Pharmaceutical composition containing amorphous tegoprazan and method for preparing same

Abstract

The present invention relates to a pharmaceutical composition containing amorphous tegoprazan and a method for preparing same. More specifically, the present invention relates to a pharmaceutical composition containing amorphous tegoprazan and a method for preparing same, the method comprising the steps of: dissolving amorphous tegoprazan, a mesoporous silica-based compound, and a water-soluble polymer in an organic solvent to prepare a binding solution containing amorphous tegoprazan; spraying the binding solution on a carrier in a fluidized bed processor and then drying same to prepare primary granules; dissolving 0.5-10 parts by weight of a water-soluble polymer in water to prepare an aqueous solution of the water-soluble polymer; and spraying the aqueous solution of the water-soluble polymer on the primary granules and then drying same to prepare secondary granules. Therefore, the pharmaceutical composition does not undergo a transition to a crystalline state and has excellent stability during storage.

Description

Pharmaceutical composition comprising amorphous tegoprazan and method for preparing the same

[0001] The present invention relates to a pharmaceutical composition comprising amorphous tegoprazan and a method for preparing the same.

[0002] Amorphous tegoprazan is a solid state that lacks regular arrangement and is thermodynamically unstable due to its high energy levels. Therefore, it is prone to crystalline transformation over time, and is particularly unstable under high temperature and humidity conditions, preventing it from maintaining its amorphous state and further accelerating crystallization.

[0003] There are three methods for producing or maintaining an amorphous state. First, the solid dispersion method is a method for producing an amorphous solid dispersion by dissolving or suspending a hydrophobic drug together with a hydrophilic matrix. This method can produce a solid dispersion using a fluidized bed processor, a cylindrical granulator, a high-speed rotary granulator, and spray drying. Second, there is the hot-melt method, which produces a solid dispersion by heat-melting a hydrophobic drug, a hydrophilic matrix, and a surfactant without using a solvent. Third, there is milling, a mechanical crushing method that reduces the degree of crystallinity, converting the regular arrangement of crystals into an irregular arrangement to produce an amorphous form.

[0004] However, a method for ensuring that a pharmaceutical composition containing amorphous tegoprazan maintains a stable amorphous form has not yet been discovered, and in particular, a method for preparing a composition that prevents conversion to a crystalline form and stably maintains an amorphous form even under harsh or accelerated conditions is not known.

[0005] The present inventors have discovered a method for preparing a pharmaceutical composition comprising amorphous tegoprazan, which enables the amorphous tegoprazan to maintain a stable amorphous form, and have completed the present invention.

[0006] The present invention aims to provide a pharmaceutical composition comprising amorphous tegoprazan.

[0007] The present invention aims to provide a method for preparing a pharmaceutical composition comprising amorphous tegoprazan.

[0008] 1. A pharmaceutical composition comprising 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica compound, and 1 to 20 parts by weight of a water-soluble polymer.

[0009] 2. A pharmaceutical composition in the above 1, wherein the mesoporous silica compound is at least one selected from the group consisting of mesoporous silica, mesoporous silicate, mesoporous calcium silicate, magnesium aluminate metasilicate, siloid, and silsol.

[0010] 3. A pharmaceutical composition in the above 1, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0011] 4. A pharmaceutical composition further comprising 30 to 150 parts by weight of at least one excipient selected from the group consisting of mannitol, sorbitol, refined sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose in the above 1.

[0012] 5. A pharmaceutical composition further comprising 1 to 30 parts by weight of at least one disintegrant selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and alginic acid in the above 1.

[0013] 6. A pharmaceutical composition further comprising 0.1 to 5 parts by weight of a lubricant selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, anhydrous silicic acid, talc, colloidal silicon dioxide, silicon dioxide, glyceryl behenate, and mineral oil in the above 1.

[0014] 7. A pharmaceutical composition manufactured in any one dosage form selected from the group consisting of tablets, capsules, liquids, powders, granules, and granules in the above 1.

[0015] 8. In the above 1, the mesoporous silica-based compound is a pharmaceutical composition having a pore diameter of 2 to 50 nm.

[0016] 9. A method for producing a pharmaceutical composition, comprising: a step of dissolving 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 0.5 to 10 parts by weight of a water-soluble polymer in an organic solvent to produce a binder solution containing amorphous tegoprazan; a step of spraying the binder solution onto a carrier in a fluidized bed process unit and then drying to produce primary granules; a step of dissolving 0.5 to 10 parts by weight of the water-soluble polymer in water to produce a water-soluble polymer aqueous solution; and a step of spraying the water-soluble polymer aqueous solution onto the primary granules and then drying to produce secondary granules.

[0017] 10. A method for producing a pharmaceutical composition in the above 9, wherein the mesoporous silica compound is at least one selected from the group consisting of mesoporous silica, mesoporous silicate, mesoporous calcium silicate, magnesium aluminate metasilicate, siloid, and silsol.

[0018] 11. A method for producing a pharmaceutical composition, wherein in the above 9, the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl pyrrolidone vinyl acetate, and polyvinyl alcohol.

[0019] 12. A method for producing a pharmaceutical composition in the above 9, wherein the carrier is at least one selected from the group consisting of mannitol, sorbitol, refined sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose.

[0020] 13. A method for producing a pharmaceutical composition, further comprising the step of mixing 30 to 150 parts by weight of an excipient, 1 to 30 parts by weight of a disintegrant, and 0.1 to 5 parts by weight of a lubricant into the secondary granules in 9 above.

[0021] 14. A method for producing a pharmaceutical composition, wherein in the above 13, the excipient is at least one selected from the group consisting of mannitol, sorbitol, refined white sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose.

[0022] 15. A method for producing a pharmaceutical composition according to the above 13, wherein the disintegrant is at least one selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and alginic acid.

[0023] 16. A method for producing a pharmaceutical composition according to the above 13, wherein the lubricant is at least one selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, anhydrous silicic acid, talc, colloidal silicon dioxide, silicon dioxide, glyceryl behenate, and mineral oil.

[0024] A pharmaceutical composition comprising amorphous tegoprazan manufactured by the manufacturing method of the present invention can stably maintain an amorphous form.

