Pharmaceutical composition for reducing generation of nitrosamine impurity of vonoprazan, and preparation method therefor

Abstract

Disclosed are: a pharmaceutical composition capable of inhibiting the generation of a nitrosamine impurity of a vonoprazan drug product by means of an antioxidant; and a preparation method therefor.

Description

Pharmaceutical composition for reducing the formation of nitrosamine impurities in vonoprazan and method for preparing the same

[0001] The present invention relates to a pharmaceutical composition for reducing the production of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan, and a method for producing the same. Specifically, the present invention relates to a pharmaceutical composition capable of reducing the production of nitrosamine impurities, which comprises an antioxidant, and a method for producing the same.

[0002] Gastroesophageal reflux disease (GERD), the most common digestive disorder, is a type of stomach disorder caused by excessive gastric acid secretion or hypersensitivity to gastric acid. Proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs), commonly used to treat GERD, exhibit powerful acid-suppressing effects and are widely used to treat various acid-related conditions.

[0003] Vonoprazan, a P-CAB drug, is a drug that inhibits gastric acid secretion by competitively binding to ATPase (proton pump), an enzyme that secretes hydrogen ions into the gastric lumen in the parietal cells of the stomach. Unlike PPI drugs, it directly inhibits the proton pump without the need for a conversion process into an activated form by gastric acid, so it exhibits a rapid gastric acid secretion inhibition effect. In addition, it has a long half-life compared to PPI drugs, so it is effective in controlling nocturnal acid secretion for a long time and has the advantage of being able to be used in combination with other drugs because it interacts less with other drugs.

[0004] However, as can be seen in the chemical formula 1 below, vonoprazan is a compound of a pyrrole derivative (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-Nm ethylmethanamine fumarate), and contains a secondary amine, which potentially has the problem of forming N-nitroso vonoprazan, a nitrosamine impurity represented by the chemical formula 2 below.

[0005] [Chemical Formula 1]

[0006]

[0007] [Chemical Formula 2]

[0008]

[0009] Nitrosamine impurities are carcinogenic substances, and their presence in angiotensin II receptor blockers (ARBs) such as valsartan was first discovered in June 2018. Around 2019, N-nitrosodimethylamine (NDMA) impurities were detected in ranitidine and nizatidine, which were gastric acid secretion inhibitors, leading to sales suspensions and recalls. From late 2019 to early 2020, N-nitrosodimethylamine (NDMA) impurities were detected in metformin, a type 2 diabetes treatment, leading to a recall. In addition, as nitrosamine impurities were discovered in various other medicines, guidelines and regulations to reduce the risks caused by nitrosamine impurities are continuously being announced.

[0010] Nitrosamine impurities can be formed by the nitrification reaction of secondary, tertiary, or quaternary amines present in the active pharmaceutical ingredient (API) with nitrites. In finished pharmaceutical products, nitrosamine impurities can be formed due to various factors, including the manufacturing process of the API and / or nitrites contained in excipients in the finished product, as well as the manufacturing process, temperature, humidity, and acidic environment. The U.S. Food and Drug Administration (FDA) classifies nitrosamine impurities into N-nitroso dimethylamine (NDMA), N-nitroso diethylamine (NDEA), N-nitroso methylphenylamine (NMPA), N-nitroso diisopropylamine (NDIPA), N-nitroso isopropylethylamine (NIPEA), N-nitroso dibutylamine (NDBA), and N-nitroso-N-methyl-4-aminobutyric acid (NMBA). In pharmaceuticals, N-nitroso dimethylamine (NDMA), N-nitroso diethylamine (NDEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso isopropylethylamine (NIPEA), and N-nitroso methylphenylamine (NMPA) have been identified.

[0011] Therefore, various studies are actively being conducted to reduce the production of nitrosamine impurities in vonoprazan, such as improving the synthetic route (avoiding reactions that cause the production of nitrosamine impurities or minimizing the production of impurities by developing alternative routes) and optimizing the management of raw materials and intermediates, but no clear results have been achieved.

