Pathologic Duodenogastric Reflux and Inhibited Gastric Acid Secretion as Potential Factors Decreasing Omeprazole Stability

Abstract

Bioequivalence studies are usually conducted with healthy volunteers. However, there are some differences in conditions of enteric-coated acid-labile drug release and absorption between healthy subjects and gastrointestinal patients. Pathologic duodenogastric reflux (PDGR) with high-amplitude changes in gastric pH can lead to destruction of the coating layer, resulting in degradation of the active compounds due to decrease in pH level after a reflux. The pH increasing ≥4 within PPIs administration also promotes dissolution of poor-quality coating. Modified comparative dissolution testing of original omeprazole (OO) and Generics1;2;3;4 proceeded in two stages. At first, we moved drugs from solution with Ph=1.2 (1.2 ± 0.05) to рН=7.0 (7.0 ± 0.05) and examined concentration of omeprazole in solution using high-performance liquid chromatography (HPLC). According to our self-developed formula, pH 7 exposure time of resistance to PDGR for omeprazole is 4 minutes, i.e. the active substance should not be released within 4 minutes at pH 7. The exposure at the second stage was conducted with pH 4 (4.0 ± 0.05), which imitated gastric pH after PPI administration. And then we also moved drugs to pH 7 with the subsequent measurement of omeprazole concentration. Omeprazole concentrations after 4, 10, 15, 20, 30, 45, 60 minutes in pH 7 solution at the first stage (pH 1.2 exposure) were different for OO and generics. For OO, these values were 4,7 ± 0,7%; 41,4 ± 3,0%; 62,8 ± 4,0%; 79,5 ± 2,9%; 83,5 ± 2,9%; 81,6 ± 2,9% (partly degradation of omeprazole); 80,6 ± 4,4%; for Generic1 - 0; 49,3 ± 9,9%; 88,8 ± 2,8%; 90,4 ± 3,7%; 88, 2 ± 2,2%; 87,3 ± 2,0%; 85,9 ± 1,1%; for Generic2 - 0; 30, 6 ± 6,3%; 66,7 ± 8,2%; 76,4 ± 7,4%; 82,8 ± 5,3%; 86,0 ± 3,7%; 84,6 ± 3,3%: for Generic3 - 80,8 ± 3,6%; 83,5 ± 1,9%; 83, 8 ± 3,2%; 83,3 ± 2,7%; 81,9 ± 2,1%; 82,1 ± 2,0%; 82,0 ± 2,4%; for Generic4 - 82,5 ± 1,7%; 84,4 ± 0,8%; 84,2 ± 1,2%; 82, 9 ± 0,9%; 82,9 ± 0,9%; 82,9 ± 0,9%; 82,8 ± 1,1%, respectively. An analysis of the omeprazole concentration in pH 7 solution at the second stage (pH 4 exposure) revealed the following parameters after 4, 10, 15, 20, 30, 45, 60 minutes: for OO - 4,4 ± 0,6%; 40, 5 ± 3,0%; 62,8 ± 2,0%; 80,0 ± 3,1%; 85,4 ± 2,9%; 82,8 ± 3,4%; 80,9 ± 3,5%; for Generic1 – 0; 67,0 ± 7,8%; 89,7 ± 2,3%; 91, 9 ± 4,3%; 89,1 ± 1,6%; 88,3 ± 1,4%; 87,8 ± 1,2%; for Generic2 – 0; 42,2 ± 5,6%; 75,1 ± 7,3%; 81,0 ± 6,0%; 88,4 ± 3,2%; 88, 6 ± 1,3%; 87,9 ± 1,0%; for Generic4 – 85,5 ± 0,5%; 85,6 ± 0,5%; 84,7 ± 0,9%; 82,7 ± 3,0%; 84,4 ± 0,3%; 84,4 ± 0,3%; 84,3 ± 0,4%, respectively. Generic3 release and degradation were completely realized at pH 4. Gastric stability of Generic3 and Generic4 has been decreasing due to PDGR and pharmacodynamic effect of the PPIs themselves.