Using Taste-Masking and Appearance to Address Patient-Specific Needs

Challener,Cynthia;

Taking patient needs and expectations into consideration when designing and developing new drugs has become increasingly important as evidence mounts that more convenient and easier-to-take products increase medication compliance. To be effective, drug therapies require patient adherence. For oral dosage drugs, particularly liquids, dispersible powders (granules), orally disintegrating tablets or films, chewable tablets, and minitablets, taste-masking can be critical for increasing patient compliance, as these dosage forms result in exposure of taste buds to the APIs, which can be an unpleasant experience, according to Liliana Miinea, technology manager, Pharmaceutical Excipients, at Lubrizol Life Science.

Leveraging taste-masking technologies and solutions that impart an attractive appearance help overcome such issues. It is a complex task, however, that requires consideration of numerous variables including patient profiles, drug product characteristics, and regulatory rules, among others, observes Nasrin Mahmoudi, Sr., lead applications scientist at IFF Pharma Solutions. As such, expertise in these formulation technologies is essential to implementing a patient-centered approach to drug development and ultimately improved therapy outcomes.

Important factors influencing patient compliance

With respect to factors influencing patient compliance, most experts agree that taste and appearance are two of the most important. For oral administration, they may only fall below ease of swallowing and dosing frequency, says Steve Amoussou-Guenou, technical development manager Europe at Roquette.

In addition to palatability and swallowability, other attributes that help ensure patients follow medication regimens as recommended and without delays, skips, or increasing/lowering the dose include acceptable aroma/smell and product packaging, adds Mahmoudi. “In 2006, the [European Medicines Agency] (EMA) reported that taste, smell, and texture were all integral factors in determining a medication’s acceptability for patients,” she says (1).

Bitter blockers

Excipients that can be used to taste-mask bitter APIs are referred to as bitter blockers. These compounds inhibit the molecular pathway that ultimately results in a bitter taste in the mouth on the cellular level (1). Compounds that block bitter receptors could potentially be used as excipients and replace other more complex taste-masking technologies.

Bitter tastes are detected by G-protein coupled receptors (GPCRs), predominantly those in the taste 2 receptor family (TAS2R), which comprises approximately 25 GPCRs (1). Molecules that preferentially bind to these receptors can prevent the detection of bitter tastes. However, genetics has a role to play in how each person perceives bitterness. In fact, more than 150 single-nucleotide polymorphisms have been found in TAS2R coding regions, all of which can influence the sensitivity of an individual to bitter tastes.

Another challenge is the need to identify which taste receptor(s) are targeted by a given API, as the bitter blocker must target the same receptor(s) to be effective (1). Often multiple receptors are involved, and therefore, a single bitter blocker will need to bind to most of them to truly block, rather than simply reduce, the perceived bitterness of an API.

Reference

1. Andrews, D.; Salunke, S.; Cram, A.; et al. Bitter-Blockers as a Taste Masking Strategy: A Systematic Review Towards Their Utility in Pharmaceuticals. Eur. J. Pharm. Biopharm. 2021, 158, 35–51. DOI:10.1016/j.ejpb.2020.10.017

“The importance of taste masking can be attributed to the fact that many APIs can be unpleasant or even impossible to consume without an effective taste-masking strategy—literally the spoonful of sugar that helps the medicine go down,” Amoussou-Guenou says.

Appearance, meanwhile, can be viewed by patients as an indication of quality. In certain markets such as Japan, Amoussou-Guenou notes, even a slight visual defect such as black specs or color heterogeneity will immediately cause concern. A consistent appearance is therefore vital for securing patient trust, as well as their attention. Some drug companies also use a unique visual appearance as a marketing tool and/or to help consumers identify their medications, limit cross contamination, and avoid potential toxicity.

Taking a patient-centric approach to formulation design

The most effective strategy for developing patient-centric formulations and achieving higher levels of medication adherence is to adopt a patient-centric design approach from the outset, Mahmoudi contends.

