TLR7 / 8 agonist injection as well as preparation method and application thereof

Abstract

The invention provides an injection which comprises a compound shown as a formula (I) or pharmaceutically acceptable salt of the compound, and a preparation method of the injection. The injection is simple in preparation process, stable in quality and convenient for clinical administration, and meets subsequent clinical test requirements. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a TLR7 / 8 agonist compound of formula (I) injection, 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 barrier in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can recognize 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 development of many diseases, such as type I diabetes, sepsis, cancer, viral infectious diseases, etc. Therefore, the strategy of manipulating the inflammatory response through small molecule TLRs modulators to treat related diseases is promising.

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

[0004] Both TLR7 and TLR8 can recognize RNA molecules (ssRNA) from single-stranded RNA viruses. TLR7 is mainly expressed in plasmacytoid dendritic cells and B cells. TLR8 is mainly distributed in mDC, macrophages and monocytes, and is also expressed in T cells. TLR7 stimulation mainly 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 mainly distributed in mDC, macrophages and monocytes, and is also expressed in T cells. TLR8 activation mainly produces a pro-inflammatory response, stimulating immune cells to secrete pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and IL-6. There is overlap in the distribution and downstream signaling pathways of TLR7 / 8, so there are functional similarities. After TLR7 / 8 is activated, it can exert direct antiviral activity through type I interferon response, and can also regulate innate immunity through pro-inflammatory response to promote the activation of NK and NKT cells, as well as induce adaptive immunity, improve antigen presentation and activate dendritic cells, thereby enhancing T cell response and promoting the differentiation of antibody-producing B cells. The development of TLR7 / 8 agonists has great clinical value in both antiviral and anti-tumor therapy, 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 which is

[0006] (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, the molecular formula is C 26 H 37 N7O3, molecular weight 495.63; hydrochloride (II) chemical name 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 C 26 H 39 Cl2N7O3, molecular weight is 568.54. Its chemical structure is as follows:

[0007]

[0008] 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 solution.

[0009] 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 simple preparation process, stable quality and good patient compliance. Summary of the invention

[0010] 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.

[0011] In a first aspect, the present invention provides an injection.

[0012]

[0013] Characterized in that the injection comprises:

[0014] (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0015] (2) Metal chelators;

[0016] (3) Buffer;

[0017] (4) pH adjuster;

[0018] (5) Solvent.

[0019] In another preferred embodiment, the injection consists of the above components (1)-(5).

[0020] In some embodiments, 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, and more preferably 1-5 mg / mL, calculated as the concentration of the compound of formula (I).

[0021] In another preferred embodiment, the pharmaceutically acceptable salt is the hydrochloride of the compound of formula (I).

[0022] In another preferred embodiment, the pharmaceutically acceptable salt is a compound of formula (II).

[0023] In some embodiments, the metal chelator is selected from the group consisting of disodium edetate, ethylenediaminetetraacetic acid, calcium disodium edetate, diethylenetriaminepentaacetic acid, or a combination thereof.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] In some embodiments, 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] In another preferred embodiment, the filling volume of the injection is 1 ml, 2 ml, 4 ml, 5 ml, 10 ml or 20 ml.

[0033] In some embodiments, in the injection:

[0034] The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II);

[0035] The metal chelating agent is disodium edetate;

[0036] The buffer is acetate buffer;

[0037] The pH regulator is acetic acid or sodium hydroxide;

[0038] The solvent is water for injection; preferably, the filling volume of the injection is 5 ml.

[0039] In the second aspect of the present invention, there is provided a method for preparing the injection according to the first aspect of the present invention, characterized in that it comprises the following steps:

[0040] 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;

[0041] 2) Add the remaining amount of solvent to the full amount, mix, and obtain the injection.

[0042] In some embodiments, the method further comprises the steps of:

[0043] 3) filtering the injection with a 0.22 μm filter membrane, filling with nitrogen, and filling;

[0044] 4) Sterilize to obtain the desired injection.

[0045] In another preferred embodiment, in the step 1), the pH of the injection is adjusted to a range of 5.0 to 6.0.

[0046] In another preferred embodiment, the filling volume of the injection is 5 ml.

[0047] In another preferred embodiment, the injection is filled with nitrogen in a 10 ml light-proof glass made of medium borosilicate glass.

[0048] In some embodiments, the sterilization method is moist heat sterilization or sterile filtration.

