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。     

A Proposed Methodology for In Vitro Evaluation of Bitterness in Drug Solutions and In Vitro Drug Release Samples

Purpose

Ethical and safety concerns, paediatric taste panels and predictivity in early drug development for strategic decisions are some of the reasons for seeking in vitro methods of bitterness evaluation for drugs and drug products. In this study, taste panel studies and in vitro drug release studies have been performed, correlated to each other and proposed as an analytical tool for evaluation of bitterness.

Methods

Bitterness threshold and bitterness scores for different solutions of ondansetron hydrochloride (ONS) were estimated by taste panel studies. In vitro drug release studies on taste-masked drug product in pharmacopoeial apparatus and an in-house-developed apparatus were performed and correlated to drug release studies in oral cavity.

Results

Concentration of 22 μg/ml and below was perceived bitterless by all the volunteers of taste panel. A second-order polynomial equation (y?=?0.6206x ²???0.2011x???0.7796; correlation coefficient R ²?=?0.991) was derived as a relationship between bitterness score and log ONS concentration. Drug release in in-house-assembled apparatus and oral cavity were not statistically different (α?=?0.05) at both 60 and 120 s.

Conclusions

Bitterness threshold and bitterness scores are helpful in evaluation of bitterness in drug solutions and samples obtained from drug release studies.     

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.     

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.     

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.     

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.     

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.     

Placebo preparation for the proper clinical trial of herbal medicine--requirements, verification and quality control

Randomized controlled trials (RCT) have been recognized as the gold standard for interventional clinical trials. In many clinical trials of herbal medicine, it is very difficult to create a quality placebo. To achieve the purpose of blinding, the characteristics of the real drug and placebo should be identical in color, appearance, smell and taste. The quality placebo should be identical to the real drug in physical form, sensory perception, packaging, and labeling, and it should have no pharmaceutical activity. The aim of this study was to evaluate a placebo capsule and its matching herbal medicine D&G capsule in physical form, chemical nature, appearance, packaging and labeling. The assessment results suggested that the placebo was satisfactory in these aspects. The results demonstrated that a placebo could be created for a RCT involving herbal medicine. This report also discusses the means to acquire patent.     

Usefulness and limitations of taste sensors in the evaluation of palatability and taste-masking in oral dosage forms

The purpose of this review is to discuss the advantages and limitations of taste sensors in the evaluation of the taste of palatability of different oral dosage forms. First, we consider some ways in which the palatability of various pharmaceutical formulations including orally disintegrating tablets (ODTs) are tested using two different taste sensors. Second, we focus on the evaluation of palatability of ODTs. We compare the usefulness of three pieces of apparatus for estimating the disintegration time of ODTs. Finally, we compare the characteristics of the two taste sensors in the evaluation of palatability of various kinds of drug formulations.     

Cyclodextrin complexes: Perspective from drug delivery and formulation

Cyclodextrins (CDs) have been widely investigated as a unique pharmaceutical excipient for past few decades and is still explored for new applications. They are highly versatile oligosaccharides which possess multifunctional characteristics, and are mainly used to improve the physicochemical stability, solubility, dissolution rate, and bioavailability of drugs. Stability constant, factors affecting complexation, techniques to enhance complexation efficiency, the preparation methods for molecular inclusion complexes and release of guest molecules are discussed in brief. In addition, different CD derivatives and their pharmacokinetics are elaborated. Further, the significance of CD complex in aqueous solubility, dissolution and bioavailability, stability, and taste masking is explained. The recent advancement of CDs in developing various drug delivery systems is enlightened. Indeed, the potential of CDs by means of inclusion complex formation have widen the applicability of these materials in various drug delivery systems including ocular, osmotic, mucoadhesive, transdermal, nasal, and targeted delivery systems. Feasibility studies have been performed on the benefit of these cyclic oligomers as nanocarriers, a strategy that can modify the drugs with improved physicochemical properties. Studies also demonstrated the feasibility of CDs to self‐assemble in the form of stable nanoaggregates, which may extend the scope of CDs in drug delivery to the continually expanding list of new drug entities.     

