Stable pharmaceutical composition comprising ilaprazole, antacid, and alkalizing agent and method for preparing same

Abstract

The present invention relates to a pharmaceutical combination preparation comprising ilaprazole, an antacid, and an alkalizing agent and, more specifically, to a pharmaceutical combination preparation and a method for preparing same, wherein decomposition of ilaprazole in the stomach is prevented without enteric coating to improve stability, thereby increasing bioavailability, and the quality and productivity of pharmaceutical products are improved due to uncomplicated manufacturing processes and excellent storage stability of the preparation.

Description

Stable pharmaceutical composition comprising ilaprazole, antacid and alkalizing agent and method for preparing the same

[0001] The present invention relates to a pharmaceutical combination preparation comprising ilaprazole, an antacid, and an alkalizing agent, and more specifically, to a pharmaceutical combination preparation that improves stability by preventing gastric decomposition of ilaprazole without enteric coating, thereby increasing bioavailability, and that has excellent storage stability of the preparation without a complex manufacturing process, thereby improving pharmaceutical quality and productivity, and a method for manufacturing the same.

[0002] Proton pump inhibitors (PPIs) reduce gastric acidity by inhibiting the proton pump (H+ / K+-ATPase) that causes acid secretion in the gastric parietal cells, and are effective in treating gastroesophageal reflux disease, gastric and duodenal ulcers, indigestion, and esophagitis. When administered orally, PPIs are absorbed from the upper duodenum or small intestine, reach the gastric parietal cells through the bloodstream, and irreversibly inhibit the proton pump by binding to the proton pump inside the gastric parietal cells. Examples of such PPIs include ilaprazole, omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole.

[0003] Ilaprazole is a third-generation proton pump inhibitor with the chemical name 2-[[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole. It is effective in treating gastric and duodenal ulcers, reflux esophagitis, and Helicobacter pylori infection. Ilaprazole has a longer half-life than other proton pump inhibitors, and has been proven to be particularly effective in treating nocturnal acid breakthrough.

[0004] However, as is well known in the industry, it is easily decomposed under the acidic conditions of gastric acid, so it is mainly administered in the form of an enteric-coated preparation. However, in the case of enteric-coated preparations, there is a problem in that the onset of the drug effect is delayed because the drug is released and absorbed in the intestine rather than being immediately absorbed in the stomach. Furthermore, the manufacture of enteric-coated tablets requires the inclusion of an excessive amount of enteric polymer, and if the enteric coating layer is lost, there is a problem in that the stability is reduced due to exposure to gastric acid.

[0005] To address these issues, Korean Patent Publication Nos. 10-2021-0012919 and 10-2021-0106857 disclose pharmaceutical compositions containing a proton pump inhibitor and sodium bicarbonate. However, the disclosed formulations contain a high content of sodium bicarbonate, resulting in low medication compliance due to the size of the tablets. In addition, the high content of sodium bicarbonate reacts with gastric acid to release CO2 gas, which may cause reflux of gastric juice or irritation of the gastric mucosa. In addition, to prevent the deterioration of the stability of the active ingredient, esomeprazole is manufactured in the form of pellets or granules, which are then mixed with an antacid layer and then compressed into tablets. However, this has the disadvantage of being a very complicated manufacturing process.

[0006] Chinese patent CN103432127A discloses both high- and low-content sodium bicarbonate formulations. However, the patent discloses a manufacturing method that involves mixing the main ingredient, ilaprazole, and a polyvinylpyrrolidone binder, wet-granulating the resulting granules, and drying the resulting granules at high temperatures for an extended period of time. This method is not very stable, as it can promote a decrease in the content of ilaprazole, which is unstable to heat and moisture, and the generation of volatile substances. Furthermore, the increased drying time also extends the manufacturing process time.

[0007] Additionally, it is not disclosed whether ilaprazole is sufficiently stable without decomposition under acidic conditions, and the results of the storage stability of the formulation are not disclosed.

[0008] Korean Patent Publication No. 10-2024-0078782 discloses a separate-compartment formulation with improved stability of ilaprazole using sodium bicarbonate. However, manufacturing the disclosed cored tablet requires 1) a tableting process for an inner core containing ilaprazole, 2) a primary coating using a polymer containing HPMC and a secondary coating using a polymer containing ethylcellulose between the inner core and the outer layer, and 3) a tableting process using a sodium bicarbonate layer on the outer layer. This significantly complicates the manufacturing process and reduces the yield. This complex manufacturing process not only reduces productivity, but also prevents the original purpose of the formulation from being achieved due to a decrease in stability if a loss occurs in the coating layer. Furthermore, the patent already states that the stability of the inner core under accelerated storage conditions was evaluated, indicating that the content of flexible substances exceeded the standard after 6 months. This indicates that sufficient stability has not been secured and further research is necessary. Additionally, since the dosage of sodium bicarbonate used as an antacid is high, low medication compliance is expected due to the size of the tablet.

[0009] Currently, no combination product combining ilaprazole and an antacid is available on the market. Therefore, there is a need for a formulation that utilizes a lower antacid content than that disclosed in the aforementioned patent disclosure, while maintaining a simple manufacturing process. This improves the stability of ilaprazole in the acidic environment, while simultaneously promoting rapid onset of efficacy through immediate stomach release and enhancing medication compliance through a convenient tablet size.

