Evolving Approaches to Taste Masking

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The careful design and development of formulated oral drug products are key to ensuring patient acceptability and compliance for achieving the desired clinical outcomes. Many APIs are extremely bitter or have other aversive attributes that can make developing palatable drug products challenging, notes Nazim Kanji, executive director of pediatric services with Quotient Sciences. Several factors can influence palatability, including the chemical structure of the drug substance and the finished medicinal product formulation, as well as the excipients used. “Undesirable taste is a common problem seen in medicines spanning all therapeutic areas, from antibiotics and painkillers to antihistamines and decongestants,” Kanji notes.

Taste masking of oral dosage forms is, therefore, an essential component of formulation development. A one-size-fits-all approach is not available, however, according to Ashish A. Joshi, pharma technical and business manager with BASF Pharma Solutions. Taste-masking strategies, he observes, must almost always be tailored to various aspects, such as the degree of inherent bitterness of the drug, the type of dosage form, the patient age-group, and whether the final formulation is in a solid or liquid form.

As the percentage of drug substances in development suffering from bitter tastes has increased and many new formulation and delivery strategies have been introduced to increase patient convenience and compliance, taste-masking technology has therefore evolved. In addition to more traditional approaches such as the use of barrier coatings, solid dispersions, and the addition of sweeteners and flavoring agents, formulators are leveraging newer strategies such as liposomes, various forms of complexation, co-crystal and pro-drug formation, emulsification, and microsphere and encapsulation technologies.

Basic advances

As part of developing palatable pediatric and patient-centric drug products such as solutions, suspensions, and orally disintegrating tablets (ODT), several recognized approaches can be taken to mitigate the poor taste of these APIs. “The most common approaches include using a combination of flavors and sweeteners to mask a bitter taste or barrier coatings to prevent the release of API from the drug product into the buccal cavity prior to the dose being swallowed,” comments Kanji.

Some advances in taste-masking technology are improving on these basic approaches. Researchers are, for instance, exploring methods to enhance both the perception and physicochemical stability of long-acting flavors through encapsulation and complexation techniques, according to Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions. Joshi adds that certain zinc salts have also demonstrated the ability to mask bitter taste effectively.

Improvements in pH-dependent barrier film coatings, meanwhile, have helped to overcome the coating inefficiencies for fine (small particle size) drug substances that require extended processing times due to their large surface areas. For these APIs, additional steps or approaches such as drug granulation to increase particle size or drug layering in inert pellets, can be used, Assis observes.

Lipids and insoluble polymers such as stearic acid, ethyl cellulose, and carnauba wax, when used in combination with surfactants, have also been shown to be promising as effective taste-masking approaches for drug particles. “These hydrophobic materials have low solubility in the mouth, contributing to improved taste-masking properties,” Joshi explains. He does caution, though, that it is important to be aware that use of lipid coatings may result in changes in a drug substance’s release profile, thus potentially impacting drug bioavailability.

Improved functional polymers

Reverse-enteric polymers have become increasingly attractive as taste-masking polymers due to their pH-dependent solubility; they do not dissolve in the mouth at salivary pH, but once exposed to the acidic pH of the stomach, dissolve immediately to release the drug substance.

When these types of polymers are employed, the coating composition and level must be carefully balanced to prevent drug release during the residence time in the buccal cavity (e.g., up to 30 seconds for orally disintegrating tablets) while still allowing adequate drug release in the gastrointestinal tract to ensure that pharmacokinetic (PK) performance is not compromised, according to Kanji. “Realizing this balance can be a challenging prospect and may not be accurately predicted by in vitro dissolution testing,” he observes.

One example noted by Assis is a copolymer of methyl methacrylate (MMA) and diethylaminoethyl methacrylate (DEAEMA), which exhibits a lipophilic characteristic and does not dissolve at neutral to basic pH due to the amino functional group. “This lipophilic quality is very beneficial to the process [because] it reduces the required coating level for taste-masking purposes and provides moisture protection for sensitive drugs,” he observes. With these attributes, the drug substance becomes more suitable for liquid taste-masked formulations, where well-coated particles can be suspended in a neutral pH liquid, enabling the creation of a taste-masked suspension.

In the dry-powder form, water-insoluble matrices have been used effectively in melt-granulation processes, Joshi adds. During extrusion, the polymer covers the drug substance and forms a stable barrier layer once the granules are cooled. “The key advantage of this process is that it does not use any water or solvents and thus achieves efficient taste-masking of a moisture-sensitive drug substance while minimizing its possible degradation due to exposure to an aqueous or organic coating process,” he comments.

Another benefit to melt-granulation is the reduced process time compared to film coating, according to Assis. It can also be implemented as a continuous process, he notes. Reverse-enteric polymers in the dry state may also be suitable for the development of hot-melt extrusion formulations, allowing the production of taste-masked amorphous solid dispersions with improved solubility and taste, Assis remarks.

Using a mixture of water-soluble and insoluble polymers represents another newer strategy. “Tailoring the ratio of a polyvinyl acetate (PVAc)-based water-insoluble polymer and a water-soluble pore former such as a polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymer in a barrier coating allows efficient taste-masking to be achieved without significantly altering the release profile of the formulation,” Joshi explains.

The assessment and optimization of the polymer coating can be efficiently undertaken by integrating drug product formulation development and manufacturing with clinical testing activities, says Kanji. Quotient Sciences, for instance, uses a proprietary drug-development platform that enables drug products to be manufactured, released, and dosed in healthy subjects in a matter of days so that compositions can be optimized based on emerging clinical data. In addition to PK data, each formulation’s palatability attributes (e.g., bitterness, mouthfeel, grittiness, and aftertaste) can also be assessed as part of the same study, Kanji adds.

