Safe administration of MMP-12 inhibitors

Abstract

A method is described for safely administering a matrix metalloproteinase 12 (MMP-12) inhibitor by oral administration, and a method is described for providing a clinically proven, safe treatment for asthma, chronic obstructive pulmonary disease (COPD), or pulmonary fibrosis by oral administration of an MMP-12 inhibitor.

Description

[Technical field]

[0001] Technical Field The present application relates to a method for safely administering matrix metalloproteinase 12 (MMP-12) inhibitors and a method for providing clinically proven and safe treatment of asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis by oral administration of matrix metalloproteinase 12 (MMP-12) inhibitors. [Background technology]

[0002] background Matrix metalloproteinases (MMPs) constitute a family of more than 20 zinc-dependent proteases that exhibit a wide range of biological activities. As a class, MMPs exhibit structural similarities and share an array of common substrates, although individual MMPs have distinct functions that are determined by their environment. Among the MMP family, MMP-12 is a macrophage elastase that is mainly detected in alveolar macrophages. Moreover, MMP-12 is produced by bronchial epithelial cells and airway smooth muscle cells. In both animals and humans, this protease is involved in type 2 inflammation as well as tissue remodeling through its ability to turn over elastin during its entire life cycle. Accumulating evidence has suggested the involvement of MMP-12 in the pathophysiology of chronic inflammatory airway diseases. In patients with asthma, chronic obstructive pulmonary disease (COPD), and / or pulmonary fibrosis, the degree of airway remodeling and / or disease severity correlate with gene expression, local airway concentration, and / or activity of MMP-12. Asthma, COPD, and pulmonary fibrosis are prevalent lung disorders worldwide. They are characterized by airflow obstruction and changes in airway architecture. It would therefore be desirable to provide new treatments with MMP-12 inhibitors that exert their effects without serious adverse effects. In particular, it would be desirable to use orally administered MMP-12 inhibitors for the treatment of asthma, COPD, and pulmonary fibrosis to achieve therapeutically adequate exposure with minimal adverse effects. Summary of the Invention

[0003] overview Disclosed herein are methods for safely administering MMP-12 inhibitors to subjects, including clinically proven safe treatments for asthma, COPD, or pulmonary fibrosis. In one general aspect, the methods described herein include a method comprising the steps of: [ka] or a pharma- ceutical acceptable salt thereof to a human subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof and a cyclodextrin.

[0004] In some embodiments, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered is from about 25 mg to about 600 mg per administration. In some embodiments, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per administration is about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, the pharmaceutical composition is administered orally once daily, twice daily, or three times daily. In some embodiments, the pharmaceutical composition is orally administered once a day. In such embodiments, the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered daily is about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered twice daily, in which the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per dose is about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, when the pharmaceutical composition is administered orally twice daily, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered daily is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered three times a day, in which the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per dose is about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, when the pharmaceutical composition is administered orally three times daily, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered daily is about 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600, 1700 mg, or 1800 mg, or any dose in between. In some embodiments, administration of the pharmaceutical composition does not result in serious adverse effects, hi certain embodiments, serious adverse effects include severe fatigue, allergic reactions, and joint pain. In some embodiments, administration of the pharmaceutical composition does not result in clinically significant changes from pre-administration baseline in laboratory assessments, vital signs, or electrocardiogram (ECG). In some embodiments, the human subject is in need of treatment for asthma, chronic obstructive pulmonary disease (COPD), or pulmonary fibrosis.

[0005] In another general aspect, the present invention provides a method for treating a disease in a human subject in need thereof, comprising combining a cyclodextrin with a compound of formula (I): [ka] or a pharma- ceutical composition comprising the steps of: orally administering to a subject a pharmaceutical composition comprising the compound of formula (I) or a pharma- ceutical acceptable salt thereof, wherein the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered is from about 25 mg to about 600 mg per administration, and the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis.

[0006] In some embodiments, the treatment is a clinically proven safe treatment. In some embodiments, the pharmaceutical composition is administered orally once daily, twice daily, or three times daily. In some embodiments, the pharmaceutical composition is orally administered once daily. In such embodiments, the pharmaceutical composition is administered to a subject in an amount sufficient to provide about 25 mg / day, 50 mg / day, 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition is orally administered twice a day.In such embodiments, the pharmaceutical composition is administered twice a day to a subject in an amount sufficient to provide about 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, or 1200 mg / day of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition is administered three times a day. In such embodiments, the pharmaceutical composition is administered to a subject three times a day in an amount sufficient to provide about 150 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, or 1800 mg / day of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. It is to be understood that the invention is not limited to the precise embodiments shown in the drawings. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 shows a diagrammatic representation of the study design of a single ascending dose clinical study with the compound of formula (I). [Diagram 2] 1 shows the maximum plasma concentration (Cmax) of the compound of formula (I) versus dose in a single ascending study. [Diagram 3] FIG. 1 shows the area under the plasma concentration curve (AUCt) of compound of formula (I) versus dose in a single titration study. [Figure 4] FIG. 1 shows a diagrammatic representation of the study design for the multiple ascending dose and food effect part of a clinical study using the compound of formula (I). [Figure 5A] 1 shows the mean plasma concentrations of the compound of formula (I) versus time on Day 1 in a multiple ascending dose study. [Figure 5B] 1 shows the mean plasma concentrations of the compound of formula (I) versus time on Day 8 in a multiple ascending dose study. [Figure 6] 1 shows the mean plasma concentrations of the compound of formula (I) versus time in a food effect study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Detailed Description Various publications, articles and patents are cited in the background and throughout the specification; each of these references is hereby incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles and the like which has been included in the specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items form part of the prior art with respect to any invention disclosed or claimed. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, certain terms used in this application have the meaning as set forth herein. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if set forth in their entirety.

[0009] definition It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, the term "about" preceding a number or series of numbers means ±10% of the number unless otherwise indicated. For example, "about 100 mg" means 90 to 110 mg. Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention. Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are understood to mean the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "comprising" can be replaced with the terms "containing" or "including," or, when used herein, "having." As used herein, "consisting of" excludes any element, step, or ingredient not recited in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the above terms "comprise," "contain," "include," and "have," whenever used herein in the context of an aspect or embodiment of the invention, can be interchanged with the terms "comprise" or "consist essentially of" to modify the scope of the disclosure.

