It’s a Matter of Taste-Masking

As most APIs have an unpleasant or bitter taste, solutions to help mask the flavor are integral in ensuring a dosage form’s palatability and commercial success. To learn more about the potential solutions currently available to formulators for taste-masking, as well as those approaches in the pipeline, best practices, and excipient considerations, Pharmaceutical Technology spoke with Kevin Hughes, manager Regulatory Affairs at Colorcon; David Tisi, technical director at Senopsys; and Bing Xun Tan, PhD, Pharmaceutical Application Laboratory manager at Roquette’s Asia Pacific Innovation Center in Singapore.

Importance of taste

PharmTech: How important is taste-masking and what formulation approaches are currently available?

Hughes (Colorcon): Many APIs inherently possess a bitter taste. If a medication is not palatable, the patient may opt to discontinue taking their dose. Failure to take medication as prescribed can lead to avoidable healthcare costs, and potentially increased morbidity and mortality. While objectionable taste may be one of several reasons for poor adherence, every measure that minimizes these reasons helps.

The most popular oral dosage forms include liquids, powders, granules, and tablets—especially orally disintegrating tablets (ODT) and chewable tablets. Each one has pros and cons, depending on the target age group. Liquids, powders, and granules provide the greatest flexibility in dosing, provided there is a simple way to meter the powders. The commonly used techniques/methods of taste-masking include organoleptic methods, polymer coating, hot-melt extrusion, microencapsulation, complexation using ion-exchange resins, and spray-drying.

A more recent application is the use of ion-exchange resins, the resin-drug complexes formed will elute only a limited percentage of the drug in the saliva pH. Thus, the taste of the drug is masked without interrupting the drug release profile.

Tisi (Senopsys): Simply put, patients will not routinely take medicines that are unpleasant to them. A patient may take their first dose or even tolerate a bad tasting acute therapy, but for chronic indications, poor palatability has a negative effect on adherence/compliance.

Aside from the ethics of improving patient quality of life and the business case made for improved adherence, there are regulatory obligations and rewards for improving palatability in special populations. Both FDA and the European Medicines Agency (EMA) require palatability to be considered in a sponsor’s Pediatric Study and Investigation Plans, respectively (1,2), in the submission package for the adult form. Such studies should include an assessment of formulation palatability.

Properly addressing the palatability challenge of a specific formulation will depend on the target form, type of API, chemical properties, and taste-masking challenge (how unpalatable the API is).

Tan (Roquette): Taste-masking solutions can enable the development of innovative orodispersible dosage forms, which are considered more patient-friendly. In the nutraceuticals market, where consumers can choose from a multitude of commercial offerings, product taste can be a deciding factor when it comes to making their purchasing decision.

Taste masking of pharmaceutical drug products is generally achieved through one, or a combination, of the following three approaches. The first approach involves chemical modification of the API to reduce bitterness.

The second approach uses excipients in formulation to facilitate a direct sweetening effect and/or reduction of the perceived API bitterness. Careful selection of excipients can enable formulation strategies using flavors, sweeteners, and bitter blockers. Pleasant-tasting, highly viscous, or lipophilic vehicles can also provide an effective taste-masking effect.

Lastly, advanced processing of the API or drug product can help minimize oral solubility and direct contact with the taste buds. Common approaches include coating of API particles with a physical barrier; tablet film coating or sugar coating; microencapsulation; embedment of API particles in a matrix; microspheres and liposomes; complexation of API with cyclodextrins or ion-exchange resins; and adsorption of the API using insoluble powders.

Best practices

PharmTech: Are there best formulation practices to follow for taste-masking?

Tan (Roquette): In formulation, the difficulty of taste-masking is increased when the API possesses a strong bitter taste, high solubility in the buccal cavity, or when a high dose of the API is required.

It’s best practice to consider taste masking early in the product development process, as major regulatory agencies now require new drug product developments to include pediatric trials. [As a result of regulatory requirements] pharmaceutical companies are focusing on taste-masking solutions and palatability studies that can aid development and demonstrate patient compliance of the drug product for children. Early consideration of the potential need and solution for taste masking can help minimize potential delays later in the process.

