Pharmaceutical composition for preventing or treating fibrosis

Abstract

The present invention relates to a pharmaceutical composition that can be useful for preventing or treating fibrosis, and is characterized in that the preventive or therapeutic effect of fibrosis can be further enhanced by using the first component and the second component together according to the present invention.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition that can be usefully used for the prevention or treatment of fibrotic diseases. [Background technology]

[0002] Fibrosis is a phenomenon in which parts of organs become hardened for some reason, with pulmonary fibrosis and liver fibrosis being typical examples. In cases like pulmonary fibrosis, the lungs almost always become hardened due to exposure to radiation or fluid accumulation in the lungs, but some people may develop pulmonary fibrosis. Currently, there are almost no cures for fibrosis symptoms, and treatments are currently being developed and researched. Types of fibrosis include interstitial lung disease (ILD), scleroderma, keloid, hypertrophic scar, non-alcoholic fatty liver disease (NFLD), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, age-related macular degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, muscular dystrophy, diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), and inflammatory bowel disease (IBD). Interstitial lung diseases include idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), and chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD).

[0003] Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease considered a rare disease with a poor prognosis and no proven treatment. To date, there is no clearly established cause, and the 5-year and 10-year survival rates after diagnosis are poor, at 43% and 15%, respectively. Despite extensive research, no treatments have been shown to improve survival rates. Considering that other interstitial lung diseases, such as nonspecific interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia (COP), have relatively favorable outcomes when properly treated, IPF is considered to have a poor prognosis among interstitial lung diseases. The most common causes of death are respiratory failure (39%) and heart disease (27%), with other causes including lung cancer, pulmonary embolism, and pneumonia. The prognosis is even worse in older patients, men, those with poor lung function at the time of diagnosis, and those with a high number of fibroblastic foci on histological examination.

[0004] Similar to nonspecific interstitial pneumonia (NSIP), various treatments for idiopathic pulmonary fibrosis have been attempted, including the use of steroids and cytotoxic drugs, but more recently, anti-fibrotic agents. Currently, the approved drugs for idiopathic pulmonary fibrosis are pirfenidone and nintedanib, but these drugs do not provide a cure; they merely slow pulmonary fibrosis and alleviate symptoms. Therefore, there is a need for more effective drugs that can improve patients' quality of life.

[0005] Systemic sclerosis-related interstitial lung disease (SSc-ILD) is a condition in which patients with systemic sclerosis (SSc) also have interstitial lung disease (ILD) as a complication, and decline in lung function is a major cause of death in SSc. Nintedanib and tocilizumab are approved therapeutic agents for this condition in the United States, and have been shown to reduce decline in lung function. However, as with idiopathic pulmonary fibrosis, there is a need for more effective drugs that can improve the quality of life of patients.

[0006] Chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD) refer to a variety of progressive fibrosing interstitial lung diseases, excluding idiopathic pulmonary fibrosis, including autoimmune interstitial lung disease and idiopathic interstitial pneumonia. Nintedanib has been approved for treatment in the United States after demonstrating its effectiveness in reducing lung function decline in patients with various fibrotic lung diseases. Fibrotic interstitial lung diseases can manifest as a progressive phenotype, resulting in pulmonary fibrosis, decreased lung function, and worsening quality of life. Therefore, if a drug's effectiveness in reducing lung function decline in a specific interstitial lung disease is demonstrated, regardless of classification or underlying disease, it may also be expected to be effective in reducing lung function decline in other interstitial lung diseases.

[0007] Meanwhile, prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase (ARS) family of enzymes that activates 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).

[0008] PRS exists and functions in the form of EPRS (Glutamyl-Prolyl-tRNA Synthetase) in the multisynthetase complex (MSC). In particular, among various MSCs, EPRS functions as a translational silencer that suppresses the production of VEGF A (vascular endothelial growth factor A), a key factor in angiogenesis, and has been reported to be closely related to various solid cancers (Nat. Rev. Cancer, 2011, 11, 708-718).

