Citric Acid Suppresses the Bitter Taste of Olopatadine Hydrochloride Orally Disintegrating Tablets

Mai Sotoyama; Shinya Uchida; Shimako Tanaka; Akio Hakamata; Keiichi Odagiri; Naoki Inui; Hiroshi Watanabe; Noriyuki Namiki

doi:10.1248/bpb.b16-00828

Abstract

Orally disintegrating tablets (ODTs) are formulated to disintegrate upon contact with saliva, allowing administration without water. Olopatadine hydrochloride, a second-generation antihistamine, is widely used for treating allergic rhinitis. However, it has a bitter taste; therefore, the development of taste-masked olopatadine ODTs is essential. Some studies have suggested that citric acid could suppress the bitterness of drugs. However, these experiments were performed using solutions, and the taste-masking effect of citric acid on ODTs has not been evaluated using human gustatory sensation tests. Thus, this study evaluated citric acid’s taste-masking effect on olopatadine ODTs. Six types of olopatadine ODTs containing 0–10% citric acid were prepared and subjected to gustatory sensation tests that were scored using the visual analog scale. The bitterness and overall palatability of olopatadine ODTs during disintegration in the mouth and after spitting out were evaluated in 11 healthy volunteers (age: 22.8±2.2 years). The hardness of the ODTs was >50 N. Disintegration time and dissolution did not differ among the different ODTs. The results of the gustatory sensation tests suggest that citric acid could suppress the bitterness of olopatadine ODTs in a dose-dependent manner. Olopatadine ODTs with a high content of citric acid (5–10%) showed poorer overall palatability than that of those without citric acid despite the bitterness suppression. ODTs containing 2.5% citric acid, yogurt flavoring, and aspartame were the most suitable formulations since they showed low bitterness and good overall palatability. Thus, citric acid is an effective bitterness-masking option for ODTs.

Orally disintegration tablets (ODTs) are easy to swallow for patients with dysphagia and easy to administer to elderly and pediatric patients. ODTs are designed to disintegrate upon contact with saliva and in the absence of water, allowing patients to take medication anywhere and at any time, such as in school or workplace. ODTs are highly convenient; hence, these formulations improve patient adherence and increase the effectiveness of pharmacotherapy. In addition, ODTs reduce the amount of water required compared to that required with conventional tablets.¹⁾ Ingestion of ODTs without water may improve QOL of patients with an overactive bladder because an ODT reduces the amount of fluid intake when taking medications.

Many drugs have unpleasant tastes, including ODTs containing drugs, which may reduce patient’s adherence. Taste and palatability of drugs are the greatest barriers to treatment not only in children but also in adults.²⁾ To improve a drug’s palatability, unpleasant tastes are masked using various methods such as physical masking, organoleptic masking, and chemical masking. Taste-masking agents such as flavorings, sweeteners, and acids are often used in organoleptic masking. Some studies reported that flavorings and sweeteners suppressed the bitterness and improved the palatability of ODTs.^3–5) Acids are widely used in many food products, beverages, and drugs to improve their taste, adjust pH, and maintain their stability.⁶⁾ Adding acids to ODTs may mask their bitterness and improve palatability because sourness has been reported to be liked by patients, particularly pediatric patients.⁷⁾

Citric acid, which is found in high levels in citrus fruits such as lemon, is an odorless carboxylic acid and one of the most popular acid ingredients. It is often added to food and beverages for its sourness and to adjust the pH. Similarly, citric acid is used in drug formulations such as “gummy” formulations.⁸⁾ Some studies, by using an electronic tongue⁹⁾ and calcium imaging analysis of human bitter taste receptor hTAS2R, demonstrated that citric acid can suppress the bitterness of drugs.¹⁰⁾ However, these studies were performed using solutions and not ODTs. Further, the taste-masking effect of citric acid in ODTs has not been evaluated using human gustatory sensation tests. The efficacy of citric acid as a taste-masking agent remains unknown.

