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This study aimed to evaluate the bitterness of famotidine (FAM) combined with each of three non-steroidal anti-inflammatory drugs (NSAIDs): ibuprofen (IBU), flurbiprofen (FLU), and naproxen (NAP), which have potential as fixed-dose combination (FDC) drugs. We evaluated the bitterness of FAM and each NSAID by taste sensor AN0 and C00, respectively. FAM showed high sensor output representing sensitivity to bitterness, whereas three NSAIDs did not show large sensor output, suggesting that the bitterness intensities of three NSAIDs were lower than that of FAM. The bitterness of FAM on sensor AN0 was suppressed in a concentration-dependent manner when mixed with IBU, FLU, or NAP. Among three NSAIDs, IBU most effectively inhibited bitterness on sensor output, and the gustatory sensation test confirmed that adding IBU to FAM reduced the bitterness of FAM in a concentration-dependent manner. MarvinSketch confirmed that the drugs were mostly present in an ionic solution when FAM was mixed with NSAIDs. The 1 H-NMR spectroscopy analysis also revealed the presence of electrostatic interactions between FAM and NSAIDs, suggesting that the electrostatic interaction between FAM and NSAIDs might inhibit the adsorption of FAM on the bitter taste sensor membrane, thereby masking the bitter taste.

The aim of this study was to evaluate bitterness by using "CCDP; Change in concentration-dependent potential" considering dose-dependency of active pharmaceutical ingredients (APIs) as new and useful bitterness evaluation index compared with bitter sensor output value which is conventional bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th edn, 2019). Solutions (0.01, 0.03, 0.1 mM) of the compounds were evaluated by an artificial taste sensor using membranes sensitive to bitterness. The dose-response slope of the sensor outputs was defined as CCDP. On the basis of principal component analysis of CCDPs, chlorpromazine hydrochloride, amitriptyline hydrochloride, propranolol hydrochloride, primaquine phosphate and haloperidol were predicted to express the strongest levels of basic bitterness, surpassing that of quinine hydrochloride. Correlation analysis (Fisher's exact tests and multiple regression analysis) was performed to determine the relation between CCDPs and various physicochemical properties participated in hydrophilicity and hydrophobicity. It is revealed that contribution physicochemical factors are different by individual basic bitterness sensor (AC0, AN0 or BT0), and this result becomes the criterion of the sensor choice to evaluate basic bitterness intensity using basic bitterness sensors. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride. The pharmaceutical products need a bitterness evaluation in consideration of concentration-dependency to vary in a dose depending on a patient individual. Thus, it was concluded that CCDP correlated to hydrophilicity and hydrophobicity is useful as a bitterness evaluation index of APIs in pediatric medicines.

Diphenhydramine, a sedating antihistamine, is an agonist of human bitter taste receptor 14 (hTAS2R14). Diphenhydramine hydrochloride (DPH) was used as a model bitter medicine to evaluate whether the umami dipeptides (Glu-Glu and Asp-Asp) and their constituent amino acids (Glu, Asp) could suppress its bitterness intensity, as measured by human gustatory sensation testing and using the artificial taste sensor. Various concentrated (0.001-5.0 mM) Glu-Glu, Asp-Asp, Glu and Asp significantly suppressed the taste sensor output of 0.5 mM DPH solution in a dose-dependent manner. The effect of umami dipeptides and their constituent amino acids was tending to be ranked as follows, Asp-Asp > Glu-Glu >> Gly-Gly, and Asp > Glu >> Gly (control) respectively. Whereas human bitterness intensity of 0.5 mM DPH solution with various concentrated (0.5, 1.0, 1.5 mM) Glu-Glu, Asp-Asp, Glu and Asp all significantly reduced bitterness intensity of 0.5 mM DPH solution even though no statistical difference was observed among four substances. The taste sensor outputs and the human gustatory sensation test results showed a significant correlation. A surface plasmon resonance study using hTAS2R14 protein and these substances suggested that the affinity of Glu-Glu, Asp-Asp, Glu and Asp for hTAS2R14 protein was greater than that of Gly-Gly or Gly. The results of docking-simulation studies involving DPH, Glu-Glu and Asp-Asp with hTAS2R14, suggested that DPH is able to bind to a space near the binding position of Glu-Glu and Asp-Asp. In conclusion, the umami dipeptides Glu-Glu and Asp-Asp, and their constituent amino acids, can all efficiently suppress the bitterness of DPH.

