In vivo comparison of enteric capsule shells composed of different HPMCAS grades after simultaneous intake by dual...

Different grades of hypromellose acetate succinate (HPMCAS) differ in their pH dependent dissolution behavior, which is of key relevance when used for enteric coating or gastroresistant capsule shells. By use of specific grades it could be possible to tailor intestinal release in terms of timing and localization. A crossover design might be the gold standard for comparison of two dosage forms but intraindividual variability in gastrointestinal transit conditions still limit robust comparability. In the present study, two prototype capsule shells made of HPMCAS grade L and M, were compared with reference Capsugel® Enprotect® capsules made of grade H. For avoidance of intraindividual variability affecting the comparison of two dosage forms with a limited group of subjects, an approach with an internal standard should be used. Thus, reference capsules and the two types of test capsules were administered by healthy young volunteers in fasted state in a 2-arm crossover study. Test capsule and reference capsule were always administered together allowing for an internal reference. To enable differentiation in magnetic resonance imaging (MRI), the reference and test capsules contained different amounts of black iron oxide. The test capsules additionally contained manganese gluconate. The capsules also contained different types of ¹³C-labeled caffeine to act as distinguishable pharmacokinetic markers. 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, allowing for very sensitive detection of opening and interesting visualization of small intestinal spreading after release. Reference HPMCAS grade H capsules mainly disintegrated in ileum, while test capsules disintegrated in more proximal regions of small intestine or in terms of HPMCAS grade L even in stomach already. Utilization of an internal standard with dual labeling by dosing test and reference simultaneously was a relevant improvement in study design. HPMCAS grade M is a robust alternative to HPMCAS grade H if faster and more proximal disintegration is desirable.