[0049] In another preferred embodiment, the injection uses 0.9% sodium chloride solution as a diluent to dilute the drug.

[0050] 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.

[0051] In another preferred embodiment, the injection is used to treat or prevent diseases such as tumors or infections caused by viruses.

[0052] 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.

[0053] 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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0054] The present invention provides a stable injection of a compound of formula (I) and a preparation method thereof, wherein 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.

[0055] An injection comprising a compound of formula (I)

[0056] 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.

[0057] 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).

[0058] The injection of the compound of formula (I) provided by the present invention is a drug combination concentrated injection, which needs to be diluted before administration and needs to be diluted or prepared by medical personnel, pharmacists or pharmacies as required when used.

[0059] The concentrated injection of the present invention can be diluted with a solution prepared by using any medically acceptable isotonicity adjusting agent (as solute) and water for injection (as solvent).

[0060] 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, formulated as a 0.9% sodium chloride solution.

[0061] 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 of formula (II) for the purpose of stable quality, safety and long-term storage, etc. These substances may include:

[0062] 1) The injection of the compound of formula (I) provided by the present invention is filled with a protective gas in order to reduce the oxidation of the raw material during storage time, and an inert gas that does not react with the raw material is filled, such as N2 gas or other inert gases. Preferably, the protective gas is N2.

[0063] 2) The injection of the compound of formula (I) provided by the present invention is selected to add a metal chelating agent that does not react with the raw material drug, such as disodium edetate, ethylenediaminetetraacetic acid, calcium disodium edetate, diethylenetriaminepentaacetic acid or other metal chelating agents, in order to avoid the influence of contact with stainless steel containers, liquid preparation tanks and pipelines, and inner packaging materials (such as vials, rubber stoppers) and other materials containing metal ions during the scale-up production process. Preferably, the metal chelating agent is disodium edetate.

[0064] 3) The injection of the compound of formula (I) provided by the present invention may be added with a suitable buffer in order to improve patient compliance and reduce pain. The buffer may be an acetate buffer, a phosphate buffer, a citrate buffer, a tartrate buffer, or a carbonate buffer. Preferably, the buffer is a phosphate or acetate buffer.

[0065] The injection of the compound of formula (I) provided by the present invention has a weight ratio of sodium acetate to the free drug of the compound of formula (I) or the hydrochloride of formula (II) in the injection of 0.30-1.34:1.

[0066] The solvent of the injection of the compound of formula (I) provided by the present invention can be any one or a combination of water for injection, glycerol, ethanol, propylene glycol, 0.9% NaCl, and 5% glucose. Preferably, the solvent is water for injection.

[0067] In the injection of the compound of formula (I) provided by the present invention, the pH regulator can be any one or a combination 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. Preferably, the pH regulator is acetic acid or sodium hydroxide.

[0068] 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.

[0069] The injection of the compound of formula (I) provided by the present invention is prepared by the following method:

[0070] 1) Take 70% to 80% of the total amount of water for injection, add the prescribed amount of the free drug of the compound of formula (I) or the hydrochloride of formula (II), sodium ethylenediaminetetraacetate, and sodium acetate in sequence, and stir to dissolve them completely; add an appropriate amount of acetic acid or sodium hydroxide solution to adjust the pH to 3.0 to 6.5;

[0071] 2) Adding water for injection to the full amount, mixing, and obtaining 1, 2 and 5 mg / ml solutions of the free drug of the compound of formula (I) or the hydrochloride of the compound of formula (II) (based on the free drug of the compound of formula (I));

[0072] 3) 0.22μm filter membrane, nitrogen filling, and filling;

[0073] 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).

[0074] The injection of the compound of formula (I) provided by the present invention may 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.

[0075] The injection of the compound of formula (I) provided by the present invention is filled in a medium borosilicate glass material that can be shielded from light. Preferably, a 10 ml medium borosilicate glass tube (brown) injection bottle.

[0076] The main advantages of the injection of the present invention include:

[0077] 1. The injection of the present invention has stable quality and is not easy to deteriorate during storage;

[0078] 2. The injection preparation of the present invention has a simple process and is convenient for clinical administration.

[0079] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0080] The free drug of the compound of formula (I) of the present invention or the hydrochloride of formula (II) raw material (the content of the compound of formula (I) is 84.1%).

