TW202308623A - Pharmaceutical composition for preventing or treating fibrosis - Google Patents

Abstract

The pharmaceutical composition according to the present invention is used at specific therapeutic regimen and dosage, and can be usefully used for the prevention or treatment of fibrosis.

Description

Pharmaceutical composition for preventing or treating fibrosis

The present invention relates to a pharmaceutical composition for preventing or treating fibrosis.

Fibrosis refers to a phenomenon in which a part of an organ hardens due to some cause, and pulmonary fibrosis or liver fibrosis is considered as a typical disease. In the case of pulmonary fibrosis, the lungs are essentially hardened primarily by radiation exposure or by filling the lungs with water. However, pulmonary fibrosis may only occur in some people. To date, few complete treatments for the symptoms of fibrosis exist, and treatments are being developed and researched. Types of fibrosis include interstitial lung disease (Interstitial lung disease, ILD), scleroderma, keloid, hypertrophic scar, nonalcoholic fatty liver disease, primary sclerosing cholangitis (Primary sclerosing cholangitis, PSC), primary Primary biliary cholangitis (PBC), diabetic retinopathy, age-related macular degeneration (Age-related Macular Degeneration, AMD), hypertrophic cardiomyopathy, myocardial infarction, muscular dystrophy, diabetic nephropathy, local Focal segmental glomerulosclerosis (FSGS), inflammatory bowel disease (Inflammatory bowel disease (IBD), and the like. Interstitial lung disease includes idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), and chronic fibrotic interstitial lung disease with a progressive phenotype. Chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD), and the like.

Idiopathic pulmonary fibrosis (IPF), one of the chronic progressive interstitial lung diseases, is a rare disease with a known disease course and no proven treatment. So far, the etiology has not been clearly confirmed, and the 5-year survival rate after diagnosis is 43%, and the 10-year survival rate is about 15%, which is not optimistic. Despite much ongoing research, no treatment to improve survival exists to date. Considering that other ILDs, such as non-specific interstitial pneumonia (NSIP) and idiopathic organized pneumonia (COP), have relatively good outcomes when properly treated, It is said that the course of disease is poor in interstitial lung disease. The most common causes of death were respiratory failure (39%) and heart disease (27%), and other causes included lung cancer, pulmonary embolism, and pneumonia. The prognosis is worse if the patient is older or male, or if pulmonary function is poor at diagnosis or if there are many fibroblastic lesions on biopsy.

Similar to nonspecific interstitial pneumonia (NSIP), idiopathic pulmonary fibrosis is treated with steroids and cytotoxic agents. Recently, anti-fibrotic agents are the main treatment, and various attempts have been made. Currently approved drugs for idiopathic pulmonary fibrosis include pirfenidone and nintedanib, and these drugs are not complete treatments, but they are used to delay pulmonary fibrosis and reduce symptoms . Therefore, there is a need to develop more effective drugs that can improve the quality of life of patients.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a disease in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) as a complication, and deterioration of lung function is the major death of systemic sclerosis reason. As treatments approved for this disease in the United States, there are nintedanib and tocilizumab, which have proven efficacy in reducing the deterioration of lung function, but similar to idiopathic pulmonary fibrosis, developments that can improve More effective medicines for patients' quality of life.

Chronic fibrotic interstitial lung disease with progressive phenotype (PF-ILD) refers to various progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis, including autoimmune interstitial lung disease, idiopathic Episodic interstitial pneumonia, and the like. Nintedanib has demonstrated efficacy in reducing lung function deterioration in patients with various fibrotic lung diseases and has been approved as a therapeutic agent in the United States. Because fibrotic interstitial lung disease can produce progressive phenotypes such as pulmonary fibrosis, worsening lung function, and poor quality of life, when efficacy in reducing lung function deterioration was demonstrated in specific interstitial lung disease, even in other interstitial lung diseases Efficacy in reducing exacerbation of lung function can also be expected in qualitative lung disease, regardless of classification and underlying disease.

At the same time, prolyl-tRNA synthetase (PRS) is one of the aminoacyl-tRNA synthetase (ARS) family and is used to activate amino acids for protein synthesis. That is, ARS performs translation functions to form aminoacyladenylate (AA-AMP), and then transfers the activated amino acid to the third end of the corresponding tRNA. Since ARS plays a key role in protein synthesis, ARS inhibition inhibits growth and growth of all cells. ARS is therefore considered a promising target for antibiotics or therapeutics for diseases in which cellular overexpression must be suppressed (Nature, 2013, 494: 121-125).

