Improvement of the bitter taste of drugs by complexation with cyclodextrins: applications, evaluations and mechanisms

Drugs having bitter tastes cause low patient compliance. Many taste-masking techniques such as physical barrier coatings, chemical modification and sensory masking have been developed. Among chemical modification, the inclusion complexation of drugs with cyclodextrins (CyDs) can provide the effective bitter taste-masking effects without complicated formulation and/or delayed dissolution of drugs. Herein, we describe some quantitative methods to evaluate the taste-masking effects of CyD complexes with drugs in solution and the solid state. In addition, we introduce the recent applications of CyDs to excipients for taste masking against various bitter-taste drugs, as well as discuss the possible mechanisms for the taste-masking effect of CyD complexation.     

Taste-masking possibilities in solid dosage forms

Increasing number of new, innovative pharmaceutical products are in the generic market. One of the important dosage forms is the group of orally disintegrating products. The feature of these products is that they disintegrate rapidly in the mouth upon contact with the saliva; therefore the dissolution of the water-soluble components begins in the mouth. Since a large part of the drug molecules is characterised by a more or less bitter taste, even a small amount of the dissolved drug can cause an unpleasant taste in the mouth. Manufacturers apply different techniques to mask the bitter taste of these products, depending on the characteristics of the dosage form and the bioavailability requirements. In this study, we reviewed the most widespread taste-masking methods based on the scientific literature and different patents and the characteristics of some important excipients, and outline an instrumental technique used for bitterness measurements.     

Validation of a rat behavioral avoidance model from a drug delivery perspective

Conventional taste-masking strategies are used to overcome the bitter taste perception of pharmaceuticals by coating the drug particles and/or adding flavoring agents. However, for certain product categories such as rapid dissolve sublingual tablets, taste-masking is challenging. Programs exploring such formulation strategies in the LO-CS phase or post CS phase possess very little toxicological information available in order to conduct human taste panel studies. The potential of a bitter taste perception can present a significant business risk. The objective of the study was to validate a rat behavioral avoidance model that identifies bitter-tasting compounds. Most classic bitter substances elicit a response in the micromolar concentration range while most drugs elicit a response in the millimolar range, hence a validation exercise was conducted to examine if the existing biological model was sensitive enough to identify known bitter tasting drugs as such. Five compounds: ergotamine tartrate, fluoxetine, sucrose, sumatriptan and povidone were chosen to represent a spectrum of compounds. The bitter tasting compounds were identified as such in the model. Based on these results, the assay may serve as a useful surrogate test to identify compounds that may have bitter taste issues.     

Quantitative prediction of the bitterness of atomoxetine hydrochloride and taste-masked using hydroxypropyl-β-cyclodextrin: A biosensor evaluation and interaction study

The bitterness of a drug is a major challenge for patient acceptability and compliance, especially for children. Due to the toxicity of medication, a human taste panel test has certain limitations. Atomoxetine hydrochloride (HCl), which is used for the treatment of attention deficit/hyperactivity disorder (ADHD), has an extremely bitter taste. The aim of this work is to quantitatively predict the bitterness of atomoxetine HCl by a biosensor system. Based on the mechanism of detection of the electronic tongue (E-tongue), the bitterness of atomoxetine HCl was evaluated, and it was found that its bitterness was similar to that of quinine HCl. The bitterness threshold of atomoxetine HCl was 8.61 µg/ml based on the Change of membrane Potential caused by Adsorption (CPA) value of the BT0 sensor. In this study, the taste-masking efficiency of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) was assessed by Euclidean distances on a principle component analysis (PCA) map with the SA402B Taste Sensing System, and the host–guest interactions were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy (SEM). Biosensor evaluation and characterization of the inclusion complex indicated that atomoxetine HCl could actively react with 2-hydroxypropyl-β-cyclodextrin.     