[0081] The following are the specific test and example parts of the present invention

[0082] Example 1

[0083] prescription

[0084]

[0085] Preparation process

[0086] 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; add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; sterilize with wet heat at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0087] Example 2

[0088] prescription

[0089]

[0090] Preparation process

[0091] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I) hydrochloride of formula (II), stir to dissolve it completely; add an appropriate amount of sodium hydroxide solution to adjust the pH to 4.3-4.7; 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).

[0092] Table 1 Properties and related substances of injections prepared by two different sterilization methods

[0093]

[0094]

[0095] As can be seen from Table 1, compared with the injection of the compound of formula (I) prepared by sterile filtration, the single impurities of related substances and the total impurities did not increase significantly by 121°C 15min wet heat sterilization. Both sterilization methods are acceptable. According to the guidelines for injection sterilization, the 121°C wet heat sterilization method was selected for subsequent example tests.

[0096] Example 3

[0097] prescription

[0098]

[0099] Preparation process

[0100] 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 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0101] Example 4

[0102] prescription

[0103]

[0104] Preparation process

[0105] Measure 75% of the total amount of water for injection, add the prescribed amount of the compound of formula (I), the 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 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0106] Table 2 Properties and related substances of injections prepared with two different solvents

[0107]

[0108] As can be seen from Table 2, when water for injection is used as a solvent and 0.9% sodium chloride is used as a solvent, the single impurities of the related substances and the total impurities are not significantly increased. Both solvents are acceptable, and water for injection is selected as the solvent for subsequent case tests.

[0109] Example 5

[0110] prescription

[0111]

[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), 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 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0114] Example 6

[0115] prescription

[0116]

[0117]

[0118] Preparation process

[0119] 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 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0120] Table 3 Properties and related substances of injections in two different borosilicate glass tube bottles after 10 days of light exposure

[0121]

[0122] As can be seen from Table 3, the injection of the compound of formula (I) is unstable under light. When the colorless and transparent medium borosilicate glass vials are used for filling, the impurities increase significantly after 10 days of light exposure, while when the brown medium borosilicate glass vials are used for filling, the impurities do not increase significantly after 10 days of light exposure. The medium borosilicate glass vials are selected for subsequent example tests.

[0123] Example 7

[0124] prescription

[0125]

[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, formula (II), disodium edetate, anhydrous disodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate, and stir to dissolve them completely; detect the pH range of 5.8 to 6.2, otherwise use sodium hydroxide or phosphoric acid to adjust the pH to 5.8 to 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 with wet heat at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0128] Example 8

[0129] prescription

[0130]

[0131] Preparation process

[0132] 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 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; sterilize with wet heat at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0133] Example 9

[0134] prescription

[0135]

[0136]

[0137] Preparation process

[0138] 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 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; sterilize with wet heat at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0139] Table 4 Properties, related substances, buffering capacity and light stability of injections prepared with three different buffers

[0140]

[0141] 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.

[0142] Example 10

[0143] prescription

[0144]

[0145]

[0146] Preparation process

[0147] 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, anhydrous disodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate, and stir to dissolve them all; measure the pH range to be 4.8-5.2; otherwise, use sodium hydroxide or phosphoric acid 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; perform wet heat sterilization at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0148] Table 5 Properties and buffering capacity of injections prepared with phosphate buffer at different pH values

[0149]

[0150] It can be seen from Table 5 that 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, and the pH value of the phosphate buffer can be selected to be 5.0-6.0.

[0151] Embodiment 11

[0152] prescription

[0153]

[0154] Preparation process

[0155] 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; add water for injection to the full amount, mix, filter through a 0.22 μm filter membrane, fill with nitrogen, and fill; sterilize with wet heat at 121° C. for 15 min to obtain a 1 mg / ml concentrated solution of the compound of formula (I).

[0156] Table 6 Properties, related substances, buffering capacity and results of injections prepared with acetate buffer at different pH values

[0157]

[0158] It can be seen from Table 6 that 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, and the pH value of acetate buffer can be selected to be 5.0-6.0.

[0159] Table 7 Example 7 Phosphate buffer stability test results

[0160]

[0161] As can be seen from Table 7, the injection of the compound of formula (I) prepared with phosphate buffer has good stability at high temperature 60°C and high temperature + high humidity (40°C + 75% RH) for 10 days.

[0162] Table 8 Example 11 Acetate buffer stability test results

[0163]

[0164]

[0165] 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 60°C and high temperature + high humidity (40°C + 75% RH) for 10 days.

[0166] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

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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