PHARMACEUTICAL PREPARATION HAVING EXCELLENT DISSOLUTION PROPERTIES, CONTAINING ESOMEPRAZOLE AND SODIUM BICARBONATE

Abstract

The present invention relates to a pharmaceutical preparation comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof, and sodium bicarbonate, and a method for preparing the same. Specifically, the present invention relates to a pharmaceutical preparation in which sodium bicarbonate is first disintegrated so as to raise pH, and then omeprazole is dissolved such that the release properties of an active ingredient are improved, and thus the dissolution pattern and bioavailability of a drug can be enhanced.

Claims

1. A pharmaceutical preparation comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof; and sodium bicarbonate, characterized in that the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is in the form of a pellet or a granule, and when the preparation is dissolved in a solution, sodium bicarbonate is first dissolved, and then the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is dissolved.

2. The pharmaceutical preparation according to claim 1, characterized in that the pellet or granule comprises 30% by weight or less of sodium bicarbonate based on the total weight of sodium bicarbonate comprised in the preparation.

3. The pharmaceutical preparation according to claim 1, characterized in that the pellet or granule is coated with a coating agent, and does not comprise sodium bicarbonate.

4. The pharmaceutical preparation according to claim 3, characterized in that the coating agent is at least one selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, ethyl cellulose, and dimethylaminoethyl methacrylate methyl methacrylate copolymer.

5. The pharmaceutical preparation according to claim 1, characterized in that when the preparation is dissolved in a solution at pH 1.2 by a flow through cell dissolution test method, the ratio of the time for the solution to reach a pH of 6.5 with respect to the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is less than 1.

6. The pharmaceutical preparation according to claim 5, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is within 20 minutes.

7. The pharmaceutical preparation according to claim 6, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is between 5 minutes and 15 minutes.

8. The pharmaceutical preparation according to claim 1, characterized in that the pH in the stomach increases within 50 minutes after the single administration of the preparation.

9. The pharmaceutical preparation according to claim 8, characterized in that the pH in the stomach increases within 45 minutes after the single administration of the preparation.

10. The pharmaceutical preparation according to claim 1, characterized in that the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is esomeprazole.

11. The pharmaceutical preparation according to claim 1, characterized in that the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is esomeprazole magnesium salt.

12. The pharmaceutical preparation according to claim 1, characterized in that the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is esomeprazole magnesium trihydrate.

13. A method for preparing a pharmaceutical preparation comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof; and sodium bicarbonate, the method comprising the steps of: (a) coating a core with a first coating solution comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof to prepare a first coated product; (b) coating the first coated product with a second coating solution comprising a coating agent to prepare a second coated product; (c) mixing the second coated product with sodium bicarbonate to obtain a mixture; (d) tableting the mixture to obtain an uncoated tablet; and (e) coating the uncoated tablet with a third coating solution and then drying to obtain a coated tablet.

14. The method for preparing a pharmaceutical preparation according to claim 13, characterized in that the coating agent is at least one selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, ethyl cellulose, and dimethylaminoethyl methacrylate⋅methyl methacrylate copolymer.

15. The method according to claim 13, characterized in that in step (c), sodium bicarbonate is wet granulated and then mixed with the coated product.

16. A method for preparing a pharmaceutical preparation comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof; and sodium bicarbonate, the method comprising the steps of: (a) mixing omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof with sodium bicarbonate to obtain a mixture; (b) kneading the mixture with a binder solution to obtain a kneaded product; (c) mixing the kneaded product with sodium bicarbonate to obtain a final mixture; (d) tableting the final mixture to obtain an uncoated tablet; and (e) coating the uncoated tablet with a coating solution and then drying to obtain a coated tablet, wherein the content of sodium bicarbonate mixed in the step (a) is 0 to 75% by weight based on the total weight of sodium bicarbonate.

17. The method according to claim 16, characterized in that the content of sodium bicarbonate mixed in the step (a) is 30% by weight or less based on the total weight of sodium bicarbonate.

18. A method for preparing a pharmaceutical preparation comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof; and sodium bicarbonate, the method comprising the steps of: (a) mixing omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof with sodium bicarbonate to obtain a mixture; (b) slugging the mixture to obtain a slugged product; (c) mixing the slugged product with sodium bicarbonate to obtain a final mixture; (d) tableting the mixture to obtain an uncoated tablet; and (e) coating the uncoated tablet with a coating solution and then drying to obtain a coated tablet.

