COMPOSITE PHARMACEUTICAL FORMULATION COMPRISING A PROTON PUMP INHIBITOR AND AN ANTACID.

Abstract

One aspect provides a composite pharmaceutical formulation comprising: a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as the active ingredient, a disintegrant, and a binder; and a second layer comprising, as the active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide, or a mixture thereof.

Description

The present disclosure relates to a compound pharmaceutical formulation that includes a proton pump inhibitor and an antacid and, more particularly, to a compound formulation having improved stability and an improved dissolution rate. BACKGROUND OF THE TECHNIQUE Gastroesophageal diseases, such as peptic ulcer disease and gastroesophageal reflux disease, occur when the attack factor prevails over the defensive factor of the mucosa in the esophagus, stomach, and duodenum, and rapid suppression of gastric acid is required to protect digestive tract diseases from gastric acid attack. Proton pump inhibitors (PPIs) inhibit a proton pump (H+ / K+-ATPase) in parietal cells and are drugs that suppress the production of hydrochloric acid and weaken the acidity in the digestive system. The drug shows its medicinal effect on indigestion, gastroesophageal reflux disease, pharyngeal reflux disease or peptic ulcer disease. In particular, a compound based on benzimidazole or a salt thereof is used as a treatment for peptic ulcer that has an action - 2 proton pump inhibitor, and some examples of this include omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole. However, such proton pump inhibitors present the problem of easily decomposing or deforming under acidic conditions. For example, esomeprazole easily decomposes in acid and is affected by moisture, heat, organic solvents, and light. As a consequence, formulation stability and drug dissolution rate can easily be reduced. To prevent this, a method of stabilizing the formulation by adding various excipients or coating it with an enteric polymer can be considered, but the compatibility of the proton pump inhibitor and the excipients included in the compound formulation is poor, resulting in poor formulation stability or delayed expression of the drug's efficacy. For example, Korean Patent Publication No.° 10-2008-0005575 proposes a stabilization method by coating with an enteric polymer to improve the stability of a benzimidazole-based proton pump inhibitor, but when a drug is prepared using this method, a relatively large amount of an enteric polymer or excessive additives are required, and decomposition of the drug may not be avoided due to unavoidable exposure. - 3 to gastric acid when the enteric coating layer is lost and the onset of drug action is delayed. Therefore, there is a need to develop a formulation capable of improving compatibility with excipients in a compounded formulation, improving the stability and dissolution rate of a proton pump inhibitor in a gastric acid environment, and providing a rapid onset of drug action. DESCRIPTION OF THE PROJECTS TECHNICAL PROBLEM An embodiment of the present disclosure provides a compound pharmaceutical formulation that includes a proton pump inhibitor or a pharmaceutically acceptable salt thereof, the compound formulation having improved stability and dissolution rate. SOLUTION According to one aspect of one or more embodiments, a compound pharmaceutical formulation comprises: a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as the active ingredient, a disintegrant, and a binder; and a second layer comprising, as the active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide, or a mixture thereof. Specific solutions to the problems are as follows. (1) A compound pharmaceutical formulation comprising a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant and a binder; and a second layer comprising, as an active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide or a mixture thereof. (2) The proton pump inhibitor is one selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole and a mixture of these. (3) The disintegrant is one selected from the group consisting of crospovidone, sodium starch glycolate and a mixture of these. (4) The binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone and a mixture thereof. (5) The amount of disintegrant is in a range of about 0.5 wt% to about 5.5 wt% based on the total weight of the first layer. (6) The amount of binder is in a range of about 5% pa to about 15% w based on the total weight of the first layer. (7) The amount of binder is in a range of about 1.5 parts to about 4.5 parts by weight based on 1 part by weight of the disintegrant included in the first layer. (8) The amount of disintegrant is in a range of about 0.9% pa to about 5% w based on the total weight of the first layer and the amount of binder is in a range of about 1.9 parts to about 4.5 parts by weight based on 1 part by weight of the disintegrant included in the first layer. (9) The amount of disintegrant is in a range of about 0.95 + pa to about 5 wt% based on the total weight of the first layer and the amount of binder is in a range of about 5 wt% to about 15 wt% based on the total weight of the first layer. (10) The compound formulation is a bi-layer tablet. (11) When tested on a mixture solution including 75 mL of 0.1 N HC1 and 225 mL of purified water at approximately 75+2 revolutions per minute (rpm) at a temperature of 37+0.5 °C according to the second method (paddle method) of the United States Pharmacopeia (USP) dissolution test, the compound formulation has - 6 simultaneously, for 10 minutes, a dissolution rate of the proton pump inhibitor in a range of about 10% to about 50% and a dissolution rate of the antacid of about 70% or greater. (12) The compound formulation simultaneously has, for 5 minutes, a dissolution rate of the proton pump inhibitor in a range of about 5% to about 30% and a dissolution rate of the antacid of about 60% or higher. FAVORABLE EFFECTS OF THE DISCLOSURE A compound pharmaceutical formulation according to one embodiment may have improved stability and dissolution rate, exhibit no discoloration during long-term storage since the stability of the properties is improved, and may reduce the total amount of related substances generated during storage, thereby improving the product quality. In addition, the compound formulation can release the proton pump inhibitor and the antacid at different times for each layer and thus has an excellent effect of preventing the degradation of the proton pump inhibitor caused by acid even in a low pH environment of gastric juice in the body. In addition, the compound formulation can provide a proton pump inhibitor. - 7 fast-acting protons by improving the dissolution rate of the proton pump inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A shows the changes in properties according to the compatibility of the excipient components included with esomeprazole in a tablet; FIG. 1B shows the changes in properties according to the compatibility of esomeprazole and ethanol; FIG. 1C shows the changes in properties of the compounded formulations prepared in the Examples 2 and 4 and Comparative Example 3; FIG. 2 is a graph showing the total contents of related substances (%) of the composite formulations prepared in Examples 2 and 4 and Comparative Example 3 according to a test under adverse conditions; FIG. 3 is a graph showing the dissolution rate (%) of esomeprazole as a function of dissolution time (min) of the compound formulations prepared in Examples 1 to 3 and Comparative Examples 1 and 2; FIG. 4 is a graph showing the dissolution rate (%) of esomeprazole as a function of dissolution time (min) of the compound formulations prepared in Examples 2, 5 and 6 and Comparative Examples 4 to 6; FIG. 5 is a graph showing the pH of the composite formulation as a function of the dissolution rate (%) of the magnesium hydroxide included in the composite formulation prepared in Example 2; and FIG. 6 is a graph showing the dissolution