[0009] Therefore, the present inventors have conducted extensive research into methods for preventing or treating fibrosis, and have found that when a specific PRS inhibitor is used in combination with an existing fibrosis treatment agent, more effective prevention or treatment of fibrosis is possible, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention provides a pharmaceutical composition that can be usefully used for the prevention or treatment of fibrotic diseases. [Means for solving the problem]

[0011] In order to solve the above problems, the present invention provides the following pharmaceutical composition for preventing or treating fibrosis: 1) a first component which is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and 2) A compound represented by the following formula 2, a pharmaceutically acceptable salt thereof, a compound represented by the following formula 3, and a pharmaceutically acceptable salt thereof, comprising any one second component selected from the group consisting of: A pharmaceutical composition for preventing or treating fibrosis, comprising: The first and second components are co-administered in the same dosage form or in different dosage forms; Pharmaceutical Compositions: [ka] [ka] [ka]

[0012] The pharmaceutical composition according to the present invention contains the first and second components as described above, and thus the preventive or therapeutic effects of each component on fibrosis are combined with each other, enabling more effective prevention or treatment of fibrosis.

[0013] The first component is a compound described in Korean Patent Registration No. 10-2084772, specifically, the compound described in Example 40 of the specification. The first component, as a PRS inhibitor, can be used together with a second component that has been used for the prevention or treatment of fibrosis, as described below, to exhibit more effective preventive or therapeutic effects for fibrosis.

[0014] The second component is a component used for the prevention or treatment of fibrosis, and the compounds 2 and 3 are known as pirfenidone and nintedanib, respectively. Compared with the conventionally known preventive or therapeutic effects of the second component on fibrosis, when used in combination with the first component as in the present invention, the effect is further enhanced.

[0015] The weight ratio of the first component to the second component is preferably 1:0.5 to 1:30. Within this range, the effects of the first component and the second component interact with each other to enhance the prevention or treatment of fibrosis. More preferably, the weight ratio of the first component to the second component is 1:0.6 to 1:25.

[0016] Preferably, the second component is a compound represented by Chemical Formula 2 or a pharmaceutically acceptable salt thereof, and the weight ratio of the first component to the second component is 1:2 to 1:25, more preferably 1:2 to 1:20, 1:2 to 1:12, 1:2 to 1:8, 1:6 to 1:12, or 1:6 to 1:8.

[0017] Preferably, the second component is a compound represented by Chemical Formula 3 or a pharmaceutically acceptable salt thereof, and the weight ratio of the first component to the second component is 1:0.6 to 1:10, more preferably 1:0.6 to 1:6, 1:0.6 to 1:1.5, or 1:1 to 1:1.5.

[0018] In addition, in the pharmaceutical composition according to the present invention, the first component is contained in an amount of 100 to 150 mg. Furthermore, the content of the second component can be adjusted in accordance with the content of the first component.

[0019] Preferably, in the pharmaceutical composition according to the present invention, the second component is a compound represented by Chemical Formula 2 or a pharmaceutically acceptable salt thereof, and the composition contains 100 to 150 mg of the first component and 200 to 800 mg of the second component.

[0020] Preferably, in the pharmaceutical composition according to the present invention, the second component is a compound represented by Chemical Formula 3 or a pharmaceutically acceptable salt thereof, and the composition contains 100 to 150 mg of the first component and 100 to 150 mg of the second component.

[0021] Preferably, the first and second components are each administered twice a day or three times a day, preferably the first component is administered twice a day and the second component is administered three times a day, or the first component is administered three times a day and the second component is administered twice a day.

[0022] Meanwhile, the compounds represented by Chemical Formulas 1 to 3 can be used in the form of pharmaceutically acceptable salts, and useful salts include acid addition salts formed with pharmaceutically acceptable free acids. The free acids can be inorganic or organic. Examples of inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid. Examples of organic acids include citric acid, acetic acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, and aspartic acid.

[0023] Furthermore, the compounds represented by Chemical Formulas 1 to 3 can be prepared in crystalline or non-crystalline form, and when prepared in crystalline form, they are optionally hydrated or solvated. The present invention includes not only stoichiometric hydrates of the compounds represented by Chemical Formulas 1 to 3, but also compounds containing various amounts of water. The solvates of the compounds represented by Chemical Formulas 1 to 3 include both stoichiometric and non-stoichiometric solvates.

