High-Intensity Sweeteners for Taste Optimization

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.

Originally published on PharmasAlmanac.com on November 28, 2022.

Viscosity Reduction with An Excipient Platform and Feasibility Testing Service

Higher viscosities for injectable drugs can present significant problems for both manufacturers and patients. The typical approach of using a single excipient to achieve appropriate viscosity in the drug formulation is insufficient, given that each therapeutic protein is unique and behaves differently at high concentrations and in different formulation conditions. Lowering the viscosity of the drug product can also reduce downstream processing times and thus lead to improved process economics. The SAFC® Viscosity Reduction Platform provides formulation viscosity and protein stability to achieve optimum results. Scientists interested in evaluating the platform can request a sample kit or leverage MilliporeSigma’s raw material expertise and analytical capabilities through its new Feasibility Testing Service. In this Q&A, Alana Gouveia, Protein Formulation Scientist for SAFC® Raw Materials at MilliporeSigma, explains the application of the platform and how it is evolving to meet customer needs, with Pharma’s Almanac’s David Alvaro, Ph.D.

David Alvaro (DA): What can you share about the challenges formulators are facing with regard to viscosity?

Alana Gouveia (AG): Higher viscosities for injectable drugs can be a significant problem for both drug manufacturers and patients themselves. For subcutaneous administration, there is a limit to the acceptable viscosity of formulations, which is approximately 20–25 millipascal seconds (mPa·s). During the biomanufacturing process, usually tangential flow filtration (TFF), therapeutic proteins undergo purification and concentration steps, which may result in an increase in viscosity, as well as decrease in membrane penetration, hence low yields. This is when high viscosities can present difficulties.

Viscosity can become a challenge at concentrations of about 100–200 mg/mL. At this concentration range, viscosity challenges occur by the formation of transient protein clusters, which can be driven by an affinity of the antibody for self-interaction. Under molecular crowding conditions, which are predominant at concentrations above 200 mg/mL but might occur also at concentrations below 200 mg/mL, antibodies are forced into close proximity to each other, which yields to interactions even when the antibody has a low self-affinity.

It is important to keep in mind that interactions between different proteins and the interactions that are responsible for one protein maintaining its native structure are identical. Therefore, any viscosity-reducing excipient can also destabilize an antibody. As a result, too much interference with interactions made in the name of lowering viscosity can lead to the destabilization of the protein molecules. Adding to this challenge is the fact that each protein has a unique structure and therefore behaves differently — and not very predictably — at high concentrations.

DA: What is the best overall approach to reducing viscosity in these formulations, and how is protein stability maintained?

AG: Formulation scientists today most often choose a single excipient — generally the amino acid arginine — to reduce the viscosity of protein formulations. However, in some cases viscosity-reducing excipients may also interfere with protein stability. Moreover, there is no general excipient on the market that can reduce viscosity and maintain stability of all therapeutic proteins. Therefore, there is a need for innovative solutions in this direction.

Extensive research at MilliporeSigma revealed that the combination of an amino acid and an anionic molecule can provide a good balance between decreasing protein viscosity and maintaining protein stability, which has been showcased by long-term stability studies. The SAFC® Viscosity Reduction Platform provides a toolbox of amino acid and anionic excipients from which formulation scientists can select the most efficient, empirically determined combination for a given protein or antibody under specific formulation conditions.

Importantly, all of the excipients included in the SAFC® Viscosity Reduction Platform have been used in human applications, most in parenteral formulations in the past, either as parenteral nutrition agents, as counterions to APIs, or for pH adjustment. The respective safety evaluations from a European Registered Toxicologist can be provided.

DA: How does the platform overcome challenges faced by formulators?

AG: The ability to vary the excipient combinations with the SAFC® Viscosity Reduction Platform gives formulation scientists a high degree of flexibility for balancing formulation viscosity and protein stability, as well as helping to meet target pH levels while taking the route of administration and the requirements of the recombinant protein, plasma protein, or antibody into account.

