Controlled release pharmaceutical composition

Abstract

The present invention relates to a preparation which can inhibit the initial release of a specific PRS inhibitor and has an effect of preventing nausea or vomiting side effects that occur when an excess amount of an active ingredient is absorbed at the initial stage.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing a specific PRS inhibitor, and more particularly to an initial controlled-release pharmaceutical composition. Background Art

[0002] PRS (prolyl-tRNA synthetase) is one of the aminoacyl-tRNA synthetases (ARSs) family and is used to activate amino acids for protein synthesis. That is, ARS performs a translational function to form aminoacyl adenylate (AA-AMP), and then transfers the activated amino acid to the 3'-end of the corresponding tRNA. Since ARS plays an important role in protein synthesis, inhibiting ARS inhibits the growth of all cells. Therefore, ARS has been regarded as a promising target for therapeutic agents for treating diseases that should inhibit antibiotics or overexpress cells (Nature, 2013, 494: 121-125).

[0003] PRS exists in or functions as a multi-synthetase complex (MSC) in the form of EPRS (glutamyl-prolyl-tRNA synthetase). In particular, among various MSCs, EPRS functions as a translational silencer that inhibits the production of VEGF (vascular endothelial growth factor A), where VEGF is a key factor in angiogenesis. In addition, it has been reported that EPRS is closely related to various solid tumors (Nat. Rev. Cancer, 2011, 11, 708-718).

[0004] On the other hand, Korean Patent No. 10-2084772 discloses a PRS inhibitor having the following structure, which is a substance attracting attention as a preventive or therapeutic agent for diseases related to PRS, especially fibrosis.

[0005]

[0006] However, as a result of various clinical tests on the above substance, side effects such as nausea or vomiting were confirmed. Therefore, the inventors of the present invention conducted in-depth research on methods to overcome these side effects, and as a result, found that this problem can be solved by preparing a preparation containing the above substance to meet specific conditions, and completed the present invention. Summary of the Invention

[0007] Technical Problem

[0008] An object of the present invention is to provide a pharmaceutical composition containing a specific PRS inhibitor that can control the initial release of the specific PRS inhibitor.

[0009] Technical Solution

[0010] To achieve the above object, according to the present invention, there is provided 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 excipients, wherein, based on the uncoated tablet, at 37 °C, in a solution of pH 6.8, within 5 minutes, the pharmaceutical composition exhibits a dissolution rate of 75% or less.

[0011] [Chemical Formula 1]

[0012]

[0013] The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is the compound described in Korean Patent No. 10-2084772, specifically a substance described in Example 40 of the specification of this Korean patent. The above substance is expected to be used as a PRS inhibitor for preventing or treating fibrosis, but as a result of various clinical trials, there is a problem of poor drug resistance due to side effects such as nausea or vomiting. Therefore, in order to improve drug compliance, these side effects must be overcome. After studying the causes of the above side effects from various perspectives, it was found that they are side effects caused by gastrointestinal irritation. In particular, it has been confirmed that the possibility of side effects is high when a super-large amount of the drug is absorbed in the initial stage.

[0014] Therefore, the inventors of the present invention have confirmed that when the initial release rate is controlled to be low in the preparation of a preparation containing the above substance, the side effects that occur when a super-large amount of the drug is absorbed in the initial stage can be significantly reduced.

[0015] In particular, in a preparation containing a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active ingredient"), the present invention is characterized in that there is provided a controlled-release pharmaceutical composition which, based on the uncoated tablet, at 37 °C, in a solution of pH 6.8, within 5 minutes, exhibits a dissolution rate of 75% or less. In particular, it is characterized in that the active ingredient is physically bound to the components contained in the preparation using a binder to control the initial release.

[0016] Preferably, based on the uncoated tablets, at 37 °C, in a solution of pH 6.8, within 5 minutes, the controlled release pharmaceutical composition according to the present invention shows a dissolution rate of 65% or less. Preferably, based on the uncoated tablets, at 37 °C, in a solution of pH 6.8, within 30 minutes, the controlled release pharmaceutical composition according to the present invention shows a dissolution rate of 90% or more. Preferably, based on the uncoated tablets, at 37 °C, the controlled release pharmaceutical composition according to the present invention does not dissolve in a solution of pH 1.2. In other words, the controlled release pharmaceutical composition according to the present invention is acid-resistant and has the characteristics that the initial dissolution rate is inhibited but all the drugs are released after a certain period of time.

