Liquid composition of MOR receptor agonist, preparation method therefor, and use thereof

Abstract

A liquid composition of an MOR receptor agonist, a preparation method therefor, and use thereof. The liquid composition comprises a compound represented by formula I or a salt thereof, a buffering salt, and a pH regulator. The pH value of the liquid composition is 6.0-7.4. The liquid composition exhibits good stability and has a total impurity content of ≤3.0% under long-term storage, high temperature, or light exposure. The impurity risk is controllable, and the safety is guaranteed.

Description

Liquid composition of MOR receptor agonist and preparation method and application thereof

[0001] This application claims priority to the Chinese patent application No. 202410887609.9, filed on July 3, 2024, and entitled "Liquid composition of MOR receptor agonist and preparation method and application thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a liquid composition of MOR receptor agonist and a preparation method and application thereof. BACKGROUND

[0003] Opioid receptors are an important class of G protein coupled receptors (GPCRs), and are the target of endogenous opioid peptides and opioid drugs. After the activation of opioid receptors, the nervous system and the endocrine system are regulated. Opioid drugs are the strongest and most commonly used central analgesics. There are corresponding opioid receptors in the central nervous system, including mu (MOR), delta (DOR), kappa (KOR) receptors, etc. Studies have found that the strength of the analgesic effect of endogenous opioid peptides mainly depends on the expression of opioid receptors, and MOR is the target of endogenous enkephalins and opioid analgesic drugs such as morphine.

[0004] [According to Rule 26 Correction 16.01.2026] The currently disclosed MOR agonist patent applications include WO2017106547, WO2017063509, WO2012129495, WO2017106306, etc. WO2023284788A1 also discloses a class of MOR receptor agonists and acceptable salts thereof, wherein the acceptable salts are maleate, L-tartrate or succinate, and the structure of the MOR receptor agonist is as follows:

[0005] [According to Rule 26 Correction 16.01.2026] For a new MOR receptor agonist, a new dosage form that can maintain strong stability in the preparation process, storage and subsequent use, has a rapid effect in the clinic and has low side effects, and provides a better choice for clinical application needs to be selected. SUMMARY

[0006] To solve the above technical problems, the present application provides a liquid composition of MOR receptor agonist, which comprises a compound represented by formula I or a salt thereof, a buffer salt and a pH adjuster, the pH value of the liquid composition is 6.0-7.1,

[0007] The liquid composition provided by the present application has good stability, small types of impurities and total impurity content ≤3.0% under long-term, high-temperature or light irradiation, and controllable impurity risk; no visible foreign matter in the preparation and sterilization process, and high safety.

[0008] The present application is realized by the following technical solutions:

[0009] [According to the rules 26 correction 16.01.2026] A liquid composition of a MOR receptor agonist comprising a compound represented by formula I or a salt thereof, a buffer salt and a pH adjuster, the pH value of the liquid composition is 6.0-7.4, preferably, the pH value of the liquid composition is 6.0-7.1,

[0010] In some embodiments, a liquid composition of a MOR receptor agonist comprising a salt of a compound represented by formula I, a buffer salt and a pH adjuster, the pH value of the liquid composition is 6.0-7.4.

[0011] In some embodiments, the salt of the compound represented by formula I of the present application includes a maleate salt, a fumarate salt, an L-tartrate salt or a succinate salt.

[0012] According to the process feasibility of the salt type, the crystallinity, the melting point, the solubility, the physical and chemical stability and other factors, preferably, the salt of the compound represented by formula I is an L-tartrate salt.

[0013] In some embodiments, the present application provides a liquid composition of a MOR receptor agonist comprising an L-tartrate salt of a compound represented by formula I, a buffer salt and a pH adjuster, the pH value of the liquid composition is 6.0-7.1.

[0014] In some embodiments, the buffer salt described in the present application includes at least one of a phosphate salt, an acetate salt, a histidine, a citrate salt, a borate salt, an oxalate salt, a formate salt, a succinate salt, a lactate salt, a tartrate salt and a fumarate salt. Preferably, the buffer salt is selected from at least one of a phosphate salt, an acetate salt, a histidine and a citrate salt.

[0015] In some embodiments, the phosphate salt described in the present application is selected from at least one of sodium phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate. Preferably, the phosphate salt is selected from sodium phosphate.

[0016] In some embodiments, the acetate salt described in the present application is selected from at least one of sodium acetate, ammonium acetate, lithium acetate and potassium acetate. Preferably, the acetate salt is selected from sodium acetate.

[0017] In some embodiments, the citrate salt according to the present application is selected from at least one of monosodium citrate, disodium citrate, sodium citrate and magnesium citrate. Preferably, the citrate salt according to the present application is selected from sodium citrate.

