Controlled-Release Pharmaceutical Composition

Abstract

The present invention relates to a dosage form that can suppress the initial release of a specific PRS inhibitor, and is effective in preventing side effects such as nausea or vomiting that occur when too much active ingredient is absorbed in the early stage.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions containing specific PRS inhibitors, and in particular to early-release controlled pharmaceutical compositions. [Background technology]

[0002] Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase (ARS) family of enzymes that activate amino acids for protein synthesis. After forming aminoacyl adenylate (AA-AMP), ARS performs the translational function of transferring the activated amino acid to the 3′ terminus of the corresponding tRNA. Because ARS plays a crucial role in protein synthesis, ARS inhibition suppresses the growth and development of all cells. Therefore, ARS is recognized as a promising target for antibiotics and therapeutic agents that suppress cellular overexpression (Nature, 2013, 494:121-125).

[0003] PRS exists and functions in the form of EPRS (Glutamyl-Prolyl-tRNA Synthetase) in the multisynthetase complex (MSC). In particular, EPRS functions as a translational silencer that suppresses the production of VEGF A (vascular endothelial growth factor A), a key factor in angiogenesis, in various MSCs. It has also been reported to be closely associated with various solid cancers (Nat. Rev. Cancer, 2011, 11, 708-718).

[0004] Meanwhile, Korean Patent Registration No. 10-2084772 describes a PRS inhibitor having the following structure, which is a substance that has attracted attention as a preventive or therapeutic agent for PRS-related diseases, particularly fibrosis. JPEG2026505928000002.jpg2363

[0005] However, it has been found that the substance has various clinical effects, including side effects such as nausea and vomiting. As a result of extensive research into methods to improve such side effects, the inventors have found that this can be resolved by preparing a dosage form containing the substance to meet specific conditions, and have thus completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides pharmaceutical compositions containing specific PRS inhibitors capable of controlled initial release. [Means for solving the problem]

[0007] In order to solve the above problems, the present invention provides a controlled-release pharmaceutical composition comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; a binder; and one or more pharmaceutically acceptable additives, the composition exhibiting a dissolution rate of 75% or less in a pH 6.8 solution at 37°C within 5 minutes based on the uncoated tablet: [Chemical formula 1] JPEG2026505928000003.jpg2363

[0008] The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is a compound disclosed in Korean Patent Registration No. 10-2084772, specifically, the substance described in Example 40 of the specification. While the substance is expected to be useful as a PRS inhibitor for the prevention or treatment of fibrosis, it has had problems with poor drug tolerance due to various clinical results and side effects such as nausea and vomiting. Therefore, improving these side effects is necessary to improve drug tolerance. After extensive investigation into the causes of these side effects, it was found that they are caused by gastrointestinal irritation, and it was confirmed that the possibility of side effects is particularly high when excessive drug is absorbed initially.

[0009] Therefore, in the present invention, it has been confirmed that when a dosage form containing the above substance is manufactured by controlling the initial release rate to be low, side effects that occur when an excessive amount of drug is absorbed in the early stages can be significantly reduced.

[0010] In particular, the present invention provides a controlled-release pharmaceutical composition containing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active ingredient") in a dosage form that shows a dissolution rate of 75% or less in a pH 6.8 solution at 37°C within 5 minutes based on the uncoated tablet. In particular, the present invention is characterized in that the active ingredient and the ingredients contained in the dosage form are physically bound together using the binder, thereby controlling the initial release.

[0011] Preferably, the controlled-release pharmaceutical composition of the present invention exhibits a dissolution rate of 65% or less in 5 minutes in a pH 6.8 solution at 37°C based on the uncoated tablet. Preferably, the controlled-release pharmaceutical composition of the present invention exhibits a dissolution rate of 90% or more in 30 minutes in a pH 6.8 solution at 37°C based on the uncoated tablet. Preferably, the controlled-release pharmaceutical composition of the present invention does not dissolve in a pH 1.2 solution at 37°C based on the uncoated tablet. In other words, the controlled-release pharmaceutical composition of the present invention is acid-resistant, suppresses the initial dissolution rate, and completely releases the drug after a certain period of time.