The purpose of this study was to investigate the relationship between response to the bitterness taste sensor and physicochemical parameters of 47 pediatric medicines and to classify these medicines according to the biopharmaceutics classification system (BCS). Forty-seven bitter compounds, most of which were on the WHO model list of essential medicines for children (March 2017), were used in the study. Solutions (0.1 mM) were evaluated by an artificial taste sensor using membranes sensitive to bitterness. On the basis of principal component analysis of taste sensor measurements, chlorpromazine, haloperidol, propranolol, amitriptyline, diphenhydramine were predicted to express the strongest levels of basic bitterness, surpassing that of quinine. Correlation tests between bitter taste sensor outputs and physicochemical properties were then carried out and the compounds classified in terms of their biopharmaceutical properties. High log P values (≥2.82), physiological charge (≥1), low log S values (<-3) and small polar surface area (PSA; <45.59 Å 2 ) were found to correlate significantly with the responses of bitter taste sensors. Forty-one of the 47 compounds could be placed into one of four groups in the BCS, on the basis of dose number (D 0 ), an indicator of solubility which takes into account clinical dosage, and fractional absorption (Fa). For medicines classified in group 4, the factors D 0  > 1 and Fa < 0.85 significantly correlated with the responses of the taste sensor for basic bitterness. It was concluded that lipophilicity, physiological charge, solubility, PSA and D 0 are the main factors affecting the bitterness of pediatric medicines.

The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1 H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.

The purpose of the study was to prepare a poly-γ-glutamic acid hydrogel (PGA gel), to evaluate physicochemical properties, its ease of swallowing using texture profile analysis (TPA) and its taste-masking effects on amlodipine besylate (AML) using the artificial taste sensor and human gustatory sensation testing. Using TPA, 0.5 and 1.0% (w/v) PGA gels in the absence of drug were within the range of acceptability for use in people with difficulty swallowing according to permission criteria published by the Japanese Consumers Affairs Agency. The elution of AML from prepared PGA gels was complete within an hour and the gel did not appear to influence the bioavailability of AML. The sensor output of the basic bitterness sensor AN0 in response to AML mixed with 0.5 and 1.0% PGA gels was suppressed to a significantly greater degree than AML mixed with 0.5 and 1.0% agar. In human gustatory sensation testing, 0.5 and 1.0% PGA gels containing AML showed a potent bitterness-suppressing effect. Finally, 1 H-NMR spectroscopic analysis was carried out to examine the mechanism of bitterness suppression when AML was mixed with PGA gel. The signals of the proton nearest to the nitrogen atom of AML shifted clearly upfield, suggesting an interaction between the amino group of AML and the carboxyl group of PGA gel. In conclusion, PGA gel is expected to be a useful excipient in formulations of AML, not only increasing ease of swallowing but also masking the bitterness of the basic drug.

The purpose of this study was to examine the ability of the artificial taste sensor to evaluate the bitterness of drugs by comparing the responses of the taste sensor with documented responses of human TASTE2 receptors (hTAS2Rs). For this purpose 22 bitter compounds, used as ingredients of pharmaceutical medicines in Japan and known ligands of hTAS2Rs, were selected for testing. Their solutions (0.01, 0.03, 0.1 mM) were evaluated by five different taste sensors (AC0, AN0, BT0, C00, AE1). Correlations between physicochemical parameters of the compounds and the responses of the taste sensors and hTAS2Rs were evaluated. From taste sensor measurements, diphenidol, haloperidol, diphenhydramine, dextromethorphan and papaverine, all ligands of hTAS2R 10 and/or hTAS2R14, were predicted to express strong bitterness, surpassing that of quinine. Responses of taste sensors BT0 were found to be significantly correlated with responses of hTAS2R14. High log P values (≧2.73) and responses of hTAS2R14 were also significantly correlated (** p<0.01, chi-square test). In conclusion, taste sensor BT0 is highly sensitive to bitterness and correlates significantly with hTAS2R14, making it useful for evaluating the bitterness of hydrophobic compounds which respond to hTAS2R14 and their inhibitors.

