TW202227066A - Pharmaceutical compositions in a tablet form comprising omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof and processes for preparing the same - Google Patents

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 containing omeprazole, esomeprazole or their pharmaceutically acceptable salts in the form of lozenges and their preparation procedures

The present invention relates to a pharmaceutical composition, which is a tablet comprising a mixture of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate, which can be rapidly disintegrated in the stomach. The invention also relates to the procedure for its preparation.

The chemical name of omeprazole is 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methanesulfinyl]-1hydro-benzimidazole , which is a proton pump inhibitor (PPI). Esomeprazole (or (S)-(-)-omeprazole) is the enantiomer of omeprazole. Omeprazole or esomeprazole is used clinically in the form of a salt, such as a magnesium salt. For example, esomeprazole is used in the form of esomeprazole magnesium trihydrate. Omeprazole, esomeprazole or their pharmaceutically acceptable salts (including their hydrates, such as their trihydrates) are used as anti-ulcer agents by inhibiting H+/K+-ATPase in gastric parietal cells The effect of acid secretion.

Although omeprazole, esomeprazole or their pharmaceutically acceptable salts have an excellent effect of inhibiting gastric acid secretion, they are extremely unstable when exposed to water, heat and acid. In particular, when omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof is used for oral administration, it is rapidly decomposed by gastric acid and thus difficult to absorb. In order to prevent decomposition by gastric acid, omeprazole, esomeprazole or their pharmaceutically acceptable salts on the market are prepared by using techniques such as enteric-coated granules or enteric-coated tablets to reduce gastric acid decomposition. (For example, AstraZeneca's Nexion Tablets 20 mg, 40 mg).

Furthermore, when formulations prepared using techniques such as enteric-coated tablets or enteric-coated granules are administered orally, these formulations release the drug in the intestine after passing through the stomach, thus significantly delaying the onset of efficacy. In order to solve the above shortcomings, in addition to PPIs such as omeprazole or esomeprazole, other active ingredients that can provide rapid onset efficacy are also added to the combination; A combination of ingredients.

Examples of such combination formulations include the lozenge disclosed in Korean Patent No. 10-2080023, which contains esomeprazole magnesium salt and sodium bicarbonate, wherein the esomeprazole magnesium salt is present in an amount of 20 mg or 40 mg based on the weight of esomeprazole; sodium bicarbonate is present in an amount of 800 mg; esomeprazole magnesium salt is in the form of pellets or granules; and the pellets or granules do not contain bicarbonate sodium, and its surface is covered with a coating agent. In addition, Korean Patent No. 10-2006777 discloses a pharmaceutical preparation comprising a first layer, a second layer surrounding the first layer, and a third layer surrounding the second layer; the first layer includes omeprazole, which enantiomer, or a pharmaceutically acceptable salt thereof; the second layer contains polyvinyl alcohol as a capping agent; and the third layer contains sodium bicarbonate as an antacid. In addition, Korean Patent Application Publication No. 10-2020-0023185 discloses a pharmaceutical preparation, when the preparation is dissolved in a solution, sodium bicarbonate will precede omeprazole, its enantiomer or its pharmaceutically acceptable The salt is released. The formulations disclosed in Korean Patent No. 10-2080023, Korean Patent No. 10-2006777 and Korean Patent Application Publication No. 10-2020-0023185 are all released after neutralizing gastric acid with sodium bicarbonate. Prazol (that is, after stomach acid has been neutralized by acid-base neutralization between stomach acid and sodium bicarbonate).