PRS is in the form of glutamyl-prolyl-tRNA synthetase (Glutamyl-Prolyl-tRNA Synthetase, EPRS) in the multi-synthetase complex (multisynthetase complex, MSC) or as a multi-synthetase complex. Specifically, among various MSCs, EPRS acts as a transcriptional silencer that suppresses the production of vascular endothelial growth factor A (vascular endothelial growth factor A, VEGF A), which is a key factor in angiogenesis. In addition, EPRS has been reported to be closely related to various solid cancers (Nat. Rev. Cancer, 2011, 11, 708-718).

Therefore, the present inventors intensively studied methods for preventing or treating fibrosis, and confirmed that effective prevention or treatment of fibrosis is possible when a specific PRS inhibitor to be described later is used in a specific treatment regimen and dose, by This completes the invention.

[ technical challenge ]

One object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrosis. [ Technical solution ]

In order to achieve the above goals, a pharmaceutical composition for preventing or treating fibrosis is provided as follows:

。 A pharmaceutical composition for preventing or treating fibrosis, comprising a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof, for twice-a-day (BID) administration of 100 to 150 mg. [chemical formula 1]

.

The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is the compound described in Korean Patent Registration No. 10-2084772, and specifically, the substance described in Example 40 of the specification. The substance is useful as a PRS inhibitor for preventing or treating fibrosis.

Specifically, when 100 to 150 mg is administered twice a day (BID) as in the present invention, it is possible to effectively prevent or treat fibrosis. The above doses are the doses that can prevent potential risks to the greatest extent while increasing the preventive or therapeutic efficacy of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof on fibrosis. In addition, depending on the dose, the area of the plasma drug concentration-time curve (AUCinf) after administration of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, that is, the exposure to the body can exhibit prophylactic or therapeutic fiber for best results.

Meanwhile, the compound represented by Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt. As salts, acid addition salts formed from pharmaceutically acceptable free acids are useful. As the free acid, inorganic acids and organic acids can be used. Examples of inorganic acids may include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like. Examples of organic acids may include citric acid, acetic acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, aspartic acid, or the like. Preferably, the pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 is hydrochloride.

In addition, the compound represented by Chemical Formula 1 may be prepared in a crystalline or non-crystalline form. When the compound represented by Chemical Formula 1 is produced in a crystalline form, it may be hydrated or solvated as appropriate. The present invention may include not only stoichiometric hydrates of the compound represented by Chemical Formula 1 but also compounds containing various amounts of water. The solvates of the compound represented by Chemical Formula 1 include both stoichiometric solvates and non-stoichiometric solvates.

Meanwhile, examples of fibrosis include interstitial lung disease (ILD), scleroderma, keloid, hypertrophic scar, nonalcoholic 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 nephropathy, focal segmental glomerulosclerosis (FSGS), or inflammatory bowel disease disease (IBD). Interstitial lung disease (ILD) includes idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), or chronic fibrotic interstitial lung disease with a progressive phenotype (PF-ILD ).

As used herein, the term "prevention" refers to any act of delaying or inhibiting the onset, spread, or recurrence of cancer, inflammatory disease, autoimmune disease, or fibrosis by administering a composition of the invention, and "Treatment" refers to any action to improve or make the symptoms of the above diseases better by administering the composition of the present invention.

Pharmaceutical compositions according to the invention may be formulated in accordance with standard pharmaceutical practice in a type for oral or parenteral administration. These formulations may also contain additives such as pharmaceutically acceptable carriers, adjuvants, or diluents in addition to the active components.

Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and the like. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine, and the like, but are not limited thereto. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injection solutions. Additionally, the compounds of the present invention may be formulated for topical application in ointments or creams.

The pharmaceutical dosage forms of the compounds of the present invention can also be used in the form of their pharmaceutically acceptable salts or solvates, and they can be used alone or in combination with other pharmaceutically active compounds and in appropriate combinations. In one example, the pharmaceutical composition according to the present invention may further include other active ingredients for preventing or treating fibrosis. Examples of such other active ingredients include pirfenidone or nintedanib. In addition, when the pharmaceutical composition according to the present invention further comprises other active components, the weight ratio of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to other active components is preferably 1:0.1 to 1:10 .

