Tlr7 / 8 agonist injection as well as preparation method therefor and use thereof

Abstract

An injection, the injection comprising a compound shown as formula (I) or a pharmaceutically acceptable salt thereof; and a preparation method for the injection. The injection involves a simple preparation process, has stable quality, is convenient for clinical administration, and satisfies requirements for subsequent clinical tests.

Description

A TLR7 / 8 agonist injection, its preparation method and use Technical Field

[0001] The present invention relates to an injection of a TLR7 / 8 agonist compound of formula (I), a preparation method and use thereof, and relates to the research and development of an injection of a free drug of the TLR7 / 8 agonist compound of formula (I) or its hydrochloride formula (II) disclosed in WO 2023 / 104165, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Toll-like receptors (TLRs) are a class of structurally conserved proteins that form the first line of defense in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can identify invasive microorganisms and endogenous molecules released after tissue damage or non-physiological cell death, and activate signaling cascades, leading to the production of pro-inflammatory cytokines. The inflammatory process is crucial to the occurrence and progression of many diseases, such as type 1 diabetes, sepsis, cancer, and viral infections. Therefore, the strategy of manipulating the inflammatory response through small molecule TLRs modulators to treat related diseases is very promising.

[0003] The human TLRs family has 10 known members, which are type I transmembrane proteins characterized by a leucine-rich extracellular domain and a cytoplasmic tail containing the conserved Toll / interleukin (IL)-1 receptor (TIR) ​​domain. In this family, TLR3, TLR7, TLR8, and TLR9 are localized in the endosomal compartment.

[0004] Both TLR7 and TLR8 recognize RNA molecules (ssRNA) from single-stranded RNA viruses. TLR7 is primarily expressed in plasmacytoid dendritic cells and B cells. TLR8 is primarily distributed in mDCs, macrophages, and monocytes, and is also expressed in T cells. TLR7 stimulation primarily induces the production of type I interferons, including interferon-α (IFN-α), and causes the transcription of interferon-stimulated genes (ISGs). Interferon-α is one of the main drugs for the treatment of chronic hepatitis B or C. TLR8 is primarily distributed in mDCs, macrophages, and monocytes, and is also expressed in T cells. TLR8 activation primarily produces a pro-inflammatory response, stimulating immune cells to secrete pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and IL-6. The distribution and downstream signaling pathways of TLR7 / 8 overlap, and therefore they share functional similarities. Upon activation, TLR7 / 8 can exert direct antiviral activity through the type I interferon response. It can also regulate innate immunity through pro-inflammatory responses, promoting the activation of NK and NKT cells. It can also induce adaptive immunity, improve antigen presentation, and activate dendritic cells, thereby enhancing T cell responses and promoting the differentiation of antibody-producing B cells. The development of TLR7 / 8 agonists has significant clinical value in both antiviral and anti-tumor therapies, and can also be used in antibody-drug conjugates and vaccine adjuvants.

[0005] WO 2023 / 104165 provides a TLR7 / 8 agonist free drug formula (I), the chemical name of the free drug formula (I) is (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)benzyl)pyrido[4,3-d]pyrimidin-5(6H)-one, and the molecular formula is C 26 H 37 N7O3, molecular weight is 495.63; the chemical name of hydrochloride (II) is (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)benzyl)pyrido[4,3-d]pyrimidin-5(6H)-one dihydrochloride, molecular formula is C 26 H 39 Cl2N7O3, molecular weight is 568.54. Its chemical structure is as follows:

[0006] The compound of formula (I) is a TLR7 / 8 agonist. In order to conduct subsequent clinical trials, it is necessary to prepare a suitable dosage form for human administration. TLR7 / 8 agonists are used as drugs. Currently, the commonly used dosage forms in clinical and preclinical studies are injections and solid oral preparations. The compound is preferably an injection.

[0007] Therefore, in order to meet the requirements of subsequent long-term clinical trials and facilitate clinical administration, it is now necessary to develop an injection of the compound of formula (I) with a simple preparation process, stable quality and good patient compliance.

