Novel oral preparations containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine

Abstract

The present invention relates to oral formulations comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine which exhibit improved dissolution characteristics.

Description

[Technical Field]

[0001] The present invention relates to a novel oral formulation containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. [Background technology]

[0002] It is known that even formulations containing the same active ingredient can exhibit differences in pharmaceutically important properties such as the solubility, dissolution characteristics, and bioavailability of the active ingredient depending on the additional components contained in the formulation. Therefore, along with the development of new compounds, it is also very important to develop components to be contained in formulations that maximize the pharmacological effects of the developed compounds.

[0003] Meanwhile, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine is a pharmaceutically active ingredient described in Korean Patent No. 10-1613245, and is a useful substance for the prevention and treatment of peptic ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori, due to its excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori eradication activity, and GPCR inhibitory activity.

[0004] However, these compounds have low aqueous solubility, which leads to a problem that the dissolution rate decreases over storage time. However, in order to improve the dissolution properties of a pharmaceutically active ingredient with low aqueous solubility, an excess of soluble additives is generally used, but this poses the problem of the possibility of hypersensitivity when administered to a drug containing a large amount of soluble additives. Therefore, in order to develop an oral formulation that can improve the dissolution properties of a compound with low aqueous solubility without adding a separate functional additive such as a soluble additive, it is necessary to research the combination of various ingredients other than the pharmaceutically active ingredient.

[0005] Therefore, the present inventors have attempted to formulate various formulations to improve the dissolution properties of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. As a result, they have found that the compound exhibits excellent dissolution properties in oral formulations containing microcrystalline cellulose and lactose hydrate as excipients in a specific weight ratio, and that such excellent dissolution properties can be more effectively achieved by adjusting the particle size to a specific size or less, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a formulation for oral administration of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof, which exhibits excellent dissolution characteristics, prevents a decrease in dissolution rate, and has excellent storage stability. [Means for solving the problem]

[0007] In order to solve the above problems, the present invention provides a formulation for oral administration, comprising: 1) a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and 2) an excipient comprising lactose hydrate and microcrystalline cellulose, wherein the lactose hydrate and the microcrystalline cellulose are contained in a weight ratio of 1:1.5 to 1:90: [Chemical formula 1] TIFF0007777136000001.tif43145 The chemical name of the compound represented by Chemical Formula 1 is 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, which is a pharmaceutical active ingredient having a molecular weight of 410.41 and is a substance described in Korean Patent No. 10-1613245.

[0008] The compound represented by Chemical Formula 1 is an active ingredient that exhibits pharmacological effects in the oral preparation, and has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori (H. pylori) eradication activity, and GPCR inhibitory activity, making it a useful substance for preventing and treating peptic ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0009] In addition to the compound represented by Chemical Formula 1, pharmaceutically acceptable salts thereof may also be used as the active ingredient exhibiting the pharmacological effects of the oral administration formulation of the present invention. Such salts include, without limitation, salts commonly used in the art, such as acid addition salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to any and all organic or inorganic addition salts of the compound represented by Chemical Formula 1, which have a relatively non-toxic and harmless effective concentration in patients, and whose side effects do not diminish the beneficial effects of the compound.

[0010] A pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 can be obtained by a conventional method using an inorganic or organic acid. For example, the compound represented by Chemical Formula 1 can be dissolved in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, and an organic or inorganic acid can be added. The precipitated crystals can be filtered and dried to obtain a pharmaceutically acceptable salt. Alternatively, the solvent and excess acid can be removed from the acid addition reaction mixture under reduced pressure, and the residue can be dried, or another organic solvent can be added and the precipitated salt can be filtered to obtain a pharmaceutically acceptable salt. In this regard, preferred salts include salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. More preferably, the pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 may be a hydrochloride or a fumarate.

[0011] As mentioned above, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has low aqueous solubility, resulting in a decrease in dissolution rate over storage, resulting in unstable bioavailability and pharmacological efficacy. However, when a specific excipient is used in combination with a specific weight ratio, the dissolution of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is significantly improved, allowing it to be used as a formulation with ensured storage stability. Specifically, an oral formulation containing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof and two excipients, lactose monohydrate and microcrystalline cellulose (MCC), in a specific weight ratio exhibits a high initial dissolution rate and excellent dissolution characteristics over time. As a result, the oral formulation exhibits stable dissolution in the in vivo gastric environment, ensuring sustained pharmacological efficacy.