[0012] [Prior Art Literature]

[0013] [Patent Document]

[0014] (Patent Document 1) International Patent Publication No. WO 2019 / 013310

[0015] The purpose of the present invention is to provide a pharmaceutical composition capable of suppressing the formation of nitrosamine impurities during the manufacture and storage of a finished vonoprazan pharmaceutical product, and a method for manufacturing the same.

[0016] Specifically, the present invention provides a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, which can minimize the production of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan, at the stage of the manufacturing process of a finished pharmaceutical product and reduce the production of N-nitroso vonoprazan during storage of the finished pharmaceutical product, and a method for producing the same.

[0017] To achieve the above purpose, the pharmaceutical composition is characterized by including an antioxidant.

[0018] In order to solve the above problem, the present invention discloses the following means.

[0019] In one aspect, the present invention provides a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition comprises an antioxidant and is characterized in that it inhibits the production of N-nitroso vonoprazan, which is a nitrosamine impurity of vonoprazan.

[0020] In another aspect, the present invention provides a method for preparing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the method for preparing the pharmaceutical composition is performed by performing a wet granulation or dry granulation process, and the wet granulation process is characterized in that the granules are dried using a vacuum dryer or a fluidized bed dryer after preparing the mixture.

[0021] The present invention has the advantage of increasing stability by suppressing the production of nitrosamine impurities in the finished vonoprazan pharmaceutical product during the manufacturing process or storage stage of the finished pharmaceutical product.

[0022] Specifically, the present invention can provide a pharmaceutical product in tablet form that can suppress the production of N-nitroso vonoprazan, a nitrosamine impurity produced by the secondary amine of vonoprazan during storage of the finished pharmaceutical product, by including an antioxidant.

[0023] In addition, the present invention can provide a pharmaceutical product in tablet form with significantly reduced initial nitrosamine impurities by suppressing the production of N-nitroso vonoprazan, a nitrosamine impurity that may increase during the manufacturing process of a finished vonoprazan pharmaceutical product, through vacuum drying or fluidized bed drying.

[0024] Strict quality control standards must be applied to minimize the production of nitrosamine impurities, but there is an advantage in that the initial nitrosamine impurities can be significantly reduced during the manufacturing of vonoprazan finished pharmaceutical products, thereby reducing the cost of quality control.

[0025] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0026] Figure 1 shows the results obtained by measuring N-nitroso vonoprazan generated when a mixture not including an antioxidant according to Example 5 and a mixture including antioxidants according to Examples 6 to 8 are stored at 60°C for two weeks using liquid chromatography-mass spectrometry (LC-MS / MS).

[0027] Figure 2 shows the results obtained by measuring N-nitroso vonoprazan generated when a film-coated tablet according to Example 9 that does not contain butylhydroxyanisole and a film-coated tablet according to Examples 10 to 15 with different contents of butylhydroxyanisole are stored at 60°C for 4 weeks using LC-MS / MS.

[0028] Hereinafter, the present specification will be described in more detail.

[0029] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0030] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0031] Terms defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of the relevant technology, and will not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

[0032] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0033] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0034] Expressions such as “comprising” as used herein should be understood as open-ended terms that imply the possibility of including other embodiments.

[0035] The inventors of the present invention, while developing a pharmaceutical product containing vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, confirmed that N-nitroso vonoprazan, a nitrosamine impurity, is generated by a secondary amine included in the structure of vonoprazan, and that the generation is promoted by heat.

[0036] Nitrosamine impurities are known to be potential carcinogens and are therefore an important issue for pharmaceutical safety. Therefore, the inventors of the present invention conducted research to inhibit the production of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan, and through research, confirmed that when an antioxidant is included in a pharmaceutical composition containing vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, the nitrosation reaction with nitrite, which is a cause of the production of nitrosamine impurities, can be inhibited. Accordingly, the inventors designed a pharmaceutical composition including an antioxidant, particularly a dosage form in the form of a tablet (film-coated tablet), and devised a method for minimizing a heat-induced process that can accelerate the production of nitrosamine impurities during the manufacturing process. The present invention was completed by confirming that the finished pharmaceutical product in the form of a tablet (film-coated tablet) containing vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient inhibits the production of N-nitroso vonoprazan when stored for 6 months under accelerated stability conditions (40°C / 75%).