[0024] On the other hand, examples of the fibrosis include interstitial lung disease (ILD), scleroderma, keloid, hypertrophic scar, non-alcoholic fatty liver disease (Non-alcoholic Fatty Liver Disease), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, age-related macular degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, muscular dystrophy, diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), and inflammatory bowel disease (IBD). bowel disease (IBD). The interstitial lung diseases include idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), and chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD).

[0025] As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" refers to any action that improves or favorably alters the symptoms of the disease by administering the composition of the present invention.

[0026] The pharmaceutical compositions of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practice. These dosage forms may contain, in addition to the active ingredient, additives such as pharmaceutically acceptable carriers, adjuvants, or diluents.

[0027] Suitable carriers include, but are not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. The compound of the present invention can also be dissolved in oil, propylene glycol, or other solvents commonly used in the preparation of injection solutions. For topical application, the compound of the present invention can also be formulated into ointments or creams.

[0028] The pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts or solvates, and may be used alone or in combination with other pharmaceutically active compounds or in suitable groups.

[0029] The compounds of the present invention are formulated into injections by dissolving, suspending, or emulsifying them in aqueous solvents such as common saline, 5% dextrose, or non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters, or propylene glycol. The dosage forms of the present invention may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0030] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the drug form, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for optimal efficacy, the compound of the present invention is administered at 0.0001 to 100 mg / kg (body weight) per day, preferably 0.001 to 100 mg / kg (body weight). Administration can be once a day or in divided doses, via oral or parenteral routes. Depending on the administration method, the composition can contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight, of the compound of the present invention.

[0031] The pharmaceutical composition of the present invention can be administered to mammals, including rats, mice, livestock, and humans, by a variety of routes, including oral, rectal, or intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebroventricular injection, although any route of administration is contemplated. [Effects of the Invention]

[0032] As described above, the pharmaceutical composition according to the present invention can be useful for preventing or treating fibrosis by using the first component and the second component together. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 shows the results of expression of genes involved in collagen synthesis in Experimental Example 1 of the present invention. [Figure 2] FIG. 1 shows the results of expression of genes involved in collagen synthesis in Experimental Example 1 of the present invention. [Figure 3] FIG. 1 shows the results of lung function evaluation in Experimental Example 2-1 of the present invention. [Figure 4] FIG. 1 shows the results of histopathological analysis in Experimental Example 2-3 of the present invention. [Figure 5] 10 is a micrograph of the lung tissue of a vehicle individual in Experimental Example 2-3 of the present invention. [Figure 6] 1 shows a micrograph of lung tissue from an individual to which the first and second components (PID) were administered in combination in Experimental Example 2-3 of the present invention. [Figure 7] FIG. 1 shows the results of analyzing inflammatory cell infiltration in Experimental Example 2-4 of the present invention. [Figure 8] FIG. 1 shows the results of measuring changes in body weight in Experimental Example 2-5 of the present invention. [Figure 9] FIG. 1 shows changes in blood concentration of the active ingredient in Experimental Example 3 of the present invention. [Figure 10] FIG. 1 shows changes in plasma concentration following a single administration of Experimental Example 4 of the present invention. [Figure 11] FIG. 1 shows changes in plasma concentration following multiple administrations of Experimental Example 4 of the present invention. [Figure 12] FIG. 10 is a graph showing the correlation between AUC and the administered dose in Experimental Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention will be described in more detail below with reference to the following examples, but the following examples are merely for illustrative purposes and are not intended to limit the scope of the present invention.

[0035] Production example 1: 1st component The following compound was prepared in the same manner as in Example 40 of Korean Patent Registration No. 10-2084772, and is hereinafter referred to as "First Component" or "Example". [ka] 1 H NMR (500 MHz, MeOD): δ 9.67 (s, 1H). 8.02 (d, 1H), 7.82 (d, 1H), 4.62 (m, 2H), 3.60 (m, 1H), 3.28 (m, 1H), 2.99 (m, 2H), 2.25 (m, 2H), 2.08 (m, 2H), 1.99 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H)

[0036] Production example 2: 2nd component Nintedanib (hereinafter referred to as "second ingredient (NIN)") and pirfenidone (hereinafter referred to as "second ingredient (PID)") were purchased as commercial products and used, as follows:

[0037] [Table 1]

[0038] Experimental Example 1: Non-clinical anti-fibrotic efficacy evaluation The first component (10 mM) was diluted with DMSO to 100 μM. It was then diluted with DMSO to 10, 3, and 1 μM, and the second component (NIN) (10 mM) was diluted with DMSO to 50 nM.