Recently, the prevalence of allergic rhinitis has increased in Japan, not only in adults but also in children. The three cardinal symptoms in allergy are sneezing, nasal obstruction, and rhinorrhea, which may lead to a loss of concentration and disturb study, work, and daily life. They also deeply affect the QOL. Treatment of allergic rhinitis is important since by controlling the symptoms it improves work productivity and QOL. The international guideline for allergic rhinitis “Allergic Rhinitis and its Impact on Asthma (ARIA)” recommends second-generation antihistamines as therapeutic agents for allergic rhinitis.¹¹⁾ Olopatadine hydrochloride, a second-generation antihistamine, is widely used for the treatment of allergy in both pediatric and adult patients worldwide. However, olopatadine hydrochloride has a bitter taste; thus, effective taste masking of olopatadine ODTs is necessary in the development of ODTs. Olopatadine hydrochloride ODTs could reduce problems with administration and also enhance patient adherence, since patients are usually required to follow a long-term course of treatment. In addition, long-term medication is often associated with a decreased QOL.

The aim of our study was to clarify the effect of citric acid in masking the bitter taste and improving the overall palatability of olopatadine ODTs. Six types of olopatadine ODTs containing 0–10% citric acid were prepared and the taste-masking effect of citric acid was evaluated using human gustatory sensation tests.

MATERIALS AND METHODS

Materials

All samples were commercially obtained as follows: olopatadine hydrochloride from Sumitomo Chemical Co., Ltd. (Tokyo, Japan); D-mannitol (Mannit P) from Mitsubishi Shoji Foodtech Co., Ltd. (Tokyo, Japan); low-substituted hydroxypropyl cellulose (L-HPC LH-20) from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan); methacrylate copolymer (Eudragit^® L 30 D-55) from Evonik Japan Co., Ltd. (Tokyo, Japan); yellow ferric oxide from Kishi Kasei Co., Ltd. (Kanagawa, Japan); talc (CROWN TALC) from Matsumura Sangyo Co., Ltd. (Osaka, Japan); triethyl citrate and citric acid from Wako Pure Chemical Industries, Ltd. (Osaka, Japan); Ludiflash^® and crospovidone (Kollidon^® CL-SF) from BASF Japan Ltd. (Tokyo, Japan); sodium stearyl fumalate from Higuchi Inc. (Tokyo, Japan); yogurt flavor from Ogawa & Co., Ltd. (Tokyo, Japan); and aspartame from Ajinomoto Co., Inc. (Tokyo, Japan). All raw materials used in the formulations were Japanese Pharmacopeia (JP)-compliant products, and the reagents used were either JP listed or commercial special grade chemicals.

Preparation of ODTs

The core particles containing olopatadine hydrochloride were granulated by using a mixer granulator (VG-01, Powrex Corp., Hyogo, Japan), composed olopatadine hydrochloride, D-mannitol, L-HPC, yellow ferric oxide, and Eudragit L 30 D-55. The core particles were coated with a coating solution comprising of D-mannnitol, triethyl citrate, Eudragit L 30 D-55, and talc using a fluidized-bed granulator (MP-01, Powrex Corp.).

The ODTs were prepared by a direct powder compression method using a tablet compressor (HANDTAB-100, Ichihashi Seiki Co., Ltd., Kyoto, Japan). The ODTs formulations are shown in Table 1. The ODTs contained 5 mg olopatadine hydrochloride, and the diameter and weight of the ODTs were 9 mm and 250 mg, respectively. Citric acid was added to the ODTs at concentrations of 0, 0.1, 1.0, 2.5, 5.0, and 10% (C0-, C0.1-, C1-, C2.5-, C5-, and C10-ODTs, respectively).