The compounds of the present invention can be dissolved, suspended, or emulsified in aqueous solvents such as common physiological saline or 5% dextrin or in non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters, or propylene glycol And deploy into injection. The formulations of the present invention may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

The pharmaceutical composition according to the present invention can be administered orally or parenterally. Depending on the administration method, the composition according to the present invention may contain 0.001% to 99% by weight, preferably 0.01% to 60% by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition according to the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes. The administration can be performed via all possible methods, such as oral, rectal, intravenous, intramuscular, subcutaneous, intraendometrial, intracerebroventricular injection. [ Beneficial effect ]

As described above, the pharmaceutical composition according to the present invention is used in a specific treatment regimen and dosage, and can be effectively used for preventing or treating fibrosis.

Hereinafter, the present invention will be described in more detail by means of examples. However, these examples are provided for the purpose of illustration only, and should not be construed as limiting the scope of the present invention to these examples. Example

¹H 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) 實驗實施例 1 ： 按照劑量之抗纖維化功效之動物實驗 The following compounds were prepared in the same manner as in Example 40 of Korean Patent Registration No. 10-2084772, and are hereinafter referred to as "active component" or "Example".

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) Experimental Example 1 : According to Anti-fibrosis efficacy of dosage in animal experiments

70-100 μL of BLM solution (bleomycin 1 to 3 mg/kg) was administered using a catheter into the lungs of acclimated experimental animals for 5 days or longer. According to the purpose of the test, the test drug was administered 7 days after the BLM administration, and the drug was orally administered for 2 weeks until the BLM administration on the 21st day. The composition of the experimental groups is shown in Table 1 below. Body weight, SpO2, hydroxyproline and inflammatory cell count were measured to determine the anti-fibrosis effect of the active ingredients.

As a control group, nintedanib (hereinafter referred to as "NIN") and pirfenidone ( Hereinafter referred to as "PID"). The effective dose of NIN used was confirmed by the in vivo efficacy data in the literature published by Boehringer Ingelheim, the development company of NIN, and the effective dose of PID was based on the FDA Pharmacology Review for mice In vivo efficacy (rat) data and 2-week repeated toxicity dose (rat) setting. [Table 1] group drug Number of animals (male) dose 1 dose 2 volume Administration method (mg/kg) (mg/kg) (SoC) (μL) G1 (NC) brine 9 N/A N/A 100 oral G2 (PC) brine 9 N/A N/A 100 oral G3 (test) active ingredient 9 3 N/A 100 oral G4 (test) active ingredient 9 10 N/A 100 oral G5 (test) active ingredient 9 30 N/A 100 oral G6 (test) Nedanib 9 N/A 60 100 oral G7 (test) Pirfenidone 9 N/A 200 100 oral Experimental Example 1-1 : Pulmonary Function Evaluation

This lung function evaluation 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 it is the most direct way to demonstrate the improvement of pulmonary fibrosis animal models by measuring the oxygen concentration in the body Experiments on the efficacy of lung function.

On day 21, it was measured with a SpO2 measuring device (Berry, Veterinary Pulse Oximeter) through the ventral side of the mice, and the results are shown in Table 2 and FIG. 1 .

Attempts were made to confirm the oxygen permeability of the lungs by taking SpO2 measurements on the mouse abdomen. Functional improvements of 18% or more at 10 mg/kg "active ingredient" and 28% or more at 30 mg/kg were demonstrated compared to vehicle. This was confirmed to be the same degree of improvement in the oxygen permeability function of existing SoC materials. This result demonstrates that when administered the "active ingredient" there is an effect of directly improving lung function by increasing oxygen permeability which is reduced during pulmonary fibrosis. [Table 2] normal medium active ingredient Pirfenidone Nedanib 3 mg/kg 10 mg/kg 30 mg/kg 200mg/kg 60mg/kg 99.89 74.44 75.00 77.89 81.33 82.00 78.67 Experimental Example 1-2 : Measurement of Total Collagen Content in the Lung

Pulmonary fibrosis is the accumulation of collagen in the lungs that hardens the lungs. The main cause of pulmonary fibrosis is collagen accumulation, and the progress of fibrosis can be predicted by measuring the collagen content in lung tissue.

