药物制剂中掩味技术的研究进展

目的:介绍国内外药物掩味技术及其评价方法的发展近况。方法:查阅相关文献,对国内外最新的药物制剂的掩味方法和评价方法进行综述。结果:现有的掩味技术包括添加矫味剂、包衣、盐析包衣、制备包合物、制备微囊或微球、制备离子交换树脂复合物等;评价方法有传统的口尝评价和电子舌评价等。结论:以上各种掩味技术均能达到一定的掩味目的,但没有一种方法对改善苦味具有普适性。掩味评价方法相对于掩味技术的发展较缓慢,电子舌虽然克服了口尝评价的缺点,但目前多用在实验研究中。     

环糊精对蓝芩提取物掩味作用的研究

目的 制备蓝芩提取物环糊精复合物,考察不同种类环糊精对蓝芩提取物的掩味效果。方法 采用离子交换树脂吸附和HPLC对提取物中苦味成分进行研究,通过人工口尝法筛选复合物处方;采用喷雾干燥法制备蓝芩提取物与环糊精复合物,并采用电子扫描显微镜、差示扫描量热法及引湿性测定对复合物进行表征;采用电子舌味觉评价系统对复合物进行苦味评价并结合人工口尝法对结果加以验证。结果 蓝芩提取物的苦味主要由其中的碱性成分引起,以磺丁基-β-环糊精钠为主的多种环糊精联用处方可在较低用量下对蓝芩提取物实现良好的苦味抑制;电子扫描显微镜、差示扫描量热及引湿性结果表明,复合物中蓝芩提取物和环糊精可能形成包合物而非物理混合;电子舌和口尝结果表明,相比于提取物,优选复合物的口感特征更接近空白辅料,苦度值显著降低。结论 本研究制备的蓝芩提取物环糊精复合物具有较好的口感,且环糊精总用量少,工艺简单,较适合工业化生产,对蓝芩相关掩味产品开发具有重要的意义。     

基于电子舌智能感官评定与人工评价结合的五汁饮矫味技术研究

目的 通过电子舌智能感官评定与人工口尝评价相结合的方法筛选五汁饮的最优矫味剂。方法 首先基于电子舌技术综合评分从常用的20组矫味剂中筛选出味觉响应值相近的矫味剂,再通过人工口尝评价优选出一种最佳的矫味剂。电子舌智能感官评定统计分析采用完全随机单因素试验多组间的两两比较,人工口尝评价采用DPS统计软件中单向有序列联表项下的秩和检验法处理数据。结果 电子舌智能感官评定结果筛出4组矫味剂组合,皆对增加甜味作用显著,对降低涩味、涩味回味作用也非常显著,对掩盖苦味、苦味回味具有一定作用(本品不苦),对改善鲜味作用不显著,但对改善鲜味回味作用显著。人工口尝评价选出最优的矫味剂组合比例是:五汁饮原料干浸膏62%,白砂糖19%,甘露醇19%。该矫味剂组合对应的电子舌智能感官评定味觉响应值数据显示,甜味由8.367提高到16.24;苦味由9.528降低到6.923;涩味由5.790降低到0.316 7;鲜味由6.473增加到7.453;苦味回味由1.157降低到0.000;涩味回味由1.320降低到0.043 3;鲜味回味由0.237 8提高到0.680 0。结论 通过电子舌智能感官评定与人工口尝评价相结合的方法可以科学合理地筛选出五汁饮的最佳矫味剂组合,显著地改善了口感,优化了制剂配方。     

基于电子舌技术的盐酸左西替利嗪掩味研究

目的 研究不同种类及用量的矫味剂对盐酸左西替利嗪口味的改善情况,以达到掩盖其苦味的目的。方法 以盐酸小檗碱作为参比制剂,通过人工口尝的方式确定盐酸左西替利嗪待测中间体溶液浓度;通过对电子舌测定信号值进行主成分分析及计算标准化欧式距离确定甜味剂种类及环糊精的种类及用量;采用傅里叶红外光谱法、差示扫描量热法（DSC）、扫描电子显微镜（SEM）技术对冻干干燥后的环糊精包合物粉末进行表征;对添加三氯蔗糖、β-环糊精掩味之后的盐酸左西替利嗪溶液进行口尝,对掩味效果进行验证。结果 盐酸左西替利嗪待测中间体溶液质量浓度为1.25 mg·mL^-1;三氯蔗糖掩味效果较好且更为安全,中间体溶液中的添加量为0.3%;8倍量的β-环糊精可以掩盖药物的苦味;表征结果显示,盐酸左西替利嗪β-环糊精包合物制备成功;志愿者口尝结果表明,添加了三氯蔗糖、β-环糊精掩味之后的盐酸左西替利嗪溶液苦味已完全被掩盖。结论 利用电子舌技术可以对盐酸左西替利嗪进行掩味研究,且操作简单、耗时短,客观性较强,结果可行性好。     