[0010] The purpose of the present invention is to provide a novel pharmaceutical composition comprising ilaprazole or a pharmaceutically acceptable salt thereof; and an antacid selected from sodium bicarbonate, magnesium hydroxide, magnesium oxide, almagate, hydrotalcite, precipitated calcium carbonate, or a mixture thereof; as active ingredients, and including an alkalizing agent, with improved stability and bioavailability. Another purpose of the present invention is to provide a stable manufacturing method that is simple and commercially applicable to the manufacturing method of the pharmaceutical composition and has reduced impurities compared to the manufacturing method disclosed in the above-mentioned Korean Patent Publication No. 2014-018228, and is not limited to the types of antacids presented above.

[0011] In order to achieve the above purpose, the inventors of the present invention have completed the present invention by including an alkalizing agent in a pharmaceutical composition comprising ilaprazole or a pharmaceutically acceptable salt thereof and an antacid, and by disintegrating and dissolving the tablet composition within 30 minutes in the stomach, unlike an existing enteric-coated preparation in which the tablet disintegrates and dissolves as it passes through the stomach and reaches the small intestine.

[0012] One aspect of the present invention provides a pharmaceutical composition in tablet form comprising ilaprazole or a pharmaceutically acceptable salt thereof; an antacid selected from sodium bicarbonate, magnesium hydroxide, magnesium oxide, almagate, hydrotalcite, precipitated calcium carbonate, and mixtures thereof; and an alkalizing agent, wherein the content of ilaprazole is 10 to 40 mg per unit tablet.

[0013] In the pharmaceutical composition, ilaprazole or a pharmaceutically acceptable salt thereof may contain ilaprazole in an amount of preferably 10 mg to 20 mg and sodium bicarbonate as an antacid in an amount of 400 to 800 mg, or magnesium oxide in an amount of 300 mg to 500 mg, or magnesium hydroxide in an amount of 300 mg to 700 mg.

[0014] The content of sodium bicarbonate in the above pharmaceutical composition may be 500 to 700 mg, more preferably 500 mg.

[0015] In the above pharmaceutical composition, the content of magnesium hydroxide as an antacid may be 300 to 500 mg, more preferably 300 mg.

[0016] Specifically, the alkalizing agent may be selected from the group consisting of magnesium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, calcium hydroxide, dried sodium carbonate, magnesium carbonate, calcium carbonate, potassium phosphate, sodium phosphate, pharmaceutically acceptable salts thereof, and mixtures thereof, but is not limited thereto, and any alkalizing agent capable of exhibiting the effects of the present invention may be applied as needed. In addition, magnesium hydroxide among the alkalizing agents may also be used as a component of an antacid.

[0017] In addition, the dried sodium carbonate may be included in an amount of 0.5 to 10 parts by weight based on 1 part by weight of ilaprazole, but is not limited thereto. More specifically, the dried sodium carbonate may be included in an amount of 0.5 to 5 parts by weight based on 1 part by weight of ilaprazole.

[0018] In addition, specifically, the magnesium hydroxide may be included in an amount of 0.5 to 5 parts by weight based on 1 part by weight of ilaprazole, but is not limited thereto. More specifically, the magnesium hydroxide may be included in an amount of 0.5 to 3 parts by weight based on 1 part by weight of ilaprazole.

[0019] In addition, the pharmaceutical composition of the present invention may additionally contain additives such as alkalizing agents, excipients, binders, disintegrants, and lubricants commonly used pharmaceutically, as needed. More specifically, the excipients are at least one selected from the group consisting of lactose, microcrystalline cellulose, crystalline cellulose, D-mannitol, D-sorbitol, pregelatinized starch, and calcium hydrogen phosphate; and the disintegrants are at least one selected from the group consisting of sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethylcellulose calcium; The binder is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and microcrystalline cellulose; the alkalizing agent is at least one selected from the group consisting of magnesium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, calcium hydroxide, dried sodium carbonate, magnesium carbonate, calcium carbonate, potassium phosphate, sodium phosphate, pharmaceutically acceptable salts thereof, and mixtures thereof; and the lubricant may be at least one selected from the group consisting of stearic acid, magnesium stearate, sodium stearyl fumarate, calcium silicate, stearic acid salt, corn starch, talc, light anhydrous silicic acid, calcium hydrogen phosphate, and magnesium silicate, but is not limited thereto.

[0020] The pharmaceutical composition of the present invention may be a tablet, and may have a single-compartment formulation, such as a bilayer tablet, a trilayer tablet, a cored tablet, or a pellet-containing capsule, and may be manufactured according to a tablet manufacturing method generally known in the pharmaceutical field, such as a dry granulation method, a wet granulation method, or a direct compression method.