[0025] The pharmaceutical composition comprising the amorphous tegoprazan of the present invention comprises a mesoporous silica-based compound, so that the amorphous tegoprazan can be impregnated or adsorbed into the pores of the mesoporous silica-based compound to stably maintain the amorphous form.

[0026] The pharmaceutical composition comprising amorphous tegoprazan manufactured by the manufacturing method of the present invention can maintain an amorphous form more stably by using a water-soluble polymer dissolved together with the amorphous tegoprazan and the mesoporous silica-based compound.

[0027] The pharmaceutical composition comprising the amorphous tegoprazan of the present invention can maintain an amorphous state in a stable manner without transformation into a crystalline form under long-term test conditions, accelerated test conditions, and harsh conditions. The amorphous form was maintained even after storage for 6 months under the accelerated test conditions or 4 weeks under harsh conditions.

[0028] The pharmaceutical composition comprising amorphous tegoprazan manufactured by the manufacturing method of the present invention has higher storage stability and amorphous stability than when the pharmaceutical composition is manufactured using a direct tableting method and a wet granulation method.

[0029] Figures 1a to 1c show the results of measuring the phase transition temperatures of crystalline form A, crystalline form B, and amorphous tegoprazan using differential scanning calorimetry.

[0030] Figures 2a to 2c show the results of measuring X-ray powder diffraction spectra of crystalline form A, crystalline form B, and amorphous tegoprazan.

[0031] FIGS. 3a to 3l are results of confirming amorphous stability by measuring X-ray powder diffraction spectra of a pharmaceutical composition containing amorphous tegoprazan of the present invention. FIGS. 3a to 3d are results at the start of an experiment under harsh conditions, FIGS. 3e to 3h are results 4 weeks after the start of an experiment under harsh conditions, and FIGS. 3i to 3l are results 6 months after the start of an experiment under accelerated conditions.

[0032] Figures 4a to 4d show the results of measuring the X-ray powder diffraction spectrum of a composition containing amorphous tegoprazan that does not contain a mesoporous silica-based compound. Figures 4a and 4b show the results at the start of the experiment under accelerated conditions, and Figures 4c and 4d show the results one month after the start of the experiment under accelerated conditions.

[0033] The present invention provides a pharmaceutical composition comprising amorphous tegoprazan and a method for preparing the same.

[0034] The present invention relates to a pharmaceutical composition comprising amorphous tegoprazan and a method for preparing the same, and more particularly, to a pharmaceutical composition comprising amorphous tegoprazan, which does not undergo conversion into a crystalline form and has excellent stability during storage, and a method for preparing the same, comprising the steps of: dissolving amorphous tegoprazan, a mesoporous silica-based compound, and a water-soluble polymer in an organic solvent to prepare a binder solution containing amorphous tegoprazan; spraying the binder solution onto a carrier in a fluidized bed process unit and then drying the same to prepare primary granules; dissolving 0.5 to 10 parts by weight of a water-soluble polymer in water to prepare a water-soluble polymer aqueous solution; and spraying the water-soluble polymer aqueous solution onto the primary granules and then drying the same to prepare secondary granules.

[0035] The present invention provides a pharmaceutical composition comprising 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 1 to 20 parts by weight of a water-soluble polymer.

[0036] Tegoprazan is a compound represented by the following chemical formula 1, and refers to a raw material of a medicine used for the prevention and treatment of diseases or conditions such as gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease, peptic ulcers, gastric ulcers, duodenal ulcers, ulcers induced by NSAIDs, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, salivary secretion, airway disorders, and asthma.

[0037] [Chemical Formula 1]

[0038]

[0039] The tegoprazan of the present invention is amorphous. Amorphous tegoprazan is a solid that does not form a regular arrangement, is thermodynamically unstable due to its high energy levels, and tends to crystallize over time. In particular, under harsh or accelerated conditions such as high temperature or humidity, crystallization can be accelerated, accelerating the time of transformation into a crystalline form.

[0040] A mesoporous silica-based compound is a porous material containing a large number of pores with a diameter of 2 to 50 nm. Since the mesoporous compound has numerous pores and a large surface area, and thus has excellent atom or molecule adsorption properties, the mesoporous silica-based compound can allow the dissolved amorphous tegoprazan in the present invention to be impregnated or adsorbed into the pores to maintain a stable amorphous form. The mesoporous silica-based compound of the present invention may refer to any one or more selected from the group consisting of mesoporous silica, mesoporous silicate, mesoporous calcium silicate, magnesium aluminate metasilicate, Syloid™, and Silsol™. The mesoporous silica-based compound of the present invention may have a pore diameter of 2 to 50 nm.

[0041] Mesoporous silica may be mesoporous silicon dioxide.

[0042] In one embodiment, the mesoporous silica is silicon dioxide having a pore size of 2 to 50 nm and an average particle size of 2 to 40 μm.

[0043] Syloid is a porous amorphous silica with numerous pores, a large internal surface area, and a strong affinity for organic solvents. Among the syloids, SYLOID® 244 FP SILICA, commercially available from Grace, can be used as an excipient in pharmaceuticals and exhibits excellent compatibility with active ingredients.

[0044] The pore volume of the syloid is 1.6 mL / g, and the average particle size can be 2.5 to 3.7 μm.

[0045] SILSOL®, a mesoporous silica, can enhance drug bioavailability by delivering active ingredients in an amorphous form and maintain sustained stability by preventing crystallization and recrystallization. Among these, SILSOL®, commercially available from Grace, can be used as an excipient in pharmaceuticals and exhibits excellent compatibility with active ingredients.

[0046] The pore size of the silk may be 2 to 50 nm, and the average particle size may be 37 μm.

[0047] A water-soluble polymer may refer to a polymeric substance that dissolves in water. The water-soluble polymer of the present invention can be dissolved in a solution of amorphous tegoprazan and a mesoporous silica-based compound, thereby enabling tegoprazan to maintain an amorphous form more stably and improving fluidity and tableting properties. The water-soluble polymer of the present invention can function as a binder.

[0048] The water-soluble polymer of the present invention may be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0049] The pharmaceutical composition of the present invention may comprise 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 1 to 20 parts by weight of a water-soluble polymer.

