Most of the drugs are either weak bases/acids or salts thereof, which exhibit pH-dependent solubility that can lead to insufficient absorption and bioavailability. pH modifiers can optimise pH (pHM) in the pharmaceutical dosage form in the intimate vicinity of the drug and therefore, improve pH-dependent solubility and release. Hydrophilic matrices travel along the GIT in non-disintegrated form being exposed to mechanical stress, that cannot be mimicked appropriately by the pharmacopeial dissolution apparatuses, like USP2. In Lek d.d. two biorelevant in vitro dissolution apparatuses were developed - AGS (»advanced gastric simulator«) and IMSPA (»intestinal model for simulation of peristaltic action«). Their main advantages are anatomical similarity with human digestive system and ability to mimic gastric and intestinal peristaltic action.
Initially dissolution profiles of 3 model drugs with pH-dependent solubility (dipyridamole, Na diclofenac and propranolol HCl) from HPMC matrix tablets were generated in two dissolution systems – USP2 and combination of biorelevant apparatuses AGS and IMSPA incubating tablets for 2 hours in acidic media, followed by dissolution media replacement with neutral pH, simulating transition from stomach to small intestine. All model drugs showed pH-dependent release profiles. As expected, in AGS+IMSPA, due to stronger mechanical stress and hydrodynamics, all drugs were released from matrices faster and to a greater extent in comparison to USP2. When pH modifiers were added to initial formulations, we observed faster and greater extent of released dipyridamole in the presence of fumaric acid in both dissolution systems, while added tartaric acid improved dissolution behaviour of propranolol HCl only in AGS+IMSPA. In contrast, presumably due to insufficient amount of basic Eudragit E, its addition did not result in faster or more extensive release of Na diclofenac. Cryostatic method was used to evaluate pH gradient in the gel layer of matrix tablets with no added pH modifiers. A more pronounced effect of acidic media on pHM in the gel layer was observed in AGS, where stronger mechanical stress was applied in comparison to USP2. Additionally, pHM was also observed visually by the use of pH indicator methyl orange, where we confirmed the influence of penetrating media pH, presence of drugs and pH modifiers on the pHM. By the use of both methods for observing pHM we could evaluate the influence of dynamic changes of pHM after simulated transition from stomach to small intestine on the kinetics of model drug release.
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