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Editor of Pharmaceutical Technology Europe
Taste-masking can be of significant importance in ensuring success of a drug product, particularly those targeted to pediatric or geriatric populations.
It is well-documented that many APIs are bitter in taste and as a result need to be taste-masked to improve palatability and acceptability for the patient population. “Taste is a critical attribute that determines the palatability of oral dosage forms and patient compliance,” emphasizes Jin Zhao, principle investigator, DuPont.
As taste can be such a key attribute to ensuring a successful drug product is developed, there is a vast array of options available to developers to mask any unwanted bitterness or taste of the ingredients. A common approach, and possibly the simplest of all, is the addition of sweeteners, sugar coating, or flavors. “This approach is suitable for some of the less bitter compounds as the perception of the sweetener or flavor will be stronger than the taste of the drug,” notes Andrew Mound, application development and innovation scientist, DuPont.
“A judicious selection of excipients can enable formulation strategies utilizing flavors, sweeteners, and bitter blockers,” adds Bing Xun Tan, pharmaceutical application laboratory manager at Roquette’s Asia Pacific Innovation Center in Singapore. “Pleasant-tasting, highly viscous, or lipophilic vehicles can also provide an effective taste-masking effect.”
However, for APIs that are extremely bitter or have a complex aversive taste profile, the addition of sweeteners or flavors becomes less viable as their effective taste-masking amount will either increase the overall size of the dosage form which decrease the swallowability of the dosage or will erode the therapeutic dose amount in the dosage form. Another option is to coat the drug, which is possible to do on the tablet, capsule, granule, or API itself, continues Zhao.
“Coating or microencapsulation provide a barrier membrane to prevent the drug from dissolving in the mouth, which is a requisite for taste perception, and depending on the drug properties, coating can be applied in several ways,” says Zhao. “Water insoluble polymers, such as ETHOCEL and Aquacoat ECD, can effectively create barrier membranes and the polymer amount can be adjusted to ensure taste perception is minimized without affecting the release profile.”
Coating can be considered an efficient method, notes Tan; however, the coating process efficiency and coat homogeneity require careful optimization and can be dependent on factors such as the API particle morphology. “Also, depending on the administration technique, interaction of the taste-masking coat and potential food-based dosing vehicles may lead to premature failure of the coating and unmasking of the bitter taste,” he says.
A matrix granulation can be employed to trap a bitter API in a matrix formulation, asserts Zhao. “The matrix may contain gelling or lipid polymers,” she explains. “In granulation-based approaches, the amount of API on the surface of the dosage form is reduced, thereby limiting the amount available to dissolve in the mouth. These approaches work more effectively for drugs with lower solubility or higher taste thresholds.”
Advanced processing techniques such as spray drying or hot-melt extrusion can be used to create a matrix formulation with ethyl cellulose, hydroxypropyl methyl cellulose, or acrylate polymers. “Using these processes, a dispersion can be created in a matrix that is insoluble in the mouth, which will prevent the interaction of drug with taste buds,” explains Zhao. “However, solid dispersion is often less effective as the drug is in a highly soluble state and may be present on the surface of the spray dried or extruded articles.”
Chemically modifying the API is another way to reduce the bitter taste of drugs, adds Tan. “For this approach, the originally bitter APIs are chemically modified to develop prodrug or salt forms with a reduced bitter taste,” he says.
“Complexation with an API, creating a stable complex with ion exchange resin or cyclodextrin, which reduces taste exposure, and a prodrug or salt formation approach can also be useful for taste-masking,” agrees Vinay Muley, technology and innovation leader, India, DuPont.
Tan reveals that an excipient, made from a pea maltodextrin, is available that has been primarily designed for taste-masking and solubility enhancement applications. “The KLEPTOSE Linecaps excipient can decrease the exposure of API to the taste buds through a different mechanism of action to complement the current range of taste-masking excipients available to formulators,” he specifies. “The pea maltodextrin has been reported to exhibit a taste-masking effect on model APIs, such as loperamide hydrochloride and dextromethorphan hydrobromide” (1).
A technique that is rapidly advancing and finding use for taste-masking is 3D printing, according to Zhao. “Personalized medicine is seeing growth opportunities and has the potential to revolutionize the health system,” she says. “Three-dimensional printing is a key enabling technology for personalized medicine and, therefore, there is a need to develop tailor-made taste-masking techniques in conjunction with 3D printed medicine.”
Taste-masking is particularly important for dosage forms and drug products that are targeted to geriatric and pediatric patient populations. “Overall, drug products and dosage forms targeted to pediatric and geriatric populations need to pay particular attention to sensory attributes. Clearly children can be picky and need an appealing dosage form to take the required medicine or vitamin,” confirms Mound. “For older populations with difficulty in swallowing or chewing, taste-masking plays a role in the overall experience of taking medicines.”
Common dosage forms for these target patient populations include chewable tablets, orally disintegrating tablets, gummies, and liquid dosage forms, which are prime for taste-masking and sensory improvement, adds Mound. “These formats are growing in popularity, making them ripe for innovation in the application,” he says.
