Stable pharmaceutical composition comprising esomeprazole and sodium bicarbonate

Abstract

The present invention relates to a stable pharmaceutical composition comprising omeprazole, its enantiomer, or its pharmaceutically acceptable salt, and sodium bicarbonate. Specifically, the present invention relates to a pharmaceutical composition with improved stability comprising a low dose of sodium bicarbonate, so that it has improved dissolution rate and bioavailability and also reduces side effects resulting from a high dose of sodium bicarbonate.

Claims

1. A tablet comprising: 20 mg or 40 mg of a magnesium salt of esomeprazole based on the weight of esomeprazole; and 800 mg of sodium bicarbonate; wherein: the magnesium salt of esomeprazole is in the form of a plurality of pellets or granules; the pellets or granules do not comprise the sodium bicarbonate; the pellets or granules are coated with a coating agent; the sodium bicarbonate does not contact the magnesium salt of esomeprazole in the tablet; and the tablet dissolves at pH 1.2.

2. The tablet according to claim 1, wherein the magnesium salt of esomeprazole is esomeprazole magnesium trihydrate.

3. The tablet according to claim 1, wherein the coating agent separates the sodium bicarbonate from the magnesium salt of esomeprazole.

4. The tablet according to claim 1, wherein the coating agent does not comprise sodium bicarbonate.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows the results of the analysis on the assay of esomeprazole and omeprazole according to pH.

(2) FIG. 2 shows the results where the pH of simulated gastric juice was measured according to the dose of sodium bicarbonate.

(3) FIG. 3 shows the results of the dissolution test on the formulations of Example 1 and Comparative Example 1.

(4) FIG. 4 shows the results of the blood concentration change of esomeprazole in the test drug and the reference drug.

(5) FIG. 5 shows the results where the change of pH in the stomach was measured after the single dose and the repeated doses for each of the test drug and the reference drug.

BEST MODE FOR CARRYING OUT THE INVENTION

(6) Hereinafter, the present invention will be more detailed through the following examples. However, the examples are merely provided for a better understanding of the present invention for the purpose of illustration, but are not to be construed as the limitation of the claimed scope.

EXAMPLE 1

(7) Preparation of a Tablet of Esomeprazole Comprising Sodium Bicarbonate

(8) A tablet comprising esomeprazole and sodium bicarbonate was prepared according to the following method.

(9) 1. First Coating

(10) Hydroxypropyl cellulose was added and dissolved in purified water, followed by adding arginine, simethicone, purified water, esomeprazole magnesium trihydrate (22.3 mg; 20.00 mg based on the weight of esomeprazole), magnesium oxide, and talc, and dispersing them, to prepare a coating solution. Sugar spheres were put into a fluidized bed granulation-coating machine, spraying the coating solution, to prepare a first pellet.

(11) 2. Second Coating

(12) Polyvinyl alcohol, talc, titanium oxide, glycerol monocaprylocaprate, and sodium lauryl sulfate were added and dispersed in purified water to prepare a coating solution.

(13) The coated materials from the first coating process were put into a fluidized bed granulation-coating machine, spraying the coating solution, to prepare a second pellet.

(14) 3. Blending and Tableting

(15) The second pellet, sodium bicarbonate (800 mg), copovidone, and crospovidone were put in a mixer to be mixed, followed by adding sodium stearyl fumarate and lubricating to prepare granules. The prepared granules were tableted.

(16) 4. Third Coating

(17) Polyvinyl alcohol, talc, titanium oxide, glycerol monocaprylocaprate, sodium lauryl sulfate, red iron oxide, black iron oxide, and yellow iron oxide were added in purified water to prepare a coating solution. The core tablets were put into a coating machine, spraying the coating solution, coating, and drying to obtain the final film coated tablet.

COMPARATIVE EXAMPLE 1

(18) Preparation of a Tablet of Esomeprazole which Does Not Comprise Sodium Bicarbonate

(19) A tablet of esomeprazole which does not comprise sodium bicarbonate was prepared according to the following method.

(20) 1. First Coating

(21) Hydroxypropyl cellulose was added and dissolved in purified water, followed by adding arginine, simethicone, purified water, esomeprazole magnesium trihydrate, magnesium oxide, and talc, and dispersing them, to prepare a coating solution. Sugar spheres were put into a fluidized bed granulation-coating machine, spraying the coating solution, to prepare a first pellet.

(22) 2. Second Coating

(23) Polyvinyl alcohol, talc, titanium oxide, glycerol monocaprylocaprate, and sodium lauryl sulfate were added and dispersed in purified water to prepare a coating solution. The first coated materials were put into a fluidized bed granulation-coating machine, spraying the coating solution, to prepare a second pellet.

(24) 3. Blending and Tableting

(25) The second pellet, lactose, microcrystalline cellulose, copovidone, and crospovidone were put in a mixer to be mixed, followed by adding sodium stearyl fumarate and lubricating to prepare granules. The granules were tableted.