Evaluation of a taste sensor instrument (electronic tongue) for use in formulation development

A taste sensor instrument (electronic tongue) was evaluated to determine its utility in developing a taste-enhanced liquid formulation. To train the electronic tongue, human sensory panel data were collected for two prototype formulations, a solution of the drug in water and several marketed products. Studies using the electronic tongue were conducted to determine taste-masking effectiveness of formulations compared to a matching placebo, to establish correlation with human sensory data, and to evaluate unknown formulations and predict their bitterness scores. In the first experiment, the effectiveness of a proposed taste-masking strategy was determined by comparing formulation prototypes containing a bitter active pharmaceutical ingredient (API) against corresponding placebos (i.e. formulations without an active ingredient) using electronic tongue data. The analysis of the electronic tongue data was based on the assumption that the drug was well taste masked if the placebo matched the formulation with API. In a second set of experiments, electronic tongue data were compared to existing data from a human taste panel for several marketed products and prototype formulations. A good correlation (r(2)=0.99) was achieved from this comparison, and the relative taste of prototype formulations not tasted by humans was predicted.     

Effects of caffeine deprivation on taste and mood

Despite its ubiquitous consumption in the natural environment, caffeine has not been a reliable reinforcer in laboratory settings. The reinforcing effects of caffeine are greater in caffeine-dependent subjects relative to non-dependent subjects, but the mechanism underlying this difference remains unclear. We hypothesized that deprivation from caffeine would produce alterations in subjective ratings of stimuli commonly associated with caffeine consumption. Specifically, we hypothesized that hedonic ratings of the coffee taste would be selectively enhanced following caffeine deprivation. Twelve regular caffeine users received acute doses of caffeine (300mg) or placebo after 33h of caffeine deprivation or non-deprivation. They rated the taste of coffee and sucrose, saccharin, and quinine solutions on intensity, bitterness, sweetness, pleasantness, and unpleasantness. Contrary to our hypothesis, subjects' ratings of the pleasantness of the coffee taste were not significantly altered by caffeine deprivation. However, subjects' ratings of the bitterness and sweetness of the coffee taste and ratings of the sucrose solution were altered by caffeine. Implications of these data for caffeine self-administration are discussed.     

Evaluation of the bitterness of antibiotics using a taste sensor

The bitterness of nine commercial antibiotics (clarithromycin, erythromycin, cefdinil, doxycycline, vancomycin, tetracycline, minocycline, oxytetracycline and bacampicillin) was evaluated in human gustatory sensation tests with nine volunteers. The bitterness of 0.1-0.3 mM solutions (or suspensions in the case of clarithromycin) of the antibiotics was then measured using an artificial multichannel taste sensor. In the sensor measurements, three variables were used to predict estimated bitterness in single and multiple regression analysis and principal component analysis: sensor output as relative value (R), the change of membrane potential caused by adsorption (C) and C/R. Particularly good correlation was obtained between obtained bitterness scores and predicted scores using C from channel 2 of the sensor (r2=0.870, P<0.005) and C/R values for channels 2 and 3 (r2=0.947, P<0.005). The taste sensor was also successful in assessing the bitterness intensity of clarithromycin powder suspensions of various concentrations. Clarithromycin has a low aqueous solubility but is the most bitter of the nine antibiotics. Sensory data from channel 3 of the sensor predicted the bitterness of clarithromycin powder suspensions and their filtered solutions well. Finally, the bitterness intensity of a commercial clarithromycin dry syrup product (Clarith dry syrup, Taisho Pharmaceutical Co. Ltd, Tokyo, Japan) was evaluated in gustatory sensation tests and using the taste sensor. In Clarith dry syrup the drug is coated with aminoalkyl methacrylate polymer using a spray congealing method. The taste sensor results confirmed that the polymer was successful in almost completely masking the bitter taste of the dry syrup product.     

Pulmonary peptide delivery: effect of taste-masking excipients on leuprolide suspension metered-dose inhalers.