基于苦味产生机制的掩味策略与评价

口服制剂中许多药物尤其是中药常常会由于不良口味的影响,致使患者的顺应性降低,限制了临床应用。文章以苦味产生机制为主线,综述目前药物掩味技术的原理、特点和制备过程,并简述掩味技术评价方法的最新进展。     

银杏叶提取物掩味方法筛选及口腔崩解片制备

目的研究用不同方法对银杏叶提取物掩味,并将其制备成口腔崩解片,对所得的片剂进行质量考察。方法以明胶为载体材料,采用研磨法、溶剂法及喷雾干燥法3种固体分散技术掩味;以口服后有无苦感为掩味评价指标,比较了研磨法、溶剂法及喷雾干燥法对银杏叶提取物的掩味效果;采用粉末直接压片制备其相应的口腔崩解片。结果3种掩味方法均基本可达到掩盖银杏叶提取物苦味的目的,制得的口腔崩解片口腔中60 s内完全崩解,且无苦味,无砂粒感,硬度均在2.0以上,脆碎度均小于0.5%,可满足片剂生产的基本要求,研磨法制备的片剂外观最好。结论采用固体分散技术可以达到掩盖银杏叶提取物苦味的目的,其口腔崩解片质量合格。     

国内外口服制剂掩味技术的研究进展

苦味药物口服制剂的掩味问题是制剂学面临的一个重大挑战。传统的掩味方法主要是添加矫味剂等辅料,但其在应用中存在很大局限。本文综述目前固体分散、包衣、包合、微囊化/微球、离子交换等技术应用到药物掩味技术研究之中的进展,这些技术克服了传统掩味方法的局限和不足,必将促使药物更为广泛地应用。但是这些新出现的掩味技术在标准化、产业化以及效果评价等方面存在一些问题。此外,国内口服制剂掩味技术的研究与应用明显落后于国外,要加快研发步伐。     

电子舌在药学领域的应用

目的:介绍电子舌在药学领域的应用及前景。方法:通过查阅国内外相关文献,介绍电子舌技术的原理与其传感器的分类,综述电子舌技术在药学领域已有的应用及发展前景。结果:电子舌技术在药品质量控制、有效成分分析、不同味道区分、不良味道的掩盖及掩味效果评价等多个方面均有应用。结论:在新药研究、药物鉴别、药物质控与分析等方面,电子舌技术的发展潜力较大,未来的应用将更加广泛。     

双螺杆挤出技术在制备掩味制剂中的应用

大多数药物在口服给药时有苦味,因此在口服制剂中掩盖其不适的口感十分必要,但也面临着巨大的挑战。双螺杆挤出,是目前在医药领域被广泛发展的一种新技术,其在掩味制剂中的应用也成为一种新的研究趋势。双螺杆挤出技术实现苦味药物的掩味,其选择合适的载体材料和制备工艺尤为重要,本文就这两方面及其掩味原理进行了综述,为掩味技术提供新的研究方向。     

药物制剂中苦味掩盖方法的研究进展

药物具有较好的口感是提高患者服药顺应性的重要参数。为了使终产品具有较好的市场前景,应该将掩盖药物的不良气味(通常是苦味)作为处方设计时考虑的重要因素之一。现综述近年来有关文献资料中掩盖药物苦味的各种方法以及这些方法的掩味机制,从而为掩味技术的发展提供参考。     

The latest trends in the taste assessment of pharmaceuticals

To date, the most widely used method for measuring the taste characteristics of pharmaceutical preparations is psychophysical evaluation by a taste panel. However, conventional chemical analyses, on the basis of release studies, have been shown to be useful subsidiary methods. More recently, novel in vitro taste assessment apparatus and methodologies have been developed for high-throughput taste screening and quality control. Biomimetic taste sensing systems (BMTSSs), such as multichannel taste sensors or electronic tongues with global selectivity, have been welcomed by both pharmaceutical scientists and the industry as a whole. As we discuss here, the emerging in vitro approaches for assessing taste characteristics of taste masked drug and drug products will result in a decreased reliance on human panel tests.     

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.     

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.     

掩盖药物苦味技术的新进展

目的为掩盖药物苦味提供参考依据。方法将近年来国内外的有关文献分类、整理,归纳。结果和结论近年来涌现出许多掩盖药物苦味的新技术,如流化床技术、熔融制粒技术等;这些技术可有效掩盖药物的苦味,增加患者尤其是儿童和老年患者服药时的顺应性。     

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.     

