Quantitative evaluation of the bitterness of commercial medicines using a taste sensor

The bitterness of 11 commercial medicines was evaluated both by a multichannel taste sensor and in human gustatory sensation tests with 15 volunteers. For basic drugs with amino groups in the molecule, such as quinine, there was a comparatively strong relative response electric potential (mV) of channels 1 or 2, those containing negatively charged membranes and the bitterness determined by human gustatory sensation tests. The suppression of the bitterness of quinine by sucrose and aspartame could be quantified using the artificial taste sensor and the results concurred with those from gustatory sensation tests. The usefulness of the sensor was thus confirmed for this type of compound. Anionic drugs, such as diclofenac sodium or salicylic acid gave rise in a negative response electric potential in channels 5 or 6, those containing positively charged membrane, seemed to be useful information even though their tastes are being sour rather than bitter. For drugs with both an amino (cationic) group and carboxylic acid (anionic) group in the molecule, such as theophylline, caffeine, and metronidazole, the relative response electric potential (mV) of channels containing negatively charged membranes was not increased, even though bitterness was observed in human gustatory sensation tests. Therefore, a different design of membrane component is required for more general evaluation of the bitterness of various medicines.     

A new method for evaluating the bitterness of medicines by semi-continuous measurement of adsorption using a taste sensor

We describe a new method for the evaluation of the bitterness of medicines by semi-continuous measurement of adsorption using a multichannel taste sensor or 'electric tongue'. The bitterness of 10 basic medicines was evaluated by both the taste sensor and in human gustatory sensation tests with 11 volunteers. The sensor part of the taste sensor consists of eight electrodes made of lipid/polymer membranes. Three variables were obtained from the taste sensor data: sensor output (S), the change of membrane potential caused by adsorption, corresponding to aftertaste (C), and the ratio C/S. These variables were used to predict an estimated bitterness score in multiple regression analysis. Semi-continuous measurement of C (every 30 s up to 150 s) was adopted as an additional explanatory variable, and the attenuation rate of C was defined as C'. These data were also subjected to multiple regression analysis. The correlation coefficient (r) estimated for the bitterness score predicted by the taste sensor, using C' for channel 2 and C/S for channel 4, and the score obtained by human gustatory sensation, was 0.824. This value was greater than that obtained using C/S for both channels 2 and 4 (0.734). The method described in the present study seems to offer good predictability for the evaluation of bitterness.     

Method of evaluation of the bitterness of clarithromycin dry syrup

The degree of bitterness of clarithromycin (CAM) dry syrup was evaluated using several methods. Using the inversion method, shaking method, and paddle method, a reasonable correlation between the bitter taste and the amount dissolved was not observed. A mini-column with inner diameter of 0.76 cm and height of 5 cm packed with CAM dry syrup was used for the release test. The release rate of CAM in test solution, which passed through the mini-column, was then measured to evaluate bitterness. The release rate of CAM in the release test using the mini-column correlated well with the results of a sensory test for the bitterness of CAM dry syrup. The dissolution rate constant, defined as the percentage of CAM dissolved from the unit void surface multiplied by the void volume, was inversely proportional to the linear velocity of the test solution. The critical factors affecting evaluation of bitterness were the void volume of the column and linear velocity of the test solution. The optimum linear velocity and void volume were 0.048-0.021 cm/min and 0.27-0.12 cm3, respectively. In addition, the threshold of bitterness of CAM dry syrup was defined as the concentration at which half of the volunteers recognized bitterness in the sensory test. This threshold was found to be 135 microg/ml using the mini-column.     

The effect of various substances on the suppression of the bitterness of quinine-human gustatory sensation,binding, and taste sensor studies