Plasma proteins are a notable example, because the typical treatment volumes are high, and thus approaches that allow an increase in the maximum dose per volume would be highly beneficial for patients. Indeed, the excipient combinations offered through the SAFC® Viscosity Reduction Platform not only enable higher concentrations while preserving long-term stability; they make the treatment as a whole more patient-friendly and more economical. Our unique excipient combinations can also be used to formulate biobetters with increased concentrations, offering patients the opportunity to receive their medications in a more convenient manner, potentially contributing to increased patient compliance.

DA: Does the SAFC® Viscosity Reduction Platform also impact the downstream process?

AG: For downstream operations, reducing viscosity enables higher concentrations to be achieved during tangential flow filtration (TFF). TFF is used for the ultrafiltration/diafiltration step preceding fill/finish operations, and very high protein concentrations are often involved, leading to the generation of back pressure in the system that can be challenging to manage. Reducing the viscosity can reduce these issues during this critical step. At MilliporeSigma, we have conducted studies which show that a significant increase in protein concentration can be achieved with a reduced processing time by using combinations from the SAFC® Viscosity Reduction Platform. Shorter processing times, in turn, contribute to improved downstream process economics. This approach supports small-volume formulations of protein drugs necessary for subcutaneous delivery by enabling high concentration.

DA: I understand that the Viscosity Reduction Platform has evolved since it was first introduced. Can you tell me about the recent addition and how it completes the offering?

AG: The addition of IPEC/PQG GMP pyridoxine hydrochloride (vitamin B6) to the SAFC® Viscosity Reduction Platform rounds out the full offering of the platform. In addition to vitamin B6, the other excipients include IPEC/PQG GMP-quality L-ornithine hydrochloride, L-phenylalanine, L-arginine, benzenesulfonic acid, and thiamine phosphoric acid ester chloride dihydrate (vitamin B1 derivate). These excipients are part of the Emprove® Expert portfolio of chemicals, designed for high-risk applications where the lowest microbiological and endotoxin levels are essential. The six platform excipients can be used in up to nine different combinations, giving formulation scientists a high degree of flexibility for balancing formulation viscosity and protein stability.

To be able to evaluate the feasibility of the viscosity-reducing agents to the specific protein or development project, a test kit that contains samples of the six viscosity-reducing excipients included in the platform, along with a detailed user guide describing proof-of-concept screening procedures, is available free-of-charge. Researchers who are interested in a specific combination of excipients for the formulation of a protein of interest can obtain a commercial technology license. The benefit for the customer is the opportunity to exclusively protect that specific solution.

All of the components in the platform are available at commercial scale under MilliporeSigma’s Emprove® Program, which combines high-quality products, comprehensive documentation, and superior customer support to facilitate qualification, risk assessment, and process optimization.

DA: Beyond providing the SAFC® Viscosity Reduction Platform itself, does MilliporeSigma also offer a dedicated service to help scientists that may not have the necessary expertise to get the best results from the platform?

AG: As an alternative to evaluating the platform in their own laboratories, scientists can access MilliporeSigma’s newly launched Feasibility Testing Service to support their efforts to formulate low-viscosity, high-concentration drug products. This service is ideally suited for those seeking a fast evaluation of viscosity-reducing excipient combinations and for scientists that do not have experience working with high-concentration biologics and/or lack the full analytical capabilities necessary to ensure comprehensive evaluation of performance. Using the feasibility testing service allows them to avoid significant investments in resources while still at the technical proof-of-concept stage.

The benefit to scientists of accessing the Feasibility Testing Service is rapid identification of the most effective excipient combination from the SAFC® Viscosity Reduction Platform for their specific drug candidates and formulations. The work is completed by dedicated application experts with extensive experience in high-concentration drug formulation and the analytical expertise and capabilities needed to thoroughly characterize formulation performance.