However, since the preparations disclosed in Korean Patent Case No. 10-2080023, Korean Patent Case No. 10-2006777 and Korean Patent Application Publication No. 10-2020-0023185 have relatively high sodium bicarbonate content (800 mg), The resulting increase in lozenge size may make it difficult for elderly patients to swallow. In addition, sodium bicarbonate rapidly releases a large amount of carbon dioxide gas when neutralizing gastric acid, which may lead to gastric reflux; increased gastric acid secretion due to stimulation of the gastric mucosa (ie, acid reflux); and side effects caused by excessive sodium intake, such as electrolyte imbalance in the body , high blood pressure, heart failure, kidney failure, etc. In particular, the formulations disclosed in Korean Patent Nos. 10-2080023 and/or 10-2006777 are prepared by first preparing pellets or granules, and then coating the pellets or pellets with a coating agent (such as polyvinyl alcohol). particles, thereby solving the stability problem caused by sodium bicarbonate (ie, sodium bicarbonate makes the magnesium salt esomeprazole less stable). Therefore, its preparation procedure is complicated, and it is difficult to implement in a manufacturing place.

technical problem

The inventor of the present case has carried out various researches and has been able to develop a formulation that can solve the shortcomings of formulations containing omeprazole, esomeprazole or their pharmaceutically acceptable salts and sodium bicarbonate. Coating procedure of granules/pellets. After conducting various compatibility evaluations, the inventors of the present application unexpectedly found that when the stability evaluations of various combinations were performed under stress conditions, compared to the mixture of sodium bicarbonate and esomeprazole magnesium trihydrate, the Decay products derived from esomeprazole magnesium trihydrate mixtures were significantly reduced. That is, the inventors of the present application found that when calcium carbonate is used as an antacid, the granules/pills that must be performed in the preparation of conventional formulations (formulations containing sodium bicarbonate and esomeprazole magnesium trihydrate) can be dispensed with. Granule envelope procedure. In particular, the inventors of the present application found that when calcium carbonate is used instead of sodium bicarbonate in the formulation process, the prepared medicine can be rapidly disintegrated, so that rapid absorption of the medicine can be achieved. In addition, the inventors of the present application found that, compared with sodium bicarbonate, calcium carbonate has a strong antacid activity (that is, a strong neutralizing activity for acids), so it can promote a rapid increase in pH and reduce the amount of calcium carbonate by reducing the amount of calcium carbonate. Reduce formulation size.

Therefore, the object of the present invention is to provide a pharmaceutical composition in the form of a lozenge, which comprises a mixture consisting of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate, which can be quickly put into the stomach Broken in.

Another object of the present invention is to provide a procedure for preparing the pharmaceutical composition in tablet form.

technical solutions

According to one aspect of the present invention, the present invention provides a pharmaceutical composition in the form of a lozenge, which comprises a mixture consisting of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate, wherein In a disintegration test performed in an aqueous medium of pH 1.2 according to the Korean Pharmacopoeia, the pharmaceutical composition disintegrated within 30 minutes.

According to another aspect of the present invention, the present invention provides a procedure for preparing a pharmaceutical composition in the form of a lozenge, the procedure comprising:

(a) prepare a solution-type adhesive comprising surfactant and adhesive;

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

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

(d) mixing the granules obtained in step (c) with a lubricant or a mixture consisting of a lubricant and a disintegrant, and then compacting the resulting mixture.

Beneficial effect

The present invention found that, compared with the mixture of sodium bicarbonate and esomeprazole magnesium trihydrate, the mixture of calcium carbonate and omeprazole, esomeprazole or its pharmaceutically acceptable salt (for example, esomeprazole) The mixture of prazole magnesium trihydrate) can greatly reduce the generation of decay products. Since the pharmaceutical composition of the present invention does not need to perform the step of coating the granules/pellets, its preparation procedure is relatively simple, and thus it can be easily implemented in the manufacturing site. In addition, the pharmaceutical composition of the present invention can be rapidly disintegrated, so that the rapid absorption of the drug can be achieved. In addition, the calcium carbonate contained in the pharmaceutical composition of the present invention has a strong antacid activity (that is, a strong neutralizing activity for acids), so it can promote the rapid increase of the pH value and reduce the amount of calcium carbonate. Therefore, the pharmaceutical composition of the present invention can reduce the size of the preparation, reduce the acid kickback caused by the release of carbon dioxide gas, and fundamentally avoid the side effects caused by excessive sodium intake.