The purpose of this study was to evaluate the effect of taste-masking excipients on in vitro and in vivo performance of a leuprolide metered-dose inhaler (MDI) suspension formulation. Taste-masking excipients (aspartame and menthol) were added to a leuprolide suspension MDI formulation. The leuprolide MDI formulation with the taste-masking excipients was characterized in terms of milling time, particle size distribution, dose delivery and uniformity, and drug absorption in dogs. The data were compared with a formula that did not contain taste-masking excipients. It was found that the longer milling time for the leuprolide suspension with the taste-masking excipients was required to obtain a similar particle size distribution compared with the formula without taste-masking excipients using a fluid energy mill. Although measurable differences in mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were not observed between the two formulations, the percent of particles < or = 5 microns and the actuator retention for the formula with the taste-masking excipients were significantly different from the formula without taste-masking excipients using the Marple-Miller cascade impactor. Taste-masking excipients did not show a significant effect on valve delivery and through-can dose uniformity. However, the mean ex-actuator dose was 150.4 mg for the formula with the taste-masking excipients and 162.2 mg for the reference formula, respectively, indicating a significant difference. In tracheostomized dogs, both formulations showed comparable pharmacokinetic parameters including Cmax, Tmax, AUC0-12 and bioavailability (F%), indicating that the taste-masking excipients do not have an effect on lung absorption of leuprolide acetate. Therefore, inclusion of taste-masking excipients in the leuprolide MDI suspension formulation showed a significant impact on drug micronization, exactuator dose, and particle deposition pattern. Mechanistically, the unfavorable performance of leuprolide MDI in the presence of taste-masking excipients could be due to modification of the properties of the suspension itself and alteration of propellant evaporation following actuation.     

中药制剂掩味用包衣材料的研究进展

中药口服制剂多为复杂体系,口感较差,影响着患者服药的依从性,因此对其进行口感改良具有现实意义。矫掩味方法多样,其中包衣法较为常用,包衣层可减少药物与苦味受体的接触,从而达到掩味的目的。采用包衣法掩味时,除需保证良好的掩味效果外还需保证药物的释放,包衣材料的选择至关重要。中药制剂常用的包衣材料主要包括糖类如壳聚糖、环糊精、纤维素衍生物等,树脂类如丙烯酸树脂等,脂类如巴西棕榈蜡、山嵛酸甘油酯等。对常用的掩味用包衣辅料进行了综述,以期能为中药掩味包衣材料的选择提供参考。     

Quantification of suppression of bitterness using an electronic tongue.

Phospholipids, such as phosphatidic acid, suppress bitter taste without affecting other taste qualities. In the present study, we detected and quantified this suppression effect with an electronic tongue whose transducer is composed of several kinds of lipid/polymer membranes with different characteristics. We measured a phospholipid cocktail and various kinds of taste substances with five basic taste qualities. The responses to quinine hydrochloride and L-tryptophan, which have a bitter taste, were reduced as the phospholipid concentration was increased, and the responses to the other taste substances were not affected by the phospholipids, as with the human sensation test. Furthermore, the change of bitter intensity caused by phospholipid was quantified by principal component analysis and the tau scale, which expresses the relationship between taste intensity and taste substance concentration. The results are compared with those of the human sensory test and discussed.     

Taste disorder in hypo and hyperthyroidism.

Gustatory responses to the basic taste substances (sweet, salty, sour and bitter) were studied in hypothyroid and hyperthyroid subjects. The intensity and hedonic responses were evaluated using "category scaling" for 7 concentrations of glucose, sodium chloride, citric acid and quinine sulphate. The intensity and hedonic values decrease in hyperthyroidism for salt and bitter solution, and sourness is perceived as more unpleasant. In hypothyroid subjects intensity and hedonic value decreases for sweetness, the pleasant responses to salt and bitter increase, though intensity perception decreases for bitter solutions.     

Carboxylic acid replacement structure-activity relationships in suosan type sweeteners. A sweet taste antagonist. 1.

N-(4-Cyanophenyl)-N'-(2-carboxyethyl)urea (2), an analogue of suosan [1,N-(4-nitrophenyl)-N'-(2-carboxyethyl)urea], is a known high-potency sweetener derived from beta-alanine. Sulfonic and phosphonic acid analogues of 2 were prepared to develop structure-activity relationships through modification of the carboxylic acid region of this family of sweeteners. Neither of the carboxylic acid replacements resulted in sweet analogues. However, we found that N-(4-cyanophenyl)-N'-[(sodiosulfo)methyl]urea (7) is an antagonist of the sweet taste response. The bitter taste response to caffeine, quinine, and naringin was also antagonized. Antagonist 7 was found to inhibit the sweet taste perception of a variety of sweeteners. Antagonist 7 had no effect on the sour or salty taste response.     