DA: Can you expand on the Feasibility Testing Service and how it is structured to support the unique needs of different customers?

AG: The new Feasibility Testing Service launched two study packages, including a basic package with optimally selected methods to make a quick and accurate decision on which excipient combination works best for a specific protein of interest. Such methods include a viscosity profiling at different protein concentrations by microfluidic viscometry; an excipient screening using our SAFC® Viscosity Reduction Platform excipients as well as other optional benchmarks excipients to identify the best excipient combinations, and a rounded-off analytical package to analyze the protein integrity in the new formulation, including buffer osmolalities; a nano differential scanning fluorimetry (nanoDSF) to check the conformational stability, size-exclusion ultra-high-performance liquid chromatography (SE-UHPLC) for protein integrity and purity analysis, and dynamic light scattering (DLS) to determine the hydrodynamic radius of the protein. A more extensive analytical package is also available that includes assessment of the viscosity profiles of the optimal formulations to determine the maximum protein concentrations that can be reached.

The stability extension package includes an extended stability study to assess the long-term stability of the optimal formulation. It is conducted in compliance with regulatory requirements, and thus customers can refer to the results when planning for regulatory approval. Samples are stored in a climate-controlled chamber, either at 2–8 °C or 25 °C for three months or at 40 °C for three weeks. Analyses once again include the nanoDSF for conformational stability and SE-UHPLC for protein integrity and purity, as well as capillary electrophoresis (CE) to detect any protein fragmentation, turbidity analysis, optical imaging to detect visible particles, and dynamic light scattering (DLS) for particle size analysis. Elective assays include microfluidic imaging for particle size analysis and reversed-phase ultra-high-performance liquid chromatography (RP-UHPLC) for placebo content determination.

Separately, MilliporeSigma has investigated the long-term stability of the excipients included in the SAFC® Viscosity Reduction Platform, particularly on the nine functional excipient combinations. This information provides real value to scientists because they can have confidence at the outset that these excipients are suitable for use in their formulations.

The overall goal of the Feasibility Testing Service is to design tailor-made excipient solutions for therapeutic protein candidates for each customer. Customers provide MilliporeSigma with samples of their protein of interest and experiments are performed in the application lab in Darmstadt. During the trials, intermediate results are communicated and discussed, and the studies are concluded with a detailed experimental report that is presented and provided to the customers. 

DA: To close, would you like to underline how the SAFC® Viscosity Reduction Platform and the Feasibility Testing Service fit into MilliporeSigma’s broader mission and the rest of the company’s offering?

AG: MilliporeSigma’s aim is to support its customers’ efforts to simplify drug formulation and reduce the time to market for new drugs desperately needed by patients. For this reason, in addition to the SAFC® Viscosity Reduction Platform, we offer a wide range of IPEC-GMP grade chemicals for the manufacturing and formulation of protein-based therapeutics (such as buffers, surfactants, salts, and stabilizers) and are continuously expanding our offering in terms of both products and services to target unmet needs.

The comprehensive portfolio for biopharmaceutical applications, together with innovative solutions and services like the SAFC® Viscosity Reduction Platform and Feasibility Services, backed by comprehensive regulatory support, enables formulators and researchers to overcome potential challenges in processing and formulation development.

Originally published on PharmasAlmanac.com on August 10, 2023.

Simplifying Modified-Release Drug Formulations with High-Quality Multiparticulate Cores

Advanced controlled-release formulations are increasingly sought across the pharmaceutical industry to unlock new dosing possibilities, create more patient-friendly regimens and increase compliance, and extend patent protection for existing drug substances. In particular, multiparticulate formulations leveraging spheres or pellets as a starting substrate enable independent control of the performance of the active pharmaceutical ingredient (API) across a wide range of dose strength, as well as the API release and taste profiles, each of which of these is an important benefit to both the formulator and patient. To support these aims, SPI Pharma is expanding its portfolio to include specialized excipients for modified-release and multiparticulate formulations. Distribution rights to CELLETS® MCC Microcrystalline Cellulose Pellets and TAP® Tartaric Acid Pellets, acquired from Glatt, are the first step toward building a more comprehensive set of formulation solutions.

