Pharmaceutical composition containing polypeptide compounds and preparation method and use thereof

Abstract

The present application provides a pharmaceutical composition containing a polypeptide compound and a preparation method thereof, wherein the polypeptide compound has peripheral κ opioid receptor agonist activity. Therefore, the present application also relates to the use of the pharmaceutical composition in the preparation of a drug for preventing or treating diseases associated with κ opioid receptors.

Description

[0001] This application is based on an application with CN application number 201811357621.X and filing date November 15, 2018, and claims priority. The disclosed content of the CN application is hereby introduced as a whole into this application. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition containing a polypeptide compound and a preparation method thereof, wherein the polypeptide compound has peripheral kappa opioid receptor agonist activity. Therefore, the present application also relates to the use of the pharmaceutical composition in the preparation of a drug for preventing or treating diseases associated with kappa opioid receptors. Background Art

[0003] Peripheral κ opioid receptor agonists can bind to κ opioid receptors, causing the opioid receptor-coupled Gi / Go protein to be activated, and then reduce cAMP by inhibiting adenylate cyclase activity, or by inhibiting calcium channels, thereby increasing Ca 2+ Inflow decreases, K + Increased outflow causes hyperpolarization of membrane potential, which reduces the release of neurotransmitters and the excitability of neurons that transmit pain information, thereby inhibiting the transmission of pain signals.

[0004] The applicant disclosed in WO 2018 / 059331 A1 a polypeptide compound having peripheral κ opioid receptor agonist activity as shown in the following formula, which has a completely new structure, clear pharmacological effects and important clinical value.

[0005]

[0006] Clinically, there is an urgent need to develop pharmaceutical preparations of this type of compound that have a sterility assurance level, good stability and are compatible with clinical administration routes. Summary of the invention

[0007] One object of the present application is to provide a pharmaceutical preparation of a polypeptide compound having peripheral kappa opioid receptor agonist activity, which is compatible with the clinical administration route and can simultaneously ensure the safety of the polypeptide compound during clinical use.

[0008] Therefore, in one aspect, the present application provides a pharmaceutical composition, which contains an active ingredient, a buffer, a pH adjuster and water for injection, and optionally, further contains a stabilizer; wherein,

[0009] The active ingredient is selected from the compounds described in WO2018059331A1, or stereoisomers, polymorphs, solvates, or metabolites or pharmaceutically acceptable salts or esters thereof;

[0010] The content of the pH adjuster is such that the pH of the pharmaceutical composition is between 3.5 and 5.5.

[0011] WO2018059331A1 is incorporated herein by reference in its entirety. Unless otherwise specified, the active ingredient in the pharmaceutical composition described in the present application refers to any compound in WO2018059331A1, or its stereoisomers, polymorphs, solvates, or metabolites or pharmaceutically acceptable salts or esters.

[0012] In some preferred embodiments, the active ingredient is selected from the following compound of formula I, or its stereoisomers, polymorphs, solvates, or metabolites or pharmaceutically acceptable salts or esters:

[0013]

[0014] In some preferred embodiments, the pharmaceutically acceptable salt is an acid addition salt. In some preferred embodiments, the pharmaceutically acceptable salt is selected from formate, acetate, hydrochloride and trifluoroacetate. In some preferred embodiments, the pharmaceutically acceptable salt is acetate or hydrochloride. In some preferred embodiments, the pharmaceutically acceptable salt is acetate. In some preferred embodiments, the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1: (0.5-3), for example 1: (0.5-2.5), 1: (0.5-2), 1: (0.5-1.5) or 1: (0.5-1). In some preferred embodiments, the active ingredient is the acetate of the compound of formula I, wherein the molar ratio of the compound of formula I to acetic acid is 1: (0.5-1).

[0015] In some preferred embodiments, the content of the pH regulator is such that the pH of the pharmaceutical composition is between 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7, such as 4.5. When the pH of the pharmaceutical composition is between 4.0-5.0, the impurity content generated at the beginning of placement (e.g., day 0) is less than 0.1%, and the impurity content is almost unchanged when placed at 40° C. for 10 days, for example, the change in impurity content is less than 0.05%, for example, 0.01%, 0.02%, 0.03%, 0.04%.

[0016] In some preferred embodiments, the content of the active ingredient is 0.01-0.1% (w / v), such as 0.01-0.02% (w / v).

