Drugs and combinations for treating hepatitis b

Abstract

Disclosed are a class of drugs and combinations for treating hepatitis B, which specifically relate to a compound of formula (I) for treating hepatitis B, and combinations with other drugs for treating hepatitis B and administration methods, as well as uses of the compound and the drug combinations in the preparation of a drug for treating hepatitis B.

Description

Medicaments and combinations for the treatment of hepatitis B

[0001] This application claims priority to Chinese patent application 2024112492513 with the filing date of 2024 / 9 / 6. This application incorporates the entire text of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application belongs to the field of biological medicine, and relates to a kind of combination of formula (I) compound for treating hepatitis B and other drugs for treating hepatitis B and administration method, and the purposes of the compound and the drug combination in the preparation of treating hepatitis B drugs. BACKGROUND

[0003] Hepatitis B virus (HBV, simply hepatitis B) infection is a serious public health burden worldwide, with more than 250 million people chronically infected. About one-fourth of patients may develop severe liver disease, such as cirrhosis and hepatocellular carcinoma (HCC). It is estimated that there are currently more than 80 million cases of chronic HBV infection in China, and the diagnosis rate and treatment rate of CHB in China are only about 22% and 15%, respectively. In addition, studies have shown that even if hepatitis B patients receive hepatitis B virus antiviral treatment, a portion of the patients with chronic hepatitis B are still in a state of low viral load, and patients in this state for a long time still have certain risks, including drug resistance, virological breakthrough, and even progression to cirrhosis and liver cancer, even if they insist on taking antiviral drugs every day.

[0004] At present, there is no specific drug for treating hepatitis B worldwide, and the first-line drugs for hepatitis B treatment in China are mainly nucleoside drugs, interferon and traditional Chinese medicine, but there are problems such as long medication period and inability to cure, so it is imperative to develop new types of anti-hepatitis B drugs.

[0005] WO2018153285A1 patent discloses a compound of formula (I) and its use, which is a hepatitis B core protein inhibitor or called nucleocapsid modulator. The present application further provides a composition of the compound and an effective administration method and its dosage form. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the limitation of the type of drug composition for treating hepatitis B in the prior art. A medicament and combination for treating hepatitis B are provided. The medicament and combination for treating hepatitis B have good effect on treating hepatitis B and good application prospect.

[0007] The present application provides a pharmaceutical dosage unit composition, which comprises 10-200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0008] The present application provides a pharmaceutical dosage unit composition comprising 10-200 mg of a compound of the following formula (I):

[0009] The dosage unit form is suitable for oral administration.

[0010] Further, the composition comprises 20 to 100 mg of the compound of formula (I) in the dosage unit form.

[0011] Further, the composition comprises 10 mg or 20 mg or 25 mg or 50 mg or 100 mg or 200 mg of the compound of formula (I) in the dosage unit form.

[0012] Preferably, the composition comprises 50 mg or 100 mg of the compound of formula (I) in the dosage unit form.

[0013] Preferably, the pharmaceutical dosage unit composition is a tablet.

[0014] Preferably, the pharmaceutical dosage unit composition is a tablet.

[0015] Preferably, the composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0016] In an aspect of the present application, the pharmaceutically acceptable carrier and / or excipient is selected from one or more of a filler, a disintegrant, a binder, a surfactant and a lubricant.

[0017] In an aspect of the present application, the filler is lactose and / or microcrystalline cellulose.

[0018] In an aspect of the present application, the disintegrant is croscarmellose sodium.

[0019] In an aspect of the present application, the binder is hypromellose.

[0020] In an aspect of the present application, the surfactant is sodium lauryl sulfate.

[0021] In an aspect of the present application, the lubricant is sodium stearyl fumarate.

[0022] In an aspect of the present application, when the composition further comprises a pharmaceutically acceptable carrier and / or excipient; the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5wt%-40wt%; preferably 15wt%-20wt%; and more preferably 17wt%.

[0023] In some embodiments of the present application, the pharmaceutically acceptable carrier and / or excipient is present in an amount of 60wt%-95wt% (based on the weight of the compound of formula I); preferably 80wt%-85wt%; and more preferably 83wt%.

