4.

Pharmacological effects

INDICATION
Lansoprazole is used to reduce gastric acid secretion and is approved for short term
treatment of active gastric ulcers, active duodenal ulcers, erosive reflux oesophagitis,
symptomatic gastroesophageal reflux disease, and non-steroidal anti-inflammatory
drug (NSAID) induced gastric and duodenal ulcers. It may be used in the maintenance
and healing of several gastric conditions including duodenal ulcers, NSAID related
gastric ulcers, and erosive esophagitis. Lansoprazole prevents recurrence of gastric
ulcers in patients who have a documented history of gastric ulcers who also use
NSAIDs chronically. Predictably, it is also useful in the management of hypersecretory
conditions including Zollinger-Ellison syndrome. Lansoprazole is effective at eradicating
H. pylori when used in conjunction with amoxicillin and clarithromycin (triple therapy) or
with amoxicillin alone (dual therapy).

PHARMACODYNAMICS
Since the sulfenamide metabolite of lansoprazole covalently binds at critical sites of the
H+/K+ATPase, the final common pathway of gastric acid secretion, this agent inhibits
both basal and stimulated acid secretion. In adults, lansoprazole (30 mg) decreased
meal-stimulated gastric acid secretion to 19 ± 2 mmol/h compared to 96 - 114 ± 12 - 16
mmol/h with placebo. In geriatric patients > 60 years of age, the decrease in gastric acid
secretion was even more significant to a rate of 2 ± 1 mmol/h. Lansoprazole increased
the mean gastric pH in a dose-dependant manner. The median gastric pH increased to
4.3 - 5.4 with lansoprazole administration (30 mg) and to 6.47 with a 60 mg dose
compared to a median pH of 1.4 - 2.1 after placebo. The gastric pH was > 4 for 35.2% of
the time for 24 h after lansoprazole administration (30 mg) com pared to 3.5% with
placebo. When given at a dose of 30 mg every 12 h, lansoprazole maintained the gastric
pH > 4 a median of 75.8% of the time.
In paediatric patients who received lansoprazole daily for 5 days, the mean gastric pH
increased from pH 2.5 (baseline) to pH 3.6 with lansoprazole (15 mg) and from pH 2.3
to 3.8 with lansoprazole (30 mg). In children < 30 kg, lansopra zole (15 mg) maintained
a gastric pH > 3 - 4 on day 5 for 23 - 54% of the time compared to 12 - 41% prior to
lansoprazole therapy. In paediatric patients > 30 kg who received lanso prazole (30
mg/day), the percentage of time the gastric pH > 3 - 4 was increased from 20 - 60%,
compared to 9 - 49% prior to treatment, respectively.
Serum gastrin concentration increases with PPI therapy. Suppression of gastric acid
secretion stimulates the release of gastrin, a polypeptide hormone secreted by antral G
cells in the stomach. Patients with duodenal or gastric ulcers treated with lansoprazole
(30 mg/day) for 8 weeks experienced an increase in mean serum gastrin concentration
to 286 ng/ml from 118 ng/ml prior to treatment. The mean serum gas trin level
remained elevated at 185 ng/ml in patients who received maintenance therapy with H2-
receptor antagonists but returned to normal in patients who did not require
antisecretory therapy. Phase II studies of lansoprazole in paediatric subjects age 1 - 11
years yielded similar results, with an increase in the median serum gastrin
concentration from 50 to 100 ng/ml after 8 - 12 weeks of lansoprazole (15 mg daily)
and from 52 to 91 ng/ml with lansoprazole (30 mg daily).
H. pylori infection is also associated with hypergastrinae mia. Eradication of H. pylori
infection was reported to minimise the increase in serum gastrin concentration during
omeprazole therapy compared to the rise in gastrin levels observed in patients in whom
H. pylori was not eradicated.
Morphological changes in gastric mucosa occur in experimental animals receiving long-
term therapy with high doses of lansoprazole. Hypertrophy of the parietal cells and
gastric glands occurred in rats given lansoprazole 50 mg/kg/day for 1 year.
Hypergastrinaemia induced gastric enterochromaf fin-like (ECL) cell hyperplasia and
ECL carcinoids in some animal modelsa. However, no significant increase in ECL
density was observed in humans in one study with long-term use of up to 5.5 years.
Another study identified H. pylori infection as a risk factor for argyrophil cell hyperplasia
in patients who received lansoprazole for 5 years.

