(T1430-07-42) The Influence of Different HPMCAS Grades for Preparation of Enteric Capsules Investigated by MRI in Human Volunteers

Purpose: Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) as pharmaceutical excipient can be used for various applications including preparation of amorphous solid dispersions e.g. by hot melt extrusion or enteric coatings of tablets or granules as well as shell material for enteric capsules. It is available in different grades which mainly differ in substitution grade of functional groups. The most common grades H, M and L therefore differ in their dissolution behavior. Grade L dissolves at pH ≥ 5.5, grade M at pH ≥ 6.0 and grade H at pH ≥ 6.8 [1]. This is of key relevance when used for enteric coating or preparation of gastro-resistant capsule shells and subsequent intestinal release. By use of specific HPMCAS grades it could be possible to tailor intestinal release in terms of timing and localization. Thus, it was the aim of this study to compare two prototype capsule shells made of HPMCAS grade L and M, with reference Capsugel® Enprotect® capsules made of HPMCAS grade H.

Methods: A human study was performed with 8 healthy subjects with mean age of 24.8 ± 4.5 years and mean BMI of 23.3 ± 2.9 kg/m². In a 2-arm crossover design, test capsules made of HPMCAS grade L or M were administered together with a Capsugel® Enprotect® reference capsule made of HPMCAS grade H with 240 mL water after fasting overnight. Thus, test capsule and reference capsule were always administered together. This internal reference allowed reduction of study arms and subjects, while still increasing power due to reduced variability in transit conditions between test and reference. Reference capsules of size 0 were filled with 17.9 mg black iron oxide, 25 mg ¹³C₃ labelled caffeine, croscarmellose and standard filling powder of mannitol and colloidal silicon dioxide. Test Capsules of size 0 were filled with 2.2 mg black iron oxide, 25 mg ¹³C₁ labelled caffeine, 125 mg manganese gluconate, croscarmellose and standard filling powder of mannitol and colloidal silicon dioxide as well. Different amounts of iron oxide led to distinguishable artifacts in TRUFI sequences. Manganese gluconate led to a bright “cloud” in VIBE sequences when test capsule disintegrated. This way, differentiation was possible. Furthermore the different isotope labelled caffeine species offered distinguishable and sensitive evaluation of release, which will be addressed elsewhere. The study was conducted using a Siemens MAGNETOM Avanto 1.5T scanner. During imaging, subjects were in supine position. Capsules were tracked by their characteristic susceptibility artifacts resulting from the included black iron oxide. For imaging, first a coronal T2*/T1 weighted TRUFI sequence was used. For sensitive evaluation of manganese release from test capsules, a VIBE sequence in coronal orientation was performed. Subjects were asked to hold their breath during measurements to reduce motion artifacts. Imaging was performed before capsule intake and after intake of both capsules in intervals of 15 min for up to 4 h. Exemplary MR images are given in Figure 1. The obtained MR images were evaluated manually using HOROS v3.3.6 64bit for localization and dispersion of the filling. Capsule localization in GI tract, gastric emptying time and evaluation of disintegration time and place were performed manually by two trained observers. In case of differences in tracking, these cases were discussed until consensus. Data curation and depictions were performed with GraphPad Prism 5.01.

Results: From gastric residence time and visual dispersion time in MRI as evaluated, dispersion time after gastric emptying was calculated. In study arm A, this amounted to 84 ± 28 min for HPMCAS grade H reference capsule and 34 ± 28 min (n=7) for HPMCAS grade L test capsule. One test capsule disintegrated in stomach. In study arm B, this amounted to 66 ± 28 min for HPMCAS grade H reference capsule and 21 ± 14 min for HPMCAS grade M test capsule. Results are given in Figure 2. Statistical significant differences (Wilcoxon signed rank test with Bonferroni correction) were found between H vs. L and H vs. M (each p=0.0312). As can be seen in Figure 3, reference Capsugel® Enprotect® capsules mainly disintegrated in ileum, while test capsules disintegrated in more proximal regions of small intestine or even in stomach already.

Conclusion: The utilization of an internal standard by dosing test and reference at the same time was a relevant improvement in study design. This was only possible due to novel dual labeling for differentiation of two dosage forms and their disintegration when taken at the same time, which offered new insights and will be further enhanced with pharmacokinetic data. Reference Capsugel® Enprotect® capsules made of HPMCAS grade H provided robust intestinal release mainly in ileum as expected [2]. The utilization of grades L and M led to faster disintegration, thus targeting more proximal regions but also increasing the risk of preliminary intragastric disintegration. If faster and more proximal disintegration than with HPMCAS grade H is wished, probably the best choice is HPMCAS grade M.

References: [1] S. Sarabu, V.R. Kallakunta, S. Bandari, A. Batra, V. Bi, T. Durig, F. Zhang, M.A. Repka, Hypromellose acetate succinate based amorphous solid dispersions via hot melt extrusion: Effect of drug physicochemical properties, Carbohydr. Polym. 233 (2020) 115828. doi:10.1016/j.carbpol.2020.115828.
[2] A. Rump, M. Kromrey, E. Scheuch, V. Jannin, L. Rehenbrock, M.V. Tzvetkov, W. Weitschies, M. Grimm, In Vivo Evaluation of a Gastro-Resistant HPMC-Based “Next Generation Enteric” Capsule, Pharmaceutics. 14 (2022) 1999. doi:10.3390/pharmaceutics14101999.

Acknowledgements: The authors would like to thank the team at the Department of Diagnostic Radiology and Neuroradiology for their excellent support.

Funding: This research was funded by Capsugel France SAS (Colmar, France). Other Disclosure: Before conduction of the human study, ethical approval was obtained from Ethics committee at the University Medicine Greifswald under BB 150/24a. Conflict of Interest statement: Vincent Jannin and Camille Dumont are employees of the funder, which is the producer of the tested capsule shells. The funder influenced the study design and gave final permission for presentation. Conduction of the study and interpretation of results were performed independently by employees of the University of Greifswald. Conduction and interpretation of the study were not influenced by the funder. The other authors are only affiliated with the University of Greifswald and declare no conflict of interest.


Figure 1: Exemplary MR images of differentiation between test capsule (green) and reference capsule (orange) in TRUFI (A), dispersion of black iron oxide after capsule disintegration in TRUFI (B) and signal increase after dissolution of manganese gluconate due to premature intragastric disintegration in T1 weighted VIBE (C).


Figure 2: Dispersion time of filling in MRI after gastric emptying of the capsules with * corresponding to p < 0.05 after Wilcoxon signed rank test with Bonferroni correction (n=8 / n=7 grade L).


Figure 3: Gastrointestinal localization of capsule disintegration.