[0010] As used herein, the term "and / or" between multiple listed elements is understood to include both individual and combined options. For example, when two elements are joined by "and / or", the first option refers to the application of the first element without the second element. The second option refers to the application of the second element without the first element. The third option refers to the application of the first element and the second element together. Any of these options are understood to fall within the meaning and thus meet the requirements of the term "and / or" as used herein. The simultaneous application of more than one option is also understood to fall within the meaning and thus meet the requirements of the term "and / or". As used herein, unless otherwise specified, the term "clinically proven" (used independently or to modify the term "safe") means that it is proven by a clinical study in human subjects and that meets the approval criteria of the US Food and Drug Administration, the European Medicines Evaluation Agency (EMEA) or a corresponding national regulatory agency. In one embodiment of the present application, the clinical study is a first-in-human, Phase I, randomized, double-blind, placebo-controlled, single ascending dose study of the compound of formula (I), which is an MMP-12 inhibitor, in healthy human subjects. In another embodiment of the present application, the clinical study is a Phase I, randomized, double-blind, placebo-controlled, multiple ascending dose and food effect study of the compound of formula (I) in healthy human subjects.

[0011] As used herein, the expressions "adverse event (AE)", "treatment-emergent adverse event", "adverse reaction", and "adverse effect" mean any adverse, untoward, unintended or unwanted symptom or outcome associated with or caused by the administration of a pharmaceutical composition or therapeutic agent. However, abnormal values ​​or findings are not reported as adverse events unless they are deemed clinically significant by the researcher or physician. As used herein, the expressions "serious adverse event (SAE)" and "serious adverse effect" refer to any adverse event that is serious as defined by the Food and Drug Administration's (FDA) Code of Federal Regulations (CFR), Chapter 21. An SAE can be any AE or suspected adverse reaction that, in the view of the researcher or physician, results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or substantial disruption of the ability to perform normal life functions, or congenital anomalies / birth defects. Significant medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based on sound medical judgment, they may compromise the patient or subject and may require medical or surgical treatment to prevent one of the outcomes listed in the definition above. Examples of such medical events include, but are not limited to, severe fatigue, allergic reactions, and joint pain.

[0012] As used herein when referring to the safety evaluation of administration of an MMP-12 inhibitor, "clinically significant changes" refers to clinically evident changes as determined by a physician or researcher using criteria accepted by those skilled in the art. If the adverse event damage or undesirable outcome reaches such a level of severity, a regulatory agency may deem the pharmaceutical composition or treatment unacceptable for the proposed use. Such changes may be measured by physical examinations, such as respiratory, cardiovascular, and gastrointestinal examinations; laboratory evaluations, such as hematology, blood chemistry, urinalysis, viral serology, urine drug screening test, alcohol breath test, cotinine test, follicle stimulating hormone (FSH) and urine pregnancy test; vital signs, such as temperature, respiratory rate, blood pressure, and heart rate; and electrocardiogram (ECG) monitoring, such as a 12-lead safety ECG.

[0013] As used herein, "treatment" or "treating" refers to the treatment of a disease, disorder, or medical condition (e.g., gastrointestinal inflammatory disease) in a patient, e.g., a mammal (particularly a human), and includes one or more of the following: (a) preventing the occurrence of a disease, disorder, or medical condition, i.e., preventing the recurrence of the disease or medical condition or the prophylactic treatment of a patient predisposed to the disease or medical condition; (b) ameliorating a disease, disorder, or medical condition, i.e., eliminating or causing the regression of a disease, disorder, or medical condition in a patient, including counteracting the effects of other therapeutic agents; (c) inhibiting a disease, disorder, or medical condition, i.e., slowing or halting the onset of a disease, disorder, or medical condition in a patient; or (d) alleviating the symptoms of a patient's disease, disorder, or medical condition.

[0014] The terms "efficacy" and "effective" as used herein in the context of a dose, dosing regimen, treatment or method refer to the effectiveness of a particular dose, dosing regimen or treatment regimen. Efficacy can be measured based on changes in response to the agent of the present invention during the course of a disease. For example, a compound of formula (I) can be administered to a subject in an amount and for a sufficient time to induce an improvement, preferably a sustained improvement, in at least one indicator reflecting the severity of the disorder being treated. Various indicators reflecting the extent of the disease, disorder or condition of the subject can be evaluated to determine whether the amount and time of treatment is sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestation of the disorder in question. The degree of improvement is generally determined by a physician who can make this determination based on signs, symptoms, biopsies, or other test results, and may also utilize questionnaires administered to the subject, such as quality of life questionnaires developed for a given disease. For example, a compound of formula (I) can be administered to achieve improvement in the subject's condition related to asthma, chronic obstructive pulmonary disease (COPD), or pulmonary fibrosis. The term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a patient in need of treatment.

[0015] Safe administration method In one general aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof to a human subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof and a cyclodextrin.

[0016] According to an embodiment of the present invention, the compound of formula (I) has activity as an MMP-12 inhibitor. The compound of formula (I), its synthesis, biological activity, use or other related information is described, for example, in U.S. Patent Application Publication No. US2006 / 0041000, published on February 23, 2006, the contents of which are incorporated herein by reference in their entirety. In addition, pharmaceutical compositions comprising the compound of formula (I) are described, for example, in International Patent Application Publication No. WO2018 / 035459, published on February 22, 2018, the contents of which are incorporated herein by reference in their entirety. The total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof per administration is selected to provide safe / effective dosing and / or safe / effective treatment as determined in clinical trials. According to an embodiment of the invention, the total dose of the compound of formula (I) or a pharma-ceutically acceptable salt thereof administered is about 25 mg to about 600 mg per administration, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In a preferred embodiment, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per administration is from about 50 mg to about 450 mg, e.g., 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg, or any dose in between. In another preferred embodiment, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per dose is from about 100 mg to about 400 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or any dose in between.

[0017] In some embodiments, the pharmaceutical composition is administered to a subject in an amount sufficient to provide about 25 mg per day to about 1800 mg per day of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, e.g., 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg, or any dose in between. In some embodiments, the pharmaceutical composition is administered to a subject in an amount sufficient to provide about 100 mg per day to about 1200 mg per day, e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, or any dose in between, of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is administered to a subject in an amount sufficient to provide about 150 mg per day to about 1800 mg per day of the compound of formula (I) or a pharma- ceutical acceptable salt thereof, e.g., 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600, 1700 mg, or 1800 mg, or any dose in between.

[0018] According to embodiments of the invention, the pharmaceutical compositions may be administered once daily, twice daily, three times daily, once weekly, twice every two weeks, etc. In some embodiments, the pharmaceutical composition is orally administered once a day. In such embodiments, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered daily is about 25 mg to about 600 mg, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered once a day, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered daily is about 50 mg to about 450 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered twice daily, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered per dose is about 50 mg to about 600 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered twice daily, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered per dose is about 100 mg to about 400 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered twice a day, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered daily is about 100 mg to about 1200 mg, for example, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered twice daily, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered daily is about 200 mg to about 800 mg, for example, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, or any dose in between.