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

Omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof can 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 lozenge, but not limited thereto. In one embodiment, esomeprazole may be present in an amount of 20 mg or 40 mg per unit lozenge. In another embodiment, esomeprazole magnesium trihydrate may be present in an amount of 22.3 mg or 44.5 mg per unit lozenge.

The present invention found that, compared to the formulation procedure performed using the mixture of sodium bicarbonate and esomeprazole magnesium trihydrate, when calcium carbonate was used in combination with omeprazole, esomeprazole or a pharmaceutically acceptable compound thereof When a salt (eg, esomeprazole magnesium trihydrate) is used in the formulation procedure as a mixture, the production of decay products is greatly reduced. In this context, expressions such as "a mixture of calcium carbonate and esomeprazole or a pharmaceutically acceptable salt thereof" means a mixture of esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate (if desired, together with pharmaceutically acceptable excipients) mixed with each other by direct contact. Therefore, since the preparation of the pharmaceutical composition of the present invention does not require performing a granule/pellet coating step, its preparation procedure is simple and thus easy to implement at the manufacturing site. Moreover, according to the present invention, the pharmaceutical composition using the calcium carbonate as an antacid exhibits rapid disintegration, thereby achieving rapid absorption of the drug. In addition, the calcium carbonate contained in the pharmaceutical composition of the present invention has an antacid activity (that is, a strong neutralizing activity for acids) that is much higher than that of sodium bicarbonate, so it can promote a rapid increase in pH value And reduce the amount of calcium carbonate. Therefore, the pharmaceutical composition of the present invention can reduce the size of the preparation, avoid acid kickback caused by the release of carbon dioxide gas, and fundamentally avoid side effects caused by excessive sodium intake. Since calcium carbonate is absorbed in the form of calcium, its amount is only 9 to 16%, which 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 size of the lozenge and avoid acid kickback caused by the release of carbon dioxide gas, calcium carbonate is preferably present in an amount of 500 mg to 700 mg per unit lozenge, more preferably about 600 mg per unit lozenge.

The pharmaceutical composition of the present invention may further comprise excipients commonly used in the pharmaceutical field. That is, the pharmaceutical composition of the present invention may further comprise one or more excipients selected from the group consisting of diluents, disintegrants, surfactants, binders and lubricants. The diluent may be one or more selected from lactose, pregelatinized starch, microcrystalline cellulose, D-mannitol, D-sorbitol and calcium hydrogen phosphate. The disintegrating agent may be selected from the group consisting of sodium starch glycolate, crospovidone, calcium carboxymethyl cellulose, sodium croscarmellose, low-substituted hydroxypropyl cellulose and methyl cellulose one or more of them. The surfactant may be selected from polysorbate, sodium lauryl sulfate, sodium docusate, poloxamer (a polyoxyethylene polyoxypropylene block copolymer), meglumine and sorbitan one or more. The binder may be one or more selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and methyl cellulose. The lubricant may be one or more selected from the group consisting of sodium stearyl fumarate, colloidal silica, stearic acid, calcium stearate, magnesium stearate and glyceryl behenate . In one embodiment, the excipient may be selected from lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, polysorbate 80, povidone, stearyl rich One or more of sodium malate and colloidal silica. Excipients such as diluents, disintegrants, surfactants, binders, and a lubricant can be used, and the amounts thereof can be appropriately selected by those who are familiar with the agents according to the usual practice in the pharmaceutical field.

The pharmaceutical composition of the present invention can be rapidly disintegrated in the stomach. Specifically, the disintegration test of the pharmaceutical composition of the present invention is performed according to the Korean Pharmacopoeia with an aqueous medium with a pH value of 1.2 (such as the first fluid of the disintegration test method described in the Korean Pharmacopoeia, or its mixed solution with water). , disintegrates within 30 minutes. In one embodiment, the pharmaceutical composition disintegrates within 20 minutes in a disintegration test performed in an aqueous medium with a pH of 1.2 according to the Korean Pharmacopoeia. In another embodiment, the pharmaceutical composition disintegrates within 15 minutes in a disintegration test performed in a pH 1.2 aqueous medium according to the Korean Pharmacopoeia.

