PHARMACEUTICAL COMPOSITION COMPRISING ESOMEPRAZOLE AND SODIUM BICARBONATE HAVING EXCELLENT RELEASE PROPERTIES

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, wherein a first mixed part comprising esomeprazole comprises 40% by weight or less of sodium bicarbonate based on the total weight of sodium bicarbonate comprised in the preparation, and thus sodium bicarbonate is first dissolved so as to raise pH, and then esomeprazole 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 a first mixed part comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof; and a second mixed part comprising sodium bicarbonate, characterized in that the first mixed part comprises 40% by weight or less of sodium bicarbonate based on the total weight of sodium bicarbonate comprised in the preparation, 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 first mixed part 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 first mixed part and the second mixed part are powders, granules, microgranules, beads, microcapsules, pellets, tablets, or any combination thereof.

4. The immediate release pharmaceutical preparation according to claim 1, characterized in that when the preparation is dissolved in water, 80% of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is dissolved within 1 hour.

5. The immediate release pharmaceutical preparation according to claim 4, characterized in that 90% of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is dissolved within 1 hour.

6. The immediate release pharmaceutical preparation according to claim 4, characterized in that 80% of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof is dissolved within 45 minutes.

7. The pharmaceutical preparation according to claim 1, characterized in that the pH in the stomach increases within 60 minutes after the single administration of the preparation.

8. The pharmaceutical preparation according to claim 7, characterized in that the pH in the stomach increases within 45 minutes after the single administration of the preparation.

9. The pharmaceutical preparation according to claim 1, characterized in that the pH in the stomach increases within 30 minutes after the repeated administration of the preparation.

10. The pharmaceutical preparation according to claim 9, characterized in that the pH in the stomach increases within 25 minutes after the repeated administration of the preparation.

11. The pharmaceutical preparation according to claim 1, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof upon the single administration of the preparation is within 1.5 hours.

12. The pharmaceutical preparation according to claim 11, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof upon the single administration of the preparation is within 1 hour.

13. The pharmaceutical preparation according to claim 1, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof upon the repeated administration of the preparation is within 1.25 hours.

14. The pharmaceutical preparation according to claim 13, characterized in that the time to reach the highest concentration of the omeprazole, the enantiomer thereof or the pharmaceutically acceptable salt thereof upon the repeated administration of the preparation is within 1 hour.

15. The pharmaceutical preparation according to claim 1, characterized in that the time to maintain the pH in the stomach of 4 or less upon the administration of the preparation is reduced by 30% or more.

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

17. 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.

18. 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.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0062] FIG. 1 is a graph showing the average pH value in the stomach after the single administration of the preparation of Example 1 and the reference drug.

[0063] FIG. 2 is a graph showing the average pH value in the stomach after the repeated administration of the preparation of Example 1 and the reference drug.

DETAILED DESCRIPTION FOR CARRYING OUT THE INVENTION

[0064] Hereinafter, the embodiments and examples of the present application will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art to which the present invention belongs may easily practice the present invention. However, the present application can be implemented in various forms and is not limited to the embodiments and examples described herein.

[0065] Throughout the specification of the present application, unless otherwise stated, when a certain part “comprises” a certain constituent element, it means that the certain part may further comprise other constituent elements rather than exclude other constituent elements.

[0066] As used herein, the term “multi-layered tablet” refers to a preparation consisting of several layers, and includes a laminated structure in which one side of one layer is in contact with one side of another layer and a surrounded structure in which all sides of one layer is in contact with another layer, but is not limited thereto. In the multi-layered tablet, one ingredient is not necessarily included in only one layer, and each layer may be prepared in two, three or more layers in a flat shape or a spherical shape.

[0067] As used herein, the term “nucleated tablet” refers to a preparation in the form of surrounding one preparation with another preparation. In this case, one ingredient is not necessarily included in only one layer.

[0068] Hereinafter, the present invention is to be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Examples 1 to 11: Preparation of Combination Preparation of Esomeprazole and Sodium Bicarbonate

Example 1

[0069] The preparation of Example 1 was prepared according to the following preparation method.

[0070] 1. Preparation of First Mixed Part (Pellet)

[0071] 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 prepare a first mixed part.

[0072] 2. Coating of First Mixed Part

[0073] 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 coated product of the first mixed part was added to a fluidized bed coating machine, and the second coating solution was sprayed to coat the first mixed part.

[0074] 3. Preparation of Second Mixed Part (Simple Mixing)

[0075] The coated first mixed part 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 and mixed to form the second mixed part (a part excluding the first mixed part) together with sodium bicarbonate to obtain a final mixture.