[0012] Furthermore, the controlled-release pharmaceutical composition according to the present invention may contain a coating agent, specifically, a coating layer formed of the coating agent on a plain tablet. Preferably, the controlled-release pharmaceutical composition according to the present invention is a coated tablet containing a coating agent, and the coated tablet exhibits a dissolution rate of 20% or less within 10 minutes in a pH 6.8 solution at 37°C. Preferably, the controlled-release pharmaceutical composition according to the present invention exhibits a dissolution rate of less than 60% within 15 minutes in a pH 6.8 solution at 37°C. Preferably, the controlled-release pharmaceutical composition according to the present invention exhibits a dissolution rate of 90% or more within 30 minutes in a pH 6.8 solution at 37°C. Preferably, the controlled-release pharmaceutical composition according to the present invention does not dissolve in a pH 1.2 solution at 37°C. In other words, the controlled-release pharmaceutical composition according to the present invention is acid-resistant, suppresses the initial dissolution rate, and completely releases the drug after a certain period of time. Preferably, the coated tablet is an enteric-coated tablet. Preferably, the coating agent is contained in an amount of 6 to 12 parts by weight relative to 100 parts by weight of the plain tablet.

[0013] Meanwhile, the initial release rate of the controlled-release pharmaceutical composition according to the present invention can be adjusted by adjusting the amount of the binder used. From this viewpoint, the binder is preferably contained in an amount of 1 to 20 parts by weight per 100 parts by weight of the plain tablet. More preferably, the binder is contained in an amount of 1.5 parts by weight or more, or 2.0 parts by weight or more, and is 19 parts by weight or less, 18 parts by weight or less, 17 parts by weight or less, 16 parts by weight or less, 15 parts by weight or less, 14 parts by weight or less, 13 parts by weight or less, 12 parts by weight or less, 11 parts by weight or less, or 10 parts by weight or less, per 100 parts by weight of the plain tablet.

[0014] The binder is not particularly limited as long as it can exhibit the above-mentioned initial release rate, but preferably, polyvinylpyrrolidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gelatin, gum arabic, or xanthan gum can be used.

[0015] Preferably, the viscosity of the binder is 5 to 1000 mPa·s in a 10% w / v aqueous solution at 20° C. If the viscosity of the binder is less than 5 mPa·s in a 10% w / v aqueous solution at 20° C., the viscosity is too low, the binder's function is insufficient, and initial release control is difficult; if the viscosity exceeds 1000 mPa·s, the viscosity is too high, and it takes an excessively long time for the active ingredient to be released. Preferably, the viscosity of the binder in a 10% w / v aqueous solution at 20°C is 10 mPa·s or more, 50 mPa·s or more, 100 mPa·s or more, 150 mPa·s or more, 200 mPa·s or more, 250 mPa·s or more, or 300 mPa·s or more, and 950 mPa·s or less, 900 mPa·s or less, 850 mPa·s or less, 800 mPa·s or less, 750 mPa·s or less, or 700 mPa·s or less. Preferably, the binder is polyvinylpyrrolidone, and the above-mentioned viscosities can be applied.

[0016] Preferably, the viscosity of the binder is 5 to 500 mPa·s in a 2% w / v aqueous solution at 20°C. As described above, if the viscosity of the binder is less than 5 mPa·s in a 2% w / v aqueous solution at 20°C, the viscosity is too low, the binder's function is insufficient, and initial release control is difficult. If the viscosity exceeds 500 mPa·s, the viscosity is too high, and an excessively long time is required for the active ingredient to be released. Preferably, the viscosity of the binder is 5.5 mPa·s or more, or 6 mPa·s or more, in a 2% w / v aqueous solution at 20°C, and is 400 mPa·s or less, 300 mPa·s or less, 200 mPa·s or less, 100 mPa·s or less, 50 mPa·s or less, 40 mPa·s or less, 30 mPa·s or less, 20 mPa·s or less, or 10 mPa·s or less. Preferably, the binder is hydroxypropyl cellulose, and the above-mentioned viscosity can be applied.

[0017] The one or more pharmaceutically acceptable additives are not particularly limited as long as the initial release controlled effect is maintained. Examples of the additives include disintegrants, excipients, lubricants, diluents, etc.

[0018] Among the additives, disintegrants play an opposite role to binders, so it is preferable not to use a disintegrant. Alternatively, if a disintegrant is used, it should be used within a range that does not inhibit the initial release effect of the binder. For example, a disintegrant with low disintegrating effect is used, or it is used in as small a quantity as possible. From this perspective, the controlled-release pharmaceutical composition of the present invention preferably contains 0 to 10 parts by weight of the disintegrant per 100 parts by weight of the plain tablets. That is, the composition does not contain a disintegrant, or contains 10 parts by weight or less of the disintegrant per 100 parts by weight of the plain tablets. Furthermore, if the disintegrant is a superdisintegrant with high disintegrating effect, the composition contains 50 parts by weight or less of the disintegrant per 100 parts by weight of the binder. That is, the composition does not contain a superdisintegrant, or contains 50 parts by weight or less of the superdisintegrant per 100 parts by weight of the binder.