19. The method for preparing a pharmaceutical preparation according to claim 13, characterized in that when the preparation is dissolved in a solution at pH 1.2 by a flow through cell dissolution test method, the ratio of the time for the solution to reach a pH of 6.5 with respect to the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is less than 1.

20. The method for preparing a pharmaceutical preparation according to claim 19, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is within 20 minutes.

21. The method for preparing a pharmaceutical preparation according to claim 20, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is between 5 minutes and 15 minutes.

22. The method for preparing a pharmaceutical preparation according to claim 13, characterized in that the pH in the stomach increases within 50 minutes after the single administration of the preparation.

23. The method for preparing a pharmaceutical preparation according to claim 22, characterized in that the pH in the stomach increases within 45 minutes after the single administration of the preparation.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0050] FIG. 1 is a graph showing the dissolution rate and pH change over time in Example 1.

[0051] FIG. 2 is a graph showing the dissolution rate and pH change over time in Example 3.

[0052] FIG. 3 is a graph showing the dissolution rate and pH change over time in Example 4.

[0053] FIG. 4 is a graph showing the average pH value after the single administration of the test drug and the reference drug.

[0054] FIG. 5 is a graph showing the average pH value after the repeated administration of the test drug and the reference drug.

[0055] FIG. 6 is a graph showing the ratio of dissolution rate according to the content of sodium bicarbonate in esomeprazole granules.

[0056] FIG. 7 is a graph showing the ratio of AUC (area under the curve) of dissolution rate according to the content of sodium bicarbonate in esomeprazole granules.

BEST MODE FOR CARRYING OUT THE INVENTION

[0057] Hereinafter, the present invention is to be described in more detail through the following examples. However, these examples are merely provided for a better understanding of the present invention for the purpose of illustration, but are not intended to limit the scope of the present invention.

EXAMPLE 1

Preparation of Combination Tablet of Esomeprazole and Sodium Bicarbonate (Pellet)

[0058] The tablets of Example 1 were prepared according to the following preparation method.

1. First Pellet Coating

[0059] Hydroxypropyl cellulose was added and dissolved in purified water, and then arginine, simethicone, esomeprazole magnesium trihydrate (20 mg to 40 mg as esomeprazole), magnesium oxide, and talc were added and dispersed to prepare a first coating solution. White sugar sphere was added to a fluidized bed coating machine, and the first coating solution was sprayed to perform a first pellet coating process (first coated product).

2. Second Pellet Coating

[0060] Purified water, polyvinyl alcohol, talc, titanium oxide, glycerol monocaprylocaprate, and sodium lauryl sulfate were added to the preparation tank and dispersed to prepare a second coating solution. The first coated product was added to a fluidized bed coating machine, and the second coating solution was sprayed to perform a second pellet coating process (second coated product).

3. Post Mixing (Simple Mixing Method)

[0061] The second coated product was added to a mixing machine, and sodium bicarbonate (800 mg) was added. In this case, purified water may be included depending on the moisture content. Further, copovidone, crospovidone and sodium stearyl fumarate were added thereto and mixed (final mixture).

4. Tableting

[0062] The final mixture was tableted by a tablet press machine (uncoated tablet).

5. Third Coating

[0063] Polyvinyl alcohol, talc, titanium oxide, glycerol monocaprylocaprate, sodium lauryl sulfate, red iron oxide, black iron oxide, yellow iron oxide, and purified water were added to the preparation tank and dissolved to prepare a third coating solution. The uncoated tablets were added to a coating machine, and coated with the third coating solution, and then dried to obtain the coated tablets.

EXAMPLE 2

Preparation of Combination Tablet of Esomeprazole and Sodium Bicarbonate (Pellet)

[0064] The tablets of Example 2 were prepared according to the preparation method of Example 1 above, and a wet granulation process was used instead of simple mixing in the post mixing process of step 3 in the preparation method.

3. Post Mixing (Wet Granulation Method)

[0065] A binder solution was prepared with copovidone and water in a separate container, and then kneaded with sodium bicarbonate (800 mg), and dried to prepare a kneaded product. Thereafter, the kneaded product and the second coated product were added to a mixing machine, and copovidone, crospovidone, and sodium stearyl fumarate were added and mixed (final mixture).