(26) 4. Third Coating

(27) Polyvinyl alcohol, talc, titanium oxide, glycerol monocaprylocaprate, sodium lauryl sulfate, red iron oxide, black iron oxide, and yellow iron oxide were added in purified water to prepare a coating solution. The core tablets were put into a coating machine, spraying the coating solution, coating, and drying to obtain the final film coated tablet.

TEST EXAMPLE 1

(28) Stability Test of Esomeprazole and Omeprazole According to pH

(29) The esomeprazole solution and the omeprazole solution, which are at a concentration of 20 mg/mL, were respectively added in 2 mL into 100 mL of a buffer solution, followed by analyzing the concentration of esomeprazole and omeprazole according to pH based on the analysis method as follows:

(30) <Analysis method>

(31) A) Detector: UV-Visible spectrophotometer (measurement wavelength:280 nm)

(32) B) Column: Inertsil C8-3 (4.6×150 mm, 5 μm) or equivalent column

(33) C) Injection amount: 20 μl

(34) D) Flow rate: 1.5 mL/min

(35) E) Column temperature: Constant temperature near 40° C.

(36) F) Sample temperature: Constant temperature near 10° C.

(37) G) Analysis time: 6 minutes

(38) H) Mobile phase: Buffer solution at pH 7.6 and acetonitrile (65:35)

(39) The buffer solution at pH 7.6 was prepared as follows: 0.725 g of sodium dihydrogen phosphate monohydrate (NaH.sub.2PO.sub.4.H.sub.2O) and 4.472 g of anhydrous disodium hydrogen phosphate (Na.sub.2HPO.sub.4) were weighed to be put in an 1 L volumetric flask and dissolved in purified water, followed by filling the flask with purified water up to the calibration mark. 250 mL of the liquid was taken to be put in an 1 L volumetric flask, followed by filling the flask with purified water up to the calibration mark and adjusting the pH to 7.6 with phosphoric acid.

(40) The analysis results were shown in Table 1 below and FIG. 1.

(41) TABLE-US-00001 TABLE 1 5 min 10 min 15 min 30 min 45 min 60 min 120 min pH 4.0 S-omeprazole 64.1 31.0 15.9 6.9 1.7 0.9 0.1 Omeprazole 57.2 29.4 15.3 6.7 1.6 0.8 0.1 pH 6.0 S-omeprazole 74.4 72.8 71.0 68.9 66.3 63.6 54.9 Omeprazole 74.9 74.2 71.7 69.6 65.4 64.1 55.1 pH 6.8 S-omeprazole 95.6 90.8 90.5 89.7 88.9 88.3 86.2 Omeprazole 91.5 90.5 89.9 89.8 88.8 88.3 85.5 pH 7.0 S-omeprazole 99.6 99.0 99.3 98.9 98.7 98.1 96.8 Omeprazole 100.5 99.0 98.9 98.2 97.9 97.5 95.8 pH 7.3 S-omeprazole 100.1 100.1 100.0 100.0 100.0 100.0 99.90 Omeprazole 99.8 100.0 99.9 99.8 99.8 99.8 99.86 pH 7.5 S-omeprazole 99.4 99.3 99.2 99.1 99.3 99.1 98.2 Omeprazole 100.5 99.7 99.7 99.4 99.2 98.9 98.2 pH 8.0 S-omeprazole — — 101.1 100.9 100.7 100.7 100.0 Omeprazole — — 99.7 99.6 99.5 99.5 98.6

(42) As shown in Table 1 above, it was confirmed that esomeprazole and omeprazole are stable for at least 2 hours in case of pH 7.0 or more.

TEST EXAMPLE 2

(43) pH Test of Simulated Gastric Juice According to the Dose of Sodium Bicarbonate

(44) To determine the dose of sodium bicarbonate, the conditions on drug release and gastric juice were set as follows: in particular, 1) the amount of gastric juice in a fasting condition is generally 20 to 50 mL; 2) the amount of gastric juice secretion is about 2 L/day (about 83 mL/hr); 3) the total amount of gastric juice that reacts with a drug (formulation) is assumed as about 200 mL; and 4) a drug is taken with water where the water amount is 200 mL.

(45) A pH was measured according to the change of the dose of sodium bicarbonate in a solution (37° C.) where 200 mL of purified water was put in 200 mL of simulated gastric juice. The measurement results were shown in Table 2 below and FIG. 2.

(46) TABLE-US-00002 TABLE 2 sodium bi-carbonate (mg) 500 600 700 800 900 1,000 1,100 1,200 1,300 pH 5.77 6.51 7.30 7.30 7.31 7.37 7.38 7.38 7.40

(47) As shows in Table 2 above, it was confirmed that as the dose of sodium bicarbonate increased, the pH value increased. Further, few changes of the pH value were found in 1,000 mg or more of sodium bicarbonate.

(48) It was also confirmed that the dose of sodium bicarbonate that can neutralize 200 mL of simulated gastric juice to show neutral pH was at least 600 mg.

