WO2022050670A1

WO2022050670A1 - Pharmaceutical compositions in a tablet form comprising omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof and processes for preparing the same

Info

Publication number: WO2022050670A1
Application number: PCT/KR2021/011714
Authority: WO
Inventors: Ji-Hyuk YU; Jong-Yeon Kim; Mi-Sun Park; Hyeon-Soo YANG; Yoo-Sang JOO; Tae-Won Lee
Original assignee: Yuhan Corporation; Addpharma Inc.
Priority date: 2020-09-04
Filing date: 2021-09-01
Publication date: 2022-03-10
Also published as: TW202227066A; KR102276547B1

Abstract

The present invention provides a pharmaceutical composition in a tablet form, comprising a mixture of omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof and calcium carbonate, the pharmaceutical composition of which is rapidly disintegrating in the stomach; and a method for preparing the same. Since the pharmaceutical composition of the present invention can be prepared by avoiding performing the step for coating granules/pellets during the manufacture thereof, the process for the preparation thereof is simple and thus can be easily applied at production sites. And, the pharmaceutical composition according to the present invention shows rapid disintegration, thereby being able to accomplish rapid absorption of the drug. In addition, the calcium carbonate contained in the pharmaceutical composition of the present invention exhibits potent antacid activity (i.e., potent neutralizing activity against acid), which makes it possible to induce a rapid pH increase, as well as to reduce the formulation size by minimizing the amount of calcium carbonate.

Description

PHARMACEUTICAL COMPOSITIONS IN A TABLET FORM COMPRISING OMEPRAZOLE, ESOMEPRAZOLE, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PROCESSES FOR PREPARING THE SAME

The present invention relates to a pharmaceutical composition in the form of a tablet comprising a mixture of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate, which is rapidly disintegrated in the stomach, and a process for preparing the same.

Omeprazole, whose chemical name is 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole, is one of the proton pump inhibitors (PPIs). Esomeprazole (or (S)-(-)-omeprazole) is the enantiomer of omeprazole. Omeprazole or esomeprazole is clinically used in a salt form, e.g., in the form of a magnesium salt. For example, esomeprazole is used in the form of esomeprazole magnesium trihydrate. Omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof (including the hydrates thereof, e.g., the trihydrate thereof) is used as an antiulcer agent that inhibits the acid secretion, through inhibition of H+/K+-ATPase, in gastric parietal cells.

Omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof shows very excellent effects in suppressing gastric acid secretion, but is known to be very unstable to water, heat, and acid. In particular, it is known that, when omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof is orally administered, it is rapidly decomposed by gastric acid and thus hardly absorbed. In order to prevent the decomposition by gastric acid, omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof is marketed in the form of a formulation that minimizes the decomposition by gastric acid, through using technologies such as enteric coating tablets or enteric-coated pellets (e.g., Nexium Tab. 20 mg, 40 mg, AstraZeneca).

Meanwhile, when the formulations obtained by using technologies such as enteric coating tablets or enteric-coated pellets are orally administered, those pass through the stomach and release the drug in the intestine, thereby significantly delaying the onset of the efficacy thereof. In order to solve such disadvantages, other active ingredients capable of providing a fast-onset efficacy, in addition to PPIs such as omeprazole or esomeprazole, have been used in combination; or combination formulations of a PPI and an antacid such as sodium bicarbonate have been developed.

As an example of such combination formulations, Korean Patent No. 10-2080023 has disclosed a tablet comprising a magnesium salt of esomeprazole and sodium bicarbonate, wherein the magnesium salt of esomeprazole is present in 20 mg or 40 mg based on the weight of esomeprazole; the sodium bicarbonate is present in 800 mg; the magnesium salt of esomeprazole is in the form of pellets or granules; and the pellets or granules do not comprise sodium bicarbonate and are coated with a coating agent. And, Korean Patent No. 10-2006777 has disclosed a pharmaceutical formulation comprising a first layer, a second layer surrounding the first layer, and a third layer surrounding the second layer; the first layer comprising omeprazole, its enantiomer, or its pharmaceutically acceptable salt; the second layer comprising polyvinyl alcohol as a coating agent; and the third layer comprising sodium bicarbonate as an antacid. In addition, Korean Laid-Open Patent Publication No. 10-2020-0023185 has disclosed a pharmaceutical formulation designed so that, when the formulation is dissolved in a solution, sodium bicarbonate is released before omeprazole, its enantiomer, or a pharmaceutically acceptable salt thereof is released. The formulations disclosed in Korean Patent No. 10-2080023, Korean Patent No. 10-2006777, and Korean Laid-Open Patent Publication No. 10-2020-0023185 are the formulation designed to release esomeprazole after gastric acid is neutralized by sodium bicarbonate (i.e., after the neutralization of gastric acid through the acid-base neutralization between gastric acid and sodium bicarbonate).