[0017] In some preferred embodiments, the buffer is selected from carbonate, phosphate, citrate, acetate, barbiturate, tris(hydroxymethyl)aminomethane) and borate. In some preferred embodiments, the buffer is selected from phosphate, citrate and acetate, such as sodium dihydrogen phosphate, sodium citrate and sodium acetate. In some preferred embodiments, the buffer is sodium acetate or sodium acetate trihydrate. The sodium acetate buffer system has good compatibility with the pharmaceutical composition. For example, the sodium acetate buffer system makes the pharmaceutical composition produce less impurities at the beginning of placement (e.g., 0 days), which is less than the instrument detection limit, and the impurities increase less when placed at 60°C for 10 days, for example, the change in the number of impurities is less than 10.

[0018] In some preferred embodiments, the molar concentration of the buffer is 1-5 mM, such as 1, 2, 3, 4 or 5 mM, preferably 2 mM. When the concentration of the buffer (such as sodium acetate or sodium acetate trihydrate) is 2 mM, the pharmaceutical composition has less increase in impurities when placed at 60° C. for 15 days or 30 days.

[0019] In some preferred embodiments, the pH regulator is selected from one or more of hydrochloric acid, phosphoric acid, citric acid, glacial acetic acid, barbituric acid, boric acid, sodium hydroxide and potassium hydroxide. In some preferred embodiments, the pH regulator is glacial acetic acid, hydrochloric acid or sodium hydroxide.

[0020] In some preferred embodiments, the pharmaceutical composition further contains an osmotic pressure regulator.

[0021] In some preferred embodiments, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, glycerol, propylene glycol, polyethylene glycol, sorbitol, mannitol, and xylitol. In some preferred embodiments, the osmotic pressure regulator is sodium chloride.

[0022] In some preferred embodiments, the amount of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 250-350 mOsm / kg, such as 260-330 mOsm / kg, 290-310 mOsm / kg. In some preferred embodiments, the content of the osmotic pressure regulator is 0.80-1.05% (m / v), such as 0.90-0.95% (m / v).

[0023] In some preferred embodiments, the stabilizer is an antioxidant or a metal ion chelator. In some preferred embodiments, the antioxidant is selected from sodium bisulfite, sodium thiosulfate and sodium pyrosulfite. In some preferred embodiments, the metal ion chelator is selected from disodium edetate and calcium sodium edetate. In some preferred embodiments, the stabilizer is selected from sodium thiosulfate and calcium sodium edetate. In some preferred embodiments, the stabilizer is calcium sodium edetate.

[0024] In some preferred embodiments, the content of the stabilizer is 0.05-0.2% (w / v), preferably 0.05-0.1% (w / v).

[0025] In some preferred embodiments, the composition consists of the following ingredients:

[0026]

[0027]

[0028] Wherein, the pH adjusting agent is selected from hydrochloric acid, sodium acetate and sodium hydroxide;

[0029] The stabilizer is selected from sodium thiosulfate and calcium sodium edetate.

[0030] In some preferred embodiments, the composition consists of the following ingredients:

[0031]

[0032] Wherein, the pH adjusting agent is selected from hydrochloric acid, sodium acetate and sodium hydroxide;

[0033] The stabilizer is selected from sodium thiosulfate and calcium sodium edetate.

[0034] In some preferred embodiments, the pharmaceutical composition consists of an active ingredient, sodium acetate or sodium acetate trihydrate, sodium chloride, a pH adjuster, water for injection, and an optional stabilizer, wherein the stabilizer is selected from sodium thiosulfate and sodium calcium edetate, and the pH value of the pharmaceutical composition is 4.0-5.5.

[0035] In some preferred embodiments, the pharmaceutical composition is selected from formula (1)-(3):

[0036] Recipe (1):

[0037]

[0038] Recipe (2):

[0039]

[0040]

[0041] Recipe (3):

[0042]

[0043] In some preferred embodiments, the pharmaceutical composition is an injection, an emulsion or a suspension.

[0044] In another aspect, the present application provides a method for preparing the pharmaceutical composition, comprising the following steps:

[0045] (1) dissolving the buffer, osmotic pressure regulator (if any) and optional stabilizer in water for injection to obtain solution 1;

[0046] (2) dissolving the active ingredient in the solution 1 to obtain solution 2;

[0047] (3) adjusting the pH of the solution 2 to 3.5-5.5 with the pH adjuster to obtain the pharmaceutical composition;

[0048] Optionally, the preparation method further comprises the step of sterilizing the pharmaceutical composition;

[0049] Optionally, the method further comprises the step of adjusting the pH value of solution 1 to 3.5-5.5 with a pH adjuster after step (1);

[0050] Optionally, after the sterilization step, a nitrogen filling step is also included;

[0051] Optionally, after the nitrogen filling step, a filling step is also included.