Table 1. Formulations of the Orally Disintegrating Tablets Containing Citric Acid

Ingredients	ODTs
Ingredients	C0	C0.1	C1	C2.5	C5	C10
Olopatadine granules (mg)	37.71	37.71	37.71	37.71	37.71	37.71
Ludiflash (mg)	198.54	198.29	196.04	192.29	186.04	173.54
Kollidon CL-SF (mg)	12.50	12.50	12.50	12.50	12.50	12.50
Citric acid (mg)	—	0.25	2.50	6.25	12.50	25.00
Sodium stearyl fumalate (mg)	1.25	1.25	1.25	1.25	1.25	1.25
Total (mg)	250.00	250.00	250.00	250.00	250.00	250.00

In addition, to further improve the palatability of the ODTs, ODTs containing other taste-masking agents, a flavoring and a sweetener, were prepared with 2.5% citric acid. ODTs; CF-ODT contained 2.5% citric acid and 0.1% yogurt flavoring, and CFS-ODT contained 2.5% citric acid, 0.1% yogurt flavoring, and 0.3% aspartame.

Tablet Hardness

The hardness of the tablets was measured using a load-cell-type hardness tester (PC-30, Okada Seiko Co., Ltd., Tokyo, Japan). Five tablets of each type of ODTs were evaluated and the mean hardness was calculated.

In Vitro Disintegration Time

The in vitro disintegration time of the tablets was measured using Tricorptester (Okada Seiko Co., Ltd.) as described previously.¹²⁾ Artificial saliva (NaCl, 1.44 g/L; KCl, 1.47 g/L; Tween 80, 0.3%) warmed to 37°C was used as the test solution, and was dripped from a height of 80 mm at a flow rate of 6.0 mL/min. Five tablets of each type of ODTs were evaluated and the mean disintegration time was calculated.

Dissolution

The dissolution test was performed in accordance with the JP Dissolution Test Method 2 (paddle method) at 50 rpm using a JP dissolution tester (PJ-6S, Miyamoto Riken Ind. Co., Ltd., Osaka, Japan). One tablet was placed in 900 mL of purified water that was kept at 37±0.5°C. Samples of the dissolved solutions were taken at 15 min, and the concentration of olopatadine hydrochloride was determined using HPLC.

Dissolution in a Small Volume of Solution

To evaluate the dissolution of olopatadine hydrochloride ODTs in the mouth, the dissolution test was performed with small volumes of solution. One tablet of each ODTs was dissolved for 45 s under magnetic stirring in 10 mL of purified water. The solution was filtered through a 0.45-µm disposable membrane filter (Toyo Roshi Kaisya, Ltd., Tokyo, Japan) and the concentration of olopatadine hydrochloride was determined using HPLC.

HPLC Condition

The concentration of olopatadine hydrochloride was determined using a HPLC system (Prominence UFLC, Shimadzu Corporation, Kyoto, Japan) comprising of a pump (LC-20AD, Shimadzu Corporation), an online degassing unit (DGU-20A3, Shimadzu Corporation), a column oven (CTO-20AC, Shimadzu Corporation), an autosampler (SIL-20AC, Shimadzu Corporation), and a photodiode array detector (SPD-M20A, Shimadzu Corporation), and was integrated using a system controller (CBM-20 A, Shimadzu Corporation). HPLC was performed using an analytical column (L-column ODS, 4.6×250 mm, Chemicals Evaluation and Research Institute, Tokyo, Japan) with a mobile phase (0.05 M phosphate buffer (pH 3.5)/acetonitrile (11 : 9, v/v) containing 8 mM sodium lauryl sulfate) delivered at a flow rate of 1 mL/min. The column temperature was kept at 40°C. Detection was based on UV absorbance at 299 nm.

