Characterization of potential bitterness critical quality attributes in Xiaoer Ganmao Oral Liquid based on UHPLC-LTQ-Orbitrap MSn / 药学学报

To identify the bitter compounds of real-world Xiaoer Ganmao Oral Liquid sugar-free intermediates, an integrated strategy has been developed by using ultra-high performance liquid chromatography with linear ion trap-Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MSn) method and BitterX database prediction. The chromatographic operating conditions were as follows, chromatographic column: Acquity UPLC BEH C18 (100 mm × 2.1 mm, 1.7 μm), mobile phase: 0.1% formic acid-water solution (A)-acetonitrile (B) with gradient elution. The data were collected in positive and negative ion modes, respectively. The accurate molecular mass and structural information of the target compounds were obtained based on quasi-molecular ions and fragmentation ions provided by high-resolution mass spectrometry. The compounds were identified by combining retention time, reference substances, reports, and other relevant data, and a total of 57 constituents including flavonoids, alkaloids, and phenylpropanoids were finally identified. Further, the BitterX database was used to predict binding probability of compounds to bitter receptors and identify potential bitter critical quality attributes, finally 33 potential bitter compounds, including kukoamine A and linarin, were predicted. This study comprehensively characterized the material basis of Xiaoer Ganmao Oral Liquid sugar-free intermediates, it provides an effective method for bitter compound screening and a reference for further improving the undesirable taste of Xiaoer Ganmao Oral Liquid.

Identification of taste critical quality attribute and formulation optimization of Xiaoer Qingrening Granules based on electronic tongue and human senses / 药学学报

This study primarily concentrated on scientific problems of poor taste caused by unclear critical quality attributes of oral preparations manufactured by Chinese materia medica, successfully established an identification method for taste critical quality attribute and a taste improvement method combining electronic tongue with human senses, and determined the optimal taste formula, to improve patients' oral medication compliance. The study received ethical approval from the Review Committee of the Beijing University of Chinese Medicine. The results showed that the proportion of bitterness of Xiaoer Qingrening Granule was 61.8%, and its bitterness grade was 3.70, it was determined that bitterness is the critical quality attribute that caused the poor taste of Xiaoer Qingrening Granule. Additionally, the optimal taste formula per milliliter of Xiaoer Qingrening sugar-free intermediate was determined with allowable daily intake, solubility, and sweetness as the limiting conditions, which was 40 mg hydroxypropyl β-cyclodextrin, 180 mg trehalose, and 1.5 mg acesulfame potassium. Compared with the Xiaoer Qingrening Granule, the sensory evaluation score of the optimal taste formula was increased by 37.5 points. In conclusion, this study achieved the taste improvement of Xiaoer Qingrening Granule and formed a set of taste improvement strategies including the identification of taste critical quality attribute, the selection of the type and dosage of corrigent, and the optimization of taste formula, which provided a thought reference for the taste improvement of other oral preparations and a new perspective for quality control of intelligent manufacturing of traditional Chinese medicines.

Establishment of Elimination Method of Outliers Based on Grubbs Rule and MATLAB Language and Its Application in Ev- aluating Drug Bitterness / 中国药房

OBJECTIVE： To establish the elimination method of outliers based on Grubbs rule and MATLAB language， and to evaluate the effects of it on drug bitterness evaluation. METHODS： Referring to Grubbs rule， the automatic cyclic outliers elimination method based on MATLAB language was established. Totally 20 volunteers were included in single oral taste test （Tetrapanax papyrifer） and multiple oral taste test （10 kinds of medicinal material as T. papyrifer， Changium smyrnioides， Poria cocos， etc.）. Seven sensors were selected for electronic tongue test （Clematis armandii）. The data of bitterness evaluation in above tests （oral taste test as bitterness value， electronic tongue test as response value of sensors） were used as the data source. Five researchers were selected and adopted table-by-table elimination method based on Grubbs rule （method one）， Excel software elimination method based on Grubbs rule （method two） and automatic cyclic outliers elimination method based on Grubbs rule and MATLAB language （method three） to judge and eliminate the outliers. The effects of above three methods were evaluated with the removal time and error rate of outliers as indexes. RESULTS： There were two outliers in the data of bitterness evaluation in single oral taste test； the elimination time of the three methods were（745.400 0±25.904 4），（288.333 3±31.253 1）and（0.000 3±0.000 0）s， respectively； error rates were 20.0％， 0 and 0， respectively. There were six outliers in the data of bitterness evaluation in multiple oral taste test； the elimination time of three methods were （3 693.107 7±75.023 3）， （1 494.761 4±53.826 9）， （0.005 2±0.000 0）s， respectively； error rates were 10.0％， 4.0％， 0， respectively. There were three outliers in the data of bitterness evaluation in electronic tongue test； the elimination time of three methods were （2 992.673 3±84.117 6）， （1 276.367 1±55.024 5）， （0.002 3±0.000 0）s， respectively； error rates were 5.7％， 2.9％， 0， respectively. The elimination results of the three methods were consistent. The elimination time of method two was significantly shorter than that of method one （P＜0.01）； the elimination time of method three was significantly shorter than those of method one and method two （P＜0.01）. There was no significant difference in error rate of 3 methods （P＞0.05）. CONCLUSIONS： The automatic cyclic elimination method of outliers based on Grubbs rule and MATLAB language can significantly shorten the elimination time of outliers in data of drug bitterness evaluation， improve the efficiency of data processing， and is suitable for drug bitterness evaluation.