rate (%) of the magnesium hydroxide as a function of the dissolution time (min) of the composite formulations prepared in Examples 1 to 3 and Comparative Examples 1 and 2. DETAILED DESCRIPTION OF THE INVENTION Hereinafter, this disclosure will be described in more detail. Unless otherwise defined, all technical terms used herein have the same meaning as those commonly interpreted by one skilled in the art to which this disclosure pertains. Furthermore, although preferred methods or samples are described herein, similar or equivalent descriptions are included within the scope of this disclosure. All publications mentioned herein by reference are incorporated by reference in their entirety. According to one embodiment of the present disclosure, there is provided a compound pharmaceutical formulation comprising a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant and a binder; and - 9 a second layer comprising, as an active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide or a mixture of these. As used herein, the term proton pump inhibitor (PPI) refers to any drug that has pharmacological activity as a Ph-K* ATPase (proton pump) inhibitor, and forms of a PPI include salts, esters, amides, enantiomers, isomers, tautomers, prodrugs, and derivatives of known PPI-type inhibitor drugs. The final step in gastric acid secretion in the body is the release of H'-K' ATPase (proton pump) into the gastric lumen and the translocation of K ions into the gastric lumen, where the proton pump inhibitor significantly suppresses gastric acid secretion by inhibiting the pump. In one embodiment, the proton pump inhibitor may be one selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole, and a mixture thereof. Esomeprazole ((S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzimidazole) is the (S) optical isomer known for its excellent safety and efficacy among the two optical isomers of omeprazole. Lansoprazole (2-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2- 10 yl]methanesulfinyl}-1Η-1,3-benzodiazole) is marketed under the brand name Lanston. A pharmaceutically acceptable salt of the proton pump inhibitor is any pharmaceutically acceptable salt that can be commonly used in the art, and examples of the salt may include a metal salt such as a magnesium (Mg) salt, a strontium (Sr) salt, a lithium salt, a sodium salt, a potassium salt, or a calcium salt; or an ammonium salt, but embodiments are not limited thereto. Furthermore, the proton pump inhibitor or a pharmaceutically acceptable salt thereof may be used in the form of an anhydride or hydrate, such as a monohydrate, dihydrate, or trihydrate. For example, the proton pump inhibitor or a pharmaceutically acceptable salt thereof may be a magnesium salt of esomeprazole or lansoprazole. For example, the proton pump inhibitor may be esomeprazole magnesium trihydrate. As used herein, the term disintegrant refers to a material that absorbs moisture to promote disintegration of a formulation and can be used to enhance dissolution of a drug product. The disintegrant can be at least one selected from the group consisting of corn starch, crospovidone, polyvinylpyrrolidone (PVP), sodium starch glycolate, substituted hydroxypropyl cellulose, low-density starch, and hydroxypropyl cellulose. - 11 pregelatinized, alginic acid, sodium alginate and a mixture thereof, but the embodiments are not limited to these. In one embodiment, the disintegrant comprised in the first layer of the composite formulation may be one selected from the group consisting of crospovidone, sodium starch glycolate, and a mixture thereof. The disintegrant exhibits excellent compatibility when combined with the proton pump inhibitor. The disintegrant shows no discoloration when mixed with a proton pump inhibitor, such as esomeprazole, has excellent stability of properties, and can improve product quality by reducing the amount of related substances produced. Residual solvents in pharmaceutical products refer to volatile organic chemicals used or generated in the manufacturing process of drug substances or excipients, or in the manufacturing process of formulations. Since none of the residual solvents have therapeutic benefits, they must be removed to a level suitable for product standards, Good Manufacturing Practices (GMP), or other quality standards (Guide for Residual Solvents in Drug Products, Korea Food and Drug Administration). As a method of analyzing residual solvents, a chromatographic method such as - 12 gas chromatography. For example, croscarmellose sodium involves an extraction process of aqueous alcohols such as ethanol in the synthesis process (Handbook of Pharmaceutical Excipients, 6th Edition). Therefore, the use of croscarmellose sodium in the manufacturing process is not economical because additional analysis of the residual ethanol solvent in the formulation is required. Since the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, and a mixture thereof, according to one embodiment, it does not include ethanol and is therefore not subjected to a residual ethanol solvent test. Thus, despite the disintegrant being included, there is no inconvenience in performing a separate analysis of the residual ethanol solvent in the final formulation. Furthermore, ethanol was determined to exhibit poor stability when combined with esomeprazole (FIG. IB). The amount of disintegrant comprised in the first layer of the compound formulation according to one embodiment was sufficient to prevent acidic decomposition of the proton pump inhibitor in the first layer of the compound formulation in the stomach and to dissolve at least about 80% of the proton pump inhibitor during the 60 minutes of the dissolution test measurement. - 13 The amount of disintegrant comprised in the first layer of the composite formulation may be in a range of from about 0.01 to about 6.5 wt.-%, from about 0.1 wt.-% to about 6 wt.-%, from about 0.5 wt.-% to about 5.5 wt.-%, from about 0.5 wt.-% to about 5 wt.-%, from about 0.9 wt.-% to about 5 wt.-%, based on the total weight of the first layer. When the amount of disintegrant is within these ranges, the proton pump inhibitor and antacid present in different layers of the composite formulation exhibit release with a difference in time for each layer and, because the antacid in the composite formulation is released first followed by the release of the proton pump inhibitor, decomposition of the inhibitor by gastric acid can be avoided and a desired dissolution rate can be obtained. The amount of disintegrant included in the first layer of the composite formulation according to one embodiment may be shown based on the total weight of the formulation, and may be in a range of about 0.01% pa to about 5 ip, for example, from about 0.01% pa to about 2.2% w, from about 0.05% ρ to about 2 ” w, from - 14 approximately 0.3 ipa approximately 2 1 po of approximately 0.1% pa approximately 1.7 ip, based on the total weight of the formulation. As used herein, the term binder refers to a material used to cause adhesion of powder particles in a formulation. The binder may be hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose), polyvinylpyrrolidone, pregelatinized starch, or a combination thereof, but embodiments are not limited to these. In one embodiment, the binder included in the first layer of the composite formulation may be one selected from the group consisting of hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, and a mixture thereof. The amount of binder comprised in the first layer of the composite formulation according to one embodiment was sufficient to prevent acidic decomposition of the proton pump inhibitor in the first layer of the composite formulation in the stomach and to dissolve at least about 80% of the proton pump inhibitor during the 60 minutes of the dissolution test measurement. The amount of binder included in the first layer of the composite formulation may be in a range of about 4% p to about 18% p, from about 4.1 p to about 16% p, from about 1.5 p to about 