The purpose of this study was to quantify the degree of suppression of the perceived bitterness of quinine by various substances and to examine the mechanism of bitterness suppression. The following compounds were tested for their ability to suppress bitterness: sucrose, a natural sweetener; aspartame, a noncaloric sweetener; sodium chloride (NaCl) as the electrolyte; phosphatidic acid, a commercial bitterness suppression agent; and tannic acid, a component of green tea. These substances were examined in a gustatory sensation test in human volunteers, a binding study, and using an artificial taste sensor. Sucrose, aspartame, and NaCl were effective in suppressing bitterness, although at comparatively high concentrations. An almost 80% inhibition of bitterness (calculated as concentration %) of a 0.1 mM quinine hydrochloride solution required 800 mM of sucrose, 8 mM of aspartame, and 300 mM NaCl. Similar levels of bitterness inhibition by phosphatidic acid and tannic acid (81.7, 61.0%, respectively) were obtained at much lower concentrations (1.0 (w/v)% for phosphatidic acid and 0.05 (w/v)% for tannic acid). The mechanism of the bitterness-depressing effect of phosphatidic acid and tannic acid was investigated in terms of adsorption and masking at the receptor site. With phosphatidic acid, 36.1% of the bitterness-depressing effect was found to be due to adsorption, while 45.6% was due to suppression at the receptor site. In the case of 0.05 (w/v)% tannic acid, the total bitterness-masking effect was 61.0%. The contribution of the adsorption effect was about 27.5% while the residual masking effect at the receptor site was almost 33%. Further addition of tannic acid (0.15 (w/v)%), however, increased the bitterness score of quinine, which probably represents an effect of the astringency of tannic acid itself. Finally, an artificial taste sensor was used to evaluate or predict the bitterness-depressing effect. The sensor output profile was shown to reflect the depressant effect at the receptor site rather well. Therefore, the taste sensor is potentially useful for predicting the effectiveness of bitterness-depressant substances.     

Bitterness evaluation of medicines for pediatric use by a taste sensor

The purpose of this study was to evaluate the bitterness of 18 different antibiotic and antiviral drug formulations, widely used to treat infectious diseases in children and infants, in human gustatory sensation tests and using an artificial taste sensor. Seven of the formulations were found to have a bitterness intensity exceeding 1.0 in gustatory sensation tests (evaluated against quinine as a standard) and were therefore assumed to have an unpleasant taste to children. The bitterness intensity scores of the medicines were examined using suspensions in water or an acidic sports drink. In the case of three macrolide antibiotic formulations containing erythromycin (ERYTHROCIN dry syrup), clarithromycin (CLARITH dry syrup for pediatric), and azithromycin (ZITHROMAC fine granules for pediatric use), the bitterness intensities of suspensions in acidic sports drinks were dramatically enhanced compared with the corresponding scores of suspensions in water. This enhancement could be predicted using the taste sensor. On the other hand, a reduction of bitterness intensity was observed for an acidic sports drink suspension of an amantadine product (SYMMETREL fine granules) compared with an aqueous suspension. This reduction in bitterness could also be predicted using the taste sensor output value. Thus, the taste sensor could predict whether or not suspension in an acidic sports drink would enhance or reduce the bitterness intensity of pediatric drug formulations, compared with suspensions in water.     

The quantitative prediction of bitterness-suppressing effect of sweeteners on the bitterness of famotidine by sweetness-responsive sensor

The purpose of the present study was the quantitative prediction of the bitterness-suppressing effect of sweeteners (sucrose or sugar alcohols) on the bitterness of famotidine (or quinine sulfate as control) solutions using an artificial taste sensor. Firstly, we examined the response characteristics of the sensor response to sweetness. The sensor membrane is charged negatively in the presence of sweeteners, which tend to receive protons from one of the components of the sensor membrane. The magnitude of the sensor response was shown to increase in direct proportion to the concentration of the sweetener. Secondly, we used direct or indirect methods to evaluate and predict the bitterness-suppressing effect of sweeteners on 1 mg/ml famotidine and 81.4 microM quinine sulfate solutions. In direct method, a regression between the sensor output of the sweetness-responsive sensor and the bitterness intensity obtained in human gustatory tests of famotidine solutions containing sweeteners at various concentrations, was performed. As a result, we were able to predict directly the bitterness intensity of the mixed solution. Finally, we also evaluated the bitterness intensity of the dissolution media of commercially available, orally disintegrating tablets containing famotidine by the combined usage of bitterness- and sweetness-responsive sensor. We found that the sugar alcohols in the tablet seem to be effective in the bitterness-suppression of famotidine from these tablets, especially in the initial phase (within 30 s) of the disintegration process.     