Human Gustatory Sensation and Clinical Disintegration Time

First, the taste-masking effect of citric acid was assessed. Eleven healthy volunteers (2 male and 9 female volunteers; age, 22.8±2.2 years, mean±standard deviation (S.D.)) participated in this study after providing written informed consent. The study protocol was approved by the Ethics Committee of Hamamatsu University School of Medicine, Japan. The study was registered at the UMIN Clinical Trials Registry (UMIN000022590). The subjects placed each ODT in their mouth and allowed the ODT to disintegrate. Thereafter, the bitterness and overall palatability of the ODTs were evaluated using a visual analog scale (VAS) (1st evaluation). All subjects were asked to place a mark along the VAS line. The strongest sensation for each parameter was marked at 100 mm. VAS bitterness scores of 0 and 100 indicate “none” and “very bitter,” respectively, whereas VAS overall palatability scores of 0 and 100 indicate “bad” and “good,” respectively. Parallel with the VAS evaluation, the clinical disintegration time was measured using stopwatches. After the disintegrated tablet was removed, the subjects were immediately subjected to the VAS evaluation again (2nd evaluation). Thereafter, the subjects rinsed their oral cavity with 120 mL of water and were given a 15-min interval before the testing of the next tablets.

Further tests were performed to clarify the effect of combining the taste-masking agents. The ODTs (C2.5-, CF-, and CFS-ODTs) were evaluated in 13 healthy volunteers (3 males and 10 females; age, 23.3±2.5 years, mean±S.D.) as described above.

Electronic Gustatory Test

The Astree e-tongue system electronic gustatory system (Alpha M.O.S. Japan K.K., Tokyo, Japan) was used for the taste evaluation of the sample solutions. The solutions were prepared as follows: one tablet of each ODTs was dissolved for 30 min under magnetic stirring in 100 mL of purified water. The solution was then filtered through a 0.45-µm disposable membrane filter and subjected to the electronic gustatory tests. Each ODT was analyzed in triplicate. For the analysis, we prepared the placebo ODTs corresponding to C0-, C0.1-, C1-, C2.5-, C5-, and C10-ODTs by replacing olopatadine hydrochloride with Ludiflash.

The data obtained from the Astree sensors were analyzed using AlphaSoft V14 (Alpha M.O.S. Japan K.K.). In this study, principal component analysis (PCA) was employed. PCA can reduce the dimension of data and visualize the differences between the samples on a two-dimensional graph, PCA map. On the PCA map, data points of the sample were compared using the calculated distance between them. The Euclidean distance (the distance between the center of gravity of the placebo and that of the drug samples) was calculated. The Euclidean distance was calculated according to equation below, where d_PQ, n, P, and Q represent the Euclidean distance, the number of sensors, the value measured by sensor of ODT, and the value measured by sensor of placebo, respectively. If the Euclidean distance between two samples is small, then the taste of the drug sample is similar to that of the placebo.

Statistical Analysis

All data are expressed as the mean±S.D. Statistical analysis was performed by using paired t-test with Bonferroni correction by using GraphPad Prism ver.5.02 (GraphPad Software, Inc., San Diego, U.S.A.).

RESULTS

Tablet Characteristics

Table 2 shows the hardness, in vivo and clinical disintegration time, and dissolution at 45 s and 15 min of C0-, C0.1-, C1-, C2.5-, C5-, and C10-ODTs. The hardness of the ODTs was >50 N. The in vitro and clinical disintegration times were 10.5–13.5 and 14.4–15.7 s for all tablets, respectively. The disintegration times of the ODTs containing citric acid (C0.1-, C1-, C2.5-, C5-, and C10-ODTs) were similar to that of C0-ODT. The dissolution of C0, C0.1, C1, C2.5, and C5-ODTs in water at 45 s was 50.2–55.9%, whereas that of C10-ODT in water at 45 s was higher than that of the other tablets. The dissolution of C0, C0.1, C1, C2.5, C5, and C10-ODTs in water at 15 min was 82.9–88.4%.

