Category: Excipients

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.

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.

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. 

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Figure 1: 
API particle encapsulated in Actimask^® barrier coating

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. 

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

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).

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

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.