[0039] DHLF cell lines (FGM™-2 Bullet Kit™, 10% FBS), a pulmonary fibrosis cell line, were prepared and cultured in FBM medium in T75 Easy Flask filters at 37°C and 5% CO2. The cultured DHLF cells were treated with 10 ng / mL TGF-β and test drugs, either alone or in combination, for 72 hours. After incubation, the media was removed, proteins were extracted, and quantified using a BCA Protein Assay Kit. Based on the quantification value of each extracted protein, 10–20 μg of protein was subjected to Western blotting. After running, the proteins were transferred to a PVDF membrane and washed three times with TBS-T. Each PVDF membrane was then treated with 1 mL of ECL solution, and protein expression levels were measured using an AI680 imager. Each band value was normalized to β-actin using ImageJ and is shown in Tables 2 and 3 and Figures 1 and 2.

[0040] [Table 2]

[0041] [Table 3]

[0042] These results confirmed that the effect of reducing the expression of genes involved in collagen synthesis was greater when used in combination than when used alone. Specifically, it was confirmed that even at half the existing effective concentrations (Nintedanib 100nM, first component 10ug / ml) (Nintedanib 50nM, first component 5ug / ml), the inhibitory effect on fibrosis factors was even greater than when used at the effective concentrations of each compound.

[0043] Experimental Example 2: Animal experiment on anti-fibrotic efficacy Experimental animals were acclimated for at least 5 days, and 70-100 μL of BLM solution (bleomycin 1-3 mg / kg) was administered into the lungs via a catheter. Depending on the purpose of the study, the test drug was administered 7 days after BLM administration, and then orally for 2 weeks until 21 days after BLM administration. The experimental groups are shown in Table 4 below, and body weight, SpO2, hydroxyproline, and inflammation cell count were measured to assess anti-fibrotic efficacy.

[0044] [Table 4]

[0045] Experimental Example 2-1: Lung Function Evaluation This pulmonary function assessment is the most direct and important evaluation index that has the greatest impact on the symptoms and quality of life of patients with pulmonary fibrosis, and by measuring the oxygen concentration in the body, this experiment can most directly demonstrate the effect of improving lung function in an animal model of pulmonary fibrosis.

[0046] On day 21, SpO2 was measured using a veterinary pulse oximeter (Berry) through the abdominal side of the mice. The results are shown in Table 5 and Figure 3.

[0047] [Table 5]

[0048] The lung oxygen permeability was confirmed by measuring SpO2 in the abdominal area of ​​the mice, and it was confirmed that the combined administration (PID and the first component, 12%) improved by more than 50% compared to the single administration (PID, 7%). This result confirms that the direct improvement effect on lung function is enhanced by the combined administration due to the increase in oxygen permeability, which decreases during the pulmonary fibrosis process.

[0049] Experimental Example 2-2: Measurement of total collagen content in lung Pulmonary fibrosis occurs when collagen accumulates in the lungs, causing them to harden. The main cause of pulmonary fibrosis is the accumulation of collagen, and the degree of progression of fibrosis can be predicted by measuring the collagen content in lung tissue.

[0050] In this experiment, analysis was performed using an insoluble collagen assay (Biocolor, S2000). Lung tissue, which had been cryopreserved after sacrifice on day 21, was crushed in 100 μL of fragmentation reagent, followed by the addition of 100 μL of 37% HCl and incubation at 65°C for 3 hours. The contents of the tube were shaken every 30 minutes to aid in tissue disintegration. After centrifugation, the concentration was adjusted to 100 μL, and collagen staining was performed to prepare samples. The absorbance at 560 nm was measured. The hydroxyproline value was compared to the normal group, and the ratio was calculated. The results are shown in Table 6.

[0051] [Table 6]

[0052] This experiment confirmed that the combined use of PID and the first component reduced the amount of collagen in the lung compared to either component alone, which indicates that the degree of pulmonary fibrosis was alleviated.