[0008] Summary of the Invention

[0009] The purpose of the present invention is to provide an injection of a compound of formula (I) with simple preparation process, stable quality and good patient compliance.

[0010] The first aspect of the present invention provides an injection.

[0011] Characterized in that, the injection comprises:

[0012] (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0013] (2) Metal chelators;

[0014] (3) buffer;

[0015] (4) pH regulator;

[0016] (5) Solvent.

[0017] In another preferred embodiment, the injection consists of the above components (1)-(5).

[0018] In some embodiments, in the injection, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.1-20 mg / mL, preferably 0.5-10 mg / mL, and more preferably 1-5 mg / mL, calculated based on the concentration of the compound of formula (I).

[0019] In another preferred embodiment, the pharmaceutically acceptable salt is the hydrochloride of the compound of formula (I).

[0020] In another preferred embodiment, the pharmaceutically acceptable salt is a compound of formula (II).

[0021] In some embodiments, the metal chelator is selected from the group consisting of edetate disodium, ethylenediaminetetraacetic acid, edetate calcium disodium, diethylenetriaminepentaacetic acid, or a combination thereof.

[0022] In another preferred embodiment, the content of the metal chelator in the preparation is 0.1-10 mg / mL, preferably 0.2-5 mg / mL, and more preferably 0.5-2 mg / mL.

[0023] In some embodiments, the buffer is selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, tartrate buffer, carbonate buffer, or a combination thereof.

[0024] In another preferred embodiment, the content of the buffer in the preparation is 0.1-10 mg / mL, preferably 0.2-5 mg / mL, and more preferably 0.5-2 mg / mL.

[0025] In another preferred embodiment, in the injection, the weight ratio of the buffer (sodium acetate) to the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.2-1.5:1, preferably 0.30-1.34:1.

[0026] In some embodiments, the pH adjuster is selected from the group consisting of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, potassium citrate, sodium acetate, potassium acetate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof.

[0027] In another preferred embodiment, the content of the pH regulator in the preparation is 0.1-10 mg / mL, preferably 0.2-5 mg / mL, and more preferably 0.5-2 mg / mL.

[0028] In another preferred embodiment, the pH value of the injection is 3.0-6.5, preferably 4.0-6.3, and more preferably 4.3-4.7 or 5.8-6.2.

[0029] In some embodiments, the solvent can be water for injection, glycerol, ethanol, propylene glycol, 0.9% NaCl aqueous solution, 5% glucose aqueous solution, or a combination thereof.

[0030] In another preferred embodiment, the filling volume of the injection is 1 ml, 2 ml, 4 ml, 5 ml, 10 ml or 20 ml.

[0031] In some embodiments, in the injection:

[0032] The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II);

[0033] The metal chelating agent is disodium edetate;

[0034] The buffer is acetate buffer;

[0035] The pH regulator is acetic acid or sodium hydroxide;

[0036] The solvent is water for injection; preferably, the filling volume of the injection is 5 ml.

[0037] In a second aspect of the present invention, a method for preparing the injection according to the first aspect of the present invention is provided, characterized in that it comprises the following steps:

[0038] 1) adding the prescribed amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a metal chelating agent, and a pH adjuster to a solvent at 70% to 80% (v / v) of the prescribed amount until completely dissolved; adding an appropriate amount of the pH adjuster to adjust the pH to 3.0 to 6.5;

[0039] 2) Add the remaining amount of solvent to the full amount, mix, and obtain the injection.

[0040] In some embodiments, the method further comprises the steps of:

[0041] 3) filtering the injection through a 0.22 μm filter membrane, filling with nitrogen, and filling;

[0042] 4) Sterilize to obtain the desired injection.

[0043] In another preferred embodiment, in the step 1), the pH of the injection is adjusted to be in the range of 5.0 to 6.0.

[0044] In another preferred embodiment, the filling volume of the injection is 5 ml.

[0045] In another preferred embodiment, the injection is filled with nitrogen in a 10 ml light-proof glass made of medium borosilicate glass.

[0046] In some embodiments, the sterilization method is moist heat sterilization or sterile filtration.

[0047] In another preferred embodiment, the injection uses 0.9% sodium chloride solution as a diluent to dilute the drug.