[0037] In this specification, "bonoprazan" may refer to bonoprazan or a pharmaceutically acceptable salt thereof. Accordingly, in this specification, "a pharmaceutical composition comprising bonoprazan and a method for preparing the same" may refer to a pharmaceutical composition comprising bonoprazan or a pharmaceutically acceptable salt thereof and a method for preparing the same.

[0038] Hereinafter, the present invention will be described in detail.

[0039] Pharmaceutical composition inhibiting the production of N-nitroso vonoprazan, a nitrosamine impurity

[0040] In one aspect, the present invention discloses a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition comprises an antioxidant and is characterized in that it inhibits the production of N-nitroso vonoprazan, which is a nitrosamine impurity of vonoprazan.

[0041] In the present invention, the term “active ingredient” means vonoprazan or a pharmaceutically acceptable salt thereof for use in gastric ulcer, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, and prevention of recurrence of gastric ulcer or duodenal ulcer when administering nonsteroidal anti-inflammatory drugs (NSAIDs), and is also expressed as a main ingredient.

[0042] In the present invention, the term "pharmaceutically acceptable salt" includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base. Specifically, in the present invention, the pharmaceutically acceptable salt of vonoprazan may be vonoprazan fumarate, vonoprazan succinate, vonoprazan benzoate, vonoprazan citrate, vonoprazan mesylate, vonoprazan tartrate, or vonoprazan besylate, and specifically, vonoprazan fumarate.

[0043] In the present invention, the bonoprazan fumarate can be easily manufactured and used by a person skilled in the art by chemical synthesis using a known synthetic method, or a commercially manufactured product can be purchased and used.

[0044] In the present invention, the pharmaceutical composition is characterized by including an antioxidant, and the technical significance lies in the ability to suppress the formation of nitrosamine impurities that may be formed by secondary amines of vonoprazan or a pharmaceutically acceptable salt thereof by using the antioxidant.

[0045] In the present invention, the amount of vonoprazan may be 10 mg or 20 mg as vonoprazan, and 13.36 mg or 26.72 mg as vonoprazan fumarate, based on a unit dosage form (specifically, per tablet when the dosage form of the pharmaceutical composition is a tablet or film-coated tablet).

[0046] In the present invention, the antioxidant characterized by inhibiting the production of nitroso compounds may be, for example, at least one selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic acid, α-tocopherol, L-cystine, glycine, and arginine, preferably butylated hydroxyanisole, but is not limited thereto.

[0047] In the present invention, the pharmaceutical composition may contain 0.01 to 2 mg of butylhydroxyanisole per unit dosage form, preferably 0.5 to 2 mg, but is not limited thereto.

[0048] Specifically, the amount of the butylhydroxyanisole may be 0.5 to 2 mg based on the unit dosage form in the case of a pharmaceutical composition containing 10 mg of vonoprazan (specifically, per tablet if the dosage form of the pharmaceutical composition is a tablet or a film-coated tablet), and may be 1 to 2 mg based on the unit dosage form in the case of a pharmaceutical composition containing 20 mg of vonoprazan, but is not limited thereto.

[0049] In the present invention, the pharmaceutical composition comprises the active ingredient vonoprazan or a pharmaceutically acceptable salt thereof and an antioxidant, and may further comprise one or more pharmaceutical additives selected from among excipients, stabilizers, binders, disintegrants, and lubricants, but is not limited thereto.

[0050] In the present invention, the "excipient" is a substance that increases productivity and stability and aims to increase the volume or weight of a tablet. Specifically, the excipient may be at least one selected from the group consisting of D-mannitol, lactose, silicate microcrystalline cellulose, and microcrystalline cellulose, but is not limited thereto.

[0051] In the present invention, the "stabilizer" is a substance that helps to improve the stability of vonoprazan, improve the solubility, and stabilize the formulation. Specifically, the stabilizer may be fumaric acid, but is not limited thereto.

[0052] In the present invention, the binder may be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, sodium methyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone, but is not limited thereto.

[0053] In the present invention, the "disintegrant" is used to promote disintegration of the formulation and improve drug dissolution. Specifically, the disintegrant may be at least one selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose, but is not limited thereto.