Benefits of Multiparticulate Dosage Forms

Multiparticulate oral drug formulations are used for many different applications, most commonly to achieve modified drug release of a single API or multiple APIs with different release profiles. Pellets or spheres serve as inert cores to which one or more APIs are applied. A modified-release coating is then typically applied, and the coated pellets or spheres are filled into a capsule, sachet, or other delivery vehicle. Once administered to (or by) the patient, the modified-release coating dissolves under specific pH conditions to enable consistent release of the API at the desired location in the gastrointestinal (GI) tract.

Sustained-release products allow for the reduction of dosage frequency, simplifying treatment regimens, which in turn reduces the burden on patients and increases compliance, especially for patient populations that have difficulty taking medications. Incorporation of multiple APIs in one product helps to further increase ease of use for patients.

Sophisticated Technology

The equipment and sophisticated expertise required for the successful development of prototype multiparticulate solutions using pellets in particular is currently limited in the marketplace. Creating a high-quality drug product that provides consistent API release requires starting pellets (or spheres) of sufficiently high quality, uniform sphericity, and narrow particle size distribution.

Often, multiparticulate formulations are developed using APIs that are already marketed in order to offer a new patient benefit — often modified-release capability — and provide an alternative to the existing branded product.

ACTILLETS® Pellets

A number of different substrates have been developed in pellet and sphere form for use in multiparticulate formulations. Sugar spheres are the most widely used starting materials, with a long history of use across applications. In many cases, however, there is a specific technical need for alternative substrates, such as microcrystalline cellulose (MCC) and tartaric acid.

With respect to the pellets/spheres themselves, there are three main critical quality attributes (CQAs) that enable the effective drug loading and coating of the particles: particle size distribution, sphericity, and friability. The particle size distribution must be fairly narrow, and the pellets must be as spherical as possible and must be able to withstand the process conditions involved in manufacturing the final drug product. All three properties can impact the release profile of the API(s). As a result, close attention must be paid during production of the pellets/spheres to ensure that the desired CQAs are achieved. It is also critical that formulators pay close attention to CQAs to ensure that the products they create are high functioning and reproducible, because not all manufacturers produce spheres with suitable CQAs.

MCC spheres are attractive for applications where the pellet must be inert, not friable, and smoother and more spherical. In addition, compared with sugars, MCC can be formed into much smaller particles that still retain good friability and sphericity. Smaller particles are typically preferred for multiparticulate formulations that contain higher drug loads or several APIs. Furthermore, MCC is widely used as an excipient and is recognized and accepted in the pharmaceutical industry, simplifying regulatory compliance.

Tartaric acid pellets (TAPs)/spheres enable the formulation of weakly basic APIs, which otherwise can be quite challenging because they tend to exhibit poor dissolution in the gastrointestinal (GI) tract. The tartaric acid provides a local acidic environment that facilitates dissolution of weakly basic APIs in higher-pH regions of the GI tract, even in modified- and controlled-release products.

ACTILLETS® MCC Microcrystalline Cellulose Pellets and TAP® Tartaric Acid Pellets from SPI Pharma are used to create modified-release drugs and multi-unit particulate systems (MUPS) when used as starter cores for drug layering and coating. ACTILLETS® MCC pellets have low friability, high sphericity, and smooth surfaces for consistent coating. TAP® tartaric acid pellets can be used to improve the solubility of weakly basic pharmaceutical actives.

