INTRODUCTION
Formulating live biotherapeutics and accelerating drug development can be challenging. The following study focuses on the development of a customized functional coated capsule, EUDRACAP® Select, for the delivery of live biotherapeutics and demonstrates its effectiveness in the oral delivery of a sensitive proprietary microbiome ecosystem while simplifying the drug development process.
Growing scientific evidence strongly suggests the microbiome plays a crucial role in various diseases, impacting everything from immune function and inflammation to metabolism and mental health. Understanding these implications could lead to groundbreaking advancements in disease prevention, diagnosis, and treatment. Cancer and its treatments can disrupt the gut microbiota, impair gut epithelial repair mechanisms, and compromise immune homeostasis and responsiveness. Microbiome therapy can prevent the decay of the gut ecosystem, preserve immune homeostasis, and optimize gut function[1]. To achieve the desired clinical outcome, a robust and targeted delivery system is crucial.
Microorganisms are normally sensitive to acidic conditions and therefore require an acid-resistant delivery system. At the same time, they should not be exposed to the high moisture and temperatures of standard enteric coating processes, which could lead to a reduction in the number of viable microorganisms. The use of a customized, empty, ready-to-fill, modified-release coated capsule is a viable alternative for this type of therapy and this development is described in this study.
DEVELOPMENT OF CUSTOMIZED EUDRACAP® SELECT CAPSULES
Pre-locked, hard HPMC capsules were used for this study. Empty capsules were coated with a proprietary combination of EUDRAGIT® polymers to a specific weight gain based on their surface area. These empty, ready-to-fill, coated enteric capsules were compatible with standard filling equipment and required no banding or additional downstream processing.
The developed capsules met all the specification of a three-stage dissolution test USP Type II apparatus (37°C, with a basket speed of 75 rpm; filled capsules were exposed for 2 hours to 0.1 N HCl; 1 hour to pH 6.8; and 2 hours to pH 7.2. The data was published in a previous article and is not shown here. The capsules were also stable in 4 different conditions, including accelerated.[2]
The capsules were also subjected to a biorelevant dissolution test with sequences of agitation, including movement and pressure fluctuations, alternating with static phases, as observed in vivo. The intermittent contact of the dosage form with the dissolution medium and the intestinal pH profiles, characteristic of fasting intake conditions, were also simulated with a biorelevant medium.
For the Phase 1b clinical study, the capsules developed were filled with a specific amount of MaaT’s proprietary standardized, high-richness, high-diverse microbiome ecosystem, containing a group of bacterial species known to produce anti-inflammatory short-chain-fatty acids. The study was performed according to the approved protocol (identifier of the study: NCT04150393).
IN VITRO PREDICTION OF CAPSULE BEHAVIOR AND ROBUSTNESS
The cost of clinical trials in drug development has been increasing in recent years and has a significant influence on the overall development costs. Therefore, it is advisable to stress the developed drug as much as possible in in vitro tests to reduce the risk of failure in later clinical studies. Dissolution of modified-release products can be significantly influenced by physical stress of biorelevant magnitude in the human gastrointestinal (GI) tract, such as high pressure, low buffering capacity, and jet-like propulsions.[3] The physicochemical conditions of the GI tract were simulated by a dissolution stress test performed by a specific device that mimics physiological mechanical stresses that occur during the passage of a solid dosage form through the GI tract.
Figure 1 shows a schematic of the test set-up. Movements and pressures are applied according to a defined protocol (Figure 1), which also shows there is no release of capsule contents for up to 2 hours. During simulated gastric emptying (1), the capsules yielded no deformation and signs of leakage. Low-intensity mechanical stress simulated at 1 hour (2) and 2 hours (3) did not affect drug release. The mechanical agitation simulated at 3 hours (4) triggered fast dissolution of part of the tested capsules. Ileocecal passage at 4 hours (5) triggered fast drug release with deformation and perforation of the capsules. The results indicate that the developed, empty, ready-to-fill capsule is capable of delivering live biotherapeutics to the distal small intestine and proximal colon, making it suitable for first-in-human trials.
Figure 1
ENCAPSULATED FULL-ECOSYSTEM MICROBIOTA WAS TESTED IN PHASE 1B CLINICAL TRIAL
EUDRACAP® Select capsule was filled in with a lyophilized pooled full ecosystem fecal microbiota drug candidate (MaaT033) and was tested for tolerability, safety, and efficacy in a Phase 1b clinical trial. The study was an open-label, single-arm with 21 patients divided into 5 different cohorts. This study, sponsored by MaaT Pharma, took place at six investigational sites in France. The dose regimen is shown in Figure 2. Cohort 5 was not performed, as enough data was generated form cohorts 1 to 4.
STRONG ENGRAFTMENT & INCREASED MICROBIOTA RICHNESS OBSERVED
The results of the Phase 1b clinical trial were first reported at the 64th edition of the American Society of Hematology.[4] Figure 2 (A) shows strong and sustained engraftment was observed in all four cohorts, even stronger for cohort 3 and cohort 4, in which three capsules per day were administered. The engraftment level refers to the ratio of operational taxonomic units (OTU) that were not present in the patient at baseline, but were present in MaaT033 and were found in the patient following treatment. For this analysis, shared OTUs between MaaT033 and patients at baseline were excluded. Persistent engraftment can be observed by relatively stable OTU levels at V4, following consolidation of chemotherapy and about 4 weeks following the treatment with MaaT033 was finished.
The richness of the microbiota was also evaluated in terms of variety of engrafted OTUs. Similar to the engraftment results, an increase in the number of OTUs was induced by MaaT033, which was also persistent, especially for cohort 2, cohort 3, and cohort 4, as shown in Figure 2 (B).
Figure 2
CONCLUSION
MaaT033 formulated with EUDRACAP® Select appears to be safe and effective in restoring gut microbiota in AML patients receiving IC and ATB. Evonik has provided a capsule that is effective and robust enough to deliver even sensitive molecules. The capsule is ideal for powders, pellets, granules, and other dosage forms and is compatible with high-speed capsule filling machines. Using EUDRACAP® capsules saves developers time in process scale-up and validation, and has the benefit of using EUDRAGIT®polymers, which have been around for 70 years.
[1] Ghani R et al, Disease Prevention Not Decolonization: A Model for Fecal Microbiota Transplantation in Patients Colonized With Multidrug-resistant Organisms. Clin Infect Dis. 2021 Apr 26;72(8):1444-1447 doi: 10.1093/cid/ciaa948.
[2] Kamlesh Oza et al, EUDRACAP® Select – Examining a Case From Development to Clinical Trial. Drug Development & Delivery. March 2024.
[3] G. Garbacz, S. Klein, Dissolution testing of oral modified-release dosage forms, J Pharm Pharmacol, 64 (2012) 944-968. Peled, J.U. et al. Microbiota as Predictor of Mortality in Alloceneic Hematopoietic-Cell Transplantation. N Engl J Med 382, 822-34 (2020). doi: 10.1056/NEJMoa1900623.
[4] Jenq RR. et al, Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease Biol Blood Marrow Transplant 2015 Aug 21(8): 1373-1383 doi: 10.1016/j.bbmt.2015.04.016.