20% p. - 15 approximately 5% pa approximately 15 ipo of approximately 7% pa approximately 14 ip, depending on the total weight of the first layer. The amount of binder included in the first layer of the composite formulation may be shown based on the total weight of the formulation and may be in a range of about 0.01% pa to about 5% wt, for example, about 1% pa to about 5% wt, about 1.5 ipa to about 5.5% wt, based on the total weight of the formulation. In one embodiment, the amount of binder included in the first layer of the composite formulation may be in a range of about 1.5 parts to about 4.5 parts by weight based on 1 part by weight of the disintegrant included in the first layer. For example, the amount of binder may be in a range of about 1.5 parts to about 4.0 parts by weight or about 2 parts to about 4 parts by weight. For example, the amount of binder included in the first layer of the composite formulation may be in a range of about 1.5 parts to about 4.5 parts by weight based on 1 part by weight of the disintegrant in the first layer, for example, crospovidone, sodium starch glycolate, and a mixture thereof. - 16In the first layer of the composite formulation according to one embodiment, the amount of disintegrant may be in a range of about 0.5 wt% to about 5.5 wt% based on the total weight of the first layer and the amount of binder may be in a range of about 5 wt% to about 15 wt% based on the total weight of the first layer. In the first layer of the composite formulation according to one embodiment, the amount of disintegrant may be in a range of about 0.95 wt% to about 5 wt% based on the total weight of the first layer and the amount of binder may be in a range of about 5 wt% to about 15 wt% based on the total weight of the first layer. Furthermore, in the first layer of the composite formulation according to one embodiment, the amount of disintegrant may be in a range of about 0.9 wt% to about 5 wt% based on the total weight of the first layer and the amount of binder may be in a range of about 5 wt% to about 15 wt% based on the total weight of the first layer. In addition, the amount of disintegrant may be in a range of approximately 0.5% pa - 17 about 6% wt based on the total weight of the first layer and the amount of binder may be in a range of about 1.5 parts to about 10 parts by weight based on 1 part by weight of the disintegrant in the first layer. Furthermore, the amount of disintegrant may be in a range of about 0.9% pa to about 5% wt based on the total weight of the first layer and the amount of binder may be in a range of about 1.9 parts to about 4 parts by weight based on 1 part by weight of the disintegrant in the first layer. When the amount of disintegrant in the first layer of the composite formulation according to one embodiment is in a range of about 3 wt % to about 6 wt % based on the total weight of the first layer, the amount of binder in the first layer may be in a range of more than about 1 part to less than about 5 parts by weight based on 1 part by weight of the disintegrant. For example, the amount of binder in the first layer of the composite formulation may be in a range of about 1.5 parts to about 4.5 parts by weight based on 1 part by weight of the disintegrant. For example, the amount of binder in the first layer of the composite formulation - 18 may be in a range of about 1.5 parts to about 4.0 parts by weight or about 2 parts to about 4 parts by weight, based on 1 part by weight of the disintegrant. Furthermore, when the amount of disintegrant may be in a range of about 3% pa ​​to about 5.5% wt based on the total weight of the first layer, the amount of binder may be in a range of about 1.5 parts to about 4.5 parts by weight based on 1 part by weight of the disintegrant in the first layer. Furthermore, when the amount of disintegrant may be in a range of about 3% pa ​​to about 4% wt based on the total weight of the first layer, the amount of binder may be in a range of about 2 parts to about 4 parts by weight based on 1 part by weight of the disintegrant in the first layer. When the amounts of disintegrant and binder are within these ranges, the proton pump inhibitor and antacid present in different layers of the composite formulation can ensure a release with a difference in time for each layer and, because the formulation is controlled to release the antacid from the composite formulation first and then release - 19 the proton pump inhibitor, the decomposition of the drug by gastric acid can be avoided and a desired dissolution rate of the proton pump inhibitor can be obtained. As used herein, the term "antacid" or "antacid agent" refers to a compound capable of relieving the common sensation of heartburn (or pyrosis) due to acid hypersecretion. Furthermore, antacids refer to drugs that act either directly on excess gastric acid and gastroesophageal reflux, i.e., by buffering the pH of the gastric mucosa, or indirectly, for example, by inhibiting acid secretion from the stomach. For example, antacids include substances that reduce all symptoms manifested either indirectly by inhibiting acid secretion at the gastric level or directly by neutralizing the effect of gastric acidity. In one embodiment, the antacid may be magnesium hydroxide, magnesium oxide, sodium bicarbonate, potassium carbonate or a mixture thereof and may preferably be magnesium hydroxide, magnesium oxide or a mixture thereof. For example, the amount of antacid may be in the range of about 2 parts to about 20 parts by weight, about 4 parts - 20 to about 16 parts by weight or about 6 parts to about 10 parts by weight, based on 1 part by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof included in the compounded formulation. In addition, the amount of antacid may be in a range of about 1 to about 70 wt. %, about 10 to about 60 wt. %, about 20 to about 55 wt. %, or about 20 to about 50 wt. %, based on the total weight of the compounded formulation. In addition, the amount of antacid may be in a range of about 1 to about 90 wt. %, about 10 to about 80 wt. %, or about 20 to about 10 wt. %, based on the total weight of the second layer. The composite formulation may further include an additive selected from a diluent, a binder, a disintegrant, a lubricant, a fluidizer, and a mixture thereof. In one embodiment, the composite formulation may include a diluent, a binder, a disintegrant, a lubricant, or a mixture thereof in the first layer. In one embodiment, the composite formulation may include a diluent, a disintegrant, a fluidizer, a lubricant, or a mixture thereof in the first layer. - 21 As used herein, the term diluent refers to a material that increases the volume of a formulation. The diluent may be at least one selected from the group consisting of microcrystalline cellulose, lactose, dextrin, mannitol, sorbitol, starch, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, saccharides, and mixtures thereof, but embodiments are not limited thereto. For example, the total amount of diluent included in the compounded formulation is in a range of about 1% w / w to about 50% w / w, about 10% w / w to about 40% w / w, about 30% w / w to about 50% p / o, about 20% w / w to about 30% w / w, based on the total weight of the formulation.Furthermore, the amount of diluent comprised in the first layer of the composite formulation is in a range of from about 1 μg to about 90 wt. %, from about 20 wt. % to about 80 wt. % to about 40 wt. % to about 75 wt. %, based on the total weight of the first layer. The amount of diluent comprised in the second layer of the composite formulation is in a range of from about 1 μg to about 60 wt. %, from about 10 wt. % to about 50 wt. %, from about 20 wt. % to about 40 wt. %, based on the total weight of the second layer. - 22 As used herein, the term binder may be at least one selected from hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose), polyvinylpyrrolidone, pregelatinized starch, or a mixture thereof, but embodiments are not limited thereto. For example, the