Both types of pellets are manufactured using a process designed to generate highly robust pellets of high sphericity and very low friability. Notably, the particle size distribution of ACTILLETS® pellets is tightly controlled, and they are available in various particle sizes for use with different APIs in a variety of applications. TAP® Tartaric Acid Pellets are ideal for use with APIs that exist in the bitartrate salt form.

SPI Pharma Acquires ACTILLETS® Distribution Rights

SPI Pharma acquired sole distribution rights for CELLETS® MCC pellets and TAP® tartaric acid pellets for North America, Latin America, New Zealand, and Australia from Glatt. The MCC products will be distributed under the ACTILLETS™ brand name in these regions.

The Business Case for SPI Acquisition of ACTILLETS® Technology

SPI Pharma creates value by combining our technical knowledge with specialized materials to generate products designed to perform at the highest level in specific applications, focusing largely on patient-friendly formulations. An important aspect of the company’s growth strategy is to expand into adjacent technologies and markets that allow us to leverage that combination of resources and create new valuable solutions for our customers.  

Modified-release, oral dosage formulations represent a technology and market directly adjacent to immediate-release oral dispersible formulations, which is an area of specialization for SPI Pharma. This market is growing at 6–8% annually, a growth rate much higher than that of most other technologies used for life cycle management of existing APIs. Given our longstanding formulation expertise and technical knowledge base, neutral cores and spheres — particularly high-performing spheres — are an ideal fit for a portfolio expansion. ACTILLETS™ MCC and TAP® products give SPI Pharma the ability to support the modified-release market with highly specialized, high-performing excipients.

Providing Formulating Services and Support

Rebranding both the MCC and TAP® excipients as ACTILLETS™ products rather than just reselling them allows SPI Pharma to combine this exciting solution for modified-release and multiparticulate formulations with our specialized formulation expertise and other advanced excipient technologies. Formulation is always the key barrier to adoption, no matter how compelling a technology might be. Multiparticulate and modified-release dosage forms are no exception.

SPI Pharma is always focused on the concerns and pain points of the customer and on developing solutions to address these challenges. In the process, we seek to form long-term relationships with our customers that go well beyond simply selling them the ingredients that they require. Of course, for those customers that have relevant in-house formulation expertise, SPI Pharma is happy to provide ACTILLETS™ MCC and TAP® products by themselves. For customers that lack the specialized expertise needed to use these sophisticated excipients, SPI provides assistance in addressing the challenges of preparing loaded pellets/spheres and then formulating them into final drug products. Preparing the modified release pellet is only the first step — those pellets must then be matched with the right delivery system to ensure that the pellets/spheres reach the right location within the body for the API’s action.

Unlike other excipient manufacturers, sellers, and distributors that focus solely on the material, SPI Pharma is a highly specialized excipient company that collaborates with customers to ensure that the excipients we sell are used optimally and cost-effectively. With SPI Pharma, drug developers get access not only to ACTILLETS™ technology but to a portfolio of other innovative excipients that can be used in combination to provide unique formulation solutions. In addition, through our partnership with Glatt, we can offer additional expertise in making these different dosage forms and the processing that is involved in realizing their full potential.

Focus on SPI’s Mannitol Advantage

SPI Pharma’s knowledge of mannitol and our Mannogem XL grades of this important excipient, combined with ACTILLETS™ pellet technology, put the company in a unique position in the market. Mannitol complements the pellet technology in many different modified-release applications. Mannogem XL grades, specifically, offer higher compactability and faster disintegration times than standard spray-dried or granular grades. They can be used as the binder for coated pellets/spheres in multiparticulate tablet formulations to ensure robust tablet formation combined with the appropriate disintegration time that allows release of the pellets/spheres and ultimately release of the API. Such tablets are highly complementary to oral dispersible tablets, formulations for which SPI Pharma already provides extensive excipient technologies and expertise.