[0050] In the pharmaceutical composition of the present invention, the mesoporous silica-based compound may be included in an amount of 25 to 165 parts by weight based on 45 to 55 parts by weight of amorphous tegoprazan, for example, 25 to 165 parts by weight, 25 to 150 parts by weight, 25 to 135 parts by weight, 25 to 125 parts by weight, 25 to 110 parts by weight, 25 to 95 parts by weight, 25 to 80 parts by weight, 25 to 65 parts by weight, 30 to 65 parts by weight, 35 to 60 parts by weight, 35 to 55 parts by weight, 40 to 55 parts by weight, or 45 to 55 parts by weight.

[0051] In the pharmaceutical composition of the present invention, the weight ratio of the mesoporous silica compound to the amorphous tegoprazan may be 1:0.5 to 1:3, for example, 1:0.5 to 1:2.5, 1:0.5 to 1:2, or 1:0.5 to 1:1.5.

[0052] In one embodiment, silicon dioxide was included in a weight ratio of 1:1 to amorphous tegoprazan.

[0053] In the pharmaceutical composition of the present invention, the water-soluble polymer may be included in an amount of 1 to 20 parts by weight based on 45 to 55 parts by weight of amorphous tegoprazan, for example, 1 to 20 parts by weight, 3 to 18 parts by weight, 5 to 16 parts by weight, 7 to 14 parts by weight, or 9 to 12 parts by weight.

[0054] In the pharmaceutical composition of the present invention, the water-soluble polymer may be included in an amount of 1 to 20 wt% of the pharmaceutical composition.

[0055] In one embodiment, the water-soluble polymer comprised 4.85 wt% of the pharmaceutical composition.

[0056] In one embodiment, hydroxypropyl cellulose was included in a weight ratio of 1:0.2 to amorphous tegoprazan.

[0057] The pharmaceutical composition of the present invention may further comprise an excipient.

[0058] The excipient may be at least one selected from the group consisting of mannitol, sorbitol, refined sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose.

[0059] In the pharmaceutical composition of the present invention, the excipient may be included in an amount of 30 to 150 parts by weight based on 45 to 55 parts by weight of amorphous tegoprazan, for example, 30 to 150 parts by weight, 30 to 130 parts by weight, 30 to 110 parts by weight, 30 to 90 parts by weight, 30 to 70 parts by weight, 30 to 50 parts by weight, or 30 to 40 parts by weight.

[0060] In one embodiment, 15.3 g of microcrystalline cellulose and 15.3 g of pregelatinized starch were included for 50 g of amorphous tegoprazan.

[0061] The pharmaceutical composition of the present invention may further comprise a disintegrant.

[0062] The disintegrant may be at least one selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and alginic acid.

[0063] In the pharmaceutical composition of the present invention, the disintegrant may be included in an amount of 1 to 30 parts by weight based on 45 to 55 parts by weight of amorphous tegoprazan, for example, 1 to 20 parts by weight, 1 to 15 parts by weight, 1 to 10 parts by weight, 1 to 9 parts by weight, 2 to 9 parts by weight, 3 to 9 parts by weight, 3 to 8 parts by weight, or 4 to 8 parts by weight.

[0064] In one embodiment, 50 g of amorphous tegoprazan contained 1.9 g of croscarmellose sodium and 5.5 g of crospovidone.

[0065] In one embodiment, 50 g of amorphous tegoprazan contained 3.7 g of croscarmellose sodium and 3.7 g of crospovidone.

[0066] In one embodiment, 50 g of amorphous tegoprazan contained 1.0 g of croscarmellose sodium and 3.7 g of crospovidone.

[0067] The pharmaceutical composition of the present invention may further include a lubricant.

[0068] The lubricant may be at least one selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, anhydrous silicic acid, talc, colloidal silicon dioxide, silicon dioxide, glyceryl behenate, and mineral oil.

[0069] In the pharmaceutical composition of the present invention, the lubricant may be included in an amount of 0.1 to 5 parts by weight based on 45 to 55 parts by weight of amorphous tegoprazan, for example, 0.1 to 5 parts by weight, 0.1 to 4 parts by weight, 0.1 to 3 parts by weight, 0.1 to 2 parts by weight, or 0.1 to 1 part by weight.

[0070] In one embodiment, 0.5 g of sodium stearate was included for 50 g of amorphous tegoprazan.

[0071] The pharmaceutical composition of the present invention can be prepared in various dosage forms, such as tablets, capsules, liquids, powders, granules, and granules. The formulation method can be performed according to the method described in the examples of the present invention.

[0072] If the pharmaceutical composition of the present invention is a tablet, it may additionally include a coating layer on the outside, and the coating layer may be formed according to a film coating layer forming method commonly used on the surface of a tablet.

[0073] The present invention provides a method for preparing a pharmaceutical composition comprising amorphous tegoprazan.

[0074] The method for preparing a pharmaceutical composition comprising amorphous tegoprazan of the present invention comprises the steps of: dissolving 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 0.5 to 10 parts by weight of a water-soluble polymer in an organic solvent to prepare a binder solution containing amorphous tegoprazan; spraying the binder solution onto a carrier in a fluidized bed process unit and then drying to prepare primary granules; dissolving 0.5 to 10 parts by weight of the water-soluble polymer in water to prepare a water-soluble polymer aqueous solution; and spraying the water-soluble polymer aqueous solution onto the primary granules and then drying to prepare secondary granules.

[0075] The method for preparing a pharmaceutical composition comprising amorphous tegoprazan of the present invention comprises the step of preparing a binding solution comprising amorphous tegoprazan by dissolving amorphous tegoprazan, a mesoporous silica-based compound, and a water-soluble polymer in an organic solvent.

[0076] Tegoprazan is a compound represented by the following chemical formula 1, and refers to a raw material of a medicine used for the prevention and treatment of diseases or conditions such as gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease, peptic ulcers, gastric ulcers, duodenal ulcers, ulcers induced by NSAIDs, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, salivary secretion, airway disorders, and asthma.

[0077] [Chemical Formula 1]

[0078]

[0079] The tegoprazan of the present invention is amorphous. Amorphous tegoprazan is a solid that does not form a regular arrangement, is thermodynamically unstable due to its high energy levels, and tends to crystallize over time. In particular, under harsh or accelerated conditions such as high temperature or humidity, crystallization can be accelerated, accelerating the time of transformation into a crystalline form.

