Taste-masking of bitter active pharmaceutical ingredients (APIs) is essential for achieving medication adherence for oral dosage forms. High-intensity sweeteners provide an effective means for overcoming both onset and aftertaste bitterness. Neotame and sucralose from MilliporeSigma are well demonstrated to be safe, potent, and effective alternatives to other sweeteners for taste optimization. Almut von der Brelie, Senior Manager Strategic Marketing for Excipients of the SAFC® Pharm/BioPharm Raw Materials portfolio at MilliporeSigma, discusses the sweeteners and their uses and benefits with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.
David Alvaro (DA): Why is the taste of medications becoming more of a focus for pharma companies, and in which applications is it most important?
Almut von der Brelie (AvdB): The first role that the taste of drugs plays is for patient compliance. Attention to patient-centric issues has increased as the industry seeks to find new ways to reduce the current level of medication non-compliance. Proper attention to taste and palatability support patient compliance and thus the therapeutic benefits offered by the medications. For pediatric and geriatric applications in particular, taste and palatability are crucial. In the last few years, a greater focus has been placed on pediatric and geriatric applications, as industry efforts to design formulations that meet the specific needs of different patient populations have increased.
With respect to dosage forms, products that disintegrate or dissolve in the mouth are most relevant, such as orally disintegrating tablets (ODTs) and lozenges, as well as liquid formulations, such as cough syrups for children, effervescent tablets, and dissolvable films and strips. The latter are quickly absorbed into the bloodstream and are ideal for people who struggle to swallow tablets and capsules or liquids. For this type of application, it is particularly beneficial to use high-intensity sweeteners, as they do not add significant bulk to the formulation compared with other sweetening agents. All of these dosage forms are increasingly popular, because they can be easier for patients to take than traditional tablets and capsules.
DA: Can you talk a little about onset taste versus aftertaste and how that impacts the taste of oral medications?
AvdB: There are important differences between the initial taste and the last impression. As such, the formulator has to make a choice depending on the taste of the API, particularly for bitter-tasting APIs. There are different approaches to improve the taste of an oral medication, including the use of sweeteners, flavors, or polymer coatings and/or the formation of inclusion complexes via freeze-drying. In general, the use of sweeteners is the most common strategy and typically the formulator’s first choice, as it is easy to realize and efficient. Various sweeteners are offered with different sets of properties. No one sweetener will fit for all purposes, and thus a selection has to be made in accordance with the sensory profile of the sweetener.
DA: What are high-intensity sweeteners, and what additional benefits do they offer?
AvdB: We should start this discussion with the definition of a high-intensity sweetener. These sweeteners are exceptionally more sweet than sucrose. Neotame, the product we ‘ve just recently launched as part of our SAFC® formulation excipient portfolio, is approximately 8,000 times sweeter than sucrose. This very high level of sweetness offers advantages in use and cost-effectiveness.
DA: Can you expand on the characteristics of neotame and sucralose?
AvdB: The introduction of neotame builds on our history in the high-intensity sweetener excipient space. We are the leading global supplier of pharma-grade sucralose, which has long been used in different pharmaceutical applications. With the launch of our new product Neotame Emprove® Essential NF, we are expanding our taste optimization portfolio and offering more options to formulators, in addition to giving them a new way to be more cost efficient. And neotame is not only orders of magnitude sweeter than sucralose but also has very good heat stability properties.
Both neotame and sucralose are approved food additives in the United States, Europe, and China, and safety evaluations by the Joint FAO/WHO Expert Committee on Food Additives are available for each. Our high-quality products neotame and sucralose ensure consistent and reliable high performance at every stage and scale.
DA: How do sucralose and neotame compare to aspartame?
The question isn’t so much about taste when comparing sweeteners, but about effectiveness of use. For example, neotame is 50 times sweeter than aspartame, while sucralose is four times sweeter.
We conducted a sensory study with sucralose, neotame, aspartame, and sodium saccharin as sweeteners and quinine as the bitter active. In contrast to sodium saccharin with a bitter aftertaste, both neotame and sucralose were found to provide a sugar-like taste with a slightly delayed onset and a lasting sweetness. Therefore, these two high-intensity sweeteners can play important roles in taste masking, as many APIs have long-lasting bitterness profiles that require the use of a lingering sweetness for palatability.
In the same study, neotame was found to have a sensory profile similar to aspartame. It does, however, have many additional advantages, including not only superior use effectiveness but enhanced heat stability. Aspartame is known to lose sweetness when heated and to undergo Maillard-type reactions with primary amine groups. Neotame is significantly more stable than aspartame in the neutral pH range and at high temperatures, which considerably widens its potential applications. Neotame also has flavor-enhancing properties and was approved by the U.S. FDA as a sweetener agent and as a flavor enhancer.
The overall conclusion that can be made about neotame and sucralose is that these two high-intensity sweeteners have been well demonstrated to be potent and effective alternatives to aspartame for taste optimization.
DA: Given that there are some differences in sweeteners, is there ever a reason for using more than one in a formulation?
AvdB: Yes, the use of multiple sweeteners can in fact be very interesting for the formulator in product development, because synergistic effects are possible. It would be dictated by the sensory profile of the bitter-tasting component in the formulation. It really is a case-by-case decision, but the ability to reduce the total amount of sweeteners needed due to synergistic effects is very attractive. Both sucralose and neotame are compatible with other sweeteners, as well as sucrose and reducing sugars.
DA: What can you tell me about the production of neotame?
