Advances in live biotherapeutic products and key formulation challenges
Live Biotherapeutic Products (LBPs) are living bacterial drugs that can be used to prevent or treat certain human diseases. This rising class of pharmaceutical drugs is now at the forefront of drug development research and has undergone significant regulatory developments in the microbiome field.
In December 2022, the U.S. Food and Drug Administration (FDA) approved Rebyota®, the first fecal microbiota product approved by the agency to prevent the recurrence of Clostridioides difficile infection (CDI). Only a few months later, the FDA approved Vowst®, the first fecal microbiota product that is taken orally. Furthermore, Muvagyn®, a vaginal microbial drug was authorized in Europe. Additionally, positive progress has been reported for several drugs in clinical development with positive Phase 1 and 2 results by Vedanta Biosciences, Enterome, Maat Pharma, MRM Health, AOBiome and BiomX and others across a broad range of indications.
LBPs are normally sensitive to acidic conditions and therefore require an acid-resistant delivery system. To increase the efficacy of the treatment and enable the treatment of local diseases, targeted drug delivery has become a very important development goal for pharmaceutical formulators.
EUDRACAP® functional ready-to-fill capsules
The EUDRACAP® platform was launched in 2021 and consists of a portfolio of functional ready-to-fill capsules. EUDRACAP® capsules provide reliable protection of active ingredients which are sensitive to heat, moisture or gastric acid and enable precise pH targeting of gastrointestinal sites, such as the mid-to-upper small intestine and the ileo-colonic region. EUDRACAP® capsules consist of a functional coating with a proprietary combination of EUDRAGIT® polymers, which have a long track record in the industry for targeted drug release. The EUDRAGIT® polymers are applied to pre-locked, empty, hard HPMC capsules which makes the capsules functional, allowing them to resist acidic pH environments and release the content in the target region.
EUDRACAP® enteric, the first functional ready-to-fill capsule launched for targeted release in the upper small intestine, has been successfully used in several clinical studies of novel LBPs, demonstrating reliable acid protection and target release of the actives.
Robust colon targeting for improved microbiome therapies
The human gut microbiota is diverse, complex, and unique to each individual. Bacterial types outnumber the genes in the human genome by 10 to 50 times. The majority of the gut microbiota resides in the colon, where it plays a crucial role in maintaining overall health[1]. Growing scientific evidence strongly suggests that the microbiome is involved in various diseases, affecting everything from immune function and inflammation to metabolism and mental health. Disruptions in the microbiota can lead to numerous health issues, underscoring the importance of maintaining a balanced microbial ecosystem[2]. The heightened interest in microbiome therapies reflects this understanding.
For several years ileo-colon targeted drug release has proven to be an efficient method for treating local conditions, such as inflammatory bowel disease (IBD). More recently, targeting the colon for the delivery of LBPs has been shown to restore or improve the gut ecosystem, yielding positive systemic effects.
When formulating LBPs, it is important to prevent exposure to the high moisture and temperatures associated with standard coating processes, which could lead to a reduction in the number of viable cells. Consequently, using an empty, ready-to-fill, delayed release coated capsule is a viable alternative for this type of therapy.
Optimizing microbiome engraftment through targeted delivery
As mentioned, an ideal drug delivery system (DDS) for microbiome therapy should minimize the exposure of live microorganisms to stressful conditions during the formulation of the final dosage form. Additionally, this DDS must ensure that the microbiome is prepared for engraftment starting from the proximal colon region.
Lyophilized bacterial formulations require a specific environment to rehydrate and become metabolically active. This process is crucial for their successful engraftment in the colon. Therefore, the release of these biotherapeutic products in the terminal small intestine is preferred, allowing sufficient time for the rehydration process so that engraftment can occur in the colon.
The human gastrointestinal (GI) tract exhibits a distinct pH profile, which plays a significant role in the release and activation of LBPs. The pH in the terminal section of the small intestine is higher than 7.0, the highest within the GI tract. Upon entering the colon, the pH drops to a range of 5.5 to 7.0 with high inter-subject variability.
EUDRACAP® colon for targeted release in the ileo-colonic region
The newly launched EUDRACAP® colon functional ready-to-fill capsules are designed for drug products targeted for release in the ileo-colonic region. Like EUDRACAP® enteric, these capsules prevent sensitive actives like LBPs from being subjected to the stressful conditions of formulation processes and provide reliable protection from gastric acids. The functional coating uses a proprietary combination of EUDRAGIT® polymers, allowing EUDRACAP® colon capsules to resist acidic pH environments and to release their content starting in the terminal section of the small intestine, followed by rapid release when entering the colon.
In vitro testing results of EUDRACAP® colon
Figure 1 illustrates the caffeine release profiles of EUDRACAP® colon in comparison to EUDRACAP® enteric capsules over time under different pH conditions. Like for EUDRACAP® enteric, no caffeine release occurs during the 2 hours at the acid stage, demonstrating reliable acid resistance. For EUDRACAP® colon, no caffeine release is found at buffer stage pH 6.8 – in contrast to EUDRACAP® enteric, which shows fast release at pH 6.8. After conversion to buffer stage at pH 7.2, caffeine release from the EUDRACAP® colon capsules starts in alignment with the conditions in the ileo-colonic region. It can be concluded that EUDRACAP® colon provides significantly more delayed release at a higher pH compared to EUDRACAP® enteric.
Figure 1.
Figure 2 shows the disintegration behavior of EUDRACAP® colon compared to EUDRACAP® enteric capsules under varying pH conditions. Integrity of the EUDRACAP® colon capsules is confirmed after 2 hours at gastric conditions at pH 1.2. After 1 hour at buffer stage at pH 6.8, the EUDRACAP® colon capsules are still completely intact in contrast to the EUDRACAP® enteric capsules, which completely disintegrated at this pH. Fast disintegration of the EUDRACAP® colon capsules occurs after conversion to the second buffer stage at pH 7.2.
Figure 2.
Conclusion
Advances in live biotherapeutic products (LBPs) represent a leap forward in the treatment and prevention of various human diseases. EUDRACAP® functional ready-to-fill capsules address key formulation challenges by protecting sensitive actives from harsh formulation processes and gastric acid, while ensuring the release of the live biotherapeutic products in the target region. The newly launched EUDRACAP® colon provides reliable gastric resistance and target release in the ileo-colonic region which makes EUDRACAP® colon a promising delivery system for live biotherapeutic products.
[1] Di Vincenzo, F., Del Gaudio, A., Petito, V. et al. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med 19, 275–293 (2024). https://doi.org/10.1007/s11739-023-03374-w
[1] Lucas Paulo Cusin, Kamlesh Oza, PhD, Steven Smith, PhD, Carole Schwintner, Cécile Billa Nys, Marianne Robin, and Hervé Affagard. EUDRACAP® Select – Examining a Case From Development to Clinical Trial. Drug Development & Delivery March 2024 Vol 24 No 2.
Bettina Hoelzer