Table 2. Hardness, in Vitro Disintegration Time, Clinical Disintegration Time, and Dissolution at 45 s and 15 min of C0, C0.1, C1, C2.5, C5, and C10

ODTs	Hardness (N)	Disintegration time (s)		Dissolution (%) ^a)
ODTs	Hardness (N)	In vitro	Clinical	At 45 s	At 15 min
C0	69.6±2.8	10.5±0.20	14.4±3.1	52.3±15	87.2±2.2
C0.1	62.8±6.4	13.5±0.45	14.8±4.9	55.9±2.1	82.9±4.6
C1	55.2±3.0	12.6±0.41	15.7±6.0	50.2±16	84.9±2.9
C2.5	55.0±3.4	11.2±0.58	14.7±4.6	51.7±15	87.8±3.2
C5	52.8±2.7	11.1±0.41	15.5±7.8	52.8±16	88.4±2.0
C10	50.2±2.3	11.6±0.63	15.1±5.6	66.3±8.0	88.1±1.8

Data of hardness and in vitro disintegration time are shown as the mean±S.D. (n=5). Data of clinical disintegration time are shown as the mean±S.D. (n=11). Data of dissolution are shown as the mean±S.D. (n=3). a) Dissolution at 45 s and 15 min was determined via the dissolution test in a small volume of solution, and the JP dissolution test, respectively. C0-ODT, ODT without organoleptic masking; C0.1-ODT, ODT contained 0.1% citric acid; C1-ODT, ODT contained 1% citric acid; C2.5-ODT, ODT contained 2.5% citric acid; C5-ODT, ODT contained 5% citric acid; C10-ODT, ODT contained 10% citric acid.

Taste Evaluation of ODTs in Human Gustatory Sensation Test

To evaluate the taste-masking effect of citric acid, gustatory sensation tests were performed. The bitterness and overall palatability of the ODTs were evaluated with 11 volunteers using the VAS. Bitterness VAS scores of ODTs in the 1st and 2nd evaluation are shown in Figs. 1a and b, respectively. Bitterness scores of C0-ODT were the highest in the 1st and 2nd evaluations (47 and 40) in all the tablets tested. Bitterness scores of ODTs decreased with increasing concentration of citric acid in the 1st evaluation (Fig. 1a). In the 2nd evaluation, the bitterness scores of the ODTs containing citric acid (C0.1-, C1-, C2.5-, C5-, and C10-ODTs) were lower than that of C0-ODT; C2.5-ODT showed the lowest score (Fig. 1b).

Fig. 1. Bitterness VAS Score in 1st Evaluation (during Disintegration) (a) and 2nd Evaluation (after Spiting) (b), and the Overall Palatability VAS Score of C0-, C0.1-, C1-, C2.5-, C5-, and C10-ODTs in 1st Evaluation (c) and 2nd Evaluation (d) Using the Gustatory Sensation Test

Each column presents the mean+S.D. (n=11). Paired t-test with Bonferroni correction was used to detect any significant differences among the orally disintegrating tablets for each test compared with C0-ODT. p<0.01 was considered significant.

Overall palatability VAS scores of ODTs in the 1st and 2nd evaluations are shown in Figs. 1c and d, respectively. Overall palatability scores of C0-, C0.1-, C1-, and C2.5-ODTs in the 1st evaluation were similar (38–46), but those of C5-ODT and C10-ODT were lower (26 and 20, respectively) than those of C0-, C0.1-, C1-, and C2.5-ODTs (Fig. 1c). In the 2nd evaluation, the overall palatability scores of C0.1-ODT and C2.5-ODT (54 and 55) were higher than that of C0-ODT (44) (Fig. 1d).

Electronic Gustatory Test

The sensor data obtained from the sample solutions were analyzed using PCA, and the Euclidean distances were calculated. The Euclidean distance is the distance between each drug-containing ODT and its corresponding placebo. The Euclidean distances are shown in Fig. 2a. The Euclidean distances decreased with increasing content of citric acid, from C0-ODT (373) to C10-ODT (33.8). The relationship between the Euclidean distances and the bitterness VAS scores in the 1st evaluation of each ODT obtained by the human gustatory sensation test is shown in Fig. 2b. A good correlation was observed between these 2 parameters (correlation coefficient (r²)=0.982; p<0.001).