[0021] Another aspect of the present invention relates to a method for preparing the pharmaceutical composition,

[0022] (a) preparing a pharmaceutically acceptable mixture comprising sodium bicarbonate and an alkalizing agent in an amount of 400 to 800 mg per unit tablet;

[0023] (b) a step of granulating the mixture to produce a granule and then drying it; and

[0024] (c) a step of adding ilaprazole and an alkalizing agent in an amount of 10 to 40 mg per unit tablet to the granules and mixing them;

[0025] The mixture in step (a) may comprise sodium bicarbonate in an amount of 500 mg to 700 mg. The amount of ilaprazole in step (c) may be 10 mg to 20 mg per unit tablet.

[0026] The oral immediate-release preparation according to the present invention exhibits a strong antacid effect together with an alkalizing agent while using a minimum amount of antacid, thereby effectively preventing the decomposition of ilaprazole by gastric acid, and has an appropriate size for taking, thereby improving medication compliance.

[0027] Specifically, the oral immediate-release formulation according to the present invention exhibits excellent storage stability despite being a single tablet that does not undergo a complex manufacturing process, unlike a separate compartment formulation.

[0028] In addition, the oral immediate-release preparation according to the present invention improves bioavailability through rapid onset of drug effect even without an enteric coating agent.

[0029] Therefore, the oral immediate-release preparation according to the present invention not only exhibits excellent storage stability with a simple manufacturing process compared to existing preparations and preparations disclosed in patents, but also can expect rapid onset of efficacy through a strong and rapid antacid effect even with a low antacid content, and can increase convenience of taking by providing an appropriate size for taking.

[0030] Figure 1 shows the results of measuring the pH of an artificial gastric juice mixture according to an acid-reducing power test for Examples 1 to 3 and Comparative Examples 1 to 10 according to Test Example 1.

[0031] Figure 2 shows the results of a time-dependent stability test of ilaprazole in artificial gastric juice mixtures of Examples 1 to 3 and Comparative Examples 1 to 10 according to Test Example 2.

[0032] Figure 3 shows the results of the ilaprazole solubility test for Example 3, Comparative Example 5, Comparative Example 8, and Comparative Example 10 according to Test Example 3.

[0033] Figure 4 shows the results of a comparative dissolution test for Example 3 and a control drug according to Test Example 5.

[0034] Figure 5 shows the results of measuring changes in the blood concentration of ilaprazole for the test drug and the control drug according to Test Example 6.

[0035] Hereinafter, the present invention will be described in more detail by way of examples. However, the examples are merely illustrative of the present invention, and the present invention is not limited to the following examples.

[0036]

[0037] [Example 1-3] Preparation of single tablets of ilaprazole and sodium bicarbonate containing magnesium hydroxide and dried sodium carbonate as alkalizing agents and sodium bicarbonate as an antacid.

[0038] According to the ingredients and contents of Examples 1-3 in Table 1 below, a single tablet containing magnesium hydroxide and dried sodium carbonate as an alkalizing agent and sodium bicarbonate as an antacid was manufactured. The contents listed in Table 2 represent the weight (mg) per unit tablet.

[0039] (1) Granule manufacturing (wet granulation)

[0040] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binding solution. Sodium bicarbonate, magnesium hydroxide, mannitol, and crospovidone are sieved through a 30 mesh sieve and then mixed with the binding solution prepared above to prepare wet granules.

[0041] (2) Drying and establishment

[0042] The above granules are dried under conditions of an appropriate supply temperature for a drying time of approximately 1 hour, and then ground into a uniform size using a 30 mesh sieve.

[0043] (3) Preparation of post-mixture

[0044] After mixing ilaprazole and magnesium hydroxide, sift through a 30 mesh sieve. Separately, sifted through a 30 mesh sieve, pregelatinized starch, microcrystalline cellulose 102, dried sodium carbonate, and croscarmellose sodium are mixed, and then mixed with the ilaprazole mixture. Separately, sifted through a 30 mesh sieve, hydroxypropyl cellulose (Klucel EXF) is added to the mixture, mixed, and then sifted again. Sifted through a 30 mesh sieve, sodium stearyl fumarate is mixed with the mixture.

[0045] (4) Tableting and coating

[0046] The obtained mixture is compressed to produce a single matrix tablet having a hardness (kp) of an appropriate solid dosage form level, and the obtained tablet is then placed in a coating pan and subjected to primary and secondary coating.

[0047] [Table 1]

[0048]

[0049]

[0050] [Comparative Example 1] Preparation of ilaprazole and almagate single tablets containing almagate as an antacid

[0051] A single tablet containing Almagate as an antacid was manufactured according to the ingredients and contents of Comparative Example 1 in Table 1 above. The contents listed in Table 1 represent the weight (mg) per unit tablet.

[0052] (1) Granule manufacturing (wet granulation)

[0053] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binding solution. Almagate, mannitol, and crospovidone are sieved through a 30 mesh sieve and then mixed with the binding solution prepared above to prepare wet granules.

[0054] (2) Drying and establishment

[0055] The above granules are dried under conditions of an appropriate supply temperature for a drying time of approximately 1 hour, and then ground into a uniform size using a 30 mesh sieve.

[0056] (3) Preparation of post-mixture

[0057] After mixing ilaprazole and pregelatinized starch, sift through a 30 mesh sieve. Separately, microcrystalline cellulose 102 and croscarmellose sodium are sieved through a 30 mesh sieve and then mixed with the ilaprazole mixture. This mixture is mixed with the Almagate granules, and separately, hydroxypropyl cellulose (Klucel EXF) is sieved through a 30 mesh sieve and then added to the mixture, mixed, and sieved again. Sodium stearyl fumarate is sieved through a 30 mesh sieve and then mixed with the mixture.