Optimum heat treatment conditions for masking the bitterness of the clarithromycin wax matrix

The effects of the contents of aminoalkyl methacrylate copolymer E (AMCE) in a wax matrix on the mechanism of polymorphic transformation of glyceryl monostearate (GM) were clarified by evaluating the enthalpy change defined as 1.51 (DeltaH(1)-DeltaH(2))/DeltaH(2), where DeltaH(1) and DeltaH(2) denote the enthalpies in the first and second thermal analyses, respectively. Using this value, K(1), the rate constant of transformation from alpha-form to beta'-form, and K(2), the rate constant of transformation from beta'-form to beta-form, could be obtained. As the ratio of AMCE increased, K(2) increased, but a minimum point existed for K(1). K(1) was always larger than K(2), but gradually approached K(2) as the ratio of AMCE increased. The optimum temperature for the transformation of GM was 50 degrees C, at which the enthalpy change was maximum. To prepare the wax matrix preparation of clarithromycin (CAM), we considered 40 degrees C the optimum treatment temperature for the transformation of GM in a CAM wax matrix compounded from CAM, GM and AMCE, since the matrices were mutually welded at above 45 degrees C during the spray congealing process. Although K(1) and K(2) were almost the same at 40 degrees C, the rate of transformation was accelerated by tumbling. By applying the tumbling that accelerated the transformation of GM in a CAM wax matrix, almost all of the alpha-form disappeared, and the release of CAM from the wax matrix diminished when the enthalpy change was more than 0.8.     

Suppression of the bitterness of enteral nutrients using increased particle sizes of branched-chain amino acids (BCAAs) and various flavours: a taste sensor study

An improved formulation of the enteral nutrient Aminoleban EN (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), has been commercially available since Spring 2004. Like the previous formulation, the improved product contains branched-chain amino acids (BCAAs) L-isoleucine (L-Ile), L-leucine (L-Leu), and L-valine (L-Val), but the average particle size of these amino acids has been increased to 180 to 250 microm in the improved formulation, compared with 40 to 90 microm in the old product. The improved formulation has a significantly lower bitterness intensity score than the older formulation, as evaluated both in human gustatory tests and using the artificial taste sensor. We propose that this improved taste masking is due to the larger particle size of the BCAA crystals, due to which their release rates are reduced. The addition of improved flavours has also helped to reduce the bitterness of the improved Aminoleban EN formulation significantly. Analysis of the taste sensor data suggests that the sourness and sweetness of the added flavours were critical in diminishing the bitterness of Aminoleban EN.     

The suppression of enhanced bitterness intensity of macrolide dry syrup mixed with an acidic powder

The aim of the present study was to identify a medicine which strongly enhanced the bitterness of clarithromycin dry syrup (CAMD) when administered concomitantly and to develop a method to suppress this enhanced bitterness. The bitterness enhancement was evaluated not only by gustatory sensation tests but also using pH and taste sensor measurements of the mixed sample. A remarkable bitterness enhancement was found when CAMD was mixed with the acidic powder L-carbocysteine. The acidic pH (pH 3.40) of the suspension made from these two preparations, seemed to be due to enhanced release of clarithromycin caused by the dissolution of the alkaline polymer film-coating. Several methods for preventing this bitterness enhancement were investigated. Neither increasing the volume of water taken with the mixture, nor changing the ratio of CAMD:L-carbocysteine in the mixture, were effective in reducing the bitterness intensity of the CAMD/L-carbocysteine mixture. The best way to achieve taste masking was to first administer CAMD mixed with chocolate jelly, which has a neutral pH, followed by the L-carbocysteine suspension. Similar results were obtained for the bitterness suppression of azithromycin fine granules with L-carbocysteine. The chocolate jelly will be useful for taste masking of bitter macrolide drug formulations, when they need to be administered together with acidic drug formulations.     

Optimum spray congealing conditions for masking the bitter taste of clarithromycin in wax matrix