[0054] In the present invention, the lubricant may be magnesium stearate, but is not limited thereto.

[0055] In the present invention, the pharmaceutical composition may be a tablet or a film-coated tablet, but is not limited thereto.

[0056] In the present invention, the film-coated tablet may use a coating agent widely known in the art, and specifically, may be an Opadry coating agent, but is not limited thereto.

[0057] In the present invention, the pharmaceutical composition may be manufactured by a wet granulation process or a dry granulation process, but is not limited thereto.

[0058] In the present invention, the wet granulation process may be performed by vacuum drying at room temperature after manufacturing the compound or by using a fluidized bed dryer at 30 to 60°C, but is not limited thereto.

[0059] Here, “room temperature” is defined in the Korean Pharmacopoeia, and the specific temperature range is 1 to 30℃.

[0060] Method for producing a pharmaceutical composition in which the production of N-nitroso vonoprazan, a nitrosamine impurity, is inhibited

[0061] In another aspect, the present invention discloses a method for manufacturing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the method for manufacturing the pharmaceutical composition is performed by performing a wet granulation or dry granulation process, and the wet granulation process is characterized in that the granules are dried using a vacuum dryer or a fluidized bed dryer after manufacturing the mixture.

[0062] In the present invention, an antioxidant may be added during the process of manufacturing the compound using a wet granulation process, but is not limited thereto.

[0063] Specifically, when drying the mixture in tray drying using a hot air circulation method, nitrosamine impurities increase significantly, whereas when vacuum drying at room temperature or fluidized bed drying at 30 to 60°C according to the present invention is performed, there is an advantage in that nitrosamine impurities can be reduced. Therefore, the manufacturing method of the present invention is characterized in that it does not apply a method using tray drying using a hot air circulation method during manufacturing by performing a wet granulation process.

[0064] In the present invention, when drying is performed at 30 to 60°C using a fluidized bed dryer, the time of exposure to heat is shortened compared to tray drying, thereby reducing the generation of nitrosamine impurities that may occur during the manufacturing process.

[0065] In addition, in the case of dry granules, there is an advantage in that less nitrosamine impurities can be generated during the manufacturing process because there is no drying process.

[0066] A detailed description of a manufacturing method using a wet granulation process includes the steps of mixing vonoprazan fumarate, D-mannitol, microcrystalline cellulose, and butylhydroxyanisole in a high-speed stirrer, and combining them with an aqueous solution of fumaric acid and hydroxypropyl cellulose; drying the combined product in a vacuum at room temperature or using a fluidized bed dryer at 30 to 60°C, and then sizing the resulting product; post-mixing croscarmellose sodium and magnesium stearate with the resulting product and compressing the resulting product; and coating the resulting tablet.

[0067] And, a detailed description of the manufacturing method through a dry granulation process includes a step of mixing vonoprazan fumarate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose and fumaric acid, compressing the mixture using a roller compactor and then sizing; a step of mixing croscarmellose sodium and magnesium stearate into the sizing material and compressing the mixture; and a step of coating the tablet.

[0068] The contents of the pharmaceutical composition described above can be applied to all methods for manufacturing the pharmaceutical composition, as long as they are not contradictory to each other.

[0069] Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0070] Example

[0071] Examples 1-4. Preparation of tablets (film-coated tablets) (wet granulation / dry granulation)

[0072] Example 1. Preparation of tablets (film-coated tablets) I (wet granulation method)

[0073] According to the composition described in Table 1 below, croscarmellose sodium, magnesium stearate, and vonoprazan fumarate excluding fumaric acid, D-mannitol, and microcrystalline cellulose were mixed in a high-speed stirrer, and kneaded with fumaric acid and an aqueous hydroxypropyl cellulose solution (binding solution). The kneaded product was dried using a tray with a hot air circulation system at 50°C, and the kneaded product was dried and then granulated. Croscarmellose sodium and magnesium stearate were post-mixed with the kneaded product, and granules for tableting were formed, which were then compressed to prepare uncoated tablets. Film-coated tablets were prepared by spraying a coating solution (coating solvent: water) on the prepared uncoated tablets.

