The Inhibitory Effect of Adenylic Acid on the Bitterness of the Antibacterial Combination Drug Trimethoprim/Sulfamethoxazole.

The purpose of the present study was to evaluate bitterness suppression effect of adenylic acid (AMP) as a nucleotide-derived nutrient enhancer on a bitter commercial drug. In the present study, we evaluated peripheral bitterness inhibition effect of AMP on the trimethoprim (TMP) and sulfamethoxazole (SMZ) combination formulation based on taste sensor. The taste sensor values of TMP solutions with different concentrations show large sensor output in correlation with the concentration of TMP, whereas no sensor output in shown for the SMZ solutions. Therefore, the bitterness of this combination formulation is mainly due to TMP. We evaluated the TMP bitterness inhibitory effects of AMP, sodium salt of AMP (AMP Na; sodium adenylate), sodium salt of GMP (GMP Na; sodium guanylate), and sodium salt of inosine monophosphate (IMP Na; sodium inosinate), and found that only AMP displayed very effective bitterness inhibition. MarvinSketch analysis revealed that potential electrostatic interaction between cationized TMP and anionized forms (II and III) of AMP may cause bitterness suppression. 1H-NMR study suggested an interaction of TMP and AMP molecules based on chemical shift perturbations and an interaction between the phosphate group of AMP and amino group of TMP. Lastly, conventional elution analysis simulating oral cavity capacity for up to one minute were performed using commercial TMP/SMZ combination granules. The sensor output gradually increased up to 60 s. The addition of AMP solution to the eluted sample at 60 s significantly decreased the bitterness sensor output of the eluted sample.

Masking the Taste of Fixed-Dose Combination Drugs: Particular NSAIDs Can Efficiently Mask the Bitterness of Famotidine.

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 1H-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.

A New Bitterness Evaluation Index Obtained Using the Taste Sensor for 48 Active Pharmaceutical Ingredients of Pediatric Medicines.

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.

Development of Taste Sensor to Detect Non-Charged Bitter Substances.

A taste sensor with lipid/polymer membranes is one of the devices that can evaluate taste objectively. However, the conventional taste sensor cannot measure non-charged bitter substances, such as caffeine contained in coffee, because the taste sensor uses the potentiometric measurement based mainly on change in surface electric charge density of the membrane. In this study, we aimed at the detection of typical non-charged bitter substances such as caffeine, theophylline and theobromine included in beverages and pharmaceutical products. The developed sensor is designed to detect the change in the membrane potential by using a kind of allosteric mechanism of breaking an intramolecular hydrogen bond between the carboxy group and hydroxy group of aromatic carboxylic acid (i.e., hydroxy-, dihydroxy-, and trihydroxybenzoic acids) when non-charged bitter substances are bound to the hydroxy group. As a result of surface modification by immersing the sensor electrode in a modification solution in which 2,6-dihydroxybenzoic acid was dissolved, it was confirmed that the sensor response increased with the concentration of caffeine as well as allied substances. The threshold and increase tendency were consistent with those of human senses. The detection mechanism is discussed by taking into account intramolecular and intermolecular hydrogen bonds, which cause allostery. These findings suggest that it is possible to evaluate bitterness caused by non-charged bitter substances objectively by using the taste sensor with allosteric mechanism.

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing.

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 Relationship between Bitter Taste Sensor Response and Physicochemical Properties of 47 Pediatric Medicines and Their Biopharmaceutics Classification.

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 Å2) 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 (D0), an indicator of solubility which takes into account clinical dosage, and fractional absorption (Fa). For medicines classified in group 4, the factors D0 > 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 D0 are the main factors affecting the bitterness of pediatric medicines.

A new strategy for taste masking on bitter drug by other combined drug in fixed-dose combination: bitterness of Amlodipine besylate could be masked efficiently by Valsartan.