The effects of operating conditions in the spray-congealing process on the release and the micromeritic properties of clarithromycin (CAM) wax matrix were evaluated. CAM wax matrix with 30% CAM, 60% glyceryl monostearate (GM) and 10% aminoalkyl methacrylate copolymer E (AMCE) was manufactured at various atomizer wheel speeds and liquid feed rates with a spray dryer. Release of CAM from the matrix exhibited a two-phase pattern, probably due to the dissolution of the fine portions broken on the surface of the matrix. The slope and the extrapolated y-intercept of the subsequent release pattern were defined as the release rate and the initial amount of release of CAM from the matrix, respectively. These release parameters, as well as the volume median diameter and the specific surface area of matrix, were selected as response variables, and multiple regression analysis was performed. For specific surface area and initial amount of release, a minimum point was observed on the contour curve when the atomizer wheel speed was constant and the liquid feed rate was varied. For the release rate, a maximum point was observed on the contour curve under the same conditions. These points were considered preferable for masking the bitter taste of CAM preparation. Microscopic observation revealed that a small spherical matrix with a smooth surface could be obtained with a high atomizer wheel speed and optimum liquid feed rate. This matrix also possessed excellent properties for taste masking, with small initial amount of release and subsequent high rate of release. In conclusion, the congealing speed of melt droplets was the dominant factor in masking the bitter taste of CAM.     

克拉霉素与百里酚蓝荷移配合物的光度分析研究

利用克拉霉素与百里酚蓝在乙醇介质发生荷移反应,建立了荷移分光光度法测定克拉霉素含量的方法.结果表明,荷移反应生成1∶1型配合物,最大吸收波长为442 nm,表观摩尔吸光系数为ε=1.66×104L·mol-1·cm-1,克拉霉素测定线性范围为8.278～57.59 mg/L.     

Evaluation of bitterness suppression of macrolide dry syrups by jellies

The purpose of this study was to evaluate the bitterness-suppressing effect of three jellies, all commercially available on the Japanese market as swallowing aids, on two dry syrups containing the macrolides clarithromycin (CAM) or azithromycin (AZM). The bitterness intensities of mixtures of the dry syrups and acidic jellies were significantly greater than those of water suspensions of the dry syrups in human gustatory sensation tests. On the other hand, the mixture with a chocolate jelly, which has a neutral pH, was less bitter than water suspensions of the dry syrups. The bitterness intensities predicted by the taste sensor output values correlated well with the observed bitterness intensities in human gustatory sensation tests. When the concentrations of CAM and AZM in solutions extracted from physical mixtures of dry syrup and jelly were determined by HPLC, concentrations in the solutions extracted from mixtures with acidic jellies were higher than those from mixtures with a neutral jelly (almost 90 times higher for CAM, and almost 7-10 times higher for AZM). Thus, bitterness suppression is correlated with the pH of the jelly. Finally, a drug dissolution test for dry syrup with and without jelly was performed using the paddle method. There was no significance difference in dissolution profile. It was concluded the appropriate choice of jelly with the right pH is essential for taste masking. Suitable jellies might be used to improve patient compliance, especially in children. The taste sensor may be used to predict the bitterness-suppressing effect of the jelly.     

The adhesion coefficient of fiber-reinforced polymers evaluated by dynamic measurements

A theoretical model, consisting of a series of infinite concentric cylinders surrounding a fiber in a composite material, was introduced in this paper to give a quantitative account of interface phenomena, already experimentally observed. A series of specimens, conveniently designed to represent the theoretical model, were subjected to dynamic modes of loading to measure the amount of adhesion between fibers and matrices by means of an adhesion coefficient developed in the theory. It was found that theoretical results for the adhesion between matrix and filler were compatible with the structural characteristics of the specimens tested.     

Scattered intensity by a cross-linked polymer blend

Cross-linked mixtures of polystyrene and poly(vinyl methyl ether) exhibit a non-vanishing zero-angle intensity in small-angle neutron scattering experiments. A possible explanation is that fluctuations in composition in the mixture may be frozen by the presence of cross-links. Assuming this, we introduce a screening length κ by the condition that the scattered intensity should not be changed by cross-linking. We find κ² ∼ C/(χ − χ_i), where C is an elastic constant, χ and χ_i, respectively, the inverse temperature and that where cross-linking is performed. When the temperature is varied, we find three regimes. In the first one, the scattered intensity is monotonously decreasing. In the second one, it has a finite maximum. In the last one, the maximum eventually diverges.     