[0017] In addition, the controlled release pharmaceutical composition according to the present invention may include a coating agent. In particular, it may include a coating layer formed with a coating agent on the uncoated tablets. Preferably, the controlled release pharmaceutical composition according to the present invention is a coated tablet containing a coating agent, and at 37 °C, in a solution of pH 6.8, within 10 minutes, it shows a dissolution rate of 20% or less. Preferably, based on the coated tablets, at 37 °C, in a solution of pH 6.8, within 15 minutes, the controlled release pharmaceutical composition according to the present invention shows a dissolution rate of less than 60%. Preferably, based on the coated tablets, at 37 °C, in a solution of pH 6.8, within 30 minutes, the controlled release pharmaceutical composition according to the present invention shows a dissolution rate of 90% or more. Preferably, based on the coated tablets, at 37 °C, the controlled release pharmaceutical composition according to the present invention does not dissolve in a solution of pH 1.2. In other words, the controlled release pharmaceutical composition according to the present invention is acid-resistant and has the characteristics that the initial dissolution rate is inhibited but all the drugs are released after a certain period of time. Preferably, the coated tablet is an enteric-coated tablet. Further, preferably, relative to 100 parts by weight of the uncoated tablets, the coating agent is included in an amount of 6 to 12 parts by weight.

[0018] On the other hand, the amount of the binder used can be adjusted, thereby adjusting the initial release rate of the controlled release pharmaceutical composition according to the present invention. From this perspective, preferably, relative to 100 parts by weight of the uncoated tablets, the binder is included in an amount of 1 to 20 parts by weight. More preferably, relative to 100 parts by weight of the uncoated tablets, the binder is included in an amount of 1.5 parts by weight or more, or 2.0 parts by weight or more, and 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.

[0019] The binder is not particularly limited as long as it can exhibit the initial release rate as described above. Preferably, polyvinylpyrrolidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gelatin, gum arabic, or xanthan gum can be used.

[0020] Preferably, at 20 °C, the viscosity of the binder in a 10% w / v aqueous solution is 5 to 1000 mPa·s. If the viscosity of the binder in a 10% w / v aqueous solution at 20 °C is less than 5 mPa·s, the viscosity is too low and the effect of the binder is insufficient, making it difficult to control the initial release. If the viscosity of the binder exceeds 1000 mPa·s, the viscosity is too high and it takes too long to release the active ingredient. Preferably, at 20 °C, in a 10% w / v aqueous solution, the viscosity of the binder is 10 mPa·s or higher, 50 mPa·s or higher, 100 mPa·s or higher, 150 mPa·s or higher, 200 mPa·s or higher, 250 mPa·s or higher, or 300 mPa·s or higher, and 950 mPa·s or lower, 900 mPa·s or lower, 850 mPa·s or lower, 800 mPa·s or lower, 750 mPa·s or lower, or 700 mPa·s or lower. Preferably, the binder is polyvinylpyrrolidone, and the above viscosity can be applied.

[0021] Preferably, at 20 °C, the viscosity of the binder in a 2% w / v aqueous solution is 5 to 500 mPa·s. In the same manner as above, if the viscosity of the binder in a 2% w / v aqueous solution at 20 °C is less than 5 mPa·s, the viscosity is too low and the effect of the binder is insufficient, making it difficult to control the initial release. If the viscosity of the binder exceeds 500 mPa·s, the viscosity is too high and it takes too long to release the active ingredient. Preferably, at 20 °C, in a 2% w / v aqueous solution, the viscosity of the binder is 5.5 mPa·s or higher, or 6 mPa·s or higher, and 400 mPa·s or lower, 300 mPa·s or lower, 200 mPa·s or lower, 100 mPa·s or lower, 50 mPa·s or lower, 40 mPa·s or lower, 30 mPa·s or lower, 20 mPa·s or lower, or 10 mPa·s or lower. Preferably, the binder is hydroxypropyl cellulose, and the above viscosity can be applied.

[0022] One or more pharmaceutically acceptable additives are not particularly limited as long as they can maintain the above initial release control effect. For example, the additives can include disintegrants, excipients, lubricants, diluents, etc.

[0023] Among the above additives, the disintegrant has an effect opposite to that of the binder. Therefore, it is preferably not used. Alternatively, when a disintegrant is used, it should be used within a range that does not inhibit the initial release effect produced by the use of the binder. For example, a disintegrant having a low disintegration effect is used, or the disintegrant is used in the smallest possible amount. From this perspective, preferably, relative to 100 parts by weight of the uncoated tablet, the controlled release pharmaceutical composition according to the present invention contains 0 to 10 parts by weight of the disintegrant. That is, it does not contain a disintegrant, or contains 10 parts by weight or less of the disintegrant relative to 100 parts by weight of the uncoated tablet. Further, if the disintegrant is a super disintegrant having a high disintegration effect, the disintegrant is contained in an amount of 50 parts by weight or less relative to 100 parts by weight of the binder. That is, the composition does not contain a super disintegrant, or contains 50 parts by weight or less of the super disintegrant relative to 100 parts by weight of the binder.