[0012] This will be demonstrated by the experimental examples described below. Specifically, it was found that a formulation containing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof exhibited stable dissolution rates at pH 1.2, pH 4.0, and pH 6.8 according to the dissolution test method of the general test methods in the Korean Pharmacopoeia. Therefore, since the formulation exhibits stable dissolution rates under such conditions representing the pH in vivo, it is expected that the bioavailability of the active ingredient in the formulation will also be improved in both the stomach and small intestinal environments in vivo.

[0013] The term "excipient" as used herein refers to a pharmaceutically acceptable ingredient used to form a product that facilitates administration of the active ingredient exhibiting the pharmacological effect of the oral administration formulation of the present invention. Commonly used excipients include microcrystalline cellulose and lactose monohydrate, as well as sucrose, D-mannitol, starch, cornstarch, and soft anhydrous silicic acid. However, among various known excipients, a combination of microcrystalline cellulose and lactose monohydrate in a specific weight ratio is preferred for improving the dissolution characteristics of the active ingredient. This can be confirmed in the examples below.

[0014] Preferably, the oral formulation uses a combination of lactose hydrate and microcrystalline cellulose as the excipient without the use of other excipients. In other words, the excipient consists of lactose hydrate and microcrystalline cellulose, with the lactose hydrate and microcrystalline cellulose contained in a weight ratio of 1:1.5 to 1:90. If the lactose hydrate and microcrystalline cellulose are contained in a weight ratio of less than 1:1.5, or if only one of the excipients is used, it may be difficult to ensure a desirable level of tablet hardness that can be produced, or the active ingredient may not be completely dissolved even after a long period of time. Furthermore, even if the lactose hydrate and microcrystalline cellulose are contained in a weight ratio of more than 1:90, the initial dissolution rate of the active ingredient may be low due to the poor water-solubility of microcrystalline cellulose.

[0015] Specifically, an oral formulation containing the active ingredient, lactose monohydrate, and microcrystalline cellulose in a weight ratio of 1:1.5 to 1:90 has an initial dissolution rate (dissolution rate at 5 minutes) of 60% or more and a final dissolution rate (dissolution rate at 120 minutes) of 100% as tested by Method 2 (paddle method) of the Dissolution Test of General Tests in the 11th Revision of the Korean Pharmacopoeia. If the initial dissolution rate (dissolution rate at 5 minutes) of the active ingredient in the oral formulation is less than 60%, it is difficult to demonstrate immediate and effective efficacy. If the final dissolution rate (dissolution rate at 120 minutes) does not reach 100%, the intended efficacy is unlikely to be fully demonstrated, making it unsuitable for use as a formulation.

[0016] More preferably, the lactose hydrate and microcrystalline cellulose are contained in the oral formulation at a weight ratio of 1:3.4 to 1:5.0. Specifically, the lactose hydrate and microcrystalline cellulose are contained in the oral formulation at a weight ratio of 1:1.5 or more, 1:2.0 or more, 1:2.5 or more, 1:3.0 or more, 1:3.2 or more, or 1:3.4 or more, and at a weight ratio of 1:80 or less, 1:70 or less, 1:60 or less, 1:50 or less, 1:40 or less, 1:30 or less, 1:25 or less, 1:20 or less, 1:10 or less, or 1:5.0 or less.

[0017] Preferably, the excipient is included in the oral formulation in an amount of 100 to 1,400 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the content of the excipient is less than 100 parts by weight, it may be difficult to ensure a desirable level of manufacturable granules and tablets, while if the content of the excipient is more than 1,400 parts by weight, the total weight of the formulation may be unnecessarily large, reducing patient convenience or delaying dissolution. Preferably, the excipient is included in an amount of 200 to 650 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. More specifically, the excipient is included in an amount of 200 parts by weight or more, 210 parts by weight or more, 220 parts by weight or more, 230 parts by weight or more, or 240 parts by weight or more, and 650 parts by weight or less, 550 parts by weight or less, 500 parts by weight or less, 450 parts by weight or less, 400 parts by weight or less, 350 parts by weight or less, or 300 parts by weight or less, relative to 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0018] Preferably, the lactose hydrate is contained in the oral formulation in an amount of 1 to 350 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the lactose hydrate is contained in an amount less than 1 part by weight, the initial dissolution rate is low and it is difficult to exhibit appropriate efficacy, whereas if the lactose hydrate is contained in an amount greater than 350 parts by weight, the total weight of the formulation becomes unnecessarily large or dissolution is delayed.