However, since the formulations disclosed in Korean Patent No. 10-2080023, Korean Patent No. 10-2006777, and Korean Laid-Open Patent Publication No. 10-2020-0023185 contain sodium bicarbonate in a relatively high amount (800 mg), the size of the tablets increases, which may bring about difficulty in elderly patients' taking. And, sodium bicarbonate rapidly releases a large amount of CO₂ gas through the neutralization of gastric acid, which may bring about reflux of gastric juice; increase in gastric acid secretion according gastric mucosa stimulation (i.e., acid rebound); and side effects caused by excessive sodium intake, such as electrolyte imbalance in the body, high blood pressure, heart failure, kidney failure, and the like. Especially, the formulations disclosed in Korean Patent Nos. 10-2080023 and/or 10-2006777 are obtained through carrying out the step for preparing pellets or granules and then the step for coating the pellets or granules with a coating agent (e.g., polyvinyl alcohol), in order to solve the stability problems caused by sodium bicarbonate (i.e., the decrease in stability of the magnesium salt esomeprazole by sodium bicarbonate). Therefore, the processes for the preparation thereof are complicated and thus are difficult to apply at production sites.

The present inventors carried out various studies to develop a formulation capable of solving the disadvantages of a formulation containing omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and sodium bicarbonate, especially a formulation capable of avoiding performing the coating processes of granules/pellets. The present inventors have performed various compatibility evaluations, and surprisingly found that, when stability evaluations on various combinations were carried out in the stress condition, the degradation products derived from the mixture of calcium carbonate and esomeprazole magnesium trihydrate was significantly reduced, in comparison with those derived from the mixture of sodium bicarbonate and esomeprazole magnesium trihydrate. That is, the present inventors have found that, when calcium carbonate is used as an antacid, it is possible to avoid performing the coating processes of granules/pellets which should be performed in the preparation of conventional formulations (the formulations comprising sodium bicarbonate and esomeprazole magnesium trihydrate). Especially, the present inventors have found that, when a formulation process is carried out using calcium carbonate instead of sodium bicarbonate, the resulting formulation shows rapid disintegration, thereby being able to accomplish rapid absorption of the drug. In addition, the present inventors have found that calcium carbonate exhibits potent antacid activity (i.e., potent neutralizing activity against acid) compared to sodium bicarbonate, which makes it possible to induce a rapid pH increase, as well as to reduce the formulation size by minimizing the amount of calcium carbonate.

Therefore, it is an object of the present invention to provide a pharmaceutical composition in the form of a tablet comprising a mixture of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate, which is rapidly disintegrated in the stomach.

It is another object of the present invention to provide a process for preparing said pharmaceutical composition in the form of a tablet.

In accordance with an aspect of the present invention, there is provided a pharmaceutical composition in a tablet form, comprising a mixture of omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof and calcium carbonate, wherein the pharmaceutical composition is disintegrated within 30 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.

In accordance with another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition in a tablet form, the process of which comprises:

(a) preparing a binder solution comprising a surfactant and a binder;

(b) preparing a mixture of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof; calcium carbonate; a diluent; and a disintegrating agent,

(c) granulating the mixture prepared in step (b) using the binder solution prepared in step (a), and

(d) mixing the granules obtained in step (c) with a lubricant or a mixture of a lubricant and a disintegrating agent, and then compressing the resulting mixture.