[0024] Among the above additives, the excipient is not particularly limited as long as it can be used in the preparation of a pharmaceutical composition. Although it is not closely related to the control of drug release, it can affect the uniformity of the preparation, which indicates the degree of uniformity of the content of the main components during the preparation process of the pharmaceutical composition. Preferably, relative to 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the excipient is contained in an amount of 100 to 200 parts by weight. More preferably, relative to 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the excipient is contained in an amount of 110 parts by weight or more, 120 parts by weight or more, or 130 parts by weight or more, and 190 parts by weight or less, 180 parts by weight or less, 170 parts by weight or less, or 160 parts by weight or less.

[0025] On the other hand, the pharmaceutical composition according to the present invention may include: (i) premixed granules containing a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, a binder, and an excipient; and (ii) a post-mixed material containing an excipient. As described below, the premixed granules can be first prepared and then tableted together with the post-mixed material to prepare the pharmaceutical composition. At this time, the weight ratio of the excipient contained in the premixed granules and the post-mixed material will have a certain influence on the uniformity of the preparation. From this perspective, in order to ensure the uniformity of the preparation in the present invention, the weight ratio of the excipient contained in the premixed granules to the excipient contained in the post-mixed material is preferably 4:6 to 6:4.

[0026] On the other hand, the pharmaceutical composition according to the present invention includes: mixing a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, a binder, and one or more pharmaceutically acceptable additives; and molding the prepared mixture by pressing.

[0027] More specifically, the pharmaceutical composition according to the present invention can be prepared by a preparation method including the following steps: a step of mixing components including a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, a binder, and an excipient to prepare pre-mixed granules; and a step of mixing the pre-mixed granules with a post-mixed material containing an excipient and then molding the mixture by pressing.

[0028] Advantageous Effects

[0029] As described above, the present invention prepares a preparation that can inhibit the initial release of an active ingredient and has the effect of preventing side effects such as nausea or vomiting that occur when a large amount of the drug is absorbed in the initial stage. Brief Description of the Drawings

[0030] Figure 1 Shows the results of Experimental Example 1 of the present invention.

[0031] Figure 2 and Figure 3 Shows the results of Experimental Example 2 of the present invention. Detailed Description of the Invention

[0032] Hereinafter, the present invention will be explained in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and do not limit the scope of the present invention in any way.

[0033] Preparation Examples

[0034]

[0035] Step 1) Preparation of Compounds 1-3

[0036] (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100.0 g, 0.27 mol, 1.0 eq) (which is Compound 1-1) was dissolved in 1000 mL of tetrahydrofuran, and 1,2-dichloro-4-fluoro-3-nitrobenzene (56.4 g, 0.27 mol, 1.0 eq) (which is Compound 1-2) and potassium carbonate (K 2 CO 3, 74.2 g, 0.54 mol, 2.0 eq), and the mixture was stirred for 1 to 3 hours under reflux conditions of tetrahydrofuran (80 °C to 100 °C). At the completion of the reaction, 1000 mL of pure water was added to extract the organic layer, and then 1000 mL of ethyl acetate was added for re - extraction. After completion of concentration under reduced pressure, 100 mL of ethanol was added to the concentrated residue, and the mixture was concentrated again. 400 mL of ethanol was added to the concentrated residue, dissolved, and then crystallized. After crystals were formed, 400 mL of pure water was added, and then crystallization was carried out at 0 - 5 °C for 2 hours. It was filtered under reduced pressure using a filter and washed with a mixture of 100 mL of EtOH and 100 mL of pure water cooled to 0 to 5 °C. It was dried under vacuum at 45 - 55 °C for 12 hours to obtain compound 1 - 3 as an orange or red solid, 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%).

[0037] Step 2) Preparation of compound 1 - 4

[0038] Compound 1 - 3 (120.0 g, 0.21 mol, 1.0 eq) obtained in Step 1 was dissolved in 1200 mL of ethanol, then potassium carbonate (176.9 g, 1.28 mol, 6.0 eq) was added, and 1400 mL of aqueous sodium bisulfite solution (content of Na 2 S 2 O 4 in the aqueous solution: 222.8 g, 1.28 mol, 6.0 eq) was added, and then the mixture was stirred at room temperature for 1 hour. At the completion of the reaction, ethanol was concentrated under reduced pressure, then 600 mL of pure water and 1200 mL of ethyl acetate were added for extraction. 600 mL of ethyl acetate was added for re - extraction. 1200 mL of brine was added to wash the organic layer. Sodium sulfate was added to dry the water, and the excess water was removed. It was concentrated under reduced pressure to obtain compound 1 - 4 as a brown liquid, 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%). The compound obtained was used in the next step without purification.