[0019] More preferably, the lactose hydrate is contained in the oral formulation in an amount of 2.55 to 150 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. Specifically, the oral formulation contains the lactose hydrate in an amount of 2.55 or more, 5 or more, 10 or more, 20 or more, 30 or more, 40 or more, or 50 or more parts by weight, and 150 or less, 130 or less, 120 or less, or 110 or less parts by weight, per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0020] Preferably, the microcrystalline cellulose is contained in the oral formulation in an amount of 50 to 1100 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the microcrystalline cellulose is contained in an amount less than 50 parts by weight, it is difficult to achieve the appropriate and intended medicinal effect, whereas if it is contained in an amount greater than 1100 parts by weight, the total weight of the formulation becomes unnecessarily large or dissolution is delayed.

[0021] More preferably, the microcrystalline cellulose is contained in an amount of 150 to 500 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. Specifically, in the oral administration formulation, the microcrystalline cellulose is contained in an amount of 150 parts by weight or more, 160 parts by weight or more, 180 parts by weight or more, or 190 parts by weight or more, and 540 parts by weight or less, 530 parts by weight or less, 520 parts by weight or less, 500 parts by weight or less, 400 parts by weight or less, 300 parts by weight or less, or 250 parts by weight or less, per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0022] Meanwhile, the oral formulation may further contain a disintegrant. As used herein, the term "disintegrant" refers to a pharmaceutically acceptable ingredient added to promote disintegration of an active ingredient by swelling. Examples of disintegrants that can be used include croscarmellose sodium, granular powdered mannitol, crospovidone, carboxymethylcellulose calcium, sodium starch glycolate, and starch. In this regard, it is preferable to use one or more disintegrants selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate, as they do not cause a decrease in dissolution rate or content under conditions similar to the gastrointestinal environment of the living body and can further improve storage stability.

[0023] Preferably, the disintegrant is contained in the oral formulation in an amount of 3.5 to 80 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the amount of disintegrant is less than 3.5 parts by weight, disintegration of the active ingredient is excessively delayed, making it impossible to achieve the desired bioavailability. If the amount of disintegrant is more than 80 parts by weight, swelling occurs due to the wettability of the disintegrant, making it impossible to ensure compatibility of the properties and quality of the formulation. More preferably, the disintegrant is contained in an amount of 5 parts by weight or more, 10 parts by weight or more, 12 parts by weight or more, or 14 parts by weight or more, and 70 parts by weight or less, 60 parts by weight or less, 50 parts by weight or less, 40 parts by weight or less, or 35 parts by weight or less, per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0024] The oral administration formulation may further comprise one or more additives selected from the group consisting of binders, lubricants, colorants, and coating agents.

[0025] The binder is added to maintain the form of the formulation, and examples of the binder that can be used include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silicon dioxide, mannitol, lactose, polyethylene glycol, and mixtures thereof.

[0026] The lubricant is added to improve the fillability of the formulation and facilitate compression, and may be one or more of stearic acid, magnesium stearate, calcium stearate, sodium benzoate, sodium stearyl fumarate, glyceryl monooleate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, zinc stearate, and paraffins, but is not limited thereto. Preferably, magnesium stearate is used as the lubricant in view of ease of manufacturing process.

[0027] The colorant may be, but is not limited to, titanium oxide, yellow iron oxide, red iron oxide, black iron oxide, titanium dioxide, talc, etc. Preferably, yellow iron oxide is used as the colorant from an aesthetic point of view.

[0028] In addition, Opadry (registered trademark) including Opadry white, Opadry pink, Opadry green, Opadry orange, Opadry blue, Opadry yellow, Opadry beige, etc. may be used as the coating agent.

[0029] Preferably, the formulation for oral administration further comprises one or more compounds selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate; and magnesium stearate.

[0030] More preferably, the oral formulation further comprises one or more compounds selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate; magnesium stearate; and yellow iron oxide.

[0031] More specifically, the oral formulation may comprise 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof; 200 to 650 parts by weight of an excipient including lactose hydrate and microcrystalline cellulose; 5 to 35 parts by weight of one or more disintegrants selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate; 5 to 20 parts by weight of a magnesium stearate lubricant; and 0.01 to 1 part by weight of a yellow iron oxide colorant.

[0032] Meanwhile, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the oral formulation in an amount of 5 to 50 wt % based on the total weight of the oral formulation. When the oral formulation contains the active ingredient in the above range, the pharmacological activity of the active ingredient can be effectively exhibited.

[0033] More preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in an amount of 10 to 30 wt % based on the total weight of the oral administration formulation. Specifically, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in an amount of 10 wt % or more, 10.5 wt % or more, 11 wt % or more, 11.5 wt % or more, 12 wt % or more, or 12.5 wt % or more, and 30 wt % or less, 29.5 wt % or less, 29 wt % or less, 28.5 wt % or less, 28 wt % or less, 27.5 wt % or less, or 27 wt % or less, based on the total weight of the oral administration formulation.