If desired, the pharmaceutical composition in tablet form of the present invention may further comprise a conventional coating, such as a film coating. The film coating can be prepared by spraying a coating solution commonly used in the pharmaceutical field on the tablet of the present invention according to a conventional method [for example, dissolving Opadry ^™ 03B62323, sodium hydroxide, polyethylene glycol 6000, talc, etc. in an aqueous ethanol solution ( For example, a coating solution prepared from 80% to 95% ethanol aqueous solution), and the resultant is dried to form.

The scope of the present invention includes procedures for preparing the aforementioned pharmaceutical compositions. The preparation of the pharmaceutical composition of the present invention can be carried out through the conventional lozenge preparation procedure in the pharmaceutical field, using omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof, calcium carbonate and pharmaceutically acceptable excipients production.

For example, the present invention provides a procedure for preparing a pharmaceutical composition in the form of a lozenge, the procedure comprising:

(a) preparing a solution adhesive comprising a surfactant and an adhesive;

(b) the preparation of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof; calcium carbonate; diluent; mixture with disintegrant,

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

(d) mixing the granules obtained in step (c) with a lubricant or a mixture consisting of a lubricant and a disintegrant, and then compacting the resulting mixture.

In the procedure, omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof, calcium carbonate, diluent, disintegrant, surfactant, binder and lubricant are used in conjunction with the medicine of the present invention. The same as those mentioned in the description of the composition. Moreover, those skilled in the art should know that steps (a) and (b) can be performed sequentially or in reverse order.

The preparation method of the solution-type adhesive in step (a) can be to dissolve the surfactant and the adhesive in ethanol or an ethanol aqueous solution (eg, 80% to 95% ethanol aqueous solution).

In the step (b), the mixture can be prepared by mixing omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof; calcium carbonate; diluent; The total amount of disintegrant used in the pharmaceutical composition of the present invention can be used to prepare the mixture of step (b). Alternatively, a portion of the total amount of disintegrant used in the pharmaceutical composition of the present invention can be used to prepare the mixture of step (b); and the remaining amount can be used to prepare the mixture of step (d) [ie, to prepare the lubricant and mixture of disintegrants]. In this case, the disintegrants used in step (b) and step (d) may be different from each other. In one embodiment, the disintegrant used in step (b) can be a mixture of sodium starch glycolate and crospovidone, and the disintegrant used in step (d) can be crospovidone. In a preferred embodiment, the disintegrant used in step (b) may be 0.5 to 5 wt% sodium starch glycolate and 1.0 to 10.0 wt% per unit tablet (ie, each uncoated tablet). The mixture of crospovidone; and the disintegrant used in step (d) may be 0.5 to 5.0 wt% of crospovidone per unit tablet (ie, each uncoated tablet).

An embodiment of step (c) is to granulate the mixture prepared in step (b) using the solution binder prepared in step (a). Granulation is carried out according to methods conventional in the pharmaceutical field, for example, according to wet granulation procedures. Granulation involves drying the resulting wet granules. Drying is carried out according to methods customary in the pharmaceutical field. If necessary, step (c) may further comprise the step of screening the obtained dried particles to obtain dried particles of uniform size.

The embodiment of step (d) is to mix the granules obtained in step (c) with a lubricant or a mixture consisting of a lubricant and a disintegrant, and then compact the resulting mixture. The above-mentioned mixing and compacting can be carried out according to methods commonly used in the pharmaceutical field. For example, considering the medication compliance of elderly patients, the lozenge can be compressed to a size of about 12×6 mm to 17×10 mm, but not limited thereto.

If desired, the process of the present invention may further comprise the step of forming a conventional cladding layer, such as a thin film cladding layer. The step of forming the thin film coating layer may include spraying a coating solution (such as Opadry ^™ 03B62323, sodium hydroxide, polyethylene glycol 6000, talc, etc.) on the tablet obtained in step (d) according to a conventional method. A coating solution prepared by dissolving in an aqueous ethanol solution (eg, 80% to 95% aqueous ethanol solution)], and then drying the resultant.