[0019] Among the additives, the excipient is not particularly limited as long as it is used in the preparation of a pharmaceutical composition. Although not closely related to controlled release of a drug, it can affect the formulation uniformity, which indicates the degree of uniformity of the main ingredient content during the preparation of a pharmaceutical composition. Preferably, the excipient is contained in an amount of 100 to 200 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. More preferably, the excipient is contained in an amount of at least 110 parts by weight, at least 120 parts by weight, or at least 130 parts by weight, and at most 190 parts by weight, at most 180 parts by weight, at most 170 parts by weight, or at most 160 parts by weight per 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0020] Meanwhile, the pharmaceutical composition according to the present invention may comprise (i) pre-blended granules containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, a binder, and an excipient, and (ii) a post-blended material containing an excipient. As described below, the pre-blended granules may be prepared first and then compressed together with the post-blended material to produce a pharmaceutical composition. In this regard, the weight ratio of the excipients contained in the pre-blended granules to the post-blended material may partially affect the formulation uniformity. From this perspective, in the present invention, the weight ratio of the excipients contained in the pre-blended granules to the post-blended material is preferably 4:6 to 6:4, in order to ensure formulation uniformity.

[0021] Meanwhile, the pharmaceutical composition according to the present invention may be prepared by a method including the steps of mixing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; a binder; and one or more pharmaceutically acceptable additives; and compressing the mixture.

[0022] More specifically, the pharmaceutical composition according to the present invention can be prepared by a method including the steps of: preparing pre-blended granules by blending ingredients including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, a binder, and an excipient; blending the pre-blended granules with a post-blended material including the excipient, and then compressing the blend. In addition, when the pharmaceutical composition according to the present invention is a coated tablet, the dosage form prepared by the above method can be coated with a coating base to prepare a coated tablet. [Effects of the Invention]

[0023] As described above, the present invention provides a dosage form that can suppress the initial release of the active ingredient, thereby preventing side effects such as nausea or vomiting that occur when too much drug is absorbed in the early stages. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a diagram showing the results of Experimental Example 1 of the present invention. [Figure 2]FIG. 10 is a diagram showing the results of Experimental Example 2 of the present invention. [Figure 3] FIG. 10 is a diagram showing the results of Experimental Example 2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention will be described in more detail with reference to the following examples, but the following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0026] Manufacturing example TIFF2026505928000004.tif54155

[0027] Step 1) Preparation of Compounds 1-3 Compound 1-1, tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (100.0 g, 0.27 mol, 1.0 eq) was dissolved in 1000 mL of tetrahydrofuran. Compound 1-2, 1,2-dichloro-4-fluoro-3-nitrobenzene (56.4 g, 0.27 mol, 1.0 eq) and potassium carbonate (K2CO3, 74.2 g, 0.54 mol, 2.0 eq) were added, and the mixture was stirred under tetrahydrofuran reflux conditions (80-100 °C) for 1-3 hours. Upon completion of the reaction, 1000 mL of purified water was added to extract the organic layer, followed by re-extraction with 1000 mL of ethyl acetate. After vacuum concentration, 100 mL of ethanol was added to the concentrated residue, and the residue was re-concentrated. The concentrated residue was dissolved in 400 mL of ethanol and crystallized. After crystals were formed, 400 mL of purified water was added and crystallization was allowed to proceed at 0-5°C for 2 hours. The crystals were filtered under reduced pressure using a filter and washed with a mixture of 100 mL of EtOH and 100 mL of purified water cooled to 0-5°C. The resulting mixture was dried under vacuum at 45-55°C for 12 hours to obtain compound 1-3, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-((3,4-dichloro-2-nitrophenyl)amino)propyl)piperidine-1-carboxylate (143.0 g, yield: 95%), as an orange or red solid.