[0019] In some embodiments, the pharmaceutical composition is orally administered three times a day, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered per dose is about 50 mg to about 600 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered three times per day, in which the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per dose is from about 100 mg to about 400 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered three times a day. In such embodiments, the total dose of the compound of formula (I) or its pharma- ceutical acceptable salt administered daily is about 150 mg to about 1800 mg, for example, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600, 1700 mg, or 1800 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered three times a day, in which the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered daily is about 300 mg to about 1200 mg, for example, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, or any dose in between.

[0020] In some embodiments, a pharma- ceutically acceptable salt of a compound of Formula (I) refers to a salt that is acceptable for administration to a patient or mammal, such as a human (e.g., a salt that has acceptable mammalian safety for a given dosing regimen). Representative pharma- ceutically acceptable salts include, but are not limited to, salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and xinafoic acid. In some embodiments, the compound of formula (I) is amorphous.

[0021] In some embodiments, administration of the pharmaceutical composition does not result in serious adverse effects, hi particular embodiments, serious adverse effects are severe fatigue, allergic reactions, or joint pain. In some embodiments, administration of the pharmaceutical composition does not result in clinically significant changes from pre-administration baseline in laboratory assessments, vital signs, or electrocardiogram (ECG). In particular embodiments, the laboratory evaluation is selected from the group consisting of hematology, blood chemistry, urinalysis, viral serology, urine drug screening test, alcohol breath test, cotinine test, follicle stimulating hormone (FSH) and urine pregnancy test. In certain embodiments, the vital sign is selected from the group consisting of heart rate, temperature, sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), orthostatic SBP, and orthostatic DBP. In a particular embodiment, the ECG is a safety 12-lead electrocardiogram. According to embodiments of the present invention, clinical trials, such as those described above, can be used to analyze various factors to determine whether a particular dose of a compound of formula (I) provides safe oral administration. For example, the safety of a particular dose of an orally administered MMP-12 inhibitor can be determined based on pharmacokinetic studies (e.g., area under the concentration-time curve (AUC), and maximum observed concentration (C max The safety of orally administered MMP-12 inhibitors can also be monitored by subject physical examination, allergic reactions, electrocardiograms, clinical laboratory tests, vital signs, and monitoring of other adverse events.

[0022] In some embodiments, the clinically proven safe administration of a compound of Formula (I) is based on the pharmacokinetic (PK) parameters of the inhibitor in the plasma of a subject, such as the area under the concentration-time curve (AUC), and the maximum observed concentration (C max In view of the present disclosure, the plasma samples are analyzed to determine the concentration of the inhibitor by any method known in the art. Pharmacokinetic parameters are then analyzed, for example, by noncompartmental analysis (NCA), to determine pharmacokinetic parameters, e.g., AUC, C max , terminal half-life (T 1 / 2 ), total systemic clearance over bioavailability (CL / F) and volume of distribution at terminal phase over bioavailability (V z In particular, AUC is the area under the concentration-time curve (AUC 0-12 ), and the area under the concentration-time curve from 0 to 24 hours (AUC 0-24 ), the area under the concentration-time curve extrapolated from time 0 to infinity (AUC 0-inf ), the area under the concentration-time curve (AUC 0-t ), the area under the concentration-time curve during the dosing interval (τ) at steady state (AUC 0-τ), or the area under the concentration-time curve (AUC ss0-t ).

[0023] In some embodiments, a single administration of the pharmaceutical composition in an amount sufficient to provide from about 25 mg to about 600 mg of the compound of formula (I) or a pharma- ceutical acceptable salt thereof, produces an average area under the concentration-time curve (AUC), extrapolated from time 0 to infinity, of from about 1680 ng.hr / mL to about 26000 ng.hr / mL in the plasma of a subject. 0-inf ) to be achieved. In some embodiments, a single administration of the pharmaceutical composition in an amount sufficient to provide from about 25 mg to about 600 mg of the compound of formula (I) or a pharma- ceutical acceptable salt thereof, provides an average area under the concentration-time curve (AUC) from time 0 to the last non-zero observed concentration time (t) of from 1580 ng.hr / mL to about 25400 ng.hr / mL in the plasma of a subject. 0-t ) to be achieved. In some embodiments, a single administration of the pharmaceutical composition in an amount sufficient to provide about 25 mg to about 600 mg of the compound of Formula (I) or a pharma- ceutical acceptable salt thereof results in a mean maximum observed concentration (C) of about 2570 ng / mL or less in the plasma of a subject. max ) to be achieved. In some embodiments, a single administration of the pharmaceutical composition has a time to maximum plasma concentration (T) of about 1 hour to about 6 hours, preferably about 1 hour to about 3 hours. max ) to be achieved. In some embodiments, a single administration of the pharmaceutical composition has a mean terminal elimination half-life (T ) of about 6 hours to about 7 hours, preferably about 6.2 hours to about 6.9 hours. 1 / 2 ) to be achieved. In some embodiments, a single administration of the pharmaceutical composition achieves a mean apparent total clearance (CL / F) of about 17.9 L / h to about 31.8 L / h. In some embodiments, a single administration of the pharmaceutical composition achieves a mean apparent volume of distribution (Vz / F) that is from about 169L to about 253L.

[0024] In some embodiments, when the pharmaceutical composition is orally administered twice daily and the total dose of the compound of formula (I) or a pharmacologic salt thereof administered per dose is from about 50 mg to about 600 mg, administration of the pharmaceutical composition produces an average area under the concentration-time curve (AUC), extrapolated from time 0 to infinity, of from about 3550 ng.hr / mL to about 36300 ng.hr / mL in the plasma of the subject. 0-inf ) average. In some embodiments, when the pharmaceutical composition is orally administered twice daily and the total dose of the compound of Formula (I) or a pharma- ceutical acceptable salt thereof administered per dose is about 50 mg to about 600 mg, administration of the pharmaceutical composition results in a mean maximum observed concentration (C) of about 3710 ng / mL or less in the plasma of a subject. max ) to be achieved. In some embodiments, when the pharmaceutical composition is orally administered twice daily, administration of the pharmaceutical composition is performed within a time to maximum plasma concentration (T) of about 0.5 hours to about 6 hours, preferably about 1 hour to about 3 hours. max ) to be achieved. In some embodiments, administration of the pharmaceutical composition achieves a steady state condition of the compound of Formula (I) within 6 days after administration, when the pharmaceutical composition is administered orally twice daily. In some embodiments, when the pharmaceutical composition is orally administered twice daily, administration of the pharmaceutical composition provides a mean terminal elimination half-life (T ) of about 6 hours to about 9 hours, preferably about 6.6 hours to about 8.4 hours. 1 / 2 ) to be achieved. In some embodiments, administration of the pharmaceutical composition achieves a mean apparent total body clearance (CL / F) of about 16.2 L / h to about 23.1 L / h when the pharmaceutical composition is administered orally twice daily. In some embodiments, administration of the pharmaceutical composition achieves a mean apparent volume of distribution (Vz / F) that is about 158 ​​L to about 291 L when the pharmaceutical composition is administered orally twice daily. In some embodiments, the human subject is in need of treatment for a disease selected from the group consisting of chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis.