[0074] Ingredients (1T / mg) Bonoprazan fumarate (as bonoprazan) 26.72 (20.00) D-mannitol 169.18 Microcrystalline cellulose 10.00 Hydroxypropyl cellulose 3.00 Fumaric acid 0.10 Sodium croscarmellose 3.00 Magnesium stearate 2.00 Opadry 7.00 Tablet (film-coated tablet) weight 221.00

[0075] Example 2. Preparation of tablets (film-coated tablets) II (wet granulation method)

[0076] A film-coated tablet was manufactured by performing the same process as in Example 1, except that the drying of the compound was performed using a vacuum dryer at room temperature instead of a tray dryer using a 50°C hot air circulation method.

[0077] Example 3. Preparation of tablets (film-coated tablets) III (wet granulation method)

[0078] A film-coated tablet was manufactured by performing the same process as in Example 1, except that a 50°C fluidized bed dryer was used instead of a 50°C hot air circulation tray dryer for drying the combined product.

[0079] Example 4. Preparation of tablets (film-coated tablets) IV (dry granulation method)

[0080] According to the composition described in Table 1 above, vonoprazan fumarate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and fumaric acid components excluding croscarmellose sodium and magnesium stearate were mixed, compressed using a roller compactor, and then granulated. Croscarmellose sodium and magnesium stearate were mixed with the granules, manufactured into tableting granules, and then compressed into tablets. Film-coated tablets were manufactured by spraying a coating solution (coating solvent: water) onto the manufactured tablets.

[0081] Examples 5-8. Preparation of mixtures containing / not containing antioxidants

[0082] All of the compounding ingredients listed in the prescription in Table 2 below were weighed, simply mixed, stored at 60°C for 2 weeks, and then N-nitroso vonoprazan was measured by LC-MS / MS. Butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate were selected as antioxidants, and the amount of each antioxidant was selected as 5.55 μM and added in equal molar amounts (Examples 6 to 8).

[0083] Example 5 (1T / mg) Example 6 (1T / mg) Example 7 (1T / mg) Example 8 (1T / mg) Bonoprazan fumarate (as bonoprazan) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) D-mannitol 169.18 169.18 169.18 169.18 Microcrystalline cellulose 10.00 10.00 10.00 10.00 Butylhydroxyanisole - 1.00 - - Dihydroxytoluene--1.22-propyl gallate---1.18-hydroxypropylcellulose 3.003.003.003.00 Fumaric acid 0.100.100.100.100.10 Croscarmellose sodium 3.003.003.003.00 Magnesium stearate 2.002.002.002.00 Opadry 7.007.007.007.00

[0084] Examples 9-15. Preparation of tablets (film-coated tablets) containing / not containing butylhydroxyanisole (wet granulation method)

[0085] In order to determine the extent to which butylhydroxyanisole, an antioxidant included in a tablet (film-coated tablet), can effectively inhibit N-nitroso vonoprazan, a film-coated tablet was manufactured with the ingredients and contents shown in Table 3 below.

[0086] Specifically, croscarmellose sodium, magnesium stearate, and vonoprazan fumarate excluding fumaric acid, D-mannitol, microcrystalline cellulose, butylhydroxyanisole (butylhydroxyanisole not included in Example 9) were mixed in a high-speed stirrer and combined with an aqueous solution of fumaric acid and hydroxypropyl cellulose (binding solution). The combined product was dried using a vacuum dryer at room temperature and then granulated. Croscarmellose sodium and magnesium stearate were mixed with the combined product, and granules for tableting were manufactured, which were then compressed to manufacture uncoated tablets. Film-coated tablets were manufactured by spraying a coating solution (coating solvent: water) onto the manufactured uncoated tablets.