[0034] Meanwhile, the dissolution profile of the compound represented by Chemical Formula 1 may vary depending on the particle size distribution of the compound. In particular, since the compound represented by Chemical Formula 1 is preferably formulated as an immediate release drug due to its drug properties, it is necessary to control the particle size distribution of the compound represented by Chemical Formula 1 to achieve this.

[0035] Preferably, the particle size D of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is 50 The particle size D of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is 100 μm or less. 50 If the particle size D of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is greater than 100 μm, not only is the initial dissolution rate very poor, but the final dissolution rate is also poor, making it difficult to formulate it into an immediate release formulation. 50 can be 90 μm or less, 85 μm or less, 80 μm or less, 75 μm or less, 70 μm or less, or 65 μm or less.

[0036] More preferably, the particle size D of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is 50 Specifically, the particle size D of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is 10 μm to 65 μm. 50 may be 10 μm or more, 11 μm or more, 12 μm or more, 13 μm or more, 14 μm or more, or 15 μm or more, and may be 65 μm or less, 60 μm or less, 50 μm or less, 40 μm or less, 30 μm or less, 25 μm or less, 20 μm or less, 19 μm or less, or 18 μm or less.

[0037] When the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has a particle size within the above range, the dissolution rate of the compound is further improved, and the absorption rate in the body is accelerated, thereby increasing the pharmacological activity in the human body. In addition, compounds having a particle size within the above range can be formulated into immediate-release formulations.

[0038] Here, the aforementioned "particle size D X = Y (where X and Y are positive numbers) means that when the particle size distribution obtained by measuring particle diameters is expressed as a cumulative curve, the particle diameter at the point where the particle size distribution reaches X% (% is calculated based on number, volume, or weight) when accumulated in ascending order of particle size is Y. Therefore, the particle size D 10 means the particle diameter at the 10% point on the particle size distribution cumulative curve, and particle size D 50 means the particle diameter at the 50% point on the particle size distribution cumulative curve, and particle size D 90 means the diameter of the particle at the 90% point on the particle size distribution cumulative curve. X Methods for measuring particle size distribution and the associated percentage types are known in the art, although this may vary depending on whether it is expressed as a percentage of the total cumulative particles on a number, volume, or weight basis.

[0039] At this time, the particle size D of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof XThe measurement is preferably carried out by the laser diffraction method, which records the particle size as the diameter of a volume-equivalent sphere. In other words, when measuring the particle size distribution by the laser diffraction method, the particle size D X The X value in indicates the percentage calculated by volume average. Therefore, the laser diffraction method is sensitive to the volume of the particles and provides the volume average particle size, which corresponds to the weight average particle size when the density is constant.

[0040] Measurement of the volume average particle size distribution of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof by such a laser diffraction method can be carried out using a known commercially available device based on a laser diffraction / scattering method based on Mie theory. For example, the particle size of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof can be measured using a Mastersizer laser diffraction device manufactured by Malvern Instruments. This device utilizes the fact that when particles are irradiated with a helium-neon laser beam and a blue light-emitting diode, scattering occurs and a light scattering pattern appears on the detector. The particle size distribution is determined by interpreting this light scattering pattern according to Mie theory, and has the advantage of being capable of both dry and wet measurements.

[0041] Furthermore, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof having a desired particle size distribution can be obtained by pulverizing the compound using a micronizer and then classifying the resulting product according to particle size. Specifically, pulverization can be performed using a conventional mill such as a jet mill, hammer mill, ball mill, or fluid energy mill. The resulting pulverized product can then be refined to a smaller particle size using a size classification method such as sieving or air current classification. More specifically, methods for adjusting the desired particle size are well known in the art (Pharmaceutical Dosage Forms: Volume 2, 2nd Edition, Ed.: H. A. Lieberman, L. Lachman, J. B. Schwartz (Chapter 3: Size Reduction)).

[0042] Meanwhile, the dosage of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, which is an active ingredient in the formulation, is appropriately determined for each individual case, taking into consideration the symptoms, age, sex, etc. of the patient. In general, when administered orally, the dosage for an adult is 0.01 mg / kg to 100 mg / kg per day, which can be administered once.

[0043] The total weight of the formulation may be 80 mg to 650 mg. Preferably, the total weight of the formulation is 80 mg to 350 mg. Specifically, the total weight of the formulation is 80 mg or more, or 90 mg or more, and 350 mg or less, 320 mg or less, 250 mg or less, 200 mg or less, or 180 mg or less.