[0025] In another general aspect, the present invention provides a method for treating a disease in a human subject in need thereof, comprising combining a cyclodextrin with a compound of formula (I): [ka] or a pharma- ceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof to a subject, wherein the total dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof administered is from about 25 mg to about 600 mg per administration, and the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis.

[0026] In a preferred embodiment, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per administration is from about 50 mg to about 450 mg, e.g., 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg, or any dose in between. In another preferred embodiment, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per dose is from about 100 mg to about 400 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or any dose in between. In some embodiments, the treatment is a clinically proven safe treatment. In some embodiments, the pharmaceutical composition is administered orally once daily, twice daily, or three times daily. In some embodiments, the pharmaceutical composition is orally administered once a day. In such embodiments, the pharmaceutical composition is administered to the subject in an amount sufficient to provide about 25 mg / day to about 600 mg / day, for example, about 25 mg / day, 50 mg / day, 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day, or any dose in between, of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In certain embodiments, the pharmaceutical composition is administered to the subject in an amount sufficient to provide about 50 mg / day to about 450 mg / day, for example, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, or 450 mg / day, or any dose in between, of the compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0027] In some embodiments, the pharmaceutical composition is orally administered twice a day. In this embodiment, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per administration is about 50 mg to about 600 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In certain embodiments, the total dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof administered per administration is about 100 mg to about 400 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered twice a day. In such embodiments, the pharmaceutical composition is administered twice a day to a subject in an amount sufficient to provide about 100 mg / day to about 1200 mg / day, for example, 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, or 1200 mg / day, or any intermediate dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In certain embodiments, the pharmaceutical composition is administered to a subject twice daily in an amount sufficient to provide about 200 mg per day to about 800 mg per day, e.g., 200 mg per day, 300 mg per day, 400 mg per day, 500 mg per day, 600 mg per day, 700 mg per day, or 800 mg per day, or any dose in between, of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0028] In some embodiments, the pharmaceutical composition is orally administered three times a day. In this embodiment, the total dose of the compound of formula (I) or its pharma- ceutically acceptable salt administered per administration is about 50 mg to about 600 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. In certain embodiments, the total dose of the compound of formula (I) or its pharma- ceutically acceptable salt administered per administration is about 100 mg to about 400 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or any dose in between. In some embodiments, the pharmaceutical composition is orally administered three times a day. In such embodiments, the pharmaceutical composition is administered to a subject three times a day in an amount sufficient to provide about 150 mg / day to about 1800 mg / day, for example, 150 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, or 1800 mg / day, or any intermediate dose of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In certain embodiments, the pharmaceutical composition is administered to a subject three times daily in an amount sufficient to provide about 300 mg per day to about 1200 mg per day of the compound of Formula (I) or a pharma- ceutical acceptable salt thereof, e.g., 300 mg per day, 400 mg per day, 500 mg per day, 600 mg per day, 700 mg per day, 800 mg per day, 900 mg per day, 1000 mg per day, 1100 mg per day, or 1200 mg per day, or any dose in between. In some embodiments, the compound of formula (I) is present in amorphous form.

[0029] Pharmaceutical Compositions According to an embodiment of the present invention, the cyclodextrin used in the pharmaceutical compositions herein is a water-soluble unsubstituted or substituted alpha cyclodextrin (ACD), beta cyclodextrin (BCD), or gamma cyclodextrin (GCD). In some embodiments, the beta cyclodextrin is selected from the group consisting of methyl beta cyclodextrin (MBCD), hydroxypropyl beta cyclodextrin (HPBCD), and sulfobutyl ether beta cyclodextrin (SBEBCD). In some embodiments, the beta cyclodextrin is methyl beta cyclodextrin or hydroxypropyl beta cyclodextrin. In some embodiments, the gamma cyclodextrin is hydroxypropyl gamma cyclodextrin (HPGCD). In one preferred embodiment, the cyclodextrin is hydroxypropyl beta cyclodextrin (HPBCD) or methyl beta cyclodextrin (MBCD).

[0030] According to an embodiment of the present invention, in the pharmaceutical composition, the mass ratio of the compound of formula (I) to cyclodextrin is 1:1 to 1:300, preferably 1:1 to 1:50, and more preferably 1:1 to 1:10. In some embodiments, the mass ratio of the compound of formula (I) to hydroxypropyl beta cyclodextrin (HPBCD) is 1:1 to 1:300, preferably 1:1 to 1:50, and more preferably 1:1 to 1:10. In some embodiments, the compound of formula (I) and hydroxypropyl beta-cyclodextrin (HPBCD) are in the form of an amorphous solid dispersion (ASD). According to an embodiment of the present invention, the pharmaceutical composition of the present invention typically contains a therapeutically effective amount of the compound of formula (I). However, those skilled in the art will recognize that the pharmaceutical composition may contain more than a therapeutically effective amount of the compound of formula (I), for example, a bulk composition, or individual unit doses designed for multiple administration to achieve a less than therapeutically effective amount, for example, a therapeutically effective amount. Typically, the pharmaceutical composition contains from about 0.1% to about 95% by weight of a compound of formula (I), for example from about 5% to about 70% by weight of a compound of formula (I).

[0031] The pharmaceutical composition of the present invention comprising a compound of formula (I) and a cyclodextrin may further comprise a pharma- ceutically acceptable carrier. As used herein, the term "carrier" refers to any excipient, diluent, buffer, stabilizer, or other substance known in the art of pharmaceutical formulation. Pharmaceutically acceptable carriers are particularly non-toxic and should not interfere with the effectiveness of the active ingredient. Pharmaceutically acceptable carriers include excipients and / or additives known in the art that are suitable for use in pharmaceutical compositions, for example, as listed in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, NJ (1998), the disclosures of which are incorporated herein by reference in their entirety. Any conventional carrier or excipient may be used in the pharmaceutical composition of the present invention. The selection of a particular carrier or excipient, or combination of carriers or excipients, will depend on the type of administration mode or medical or disease state used to treat a particular patient. In this regard, preparation of a pharmaceutical composition suitable for a particular administration mode is well within the scope of one skilled in the art of pharmaceuticals. In addition, the carriers or excipients used in the pharmaceutical composition of the present invention are commercially available. As further examples, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and HC Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).