Global Ambitions

SPI Pharma’s ambition is global, multi-material, and application-focused. While the current agreement regarding ACTILLETS™ MCC and TAP® products is limited to specific geographies, it will enable SPI Pharma to gain a foothold in the controlled-release market. Modified-release solutions leveraging the ACTILLETS™ technology and SPI’s knowledge will be developed for the regions covered in the agreement and shared with interested scientists, globally.

We welcome requests for information about ACTILLETS™ pellets/spheres from anyone anywhere in the world, not just people located in regions covered by this recent agreement. We are looking to drive interest in the use of MCC and TAP cores for the formulation of modified-release drug products, regardless of where the purchase of those materials occurs. We are willing to engage with anyone and connect them with the authorized distributors for their markets.

Expect More Innovation from SPI Pharma

The partnership with Glatt is just the first example of moves SPI Pharma will be making going forward. The company hopes to announce multiple product launches and new partnerships annually in order to expand our product and service portfolios quickly. Look for more exciting news from SPI about innovations coming both from partnerships and as the result of internal development activities, all with the goal of offering more solutions for our customers.

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Sidebar: Expanding SPI Pharma’s Portfolio

In addition to ACTILLETS™ MCC and TAP® products, the agreement with Glatt includes distribution rights for Ibuprofen DC100, a 100% active granule from IPC produced without further excipients, enabling simpler, more cost-effective ibuprofen formulations. This specialty API expands SPI Pharma’s portfolio of APIs, which includes taste-masked ibuprofen and acetaminophen.

We are excited to explore various formulating opportunities with Ibuprofen DC100. Ibuprofen is one of the most widely prescribed APIs in the United States and Europe (with even greater nonprescription sales). It is a non-opioid pain reliever that is highly effective and is associated with relatively moderate liver toxicity. For these reasons, there are significant opportunities for growth in this market. Ibuprofen DC100 addresses some of the shortcomings of immediate-release ibuprofen, but SPI Pharma is looking to advance the technology even further.

Originally published on PharmasAlmanac.com on June 6, 2023

Formulating Flexibility with ActiMask® Taste Masking

While drug discovery continues to accelerate, and the range of active pharmaceutical ingredients (APIs) available to patients continues to expand, most APIs are not palatable in oral solid dosage forms. Patient-centric formulations that mask the taste of APIs are a key factor in ensuring adherence to medication regimens and improving patient experiences. Wayne Camarco and Donald Loveday discuss SPI Pharma’s innovative technology to encapsulate API particles, the company’s relaunched Actimask® taste-masked ibuprofen product, and how their taste-masking formulation development services support product launches worldwide. 

The Value of Patient-Centric Formulations

Patient non-compliance with treatment regimens costs the U.S. healthcare system billions of dollars each year. Many of the causes of poor medication adherence relate directly to properties of the drugs on the market themselves. Among oral solid dosage forms, many are large and difficult to swallow or present organoleptic issues like poor taste or mouthfeel. Some require frequent dosing that can be inconvenient, especially if they are not easy to take when on the go. These administration challenges are magnified among certain populations, including children, the elderly, and anyone with physiological difficulties in swallowing, making non-adherence an even more pressing issue for these patients.

Cap Gemini Consulting estimated 10 years ago that increasing adherence rates by only 10 percentage points would translate into a $41 billion pharmaceutical revenue opportunity in the United States and $124 billion globally. As importantly, those gains would be accompanied by improved health outcomes and decreased healthcare spending.1 

The Importance of Taste Masking

The success of orally administered tablets that have residence times in the oral cavity depends on how easy and pleasant it is for patients to take them. Palatability, including mouthfeel (smooth vs. gritty) and taste, is therefore a very important consideration. Most active pharmaceutical ingredients (APIs), however, have a very bitter taste. Others have unpleasant odors or textures, and some may even be irritating. Thus, patient-centric formulations that can contribute to increased patient adherence must incorporate technology to not only overcome these negative attributes but create a pleasant taste and mouthfeel.