[0024] In some embodiments of the present application, the excipient is present in an amount of 20wt%-50wt%; preferably 35wt%.

[0025] In some embodiments of the present application, the filler is present in an amount of 20wt%-50wt%; preferably 35wt%.

[0026] In some embodiments of the present application, the disintegrant is present in an amount of 6wt%-10wt%; preferably 8wt%.

[0027] In some embodiments of the present application, the binder is present in an amount of 1wt%-5wt%; preferably 3wt%.

[0028] In some embodiments of the present application, the surfactant is present in an amount of 0.5wt%-2wt%; preferably 1wt%.

[0029] In some embodiments of the present application, the lubricant is present in an amount of 0.5wt%-2wt%; preferably 1wt%.

[0030] In the present application, wt% refers to weight percent.

[0031] In some embodiments of the present application, the components of the composition are as follows:

[0032] Scheme 1: a compound of formula (I); preferably the compound of formula (I) is present in an amount as described in any of the embodiments of the present application.

[0033] Scheme 2: a compound of formula (I), a pharmaceutically acceptable carrier and / or excipient; preferably a compound of formula (I), a filler, a disintegrant, a binder, a surfactant and a lubricant; and more preferably a compound of formula (I), lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate and sodium stearyl fumarate; preferably the compound of formula (I) is present in an amount as described in any of the embodiments of the present application; preferably the components of the composition are 17wt% of a compound of formula (I), 35wt% of lactose, 35wt% of microcrystalline cellulose, 8wt% of croscarmellose sodium, 3wt% of hypromellose, 1wt% of sodium lauryl sulfate and 1wt% of sodium stearyl fumarate.

[0034] In some embodiments of the present application, the pharmaceutical dosage unit composition is administered once a day, twice a day or three times a day, independently; preferably twice a day.

[0035] In an aspect of the present application, the administration cycle of the pharmaceutical dosage unit composition is adjusted according to clinical needs, independently preferably 12 weeks to 96 weeks, more preferably 12 weeks, 24 weeks or 48 weeks; further preferably 24 weeks.

[0036] The present application provides a pharmaceutical composition comprising a first component and a second component, the first component comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, the second component comprising a nucleotide reverse transcriptase inhibitor;

[0037] In an aspect of the present application, the nucleotide reverse transcriptase inhibitor is one or more of the conventional nucleotide reverse transcriptase inhibitors in the art: for example adefovir dipivoxil, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, telbivudine, emtricitabine or preladenant mesylate; preferably entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide.

[0038] In an aspect of the present application, the first component further comprises a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any aspect of the present application.

[0039] In an aspect of the present application, the first component is any one of the following aspects:

[0040] Aspect 1: a compound of formula (I);

[0041] Aspect 2: a compound of formula (I), a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any aspect of the present application; preferably a compound of formula (I), the filler, the disintegrant, the binder, the surfactant and the lubricant; more preferably a compound of formula (I), lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate and sodium stearyl fumarate; further preferably 17wt% of a compound of formula (I), 35wt% of lactose, 35wt% of microcrystalline cellulose, 8wt% of croscarmellose sodium, 3% of hypromellose, 1wt% of sodium lauryl sulfate and 1wt% of sodium stearyl fumarate.

[0042] In an aspect of the present application, the second component further comprises a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any aspect of the present application.

[0043] In some embodiments of the present application, the pharmaceutical composition is a first component and a second component; wherein the first component is the compound of formula (I); and the second component is adefovir, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, telbivudine, emtricitabine or preveir.

[0044] In some embodiments of the present application, the pharmaceutical composition is a first component and a second component; wherein the first component is the compound of formula (I), a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any embodiments of the present application; and the second component is adefovir, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, telbivudine, emtricitabine or preveir; preferably entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide.

[0045] In some embodiments of the present application, the first component is administered independently at a dosage of 10-200 mg; preferably 20-100 mg; more preferably 50-100 mg.

[0046] In some embodiments of the present application, the first component is administered independently at a dosage of 10 mg or 20 mg or 25 mg or 50 mg or 100 mg or 200 mg; preferably 50 mg or 100 mg.