In this experimental example, analysis was performed using the INSOLUBLE collagen assay (Biocolor, S2000). After sacrifice on day 21, cryopreserved lung tissue was minced by adding 100 μL of fragmentation reagent, and then 100 μL of 37% HCl was added and incubated at 65° C. for 3 hours. The contents of the tubes were shaken at 30 minute intervals to aid disintegration of the tissue. After centrifugation, the concentration was adjusted to 100 μL and collagen staining was performed to prepare a sample. Absorbance was measured at 560 nm. The ratio value was measured by comparing the hydroxyproline value with the normal group, and the results are shown in Table 3 and FIG. 2 . [table 3] normal medium active ingredient Pirfenidone Nedanib 3 mg/kg 10 mg/kg 30 mg/kg 200mg/kg 60mg/kg 96.11 260.33 253.56 217.22 171.33 177.44 239.78

According to this experiment, it was confirmed that the content of collagen in the lung was significantly reduced at 10 and 30 mg/kg "active ingredient" compared to the vehicle, which is a result similar to that of PID as the existing SoC material. From this experiment it can be seen that the degree of pulmonary fibrosis is reduced during the administration of the active ingredient. Experimental Examples 1-3 : Histopathological (Ashcroft Score ) Analysis

The degree of fibrosis and inflammation of the lung tissue was visually observed through a microscope, and the degree of fibrosis of the lung tissue was measured with the fibrosis index according to the normalized criteria. The higher the fibrosis index value, the more serious the degree of fibrosis and symptoms. It should be interpreted that when this value is lowered, the symptoms are relieved.

On day 21, lung tissue was isolated and stained using H&E and MT stains and visualized at 20Ox magnification. Observations were scored by Ashikoff (Hubner et al., 2008). The fibrosis index was calculated by dividing the sum of the adjusted Ashkov area scores by the number of tested areas and is shown in Table 4 and Figure 3 . [Table 4] group number of individuals Fibrosis index (±SEM) normal 9 0.1 (±0.1) medium 9 5.2 (±0.2) Active ingredient 3 mg/kg 9 4.6 (±0.3) Active ingredient 10 mg/kg 9 2.7 (±0.6) Active ingredient 30 mg/kg 9 2.8 (±0.4) Pirfenidone 200 mg/kg 9 4.1 (±0.3) Nintedanib 60 mg/kg 9 3.1 (±0.6)

In the case of 10 and 30 mg/kg "active ingredient", the tissue-improving efficacy equivalent to or greater than that of NIN was confirmed, and the excellent tissue-improving efficacy compared with PID was confirmed. Experimental Example 1-4 : Inflammatory cell count analysis

Since fibrosis is a chronic inflammatory disease characterized by excess collagen deposition, the infiltration of inflammatory cells was analyzed to determine the degree of inflammation in lung tissue.

When sacrificed on the 21st day of administration, Bronchoalveolar lavage fluid (BALF) cells obtained by washing the airways of the mice were diluted with 1.05×PBS and attached to slides, and then the slides were washed with 1,2, 3 Sequences of diff quick staining solutions were submerged and removed for 30 seconds and stained. They were counted based on 500 cells. Macrophages are the largest, mononuclear and stained blue. Neutrophils and eosinophils form multinucleated cells, but eosinophils are stained red with eosin and are distinguished from neutrophils. Lymphocytes have very little cytoplasm and are small in size as mononuclear spheres. Total cells were counted and converted to % and are shown in Table 5 and Figure 4. [table 5] normal medium active ingredient Pirfenidone Nedanib 3mg/kg 10 mg/kg 30 mg/kg 200mg/kg 60mg/kg Macrophages 0.42 6.96 7.80 5.60 4.91 5.01 5.61 Neutrophils 0.00 2.12 1.74 1.54 0.82 0.68 1.29 Lymphocytes 0.00 0.87 0.79 0.51 0.46 0.46 0.68 total cells 0.42 9.93 10.32 7.66 6.19 6.14 7.57

From this experiment it can be seen that the total cell level is improved by 20% or more at 10 mg/kg "active ingredient" and 30% or more at 30 mg/kg compared to vehicle, thereby improving lung tissue inflamed. In particular, it has been demonstrated that neutrophils exhibit a high rate of inflammatory cells inflamed by pulmonary fibrosis and that the number of these cells was reduced by 20% at 10 mg/kg "active ingredient" or More and a reduction of 60% or more at 30 mg/kg resulted in a significant improvement in the ratio of major inflammatory cells. It can be seen that this is equivalent to the level of PID as the existing SoC material, and it is better than NIN. Experimental Example 1-5 : 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. When the degree of weight loss is small, it can be inferred that the general physical condition or the symptoms of the disease are improved.