Methyl xanthines enhance taste: evidence for modulation of taste by adenosine receptor

The methyl xanthines (MX), theophylline, caffeine, and theobromine, are potent antagonists of adenosine receptors. Adaptation of the human tongue to methyl xanthines at concentrations ranging from 10(-5) M to 10(-2) M was found to potentiate taste. The artificial sweetener acesulfam-K, which has a bitter component, was potentiated the most by MX, i.e., approximately 100%. This increase in perceived intensity for acesulfam-K occurred at 10(-5) M MX, a concentration known to inhibit adenosine receptors but below that required to inhibit phosphodiesterase. Increasing the concentration of MX as high as 10(-2) M did not increase the degree of enhancement appreciably. Taste enhancement was found for NaCl and quinine hydrochloride as well. When 10(-5) M adenosine was added to the MX, the potentiation was reversed. The human results were confirmed by animal studies in which single unit extracellular recordings were made from the nucleus of the solitary tract. These results suggest that the inhibitory A1 adenosine receptor plays an important local role in taste perception.     

Bitter substances from plants used in traditional Chinese medicine exert biased activation of human bitter taste receptors

The number and variety of bitter compounds originating from plants are vast. Whereas some bitter chemicals are toxic and should not be ingested, other compounds exhibit health beneficial effects, which is manifest in the cross‐cultural believe that the bitterness of medicine is correlated with the desired medicinal activity. The bitter taste receptors in the oral cavity serve as sensors for bitter compounds and, as they are expressed in numerous extraoral tissues throughout the body, may also be responsible for some physiological effects exerted by bitter compounds. Chinese herbal medicine uses bitter herbs since ancient times for the treatment of various diseases; however, the routes by which these herbs modify physiology are frequently not well understood. We therefore screened 26 bitter substances extracted from medical herbs for the activation of the 25 human bitter taste receptors. We identified six receptors activated by in total 17 different bitter compounds. Interestingly, we observed a bias in bitter taste receptor activation with 10 newly identified agonists for the broadly tuned receptor TAS2R46, seven agonists activating the TAS2R14 and two compounds activating narrowly tuned receptors, suggesting that these receptors play dominant roles in the evaluation and perhaps physiological activities of Chinese herbal medicines.     

Bitterness Suppression with Zinc Sulfate and Na-Cyclamate: A Model of Combined Peripheral and Central Neural Approaches to Flavor Modification

Purpose Zinc sulfate is known to inhibit the bitterness of the antimalarial agent quinine [R. S. J. Keast. The effect of zinc on human taste perception. J. Food Sci. 68:1871–1877 (2003)]. In the present work, we investigated whether zinc sulfate would inhibit other bitter-tasting compounds and pharmaceuticals. The utility of zinc as a general bitterness inhibitor is compromised, however, by the fact that it is also a good sweetness inhibitor [R. S. J. Keast, T. Canty, and P. A. S. Breslin. Oral zinc sulfate solutions inhibit sweet taste perception. Chem. Senses 29:513–521 (2004)] and would interfere with the taste of complex formulations. Yet, zinc sulfate does not inhibit the sweetener Na-cyclamate. Thus, we determined whether a mixture of zinc sulfate and Na-cyclamate would be a particularly effective combination for bitterness inhibition (Zn) and masking (cyclamate). Method We used human taste psychophysical procedures with chemical solutions to assess bitterness blocking. Results Zinc sulfate significantly inhibited the bitterness of quinine–HCl, Tetralone, and denatonium benzoate (DB) (p < 0.05), but had no significant effect on the bitterness of sucrose octa-acetate, pseudoephedrine (PSE), and dextromethorphan. A second experiment examined the influence of zinc sulfate on bittersweet mixtures. The bitter compounds were DB and PSE, and the sweeteners were sucrose (inhibited by 25 mM zinc sulfate) and Na-cyclamate (not inhibited by zinc sulfate). The combination of zinc sulfate and Na-cyclamate most effectively inhibited DB bitterness (86%) (p < 0.0016), whereas the mixture's inhibition of PSE bitterness was not different from that of Na-cyclamate alone. Conclusion A combination of Na-cyclamate and zinc sulfate was most effective at inhibiting bitterness. Thus, the combined use of peripheral oral and central cognitive bitterness reduction strategies should be particularly effective for improving the flavor profile of bitter-tasting foods and pharmaceutical formulations.     