[0052] In some preferred embodiments, in step (3), the pH of the solution 2 is adjusted to 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7 using the pH adjuster.

[0053] In some preferred embodiments, step (1) and step (2) are performed at a temperature of 15-40° C. In some preferred embodiments, step (1) and step (2) are performed at a temperature of 15-25° C.

[0054] In some preferred embodiments, the above sterilization refers to filtration sterilization, for example, sterilization through a 0.22 μm filter membrane. In some preferred embodiments, filtration sterilization is performed using a 0.22 μm polyethersulfone filter membrane.

[0055] In another aspect, the present application provides an injection product, which includes the above-mentioned pharmaceutical composition and a sealed container for containing the pharmaceutical composition, wherein the volume of the pharmaceutical composition is less than or equal to the volume of the sealed container, and when the volume of the pharmaceutical composition is less than the volume of the sealed container, the remaining space of the sealed container is filled with an inert gas.

[0056] In some preferred embodiments, the sealed container is a glass or plastic sealed container, such as an ampoule or a vial (such as a borosilicate glass controlled injection bottle). In some preferred embodiments, the inert gas is nitrogen.

[0057] In another aspect, the present application provides use of the pharmaceutical composition in preparing a medicament for preventing or treating a disease associated with a kappa opioid receptor.

[0058] In another aspect, the present application provides the pharmaceutical composition for preventing or treating diseases associated with κ opioid receptors.

[0059] In another aspect, the present application provides a method for preventing or treating a disease associated with a κ opioid receptor, comprising the step of administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof.

[0060] In some preferred embodiments, the disease associated with the kappa opioid receptor is selected from pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma. In some preferred embodiments, the disease associated with the kappa opioid receptor is pain. In some preferred embodiments, the pain is selected from neuropathic pain, somatic pain, visceral pain and cutaneous pain. In some preferred embodiments, the pain is selected from arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, post-medical treatment pain, eye pain, otitis pain, cancer pain and pain associated with gastrointestinal disorders.

[0061] In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Meanwhile, in order to better understand the present invention, the definitions and explanations of the relevant terms are provided below.

[0062] As used herein, "w / v" and "m / v" refer to Kg / L.

[0063] The water for injection mentioned herein generally refers to water suitable for in vivo injection, that is, it should meet the requirements of the bacterial endotoxin test for injectable products. The water for injection can be water obtained by distillation of pure water.

[0064] Advantageous Effects of the Invention

[0065] The present application provides a pharmaceutical composition containing a polypeptide compound, a preparation method and use thereof. The pharmaceutical composition of the present application can achieve at least one of the following technical effects:

[0066] 1. The pharmaceutical composition improves the stability of the polypeptide compound while ensuring the sterility level, thereby improving the safety of application.

[0067] 2. The pH of the pharmaceutical composition meets the requirements for injection (pH 4-9), improving its developability as an intravenous injection preparation. DETAILED DESCRIPTION

[0068] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0069] Unless otherwise specified, the active ingredients used in the following examples and comparative examples are all acetates of the compound of formula I, wherein the molar ratio of the compound of formula I to acetic acid in the active ingredients used in Examples 1-2 and Comparative Examples 1-2 is 1:0.8, and the molar ratio of the compound of formula I to acetic acid in the active ingredients used in Examples 3-6 and Comparative Examples 3-4 is 1:0.6. Unless otherwise specified, glacial acetic acid, hydrochloric acid and / or sodium hydroxide are used to adjust the pH of the system in each example, and sodium acetate specifically refers to sodium acetate trihydrate.

[0070] Example 1

[0071] Experimental purpose: To investigate the effect of different pH values ​​on solution stability.

[0072] Experimental method: According to the prescription composition in Table 1, the active ingredient and sodium acetate were weighed to prepare a 1 mg / ml drug solution, and the pH value was adjusted to pH 4.0-pH 5.5 with glacial acetic acid or sodium hydroxide solution, respectively. After filtering through a 0.22 μm filter membrane, the solution was filled into an ampoule to prepare a sample.

[0073] Each sample was placed at 40°C for 10 days and the changes of related substances were detected. The results are shown in Table 2.

