana flavor M; Cof, coffee flavor; Che, cherry flavor; Cho, chocolate flavor; Grp, grape flavor; GF, grapefruit flavor; Lem, lemon flavor; Pea, peach flavor; Pin, pineapple flavor; SB, strawberry flavor; Van, vanilla flavor; WM, doublemint flavor; Yog, yoghurt flavor.
Each bar represents the mean and standard deviation (n = 10). * p < 0.05 vs. Non-flavor. Non-flavor, non-flavored ODT; Apl, apple flavor; BB, blueberry flavor; BanC, banana flavor C; BanM, banana flavor M; Cof, coffee flavor; Che, cherry flavor; Cho, chocolate flavor; Grp, grape flavor; GF, grapefruit flavor; Lem, lemon flavor; Pea, peach flavor; Pin, pineapple flavor; SB, strawberry flavor; Van, vanilla flavor; WM, doublemint flavor; Yog, yoghurt flavor.
Each bar represents the mean and standard deviation (n = 10). Non-flavor, non-flavored ODT; Apl, apple flavor; BB, blueberry flavor; BanC, banana flavor C; BanM, banana flavor M; Cof, coffee flavor; Che, cherry flavor; Cho, chocolate flavor; Grp, grape flavor; GF, grapefruit flavor; Lem, lemon flavor; Pea, peach flavor; Pin, pineapple flavor; SB, strawberry flavor; Van, vanilla flavor; WM, doublemint flavor; Yog, yoghurt flavor.
Each bar represents the mean and standard deviation (n = 10). Non-flavor, non-flavored ODT; Apl, apple flavor; BB, blueberry flavor; BanC, banana flavor C; BanM, banana flavor M; Cof, coffee flavor; Che, cherry flavor; Cho, chocolate flavor; Grp, grape flavor; GF, grapefruit flavor; Lem, lemon flavor; Pea, peach flavor; Pin, pineapple flavor; SB, strawberry flavor; Van, vanilla flavor; WM, doublemint flavor; Yog, yoghurt flavor.
Each bar represents the mean and standard deviation (n = 10). * p < 0.05 vs. Non-flavor. Non-flavor, non-flavored ODT; Apl, apple flavor; BB, blueberry flavor; BanC, banana flavor C; BanM, banana flavor M; Cof, coffee flavor; Che, cherry flavor; Cho, chocolate flavor; Grp, grape flavor; GF, grapefruit flavor; Lem, lemon flavor; Pea, peach flavor; Pin, pineapple flavor; SB, strawberry flavor; Van, vanilla flavor; WM, doublemint flavor; Yog, yoghurt flavor.
As shown in Fig. 1, although the mean bitterness VAS score during disintegration of non-flavored ODT was 32.9, those of 7 kinds of flavored ODTs tended to be lower compared to those of non-flavored ODT.
Furthermore, while the mean bitterness VAS score after disintegration was 25.0 for the non-flavored ODT, the scores for the 14 flavored ODTs tended to be lower. The flavors that greatly reduced the mean bitterness VAS scores during and after disintegration were grape (14.2 and 18.5, respectively) and vanilla (23.6 and 12.2, respectively). Strawberry flavor also has a tendency to reduce the mean bitterness VAS scores (26.0 and 11.8, respectively).
Figure 2 shows the mean sweetness VAS score for each ODT. While the mean sweetness VAS score during and after disintegration for the non-flavored ODTs were 3.5 and 7.3, those for most of the flavored ODTs tended to be higher both during and after disintegration. The flavors with significantly intensified sweetness during disintegration were blueberry (23.6) and yoghurt (23.4). Moreover, the mean sweetness VAS scores had the potential to increase with strawberry (21.5 and 30.9 during and after disintegration, respectively), banana-C (20.5 and 21.0, respectively), and banana-M flavors (19.2 and 28.9, respectively).
Figure 3 shows the mean astringency VAS score for each ODT. While the mean astringency VAS score during disintegration was 45.0 for the non-flavored ODT, the scores for the flavored ODTs tended to be lower, with the exception of coffee-flavored ODTs. With regard to the flavored ODTs with a lower score, the mean astringency VAS scores were likely to be greatly reduced by blueberry (25.7), pineapple (29.5), apple (29.6), strawberry (30.0), and chocolate (30.6) flavors. In contrast, while the mean astringency VAS score after disintegration was 25.2 for the non-flavored ODT, the scores for the flavored ODTs, with the exception of coffee-flavored ODT, tended to be lower. The mean astringency VAS scores were likely to be reduced by the strawberry (7.2), banana-M (12.8), and vanilla (11.6) flavors.
