Taste sensing systems (electronic tongues) for pharmaceutical applications

Electronic tongues are sensor array systems able to detect single substances as well as complex mixtures by means of particular sensor membranes and electrochemical techniques. Two systems are already commercially available, the Insent taste sensing system and the αAstree electronic tongue. In addition, various laboratory prototype versions exist. Besides the successful use in food industry, the implementation for pharmaceutical purposes has strongly grown within the recent years. A reason for this is the increased interest of developing palatable formulations, especially for children. As taste assessment of drugs comes along with challenges due to possible toxicity and subjectivity of the taste assessors, electronic tongues could offer a safe and objective alternative. In order to provide guidance on the use of these systems, possible fields of interest are presented in this review, as for example, system qualification, quality control, formulation development, comparison between marketed drug products, and the validation of the methods used. Further, different approaches for solid and liquid dosage forms are summarized. But, also the difficulty to obtain absolute statements regarding taste was identified and the need of more validated data was discussed to offer guidance for the next years of research and application of electronic tongues for pharmaceutical applications.     

Development of a taste-masked generic ibuprofen suspension: Top-down approach guided by electronic tongue measurements

Electronic tongues are sensor array systems that are increasingly being used in the field of pharmaceutics to provide taste assessment data of formulations. The applicability of an electronic tongue in the development of a taste masked generic ibuprofen suspension, starting from a commercial taste masked product, was evaluated in this study. The initial screening study on 3 proprietary and 11 generic products showed that sensors of the taste sensing system TS-5000Z could clearly detect differences between the products. The variation of sensor responses were mainly caused by sodium salts, sweeteners, and preservatives, whereas pH and viscosity did not affect sensor response. In addition, the presence of the particles (20–100 µm) did not damage the sensor membranes. Based on this screening, and the known qualitative composition of the proprietary formulations, the approximate quantitative composition of a proprietary formulation could be deduced and a taste masked generic formulation could be developed using the electronic tongue data. Differences in sensor responses between the proprietary and optimized generic formulation were smaller than 11 mV for each sensor. Based on these results a rational approach of implementing an electronic tongue to simplify the development of a taste masked generic formulation could be introduced. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4460–4470, 2011     

Taste masking analysis in pharmaceutical formulation development using an electronic tongue

The purpose of this study is to assess the feasibility for taste masking and comparison of taste intensity during formulation development using a multichannel taste sensor system (e-Tongue). Seven taste sensors used in the e-Tongue were cross-selective for five basic tastes while having different sensitivity or responsibility for different tastes. Each of the individual sensors concurrently contributes to the detection of most substances in a complicated sample through the different electronic output. Taste-masking efficiency was evaluated using quinine as a bitter model compound and a sweetener, acesulfame K, as a bitterness inhibitor. In a 0.2 mM quinine solution, the group distance obtained from e-Tongue analysis was reduced with increasing concentration of acesulfame K. This result suggests that the sensors could detect the inhibition of bitterness by a sweetener and could be used for optimization of the sweetener level in a liquid formulation. In addition, the bitterness inhibition of quinine by using other known taste-masking excipients including sodium acetate, NaCl, Prosweet^® flavor, and Debittering^® powder or soft drinks could be detected by the e-Tongue. These results further suggest that the e-Tongue should be useful in a taste-masking evaluation study on selecting appropriate taste-masking excipients for a solution formulation or a reconstitution vehicle for a drug-in-bottle formulation. In another study, the intensity of the taste for several drug substances known to be bitter was compared using the e-Tongue. It was found that the group distance was 695 for prednisolone and 686 for quinine, which is much higher than that of caffeine (102). These results indicate that the taste of prednisolone and quinine is stronger or more bitter than that of caffeine as expected. Based on the group distance, the relative intensity of bitterness for these compounds could be ranked in the following order: ranitidine HCl > prednisolone Na > quinine HClphenylthiourea > paracetamol  sucrose octaacetate > caffeine. In conclusion, the multichannel taste sensor or e-Tongue may be a useful tool to evaluate taste-masking efficiency for solution formulations and to compare bitterness intensity of formulations and drug substances during pharmaceutical product development.     