total amount of binder in the formulation may be in a range of about 0.05% w / w to about 20% w / w, about 0.1% w / w to about 15% w / w, about 0.1% w / w to about 10% w / w, or about 1.0% w / w to about 5% w / w, based on the total weight of the formulation. As used herein, disintegrant refers to a material that is used to enhance the dissolution of a drug by promoting disintegration of a formulation, which may be at least one selected from the group consisting of croscarmellose sodium, corn starch, crospovidone, polyvinylpyrrolidone (PVP), sodium starch glycolate, low substituted hydroxypropyl cellulose, pregelatinized starch, alginic acid, sodium alginate, and a mixture thereof, but embodiments are not limited thereto. For example, the total amount of disintegrant in the formulation may be in a range of about 0.05% w / w to about 20% w / w, about 0.1% w / w to about 10% w / w, or about 1% - 23 pa approximately 5% w, based on the total weight of the formulation. As used herein, the term lubricant refers to a material that improves the fluidity of particulate materials to increase the filling property in a die, which is the lower part of the tablet forming machine and, thereby, reduces friction between the particulate materials or between the particulate materials, the punch, which is the upper part of the tablet forming machine, and the die to facilitate compression and release of the tablets. The lubricant may be at least one selected from the group consisting of stearic acid, stearic acid salt, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, talc and mixtures thereof, but embodiments are not limited thereto.For example, the total amount of lubricant included in the compound formulation may be in a range of from about 0.01% pa to about 10% wt, from about 0.05% pa to about 5% wt, from about 0.5% pa to about 3% wt, from about 0.06% pa to about 1 wt, based on the total weight of the formulation. In addition, the amount. - 24 of lubricant included in the first layer of the composite formulation may be in a range of about 0.05% pa to about 20 1 p, about 0.1% pa to about 10% p o to about 0.5% pa to about 5% p o, based on the total weight of the first layer in the formulation. The amount of lubricant included in the second layer of the composite formulation may be in a range of about 0.01% pa to about 10 1 p, about 0.01% pa to about 5 1 p o to about 0.05 1 pa to about 3 rp, based on the total weight of the second layer in the formulation. As used herein, the term “flowable” refers to a component that improves the flow characteristics of the active ingredients, excipients, or mixtures thereof included in a compounded formulation and may be included to maximize the effect without affecting other components. The flowable may be at least one selected from the group consisting of silicon dioxide, colloidal silicon dioxide, talc, and mixtures thereof, but embodiments are not limited thereto. In one embodiment, the flowable included in the second layer of the compounded formulation may be colloidal silicon dioxide. For example, the total amount of flowable included in the compounded formulation may be in a range of - 25 about 0.1% pa about 10 ip, about 0.1% pa about 5 1 po about 0.5 ipa about 3 p, based on the total weight of the formulation. The amount of fluidizer included in the second layer of the composite formulation may be in a range of about 0% pa about 10 1 p, about 0.5% pa about 5% po about 1% pa about 3% p, based on the total weight of the second layer in the formulation. The amount of disintegrant included in the second layer of the composite formulation according to one embodiment may be in a range of about 0% pa to about 10% wt, about 0.1 1% pa to about 7% wt, about 0.1% pa to about 5% p o to about 1 1 pt to about 3 1 pt, based on the total weight of the second layer in the formulation. The amount of disintegrant included in the second layer of the composite formulation may be shown based on the total weight of the formulation and may be in a range of about 0.01% pa to about 5% pa, for example, about 0.05% pa to about 3% pa ​​to about 0.5% pa. - 26 approximately 2.5 ip, depending on the total weight of the formulation. Furthermore, any pharmaceutical additive commonly used in the art may be included in the formulation in a suitable amount. For example, at least one additive selected from the group consisting of a surfactant, an antioxidant, a preservative, a stabilizer, a flavoring agent, a colorant, a solubilizer, a pH adjusting agent, a coating agent, and any combination thereof may be further included, and embodiments are not limited thereto. The coating agent may be at least one selected from the group consisting of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and mixtures thereof, but embodiments are not limited to these. The compound formulation according to one embodiment may be a tablet, a capsule, or a granule. For example, the compound formulation may be in the form of a multi-layer tablet, such as a bi-layer tablet or a tri-layer tablet, or a tablet-in-a-tablet, where the hardness of the tablet may be, for example, in a range of about 10 kP to about 20 kP. For example, when the compound formulation is a bi-layer tablet, the formulation - 27 composite may comprise: a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as active ingredient, a disintegrant and a binder; and a second layer comprising, as active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide or a mixture thereof. Furthermore, for example, when the composite formulation is a tri-layer tablet, the composite formulation may comprise: a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as the active ingredient, a disintegrant, and a binder; a second layer comprising, as the active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide, or a mixture thereof; and at least one additional layer. Furthermore, for example, when the compound formulation is a bilayer tablet, the compound formulation may comprise: an inner layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as the active ingredient, a disintegrant, and a binder; and an outer layer comprising, as the active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide, or a mixture thereof. The compound formulation according to one embodiment may be a multi-layer tablet, for example, a bi-layer tablet, and the proton pump inhibitor - 28 and the antacid present in different layers can be released with a difference in time for each layer. For example, when the antacid present in the antacid-containing layer of the composite formulation is released first to increase the pH in the stomach and then the proton pump inhibitor present in the proton pump inhibitor-containing layer is released to neutralize the acidic environment of the stomach, the decomposition of the proton pump inhibitor by gastric acid can be prevented. The compound formulation is a compound pharmaceutical formulation comprising a proton pump inhibitor and an antacid as active ingredients, and unlike marketed enteric formulations, the antacid in the compound formulation rapidly neutralizes gastric acid without enteric coating to prevent the decomposition of the proton pump inhibitor, and the proton pump inhibitor is rapidly diluted and absorbed in the body, which does not delay the expression of the drug's efficacy. In addition, the compound formulation prevents the decomposition of the proton pump inhibitor in the stomach according to a release having a difference in time for the proton pump inhibitor and the antacid, improves stability and thus can provide a compound pharmaceutical composition showing a pattern of - 29 optimal drug release. In one embodiment, the total amount of related substances of the proton pump inhibitor or a pharmaceutically acceptable salt thereof in the compounded formulation is based on 2.0% or less with respect to the total weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof. The total amount of related substances can be stored in a 60 °C adverse stability chamber for 7 days