PHARMACOKINETICS AND METABOLISM

Lansoprazole is rapidly absorbed, with the mean Cmax in adults occurring 1.7 ± 0.8 h
(mean ± SD) after oral adminis tration. The maximum serum concentration is 824 ± 419
ng/ ml (mean ± SD) in adults given 30 mg of lansoprazole orally. Its mean area under
the curve (AUC) is 2133 ± 1797 ng.h/ml (mean ± SD) in adults after a dose of 30 mg.
Cmax and AUC are approximately proportional in adults in single doses from 15 - 60
mg. Lansoprazole pharmacokinetics are not altered by multiple dosing since this drug
does not accumulate. The serum half-life of lansoprazole is 1.2 ± 0.5 h (mean ± SD) in
adults. A comparison of pharmacokinetic data between paedi atric patients and adults
is presented in Table 1. There are age related differences in the elimination half-life of
lansoprazole. The elimination half-life of lansoprazole in pre-adolescent paediatric
patients is 0.7 ± 0.2 h (mean ± SD) compared to 1.2 ± 0.5 h in adults. In contrast, the
pharmacokinetics of lansoprazole in adolescents are similar to those in adults. Age-
related differences are also observed in geriatric patients. The elimination half-life of
lansoprazole is 1.9 - 2.9 h in the elderly. Despite age-related differences in half-life,
Cmax and AUC for lansoprazole are similar in patients of all ages.
Lansoprazole has minimal first pass metabolism. The two main excretory metabolites
of lansoprazole are lansoprazole sulfone and hydroxylansoprazole. Lansoprazole
sulfone is formed through the cytochrome P450 (CYP3A4) pathway, while
hydroxylansoprazole may be formed by CYP3A4, CYP2C18, or the CYP2C19 pathways.
An elimination study of 14C-lansoprazole revealed that approximately one third of the
radiation administered was recovered in the urine, while two-thirds was recovered in
faeces, indicating predomi nantly biliary excretion. Patients with renal insufficiency have
a shortened elimination half-life and decreased AUC of lansoprazole. In contrast, the
half-life of lansoprazole is increased from 1.5 to 3.2 - 7.2 h in patients with impaired
hepatic function.
Lansoprazole absorption is relatively complete with absolute bioavailability > 80% in the
fasted state. The presence of food affects its absorption, with a 27% reduction in
bioavailability occurring when lansoprazole is given with food. There is no significant
effect on absorption if lansoprazole is given before meals.
SIDE EFFECTS
Lansoprazole oral capsule doesn’t cause drowsiness, but it can cause other side
effects.
The more common side effects of lansoprazole can include:
 diarrhea
 stomach pain
 nausea
 constipation
 headache

5. Pharmacopoeia standards (European)

LANSOPRAZOLE
Lansoprazolum

DEFINITION
2-[(RS)-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl]sulfinyl]-1H-benzimidazole.
Content: 99.0 per cent to 101.0 per cent (anhydrous substance).

CHARACTERS

Appearance: white or brownish powder.

Solubility: practically insoluble in water, soluble in anhydrous ethanol, very slightly

soluble in acetonitrile.

It shows polymorphism (5.9).

IDENTIFICATION

Infrared absorption spectrophotometry (2.2.24).

Comparison: lansoprazole CRS.

If the spectra obtained in the solid-state show differences, dissolve the substance to be
examined and the reference substance separately in anhydrous ethanol R, evaporate to
dryness and record new spectra using the residues.

TESTS

Appearance of solution. The solution is clear (2.2.1) and not more intensely coloured
than reference solution B2 or BY2 (2.2.2, Method II).

Dissolve 1.0 g in dimethylformamide R and dilute to 20 mL with the same solvent.

Related substances. Liquid chromatography (2.2.29). Prepare the solutions immediately

before use and protect them from light.