[0039] Step 3) Preparation of compound 1 - 5

[0040] Dissolve the compound 1-4 (113.6 g, 0.21 mol, 1.0 eq) obtained in Step 2 in 1136 mL of toluene, then add trimethyl orthoformate (TMOF, 30.3 mL, 0.28 mol, 1.3 eq) and p-toluenesulfonic acid (0.4 g, 0.02 mol, 0.1 eq), and stir the mixture at 50 - 60 °C for 1 - 2 hours. When the reaction is complete, remove the 1136 mL of toluene used in the reaction by concentration under reduced pressure. Add 122 mL of aqueous sodium bicarbonate solution, 1136 mL of ethyl acetate, and 1136 mL of pure water, and perform extraction. At this time, layer separation is easily carried out. Then, add 568 mL of EA to the aqueous layer for re-extraction. To color the organic layer, add activated carbon (11.4 g, 0.1 eq) and stir for 15 minutes. Add sodium sulfate to remove moisture, stir for 15 minutes, and then stir through diatomaceous earth. After completion of concentration of the filtrate under reduced pressure, add 227 mL of n-hexane to the concentrated residue, and concentrate under reduced pressure. Add 340 mL of n-hexane thereto, reflux and stir the mixture for 30 minutes to loosen the crystals, then cool to 0 - 5 °C, and stir at the same temperature for 4 hours. Filter it under reduced pressure using a filter, and wash it with 113 mL of n-hexane cooled to 0 - 5 °C. Dry it under vacuum at 45 - 55 °C for 12 hours to obtain the compound 1-5 as a white solid, 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%). Further, concentrate the filtrate and perform the crystallization process in the same manner to further obtain the above compound 1-5 as a white solid (8.0 g, yield: 8%). Obtain the final compound 1-5 (108 g, yield: 94%).

[0041] 1 H 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).

[0042] Step 4) Preparation of the compound represented by Chemical Formula 1

[0043] Dissolve the compound 1-5 (90.0 g, 0.17 mol, 1.0 eq) obtained in step 3 in 540 mL of ethyl acetate and cool to 0-10 °C. Add concentrated hydrochloric acid (146.4 mL, 10.0 eq) and stir for 1 to 2 hours. After the reaction is complete, add 540 mL of pure water and perform extraction at room temperature (under acidic conditions, the product is present in the aqueous layer). Add 540 mL of ethyl acetate to the aqueous layer again for re-extraction (to remove impurities with EA). Discard the organic layer, slowly add 8N aqueous sodium hydroxide solution to adjust the pH to 12.5 or higher. Add 900 mL of dichloromethane thereto for extraction (under basic conditions, the product is present in the MC layer). Add 450 mL of dichloromethane for re-extraction. After concentration under reduced pressure is completed, add the concentrated residue, free base (salt-free), (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol to 1100 mL of acetone and 54 mL of pure water to dissolve it. Add 1 equivalent of concentrated hydrochloric acid dropwise in 3 portions and stir the resulting crystals at 0-5 °C for 4 hours for crystallization. Filter it under reduced pressure using a filter and wash it with 109 mL of acetone cooled to 0-5 °C. Dry it under vacuum at 45-55 °C for 12 hours to obtain the compound represented by Chemical Formula 1, (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol 1HCl (58.5 g, yield: 97%) as a white solid.

[0044] 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).

[0045] Step 5) Further purification step

[0046] 110 mL of pure water was added to the compound represented by Chemical Formula 1 (55 g, 0.15 mol, 1.0 eq) obtained in Step 4, and the mixture was stirred at 70 - 75 °C for 1 hour, then cooled to 0 - 5 °C and stirred at the same temperature for 4 hours. It was filtered under reduced pressure using a filter, and washed with 55 mL of acetone cooled to 0 - 5 °C. It was dried under vacuum at 45 - 55 °C for 12 hours to obtain the compound represented by Chemical Formula 1 (52.0 g, yield: 94%), which is a purified white solid. Hereinafter, the compound represented by Chemical Formula 1 is referred to as "API" or "active ingredient".

[0047] 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).

[0048] Experimental Example 1

[0049] To confirm the safety / tolerance of the active ingredient in humans, side effects were examined in healthy adult subjects.