If a coating technology is to be em­ployed, the coating must provide sufficient barrier properties to mask taste when the dose form is in the oral cavity yet dissolve quickly enough to not retard drug release when the drug particles pass into the GI tract. The next challenge is to formulate the taste-masked drug into a solid dosage form with acceptable organoleptic properties.

Taste-Masking Techniques

A range of taste-masking technologies are employed in the formulation of oral dosage forms. The simplest are flavorants and sweeteners. However, the use of these excipients is often insufficient to provide the right taste and texture to a given formulation. Changing the structure of the API so that it cannot interact with taste receptors is another approach. Salt formation and the generation of a pro-drug that is degraded in the gastrointestinal (GI) tract to release the actual API are two methods frequently used. Complexation with cyclodextrin or ion-exchange resins can also prevent interaction of the API with taste receptors. Spray granulation to form solid dispersions and co-extrusion are other options. 

Applying a barrier coating to API particles or the final tablet is another approach. Synthetic polymer coatings can be applied using various well-established coating techniques, such as fluid-bed and Wurster/rotor coating. Coacervation — separating a solution into two immiscible liquid phases — is also applicable for producing thin protective barriers that aid in taste maskin

Many Challenges to Effective Taste 

  • Bitterness
  • Dose
  • Particle size
  • Particle shape
  • Solubility

If a coating technology is to be employed, the coating must provide sufficient barrier properties to mask taste when the dose form is in the oral cavity yet dissolve quickly enough to not retard drug release when the drug particles pass into the GI tract. The next challenge is to formulate the taste-masked drug into a solid dosage form with acceptable organoleptic properties. Finding the balance between dissolution and taste masking while achieving desirable mouthfeel is not easy and requires materials and formulation expertise. 

Actimask® Technology: A Better Barrier Solution 

SPI Pharma has developed a taste-masking technology that involves the production of a thin (micron), uniform, smooth hydrogel coating encapsulating API particles (see Figure 1). The proprietary Actimask® aqueous coacervation process uses gelatin as the cationic, hydrophilic polymer. By carefully controlling the pH and temperature and through the use of specific initiating agents, the gelatin is forced out of solution to form a thin layer on the API particles. 


Figure 1: 
API particle encapsulated in Actimask® barrier coating
2022_Q2_img1_SPI

Because the Actimask® process is water-based, there is no concern of residual solvents, as can be the case with many other taste-masked products. When APIs are insoluble or only modestly soluble in water, high assays ( >85%) are readily obtained, allowing for the formulation of smaller tablets than can be realized using other coating technologies. The thinness of the coating layer also does not impact the particle size, and thus the particle size of the coated particles is controlled by the API particle size. 

Notably, Actimask® technology provides an excellent taste barrier and mouthfeel without hindering API release and onset of therapeutic relief. The hydrogel layer is smooth and slippery, providing excellent flowability for processing and formulation, as well as an attractive mouthfeel and easy swallowing for a pleasant patient experience. The coating is also robust and remains intact during direct compression of the API particles into traditional tablets, orally disintegrating tablets (ODTs), or orally dispersible powders (ODPs). Finally, Actimask® coatings meet the requirements of various monographs for dissolution and other properties.

SPI Pharma offers two Actimask® products: taste-masked acetaminophen and ibuprofen, two popular analgesic/antipyretic drugs that have historically been challenging to formulate given their bitterness and other properties. 


Figure 2:
In vitro dissolution of Actimask® IBU with 86% assay
2022_Q2_fig1_SPI

Relaunch of Actimask® Ibuprofen

It is well known that uncoated ibuprofen causes an intense burning sensation when exposed to the oral cavity and throat. Actimask® taste-masked ibuprofen is an ideal choice for the formulation of chewable or orally dispersible dosage forms, because the Actimask® coating reduces — to extremely low levels — the burning sensation that many patients experience with poorly masked or unmasked ibuprofen products.