[0074] Table 1 Prescription composition of different pH values

[0075] Sample No. Active ingredient (mg / ml) Sodium acetate (mg / ml) Add water to (ml) pH No.1 1.01 3.40 40 4.00 No.2 1.01 3.40 40 4.50 No.3 1.01 3.40 40 5.01 No.4 1.01 3.40 40 5.51

[0076] Table 2 Test results of related substances

[0077]

[0078] Experimental results: The results of the above examples show that the total impurity content of the pH4.0-pH5.0 solution is less than 0.1% on day 0; after being placed at 40°C, the total impurity content of the pH4.0-pH5.0 drug solution has almost no change, for example, the change in the total impurity content is less than 0.05%. Therefore, the pH4.0-pH5.0 drug solution is relatively stable.

[0079] Example 2

[0080] Experimental purpose: To investigate the effect of buffer system type on solution stability.

[0081] According to the prescription composition in Table 3, the active ingredient and sodium acetate were weighed to prepare a drug solution with a concentration of 1 mg / ml, the pH value was adjusted to 4.5 with glacial acetic acid, and the solution was filtered through a 0.22 μm filter membrane and filled into an ampoule to prepare a sample.

[0082] Each sample was placed at a high temperature of 60°C for 10 days to detect changes in related substances.

[0083] Table 3 Prescription composition of buffer system

[0084]

[0085] Experimental results: Under the condition of 60℃ for 10 days, the maximum single impurity of the sample was only 0.17%, the total impurity was only 0.58%, and the number of impurities was 10. This shows that the active ingredients in the sample are well compatible with the sodium acetate buffer system.

[0086] Example 3

[0087] Experimental purpose: To investigate the effects of stabilizers and nitrogen filling on solution stability.

[0088] Experimental content: According to the prescription composition of samples 1-4 (see Table 4), weigh the prescribed amount of sodium acetate, sodium chloride, sodium thiosulfate and sodium calcium edetate, add them to water, stir and dissolve, use hydrochloric acid to adjust the pH to 4.3, add active ingredients, prepare a drug solution with a concentration of 0.1 mg / ml, use hydrochloric acid to adjust the pH to 4.5, filter through a 0.22μm filter membrane and fill it into a medium borosilicate glass tube injection bottle to prepare samples 1-3. In the same way, prepare a drug solution with an active ingredient concentration of 0.1 mg / ml without a stabilizer, fill the headspace with nitrogen before filling, and prepare sample 4.

[0089] The above samples were placed at 60°C and the changes of related substances were detected. The test results are shown in Table 5.

[0090] Table 4: Composition of formulations with different stabilizers added

[0091] Sample No. 1 2 3 4 Sodium acetate (mg) 27 27 27 27 Sodium chloride (mg) 900 900 900 900 Active ingredient (mg) 10 10 10 10 Sodium thiosulfate (mg) / 200 / / Edetate calcium sodium (mg) / / 50 / <![CDATA[Nitrogen (N2)]]> / / / Nitrogen filling Water to (ml) 100 100 100 100

[0092] Note: “ / ” means the material is not added.

[0093] Table 5 Test results of related substances with different stabilizers added

[0094]

[0095] Note: “ / ” means not detected.

[0096] Experimental results: Compared with the drug solution without antioxidants and stabilizers, after sodium thiosulfate or sodium calcium edetate was added, the total impurity content of the drug solution stored at 60°C for 15 days was less than 0.9%, and the total impurity content of the drug solution stored for 30 days was less than 1.1%; compared with the non-nitrogen-filled solution, the drug solution using the nitrogen filling process had the smallest change in total impurity content when stored at 60°C for 15 days, and the drug solutions of samples 2-4 all achieved good stability.

[0097] Example 4

[0098] Experimental purpose: To investigate the effects of different preparation temperatures and preparation times on solution stability.

[0099] Experimental content: According to the prescription composition in Table 6, weigh sodium chloride and sodium acetate in water, stir and dissolve, use hydrochloric acid to adjust the pH to 4.3, add active ingredients, prepare a drug solution with a concentration of 0.1 mg / ml, use hydrochloric acid to adjust the pH to 4.5, stir at 25℃, 30℃ and 40℃ for 0h, 2h, 5h, 8h, take samples, observe the properties of the solution, and detect related substances and pH value at the same time. The test results are shown in Table 7.

[0100] Table 6 Prescription composition at different preparation temperatures and preparation times

[0101] Element Dosage Sodium acetate (mg) 27 Sodium chloride (mg) 900 Active ingredient (mg) 10 Water to (ml) 100

[0102] Table 7 pH and related substances test results of each sample

[0103]

[0104]

[0105] Experimental results: The results of the above examples show that within the temperature range of 25°C-40°C, the solution prepared within 8 hours has good stability.