[0028] Step 2) Preparation of Compounds 1-4 Compound 1-3 (120.0 g, 0.21 mol, 1.0 eq) obtained in Step 1 was dissolved in 1200 mL of ethanol, followed by the addition of potassium carbonate (176.9 g, 1.28 mol, 6.0 eq) and 1400 mL of aqueous sodium hydrosulfite solution (NaSO content in the aqueous solution: 222.8 g, 1.28 mol, 6.0 eq). The mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the ethanol was concentrated under reduced pressure, followed by extraction with 600 mL of purified water and 1200 mL of ethyl acetate. Another 600 mL of ethyl acetate was added for further extraction. The organic layer was washed with 1200 mL of brine. Sodium sulfate was added for drying to remove excess water. The mixture was concentrated under reduced pressure to give compound 1-4, tert-butyl (2R,3S)-2-(3-((2-amino-3,4-dichlorophenyl)amino)propyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (113.6 g, yield: 100%), as a brown liquid. The resulting compound was used in the next step without purification.

[0029] Step 3) Preparation of Compounds 1-5 Compound 1-4 (113.6 g, 0.21 mol, 1.0 eq) obtained in Step 2 was dissolved in 1136 mL of toluene, followed by the addition of trimethyl orthoformate (TMOF, 30.3 mL, 0.28 mol, 1.3 eq) and paratoluenesulfonic acid (0.4 g, 0.02 mol, 0.1 eq). The mixture was stirred at 50-60°C for 1-2 hours. Upon completion of the reaction, the 1136 mL of toluene used in the reaction was removed by concentration under reduced pressure. Extraction was performed by adding 122 mL of aqueous sodium bicarbonate solution, 1136 mL of ethyl acetate, and 1136 mL of purified water; the layers were easily separated. Then, 568 mL of EA was added to the aqueous layer for re-extraction. Activated carbon (11.4 g, 0.1 eq) was added to the organic layer to remove color and stirred for 15 minutes. Sodium sulfate was added to remove moisture and stirred for 15 minutes, then the mixture was filtered through a Celite filter. After the filtrate was concentrated under reduced pressure, 227 mL of n-hexane was added to the concentrated residue. After concentration under reduced pressure, 340 mL of n-hexane was added and refluxed and stirred for 30 minutes to loosen the crystals. The mixture was then cooled to 0-5°C and stirred at the same temperature for 4 hours. The mixture was filtered under reduced pressure using a filter and washed with 113 mL of n-hexane cooled to 0-5°C. The mixture was dried under vacuum at 45-55°C for 12 hours to obtain compound 1-5, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidine-1-carboxylate (100 g, yield: 86%), as a white solid. The filtrate was concentrated and the crystallization process was repeated to obtain an additional white solid of Compound 1-5 (8.0 g, yield: 8%), and the final Compound 1-5 (108 g, yield: 94%) was obtained. 1H NMR (500 MHz, MeOD): δ 8.30 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.30 (m, 2H), 4.17 (s, 1H), 4.05 (s, 1H), 3.91 (d, 1H), 3.73 (s, 1H), 2.68 (s, 1H), 1.87 (s, 3H), 1.70 (t, 2H), 1.55 (d, 1H), 1.45 (m, 10H), 1.42 (s, 1H), 0.90 (s, 9H), 0.07 (d, 6H)