[0076] 4. Tableting

[0077] The final mixture was tableted by a tablet press machine (uncoated tablet).

[0078] 5. Coating

[0079] 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

[0080] The preparation of Example 2 was prepared in the same manner as in Example 1, except that the following wet granulation process was used instead of simple mixing in the preparation process of the second mixed part of step 3 in the preparation method of Example 1 above.

[0081] 3. Preparation of Second Mixed Part (Wet Granulation) and Mixing

[0082] 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 wet granules of a second mixed part. Thereafter, the first mixed part and the second mixed part were added to a mixing machine, and copovidone, crospovidone, and sodium stearyl fumarate were added and mixed (final mixture).

Example 3

[0083] The preparation of Example 3 (20 mg to 40 mg of esomeprazole, 800 mg of sodium bicarbonate) was prepared according to the following preparation method.

[0084] 1. Mixing

[0085] Esomeprazole magnesium trihydrate and microcrystalline cellulose were added and mixed by a High Speed Mixer.

[0086] 2. Preparation of First Mixed Part (Wet Granulation)

[0087] Hydroxypropyl cellulose was added and dissolved in purified water to prepare a binder solution. The binder solution was added to the mixture, kneaded, and dried to prepare wet granules of the first mixed part.

[0088] 3. Preparation of Second Mixed Part, Mixing and Lubricating

[0089] The wet granules of the first mixed part, 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. In this case, a part excluding the first mixed part forms a second mixed part.

[0090] 4. Tableting and Coating

[0091] 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

[0092] The preparation of Example 4 (20 mg to 40 mg of esomeprazole, 800 mg of sodium bicarbonate) was prepared according to the following preparation method.

[0093] 1. Mixing and Lubricating

[0094] 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.

[0095] 2. Preparation of First Mixed Part (Dry Granulation)

[0096] The mixture was slugged by a slugging machine to prepare a first mixed part.

[0097] 3. Preparation of Second Mixed Part, Mixing, and Lubricating

[0098] The first mixed part, sodium bicarbonate, copovidone and crospovidone were added and mixed, and then sodium stearyl fumarate was added and lubricated to prepare a final mixture. In this case, a part excluding the first mixed part forms a second mixed part.

[0099] 4. Tableting and Coating

[0100] 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.

Example 5

[0101] 1. Preparation of First Mixed Part

[0102] Esomeprazole magnesium trihydrate, mannitol, copovidone, crospovidone, and sodium stearyl fumarate were uniformly mixed to prepare a first mixed part.

[0103] 2. Preparation of Second Mixed Part

[0104] Sodium bicarbonate, copovidone, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate were uniformly mixed to prepare a second mixed part.

[0105] 3. Tableting

[0106] The first mixed part and the second mixed part were tableted by a tablet press machine (uncoated tablet).

[0107] 4. Coating

[0108] 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.

Examples 6 and 7

[0109] The preparations of Examples 6 and 7 were prepared according to the preparation method of Example 5 above, except that in the preparation process of the first mixed part of step 1 in the preparation method, sodium bicarbonate was further mixed to allow sodium bicarbonate to be included in a first mixed part and a second mixed part. The first mixed part of Examples 6 and 7 comprised 5 and 10% by weight of sodium bicarbonate based on the weight (800 mg) of sodium bicarbonate of the whole preparation, respectively.

Examples 8 to 12

[0110] The preparations of Examples 8 to 12 were prepared according to the preparation method of Example 3 above, except that in the mixing process of step 1 in the preparation method, sodium bicarbonate was further mixed to allow sodium bicarbonate to be included in a first mixed part and a second mixed part. The first mixed part of the preparations of Examples 8 to 12 comprised 10, 30, 40, 50 and 75% by weight of sodium bicarbonate based on the weight (800 mg) of sodium bicarbonate of the whole preparation, respectively.

Test Example 1

[0111] Comparative Dissolution Rate Test According to Content of Sodium Bicarbonate in First Mixed Part

[0112] The following test was performed to confirm the change in the dissolution rate and AUC of the preparations according to the formulation, and to confirm the content of sodium bicarbonate in the first mixed part exhibiting excellent dissolution rate and AUC.

[0113] The dissolution test was performed on the preparations of Examples 1, 3 and 8 to 12 (20 mg of esomeprazole/800 mg of sodium bicarbonate) prepared above, and the dissolution test and analysis conditions are as follows.

[0114] <Dissolution Test Condition>

[0115] 1) Dissolution method: the Korean Pharmacopoeia, General tests, Dissolution test, Method 3 (Flow Through Cell Method)

[0116] 2) Dissolution medium: pH 1.2.fwdarw.pH 4.0

[0117] 3) Dissolution temperature: 37±0.5° C.