It has been found by the present invention that a mixture of calcium carbonate and omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof (e.g., esomeprazole magnesium trihydrate) can significantly reduce the generation of degradation products, compared to a mixture of sodium bicarbonate and esomeprazole magnesium trihydrate. Therefore, since the pharmaceutical composition of the present invention can be prepared by avoiding performing the step for coating granules/pellets during the manufacture thereof, the process for the preparation thereof is simple and thus can be easily applied at production sites. Also, the pharmaceutical composition according to the present invention shows rapid disintegration, thereby being able to accomplish rapid absorption of the drug. In addition, the calcium carbonate contained in the pharmaceutical composition of the present invention exhibits potent antacid activity (i.e., potent neutralizing activity against acid), which makes it possible to induce a rapid pH increase, as well as to minimize the amount of calcium carbonate. Therefore, the pharmaceutical composition of the present invention can reduce the formulation size, minimize acid rebound due to the release of CO₂ gas, and fundamentally avoid the occurrence of side effects due to excessive sodium intake.

The present invention provides a pharmaceutical composition in a tablet form, comprising a mixture of omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof and calcium carbonate, wherein the pharmaceutical composition is disintegrated within 30 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.

Omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, respectively. For example, omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof may be present in an amount ranging from 10 mg to 80 mg per unit tablet, but not limited thereto. In an embodiment, esomeprazole may be present in an amount of 20 mg or 40 mg per unit tablet. In another embodiment, esomeprazole magnesium trihydrate may be present in an amount of 22.3 mg or 44.5 mg per unit tablet.

It has been found by the present invention that, when formulation processes are performed by using the mixture of calcium carbonate and omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof (e.g., esomeprazole magnesium trihydrate), the generation of degradation products therefrom can be significantly reduced, in comparison with the formulation processes performed by using the mixture of sodium bicarbonate and esomeprazole magnesium trihydrate. As used herein, e.g., the expression 'the mixture of calcium carbonate and esomeprazole or a pharmaceutically acceptable salt thereof' refers to a mixture in which esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate (if necessary, together with a pharmaceutically acceptable excipient) are mixed each other through direct contact. Therefore, since the pharmaceutical composition of the present invention can be prepared by avoiding performing the step for coating granules/pellets during the manufacture thereof, the process for the preparation thereof is simple and thus can be easily applied at production sites. And, the pharmaceutical composition comprising calcium carbonate as an antacid according to the present invention shows rapid disintegration, thereby being able to accomplish rapid absorption of the drug. In addition, the calcium carbonate contained in the pharmaceutical composition of the present invention exhibits potent antacid activity (i.e., potent neutralizing activity against acid) compared to sodium bicarbonate, which makes it possible to induce a rapid pH increase, as well as to minimize the amount of calcium carbonate. Therefore, the pharmaceutical composition of the present invention can reduce the formulation size, minimize acid rebound due to the release of CO₂ gas, and fundamentally avoid the occurrence of side effects due to excessive sodium intake. Since calcium carbonate is absorbed, as calcium, only in an amount of 9 to 16%, it can reduce the risk of electrolyte imbalance in the body.

In the pharmaceutical composition of the present invention, calcium carbonate may be present in an amount of at least 500 mg per unit tablet. In order to reduce the tablet size as well as to minimize acid bound due to the release of CO₂ gas, the calcium carbonate may be present preferably in an amount ranging from 500 mg to 700 mg per unit tablet, more preferably in an amount of about 600 mg per unit tablet.

The pharmaceutical composition of the present invention may further comprise an excipient conventionally used in the field of pharmaceutics. That is, the pharmaceutical composition of the present invention may further comprise one or more excipients selected from the group consisting of a diluent, a disintegrating agent, a surfactant, a binder, and a lubricant. The diluent may be one or more selected from the group consisting of lactose, pregelatinized starch, microcrystalline cellulose, D-mannitol, D-sorbitol, and calcium hydrogen phosphate. The disintegrating agent may be one or more selected from the group consisting of sodium starch glycolate, crospovidone, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, and methyl cellulose. The surfactant may be one or more selected from the group consisting of polysorbate, sodium lauryl sulfate, docusate sodium, Poloxamer (a polyoxyethylene-polyoxypropylene block copolymer), meglumine, and sorbitan. The binder may be one or more selected from the group consisting of povidone, hydroxypropyl cellulose, hypromellose, and methyl cellulose. The lubricant may be one or more selected from the group consisting of sodium stearyl fumarate, colloidal silicon dioxide, stearic acid, calcium stearate, magnesium stearate, and glyceryl behenate. In an embodiment, the excipients may be one or more selected from the group consisting of lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, polysorbate 80, povidone, sodium stearyl fumarate, and colloidal silicon dioxide. The excipients such as a diluent, a disintegrating agent, a surfactant, a binder, and a lubricant may be used in an amount conventionally used in the field of pharmaceutics, which may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is rapidly disintegrated in the stomach. Specifically, the pharmaceutical composition of the present invention is disintegrated within 30 minutes in a disintegration test carried out in a pH 1.2 aqueous medium (for example, the First Fluid of the Disintegration Test Method described in the Korean Pharmacopoeia or a mixed solution thereof with water) according to the Korean Pharmacopoeia. In an embodiment, the pharmaceutical composition is disintegrated within 20 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia. In another embodiment, the pharmaceutical composition is disintegrated within 15 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.