[0050] This clinical test was designed to be used for 32 healthy adult subjects in a randomized, double - blind, placebo - controlled, single - dose escalation manner as shown in Table 1 below. The capsule tablets used in this clinical test were prepared by using enteric - coated capsules and filling the capsules by volume, where the enteric - coated capsules contained only the active ingredient in the form of hydrochloride and no other excipients. The composition of the enteric - coated tablets (1 tablet) used in this clinical test is shown in Table 2 below and is referred to as "Comparative Example 1". In addition, for the enteric - coated tablet administration group, 5 tablets were administered at a time.

[0051] Table 1

[0052]

[0053] Table 2

[0054]

[0055] ​As a result of confirming the safety and drug resistance of single-dose administration, the most frequently occurring adverse reactions were gastrointestinal adverse reactions, including nausea, vomiting, diarrhea, and abdominal pain. Among them, nausea and vomiting were evaluated to have a greater impact on safety and drug resistance, and it was confirmed that this was caused by the active ingredient itself.

[0056] As Figure 1 shown, the relationship between the onset time of these nausea and vomiting side effects and the in vivo exposure was confirmed, and as a result, it was confirmed that most cases occurred before the increase in in vivo blood concentration. This is understood to mean that the nausea and vomiting that occur when administering the active ingredient act on the gastrointestinal tract, thereby stimulating the vagus nerve and activating the vomiting center, rather than acting on the vomiting center activation pathway through chemosensory-induced site stimulation due to exposure to in vivo blood.

[0057] Experimental Example 2

[0058] Independent of the clinical test in Experimental Example 1, this clinical test was designed to be used in 32 healthy adult subjects in a randomized, double-blind, placebo-controlled, multi-dose escalation manner as shown in Table 3 below. For the MAD1 and MAD2 dosing groups, one and two tablets as shown in Table 4 below (named "Comparative Example 2") were administered. For MAD3 and MAD4, one and two tablets of the enteric-coated preparation of the previous Experimental Example 1 (Comparative Example 1) were administered respectively.

[0059] Table 3

[0060]

[0061] Table 4

[0062]

[0063] As a result, as Figure 2 shown, it was confirmed that the side effects of nausea / vomiting had a low correlation with the drug dosing dose, while as Figure 3 shown, there was a correlation between the number of tablets administered and the occurrence of side effects. It is speculated that this is because as the number of tablets increases, the surface area increases, thereby affecting the increase in the initial dissolution rate.

[0064] Based on the above clinical results, it can be expected that the side effects of nausea / vomiting are correlated with the initial dissolution rate rather than the dosing dose of the API. Accordingly, the following tablets were developed to overcome the side effects of nausea / vomiting.

[0065] Example 1

[0066] The active ingredient was prepared into a preparation by a dry granulation method as described below.

[0067] (Step 1)

[0068] Mix 166.65 mg of the active ingredient, 62.20 mg of microcrystalline cellulose (JRS-101), 62.15 mg of lactose hydrate (Supertab 30GR), 10.00 mg of polyvinylpyrrolidone (PVP K90), and 3.00 mg of magnesium stearate.

[0069] (Step 2)

[0070] Use a dry granulator to prepare the mixture from Step 1 into a disk-shaped pressed product, and use an oscillator to pulverize it to prepare dry granular material.

[0071] (Step 3)

[0072] Add 57.00 mg of microcrystalline cellulose (Vivapur12), 57.00 mg of lactose hydrate (Supertab30GR), and 2.00 mg of magnesium stearate to the granules from Step 2 and mix.

[0073] (Step 4)

[0074] Press the mixture from Step 3 into tablets (uncoated tablets) with a total weight of 420.00 mg. This is named "#1-1", and the content of the ingredients contained in this tablet is the same as that shown for #1-1 in Table 5 below.

[0075] Furthermore, as shown in Table 5 below, by changing each ingredient and its content, prepare #1-2 and #1-3 in the same manner as #1-1.

[0076] Perform a dissolution test on each of the above-prepared uncoated tablets under the following conditions according to the second dissolution method (paddle method) of the Korean Pharmacopoeia. The results are shown in Table 5 below.

[0077] Dissolution medium: pH 6.8 buffer solution, 900 mL

[0078] Rotation rate: 50 rpm

[0079] Temperature: 37.0 ± 0.5 °C

[0080] Dissolution sample collection times: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min

[0081] Analysis method: HPLC analysis method

[0082] Detector: Ultraviolet absorption instrument (measurement wavelength: 260 nm)

[0083] Column: C8 5 μm / 4.6 × 250 mm column

[0084] Mobile phase: distilled water + methanol + trifluoroacetic acid

[0085] Table 5

[0086]

[0087] As described above, when only the type of binder was changed, for PVP K90, HPC-L, and PVP K30, the dissolution rate of the uncoated tablets within 5 minutes was within 75%. Further, when PVP K90 and HPC-L were used as binders (#1-1 and #1-2), the initial release inhibition effect was higher than that when PVP K30 was used (#1-3).