[0018] In some embodiments, the phosphate salt according to the present application contains 1-12 crystal water, such as NaH2PO4-H2O, Na2HPO4-12H2O, K2HPO4-3H2O.

[0019] In some embodiments, the buffer salt according to the present application is selected from at least one of sodium phosphate monobasic, sodium acetate, histidine and sodium citrate; more preferably, the buffer salt is sodium phosphate monobasic and / or sodium citrate.

[0020] In some embodiments, the inventors found that the amount of buffer salt has a great impact on the visible foreign matter and related substances in the liquid composition of the salt of the compound of Formula I, and found that reducing the amount of buffer salt can reduce the risk of visible foreign matter, but increase the risk of related substances, and the amount of buffer salt is a high risk factor in the technical solution of the present application. Therefore, preferably, the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition in terms of mass-volume concentration is < 3.4 (for example, the mass-volume concentration unit is mg / ml, g / l, g / ml, mg / l, etc.); preferably, the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base is 0.1-2.0; more preferably, the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base is 0.2-1.7, and more preferably, the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base is 0.4-1.7.

[0021] In some embodiments, the concentration of the buffer salt in the liquid composition according to the present application is < 6.8 mg / ml; preferably, the concentration of the buffer salt in the liquid composition is < 3.4 mg / ml.

[0022] In some embodiments, the concentration of the buffering salt in the liquid composition is 0.1-2.0 mg / ml; the concentration can be selected from 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml or 2.0 mg / ml.

[0023] Further preferably, the concentration of the buffering salt in the liquid composition is 0.2-1.7 mg / ml; further more preferably, the concentration of the buffering salt in the liquid composition is 0.4-1.7 mg / ml.

[0024] In some embodiments, the concentration of the salt (e.g. L-tartaric acid salt) of the compound of Formula I in the liquid composition is 0.1-5.0 mg / ml in terms of free base; the concentration can be selected from 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3 mg / ml, 2.4 mg / ml, 2.5 mg / ml, 2.6 mg / ml, 2.7 mg / ml, 2.8 mg / ml, 2.9 mg / ml, 3.0 mg / ml, 3.2 mg / ml, 3.4 mg / ml, 3.6 mg / ml, 3.8 mg / ml, 4.0 mg / ml, 4.2 mg / ml, 4.4 mg / ml, 4.6 mg / ml, 4.8 mg / ml or 5.0 mg / ml.

[0025] The free base as used herein refers to (4S,6S)-6-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-amine (the compound of Formula I).

[0026] In some embodiments, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0-5.0 mg / ml as free base; more preferably, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0 mg / ml or 2.0 mg / ml as free base.

[0027] In some embodiments, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0-2.0 mg / ml as free base, the concentration of the buffering salt in the liquid composition is less than 3.4 times the concentration of the salt of the compound of Formula I in the liquid composition as free base, and the buffering salt is sodium phosphate dibasic or sodium citrate.

[0028] In some embodiments, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0 mg / ml as free base, the buffering salt is sodium phosphate dibasic or sodium citrate, and the concentration of the buffering salt in the liquid composition is less than 3.4 mg / ml; preferably, the buffering salt is sodium phosphate dibasic or sodium citrate, and the concentration of the buffering salt in the liquid composition is 0.1-2.0 mg / ml; preferably, the buffering salt is sodium phosphate dibasic or sodium citrate, and the concentration of the buffering salt in the liquid composition is 0.2-1.7 mg / ml; more preferably, the buffering salt is sodium phosphate dibasic or sodium citrate, and the concentration of the buffering salt in the liquid composition is 0.4-1.7 mg / ml.

[0029] In some embodiments, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0 mg / ml as free base, the buffering salt is sodium phosphate dibasic, the concentration of the buffering salt in the liquid composition is 0.8-2.0 mg / ml, and the pH of the liquid composition is 6.0-7.1. The concentration of the sodium phosphate dibasic can be selected from 0.80 mg / ml, 0.85 mg / ml, 0.90 mg / ml, 0.95 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, or 2.0 mg / ml.

[0030] In some embodiments, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0 mg / ml as free base, the buffering salt is sodium phosphate dibasic, the concentration of the buffering salt in the liquid composition is less than 0.6 mg / ml, and the pH of the liquid composition is 6.0-7.4. The concentration of the sodium phosphate dibasic can be selected from 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, or 0.5 mg / ml.

[0031] In some embodiments, the salt of the compound of Formula I is present in a liquid composition at a concentration of 1.0 mg / ml as free base, the buffering salt is sodium phosphate monobasic, which is present in the liquid composition at a concentration of 0.1-0.4 mg / ml, and the liquid composition has a pH of 6.0-7.4. The concentration of sodium phosphate monobasic can be selected from 0.10 mg / ml, 0.15 mg / ml, 0.20 mg / ml, 0.25 mg / ml, 0.30 mg / ml, 0.35 mg / ml, 0.40 mg / ml.