[0058] (4) Tableting and coating

[0059] The obtained mixture is compressed to produce a single matrix tablet having a hardness (kp) of an appropriate solid dosage form level, and the obtained tablet is then placed in a coating pan and subjected to primary and secondary coating.

[0060]

[0061] [Comparative Example 2] Preparation of single tablets of ilaprazole and magnesium hydroxide containing magnesium hydroxide as an antacid

[0062] A single tablet containing magnesium hydroxide as an antacid was manufactured according to the ingredients and contents of Comparative Example 2 in Table 1 above. The contents listed in Table 1 represent the weight (mg) per unit tablet.

[0063] (1) Granule manufacturing (wet granulation)

[0064] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binding solution. Magnesium hydroxide, mannitol, and crospovidone are sieved through a 30 mesh sieve and then mixed with the binding solution prepared above to prepare wet granules.

[0065] (2) Drying and establishment

[0066] The above granules are dried under conditions of an appropriate supply temperature for a drying time of approximately 1 hour, and then ground into a uniform size using a 30 mesh sieve.

[0067] (3) Preparation of post-mixture

[0068] After mixing ilaprazole and pregelatinized starch, sift through a 30 mesh sieve. Separately, microcrystalline cellulose 102 and croscarmellose sodium are sieved through a 30 mesh sieve and then mixed with the ilaprazole mixture. This mixture is mixed with the magnesium hydroxide granules, and separately, hydroxypropyl cellulose (Klucel EXF) is sieved through a 30 mesh sieve and then added to the mixture, mixed, and then sieved again. Sodium stearyl fumarate is sieved through a 30 mesh sieve and then mixed with the mixture.

[0069] (4) Tableting and coating

[0070] The obtained mixture is compressed to produce a single matrix tablet having a hardness (kp) of an appropriate solid dosage form level, and the obtained tablet is then placed in a coating pan and subjected to primary and secondary coating.

[0071]

[0072] [Comparative Example 3] Preparation of a single tablet of ilaprazole and sodium bicarbonate containing magnesium stearate as a lubricant and sodium bicarbonate as an antacid.

[0073] A single tablet containing sodium bicarbonate as an antacid was manufactured according to the ingredients and contents of Comparative Example 3 in Table 1 above. The contents listed in Table 1 represent the weight (mg) per unit tablet.

[0074] (1) Granule manufacturing (wet granulation)

[0075] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binding solution. Sodium bicarbonate, mannitol, and crospovidone are sieved through a 30 mesh sieve and then mixed with the binding solution prepared above to prepare wet granules.

[0076] (2) Drying and establishment

[0077] The above granules are dried under conditions of an appropriate supply temperature for a drying time of approximately 1 hour, and then ground into a uniform size using a 30 mesh sieve.

[0078] (3) Preparation of post-mixture

[0079] After mixing ilaprazole and pregelatinized starch, sift through a 30 mesh sieve. Separately, microcrystalline cellulose 102 and croscarmellose sodium are sieved through a 30 mesh sieve and then mixed with the ilaprazole mixture. This mixture is mixed with the sodium bicarbonate granules, and separately, hydroxypropyl cellulose (Klucel EXF) is sieved through a 30 mesh sieve and then added to the mixture, mixed, and then sieved again. Magnesium stearate is sieved through a 30 mesh sieve and then mixed with the mixture.

[0080] (4) Tableting and coating

[0081] The obtained mixture is compressed to produce a single matrix tablet having a hardness (kp) of an appropriate solid dosage form level, and the obtained tablet is then placed in a coating pan and subjected to primary and secondary coating.

[0082]

[0083] [Comparative Examples 4 and 5] Preparation of single tablets of ilaprazole and sodium bicarbonate containing sodium bicarbonate as an antacid

[0084] A single tablet containing sodium bicarbonate as an antacid was manufactured according to the ingredients and contents of Comparative Examples 4 and 5 in Table 2 below. The contents listed in Table 2 represent the weight (mg) per unit tablet.

[0085] (1) Granule manufacturing (wet granulation)

[0086] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binding solution. Sodium bicarbonate, mannitol, and crospovidone are sieved through a 30 mesh sieve and then mixed with the binding solution prepared above to prepare wet granules.

[0087] (2) Drying and establishment

[0088] The above granules are dried under conditions of an appropriate supply temperature for a drying time of approximately 1 hour, and then ground into a uniform size using a 30 mesh sieve.

[0089] (3) Preparation of post-mixture

[0090] After mixing ilaprazole and pregelatinized starch, sift through a 30 mesh sieve. Separately, microcrystalline cellulose 102 and croscarmellose sodium are sieved through a 30 mesh sieve and then mixed with the ilaprazole mixture. This mixture is mixed with the sodium bicarbonate granules, and separately, hydroxypropyl cellulose (Klucel EXF) is sieved through a 30 mesh sieve and then added to the mixture, mixed, and then sieved again. Sodium stearyl fumarate is sieved through a 30 mesh sieve and then mixed with the mixture.