[0088] Example 2

[0089] Based on the results of Example 1, the dissolution rate due to the use of disintegrants was evaluated. Specifically, uncoated tablets were prepared in the same manner as in Example 1, but the ingredients used in the preparation of the uncoated tablets were changed as shown in Table 6 below, and the dissolution rate was evaluated.

[0090] Table 6

[0091]

[0092] Comparing #2-1 with #2-2, the initial release inhibition effect decreased as the amount of disintegrant used increased. However, when the amount of binder used increased (#2-3, #2-4), the initial release inhibition effect could decrease again. In addition, when a disintegrant was used, if the binding degree of the binder was low (#2-5 and #2-6), the initial release inhibition effect was reduced. Therefore, it was necessary to consider the adhesive force of the binder to adjust the type and amount of disintegrant used.

[0093] Example 3

[0094] Based on the results of Example 2, the dissolution rate was evaluated based on the type and amount of disintegrant used. Specifically, uncoated tablets were prepared in the same manner as in Example 1, but the ingredients used in the preparation of the uncoated tablets were changed as shown in Table 7 below, and the dissolution rate was evaluated.

[0095] Table 7

[0096]

[0097]

[0098] When the disintegration effect of the disintegrant is low, as in #3-1 to #3-3, the initial release inhibition effect is high, even when the amount used is increased. However, when the disintegration effect of the disintegrant is high (#3-4 and #3-5), the initial release inhibition effect is slightly lower. Therefore, in order to increase the initial release inhibition effect, the disintegrant should not be used, or should be used in the smallest possible amount, or a disintegrant with a lower disintegration effect should be used.

[0099] Example 4

[0100] In the previous Example 1, the initial release effect was evaluated based on the type of binder. In this Example 4, based on the results of Example 1, the effect of inhibiting the initial release when adjusting the amount of excipient during premixing and postmixing was verified. Specifically, uncoated tablets were prepared in the same manner as in Example 1, but the ingredients used in the preparation of the uncoated tablets were changed as shown in Table 8 below, and the dissolution rate was evaluated.

[0101] Table 8

[0102]

[0103]

[0104] As described above, even when the total amount of excipient used is the same, when more excipient is used in premixing (#4-3 and #4-4), the initial release inhibition effect is higher than when more excipient is used in postmixing (#4-1 and #4-2).

[0105] However, when the ratio of the premixing part to the postmixing part is biased to one side, it was confirmed that the quality of the uncoated tablets was not constant during the tableting process. To evaluate this aspect, a formulation uniformity test was conducted. The formulation uniformity test was conducted as follows, and the results are shown in Table 9.

[0106] Test method for formulation uniformity: Take 1 tablet of the formulation, place it in a 50 mL volumetric flask, add 30 mL of diluent thereto, and stir the mixture until the tablet is completely disintegrated, then ultrasonically extract for 15 minutes or longer, and then make the diluent coincide with the marking line. Centrifuge an appropriate amount of this solution at 3000 rpm for 10 minutes, then take exactly 7 mL of the suspension, place it in a 200 mL volumetric flask, and add diluent to coincide with the marking line. Take an appropriate amount of this solution, filter it through a 0.45 μm membrane filter, discard the first 2 mL, and use the filtrate as the sample solution.

[0107] Diluent: water + methanol

[0108] Analysis method: HPLC method

[0109] Detector: Ultraviolet Absorbance Meter (measurement wavelength: 260 nm)

[0110] Column: C8 5 μm / 4.6×250 mm column

[0111] Mobile phase: Distilled water + methanol + trifluoroacetic acid

[0112] Table 9

[0113]

[0114]

[0115] It was confirmed that when the excipient ratio of the premix part and the postmix part was used in a manner similar to that described above, the preparation uniformity was excellent. When considered together with the effect of suppressing the initial release, the excipient ratio of the premix part and the postmix part was similar, but it could be judged that when the excipient ratio of the premix part was slightly higher (#1-1, #4-3), it had an initial release suppressing effect and it was possible to prepare tablets of the same quality.

[0116] Example 5

[0117] When combining the results of Examples 1 to 4, the uncoated tablets of #1-1, in which the viscosity of the binder was high, the disintegrant was insoluble, and the excipients were used in similar amounts in the premix and postmix, but the amount of excipient used in the premix was slightly more, showed the best results. In this Example 5, based on this, coated tablets were prepared by applying a coating agent to the uncoated tablets, and the dissolution of the coated tablets was evaluated.