[0047] In some embodiments of the present application, when the first component further comprises a pharmaceutically acceptable carrier and / or excipient, the dosage refers to the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments of the present application, the first component and the second component are in the form of active ingredients.

[0049] In some embodiments of the present application, the first component and the second component have a synergistic effect.

[0050] In some embodiments of the present application, the first component and the second component can be independently used in a conventional dosage form in the art, preferably independently used in a dosage form for gastrointestinal administration or a dosage form for non-gastrointestinal administration, more preferably independently used in a dosage form for gastrointestinal administration. The dosage form for gastrointestinal administration can be, for example, a liquid, a tablet and a capsule; the capsule can be a gel capsule.

[0051] In some embodiments of the present application, the first component and the second component are administered independently by oral administration or injection (for example, subcutaneous, intradermal, intravenous, intraperitoneal or intramuscular administration), preferably by oral administration.

[0052] The dosing of the first component and the second component is not particularly limited and can be selected according to the routine in the art.

[0053] In an embodiment of the present application, the frequency of administration of the first component and the second component is adjusted according to the clinical needs, and is independently preferably once a day, twice a day or three times a day; preferably twice a day.

[0054] In an embodiment of the present application, the administration cycle of the first component and the second component is adjusted according to the clinical needs, and is independently preferably 12 weeks to 96 weeks, and is more preferably 12 weeks, 24 weeks or 48 weeks; further preferably 24 weeks.

[0055] The present application also provides a method for treating hepatitis B, which comprises administering to a subject (e.g. a patient or an animal) in need thereof a therapeutically effective amount of a pharmaceutical dosage unit composition or a pharmaceutical composition as described herein.

[0056] In the present application, the animal is a mouse.

[0057] In the present application, the patient is a human.

[0058] In an embodiment of the present application, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical dosage unit composition as described herein and / or a combination thereof with a nucleotide reverse transcriptase inhibitor.

[0059] In another aspect, the present application provides a method for treating hepatitis B, which comprises orally administering to a patient in need thereof a pharmaceutical dosage unit composition as described above.

[0060] In the above method, the patient is a patient infected with hepatitis B virus, who has received or has not received anti-hepatitis B drug treatment.

[0061] Further, the method for treating hepatitis B comprises simultaneously orally administering to a patient in need thereof a nucleotide reverse transcriptase inhibitor;

[0062] In the above method, the nucleotide reverse transcriptase inhibitor is selected from oral dosage forms of adefovir dipivoxil, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, telbivudine, emtricitabine or preveir fumarate; preferably selected from oral dosage forms of adefovir dipivoxil, lamivudine, entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide; more preferably entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide; further, the nucleotide reverse transcriptase inhibitor is administered at its commonly used therapeutic dose.

[0063] The preferred administration frequency of the pharmaceutical dosage unit composition for oral administration of the present application is once daily or twice daily or thrice daily. The administration period can be 12 weeks to 96 weeks, preferably 12 weeks, 24 weeks, 48 weeks.

[0064] Again, the present application also provides the use of the pharmaceutical dosage unit composition and the pharmaceutical composition as described in any of the aspects of the present application in the preparation of a medicament for the prevention and / or treatment of hepatitis B.

[0065] The present application provides the use of the pharmaceutical dosage unit composition described above and / or the combination thereof with a nucleotide reverse transcriptase inhibitor in the preparation of a medicament for the treatment of hepatitis B.

[0066] In some aspects of the present application, the use comprises orally administering to a patient in need thereof the pharmaceutical dosage unit composition as described in any of the aspects of the present application.

[0067] In some aspects of the present application, the use comprises orally administering to a patient in need thereof a nucleotide reverse transcriptase inhibitor simultaneously.

[0068] In some aspects of the present application, the nucleotide reverse transcriptase inhibitor is adefovir, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, telbivudine, emtricitabine or preveir.

[0069] The hepatitis B of the present application includes hepatitis B with low viral load or hepatitis B with low viral load state.

[0070] In some aspects of the present application, the pharmaceutical dosage unit composition comprises the compound of formula (I) and a pharmaceutically acceptable carrier and / or excipient.