[0030] Step 4) Preparation of the compound represented by formula 1 Compound 1-5 (90.0 g, 0.17 mol, 1.0 eq) obtained in Step 3 was dissolved in 540 mL of ethyl acetate and cooled to 0-10°C. Concentrated hydrochloric acid (146.4 mL, 10.0 eq) was added and stirred for 1-2 hours. After the reaction was completed, 540 mL of purified water was added and extracted at room temperature (the product was present in the aqueous layer under acidic conditions). 540 mL of ethyl acetate was added to the aqueous layer again and re-extracted (impurities were removed with EA). The organic layer was discarded, and 8N aqueous sodium hydroxide was slowly added to adjust the pH to 12.5 or higher. 900 mL of dichloromethane was added and extraction was performed (the product was present in the MC layer under basic conditions). 450 mL of dichloromethane was added and re-extraction was performed. After completion of concentration under reduced pressure, the concentrated residue, freebase (salt-free) (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, was dissolved in 1100 mL of acetone and 54 mL of purified water. One equivalent of concentrated hydrochloric acid was added dropwise in three portions, and the resulting crystals were stirred at 0-5°C for 4 hours to allow crystallization to proceed. The crystals were filtered under reduced pressure using a filter and washed with 109 mL of acetone cooled to 0-5°C. The crystals were dried under vacuum at 45-55°C for 12 hours to obtain a white solid, (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol 1HCl (58.5 g, yield: 97%), which is the compound represented by Chemical Formula 1. 1H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0031] Step 5) Additional purification steps The compound represented by Formula 1 (55 g, 0.15 mol, 1.0 eq) obtained in Step 4 was added to 110 mL of purified water and stirred at 70-75°C for 1 hour, then cooled to 0-5°C and stirred at the same temperature for 4 hours. The mixture was filtered under reduced pressure using a filter and washed with 55 mL of acetone cooled to 0-5°C. The purified compound represented by Formula 1 (52.0 g, yield: 94%) was obtained as a white solid by drying in vacuo at 45-55°C for 12 hours. Hereinafter, the compound represented by Formula 1 will be referred to as "API" or "active ingredient." 1 H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0032] Experimental Example 1 To confirm the safety and tolerance of the active ingredient in humans, side effects were examined in healthy adults. As shown in Table 1 below, a randomized, double-blind, placebo-controlled, single-dose ascending clinical trial was conducted on 32 healthy adults. The capsule tablets used in this clinical trial were prepared by filling the active ingredient in hydrochloride form, without any additional excipients, into capsules according to dosage using Vcaps enteric-coated capsules. The ingredients of the enteric-coated tablet (1 tablet) used in the clinical trial are shown in Table 2 below and are referred to as "Comparative Example 1." The enteric-coated tablet group received 5 tablets at a time.

[0033] [Table 1]

[0034] [Table 2]

[0035] As a result of safety and tolerability checks after a single dose, the most frequently occurring abnormal reactions were gastrointestinal abnormal reactions, including nausea, vomiting, diarrhea, and abdominal pain. Of these, nausea and vomiting were assessed to have the greatest impact on safety and drug tolerance, and it was confirmed that this was caused by the active ingredient itself.

[0036] As a result of examining the relationship between the timing of occurrence of nausea and vomiting side effects and exposure in the body (Figure 1), it was confirmed that they mostly occur before the blood concentration in the body rises. This means that the nausea and vomiting that occur when the active ingredient is administered does not activate the vomiting center by stimulating the chemical receptor induction site due to exposure in the blood, but acts on the gastrointestinal tract, stimulating the vagus nerve and activating the vomiting center.

[0037] Experimental Example 2 Separately from the clinical trial of Experimental Example 1, a randomized, double-blind, placebo-controlled, multiple-dose ascending clinical trial was designed for 32 healthy adults, as shown in Table 3 below. The MAD1 and MAD2 groups were administered one and two tablets, respectively, of the tablets shown in Table 4 below (referred to as "Comparative Example 2"), while the MAD3 and MAD4 groups were administered one and two tablets, respectively, of the enteric-coated dosage form of Experimental Example 1 (Comparative Example 1).

[0038] [Table 3]

[0039] [Table 4]

[0040] As a result, as can be seen in Figure 2, the side effect of nausea / vomiting has little correlation with the administered dose of the drug, but rather there is a correlation between the number of tablets administered and the frequency of side effects, as can be seen in Figure 3. This is presumably due to the fact that as the number of tablets increases, the surface area increases, resulting in an increased initial dissolution rate.

[0041] Based on the clinical results, it was predicted that the side effects of nausea and vomiting were correlated with the initial dissolution rate of the API, not with the administered dose. Therefore, the following tablet was developed to improve the side effects of nausea and vomiting.

[0042] Example 1 The active ingredient is prepared into a formulation by a dry granulation process, specifically as follows: (Stage 1) 166.65 mg of the active ingredient, 62.20 mg of microcrystalline cellulose (JRS-101), 62.15 mg of lactose monohydrate (Supertab 30GR), 10.00 mg of povidone (PVP K90), and 3.00 mg of magnesium stearate were mixed. (Stage 2) The mixture of step 1 was compressed into a plate using a dry granulator and pulverized using an oscillator to produce dry granules. (Stage 3) The granules from step 2 were mixed with 57.00 mg of microcrystalline cellulose (Vivapur 12), 57.00 mg of lactose monohydrate (Supertab 30GR), and 2.00 mg of magnesium stearate. (Stage 4) The mixture of Step 3 was compressed into tablets (plain tablets) with a total weight of 420.00 mg. These tablets were designated "#1-1." The contents of the ingredients contained in the tablets are shown in Table 5 #1-1 below.