[0118] Specifically, the uncoated 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 (which is an enteric coating agent). The amount of the coating base was applied as shown in Table 10 below. To examine the acid resistance and dissolution rate of each of the prepared coated tablets, tests were conducted according to the following methods and conditions.

[0119] Dissolution method: The second dissolution method (paddle method) of the Korean Pharmacopoeia

[0120] Dissolution medium: Buffer change (pH 1.2 → pH 6.8)

[0121] Volume of dissolution medium: 900 → 1000 mL

[0122] Temperature of the elutriator: 37.5°C ± 0.5°C

[0123] Paddle speed: 100 rpm

[0124] Analysis method: HPLC method

[0125] Detector: Ultraviolet absorption instrument (measurement wavelength: 260 nm)

[0126] Column: C8 5μm / 4.6×250 mm column

[0127] Mobile phase: Distilled water + methanol + trifluoroacetic acid

[0128] Table 10

[0129]

[0130] When checking the dissolution results based on the progress of the first coating (#5-1, #5-2), it was confirmed that when the second coating of enteric coating was carried out in the same manner, acid resistance was obtained under both conditions. However, compared with #5-1 (which had the first coating), the dissolution of #5-2 progressed more rapidly under the condition of pH 6.8. It was confirmed that #5-3 (which did not have the second coating) could not obtain the expected acid resistance. The first coating was carried out in the same manner, and as a result of checking the dissolution rate based on the amount of the second coating, acid resistance was obtained in all examples when the coating was carried out at 4% to 12% relative to 100 parts by weight of the uncoated tablets. However, in the example of #5-4 (which was coated at a rate of 4% relative to 100 parts by weight of the uncoated tablets), it was found that some tablets swelled due to the moisture retained in the eluator. Based on these results, it was confirmed that acid resistance was obtained, but the coating amount of #5-4 was insufficient because the tablet shape was not maintained under acidic conditions. When the second coating base was used at 6% to 12% relative to 100 parts by weight of the uncoated tablets, acid resistance was obtained and the performance did not change after dissolution under acidic conditions.

[0131] Example 6

[0132] In order to confirm the difference in the initial dissolution rate between Comparative Example 1 and Comparative Example 2 (in which nausea / vomiting was confirmed as a side effect in Experimental Example 1 and Experimental Example 2, respectively) and the coated tablets of #5-1 prepared in Example 5, the comparative dissolution behavior was confirmed under the following three conditions, and the results are shown in Tables 11 to 13, respectively.

[0133] 1) Simple comparative dissolution behavior: For one tablet each of Comparative Example 1, Comparative Example 2, and formulation #5-1, the dissolution test was carried out in the same manner as in Example 1, and the results are shown in Table 11.

[0134] 2) Comparative dissolution behavior at the same dose: Two tablets of Comparative Example 1 and one tablet of Comparative Example 2 were evaluated together, and one tablet of Formulation #5-1 was evaluated. The dissolution test was carried out in the same manner as in Example 1. The results are shown in Table 12 below.

[0135] 3) Comparative dissolution behavior under in vivo pH conditions: One tablet each of Comparative Example 1, Comparative Example 2, and Formulation #5-1 was subjected to a dissolution test in the same manner as in Example 5. The results are shown in Table 13 below.

[0136] Table 11

[0137] Time (min) 5 10 15 30 45 60 90 120 Comparative Example 1 0.00 24.51 75.66 89.01 94.59 96.14 97.81 98.84 Comparative Example 2 0.00 16.10 52.38 88.39 95.84 97.70 99.77 101.47 #5-1 0.00 0.85 19.36 91.40 100.59 101.12 101.54 102.12

[0138] Table 12

[0139]

[0140] Table 13

[0141]

[0142] As described above, it was confirmed that Formulation #5-1 according to the present invention is controlled in the initial release when compared with Comparative Example 1 and Comparative Example 2.

[0143] Experimental Example 3

[0144] In order to confirm the effect of suppressing side effects of Formulation #5-1 prepared in the form of the coated tablets as described above, a Phase 1 clinical trial was conducted in healthy adult subjects.

[0145] Experimental Example 3-1

[0146] In 24 and 12 healthy adult subjects, two Phase 1 single-dose case clinical trials were designed in an open-label, two-part, fixed-sequence, three-period manner. A single dose of Tablet #5-1 was administered. As a control group, a Phase 1 single-dose case clinical trial was designed in a random, open-label, and crossover manner in 36 healthy adults, and a clinical trial was conducted in which Comparative Example 1 was administered as a single dose of two tablets. Table 14 below shows the comparison results of the incidence of nausea / vomiting side effects based on the relevant clinical results.