The purpose of this study was to evaluate the taste-masking effects of chlorogenic acid (CGA) on bitter drugs using taste sensor measurements and surface plasmon resonance (SPR) analysis of CGA-drug interactions. Six different bitter drugs were used: amlodipine besylate (AMD), diphenhydramine hydrochloride (DPH), donepezil hydrochloride (DNP), rebamipide (RBM), diclofenac sodium (DCF) and etodolac (ETD). Taste sensor outputs were significantly inhibited by the addition of CGA to all drugs. The inhibition ratio of the taste sensor output decreased in the following order DPH>DNP>AMD≈DCF≈RBM≈ETD. The association rate constant (k a ) for the interaction between drugs and CGA as evaluated by SPR measurement also decreased in the following order DPH>DNP>AMD>DCF≈ETD≈RBM. It was suggested that basic drugs (AMD, DNP, DPH) associate more easily with CGA than acidic drugs (DCF, RBM, ETD). The inhibition ratios (%) of the taste sensor output of bitter drugs caused by CGA and the association rate constants (k a ) between the drugs and CGA were significantly correlated (r s =0.886, p<0.05, Spearman's correlation test). Our findings suggest that the taste-masking effects of CGA are due to its direct association with the drugs. CGA may therefore be a useful taste-masking agent for basic drugs.

The purpose of the study was to evaluate suppression of the bitterness intensity of bitter basic drugs by chlorogenic acid (CGA) using the artificial taste sensor and human gustatory sensation testing and to investigate the mechanism underlying bitterness suppression using 1 H-NMR. Diphenhydramine hydrocholoride (DPH) was the bitter basic drug used in the study. Quinic acid (QNA) and caffeic acid (CFA) together form CGA. Although all three acids suppressed the bitterness intensity of DPH in a dose-dependent manner as determined by the taste sensor and in gustatory sensation tests, CFA was less effective than either CGA or QNA. Data from 1 H-NMR spectroscopic analysis of mixtures of the three acids with DPH suggest that the carboxyl group, which is present in both QNA and CGA but not CFA, interact with the amine group of DPH. This study showed that the bitterness intensity of DPH was suppressed by QNA and CGA through a direct electrostatic interaction with DPH as confirmed in 1 H-NMR spectroscopic analysis. CGA and QNA may therefore be useful bitterness-masking agents for the basic drug DPH.

The purpose of this study was to determine which foods and/or drinks are capable of reducing the bitterness of topiramate when consumed together with the medicine. The inhibitory effects of foods/drinks (yoghurt and nine other foods/drinks) on the bitterness of topiramate (5 mg/mL) were evaluated with a taste sensor using a bitterness-responsive membrane (C00). The effect of topiramate on the taste characteristics of the foods/drinks themselves was also evaluated by taste sensor outputs. The viscosities of the foods/drinks and the influence of the lactic acid and orotic acid components of yoghurt, the most successful of the tested substances in taste masking, on the bitterness of topiramate were also measured. Yoghurt was predicted to be the most effective of the foods/drinks tested in reducing the acidic bitterness-responsive sensor output of topiramate. The outputs of the astringency sensor, sourness sensor, and saltiness sensor to yoghurt were not reduced by the addition of topiramate. The viscosity and lactic acid and orotic acid components of yoghurt seemed to be the keys in reducing the bitterness of topiramate. Yoghurt is predicted to be the food/drink most capable of reducing the bitterness of topiramate without losing the taste of the food/drink itself.

