In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status.
To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status.



A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent.



Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (VMAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of VMAXdepended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm).



The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.
Pharmacometrics Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden.
Benjamin
B
Guiastrennec
Pharmaceutical Technology and Development, AstraZeneca, Gothenburg, Sweden.|Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
Erik
E
Söderlind
Advanced Drug Delivery, Pharmaceutical Sciences, Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden.
Sara
S
Richardson
Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden.
Alexandra
A
Peric
Pharmacometrics Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden. martin.bergstrand@farmbio.uu.se.
Martin
M
Bergstrand
D000328:Adult; D002130:Calcium Phosphates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003106:Colon / Q000378:metabolism; D003198:Computer Simulation; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005215:Fasting; D005290:Ferric Compounds / Q000737:chemistry; D005650:Fumarates / Q000737:chemistry; D005753:Gastric Mucosa / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives / Q000737:chemistry* / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D019518:Postprandial Period; D012995:Solubility; D013314:Stress, Mechanical; D013607:Tablets / Q000737:chemistry*
D002130:Calcium Phosphates; D003692:Delayed-Action Preparations; D005290:Ferric Compounds; D005650:Fumarates; D013607:Tablets; C000499:ferric oxide; D065347:Hypromellose Derivatives; C519579:sodium stearyl fumarate; C485829:calcium phosphate, dibasic, anhydrous
NONMEM; food effect; hydroxypropyl methylcellulose; in vitro in vivo correlation; magnetic marker monitoring