[0048] In another preferred embodiment, the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof after dilution of the injection is 0.01 mg / ml to 1 mg / ml.

[0049] In another preferred embodiment, the injection is used to treat or prevent diseases such as tumors or infections caused by viruses.

[0050] In another preferred embodiment, the virus is selected from the group consisting of HBV, HCV, HIV, influenza virus, or a combination thereof; and / or the tumor is preferably lung cancer, pancreatic cancer, kidney cancer, head and neck cancer, breast cancer, lymphoma, skin cancer, urothelial carcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer.

[0051] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0052] The present invention provides a stable injection of a compound of formula (I) and a method for preparing the same. The injection has a simple preparation process, stable quality, convenient clinical administration, and meets the requirements of subsequent clinical trials. Based on the above findings, the inventors have completed the present invention.

[0053] An injection comprising a compound of formula (I)

[0054] The injection of the compound of formula (I) provided by the present invention uses the free drug of the compound of formula (I) or the hydrochloride of formula (II) as the raw material.

[0055] The injection of the compound of formula (I) provided by the present invention is prepared into a concentrated solution with a concentration of 1, 2, or 5 mg / ml based on the compound of formula (I).

[0056] The injection of the compound of formula (I) provided by the present invention is a concentrated drug combination injection. The composition needs to be diluted before administration and needs to be diluted or prepared by medical personnel, pharmacists or pharmacies as required when used.

[0057] The concentrated injection of the present invention can be diluted with a solution prepared by using any medically acceptable isotonicity adjusting agent (as a solute) and water for injection (as a solvent).

[0058] Suitable isotonicity adjusting agents include, but are not limited to, anhydrous or aqueous sodium chloride, glucose, sucrose, fructose, glycerol, sorbitol, mannitol, potassium chloride, calcium chloride and other inorganic salts. The preferred osmotic pressure adjusting agent is sodium chloride, prepared as a 0.9% sodium chloride solution.

[0059] The injection of the compound of formula (I) provided by the present invention needs to be added with some harmless substances that do not react with the free drug of the compound of formula (I) or the hydrochloride drug substance of formula (II) for the purpose of stable quality, safety and long-term storage, etc. These substances may include:

[0060] 1) To reduce oxidation of the API during storage, the injection of the compound of formula (I) provided by the present invention is preferably filled with a protective gas, an inert gas that does not react with the API, such as N2 or other inert gases. Preferably, the protective gas is N2.

[0061] 2) In order to avoid the effects of contact with stainless steel containers, dispensing tanks, pipelines, and inner packaging materials (such as vials and stoppers) containing metal ions during scale-up production, the injection of the compound of formula (I) provided by the present invention is preferably prepared by adding a metal chelating agent that does not react with the API, such as disodium edetate, ethylenediaminetetraacetic acid, calcium disodium edetate, diethylenetriaminepentaacetic acid, or other metal chelating agents. Preferably, the metal chelating agent is disodium edetate.

[0062] 3) The injection of the compound of formula (I) provided by the present invention may be supplemented with a suitable buffer to improve patient compliance and reduce pain. The buffer may be acetate buffer, phosphate buffer, citrate buffer, tartrate buffer, or carbonate buffer. Preferably, the buffer is phosphate or acetate buffer.

[0063] The present invention provides an injection of the compound of formula (I), wherein the weight ratio of sodium acetate to the free drug of the compound of formula (I) or the hydrochloride of formula (II) in the injection is 0.30-1.34:1.

[0064] The solvent for the injection of the compound of formula (I) provided by the present invention can be any one of water for injection, glycerol, ethanol, propylene glycol, 0.9% NaCl, and 5% glucose, or a combination thereof. Preferably, the solvent is water for injection.

[0065] In the injection of the compound of formula (I) provided by the present invention, the pH adjuster can be any one of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, potassium citrate, sodium acetate, potassium acetate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, or a combination thereof. Preferably, the pH adjuster is acetic acid or sodium hydroxide.

[0066] In the injection of the compound of formula (I) provided by the present invention, the pH value of the solution adjusted by the pH adjuster is 3 to 6.5, preferably, the pH value is 4.5 to 6.0.