[0032] Representative examples of materials which may serve as pharma- ceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses such as microcrystalline cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances utilized in pharmaceutical compositions.

[0033] The pharmaceutical composition of the present disclosure is preferably packaged in unit dosage form.The term "unit dosage form" refers to a physically separate unit suitable for administration to a patient, that is, each unit contains a predetermined amount of active drug calculated to produce desired therapeutic effect, alone or in combination with one or more additional units.For example, the unit dosage form can be capsule, tablet, pill, etc., or unit package suitable for parenteral administration. According to embodiments of the present invention, pharmaceutical compositions suitable for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup, etc., each containing a predetermined amount of a compound of the present disclosure as an active ingredient.

[0034] When intended for oral administration in a solid dosage form (e.g., as a capsule, tablet, pill, etc.), the pharmaceutical composition will typically include the active agent (the compound of formula (I)), a cyclodextrin, and one or more pharma- ceutically acceptable carriers. Optionally, the solid dosage forms may contain: fillers or extenders such as starches, microcrystalline cellulose, lactose, dicalcium phosphate, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; humectants such as glycerol; disintegrating agents such as croscarmellose sodium, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and / or sodium carbonate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and / or glycerol monostearate; absorbents such as kaolin and / or bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and / or mixtures thereof; colorants; and buffers.

[0035] Releasing agents, wetting agents, coating agents, sweetening agents, flavoring and fragrance agents, preservatives and antioxidants can also be present in the pharmaceutical compositions of the present disclosure. Examples of pharma-ceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium hydrogen sulfate, sodium metabisulfate, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, etc.; and metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid, etc. Coating agents for tablets, capsules, pills, etc. include those used for enteric coating, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid, methacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate, etc.

[0036] For example, the pharmaceutical composition of the present invention can be formulated to provide slow or controlled release of the active agent using hydroxypropylmethylcellulose in various proportions; or other polymer matrices, liposomes and / or microspheres. In addition, the pharmaceutical composition of the present invention can optionally contain opacifying agents, and they can be formulated to release the active agent only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active agent can also be in microencapsulated form, if appropriate, with one or more of the above excipients. Liquid dosage forms suitable for oral administration include, by way of example, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.Liquid dosage forms typically contain an active agent and an inert diluent, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), oleic acid, glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.Alternatively, certain liquid preparations can be converted into powders, for example, by spray drying, which are used to prepare solid dosage forms by conventional procedures. Suspensions may contain, in addition to the active ingredient, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. According to an embodiment of the invention, the pharmaceutical composition may be administered via a nasogastric tube, in which the solid dosage form is either opened (capsules and pills) or crushed into a powder (tablets) and then supplied as a suspension of solution in a liquid, either neat or with another liquid. EXAMPLES

[0037] Example 1: Study I: A Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of the compound of formula (I) in healthy subjects This clinical study was a first in human study of the compound of formula (I) conducted at Taipei Veterans General Hospital, Taipei, Taiwan. The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of the compound of formula (I) by single ascending dose administration in healthy subjects. Methods and Subjects subject Eligible participants were healthy men between the ages of 18 and 65 years, and in good general health as determined by medical history and physical, vital sign, laboratory, and electrocardiogram (ECG) examinations. Other inclusion criteria were a body weight of 18 kg / m 2 and 30 kg / m 2 Exclusion criteria consisted of a body mass index between 0.01 and 0.25, a resting pulse rate between 50 and 100 beats / min, and a resting blood pressure of systolic blood pressure ≦140 mmHg and diastolic blood pressure ≦90 mmHg. Male subjects had to use adequate contraception during the study and until 3 months after completion of the study. Major exclusion criteria consisted of a history of alcohol or drug abuse, or current smoker or user of other nicotine products; use of any prescription or non-prescription drug, herbal medicine, vitamin, or mineral within 2 weeks prior to first dose (or within 5 half-lives prior to inclusion of any ingested drug, whichever was longer); or a positive test for hepatitis B or C virus, or human immunodeficiency virus, or a QT interval greater than 450 milliseconds (by ECG examination after Bazett correction).

[0038] Single Ascending Dose (SAD) Eight cohorts of eight subjects each (six active and two placebo) were enrolled. Two different oral formulations of the compound of formula (I) were tested. The initial formulation was the pure active pharmaceutical ingredient (API) of the compound of formula (I) in oral capsules (API in capsules) and was tested at three dose levels: 200 mg, 400 mg, and 800 mg. Then, an improved oral formulation, an amorphous solid dispersion (ASD) of the compound of formula (I) (ASD in capsules) was tested at five dose levels: 50 mg, 100 mg, 200 mg, 350 mg, and 450 mg (Figure 1). API in capsule cohorts: 200 mg, 400 mg, and 800 mg. ASD cohort in capsules: 50 mg, 100 mg, 200 mg, 350 mg, and 450 mg. Study Drug The ASD was prepared according to the procedure described in Example 6 of U.S. Patent No. 10,532,102. The ASD consisted of 25% compound of formula (I) and 75% hydroxypropyl beta cyclodextrin (HPBCD) by mass. A matching dose placebo capsule was also tested in this study.

[0039] Research evaluation Safety and tolerability evaluation Safety and tolerability were assessed by AE reporting, vital sign measurements, physical examinations, laboratory tests, and ECG testing at pre-specified time points throughout the study. Pharmacokinetic evaluation Blood samples (6 mL / sample) were collected for plasma concentrations of the compound of formula (I) at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, and 36 hours after each single dose. Within 15 minutes of collection, blood samples were centrifuged at 2000 rpm for 10 minutes at 4° C., after which the plasma was aliquoted, frozen, and stored at −70° C. until PK analysis. Samples were subjected to liquid chromatography followed by tandem mass spectrometry. The lower limit of quantification of the compound of formula (I) was 5 ng / mL. Plasma PK parameters were derived from non-compartmental analyses using Phoenix® WinNonlin® version 6.3 or higher (Pharsight Corporation Inc., Mountain View, CA, USA). PK variables were summarized using arithmetic mean, standard deviation, median, minimum, maximum, percent coefficient of variation, geometric mean, and two-sided 95% confidence interval limits for the arithmetic and geometric means.