If necessary, the pharmaceutical composition in a tablet form according to the present invention may further comprise a conventional coating layer, for example, a film coating layer. The film coating layer may be formed by spray coating a coating solution conventionally used in the field of pharmaceutics [for example, a coating solution prepared by dissolving Opadry^TM 03B62323, sodium hydroxide, polyethylene glycol 6000, talc, etc. in an aqueous solution of ethanol (e.g., 80% to 95% aqueous solution of ethanol)] on the tablet obtained according to the present invention, according to a conventional method, and then drying the resultant.

The present invention includes, within its scope, a process for preparing the pharmaceutical composition of the present invention as described above. The pharmaceutical composition of the present invention may be prepared using omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof, calcium carbonate, and a pharmaceutically acceptable excipient, through a process for preparing a tablet conventionally used in the field of pharmaceutics.

For example, the present invention provides a process for preparing a pharmaceutical composition in a tablet form, the process of which comprises:

(a) preparing a binder solution comprising a surfactant and a binder;

In said process, omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof, calcium carbonate, the diluent, the disintegrating agent, the surfactant, the binder, and the lubricant are the same as those mentioned in relation to the pharmaceutical composition of the present invention. Also, those skilled in the art will recognize that steps (a) and (b) may be performed sequentially or in reverse.

The binder solution of step (a) may be prepared by dissolving a surfactant and a binder in ethanol or an aqueous solution of ethanol (e.g., 80% to 95% aqueous solution of ethanol).

The mixture of step (b) may be prepared by mixing omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof; calcium carbonate; the diluent; and the disintegrating agent, according to a conventional method used in the field of pharmaceutics. The total amount of the disintegrating agent used in the pharmaceutical composition of the present invention may be used in the preparation of the mixture of step (b). Alternatively, a part of the total amount of the disintegrating agent used in the pharmaceutical composition of the present invention may be used in the preparation of the mixture of step (b); and the remaining amount thereof may be used in the preparation of the mixture of step (d) [i.e., in the preparation of the mixture of a lubricant and a disintegrating agent of step (d)]. In this case, the disintegrating agents used in step (b) and step (d) may be different from each other. In an embodiment, the disintegrating agent used in step (b) may be a mixture of sodium starch glycolate and crospovidone, and the disintegrating agent used in step (d) may be crospovidone. In a preferred embodiment, the disintegrating agent used in step (b) may be a mixture of 0.5 to 5 wt% of sodium starch glycolate and 1.0 to 10.0 wt% of crospovidone per unit tablet (i.e., per uncoated tablet); and the disintegrating agent used in step (d) may be 0.5 to 5.0 wt% of crospovidone per unit tablet (i.e., per uncoated tablet).

Step (c) is carried out by granulating the mixture prepared in step (b) using the binder solution prepared in step (a). The granulating may be carried out according to a method conventionally used in the field of pharmaceutics, for example, according to a wet granulation process. The granulating includes drying the obtained wet granules. The drying may be carried out according to a method conventionally used in the field of pharmaceutics. If necessary, step (c) may further comprise sieving the obtained dry granules to have a uniform size.

Step (d) is carried out by mixing the granules obtained in step (c) with a lubricant or a mixture of a lubricant and a disintegrating agent, and then compressing the resulting mixture. The mixing and compressing may be carried out according to a method conventionally used in the field of pharmaceutics. For example, in consideration of the elderly patients' drug compliance, the compressing may be carried out to have a tablet size ranging from about 12 X 6 mm to 17 X 10 mm, but not limited thereto.