[0080] A mesoporous silica-based compound is a porous material containing a large number of pores with a diameter of 2 to 50 nm. Since a mesoporous compound has numerous pores and a large surface area, and thus has excellent atomic or molecular adsorption properties, the mesoporous silica-based compound can allow the dissolved amorphous tegoprazan of the present invention to be impregnated or adsorbed into the pores to maintain a stable amorphous form. The mesoporous silica-based compound of the present invention may refer to at least one selected from the group consisting of mesoporous silica, mesoporous silicate, mesoporous calcium silicate, magnesium aluminate metasilicate, Syloid™, and Silsol™. The mesoporous silica-based compound of the present invention may have a pore diameter of 2 to 50 nm. In a method for preparing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention, the mesoporous silica-based compound can function as an excipient.

[0081] The mesoporous silica may be mesoporous silicon dioxide.

[0082] In one embodiment, the mesoporous silica is mesoporous silicon dioxide having a pore size of 2 to 50 nm and an average particle size of 2 to 40 μm.

[0083] Syloid is a porous amorphous silica with numerous pores, a large internal surface area, and a strong affinity for organic solvents. Among the syloids, SYLOID® 244 FP SILICA, commercially available from Grace, can be used as an excipient in pharmaceuticals and exhibits excellent compatibility with active ingredients.

[0084] The pore volume of the syloid may be 1.6 mL / g, and the average particle size may be 2.5 to 3.7 μm.

[0085] SILSOL®, a mesoporous silica, can enhance drug bioavailability by delivering active ingredients in an amorphous form and maintain sustained stability by preventing crystallization and recrystallization. Among these, SILSOL®, commercially available from Grace, can be used as an excipient in pharmaceuticals and exhibits excellent compatibility with active ingredients.

[0086] The pore size of the silk may be 2 to 50 nm, and the average particle size may be 37 μm.

[0087] A water-soluble polymer may refer to a polymeric substance that dissolves in water. The water-soluble polymer of the present invention can be dissolved in a solution of amorphous tegoprazan and a mesoporous silica-based compound, thereby enabling tegoprazan to maintain an amorphous form more stably and improving fluidity and tableting properties. The water-soluble polymer of the present invention can function as a binder.

[0088] The water-soluble polymer of the present invention may be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0089] The amorphous tegoprazan-containing binding solution prepared by the above method can function as a primary binding solution.

[0090] A binding solution containing amorphous tegoprazan can be prepared by dissolving 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 0.5 to 10 parts by weight of a water-soluble polymer in an organic solvent.

[0091] The above organic solvent may refer to an alcohol having 1 to 3 carbon atoms, and may be, for example, ethanol.

[0092] In preparing the above amorphous tegoprazan-containing binding solution, the mesoporous silica-based compound may be included in an amount of 25 to 165 parts by weight based on 45 to 55 parts by weight of the amorphous tegoprazan, for example, 25 to 165 parts by weight, 25 to 150 parts by weight, 25 to 135 parts by weight, 25 to 125 parts by weight, 25 to 110 parts by weight, 25 to 95 parts by weight, 25 to 80 parts by weight, 25 to 65 parts by weight, 30 to 65 parts by weight, 35 to 60 parts by weight, 35 to 55 parts by weight, 40 to 55 parts by weight, or 45 to 55 parts by weight.

[0093] In preparing the above amorphous tegoprazan-containing binding solution, the weight ratio of the mesoporous silica-based compound to the amorphous tegoprazan may be 1:0.5 to 1:3, for example, 1:0.5 to 1:2.5, 1:0.5 to 1:2, or 1:0.5 to 1:1.5.

[0094] In one embodiment, a binding solution containing amorphous tegoprazan was prepared by using a weight ratio of amorphous tegoprazan to silicon dioxide of 1:1.

[0095] In preparing the above amorphous tegoprazan-containing binding solution, the water-soluble polymer may be included in an amount of 0.5 to 10 parts by weight relative to 45 to 55 parts by weight of the amorphous tegoprazan, for example, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 to 8 parts by weight, 2 to 8 parts by weight, 3 to 8 parts by weight, 4 to 7 parts by weight, or 5 to 7 parts by weight.

[0096] In one embodiment, 50 g of amorphous tegoprazan, 50 g of silicon dioxide, and 6 g of hydroxypropyl cellulose were dissolved in ethanol to prepare a binding solution containing amorphous tegoprazan.

[0097] The method for preparing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention may include spraying and drying a binding solution comprising the amorphous tegoprazan to prepare granules. The method for preparing granules using the binding solution may include, for example, spraying the solution onto a carrier in a fluidized bed process followed by drying, using a cylindrical granulator, using a high-speed rotary granulator, or spray drying, and preferably, using a fluidized bed process.

[0098] The method for manufacturing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention includes a step of spraying the binding solution onto a carrier in a fluidized bed process and then drying to manufacture primary granules.

[0099] The primary granules of the present invention may refer to granules obtained by spraying the above-mentioned binding solution onto a carrier in a fluidized bed process and then drying the same.

[0100] The operating conditions of the fluidized bed process machine can be appropriately selected, and for example, under the conditions of a supply air temperature of 50 to 100°C, a product temperature of 35 to 55°C, a spray pressure of 1.5 to 3.0 bar, a spray speed of 10 to 25 Dial, and an air exhaust of 30 to 60%, the binding solution is sprayed onto a carrier in the fluidized bed process machine and then dried to produce primary granules.

[0101] The carrier is pharmaceutically acceptable and excipients may be used.

[0102] The carrier may be at least one selected from the group consisting of mannitol, sorbitol, refined white sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose.

[0103] The carrier may be included in an amount of 20 to 60 wt% of the pharmaceutical composition manufactured by the manufacturing method of the present invention.

[0104] In one embodiment, microcrystalline cellulose and pregelatinized starch were used as carriers.

[0105] By spraying and drying the binding solution in a fluidized bed process according to the manufacturing method of the present invention to manufacture granules, the storage stability and amorphous stability of the finally manufactured pharmaceutical composition can be improved.

[0106] The method for preparing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention comprises a step of preparing a water-soluble polymer aqueous solution.