[0043] Additionally, as shown in Table 5 below, #1-2 and #1-3 were produced in the same manner as #1-1, except that the components and their contents were changed.

[0044] The prepared plain tablets were subjected to a dissolution test under the following conditions according to Dissolution Method 2 (paddle method) of the Korean Pharmacopoeia, and the results are shown in Table 5 below. -Eluate: pH6.8 buffer solution, 900mL -Rotation speed: 50 rpm -Temperature: 37.0±0.5℃ -Dissolution test solution sampling time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes -Analysis method: HPLC analysis method -Detector: ultraviolet absorption photometer (measurement wavelength: 260 nm) -Column: C8 5μm / 4.6x250mm column - Mobile phase: distilled water + methanol + trifluoroacetic acid

[0045] [Table 5]

[0046] As mentioned above, when only the type of binder was changed, the dissolution rate of the plain tablets was within 75% within 5 minutes for all of PVP K90, HPC-L, and PVP K30. Furthermore, when PVP K90 and HPC-L were used as binders (#1-1 and #1-2), the initial release-inhibiting effect was greater than when PVP K30 was used (#1-3).

[0047] Example 2 Following the results of Example 1, the dissolution rate was evaluated using a disintegrant. Specifically, plain tablets were produced in the same manner as in Example 1, except that the ingredients used in producing the plain tablets were changed as shown in Table 6 below, and the dissolution rate was evaluated.

[0048] [Table 6]

[0049] Comparing #2-1 and #2-2, the initial release inhibitory effect decreases as the amount of disintegrant used increases, but the initial release inhibitory effect can be increased again by increasing the amount of binder used (#2-3 and #2-4).Furthermore, when a disintegrant is used, if the degree of binder binding is low (#2-5 and #2-6), the initial release inhibitory effect decreases.Therefore, the type and amount of disintegrant used must be adjusted taking into account the binding strength of the binder.

[0050] Example 3 Following the results of Example 2, the dissolution rate was evaluated depending on the type and amount of disintegrant used. Specifically, plain tablets were produced in the same manner as in Example 1, except that the ingredients used in producing the plain tablets were changed as shown in Table 7 below, and the dissolution rate was evaluated.

[0051] [Table 7]

[0052] When the disintegrant had a low disintegrating effect, as in #3-1 to #3-3, the initial release-inhibiting effect was high even when the amount used was increased, but when the disintegrant had a high disintegrating effect (#3-4 and #3-5), the initial release-inhibiting effect was slightly lower. Therefore, to increase the initial release-inhibiting effect, it is necessary to use no disintegrant, or to use as little as possible of a disintegrant, or to use a disintegrant with a low disintegrating effect.

[0053] Example 4 In Example 1, the initial release effect was evaluated depending on the type of binder. In Example 4, based on the results of Example 1, the initial release suppression effect was confirmed when the amount of excipient used during pre-mixing and post-mixing was adjusted. Specifically, plain tablets were produced in the same manner as in Example 1, except that the ingredients used during plain tablet production were changed as shown in Table 8 below, and the dissolution rate was evaluated.

[0054] [Table 8]

[0055] As mentioned above, even though the total amount of excipients used was the same, the use of more excipients in the pre-mixing step (#4-3 and #4-4) had a greater initial release-inhibiting effect than the use of more excipients in the post-mixing step (#4-1 and #4-2).

[0056] However, if the ratio of the pre-mixing portion to the post-mixing portion is biased to one side, it was confirmed that the weight of the plain tablets was not constant during the tableting process, and a dosage uniformity test was performed to evaluate this. The dosage uniformity test was performed as follows, and the results are summarized in Table 9. - Formulation uniformity test method: Place one tablet of the formulation in a 50mL flask, add 30mL of diluent, and stir until the tablet is completely disintegrated. After ultrasonic extraction for at least 15 minutes, the diluent is added to the gauge line. A suitable amount of this solution is centrifuged at 3000 rpm for 10 minutes, and then 7mL of the supernatant is accurately taken and placed in a 200mL flask. Add the diluent and the gauge line is adjusted. A suitable amount of this solution is filtered through a 0.45μm membrane filter, and the first 2mL is discarded, and the filtrate is used as the test solution. -Dilution: Water + Methanol -Analysis method: HPLC method -Detector: ultraviolet absorption photometer (measurement wavelength: 260 nm) -Column: C8 5μm / 4.6x250mm column - Mobile phase: distilled water + methanol + trifluoroacetic acid

[0057] [Table 9]

[0058] As mentioned above, when the excipient ratios in the pre-mixing and post-mixing parts are similar, it was confirmed that excellent formulation uniformity was achieved. Considering the initial release suppression effect, it is believed that when the excipient ratios in the pre-mixing and post-mixing parts are similar and the excipient ratio in the pre-mixing part is higher (#1-1, #4-3), tablets with initial release suppression and uniform quality can be manufactured.