[0044] Preferably, when the active ingredient of the formulation, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, is used primarily for the prevention and treatment of peptic ulcer, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori, the active ingredient is contained in a content of 10 mg to 80 mg per formulation. For example, the active ingredient is contained in a content of 10 mg, 20 mg, 40 mg, or 80 mg per formulation.

[0045] Furthermore, the oral formulation may be prepared in the form of tablets, capsules, granules, powders, etc., taking into consideration the intended use, function, route of administration, etc., and preferably, the oral formulation is a tablet.

[0046] In addition, the oral formulation can be prepared by mixing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof with lactose hydrate and microcrystalline cellulose, and optionally a lubricant, followed by compressing and pulverizing to prepare dry granules; and mixing the dry granules with a disintegrant and optionally other additives, and compressing them into tablets.

[0047] However, the preparation is not limited to this production method, and the preparation for oral administration can be produced by any method known in the art. [Effects of the Invention]

[0048] As described above, the oral formulation of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof of the present invention contains lactose hydrate and microcrystalline cellulose as excipients in a specific weight ratio and can exhibit excellent dissolution properties, and therefore can be used as an oral formulation useful for the prevention and treatment of peptic ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori. [Brief explanation of the drawings]

[0049] [Figure 1] 1 is a graph comparing the dissolution rates in a test solution of pH 1.2 of the tablets produced in Comparative Example 1-1, Comparative Example 1-2, and Example 1-4. [Figure 2] 1 is a graph comparing the dissolution rates in a test solution of pH 4.0 of the tablets produced in Comparative Examples 1-1 to 1-3, Examples 1-4 and 1-5. [Figure 3] 1 is a graph comparing the dissolution rates of the tablets produced in Example 2-1 in a test solution of pH 6.8 under initial and accelerated conditions. [Figure 4] 1 is a graph comparing the dissolution rates of the tablets produced in Example 2-2 in a test solution of pH 6.8 under initial and accelerated conditions. [Figure 5] 1 is a graph comparing the dissolution rates of the tablets produced in Example 2-3 in a test solution of pH 6.8 under initial and accelerated conditions. [Figure 6] 1 is a graph comparing the dissolution rates in a test solution of pH 1.2 of the tablets produced in Examples 3-1 to 3-3 and Reference Example 3-1. DETAILED DESCRIPTION OF THE INVENTION

[0050] Preferred examples are presented below to aid in understanding the present invention. However, the following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0051] Example 1-1 The main ingredient, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (hereinafter referred to as API (active pharmaceutical ingredients)), which is the compound represented by Chemical Formula 1, was prepared by the method described in the Examples of Korean Patent Registration No. 10-2126576 and then mixed with microcrystalline cellulose, lactose hydrate, and magnesium stearate. The mixture was then compressed using a roller compactor to produce a compacted plate, which was then subjected to oscillator milling and granulation to produce dry granules. Croscarmellose sodium, yellow iron oxide, and magnesium stearate were added to the prepared granules and mixed, and the resulting mixture was compressed to produce tablets. The contents of the ingredients contained in the tablets of Example 1-1 are shown in Table 1 below.

[0052] Examples 1-2 to 1-16 and Comparative Examples 1-1 to 1-3 Tablets were prepared in the same manner as in Example 1-1, except that the ratios of microcrystalline cellulose and lactose hydrate used as excipients were changed as shown in Tables 1 to 3 below.

[0053] [Table 1]

[0054] [Table 2]

[0055] [Table 3]

[0056] Experimental example 1: Elution evaluation test The tablets produced in Examples 1-1 to 1-16 and Comparative Examples 1-1 to 1-3 were subjected to in vitro dissolution tests and HPLC analysis in test solutions of pH 1.2 and pH 4.0 to measure the dissolution rates (%), and the results of the dissolution rate measurement in the test solution of pH 1.2 are shown in Table 4 and Figure 1, and the results of the dissolution rate measurement in the test solution of pH 4.0 are shown in Table 5 and Figure 2. The dissolution test conditions were as follows: 1) Dissolution test basis: Dissolution test method in the general test method in the 11th revision of the Korean Pharmacopoeia 2) Dissolution test method: Dissolution test method 2, paddle method 3) Dissolution test solution: 900 mL of test solution at pH 1.2, 900 mL of test solution at pH 4.0 4) Temperature conditions: Maintained at 37.2°C ± 0.5°C 5) Analysis method: HPLC method -Detection device: UV-visible spectrophotometer (measurement wavelength: 254 nm) -Column: C8 5um / 4.6 x 250mm column -Mobile phase: hydrogen phosphate buffer solution: methanol * pH 1.2 test solution: The first solution in the Korean Pharmacopoeia dissolution test, a buffer solution prepared using hydrochloric acid with a concentration of 0.1 mol / L and sodium chloride. * pH 4.0 test solution: 0.05 mol / L sodium acetate buffer solution