[0071] The components in the combination of the present application can be formulated into pharmaceutical compositions separately or formulated into pharmaceutical compositions together.

[0072] In some aspects, the combination of the present application can be formulated into pharmaceutical compositions suitable for single or multiple administration.

[0073] The components in the combination of the present application can be administered separately or administered together, and can have the same or different administration period.

[0074] In the above-mentioned uses and treatment methods:

[0075] In some aspects of the present application, the pharmaceutical dosage unit composition and the pharmaceutical composition have an inhibitory effect on hepatitis B; the inhibitory rate of hepatitis B can be 78-90%; preferably 84.0% or 81.5%.

[0076] The present application also provides a use of the first component as described in any of the embodiments of the present application in the preparation of a medicament for use in combination with the second component as described in any of the embodiments of the present application for the prevention and / or treatment of hepatitis B.

[0077] The present application also provides a use of the second component as described in any of the embodiments of the present application in the preparation of a medicament for use in combination with the first component as described in any of the embodiments of the present application for the prevention and / or treatment of hepatitis B.

[0078] The present application also provides a combination kit comprising:

[0079] a first container comprising the first component as described in any of the embodiments of the present application; and,

[0080] a second container comprising the second component as described in any of the embodiments of the present application.

[0081] In the use and the combination kit of the present application, the hepatitis B can be low-viremic hepatitis B or a low-viremic state of hepatitis B.

[0082] The present application also provides a method for preparing a tablet, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a tablet by wet granulation in the presence of a pharmaceutically acceptable carrier and / or excipient, which is as described in any of the embodiments of the present application.

[0083] In an embodiment of the present application, the method for preparing a tablet comprises the following steps: preparation of a granulation liquid, mixing granulation, drying, granulation, total mixing and tabletting.

[0084] In an embodiment of the present application, when the pharmaceutical dosage unit composition and the pharmaceutical composition further comprise a pharmaceutically acceptable carrier and / or excipient, the tablet is a pharmaceutical dosage unit composition as described in any of the embodiments of the present application or a pharmaceutical composition as described in any of the embodiments of the present application.

[0085] Technical effects

[0086] The composition of the compound of formula (I) has a rapid effect in vivo, and achieves the maximum inhibitory effect on HBV DNA after 2 weeks of treatment, and the effect is stable without obvious fluctuation in the later period, and the pgRNA is significantly reduced. The pgRNA is directly transcribed from HBV cccDNA, and the composition of the compound of formula (I) of the present application has obvious effects of inhibiting HBV replication and potentially depleting cccDNA.

[0087] After 24 weeks of treatment with the combination of the compound of formula (I) and nucleos(t)ide reverse transcriptase inhibitors, the proportion of patients with HBV DNA below the detection limit in the 50 mg dose group and the 100 mg dose group reached 84.0% and 81.5%, respectively, which was much higher than the inhibition rate of the nucleos(t)ide analog monotherapy group (32.1%). This indicates that the combination, the dosage, the mode of administration and the cycle have obvious therapeutic effects. At the same time, the method is safe, and no obvious adverse events have occurred in a long administration cycle.

[0088] Definitions and Descriptions

[0089] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but should be interpreted according to the ordinary meaning.

[0090] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients or agents of the present application with a pharmaceutically acceptable excipient that is useful in preparing the compositions given to a subject. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or agents thereof to a subject.

[0091] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that does not interfere with the effectiveness of the active substance and is not toxic to the host or patient in which it is administered.

[0092] The term "excipient" generally refers to a carrier, diluent, and / or vehicle with which an active ingredient is formulated to facilitate administration of the pharmaceutical composition.

[0093] The words "comprise" or "comprising" and other variants such as "comprises" or "comprising", are to be construed in an open, non-exclusive sense, i.e., in the sense of "including, but not limited to".

[0094] The term "treatment" means the administration of a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0095] (i) preventing the disease or condition from occurring in a subject, particularly when such subject is predisposed to the disease but has not yet been diagnosed as having it;

[0096] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0097] (iii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0098] As used herein, "in combination" or "in combination with" means that two or more active substances can be administered to a subject each as a single formulation, simultaneously, or each as a single formulation in any order sequentially.