苦味评价方法的国内外研究进展

随着掩味技术的发展,与掩味相关的评价技术也取得了巨大的进展。文中就目前国内外药学中的苦味评价方法进行综述。人群口感实验是最常用的方法,然而许多体外方法已出现。最新的是采用电子舌的方法,它具有客观性、重复性、不疲劳、检测速度快、数据电子化和易描述、易保存的优点,文中具体介绍了离子选择电极、多通道类脂膜传感器、伏安法式电子舌和Astree电子舌的特点和应用现状;溶出实验是通过测定掩味颗粒的包衣完整性来衡量掩味效果,改进的溶出装置包括改进的转篮、溶出杯、注射器、Mini柱等;电生理方法是利用牛蛙和小鼠的舌咽肌及鼓索神经纤维或纤维束对苦味物质敏感特征来用做味觉评价;生化实验可大量筛选苦味抑制剂,适合高通量筛选。体外评价方法的发展将降低对人群试验的依赖。     

Taste masking of roxithromycin by spray drying technique

The spray drying technique was used to obtain the roxithromycin containing microcapsules with high taste masking efficiency. Eudragit L30D-55 was chosen as a barrier coating. The taste was evaluated by an electronic tongue, and taste-masking effect in water lasted at least several dozen hours.     

Flavor analysis in a pharmaceutical oral solution formulation using an electronic-nose

Flavors are commonly used in pharmaceutical oral solutions and oral suspensions to mask drug bitterness and to make the formulation more palatable. Flavor analysis during product development is typically performed by human organoleptic analysis, which is often expensive and less objective. A novel approach using a metal oxide sensor-based instrument (electronic-nose) for headspace analysis was explored to replace human sensory perception for consistent qualitative and quantitative analysis of flavors in a pharmaceutical formulation. The use of the electronic-nose technique to qualitatively distinguish among six common flavoring agents (raspberry, red berry, strawberry, pineapple, orange, and cherry) in placebo formulations was demonstrated. The instrument was also employed to identify unknown flavors in drug formulation placebos. Raspberry flavor samples from different lots made by the same manufacturer, as well as freshly prepared and aged samples, were also distinguished by electronic-nose. Therefore, the instrument can potentially be used for identity testing of different flavor raw materials and the flavored solution formulations. The electronic-nose was also employed successfully for quantitative analysis of flavors in an oral solution formulation. The quantitative method might be used to assay the flavor concentration during release testing of the oral solution formulation or to monitor flavor shelf-life in the marketed container. It can also be implemented for packaging selection for the formulation in order to ensure the flavor shelf-life. Chemometric methodologies including principal component analysis (PCA), discriminant factorial analysis (DFA), and partial least squares (PLS), were used for data processing and identification.     

Taste Masking Study Based on an Electronic Tongue: the Formulation Design of 3D Printed Levetiracetam Instant-Dissolving Tablets

Pharmaceutical Research - Proper taste-masking formulation design is a critical issue for instant-dissolving tablets (IDTs). The purpose of this study is to use the electronic tongue to design the...     

A Novel Technique to Assess Drug Substance Particle Size in a Complex Inhaled Formulation

Dry powder inhalers, comprising an active pharmaceutical ingredient (API) and carrier excipients, are often used in the delivery of pulmonary drugs. The stability of the API particle size within a formulation blend is a critical attribute for aerodynamic performance but can be challenging to measure. The presence of excipients, typically at concentrations much higher than API, makes measurement by laser diffraction very difficult. This work introduces a novel laser diffraction approach that takes advantage of solubility differences between the API and excipients. The method allows insight into the understanding of drug loading effects on API particle stability of the drug product. Lower drug load formulations show better particle size stability compared with high drug load formulations, likely due to reduced cohesive interactions.     

Following drug degradation and consequent taste deterioration of an oral reconstituted paediatric suspension during dosing interval via electronic tongue

BackgroundThe taste of oral liquid dosage forms is a crucial factor that impacts pediatric patient compliance. Taste of suspensions can be typically evaluated by human volunteers. Recently, the electronic tongue (ET) has been proven as an emerging tool that could be useful to follow up various formulations’ properties like taste and composition. This study aimed to evaluate the potential use of ET in assessing the taste deterioration of reconstituted oral suspensions and compare the results obtained with the typical in vivo panel taste method.MethodsFour commercially available brands of amoxicillin/ clavulanic acid suspensions (one brand and three generic formulations) were reconstituted and stored in refrigerator to assess their taste on a daily basis. The taste of these products was assessed using Alpha-Astree ET and the obtained results were compared with those obtained from an in vivo panel taste assessment using a hedonic panel test (the 5-point hedonic scale).ResultsAll evaluated suspensions exhibited similar trends. ET and in vivo analysis indicated low taste scores for all evaluated suspensions immediately after reconstitution, possibly due to the incomplete dissolution of sucrose. The scores for all formulations were higher on day 2, followed by a steady state for the next two days. After that, a significant decay in the scores was observed in the fifth day for all evaluated suspensions. ET results were in excellent agreement with the results obtained via in vivo panel test method.ConclusionThe ET seems to be promising for testing the taste of pharmaceutical liquid preparations and evaluate possible deterioration upon storage or after reconstitution. It may provide a platform to avoid the involvement of pediatric volunteers in clinical evaluation and can be employed as a quality control tool during manufacturing.     