If necessary, the process of the present invention may further comprise a step for forming a conventional coating layer, for example, a film coating layer. The step for forming a film coating layer may be carried out through spray coating a coating solution conventionally used in the field of pharmaceutics [for example, a coating solution prepared by dissolving Opadry^TM 03B62323, sodium hydroxide, polyethylene glycol 6000, talc, etc. in an aqueous solution of ethanol (e.g., 80% to 95% aqueous solution of ethanol)] on the tablet obtained in step (d), according to a conventional method, and then drying the resultant.

The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: Compatibility Evaluations

Compatibility Evaluations were carried out using esomeprazole magnesium trihydrate, a mixture of esomeprazole magnesium trihydrate and calcium carbonate, and a mixture of esomeprazole magnesium trihydrate and sodium bicarbonate. For the compatibility evaluation, esomeprazole magnesium trihydrate and the respective mixtures were placed in a tight container, stored in the stress condition (60℃, 80% of relative humidity) for 2 weeks, and then the amounts of esomeprazole magnesium trihydrate and degradation products at the initial stage (at the initiation of the test) and after 2 weeks were respectively analyzed by high performance liquid chromatography (HPLC) under the following conditions.

- Detector: UV-vis spectrometer (wavelength: 302 nm)

- Column: XTerraRP 8 4.6 X 150 mm, 3.5 μm or equivalent column

- Column temperature: about 30℃

- Sample inlet temperature: about 8℃

- Mobile phase A: a pH 9.0 phosphate buffer

- Mobile phase B: a mixture of acetonitrile and methanol (85:15 (v/v))

- Flow rate: 1.0 mL/min

The amounts of esomeprazole and the amount of total degradation products analyzed as described above are shown in the following Table 1.

	Amounts (%)
	Esomeprazole		Total degradation products
	Initial	After 2 weeks	Initial	After 2 weeks
Esomeprazole magnesium trihydrate	102.90	87.32	Below RL	4.78
Esomeprazole magnesium trihydrate + CaCO₃	102.44	97.25	Below RL	2.14
Esomeprazole magnesium trihydrate + NaHCO₃	102.12	72.23	Below RL	9.69

*RL: Reporting Limit

From the results of Table 1, it can be confirmed that the simple mixture of esomeprazole magnesium trihydrate and calcium carbonate may significantly reduce the production of degradation products, in comparison with esomeprazole magnesium trihydrate alone and the mixture of esomeprazole magnesium trihydrate and sodium hydrogen carbonate.

Example 2: Evaluations on antacid activity

The amount of gastric juice on an empty stomach in the human body is known to be about 70 mL (Amount of gastric juice: averaging 51-70 ml /M Feldman, Comparison of acid secretion rates measured by gastric aspiration and by in vivo intragastric titration in healthy human subjects, Gastroenterology, 76: 954-957, 1979). The amount of water consumed when taking a drug is usually 100 to 200 ml. Therefore, the antacid activities of calcium carbonate and sodium bicarbonate were evaluated using a mixture of 100 ml of the artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water. In addition, the antacid activity of almagate, one of the representative antacids, was also evaluated. Specifically, while stirring a mixture of 100 ml of the artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water (300 ml in total) at 250 rpm at room temperature, 300 to 800 mg of calcium carbonate, sodium hydrogen carbonate, and almagate were respectively added thereto. Each pH was measured after 30 minutes. The results are shown in the following Table 2.

	pH
	300 mg	500 mg	600 mg	700 mg	800 mg
NaHCO₃	1.84	2.10	2.36	3.37	5.63
CaCO₃	1.85	4.41	5.68	5.78	6.02
Almagate	2.03	3.89	4.70	5.14	5.60

From the results of Table 2, it can be seen that calcium carbonate shows a significantly higher antacid activity, in comparison with sodium bicarbonate and almagate. Especially, it can be seen that, when the amount of calcium carbonate is 500 mg or more, it shows about twice the antacid activity, compared to sodium bicarbonate.

Example 3: Evaluations of the pH and the amount of esomeprazole, according to the amount of calcium carbonate

While stirring a mixed solution of 100 ml of the artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water (300 ml in total) at 250 rpm at room temperature, calcium carbonate (300 to 700 mg) and esomeprazole (20 mg) were added thereto. Each pH and the amount of esomeprazole were measured after 30 minutes. The amount of esomeprazole was analyzed by high performance liquid chromatography (HPLC) under the same conditions as in Example 1. The results thereof are shown in the following Table 3.