AC biosusceptometry in the study of drug delivery

Conventionally, pharmaceutical substances are administered orally because the gastrointestinal tract possesses the appropriate features for drug absorption. Nevertheless, the gastrointestinal tract physiology is complex and influenced by many factors. These factors must be completely understood for the optimization of oral drug delivery systems. Although in vitro tests provide information about release and drug absorption profiles, in vivo studies are essential, due to the biological variability. Several techniques have been employed in an attempt to conveniently characterize the behavior of solid dosage forms in vivo. The noninvasive biomagnetic technique of alternate current biosusceptometry (ACB) has been used in studies focusing on gastrointestinal motility and, more recently, to evaluate the performance of magnetic dosage forms. This article will discuss the main characteristics of AC biosusceptometry and its applicability for determination of the relationship between the human gastrointestinal tract and orally administered pharmaceutical dosage forms.     

Lipid excipients and delivery systems for pharmaceutical development: a regulatory perspective

The use of lipid-based dosage forms for enhancement of drug absorption or delivery has drawn considerable interest from pharmaceutical scientists. The unique characteristics of these dosage forms, however, present significant challenges to pharmaceutical industry and regulatory agencies in many ways. For example, safety assessment is necessary when the use of a new lipid excipient is considered. An important question for lipid formulation is whether the drug remains in solubilised form along the gastrointestinal (GI) tract after it is administered. Certain lipid excipients and surfactants have been reported to change intestinal permeability or interfere with enzyme/transporter activity, thereby affecting drug bioavailability. The potential influence of biopharmaceutical and/or pathophysiological factors on the drug or lipid excipient(s) needs to be explored. For a complex lipid-based dosage form, the conventional in vitro dissolution methods may not be appropriate for predicting in vivo performance in view of the convoluted GI processing of the lipid vehicle and formulation Of paramount importance is to identify any gaps in the scientific understanding of lipid-based dosage forms so that regulatory issues can be addressed. More mechanistic studies should be encouraged to facilitate a better understanding of the pharmaceutical characteristics of lipid formulations and complex interactions between lipid excipient, drug and physiological environment. This review discusses some regulatory considerations in the use of lipid excipients and delivery systems for pharmaceutical development. Implications in the regulatory determination of pharmaceutical equivalence, bioequivalence and therapeutic equivalence are also illustrated.     

Melt extrusion: process to product

INTRODUCTION: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues. AREAS COVERED: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems. EXPERT OPINION: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.     

Development of Taste Masked Oral Formulation of Ornidazole

Taste masked microspheres of ornidazole were prepared using amino alkyl methacrylate copolymers (Eudragit E-100) by solvent evaporation technique. Taste assessment of these microspheres was done by both spectrophotometric taste evaluation technique and panel testing. Compressed tablets of taste masked ornidazole microspheres which rapidly disintegrated in the oral cavity were prepared using microcrystalline cellulose as directly compressible filler and sodium starch glycolate as a super-disintegrant. These were subsequently evaluated for various pharmacopoeial tests, drug release, and disintegration time in the oral cavity. Sensory taste evaluation was carried by panel testing in 20 healthy human volunteers. Results indicate successful formulation of oral fast disintegrating tablets which disintegrated in the oral cavity in about 30 s and possessed good taste.     

Sense and nonsense in the prediction of drug-drug interactions

Drug interactions are always a major concern in medicine and within the pharmaceutical industry. Fatal drug interactions have been reported, and several prominent drugs have been withdrawn from the market because of serious adverse reactions related to drug interactions. Therefore, drug interactions represent not only a medical problem for clinicians, but also an economic loss for pharmaceutical companies. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates in an attempt to minimize such losses and to more effectively safeguard the welfare of patients. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? These are the fundamental questions that industrial drug metabolism scientists must confront daily. Prediction of in vivo drug interactions from in vitro metabolic data is highly controversial, because of the complexities of factors that are involved in drug interactions. Some scientists believe that quantitative prediction of drug interaction is possible, whereas others are less optimistic, and believe that quantitative prediction is extremely difficult, if not impossible. The purpose of this review is to present and discuss the technical problems inherent in estimating in vitro Ki values and in measuring inhibitor concentration at the active-site of enzymes. Theoretic considerations are briefly reviewed, and representative examples are drawn from literature to illustrate the sense and nonsense in predicting in vivo drug interactions.     