[0118] 4) Flow rate: 2 m/min

[0119] 5) Test time: pH 1.2 (15 minutes).fwdarw.pH 4.0 (15 minutes)

[0120] 6) Cell size: 22.4 mm

[0121] <HPLC Analysis Condition>

[0122] 1) Detector: UV spectrophotometer (measurement wavelength: 302 nm)

[0123] 2) Column: Capcell Pak C18 (4.6×150 mm, 5 μm) or a column equivalent thereto

[0124] 3) Injection amount: 20 μL

[0125] 4) Flow rate: 1.0 m/min

[0126] 5) Column temperature: constant temperature near 30° C.

[0127] 6) Sample temperature: constant temperature near 10° C.

[0128] 7) Mobile phase: a mixture of acetonitrile, a buffer solution at pH 7.3*, and water (350:500:150)

[0129] * 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.

[0130] The results of the dissolution test are shown in Table 1.

TABLE-US-00001 TABLE 1 Example 1 3 8 9 10 11 12 % by weight of 0 0 10 30 40 50 75 sodium bicarbonate in first mixed part % by weight of 100 100 90 70 60 50 25 sodium bicarbonate in second mixed part *Esomeprazole  5 minutes 0.52 1.00 1.00 0.96 0.96 0.92 0.91 concentration 10 minutes 1 0.80 0.79 0.70 0.79 0.60 0.64 15 minutes 0.75 0.58 0.58 0.54 0.57 0.30 0.27 30 minutes 0.21 0.14 0.14 0.19 0.11 0.02 0.02 AUC 15.76 15.05 15.00 14.63 14.33 9.76 9.70 T/R ** 1 0.95 0.95 0.93 0.91 0.62 0.62 *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 10 minutes of the preparation of Example 1. ** R is the AUC of the preparation of Example 1, and T represents the AUC of the preparation of each Example.

[0131] As shown in Table 1 above, it was confirmed that the AUC and dissolution rate were reduced as the content of sodium bicarbonate in the first mixed part increased based on the weight (800 mg) of sodium bicarbonate of the whole preparation.

[0132] In particular, it was confirmed that in Examples 11 and 12 comprising sodium bicarbonate in the content of 50% and 75% in the first mixed part based on the weight (800 mg) of sodium bicarbonate of the whole preparation, respectively, the AUC and the dissolution rate were rapidly reduced.

[0133] Therefore, it can be seen that it is suitable to use 40% by weight or less of sodium bicarbonate in the first mixed part based on the weight (800 mg) of sodium bicarbonate of the whole preparation.

Test Example 2

[0134] Clinical Trial of Combination of Esomeprazole and Sodium Bicarbonate—Measurement of Tmax

[0135] In order to compare and evaluate the pharmacokinetic and pharmacodynamic properties and safety after the single administration and the repeated administration of the preparation of Example 1 (20 mg or 40 mg of esomeprazole/800 mg of sodium bicarbonate) and Nexium tablets (D027 20 mg or 40 mg) as the reference drug 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 Numberof 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 the preparation of Example 1, repeated orally administered once a day for 7 days under fasting conditions R: 1 tablet of D027, repeated orally administered once a day for 7 days under fasting conditions

[0136] The clinical trials for the preparation of Example 1 of 20 mg of esomeprazole and the reference drug of 20 mg were performed separately from the preparation of Example 1 of 40 mg of esomeprazole and the reference drug of 40 mg.

[0137] 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.

[0138] 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.

[0139] 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. In Period 2 of clinical trial, Subjects were subjected to baseline pH monitoring for 24 hours in the same manner as in Period 1, and then administered with the investigational drug once a day for a total of 7 days according to the assigned group from the first day of Period 2. However, unlike Period 1, the subjects of Group A were administered with the reference drug and the subjects of Group B were administered with the preparation of Example 1 at a certain time, and were supposed to start the given standard meal about 1 hour after administration and end the meal within 20 minutes.