[0040] statistical methods Safety and tolerability data were evaluated for the treated population (all participants who received at least one dose of study drug). PK analysis was based on data from treated participants for whom at least one PK parameter could be calculated and who did not commit any protocol violations that could have prevented these evaluations. Safety and tolerability data were evaluated using descriptive statistics and for plasma concentrations and PK parameters of the compound of formula (I). No formal sample size calculations were performed. Based on the descriptive nature of the studies, the number of participants enrolled in each cohort was deemed sufficient to achieve the objectives of these Phase I studies and to allow for the evaluation of PK parameters. For the evaluation of food effect on the PK profile of the compound of formula (I), analysis of variance (ANOVA) models included sequence, treatment, and period as fixed effects and subject nested within sequence as a random effect using the SAS® mixed model procedure. Each ANOVA included calculation of least squares mean (LSM), the difference between LSM in the fed state (Test) compared to the fasted state (Reference), and the standard error associated with this difference. At each time point, numerical parameters were summarized: mean, median, standard deviation, minimum, maximum, number of available findings, and change from baseline.

[0041] Results and Discussion Subject quality and blinding In this study, 88 male subjects were screened and 64 were randomized (Figure 1). All subjects completed the study. Overall, subjects at the different dose levels were similar with respect to age, weight, height, and BMI distribution (Table 1).

[0042] Table 1 Demographic and baseline characteristics of subjects involved in SAD [Table 1] Note: Data are presented as mean (standard deviation) unless otherwise stated. API = active pharmaceutical ingredient; ASD = amorphous solid dispersion system.

[0043] safety results All reported AEs were considered self-limited and of mild intensity. No severe or critical AEs were reported. No subjects discontinued the study due to AEs. No clinically relevant changes from baseline assessments were observed in body weight, vital signs, physical examination, laboratory or ECG data following administration of a compound of formula (I) at any time point. Only one potentially relevant AE was reported during the SAD study (Table 2). This AE, mild diarrhea, was experienced by one subject after administration of 800 mg API-in-capsule and resolved spontaneously prior to the follow-up visit.

[0044] Table 2: Potentially medication-related adverse events reported during SAD [Table 2] Note: API = active pharmaceutical ingredient; ASD = amorphous solid dispersion system.

[0045] Pharmacokinetic results In the capsule API cohort, median T max were similar for the 200 and 400 mg doses, i.e., 5 and 6 hours, respectively, whereas for the 800 mg dose the median T max The onset was short (3.5 hours). Over the dose range of 200 to 400 mg, the mean C max , AUC 0-t , and AUC 0-inf increased in a more than dose-proportional manner, but then decreased with dose (Table 3, Figures 2 and 3). In general, exposure to compound of formula (I) was low with the API formulation in capsules, consistent with substantial intersubject variability.

[0046] Table 3: Pharmacokinetic parameters of compound of formula (I) after SAD [Table 3] Note: Data are reported as median (range). max are arithmetic means (standard deviations) except for . For some parameters, the total number was less than 3 so standard deviations were not calculated. API = active pharmaceutical ingredient; ASD = amorphous solid dispersion; AUC 0-t = AUC from the minimum measurable concentration from time zero to time t; AUC 0-inf = AUC from time zero to infinity;C max = maximum observed plasma concentration; CL / F = apparent total body clearance; T 1 / 2 = apparent terminal elimination half-life; T max = time to reach maximum plasma concentration; V z / F = apparent total volume of distribution; λz = terminal phase elimination rate constant.

[0047] In contrast, in the capsule ASD cohort, median T max ranged from 1 to 2.5 hours after ingestion of a single dose over the dose range of 50 to 450 mg. max , AUC 0-t and AUC 0-inf increased in a more than dose-proportional manner over the dose range between 50 and 100 mg. Drug exposure (mean C max , AUC 0-t , and AUC 0-inf ) increased in an approximately dose-proportional manner from 100 to 450 mg after ingestion of a single dose of the compound of formula (I) (Table 3, Figures 2 and 3). C max , AUC 0-t , and AUC 0-inf Dose proportionality was observed for

[0048] conclusion The unique feature of this amorphous form of compound of formula (I) is that it not only significantly increases the bioavailability compared to API in capsule, but also destroys the exposure saturation set by the API itself. This is quite surprising and completely unexpected. Typically, due to exposure saturation, the API in capsule formulation would have to stop the program at about 1380ng.h / mL AUC, since the same bioavailability can only be achieved by simply administering a larger amount of API (see Figure 3). However, using the ASD in capsule formulation of the present invention, a much higher AUC, i.e., an AUC of 25000ng.h / mL, was achieved in a somewhat linear manner with the ASD in capsule formulation (Figures 2 and 3). T 1 / 2 The mean apparent total body clearance (CL / F) and apparent volume of distribution (V z / F) was independent of the administered dose over the range of 100 to 350 mg. The exposure of the compound of formula (I) appeared to be substantially increased with the ASD-based formulation, which has been commonly used to improve the oral absorption of low-solubility drugs (Jermain SV, et al., Int J Pharm, Jan. 15, 2018, 535(1-2):379-392). The highest exposure was observed in the 450 mg group (Table 3). Compared to the API-in-capsule formulation, dosing with the ASD-in-capsule formulation achieved not only higher and more consistent exposure, but also lower intersubject variability.

[0049] In summary, the exposure of the compound of formula (I) appears to be substantially increased with the ASD-based formulation. We also found that the ASD-in-capsule formulation resulted in shorter peak times, peak concentration increases, and higher overall plasma exposure. Furthermore, intersubject variability in PK parameters was less in the ASD-in-capsule group, and an overall dose-proportional increase was observed across most of the dose range tested. For example, at the 200 mg dose, the ASD-in-capsule formulation showed a 30-fold higher C compared to the API-in-capsule formulation. max and AUC 0-inf The percent coefficient of variation for these parameters was also reduced from approximately 30-40% to less than 30%. The reduction in intersubject variability was more evident at higher doses. Across all dose levels studied, administration of compounds of formula (I) was safe and generally well tolerated.

[0050] Example 2: Study II: A Phase 1, randomized, double-blind, placebo-controlled, multiple-dose study of a compound of formula (I) in healthy subjects The objectives of this study were to evaluate the safety, tolerability, and pharmacokinetics of an MMP-12 inhibitor after multiple oral ascending doses, as well as the food effect after a single oral dose in healthy subjects. This Phase I study consisted of two parts. The first part was a multiple ascending dose (MAD) part with a randomized, double-blind, placebo-controlled design in three treatment arms of eight subjects (six active; two placebo). The second part was a food effect (FE) part with a randomized, open-label, two-period, two-way crossover, single-dose design in eight subjects. The study was conducted at QPS-Netherlands, Groningen, the Netherlands.