The heat conductivity of liquid crystal phases of a soft ellipsoid string-fluid evaluated by molecular dynamics simulation

We have applied a nonequilibrium molecular dynamics heat flow algorithm to calculate the heat conductivity of a molecular model system, which forms uniaxial and biaxial nematic liquid crystals. The model system consists of a soft ellipsoid string-fluid where the ellipsoids interact according to a repulsive version of the Gay-Berne potential. On compression, this system forms discotic or calamitic uniaxial nematic phases depending on the dimensions of the molecules, and on further compression a biaxial nematic phase is formed. In the discotic nematic phase, the heat conductivity has two components, one parallel and one perpendicular to the director, where the last mentioned component is the largest one. This order of magnitudes is reversed in the calamitic nematic phase. In the biaxial nematic phase there are three components of the heat conductivity, one in the direction around which the long axes of the molecules are oriented, this is the largest component, another one in the direction around which the normals of the broadsides of the molecules are oriented, this is the smallest component, and one in the direction perpendicular to these two directions with a magnitude in between those of the first mentioned components. The relative magnitudes of the components of the heat conductivity span a fairly wide interval so it should be possible to use the model to parameterise experimental data.     

Catalytic degradation of polyethylene evaluated by TG

HZSM-5 zeolite was screened as catalyst for high density polyethylene degradation at 450C, under nitrogen static atmosphere. Two different samples were studied in this condition: HDPE alone and mixed with HZSM-5. The reactor was connected on line to an HP 5890-II gas Chromatograph. Sample degradation was investigated using a Perkin-Elmer Delta 7 Thermobalance, from room temperature to 800C, with heating rates of 5.0, 10.0 and 20.0C min^–1. From TG curves, the activation energies, calculated using an integral kinetic method, decreased 60.6% in the presence of the zeolite.This work was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) and CoordenaÇÃo de Apoio ao Pessoal de Ensino Superior (CAPES).     

Characterizing bitterness: identification of key structural features and development of a classification model

This work describes the first approach in the development of a comprehensive classification method for bitterness of small molecules. The data set comprises 649 bitter and 13 530 randomly selected molecules from the MDL Drug Data Repository (MDDR) which are analyzed by circular fingerprints (MOLPRINT 2D) and information-gain feature selection. The feature selection proposes substructural features which are statistically correlated to bitterness. Classification is performed on the selected features via a na?ve Bayes classifier. The substructural features upon which the classification is based are able to discriminate between bitter and random compounds, and thus we propose they are also functionally responsible for causing the bitter taste. Such substructures include various sugar moieties as well as highly branched carbon scaffolds. Cynaropicrine contains a number of the substructural features found to be statistically associated with bitterness and thus was correctly predicted to be bitter by our model. Alternatively, both promethazine and saccharin contain fewer of these substructural features, and thus the bitterness in these compounds was not identified. Two different classes of bitter compounds were identified, namely those which are larger and contain mainly oxygen and carbon and often sugar moieties, and those which are rather smaller and contain additional nitrogen and/or sulfur fragments. The classifier is able to predict 72.1% of the bitter compounds. Feature selection reduces the number of false-positives while also increasing the number of false negatives to 69.5% of bitter compounds correctly predicted. Overall, the method presented here presents both one of the largest databases of bitter compounds presently available as well as a relatively reliable classification method.     

The intensity change of IR OH bands by H-bonds

The integrated intensity change by H-bonds are measured for CH₃OH solved in different solvents of fundamental, 1. and 2. overtone OH stretching bands. A function A=f(ν) for the strong intensity change by H-bonds of the fundamental band is given, it shows a kink between pure van der Waals solvents and H-bond acceptors. - The contrary behavior of fundamental and 1. overtone bands for the T-dependence of pure CH₃OH and its LiClO₄-solutions could be canceled if the fundamental spectra are intensity corrected by A=f(ν). It is shown that the discussions between species and continuum models of water could become unique taking into account the function f(ν) and its kink, different for fundamental and overtone bands.     

克拉霉素的示波极谱测定及其电化学行为

在 0 .0 5mol LNaOH(pH 1 2 .7)介质中 ,克拉霉素在滴汞电极上产生一灵敏的还原峰 ,峰电位Ep=- 1 .35V(vs.SCE)。其一阶导数峰电流ip′与克拉霉素浓度在 8.0× 1 0 -6～ 4.8× 1 0 -5mol L范围内有良好的线性关系 (r=0 .9991 ) ,检出限为 4 .0× 1 0 -6mol L。此法已用于片剂的测定。用线性扫描和循环伏安法研究了体系性质 ,结果表明 ,克拉霉素的电极过程为具有吸附的不可逆过程