[0057] [Table 4]

[0058] [Table 5] TIFF0007777136000007.tif15158

[0059] Referring to Table 4 and Figure 1 above, the tablets of Examples 1-4 reached a final dissolution rate (dissolution rate 120 minutes after the start of dissolution) of 100% at pH 1.2. However, the tablets of Comparative Example 1-1, in which the weight ratio of lactose hydrate to microcrystalline cellulose was less than 1:1.5, and Comparative Example 1-2, in which the weight ratio of lactose hydrate to microcrystalline cellulose was more than 1:90, failed to completely dissolve the main ingredient even after 120 minutes, which was the final dissolution time.

[0060] 2, the tablets of the Examples had an initial dissolution rate (dissolution rate 5 minutes after the start of dissolution) of 60% or more and a final dissolution rate (dissolution rate 120 minutes after the start of dissolution) of 100%, whereas the tablets of Comparative Example 1-1, in which the weight ratio of lactose hydrate to microcrystalline cellulose was less than 1:1.5, the tablets of Comparative Example 1-2, in which the weight ratio of lactose hydrate to microcrystalline cellulose was more than 1:90, and the tablets of Comparative Example 1-3, which used only microcrystalline cellulose as an excipient, all had initial dissolution rates less than 60%, indicating poor initial dissolution characteristics. Furthermore, it was confirmed that the main ingredient did not completely dissolve in the tablets of Comparative Examples 1-1 and 1-3 even after 120 minutes, which is the final dissolution time.

[0061] Therefore, it was found that the oral formulation of the present invention, which contains the lactose hydrate and the microcrystalline cellulose as the main ingredient and excipient in a weight ratio of 1:1.5 to 1:90, exhibits an effect of improving the initial dissolution rate at pH 1.2 and pH 4.0, which are the gastrointestinal environments of the living body, and that the entire amount of the main ingredient can be dissolved before the final dissolution point.

[0062] Example 2-1 The main ingredient, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (API), a compound represented by Chemical Formula 1, was mixed with microcrystalline cellulose, lactose hydrate, and magnesium stearate. The mixture was then compressed using a roller compactor to produce a compacted plate, which was then subjected to oscillator milling and granulation to produce dry granules. Croscarmellose sodium as a disintegrant, yellow iron oxide as a colorant, and magnesium stearate as a lubricant were added to the produced granules and mixed, and the resulting mixture was compressed to produce uncoated tablets. The produced uncoated tablets were coated with a coating solution prepared by dissolving / dispersing Opadry (Colorcon) in purified water for 1 hour and then dried to produce coated tablets. The first coated tablets were coated with a coating solution prepared by dissolving / dispersing Opadry II (Colorcon) in purified water and ethanol for 1 hour to prepare the final tablets. The contents of the ingredients contained in the tablets of Example 2-1 are shown in Table 5 below.

[0063] Examples 2-2 to 2-3 and Reference Examples 2-1 to 2-3 Tablets were prepared in the same manner as in Example 2-1, except that the compounds listed in Table 6 were used instead of croscarmellose sodium used as a disintegrant in Example 2-1.

[0064] [Table 6]

[0065] Experimental Example 2: Storage stability test The tablets prepared in Examples 2-1 to 2-3 and Reference Examples 2-1 to 2-3 were placed in containers (high-density polyethylene bottles, HDPE bottles) and stored with the caps open under accelerated conditions (40°C, 75% RH) for 4 or 8 weeks. After this, an in vitro dissolution test and HPLC analysis were performed to measure the dissolution rate (%). The results are shown in Table 7, along with the dissolution rate (initial) under the initial conditions before storage. The dissolution rates under the initial and accelerated conditions for the tablets prepared in Example 2-1, Reference Examples 2-2, and Reference Examples 2-3 are shown in Figures 3 to 5, respectively. The dissolution test conditions were as follows: 1) Dissolution test basis: Dissolution test method in the general test method in the 11th revision of the Korean Pharmacopoeia 2) Dissolution test method: Dissolution test method 2, paddle method 3) Dissolution test solution: 900 mL of test solution at pH 6.8 4) Temperature conditions: Maintained at 37.2°C ± 0.5°C 5) Analysis method: HPLC method -Detection device: UV-visible spectrophotometer (measurement wavelength: 254 nm) -Column: C8 5um / 4.6 x 250mm column -Mobile phase: hydrogen phosphate buffer solution: methanol * pH 6.8 test solution: The second solution in the Korean Pharmacopoeia dissolution test, prepared by mixing phosphate buffer solution and water in a 1:1 ratio.