Hughes (Colorcon): Several factors go into the decision process for the formulation, including properties of the API, dose level, dosage form, desired release profile, and so on. Both dissolution profile and taste profile contribute to the acceptability criteria for taste-masked formulations. However, each drug product will have different release profile requirements to meet an acceptable level of taste-masking depending on the dose strength and organoleptic response to the API. Ideally, the taste-masked dosage form should prevent the release of an unacceptable tasting medicine until the API has left the mouth, then allow for immediate release once the dosage has been ingested.

There are two main categories of coatings for taste-masking: pH-independent and pH-dependent. For most solid oral dosage forms or tablets, the active (API) is blended with several excipients, and a well-designed film coating, either pH-dependent or pH-independent, to adequately mask objectionable tastes for the brief residence time in the mouth before swallowing. Alternative dosages forms, such as chewables and granules, can increase the contact time in the mouth, giving an unpleas­ant experience and/or lingering aftertaste. In these cases, it is often necessary to create a barrier, such as a specific taste-mask coating, between the API and the taste buds to improve palatability and aid compliance.

Tisi (Senopsys): Formulators need to establish a target product profile (TPP) as soon as possible, as it guides all downstream development. The TPP outlines important questions including identifying the drug form, clinical strength, and dose volume. If these are initially unknown, an understanding of a drug’s sensory properties early on will focus development on those formulations most suitable to the challenges of the molecule.

Many (though not all) drugs have bitter or other aversive sensory characteristics, which may include a negative taste, smell, or irritation. These characteristics represent different perception pathways and importantly, the approach for dealing with each is fundamentally different. For instance, an API with only slight or moderate aversive sensory characteristics has many more formulation options than does a very intense or lingering API, which will require physical encapsulation as part of the formulation.

Additional challenges

PharmTech: Is the use of alternative dosage forms creating new challenges for taste-masking?

Tisi (Senopsys): Special populations such as pediatrics or geriatrics can have difficulty swallowing adult oral solid forms (dysphagia). Without exception, easier-to-swallow dosage forms increase the opportunity for contact with relevant sensory receptors of the patient. Accordingly, alternative formulations have an increased palatability challenge compared to traditional tablets and capsules. Some API sequestration taste-masking approaches (e.g., particle coating) result in an increase in particle size that often results in a gritty texture. Grittiness may reduce palatability in infants who have not been introduced to particulate foods. In addition, the presence of particulates can encourage chewing as part of normal oral processing. This can rupture coatings, releasing API in the oral cavity where it will be perceived. Additionally, some multiparticulate formulations are intended for dosing in foods, and the physiochemical properties of the foods may affect palatability, particularly if they are coated with a pH sensitive polymer.

Tan (Roquette): The pharmaceutical industry is actively looking into more patient-centric and age-appropriate dosage forms. Alternative dosage forms such as ODTs or orally disintegrating films (ODFs) are examples of these developments, to name a few.

Such products are designed to rapidly disintegrate in the mouth, where bitter APIs can have a prolonged direct exposure to taste buds, which results in poor palatability. However, excipients such as hydroxypropyl-β-cyclodextrin and pea-based maltodextrin have been successfully used to mask ODFs containing dimenhydrinate, an antihistamine used to treat motion sickness and nausea, and loratadine, also an antihistamine used to treatallergies (3,4).

Hughes (Colorcon): Alternative dosage forms such as sachets, ODTs, and chewable dosage forms pose additional challenges in taste-masking due to increased contact surface area as well as residence time in the mouth, enhancing any unpleasant taste and/or lingering aftertaste. In these cases, it is often necessary to create a barrier, such as a specific taste-mask coating, between the API and the taste buds to improve palatability and aid compliance.

Excipient opportunities

PharmTech: What impact might the new excipient pilot program, launched by the FDA’s Center for Drug Evaluation and Research (CDER), have on taste-masking?

Hughes (Colorcon): The new CDER pilot program for novel excipients is a welcome initiative from FDA, it offers a new pathway for drug manufacturers to get an FDA review of novel excipients before the excipients are used in a formulation. Before this, the selection of a novel excipient by a drug manufacturer carried a higher risk, the New Drug Application could get held up by questions being asked about the safety and quality of a new excipient for example. With this initiative, the drug manufacturer can do this up-front, and this will reduce the risk to their timeline and make it much easier to select a novel excipient for dosage forms. Taste masking is one of the areas where different approaches and new materials are being explored all the time, and new materials that have no history of use in pharmaceuticals or foods can be assessed more quickly under this program.