When the administration was completed, the body weight was measured on the 21st day using a body scale, and the results are shown in Table 6 below and FIG. 5 . [Table 6] normal medium active ingredient Pirfenidone Nedanib 3mg/kg 10 mg/kg 30 mg/kg 200mg/kg 60mg/kg 13.22 -23.33 -22.44 -19.11 -16.78 -14.67 -19.44

It was demonstrated that the degree of body weight loss was improved at 10 mg/kg and 30 mg/kg compared to the vehicle group. This demonstrates that when the "active ingredient" is administered, efficacy is improved at a level similar to or greater than that of the SoC material, and overall symptoms are improved.

Through the above series of experimental results, it can be confirmed that when the "active ingredient" is administered to mice at 10 mpk once a day, the therapeutic efficacy is equivalent to the level of the existing IPF standard care. Experimental Example 2 : 2- week repeated dose toxicity test in mice

The active ingredient is administered orally to acclimatized ICR mice for 7 days or more for 2 weeks. The composition of the experimental group is shown in Table 7 below, and body weight, general symptom observation, hematology/blood biochemistry test, organ weight measurement and histopathology test were performed. [Table 7] group gender Number of animals (only) drug substance Dose (mg/kg/day) Dosage (mL/kg/day) G1 m 6 sterile distilled water - 10 G2 m 6 active ingredient 30 10 G3 m 6 active ingredient 60 10 G4 m 6 active ingredient 120 → 90 ¹⁾ 10 1) In the initial administration (within days after dosing) in the high dose group there was evidence of death of an individual, or if the animal's condition was unlikely to persist for 2 weeks, the dose was reduced and administered for the remainder of the period.

Necropsy was performed on all animals 2 weeks after administration. At the time of autopsy, the weight of each organ was measured. In all results measured 2 weeks after repeated administration, no toxicity or significant abnormal symptoms were identified. However, as shown in Table 8 below, in the administration group of 30 mg/kg/day or more, a slight trend of weight loss was observed only in spleen and thymus among all organs. [Table 8] Dose (mg/kg) 0 30 60 120→90 spleen 0.080 ± 0.018 0.059 ± 0.011 0.070 ± 0.015 0.046 ± 0.021 % relative to body weight 0.28 ± 0.07 0.22 ± 0.04 0.25 ± 0.05 0.17 ± 0.08 thymus 0.034 ± 0.008 0.026 ± 0.008 0.029 ± 0.006 0.015 ± 0.012 % relative to body weight 0.12 ± 0.02 0.10 ± 0.03 0.11 ± 0.02 0.05 ± 0.04

Such results were considered irrelevant to toxicity, but based on the trend of spleen and thymus body weight loss, the active dose of the active ingredient was set at 10 mg/kg to prevent potential toxicity risk during long-term administration. Experimental Example 3 : Animal Pharmacokinetics / Pharmacodynamics Analysis

As shown in Table 9 below, pharmacokinetic tests were performed after a single oral administration of the active ingredient in ICR mice. According to the changes over time obtained by LC-MS/MS, the pharmacokinetic parameters of the blood drug concentration were calculated using Excel® and WinNonlin6.1 software, and the blood concentration changes of the active ingredients are shown in Table 9 and Figure 6. [Table 9] experimental animals ICR mice (male) test material active ingredient Administration route oral Dosing times single Dose (mg/kg) 10 Dosing volume (mL/kg) 10 Blood collection time (hr) 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 medium brine Number of test animals 6 (n=3, cross blood collection) [Table 10] test material active ingredient Dose (mg/kg) 10 t _1/2 (hr) 2.50 ± 2.48 T _max (hr) 2.67±1.15 C _max (μg/mL) 0.263±0.032 AUC _0-t (hr∙μg/mL) 1.07±0.21 AUCinh (hr∙ng/mL) 1190 Preparation Example 1 : Preparation of Enteric Coated Capsules Containing Active Components

For the hydrochloride form of the active ingredient, Vcaps® enteric-coated capsules without any additional excipients are used according to the dose, and only the main ingredient is filled into the capsule. Preparation Example 2 : Preparation of Enteric-Coated Tablets Containing Active Components