[0066] [Table 7]

[0067] Referring to Table 7 and FIGS. 3 to 5, it was confirmed that the tablets of Examples 2-1, 2-2, and 2-3, which used croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate, respectively, among various disintegrants, maintained their dissolution rates without any decrease even under accelerated conditions of the intestinal environment of a living body at pH 6.8, and thus exhibited excellent storage stability, compared to the tablets of Reference Examples 2-1, 2-2, and 2-3, which used granular powder mannitol, crospovidone, and starch, respectively.

[0068] Furthermore, considering the dissolution rate data under pH 6.8 conditions in Experimental Example 2, it is confirmed that the tablets of the Examples are partially released and absorbed in the stomach, and the remaining tablets exhibit a stable dissolution rate in the small intestine. Therefore, it can be expected that an oral formulation containing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof will exhibit high bioavailability in both the stomach and small intestinal environments in vivo.

[0069] Furthermore, the active ingredient (API) content of the tablets of Example 2-1 and Reference Example 2-3 was evaluated, and the results are shown in the following Table 8. At this time, the content was evaluated by the following method.

[0070] 1) Content test method: Approximately 10 g of sample to be measured was taken, placed in a 500 mL volumetric flask, and 225 mL of buffer solution was added. The mixture was subjected to ultrasonic extraction for 30 minutes to completely disperse the sample, and then cooled to room temperature while stirring for 30 minutes. Methanol was added, and the mixture was stirred for 30 minutes and cooled to room temperature. Then, methanol was added to the flask and the gauge was adjusted. An appropriate amount of the liquid was then taken, centrifuged, and 25 mL of the supernatant was taken. This was then placed in a 200 mL volumetric flask, and the dilution solution was added to the flask and the gauge was adjusted. The liquid was filtered through a 0.45 μm membrane filter to obtain the test solution. 2) Buffer solution: 1.74 g of dipotassium hydrogen phosphate was precisely weighed and dissolved in 1000 mL of water, and then 1 mL of trifluoroacetic acid was added to create a solution (pH 2.85±0.05). 3) Diluent: Buffer: MeOH=45:55 (v / v) 4) Temperature conditions: Maintained at 37.2°C ± 0.5°C 5) Analysis method: HPLC method -Detection device: UV-visible spectrophotometer (measurement wavelength: 254 nm) -Column: C8 5um / 4.6 x 250mm column -Mobile phase: hydrogen phosphate buffer solution: methanol

[0071] [Table 8]

[0072] Referring to Table 8 above, it was found that the tablet of Example 2-1, which used croscarmellose sodium as a disintegrant, did not lose any of its active ingredient content even after long-term storage under accelerated conditions, compared to the tablet of Reference Example 2-3, which used starch.

[0073] Therefore, it has been confirmed that tablets containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof as an active ingredient and containing microcrystalline cellulose and lactose hydrate as excipients in a specific weight ratio exhibit excellent dissolution properties, are immediately effective, and fully exhibit the intended medicinal effects, making them suitable for use as formulations.

[0074] Furthermore, when the tablet further comprises one of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate as a disintegrant, it can maintain excellent dissolution properties and the content of the active ingredient even under accelerated conditions of the intestinal environment, and can exhibit better storage stability.

[0075] Examples 3-1 to 3-3 and Reference Example 3-1 In order to evaluate the dissolution rate by particle size of the main component, the compound 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride, which is the main component and is represented by the above chemical formula 1, was pulverized using a jet mill, and the particle size D50 The tablets of Examples 3-1 to 3-3 and Reference Example 3-1 were prepared in the same manner as in Example 2-1, and the content of each ingredient in each tablet is shown in Table 9 below. 50 was measured by the following method.

[0076] Particle size measurement (volume average particle size measured by laser diffraction method) 1) Measuring device: Mastersizer 3000 manufactured by Malvern Instruments 2) Test solution 0.05%(v / v)Lecithin in Hexane solution 3) Test solution preparation Approximately 10.0 mg of sample is placed in a 20 mL beaker, and 15 mL of test liquid is taken out. This is then subjected to ultrasonic treatment for 30 seconds to completely disperse the sample, and used as the test liquid. 4) Analysis method Add the test solution so that the obscuration level is 5% to 10%, and after confirming that the obscuration level has stabilized, measure under the following conditions. [Operating conditions] Range: 0.02 to 2000 μm Particle RI: 1.59 Absorption: 0.01 Dispersant RI: 1.380 Obscuration Range: 5-10% Stirrer / Pump speed: 3000 RPM Ultrasonic sound:off Measurement cycle: 5