[0147] Table 14

[0148] Preparation Comparative Example 1 #5-1 #5-1 Dose (mg) 200 150 150 Number of days of administration (days) 1 1 1 Target number of people 36 24 12 Occurrence of nausea 11％ 0％ 0％ Occurrence of vomiting 6％ 0％ 0％

[0149] Experimental Example 3-2

[0150] Using the #5-1 preparation in the form of the coated tablets as described above, two Phase 1 single-dose case clinical trials were designed in an open-label, two-part, fixed-sequence, three-phase manner in 48 and 12 healthy adult subjects, respectively. Multiple dosing was performed using the preparation #5-1. In Table 15 below, the incidence of nausea / vomiting side effects caused by multiple dosing of Comparative Example 1 confirmed in Experimental Example 1 was compared with the results of two multiple-dose clinical trials of the preparation #5-1. In each clinical trial, the dosing dose was administered twice a day.

[0151] Table 15

[0152] Preparation Comparative Example 1 Comparative Example 1 #5-1 #5-1 Dose (mg) 100 200 150 150 Number of days of administration (days) 3 3 3 3 Target number of people 6 6 48 12 Nausea 17％ 33％ 15％ 0％ Vomiting 17％ 0％ 0％ 0％

[0153] As described above, it was confirmed that when the preparation #5-1 was administered, the incidence of nausea / vomiting side effects was significantly reduced compared with the existing preparation.

Claims

1. 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 excipients, wherein, based on the uncoated tablet, at 37 °C, in a solution of pH 6.8, within 5 minutes, the pharmaceutical composition exhibits a dissolution rate of 75% or less. [Chemical Formula 1] 2. The controlled-release pharmaceutical composition according to claim 1, wherein, based on the uncoated tablet, at 37 °C, in a solution of pH 6.8, within 5 minutes, the controlled-release pharmaceutical composition exhibits a dissolution rate of 65% or less.

3. The controlled-release pharmaceutical composition according to claim 1, wherein, based on the uncoated tablet, at 37 °C, in a solution of pH 6.8, within 30 minutes, the controlled-release pharmaceutical composition exhibits a dissolution rate of 90% or more.

4. The controlled-release pharmaceutical composition according to claim 1, wherein, the controlled-release pharmaceutical composition is a coated tablet containing a coating agent, and based on the coated tablet, at 37 °C, in a solution of pH 6.8, within 10 minutes, the coated tablet exhibits a dissolution rate of 20% or less.

5. The controlled-release pharmaceutical composition according to claim 4, wherein, based on the coated tablet, at 37 °C, in a solution of pH 6.8, within 15 minutes, the controlled-release pharmaceutical composition exhibits a dissolution rate of less than 60%.

6. The controlled-release pharmaceutical composition according to claim 4, wherein, based on the coated tablet, at 37 °C, in a solution of pH 1.2, the controlled-release pharmaceutical composition does not undergo dissolution.

7. The controlled-release pharmaceutical composition according to claim 4, wherein, the coated tablet is an enteric-coated tablet.

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

9. The controlled-release pharmaceutical composition according to claim 1, wherein, relative to 100 parts by weight of the uncoated tablet, the binder is contained in an amount of 1 to 20 parts by weight.

10. The controlled-release pharmaceutical composition according to claim 1, wherein, the binder is polyvinylpyrrolidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gelatin, gum arabic, or xanthan gum.

11. The controlled-release pharmaceutical composition according to claim 10, wherein, at 20 °C, the viscosity of the binder in a 10% w / v aqueous solution is 5 to 1000 mPa·s.

12. The controlled-release pharmaceutical composition according to claim 10, wherein, at 20 °C, the viscosity of the binder in a 2% w / v aqueous solution is 5 to 500 mPa·s.

13. The controlled-release pharmaceutical composition according to claim 1, The controlled release pharmaceutical composition contains 0 to 10 parts by weight of a disintegrant relative to 100 parts by weight of the uncoated tablets.

14. The controlled release pharmaceutical composition according to claim 13, wherein, the disintegrant is a super disintegrant and is contained in an amount of 50 parts by weight or less relative to 100 parts by weight of the binder.

15. The controlled release pharmaceutical composition according to claim 14, wherein, the super disintegrant is sodium starch glycolate, croscarmellose sodium or crospovidone.

16. The controlled release pharmaceutical composition according to claim 1, wherein, the pharmaceutical composition comprises: (i) premixed granules containing a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, a binder, and an excipient; and (ii) postmixed material containing an excipient.

17. The controlled release pharmaceutical composition according to claim 16, wherein, the weight ratio of the excipient contained in the premixed granules to the excipient contained in the postmixed material is 4:6 to 6:4.

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