Calcium carbonate (mg)	pH	Amount of esomeprazole (%)	SD (%)
300	2.02	15.14	0.37
500	5.30	95.61	1.16
600	5.85	95.73	1.32
700	5.89	96.02	0.90

As can be seen from the results of Table 3, the use of calcium carbonate in the amount of 500 mg or more exhibited not only the pH of at least 5.0 but also the amount of the active ingredient (i.e., esomeprazole) of at least 95%, indicating excellent stability.

Example 4: Preparation and evaluation of esomeprazole-containing tablets

(1) Preparation of esomeprazole-containing tablets

Tablets comprising esomeprazole magnesium trihydrate were prepared according to the components and amounts shown in Table 4. The amounts of Table 4 represent the weight (mg) per unit tablet. Specifically, a binder solution was prepared by dissolving povidone K30 and polysorbate 80 in ethanol. Esomeprazole magnesium trihydrate, calcium carbonate, a diluent (anhydrous lactose, microcrystalline cellulose and/or pregelatinized starch), and a disintegrating agent (sodium starch glycolate and crospovidone) were placed in a high-speed mixer, followed by mixing with the binder solution prepared above to prepare wet granules. The resulting wet granules were dried at about 60℃ for about 2 hours and then sieved with a 25 mesh sieve. The obtained granules were uniformly mixed with crospovidone and a lubricant (sodium stearyl fumarate and colloidal silicon dioxide), and then compressed to prepare tablets. A coating solution was prepared by adding Opadry^TM 03B62323, sodium hydroxide, polyethylene glycol 6000, and talc to an 80% aqueous solution of ethanol. The above-prepared tablets were placed in a coating machine, followed by spray-coating with the coating solution to prepare film-coated tablets (i.e., the tablets of Formulations 1 to 4). For comparison, the film-coated tablets of Formulation 5 were prepared in the same manner as in Formulation 1 without using calcium carbonate.

Component		Formulation (mg)
Component		1	2	3	4	5
Active ingredient	Esomeprazole magnesium trihydrate	22.3	44.5	22.3	44.5	22.3
Antacid	calcium carbonate	600	600	600	600	-
Diluent	Anhydrous lactose	100	100	-	-	100
	Microcrystalline cellulose	-	-	100	100	-
	Pregelatinized starch	15	15	15	15	15
Disintegrating agent	Sodium starch glycolate	10	10	10	10	10
	Crospovidone (in the granules)	20.0	20.0	20.0	20.0	20.0
	Crospovidone (out of granules)	10.0	10.0	10.0	10.0	10.0
Surfactant	Polysorbate 80	1.7	1.7	1.7	1.7	1.7
Binder	Povidone K30	20	20	20	20	20
Lubricant	Sodium stearyl fumarate	6	6	6	6	6
Lubricant	Colloidal silicon dioxide	5	5	5	5	5
Coating agent	Opadry^TM yellow (03B62323)	26	26	26	26	26
	Sodium hydroxide	4	4	4	4	4
	Polyethylene glycol 6000	5	5	5	5	5
	Talc	5	5	5	5	5

(2) Evaluations of esomeprazole-containing tablets

(2-1) Disintegration tests

Disintegration tests for the tablets of Formulations 1 to 5 and the commercially available enteric-coated tablet of esomeprazole (Nexium Tab. 20 mg, AstraZeneca) were carried out, in the First Fluid (pH 1.2) of Disintegration Test Method and in purified water, according to the Korean Pharmacopoeia. The disintegration times of each tablet were measured and the results thereof are shown in the following Table 5.

	Formulation					Nexium Tab.
	1	2	3	4	5	Nexium Tab.
pH 1.2	3 min 10 sec	3 min 7 sec	3 min 19 sec	3 min 12 sec	5 min 20 sec	Not disintegrated
Purified water	3 min 30 sec	3 min 20 sec	3 min 24 sec	3 min 20 sec	5 min 16 sec	5 min 20 sec

As can be seen from the results of Table 5, Formulations 1 to 4 exhibited the rapid disintegration rates (i.e., within 5 minutes). This indicates that, when the drug is taken, the drug is rapidly disintegrated thereby being able to be rapidly absorbed. The commercially available esomeprazole enteric-coated tablet was not disintegrated in the pH 1.2 environment.