[0099] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

[0100] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. BRIEF DESCRIPTION OF DRAWINGS

[0101] Figure 1 is the percentage of subjects with serum HBV DNA below the lower limit of quantification (HBV DNA <20 IU / mL) at the end of treatment in Example 6.

[0102] Figure 2 is the percentage of subjects with serum HBV pgRNA below the lower limit of quantification (100 copies / ml) at the end of treatment in Example 6. DETAILED DESCRIPTION

[0103] The present application is described in detail below by way of Examples, but it is not meant to be limited by any of the Examples. The present application has been described in detail by specific embodiments, and the specific embodiments disclosed herein, to those skilled in the art, various changes and modifications to the specific embodiments of the present application will be apparent without departing from the spirit and scope of the present application.

[0104] Example 1 General method for preparing tablets of the compound of formula (I)

[0105] The compound of formula (I) is mixed with the auxiliary filler in the proportion by weight, granulated, and granulated, dried, and lubricant is added to the hopper of the tablet press, and the tablets are pressed by the conventional method, and if necessary, film-coated, to prepare tablets containing the compound of formula (I) in each amount of 10 mg, 25 mg, 50 mg, 100 mg. Among them, the compound of formula (I) can be prepared by referring to the prior art WO2020 / 038456A1.

[0106] Example 2 Formulation specification and process for preparing tablets of the compound of formula (I) 100 mg

[0107] Formulation composition

[0108] Preparation method:

[0109] ① Preparation of granulation liquid

[0110] The prescription amount of sodium lauryl sulfate is added to purified water, and stirred until completely dissolved to prepare a granulation liquid.

[0111] ②Mixing granulation

[0112] The raw material drug, microcrystalline cellulose, lactose, croscarmellose sodium (internal), and hydroxypropyl methyl cellulose are mixed in a high-shear wet granulator. The granulation liquid is then added to perform wet granulation.

[0113] The wet granules are transferred out of the mixing granulator.

[0114] ③Drying

[0115] The wet granules are transferred into an oven for drying, with the drying temperature set to 60°C.

[0116] ④Granulation

[0117] The dried granules are sieved and granulated.

[0118] ⑤Total mixing

[0119] The amounts of croscarmellose sodium (external) and sodium stearyl fumarate are adjusted according to the weight of the granulated particles. The dry granules and croscarmellose sodium (external) are first mixed, and then sodium stearyl fumarate is added and mixed evenly.

[0120] ⑥Tabletting

[0121] Tablet formulation of the compound of formula (I) 25 mg

[0122] Formulation composition:

[0123] Preparation method: same as Example 2 above.

[0124] Tablet formulation of the compound of formula (I) 50 mg

[0125] Formulation composition:

[0126] Preparation method: same as Example 2 above.

[0127] Preparation of a placebo

[0128] The placebo is consistent with the components and preparation method of the 25 mg tablet of the compound of formula (I) in Example 3, except that it does not contain the active ingredient compound of formula (I) and hydroxypropyl methyl cellulose and sodium stearyl fumarate.

[0129] The corresponding placebo for 50 mg and 100 mg in this application is prepared by scaling up the above method by the same proportion.

[0130] Example 6 Trial of the composition of the compound of formula (I) in the treatment of low viral load chronic hepatitis B (CHB) treated with hepatitis B antiviral drugs

[0131] 6.1 Experimental process

[0132] The effectiveness and safety of different doses of the composition of the compound of formula (I) in the treatment of low viral load (LLV) CHB patients were evaluated. The patients were 18-70 years old, had been taking nucleoside analogues (entecavir [ETV], tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide fumarate [TAF]) for 1-3 years and were still receiving treatment; a total of 90 subjects were enrolled in the trial, with 30 subjects in each of the high-dose group, the low-dose group and the placebo group. The high-dose group was administered 100 mg of the compound of formula (I) tablets twice a day orally, and the low-dose group was administered 50 mg of the compound of formula (I) tablets twice a day orally. The administration period was 24 weeks.