[0091] (4) Tableting and coating

[0092] The obtained mixture is compressed to produce a single matrix tablet having a hardness (kp) of an appropriate solid dosage form level, and the obtained tablet is then placed in a coating pan and subjected to primary and secondary coating.

[0093]

[0094] [Table 2]

[0095]

[0096]

[0097] [Comparative Example 6] Preparation of ilaprazole and magnesium hydroxide cored tablets containing magnesium hydroxide as an antacid

[0098] A cored tablet containing magnesium hydroxide as an antacid was manufactured according to the ingredients and contents of Comparative Example 6 in Table 2 above. The contents listed in Table 2 represent the weight (mg) per unit tablet.

[0099] (1) Preparation of the inner core (ilaprazole layer)

[0100] 1) Manufacturing of granules

[0101] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binder solution. Magnesium hydroxide, microcrystalline cellulose 101, mannitol, and crospovidone are separately sieved through a 30 mesh sieve and then mixed. This mixture is mixed with the binder solution to prepare wet granules.

[0102] 2) Drying and establishment

[0103] The above granules are dried for about 1 hour under conditions of an appropriate supply temperature, and then ground into a uniform size using a 30 mesh sieve.

[0104] 3) Preparation of post-mixture

[0105] After mixing ilaprazole and pregelatinized starch, sift through a 30 mesh sieve. Separately, microcrystalline cellulose 102 and croscarmellose sodium are sieved through a 30 mesh sieve, and then hydroxypropyl cellulose (Klucel EXF) is sieved through a 30 mesh sieve and added to the mixture, mixed, and sieved again. Sodium stearyl fumarate is sieved through a 30 mesh sieve and mixed with the mixture.

[0106] 4) Tajeong

[0107] The resulting mixture is compressed to produce an inner core layer having a hardness (kp) of an appropriate solid formulation level.

[0108] (2) Manufacturing of the outer layer (wet granulation)

[0109] 1) Manufacturing of granules

[0110] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binder solution. Separately, mannitol and crospovidone are sieved through a 30 mesh sieve and mixed. This mixture is mixed with the binder solution to prepare wet granules.

[0111] 2) Drying and establishment

[0112] The above granules are dried at about 80°C for about 1 hour, and then ground into a uniform size using a 30 mesh sieve.

[0113] 3) Preparation of post-mixture

[0114] Croscarmellose sodium and microcrystalline cellulose 102 are sieved through a 30 mesh sieve and then mixed. This mixture is mixed with the above-mentioned sieved material, and then sodium stearyl fumarate sieved through a 30 mesh is added and mixed.

[0115] 4) Tableting and coating

[0116] The obtained mixture and the inner core are compressed together to produce a cored tablet having a hardness (kp) of an appropriate solid dosage form level, and then the obtained tablet is placed in a coating pan and subjected to primary and secondary coating.

[0117]

[0118] [Comparative Example 7] Preparation of ilaprazole and sodium bicarbonate cored tablets containing sodium bicarbonate as an antacid

[0119] A cored tablet containing sodium bicarbonate as an antacid was manufactured according to the ingredients and contents of Example 7 in Table 2 above. The contents listed in Table 2 represent the weight (mg) per unit tablet.

[0120] (1) Preparation of the inner core (ilaprazole layer)

[0121] 1) Manufacturing of granules

[0122] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binder solution. Separately, sodium bicarbonate, microcrystalline cellulose 101, mannitol, and crospovidone are sieved through a 30-mesh sieve and then mixed. This mixture is mixed with the binder solution to prepare wet granules.

[0123] 2) Drying and establishment

[0124] The above granules are dried for about 1 hour under conditions of an appropriate supply temperature, and then ground into a uniform size using a 30 mesh sieve.

[0125] 3) Preparation of post-mixture

[0126] After mixing ilaprazole and pregelatinized starch, sift through a 30 mesh sieve. Separately, microcrystalline cellulose 102 and croscarmellose sodium are sieved through a 30 mesh sieve and then mixed with the ilaprazole mixture. Separately, hydroxypropyl cellulose (Klucel EXF) is sieved through a 30 mesh sieve, mixed with the mixture, and then sieved again. Sodium stearyl fumarate is sieved through a 30 mesh sieve and then mixed with the mixture.

[0127] 4) Tajeong

[0128] The resulting mixture is compressed to produce an inner core layer having a hardness (kp) of an appropriate solid formulation level.

[0129] (2) Manufacturing of the outer layer (wet granulation)

[0130] 1) Manufacturing of granules

[0131] Hydroxypropyl cellulose (HPC-SL) is dissolved in a mixture of water and ethanol to prepare a binder solution. Separately, mannitol and crospovidone are sieved through a 30 mesh sieve and mixed. This mixture is mixed with the binder solution to prepare wet granules.

[0132] 2) Drying and establishment

[0133] The above granules are dried for about 1 hour under conditions of an appropriate supply temperature, and then ground into a uniform size using a 30 mesh sieve.

[0134] 3) Preparation of post-mixture

[0135] Croscarmellose sodium and microcrystalline cellulose 102 are sieved through a 30 mesh sieve and then mixed. This mixture is mixed with the above-mentioned sieved material, and then sodium stearyl fumarate sieved through a 30 mesh is added and mixed.