[0077] [Table 9]

[0078] Experimental Example 3: Evaluation test for elution by particle size The tablets prepared in Examples 3-1 to 3-2 and Reference Examples 3-1 to 3-2 were subjected to an in vitro dissolution test in a test solution of pH 1.2 and HPLC analysis to measure the dissolution rate (%), and the results are shown in Table 10 and Figure 6. The dissolution test conditions were as follows: 1) Dissolution test basis: Dissolution test method in the general test method in the 11th revision of the Korean Pharmacopoeia 2) Dissolution test method: Dissolution test method 2, paddle method 3) Dissolution test solution: 900 mL of test solution at pH 1.2 4) Temperature conditions: Maintained at 37.2°C ± 0.5°C 5) Analysis method: HPLC method -Detection device: UV-visible spectrophotometer (measurement wavelength: 254 nm) -Column: C8 5um / 4.6 x 250mm column -Mobile phase: hydrogen phosphate buffer solution: methanol * pH 1.2 test solution: The first solution in the Korean Pharmacopoeia dissolution test, a buffer solution prepared using hydrochloric acid with a concentration of 0.1 mol / L and sodium chloride.

[0079] [Table 10]

[0080] Referring to Table 10 and Figure 6 above, the tablets of Examples 3-1 to 3-3 had initial dissolution rates (dissolution rates 5 minutes after the start of dissolution) of 60% or more and final dissolution rates (dissolution rates 120 minutes after the start of dissolution) of 89% or more at pH 1.2, and the overall dissolution profiles were similar. However, the tablet of Reference Example 3-1 had a lower initial dissolution rate as well as a lower final dissolution rate. Furthermore, the tablets of Examples 3-2 and 3-3 were comparable to the tablet of Example 3-1, with a similarity factor (f2) value of 50% or more measured according to the pharmaceutical equivalence test standard. However, the tablet of Reference Example 3-1 showed a significant difference from the tablet of Example 3-1, with a similarity factor (f2) value of less than 50% measured according to the pharmaceutical equivalence test standard. This confirmed that the particle size of the main component affects the dissolution profile of the final formulation. The particle size D of the main component50 It is considered that uniform quality and in vivo efficacy of the formulation can be ensured when the particle size is 100 μm or less.

Claims

1. 1) a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, and 2) A formulation for oral administration comprising an excipient comprising lactose hydrate and microcrystalline cellulose, A formulation for oral administration, which is a tablet containing the lactose hydrate and the microcrystalline cellulose in a weight ratio of 1:3.2 to 1:70: 【Chemistry 1】 。

2. 2. The oral formulation according to claim 1, wherein the lactose hydrate and the microcrystalline cellulose are contained in a weight ratio of 1:3.4 to 1:5.

0.

3. The formulation for oral administration according to claim 1, wherein the excipient is contained in an amount of 100 to 1400 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

4. The formulation for oral administration according to claim 1, wherein the excipient is contained in an amount of 200 to 650 parts by weight per 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

5. 2. The formulation for oral administration according to claim 1, wherein the lactose hydrate is contained in an amount of 1 to 350 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

6. 2. The formulation for oral administration according to claim 1, wherein the microcrystalline cellulose is contained in an amount of 50 to 1100 parts by weight based on 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

7. The oral administration formulation according to claim 1 , further comprising a disintegrant.

8. 8. The formulation for oral administration according to claim 7, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate.

9. The formulation for oral administration according to claim 7, wherein the disintegrant is contained in an amount of 3.5 to 80 parts by weight based on 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

10. 2. The oral administration formulation according to claim 1, further comprising one or more additives selected from the group consisting of binders, lubricants, colorants, and coating agents.

11. 2. The oral administration formulation of claim 1, further comprising one or more compounds selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and sodium starch glycolate; magnesium stearate; and yellow iron oxide.

12. 2. The oral formulation according to claim 1, wherein the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is contained in an amount of 5 to 50 wt % based on the total weight of the oral formulation.

13. 2. The oral formulation according to claim 1, wherein the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in an amount of 10 to 30 wt % based on the total weight of the oral formulation.

14. The volume average particle size D of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof ５０ 2. The formulation for oral administration according to claim 1, wherein the particle size is 100 μm or less.

15. 2. The oral administration formulation according to claim 1, wherein the oral administration formulation has a total weight of 80 mg to 350 mg.

16. The oral formulation according to claim 1, wherein the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is contained in an amount of 10 mg to 80 mg per formulation.

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