EXAMPLE 3

Preparation of Combination Tablet of Esomeprazole and Sodium Bicarbonate (Wet Granulation)

[0066] The tablets of Example 3 (20 mg to 40 mg of esomeprazole, 800 mg of sodium bicarbonate) were prepared according to the following preparation method.

1. Mixing

[0067] Esomeprazole magnesium trihydrate, microcrystalline cellulose, and sodium bicarbonate were added and mixed by a High Speed Mixer.

2. Kneading

[0068] Hydroxypropyl cellulose was added and dissolved in purified water to prepare a binder solution. The binder solution was added to the mixture and kneaded.

3. Final Mixing and Lubricating

[0069] The kneaded product, sodium bicarbonate, copovidone, and croscarmellose sodium were added to a mixing machine and mixed, and then sodium stearyl fumarate was added and lubricated to prepare a final mixture.

4. Tableting and Coating

[0070] The final mixture was tableted by a tablet press machine (uncoated tablet). Polyvinyl alcohol, titanium oxide, polyethylene glycol, talc and purified water were added to the preparation tank and dissolved. The uncoated tablets were added to a coating machine, coated, and then dried to obtain the coated tablets.

EXAMPLE 4

Preparation of Combination Tablet of Esomeprazole and Sodium Bicarbonate (Dry Granulation)

[0071] The tablets of Example 4 (20 mg to 40 mg of esomeprazole, 800 mg of sodium bicarbonate) were prepared according to the following preparation method.

1. Mixing and Lubricating

[0072] Esomeprazole magnesium trihydrate, sodium bicarbonate, magnesium oxide, and crospovidone were added and mixed, and then sodium stearyl fumarate was added and lubricated to obtain a mixture.

2. Slugging

[0073] The mixture was slugged by a slugging machine.

3. Final Mixing and Lubricating

[0074] The slugged product, sodium bicarbonate, copovidone and crospovidone were added and mixed, and then sodium stearyl fumarate was added and lubricated to obtain a final mixture.

4. Tableting and Coating

[0075] The final mixture was tableted by a tablet press machine (uncoated tablet). Hydroxypropyl methyl cellulose, titanium oxide, polyethylene glycol, and purified water were added to the preparation tank and dissolved. The uncoated tablets were added to a coating machine, coated, and then dried to obtain the coated tablets.

Test Example 1

Comparative Dissolution Test of Tablet

[0076] The dissolution test was performed on the tablets of Examples 1, 3 and 4 (20 mg of esomeprazole/800 mg of sodium bicarbonate) prepared above, and the dissolution test and analysis conditions are as follows.

Dissolution Test Condition

[0077] 1) Dissolution method: the Korean Pharmacopoeia, General tests, Dissolution test, Method 3 (Flow Through Cell Method)

[0078] 2) Dissolution medium: pH 1.2.fwdarw.pH 4.0.fwdarw.pH 6.8

[0079] 3) Dissolution temperature: 37±0.5° C.

[0080] 4) Flow rate: 2 mL/min

[0081] 5) Test time: pH 1.2 (15 minutes).fwdarw.pH 4.0 (15 minutes).fwdarw.pH 6.8 (30 minutes)

[0082] 6) Cell size: 22.4 mm

HPLC Analysis Condition

[0083] 1) Detector: UV spectrophotometer (measurement wavelength: 302 nm)

[0084] 2) Column: Capcell Pak C18 (4.6×150 mm, 5 μm) or a column equivalent thereto

[0085] 3) Injection amount: 20 μL

[0086] 4) Flow rate: 1.0 mL/min

[0087] 5) Column temperature: constant temperature near 30° C.

[0088] 6) Sample temperature: constant temperature near 10° C.

[0089] 7) Mobile phase: a mixture of acetonitrile, a buffer solution at pH 7.3*, and water (350:500:150) [0090] 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.

[0091] The results of the dissolution test, and the results of esomeprazole concentration (ng/mL) and the pH change of the solution are shown in Table 1 below and FIGS. 1 to 3.