[0136] 4) Tableting and coating

[0137] The obtained mixture and the inner core are compressed together to produce a cored tablet having a hardness (kp) of an appropriate solid dosage form level, and then the obtained tablet is placed in a coating pan and subjected to primary and secondary coating.

[0138]

[0139] In addition, a high-content formulation (1100 mg) and a low-content formulation (500 mg) of sodium bicarbonate disclosed in Chinese patent CN103432127A were manufactured in the same manner and designated as Comparative Examples 8 and 9, respectively, and a cored tablet containing sodium bicarbonate as an antacid disclosed in Korean Patent Publication No. 10-2024-0078782 was manufactured and designated as Comparative Example 10.

[0140]

[0141] [Example 1] Acid-reduction test

[0142] For the above Examples 1 to 3 and Comparative Examples 1 to 10, the additives included as antacids and alkalizing agents corresponding to the prescriptions of each example were each added to a mixture of 100 mL of pH 1.2 buffer solution and 200 mL of purified water, and the pH was measured over time while stirring. The detailed results are as shown in Table 3 and Figure 1 below.

[0143]

[0144] [Table 3]

[0145]

[0146]

[0147] From the above results, it was confirmed that the formulations of Example 2, Example 3, Comparative Example 2, Comparative Example 5, Comparative Example 6, Comparative Example 8, and Comparative Example 10 made the pH of the artificial gastric juice mixture into a neutral environment, and in particular, it was confirmed that the antacid effect of Example 3 was excellent.

[0148] In addition, judging from the results of Examples 1 to 3, the pH of the artificial gastric juice mixture significantly increased due to the addition of an alkalizing agent, and in the case of Example 3, even though a small amount of sodium bicarbonate was used, it exhibited an antacid effect equivalent to or greater than that of Comparative Examples 5 and 8, which used an excess amount of sodium bicarbonate.

[0149]

[0150] [Test Example 2] Stability test of ilaprazole in artificial gastric fluid mixture

[0151] For the above Examples 1 to 3 and Comparative Examples 1 to 10, additives included as antacids and alkalizing agents were each mixed in an artificial gastric fluid mixture, and then ilaprazole solution (20 mg / 20 mL) was added, and the stability of ilaprazole over time was confirmed. 60 mL of pH 1.2 buffer solution and 200 mL of purified water were mixed and used as an artificial gastric fluid mixture, and the results are as shown in Table 4 and Fig. 2 below.

[0152]

[0153] [Table 4]

[0154]

[0155]

[0156] As can be seen from Examples 1 to 3 of Table 4 above, it was confirmed that the stability of ilaprazole significantly improved as the ratio of the alkalizing agent, magnesium hydroxide, and dried sodium carbonate increased.

[0157] In the case of Example 3, it showed stability similar to that of Comparative Example 5, which is a high-content sodium bicarbonate preparation (1100 mg), and Comparative Example 8, which is a high-content sodium bicarbonate preparation (1100 mg) disclosed in Chinese patent CN103432127A, and showed a better effect in preventing decomposition of ilaprazole after 30 minutes.

[0158] In addition, when compared with the cored tablet containing sodium bicarbonate as an antacid (Comparative Example 10) disclosed in Example 3 and Korean Patent Publication No. 10-2024-0078782, the stability of ilaprazole over time was similar, suggesting that the stability of ilaprazole was sufficiently maintained due to the alkalizing agent despite the use of a small amount of sodium bicarbonate.

[0159]

[0160] [Test Example 3] Solubility Test

[0161] The additives included as antacids and alkalizing agents in the tablets of the above examples were each mixed in 100 mL of a pH 1.2 buffer solution, 20 mg of ilaprazole was added, and the solubility was compared through analysis of the content of ilaprazole over time. Detailed results are shown in Table 5 and Figure 3 below.

[0162]

[0163] [Table 5]

[0164]

[0165]

[0166] As a result of the solubility test, it was confirmed that the solubility of ilaprazole in Example 3 was significantly high at all time points.

[0167] This suggests that, compared to Comparative Example 5, which is a high-content sodium bicarbonate preparation (1100 mg), and Comparative Example 8, which is a high-content sodium bicarbonate preparation (1100 mg) disclosed in Chinese patent CN103432127A, it can exhibit excellent bioavailability despite the use of about 45% of sodium bicarbonate as an antacid.

[0168] In addition, compared to Comparative Example 10, which is a core-filled tablet containing sodium bicarbonate as an antacid disclosed in Korean Patent Publication No. 10-2024-0078782, it was confirmed that a tablet exhibiting high solubility of ilaprazole can be manufactured even with a simple manufacturing method.

[0169] This suggests that a simple manufacturing method can not only ensure better bioavailability through small amounts of antacids and alkalizing agents, but also improve medication compliance by reducing tablet size.

[0170]

[0171] [Test Example 4] Storage Stability Test

[0172] Stability tests were performed on the tablets obtained from the manufacture of the above examples under long-term storage conditions (25 ± 2°C, 60RH ± 5%, 6 months) and accelerated storage conditions (40 ± 2°C, 75RH ± 5%, 6 months). The content of ilaprazole and the content of total flexible substances were analyzed, and the detailed results are shown in Tables 6 and 7 below.