“Understanding how patient needs and preferences are influenced by variables such as age, overall health, disease states, and physical condition can help to design a patient-centric drug product suitable for a target patient population,” she explains.

For oral formulations, Mahmoudi says, tablet size, shape, smell, taste, and mouthfeel—or, for liquid dosages forms, rheology and volume as well as smell and taste—all impact a drug’s overall acceptability because they all impact swallowability.

To identify the needs of the target population, formulators rely on experience, sensory analysis, and marketing studies, according to Amoussou-Guenou. “[These] data are used alongside other factors like the dosage form type and advice of marketing teams to inform decisions around the drug product’s appearance and desired properties, as well as the most effective taste-masking technique to employ,” she comments.

The dosage form can also be an important dictator of taste-masking requirements. Orally disintegrating tablets (ODTs) and films (ODFs) are good examples, according to Amoussou-Guenou. “These dosage forms are specifically designed to dissolve in the mouth, and their buccal dissolution profile makes taste masking an especially important consideration,” he explains. In these applications, Amoussou-Guenou says producers typically opt for the functional excipient route, rather than coatings, though complexing the API is a viable secondary measure. Multipurpose, co-processed excipients that impart multiple attributes to ODT/ODF formulations are often preferred, as they can support rapid disintegration as well as a pleasant mouthfeel and flavor.

Several technologies to choose from

Several different approaches to taste-masking provide formulators with options depending on the various factors in play. The main determinant is the extent and type of the unpleasant taste or smell of the drug, whether it is bitter, sour, or an irritant, according to Mahmoudi. An API’s aqueous solubility also plays an important role in selecting a taste-masking technique because it can be more challenging to cover the poor taste of highly water-soluble drug substances. It is also often easier to taste-mask low dose formulations. In addition, the particle size and shape and the texture of the API, as well as the target release profile, should be considered when selecting a taste-masking method, Mahmoudi says.

The API can be chemically modified into a salt or pro-drug form to reduce its bitterness, according to Amoussou-Guenou. This technique is limited, however, to drug substances with suitable functional properties. More commonly, excipients with a sweetening effect are added to hide the bitter/unpleasant taste of the API. Molecular complexation with compounds such as cyclodextrins can also mask the taste of the API while the drug resides in the mouth. Finally, application of a barrier coating that remains intact while in the mouth but degrades once exposed to the acidic conditions in the stomach is another widely used approach.

“If an API is only bland or mildly off-putting, formulators can simply add acids, flavorants, or sweeteners to combat the bitterness. Excipients with a naturally sweet flavor, like mannitol, are common here, as they combine good tabletability with effective taste-masking characteristics,” Amoussou-Guenou notes.Coatings are preferred if the API has a strong bitter taste that cannot be sufficiently masked with the addition of excipients to the formulation.

Formulations can also combine taste-masking techniques in the case of particularly unpleasant-tasting APIs. When formulating ODTs for example, Amoussou-Guenou observes that the API can first be complexed with cyclodextrins, hiding the bitter compounds from the patient’s taste buds. Then the complexed API can be combined with a high-performance mannitol to lend reduced friability and a better overall tablet consistency, as well as a cool, almost minty taste that makes the disintegrating tablet a pleasure to take.

With respect to polymer coating technologies used for taste masking, Mahmoudi notes there are several hydrophobic or hydrophilic polymers and lipidic compounds available that can be used as coating materials. She highlights ethyl cellulose as a hydrophobic polymer with a pH-independent release. Mahmoudi also notes that the coating level will be determined by the bitterness level of the API and the dosage form properties and can be adjusted to not only provide taste masking, but also control the API release profile.

Miinea emphasizes how taste-masking technologies are continuously evolving to align with the progress in novel oral dosage forms that address the needs for patients with difficulty in swallowing. She points to polymethacrylates as being increasingly used as barrier coatings to taste-mask bitter APIs. Miinea specifically notes that crosslinked polyacrylic acid polymers (carbomers) having structures similar to weak cation exchange resins may form complexes with weakly basic drugs. “The resultant complexes are insoluble in saliva and mask the bitter taste of the API. When they reach the stomach and are exposed to its low-pH environment, they ionize and release the API without impacting its bioavailability. These polymers may also provide additional functionality, including reduced ‘throat catch,’ or the burning sensation associated with some APIs, including ibuprofen,” she remarks.