Fig. 2. Euclidean Distances of C0-, C0.1-, C1-, C2.5-, C5-, and C10-ODTs (a), and the Relationship between the Euclidean Distance and Bitterness VAS Score in the 1st Evaluation (b)

(a) Each column represents the data from one experiment. (b) Bitterness VAS scores in the 1st evaluation as shown Fig. 1a were plotted on the y-axis, and the Euclidean distances shown in Fig. 2a were plotted on the x-axis.

Effect of Combining Taste-Masking Agents

To evaluate the effect of combining the taste-masking agents (flavoring and sweetener) with C2.5-ODT, which showed a low bitterness VAS score and a high overall palatability VAS score, we prepared 2 types of ODTs (CF- and CFS-ODT). Flavoring and flavoring plus sweetener were added to C2.5-ODT to obtain the preparations CF- and CFS-ODTs, respectively. The hardness of CF- and CFS-ODTs was 59±4.5 and 54±3.1 N, respectively. The in vitro disintegration times of CF- and CFS-ODTs were 12.4±0.38 and 13.2±1.7 s, and the clinical disintegration times of CF- and CFS-ODTs were 19.7±4.2 and 15.9±3.0 s, respectively. The dissolution of CF- and CFS-ODTs was 48.0±24 and 42.2±21% at 45 s, and 88.3±2.5 and 89.6±1.0% at 15 min, respectively.

In the human gustatory sensation tests, the bitterness VAS scores in the 1st and 2nd evaluations were decreased by the addition of flavoring and sweetener compared to those of C2.5-ODT (Figs. 3a, b). The overall palatability VAS scores were increased following the addition of flavoring and sweetener in both the 1st and 2nd evaluations (Figs. 3c, d). Overall palatability VAS score in the 2nd evaluation of CFS-ODT was significantly higher than that of C2.5-ODT.

Fig. 3. Bitterness VAS Score in 1st Evaluation (a) and 2nd Evaluation (b), and the Overall Palatability VAS Score of C2.5-, CF-, and CFS-ODTs in 1st Evaluation (c) and 2nd Evaluation (d) Using the Gustatory Sensation Test

Each column represents the mean+S.D. (n=13). Paired t-test with Bonferroni correction was used to detect significant differences among the orally disintegrating tablets for each test compared with C2.5-ODT. p<0.025 was considered significant.

DISCUSSION

The aim of this study was to clarify the taste-masking effect of citric acid on ODTs. Six types of olopatadine ODTs containing citric acid were evaluated for their bitterness and overall palatability in human gustatory sensation tests. The results suggested that citric acid effectively suppresses the bitterness of olopatadine ODTs.

In the human gustatory tests, the bitterness VAS score of the ODT without citric acid (C0-ODT) was the highest among the tested ODTs in both the 1st and 2nd evaluations, indicating that C0-ODT has the strongest bitter taste during disintegration in the mouth and after administration. We previously showed that the palatability of several ODTs could be quantitatively evaluated using the VAS in human gustatory sensation tests.^3–5,13) VAS is widely used to assess the levels of pain or palatability in humans and is regarded as a reproducible approach that provides a good representation of subjective measurements.^14–16)