[0107] The above water-soluble polymer solution can function as a secondary binder. The water-soluble polymer solution can include a binder and a solvent. A water-soluble polymer can be used as the binder, and the water-soluble polymer can be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl pyrrolidone vinyl acetate, and polyvinyl alcohol.

[0108] The above solvent may be purified water.

[0109] The above water-soluble polymer solution may be prepared by dissolving 0.5 to 10 parts by weight of a water-soluble polymer in water based on 45 to 55 parts by weight of amorphous tegoprazan, for example, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 to 8 parts by weight, 2 to 8 parts by weight, 3 to 8 parts by weight, 3 to 7 parts by weight, or 3.5 to 6.5 parts by weight of a water-soluble polymer in water.

[0110] In one example, 4 g of hydroxypropyl cellulose was dissolved in 53.1 g of purified water to prepare a water-soluble polymer solution.

[0111] The method for preparing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention includes a step of spraying the water-soluble polymer solution onto the first granules and drying them to prepare second granules.

[0112] The secondary granules of the present invention may refer to granules obtained by spraying the water-soluble polymer aqueous solution onto the primary granules and drying the same. The secondary granules may be a composition comprising amorphous tegoprazan. The manufacturing method of the present invention includes the steps of preparing primary granules, spraying the water-soluble polymer aqueous solution onto the primary granules, and drying the same to prepare secondary granules, thereby improving the storage stability and amorphous stability of the finally prepared pharmaceutical composition.

[0113] The method for preparing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention may further include a step of mixing excipients, disintegrants, and lubricants with the secondary granules. By adding pharmaceutically acceptable additives to the secondary granules, a pharmaceutical composition having a predetermined formulation can be prepared. By mixing or further adding excipients, disintegrants, and lubricants to the secondary granules, a pharmaceutical composition having a desired formulation can be prepared. The type and weight of the additives can be appropriately selected depending on the formulation of the desired pharmaceutical composition.

[0114] An additional 30 to 150 parts by weight of excipients may be mixed into the secondary granules.

[0115] The above excipient may be any one selected from the group consisting of mannitol, sorbitol, refined white sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose.

[0116] In the secondary granules, the excipient may be further mixed in an amount of 30 to 150 parts by weight based on 45 to 55 parts by weight of amorphous tegoprazan, and the excipient may be further mixed in an amount of, for example, 30 to 150 parts by weight, 30 to 130 parts by weight, 30 to 110 parts by weight, 30 to 90 parts by weight, 30 to 70 parts by weight, 30 to 50 parts by weight, 30 to 40 parts by weight, or 30 to 35 parts by weight.

[0117] In one embodiment, 15.3 g of microcrystalline cellulose and 15.3 g of pregelatinized starch were further mixed into the secondary granules.

[0118] 1 to 30 parts by weight of a disintegrant may be further mixed into the secondary granules.

[0119] The above disintegrant may be any one selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and alginic acid.

[0120] In the secondary granules, the disintegrant may be further mixed in an amount of 1 to 30 parts by weight based on 45 to 55 parts by weight of the amorphous tegoprazan, and the disintegrant may be further mixed in an amount of, for example, 1 to 30 parts by weight, 1 to 25 parts by weight, 1 to 20 parts by weight, 1 to 15 parts by weight, 1 to 10 parts by weight, 2 to 9 parts by weight, or 3 to 8 parts by weight.

[0121] In one embodiment, 1.0 g of croscarmellose sodium and 3.7 g of crospovidone were further mixed into the secondary granules.

[0122] In one embodiment, 1.9 g of croscarmellose sodium and 5.5 g of crospovidone were further mixed into the secondary granules.

[0123] 0.1 to 5 parts by weight of a lubricant may be further mixed into the secondary granules.

[0124] The above-mentioned lubricant may be at least one selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, anhydrous silicic acid, talc, colloidal silicon dioxide, silicon dioxide, glyceryl behenate, and mineral oil.

[0125] In the secondary granules, the lubricant may be further mixed in an amount of 0.1 to 5 parts by weight based on 45 to 55 parts by weight of the amorphous tegoprazan, and the lubricant may be further mixed in an amount of, for example, 0.1 to 5 parts by weight, 0.1 to 4 parts by weight, 0.1 to 3 parts by weight, 0.1 to 2 parts by weight, or 0.1 to 1 part by weight.

[0126] In one embodiment, 0.5 g of sodium stearate was further mixed into the secondary granules.

[0127] A tablet can be manufactured by additionally mixing excipients, disintegrants, and lubricants into the above secondary granules.

[0128] In one embodiment, excipients, disintegrants, and lubricants were additionally mixed into the secondary granules to manufacture tablets.

[0129] The method for manufacturing a pharmaceutical composition comprising the amorphous tegoprazan of the present invention may further include a step of mixing a coating agent into the secondary granules.

[0130] A coating agent can be further mixed into tablets manufactured by mixing excipients, disintegrants, and lubricants into the above secondary granules to manufacture coated tablets. Coated tablets can be manufactured using a film coating process that uses a coating agent on the tablets, and examples of coating agents include Opadry.

[0131] A pharmaceutical composition comprising amorphous tegoprazan manufactured by the manufacturing method of the present invention can stably maintain an amorphous form.

[0132] The pharmaceutical composition comprising the amorphous tegoprazan of the present invention comprises a mesoporous silica-based compound, so that the amorphous tegoprazan can be impregnated or adsorbed into the pores of the mesoporous silica-based compound to stably maintain the amorphous form.

[0133] A pharmaceutical composition comprising amorphous tegoprazan manufactured by the manufacturing method of the present invention can maintain an amorphous form more stably and improve fluidity and tableting properties by using a water-soluble polymer dissolved together with amorphous tegoprazan and a mesoporous silica-based compound.

[0134] The pharmaceutical composition comprising the amorphous tegoprazan of the present invention can maintain an amorphous state in a stable state without conversion to a crystalline form under long-term test conditions (25°C, 60% RH), accelerated test conditions (40°C, 75% RH), and harsh conditions (60°C). The amorphous form was maintained even when stored for 6 months under the accelerated test conditions or for 4 weeks under harsh conditions.