Meeting the needs of specific patient populations

Patient-centric formulation requires consideration of the close connections between user needs, dosage form design, and taste-masking technologies, because each patient population has its own discrete preferences and priorities, making some delivery methods more-or-less suitable, Amoussou-Guenou observes. In turn, he notes that just as the choice of delivery method stems from patients’ needs, taste-masking technologies are influenced by a drug’s format and target application.

In particular, Amoussou-Guenou notes that for groups with specialized needs such as pediatric, geriatric, and psychiatric patients, it may be necessary for drug developers to “think outside the pill box” to ensure taste-masking methods remain effective. For instance, some medications prescribed to children are not manufactured in pediatric dosage levels. For tablets, breakage in half or smaller units is therefore required. Barrier coatings used for taste masking will not be effective in this case due to exposure of the tablet core. Formulators therefore need to consider all potential patient populations when selecting a taste-masking technology for a given drug substance.

Taste masking is, in fact, extremely important for pediatric medications because it can significantly improve adherence in this population, according to Mahmoudi. It can also be more challenging, because the specific age, growth level and physiological development, underlying diseases, and regional/geographical preferences must all be considered during formulation development, including selection of the optimum taste-masking approach. As an example, Mahmoudi observes that market research suggests there are ‘favorite’ flavors that vary from country to country and indication to indication.

In the European Union, for instance, cherry and strawberry flavors are most preferred in pediatric medications for pain and infectious diseases, while lemon, peppermint, and orange are recommended for indigestion remedies (1). In the United States, meanwhile, children prefer grape, bubble gum, and cherry flavors (2).Maintaining a balance is essential

While developing palatable, pleasant-looking dosage forms is the key to improved patient compliance, it is necessary to not make drug products appear to be anything but medicines. “As an industry, we must make sure not to make drugs too appealing,” contends Amoussou-Guenou. “Drugs are just that in the end,” he continues, “and no matter how innocuous they look or taste, overconsumption can lead to serious complications. This consideration is especially important in dosage forms aimed at children,” states Amoussou-Guenou. “Producers must walk a formulation tightrope; not too bitter or bland that kids refuse their medicines, but not too craveable that they start to see potent drugs as candies,” he concludes.

A few opportunities for further development

There are two groups for which advances in taste-masking technologies could benefit. The first is infants and young children that require liquid medications or small particles that can be dosed with milk or soft food. Complicating their development is the need to meet different flavor preferences for different pediatric populations and different types of medications. The best approach, therefore, according to Mahmoudi, is to develop liquid, suspension, or ODT formulations with a neutral flavor or in a variety of flavors to be acceptable by children in different regions. Multiparticulate systems, including those based on pellets and mini-tablets, says Mahmoudi, are one approach that allows the flexibility needed for pediatric formulations.

The second group highlighted by Amoussou-Guenou is surprisingly patients who do not require any special considerations. “It may seem counterintuitive, but this group receives the least consideration when it comes to taste-masking. Of course, strategies for improving medicine accessibility for vulnerable populations are both important and necessary. However, as drug developers rightly become more sensitive to the needs of specific groups, they equally should not forget the fundamentals of making every day medicines more palatable, swallowable, and so on,” he states.

On a positive note, Amoussou-Guenou points to advances in the nutraceuticals segment, such as fun formats like functional gummies with attractive fruity flavors, that potentially have applicability for drug products as well. He also highlights steady improvements to the taste of established delivery methods like effervescent tablets. “These developments underscore the potential gains the pharmaceutical industry could realize by considering a more crowd-pleasing approach to taste masking,” he concludes.

References

About the author

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

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Citation

When referring to this article, please cite it as Challener, C.A. Using Taste-Masking and Appearance to Address Patient-Specific Needs. Pharmaceutical Technology 2024 48 (5).