[0053] Experimental example 2-3: Histopathology (Histopathology, Ashcroft Score) analysis The degree of fibrosis and inflammation in lung tissue was visually observed under a microscope, and the degree of fibrosis in lung tissue was measured using a Fibrotic Index based on a normalized standard. A higher Fibrotic Index value indicates more severe fibrosis and disease, while a lower value indicates more mitigated disease.

[0054] On day 21, lung tissues were isolated and stained with H&E and MT stain. They were then examined under a microscope at 200X magnification and scored by Ashcroft (Hubner et al., 2008). The fibrosis index was calculated by dividing the total corrected Ashcroft field scores by the number of fields examined, as shown in Table 7 and Figure 4.

[0055] [Table 7]

[0056] The degree of fibrosis and inflammation in lung tissue was observed with the naked eye under a microscope, and the degree of fibrosis in lung tissue was measured using a Fibrotic Index based on a normalized standard. As a result, it was confirmed that the combined administration of PID and the first component showed significantly improved effects compared to the administration of each component alone.

[0057] Furthermore, by comparing the micrograph of the vehicle lung tissue in Figure 5 with the micrograph of the lung tissue of the individual administered the first and second components (PID) in combination in Figure 6, it can be seen that the lung tissue of the individual administered the combination has significantly improved inflammation and fibrosis in the lung tissue, even when viewed with the naked eye, and is almost similar to normal lung tissue.

[0058] Experimental example 2-4: Inflammation cell infiltration (Inflammation cell count) analysis Since fibrosis is a chronic inflammatory disease involving excessive collagen deposition, the infiltration of inflammatory cells was analyzed to confirm the degree of inflammation in lung tissue.

[0059] On day 21 of administration, BALF (Bronchoalveolar lavage fluid) cells obtained by airway lavage of a sacrificed mouse were diluted with 1.05X PBS and attached to a slide. The slides were then stained in 1, 2, and 3diff quick stain solutions, in that order, by immersing and removing the slides for 30 seconds each time. Counts were based on 500 cells. Macrophages are the largest and mononuclear cells, staining blue. Neutrophils and eosinophils form polynuclear cells, but eosinophils are distinguished from neutrophils by the red eosin staining. Lymphocytes have very little cytoplasm and are small mononuclear cells. Total cells were counted and converted to percentages, as shown in Table 8 and Figure 7.

[0060] [Table 8]

[0061] An inflammatory cell analysis was performed to confirm the level of inflammation in lung tissue, and the total cell count improved by more than 50% when the combination drug was used compared to the individual drugs, indicating that lung tissue inflammation had improved. In particular, neutrophil cells, which are inflammatory cells that are highly prevalent in pulmonary fibrotic inflammation, decreased in number by more than 50%, indicating a significant improvement in the proportion of major inflammatory cells.

[0062] Experimental Example 2-5: Measurement of body weight change Body weight is an indirect indicator of the degree of improvement in the overall physical condition of the animal model, and if the degree of weight loss is small, it can be inferred that the overall physical condition or symptoms of the disease have improved.

[0063] The body weight was measured once every 3 days from day 14, when the drug effect became noticeable after administration. The results are shown in Table 9 below and Figure 8.

[0064] [Table 9]

[0065] The improvement in the overall symptoms of the combined administration group can be confirmed by the fact that the degree of weight loss was improved in the combined administration group compared to the single administration group.

[0066] Experimental Example 3: Animal Pharmacokinetic / Pharmacodynamic Analysis After a single oral administration of the first component to ICR mice, a pharmacokinetic study was conducted as shown in Table 10. The blood drug concentration over time obtained by LC-MS / MS was used to calculate pharmacokinetic parameters using Excel (registered trademark) and WinNonlin 6.1 software, and the changes in the blood concentration of the first component are shown in Table 11 and Figure 9.

[0067] [Table 10]

[0068] [Table 11]

[0069] Preparation Example 1: Method for producing enteric coated capsules containing the first ingredient The hydrochloride salt form of the first component was encapsulated by dose using Vcaps® enteric coated capsules, with only the active ingredient, without any additional excipients.