and measured under the test conditions of Experimental Example 2. In one embodiment, when tested in a mixing solution including 75 mL of 0.1 N HC1 and 225 mL of purified water at about 75 revolutions per minute (rpm) at a temperature of 37±0.5°C according to the second method (paddle method) of the United States Pharmacopeia (USP) dissolution test, the compounded formulation simultaneously has, for 10 minutes, a dissolution rate of the proton pump inhibitor in a range of from about 10% to about 50% and a dissolution rate of the antacid of about 70% or higher. The dissolution test can be measured using two tablets of the compounded formulation according to one embodiment. In one embodiment, the compound formulation may simultaneously have a dissolution rate of the proton pump inhibitor in a range of - 30 approximately 5% to approximately 30 1 and an antacid dissolution rate of approximately 60 í or greater. As used herein, numerical ranges represented using the expression from ... to include ranges having the numerical values ​​shown before and after a as the lower limit and the upper limit, respectively. The expression approximately or approximately indicates that the stated value may vary to some extent. For example, the value may vary by 10%, 5%, 2%, or 1%. For example, the expression approximately 5 includes any value between 4.5 and 5.5, between 4.75 and 5.25, between 4.9 and 5.1, or between 4.95 and 5.05. As used herein, numerical values ​​are considered to include the meaning of approximately even when not specified. The expression has, may have, includes or may include indicates the presence of the corresponding characteristics (for example, numerical values ​​or elements such as components) and does not exclude the presence of additional characteristics. Hereinafter, the present disclosure will now be described in detail with reference to the following examples. However, these examples are presented for illustrative purposes only and are not intended to limit - 31 the scope of any of the embodiments of this disclosure. EXAMPLES Examples 1 to 6: Preparation of bilayer tablets containing esomeprazole and magnesium hydroxide Bi-layer tablets containing esomeprazole as the active ingredient and magnesium hydroxide as an antacid according to the compositions shown in Table 1. Esomeprazole magnesium trihydrate (40 mg as esomeprazole), microcrystalline cellulose (Avrcel™ PH101), hydroxypropylcellulose, crospovidone, and sodium starch glycolate were mixed for 10 minutes. Sodium stearyl fumarate was added as a lubricant to the mixture and mixed for 5 minutes to prepare a final mixture of the top layer components. Magnesium hydroxide, microcrystalline cellulose (PH101) and crospovidone were mixed for 10 minutes. The mixture was compressed using a roller compressor (TF-1A60, Freund vector) with a hydraulic pressure of 5 MPa, a feed speed of 5 rpm and a roller speed of 1 rpm to form flakes, and the flakes were classified with a sieve having a mesh size of 0.8 mm. Colloidal silicon dioxide (Aerosil) was added as a fluidizer to the resulting classified product and mixed for 5 minutes, and then sodium stearyl fumarate was added to the mixture as a lubricant and mixed for minutes to prepare a final mixture of the bottoms. In Example 4, sodium starch glycolate was added instead of crospovidone. The final mixture of the upper part and the final mixture of the lower part were compressed to form a tablet using a tablet forming machine (Autotab-200TR, Ichihashi Seiki) to prepare a bilayer tablet (with a hardness of 18 kp). The compositions of the pharmaceutical formulations composed according to Examples 1 to 6 are shown in Table 1. TABLE 1 Component (unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Esomeprazole magnesium trihrhydrate Cellulose 44.5 44 . 5 44.5 44.5 44.5 44.5 microcrystalline Hydroxypropylcellulose 184 . 9 178.5 174 . 5 178.5 185.5 167.5 slab 25.0 25.0 25.0 25.0 18.0 36.0 Crospovidone Glycolate 2.6 9.0 13.0 - 9.0 9.0 Sodium Stearyl Fumarate 9.0 Sodium 3.0 3.0 3.0 3.0 3.0 3.0 Total amount of top layer 2 60.0 260.0 260.0 260.0 260.0 260.0 Magnesium hydroxide 350.0 350.0 350.0 350.0 350.0 350.0 Microcrystalline cellulose 135.0 135.0 135.0 135.0 135.0 135.0 Crospovidone 15.0 15.0 15.0 - 15.0 15.0 Colloidal silicon dioxide 15.0 15.0 15.0 15.0 15.0 15.0 15.0 Sodium starch glycolate - - 15.0 - - Sodium stearyl fumarate 5.0 5.0 5.0 5.0 5.0 5.0 Total amount of bottom layer 520.0 520.0 520.0 520.0 520.0 520.0 Total amount of uncoated tablet 780.0 780.0 780.0 780.0 780.0 780.0 Comparative example Comparative Examples 1 to 6: Preparation of bilayer tablets containing esomeprazole and magnesium hydroxide Bilayer tablets were prepared in the same manner as in Example 1 according to the compositions shown in Table 2. The compositions of the formulations - 34 pharmaceutical compounds according to Comparative Examples 1 to 6 are shown in Table 2. TABLE 2 Component (unit: mg) Comparative example 1 Comparative example 2 Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Esomeprazole magnesium trihydrate Microcrystalline cellulose Hydroxypropyl elulose Crospovidone Croscarmellose sodium Sodium stearyl fumarate 44 . 5 187.5 25.0 3.0 44 . 5 169.5 25.0 18.0 3.0 44 . 5 178.5 25.0 9.0 3.0 44 . 5 203.5 9.0 3.0 44 . 5 194.5 9.0 9.0 3.0 44.5 158.5 45.0 9.0 3.0 Total amount of top layer 260.0 260.0 260.0 260.0 260.0 260.0 Magnesium hydroxide 350.0 350.0 350.0 350.0 350.0 350.0 Microcrystalline cellulose (PH101) 135.0 135.0 135.0 135.0 135.0 135.0 Crospovidone 15.0 15.0 - 15.0 15.0 15.0 Croscarmellose sodium - - 15.0 - - - Silicon dioxide 15.0 15.0 15.0 15.0 15.0 15.0 colloidal Sodium stearyl fumarate 5.0 5.0 5.0 5 . 0 5.0 5.0 Total amount of bottom layer 520.0 520.0 520.0 520.0 520.0 520.0 Total amount of uncoated tablet 780.0 780.0 780.0 780.0 780.0 780.0 Experimental examples Experimental Example 1: Testing the stability of properties The changes in the properties of the compounded pharmaceutical formulations were measured under the following conditions to confirm each other's compatibilities - 36 components (e.g., excipients or antacids) and esomeprazole included in the compounded formulations, and the trends of changes are shown in FIG. 1. Compatibility After esomeprazole and each of the other components were mixed in a 1:1 weight ratio, the mixtures of a predetermined amount were each compressed to form a 200 kgf tablet using a tablet forming machine (Autotab-200TR, Ichihashi Seiki). Each of the prepared tablets was packed in an HDPE bottle and stored in an adverse stability chamber at 60°C for 7 days. The changes in the properties of the tablets prepared by varying the other components mixed with esomeprazole are shown in FIG. 1A when stored for 7 days. In FIG. 1A , a formulation that included only esomeprazole as the active ingredient and did not include the other components was used as a control group. In addition, like the other components that are included together with esomeprazole, each of the test groups included an excipient selected from microcrystalline cellulose (MCC), low substituted hydroxypropyl cellulose (HPC-L), croscarmellose sodium (Primellose™), croscarmellose sodium (Acdisol™), crospovidone (Polyplasdone™ XL-10) and crospovidone (Kollidon Cl™), or magnesium hydroxide (Mg(OH)2) as an excipient. - 37 antacids, and the tablets were labeled with the names of the excipients or antacids. FIG. 1A shows the tablets from the control and test groups after 7 days of storage in the chamber. FIG. 1A shows the trend of changes in tablet properties according to the compatibilities of esomeprazole and the other components. As shown in FIG. 1A, when croscarmellose sodium (Primellose™ or AcdisolIM) was used as the excipient, discoloration of the tablets was observed to the naked eye, indicating poor property stability. Furthermore, since croscarmellose sodium contains ethanol, a separate residual solvent test should be performed when croscarmellose sodium is included as an excipient. When formulations included another component, such