Oral administration is the most common route of drug delivery, and that’s for a very good reason. Compared to say, intravenous infusions, taking a medication by mouth can be simpler, safer, cheaper and more convenient. Unfortunately, it comes with a major challenge attached: if the drug tastes bad, this can be a roadblock to patient compliance.
Think of the 1964 children’s film Mary Poppins, in which the heroine sings about ‘a spoonful of sugar’ to help ‘the medicine go down’. Her words were intended as a metaphor for making unpleasant tasks more appealing, but they could just as easily be taken at face value. Given the unappetising taste of many active pharmaceutical ingredients, manufacturers have long-needed strategies to improve their palatability.
“Many factors influence patient acceptability, including the route of administration, dosage forms, taste, smell, texture, and appearance of the drug,” comments Laura Owens, global strategic marketing manager at International Flavors & Fragrances (IFF). “Children are particularly sensitive to taste and may resist bad-tasting medication. Studies show that poor palatability negatively impacts adherence, while good palatability improves it.”
Indeed, one small study of children on HIV medication found that more than 78% had problems with the treatment regimen. Half of that was attributed to the taste of the medication. In another study, more than 90% of paediatricians reported that a drug’s taste and palatability were the biggest barriers to completing treatment.
As well as being more bitter-sensitive than adults, children are generally less able to swallow pills whole – the easiest way of masking taste. Before the age of six to eight, they require liquid formulations, and even in later childhood and adolescence, their tolerance for tablets and capsules varies. Adults, too, can struggle with poor-tasting medications, not least because one in 17 people will develop dysphagia (problems swallowing) in their lifetimes.
“Patients should follow treatment plans without delays or dose alterations,” says Owens. “Poor adherence, especially in chronic disease patients, can worsen health outcomes and increase costs. Approximately 50% of patients with chronic diseases do not take their medications as prescribed.”
Strategies for success
So, is the solution as simple as adding a ‘spoonful of sugar’? A letter in the British Medical Journal argued that this approach is not, in fact, used often enough, stating that the bitter taste of medicines ‘is due to the current paternalistic preference for sugar-free medicines in all cases without exception’. The letter claimed that the risk of tooth decay has been overemphasised, whereas the ‘adverse impact of bitter taste on medication compliance and the resulting suboptimal therapy… has been overlooked’.
Whether or not this is a fair analysis, it is true that most modern medicines are sugar-free. Owens explains that there are two principal strategies for masking taste, the first being the addition of sweeteners or flavourings.
“This involves modifying the organoleptic properties and perception of an unpleasant taste by adding more pleasing tastes or textures,” she says. “This is the simplest approach for taste masking, especially in the case of paediatric formulations, chewable tablets, and liquid formulations.”
Sometimes manufacturers add effervescent agents such as citric acid, to improve mouthfeel. While this can be effective, Owens warns it isn’t as successful for highly bitter or highly water-soluble drugs. What’s more, artificial sweeteners are sometimes reported to have a bitter or metallic taste in themselves.
In these cases, manufacturers may choose to run a few taste-masking strategies in combination. An approach that has been gaining traction in recent years is the addition of ‘bitter blockers’ – ingredients such as adenosine monophosphate, lipoproteins or phospholipids that bind to the bitter receptors on the tongue.
As a 2021 research paper explained, there are clear advantages to blocking the bitter tastes directly, rather than trying to mask them with sweetness. Through creating a ‘taste-neutral product’ – an approach supported by current EMA guidelines – manufacturers can avoid the pitfalls of ‘an overly palatable and attractive medicine which can lead to accidental poisoning.’
Coatings great and small
In other cases, says Owen, manufacturers will adopt the second main strategy – altering the physical and chemical properties of the drug itself. Here, the idea is to prevent it from contacting the taste receptors.
“This can be achieved through methods like coatings, granulation, ion exchange, solid dispersion, inclusion, complexation, and microencapsulation,” she says. “The choice of taste-masking technique largely depends on the nature and intensity of the drug’s unpleasant taste or smell, whether it is bitter, sour, or irritating. Another factor is the drug’s dosage. Generally, it is easier to mask the taste of a low-dose formulation compared to a high-dose formulation.”
She notes that coatings are the most-used technique, accounting for more than a quarter of patent applications for taste-masking technologies in a 2009 review. They are also perhaps the simplest option. A coating will function as a physical barrier to the drug particles, minimising their contact with the taste receptors. While it stays intact in the mouth, it dissolves in the stomach, allowing the drug to release its contents.
“For aggressively bitter drugs, multilayer coatings are utilised to overcome the challenges of coating imperfections, which otherwise would lead to a decline in taste masking performance,” adds Owen. “To enhance mouth-feel, a plasticiser may be added to improve smoothness and provide additional barrier properties.
Additionally, sweeteners may also be added to the coating solution for a better taste masking performance.”
Another key approach is hot-melt extrusion, in which the bitter active ingredient is mixed with other ingredients while in a dry state, before being melted and extruded. This creates taste-masked particles, which are then incorporated into a pill or powder. Then there’s spray-drying, which creates ‘taste-masked microspheres’ through a process of dispersion, spray-air contact, and drying.
Another strategy is complexation, in which a type of sugar called cyclodextrins are used to form a shell around the bitter ingredients. Finally, there is microencapsulation, which involves applying a rigid, semi-permeable polymer to a small particle or liquid droplet. You could think about these approaches as using a kind of coating – it’s just that the coatings are applied on a much smaller scale.
As Owens points out, these approaches can be particularly useful within paediatric formulations, in which large, coated tablets are not an option. Many of IFF’s pharmaceutical clients opt for multiparticulate systems, such as mini-tabs.
“These can be coated, and small taste-masked particles can be prepared through methods like spray drying or solvent evaporation. These systems offer dose flexibility and are suitable for children,” she says.
Emerging trends
While taste masking is a technically challenging field, it has already made a huge difference to patients’ treatment quality. It’s also an area that’s advancing all the time.
“Numerous technologies are available to not only mask unwanted API tastes but also enhance the palatability of formulations,” says Owens. “Recent advancements in taste masking have led to new strategies, such as child-friendly fast-dissolving dosage forms, chewable tablets, and taste-masked suspensions.”
With research and development continuing apace, Owens points to several emerging trends. As well as microencapsulation, these include granulation (agglomerating pharmaceutical powders with a binder), suppressants (chemicals that suppress the unpleasant flavour) and potentiators (chemicals that bring out other flavours).
“We’re also seeing innovations in coating technology, such as using multilayers or spacer layers and shifting to aqueous-based coatings of hydrophobic polymers,” she says. “But over half of patents and patent filings in taste masking focus on technologies beyond coatings and sweeteners.”
The research community is also turning its attention to another area: how to assess tastemasking properties. While qualitative approaches are common (think volunteer taste panels), Owens says more analytical approaches are being developed. These include Biomimetic Taste Sensing Systems (BMTSSs), also known as an ‘electronic tongue’.
“These systems recognise three levels of biological taste including receptor level, circuit level and perceptual,” she says. “However, these systems have limitations as they cannot fully replicate patient preferences. Taste is highly subjective and varies between demographic groups and even within the same demographic.”
For companies working in this field, such as IFF, there is clearly plenty to be getting on with. Contrary to the ‘spoonful of sugar’ adage, this is not really an area that can be approached without specialist expertise.
“Even a small amount of aggressively bad-tasting medicine is enough to detect its unpleasant flavour,” points out Owen. “But by adopting a patientcentred approach, pharmaceutical companies can significantly enhance therapy adherence and improve patient outcomes.”