TEST EXAMPLE 3

(49) Dissolution Test of a Formulation According to the Presence or Absence of Sodium Bicarbonate

(50) Dissolution test on the formulations of Example 1 and Comparative Example 1 was performed where the conditions on the dissolution test and analysis were as follows:

(51) <Dissolution Test Condition>

(52) 1) Dissolution method: Korean Pharmacopoeia General test, Dissolution tests, Method 3 (Flow Through Cell Method)

(53) 2) Dissolution medium: pH 1.2.fwdarw.pH 4.0

(54) 3) Dissolution temperature: 37±0.5° C.

(55) 4) Flow rate: 2 mL/min

(56) 5) Test time: pH 1.2 (15 min).fwdarw.pH 4.0 (15 min)

(57) <Analysis Condition>

(58) 1) Detector: UV spectrophotometer (measurement wavelength:302 nm)

(59) 2) Column: Capcell Pak C18 (4.6×150 mm, 5 μm) or equivalent column

(60) 3) Injection amount: 20 μL

(61) 4) Flow rate: 1.0 mL/min

(62) 5) Column temperature: Constant temperature near 30° C.

(63) 6) Sample temperature: Constant temperature near 10° C.

(64) 7) Mobile phase: Acetonitrile, a buffer solution at pH 7.3, and water (350:500:150)

(65) The buffer solution at pH 7.3 was prepared as follows: 1 mol/L sodium dihydrogen phosphate solution and 0.5 mol/L disodium hydrogen phosphate solution were taken in 10.5 mL and 60 mL, respectively, to be put in an 1 L volumetric flask, followed by filling the flask with purified water up to the calibration mark.

(66) The results of the dissolution test were shown in Table 3 below and FIG. 3.

(67) TABLE-US-00003 TABLE 3 Dissolution rate (ng/mL) Example 1 Comparative Example 1  5 min 4,462,741 22,929 10 min 3,696,359 8,566 15 min 3,074,658 4,585 20 min 1,954,877 2,185 25 min 1,189,882 835 30 min 786,910 9,793

(68) As shows in Table 3 above, Comparative Example 1 that does not comprise sodium bicarbonate showed a very low dissolution rate, from which it was confirmed that it was rarely dissolved. Meanwhile, Example 1 comprising sodium bicarbonate showed hundreds to thousands of times higher of a dissolution rate than Comparative Example 1, especially, the highest dissolution rate at 5 minutes after the administration. As such, it was confirmed that it was rapidly dissolved.

TEST EXAMPLE 4

(69) Blood Concentration of Esomeprazole

(70) A test drug (a tablet prepared according to Example 1) and a reference drug (Nexium® tablet 20 mg as currently marketed) were taken as repeated once-daily doses for seven days at a fasting condition to measure the change on a blood concentration of esomeprazole and AUC according to the time, which were shown in Table 4 below and FIG. 4.

(71) TABLE-US-00004 TABLE 4 AUC (h .Math. ng/mL) Reference drug Test drug 2578.09 2802.25

(72) As shown in Table 4 above, the test drug had a higher AUC than the reference drug. Further, as shown in FIG. 4, it was confirmed that upon administration, the test drug, in comparison with the reference drug as an enteric-coated formulation, was immediately dissolved and absorbed to show a higher blood concentration after administration. Since it is important in view of the nature of the disease to exert immediate treatment effect, it was confirmed that the test drug shows the remarkably superior effect to the reference drug.

(73) In comparison with the reference drug, the test drug showed a higher blood concentration for up to 2 hours and a similar blood concentration after 2 hours. As such, it was confirmed that the test drug has an improved bioavailability.

TEST EXAMPLE 5

(74) Change of pH in the Stomach

(75) A test drug (a tablet prepared according to Example 1) and a reference drug (Nexium® tablet 20 mg as currently marketed) were taken as a single dose and as repeated doses for seven days to measure the change of pH in the stomach. The time holding gastric pH≤4 was measured while observing for 24 hours after administration. The results were shown in Table 5 below and FIG. 5.

(76) TABLE-US-00005 TABLE 5 Percent (%) of time with gastric pH ≤4 for 24 hours interval after single dose, repeated doses Test drug Reference drug Baseline   80%   80% Single dose 43.20% 44.49% Repeated doses 30.07% 29.84%

(77) The single dose of the reference drug and the test drug reduced the time holding gastric pH≤4 from about 80% to 44.49% and 43.20%, respectively, in comparison with the baseline. The repeated doses of the reference drug and the test drug showed 29.84% and 30.07%, respectively. As such, it was confirmed that the time holding gastric pH≤4 was all similar in cases of the baseline, single dose, and repeated doses.

(78) In sum, a formulation according to the present invention has a higher value on the initial release, absorption, and blood concentration of a drug in comparison with an enteric-coated formulation, and thus exerts an improved bioavailability and treatment effect of a gastric acid-related disease.