The bitterness VAS scores of the ODTs containing citric acid decreased with an increasing amount of citric acid. Furthermore, the ODTs without citric acid (C0-ODT) showed the longest Euclidean distance as measured by the electronic gustatory system (Astree e-tongue system) among the tested ODTs, and the distance decreased with an increasing amount of citric acid. In addition, VAS score and Euclidean distance of the ODTs showed the plateau over 5% of citric acid. These results strongly suggest that citric acid can suppress the bitterness of olopatadine ODTs in a dose-dependent manner, at least under 5% of citric acid. In vitro and clinical disintegration times and dissolution at 45 s and 15 min of the ODTs containing citric acid did not differ among the ODTs tested. Thus, the suppressive effect of citric acid on the bitterness of olopatadine ODTs was not caused by changes in tablet characteristics from the content of citric acid. The results of the in vitro evaluations demonstrated the suppressive effects of citric acid on bitterness. Rachid et al. showed that citric acid suppressed the bitterness of epinephrine by using the taste evaluation using an e-tongue.⁹⁾ Calcium imaging analysis also indicated that citric acid inhibited the response of hTAS2R16, one of the human bitter taste receptors, to salicin.¹⁰⁾ In addition, Lawless et al. demonstrated that citric acid suppressed the bitterness of calcium chloride by using human gustatory sensation tests.¹⁷⁾ Our results were consistent to these findings, and demonstrated the suppressive effect of citric acid on the bitterness of ODTs. In these previous studies, however, the effects were observed with citric acid solutions instead of tablet formulations. In this study, we demonstrated the role of citric acid as a taste-masking ingredient in ODTs.

Interestingly, the overall palatability of the olopatadine ODTs with a high content of citric acid (5–10%) were poorer than that of C0-ODT, despite its bitterness. In addition, the bitterness VAS scores of ODTs with a high content of citric acid did not differ to that of ODTs containing 2.5% citric acid. Rousmans et al. reported a confusion in taste between sour and bitter in 12% of the subjects.¹⁸⁾ Therefore, it is likely that the ODTs with a high content of citric acid could be recognized as bitter by some of the subjects because of a confusion in taste. In this context, the addition of high-content citric acid should be avoided, and C2.5-ODTs were the most suitable formulation since it is associated with low bitterness and high overall palatability.

In this study, a good correlation was observed between the bitterness VAS score determined using human gustatory test and the Euclidean distance measured using electric gustatory test. Previously, Nakamura et al. evaluated the palatability of famotidine- and amlodipine-containing ODT by using human gustatory sensation test and e-tongue, and reported a good correlation between the Euclidean distance and the VAS score.¹⁹⁾ Thus, it was suggested that the electric gustatory test of Astree e-tongue could evaluate the effects of organoleptic taste-masking ingredients including citric acid.

Various organoleptic methods have been reported to improve the palatability of ODTs.^3,5,13) Accordingly, to further improve the palatability of ODTs, ODTs containing 2.5% citric acid, yogurt flavoring, and aspartame were prepared. The ODTs containing 2.5% citric acid was thought as a basic formulation because this was the most suitable olopatadine ODTs preparation. The overall palatability VAS score of the ODT containing citric acid, yogurt flavoring, and aspartame was the highest compared to those of other ODTs in the 1st and 2nd evaluations. This result suggests that this combination of taste-masking agents is effective in improving palatability, and we could formulate olopatadine ODTs with good palatability by using a combination of citric acid, yogurt flavoring, and aspartame.

CONCLUSION

Olopatadine hydrochloride ODTs were prepared and subjected to bitterness and overall palatability evaluations using the VAS scale in human gustatory sensation tests. Our results suggested that citric acid could suppress the bitterness of olopatadine ODTs dose-dependently. Olopatadine ODT containing 2.5% citric acid was the most suitable formulation. As expected, citric acid is an effective bitterness-masking option for ODTs and could help improve patient’s adherence.

Acknowledgments

The authors are grateful to Mr. Takuya Murao, Mr. Yoshihisa Gouhara, Ms. Hikari Yamashita, and Ms. Haruka Ogawa for excellent technical assistance.

Conflict of Interest

SU and NN received a Research Grant from Kissei Pharmaceutical Co., Ltd. (Tokyo, Japan), Kyowa Hakko Kirin Co., Ltd. (Tokyo, Japan), Towa Pharmaceutical Co., Ltd. (Osaka, Japan), and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). NN serves as a consultant to Kissei Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Shiseido Japan Co., Ltd. (Tokyo, Japan). KO received research funding from Japan Research Foundation for Clinical Pharmacology. The other authors declare no conflict of interest.

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