Background
The differences in conditions of enteric-coated acid-labile drug release and absorption between healthy subjects in bioequivalence studies and gastrointestinal patients in clinical practice can lead to significant differences in gastric stability of original PPIs and generics. Thus, pathologic duodenogastric reflux (PDGR) and the pH increasing within PPIs administration still remain unaccounted for.
Methods
Two-stage modified comparative dissolution testing of original omeprazole (OO) and four generics (G1;2;
3
;
4
) was performed. At first, we moved drugs from solution with pH 1.2 (1.2±
0
.05) to pH 7.
0
(7.
0
±
0
.05) and measure concentration of omeprazole in solution by high-performance liquid chromatography. 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), that imitated gastric pH after PPI administration. And then we also moved drugs to pH 7 with the subsequent measurement of omeprazole concentration.
Results
Omeprazole concentrations after
4
, 10, 15, 20, 30, 45, 60 minutes in pH 7 solution at the first stage 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
%; 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 Generic
3
- 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 Generic
4
- 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 revealed the following parameters after the same time: 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 Generic
4
- 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. Generic
3
release and degradation were completely realized at pH
4
.
Conclusion
Decreased gastric stability of Generic
3
and Generic
4
makes PDGR and inhibited gastric acid secretion due to PPIs administration the potential causes of decreased enteric-coated acid-labile drugs stability.
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