The VAS scores for sourness of each ODT are shown in Fig. 4. While the mean sourness VAS score during disintegration was 54.8, for the non-flavored ODT, the scores for the 6 flavored ODTs tended to be lower. The mean sourness VAS scores were 50.3, 51.5, and 51.5 for grape, strawberry, and blueberry flavors, respectively. In contrast, while the mean sourness VAS score after disintegration was 32.6, the scores for the flavored ODTs had the potential to be reduced by banana-M, blueberry, banana-C, grape, grapefruit, coffee, double mint, and vanilla flavors.
The overall palatability VAS score for each ODT is shown in Fig. 5. Although the mean VAS score for overall palatability during disintegration was low for the non-flavored ODT (17.3), overall palatability was likely to be improved by all flavors, except coffee. The blueberry-, and yoghurt-flavored ODTs had significantly higher mean VAS scores of 43.2, and 43.3, respectively. Furthermore, whereas the mean VAS score for overall palatability after disintegration was 31.9 for the non-flavored ODT, the scores tended to be higher for the flavored ODTs, with the exception of coffee-flavored ODTs. Banana-M, blueberry, strawberry, yoghurt, and vanilla-flavored ODTs had particularly high mean VAS scores of 54.3, 53.3, 51.9, 53.3, and 50.3, respectively.
Multiple Linear Regression Analysis of Overall PalatabilityMultiple linear regression analysis was performed to examine the effects of the sweetness, astringency, and sourness taste sensations of each ODT on overall palatability, both during and after disintegration, using the VAS scores for each taste sensation as an explanatory variable (=Xa, a = 1–3), and the VAS scores for overall palatability as an objective variable (=Y). The results are summarized in Table 2. Although the determination coefficients adjusted for the degrees of freedom were 0.461 and 0.473 during and after disintegration, respectively, the p-values for both coefficients were 0.1% or less. The regression equations are sufficiently accurate. Based on these results, the taste sensations affecting the overall palatability during disintegration were sweetness (contribution rate: 0.640) and sourness (contribution rate: 0.193) as positive and negative influencing factors, respectively. After disintegration, sweetness was a positive influencing factor (contribution rate: 0.610), whereas sourness and astringency were negative influencing factors (contribution rates: 0.312 and 0.142, respectively). These results suggest that the VAS score for overall palatability during disintegration can be increased by intensifying sweetness and reducing sourness, and that the score after disintegration can be increased by intensifying sweetness and reducing sourness and astringency.
| Predictors | During disintegration | After disintegration | ||||
|---|---|---|---|---|---|---|
| Regression coefficient | β Coefficient | p-Value | Regression coefficient | β Coefficient | p-Value | |
| Constant | 28.148 | 43.654 | ||||
| Sweetness (X1) | 0.731 | 0.640 | <0.001 | 0.602 | 0.610 | <0.001 |
| Astringency (X2) | — | — | — | −0.138 | −0.142 | 0.018 |
| Sourness (X3) | −0.139 | −0.193 | 0.001 | −0.298 | −0.312 | <0.001 |
| Adjusted R2 | 0.461 | 0.473 | ||||
N = 170.
The mean VAS scores for each taste sensation during and after non-flavored ODT disintegration revealed that PIO was not only bitter but also intensely astringent and sour, and that these tastes persisted even after disintegration or after ODT remnants were spat out. All tested ODTs exhibited a quick disintegration time (<30 s) in the oral cavity, resulting in no influence of tablet characteristics on palatability.18)
The results of bitterness, astringency, and sourness during flavored ODT disintegration revealed that these unpleasant tastes were easily suppressed by adding only one type of flavor. Although low sweetness was reported for the non-flavored ODTs, the mean sweetness VAS scores both during and after disintegration were likely to be increased by most of the flavors used in this study. The sweetness of the PIO ODT has the potential to be by adding only flavors without sweeteners. Blueberry and yoghurt flavors significantly intensify in sweetness during disintegration.
There is a complex interplay of gustatory, olfactory, somatosensory, and emotional stimuli in the sensation of taste. Tastants are detected by taste bud cells, and the signals are transmitted via the facial nerve, glossopharyngeal nerve, and vagus nerve to the gustatory area in the midbrain, and then conveyed to the thalamus via the central tegmental tract.19) The thalamus transmits this information to the cerebral cortex.20) However, the sensation of taste is not determined only by this single pathway.19) Olfaction plays a crucial role in taste perception, exemplified in wine tasting. In previous studies, a taste-intensifying effect was often observed when odor and taste images were consistent.21–24) Scent reaches the olfactory epithelium, contributing to the perception of taste.25) Furthermore, the loss of olfactory function has been reported to restrict taste perception.26) It has been reported that past experiences, preferences, and dislikes may influence taste perception.27,28) For example, when the scent of vanilla, which is often described as sweet,” is smelled while the tongue is stimulated with a sweetener, sweetness is perceived more strongly.29) This is attributable to the fact that smelling the scent of vanilla activates the memory of “vanilla = sweet,” which has been acquired through paired-associate learning from previous dietary experiences. Odor information can affect the processing of taste sensation information to intensify sweetness. In this study, it is possible that the scents of banana M, banana-C, strawberry, blueberry, yoghurt, chocolate, vanilla, and other flavors, which evoked memories of fruits and sweeteners that the volunteers had eaten previously, tended to result in higher mean sweetness VAS scores for PIO ODTs, even though the tablets did not actually contain any sweeteners. The sweetness-enhancing effects of flavors have been reported in the formulations of various drugs.10,30–33) Mukai et al. reported that vanilla and strawberry flavors suppress the bitterness of branched-chain amino acids and evoke a sensation of sweetness.30) In contrast to vanilla flavor, fruit flavors were found to enhance not only sweetness but also the unique tastes of each fruit, such as astringency and acidity. The grape flavor, for instance, demonstrated a moderate VAS score for sweetness while exhibiting higher VAS scores for astringency. Thus, fruit flavors could likely be effectively tailored to match the specific taste of the drug, thereby enhancing the palatability of formulations.