(2-2) Evaluations of the changes in gastric pH and the releases of esomeprazole

The pH changes in the stomach and the releases of esomeprazole (when the formulations would be orally administered) were evaluated in a manner similar to Example 3. While stirring a mixed solution of 100 ml of the artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water (300 ml in total) at 250 rpm at room temperature, the tablets of Formulations 1 to 5 and the commercially available enteric-coated tablet of esomeprazole (Nexium Tab. 20 mg, AstraZeneca) were added thereto, respectively. Each pH was measured after 15 and 30 minutes, and each amount (i.e., each released amount) of esomeprazole were measured after 30 minutes. The amount of esomeprazole was analyzed by high performance liquid chromatography (HPLC) under the same conditions as in Example 1. The results thereof are shown in the following Table 6.

	Formulation					Nexium Tab.
	1	2	3	4	5	Nexium Tab.
pH after 15 minutes	4.87	5.12	3.14	4.05	1.51	1.58
pH after 30 minutes	5.89	5.87	5.92	5.89	1.53	1.67
Amount of esomeprazole (after 30 minutes, %)	78.9	79.1	74.51	78.1	21.32	0% (Not disintegrated)

As can be seen from the results of Table 6, the tablets of Formulations 1 to 4 exhibited very rapid releases from the test solution, and rapidly increased pHs. Therefore, it can be seen that the formulations according to the present invention rapidly increase the gastric pH through calcium carbonate and thus that the esomeprazole released in the stomach will be rapidly absorbed without showing the decomposition thereof in the stomach.

(3) Pharmacokinetic study

The tablet of Formulation 1 and the Nexium Tab. 20 mg (AstraZeneca) were orally administered to healthy volunteers (n=22 per group, crossover study) once a day for 7 days on an empty stomach, respectively. From the blood concentration profiles, the areas under the curve (AUC) of esomeprazole blood concentration and the times to maximum plasma concentration (Tmax) were respectively measured. The results thereof are shown in the following Table 7.

	Formulation 1	Nexium Tab. 20 mg	T/R ratio
AUCtau ss	2477.7	2648.2	0.9356
Tmax (Hr)	0.50	2.00	-

As can be seen from the results of Table 7, the tablet obtained according to the present invention were rapidly absorbed into the body and reached the maximum plasma concentration in a short time, along with exhibiting equivalent absorption rate in the body, in comparison with the enteric-coated tablet (i.e., Nexium Tab.). Therefore, it can be confirmed that the tablet obtained according to the present invention rapidly releases the active ingredients in the stomach to neutralize the gastric juice and allows esomeprazole to be rapidly absorbed.

(4) Stability test

The stability test under long-term storage conditions (25±2℃, 60RH±5%, 9 months) and the stability test under accelerated storage conditions (40±2℃, 75RH±5%, 6 months) were carried out for the tablet of Formulation 1. The amount of esomeprazole and the amount of total degradation products were analyzed by high performance liquid chromatography (HPLC) according to the same method as in Example 1. The results thereof are shown in the following Tables 8 and 9.

Stability test under accelerated storage conditions (40±2℃, 75RH±5%)

	Criteria	Initial	3 months	6 months
Amount of total degradation products	2.0 wt % or less	0.15 %	0.17 %	0.23 %
Amount of esomeprazole	90.0 ~ 110.0 wt%	102.07 %	100.40 %	101.15 %

Stability test under long-term storage conditions (25±2℃, 60RH±5%)

	Criteria	Initial	3 months	6 months	9 months
Amount of total degradation products	2.0 wt % or less	0.15 %	0.15 %	0.18 %	0.20 %
Amount of esomeprazole	90.0 ~ 110.0 wt%	102.07 %	100.96 %	101.57 %	100.56 %

As can be seen from the test results of Tables 8 and 9, when the tablets obtained according to the present invention were stored for 6 months under the accelerated storage conditions and for 9 months under the long-term storage conditions, the amounts of esomeprazole were maintained in a constant level and the amounts of total degradation products were within the criteria (below 2.0 wt% or less).