[0067] The injection of the compound of formula (I) provided by the present invention is prepared by the following method:

[0068] 1) Measure 70% to 80% of the total amount of water for injection, add the prescribed amount of the free compound of formula (I) or the hydrochloride of formula (II), sodium edetate, and sodium acetate in sequence, and stir until completely dissolved; add an appropriate amount of acetic acid or sodium hydroxide solution to adjust the pH to 3.0 to 6.5;

[0069] 2) Adding water for injection to the total amount and mixing to obtain 1, 2 and 5 mg / ml solutions of the free drug of the compound of formula (I) or the hydrochloride of formula (II) (calculated as the free drug of the compound of formula (I));

[0070] 3) 0.22μm membrane filtration, nitrogen filling, and filling;

[0071] 4) Sterilize by moist heat at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0072] The injection of the compound of formula (I) provided by the present invention can have a filling volume of 1 ml, 2 ml, 4 ml, 5 ml, 10 ml or 20 ml. Preferably, the filling volume is 5 ml.

[0073] The injection of the compound of formula (I) provided by the present invention is filled in a light-proof medium borosilicate glass material, preferably a 10 ml medium borosilicate glass tube (brown) injection bottle.

[0074] The main advantages of the injection of the present invention include:

[0075] 1. The injection of the present invention has stable quality and is not easily deteriorated during storage;

[0076] 2. The injection preparation of the present invention has a simple process and is convenient for clinical administration.

[0077] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0078] The free drug of the compound of formula (I) of the present invention or the hydrochloride of formula (II) is a raw material (the content of the compound of formula (I) is 84.1%).

[0079] The following are the specific test and example parts of the present invention

[0080] Example 1

[0081] prescription

[0082] Preparation process

[0083] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), and stir to dissolve it completely; add an appropriate amount of sodium hydroxide solution to adjust the pH to 4.4; replenish the water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; and sterilize by wet heat at 121°C for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0084] Example 2

[0085] prescription

[0086] Preparation process

[0087] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), and stir to dissolve it completely; add an appropriate amount of sodium hydroxide solution to adjust the pH to 4.3-4.7; then add water for injection to the full amount, mix, filter twice with a 0.22 μm filter membrane, fill with nitrogen, and fill to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0088] Table 1 Properties and related substances of injections prepared by two different sterilization methods

[0089] As shown in Table 1, moist heat sterilization at 121°C for 15 minutes did not significantly increase the levels of either single or total related substances in the injection of the compound of formula (I) compared to sterile filtration. Both sterilization methods were acceptable, and based on the guidelines for sterilization of injections, moist heat sterilization at 121°C was selected for subsequent case studies.

[0090] Example 3

[0091] prescription

[0092] Preparation process

[0093] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), and stir to dissolve it completely; then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; then sterilize with wet heat at 121°C for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0094] Example 4

[0095] prescription

[0096] Preparation process

[0097] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II) and sodium chloride, and stir to dissolve them completely; then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; then sterilize with wet heat at 121°C for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0098] Table 2 Properties and related substances of injections prepared with two different solvents

[0099] As can be seen from Table 2, when using water for injection as the solvent or 0.9% sodium chloride as the solvent, there was no significant increase in the level of related substances or total impurities. Both solvents were acceptable, and water for injection was selected as the solvent for subsequent case studies.

[0100] Example 5

[0101] prescription

[0102] Preparation process

[0103] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), and stir to dissolve it completely; then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill into a colorless, transparent medium borosilicate glass tube bottle; then sterilize with wet heat at 121°C for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0104] Example 6

[0105] prescription

[0106] Preparation process

[0107] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), and stir to dissolve it completely; then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill into a brown medium borosilicate glass tube bottle; then sterilize with wet heat at 121°C for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0108] Table 3 Properties and related substances of two different borosilicate glass tube injection bottles after 10 days of light exposure

[0109] As shown in Table 3, the injection of the compound of formula (I) is unstable under light. When filled in colorless, transparent medium-borosilicate glass vials, impurities increased significantly after 10 days of light exposure. However, when filled in brown medium-borosilicate glass vials, impurities did not increase significantly after 10 days of light exposure. The medium-borosilicate glass vials were selected for subsequent case studies.