[0173]

[0174] [Table 6]

[0175]

[0176]

[0177] [Table 7]

[0178]

[0179]

[0180] Based on the above results, it was confirmed that the formulation of Example 3 had excellent stability in terms of content and flexible substances, and was shown to meet the standards under accelerated conditions of 6 months and long-term conditions of 12 months.

[0181] On the other hand, in the case of Comparative Examples 2, 4, 5, and 8, it was confirmed that the total flexible material exceeded the standard (2.5%) in the 4th week of the accelerated test, and in the case of Comparative Example 9, it was confirmed that the total flexible material exceeded the standard (2.5%) in the 2nd week of the accelerated test, and in the case of Comparative Example 6, which was manufactured as a cored tablet to improve stability, it was expected that the flexible material would be unsuitable in the 3rd month of the accelerated test, judging from the increasing trend.

[0182] In addition, based on the stability test results of Comparative Example 9, a low-content sodium bicarbonate formulation (500 mg) disclosed in Chinese patent CN103432127A, and Comparative Example 4, a similar formulation, it was confirmed that there was a significant difference depending on the manufacturing method, and it was confirmed that the storage stability of ilaprazole could be significantly improved through a manufacturing method in which ilaprazole is mixed with a binder solution and then mixed by post-mixing rather than granulating.

[0183] In addition, in the case of Comparative Example 10, a core-coated tablet containing sodium bicarbonate as an antacid disclosed in Korean Patent Publication No. 10-2024-0078782, it is expected to be unsuitable after 6 months of accelerated testing, judging from the increasing trend of total flexible substances, and the stability test result of the core-coated tablet in the above patent already shows that the content of total flexible substances is above the standard after 6 months of accelerated testing, so it can be seen that the formulation does not ensure sufficient stability.

[0184] Therefore, based on the above results, it was confirmed that the stability of ilaprazole can be increased by the manufacturing method of adding ilaprazole as a post-mixture and the addition of an alkalizing agent, and it was confirmed that the tablet obtained according to the present invention (Example 3) is a single tablet that exhibits long-term stability without a complicated manufacturing process.

[0185]

[0186] [Test Example 5] Evaluation of dissolution rate

[0187] In this study, for preclinical testing, the dissolution rate of the tablet of Example 3 was compared with that of a commercially available enteric-coated tablet (Noltec Tab. 10 mg, IL-Yang Pharmaceutical Co., Ltd) to confirm the in vitro dissolution pattern. In addition, the dissolution rate of Comparative Example 8, a high-content sodium bicarbonate preparation (1100 mg) disclosed in Chinese patent CN103432127A, was also evaluated. The detailed results are shown in Table 8 and Fig. 4 below.

[0188]

[0189] [Table 8]

[0190]

[0191]

[0192] As a result of the comparative dissolution test of Example 3 and Noltec 10 mg, similar dissolution patterns were shown, and as a result of the equivalence judgment through the similarity factor (f2) according to the pharmaceutical equivalence test standards, the value of the similarity factor (f2) was 61.95, which is a value higher than the standard value of 50, so the dissolution patterns were judged to be equivalent.

[0193] In addition, compared to Comparative Example 8, which is a high-content sodium bicarbonate preparation (1100 mg), it shows a fast and high dissolution pattern, so it can be said that the tablet obtained according to the present invention (Example 3) is a combination preparation that improves the bioavailability of ilaprazole through a small amount of antacid and alkalizing agent, and has improved convenience of taking the medication due to the small size of the tablet.

[0194]

[0195] [Experimental Example 6] Pharmacokinetic (PK) Evaluation in Beagle Dogs

[0196] Pharmacokinetic (PK) evaluations were performed on the test drug (Example 3) manufactured according to the present invention and the control drug (commercially available enteric-coated tablet (Noltec Tab. 10 mg x 2 tablets, IL-Yang Pharmaceutical Co., Ltd) using beagle dogs. The concentration of ilaprazole in the plasma of beagle dogs was measured using the LC-MS / MS analysis method, and the pharmacokinetic parameters obtained for 12 beagle dogs are shown in Table 9 and Figure 5 below.

[0197]

[0198] [Table 9]

[0199]

[0200]

[0201] From the results in Table 9 and Figure 5 above, it was confirmed that the Tmax of the test drug was very fast at 0.5 hr, and the T / R ratio of AUC was at an equivalent level at 1.09.

[0202] Therefore, in summary of the above results, the tablet obtained according to the present invention can be said to be a combination preparation containing a small amount of an antacid and an alkalizing agent, which quickly neutralizes the acidic condition of the stomach, thereby improving the bioavailability and stability of ilaprazole, and which has a simple manufacturing process and a small tablet size, thereby improving the convenience of taking the medication.

Claims

1. Ilaprazole or a pharmaceutically acceptable salt thereof; An antacid selected from sodium bicarbonate, magnesium hydroxide, magnesium oxide, almagate, hydrotalcite, precipitated calcium carbonate, and mixtures thereof; and A pharmaceutical composition in tablet form comprising an alkalizing agent; The content of ilaprazole is 10 to 40 mg per unit tablet. Pharmaceutical composition.