[0051] Methods and Subjects subject Eligible participants were healthy men and women of non-childbearing potential, between the ages of 18 and 65, and in good general health as determined by medical history and physical, vital sign, laboratory, and electrocardiogram (ECG) examinations. Other inclusion criteria were a body weight of 18 kg / m 2and 30 kg / m 2 Exclusion criteria consisted of a body mass index between 0.01 and 0.25, a resting pulse rate between 50 and 100 beats per minute, and a resting blood pressure of systolic blood pressure ≦140 mmHg and diastolic blood pressure ≦90 mmHg. Subjects had to use adequate contraception during the study and until 3 months after completion of the study. Major exclusion criteria consisted of a history of alcohol or drug abuse, or current smoker or user of other nicotine products; use of any prescription or non-prescription drug, herbal medicine, vitamin, or mineral within 2 weeks prior to first dose (or within 5 half-lives prior to inclusion of any ingested drug, whichever was longer); or a positive test for hepatitis B or C virus, or human immunodeficiency virus, or a QT interval of more than 450 milliseconds (by ECG examination after Bazett correction).

[0052] Part I - Multiple Ascending Dose (MAD) Three cohorts of eight subjects each (six active and two placebo) were enrolled and subjects received the following treatments orally: ASD in capsules of 100 mg, 200 mg, and 400 mg twice daily (one dose on days 1 and 8, two doses daily on days 2-7) (Figure 4). Part II - Food Effect (FE) In this part, eight subjects received a single dose of ASD orally in a 200 mg capsule in a randomized fashion, once in the fasting state and once after ingestion of a high-fat breakfast, with a 1-week washout period between successive doses (Figure 4). Study Drug The API in capsule and the ASD in capsule were prepared similarly to Example 1.

[0053] Research evaluation Safety and tolerability evaluation Safety and tolerability were assessed by AE reporting, vital sign measurements, physical examinations, laboratory tests, and ECG testing at pre-specified time points throughout the study. Pharmacokinetic evaluation Blood samples were collected on day 1 (0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours) and day 8 (0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, and 48 hours) post-dose, as well as immediately prior to the morning dose on days 2-7 and 2 hours after the morning dose on days 4 and 6. Within 15 minutes of collection, blood samples were centrifuged at 2000 rpm for 10 minutes at 4°C, after which plasma was aliquoted, frozen, and stored at -70°C until PK analysis. Samples were subjected to liquid chromatography followed by analysis by tandem mass spectrometry. The lower limit of quantification of the compound of formula (I) was 5 ng / mL. Plasma PK parameters were derived by noncompartmental analysis using Phoenix® WinNonlin® version 6.3 or higher (Pharsight Corporation Inc., Mountain View, CA, USA). PK variables were summarized using arithmetic mean, standard deviation, median, minimum, maximum, percent coefficient of variation, geometric mean, and two-sided 95% confidence interval limits for the arithmetic and geometric means.

[0054] statistical methods Safety and tolerability data were evaluated for the treated population (all participants who received at least one dose of study drug). PK analysis was based on data from treated participants for whom at least one PK parameter could be calculated and who did not commit any protocol violations that could have prevented these evaluations. Safety and tolerability data were evaluated using descriptive statistics and for plasma concentrations and PK parameters of the compound of formula (I). No formal sample size calculations were performed. Based on the descriptive nature of the studies, the number of participants enrolled in each cohort was deemed sufficient to achieve the objectives of these Phase I studies and to allow for the evaluation of PK parameters. For the evaluation of food effect on the PK profile of the compound of formula (I), analysis of variance (ANOVA) models included sequence, treatment, and period as fixed effects and subject nested within sequence as a random effect using the SAS® mixed model procedure. Each ANOVA included calculation of least squares mean (LSM), the difference between LSM in the fed state (Test) compared to the fasted state (Reference), and the standard error associated with this difference. At each time point, numerical parameters were summarized: mean, median, standard deviation, minimum, maximum, number of available findings, and change from baseline.

[0055] Results and Discussion Subject quality and blinding In this study, 76 male and female subjects were screened and 24 of them were randomized in the multiple dose part, while 8 subjects were randomized in the food effect part of the study (Figure 4). All subjects completed the study. Overall, subjects at different dose levels were similar with respect to age, weight, height, and BMI distribution (Table 4).

[0056] Table 4: Demographic and baseline characteristics of subjects involved in MAD and FE [Table 4] Note: Data are presented as mean (standard deviation) unless otherwise stated. API = active pharmaceutical ingredient; ASD = amorphous solid dispersion system. Treatment A = oral dose of ASD in a capsule of 100 mg; Treatment B = oral dose of ASD in a capsule of 200 mg; Treatment C = oral dose of ASD in a capsule of 400 mg; Treatment D = a single oral dose of ASD in a 200 mg capsule in the fasted state; Treatment E = a single oral dose of ASD in a 200 mg capsule in the postprandial state after ingestion of a high-fat, high-calorie breakfast.

[0057] safety results All reported AEs were considered self-limited and of mild intensity. No severe or critical AEs were reported. No subjects discontinued the study due to AEs. No clinically relevant changes from baseline assessments were observed in body weight, vital signs, physical examination, laboratory or ECG data following administration of a compound of formula (I) at any time point. A total of seven AEs possibly related to treatment with the compound of formula (I) were reported in the MAD study (Table 5). Two of these events, including fatigue and cough, were reported by two subjects in the 100 mg group. The other five events were reported by three subjects in the 200 mg group: one subject had two episodes of eye irritation and erythema, one subject had dizziness, and one subject had a skin rash. Only two AEs possibly related to treatment with the compound of formula (I) were reported in one subject in the food effect part of the study. Both events were headaches and occurred in both the fed and fasted state.

[0058] Table 5: Potentially drug-related adverse events reported during MAD and FE [Table 5] Note: ASD = amorphous solid dispersion.

[0059] Pharmacokinetic results Plasma concentrations of the compound of formula (I) were measured in both the MAD and FE parts of the study. In the MAD part, 18 subjects received ASD in a dose escalation scheme (100 mg, 200 mg, and 400 mg) and 6 subjects received placebo, so only the 18 subjects who received ASD were included in the PK analysis. In the FE part, 8 subjects received 200 mg of ASD in the fasted or prandial (after ingestion of a high-fat, high-calorie breakfast) state and were included in the PK analysis. The summary statistics of the PK parameters of the compound of formula (I) in the MAD and FE parts are summarized in Tables 6 and 7, respectively. The statistical comparison of the PK parameters in the FE part is shown in Table 8.

[0060] Table 6: Pharmacokinetic parameters of compound of formula (I) after MAD [Table 6] a :median(range); RAUC1:AUC 0-12 (day 8) / AUC 0-12 (day 1); RAUC2:AUC 0-12 (day 8) / AUC 0-inf (day 1); Mean: Arithmetic mean; SD: Standard deviation; Treatment A: 14 oral doses of 100 mg of the compound of formula (I) (n=6) or placebo (n=2) on 8 days; Treatment B: 14 oral doses of 200 mg of the compound of formula (I) (n=6) or placebo (n=2) on 8 days; Treatment C: 14 oral doses of 400 mg of the compound of formula (I) (n=6) or placebo (n=2) on 8 days; Study drug was given once daily (qd) on days 1 and 8, and twice daily (bid) on days 2 through 7. Reference source: Post-text Table 14.4.2

[0061] Peak exposure (C max ) and systemic exposure (AUC) increased in a more than dose-proportional manner from 100 to 200 mg and in a nearly dose-proportional manner from 200 to 400 mg after multiple doses over a 1-week period. max was similar among the three escalating dose levels on both day 1 and day 8 (see also Figures 5A and 5B). 1 / 2were 6.90, 6.02, and 6.48 hours on day 1, respectively; the corresponding values ​​after multiple doses were 8.37, 8.14, and 6.57 hours on day 8, respectively. CL / F was 28.7, 20.3, and 24.0 L / h after single doses of 100, 200, and 400 mg, respectively. The corresponding values ​​after multiple doses were 23.1, 16.2, and 18.2 L / h, respectively. Similarly, the estimated V / F was similar between day 1 and day 8. Steady state was achieved by day 6 for all three dose levels. The AUC ratio (day 8 / day 1) of the compound of formula (I) was approximately 1.7-fold after twice daily dosing at all three dose levels.

[0062] Table 7: Pharmacokinetic parameters of compound of formula (I) after FE [Table 7] a :median(range); Mean: Arithmetic mean; SD: Standard deviation; Treatment D: a single oral dose of 200 mg of a compound of formula (I) under fasting conditions; Treatment E: A single oral dose of 200 mg of a compound of formula (I) following ingestion of a high-fat, high-calorie breakfast (post-prandial state). Reference source: Post-Text Table 14.4.3

[0063] Table 8: Statistical comparison of pharmacokinetic parameters after FE [Table 8] TIFF2024520819000013.tif6150 Least squares means and confidence intervals; GM=geometric least squares mean; GMR=geometric least squares mean ratio; CI=confidence interval; GMR and 90% CI: reported as percentages; Treatment D: a single oral dose of 200 mg of a compound of formula (I) under fasting conditions; Treatment E: A single oral dose of 200 mg of a compound of formula (I) following a high-fat, high-calorie breakfast (post-prandial state);

[0064] As shown in Tables 7 and 8, co-administration of the compound of formula (I) with food did not appear to affect overall exposure (similar AUCs were obtained with or without food), but the peak time increased from 1 hour to 2.5 hours and lower peak concentrations were observed (1050 ng / mL vs. 787 ng / mL, see FIG. 6). 1 / 2 were 9.36 and 8.09 hours under fasted and fed conditions, respectively. CL / F was 32.3 L / h for both fasted and fed conditions. Vz / F was 446 L and 383 L under fasted and fed conditions, respectively. Since the compound of formula (I) is developed for chronic disease treatment, minor changes in the PK profile may not be significant for mandate dosing with or without food.

[0065] conclusion Across all dose levels and dosing regimens studied, the compound of formula (I) was safe and generally well tolerated. There were only a few AEs that were mild, short-lived and self-limited. The frequency or intensity of AEs did not increase at higher dose levels. Our data extend and complement the limited clinical studies with previously tested MMP inhibitors, which are often nonselective. Those skilled in the art will recognize that modifications may be made to the above-described embodiments without departing from the broad inventive concept thereof. It is therefore understood that the present invention is not limited to the particular embodiments disclosed, but is intended to encompass modifications within the spirit and scope of the present invention as defined by the explicit description.

Claims

1. The compound of the following formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, for use in a method of safely administering the same to a human subject in need thereof, wherein the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and cyclodextrin, and the method comprises orally administering the pharmaceutical composition to the subject, and the total dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered is about 25 mg to about 600 mg per administration, The pharmaceutical composition.

2. The total dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per administration is 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between, the pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is orally administered once a day or twice a day.

4. Administration of the pharmaceutical composition does not result in a serious adverse effect, or administration of the pharmaceutical composition does not result in a clinically significant change from the pre - administration baseline in laboratory evaluations, vital signs, or electrocardiogram (ECG), the pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition is orally administered once a day, and administration of the pharmaceutical composition results in a) an area under the concentration - time curve (AUC) extrapolated from time 0 to infinity in the plasma of the subject of about 1680 ng.hr / mL to about 26000 ng.hr / mL 0-inf)、b) in the plasma of the subject, an average maximum observed concentration (Cmax) of about 2570 ng / mL or less, c) an average terminal phase elimination half-life (T1 / 2) of about 6 hours to about 7 hours, preferably about 6.2 hours to about 6.9 hours, d) a time to maximum plasma concentration (Tmax) of about 1 hour to about 6 hours, preferably about 1 hour to about 3 hours, e) an average apparent total clearance (CL / F) of about 17.9 L / h to about 31.8 L / h, f) an average apparent volume of distribution (Vz / F) of about 169 L to about 253 L, achieving at least one of the above, the pharmaceutical composition according to any one of claims 1 to 3.

6. The pharmaceutical composition is orally administered twice a day, and the administration of the pharmaceutical composition results in a) an area under the concentration-time curve extrapolated from time 0 to infinity (AUC 0-inf ) in the plasma of the subject of about 3550 ng·hr / mL to about 36300 ng·hr / mL, b) an average maximum observed concentration (Cmax) of about 3710 ng / mL or less in the plasma of the subject, c) a steady-state condition of the compound of formula (I) within 6 days in the plasma of the subject, d) an average terminal phase elimination half-life (T1 / 2) of about 6 hours to about 9 hours, preferably about 6.6 hours to about 8.4 hours, e) a time to maximum plasma concentration (Tmax) of about 0.5 hour to about 6 hours, preferably about 1 hour to about 3 hours, f) an average apparent total clearance (CL / F) of about 16.2 L / h to about 23.1 L / h, g) an average apparent volume of distribution (Vz / F) of about 158 L to about 291 L, achieving at least one of the above, the pharmaceutical composition according to any one of claims 1 to 3.

7. A pharmaceutical composition for use in a method of treating a disease in a human subject in need thereof, wherein the pharmaceutical composition comprises cyclodextrin and the following formula (I): 【Chemical Formula 2】 comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, said method comprising orally administering said pharmaceutical composition to said subject, the total dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered being from about 25 mg to about 600 mg per administration, and said disease being selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, said pharmaceutical composition.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is orally administered once or twice a day.

9. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition is orally administered twice a day, and the total dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per administration is about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any intermediate dose.

10. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition is orally administered twice a day, and the total dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per day is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, or any intermediate dose.

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