[0133] During the treatment period, the patients continued to take the original nucleoside analogue drugs taken before enrollment. The patients were stratified at the time of enrollment, and the distribution of patients taking the three nucleosides was as evenly distributed as possible among the groups: there were 10, 12 and 13 subjects in the low-dose group, the high-dose group and the placebo group, respectively, who were treated with entecavir [ETV] for chronic hepatitis B. There were 11, 9 and 7 subjects in the low-dose group, the high-dose group and the placebo group, respectively, who were treated with tenofovir disoproxil fumarate [TDF]. There were 8, 9 and 10 subjects in the low-dose group, the high-dose group and the placebo group, respectively, who were treated with tenofovir alafenamide fumarate [TAF]. The dosage and frequency of administration were in accordance with the requirements of the nucleoside drug instructions. During this period, one subject in the low-dose group did not receive treatment, and 29 subjects were included in the statistical analysis.

[0134] After the end of administration, the percentage of subjects with serum HBV DNA (hepatitis B virus deoxyribonucleic acid) below the lower limit of the quantitative detection value (HBV DNA < 20 IU / mL) was investigated; the percentage of subjects with serum HBV pgRNA (hepatitis B virus pregenomic RNA) below the lower limit of the quantitative detection value after the end of administration was investigated, as well as multiple other indicators; and AEs (adverse events), SAEs (serious adverse events), vital signs, physical examinations, lead electrocardiograms, laboratory test indicators, etc. were investigated.

[0135] 6.2 Experimental results

[0136] The percentage of subjects with serum HBV DNA below the lower limit of the quantitative detection value (HBV DNA < 20 IU / mL) at the end of administration was compared between groups for subjects using ETV, TDF or TAF as background treatment, and the P values were all greater than 0.05, indicating that the difference was not statistically significant.

[0137] In terms of effectiveness, the proportion of patients with HBV DNA below the detection limit in the 50 mg and 100 mg dose groups of the compound of formula (I) reached 84.0% and 81.5% respectively after 24 weeks of combined nucleos(t)ide analogue therapy, far exceeding the inhibition rate of the nucleos(t)ide analogue monotherapy control group (32.1%) (see Figure 1).

[0138] The compound of formula (I) composition has a rapid onset of action after administration and treatment, with a maximum inhibitory effect on HBV DNA (about 1 log10IU / ml) after 2 weeks of treatment, and stable efficacy without significant fluctuations at a later stage. The pgRNA reduction amplitude in the compound of formula (I) administration group also reached 1.5 log10IU / ml, and more than 50% of patients had pgRNA turned negative (9.5% in the placebo group) (see Figure 2). pgRNA is directly transcribed from HBV cccDNA and can indirectly reflect the transcriptional activity of cccDNA, and this result further verifies the effect of the compound of formula (I) composition on inhibiting HBV replication and potentially depleting cccDNA.

[0139] In terms of safety, no drug-related serious adverse events occurred in any of the groups, and no new safety signals were observed, indicating good overall safety.

[0140] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application, and are not limiting; the technical solutions described in the above examples can still be modified, or some or all of the technical features can be replaced by equivalents; and these modifications or replacements do not cause the essence of the corresponding technical solution to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