Masking Efficiency and Regularity of Bitterness Suppressants to Berberine Hydrochloride Based on Tongue Taste and Electronic Tongue Taste / 中国药学杂志

OBJECTIVE: To explore the masking efficiency and regularity of bitterness suppressants (BS) to a representative bitterness substance berberine hydrochloride (BBR). METHODS: Some quantitative evaluation methods of BS efficiency were established based on relevant literature and our previous research. Efficiency of respectively added into eight kinds of BS such as acesulfame, on bitter degree 3 BBR solution (0.05 mg•mL-1) were evaluated using the established methods. Bitterness masking regularity of BS on BBR solution were explained by respectively establishing the relationships between tongue tasted bitter decreased value (ΔI), electronic tongue tasted bitter decreased value (ΔIe) with BS concentration (ρ). RESULTS: ①Five tongue taste bitter masking efficiency (calibrated masking rate, bitterness revised standard half effect index and so on), two electronic tongue bitter masking efficiency(first taste reduce and aftertaste reduce) were established. ②Seven kinds of bitterness suppressants efficacy indicators can be used to compare the bitterness suppressants efficacy of BS to BBR solution, and the maximum bitterness reduction of 8 kinds of BS to BBR solution is above 1.8. ③ΔI-ρ Weibull regularity models of eight BS and nine ΔIe-ρ models of six BS were brlilt.HP-β-CD, glycine and crystalline fructose had good response to two sensor, stevioside, soluble soybean polysaccharide and acesulfame had a good response to one sensor and xanthan gum and aspartame had no response to any sensor. CONCLUSION: Seven evaluation indexes and methods are built based on human tongue and electronic tongue taste method. Max standard capability index of BS is suitable for the development of bitterness suppressants in taste method and two indicators of electronic tongue are also can be used as indicative indicators. Masking regularity of BS to BBR solution is exposed which could provide reference for the development and application of more BS.

Study on superposition law of drug bitterness based on tongue taste evaluation and electronic tongue evaluation / 中国中药杂志

Traditional Chinese medicine( TCM) decoction contains complex bitterness. In this paper,the simple mixing of TCM monomer bitter substances is used as the entry point to study the law of bitterness superposition. With berberine hydrochloride( alkaloids),geniposide( terpenoids),and arbutin( glycosides) as mother liquor,sophoridine( alkaloids),gentiopicroside( terpenoids),and puerarin( glycosides) as additive substances,these different additive substances were mixed with different mother liquor according to concentration gradients to form different liquid mixtures. The bitterness of the additive solution and the mixtures was evaluated by traditional human taste panel method( THTPM) and electronic tongue; the bitterness-concentration fitting model of the additive solution and the liquid mixtures was established by Weibull and logarithmic curves. By comparing and analyzing the bitterness-concentration model and the bitterness difference( ΔI_0/ΔI_e) of the additive solution and the mixture,the influence of mother liquor on the bitterness of the mixture was investigated. The results showed that both the additive solution bitterness model and the liquid mixture bitterness model were consistent with the Weibull model and the logarithmic model( THTPM: R~2≥0. 887 0,P<0. 01; electronic tongue test:R~2≥0. 753 2,P<0. 05). The fitting degree of the Weibull model was generally higher than that of the logarithmic model; the bitterness difference( ΔI_0) was monotonously decreasing; the fitting equation of tongue bitterness and electronic tongue bitterness: R~2≥0. 874 2,P<0. 01. In this article,through the superposition of different kinds of TCM bitter substances,THTPM and electronic tongue test was combined. It was found that the bitterness after superposition was still in Weibull or logarithmic relationship with the concentration of additive substances; THTPM showed that the effect of bitter mother liquor on the bitterness of the mixture decreased with the increase of the concentration of the additive; the bitterness of the electronic tongue was obviously related to the bitterness of THTPM. However,further verification is needed later by optimizing the concentration gradient and expanding the sample size.