[0070] Preparation Example 2: Method for producing enteric-coated tablets containing the first ingredient The hydrochloride form of the first ingredient was mixed with microcrystalline cellulose, lactose hydrate, crospovidone, and magnesium stearate, compressed into plates using a dry granulator, and then pulverized in an oscillator to produce dry granules. Microcrystalline cellulose, lactose hydrate, and magnesium stearate were then added to the granules, which were then compressed and molded into tablets, which were then enteric-coated.

[0071] Experimental Example 4: Human Pharmacokinetic / Pharmacodynamic Analysis To confirm safety / tolerance / pK in humans, a randomized, double-blind, placebo-controlled clinical trial was conducted in 72 healthy adults using a single dose and stepwise dose escalation method, as shown in Table 12. The dosage forms used in the clinical trial were prepared using the same methods as in Preparation Examples 1 and 2 above.

[0072] [Table 12]

[0073] As a result of the clinical trials, no serious abnormal symptoms or side effects were observed.

[0074] As a result of confirming the pK for a single administration, as can be seen from Table 13 below and Figure 10, the maximum plasma concentration was recorded within 1.5 to 8 hours after administration, the geometric mean half-life was in the range of 6.91 to 9.90 hours, and it was confirmed that the plasma concentration increased in a dose-proportional manner.

[0075] [Table 13]

[0076] Furthermore, as can be seen from Table 14 and Figure 11, the pK confirmation results for multiple doses on Day 14 showed that the maximum plasma concentration was recorded within 1.5 to 5 hours at steady state after administration, the geometric mean half-life ranged from 4.4 to 12.35 hours, and the geometric mean exposure in the body during the dosing interval (AUCτ) ranged from 183.32 to 3012.35 h·ng / mL. It was confirmed that the plasma concentration had a dose-linear relationship within the dose range of 25 mg to 200 mg of the active ingredient.

[0077] [Table 14]

[0078] Therefore, the blood drug concentrations obtained in the human multiple-dose clinical trial were used to estimate the parameters of an optimal pharmacokinetic model that could explain the concentration changes at all doses observed using Excel (registered trademark) and WinNonlin 8.1 software, and the in vivo exposure levels in humans when various doses were orally administered were predicted. The main results are shown in Table 15 below.

[0079] [Table 15]

[0080] From the mouse model experiment on pulmonary fibrosis in Experimental Example 3, administration of 10 mg / kg once a day was an effective dose for mice, and the mouse plasma AUC inf The AUC value was confirmed to be 1190 hr·ng / mL. Therefore, the AUC value in the human body was the same as that in the mouse. inf In order to predict the dose at which the value is expected to be observed, the correlation between the AUC and the administered dose was examined as shown in Figure 12. As a result, it was confirmed that a dose of 150 mg is required when administering the drug twice daily to humans.

[0081] Experimental Example 5: Checking for drug interactions To evaluate drug interactions during coadministration of the first and second ingredients, a clinical trial was conducted on 48 healthy adults, divided into two groups (24 patients each) in Part 1 and Part 2. The trial was designed in a fixed sequence with three periods, and participants were orally administered one 150 mg enteric-coated tablet of the first ingredient.

[0082] Subjects enrolled in Part 1 received a single dose of 600 mg of the second component (PID) in Period 1, a single dose of 150 mg of the first component in Period 2, followed by a 3-day washout, multiple doses of 150 mg of the first component over 3 days, and a single combined dose of the first and second components (PID) in Period 3.Subjects enrolled in Part 2 received a single dose of 150 mg of the second component (NIN) in Period 1, multiple doses of 150 mg of the first component over 3 days in Period 2, and a single combined dose of the first and second components (NIN) in Period 3.

[0083] After each administration, pK was observed for 24 hours, and the presence or absence of abnormal reactions was confirmed for 13-19 days.

[0084] In Part 1, the drug interaction evaluation results showed that no changes in exposure to each drug were observed in each administration group, and it was determined that the two drugs did not have a significant mutual effect.In Part 2, it was confirmed that there were no clinically significant drug interactions when the second component (NIN) was administered in combination with the first component compared to when it was administered alone.