Microcrystalline cellulose, lactose hydrate, crospovidone and magnesium stearate are mixed with the hydrochloride form of the active ingredient, prepared into a plate-shaped compressed product using a dry granulator, and crushed with a vibrator to prepare a dry particles. Microcrystalline cellulose, lactose hydrate and magnesium stearate were further mixed with granular material, compression molded to prepare lozenges, and enteric coating was applied to complete the process. Experimental Example 4 : Human Pharmacokinetic / Pharmacodynamic Analysis

In order to confirm the safety/tolerability/pK to human body, as shown in Table 11, a randomized grouping, double-blind, placebo-controlled trial of single administration and gradually increasing dose was designed for 72 healthy adults. Formulations used in clinical trials were prepared in the same manner as Preparation Example 1 and Preparation Example 2. [Table 11] category group active ingredient formulation Method of administration single administration SAD1 100mg Enteric coated capsules Single oral administration on an empty stomach SAD2 300mg SAD3 600mg SAD4 500mg Enteric coated lozenges multiple doses MAD1 25mg Oral administration twice a day on an empty stomach for 13 consecutive days, followed by a single morning administration on day 14 MAD2 50mg MAD3 100mg MAD4 200mg

As a result of the above clinical trials, no serious abnormalities or side effects were confirmed.

As a result of confirming the pK of a single administration, as seen in Table 12 below and Figure 7, the maximum plasma concentration was recorded within 1.5 to 8 hours after administration, and the geometric mean half-life was in the range of 6.91 hours to 9.90 hours, and the plasma concentration Increased in a dose proportional relationship. [Table 12] Project (GCV%) Active ingredient 100 mg (N=6) Active ingredient 300 mg (N=6) Active ingredient 600 mg (N=6) Active ingredient 500 mg (N=6) C _max (ng/mL) 123.96 (37.72) 276.80 (66.21) 213.43 (433.75) 513.56 (41.27) t _max (h)* 3.00 (1.50, 4.00) 2.50 (1.50, 8.00) 2.00 (1.50, 5.00) 3.01 (0.50, 5.00) AUC _{0- last} (h*ng/mL) 594.10 (61.23) 1478.84 (48.07) 1008.65 (625.00) 2282.37 (54.92) AUC _0-∞ (h*ng/mL) 639.07 (58.10) 1525.99 (47.06) 1922.64 (222.08) 2339.20 (53.27) T _1/2 (h) 6.91 (39.98) 8.33 (24.57) 9.90 (71.50) 7.80 (13.49) Vz/F(L) 1560.44 (34.98) 2361.87 (41.96) 4459.07 (84.14) 2406.62 (48.04) CL/F (L/h) 156.48 (58.10) 196.59 (47.06) 312.07 (222.08) 213.75 (53.27) MRT (h) 9.26 (33.69) 9.75 (21.76) 9.79 (25.60) 9.57 (27.28) GCV% = geometric coefficient of variation Notes: t _max expressed as median; min, max.

Additionally, as can be seen in Table 13 and Figure 8, the day 14 pK confirmation results for multiple dosing demonstrated that after administration, maximum plasma concentrations were recorded as steady state within 1.5 to 5 hours, with geometric mean half-lives ranging from 4.4 hours to 12.35 hours The geometric mean dose time interval (AUCτ) of in vivo exposure was within the range of 183.32-3012.35 h·ng/mL. A dose-linear relationship was demonstrated for plasma concentrations over the dose range of 25 mg to 200 mg of active ingredient. [Table 13] Project (GCV%) Active ingredient 25 mg ^T (N=6) Active ingredient 50 mg ^T (N=6) Active ingredient 100 mg ^T (N=6) Active ingredient 200 mg ^T (N=6) day 14 C _{max, ss} (ng/mL) 36.50 (66.19) 102.61 (67.99) 151.27 (65.36) 595.35 (36.32) t _{max, ss} (h)* 2.00 (1.50, 4.00) 3.00 (3.00, 5.00) 3.00 (1.50, 4.00) 2.00 (1.50, 5.00) AUCτ (h*ng/mL) 183.32 (76.35) 429.09 (128.63) 617.40 (60.53) 3012.35 (48.42) AUC _0-∞ (h*ng/mL) 300.73 (102.79) 565.34 (232.53) 887.97 (60.55) 4747.29 (64.90) T _1/2 (h) 7.63 (46.84) 4.40 (101.38) 9.26 (22.69) 12.35 (34.54) Vz/F _ss (L) 1433.79 (61.75) 738.97 (34.90) 2163.04 (63.58) 1182.53 (48.47) CL/F _ss (L/h) 122.65 (79.49) 116.53 (128.63) 161.97 (60.53) 66.39 (48.42) MRT (h) 10.53 (31.65) 8.44 (68.43) 10.17 (9.35) 12.07 (26.90) Accumulation rate based on AUCτ 1.94 (26.34) 2.33 (31.42) 1.88 (35.07) 3.75 (36.01) Abbreviations: GCV% = geometric coefficient of variation; n = number of individuals; SD = standard deviation; T = lozenge. Notes: * t _{max, ss} expressed as median; min, max. MRT, AUCτ, CL/F _ss , and Vz/F _ss considered 12-hour dosing intervals.