Following development of the taste-masked dosage form, confirmation of acceptability is achieved via palatability assessment of the drug product, thereby providing assurance that poor taste will not impact patient acceptability and compliance, Kanji concludes.

A new encapsulation approach

Lipid excipients are also being explored as encapsulating agents. One example highlighted by Joshi involves dispersing the drug substance in molten stearic acid or glycerol monostearate followed by atomization in a cold environment using a melt-congealing microencapsulation process. “This approach is particularly useful when the API is both extremely bitter and highly sensitive to moisture because it allows for effective taste-masking without the use of a typical aqueous barrier coating,” he contends.

Better solutions for liquid formulations

Masking the taste of highly bitter drug substances in liquid dosage forms (solutions or suspensions) remains a significant challenge. Despite advances, effective taste masking can still be difficult when a drug substance has multiple taste and/or sensorial attributes (e.g., bitter, metallic, burning sensation), according to Kanji. This situation is particularly true for liquid formulations, which typically rely on the use of flavors and sweeteners for taste masking, he notes. Barrier coatings may also lose their effectiveness over the shelf-life of the product due to continuous exposure of the API to water, Joshi adds.

One new solution is to use micelle-forming surfactants, liposomes, or cyclodextrins to protect the drug substance. “For instance, in an aqueous environment,” Joshi comments, “certain surfactants and poloxamers form micelles that can entrap the drug substance, forming transient inclusion complexes, thus shielding it from the tastebuds and effectively masking its taste. This approach, he observes, also has potential for use in other dosage forms, such as gummies.

The use of water-in-oil (W/O) emulsions for taste masking of soluble APIs is another promising approach for liquid formulations, according to Assis. “In this case, the drug substance is effectively encapsulated within the water phase, which is surrounded by the continuous oil phase, preventing it from coming in direct contact with the taste buds and thus masking unpleasant tastes such as bitterness,” he says.

The water-soluble API is dissolved in the aqueous phase. The continuous phase comprises an oil with an acceptable taste profile, with medium-chain triglycerides (MCTs) being of particular interest, as well as surfactants with both low and high hydrophilic–lipophilic balances (HLBs) as the emulsifiers, Assis observes. He notes that polyoxyl 40 hydrogenated castor oil with a high HLB of approximately 14 to 16 is recommended for solutions and suspensions because, unlike other emulsifiers, it has a more pleasant taste. Additionally, glycerol monostearate type II (mono- and di-glycerides) is an excellent alternative as a co-emulsifier due its low HLB value of approximately 3.8.

The water phase is dispersed within the continuous oil phase, and the resulting O/W emulsion has the drug substance “hidden” within the emulsion droplets, which act as a barrier between the API and the taste receptors, Assis says. The oil phase surrounding the water droplets, meanwhile, prevents release of the drug substance while it is in the mouth; release occurs only once emulsification and absorption take place in the gastrointestinal tract.

Solutions for high drug-loading formulations

One important trend in oral dosage drugs is development of high-drug-loading formulations. “High-dose drugs in solids can be very tricky and demand better approaches to improve their taste profiles,” Joshi says. For instance, he notes, traditional barrier coatings can be challenging as long coating processing times are often required to achieve the desired level of masking.

One alternative is to use a dual-granulation coating approach to establish a barrier coating. “In this process,” explains Joshi, “the coating polymer not only covers the API and excipients, but also acts as a binder that enables formation of larger granules. The result is effective taste masking combined with improved flowability and compressibility of the drug product.” It is necessary, though, to use appropriate cushioning agents/plasticizers to maintain the integrity of the polymer following compression into a tablet. Certain methacrylic acid polymers can be effectively used in this application.

Continued interest in bitter blockers

Development of additives for oral dosage drugs that block the receptors in the mouth that perceive bitterness has been a goal for many years. Taste buds elicit taste responses using G-protein coupled receptors (GPCR) or ion-channel receptors. Modulating their responses using compounds that block these receptors would be an effective means of eliminating the perception of specific tastes, according to Joshi.

This approach remains challenging, however. Such compounds need to be safe and provide transient and reversible modulation so that a patient’s taste perception is not affected for a long time after consuming the drug, Joshi says. In addition, there are at least 25 different, highly genetically diverse bitter taste receptors, and the drug substance-taste receptor pathway is not always known, Assis observes. Despite these challenges, a few specific compounds referred to as bitter blockers have been developed that interfere with the taste transduction process, at least to some degree, by inhibiting the taste cascade (interrupting the GPCR signal cascade), says Assis.

A few other approaches are also being explored. For instance, the API, which typically exists as a salt of some kind, can be converted into a more palatable compound, such as a prodrug, freebase, or different salt, according to Assis. It is necessary when using this strategy, however, to carefully consider the formulation development time and to assess any potential changes in pharmacokinetics.

Finally, complexing agents like ion-exchange resins and cyclodextrins can be used to prevent interaction of the API with bitter receptors. When using these approaches, Assis emphasizes the importance of considering factors such as the potential for drug-resin dissociation and the amount of cyclodextrin needed, respectively, as these factors may impact dosage size and costs. Cyclodextrin, for instance, can not only be very costly, but also may need to be used in a high quantity to ensure effective complexation with the drug substance at the molecular level.

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 49, No. 1
January/February 2025
Pages: 17–19

Citation

When referring to this article, please cite it as Challener, C.A. Evolving Approaches to Taste Masking. Pharmaceutical Technology 2025 49 (1).