2. A pharmaceutical composition according to claim 1, characterized in that the content of ilaprazole is 10 mg to 20 mg per unit tablet.

3. A pharmaceutical composition according to claim 1, characterized in that the antacid is sodium bicarbonate and the content of sodium bicarbonate is 500 mg to 700 mg per unit tablet.

4. A pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is a single-layer tablet, a double-layer tablet, or a cored tablet.

5. A pharmaceutical composition according to claim 1, characterized in that it disintegrates within 30 minutes in a disintegration test performed according to the general test method of the Korean Pharmacopoeia in an aqueous medium having a pH of 1.

2.

6. A pharmaceutical composition according to claim 1, characterized in that it disintegrates within 20 minutes in a disintegration test performed according to the general test method of the Korean Pharmacopoeia in an aqueous medium having a pH of 1.

2.

7. A pharmaceutical composition according to claim 1, characterized in that 75% or more of ilaprazole is dissolved within 1 hour.

8. A pharmaceutical composition according to claim 1, characterized in that the alkalizing agent is at least one selected from the group consisting of magnesium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, calcium hydroxide, dried sodium carbonate, magnesium carbonate, calcium carbonate, potassium phosphate, sodium phosphate, pharmaceutically acceptable salts thereof, and mixtures thereof.

9. A pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition further comprises at least one additive selected from the group consisting of a diluent, a disintegrant, a binder, and a lubricant.

10. In paragraph 9, the diluent is at least one selected from the group consisting of lactose, microcrystalline cellulose, crystalline cellulose, D-mannitol, D-sorbitol, pregelatinized starch, and calcium hydrogen phosphate; the disintegrant is at least one selected from the group consisting of sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose calcium; and the binder is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and microcrystalline cellulose. A pharmaceutical composition characterized in that the above-mentioned lubricant is selected from the group consisting of stearic acid, calcium silicate, stearic acid salt, corn starch, talc, light anhydrous silicic acid, calcium hydrogen phosphate, magnesium silicate, and talc.

11. A pharmaceutical composition according to claim 10, characterized in that the diluent is at least one selected from the group consisting of mannitol, pregelatinized starch, and microcrystalline cellulose.

12. In paragraph 11, the content of mannitol is in the range of 1.0 to 5.0 wt% based on the total amount of the formulation, and the content of pregelatinized starch is in the range of 2.0 to 5.0 wt% based on the total amount of the formulation. A pharmaceutical composition characterized in that the particle size of microcrystalline cellulose is in the range of 90 to 140 μm and the content thereof is in the range of 5.0 to 10.0 wt% based on the total amount of the formulation.

13. A pharmaceutical composition according to claim 10, characterized in that the disintegrant is at least one selected from the group consisting of crospovidone and croscarmellose sodium.

14. A pharmaceutical composition according to claim 13, characterized in that the particle size of crospovidone is in the range of 40 to 120 μm, the content of mannitol is in the range of 1.0 to 5.0 wt% based on the total amount of the formulation, and the content of croscarmellose sodium is in the range of 1.0 to 3.0 wt% based on the total amount of the formulation.

15. A pharmaceutical composition according to claim 10, characterized in that the binder is hydroxypropyl cellulose.

16. In the 15th paragraph, the hydroxypropyl cellulose has a viscosity of 3.0 to 5.9 mPa·s and is characterized by a range of 0.5 to 1.5 wt% based on the total amount of the preparation; and A pharmaceutical composition comprising a viscosity of 300 to 600 cps and characterized by a range of 0.5 to 1.5 wt% based on the total amount of the formulation.

17. A pharmaceutical composition according to claim 8, characterized in that the alkalizing agent is at least one selected from the group consisting of magnesium hydroxide and dried sodium carbonate.

18. A pharmaceutical composition according to claim 17, characterized in that the content of magnesium hydroxide is in the range of 3.0 to 6.0 wt% based on the total amount of the formulation, and the content of dried sodium carbonate is in the range of 5.0 to 10.0 wt% based on the total amount of the formulation.

19. A pharmaceutical composition according to claim 10, characterized in that the active agent is sodium stearyl fumarate.

20. A pharmaceutical composition according to claim 19, characterized in that the content of sodium stearyl fumarate is in the range of 1.0 to 2.0 wt% based on the total amount of the formulation.

21. A method for manufacturing the pharmaceutical composition of paragraph 1, (a) preparing a pharmaceutically acceptable mixture comprising sodium bicarbonate and an alkalizing agent in an amount of 400 to 800 mg per unit tablet; (b) a step of granulating the mixture to produce a granule and then drying it; and (c) A manufacturing method comprising a step of adding ilaprazole and an alkalizing agent in an amount of 10 to 40 mg per unit tablet to the granules and mixing them.

22. A manufacturing method according to claim 21, characterized in that the mixture of step (a) contains sodium bicarbonate in an amount of 500 mg to 700 mg.

23. A manufacturing method according to claim 21, characterized in that the content of ilaprazole in step (c) is 10 mg to 20 mg per unit tablet.

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