A pharmaceutical dosage unit composition characterized in that, The composition comprises 10 to 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof: The pharmaceutical dosage unit composition of claim 1 wherein, which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical dosage unit composition of claim 2 wherein which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: The pharmaceutical dosage unit composition of claim 2, wherein (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; The pharmaceutical dosage unit composition of claim 2, wherein (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. A pharmaceutical composition, characterized in that, which comprises a first component comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second component comprising a nucleos(t)ide reverse transcriptase inhibitor; The pharmaceutical composition of claim 6, wherein which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition of claim 7, wherein which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. which satisfies one or more of the following conditions: (1) the composition comprises 10-200 mg of the compound of formula (I); the unit dosage form is suitable for oral administration; (2) the unit dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule and a gel capsule; (3) the composition further comprises a pharmaceutically acceptable carrier and / or excipient. Scheme 2: the pharmaceutical composition is a first component and a second component; wherein the first component is a compound of formula (I), a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any one of claims 2-4; the second component is adefovir dipivoxil, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, telbivudine, emtricitabine or preveir. The pharmaceutical composition of claim 6, wherein It meets one or more of the following conditions: (1) the pharmaceutical composition is any of the following schemes: Scheme 1: the pharmaceutical composition is a first component and a second component; wherein the first component is a compound of formula (I); the second component is adefovir dipivoxil, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, telbivudine, emtricitabine or preveir; Scheme 2: the pharmaceutical composition is a first component and a second component; wherein the first component is a compound of formula (I), a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any one of claims 2-4; the second component is adefovir dipivoxil, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, telbivudine, emtricitabine or preveir; (2) the administration dose of the first component is independently 10-200 mg; (3) the first component and the second component are independently in the form of active ingredients; (4) the first component and the second component have a synergistic effect; (5) the first component and the second component are independently used in the form of a parenteral administration dosage form or a non-parenteral administration dosage form; (6) the administration mode of the first component and the second component is independently oral administration or injection administration; (7) the administration frequency of the first component and the second component is once a day, twice a day or three times a day; (8) the administration period of the first component and the second component is independently 12 weeks-96 weeks. The pharmaceutical composition of claim 9, wherein It meets one or more of the following conditions: (1) the pharmaceutical composition is any of the following schemes: Scheme 1: the pharmaceutical composition is a first component and a second component; wherein the first component is a compound of formula (I); the second component is entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide fumarate; Scheme 2: the pharmaceutical composition is a first component and a second component; wherein the first component is a compound of formula (I), a pharmaceutically acceptable carrier and / or excipient; the pharmaceutically acceptable carrier and / or excipient is as described in any one of claims 2-4; the second component is entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide fumarate; (2) the administration dose of the first component is independently 20-100 mg; preferably 50 mg-100 mg; preferably, the administration dose of the first component is independently 10 mg or 20 mg or 25 mg or 50 mg or 100 mg or 200 mg; (3) the first component and the second component are independently in the form of a parenteral administration dosage form; the parenteral administration dosage form is preferably a liquid, a tablet and a capsule; the capsule can be a gel capsule; (4) the administration mode of the first component and the second component is independently oral administration; (5) the administration cycle of the first component and the second component is independently 12 weeks, 24 weeks or 48 weeks. Use of a pharmaceutical dosage unit composition according to any one of claims 1-5 or a pharmaceutical composition according to any one of claims 6-10 in the manufacture of a medicament for the prevention and / or treatment of hepatitis B. The use as claimed in claim 11, characterized in that Use of a composition according to any one of claims 1-5 and / or a combination thereof with a nucleotide reverse transcriptase inhibitor in the manufacture of a medicament for the treatment of hepatitis B; Preferably, the use satisfies one or both of the following conditions: (1) the use comprises oral administration of a composition according to any one of claims 1-5 to a patient in need thereof; (2) the subject of the medicament is a patient or an animal; the patient is a patient infected with hepatitis B virus, who has received or has not received anti-hepatitis B drug treatment; (3) the use comprises simultaneous oral administration of a nucleotide reverse transcriptase inhibitor to a patient in need thereof; (4) the nucleotide reverse transcriptase inhibitor is adefovir, lamivudine, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, telbivudine, emtricitabine or predfonfvir pmpofosyl; preferably entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide; (5) the hepatitis B comprises hepatitis B with low viral load or hepatitis B with low viral load status; (6) the pharmaceutical dosage unit composition according to any one of claims 1-5 is administered orally once daily or twice daily or thrice daily; (7) the administration cycle of the pharmaceutical dosage unit composition according to any one of claims 1-5 is 12 weeks-96 weeks, preferably 12 weeks, 24 weeks, 48 weeks. Use of a first component according to any one of claims 6-10 in the manufacture of a medicament for use in combination with a second component according to any one of claims 6-10 for the prevention and / or treatment of hepatitis B. Use of a second component according to any one of claims 6-10 in the manufacture of a medicament for use in combination with a first component according to any one of claims 6-10 for the prevention and / or treatment of hepatitis B. A combination kit characterized in that, It comprises: a first container comprising a first component according to any one of claims 6-10; and, a second container comprising a second component according to any one of claims 6-10.

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