The present invention will be described in detail below with reference to examples. The examples given are illustrative only and should not be construed to limit the scope of the invention.

Example 1: Compatibility Assessment

Compatibility using esomeprazole magnesium trihydrate, a mixture of esomeprazole magnesium trihydrate and calcium carbonate, and a mixture of esomeprazole magnesium trihydrate and sodium bicarbonate Sexual assessment. In the compatibility evaluation, esomeprazole magnesium trihydrate and individual mixtures were placed in airtight containers, stored under pressure conditions (60 °C, 80% relative humidity) for 2 weeks, and then used high performance liquid chromatography. The amount of esomeprazole magnesium trihydrate and the amount of decay products were analyzed at the initial stage (at the beginning of the test) and after 2 weeks by HPLC according to the following conditions.

<HPLC conditions>

- Detector: UV-Vis Spectrometer (Wavelength: 302 nm)

- String: XTerraRP 8 4.6 x 150 mm, 3.5 micron or equivalent

- Column temperature: about 30 °C

- Sample injection temperature: about 8 ℃

- Mobile Phase: A: Phosphate 9.0 Phosphate Buffer

- Mobile phase: B: A mixture of acetonitrile and methanol (85:15 (v/v)) time (minutes) mobile phase A mobile phase B 0 ~ 12 94 → 88 6 → 12 12 ~ 17 88 → 82 12 → 18 17 ~ 17.5 82 → 80 18 → 20 17.5 ~ 30 80 → 60 20 → 40 30 ~ 40 60 → 54 40 → 46 40 ~ 43 54 → 15 46 → 85 43 ~ 45 15 → 94 85 → 6 45 ~ 55 94 6

- Flow rate: 1.0 ml/min

The amount of esomeprazole and the amount of all decay products were analyzed according to the above method, and the results are shown in Table 1 below. [Table 1] quantity(%) Esomeprazole All decay products initial 2 weeks later initial 2 weeks later Esomeprazole Magnesium Trihydrate 102.90 87.32 below RL 4.78 Esomeprazole Magnesium Trihydrate + CaCO ₃ 102.44 97.25 below RL 2.14 Esomeprazole Magnesium Trihydrate + NaHCO ₃ 102.12 72.23 below RL 9.69 *RL: reporting limit

It can be confirmed from the results in Table 1 that compared with the use of esomeprazole magnesium trihydrate alone and the use of the mixture composed of esomeprazole magnesium trihydrate and sodium bicarbonate, the use of esomeprazole magnesium A simple mixture of trihydrate and calcium carbonate can greatly reduce the production of decay products.

Example 2: Antacid activity assessment

The volume of gastric juice in an empty stomach is about 70 ml (gastric fluid volume: average 51-70 ml/M Feldman, the secretion rate comparison, measured by gastric aspiration and in vivo gene titration in healthy human subjects, Gastroenterology , 76: 954-957, 1979). The amount of water to drink while taking the medicine is usually 100 to 200 ml. Therefore, the antacid activity of calcium carbonate and sodium bicarbonate was evaluated using a mixture consisting of 100 ml of artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water. In addition, the representative antacids aluminum magnesium plus antacid activity were also evaluated. Specifically, a mixture consisting of 100 ml of artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water (300 ml in total) was stirred at room temperature at 250 rpm, and 300 to 800 mg of calcium carbonate and carbonic acid were added at the same time. Add sodium hydride and aluminum magnesium. The respective pH values were measured after 30 minutes. The results are shown in Table 2 below. [Table 2] pH value 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 Aluminum Magnesium Plus 2.03 3.89 4.70 5.14 5.60

It can be seen from the results in Table 2 that the antacid activity of calcium carbonate is much higher than that of sodium bicarbonate and aluminum magnesium. In particular, when the amount of calcium carbonate is 500 mg or more, its antacid activity is about twice that of sodium bicarbonate.