[0106] Example 5

[0107] Experimental purpose: To investigate the effect of different molar concentrations of buffer salts on the stability of the solution.

[0108] Experimental content: According to the prescription composition in Table 8, sodium chloride and sodium acetate trihydrate (final concentrations of 1mM and 2mM, respectively) were weighed in water, stirred and dissolved, and the pH was adjusted to 4.3 with hydrochloric acid, and the active ingredient was added to prepare a drug solution with a concentration of 0.1mg / ml. The pH value was adjusted to 4.5 with hydrochloric acid, and the solution was filtered through a 0.22μm filter membrane and filled into a medium borosilicate glass tube injection bottle, stoppered, capped, and placed at 60℃ for 15 days and 30 days, and the related substances and pH value were detected. The test results are shown in Table 9.

[0109] Table 8 Prescription composition of buffer salts with different molar concentrations

[0110] Element 1mM group 2mM group Sodium acetate trihydrate (mg) 14 27 Sodium chloride (mg) 900 900 Active ingredient (mg) 10 10 Add water to (ml) 100 100

[0111] Table 9 pH and related substance detection results of buffer salt samples with different molar concentrations

[0112]

[0113] Experimental results: The results of the above embodiment show that after being placed at 60°C for 30 days, the pH values ​​of the samples with 1 mM and 2 mM sodium acetate solutions remained basically unchanged, while the total impurity content of the sample with 2 mM sodium acetate solution changed slightly, showing good stability.

[0114] Example 6

[0115] Experimental purpose: To investigate the effect of different amounts of sodium chloride on the osmotic pressure of the solution.

[0116] Experimental content: According to the prescription composition in Table 10, sodium chloride and sodium acetate were weighed in water, stirred to dissolve, and then hydrochloric acid was used to adjust the pH to 4.3. The active ingredient was added to prepare a drug solution with a concentration of 0.1 mg / ml. The pH value was adjusted to 4.5 with hydrochloric acid. After filtering through a 0.22 μm filter membrane, the solution was filled into a borosilicate glass tube injection bottle, stoppered, and the osmotic pressure was tested. The test results are shown in Table 11.

[0117] Table 10 Prescription composition of different sodium chloride dosages

[0118] Sample No. 1 2 3 4 5 Sodium acetate (mg) 27 27 27 27 27 Sodium chloride (mg) 850 900 950 1000 1050 Active ingredient (mg) 10 10 10 10 10 Water to (ml) 100 100 100 100 100

[0119] Table 11 Osmotic pressure test results

[0120] Sample No. 1 2 3 4 5 Sodium chloride dosage (w / v) 0.85％ 0.90％ 0.95％ 1.00％ 1.05％ Osmol / kg 277 297 310 326 340

[0121] Experimental results: When the dosage of sodium chloride is 0.90%-0.95%, the osmotic pressure of the injection composition is isotonic or slightly hypertonic, which is the most suitable osmotic pressure for injection.

[0122] Example 7

[0123] Experimental purpose: To investigate the feasibility of filtration sterilization.

[0124] Experimental method: According to the prescription composition in Table 12, weigh sodium acetate and glacial acetic acid into a 100mL glass bottle, add water to 100mL, stir to dissolve, add active ingredients, and prepare a 0.1mg / ml drug solution with a pH of 4.5. Filter through a 0.22μm*13mm polyethersulfone filter membrane. Take the solution before filtration, after continuous filtration for 15min and 30min as samples to detect the changes of related substances. The results are shown in Table 13.

[0125] Table 12 Prescription composition for compatibility study between filter membrane and solution

[0126]

[0127]

[0128] Table 13 Results of the investigation on the compatibility of the filter membrane and the solution

[0129] sample Maximum single impurity % Total impurities% Number of impurities Before filtration 0.19 0.46 6 After filtration - 15min 0.11 0.32 6 After filtration - 30min 0.11 0.34 6

[0130] Experimental results: There was no significant change in the impurity content and quantity of the drug solution before and after filtration through the polyethersulfone filter membrane, indicating that the drug solution has good compatibility with the polyethersulfone filter membrane and the filtration sterilization process has no effect on the stability of the solution. The filtration sterilization process is suitable for the production of this product.

[0131] Comparative Example 1

[0132] Experimental purpose: To investigate the effect of different pH values ​​on solution stability.