Evaluation of different types of bitterness masking on inhibition of bitterness efficiency and law of four Chinese materia medicine decoctions of Gentianae Radix et Rhizoma, Sophorae Flavescentis Radix, Andrographis Herba, and Nelumbinis Plumula / 中草药

Objective To investigate the effects and the law of anti bitterness efficiency of hydroxypropyl-β-cyclodextrin (HP-β-CD) and other different types bitterness masking at different concentrations on the bitterness decoction of Chinese materia medica (BDCMM) by using the traditional human taste panel method (THTPM) and Electronic tongue (E-tongue). Methods Based on THTPM, the bitterness reduction value (ΔI), the correction rate of bitterness suppression (CRBS), and the correction rate of bitterness suppression potency index (PI50) were used as indicators to evaluate the bitterness suppression effect of four bitterness masking at different concentrations on BDCMM such as Sophorae Flavescentis Radix (SFR), and the relationship model between the concentrations of ΔI and bitterness masking was established to explore the bitterness suppression rule of bitterness masking on different BDCMM. Based on the E-tongue method, the E-tongue taste response information values of HP-β-CD and Acesulfame K to BDCMM such as SFR were measured at different concentrations, and the electronic tongue bitterness reduction value (ΔIe) was used as an index to explore the change rule of ΔIe with bitterness masking concentration. THTPM and E-tongue was combined to establish a prediction model of the effect of bitterness suppression. Results The ΔI, CRBS, and PI50 of four kinds of BDCMM with different concentrations of bitterness masking were measured, which can be used to compare the bitterness suppression effect of bitterness masking; The relation between ΔI and bitterness masking concentration accorded with Weibull curve model; Based on E-tongue, ΔIe was obtained, and the model of the relationship between ΔIe and bitterness masking concentration was established. The relationship between ΔIe and ΔI was established. The model determination coefficients of HP-β-CD for the two types of ΔIe of the two BDCMM were 0.986 1, 0.977 9, 0.989 0, and 0.982 0 respectively (P < 0.01, n = 6). Acesulfame had no response to the sensor and did not establish a model of bitterness suppression law. Conclusion Based on THTPM and E-tongue, a method for evaluating the bitterness suppression effect of bitterness masking on BDCMM was established. The bitterness suppression effect of bitterness masking on BDCMM such as SFR was studied by molecular inclusion, high-efficiency sweetening, and other bitterness suppression mechanisms were inverstigated.

Taste comparison of unprocessed and processed Siegesbeckiae puescens based on electronic tongue / 中草药

Objective: To study the taste of unprocessed and processed Siegesbeckiae puescens (SP) and establish a taste discrimination model. Methods: The sour, bitter, astringent, salty, and sweet values of 12 batches of unprocessed and processed SP were measured by electronic tongue using a paired t-test, principal component analysis (PCA), and the linear discriminant factor analysis (LDA) to study the changes of the taste of unprocessed and processed SP. Results: The paired t-test showed that the bitterness and saltiness of processed SP decreased; Astringency, sweetness, and sourness did not significantly change. The PCA can distinguish unprocessed and processed SP. The model of the taste of unprocessed and processed SP was established through the LDA, and conduct cross validation; Its correct rate reached 100%. The fingerprint of taste of unprocessed and processed SP was established through radar-graph. Conclusion: Electronic tongue can identify sour, bitter, astringent, salty, and sweet values of traditional Chinese medicine accurately. It can reflect the numerical change of taste of unprocessed and processed SP combining with statistical method. Based on it, it can be inferred that the relationship between the change of taste and clinical efficacy before and after processing of SP. Besides, the discriminant model can be used to distinguish unprocessed and processed SP.