Example 3: Assessing pH and Esomeprazole Amount Based on Calcium Carbonate Amount

Agitate a mixed solution consisting of 100 ml of artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water (300 ml in total) at room temperature at 250 rpm, while adding calcium carbonate (300 to 700 mg) and esomepramine azole (20 mg). Each pH value and the amount of esomeprazole were measured at 30 minutes. The amount of esomeprazole was analyzed by high performance liquid chromatography (HPLC) under the same conditions as in Example 1. The results are shown in Table 3 below. [table 3] Calcium Carbonate (mg) pH value 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 shown in Table 3, the use of 500 mg or more of calcium carbonate not only achieves a pH value of at least 5.0, but also achieves at least 95% of the active ingredient (ie esomeprazole), showing excellent stability.

Example 4: Preparation and evaluation of esomeprazole-containing lozenges

(1) Preparation of lozenges containing esomeprazole

Tablets containing esomeprazole magnesium trihydrate were prepared according to the ingredients and amounts shown in Table 4. The amounts in Table 4 represent the weight (mg) per unit of lozenge. Specifically, a solution-type adhesive was prepared by dissolving povidone K30 and polysorbate 80 in ethanol. Put esomeprazole magnesium trihydrate, calcium carbonate, diluents (anhydrous lactose, microcrystalline cellulose and/or pregelatinized starch) and disintegrants (sodium starch glycolate and crospovidone) into a high-speed mixer, and then mixed with the above-mentioned solution binder to prepare wet granules. The resulting wet granules were dried at about 60°C for about 2 hours and then screened using a 25 mesh screen. The resulting granules were uniformly mixed with crospovidone and lubricants (sodium stearyl fumarate and colloidal silica), and then compressed into lozenges. A coating solution was prepared by adding Opadry ^™ 03B62323, sodium hydroxide, polyethylene glycol 6000 and talc to an 80% aqueous ethanol solution. The lozenges prepared as described above were placed in a coating machine, and then the coating solution was sprayed to form coated lozenges (ie, the lozenges of Formulations 1 to 4). Coated tablets of Formulation 5 were prepared in the same manner as Formulation 1, but without the addition of calcium carbonate, as a control. [Table 4] Element Formulation (mg) 1 2 3 4 5 Active ingredients Esomeprazole Magnesium Trihydrate 22.3 44.5 22.3 44.5 22.3 Antacid calcium carbonate 600 600 600 600 - thinner anhydrous lactose 100 100 - - 100 microcrystalline cellulose - - 100 100 - pregelatinized starch 15 15 15 15 15 disintegrant Sodium starch glycolate 10 10 10 10 10 Crospovidone (intragranular) 20.0 20.0 20.0 20.0 20.0 Crospovidone (extragranular) 10.0 10.0 10.0 10.0 10.0 Surfactant Polysorbate 80 1.7 1.7 1.7 1.7 1.7 adhesive Povidone K30 20 20 20 20 20 lubricant Sodium Stearyl Fumarate 6 6 6 6 6 colloidal silica 5 5 5 5 5 coating agent Opadry™ 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) Evaluation of lozenges containing esomeprazole

(2-1) Disintegration test

According to the Korean Pharmacopoeia, the tablets of formulations 1 to 5 and the commercially available esomeprazole enteric-coated tablets (AstraZeneca's Nexion tablets 20 mg) were tested for disintegration. The disintegration time of each tablet was measured and the results are shown in Table 5 below. [table 5] preparation Nexon 1 2 3 4 5 pH 1.2 3 minutes 10 seconds 3 minutes 7 seconds 3 minutes 19 seconds 3 minutes 12 seconds 5 minutes 20 seconds Do not collapse purified water 3 minutes 30 seconds 3 minutes 20 seconds 3 minutes 24 seconds 3 minutes 20 seconds 5 minutes 16 seconds 5 minutes 20 seconds

As shown in the results in Table 5, Formulations 1 to 4 exhibited rapid disintegration rates (ie, within 5 minutes), indicating that the drug disintegrated rapidly after administration, thereby enabling rapid absorption. Commercially available esomeprazole enteric-coated tablets will not disintegrate in a pH 1.2 environment.