[0059] Example 5 Taking the results of Examples 1 to 4 together, the most optimal results were observed for plain tablets #1-1, which had a high viscosity of the binder, did not dissolve the disintegrant, and used similar amounts of excipients in pre-mixing and post-mixing, with a slightly larger amount of excipient used in pre-mixing. In Example 5, coated tablets were prepared by applying a coating agent to plain tablets based on this, and the dissolution profiles of the coated tablets were evaluated.

[0060] Specifically, the plain tablets #1-1 prepared in Example 1-1 were first coated with Opadry white 03B28796 coating agent, and then secondarily coated with Acryl EZE 93O18508, an enteric coating agent. The amounts of coating agents were adjusted as shown in Table 10 below. The acid resistance and dissolution rate of each of the prepared coated tablets were tested according to the following methods and conditions. -Dissolution method: Korean Pharmacopoeia Dissolution Method 2 (Paddle method) -Elution solution: Buffer transition (pH 1.2 → pH 6.8) -Elution volume: 900 → 1000 mL -Eluator temperature: 37.5℃±0.5℃ - Paddle speed: 100 rpm -Analysis method: HPLC method -Detector: ultraviolet absorption photometer (measurement wavelength: 260 nm) -Column: C8 5μm / 4.6x250mm column - Mobile phase: distilled water + methanol + trifluoroacetic acid

[0061] [Table 10]

[0062] When examining dissolution results with and without primary coating (#5-1, #5-2), acid resistance was maintained under both conditions by applying the same enteric coating (secondary coating). However, it was confirmed that #5-2 exhibited faster dissolution at pH 6.8 than #5-1, which had primary coating. #5-3, which did not undergo secondary coating, demonstrated poor acid resistance, as expected. When primary coating was performed identically and dissolution rates were examined depending on the amount of secondary coating, acid resistance was maintained for all tablets coated to 4%–12% of the uncoated tablet weight. However, in #5-4, which had a coating of 4% of the uncoated tablet weight, some tablets were found to have absorbed moisture and swelled in the dissolution chamber. These results indicated that acid resistance was maintained, but the amount of coating in #5-4 was insufficient, as the tablet shape could not be maintained under acidic conditions. When the secondary coating base was used in an amount of 6% to 12% based on 100 weight parts of the plain tablet, acid resistance was ensured and no change in properties occurred after dissolution under acidic conditions.

[0063] Example 6 In order to confirm the difference in the initial dissolution rate between Comparative Examples 1 and 2, in which side effects such as nausea / vomiting were observed in Experimental Examples 1 and 2, and the coated tablet #5-1 prepared in Example 5, comparative dissolution tests were conducted under the following three conditions, and the results are shown in Tables 11 to 13, respectively. 1) Simple comparative dissolution: The dissolution test was carried out in the same manner as in Example 1 for one tablet each of the dosage forms of Comparative Example 1, Comparative Example 2, and #5-1. The results are shown in Table 11. 2) Comparative dissolution at the same dose: Two tablets of Comparative Example 1 and one tablet of Comparative Example 2 were evaluated, and one tablet of the #5-1 dosage form was also evaluated. The dissolution tests were carried out in the same manner as in Example 1, and the results are shown in Table 12. 3) Comparative dissolution under different pH conditions in the body: The dissolution test was carried out in the same manner as in Example 5 for one tablet each of the dosage forms of Comparative Example 1, Comparative Example 2, and #5-1. The results are shown in Table 13.

[0064] [Table 11]

[0065] [Table 12]

[0066] [Table 13]

[0067] As described above, it was confirmed that the dosage form #5-1 according to the present invention had a controlled initial dissolution when compared with Comparative Examples 1 and 2.

[0068] Experimental Example 3 To confirm the side effect-improving effect of the #5-1 formulation prepared in the coated tablet, phase 1 clinical trials were conducted on healthy adults.