AvdB: Neotame is manufactured from aspartame via reductive amination. It is an isolated dipeptide and a methyl ester derivative of aspartame. It also differs from aspartame in structure, because it contains an additional neohexyl group. Interestingly, the development of neotame goes back to the 1980s after the commercialization of aspartame. Neotame was the result of an international project focused on finding the next-generation zero-calorie sweetener with a greater sweetness, improved stability, and a good sweetness profile, which could be produced at lower cost.
DA: How is sucralose produced, and how is sucralose for pharmaceutical applications different than the sucralose food additive?
AvdB: Our SAFC® sucralose products meet the requirements for pharmaceutical excipients. As Emprove® Essential products, both products are designated for moderate-risk applications, offering compliance to IPEC-PQG GMP Guide and EXCiPACT® Certification Standard, as well as regulatory support to assist our customers with their assessments.
Sucralose is a disaccharide produced from sucrose by replacing three hydroxyl groups. It is approximately 600 times sweeter than sucrose and, as mentioned previously, four times sweeter than aspartame. Notably, sucralose readily masks bitterness and medical off-notes.
Our sucralose product is marketed as Sucralose Emprove® Essential and complies with the specifications of the European and Chinese pharmacopeias, the Japanese Pharmaceutical Excipients, and the U.S. National Formulary (NF). It is offered in powder and granular versions. Due to its optimal dispersion behavior, sucralose powder is typically recommended for solid dose formulations, while the fast dissolution behavior of granular sucralose makes it well-suited for liquid formulations. However, both types are easily soluble in water and ethanol even at low temperatures.
DA: Can you discuss the actual use of these high-intensity sweeteners with respect to concentration ranges for typical formulations?
AvdB: Sucralose may be used in both solid and liquid formulations in doses of 0.05% to 2% while doses of only 1 to 750 parts per million are recommended for neotame due to its exceptionally high sweetness. Particularly for the application in dissolvable films and strips, these low dosages of sucralose and neotame are beneficial, as they do not add significant bulk to the formulation compared with other sweetening agents.
DA: What can you tell me about the safety profiles of MilliporeSigma’s SAFC® portfolio of high-intensity sweeteners?
AvdB: Health authorities around the globe have evaluated the safety of both sucralose and neotame. For sucralose, the U.S. FDA, for instance, has reviewed more than 100 studies and from the available information derived an acceptable daily intake (ADI) value of 5 milligrams per kilogram body weight per day. The ADI established by the Japanese and EU authorities is even higher, at 15 milligrams per kilogram body weight per day. For neotame, the U.S. FDA also conducted a comprehensive safety evaluation for its use as a sweetening agent and flavor enhancer in foods. On the basis of these results, an ADI of 18 mg / person / day has been derived.
Those values leave a sufficient safety margin for pharmaceutical use, particularly given that the intake of medications is controlled on a daily basis.
DA: What is the regulatory status of sucralose and neotame?
AvdB: Both neotame and sucralose have been widely approved and used as food additives in the United States, Europe, China, Canada, and Australia. With an available NF monograph, neotame can also be assessed as an established excipient for oral applications. Neotame is also listed in the FDA’s inactive ingredient database, which means that neotame is not considered new and that it may require a less extensive review when included in a new drug product. While there is no European monograph yet, references are available in Europe, and final pharmaceutical formulations have been registered with neotame as an ingredient. Sucralose is included in the EU and Chinese pharmacopeias and the Japanese Pharmaceutical Excipients and has an NF monograph. Of course, our SAFC® excipient complies with all of these monographs.
In summary, neotame and sucralose are well-established excipients for use in oral drugs. In addition, according to our knowledge, there are no specific restrictions known for the use of these high-intensity sweeteners in pediatric formulations.
DA: What additional advantages to your pharma customers result from offering high-intensity sweeteners within the SAFC® portfolio?
AvdB: Our Emprove® program helps our customers meet the latest regulatory requirements for risk assessment, provides assistance regarding the development of more robust processes, and anticipates industry expectations not yet covered by regulations. Each of the three offered types of Emprove® dossiers supports customers with comprehensive, readily available information throughout the different stages of their operations: qualification, risk assessment, and optimization. As a result, customer regulatory filings are simplified, and the time it takes them to work through the regulatory maze is shortened.
Customers can leverage the broad portfolio of SAFC® excipients, covered by our Emprove® program, to further accelerate their formulation development efforts. For each Emprove® product, the dossiers are consistent and already available and compiled without any need for customers to request them. As a result, our Emprove® brand is very well-established and well-known, and MilliporeSigma is setting standards in the market.
It is also important to note that we have a very strong regulatory team that is continuously monitoring trends and issues to ensure that MilliporeSigma can rapidly respond and adapt to evolving regulatory expectations and therefore is in a position to provide the most up-to-date solutions to our customers.
DA: Beyond the regulatory benefits, are there any actual formulation-relevant synergies between neotame, sucralose, and other SAFC® excipients from MilliporeSigma?
AvdB: Yes, definitely. We have particle-engineered polyols –– such as Parteck® SI sorbitol and Parteck® ODT excipient –– that are very compatible with our neotame and sucralose. Both are directly compressible, and their unique particle structures provide properties that help customers to create robust, high-quality tablets. Besides our broad SAFC® portfolio of high-quality raw material solutions for pharmaceutical formulations, I like to refer to our offering of customized application services through our global network of application centers. These include solutions for bioavailability enhancement, as well as formulation development with our high-intensity sweeteners sucralose and neotame for effective taste optimization.
Find more information on MilliporeSigma’s high-intensity sweeteners neotame and sucralose on their website.