(M1230-01-03) Characterization of the Enteric Performance of an Innovative Functional Capsule

Purpose: Oral delivery is increasingly investigated for API classes that are commonly administered by injection such as peptides, proteins, monoclonal antibodies or nucleic acid-based therapeutics. In addition, Live Biotherapeutics Products, a brand new class of APIs, are mostly formulated in capsules for oral administration. The vast majority of the above-mentioned APIs are degraded in the harsh environment of the upper gastrointestinal tract due to sensitivity to acid or enzymes. There is a clear need for a new, innovative truly enteric capsule in order to decrease time-to-market for these new medicines.

Methods: Disintegration test: the disintegration properties of capsules filled with lactose monohydrate were investigated using the method described in the European Pharmacopoeia monograph for enteric coated tablets and capsules (HCl 0.1N for 2h then phosphate buffer pH 6.8 for 1h). As recommended by regulatory bodies, pH 4.5 was also tested to simulate fed conditions (both phosphate EP and citrate USP) followed by media with increasing pH up to 6.4 to investigate up to which pH the enteric capsules maintain their properties. Dissolution test: esomeprazole magnesium trihydrate (EMT) in form of uncoated pellets was selected as an acid sensitive model drug to demonstrate the ability of the capsules to protect the content from the acid media. The dissolution was performed in a USP apparatus type II (paddle) at 100rpm. The first stage is HCl 0.1N for 2 hours where no unit should release more than 10% of EMT which is followed by a phosphate buffer pH 6.8 for 1 hour where no unit should release less than 80% of EMT after 30 minutes (USP delayed-release capsules monograph). The capsules were tested without banding nor sealing. Mechanical robustness test: the resistance to breakage of the enteric capsules was tested by subjecting the empty capsules to the impact of 100g weight released from a height of 8cm. The sample size is 50 capsules per test. Ahead of the test capsules were equilibrated at various relative humidity (10, 16, 23, 33, 45%) for 1 week. Commercially available gelatin and HPMC capsules (Vcaps® Plus) were used as standards for comparison. In vivo disintegration: an open-label, single-center study in 8 healthy volunteers was performed to investigate the localization and time to disintegrate of the capsules in fasted conditions by magnetic resonance imaging (MRI) and appearance of caffeine in saliva. Ethical approval was obtained before starting the study. Oral administration of capsules filled with black iron oxide and caffeine to fasted subjects ( >10h overnight) was done with 240 mL of water in upright position. Application of T2*/T1 weighted TRUFI sequences for tracking of capsules in the gastrointestinal tract with abdominal imaging before intake of the capsule (t=-2min) and every 15min for 4h or as soon as the pictures showed an undoubtedly disintegrated capsule. Saliva samples were taken one minute after every MRI-measurement and after 240min in intervals of 30min until t=480min.

Results: Disintegration test: no disintegration in acid media of the new enteric capsules was confirmed with various types of buffers and salts until pH 6.0 in line with pKa of the enteric polymer used in the capsule shell (Table 1). This confirms the ability of the capsules to resist to acid pH mimicking both the fasted and fed conditions. It was observed that from pH 6.4 capsules opened in less than 15 minutes. Dissolution test: the enteric properties of the capsules were confirmed using the USP method for delayed release capsules filled with EMT (Figure 1). No API release and no degradation product was detected in the acid medium after 2 hours, and complete release was observed within 30 minutes in the buffer stage (98% on average). Mechanical Robustness test: the enteric capsules demonstrated excellent mechanical properties even in dry conditions as the percentage of broken capsules is very low (4% at 10%RH, 2% at 16% and 23% RH, and 0% for RH ≥33%). The brittleness of these new capsules is in line with the mechanical properties of HPMC capsules. They also showed better resistance to impact compared to standard gelatin capsules in conditions with RH below 33%. In vivo disintegration: no opening of capsules in the stomach was observed confirming the enteric properties of the capsule. The capsules opened in the distal intestine (Figure 2A), on average in 45 minutes by MRI and 36 minutes by caffeine appearance respectively after gastric emptying. An influence of gastric residence time on subsequent disintegration was not observed. No capsule disintegrated nor released caffeine in stomach irrespective of transit times, confirming robust enteric properties by MRI and caffeine release (Figure 2B).

Conclusion: The new capsules demonstrated very encouraging enteric results both in vitro and in vivo in fasted conditions.

Figure 1: Release of esomeprazole magnesium trihydrate (EMT) uncoated pellets from the enteric capsules conforms to USP method Esomeprazole Magnesium delayed-release capsules monograph.



Figure 2: Disintegration of enteric capsules in healthy humans observed by MRI and caffeine appearance: A. Localization of the disintegration. B. Absolute disintegration time comparison by salivary caffeine appearance and MRI.



Table 1: Enteric capsules withstand disintegration in various acidic media up to pH 6.0