Playing hide and seek with poorly tasting paediatric medicines: Do not forget the excipients

The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. For example, the toxicity of excipients may differ in children compared to adults and children have different taste preferences. Acceptable palatability of oral paediatric medicinal products is of great importance to facilitate patient adherence. This has been recognised by regulatory authorities and so is becoming a key aspect of paediatric pharmaceutical development studies. Many active pharmaceutical ingredients (APIs) have aversive taste characteristics and so it is necessary to utilise taste masking techniques to improve the palatability of paediatric oral formulations. The aim of this review is to provide an overview of different approaches to taste masking APIs in paediatric oral dosage forms, with a focus on the tolerability of excipients used. In addition, where possible, the provision of examples of some marketed products is made.     

Specific interactions between diphenhydramine and alpha-helical poly(glutamic acid) - A new ion-pairing complex for taste masking and pH-controlled diphenhydramine release.

Formation of drug/excipient complex through ionic interactions has proven to be very effective for both controlled release and taste masking. Unfortunately, the ionic interactions between drugs and small molecule excipients are usually weak, and the stability of the formed complexes can be greatly influenced by solution ionic strength. In this study, we explored to formulate diphenhydramine (DPH), a very bitter tasting drug, using small molecular weight and carboxyl group containing polymers. Studies showed that DPH interacted with alpha-helical poly(glutamic acid) specifically to produce DPH/poly(glutamic acid) complexes, mostly spherical in shape with a diameter of around 1.0mum. Other drugs with similar chemical structures as DPH, such as phenylephrine and pseudoephedrine, could not form complexes with poly(glutamic acid) or other polymers under the same conditions. Although DPH in DPH/poly(glutamic acid) complexes existed amorphously, it showed increased stability.In vitro studies using electronic tongue demonstrated that poly(glutamic acid) might be as effective as sucralose for DPH bitter taste blocking. In addition, DPH/poly(glutamic acid) complexes were not stable in neutral or weak acidic (pH>5) environments and dissolved rapidly and completely. Therefore, DPH/poly(glutamic acid) complex may serve as a new formulation for taste masking and controlled DPH release in gastrointestinal tract. This is the first report that small molecule drugs can interact with peptides of specific secondary structures to form stable complexes. In addition to greatly expanded ion-pairing excipient pool, application of peptides in drug formulation may also solve the selectivity and stability problems faced by current small molecule excipients.     

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.     

Structural and in vitro in vivo evaluation for taste masking

ABSTRACT

Introduction: Although many techniques, such as complexation and microencapsulation, are used to mask the unpleasant taste of drugs, the success of all masking processes is evaluated in the same way. To evaluate the success of a masking process, a masked formulation must pass two tests: a structural test and an in vitro in vivo test.

Areas covered: This review article highlights structural evaluation and in vitro in vivo evaluation of a taste-masking process. The structural evaluation has two criteria: the absence of any chemical interaction between the drug and the masking agent and the molecular distribution of drug in the network of masking agent. The in vitro in vivo section can be verified by electronic tongues, dissolution test, and volunteers and it should confirm that the final product, after applying the masking process, will have a lower rank in terms of taste.

Expert opinion: This critical review helps researchers and industrial partners to evaluate a taste-masking process in a systematic way, leading to better understanding of taste-masking process and consequently improving the efficiency of masked dosage forms while hindering the unpleasant taste of drugs. This will ultimately improve the quality of life of many patients.     

In vitro studies-how good are they at replacing in vivo studies for measurement of skin absorption?

Measures of percutaneous penetration are required for risk assessment of exposure of man to chemicals. In vitro approaches and QSAR predictions can be used and reduce the use of in vivo animal experiments. The OECD Guidelines on in vitro dermal absorption studies were recently accepted but progress was hampered by a lack of direct in vitro/in vivo comparisons in humans or in rodents. Either flow through diffusion or static cell systems with full thickness, dermatomed skin or membranes can be used. In a study of the robustness of in vitro techniques, inter-skin variability was greater than inter-laboratory or between cell variability. Recent studies with a number of chemicals have shown a reasonably good prediction but the difference between in vitro and in vivo results was greater for lipophilic molecules as lipophilic molecules which were retained in the stratum corneum. The experimental flux obtained in vitro using conditions that reflect the potential occupational exposure may be the most appropriate figure for risk assessment purposes. A database of in vitro and in vivo dermal penetration has been established. Dermal absorption data using infinite doses has been combined in a number of databases used for predictive QSAR modelling approaches to dermal absorption. However, absorption values derived from QSAR may over estimate the actual absorption from a finite dose.