[0135] The pharmaceutical composition comprising the amorphous tegoprazan of the present invention has higher storage stability and amorphous stability than when the pharmaceutical composition is manufactured using a direct tableting method and a wet granulation method, including granules manufactured using a fluidized bed process.

[0136]

[0137] Hereinafter, the present invention will be described in more detail with manufacturing examples and experimental examples.

[0138] Manufacturing example

[0139] Manufacturing Example 1. Manufacturing of primary and secondary granules containing amorphous tegoprazan.

[0140] A binder solution containing amorphous tegoprazan, a mesoporous silica-based compound, and a water-soluble polymer that can function as a binder were dissolved in an organic solvent. Mesoporous silicon dioxide was used as the mesoporous silica-based compound. The binder solution was sprayed onto a carrier in a fluidized bed process and dried to produce primary granules. In addition, a water-soluble polymer was dissolved in water to produce a water-soluble polymer aqueous solution, which was then sprayed onto the primary granules and dried to obtain secondary granules. The specific composition is as shown in Table 1 below.

[0141] Classification, Mixing Purpose, Ingredients, Comparative Example 1-1, Comparative Example 1-2, Example 1-1, Example 1-2, Example 1-3, Example 1-4, Binder, Main Ingredient, Tegoprazan (amorphous), 50.0, 50.0, 50.0, 50.0, 50.0, 50.0, 50.0, Excipient, Silicon Dioxide, 10.0, 10.0, 50.0, 50.0, 50.0, 50.0, Binder, Hydroxypropyl Cellulose, 4.0, 4.0, 5.0, 6.0, 6.0, Binder, Eudragit, 4.0, 2.0, ----, Solvent, Ethanol, 125.0, 150.0, 125.0, 125.0, 125.0, Water-soluble Polymer Aqueous solution binder hydroxypropyl cellulose---5.36.04.0 Solvent purified water---70.470.453.1 Carrier excipient D-mannitol 72.072.0----Excipient microcrystalline cellulose--95.054.554.525.5 Excipient pregelatinized starch 50.050.032.754.054.025.0 Total 190.0188.0232.7219.8220.5160.5

[0142] Manufacturing Example 2. Manufacturing of a pharmaceutical composition containing amorphous tegoprazan using direct compression method

[0143] A pharmaceutical composition prepared by mixing amorphous or crystalline tegoprazan with a mesoporous silica compound, excipients, binders, disintegrants, and lubricants using a direct compression method was compared with a pharmaceutical composition prepared by the method of the present invention. The specific composition is as shown in Table 2 below.

[0144] Comparison of ingredients for mixing purpose Example 2-1 Comparison Example 2-2 Comparison Example 2-3 Comparison Example 2-4 Comparison Example 2-5 Main ingredient Tegoprazan (amorphous) 50.0 50.0 50.0 -- Main ingredient Tegoprazan (crystalline B) --- 50.0 50.0 Excipient D - Mannitol 50.0 - 60.0 98.0 -- Excipient Lactose monohydrate -- 40.0 70.0 -- Excipient Microcrystalline cellulose -- 30.0 - 100.0 Excipient Pregelatinized starch 30.0 --- 46.0 Excipients Silicon dioxide 50.0 27.0 10.0 2.0-25.0 Binder Hydroxypropyl methylcellulose ---- 13.0 Binder Eudragit ---- Binder Copovidone 6.0-6.5 10.0 Disintegrant Croscarmellose sodium 10.0-10.0 8.0 8.0 Lubricant Magnesium stearate 2.0-2.0 2.0 2.0 Total 198.0 77.0 215.0 240.0 244.0

[0145] Manufacturing Example 3. Manufacturing of a pharmaceutical composition containing amorphous tegoprazan using wet granulation.

[0146] Amorphous tegoprazan was granulated using excipients, a mesoporous silica compound, excipients, a binder, and purified water in a speed mixer, and then dried to produce granules. A composition prepared by mixing excipients, a disintegrant, and a lubricant into the granules was compared with a pharmaceutical composition comprising amorphous tegoprazan prepared using the method of the present invention. The specific composition is as shown in Table 3 below.

[0147] Comparison Example 3-1 Comparison Example 3-2 Granular Main Ingredient Tegoprazan (amorphous) 50.0 50.0 Excipient Microcrystalline Cellulose 50.0 100.0 Excipient Pregelatinized Starch - 30.0 Excipient Silicon Dioxide 50.0 10.0 Binder Hydroxypropyl Cellulose 6.2 Binder Povidone 8.5 Solvent Purified Water 76.5 62.7 Mixed Excipient Silicon Dioxide - 25.0 Disintegrant Croscarmellose Sodium - 6.0 Disintegrant Crospovidone - 6.0 Lubricant Magnesium Stearate - 1.3 Total 158.5 224.5

[0148] Manufacturing Example 4. Manufacturing of a pharmaceutical composition containing amorphous tegoprazan using a spray-drying method

[0149] A mesoporous silica compound, a binder, and a stabilizer were dissolved or suspended in an organic solvent, sprayed onto amorphous tegoprazan, and dried to prepare a composition containing amorphous tegoprazan. The composition was compared with a pharmaceutical composition containing amorphous tegoprazan prepared by the method of the present invention. The specific composition is as shown in Table 4 below.

[0150] Comparison Example 4-1 of the purpose of mixing ingredients Comparison Example 4-2 of the main ingredient Tegoprazan (amorphous) 50.0 50.0 Excipient Silicon dioxide - 50.0 Binder Hydroxypropyl cellulose - 5.0 Binder Copovidone 50.0 - Stabilizer Poloxamer 5.0 - Solvent Ethanol 125.0 125.0 Total 105.0 105.0

[0151]

[0152] Manufacturing Example 5. Manufacturing of a pharmaceutical composition containing amorphous tegoprazan

[0153] Excipients, disintegrants, and lubricants were added to the secondary granules obtained in Manufacturing Example 1 to manufacture tablets, and a coating agent was further mixed to obtain the final coated tablets. The specific composition is as shown in Table 5 below.