OBJECTIVES: The aim of this study was to evaluate the bitterness of amlodipine besylate (AML) combined with other five antihypertensive drugs: alacepril, benazepril, hydrochlorothiazide, telmisartan (TEL) and valsartan (VAL), which have possibility of usage as a fixed-dose combination (FDC) drugs. METHODS: The bitterness of individual six drugs and AML combined with each of the five drugs was evaluated using taste sensor SA402B (Intelligent Sensor Technology Inc.). AML combined with TEL or VAL was evaluated by taste sensor and human gustatory sensation tests. The interaction between AML with TEL or VAL was evaluated by 1 H-NMR. KEY FINDINGS: The bitterness of AML was significantly decreased by addition of VAL, whereas it remained unchanged by the addition of TEL in taste sensor and human gustatory sensation test. In the 1 H-NMR spectrum of AML with VAL, signal shifts of protons in AML were observed compared to that in AML alone. On the other hand, in the 1 H-NMR spectrum of AML with TEL, signal shifts of protons in AML were not observed. CONCLUSIONS: It was suggested that when VAL was mixed with AML, the electrostatic interactions between positive charged amino group of AML and negative charged tetrazole group of VAL were caused, and thereby led the suppression the bitterness of AML.

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs).

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.

Interlaboratory testing of Insent e-tongues.

The first interlaboratory testing of electronic taste sensing systems was performed within five participating centers, each working with the Insent (Insent Inc., Atsugi-Shi, Japan) e-tongue. Preparation of the samples for the comprised four experiments, shipping of the samples and evaluation of the results was performed at the University of Duesseldorf. The sensitivity (in this case the difference between lowest and highest sensor response) and slope of the regression line values, obtained within Experiment 1 and 2, have been found to serve as applicable evaluation criterions for interlaboratory comparability. Modified sensor responses could be attributed to aged sensors, but did not influence the results of either Experiment 3, dealing with the evaluation of film formulations, or Experiment 4, dealing with the evaluation of minitablet formulations, in a great amount. Presented PCA Score and Loading Scatter Plots as well as Euclidean distance patterns based on the raw sensor responses confirmed the comparable performance of Insent e-tongues of the participating centers.

Development and evaluation of a miniaturized taste sensor chip.

A miniaturized taste sensor chip was designed for use in a portable-type taste sensing system. The fabricated sensor chip (40 mm × 26 mm × 2.2 mm) has multiple taste-sensing sites consisting of a poly(hydroxyethyl methacrylate) hydrogel with KCl as the electrolyte layer for stability of the membrane potential and artificial lipid membranes as the taste sensing elements. The sensor responses to the standard taste substances showed high accuracy and good reproducibility, which is comparable with the performance of the sensor probe of the commercialized taste sensing system. Thus, the fabricated taste sensor chip could be used as a key element for the realization of a portable-type taste sensing system.

Advanced taste sensors based on artificial lipids with global selectivity to basic taste qualities and high correlation to sensory scores.

Effective R&D and strict quality control of a broad range of foods, beverages, and pharmaceutical products require objective taste evaluation. Advanced taste sensors using artificial-lipid membranes have been developed based on concepts of global selectivity and high correlation with human sensory score. These sensors respond similarly to similar basic tastes, which they quantify with high correlations to sensory score. Using these unique properties, these sensors can quantify the basic tastes of saltiness, sourness, bitterness, umami, astringency and richness without multivariate analysis or artificial neural networks. This review describes all aspects of these taste sensors based on artificial lipid, ranging from the response principle and optimal design methods to applications in the food, beverage, and pharmaceutical markets.

Study of sweet taste evaluation using taste sensor with lipid/polymer membranes.

The higher sensitivity for sweeteners can be achieved by newly developed lipid/polymer membranes. The membrane is composed of lipids such as phosphoric acid di-n-hexadecyl ester and tetradodecylammoniumbromid, and a plasticizer, dioctyl phenylphosphonate. As a result of changing electric charge of the membrane surface, the newly developed membrane shows 5-10 times higher sensitivity for sucrose than the conventional ones. We also applied the sensor to other sugars such as sugar alcohol which is used as alternative sweetness or food additives. The experimental results of other sweeteners relatively correspond to human sensory evaluation, though the sensitivity for some sugars need to be improved.