[0133] Experimental method: According to the prescription composition in Table 14, the active ingredient and sodium acetate were weighed to prepare a 1 mg / ml drug solution, and the pH value was adjusted to pH 3.5-pH 8.5 with glacial acetic acid or sodium hydroxide solution, respectively. After filtering through a 0.22 μm filter membrane, the solution was filled into an ampoule bottle to prepare a sample.

[0134] Each sample was placed at 40°C for 10 days and the changes in related substances were detected. The results are shown in Table 15.

[0135] Table 14 Prescription composition of different pH values

[0136]

[0137]

[0138] Table 15 Test results of related substances

[0139]

[0140] Experimental results: The solution with pH 3.5 had fewer impurities at 0 days, but after 10 days, the number of impurities and the change in impurity content increased significantly; the solution with pH 6.0-8.5 had relatively more impurities. Therefore, the drug solutions with the above pH are not in the most preferred range.

[0141] Comparative Example 2

[0142] Experimental purpose: To investigate the effects of different types of buffer systems on solution stability.

[0143] According to the prescription composition in Table 16, the active ingredient, sodium citrate and sodium dihydrogen phosphate monohydrate (calculated according to the mass of sodium dihydrogen phosphate) were weighed to prepare a drug solution with a concentration of 1 mg / ml. The pH value was adjusted to 4.5 with citric acid and phosphoric acid respectively. After filtering through a 0.22 μm filter membrane, the solution was filled into an ampoule to prepare a sample.

[0144] Each sample was placed at a high temperature of 60°C for 10 days and the changes in relevant substances were detected. The results are shown in Table 17.

[0145] Table 16 Prescription composition of different buffer systems

[0146]

[0147] Note: “ / ” means the material is not added.

[0148] Table 17 Test results of related substances

[0149]

[0150] Experimental results: The impurities in the drug solution prepared by the sodium citrate system increased rapidly under high temperature conditions, while the impurities in the drug solution prepared by the sodium dihydrogen phosphate system increased relatively quickly under high temperature conditions, both of which were significantly inferior to the acetate buffer system in Example 2.

[0151] Comparative Example 3

[0152] Experimental purpose: To investigate the effect of adding stabilizer on solution stability.

[0153] Experimental content: According to the prescription composition of samples 1-2 (see Table 18), weigh the prescribed amount of sodium acetate, sodium chloride, cysteine ​​(if any) and sodium bisulfite (if any), add them to water, stir to dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, and prepare a drug solution with a concentration of 0.1 mg / ml. Adjust the pH to 4.5 with hydrochloric acid, filter through a 0.22 μm filter membrane, and fill into a medium borosilicate glass tube injection bottle to prepare sample 1-2.

[0154] The above samples were placed at 60°C and the changes in related substances were detected. The test results are shown in Table 19.

[0155] Table 18: Composition of formulations with different stabilizers added

[0156]

[0157]

[0158] Note: “ / ” means the material is not added.

[0159] Table 19 Test results of related substances with different stabilizers added

[0160]

[0161] Experimental results: Compared with the prescription in Example 3 in which sodium thiosulfate or sodium calcium edetate stabilizer is added, after cysteine ​​and sodium bisulfite are added, the impurities in the drug solution stored at 60°C for 15 days and 30 days increase significantly.

[0162] Comparative Example 4

[0163] Experimental purpose: To investigate the effect of terminal sterilization method on solution stability.

[0164] Experimental content: Prepare drug solutions with an active ingredient concentration of 1 mg / ml containing 0.2% cysteine, 0.2% sodium thiosulfate, 0.2% sodium bisulfite, and 0.05% sodium edetate, respectively, and fill them into medium borosilicate glass tube injection bottles after adjusting the pH value to 7.5 to prepare samples 1-4. Prepare another drug solution with an active ingredient concentration of 1 mg / ml without stabilizer in the same way, and fill the headspace with nitrogen before filling to prepare sample 5.

[0165] The above samples were sterilized at 121°C for 8 minutes, and the changes in relevant substances were detected. The test results are shown in Table 20.

[0166] Table 20 Test results of related substances in terminal sterilization study

[0167]

[0168]

[0169] Experimental results: After sterilization, the impurity levels of the above samples increased significantly compared to before sterilization. Adding antioxidants, stabilizers and nitrogen filling could not improve the stability of the active ingredients after sterilization, so the terminal sterilization process is not applicable and the sterilization filtration process should be selected.