[0154] Comparative Example of Mixing Purpose Ingredients Example 4 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Granules (Secondary Granules) Comparative Example 1-2188.0-------Example 1-1-232.7------Example 1-2--219.8-----Example 1-3---220.5----Example 1-4----160.5160.5160.5160.5 Excipient Microcrystalline Cellulose----16.316.315.315.3 Excipient Pregelatinized Starch----16.316.015.315.3 Excipient Silicon Dioxide 14.8-------Disintegrant Croscarmellose Sodium 5.5-6.06.03.71.03.71 .9 Disintegrant Crospovidone 7.76.06.06.03.73.73.75.5 Lubricant Sodium Stearate 2.01.30.50.50.50.50.50.50.50.5 Coating Agent Opadry--7.07.07.07.07.07.0 Total 218.0240.0239.3240.0208.0205.0206.0206.0

[0155]

[0156] Manufacturing Example 6. Manufacturing of a pharmaceutical composition comprising amorphous tegoprazan without mesoporous silica compound

[0157] Unlike the above Preparation Example 1, a composition containing amorphous tegoprazan that does not contain a mesoporous silica-based compound was prepared and compared. A binder solution was prepared by dissolving a water-soluble polymer, such as hydroxypropyl cellulose or hydroxypromethyl cellulose, in purified water and suspending amorphous tegoprazan therein. The binder solution was sprayed onto a carrier in a fluidized bed process and dried to obtain a composition containing amorphous tegoprazan. The specific composition is as shown in Table 6 below.

[0158] Classification, Mixing Purpose, Ingredients, Comparative Example 5-1, Comparative Example 5-2, Comparative Example 5-3, Comparative Example 5-4, Binder, Main Ingredient, Tegoprazan (amorphous) 50.0 50.0 50.0 50.0 50.0 Binder, Hydroxypropyl cellulose 10.0 11.0 12.0 Binder, Hydroxypropyl methyl cellulose --- 10.0 Solvent, Purified water 117.0 129.0 141.0 117.0 Carrier, Excipient, Microcrystalline cellulose 25.5 54.5 54.5 25.5 Excipient, Pregelatinized starch 25.0 54.0 54.0 25.0 Total 190.0 188.0 232.7 219.8

[0159] Experimental example

[0160] Experimental Example 1. Measurement of Tegoprazan by Differential Scanning Calorimetry

[0161] The phase transition temperatures of tegoprazan raw material in crystalline form A, crystalline form B, and amorphous form were measured using differential scanning calorimetry (DSC). Differential scanning calorimetry is a method for measuring the amount of heat released or absorbed when a sample is heated or cooled over a specific temperature range, and can be used to characterize the thermal properties of a material or to measure the temperature at which specific phase transitions, including glass transition temperature, melting point, and crystallization, occur. The results are shown in Figures 1a to 1c, and it was confirmed that amorphous tegoprazan had no specific phase transition value.

[0162]

[0163] Experimental Example 2. Measurement of X-ray powder diffraction spectrum of Tegoprazan

[0164] X-ray powder diffraction spectra were measured for crystalline form A, crystalline form B, and amorphous form of the raw material of tegoprazan. X-ray powder diffraction spectra are obtained by irradiating a sample with specific X-rays generated from an X-ray tube, and the crystalline phases in the sample are diffracted at unique angles according to Bragg's law. The angle and intensity at which the X-rays are detected are expressed as unique values ​​that characterize the corresponding crystalline phase. The specifications of the X-ray powder diffraction spectrum were set to analyze the sample using a 4kW X-ray generator, a Cu 1.8kW (Max. 60kV 60mA) X-ray tube, a vertical goniometer (scan range 1.5<2θ<140, minimum increment: 0.0001°), a PIXcel3D (0D, 1D, 2D) detector, and a Reflection-Transmission Spinner with a 45 position sample changer (5-axes (chi, phi, x, y, z) cradle) as a sample stage. The results are shown in Figs. 2a to 2c, and it was confirmed that amorphous tegoprazan had no specific 2θ value.

[0165] Meanwhile, according to the above Manufacturing Example 6, a composition containing amorphous tegoprazan that does not contain a mesoporous silica-based compound was prepared, and the change in crystal form of the composition under accelerated conditions was measured using an X-ray powder diffraction spectrum. The test results are as shown in FIGS. 4a to 4d, and it was confirmed that the composition containing amorphous tegoprazan prepared only with a water-soluble polymer had a specific 2θ value at which it was converted to a crystalline form after one month of acceleration, and thus was not maintained in an amorphous form.

[0166]

[0167] Experimental Example 3. Differential scanning calorimetry and X-ray powder diffraction spectra under harsh conditions

[0168] In order to select the optimal manufacturing method for preparing a pharmaceutical composition containing amorphous tegoprazan, granules prepared by the direct tableting method (Comparative Example 2-2), wet granulation method (Comparative Example 3-1), and spray-drying method (Comparative Example 4-2) were placed in containers, and amorphous tegoprazan was measured by DSC and XRD under harsh conditions to determine the change in phase transition temperature and crystal form. Under harsh conditions, the sample storage container was kept open at 40°C and 75% RH (relative humidity), and under conditions of 60°C, the sample storage container was kept closed. The results are shown in Table 7, and it was confirmed that the amorphous form was maintained in the pharmaceutical composition containing amorphous tegoprazan prepared by the direct mixing method and the spray-drying method.

[0169] Differential Scanning Calorimeter (DSC) Storage Conditions Storage Period Comparison Example 2-2 Comparison Example 3-1 Comparison Example 4 - 240℃, 75%RH Start Amorphous Maintained Crystalline Change Amorphous Maintained 1 Week Amorphous Maintained - Amorphous Maintained 4 Weeks Amorphous Maintained - Amorphous Maintained 60℃ Start Amorphous Maintained Crystalline Change Amorphous Maintained 1 Week Amorphous Maintained - Amorphous Maintained 4 Weeks Amorphous Maintained - Amorphous Maintained X-ray Powder Diffraction Spectrum Storage Conditions Storage Period Comparison Example 2-2 Comparison Example 3-1 Comparison Example 4 - 240℃, 75%RH Start Amorphous Maintained - Amorphous Maintained 1 Week - Amorphous Maintained 4 Weeks Amorphous Maintained - Amorphous Maintained 60℃ Start Amorphous Maintained - Amorphous Maintained 1 Week - Amorphous Maintained 4 Weeks Amorphous Maintained - Amorphous Maintained

[0170]

