Taste Masking Study Based on an Electronic Tongue: the Formulation Design of 3D Printed Levetiracetam Instant-Dissolving Tablets
Purpose
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 additives of the 3D printed IDTs to improve palatability.
Methods
A binder jet 3D printer was used to prepare IDTs of levetiracetam. A texture analyzer and dissolution apparatus were used to predict the oral dispersion time and in vitro drug release of IDTs, respectively. The palatability of different formulations was investigated using the ASTREE electronic tongue in combination with the design of experiment and a model for masking bitter taste. Human gustatory sensation tests were conducted to further evaluate the credibility of the results.
Results
The 3D printed tablets exhibited rapid dispersion (<30 s) and drug release (2.5 min > 90%). The electronic tongue had an excellent ability of taste discrimination, and levetiracetam had a good linear sensing performance based on a partial least square regression analysis. The principal component analysis was used to analyze the signal intensities of different formulations and showed that 2% sucralose and 0.5% spearmint flavoring masked the bitterness well and resembled the taste of corresponding placebo. The results of human gustatory sensation test were consistent with the trend of the electronic tongue evaluation.
Conclusions
Owing to its objectivity and reproducibility, this technique is suitable for the design and evaluation of palatability in 3D printed IDT development.
Introduction
3D printing is a promising technology used for the fabrication of personalized pharmaceutical dosage forms. It is based on digital models that help construct objects via layer-by-layer printing, and finally turns the digital blueprints into physical objects. Binder jet 3D printing (BJ-3DP), also known as drop-on-powder 3D printing, is more widely used in the pharmaceutical industry compared to other 3D printing technologies . The first and only 3D printed drug using BJ-3DP – Spritam®, a landmark in 3D printing technology of pharmaceutical research, was approved by FDA in 2015 . Printing ink containing liquid binder is loaded into the printing head and jetted on a powder bed in precise path and dose, and the printing processes will keep repeating to produce the desired 3D product . Through the layer-by-layer bonding of printing ink and powder, the technology allows for the preparation of instant-dissolving tablets (IDTs) with a highly porous internal structure that can be rapidly dispersed in water, thus solving the problem of dysphagia in patients.
One of the most important issues with oral IDTs is their palatability in the oral cavity. 3D printed IDTs can be dissolved in water or taken directly with small sip of water. Regardless of the method of oral administration, the drug is released quickly and in full contact with the tongue, resulting in a more bitter taste compared to traditional tablets. Taste of formulations is crucial for patient compliance, especially with pediatric formulations, where taste is one of the primary determinants of market performance and commercial success of oral pharmaceuticals. Therefore, IDTs must be scrutinized more closely for palatability, and unpleasant taste should be detected and masked in final preparations, for example, by adding sweeteners and/or flavoring agents.
Taste is an important sensory characteristic that determines the acceptability of oral products. Biologically, taste transduction is mediated by specialized neuroepithelial cells, referred to as the taste receptor cells, that are organized into groups of 40–100 and form taste buds. Different taste modalities function by different transduction mechanisms . Salty taste is mediated by sodium ion flux through the apical sodium channels , while sour taste is mediated via the blockade of hydrogen ions by potassium or sodium channels. Sweet and bitter tastes are transduced via G protein-coupled receptors. Nevertheless, taste transduction mechanisms are complex and not fully elucidated.
Oral tasting is the most commonly used method to evaluate taste; however, the results depict poor reproducibility owing to individual variability and personnel subjectivity. The method also has limitations owing to the possible toxic side effects of drugs]. Taste assessment using laboratory animals, especially mammals, has been suggested as an alternative to human tasting. This approach has certain limitations related to the availability of animals with flavor perception similar to humans, as well as ethical considerations. Currently, rodents such as mice and rats are generally being used for taste evaluation studies. Notably, although laboratory animals can be used to evaluate flavor acceptability, their inability to describe sensory characteristics limits appropriate differentiation between formulations. Owing to these problems, a taste-sensing system (such as an electronic tongue) can be a safe and objective alternative.
The electronic tongue is an intelligent instrument used for taste analysis, which is based on bionics, and is capable of evaluating the masking effect through specific sensor membranes and electrochemical techniques. It has already been utilized in taste evaluation and design of pharmaceutical formulations, which may reduce the bias in the results obtained through in vivo evaluations caused by subjective differences and ethical issues. The concept of the electronic tongue can be described like the human being. The working principle is based on biological recognition, in which information is gathered using arrays of non-specific sensors in the nose or tongue, and the data is subsequently processed by the brain. The electronic tongue mimics these processes using chemometric methods and artificial intelligence, i.e., it can discriminate, identify, and/or quantify a sample . From an analytical point of view, it comprises different sensors with varying properties and characteristics of partial selectivity or cross-selectivity; the ability of these sensors to measure and characterize complex liquid matrices makes them unique in the field of analytical systems. These sensors transduce the potential of the membrane into an electronic signal and the trapping of ions or molecules on the chemically sensitive layer generates a change in the membrane potential. This change leads to finally a variation of potential between the source and drain region of the field-effect transistor (potentiometric measurement) of the sensor.
The sensor array has been designed to provide relative information of the following taste attributes (when relevant): sourness, saltiness and umami, directly based on a defined specific sensor. In addition, there are several general-purpose cross-sensing sensors. Used with a defined methodology based on standard addition methodology, this specific sensor array allows providing relative information of the other taste attributes (when relevant), such as astringency, metallic, spicy and so on. The relationship between these tastes and a sensor is done in-situ based on the corresponding analysis. This methodology allows to rank samples according to the tastes of interest and define taste according to the products analyzed. In both cases, the final result obtained is a relative unit score of taste. On a given taste attribute axis, the relative positioning of the different samples allows ranking them according to this taste perception.
In this study, levetiracetam was chosen as the model drug, and BJ-3DP was used to prepare the 3D printed IDTs with a loose internal structure and extremely high porosity. A texture analyzer and dissolution apparatus were used to predict the dispersion time in the oral cavity and in vitro drug release of the tablets, respectively. As a first-line antiepileptic drug, levetiracetam is used in large doses and has a strong bitter taste; therefore, an appropriate design for a taste-masking formulation is essential. The palatability of different formulations with sucralose as a sweetener and spearmint as a flavoring agent was investigated using the ASTREE electronic tongue in combination with design of experiments (DoE) and a model for masking the bitter taste. This study demonstrates that the electronic tongue with its seven taste sensors can be utilized to design taste-masking formulations and evaluate 3D-printed IDTs to meet individual requirements.
Materials
Levetiracetam was purchased from Zhejiang Apeloa Jiayuan Pharmaceutical Co., Ltd. (China). Microcrystalline cellulose (MCC PH101) and mannitol (Pearlitol 50C) were purchased from Asahi Kasei Corporation (Japan) and Roquette Frères (France), respectively. Spearmint flavor and sucralose were provided by Kerry Group (Ireland) and Alpha Hi-Tech (China), respectively. Colloidal silicone dioxide (Aerosil 200) and polyvinylpyrrolidone (PVP K-30) were provided by Evonik Degussa GmbH (Germany) and BASF (Germany), respectively. Glycerin was purchased from Nanchang Baiyun Pharmaceutical Co., Ltd. (China). All the solvents were of analytical grade.
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Wang, Z., Li, J., Hong, X. et al. Taste Masking Study Based on an Electronic Tongue: the Formulation Design of 3D Printed Levetiracetam Instant-Dissolving Tablets. Pharm Res (2021). https://doi.org/10.1007/s11095-021-03041-9