as microcrystalline cellulose (MCC), low-substituted hydroxypropyl cellulose (HPC-L), crospovidone (Polyplasdone™ XL-10), or crospovidone (Kollidon Cl™) as the excipient component, or magnesium hydroxide (Mg(OH)?) as the antacid, the change was negligible. Furthermore, since the excipient component does not contain ethanol as a residual solvent, a residual solvent test is not required. Furthermore, after mixing esomeprazole and ethanol with a weight ratio of 5:1, the mixture was stored in an adverse stability chamber at 60°C for 7 days. FIG. IB shows the trend of changes in properties according to the compatibility of esomeprazole and eoanol. Changes in properties were observed before (left of FIG. IB) and after (right of FIG. IB) storage of a mixture of esomeprazole and ethanol for 7 days. As shown in FIG. IB, it can be seen that discoloration occurred since the color changed significantly when esomeprazole and ethanol were mixed, compared to the initial color. Furthermore, the composite formulations prepared in Examples 2 and 4 and Comparative Example 3 were each packaged in an HDPE bottle, stored in a chamber under adverse stability conditions at 60°C for 7 days, and changes in properties were observed. FIG. 1C shows the trend of changes in the properties of the composite formulations prepared in Examples 2 and 4 and Comparative Example 3. As shown in FIG. 1C, compared with Example 2 or 4 after 7 days of storage in the chamber, the formulation of Comparative Example 3 including croscarmellose sodium as a disintegrant exhibited a significant color change compared with the initial color, and therefore, it can be seen that discoloration occurred in the formulation of Comparative Example 3. - 39 Experimental example 2: Related substance test for esomeprazole To confirm the stability of the formulations prepared in Examples 2 and 4 and Comparative Example 3, a test was carried out under adverse conditions under the same conditions as those in Experimental Example 1, and the total amounts of the related substances produced from the formulations were measured according to the analysis conditions. Analysis conditions Column: Hypersil BDS C18 100 mm x 4.6 mm, 3 pm (column temperature: 25 °C) Mobile phase A: acetonitrile:phosphate buffer (pH 7.6):water = 100:100:800 Mobile phase B: acetonitrile:phosphate buffer (pH 7.6):water = 800:10:190 (The phosphate buffers (pH 7.6) of mobile phases A and B were mixed in each case with 5.2 mL of 1.0 mol / L sodium dihydrogen phosphate and 63.0 mL of 0.5 mol / L disodium hydrogen phosphate, and water was added to prepare 1 L of buffer). Detector: Ultraviolet absorbance spectrometer (measurement wavelength 302 nm) Flow rate: 1.0 mL / min Injection volume: 20 pL Sample temperature: 4 “C - 40 FIG. 2 is a graph showing the total contents of related substances (i) of the composite formulations prepared in Examples 2 and 4 and Comparative Example 3 according to a test under adverse conditions. When the formulations prepared in Examples 2 and 4 and Comparative Example 3 were each packaged in an HDPE bottle and stored for 7 days in the 60°C harsh chamber to conduct a 4-week harsh test, as shown in FIG. 2, it can be seen that the total amounts of the related substances produced from the formulations prepared in Examples 2 and 4 were reduced compared with Comparative Example 3, met the standard content of 2.0% or less of the related substances, and exhibited excellent stability. In contrast, the formulation prepared in Comparative Example 3, after 4 weeks of the harsh test, had a total amount of related substances greater than 2.0%. From the results of evaluation of the stability of the properties and related substances according to Experimental Examples 1 and 2, it can be confirmed that crospovidone or sodium starch glycolate showed better compatibility with esomeprazole than croscarmellose sodium, which contains ethanol as a solvent. - 41 residual, and that the formulation that included crospovidone or sodium starch glycolate as a disintegrant instead of croscarmellose sodium showed relatively excellent stability. Experimental example 3: Esomeprazole dissolution test Under the following dissolution conditions and analysis conditions, the dissolution rates of esomeprazole of the formulations prepared in Examples 1 to 3 and 5 and 6 and Comparative Examples I and 2 and 4 to 6 were evaluated, and the results are shown in FIGS. 3 and 4. Dissolution conditions Eluate: 2 tablets (40 mg of esomeprazole per tablet, total of 80 mg) are evaluated in a solution prepared by mixing 75 mL of 0.1 N HC1 and 225 mL of purified water. Apparatus: 2nd method (paddle method) of the United States Pharmacopoeia (USP) dissolution test, 75 ± 2 rpm Temperature: 37 ± 0.5 °C Dissolution time: 5, 10, 15, 30, 45, 60 minutes (The collected eluate is filtered through a 0.45 pm membrane filter and then immediately mixed with 0.25 M NaOH at a ratio of 5:1 for analysis). - 42 Analysis conditions Column: Inertsil ODS-3V 150 mm x 4.6 mm, 5 pm (column temperature: 25 °C) Mobile phase: acetonitrile:phosphate buffer (pH 7.3):water = 350:500:150 (A phosphate buffer (pH 7.3) of the mobile phase was mixed with 10.5 mL of 1 mol / L sodium dihydrogen phosphate and 60.0 mL of 0.5 mol / L disodium hydrogen phosphate, and water was added to prepare 1 L of buffer.) Detector: Ultraviolet absorbance spectrometer (measurement wavelength 302 nm) Flow rate: 1.0 mL / min Injection volume: 20 pL Sample temperature: 25 °C Under these conditions, the eluate prepared by mixing 0.1 N HC1 and purified water represents the gastric juice present as 0.1 N HC1 in the stomach and the purified water as the water that humans take along with the drug to check the decomposition degree of esomeprazole, which is a proton pump inhibitor (PPI) that can be decomposed at low pH when taken by humans, and the antacid potency of the antacid. FIG. 3 is a graph showing the dissolution rate (%) of esomeprazole as a function of dissolution time (min) of the compound formulations prepared in Examples 1 to 3. - 43 3 and Comparative Examples 1 and 2. The difference between the dissolution rates of esomeprazole depending on the amounts of disintegrant in the compounded formulations can be confirmed by FIG. 3. The formulations of Examples 1 to 3 included about 1 wt. %, about 3.5 wt. %, and about 5 wt. % crospovidone as a disintegrant in the first layer, each respectively, based on the total weight of the first layer; and the formulations of Comparative Examples 1 and 2 included about 0 wt. % and about 7 wt. % crospovidone as a disintegrant in the first layer, each respectively, based on the total weight of the first layer. As shown in FIG. 3 , a difference was observed in the dissolution rates of esomeprazole depending on the amounts of disintegrant in the first layer of the bilayer tablets. Referring to FIG. 3, the dissolution rate of esomeprazole was the lowest in Comparative Example 1, and the dissolution occurred slowly due to the lack of disintegrating power of the bilayer tablet. In the case of Comparative Example 2, which refers to the results of FIG. 6, the dissolution of esomeprazole occurred faster than the increase in pH of the dissolution test solution due to the antacid in the second layer, and therefore the decomposition of the esomeprazole in an acidic medium increased. - 44 esomeprazole. The formulations of Examples 1 to 3 exhibited dissolution rates of approximately 80% or higher within 20 minutes of the dissolution test measurement, and therefore, it was considered that most of the esomeprazole in the tablets was eluted without decomposition in an acidic medium within 60 minutes, and the disintegrant rates differed depending on the amount of disintegrant. In the formulations of Examples 1 to 3, the active ingredients in the composite formulation exhibit release with a difference in time for each layer depending on the types and amounts of the excipients in the composite formulation and the antacid in the second layer of the formulation, and therefore, the formulations