Therefore, for blood drug concentrations obtained in human multiple-dose clinical trials, the parameters of the best pharmacokinetic model that can explain the concentration changes at all doses observed can be estimated using Excel® and WinNonlin8.1 software. Exposure levels in humans were predicted at various doses administered orally, and the main results are shown in Table 14 below. [Table 14] Dose (mg) parameter 50 100 150 200 T _1/2 (h) 9.753195 9.753195 9.753195 9.753195 T _max (h) 2.803 2.803 2.803 2.803 C _max (ng/mL) 38.271 76.5419 114.813 153.084 CL/F (mL/hr) 215856.7 215856.7 215856.7 215856.5 Vd/F (mL) 3037295 3037295 3037295 3037293 AUC _tau (hr*ng/mL) 231.6352 463.2704 694.9055 926.5413 AUC _{tau_24hr} (hr*ng/mL) 463.2704 926.5407 1389.811 1853.08256

From the mouse experimental model experiment of pulmonary fibrosis in Experimental Example 2, it was confirmed that 10 mg/kg administered once a day is an effective dose for rats, and in Experimental Example 3, the rat plasma AUCinf value under the effective dose is 1190 hr.ng/mL. Therefore, in order to predict the dose in humans expected to exhibit AUC values at the same level as the effective dose in rats, the correlation between the administered dose and AUC was reviewed as shown in FIG. If given twice, 150 mg is required. Experimental Example 5 : Analysis of Human Administration Safety / Drug Tolerance

The safety and drug resistance of the compound of the present invention during human administration were confirmed in the same manner as in Experimental Example 4.

As a result of confirming the safety and tolerability of a single administration, the most frequent adverse reactions were gastrointestinal adverse events, including nausea, vomiting, diarrhea and abdominal pain. Among them, nausea and vomiting have been evaluated as having a significant impact on safety and drug resistance. This has been shown to be caused by the active ingredient itself. As a result of confirming the relationship between the timing of such side effects of nausea and vomiting and the exposure to the body, as shown in FIG. 10 , it was confirmed that most of them appeared before the blood concentration in the body increased. It has been found that the nausea and vomiting that occurs during the administration of the active ingredient acts on the gastrointestinal tract, excites the vagus nerve, and thus activates the vomiting center rather than through stimulation of chemoreceptor-induced sites by in vivo blood exposure Pathway to the vomiting center.

Thus, it can be seen that a twice daily administration of an effective dose in order to reduce the rate of vagal stimulation of the gastrointestinal tract is more suitable for the active ingredient. Experimental Example 6 : Confirmation of Human Therapeutic Efficacy