Application of electronic tongue in pattern study about bitterness inhibition by hydroxypropyl-β-cyclodextrin / 中草药

Objective To study the bitterness inhibition law of hydroxypropyl-β-cyclodextrin (HP-β-CD) concentration (C) on the bitter compounds and bitter Chinese herbal medicine, and to explore the application of electronic tongue in this study. Methods Berberine, oxymatrine, Sophora flavescens, and Andrographis paniculata decoction were used as bitterness vectors to establish two models of bitterness inhibition law about ΔI-C and ΔIe-C, and to explore the prediction model of bitterness inhibition effect about ΔI-ΔIe, based on the oral taste evaluation results (ΔI) and electronic tongue information (ΔIe). Then, fitting precision and fitting goodness of the prediction model were evaluated with cross-validation and residual analysis. Results In this study, good Weibull model of bitterness inhibition pattern about ΔI-C were established for all the four bitterness vectors, the decision coefficient R2 are as followed: 0.999 6, 0.987 9, 0.996 4, and 0.998 4 (P < 0.01); The decision coefficient R2 of six (two sensors per vector) models of bitterness inhibition law about ΔIe-C of berberine, S. flavescens, and A. paniculata decoctions were as followed: 0.996 5, 0.991 6, 0.997 3, 0.989 3, 0.999 6, and 0.999 1 (P < 0.01); The decision coefficient R2 of six corresponding linear prediction models of bitterness inhibition effect about ΔI-ΔIe were as followed: 0.989 1, 0.968 3, 0.989 0, 0.982 0, 0.977 9, and 0.986 1 (P < 0.01); The correlation coefficient R calculated by correlation coefficient of six prediction models above were as followed: 0.986 0, 0.997 3, 0.988 4, 0.960 8, 0.980 2, and 0.983 9 (P < 0.01); No model was established for oxymatrine within the range of tested concentration in this research, as it didn’t respond to the four sensors with varied concentration. Conclusion Based on this method, the bitterness inhibition law of HP-β-CD with changed concentration was obtained. Prediction models based on HP-β-CD concentration or electronic tongue data were also established, they can be used to predict the relative bitterness inhibition effect. Part of the bitter compounds didn't response to the electronic tongue regularly, remain further research and development of electronic tongue technology.

Bitterness-masking Effects of Neotame on Five Bitter Chinese Herbal Ingredients / 世界科学技术-中医药现代化

This study was ai med to observe the taste-masking effects of Neotame on bitter Chinese herbal ingredients. Five kinds of herbal ingredients, which include Scutellaria baicalensis Georgi, Cortex Phellodendri chinensis, Coptis chinensis Franch, Gentiana scabra Bunge, Andrographis paniculata, were selected to measure the bitterness degree of decoctions with berberine solution as the benchmark. The decreasing of bitterness degree was used as index. Healthy volunteers were recruited to taste and compare the changes of bitterness of decoctions with the taste-masking effects of Neotame. Different concentrations of Neotame were selected in the determination of the influence on changes of bitterness. The results showed that when the concentration of Neotame was at 0.012 5‰-0.4‰, taste-masking effects of Neotame on selected herbal decoctions were in a concentration-dependent fashion. When the concentration of Neotame was 0.4‰, the reduced bitterness of S. baicalensis Georgi and Cortex P. chinensis decoctions were 1.22 and 1.77, by 70.11% and 71.88%, respectively. Three highly-bitter herbal ingredients C. chinensis Franch, G. scabra Bunge and A . paniculata were also reduced in bitter taste by 49.12%, 50.87% and 38.39%, with the bitter reduced value (△I) of 1.78, 2.02 and 1.43, respectively. It was concluded that Neotame exerted taste masking potential on bitter herbal ingredients with different bitter degrees.

Evaluation on taste-masking effect of Andrographis Herba by electronic tongue / 中草药

Objective: To evaluate the feasibility of taste-masking by electronic (E)-tongue and provide a reference for the drug taste-masking study. Methods: Andrographis Herba was used as the carrier of bitter Chinese materia medica (CMM), sodium acetate (NaAc), sodium cyclamate (SC), adenosine-5′-monophosphatedisodiumalt (AMP), and 2, 4-dihydroxyhenzoic acid (DA) as the taste-masking agents. The data obtained by the E-tongue were analyzed through principal component analysis (PCA), and Euclidean distance in the data space of different dimensions was calculated. Regarding the distance of bitterness (D) as the evaluation index, then whether the data analyzed by the E-tongue and volunteers were the same or were not investigated. Results: The evaluation results of the taste-masking agents by E-tongue were similar to the taste by volunteers except NaAc, suggesting that some conditions should be required to evaluate the effect of CMM taste-masking. Conclusion: This study shows that E-tongue could be used for evaluating the effect of CMM taste-masking under certain conditions. To evaluate the gustation information by E-tongue, we should use the professional knowledge of pharmacy, chemical and other related disciplines to analyze and improve this evaluation method and model gradually.