“The pediatric patient population has a big need for taste-masking solutions that is not yet fully met today,” asserts Tan. “As the pediatric population cannot swallow oral tablets, most pediatric drug products are either liquid, particulate, or orodispersible dosage forms where the bitter APIs can have a prolonged and direct exposure to taste buds in the buccal cavity.”
However, excipient options for pediatrics are limited, and are less well defined or understood in terms of safety, Tan continues. “Hence, current taste-masking approaches for adults may not be feasible and suited for children,” he notes. “The relatively lower commercial value of pediatric products also means that developers generally prefer simple and cost-effective taste-masking strategies, so complex processing is less desirable.”
Formulation difficulties can arise when taste-masking strongly bitter APIs, ingredients that have high solubility in the buccal cavity, or when high doses of active ingredients are required, Tan emphasizes. “In such situations, the application and efficacy of flavors and sweeteners is greatly limited, and so other methods need to be employed, as explained earlier,” he says.
“Another challenge in development is with taste evaluation techniques,” Tan continues. “A human sensory panel is still the most recognized method of taste evaluation. However, sensory evaluations are often more costly and challenging to organize, especially when potent APIs or new chemical entities are involved.” Furthermore, there is some debate over the relevance of human sensory panels for specific patient populations, such as pediatrics, he asserts.
“There is a great need to develop analytical technologies that characterize the taste and correlate well with in-vivo performance,” comments Zhao. “Advances have been made in electronic tongues, but in-vitro–in-vivo correlation (IVIVC) of taste is even more challenging than IVIVC of drug release; as simulating taste recognition in the mouth is more challenging than simulating drug absorption in digestive tract.”
Methods such as the electronic tongue are useful for the early screening of formulations during R&D, agrees Tan. “However, there remain technological limitations in these methods, and the sensitivity and reliability of the measurement depends greatly on the API properties and also the excipients used in formulation,” he adds.
“Another challenge is creating an effective taste-masking performance without affecting pharmacokinetics and pharmacodynamics of active ingredients,” asserts Zhao. “Some of the previously mentioned barrier membranes can also modulate release to the point that it changes the absorption profile. For example, ethylcellulose at a low level will provide excellent taste-masking; however, at slightly higher percentages it begins to provide a sustained release profile, which may be undesirable for a given drug and most be monitored during development.”
Additionally, there is still a need to ensure there is a robust measurement system in place that can provide qualitative and quantitative data on the taste attributes—without which optimization of taste-masking technologies is difficult, emphasizes Muley. “Finally, regulatory constraints to reduce the number of excipients in pediatric formulations presents additional challenges in providing an optimized taste-masking approach,” he says.
Industry will continue to see developments and improvements in taste-masking of dosage forms for pediatric and geriatric patient populations, states Mound. “Novel dosage forms such as orally disintegrating tablets and films, chewable tablets, and liquids will continue to evolve to boost taste-masking technology options,” he specifies.
Moreover, as there is an increasing drive from major regulatory agencies for new drug product developments to include pediatric trials, there will be advancements in taste-masking options, highlights Tan. “The Pediatric Research Equity Act (PREA) in the United States and Paediatric Regulation in Europe require submission of a Pediatric Study Plan (PSP) and Paediatric Investigation Plan (PIP), respectively,” he explains. “Because of this regulatory direction, there is a renewed focus from pharmaceutical companies on taste-masking solutions and palatability studies, which can aid development and demonstrate acceptability of the drug product for children.”
The scope of what constitutes taste sensation is also widening, Tan continues. Whereas, traditional taste-masking solutions have been focused on the bitter taste of the drug product, there will be more consideration of other attributes, such as sourness, and also aversive sensory attributes such as odors, texture, and irritation, which contribute to the overall patient experience, he explains.
“Therefore, a combination and synergism of several taste-masking strategies may be required to address different aspects of the sensory challenge,” Tan reveals. “For example, a combination of different excipients, such as a polyol (maltitol) and intense sweetener (sucralose), have been reported to display synergism leading to an optimized taste-masking of the model API, acetaminophen, in chewable tablets (2). Also, excipients that can contribute to more than one aspect of the taste-masking or formulation challenge will be advantageous in reducing formulation complexity.”
The expansion of scope for improvements in sensory attributes will also incorporate over-the-counter (OTC) and dietary supplement segments, which will provide opportunities for taste-masking technologies, highlights Mound. “As consumers continue to gravitate toward the elimination of sugars and other non-clean label sweeteners, formulators will be challenged to deliver a quality product without the traditional options at their disposal,” he says. “Cleaner label taste-masking options are needed in this space.”
Added to this, the competitive nature of the OTC and nutraceutical markets will mean that innovation, particularly in dosage forms and formulation, will be highly sought after to ensure product differentiation, Tan emphasizes. “Interest in innovative oral dosage forms will in turn increase the demand for novel taste-masking solutions,” he states.
“And as innovations, such as 3D printing, enable the development toward personalized medicine, customized taste-masking options will be possible and essential in delivering differentiated products,” summarizes Zhao.
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Vol. 44, No. 10
When referring to this article, please cite it as F. Thomas, “Masking Taste: A Key Attribute to Success,” Pharmaceutical Technology 44 (10) 2020.