[0110] Example 7

[0111] prescription

[0112] Preparation process

[0113] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), disodium edetate, anhydrous disodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate, and stir to dissolve them completely; check the pH range is 5.8-6.2, otherwise use sodium hydroxide or phosphoric acid to adjust the pH to 5.8-6.2, then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; then sterilize by wet heat at 121° C. for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0114] Example 8

[0115] prescription

[0116] Preparation process

[0117] Measure 75% of the total amount of water for injection, add the prescribed amount of the hydrochloride of the compound of formula (I) and formula (II), disodium edetate, and sodium citrate dihydrate, and stir to dissolve them completely; add an appropriate amount of citric acid solution to adjust the pH to 5.8-6.2; add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; and sterilize by wet heat at 121° C. for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0118] Example 9

[0119] prescription

[0120] Preparation process

[0121] Measure 75% of the total amount of water for injection, add the prescribed amount of the hydrochloride of the compound of formula (I) and formula (II), disodium edetate, and anhydrous sodium acetate, and stir to dissolve them completely; add an appropriate amount of sodium hydroxide solution to adjust the pH to 5.8-6.2; add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; and sterilize with wet heat at 121°C for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0122] Table 4 Properties, related substances, buffering capacity and light stability of injections prepared with three different buffers

[0123] As can be seen from Table 4, the injections of the compound of formula (I) prepared using phosphate buffer (Example 7), acetate buffer (Example 9), and citrate buffer (Example 8) respectively all have good buffering capacity, and the growth of impurities in the related substances phosphate and acetate buffers under light conditions is relatively small.

[0124] Example 10

[0125] prescription

[0126] Preparation process

[0127] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), disodium edetate, anhydrous disodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate, and stir to dissolve them completely; measure the pH range of 4.8 to 5.2; otherwise, use sodium hydroxide or phosphoric acid to adjust the pH to 4.8 to 5.2, then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; and sterilize by wet heat at 121° C. for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0128] Table 5 Properties and buffering capacity of injections prepared with phosphate buffer at different pH values

[0129] As can be seen from Table 5, the injection of the compound of formula (I) prepared with phosphate buffer has good stability and buffering capacity at a pH value of 5.0-6.0. The pH value of the phosphate buffer can be selected to be 5.0-6.0.

[0130] Example 11

[0131] prescription

[0132] Preparation process

[0133] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride, formula (II), disodium edetate, and anhydrous sodium acetate, and stir to dissolve them completely; add an appropriate amount of acetic acid solution to adjust the pH to 4.8-5.2; then add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; and sterilize by wet heat at 121° C. for 15 minutes to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0134] Table 6 Properties, related substances, buffering capacity and results of injections prepared with acetate buffer at different pH values

[0135] As can be seen from Table 6, the injection of the compound of formula (I) prepared with acetate buffer has good stability and buffering capacity at a pH value of 5.0-6.0. The pH value of acetate buffer can be selected to be 5.0-6.0.

[0136] Table 7 Example 7 Phosphate buffer stability test results

[0137] As can be seen from Table 7, the injection of the compound of formula (I) prepared in phosphate buffer has good stability at high temperature of 60°C and high temperature + high humidity (40°C + 75% RH) for 10 days.

[0138] Table 8 Example 11 Acetate buffer stability test results

[0139] As can be seen from Table 8, the injection of the compound of formula (I) prepared with acetate buffer has good stability at high temperature of 60°C and high temperature + high humidity (40°C + 75% RH) for 10 days.

[0140] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. An injection, It is characterized in that The injection comprises: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) Metal chelators; (3) Buffer; (4) pH adjuster; (5) Solvent. In another preferred embodiment, the injection consists of the above components (1)-(5).

