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Palatability is crucial for adherence and compliance to oral drug regimens.
Avoiding bad or bitter tasting finished drug products is widely accepted as a way of improving patient adherence and compliance to a therapeutic regimen, particularly when considering pediatric and geriatric populations. Many APIs in development, however, are classified as bitter compounds.
Elaborating on this point, Krizia M. Karry, global technical marketing manager, BASF Pharma Solutions, highlights a study by Dagan-Wiener et al. which revealed that two-thirds of current clinical and experimental drugs were classified as bitter (1). “Aversion to bitterness, or in general, product palatability, has been demonstrated to affect treatment completion,” she says. “For example, in 2007 the average treatment completion rate of pediatric patients was only 58% with palatability and formulation being attributed as major contributing factors. To this day, this has not changed.”
In agreement, David Tisi, director of operations, Senopsys, adds that on top of bitterness, many active ingredients have other undesirable sensory attributes, such as smell or trigeminal irritation. “Furthermore, excipients used to increase drug solubility or used for preservation are known to create or exacerbate the taste masking challenge,” he notes.
Going back 40 years, O’Mahony et al. performed a series of experiments assessing taste the perception of bitter or sour (2). In the experiments, it was realized that confusion between sour and bitter tastes existed in the general population. For Tisi, the difficulties in determining how a patient perceives the taste of an ingredient is a major challenge that must be overcome by the formulator. “Untrained healthy volunteers often describe drugs as ‘bad’ or ‘yucky’ tasting, which is not very helpful as there’s no ‘good’ or ‘yummy’ ingredient on the shelf to improve palatability,” he says.
From data compiled by Senopsys, taken from 101 taste assessment studies, it was found that the primary challenge in taste-masking was bitterness at 75%, followed by aromatics (10%), and trigeminal irritancy (8%). In APIs that were fundamentally tasteless, challenges were driven by excipient attributes (3).
“The reason these data are critically important is that the formulation strategies for mitigating bitterness, malodor, irritation, and texture are fundamentally different,” explains Tisi. “As these approaches differ, it’s important to correctly identify the aversive attributes at the outset.”
Predicting whether new compounds will be bitter or not is one of the biggest challenges, according to Karry. “Albeit unknown to most, there is not a clear understanding as to which chemical bonds, functional groups and compounds activate the bitter receptors in the tongue,” she says. “BitterDB, a database with more than 1000 bitter compounds, is available to formulators (4). Machine learning algorithms trained with these molecules are now used to predict bitterness of new compounds. This tool enables formulators to proactively think about methods to suppress bitterness and include in excipients meant for taste masking.”
Karry continues by specifying that in her opinion the second and most important challenge in bitter formulations is to prevent drug release in the mouth. “Human saliva has a pH range between 6.2 and 7.6,” she states. “The most effective taste-masking approaches employ insoluble polymers that create a barrier that limits water penetration, drug solubilization, and consequently drug diffusion to the surface such that the bitter tongue receptors are not activated, and an aversion reaction is prevented.”
However, limiting drug release in the mouth brings about other challenges. The most effective taste-masking polymers are insoluble at pH > 5 but will immediately dissolve in stomach acids, explains Karry. “A consideration with using such excipients is that the formulation should allow for complete polymer solubilization in the stomach even with shorter gastric residence times (1 hr) or when the patient is in a fed state (pH 4.2–5.8),” she says. “Special attention should be given to tablets based on multiple-unit pellet systems (MUPS), which show faster gastric emptying times due to their small size and larger surface area. For these, the pellet diameter and coating weight gain need to be optimized with respect to polymer solubilization and drug release rate.”
Understanding the magnitude of taste-masking challenges is of great importance to Tisi who specifies that although in some instances it may be possible to overcome taste issues with a traditional excipient approach (such as sweeteners, buffers, or flavors) for other ingredients it may be necessary to “sequester” them from the taste receptors to achieve palatability. “Information about the magnitude of the challenge at hand will allow the formulator to prioritize or eliminate certain dosage forms (e.g., the most difficult taste-masking challenges may not be suitable for a ready-to-use oral solution),” he stresses.
Specific patient populations, such as pediatrics and geriatrics, require more complicated taste-masking approaches. “For these patients, palatable oral formulations are required for acceptable dosing compliance,” comments Tisi. “In recognition, regulations in the United States and European Union are stimulating research into the development of drug products specifically labeled for pediatric dosing.”