[0085] Experimental Example 6: Confirmation of the combined effect of the first ingredient and pirfenidone / nintedanib To confirm the safety and efficacy of the first component in patients with idiopathic pulmonary fibrosis, clinical trials will be conducted in a randomized, double-blind, placebo-controlled manner with standard treatment or no treatment groups, as shown in Table 16. To confirm the safety and tolerability of the first component, evaluation will be performed in comparison with placebo after 24 weeks of administration of the first component. To confirm the therapeutic efficacy of the first component in idiopathic pulmonary fibrosis, evaluation will be performed to evaluate the rate of decline in forced vital capacity (FVC) from baseline 24 weeks after 24 weeks of administration of the first component. Secondary efficacy variables included: 1) time to IPF disease progression, including respiratory-related mortality or hospitalization, acute IPF worsening, relative decrease in FVC of ≥10% of predicted normal, and absolute decrease in diffusing capacity for carbon monoxide (DLCO) of ≥15% of predicted normal; 2) time to first all-cause unplanned hospitalization at 24 weeks; 3) change from baseline in functional exercise capacity assessed by distance recorded in the 6-minute walk test (6MWT) at 24 weeks; 4) change from baseline in DLCO (adjusted for Hgb) at 24 weeks; 5) categorical assessment of absolute change from baseline in FVC as a percentage of predicted normal at 24 weeks; 6) change from baseline in quantitative chest high-resolution CT (HRCT) at 24 weeks; and 7) scores on the St George's Respiratory Questionnaire, SGRQ, and Living with Idiopathic Respiratory Questionnaire at 24 weeks. Changes in patient-reported outcomes (PROs) measured by Pulmonary Fibrosis (L-IPF) compared to baseline will be evaluated. Exploratory efficacy variables will include 1) changes in IPF-specific biomarkers compared to baseline at 24 weeks; 2) changes in blood biomarkers compared to baseline at 24 weeks. Safety variables will include 1) incidence of abnormal reactions after administration of the active ingredient; 2) physical examination; 3) 12-lead electrocardiogram; 4) vital signs; and 5) clinical trial performance tests.

[0086] The study subjects were divided into three groups: those receiving pirfenidone as a standard treatment, those receiving nintedanib, and those not receiving any other treatment. Each group was administered the first component or a placebo to confirm efficacy, and the efficacy of combined administration with the standard treatment compared to administration alone was confirmed. If an abnormal reaction to the first component occurred, the patient's response was closely monitored and the dose was reduced.

[0087] [Table 16]

Claims

1. 1) a first component which is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and 2) A second component selected from the group consisting of a compound represented by the following formula 2, a pharmaceutically acceptable salt thereof, a compound represented by the following formula 3, and a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating interstitial lung disease, comprising: the first and second components are co-administered in the same dosage form or in different dosage forms; The weight ratio of the first component to the second component is 1:0.5 to 1:

30. Pharmaceutical Compositions: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】

2. The interstitial lung disease is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or chronic fibrosing interstitial lung disease with a progressive phenotype (PF-ILD). The pharmaceutical composition of claim 1.

3. The weight ratio of the first component to the second component is 1:0.6 to 1:

25. The pharmaceutical composition of claim 1.

4. The second component is a compound represented by Chemical Formula 2 or a pharmaceutically acceptable salt thereof, The weight ratio of the first component to the second component is 1:2 to 1:

25. The pharmaceutical composition of claim 1.

5. The second component is a compound represented by Chemical Formula 3 or a pharmaceutically acceptable salt thereof, The weight ratio of the first component to the second component is 1:0.6 to 1:

10. The pharmaceutical composition of claim 1.

6. Contains 100 to 150 mg of the first component; The pharmaceutical composition of claim 1.

7. The second component is a compound represented by Chemical Formula 2 or a pharmaceutically acceptable salt thereof, The first component is contained in an amount of 100 to 150 mg. Contains 200 to 800 mg of the second component; The pharmaceutical composition of claim 1.

8. The second component is a compound represented by Chemical Formula 3 or a pharmaceutically acceptable salt thereof, The first component is contained in an amount of 100 to 150 mg. Contains 100 to 150 mg of the second component; The pharmaceutical composition of claim 1.

9. the first and second components are each administered twice daily or three times daily; The pharmaceutical composition of claim 1.

10. The first component is administered twice daily and the second component is administered three times daily, or the first component is administered three times daily and the second component is administered twice daily. The pharmaceutical composition of claim 1.

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