[0069] Experimental Example 3-1 Two single-dose Phase 1 clinical trials were conducted in 24 and 12 healthy adults, respectively, using a 2-part, fixed-sequence, 3-period open clinical design, with single administration using tablet #5-1. One single-dose Phase 1 clinical trial was conducted in 36 healthy adults as a control group, using a randomized, open, crossover clinical design, with two tablets of Comparative Example 1 administered as a single dose. Table 14 below compares the incidence of nausea / vomiting side effects based on the clinical results.

[0070] [Table 14]

[0071] Experimental Example 3-2 Using the #5-1 dosage form manufactured from the coated tablets, two multiple-dose Phase 1 clinical trials were conducted in 48 and 12 healthy adult subjects, respectively. The clinical trials were designed as a 2-part, fixed-sequence, 3-period study, and multiple administration was conducted using the #5-1 dosage form. Table 15 below compares the incidence of nausea / vomiting caused by multiple administration of Comparative Example 1, as confirmed in Experimental Example 1, with the results of two multiple-dose clinical trials using the #5-1 dosage form. In each clinical trial, the dosage was administered twice daily.

[0072] [Table 15]

[0073] As described above, it was confirmed that when #5-1 dosage form was administered, the incidence of side effects such as nausea / vomiting was significantly improved compared to the existing dosage form.

Claims

1. The present invention relates to a pharmaceutical composition comprising a compound represented by the following formula 1, or a pharmaceutically acceptable salt thereof; a binder; and one or more pharmaceutically acceptable additives, The uncoated tablet shows a dissolution rate of 75% or less within 5 minutes in a pH 6.8 solution at 37°C. Controlled release pharmaceutical compositions. [Chemical formula 1]

2. The uncoated tablet shows a dissolution rate of 65% or less within 5 minutes in a pH 6.8 solution at 37°C.

10. The controlled release pharmaceutical composition of claim 1.

3. The uncoated tablet shows a dissolution rate of 90% or more within 30 minutes in a pH 6.8 solution at 37°C.

10. The controlled release pharmaceutical composition of claim 1.

4. The controlled-release pharmaceutical composition is a coated tablet containing a coating agent, The coated tablet has a dissolution rate of 20% or less within 10 minutes in a pH 6.8 solution at 37°C.

10. The controlled release pharmaceutical composition of claim 1.

5. The coated tablet has a dissolution rate of less than 60% within 15 minutes in a pH 6.8 solution at 37°C. The controlled release pharmaceutical composition of claim 4.

6. The coated tablet does not dissolve in a pH 1.2 solution at 37°C. The controlled release pharmaceutical composition of claim 4.

7. The coated tablet is an enteric coated tablet. The controlled release pharmaceutical composition of claim 4.

8. The coating agent is contained in an amount of 6 to 12 parts by weight relative to 100 parts by weight of the plain tablet. The controlled release pharmaceutical composition of claim 4.

9. The binder is contained in an amount of 1 to 20 parts by weight relative to 100 parts by weight of the plain tablet.

10. The controlled release pharmaceutical composition of claim 1.

10. The binder is polyvinylpyrrolidone, hydroxypropyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, gelatin, gum arabic, or xanthan gum.

10. The controlled release pharmaceutical composition of claim 1.

11. The viscosity of the binder is 5 to 1000 mPa s in a 10% w / v aqueous solution at 20°C.

11. The controlled release pharmaceutical composition of claim 10.

12. The viscosity of the binder is 5 to 500 mPa s in a 2% w / v aqueous solution at 20°C.

11. The controlled release pharmaceutical composition of claim 10.

13. The disintegrant is contained in an amount of 0 to 10 parts by weight based on 100 parts by weight of the plain tablet.

10. The controlled release pharmaceutical composition of claim 1.

14. The disintegrant is a super disintegrant, and the content of the disintegrant is 50 parts by weight or less relative to 100 parts by weight of the binder.

14. The controlled release pharmaceutical composition of claim 13.

15. The super disintegrant is sodium starch glycolate, croscarmellose sodium, or crospovidone.

15. The controlled release pharmaceutical composition of claim 14.

16. The pharmaceutical composition comprises: (i) a pre-blended granule comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; a binder; and an excipient; and (ii) a post-blended material comprising the excipient.

10. The controlled release pharmaceutical composition of claim 1.

17. the weight ratio of the excipient contained in the pre-blended granules to the excipient contained in the post-blended material is 4:6 to 6:4; 17. The controlled release pharmaceutical composition of claim 16.

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