TABLE-US-00001 TABLE 1 (Concentration ng/mL) Time Example 1 Example 3 Example 4 (min) Concentration pH Concentration pH Concentration pH 0 0 0 0 0 0 0 2.5 202.78 5.5 295.72 4.1 231.61 4.3 5.0 406.47 7.4 636.09 6.9 318.06 8.6 7.5 562.32 7.1 586.48 6.9 309.97 7 10.0 784.79 6.8 554.86 6.8 293.27 6.8 12.5 675.5 6.6 493.97 6.6 283.83 6.6 15.0 590.3 6.5 439.15 6.5 277.46 6.5 20.0 449.34 6 302.99 6 247.03 5.9 25.0 265.89 4.4 116.18 4.4 219.63 4.4 30.0 161.48 4.9 41.49 4.9 151.57 4.9 35.0 107.6 4.9 24.4 4.7 58.18 4.9 40.0 68.28 4.7 27.32 4.8 20.85 4.9 45.0 64.06 4.9 39.93 4.9 12.33 4.9 50.0 43.81 4.7 39.44 4.5 13.8 4.7 55.0 26.08 4.4 37.29 4.4 20.13 4.5 60.0 21.33 4.3 37.31 4.2 19.9 4.3

[0092] As shows in Table 1 above and FIGS. 1 to 3, it was confirmed that, in the tablets of Examples 1, 3 and 4, the time to reach the highest concentration of esomeprazole was about 10 minutes (Example 1), about 5 minutes (Example 3), and about 5 minutes (Example 4), respectively, and the time to reach a pH of 6.5 was all less than 5 minutes. Therefore, in the tablets of Examples 1 to 3, it was confirmed that the ratio of the time for the solution to reach a pH of 6.5 with respect to the time to reach the highest concentration of omeprazole was all less than 1.

[0093] However, it was confirmed that the maximum esomeprazole concentration was the highest in Example 1. This is due to the properties of esomeprazole that is easily degraded under acidic conditions, and it can be seen that a tablet having the release pattern, in which sodium bicarbonate is first released, and esomeprazole is rapidly released after the gastric acid is neutralized, will exhibit the most excellent drug efficacy. Therefore, it can be seen that the tablet of Example 1 first reached a pH of 6.5 between 2.5 and 5.0 minutes after administration, and reached the maximum esomeprazole concentration after 10 minutes, and thus exhibited the most excellent release pattern.

[0094] As a result, sodium bicarbonate should be rapidly disintegrated, and even in this case, sodium bicarbonate is disintegrated, and esomeprazole is released after a certain period of time to reach the maximum concentration, thereby exhibiting excellent effects.

Test Example 2

Results of Clinical Trial of a Combination of Esomeprazole and Sodium Bicarbonate

[0095] In order to compare and evaluate the pharmacokinetic and pharmacodynamic properties and safety after the single administration and the repeated administration of the tablets of Example 1 (20 mg of esomeprazole/800 mg of sodium bicarbonate) and Nexium tablets (D027 20 mg) to healthy adults, the clinical trial was performed in a randomized, open-labeled, repeated administration, 2×2 crossover design as shown in Table 2 below.

TABLE-US-00002 TABLE 2 Number of Group subjects Period 1 Period 2 Washout A 20 T R at least 7 days or more B 20 R T at least 7 days or more T: 1 tablet of Example 1, repeated orally administered once a day for 7 days under fasting conditions R: 1 tablet of D027 20 mg, repeated orally administered once a day for 7 days under fasting conditions

[0096] All subjects were supposed to take the investigational drug (R or T) at the same time in the morning, about 1 hour later, start the given standard meal (700-800 kcal, containing 5-25% fat), and end the meal within 20 minutes.

[0097] Subjects were subjected to baseline pH monitoring for 24 hours in Period 1, and then administered with the investigational drug once a day for a total of 7 days according to the each assigned group from the first day of Period 1. All subjects were supposed to start the given standard meal about 1 hour after administration of the investigational drug and end the meal within 20 minutes.

[0098] The pH monitoring and pharmacokinetic blood collection for 24 hours after the single administration were performed on the first day of Period 1, and the pH monitoring and pharmacokinetic blood collection for 24 hours after the repeated administration were performed on the 7th day of Period 1, and all subjects were discharged on the 8th day. After the last dose of Period 1, subjects were subjected to washout for 7 days or more, and then were hospitalized again, and Period 2 of clinical trial was performed.