Pharmaceutical cocrystals: a novel approach for oral bioavailability enhancement of drugs

Solid dosage forms are by far the preferred drug delivery systems. However, these often face the problem of poor and erratic bioavailability during the drug development process. Numerous formulation strategies for drug delivery are currently under development, among which the solid forms such as polymorphs, solvates, salts, and cocrystals have been considered to be the most important for improving dissolution rate and bioavailability. Cocrystallization is a fairly new approach in pharmaceutical industry that can improve the solubility and, consequently, the bioactivity of the active pharmaceutical ingredient (API) without compromising its structural integrity. Pharmaceutical cocrystals have found their place in drug delivery, primarily due to their ability to produce alternative, viable solid forms when a more standard approach of salt and polymorph formation fails to deliver the desired objectives. Over the past few years, a number of papers have been published focusing on a broad range of subjects, from traditional crystal engineering to structure-property relationships of cocrystals. The present review, however, illustrates how the cocrystalline forms of APIs have improved their in vitro dissolution rate and in vivo bioavailability, often correlating well with their improved solubility as well.     

Practical approaches of taste masking technologies in oral solid forms

In the pharmaceutical industry, taste masking techniques are applied to prevent active pharmaceutical ingredients exhibiting a bitter and unpleasant taste. The oral administration of bitter drugs through solid dosage forms requires an acceptable degree of palatability, patient tolerance and significant therapeutic value. In the recent years, enormous progress in taste masking technologies has given rise to novel strategies such as fast dissolving dosage forms, chewable tablets and coating of molten materials. Similarly, common technologies applying double coating layers, microencapsulation or even chemical modification have been employed to improve patient compliance. This review endeavours to present the practical technologies and platforms applied for taste masking and indicate the most interesting features of each approach.     

Chitosan: some pharmaceutical and biological aspects--an update

Chitosan, a natural polysaccharide, is being widely used as a pharmaceutical excipient. It is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Chitosan comprises a series of polymers varying in their degree of deacetylation, molecular weight, viscosity, pKa etc. The presence of a number of amino groups permit chitosan to chemically react with anionic systems, thereby resulting in alteration of physicochemical characteristics of such combinations. Chitosan has found wide applicability in conventional pharmaceutical devices as a potential formulation excipient, some of which include binding, disintegrating and tablet coating properties. The polymer has also been investigated as a potential adjuvant for swellable controlled drug delivery systems. Use of chitosan in novel drug delivery as mucoadhesive, gene and peptide drug administration via the oral route as well as its absorption enhancing effects have been explored by a number of researchers. Chitosan exhibits myriad biological actions, namely hypocholesterolemic, antimicrobial and wound healing properties. Low toxicity coupled with wide applicability makes it a promising candidate not only for the purpose of drug delivery for a host of drug moieties (antiinflammatories, peptides etc.) but also as a biologically active agent. It is the endeavour of the present review to provide an insight into the biological and pharmaceutical profile of chitosan. Various investigations carried out recently are reported, although references to research performed on chitosan prior to the recent reviews have also been included, where appropriate.     

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.     

Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds

Unintended inhibition of the cardiac potassium channel human ether-a-go-go-related gene (hERG) is considered the main culprit in drug-induced arrhythmias known as torsades de pointes. Electrophysiology is the most reliable in vitro screening method for identifying potential cardiac hERG liabilities, but only the recent advent of planar electrode-based voltage clamp electrophysiology promises sufficient throughput to support the drug testing needs of most drug discovery programs. We have assessed the reliability of this new format of the voltage clamp technology in measuring the activity of small molecules on the hERG channel. Based on the results herein of a screening against a panel of well-characterized hERG-active and -inactive molecules, we demonstrate that planar electrode electrophysiology, utilizing the Sealchip and PatchXpress technology platform (AVIVA Biosciences Corp., San Diego, CA), is comparable to traditional electrophysiology based on glass micropipettes in its reliability and data content. The new technology will allow significantly higher throughput and more thorough testing of pharmaceutical compounds.