2. The injection according to claim 1, characterized in that In the injection, the content of the compound of formula (I) or its pharmaceutically acceptable salt is 0.1-20 mg / mL, preferably 0.5-10 mg / mL, more preferably 1-5 mg / mL, calculated based on the concentration of the compound of formula (I). In another preferred embodiment, the pharmaceutically acceptable salt is the hydrochloride of the compound of formula (I). In another preferred embodiment, the pharmaceutically acceptable salt is a compound of formula (II).

3. The injection according to claim 1 or 2, characterized in that: The metal chelator is selected from the following group: disodium edetate, ethylenediaminetetraacetic acid, calcium disodium edetate, diethylenetriaminepentaacetic acid, or a combination thereof. In another preferred embodiment, the content of the metal chelator in the preparation is 0.1-10 mg / mL, preferably 0.2-5 mg / mL, and more preferably 0.5-2 mg / mL.

4. The injection according to claim 1 or 2, characterized in that: The buffer is selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, tartrate buffer, carbonate buffer, or a combination thereof. In another preferred embodiment, the content of the buffer in the preparation is 0.1-10 mg / mL, preferably 0.2-5 mg / mL, and more preferably 0.5-2 mg / mL. In another preferred embodiment, in the injection, the weight ratio of the buffer (sodium acetate) to the compound of formula (I) or its pharmaceutically acceptable salt is 0.2-1.5:1, preferably 0.30-1.34:

1.

5. The injection according to claim 1 or 2, characterized in that: The pH adjuster is selected from the following group: hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, potassium citrate, sodium acetate, potassium acetate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof. In another preferred embodiment, the content of the pH regulator in the preparation is 0.1-10 mg / mL, preferably 0.2-5 mg / mL, and more preferably 0.5-2 mg / mL. In another preferred embodiment, the pH value of the injection is 3.0-6.5, preferably 4.0-6.3, and more preferably 4.3-4.7 or 5.8-6.

2.

6. The injection according to claim 1 or 2, characterized in that: The solvent can be water for injection, glycerol, ethanol, propylene glycol, 0.9% NaCl aqueous solution, 5% glucose aqueous solution, or a combination thereof. In another preferred embodiment, the filling volume of the injection is 1 ml, 2 ml, 4 ml, 5 ml, 10 ml or 20 ml.

7. The injection according to claim 1 or 2, characterized in that: In the injection: The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II); The metal chelating agent is disodium edetate; The buffer is acetate buffer; The pH regulator is acetic acid or sodium hydroxide; The solvent is water for injection; preferably, the filling volume of the injection is 5 ml.

8. The method for preparing the injection according to any one of claims 1 to 7, characterized in that: The following steps are involved: 1) adding the prescribed amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a metal chelating agent, and a pH adjuster to a solvent of 70% to 80% (v / v) of the prescribed amount to dissolve them completely; adding an appropriate amount of the pH adjuster to adjust the pH to 3.0 to 6.5; 2) Add the remaining amount of solvent to the full amount, mix, and obtain the injection.

9. The method according to claim 8, characterized in that The method further comprises the steps of: 3) filtering the injection with a 0.22 μm filter membrane, filling with nitrogen, and filling; 4) Sterilize to obtain the desired injection. In another preferred embodiment, in the step 1), the pH of the injection is adjusted to be in the range of 5.0 to 6.

0. In another preferred embodiment, the filling volume of the injection is 5 ml. In another preferred embodiment, the injection is filled with nitrogen in a 10 ml light-proof glass made of medium borosilicate glass.

10. The method according to claim 9, characterized in that The sterilization method is wet heat sterilization or sterilizing filtration. In another preferred embodiment, the injection uses 0.9% sodium chloride solution as a diluent to dilute the drug. In another preferred embodiment, the concentration of the compound of formula (I) or its pharmaceutically acceptable salt after dilution of the injection is 0.01 mg / ml to 1 mg / ml. In another preferred embodiment, the injection is used to treat or prevent diseases such as tumors or infections caused by viruses. In another preferred embodiment, the virus is selected from the following group: HBV, HCV, HIV, influenza virus, or a combination thereof; and / or the tumor is preferably lung cancer, pancreatic cancer, kidney cancer, head and neck cancer, breast cancer, lymphoma, skin cancer, urothelial carcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer.

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