[0087] Compounding Ingredients Example 9 (1T / mg) Example 10 (1T / mg) Example 11 (1T / mg) Example 12 (1T / mg) Example 13 (1T / mg) Example 14 (1T / mg) Example 15 (1T / mg) Bonoprazan fumarate (as bonoprazan) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) 26.72 (20.00) D-Mannitol 169.18 169.18 169.18 169.18 169.18 Microcrystalline cellulose 10110.0010.0010.0010.0010.0010.0010.0010.00Butylhydroxyanisole00.010.10.51.01.52.0Hydroxypropylcellulose3.003.003.003.003.003.003.00Fumaric acid0.100.100.100.100.100.100.10Croscarmellose sodium 3.003.003.003.003.003.003.003.00 Magnesium Stearate 2.002.002.002.002.002.002.002.00 Opadry 7.007.007.007.007.007.007.00 Tablet (film-coated tablet) Weight 221.00221.01221.10221.50222.00222.50223.00

[0088] Test Example 1. Measurement of the content of N-nitroso vonoprazan at each manufacturing process step of Examples 1 to 4

[0089] 1. Measurement method

[0090] The raw material for vonoprazan fumarate used in Examples 1 to 4, the mixture (pre-mixture) at each stage of the manufacturing process of the film-coated tablets manufactured in Examples 1 to 4, the dried granules, the uncoated tablets, and N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan generated in the film-coated tablets, were measured by LC-MS / MS and are shown in Table 5 (unit: ppm). The LC-MS / MS analysis conditions are as shown in Table 4 below.

[0091] <LC-MS / MS 분석조건>

[0092] Column C18 (2.1 mm x 50 mm, 1.8 μm)Mobile phaseMobile phase A: 0.1% (v / v) formic acid in water;Mobile phase B: 0.1% (v / v) formic acid in methanolFlow rate0.4 mL / minDetector (MS / MS)ESI (positive ion mode)MRM mode (multiple reaction monitoring)N-nitroso vonoprazan (positive ion) 375.2 → 315

[0093] 2. Measurement results

[0094] From the results in Table 5 below, it was confirmed that the production of N-nitroso vonoprazan increased in the drying process when manufacturing tablets (film-coated tablets) through wet granulation. Specifically, the production of N-nitroso vonoprazan in the drying process showed the greatest increase in tray drying with hot air circulation (Example 1, increased from 0.19 ppm to 0.49 ppm), while in vacuum drying at room temperature (Example 2, increased from 0.19 ppm to 0.24 ppm) and fluidized bed drying at 50°C (Example 3, increased from 0.19 ppm to 0.21 ppm), the production of N-nitroso vonoprazan, a nitrosamine impurity, increased less than in tray drying with hot air circulation. It was confirmed that vacuum drying or fluidized bed drying, which have less heat exposure during the drying process, are drying processes that can produce less N-nitroso vonoprazan, a nitrosamine impurity, in the manufacturing process stage compared to hot air drying. In addition, as can be confirmed in Example 4, it was confirmed that the process of manufacturing tablets through the dry granulation method minimizes exposure to heat, thereby reducing the production of N-nitroso vonoprazan.

[0095] Semi-finished products by process Example 1 Example 2 Example 3 Example 4 Raw material 0.15 0.15 0.15 0.15 Mixture 0.19 0.19 0.19 0.19 Granular dried product (hot air dried) 0.49 --- Granular dried product (vacuum dried) - 0.24 -- Granular dried product (fluid bed dried) - 0.21 - Post-mixture 0.5 1 0.19 0.20 0.20 Uncoated tablet 0.5 7 0.20 0.23 0.22 Film-coated tablet 0.6 2 0.26 0.22 0.23

[0096] Test Example 2. Measurement of the content of N-nitroso vonoprazan produced when the mixtures of Examples 5 to 8 are stored at 60°C for 2 weeks.

[0097] 1. Measurement method

[0098] The mixtures prepared in Examples 5 to 8 were initially stored at 60°C for 2 weeks and then N-nitroso vonoprazan was measured by LC-MS / MS (measured at the initial time (0 week), 1 week, and 2 weeks) and the results are shown in Table 6 and Fig. 1 (unit: ppm). The LC-MS / MS analysis conditions are the same as those of Test Example 1.

[0099] 2. Measurement results

[0100] As can be seen in Table 6 and Fig. 1 below, it was confirmed that the production of N-nitroso vonoprazan was inhibited in Examples 6 to 8 containing antioxidants compared to Example 5 without antioxidants, and surprisingly, it was confirmed that Example 6 containing butylhydroxyanisole had a higher ability to inhibit the production of N-nitroso vonoprazan compared to Examples 7 and 8 containing butylhydroxytoluene and propyl gallate, respectively.