The overall palatability mean VAS scores during and after the disintegration of ODTs were likely to increase for most flavors used in this study. The palatability of the PIO ODTs was improved by the addition of flavors. The Banana-M, strawberry, blueberry, yoghurt, and vanilla flavors tended to increase the mean VAS scores after disintegration. These flavors could potentially have a strong sweetness-intensifying effect after disintegration.
This was consistent with the results of the multiple linear regression analysis performed to determine the effects of each taste sensation on the VAS scores for overall palatability (Table 2). The results showed that the overall palatability VAS scores increased with increasing sweetness VAS scores, both during and after disintegration. In addition, the results of multiple linear regression analysis indicated that the overall palatability VAS scores increased by suppressing sourness during disintegration, and sourness and astringency after disintegration. This suggests that to improve the overall taste of PIO ODTs, it is necessary to not only suppress bitterness and intensify sweetness, but also to select and add flavors that suppress sourness and astringency. The results of this study revealed that flavors suitable for gustatory masking of the unpleasant taste of ODTs should be selected during and after ODT disintegration. Blueberry flavors are suitable for PIO ODTs.
The human gustatory sensation test is the only method used to evaluate the effects of flavors and other scents on taste sensations. In this study, a human gustatory sensation test using the VAS was performed to comprehensively evaluate the taste of each flavored ODT. Furthermore, by analyzing the effects of each taste sensation on the overall ODT taste using multiple linear regression analysis, we identified the characteristics of the drug tastes that were preferentially masked. Consequently, a method for improving the overall taste of flavored ODTs was developed. A combination of comprehensive human gustatory sensation tests and multivariate analysis would allow the design of ODT formulations with a highly preferable taste, while easily masking the unpleasant taste of drugs.
Based on the trend in the VAS scores for each taste of the flavored ODTs, grape, strawberry, blueberry, and yoghurt flavors appeared to reduce VAS scores for bitterness, astringency, and sourness, while tending to increase sweetness VAS scores during disintegration. These flavors may improve the first impression at the time of ODT administration. Moreover, yoghurt, vanilla, strawberry, banana M, and blueberry flavors tended to reduce the bitterness and astringency VAS scores, and to increase the sweetness VAS scores after disintegration. Consequently, these flavors have the potential to improve the aftertaste of ODTs.
A limitation of this study is that the participants were healthy young volunteers. It is known that age, diseases, and concomitant medications were affected the sense of taste.34,35) The previous study reported that the taste perception of patients with diabetes mellitus differed from that of healthy volunteers.36) Because this study was conducted with healthy volunteers, the results may differ in patients with diabetes mellitus or in elderly patients. It would be interesting to determine the differences between healthy young participants and participants of different ages and those with pathological conditions. Moreover, we did not evaluate the flavor content of the test tablets. We considered that by quantifying the amount of flavor in each test tablet, it would be possible to assess the effect of flavor masking more accurately.
In this study, the results of multiple-item gustatory sensation tests using the VAS were analyzed to comprehensively evaluate the effects of flavors on the taste of PIO ODTs. The optimal flavors for masking the unpleasant taste of PIO were banana M, strawberry, blueberry, yoghurt, and vanilla. Moreover, blueberry and yoghurt flavors significantly improved taste immediately after ODT administration, while banana-M, strawberry, and vanilla flavors tended to improve the aftertaste after taking an ODT. Furthermore, there was a time difference in the onset of the flavor-masking effect.
The addition of suitable flavors has the potential not only to reduce the bitterness of drugs but also to greatly improve their overall taste by decreasing astringency and sourness and intensifying sweetness. Therefore, comprehensive human gustatory sensation tests of flavors, followed by multivariate analysis of the results, could be an effective approach for designing the taste of ODTs.
The authors thank Ms. Naho Ikegami for her excellent technical assistance. This work was supported in part by JSPS KAKENHI Grant number JP17K08454.
Dr. Nakano is an employee of Takeda Pharmaceutical Company, Ltd. The others declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.