Actimask® Ibuprofen exhibits minimal drug release in the oral cavity during the first few minutes of exposure, thus avoiding the unpleasant taste and sensation associated with this API when swallowed. However, at gastric pH, it exceeds USP/EP compendial dissolution requirements (see Figure 2). An in vivo pharmacokinetic study has shown that formulations with Actimask® Ibuprofen are comparable to other marketed products (see Figure 3).


Figure 3:
In vivo dissolution of Actimask® IBU with 86% assay in ODT and ODP formulations
2022_Q2_fig2_SPI

Randomized, open-label, crossover design in 13 adults using 100 mg ODT and ODP formulations containing Actimask® Ibuprofen 92S (92% assay) vs. 100 mg Junior
Advil® Chewable

The aqueous hydrophilic coating delivers an excellent taste barrier without any concern regarding residual solvents. In addition, the uniform hydrogel coating provides a smooth surface that has an excellent mouthfeel and is easy to swallow. Furthermore, the high assay content of Actimask® Ibuprofen allows for formulation flexibility and also helps to reduce the tablet weight of high-dose formulations.

To demonstrate the flexibility of Actimask® Ibuprofen, four different formulations were prepared using various SPI Pharma excipients and technologies: an ODT, chewables, and a fast-melt product. The formulations each contained an orange flavorant and sucralose sweetener additives, as well as one or more of SPI’s proprietary excipients, including PharmaBurst® 500 (ODT), Mannogem® XL Opal (fast-melt and chewable), and Mannogem® XL Ruby (chewable) excipients. In all cases, the tablet thickness, hardness, disintegration time, and dissolution profiles all met expectations.

Application-First Excipient Company

SPI Pharma consistently focuses on product innovation with the goal of solving customer challenges. Combining our formulation experience with deep scientific knowledge of customer end uses is a fundamental element of the SPI Pharma brand. We do not seek applications for our excipients, but instead design our excipients to address specific application needs.

This approach has been clearly demonstrated across our history. PharmaBurst® was the first ODT excipient platform developed for use in directly compressible ODT products. Seventeen years later, we introduced UltraBurst®, which offers an improved dissolution time. CS-90 and CM-90 are unique functional calcium excipients for use in antacid and nutritional tablets. The Mannogem® range of mannitol excipients offer innovative solutions for various oral solid dosage forms. Actimask® technology is yet another example.

Our range of taste-masking formulation de­velopment services includes the incorpo­ration of our highly functional excipients along with our co-processed delivery sys­tems. In addition to coacervation, SPI Phar­ma has the ability to develop taste-masked formulations leveraging complexation with ion-exchange resins, traditional polymer coating processes, and powder coating for water-soluble APIs.

Offering More than Just Excipients

Our range of taste-masking formulation development services includes the incorporation of our highly functional excipients along with our co-processed delivery systems. In addition to coacervation, SPI Pharma has the ability to develop taste-masked formulations leveraging complexation with ion-exchange resins, traditional polymer coating processes, and powder coating for water-soluble APIs.

These services are accessed through our Pharmasolutions offering, which is a comprehensive drug development service focused on patient-friendly dosage forms that can deliver convenience, compliance, and efficacy. Unlike a contract research organization, SPI Pharma is an ingredients manufacturer with materials and functionality expertise. We can use that deep material and formulation expertise to help bring new customer products to market quickly and to expand the life cycle of existing products by leveraging unique, patient-centric dosage forms and comprehensive regulatory capabilities. 

To date, we have supported more than 60 global product launches. Our applied innovation group can provide assistance with technology and business development, licensing, formulation development and optimization, product prototyping, dossier development, stability testing, analytical method development and validation, and technology transfer. 

References

1. Forissier, T.  and K. Firlike. Estimated Pharmaceutical Revenue Loss Due to Medication Non-Adherence.Cap Gemini Consulting. 2012.

Originally published on PharmasAlmanac.com on October 25, 2022