To demonstrate the safety and efficacy of the active ingredient in patients with idiopathic pulmonary fibrosis, as shown in Table 15, a randomized, double-blind, placebo-controlled trial was designed with standard treatment or no treatment. To demonstrate the safety and tolerability of the active ingredient, it was evaluated compared to placebo after 24 weeks of treatment with the active ingredient. In order to confirm the therapeutic efficacy of the active ingredient on idiopathic pulmonary fibrosis after 24 weeks of active ingredient treatment, as a primary efficacy evaluation variable, the force at week 24 relative to the baseline value was evaluated after the active ingredient was administered for 24 weeks Rate of decrease in forced vital capacity (FVC). As secondary validation variables, assess 1) respiratory-related death or hospitalization, acute exacerbation of IPF, relative decrease in FVC value of 10% or more from normal, and time to IPF disease progression, including Hgb-adjusted diffusing capacity for carbon monoxide (diffusing capacity for carbon monoxide, DLCO) value from the normal predicted value of 15% or more absolute reduction; 2) the time required for the first unplanned hospitalization for all reasons during the 24 weeks; 6-minute walk test (6-minute walk test, 6MWT) recorded distance evaluation, functional exercise capacity compared with baseline changes; 4) compared with baseline DLCO (Hgb corrected) levels at week 24 5) Categorical assessment of the absolute change in the percentage of FVC predicted value at week 24 compared with baseline; 6) Quantitative chest high-resolution CT (high-resolution CT, HRCT) value at week 24 compared with baseline 7) Patient-reported outcomes measured by St George's Respiratory Questionnaire (SGRQ) and Living with Idiopathic Pulmonary Fibrosis (L-IPF) at week 24 ( patient-reported outcome, PRO) change from baseline; and the like. As exploratory efficacy assessment variables, 1) changes from baseline in IPF-specific biomarkers at week 24 and 2) changes from baseline in blood biomarkers at week 24 were assessed. As a safety evaluation variable, 1) the incidence of abnormal reactions occurring after administration of the active ingredient; 2) physical examination; 3) 12-lead electrocardiogram; 4) vital signs; 5) clinical laboratory performance tests; and the like By.

The target population was divided into patients receiving pirfenidone as the current standard of care, patients receiving nintedanib, and patients not receiving any treatment, and the effect obtained by administering the active ingredient or placebo to each patient group was confirmed. effect. If an adverse reaction occurs due to the active ingredient, closely monitor the patient's response and consider dose reduction. [Table 15] existing therapeutics Active ingredient 150 mg, BID Active ingredient 100 mg, BID placebo (0 mg), BID Pirfenidone (mg, administered 3 times a day) 801 801 801 534 534 534 267 267 267 600 600 600 400 400 400 200 200 200 Nintedanib (mg, administered twice a day) 150 150 150 100 100 100 No therapeutic agent administered (mg) 0 0 0

none

[ Fig. 1 ] shows the results of lung function evaluation of Experimental Example 1-1. [ FIG. 2 ] shows the measurement results of the collagen content in the lung of Experimental Example 1-2. [ Fig. 3 ] shows the results of histopathological analysis of Experimental Examples 1-3. [ Fig. 4 ] shows the results of analysis of inflammatory cell infiltration in Experimental Examples 1-4. [ Fig. 5 ] shows the measurement results of body weight change in Experimental Examples 1-5. [ Fig. 6 ] Shows changes in blood concentration of the active ingredient of Experimental Example 3. [ Fig. 7 ] Shows changes in plasma concentration in a single administration of Experimental Example 4. [ Fig. 8 ] Shows changes in plasma concentrations of multiple administrations of Experimental Example 4. [ Fig. 9 ] is a graph showing the correlation between the dose administered and AUC according to Experimental Example 4. [ Fig. 10 ] Shows the relationship between the time of occurrence of side effects of nausea and vomiting and the exposure to the body in Experimental Example 5.

Claims (6)

A pharmaceutical composition for preventing or treating fibrosis, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof for twice-a-day (BID) administration of 100 to 150 mg, [chemical formula 1]

. Such as the pharmaceutical composition of claim 1, wherein: The fibrosis is interstitial lung disease (Interstitial lung disease, ILD), scleroderma, keloid, hypertrophic scar, nonalcoholic fatty liver disease, primary sclerosing cholangitis (Primary sclerosing cholangitis, PSC), primary Primary biliary cholangitis (PBC), diabetic retinopathy, age-related macular degeneration (Age-related Macular Degeneration, AMD), hypertrophic cardiomyopathy, myocardial infarction, muscular dystrophy, diabetic nephropathy, local Focal segmental glomerulosclerosis (FSGS), or inflammatory bowel disease (Inflammatory bowel disease, IBD). Such as the pharmaceutical composition of claim 2, wherein: The interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or has a progressive phenotype chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD). Such as the pharmaceutical composition of claim 1, wherein: The pharmaceutically acceptable salt is hydrochloride. Such as the pharmaceutical composition of claim 1, wherein: The pharmaceutical composition further contains other active ingredients for preventing or treating fibrosis. Such as the pharmaceutical composition of claim 5, wherein: Such other active ingredients for the prevention or treatment of fibrosis are Pirfenidone or Nintedanib.

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