Saccharin-taste discrimination by two-lever choice: A rat bioassay for sweeteners

Male hooded rats were trained to discriminate the taste of a saccharin solution from that of water by responding with a lever on one side of a food cup following 20 licks (500 μl) of a 0.002 M saccharin solution and responding with a lever on the alternate side following 20 licks (500 μl) of water for food reinforcement. All of the rats learned this discrimination reliably. The gustatory stimulus produced by saccharin was concentration-dependent. Sucrose (0.01–0.1 M) and dextrose (0.1–0.5 M) produced a concentration-dependent generalization to the saccharin taste. Solutions of sodium chloride (0.15 M), citric acid (0.01 M), caffeine citrate (0.01 M), and quinine hydrochloride (0.00001–0.01 M) did not produce saccharin-like taste. Generalization of sweet compounds and lack of generalization of salty, sour, and bitter compounds to the saccharin taste suggest that discrimination of the nonnutritive sweetener, saccharin, by the rat may possibly be used as a bioassay to detect and quantitate the sweetening property of new compounds.     

Improvement of some physicochemical properties of arundic acid, (R)-(-)-2-propyloctanonic acid, by complexation with hydrophilic cyclodextrins

Arundic acid, (R)-(-)-2-propyloctanonic acid, is a novel neurological agent for intractable neurodegenerative diseases. However, arundic acid, an oily drug, has low aqueous solubility and severe bitter/irritating tastes. Consequently, these physicochemical properties of arundic acid need to be improved to develop its pharmaceutical preparations. In the present study, we evaluated whether parent cyclodextrins (CyDs) and 2-hydroxypropylated CyDs (HP-CyDs) can interact with arundic acid, and have powderization, solubilization and taste-masking properties. Of various CyDs, HP-β-CyD had the most potent solubilizing effect for arundic acid. UV and (1)H NMR spectroscopic studies demonstrated that arundic acid formed inclusion complexes with CyDs at a molar ratio of 1:1 in solution. The complexation with CyDs changed an oily form of arundic acid to a solid form. The gustatory sensation studies indicate that of various CyDs, HP-β-CyD and γ-CyD showed the most significant taste-masking effects in solution and powders, respectively. HP-β-CyD significantly reduced the response of the electric potential caused by the adsorption of arundic acid to the taste sensor. These results suggest that hydrophilic CyDs have potential as multifunctional excipients for preparing solutions and powders containing arundic acid.     

Gustatory differences in hypothyroid and hyperthyroid tasters and non-tasters

Gustatory differences in Phenylthiocarbamide (PTC) tasters and non-tasters were studied in hypothyroid and hyperthyroid subjects. After presenting for PTC sensitivity, gustatory responses to 7 dilutions of test solutions for glucose (sweet), sodium chloride (salt), citric acid (sour) and quinine sulphate (bitter) were studied in PTC tasters and non-tasters. The intensity and pleasantness responses for 4 basic tastes were measured on a 7-point and 6-point category scale respectively. Sixty percent of subjects of hyperthyroid and 40% of hypothyroid subjects were tasters. Hypothyroid subjects showed more gustatory differences as compared to hyperthyroids. The diminished intensity perception for sweet and bitter taste was much more prominent in non-tasters than tasters hypothyroids. The greater hedonic value for salt was largely observed among hypothyroid tasters.     

Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets

Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast-disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30?mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests.