Hydronidone preparations, a medication for treating diseases

Abstract

The present invention provides methods and pharmaceutical compositions for treating subjects with hepatic fibrosis and / or cirrhosis. [Solution] A method is provided for treating a subject with hepatic fibrosis, comprising administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject. Liver stiffness measurements and / or ishax scores may be used to identify a subject for treatment of hepatic fibrosis and / or cirrhosis.

Description

[Background technology]

[0001] Liver fibrosis is a life-threatening disease with high morbidity and mortality rates. Currently, there are no FDA-approved treatments for liver fibrosis in the United States, and better treatments are needed in many parts of the world. [Overview of the Initiative]

[0002] In one embodiment, the present disclosure provides a method for treating a subject with hepatic fibrosis, comprising administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject.

[0003] In another embodiment, the present disclosure provides a method for treating a subject with cirrhosis of the liver, comprising administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject.

[0004] In another embodiment, the present disclosure provides a method for treating a subject with advanced hepatitis B virus infection, comprising administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject.

[0005] In another embodiment, the present disclosure provides a method for treating a subject with NASH fibrosis, comprising administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject.

[0006] In another embodiment, the Disclosure provides a method for treating a subject, comprising identifying a subject having a liver stiffness measurement of at least 4 kPa, and administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject.

[0007] In another embodiment, the Disclosure provides a method for treating a subject having an Ishak value of about 1 to 6, and administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to the subject.

[0008] In another embodiment, the Disclosure provides a method for treating a subject that includes identifying a subject substantially free of hepatitis B virus protein and administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to the subject.

[0009] In another embodiment, the Disclosure provides a method for treating a subject that is positive for hepatitis virus DNA testing after receiving one or more courses of antiviral treatment; and administering the subject a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive.

[0010] In another embodiment, the present disclosure provides a pharmaceutical composition comprising about 20% to about 90% by weight of hydronidone or a salt thereof and one or more pharmaceutically acceptable additives. In some examples, the weight percentage of hydronidone or a salt thereof is about 25% to about 35%. In some examples, one or more pharmaceutically acceptable additives are selected from lactose, sucrose, magnesium stearate, glucose, vegetable cellulose, calcium carbonate, zinc stearate, calcium stearate, stearic acid, palmitic acid, myristic acid, glyceryl dibehenate, and talc.

[0011] Further aspects and advantages of the present disclosure will be readily apparent to those skilled in the art from the following detailed description, which shows and describes only exemplary embodiments of the present disclosure. As will be understood, other different embodiments of the present disclosure are possible, and some of their details can be modified in various obvious ways, all without departing from the present disclosure. Accordingly, the drawings and description should be considered exemplary in nature and not restrictive.

[0012] Built-in by reference All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the incorporated publications and patents or patent applications conflict with the disclosure contained herein, this specification is intended to supersede and / or prevail over such conflicting material.

Brief Description of the Drawings

[0013] The novel features of the invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description which sets forth exemplary embodiments in which the principles of the invention are utilized, and to the appended drawings (also referred to herein as "FIGURES" and "FIG.").

[0014] [Figure 1] FIG. 1 shows the Ishak score analysis of various drug groups.

[0015] [Figure 2] FIG. 2 shows the analysis of the change in Ishak score within the group.

[0016] [Figure 3] FIG. 3 shows the analysis of patients with significant fibrosis.

[0017] [Figure 4] FIG. 4 shows the combined analysis of the 270 mg group and the 360 mg group.

[0018] [Figure 5] FIG. 5 shows the combination of various drug groups.

[0019] [Figure 6] FIG. 6 shows the change in Ishak score after 52 weeks in baseline HbeAg(+) patients.

[0020] [Figure 7]Figure 7 shows the change in Ishak score after 52 weeks in baseline HbeAg(-) patients.

[0021] [Figure 8] Figure 8 shows the change in liver stiffness measurement (LSM).

[0022] [Figure 9] Figure 9 shows the combination of drug groups in the LSM analysis.

[0023] [Figure 10] Figure 10 shows the analysis of HBV DNA(+) patients after 52 weeks of entecavir treatment.

[0024] [Figure 11] Figure 11 shows the effect of hydronidone on the induced NASH model in mice.

[0025] [Figure 12] Figure 12 shows the HE staining of hydronidone in the induced NASH model in mice.

Mode for Carrying Out the Invention

[0026] Although various embodiments of the present invention are shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, numerous variations, modifications, and substitutions can be envisioned by those skilled in the art. It should be understood that various alternatives to the embodiments of the present invention described herein can be used.

[0027] When the terms "at least", "more than", or "above" are in front of the first numerical value of a series of two or more numerical values, the terms "at least", "more than", or "above" always apply to each numerical value of that series of numerical values. For example, 1, 2 or 3 or more is equivalent to 1 or more, 2 or more or 3 or more.

[0028] Whenever the terms “not exceeding,” “maximum,” “less than,” or “less than or equal to” precede the first number in a sequence of two or more numbers, those terms apply to each number in that sequence. For example, 3, 2, or 1 or less is equivalent to 3 or less, 2 or less, or 1 or less.

[0029] (overview) Liver cirrhosis, or hepatic cirrhosis, is a condition in which the liver does not function properly due to long-term damage. Scar tissue formation, known as fibrosis, occurs during the process of liver tissue repair. The presence of significant fibrosis from chronic liver injury and subsequent repair over time can lead to cirrhosis. Liver fibrosis is typically the first stage of liver scarring. Many factors can cause liver fibrosis, processes that can impair liver homeostasis, such as inflammation, toxic damage, altered hepatic blood flow, and liver infections (virals, bacteria, fungi, and parasites).

[0030] The antifibrotic effect of hydronidone was observed in in vivo models of hepatic fibrosis of different etiologies described herein. The antifibrotic effect of hydronidone was evaluated in several animal models of hepatic fibrosis, e.g., human serum albumin (HSA)-induced hepatic fibrosis in rats, dimethylnitrosamine (DMN)-induced hepatic fibrosis in rats, and carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Across these animal models, hydronidone exhibited a potent antifibrotic effect, significantly reducing fibrosis levels and improving biochemical and pathological indicators of hepatic fibrosis, such as hydroxyproline content and levels of liver enzymes including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In mouse CCl4-induced hepatic fibrosis, some effect was observed even at a dose of 1 mg / kg / day, but the effect of hydronidone was most pronounced at doses of 3–10 mg / kg / day. In some embodiments, this dose range corresponds to a human equivalent dose (HED) range of 15–50 mg. In some embodiments, these doses are 7 to 24 times lower than the maximum daily dose of 360 mg (120 mg three times daily (TID)) administered to subjects with hepatic fibrosis due to chronic hepatitis B infection in humans. In rats, depending on the model, the antifibrotic effect of hydronidone was shown in the dose range of 10 to 250 mg / kg / day and was as potent as or more potent than silymarin extract, a known hepatoprotective agent used as a positive control. The HEDs for these rat doses range from 100 to 2400 mg, all of which have been tested to be safe in Phase I clinical trials of hydronidone, and the 100 mg dose is less than one-third of the maximum daily dose of 360 mg administered to subjects with hepatic fibrosis due to chronic hepatitis B in an ongoing Phase II clinical trial of the efficacy and safety of hydronidone in China (120 mg TID).

[0031] (Treatment method) This disclosure provides a method for treating subjects with hepatic fibrosis. The method may include administering hydronidone to a subject in need of it. The method may also include administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to a subject.

[0032] This disclosure also provides a method for treating subjects with cirrhosis of the liver. The method may include administering hydronidone to a subject in need of it. The method may also include administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to a subject.

[0033] This disclosure also provides a method for treating subjects with NASH fibrosis. The method may include administering hydronidone or a salt thereof to a subject in need. The method may include administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to a subject.

[0034] This disclosure also provides a method for treating a subject with advanced hepatitis B virus infection. The method may include administering a pharmaceutical composition comprising hydronidone or a salt to the subject.

[0035] This disclosure also provides a method for treating a subject having a certain liver stiffness measurement, comprising identifying the subject and administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject. The pharmaceutical composition comprising hydronidone or a salt thereof may be as described elsewhere in this specification. In some examples, the liver stiffness measurement is obtained by transient elastography. In some examples, the liver stiffness measurement is obtained by FibroTouch and / or FibroScan. In some examples, the liver stiffness measurement may be calibrated against a reference standard, which may be, for example, a liver biopsy. The liver stiffness measurement may be about 4–13 kPa. The liver stiffness measurement may be about 4–8 kPa. The liver stiffness measurement may be about 8–13 kPa. The liver stiffness measurement may be about 8–75 kPa. The liver stiffness measurement may be up to about 13 kPa. The liver stiffness measurement may be up to about 75 kPa.

[0036] This disclosure also provides a method for treating a subject having a certain Ishak value, and the method for treating the subject, comprising administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject. The pharmaceutical composition containing hydronidone or a salt thereof may be as described elsewhere in this specification. The Ishak value may be about 1 to 6. The Ishak value may be 1 to 3. The Ishak value may be 3 to 6.

[0037] In some embodiments, an Ishak score of 0 may indicate the absence of fibrosis. In some embodiments, an Ishak score of 1 may indicate fibrous dilation of some portal vein regions, with or without short fibrous septa. In some embodiments, an Ishak score of 2 may indicate fibrous dilation of many portal vein regions, with or without short fibrous septa. In some embodiments, an Ishak score of 3 may indicate fibrous dilation of many portal vein regions, with occasional portal-to-portal bridging. In some embodiments, an Ishak score of 4 may indicate fibrous dilation of portal vein regions with significant bridging (e.g., portal-to-portal and portal-to-central). In some embodiments, an Ishak score of 5 may indicate significant bridging (e.g., portal-to-portal and / or portal-to-central) with occasional nodules (e.g., incomplete cirrhosis). In some embodiments, an Ishak score of 6 may indicate a high probability or clear indication of cirrhosis.

[0038] In some embodiments, the Ishak value can be converted to another scoring system. The scoring system may be, for example, the METAVIR score or the Knodell score.

[0039] In some embodiments, a method for treating a subject may include identifying a subject having a certain METAVIR score and administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject. In some examples, a METAVIR of F0 may indicate the absence of fibrosis. In some examples, a METAVIR of F1 may indicate portal fibrosis without septa. In some examples, a METAVIR of F2 may indicate portal fibrosis with few septa. In some examples, a METAVIR of F3 may indicate numerous septa without cirrhosis. In some examples, a METAVIR of F4 may indicate cirrhosis. In some examples, the METAVIR score may be F0-F4, F1-F4, F2-F4, F3-F4, F1-F3, F1-F2, or F2-F3.

[0040] The disclosure also provides a method for treating a subject that is substantially free of hepatitis B virus protein, and a method for treating the subject that includes administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject.

[0041] This disclosure also provides a method for treating a subject that is positive for hepatitis virus DNA testing after receiving one or more courses of antiviral treatment; and administering a pharmaceutical composition comprising hydronidone or a salt thereof to the subject. In some examples, the hepatitis virus DNA is selected from hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus. In some examples, the hepatitis virus DNA is hepatitis B.

[0042] (Pharmaceutical composition) This disclosure provides a pharmaceutical composition. The pharmaceutical composition is of formula (I) [ka] Equation (I) The compound may include the compound represented by formula (I). The compound represented by formula (I) may be called hydronidone and / or N-(4-hydroxyphenyl)-5-methyl-2-pyridone. Hydronidone or the pharmaceutical compositions described herein may be used for the treatment of hepatic fibrosis associated with chronic liver disease. Hydronidone or the pharmaceutical compositions described herein may be used for the treatment of cirrhosis associated with chronic liver disease.

[0043] The pharmaceutical composition may contain hydronidone. The pharmaceutical composition may contain a certain weight percentage of hydronidone or a salt thereof. The weight percentage of hydronidone or a salt thereof in the pharmaceutical composition may be about 10-90%, about 10-50%, about 10-40%, about 10-30%, about 20-90%, about 20-50%, about 20-40%, about 20-30%, about 30-90%, about 30-50%, or about 30-40%. The weight percentage of hydronidone in the pharmaceutical composition may be at least about 20%, about 25%, about 30%, about 35%, or about 40%. The weight percentage of hydronidone in the pharmaceutical composition may be at most about 40%, 35%, 30%, 25%, or 20%. The weight percentage of hydronidone in the pharmaceutical composition may be about 30%.

[0044] The pharmaceutical composition may contain hydronidone and one or more additives. Examples of one or more additives include lactose, sucrose, glucose, plant cellulose, calcium carbonate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, palmitic acid, myristic acid, glyceryl dibehenate, and talc. Examples of one or more additives include magnesium stearate and lactose.

[0045] One or more additives may be present in a certain weight percentage of the pharmaceutical composition. One or more additives may be, for example, lactose. The weight percentage of lactose in the pharmaceutical composition may be about 10-90%, about 50-90%, about 60-90%, about 50-80%, about 50-80%, about 60-80%, about 65-75%, about 67-72%, or about 68-71%. The weight percentage of lactose in the pharmaceutical composition may be at least about 50%, about 60%, about 65%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 75%, or about 80%. The weight percentage of lactose in a pharmaceutical composition may be up to about 80%, about 75%, about 73%, about 72%, about 71%, about 69%, about 68%, about 67%, about 65%, about 60%, or about 50%. The weight percentage of lactose in a pharmaceutical formulation may be about 70%.

[0046] One or more additives may be, for example, magnesium stearate. The weight percentage of magnesium stearate in the pharmaceutical composition may be about 0.01-2%, about 0.1-1.5%, about 0.2-1.0%, about 0.25-0.5%, about 0.15-0.30%, about 0.2-0.3%, or about 0.21-0.29%. The weight percentage of magnesium stearate in the pharmaceutical composition may be at least about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, or about 0.40%. The weight percentage of the one or more lubricants in the pharmaceutical composition may be up to about 0.40%, about 0.35%, about 0.30%, about 0.25%, about 0.20%, about 0.15%, about 0.10%, about 0.05%, or about 0.01%.

[0047] The pharmaceutical composition may contain hydronidone, lactose, and magnesium stearate. The weight percentages of hydronidone, lactose, and magnesium may be about 30%, 69.8%, and 0.2%, respectively. The weight percentages of hydronidone, lactose, and magnesium may be about 30%, 69.7%, and 0.3%, respectively.

[0048] In certain embodiments, a composition is provided comprising either a therapeutically effective amount of a compound or a salt of hydronidone (also referred to herein as the “medicinal substance”).

[0049] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, including additives and excipients that facilitate the processing of pharmaceutical substances into pharmaceutically usable formulations. The appropriate formulation depends on the chosen route of administration. An overview of pharmaceutical compositions can be found in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0050] The compositions and methods of this disclosure may be used to treat individuals that require them. In particular embodiments, the individuals are mammals such as humans, or non-human mammals. When administered to animals such as humans, the compositions or pharmaceutical substances are preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical substance and a pharmaceutically acceptable carrier or additive. pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiological buffer saline, or other solvents or vehicles, such as glycols, glycerols, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such a pharmaceutical composition is for human administration, particularly for invasive administration routes such as injection or implantation to avoid transport or diffusion across the epithelial barrier, the aqueous solution is pyrogenic or substantially pyrogenic. Additives may be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in unit dosage forms, such as tablets, capsules, granules, lyophilized reconstituted products, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems, such as skin patches. The composition may also be present in solutions suitable for topical administration, such as eye drops.

[0051] pharmaceutically acceptable additives may include, for example, physiologically acceptable substances that act to stabilize, increase the solubility of, or increase the absorption of compounds such as pharmaceutical substances. Such physiologically acceptable substances include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or additives. The selection of pharmaceutically acceptable additives containing physiologically acceptable substances depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which, for example, the compounds of the present invention can be incorporated therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to manufacture and administer.

[0052] Pharmaceutical compositions (formulations) can be administered to a subject by any of many routes of administration, such as orally, drains such as aqueous or non-aqueous solutions or suspensions, tablets, capsules including sprinkle capsules and gelatin capsules, boluses, powders, granules, and pastes for application to the tongue.

[0053] The pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension, or emulsion, such as a microemulsion. The additives described herein are examples and are not limiting in any sense. An effective dose or therapeutically effective dose refers to the amount of one or more pharmaceutical substances administered to a subject as part of a single dose or a series of doses that is effective in producing the desired therapeutic effect.

[0054] Subjects can generally be monitored for therapeutic effects using assays and methods appropriate to the condition being treated, assays well known to those skilled in the art and described herein. The pharmacokinetics of a medicinal substance or one or more metabolites administered to a subject can be monitored by determining the levels of the medicinal substance or metabolite in physiological fluids, e.g., blood, blood fractions, e.g., serum, and / or urine, and / or other biological samples or tissues from the subject. Any method practiced in the art to detect a substance and described herein can be used to measure the levels of the medicinal substance or metabolite during a course of treatment.

[0055] The dosage of the medicinal substances described herein for treating a disease or disorder may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the general health status, as well as age, sex and weight, and other factors apparent to those skilled in the art in the medical field. The medicinal composition may be administered in a manner appropriate to the disease being treated, as determined by those skilled in the art in the medical field. In addition to the factors described herein and above relating to the use of medicinal substances for treating a disease or disorder, the appropriate duration and frequency of administration of the medicinal substance may also be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dose of the medicinal substance may generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the body mass, weight, or blood volume of the subject. It is usually preferable to use the minimum dose sufficient to provide effective treatment. The design and conduct of preclinical and clinical trials of the medicinal substances described herein, including when administered for preventive effects, are well within the scope of the art of those skilled in the art in the relevant field. When two or more medicinal substances are administered to treat a disease or disorder, the optimal dose of each medicinal substance may differ and may be less than, for example, the dose of one of the medicinal substances administered alone as monotherapy. In certain embodiments, a combination of two medicinal substances may act synergistically or additively and may be used in smaller amounts than the dose of either substance administered alone. The amount of medicinal substance that can be administered per day may be, for example, about 0.01 to 100 mg / kg, for example, about 0.1 to 1 mg / kg, about 1 to 10 mg / kg, about 10 to 50 mg / kg, or about 50 to 100 mg / kg body weight. In other embodiments, the amount of medicinal substance that can be administered per day may be about 0.01 to 1000 mg / kg, about 100 to 500 mg / kg, or about 500 to 1000 mg / kg body weight. The optimal dose per day or per course of treatment may vary depending on the disease or disorder being treated and may also vary depending on the route of administration and the treatment regimen.

[0056] Pharmaceutical compositions containing pharmaceutical substances can be formulated in a manner suitable for delivery by using techniques routinely practiced in the art. The compositions may be in the form of solids, such as tablets or capsules; semi-solids, such as gels or liquids; or gases, such as aerosols.

[0057] Medicinally acceptable excipients are well known in the pharmaceutical field, for example, Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st This is described in Ed. Mack Pub. Co., Easton, PA (2005). Exemplary pharmaceutically acceptable additives include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc., may be provided in the pharmaceutical composition. Antioxidants and suspending agents may also be used. Generally, the type of additive is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be lyophilized with one or more suitable additive solutions to solubilize and / or dilute the pharmaceutical substance of the composition at administration, or otherwise formulated as lyophilized products. In other embodiments, the pharmaceutical substance may be encapsulated in liposomes using techniques known and practiced in the art. In certain embodiments, the pharmaceutical substance is not formulated in liposomes for application to stents used to treat arteries that are not completely but highly occluded. The pharmaceutical composition may be formulated for any suitable method of administration described herein and in the art.

[0058] For example, a pharmaceutical composition for oral administration may be in liquid form. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent, e.g., water, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, a fixing oil that can function as a solvent or suspension medium, polyethylene glycol, glycerin, propylene glycol, or other solvent; an antimicrobial agent; an antioxidant; a chelating agent; a buffer and a substance for adjusting the tonicity, e.g., sodium chloride or glucose. Non-enteral compositions may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials. The use of physiological saline is preferred, and the injectable pharmaceutical composition is preferably sterile. In another embodiment, for the treatment of an ophthalmic condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. Liquid pharmaceutical compositions may be delivered orally.

[0059] For oral formulations, at least one of the pharmaceutical substances described herein may be used alone or in combination with appropriate additives to produce tablets, powders, granules, or capsules, optionally together with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. Pharmaceutical substances may be formulated with buffers to provide protection of the compound from the low pH of the gastric environment and / or an enteric coating. Pharmaceutical substances contained in pharmaceutical compositions may be formulated for oral delivery together with flavoring agents, for example, as liquid, solid, or semi-solid formulations and / or with an enteric coating.

[0060] Pharmaceutical compositions comprising any one of the pharmaceutical substances described herein may be formulated for sustained release or controlled release (also referred to as timed release or controlled release). Such compositions are generally manufactured using well-known techniques and may be administered, for example, orally, rectally, intradermally or subcutaneously, or by implantation into a desired target site. Sustained-release formulations may comprise a compound dispersed in a carrier matrix and / or a compound contained in a reservoir surrounded by a rate-controlled membrane. Additives for use in such formulations may be biocompatible and biodegradable; preferably, the formulation provides a relatively constant level of active ingredient release. The amount of pharmaceutical substance contained in a sustained-release formulation depends on the implantation site, release rate and expected release time, and the nature of the condition, disease, or disorder being treated or prevented.

[0061] Polymer formulations may also be used to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. As an example, sustained-release gels and compounds may be incorporated into a polymer matrix, such as a hydrophobic polymer matrix. Examples of polymer matrices include microparticles. The microparticles may be microspheres, and the core may be made of a different material from the polymer shell. Alternatively, the polymer may be formed as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer may also be in the form of a coating or part of a bandage, stent, catheter, artificial blood vessel or other device for facilitating the delivery of a pharmaceutical substance. The matrix may be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0062] This specification provides kits containing unit doses of one or more pharmaceutical substances, typically in oral or injectable doses. Such kits may include a container containing the unit dose, an informational leaflet describing the use of the drug in the treatment of a disease and its associated benefits, and optionally an instrument or device for delivering the composition. [Examples]

[0063] Example 1: In vitro human metabolism of hydronidone, phase 1

[0064] The in vitro phase 1 metabolism of hydronidone was evaluated by incubating human liver microsomes with hydronidone for 60 minutes. The sensitivity of the assay was demonstrated by incubating human liver microsomes with dextromethorphan (positive control) for 20 minutes to produce the metabolites dextromethorphan and 3-methoxymorphinan. After incubating hydronidone in the human liver microsome reaction system for 60 minutes, no metabolite formation was observed, indicating that CYP450 is not involved in the metabolic reaction that produces the M2 metabolite of hydronidone.

[0065] Example 2: In vitro human metabolism of hydronidone, phase 2

[0066] After incubating hydronidone in a human liver microsome reaction system for 30 minutes, the production of the M4 metabolite was detected, indicating that uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) is involved in the metabolic reaction that produces M4 in hydronidone.

[0067] Example 3: In vitro human metabolism of hydronidone and its interaction with CYP450

[0068] In vitro studies investigated whether hydronidone is an inhibitor of human cytochrome P450 (CYP450). The effects of various hydronidone concentrations were determined by the fluorescence intensity of the metabolic substrates of CYP1A2, 2C9, 2C19, 2D6, and 3A4, which are produced under the influence of the relevant enzymes. 50 The value was calculated when inhibition by hydronidone was observed. The sensitivity of the assay was demonstrated using a known CYP450 inhibitor as a positive control. The results showed that human CYP1A2 enzyme (IC) 50 IC values ​​> 100 μM vs 2.59 μM 50 Positive control fluffin with a value, CYP2C9 enzyme (IC)50 Value > 100 μM, IC of 0.49 μM 50 with the positive control sulfaphenazole), CYP2C19 enzyme (IC 50 Value > 100 μM, IC of 4.9 μM 50 with the positive control tranylcypromine), CYP2D6 enzyme (IC 50 Value > 100 μM, IC of 0.01 μM 50 with the positive control quinidine), and CYP3A4 enzyme (IC 50 Value > 100 μM vs. IC of 0.027 μM 50 Hydronidone did not show significant in vitro inhibitory activity against the positive control ketoconazole) with an IC value. It was concluded that there is no significant interaction between hydronidone and human CYP450.

[0069] Example 4: Pharmacokinetic drug-drug interaction in the in vitro human metabolism of hydronidone

[0070] The potential of hydronidone for drug-drug interaction with two antiviral drugs, entecavir and lamivudine, related to the indication of chronic hepatitis B infection in China was evaluated in vitro using human liver microsomes. Entecavir is co-administered with hydronidone in a Phase II safety and efficacy trial targeting liver fibrosis due to chronic hepatitis B infection ongoing in China. Entecavir and lamivudine were used at a concentration of 1.5 mM each, either in combination with hydronidone or individually, in an in vitro drug-drug interaction experiment. The results obtained from the drug-drug interaction test showed that a) hepatic metabolism is not the main metabolic pathway of hydronidone, and b) there was no significant difference in the residual drug concentration between the individual dosing group and the combined dosing group (P > 0.05), indicating that entecavir and lamivudine do not show drug-drug interaction with hydronidone.

[0071] Example 5: Outline of the Phase I clinical pharmacology trial of hydronidone

Table 1

[0072] Example 6: Double-blind, placebo-controlled inpatient study of single and multi-dose hydronidone

[0073] The primary objective of this study was to evaluate the tolerability of single and multiple escalating doses of hydronidone in healthy subjects, to support further Phase I trials, and to provide supporting information for dosing regimens in Phase II clinical trials.

[0074] This was a randomized, double-blind, placebo-controlled, inpatient trial of single and multiple escalating doses of hydronidone in healthy Chinese male and female subjects aged 18–45 years who met all inclusion and exclusion criteria. Hydronidone 100 mg and 200 mg capsule dose strengths were used in the trial. In all groups, subjects were randomly assigned to receive either hydronidone or placebo in a 3:1 ratio.

[0075] The single-dose components of the study included 30 subjects (6 subjects / group) who received 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg of hydronidone, respectively. Post-administration observations were performed 24 hours after administration. All subjects completed the study. Hydronidone was safe and well-tolerated at all doses tested. No deaths or serious adverse events (SAEs) were reported during the study. Mild, transient dizziness was reported in one subject each in the 800 mg hydronidone and placebo groups after administration of the test substance. The dizziness resolved spontaneously without sequelae. Post-administration values ​​of some clinical laboratory parameters were abnormal in both the hydronidone and placebo groups. However, these changes were not considered clinically significant.

[0076] The multi-dose component of the study included 20 subjects assigned to receive either 600 mg (8 subjects) three times daily (TID) (total daily dose of 1800 mg) or 800 mg of hydronidone (12 subjects) as a TID (total daily dose of 2400 mg) for 10 consecutive days. Due to several cases of hypertriglyceridemia (AE) observed in the hydronidone 600 mg TID dose group (4 out of 8 subjects), the subjects in the hydronidone 800 mg TID dose group (n=8) were divided into two subgroups, each containing 4 subjects. A stepwise enrollment approach was applied: if no SAEs were observed in the first subgroup, enrollment of subjects in the second subgroup could then proceed with the same dose of hydronidone 800 mg TID. If SAEs were observed in the first subgroup, the principal investigator performed further analysis to determine the dose level for the second subgroup. In the hydronidone 800 mg TID dose group, subgroup 1 (all 4 subjects) had a blood glucose test inadvertently omitted at the final visit to the clinic. Therefore, at the discretion of the principal investigator, enrollment was extended to include 4 new subjects, increasing the total number of subjects in this dose group to 12. Safety evaluations were performed pre-administration, on day 5 of administration, and 24 hours after the last dose of the 10-day administration period.

[0077] No deaths or SAEs were reported in this part of the study. All subjects in the 600 mg TID group completed the study. In the 800 mg TID group, all subjects completed the study except for one subject who was discontinued early on day 6 based on the investigator's perceived risk due to abnormal liver function parameters. This subject was assigned to hydronidone treatment. In the 600 mg TID group, seven adverse events (AEs) were reported: three cases of hypertriglyceridemia, and one each of chest tightness, abdominal distension, skin rash, and stomatitis. In the placebo group, one case of rash and one case of hyperlipidemia were reported. The elevated lipid parameters (triglyceridemia) in three subjects in this group (subject numbers 1, 2, and 6) were judged to be clinically significant; the elevated triglyceride levels returned to normal after one week without any treatment. In the 800 mg TID group and the placebo group, 14 and 5 AEs were reported, respectively. In the 800 mg hydronidone group, adverse events included three cases each of liver dysfunction and hyperlipidemia, and one case each of headache, dizziness, constipation, abdominal distension, nausea, heartburn, skin rash, and eosinophilia. In the placebo group, adverse events included two cases of hyperlipidemia, two cases of diarrhea, and one case of liver dysfunction.

[0078] Low-density lipoprotein cholesterol (LDL-CHOL) levels were slightly above the upper limit of normal (ULN) in two subjects each in the 800 mg TID hydronidone dose group and the placebo group. These increases were not considered clinically significant and returned to normal levels after discontinuation of the study drug. Liver function abnormalities (AEs) in subjects in the 800 mg TID hydronidone dose group included two cases of moderate but clinically significant elevation of liver parameters. In one subject in this group, ALT and AST levels were 79 U / L and 47 U / L, respectively, on day 5 of administration. At the repeat examination on day 6 of the study, ALT and AST levels were 101 U / L and 61 U / L, respectively, accompanied by heartburn, rash, headache, and other symptoms. Due to the perceived health risk to the subject from the escalating liver enzymes, the principal investigator terminated the subject's treatment. The subject was monitored the following week. Transaminases spontaneously returned to normal levels within one week of discontinuing the investigational drug without any treatment. Although this AE met the criteria for a standard adverse event (SAE), it was classified as a significant adverse event rather than an SAE by the principal investigator because no special treatment was prescribed to the subject.

[0079] In summary, the most common adverse events (AEs) associated with 10-day administration of hydronidone at 600 mg TID (total daily dose of 1800 mg) or 800 mg TID (total daily dose of 2400 mg) were hyperlipidemia (triglyceridemia) and elevated hepatic transaminases. These AEs were transient and resolved without treatment. Since they were observed in both the hydronidone and placebo groups, it is unclear whether these AEs were specifically related to hydronidone treatment.

[0080] Example 7: PK test of a single dose-escalating oral dose

[0081] This was a randomized, open-label, 4-period crossover pharmacokinetic trial of a single dose escalating oral dose of hydronidone in healthy volunteers.

[0082] A single, escalating oral dose of 200 mg, 400 mg, 600 mg, and 800 mg of hydronidone was administered under fasting conditions to 12 eligible, healthy male Chinese subjects (aged 26–38 years, meeting all inclusion and exclusion criteria, and randomly divided into four groups of three subjects each). Subjects in each group were treated with hydronidone at four different doses over four periods, according to the Williams design. PK blood samples were collected at 0 (pre-administration), and at 10, 20, 30, 40 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, and 48 hours after administration. Subjects also provided PK urine samples at 0 (pre-administration), and at 5, 12, and 24 hours after administration. There was an additional 24-hour washout period after the completion of PK sample collection, totaling 48 hours between the initial and subsequent dose levels. Blood and urine samples were analyzed to determine the plasma and urine concentrations of hydronidone and its metabolite (M3).

[0083] [Table 2]

[0084] The amounts of unchanged drug excreted in urine over 48 hours were 82.25±40.95 mg, 183.75±142.14 mg, 218.93±182.73 mg, and 234.72±210.50 mg. The urinary percentages of hydronidone were 0.634±0.57%, 0.479±0.22%, 0.476±0.2%, and 0.403±0.25%, indicating that the majority of orally administered hydronidone is not excreted unchanged in urine. The percentages of M3 excreted in urine were 29.47%, 32.94%, 26.14%, and 21.04%, indicating that hydronidone is converted and then excreted in urine in the form of metabolites.

[0085] Single oral doses of 200 mg, 400 mg, 600 mg, and 800 mg of hydronidone were safe and well-tolerated in healthy Chinese subjects, and no adverse events or SAEs were reported.

[0086] Example 8: Crossover PK study on the safety, tolerability, and effects of food on PK of a single oral dose.

[0087] This was a randomized, open-label, two-period crossover pharmacokinetic (PK) trial investigating the safety, tolerability, and effects of food on PK of a single oral dose of hydronidone in healthy Chinese subjects. PK parameters of hydronidone's M3 and M4 metabolites were also determined with and without food.

[0088] Twelve healthy Chinese subjects were enrolled, administered, and participated in this inpatient study. They were randomly assigned to two groups / periods and received a single oral dose of 600 mg (3 × 200 mg) of hydronidone under fasting or feeding (high-fat) conditions. Within each treatment period, PK blood samples were collected at 0 (pre-administration), and at 10, 20, 30, 40 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, and 48 hours after administration. The washout period between the two periods in this study was 48 hours.

[0089] The PK results showed that after a single oral dose of 600 mg of hydronidone, the presence of food (high-fat diet) slowed the absorption rate of hydronidone and its major metabolites M3 and M4, lowering their Cmax values, but there was no change in exposure levels, as indicated by the unaffected AUC value. Therefore, based on the AUC results, food intake did not affect the exposure levels of hydronidone and its major metabolites M3 and M4. Hydronidone was safe and well-tolerated, and no adverse events or SAEs were reported.

[0090] Example 9: Open-label, parallel-group PK study of multiple dose-escalating oral doses

[0091] This was a randomized, open-label, parallel-group pharmacokinetic trial of multiple dose escalations of hydronidone in healthy Chinese subjects.

[0092] In this study, hydronidone TIDs of 200 mg, 400 mg, and 600 mg were administered orally in increasing doses to 27 healthy subjects (15 males and 12 females) divided into three groups (9 subjects / group) for four consecutive days. This was an inpatient study. Hydronidone was administered under fasting conditions. Blood and urine samples were collected for PK evaluation. PK evaluation was performed after single doses (after the first dose) and after multiple doses. Standard safety assessments, including physical examination, ECG, hematology, serum biochemistry, and urinalysis, were also performed.

[0093] PK results indicated that hydronidone was rapidly absorbed, with a Tmax of approximately 1 hour. After a single dose, neither the parent drug nor its major metabolites were detectable at 36 hours post-administration. Exposure levels of hydronidone and its metabolites in human plasma, from high to low concentrations, were in the order hydronidone-M4 > hydronidone-M3 > hydronidone-M2. After a single hydronidone administration, the total recovery rates of the undiluted drug and its M2, M3, and M4 metabolites in urine were 82.7%, 85.5%, and 84.0%, respectively. PK results from single and multi-dose regimens did not show any significant accumulation of hydronidone. Male subjects had lower exposures compared to female subjects across all administered dose levels. Exposure increased with dose, but there was no strict dose-proportional relationship due to the large variability.

[0094] All 27 subjects completed the study. Hydronidone was safe and well-tolerated in this study within the single-dose range of 200–600 mg TID. No deaths or SAEs were reported in this study. Seven adverse events were reported in two subjects in the 200 mg TID multiple-dose group and five subjects in the 400 mg TID multiple-dose group. AEs reported in this part of the study included one case each of dizziness, leukopenia, and abdominal pain, and two cases each of abdominal distension and diarrhea. All AEs were thought to be likely related to hydronidone treatment. The severity of the AEs was mild, and all resolved spontaneously. All subjects with AEs completed the study.

[0095] Example 10: Open-label study of safety, tolerability, and pharmacokinetics of single dose, 7-day, and 4-week multi-dose oral doses.

[0096] This was a randomized, open-label trial evaluating the safety, tolerability, and pharmacokinetics of single-dose, 7-day, and 4-week multi-dose oral doses.

[0097] This study was conducted in three parts. In Part 1, single escalating doses of hydronidone at 15 mg, 30 mg, 60 mg, 90 mg, and 120 mg / day were administered to 6, 8, 8, 6, and 6 healthy subjects, respectively, following a Fibonacci escalation method (modified Fibonacci method). The age, height, weight, BMI, and sex distribution of subjects in each dose group were similar at baseline. Since no adverse experiences were reported at any dose level, the two highest single dose levels of hydronidone, 90 mg and 120 mg, were selected for Part 2 of the study and administered to 6 subjects in each group for 7 consecutive days as a total daily dose (TID). Therefore, the total daily dose of hydronidone in these two dose groups was 270 mg and 360 mg, respectively. All subjects completed the 7-day administration regimen without early discontinuation. No clinically significant abnormal changes were observed in vital signs, ECG, or laboratory results in subjects in each group. In the third part of the study, six subjects received orally administered hydronidone at a daily dose of 60 mg TID (total daily dose of 180 mg) for four consecutive weeks. All subjects completed the 7-day administration regimen without premature discontinuation. No clinically significant abnormal changes were observed in vital signs, ECG, or laboratory results in any of the subjects in each group.

[0098] PK evaluations were conducted in each part of the study. In the single-stage parts of the study, the PK parameters also included an assessment of the effects of food.

[0099] In the single-dose part (Part I) of the study, the primary pharmacokinetic parameter of hydronidone obtained from 36 healthy subjects who received single oral doses of 30, 60, and 120 mg of hydronidone in a fasted state was Tmax (0.60 ± 0.49).

[0100] Single doses of hydronidone in the range of 15–120 mg were safe and well-tolerated in all subjects in the study. All subjects completed all study procedures and observations. No deaths, SAEs, or AEs occurred throughout the study, and no abnormal changes in subjective symptoms or physical examination were observed after administration. At all time points, including baseline and comparisons between different dose groups, vital signs were normal after administration (p>0.05). Three subjects experienced elevated T-BIL and D-BIL levels after administration, two in the 30 mg dose group and one in the 120 mg dose group. These values ​​were within the normal range upon re-examination. The principal investigator did not consider any of these increases to be clinically significant.

[0101] Seven consecutive days of hydronidone administration at 90 mg TID (270 mg / day) and 120 mg TID (360 mg / day) were safe and well-tolerated in all subjects in the study. There were no early discontinuations, and all subjects completed the study. No deaths, SAEs, or AEs occurred throughout the study, and no abnormal changes in subjective symptoms or physical examination were observed after administration. No clinically significant abnormal changes were observed in vital signs, laboratory parameters, or ECG parameters in either dose group (p>0.05).

[0102] Hydronidone administration at 60 mg TID (180 mg / day) for four consecutive weeks was safe and well-tolerated in all subjects in the study. There were no early discontinuations, and all subjects completed the study. No deaths or SAEs were reported.

[0103] Regarding adverse events (AEs), no AEs were reported in the tolerability part of the study; in the PK group receiving multiple doses of 60 mg hydronidone TID, there were only two instances of mild transient dizziness in two female subjects (out of 12 subjects) at 30 minutes and 1.0 hour post-administration. These AEs resolved within 1 to 1.5 hours without treatment.

[0104] No clinically significant abnormal changes were observed in vital signs or ECG parameters in any of the dose groups (p>0.05). The observed fluctuations in clinical laboratory parameters were considered clinically insignificant by the principal investigator. No abnormal prolongation of the QTc interval occurred at any dose level.

[0105] In conclusion, hydronidone was safe and well-tolerated in a single oral dose range from 15 mg to 120 mg. The maximum tolerated single oral dose of hydronidone was 120 mg. Hydronidone was also safe and well-tolerated up to 360 mg / day when administered as a 120 mg TID for 7 consecutive days. Hydronidone was safe and well-tolerated at a dose of 180 mg / day when administered as a 60 mg TID for 4 consecutive weeks to healthy subjects. No drug accumulation in the body was observed, as indicated by PK analysis of key PK parameters at equivalent dose levels of hydronidone after single and multiple dosing regimens.

[0106] Example 11: Phase II clinical pharmacological study of hydronidone

[0107] This was a phase II randomized, double-blind, placebo-controlled, entecavir-based multicenter dose-range study on the efficacy and safety of hydronidone when administered for 52 consecutive weeks to Chinese subjects with hepatic fibrosis due to chronic hepatitis B.

[0108] The primary objective of this study is to investigate the effective dose and evaluate the safety of hydronidone when administered for 52 consecutive weeks in combination with the antiviral drug entecavir to Chinese subjects with hepatic fibrosis due to chronic hepatitis B infection. The secondary objective of this study is to evaluate the effect of hydronidone on improving hepatitis inflammation and liver function when administered in combination with the antiviral drug entecavir to Chinese subjects with hepatic fibrosis due to chronic hepatitis B infection.

[0109] Approximately 240 eligible subjects (approximately 60 subjects per dose group) will be enrolled in the study and will be treated daily for 52 consecutive days with hydronidone oral doses of 30 mg, 60 mg, or 120 mg TID (total daily doses of 180 mg, 270 mg, and 360 mg, respectively) or placebo, in combination with basic antiviral treatment with entecavir at a daily dose of 0.5 mg. In parallel, groups of 12 subjects will be evaluated for pharmacokinetics (PK).

[0110] Example 12: Analysis of Ishax scores in drug groups (primary endpoint)

[0111] As shown in Figure 1, hydronidone significantly reduced the ishak score ≥ 1 after 52 weeks of treatment. The 270 mg group appeared to be the best-performing group.

[0112] Example 13: Analysis of changes in Ishax score within a group

[0113] As shown in Figure 2, after 52 weeks of treatment, all drug groups showed a statistically significant reduction in the Ishak score (≥1). The placebo group did not show a statistically significant reduction in the Ishak score (≥1).

[0114] Example 14: Analysis of a patient with significant fibrosis

[0115] As shown in Figure 3, the improvement in the Ishak score is consistent with the results of the primary endpoint analysis. The 270 mg group appears to be the best dose group.

[0116] Example 15: Combination analysis of the 270 mg group and the 360 ​​mg group

[0117] As shown in Figure 4, hydronidone can improve fibrosis in patients with marked fibrosis and cirrhosis.

[0118] Example 16: Combination analysis of all drug groups

[0119] As shown in Figure 5, hydronidone can improve fibrosis in patients with significant fibrosis and cirrhosis.

[0120] Example 17: Changes in Ishak score after 52 weeks in baseline HbeAg(+) patients

[0121] As shown in Figure 6, hydronidone showed a statistically significant change when combined with other dose groups.

[0122] Example 18: Changes in Ishak score after 52 weeks in baseline HbeAg(-) patients

[0123] As shown in Figure 7, hydronidone showed a statistically significant change when combined with other dose groups. The improvement in HbeAg(-) patients was considered better than that in HbeAg(+) patients.

[0124] Example 19: Changes in liver stiffness measurement values ​​(LSM)

[0125] As shown in Figure 8, all drug groups showed a decrease in LSM(kPa) after 52 weeks of treatment (P<0.01 within the group).

[0126] Example 20: Combinations of drug groups in LSM analysis

[0127] As shown in Figure 9, the LSM score showed statistical significance in advanced fibrosis (Ishak ≥ 4).

[0128] Example 21: Analysis of HBV DNA+ patients after 52 weeks of entecavir treatment

[0129] As shown in Figure 10, all patients (Ishak > 3) responded to hydronidone treatment.

[0130] Example 22: Effect of hydronidone on a mouse (CCl4+HFD)-induced NASH model

[0131] As shown in Figure 11, various studies were conducted to demonstrate the use of hydronidone at various doses. Total HASH scores were lower at doses of 15 mg / kg (mpk) and 50 mpk.

[0132] Example 23: HE staining using hydronidone

[0133] As shown in Figure 12, the effects of HE staining using hydronidone at various doses were demonstrated. Hydronidone has a protective effect against CCl4 and Western diet (WD)-induced NASH. Hydronidone at 15 mpk and 50 mpk significantly suppressed CCl4 and WE-induced fibrosis and cell swelling. Hydronidone is more potent than pirfenidone.

Claims

1. A method for treating a subject with hepatic fibrosis, comprising administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject.

2. A method for treating a subject with cirrhosis of the liver, comprising administering to the subject a pharmaceutical composition containing hydronidone or a salt thereof.

3. A method for treating a subject with advanced hepatitis B virus infection, comprising administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject.

4. A method for treating a subject with NASH fibrosis, comprising administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject.

5. The method according to any one of claims 1 to 4, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives.

6. The method according to any one of claims 1 to 5, further comprising identifying a subject having a liver stiffness value between at least two thresholds.

7. The method according to any one of claims 1 to 5, further comprising identifying an object having an Ishak score between at least two thresholds.

8. A method for treating a subject, comprising identifying a subject whose liver stiffness measurement is at least 4 kPa, and administering a pharmaceutical composition containing hydronidone or a salt thereof to the subject.

9. The method according to claim 8, wherein the liver stiffness measurement value is approximately 4 kPa to 8 kPa.

10. The method according to claim 8, wherein the liver stiffness measurement value exceeds 8 kPa.

11. The method according to claim 6 or 8, wherein liver stiffness is measured using a FibroTouch or FibroScan device.

12. A method for treating a subject comprising: identifying a subject having an Ishak value of approximately 1 to 6; and administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to the subject.

13. The method according to claim 12, wherein the Ishak value is approximately 1 to 3.

14. The method according to claim 12, wherein the Ishak value is approximately 3 to 6.

15. A method for treating a subject, comprising identifying a subject substantially free of hepatitis B virus protein, and administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to the subject.

16. A method for treating a subject, comprising: identifying a subject that tests positive for hepatitis virus DNA after receiving one or more courses of antiviral treatment; and administering a pharmaceutical composition comprising hydronidone or a salt thereof and a pharmaceutically acceptable additive to the subject.

17. The method according to claim 16, wherein the hepatitis virus DNA is selected from hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus.

18. The method according to any one of claims 1 to 17, wherein the pharmaceutical composition comprises about 20% to about 90% by weight of hydronidone or a salt thereof and one or more additives.

19. The method according to any one of claims 1 to 18, wherein the weight percentage of hydronidone or a salt thereof is about 30%.

20. The method according to any one of claims 1 to 19, wherein the pharmaceutical additive comprises magnesium stearate and lactose.

21. A pharmaceutical composition comprising approximately 20% to 90% by weight of hydronidone or a salt thereof and one or more pharmaceutically acceptable additives.

22. The pharmaceutical composition according to claim 21, wherein the weight percentage of hydronidone or a salt thereof is about 25% to about 35%.

23. The pharmaceutical composition according to claim 22, wherein the weight percentage of hydronidone or a salt thereof is about 30%.

24. The pharmaceutical composition according to claim 23, wherein one or more pharmaceutically acceptable additives are selected from lactose, sucrose, magnesium stearate, glucose, vegetable cellulose, calcium carbonate, zinc stearate, calcium stearate, stearic acid, palmitic acid, myristic acid, glyceryl dibehenate, and talc.

25. The pharmaceutical composition according to claim 24, wherein one or more pharmaceutically acceptable additives include magnesium stearate and lactose.

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