Claims

A pharmaceutical composition in a tablet form, comprising a mixture of omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof and calcium carbonate, wherein the pharmaceutical composition is disintegrated within 30 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.
The pharmaceutical composition according to claim 1, wherein the omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof is present in an amount ranging from 10 mg to 80 mg per unit tablet.
The pharmaceutical composition according to claim 1, wherein the esomeprazole is present in an amount of 20 mg or 40 mg per unit tablet.
The pharmaceutical composition according to claim 1, wherein esomeprazole magnesium trihydrate is present in an amount of 22.3 mg or 44.5 mg per unit tablet.
The pharmaceutical composition according to claim 1, wherein the calcium carbonate is present in an amount of at least 500 mg per unit tablet.
The pharmaceutical composition according to claim 1, wherein the calcium carbonate is present in an amount ranging from 500 mg to 700 mg per unit tablet.
The pharmaceutical composition according to claim 1, wherein the calcium carbonate is present in an amount of 600 mg per unit tablet.
The pharmaceutical composition according to claim 1, further comprising one or more excipients selected from the group consisting of a diluent, a disintegrating agent, a surfactant, a binder, and a lubricant.
The pharmaceutical composition according to claim 8, wherein the diluent is one or more selected from the group consisting of lactose, pregelatinized starch, microcrystalline cellulose, D-mannitol, D-sorbitol, and calcium hydrogen phosphate; the disintegrating agent is one or more selected from the group consisting of sodium starch glycolate, crospovidone, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, and methyl cellulose; the surfactant is one or more selected from the group consisting of polysorbate, sodium lauryl sulfate, docusate sodium, a polyoxyethylene-polyoxypropylene block copolymer, meglumine, and sorbitan; the binder is one or more selected from the group consisting of povidone, hydroxypropyl cellulose, hypromellose, and methyl cellulose; and the lubricant is one or more selected from the group consisting of sodium stearyl fumarate, colloidal silicon dioxide, stearic acid, calcium stearate, magnesium stearate, and glyceryl behenate.
The pharmaceutical composition according to claim 8, wherein the excipients are one or more selected from the group consisting of lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, polysorbate 80, povidone, sodium stearyl fumarate, and colloidal silicon dioxide.
The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is disintegrated within 20 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.
The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is disintegrated within 15 minutes in a disintegration test carried out in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.
A process for preparing a pharmaceutical composition in a tablet form, the process of which comprises:

(a) preparing a binder solution comprising a surfactant and a binder;

(b) preparing a mixture of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof; calcium carbonate; a diluent; and a disintegrating agent,

(c) granulating the mixture prepared in step (b) using the binder solution prepared in step (a), and

(d) mixing the granules obtained in step (c) with a lubricant or a mixture of a lubricant and a disintegrating agent, and then compressing the resulting mixture.
The process according to claim 13, wherein the mixture of step (b) comprises omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof in an amount ranging from 10 mg to 80 mg per unit tablet.
The process according to claim 13, wherein the mixture of step (b) comprises the esomeprazole in an amount of 20 mg or 40 mg per unit tablet.
The process according to claim 13, wherein the mixture of step (b) comprises esomeprazole magnesium trihydrate in an amount of 22.3 mg or 44.5 mg per unit tablet.
The process according to claim 13, wherein the mixture of step (b) comprises the calcium carbonate in an amount of at least 500 mg per unit tablet.
The process according to claim 13, wherein the mixture of step (b) comprises the calcium carbonate in an amount ranging from 500 mg to 700 mg per unit tablet.
The process according to claim 13, wherein the mixture of step (b) comprises the calcium carbonate is present in an amount of 600 mg per unit tablet.
The process according to claim 13, wherein the diluent is one or more selected from the group consisting of lactose, pregelatinized starch, microcrystalline cellulose, D-mannitol, D-sorbitol, and calcium hydrogen phosphate; the diluent is one or more selected from the group consisting of sodium starch glycolate, crospovidone, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, and methyl cellulose; the surfactant is one or more selected from the group consisting of polysorbate, sodium lauryl sulfate, docusate sodium, a polyoxyethylene-polyoxypropylene block copolymer, meglumine, and sorbitan; the binder is one or more selected from the group consisting of povidone, hydroxypropyl cellulose, hypromellose, and methyl cellulose; and the lubricant is one or more selected from the group consisting of sodium stearyl fumarate, colloidal silicon dioxide, stearic acid, calcium stearate, magnesium stearate, and glyceryl behenate.