are considered to have a significant preventive effect on the acidic decomposition of esomeprazole.As a result, it is expected that the PPI formulation, which is unstable at low pH, can be developed into a short-acting formulation without delay in drug expression to provide greater convenience in administration. FIG. 4 is a graph showing the dissolution rate (%) of esomeprazole as a function of dissolution time (min) of the compound formulations prepared in Examples 2, 5 and 6 and Comparative Examples 4 to 6. The formulation of Example 2 was selected to include the same amount of disintegrant (the amount of - 45 disintegrant included was 3.5 1 wt based on the total weight of the first layer), but in Examples 5 and 6, the binder content ratios were changed to prepare the formulations. Accordingly, Examples 2, 5, and 6 each included a binder having a weight ratio to disintegrant of about 3:1, about 2:1, and about 4:1, respectively, in the first layer of each of the composite formulations. Furthermore, the composite formulation of Comparative Example 4 did not include any binder, and the composite formulations of Comparative Examples 5 and 6 included a binder having a weight ratio to disintegrant of about 1:1 and about 5:1, respectively, in the first layer. FIG. 4 shows the result of the dissolution of esomeprazole according to the ratios of the binder and disintegrant that were included in the first layer of the composite formulations. As shown in FIG. 4, the composite formulations of Examples 2, 5 and 6 exhibited differences in dissolution rates depending on the amount of binder, but the final dissolution rates at 60 minutes showed a similar pattern. The formulations are considered to have a significant preventive effect on the acidic decomposition of esomeprazole due to the differential release time for each layer and the - 46 antacid in the second layer. In contrast, the composite formulation of Comparative Example 4 exhibited a low dissolution rate, and it was considered that since the formulation included only the disintegrant without any binder, the release effect was reduced with a difference in time from that of the second layer, and therefore, acidic decomposition of esomeprazole occurred. In addition, the composite formulation of Comparative Example 5 included the binder with a weight ratio to the disintegrant of about 1:1 and exhibited a low dissolution rate similar to that of the composite formulation of Comparative Example 4. The composite formulation of Comparative Example 6 contained a relatively large amount of binder and therefore exhibited a low dissolution rate and a slow dissolution rate during the 60-minute measurement.The formulation of Comparative Example 6 showed a large deviation when the dissolution rate was measured, and it appears that the excessive amount of binder contained in the first layer under the dissolution test conditions weakened the antacid potency of the antacid in the second layer. Accordingly, it is considered that there will be problems related to the fact that a uniform effect of drug administration cannot be expected when the drug is administered, and the onset of drug action may appear relatively slow. From the result of FIG. 4, for. - 47 To increase the release effect with the time difference between the antacid and the PPI drug, and at the same time obtain a fast-acting PPI formulation, it is effective to include the binder in a weight ratio to the disintegrant of about 2:1 to about 4:1 in the first layer of the combined formulation. Experimental Example 4: Dissolution Test of Magnesium Hydroxide The dissolution rates of magnesium hydroxide of the composite formulations prepared in Examples 1 to 3 or Comparative Examples 1 and 2 were measured under the following dissolution conditions and analysis conditions, and the results are shown in FIGS. 5 and 6. Dissolution conditions Eluate: 2 tablets (40 mg of esomeprazole per tablet, total of 80 mg) are evaluated in a solution prepared by mixing 75 mL of 0.1 N HC1 and 225 mL of purified water. Apparatus: United States Pharmacopeia (USP) 2nd Method (Paddle Method), 75 ± 2 rpm Temperature: 37 ± 0.5 °C Analytical Conditions Detector: Atomic Absorbance Spectrometer Lamp: Magnesium Hollow Cathode Lamp Wavelength: 285.2 nm - 48 Gas used: air-acetylene FIG. 5 is a graph showing the pH of the composite formulation as a function of the dissolution rate (θ) of magnesium hydroxide included in the composite formulation prepared in Example 2. As shown in FIG. 5, the pH of the composite formulation was measured using the eluate of Experimental Example 4 when 20%, 40%, 60%, 70%, 80%, and 100% of magnesium hydroxide had been dissolved in the second layer. In FIG. 5, since about % to about 80% of the magnesium hydroxide was dissolved at the inflection point where the pH changed rapidly, it can be seen that the acidic decomposition of the proton pump inhibitor, for example, esomeprazole, in the composite formulation prepared in Example 2 can be effectively prevented based on this point. In particular, FIG. 5 shows that the pH began to rise rapidly when about 60% of the magnesium hydroxide was dissolved, and therefore, it can be seen that the proton pump inhibitor in the composite formulation can be preferentially dissolved when about 60% or more of magnesium hydroxide is released to ensure stability. FIG. 6 is a graph showing the dissolution rate (%) of magnesium hydroxide as a function of dissolution time (min) of the composite formulations prepared in Examples 1 to 3 and Comparative Examples 1 and 2. As shown in FIG. 6, the magnesium hydroxide in the second layer of the composite formulation prepared in Example 2 exhibited dissolution rates of about 64% and about 70% at 5 minutes and 10 minutes, respectively. The magnesium hydroxide in the second layer of the composite formulations prepared in Examples 1 to 3 and Comparative Examples 1 and 2 all exhibited a similar dissolution rate pattern, and it can be seen that the dissolution of the magnesium hydroxide is not influenced by the composition of the first layer in the composite formulation. Considering both the results in FIG. 6 and the results in FIG. 3, the acidic decomposition of esomeprazole in the composite formulation prepared in Example 2 was effectively prevented, and thus, it was confirmed that the composite formulation exhibited a stable dissolution rate of esomeprazole. Considering both the results in FIG. 6 and the results in FIGS. 3 and 4, esomeprazole in the first layer of the composite formulations prepared in Comparative Examples 2, 5, and 6 was eluted by about 30% or more and about 50% or more at 5 minutes and 10 minutes, respectively, which was an eluting rate of about 10%. - 50 faster dissolution than magnesium hydroxide, and it was confirmed that the compound formulations had unstable dissolution rates due to acidic decomposition of esomeprazole in an acidic environment. Although illustrative embodiments have been shown and described particularly with reference to the illustrative embodiments thereof, it will be understood by those skilled in the art that various changes may be made in the form and details thereof without departing from the nature and scope of the illustrative embodiments as defined in the following claims. The described embodiments are to be considered for descriptive purposes only and not for limiting purposes. Therefore, the scope of the disclosure is not defined by the detailed description of the disclosure but by the appended claims (and equivalents thereof), and all differences within the scope shall be construed as being included in the present disclosure. It is noted that in relation to this date, the best method known to the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A compound pharmaceutical formulation comprising: a first layer comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant and a binder; and a second layer comprising, as an active ingredient, an antacid selected from magnesium hydroxide, magnesium oxide or a mixture thereof.