[0170] Although the specific embodiments of the present invention have been described in detail, according to all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solution of the present invention, and these changes are within the protection scope of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A pharmaceutical composition comprising an active ingredient, a buffer, a pH adjuster and water for injection; wherein: The active ingredient is selected from the following compound of formula I or a pharmaceutically acceptable salt thereof; the content of the active ingredient is 0.01-0.1% (w / v); The content of the pH regulator is such that the pH of the pharmaceutical composition is between 4.0 and 5.5; The buffer is sodium acetate or sodium acetate trihydrate; the molar concentration of the buffer is 1-5mM; Formula I.

2. The pharmaceutical composition according to claim 1, further comprising a stabilizer, wherein the stabilizer is selected from sodium thiosulfate and sodium calcium edetate, and the content of the stabilizer is 0.05-0.2% (w / v).

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of the pH adjuster is such that the pH of the pharmaceutical composition is between 4.0 and 5.

0.

4. The pharmaceutical composition according to claim 1 or 2, wherein the content of the pH adjuster is such that the pH of the pharmaceutical composition is between 4.3 and 4.

7.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of formate, acetate, hydrochloride and trifluoroacetate. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable salt is acetate or hydrochloride.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is acetate.

8. The pharmaceutical composition of any one of claims 5 to 7, wherein the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1:(0.5-3).

9. The pharmaceutical composition of any one of claims 5-7, wherein the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1:(0.5-2.5).

10. The pharmaceutical composition of any one of claims 5-7, wherein the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1:(0.5-2).

11. The pharmaceutical composition of any one of claims 5 to 7, wherein the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1:(0.5-1.5).

12. The pharmaceutical composition of any one of claims 5-7, wherein the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1:(0.5-1).

13. The pharmaceutical composition of claim 1 or 2, wherein the content of the active ingredient is 0.01-0.02% (w / v).

14. The pharmaceutical composition of claim 1 or 2, wherein the content of the active ingredient is 1, 2, 3, 4 or 5 mM.

15. The pharmaceutical composition of claim 1 or 2, wherein the content of the active ingredient is 2 mM.

16. The pharmaceutical composition of claim 1 or 2, wherein the pH adjuster is selected from one or more of hydrochloric acid, phosphoric acid, citric acid, acetic acid, barbituric acid, boric acid, sodium hydroxide and potassium hydroxide.

17. The pharmaceutical composition according to claim 1, further comprising an osmotic pressure regulator.

18. The pharmaceutical composition of claim 17, wherein the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, glycerol, propylene glycol, polyethylene glycol, sorbitol, mannitol, and xylitol.

19. The pharmaceutical composition of claim 17, wherein the osmotic pressure regulator is sodium chloride.

20. The pharmaceutical composition according to any one of claims 17 to 19, wherein the amount of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 250-350 mOsm / kg.

21. The pharmaceutical composition of any one of claims 17 to 19, wherein the osmotic pressure regulator is used in an amount such that the osmotic pressure of the pharmaceutical composition is 260-330 mOsm / kg.

22. The pharmaceutical composition of any one of claims 17 to 19, wherein the osmotic pressure regulator is used in an amount such that the osmotic pressure of the pharmaceutical composition is 290-310 mOsm / kg.

23. The pharmaceutical composition according to any one of claims 17 to 19, wherein the content of the osmotic pressure regulator is 0.80-1.05% (m / v).

24. The pharmaceutical composition of any one of claims 17 to 19, wherein the content of the osmotic pressure regulator is 0.90-0.95% (m / v).

25. The pharmaceutical composition of claim 2, wherein the stabilizer is edetate calcium sodium.

26. The pharmaceutical composition of claim 2 or 25, wherein the content of the stabilizer is 0.05-0.1% (w / v).

27. The pharmaceutical composition of claim 1, which consists of an active ingredient, sodium chloride, sodium acetate or sodium acetate trihydrate, a pH adjuster and water for injection, and the pH value of the pharmaceutical composition is 4.0-5.

5.

28. The pharmaceutical composition of claim 1, which consists of an active ingredient, sodium chloride, sodium acetate or sodium acetate trihydrate, a pH regulator, water for injection and a stabilizer, wherein the stabilizer is selected from sodium thiosulfate and calcium sodium edetate, and the pH value of the pharmaceutical composition is 4.0-5.

5.

29. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is selected from formula (1)-(3): Recipe (1): Acetate salt of the compound of formula I 0.01% (m / v); Sodium acetate or sodium acetate trihydrate 0.027% (m / v); Sodium chloride 0.9% (m / v); The pH adjuster is used in an amount such that the pH of the formulation is 4.5; The remaining amount of water for injection; Recipe (2): Acetate salt of the compound of formula I 0.01% (m / v); Sodium acetate or sodium acetate trihydrate 0.027% (m / v); Sodium chloride 0.9% (m / v); Sodium thiosulfate 0.2% (m / v); The pH adjuster is used in an amount such that the pH of the formulation is 4.5; The remaining amount of water for injection; Recipe (3): Acetate salt of the compound of formula I 0.01% (m / v); Sodium acetate or sodium acetate trihydrate 0.027% (m / v); Sodium chloride 0.9% (m / v); Edetate calcium sodium 0.05% (m / v); The pH adjuster is used in an amount such that the pH of the formulation is 4.5; The balance is water for injection.

30. The pharmaceutical composition of claim 1, which is an injection, emulsion or suspension.

31. A method for preparing the pharmaceutical composition of any one of claims 1, 3-16 and 30, comprising the following steps: (1) dissolving the buffer in water for injection to obtain solution 1; (2) dissolving the active ingredient in the solution 1 to obtain solution 2; (3) The pH of the solution 2 is adjusted to 4.0-5.5 using the pH adjuster to obtain the pharmaceutical composition.

32. A method for preparing the pharmaceutical composition of any one of claims 17 to 24, 27 and 29, comprising the following steps: (1) dissolving the buffer and osmotic pressure regulator in water for injection to obtain solution 1; (2) dissolving the active ingredient in the solution 1 to obtain solution 2; (3) The pH of the solution 2 is adjusted to 4.0-5.5 using the pH adjuster to obtain the pharmaceutical composition.

33. A method for preparing the pharmaceutical composition of any one of claims 2-4, 13-16 and 25-26, comprising the following steps: (1) dissolving the buffer and stabilizer in water for injection to obtain solution 1; (2) dissolving the active ingredient in the solution 1 to obtain solution 2; (3) The pH of the solution 2 is adjusted to 4.0-5.5 using the pH adjuster to obtain the pharmaceutical composition.

34. A method for preparing the pharmaceutical composition of claim 28 or 29, comprising the following steps: (1) Dissolve the buffering agent sodium acetate or sodium acetate trihydrate, the osmotic pressure regulating agent sodium chloride, and the stabilizer sodium thiosulfate or sodium calcium edetate in water for injection to obtain solution 1; (2) dissolving the active ingredient in the solution 1 to obtain solution 2; (3) The pH of the solution 2 is adjusted to 4.0-5.5 using the pH adjuster to obtain the pharmaceutical composition.

35. The preparation method according to any one of claims 31 to 34, further comprising the step of sterilizing the pharmaceutical composition.

36. The preparation method according to any one of claims 31 to 34, further comprising the step of adjusting the pH value of solution 1 to 3.5-5.5 with a pH adjuster after step (1).

37. The preparation method according to claim 35, further comprising a nitrogen filling step after the sterilization step.

38. The preparation method according to claim 37, further comprising a filling step after the nitrogen filling step.

39. The preparation method according to any one of claims 31 to 34, wherein the pH of the solution 2 is adjusted to 4.0-5.0 using the pH adjuster.

40. The preparation method according to any one of claims 31 to 34, wherein the pH of the solution 2 is adjusted to 4.3-4.7 using the pH adjuster.

41. The preparation method according to any one of claims 31 to 34, wherein step (1) and step (2) are carried out at a temperature of 15-40°C.

42. The preparation method according to any one of claims 31 to 34, wherein step (1) and step (2) are carried out at a temperature of 15-25°C. The preparation method according to claim 35 , wherein the sterilization refers to filtration sterilization.

44. The preparation method according to claim 35, wherein the product is sterilized by filtering through a 0.22 μm filter membrane.

45. The preparation method according to claim 35, wherein the sterilization is performed by filtration through a 0.22 μm polyethersulfone filter membrane.

46. ​​An injection product, comprising a pharmaceutical composition according to any one of claims 1 to 30 and a sealed container for containing the pharmaceutical composition, wherein the volume of the pharmaceutical composition is less than or equal to the volume of the sealed container, and when the volume of the pharmaceutical composition is less than the volume of the sealed container, the remaining space of the sealed container is filled with an inert gas.

47. The injection product of claim 46, wherein the sealed container is a glass or plastic sealed container.

48. The injection product of claim 46, wherein the sealed container is an ampoule or a vial.

49. The injection product of claim 46, wherein the sealed container is a borosilicate glass tube injection bottle.

50. The injection product of claim 46, wherein the inert gas is nitrogen.

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