(2-2) Assessment of gastric pH changes and esomeprazole release

Stomach pH changes and esomeprazole (formulation for oral administration) release were assessed in a manner similar to Example 3. A mixed solution consisting of 100 ml of artificial gastric juice described in the Korean Pharmacopoeia and 200 ml of purified water (total 300 ml) was stirred at room temperature at 250 rpm, while adding the lozenges of formulations 1 to 5 and the commercially available Esso, respectively. Melprazole enteric-coated tablet (Nexion 20 mg from AstraZeneca). The respective pH values were measured after 15 and 30 minutes, and the respective amounts of esomeprazole (ie, the respective released amounts) were measured after 30 minutes. The amount of esomeprazole was analyzed under the same conditions as in Example 1 using high performance liquid chromatography (HPLC). The results are shown in Table 6 below. [Table 6] preparation Nexon 1 2 3 4 5 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% (do not collapse)

As shown in the results in Table 6, the lozenges of formulations 1 to 4 were released very quickly from the test solution and increased pH rapidly. Therefore, it can be seen that the preparation of the present invention rapidly increases the pH value of the stomach through calcium carbonate, and the esomeprazole released in the stomach will be absorbed rapidly and will not be decomposed in the stomach.

(3) Pharmacokinetic studies

Healthy volunteers (22 in each group, crossover study) were given the tablet of Formulation 1 and Nexion tablet 20 mg (AstraZeneca) once a day orally on an empty stomach for seven consecutive days. According to the blood concentration change, the esomeprazole blood concentration and the under-curve aspect of the time to maximum plasma concentration (Tmax) were measured, respectively. The results are shown in Table 7 below. [Table 7] Formulation 1 Nexion Tablets 20mg T/R ratio AUCtau ss 2477.7 2648.2 0.9356 Tmax (Hr) 0.50 2.00 -

From the results in Table 7, it can be seen that the lozenge obtained according to the present invention can be rapidly absorbed by the body, and reaches the maximum plasma concentration in a short period of time, while exhibiting an absorption rate equal to that of the enteric-coated tablet (namely, Nexon lozenge). Therefore, it was confirmed that the lozenge obtained according to the present invention rapidly released the active ingredient in the stomach to neutralize gastric juice and allow the rapid absorption of esomeprazole.

(4) Stability test

Stability test under long-term storage conditions (25±2°C, 60 RH±5%, 9 months) and accelerated storage condition stability test (40±2°C, 75 RH±5%, 6 months). The amount of esomeprazole and the amount of total decay products were analyzed according to the same method as in Example 1 using high performance liquid chromatography (HPLC). The results are shown in Tables 8 and 9 below. [Table 8] Stability test under accelerated storage conditions (40±2 ℃, 75 RH±5%) standard initial 3 months 6 months total amount of decay 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 [Table 9] Stability test under long-term storage conditions (25±2 ℃, 60 RH±5%) standard initial 3 months 6 months 9 months total amount of decay 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 shown in the test results in Tables 8 and 9, when the lozenges obtained according to the present invention were stored under accelerated storage conditions for 6 months and under long-term storage conditions for 9 months, the amount of esomeprazole remained constant and all The amount of decay products is within the norm (below 2.0 wt% or less).

Claims (20)