[0099] After the single administration and after the repeated administration, the average pH value in minutes is shown in FIGS. 4 and 5. As shows in FIG. 4, it was confirmed that the pH increased from about 30 minutes after the single dose of the tablet of Example 1, whereas the pH increased from 1 hour after the single dose of the reference drug.

[0100] In addition, as shows in FIG. 5, it was confirmed that the pH increased from about 20 minutes after the repeated dose of the tablet of Example 1, whereas the pH gradually increased from 30 minutes after the repeated dose of the reference drug.

[0101] As a result, as confirmed in Test Example 1, it can be seen that the tablet of Example 1 rapidly raises the pH in the stomach when administered.

Test Example 3

Comparative Dissolution Rate Test According to Content of Sodium Bicarbonate in Esomeprazole Granules

[0102] The following test was performed to confirm the appropriate % by weight of sodium bicarbonate comprised in esomeprazole granules.

[0103] According to the preparation method of Example 3 above, the tablets of Examples 5 to 10 were prepared, but in step <1. mixing> of Example 3, when preparing esomeprazole granules, the tablets comprising 0, 10, 30, 40, 50 and 75% by weight of sodium bicarbonate based on the weight (800 mg) of sodium bicarbonate of the whole tablet were prepared. A dissolution test was performed on the tablets of Examples 5 to 10 prepared above, and the dissolution test and analysis conditions are as follows.

Dissolution Test Condition

[0104] 1) Dissolution method: the Korean Pharmacopoeia, General tests, Dissolution test, Method 3 (Flow Through Cell Method)

[0105] 2) Dissolution medium: pH 1.2.fwdarw.pH 4.0

[0106] 3) Dissolution temperature: 37±0.5° C.

[0107] 4) Flow rate: 2 mL/min

[0108] 5) Test time: pH 1.2 (15 minutes).fwdarw.pH 4.0 (30 minutes)

[0109] 6) Cell size: 22.4 mm

HPLC Analysis Condition

[0110] 1) Detector: UV spectrophotometer (measurement wavelength: 302 nm)

[0111] 2) Column: Capcell Pak C18 (4.6×150 mm, 5 μm) or a column equivalent thereto

[0112] 3) Injection amount: 20 μL

[0113] 4) Flow rate: 1.0 mL/min

[0114] 5) Column temperature: constant temperature near 30° C.

[0115] 6) Sample temperature: constant temperature near 10° C.

[0116] 7) Mobile phase: a mixture of acetonitrile, a buffer solution at pH 7.3*, and water (350:500:150) [0117] 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.

[0118] The results of the dissolution test are shown in Table 3, and FIGS. 6 and 7.

TABLE-US-00003 TABLE 3 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 % by weight of sodium 0 10 30 40 50 75 bicarbonate in granules % by weight of sodium 100 90 70 60 50 25 bicarbonate in post mixing Esomeprazole 5 minutes 1.00 1.00 0.96 0.96 0.92 0.91 concentration* 10 minutes 0.80 0.79 0.70 0.79 0.60 0.64 15 minutes 0.58 0.58 0.54 0.57 0.30 0.27 30 minutes 0.14 0.14 0.19 0.11 0.02 0.02 45 minutes 0.05 0.05 0.07 0.02 0.00 0.00 AUC 16.29 16.24 16.15 15.07 9.89 9.84 a/b** 1.00 1.00 0.99 0.93 0.61 0.61 *The concentration of esomeprazole is expressed as a ratio of the dissolution rate (ng/mL) at each time point with respect to the dissolution rate (ng/mL) at 5 minutes of the tablet of Example 5. **b is the AUC (area under the curve) of the dissolution rate of Example 5, and a represents the AUC of each of Examples 5 to 10.

[0119] As shown in Table 3 above, it was confirmed that the AUC was reduced in Examples 8 to 10 comprising more than 30% by weight of sodium bicarbonate in the granules based on the weight (800 mg) of sodium bicarbonate of the whole tablet. Therefore, it can be seen that it is suitable to use 30% by weight or less of sodium bicarbonate inside the granules based on the weight (800 mg) of sodium bicarbonate of the whole tablet.