[0101] Storage period Example 5 Example 6 Example 7 Example 8 First 0.22 0.19 0.19 0.21 Week 18.65 5.02 17.48 20.28 2 Week 46.19 6.38 38.64 34.68

[0102] Test Example 3. Evaluation of the harsh stability of tablets (film-coated tablets) with and without butylhydroxyanisole.

[0103] 1. Measurement method

[0104] The tablets (film-coated tablets) manufactured in Examples 9 to 15 were stored under harsh stability storage conditions at 60°C for 4 weeks, and N-nitroso vonoprazan produced was measured by LC-MS / MS (measured at the initial (0 week), 1 week, and 4 week points) and shown in Table 7 and Fig. 2 (unit: ppm). The LC-MS / MS analysis conditions are the same as those of Test Example 1.

[0105] 2. Measurement results

[0106] As can be seen in Table 7 and Fig. 2 below, under harsh stability storage conditions at 60℃, the inhibitory effect on N-nitroso vonoprazan was shown in all cases containing butylhydroxyanisole, and the maximum inhibitory effect was shown in tablets containing 1 mg or more of butylhydroxyanisole per tablet (20 mg as vonoprazan). Through this, it can be clearly seen that the maximum inhibitory effect on N-nitroso vonoprazan will be shown even when tablets containing 10 mg as vonoprazan contain 0.5 mg or more of butylhydroxyanisole per tablet.

[0107] Storage period Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 First 0.44 0.20 21 0.14 0.15 0.13 0.14 1 Week 5.0 7 1.6 2 0.9 5 0.7 1 0.76 0.75 0.74 4 Week 7.8 7 3.6 4 3.2 1 2.0 2 1.4 4 1.3 8 1.3 6

[0108] Test Example 4. Accelerated stability evaluation of tablets (film-coated tablets) with and without butylhydroxyanisole

[0109] 1. Measurement method

[0110] The tablets (film-coated tablets) according to Examples 9 and 13 were stored in a sealed state for 6 months under accelerated stability storage conditions of 40°C / 75%, and the amount of N-nitroso vonoprazan was measured by LC-MS / MS (measured at the initial (0 month), 1 month, 3 months, and 6 months), and the results are shown in Table 8 (unit: ppm). The LC-MS / MS analysis conditions are the same as those of Test Example 1.

[0111] 2. Measurement results

[0112] As can be seen in Table 8 below, it was confirmed that the tablet (film-coated tablet) according to Example 13 containing butylhydroxyanisole under accelerated stability storage conditions of 40℃ / 75% showed a sufficient reduction effect of nitrosamine impurities for up to 6 months of acceleration compared to the tablet (film-coated tablet) according to Example 9 not containing butylhydroxyanisole.

[0113] Storage period Example 9 Example 13 Seconds 0.44 0.15 Acceleration 1 month 1.84 0.28 Acceleration 3 months 2.54 0.37 Acceleration 6 months 3.00 0.43

[0114] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, Contains antioxidants, A pharmaceutical composition characterized by inhibiting the production of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan.

2. In paragraph 1, A pharmaceutical composition characterized in that the antioxidant is at least one selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic acid, α-tocopherol, L-cystine, glycine, and arginine.

3. In paragraph 1, A pharmaceutical composition characterized in that the antioxidant is butylhydroxyanisole.

4. In paragraph 3, A pharmaceutical composition characterized in that the pharmaceutical composition contains 0.01 to 2 mg of butylhydroxyanisole per unit dosage form.

5. A pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is a tablet or a film-coated tablet.

6. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is manufactured by a wet granulation process or a dry granulation process.

7. A pharmaceutical composition according to claim 6, characterized in that the wet granulation process is performed by drying the mixture using a vacuum dryer or a fluidized bed dryer after preparation of the mixture.

8. A method for manufacturing a pharmaceutical composition comprising bonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, The method for manufacturing a pharmaceutical composition is to manufacture it by performing a wet granulation or dry granulation process. The above wet granulation process is a method for manufacturing a pharmaceutical composition, characterized in that the granules are dried using a vacuum dryer or a fluidized bed dryer after manufacturing the compound.

Images