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.     

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.     

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.     

Application of melt granulation technology using twin-screw extruder in development of high-dose modified-release tablet formulation

Development of modified-release oral tablets of drug products usually requires release-modifying polymers at the level of above 50% of the total weight. This makes the development of high-dose products, especially with doses in the range of 750-1000 mg, difficult because the tablet size becomes unacceptably high. This report presents the development of high-dose modified-release formulation of an active pharmaceutical ingredient (API), imatinib mesylate, with a drug load of approximately 90%, by melt granulation using a twin-screw extruder. For an 800 mg dose, 956 mg of drug substance (salt) was needed and the final weight of tablet was approximately 1074 mg. By carefully selecting polymers based on their physicochemical properties, the release rate could be modified between desired times of 4 to >10 h for the total drug release. Mixtures of API and polymer were melt granulated at 185 °C, which is below the melting point of API (212 °C) but above the glass transition temperatures of polymers used. The confocal Raman microscopic imaging revealed that the API remained as unmelted, crystalline particles, and polymers were finely distributed on the surface and in between API particles. The formulations were found to be robust as no change in tableting and drug release properties was observed when manufacturing parameters were altered to challenge the process. The in vivo modified-release properties of formulations were demonstrated in human pharmacokinetic studies.     

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.     

Research design strategies to evaluate the impact of formulations on abuse liability

Scheduling of a chemical drug substance under the Controlled Substances Act (CSA) includes an evaluation of preclinical and clinical safety, and experimental abuse liability studies, as well as information on diversion and overdose. Formulations that mitigate abuse liability, dependence potential and public health risks (e.g., altered absorption rate and tamperability, long half-life, pro-drugs and combination products) are amenable to preclinical and clinical studies to compare their abuse potential to reference compounds. For new formulations (NF) as marketed agents, direct comparison to the immediate release (IR) formulation of the reference compound is typically needed across the full range of potential studies. While the public health advantage of formulation changes in the marketplace can be conceptualized in behavioral economic terms, generating persuasive data is challenging. Study complexity increases because of additional conditions (e.g., placebo, 2-3 doses of the IR formulation, 2-3 doses of the new formulation, and 2-3 doses of the unscheduled or negative control drug), larger sample sizes (study power driven by the comparison of the new formulation versus the IR or placebo), and associated increases in study duration. However, the use of single maximal doses of well-characterized controls can reduce the number of study arms, and using incomplete block designs can reduce study duration. Less typical experimental approaches may also be useful, such as human choice or discrimination procedures, or pre-marketing consumer studies among experienced drug tamperers. New formulations that demonstrate a substantial difference from marketed or reference products have a potential marketing advantage and should require less onerous risk management. Post-marketing epidemiological data demonstrating the lack of abuse will carry the most weight from a public health and physician perspective.     

Stability, Dose Uniformity, and Palatability of Three Counterterrorism Drugs—Human Subject and Electronic Tongue Studies

Purpose These studies evaluated the ability of common household food and drink products to mask the bitter taste of three selected anti-terrorism drugs. Methods Three anti-terrorism drugs (doxycycline, ciprofloxacin hydrochloride, and potassium iodide) were mixed with a variety of common household food and drinks, and healthy adult volunteers evaluated the resulting taste and aftertaste. In parallel, the ASTREE Electronic Tongue was used to evaluate taste combinations. Stability of the mixtures over time was monitored, as was the dosage uniformity across preparations. Results Foods and drinks were identified that satisfactorily masked the bitter flavor of each drug. Dose uniformity and stability were also acceptable over the range studied, although some combinations were significantly less stable than others. The electronic tongue was able to differentiate between tastes, but ranked masking agents in a different order than human volunteers. Conclusions Doxycycline, potassium iodide, and ciprofloxacin, which are stockpiled in solid tablet form, can conveniently be prepared into more palatable formulations, using common household foods and drinks. The electronic tongue can be used to perform an initial screening for palatability.     

A comparative study on two electronic tongues for pharmaceutical formulation development

Electronic tongues are sensor array systems which are able to determine single substances as well as complex mixtures of various substances. They are increasingly used for taste assessment of pharmaceutical formulations. Two systems are available on the market, the AlphaMOS electronic tongue Astree2 and the Insent taste sensing system TS-5000Z. Both systems measure based on potentiometry but sensor technologies are different. Therefore, these electronic tongue systems were compared to each other with respect to general aspects like software handling, sensors, and measurement procedure, but also on the basis of analytical experiments in order to figure out the applicability and limitations for use in the pharmaceutical field. By investigation of substances with different ionic character, like sodium saccharin, acetaminophen, ibuprofen, quinine, and caffeine, it was shown for both systems that ionic substances are easier to detect than neutral ones. Further, the performance qualification could only be done for the TS-5000Z, whereas the validation step, a correlation to human taste assessment, was passed by both systems. The results were even more reproducible than those from the panel. Taste masking by complexation of ibuprofen and quinine hydrochloride by maltodextrin, could be evaluated by both systems. Data from the Astree2 system have to be normalized in order to compare inter-day results, while the Insent taste sensing system refers each measurement to a standard solution and therefore reaches better inter-day results. Both systems offer the opportunity to be used for the development of taste-masked pharmaceutical formulations.     