Study on Application of Electronic Tongue in the Evaluation of Taste-masking Effect of Pharmaceutical Formulation / 世界科学技术-中医药现代化

Taste-masking effect of pharmaceutical formulation is important for the pharmacy worker to carry out study on taste-masking of pharmaceutical formulation. This study discussed the feasibility of electronic tongue in the evaluation of taste-masking effect. The berberine hydrochloride was used as model drug of bitterness. Sodium cycla-mate, 2,4-Dihydroxybenzoic acid and sodium cyclamate were used as bitterness inhibitors. Through detection of elec-tronic tongue, results from principal component analysis (PCA), and indexes such as distance of bitterness (D), dis-tance of bitterness reduction, inhibition rate (Ir), the determination was given on whether results from the bitterness inhibition of berberine hydrochloride and taste results from volunteers were the same. In addition, sodium cyclamate, which was the best bitterness inhibition, was made into different concentrations in order to optimize its using dosage. The data analysis results showed that in the berberine hydrochloride solution with the concentration of 0.005 mg/mL, the ranking order of the bitterness-masking efficiency was sodium cyclamate > 2,4-Dihydroxybenzoic acid > sodium acetate anhydrous. Along with the increasing concentration of sodium cyclamate, the taste-masking effect is better. However, after the concentration level of 0.2%, the change on taste-masking effect was relatively small. In the prac-tical work, the concentration of sodium cyclamate can be selected at the level of 0.2%. This experiment effect was the same as the human taste results. This study showed that the electronic tongue may be a useful tool in the evalua-tion of taste-masking efficiency to some extent.

Botox Therapy for Deep Nasolabial Fold and Bitterness Furrow after Facial Nerve Paralysis / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Facial sequelae after facial paralysis cause serious functional and aesthetical problems including facial asymmetry, symkinesis and facial crease. The most common aesthetical problem is facial furrow and crease induced by facial hyperkinestic movement due to incomplete facial recovery. The aim of this study is to investigate the efficacy of botulinum toxin A injection in patients with deep nasolabial fold and bitterness furrow after facial paralysis. SUBJECTS AND METHOD: Thirty-five patients who recovered partially from facial paralysis, had deep nasolabial fold and bitterness furrow with or without facial asymmetry. Botulinum toxin A intramuscular injection on perioral area for mouth corner deviation, subcutaneous injection on deepen nasolabial fold, and intramuscular injection on bitterness furrows had improved lower facial symmetry and cosmetic configuration without Pseudo Bell's palsy. RESULTS: Of 26 patients who had facial palsy side nasolabial fold before the injection, 21 patients improved. Of the 21 patients who had facial palsy side bitterness furrow, 16 patients improved after the injection. Of 11 patients who had contralateral nasolabial fold, 4 patients improved after the injection. Of 13 patients who had contralateral bitterness furrow, 7 patients improved after the injection. CONCLUSION: After botulinum toxin A injection, the patients showed marked improvement of nasolabial fold, bitterness furrow and lower facial asymmetry.

Study on Quantitation of Bitterness Intensity and Relationship between Bitterness Intensity & Concentration of Bitter Drug / 世界科学技术-中医药现代化

This paper was aimed to study the quantitation method of bitterness intensity of bitter drug, and to ex-plore the mutual relations between the bitterness intensity and the concentration of bitter drugs solution. The mod-el drug of berberine hydrochloride, which was made into a series of solutions of different concentrations, was ap-plied. Twenty volunteers, who were screened, trained and qualified, tasted the different concentration of aqueous solution, with the purpose of detecting the rank bitterness intensity. After analyzing the features of the data and testing the logarithm model and Weibull curve model, as well as nonlinear fitting, we finally set up the appropri-ate relationship curve between the concentration and the bitterness intensity. There is a good curve positive corre-lation between the bitterness intensity and the concentration, which is consistent with the Weibull curve model (R2= 0.9973, RMSE = 0.0976, RMSECV = 0.1453). The fitting degree of the model established in this paper is high, which provides a reference for quantitation and forecast of the drug bitterness.