Regulatory requirements and guidance are present in both the US and EU to help companies develop age-appropriate dosage forms for patients. Examples include the Pediatric Research Equity Act (PREA) in the US (5), and the Paediatric Regulation from EMA (6). These requirements typically lead to alternative dosage forms due to difficulties that are encountered by young children in swallowing traditional solid oral dosage forms, confirms Tisi.
“However,” he continues, “children are not the only ones who suffer from difficulty of swallowing, a condition known as dysphagia. In the US, dysphagia affects 1 in 25 adults annually, not including patients with certain neurological and degenerative disorders (7). Accordingly, swallowability and palatability are important determinants of dosing compliance for all ages and conditions.”
Dose and tablet size are important considerations in addition to palatability when designing products for both pediatric and geriatric patient groups, adds Karry. “Parents prefer smaller tablets for their children but minitablets may be difficult to handle by geriatric patients,” she says. “To satisfy both requirements a formulator may opt to create a small tablet with a rocking design. In terms of palatability, children prefer flavored medications, but the opposite is true for older patients. In this case taste-masking polymers can be used to suppress bitterness and achieve a tasteless drug product that also limits drug abuse by children who ‘want more candy’.”
In addition to the traditional methods of sweeteners, flavors, buffers, and viscosity and pH modifying agents that help avoid dissolution in the mouth, there are other taste-masking technologies that formulators can utilize. “Other technologies, such as salt formation, prodrugs, complexation, and so on, exist,” explains Karry. “Additionally, coating is gaining further traction in the industry as an effective technology for aggressively bitter APIs.” Limitations of coating techniques include imperfections and adequate in-vivo drug release, she adds.
“Broadly speaking, there are five general masking approaches that are available to the formulator,” states Tisi. “But, each of these approaches comes with its own set of advantages and disadvantages.” (See Table I.)
In terms of future approaches, Tisi believes that there is a trend towards increased mutliparticulate dosage forms. “These serve as an alternative to more established formulation options, but generally require extemporaneous preparation in a dosing vehicle-a complexity for some caregiver situations.”
Karry agrees that technologies such as microencapsulation, the addition of pH-modifying agents, suspensions, complex formations, solid dispersions, use of taste suppressants and potentiators, and dry coating bitter APIs are being studied; however, she emphasizes that growth of these technologies is relatively marginal compared with film-coating technologies.
“There is continuing interest in the development of a ‘universal’ taste-masking technology that produces small, spherical particles with a polymeric coating optimized for both taste and bioavailability,” notes Tisi. “Advances have been made in these dimensions as well as taste masking; however, bioavailability and manufacturability of a uniform particle size reportedly remains a challenge.”
Basic research into how patients perceive taste is continually advancing with many receptors for sweet and bitter tastes being identified, he adds. “This is enabling screening and identification of compounds that can modulate these tastes,” Tisi explains. “However, for drug products, the regulatory landscape is uncertain for these new compounds.”
Particularly exciting advances for Tisi are those in the field of signal interruption. “A number of players are now working in this field, and each has a proprietary method for discovering novel taste receptor modulators,” he says. “High throughput screening of candidate compounds is a must, as humans possess more than two dozen known bitter taste receptor cells, and a signal interruption chemical must act on the same set of receptors that the drug does.”
“Now more than ever patients are looking for convenience (i.e., small tablets that can be taken ‘on-the-go’ with minimal or no liquid),” concludes Karry. “As a result, patient convenience and compliance have become important pillars in formulation optimization for new drug products.”
1. A. Dagan-Wiener, et al., “Bitter or Not? BitterPredict, a Tool for Predicting Taste from Chemical Structure,” Scientific Reports, Sept. 21, 2017.
2. M. O’Mahony, et al., Chemical Senses and Flavour, 4 (4) 77–94 (1979).
3. Senopsys, “Taste Masking-There’s More Beneath the Hood than Bitterness,” senopsys.com, July 3, 2017.
4. A. Wiener, et al., Nucleic Acids Res., 40 D413–419 (2012).
5. FDA, “Pediatric Research Equity Act | PREA,” fda.gov [accessed Oct. 16, 2019].
6. EMA, “Paediatric Regulation,” ema.europa.com [accessed Oct. 16, 2019].
7. N. Bhattacharyya, Otolaryngol. Head Neck Surg., 151 (5) 765–769 (2014).
Vol. 43, No. 11
When referring to this article, please cite it as F. Thomas, “Avoiding Bitter Taste,” Pharmaceutical Technology 43 (11) 2019.