Silver acetate interactions with nicotine and non-nicotine smoke components

Oral topical silver-containing formulations were marketed in the 1970s and 1980s as smoking deterrents, based on the finding that when using such formulations, an unpleasant taste occurs upon smoking. This approach has not been widely adopted, however, in part because of a lack of efficacy data. The advent of new pharmacologic treatments for smoking cessation renews the possibility that such a taste aversion approach may be a useful adjunct to smoking cessation treatment. This study explored the basic mechanistic question of whether topical oral silver acetate solution interacts with nicotine as opposed to non-nicotine smoke constituents. We recruited 20 smoking volunteers to rate nicotine-containing or denicotinized cigarettes, as well as the Nicotrol nicotine vapor inhaler and sham (air) puffs. In two sessions, subjects rated the sensory and hedonic qualities of puffs after rinsing their mouths with either silver acetate solution or deionized water (placebo). Silver acetate relative to placebo solution substantially reduced liking and satisfaction ratings for the usual brand and denicotinized cigarettes; in contrast, for the nicotine inhaler these ratings were unaffected by the silver-based treatment. These results support the conclusion that silver acetate not only renders the taste of cigarette smoke less appealing, but also that the compound appears to interact selectively with non-nicotine smoke constituents. Moreover, these data suggest silver acetate would be compatible with buccal nicotine delivery systems (e.g., nicotine lozenge or gum). Combined use of taste aversion with nicotine replacement therapy could provide the smoker with additional assistance to resist relapse. Further exploration is warranted of the use of silver-based preparations as a short-term adjunct to smoking cessation treatment.     

Nebulization of Active Pharmaceutical Ingredients with the eFlow®rapid: Impact of Formulation Variables on Aerodynamic Characteristics

Nebulization of active pharmaceutical ingredient (API) solutions is a well-established means to achieve pulmonary drug deposition. The current study identified the impact of formulation variables on the aerosolization performance of the eFlow®rapid with special respect to optimized lung application. API formulations (including excipient-supplemented samples) were investigated for physicochemical properties, then nebulized using vibrating-mesh technology. The generated aerosol clouds were analyzed by laser diffraction. Aerosol deposition characteristics in the human respiratory tract were estimated using an algebraic model. Remarkable effects on aerosolization performance [i.e., mass median aerodynamic diameter (MMAD)] of API solutions were obtained when the sample conductivity (by API concentration and type, sodium chloride addition) and dynamic viscosity (by application of sucrose and poly(ethylene glycol) 200) were elevated. A similar influence was observed for a decline in surface tension (by ethanol addition). Thus, a defined adjustment of formulation parameters allowed for a decrease of the MMAD from ∼8.0 μm to values as small as ∼3.5 μm. Consequently, the pattern and efficiency of aerosol deposition in the human respiratory tract were improved. In conclusion, identification of physicochemical variables and their way of influencing vibrating-mesh nebulization has been provided to deliver a platform for tailoring aerosol characteristics and thus, advancing pulmonary therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2585–2589, 2014     

Orally disintegrating dosage forms and taste-masking technologies; 2010

INTRODUCTION: In the last decade the development of orally disintegrating tablets (ODTs) and thin-film platforms has grown enormously in the field of pharmaceutical industry. A wide variety of new masking technologies combined with the aforementioned platforms have been developed in order to mask the taste of bitter active substances and achieve patient compliance. The commercial success and viability of such products requires the development of robust formulations with excellent palatability, disintegration times, physicochemical stability and pharmacokinetic profiles. AREAS COVERED: In this review, emerging taste-masking technologies applied to solid dosage form manufacturing are summarized. The unique features and principles of taste-masking approaches used with ODT platforms are discussed, including the advantages and limitations of each technology. A brief discussion is also included on the taste masking of thin-film technologies, owing to their similar applications and requirements. EXPERT OPINION: This review elucidates the unique features of current commercially available or highly promising ODT and thin-film technologies, along with taste-masking approaches used in the manufacturing of oral solid dosage forms. A better understanding of these drug delivery approaches will help researchers to select the appropriate platform, or to develop innovative products with improved safety, compliance and clinical value.