P-glycoprotein (P-gp) regulates absorption of many drugs in the gastrointestinal tract and their accumulation in tumor tissues, but the basis of substrate recognition by P-gp remains unclear. Bitter-tasting phenylthiocarbamide, which stimulates taste receptor 2 member 38 (T2R38), increases P-gp activity and is a substrate of P-gp. This led us to hypothesize that bitterness intensity might be a predictor of P-gp-inhibitor/substrate status. Here, we measured the bitterness intensity of a panel of P-gp substrates and nonsubstrates with various taste sensors, and used multiple linear regression analysis to examine the relationship between P-gp-inhibitor/substrate status and various physical properties, including intensity of bitter taste measured with the taste sensor. We calculated the first principal component analysis score (PC1) as the representative value of bitterness, as all taste sensor's outputs shared significant correlation. The P-gp substrates showed remarkably greater mean bitterness intensity than non-P-gp substrates. We found that Km value of P-gp substrates were correlated with molecular weight, log P, and PC1 value, and the coefficient of determination (R(2) ) of the linear regression equation was 0.63. This relationship might be useful as an aid to predict P-gp substrate status at an early stage of drug discovery., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The purpose of this study was to evaluate the palatabilities of the original and nine generic versions of famotidine orally disintegrating tablets (FODTs) by means of disintegration times and bitterness intensities determined using in combination disintegration device and taste sensor comparison of human gustatory sensation tests. The disintegration times were determined using a new disintegration testing equipment for ODTs, the OD-mate and bitterness intensities were determined using the SA501C taste-sensing system. The disintegration time and bitterness of each FODT was evaluated in gustatory sensation tests. There was a good correlation between the disintegration times of 10 FODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of FODTs at 10, 20 and 30 s after starting the disintegration using the OD-mate and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing. A combination of the OD-mate and the SA501C was capable of predicting the palatabilities, disintegration properties and bitterness intensity of FODTs.

Because stomatitis is a painful condition, gargling with lidocaine is often prescribed before meals. However, because lidocaine inhibits nerve conduction, lidocaine gargling may affect taste perception. Therefore, we studied the effects of lidocaine gargle on taste. We prepared samples of the 5 basic tastes at equivalent concentration levels in terms of the taste quotient. We conducted sensory tests to judge whether the samples could be tasted, and the threshold concentrations (50% taste rate) were estimated from the taste rates. The sensory test was repeated after the subjects gargled with lidocaine, and the efficacy ratio was calculated by comparing the threshold concentrations. Although no interaction was observed between the lidocaine gargle and the threshold concentration levels in the logistic regression analysis, significant differences were observed in the primary effects of each standard, such as the concentration levels, flavor, and bitterness. When the efficacy ratios based on the threshold values were calculated, increases in the thresholds for flavor and bitterness were observed. The results of this study suggested that gargling with lidocaine before a meal increases the thresholds for the appreciation of flavor and bitterness. This increase in the threshold values due to lidocaine was associated not with the pharmacological effect of the drug but with its strong bitterness.

The objective of this study was to evaluate an improved bitterness sensor which has been developed to allow the precise and sensitive prediction of the bitterness of acidic bitter pharmaceutical active ingredients, using as examples nine non-steroidal anti-inflammatory drugs (NSAIDs). The bitterness of the nine NSAIDs was measured using a multichannel taste-sensing system incorporating a bitterness sensor, C00, which has a membrane surface with high hydrophobicity, and was developed to allow an enhanced hydrophobic interaction with acidic bitter substances. The sourness intensities of the nine NSAIDs were also determined in gustatory sensation testing and by a taste sensor using a sourness-sensitive membrane, CA0. The 'Change in membrane Potential caused by Adsorption' (CPA) of sodium diclofenac and etodolac were also determined in the presence of increasing concentrations of tartaric acid using membrane C00. Multiple regression analysis performed on the data on bitterness intensity obtained using the taste sensor and in gustatory sensation testing showed that CPA values from C00 could be used to predict the bitterness of the NSAIDs. The derived equation was y = -0.0413 × CPA + 0.3164, where y represents the predicted bitterness intensity. There were concentration-dependent changes in the bitterness intensities of diclofenac sodium and etodolac without any change in their sourness intensities. For diclofenac sodium and etodolac, there was a good correlation between predicted and actual bitterness intensities in the presence of increasing concentrations of tartaric acid. The taste sensor may be useful for predicting the bitterness intensity of acidic bitter pharmaceutical active ingredients such as NSAIDs.