A pharmaceutical composition in the form of a lozenge comprising a mixture of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof and calcium carbonate, wherein the pharmaceutical composition is in a Disintegration within 30 minutes was performed in a disintegration test in an aqueous medium with a pH of 1.2 according to the Korean Pharmacopoeia. The pharmaceutical composition of claim 1, wherein the omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof is present in an amount of 10 mg to 80 mg per unit tablet. The pharmaceutical composition of claim 1, wherein the esomeprazole is present in an amount of 20 mg or 40 mg per unit lozenge. The pharmaceutical composition of claim 1, wherein the amount of esomeprazole magnesium trihydrate present is 22.3 mg or 44.5 mg per unit lozenge. The pharmaceutical composition of claim 1, wherein the calcium carbonate is present in an amount of at least 500 mg per unit lozenge. The pharmaceutical composition of claim 1, wherein the calcium carbonate is present in an amount of 500 mg to 700 mg per unit tablet. The pharmaceutical composition of claim 1, wherein the calcium carbonate is present in an amount of 600 mg per unit tablet. The pharmaceutical composition of claim 1, further comprising one or more excipients selected from the group consisting of a diluent, a disintegrant, a surfactant, a binder and a lubricant one or more. The pharmaceutical composition of claim 8, wherein the diluent is selected from the group consisting of lactose, pregelatinized starch, microcrystalline cellulose, D-mannitol, D-sorbitol and calcium hydrogen phosphate One or more; the disintegrant is selected from sodium starch glycolate, crospovidone, calcium carboxymethyl cellulose, sodium croscarmellose, low-substituted hydroxypropyl cellulose and methyl cellulose One or more of the group consisting of: the surfactant is selected from polysorbate, sodium lauryl sulfate, sodium docusate, monopolyoxyethylene polyoxypropylene block copolymer, meglumine and One or more of the group consisting of sorbitan; the binder is selected from one of the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and methyl cellulose or more; and the lubricant is selected from the group consisting of sodium stearyl fumarate, colloidal silica, stearic acid, calcium stearate, magnesium stearate and glyceryl behenate one or more. The pharmaceutical composition according to claim 8, wherein the excipient is selected from lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, polysorbate 80, One or more of the group consisting of povidone, sodium stearyl fumarate and colloidal silica. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition disintegrates within 20 minutes in a disintegration test performed in an aqueous medium of pH 1.2 according to the Korean Pharmacopoeia. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition disintegrates within 15 minutes in a disintegration test performed in an aqueous medium of pH 1.2 according to the Korean Pharmacopoeia. A procedure for preparing a pharmaceutical composition in the form of a lozenge, the procedure comprising: (a) preparing a solution-type adhesive comprising a surfactant and an adhesive; (b) preparing a mixture consisting of omeprazole, esomeprazole, or a pharmaceutically acceptable salt thereof; calcium carbonate; a diluent; and a disintegrant, (c) granulating the mixture prepared in step (b) using the solution binder prepared in step (a), and (d) mixing the granules obtained in step (c) with a lubricant or a mixture consisting of a lubricant and a disintegrant, and then compacting the resulting mixture. The process of claim 13, wherein, in the mixture in step (b), the amount of omeprazole, esomeprazole or a pharmaceutically acceptable salt thereof is 10 mg to 80 mg per unit tablet mg. The process of claim 13, wherein the amount of esomeprazole in the mixture of step (b) is 20 mg or 40 mg per unit lozenge. The process of 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 lozenge. The process of 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 of claim 13, wherein the mixture of step (b) comprises the calcium carbonate in an amount of 500 mg to 700 mg per unit lozenge. The process of claim 13, wherein the mixture of step (b) comprises the calcium carbonate present in an amount of 600 mg per unit lozenge. The process of claim 13, wherein the diluent is selected from one of the group consisting of lactose, pregelatinized starch, microcrystalline cellulose, D-mannitol, D-sorbitol and calcium hydrogen phosphate or The diluent is selected from the group consisting of sodium starch glycolate, crospovidone, calcium carboxymethyl cellulose, sodium croscarmellose, low-substituted hydroxypropyl cellulose and methyl cellulose One or more of the group; the surfactant is selected from the group consisting of polysorbate, sodium lauryl sulfate, sodium docusate, monopolyoxyethylene polyoxypropylene block copolymer, meglumine and sorbitol one or more of the group consisting of anhydrides; the adhesive is selected from one or more of the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and methyl cellulose and the lubricant is selected from the group consisting of sodium stearyl fumarate, colloidal silica, stearic acid, calcium stearate, magnesium stearate and glyceryl behenate or many.