Solvent mixture: mix 1 volume of triethylamine R and 60 volumes of water R and adjust
to pH 10.5 with phosphoric acid R; mix this solution with 40 volumes of acetonitrile R1.

Test solution. Dissolve 10 mg of the substance to be examined in the solvent mixture

and dilute to 10 mL with the solvent mixture.

Reference solution (a). Dissolve the contents of a vial of lansoprazole for peak
identification CRS (containing impurities A and B) in 1.0 mL of the solvent mixture.

Reference solution (b). Dilute 2.0 mL of the test solution to 100.0 mL with the solvent
mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.

Reference solution (c). Dissolve 5 mg of 2-hydroxybenzimidazole R (impurity D) and 5

mg of 2-mercaptobenzimidazole R (impurity E) in the solvent mixture and dilute to 100
mL with the solvent mixture. Dilute 1 mL of this solution to 10 mL with the solvent
mixture.

Column:

– size: l = 0.25 m, Ø = 4.6 mm;

– stationary phase: amidohexadecylsilyl silica gel for chromatography R (5 μm).

Mobile phase: mix 1 volume of triethylamine R and 60 volumes of water R and adjust to
pH 6.2 with phosphoric acid R; mix this solution with 40 volumes of acetonitrile R1.

Flow rate: 1.2 mL/min.

Detection: spectrophotometer at 285 nm.

Injection: 10 μL.

Run time: 3 times the retention time of lansoprazole.

Identification of impurities: use the chromatogram supplied with lansoprazole for peak
identification CRS and the chromatogram obtained with reference solution (a) to identify
the peaks due to impurities A and B; use the chromatogram obtained with reference
solution (c) to identify the peaks due to impurities D and E.

Relative retention with reference to lansoprazole (retention time = about 7 min): impurity
D = about 0.4; impurity A = about 0.5; impurity E = about 0.6; impurity B = about 1.2.

System suitability: reference solution (a):

– resolution: minimum 3.0 between the peaks due to lansoprazole and impurity B.

Limits:

– correction factor: for the calculation of content, multiply

the peak area of impurity E by 0.4;

– impurity B: not more than twice the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.4 per cent);

– impurities A, D, E: for each impurity, not more than 0.5 times the area of the principal
peak in the chromatogram obtained with reference solution (b) (0.1 per cent);

– unspecified impurities: for each impurity, not more than 0.5 times the area of the
principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);

– total: not more than 3 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.6 per cent);

– disregard limit: 0.25 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.05 per cent).

Water (2.5.32): maximum 0.1 per cent, determined on 0.150-0.200 g using the
evaporation technique:

– temperature: 50-70 °C;

– heating time: 15 min;

– flow rate: 150 mL/min.

Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g.

ASSAY

Dissolve 0.300 g in 40 mL of ethanol (96 per cent) R and dilute to 50 mL with water R.
Titrate with 0.1 M sodium hydroxide, determining the end-point potentiometrically
(2.2.20).

1 mL of 0.1 M sodium hydroxide is equivalent to 36.94 mg of C16H14F3N3O2S.

STORAGE

In an airtight container, protected from light.

IMPURITIES

Specified impurities: A, B, D, E.

Other detectable impurities (the following substances would, if present at a sufficient

level, be detected by one or other of the tests in the monograph. They are limited by the
general acceptance criterion for other/unspecified impurities and/or by the general
monograph Substances for pharmaceutical use (2034). It is therefore not necessary to
identify these impurities for demonstration of compliance. See also 5.10. Control of
impurities in substances for pharmaceutical use): C, F.

A. 2-[(RS)-[[3-methyl-1-oxido-4-(2,2,2-trifluoroethoxy)- pyridin-2-yl]methyl]sulfinyl]-1H-
benzimidazole,

B. X = SO2: 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl]sulfonyl]-1H-
benzimidazole,

C. X = S: 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl]sulfanyl]-1H-
benzimidazole,

D. R = OH: 1H-benzimidazol-2-ol,

E. R = SH: 1H-benzimidazole-2-thiol,

F. 2-[(RS)-[(4-chloro-3-methylpyridin-2-yl)methyl]sulfinyl]- 1H-benzimidazole.pearance:
white or brownish powder.