Objectives: The purpose of this study was to evaluate and compare the palatability of 10 formulations (the original manufacturer's formulation and nine generics) of amlodipine orally disintegrating tablets (ODTs) by means of human gustatory sensation testing, disintegration/dissolution testing and the evaluation of bitterness intensity using a taste sensor., Methods: Initially, the palatability, dissolution and bitterness intensity of the ODTs were evaluated in gustatory sensation tests. Second, the disintegration times of the ODTs were measured using the OD-mate, a newly developed apparatus for measuring the disintegration of ODTs, and lastly, the bitterness intensities were evaluated using an artificial taste sensor., Key Findings: Using factor analysis, the factors most affecting the palatability of amlodipine ODTs were found to be disintegration and taste. There was high correlation between the disintegration times of the 10 amlodipine ODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of amlodipine ODTs 10, 20 and 30 s after starting the conventional brief dissolution test and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing., Conclusions: The OD-mate and the taste sensor may be useful for predicting the disintegration and bitterness intensity of amlodipine ODTs in the mouth., (© 2013 Royal Pharmaceutical Society.)

Objective: Vesicare tablets, whose main component is solifenacin succinate, are known to be extremely bitter. The purpose of this study was to evaluate the effect of crushing on the bitterness of the Vesicare orally disintegrating tablets (ODTs)., Method: Vesicare ODTs and conventional Vesicare tablets (CTs) were crushed either heavily or lightly. The bitterness scores and release rates of sample solutions obtained 5, 10, 30, 60, 90 or 120 s after placing a crushed CT or ODT containing 5 mg solifenacin in 40 ml of water were predicted using two taste sensors (SA402B and a-ASTREE) and HPLC, respectively. The particle size and the surfaces of the crushed tablets were observed microscopically., Key Findings: The predicted bitterness scores and the drug release rates of CTs were high, irrespective of the degree of crushing. The lightly crushed ODT was predicted to be less bitter than the heavily crushed ODT. In lightly crushed ODTs, spherical particles were observed, about 200 mm in diameter., Conclusions: The degree of crushing was a critical factor in determining the expression of bitterness by crushed ODTs. When intact tablets of Vesicare must be crushed to adjust the dosage, it is strongly recommended that ODTs be crushed gently., (© 2013 Royal Pharmaceutical Society.)

The study objective was to quantitatively predict a drug's bitterness and estimate bitterness masking efficiency using an electronic tongue (e-Tongue). To verify the predicted bitterness by e-Tongue, actual bitterness scores were determined by human sensory testing. In the first study, bitterness intensities of eight H(1)-antihistamines were assessed by comparing the Euclidean distances between the drug and water. The distances seemed not to represent the drug's bitterness, but to be greatly affected by acidic taste. Two sensors were ultimately selected as best suited to bitterness evaluation, and the data obtained from the two sensors depicted the actual taste map of the eight drugs. A bitterness prediction model was established with actual bitterness scores from human sensory testing. Concerning basic bitter substances, such as H(1)-antihistamines, the predictability of bitterness intensity using e-Tongue was considered to be sufficiently promising. In another study, the bitterness masking efficiency when adding an artificial sweetener was estimated using e-Tongue. Epinastine hydrochloride aqueous solutions containing different levels of acesulfame potassium and aspartame were well discriminated by e-Tongue. The bitterness masking efficiency of epinastine hydrochloride with acesulfame potassium was successfully predicted using e-Tongue by several prediction models employed in the study., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The bitterness of 10 different products with ambroxol as active ingredient, the original and nine generics, were evaluated by human gustatory sensation tests in which the tablets were kept in the mouth, with water, at 20 and 37°C. The products all showed different bitterness intensities. The original and some of the generic products had comparatively low bitterness intensities but some of the generic products had comparatively high bitterness intensities. The bitterness intensities of these 10 was found to be significantly correlated with both the disintegration time, as evaluated using the ODT-101 (a recently developed apparatus), and the drug concentration in dissolved medium, as measured in a conventional dissolution test. The bitterness threshold of ambroxol solution was found to increase when the temperature of the water with which the tablets were taken, was raised from 20 to 37°C. The equation was calculated to predict the bitterness intensity of ambroxol, a function based on temperature and the ambroxol concentration using data from a standard ambroxol solution at 4, 20 and 37°C. The bitterness intensities obtained for the 10 ambroxol formulations with water at 20 and 37°C, coincided with the bitterness values predicted by the equation.