2. The pharmaceutical formulation of claim 1, wherein the proton pump inhibitor is one selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole and a mixture thereof.

3. The pharmaceutical formulation of claim 1, wherein the disintegrant is one selected from the group consisting of crospovidone, sodium starch glycolate, and a mixture thereof.

4. The pharmaceutical formulation of claim 1, wherein the binder is one selected from the group consisting of hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone and a mixture thereof.

5. The pharmaceutical formulation of claim 1, wherein the amount of disintegrant is in the range of approximately 0.5% by weight - approximately 5.5% by weight depending on the total weight of the first layer.

6. The pharmaceutical formulation of claim 1, wherein the amount of binder is in the range of approximately 5% ρ to approximately 15% p depending on the total weight of the first layer.

7. The pharmaceutical composition of claim 1, wherein the amount of binder is in the range of approximately 1.5 parts to approximately 4.5 parts by weight based on 1 part by weight of the disintegrant comprising the first layer.

8. The pharmaceutical composition of claim 1, wherein the amount of disintegrant is in the range of approximately 0.9% to approximately 5% by weight based on the total weight of the first layer and the amount of binder is in the range of approximately 1.9 parts to approximately 4.5 parts by weight based on 1 part by weight of the disintegrant in the first layer.

9. The pharmaceutical composition of claim 1, wherein the amount of disintegrant is in the range of approximately 0.95 to 5% (p) based on the total weight of the first layer and the amount of binder is in the range of approximately 5 to 15% (p) based on the total weight of the first layer.

10. The compound pharmaceutical formulation of claim 1, wherein the compound formulation is a bi-layer tablet.

11. The compound pharmaceutical formulation of claim 1, wherein, when a test is performed on a mixture solution comprising 75 mL of 0.1 N HCl and 225 mL of purified water at approximately 75±2 revolutions per minute (rpm) at a temperature of 3710.5 °C according to the second method (paddle method) of the United States Pharmacopeia (USP) dissolution test, the compound formulation simultaneously has, for 10 minutes, a dissolution rate of the proton pump inhibitor in the range of approximately 10 to approximately 50% and a dissolution rate of the antacid of approximately 70% or higher.

12. The composite pharmaceutical composition of claim 1, wherein the composite formulation simultaneously has, for 5 minutes, a dissolution rate of the proton pump inhibitor in the range of approximately 5% to approximately 30% and a dissolution rate of the antacid of approximately 60% or higher.