[0140] In order to compare the pharmacokinetic properties of the preparation of Example 1 and the reference drug, the pharmacokinetic blood collection after the single administration was performed on the first day of each of Period 1 and Period 2, and the pharmacokinetic blood collection after the repeated administration was performed on the 7th day of each of Period 1 and Period 2, just before administration and 0.17 (=10 min), 0.33 (=20 min), 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12 h (18 times for each period) after administration. The concentration of esomeprazole in plasma isolated from the collected blood was measured to analyze the median value (minimum value, maximum value) of the time to reach the highest blood concentration (T.sub.max), and the results are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Tmax (h) Single Repeated Dose Example 1 D026 Example 1 D026 20/800 mg 0.50 1.50 0.75 1.25 (0.33, 1.25) (1.00, 4.00) (0.33, 1.50) (0.75, 5.00) 40/800 mg 0.50 1.50 0.75 1.25 (0.33, 1.25) (1.25, 4.83) (0.33, 2) (0.75, 4.83)

[0141] The time to reach the highest blood concentration of the preparation of Example 1 was much shorter than that of the reference drug in case of both of the single administration and the repeated administration of 20 mg and 40 mg doses. Thus, it was confirmed that the preparation of Example 1 can exhibit rapid drug efficacy by rapidly releasing esomeprazole.

Test Example 3

[0142] Results of Clinical Trial of Combination of Esomeprazole and Sodium Bicarbonate—Measurement of pH in the Stomach

[0143] In the above clinical trial, the pH in the stomach was measured through pH monitoring for 24 hours. The pH monitoring for 24 hours after the single administration was performed on the first day of each of Period 1 and Period 2, and the pH monitoring for 24 hours after the repeated administration was performed on the 7th day of each of Period 1 and Period 2, and the measurement of the pH in the stomach used MMS Ohmega R pH. The catheter of pH meter was calibrated using a standard solution, and only the catheter and pH test instrument successfully calibrated were prepared to be used for the test of the pH in the stomach for 24 hours. Thereafter, the catheter was sufficiently moistened with lubricating gel or water to reduce foreign body sensation, and then inserted into the stomach through the nasal cavity to measure the pH.

[0144] After the single administration and after the repeated administration, the average value of the pH in minutes is shown in FIGS. 1 and 2. As shown in FIG. 1, it was confirmed that for the preparation of Example 1, the pH increased from about 30 minutes after the single dose, whereas for the reference drug, the pH increased from 1 hour after the single dose.

[0145] In addition, as shown in FIG. 2, it was confirmed that for the preparation of Example 1, the pH increased from about 20 minutes after the repeated dose, whereas for the reference drug, the pH gradually increased from 30 minutes after the repeated dose.

[0146] As a result, it can be seen that the preparation of Example 1 rapidly raises the pH in the stomach when administered.

Test Example 4

[0147] Results of Clinical Trial of Combination of Esomeprazole and Sodium Bicarbonate—Measurement of pH in the Stomach

[0148] According to Test Example 3 above, the fraction (%) of the time to maintain pH≤4 of the pH in the stomach observed for 24 hours after the administration of each investigational drug was measured, and the difference compared to the fraction (%) of the time to maintain pH≤4 of the pH in the stomach observed for 24 hours before the administration of the drug was measured. The results are shown in Table 4 below.

TABLE-US-00004 TABLE 4 Dose Single Repeated 20/800 mg 36.85% 49.98% 40/800 mg 54.36% 65.81%

[0149] It was confirmed that the time to maintain the pH in the stomach of 4 or less upon the administration of the preparation of Example 1 was reduced.

Test Example 5

[0150] Esomeprazole Dissolution Test

[0151] For the tablet of Example 1, the dissolution test was performed in water according to the Korean Pharmacopoeia, General tests, Dissolution test, Paddle method, Method 2 (50 rpm, 900 mL), and the analysis conditions are as follows.

[0152] <Analysis condition>

[0153] 1) Detector: UV spectrophotometer (measurement wavelength: 302 nm)

[0154] 2) Column: Waters BEH C.sub.18 (2.1×50 mm, 1.7 μm)

[0155] 3) Column temperature: constant temperature near 30° C.

[0156] 4) Sample temperature: constant temperature near 10° C.

[0157] 5) Injection amount: 5 μL

[0158] 6) Flow rate: 0.3 m/min

[0159] 7) Mobile phase: a mixture of a buffer solution at pH 7.3* and acetonitrile (60:40)

[0160] * 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.

[0161] The results of the dissolution test are shown in Table 5.

TABLE-US-00005 TABLE 5 Average dissolution rate (%) (mean ± standard deviation) Test Test 5 10 15 30 45 60 solution group minutes minutes minutes minutes minutes minutes Water Example 1 3.1 ± 0.8 17.6 ± 3.5 38.7 ± 8.4 75.2 ± 7.4 87.8 ± 4 93.3 ± 1.8

[0162] As described above, it was confirmed that the preparation of Example 1 dissolves 90% or more of esomeprazole within 1 hour and 80% or more of esomeprazole within 45 minutes even in water to show the dissolution pattern of immediate release, and thus can exhibit rapid drug efficacy by rapidly releasing esomeprazole.