Tisi (Senopsys): Senopsys is a strong supporter of CDERs’ pilot program to expedite the use of novel excipients. Co-processed flavor and sweetener system technologies similar to those used in the confectionery and chewing gum industry can sustain release of the flavor system over time. Such development has been hindered by the current lengthy excipient approval path.

Tan (Roquette): There are limited excipient options today that may be used to taste-mask APIs, and even fewer for formulations meant for pediatric patients. New pharmaceutical processing techniques used in taste-masked formulations, such as 3D-printing, also require suitable excipients better designed to facilitate these modern processes (5). The new pilot program, launched by CDER, could enable the introduction of novel excipients, which may have a precedence of use and/or research in other industries—such as food—where there is already existing emphasis and expertise in terms of taste.

In the pipeline?

PharmTech: Are there any approaches in the pipeline that you believe will hold great promise for taste-masking in the future?

Tan (Roquette): A pea maltodextrin product from Roquette (KLEPTOSE Linecaps) has been primarily designed for taste-masking and solubility enhancement applications, with a particular suitability for pediatric formulations.

The pea maltodextrin can decrease exposure of the API to the taste buds through a specific mechanism of action and complements the current range of taste-masking excipients available to formulators. This excipient has been shown to exhibit a taste-masking effect on model APIs, such as loperamide hydrochloride and dextromethorphan hydrobromide (6).

Hughes (Colorcon): The traditional way to taste mask a bitter-tasting active material is to put a barrier between the active material and the sensory receptors for taste or to hide the bitterness of the material by including a flavor or sweetener in the formulation. It is common for both methods to be used at the same time.

New ways of placing that physical barrier around the bitter API are being evaluated, such as ion-exchange resins that can be used to create an API-resin complex that blocks the taste of the API but does not impact its bioavailability; hot melt coatings can be applied to the API or tablet to become a barrier that does not dissolve in the mouth and pH-sensitive polymers that are insoluble in the mouth but dissolve in the stomach pH can also perform this function.

Another interesting approach is to block the taste receptors, Danielle Andrews from University College London in the United Kingdom had a poster at the European Paediatrics Formulation Initiative Conference in September 2021 where she showed that sodium salts could be used as a ‘bitter blocker’ to effectively switch off the taste receptor temporarily (7). There is plenty of activity in this area, especially around pediatric medicine development.

Tisi (Senopsys): One of the more interesting technologies that has not yet been fully employed in formulation development is the use of novel flavoring materials that disrupt taste signal perception. In humans, bitter taste is detected by a family of several dozen bitterness receptors (TAS2Rs). APIs are typically promiscuous in their receptor targets, activating multiple TAS2Rs simultaneously. Novel compounds are under development which act as antagonists to these receptors.

While promising, there are a number of hurdles to this approach. By their very nature, molecules that disrupt the taste signal cascade are bioactive compounds, and most drug developers are reluctant to risk their drug on possible interaction with an excipient. Next, signal disrupting excipients are proprietary compounds that have to be matched to the specific set of receptors that act upon their API, so this approach is not a one-size-fits-all-compounds magic bullet. Finally, the published data on this class of materials shows some bitter attenuation, but not complete masking. Accordingly, if used it would be one of a multi-pronged approach to palatability.

References

1. FDA, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans, Industry Guidance, July 2020.
2. EMA, “Paediatric Investigation Plans,” ema.europa.eu [accessed Nov. 10, 2021].
3. M. Preis, M. Pein, and J. Breitkreutz, Pharmaceutics, 4 (4) 551–562 (2012).
4. W.C. Foo, et al., “A Multifunctional Orodispersible Film System with Hydroxypropyl-β-Cyclodextrin,” poster presentation at AAPS PharmSci 360 (virtual conference), October 2020.
5. Z. Wang, et al., Pharm. Res., 38 (5) 831–842 (2021).
6. M. Preis, et al., Sens. Actuators B Chem., 193, 442–450 (2014).
7. D. Andrews, et al., “Applicability of Sodium Salts as Bitter-Blocking Excipients: A BATA Case Study with 2 Bitter Paediatric Drugs,” poster presentation at EuPFi (virtual conference), September 2021.

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology
Vol. 45, No. 12
December 2021
Pages: 26–28

Citation

When referring to this article, please cite it as F. Thomas, “It’s a Matter of Taste-Masking,” Pharmaceutical Technology 45 (12) 2021.