[0171] Experimental Example 4. Stability Evaluation of Pharmaceutical Compositions Containing Amorphous Tegoprazan

[0172] Amorphous tegoprazan was prepared according to the compositions of Examples 3, 5, 6 and 8 of Manufacturing Example 5, and an excipient, a disintegrant and a lubricant were mixed with a pharmaceutical composition to prepare a tablet, and the tablet coated with the coating agent was stored for 4 weeks under harsh conditions and 6 months under accelerated conditions to confirm the change in crystalline form. The sample was placed in a storage container and stored in a closed state at 60°C under harsh conditions and in an airtight state at 40°C and 75% RH (relative humidity) under accelerated conditions for 6 months, and the change in crystalline form was confirmed by X-ray powder diffraction spectrum. The results are shown in Table 8 and Figures 3a to 3l below, and it was confirmed that all of the peaks observed in the crystalline form were maintained because the peaks observed in the crystalline form did not appear even when the storage conditions were changed, thereby maintaining the amorphous form of tegoprazan.

[0173] Harsh ConditionsStorage ConditionsStorage PeriodExample 3Example 5Example 6Example 860℃Start Maintain Amorphous Maintain Amorphous Maintain Amorphous Maintain Amorphous Maintain 4 Weeks Maintain Amorphous Maintain Amorphous Maintain Amorphous Maintain Accelerated ConditionsStorage ConditionsStorage PeriodExample 3Example 5Example 6Example 840℃, 75%RHStart Maintain Amorphous Maintain Amorphous Maintain Amorphous Maintain Amorphous Maintain 6 Months Maintain Amorphous Maintain Amorphous Maintain Amorphous Maintain

[0174]

[0175] Experimental Example 5. Content Test

[0176] The content changes of samples stored for 4 weeks under harsh conditions and 6 months under accelerated conditions were confirmed. The samples were stored in storage containers at 60℃ in a closed state under harsh conditions and at 40℃, 75% RH (relative humidity), and sealed for 6 months under accelerated conditions. A content test was conducted on tablets containing amorphous tegoprazan manufactured according to the compositions of Examples 3, 5, 6, and 8 to confirm the content changes during the storage period. The sample analysis was performed using high-performance liquid chromatography (HPLC), with an ultraviolet spectrophotometer (measuring wavelength 262 nm) as the detector, a column filled with octadecylsilylated silica gel, and the gradient conditions of mobile phase A and mobile phase B were used. Mobile phase A was a 0.01 mol / mL ammonium acetate buffer: acetonitrile mixture (19:1), and mobile phase B was acetonitrile. The results are shown in Table 9, and it was confirmed that the content of the pharmaceutical composition including amorphous tegoprazan manufactured by the manufacturing method of the present invention was stably maintained within the standard even under harsh and accelerated conditions.

[0177] Harsh ConditionsStorage ConditionsStorage PeriodExample 3Example 5Example 6Example 860℃Start 97.998.899.897.04 Weeks 100.397.297.298.7Accelerated ConditionsStorage ConditionsStorage PeriodExample 3Example 5Example 6Example 840℃, 75%RHStart 97.998.899.897.06 Months 100.496.496.299.5

Claims

A pharmaceutical composition comprising 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 1 to 20 parts by weight of a water-soluble polymer. A pharmaceutical composition according to claim 1, wherein the mesoporous silica-based compound is at least one selected from the group consisting of mesoporous silica, mesoporous silicate, mesoporous calcium silicate, magnesium aluminate metasilicate, siloid, and silsol. A pharmaceutical composition according to claim 1, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol. A pharmaceutical composition according to claim 1, further comprising 30 to 150 parts by weight of at least one excipient selected from the group consisting of mannitol, sorbitol, refined sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose. A pharmaceutical composition according to claim 1, further comprising 1 to 30 parts by weight of at least one disintegrant selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and alginic acid. A pharmaceutical composition according to claim 1, further comprising 0.1 to 5 parts by weight of a lubricant selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, anhydrous silicic acid, talc, colloidal silicon dioxide, silicon dioxide, glyceryl behenate, and mineral oil. A pharmaceutical composition according to claim 1, prepared in any one dosage form selected from the group consisting of tablets, capsules, liquids, powders, granules, and granules. A pharmaceutical composition according to claim 1, wherein the mesoporous silica compound has a pore diameter of 2 to 50 nm. A step of preparing a binding solution containing amorphous tegoprazan by dissolving 45 to 55 parts by weight of amorphous tegoprazan, 25 to 165 parts by weight of a mesoporous silica-based compound, and 0.5 to 10 parts by weight of a water-soluble polymer in an organic solvent; A step of manufacturing primary granules by spraying the above-mentioned binding solution onto a carrier in a fluidized bed process and then drying it; A step of preparing a water-soluble polymer solution by dissolving 0.5 to 10 parts by weight of a water-soluble polymer in water; and A method for producing a pharmaceutical composition, comprising a step of spraying the water-soluble polymer solution onto the first granules and then drying the same to produce second granules. A method for producing a pharmaceutical composition according to claim 9, wherein the mesoporous silica-based compound is at least one selected from the group consisting of mesoporous silica, mesoporous silicate, mesoporous calcium silicate, magnesium aluminate metasilicate, siloid, and silsol. A method for producing a pharmaceutical composition according to claim 9, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl pyrrolidone vinyl acetate, and polyvinyl alcohol. A method for producing a pharmaceutical composition according to claim 9, wherein the carrier is at least one selected from the group consisting of mannitol, sorbitol, refined white sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose. A method for producing a pharmaceutical composition according to claim 9, further comprising a step of mixing 30 to 150 parts by weight of an excipient, 1 to 30 parts by weight of a disintegrant, and 0.1 to 5 parts by weight of a lubricant into the secondary granules. A method for producing a pharmaceutical composition according to claim 13, wherein the excipient is at least one selected from the group consisting of mannitol, sorbitol, refined sugar, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, and crystalline cellulose. A method for producing a pharmaceutical composition according to claim 13, wherein the disintegrant is at least one selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and alginic acid. A method for producing a pharmaceutical composition according to claim 13, wherein the lubricant is at least one selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, anhydrous silicic acid, talc, colloidal silicon dioxide, silicon dioxide, glyceryl behenate, and mineral oil.

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