[0032] In some embodiments, the salt of the compound of Formula I is present in a liquid composition at a concentration of 1.0 mg / ml as free base, the buffering salt is sodium citrate, which is present in the liquid composition at a concentration of < 3.0 mg / ml, and the liquid composition has a pH of 6.0-7.1; preferably, the buffering salt is sodium citrate, which is present in the liquid composition at a concentration of 0.75-1.5 mg / ml. The concentration of sodium citrate can be selected from 0.75 mg / ml, 0.80 mg / ml, 0.85 mg / ml, 0.90 mg / ml, 0.95 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, or 1.5 mg / ml.

[0033] In some embodiments, the salt of the compound of Formula I is present in a liquid composition at a concentration of 2.0 mg / ml as free base, the buffering salt is sodium phosphate monobasic, which is present in the liquid composition at a concentration of < 6.8 mg / ml; preferably, the buffering salt is sodium phosphate monobasic, which is present in the liquid composition at a concentration of 1.0-3.5 mg / ml. The concentration of sodium phosphate monobasic can be selected from 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3 mg / ml, 2.4 mg / ml, 2.5 mg / ml, 2.6 mg / ml, 2.7 mg / ml, 2.8 mg / ml, 2.9 mg / ml, 3.0 mg / ml, 3.1 mg / ml, 3.2 mg / ml, 3.3 mg / ml, 3.4 mg / ml, or 3.5 mg / ml. Further preferred is 1.7-3.4 mg / ml.

[0034] In some embodiments, the salt of the compound of Formula I is present in the liquid composition in a concentration of 1.0-2.0 mg / ml as free base, and the buffer salt is sodium acetate, which is present in the liquid composition in a concentration of 0.7-3.2 mg / ml; the concentration of sodium acetate can be selected from the group consisting of 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3 mg / ml, 2.4 mg / ml, 2.5 mg / ml, 2.6 mg / ml, 2.7 mg / ml, 2.8 mg / ml, 2.9 mg / ml, 3.0 mg / ml, 3.1 mg / ml, or 3.2 mg / ml. Further preferred is a concentration of 0.7-2.3 mg / ml.

[0035] In some embodiments, the salt of the compound of Formula I is present in the liquid composition in a concentration of 1.0-2.0 mg / ml as free base, and the buffer salt is histidine, which is present in the liquid composition in a concentration of 3.0-6.5 mg / ml. The concentration of histidine can be selected from the group consisting of 3.1 mg / ml, 3.2 mg / ml, 3.3 mg / ml, 3.4 mg / ml, 3.5 mg / ml, 3.6 mg / ml, 3.7 mg / ml, 3.8 mg / ml, 3.9 mg / ml, 4.0 mg / ml, 4.1 mg / ml, 4.2 mg / ml, 4.3 mg / ml, 4.4 mg / ml, 4.5 mg / ml, 4.6 mg / ml, 4.7 mg / ml, 4.8 mg / ml, 4.9 mg / ml, 5.0 mg / ml, 5.1 mg / ml, 5.2 mg / ml, 5.3 mg / ml, 5.4 mg / ml, 5.5 mg / ml, 5.6 mg / ml, 5.7 mg / ml, 5.8 mg / ml, 5.9 mg / ml, 6.0 mg / ml, 6.1 mg / ml, 6.2 mg / ml, 6.3 mg / ml, 6.4 mg / ml, or 6.5 mg / ml.

[0036] In some embodiments, the pH adjusting agent described herein can be selected from the group consisting of a basic pH adjusting agent and / or an acidic pH adjusting agent; for example, an agent suitable as a pH adjusting agent for the liquid composition, which adjusts the pH of the final liquid composition.

[0037] In some embodiments, the basic pH adjusting agent can be selected from at least one of a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate solution, a sodium bicarbonate solution, a sodium acetate solution, a triethylamine solution, a diethanolamine solution, a sodium phosphate solution, and a Tris (tris-hydroxymethyl aminomethane) solution.

[0038] In some embodiments, the acidic pH adjusting agent can be selected from at least one of an ascorbic acid solution, a lactic acid solution, a malic acid solution, a fumaric acid solution, a citric acid solution, a tartaric acid solution, a succinic acid solution, a sulfuric acid solution, a hydrochloric acid solution, a histidine solution, a phosphoric acid solution, and an acetic acid solution.

[0039] In some embodiments, the pH adjusting agent is selected from at least one of a sodium hydroxide solution, a sodium acetate solution, a potassium hydroxide solution, a sulfuric acid solution, an acetic acid solution, and a hydrochloric acid solution. Preferably, the pH adjusting agent is a sodium hydroxide solution and / or a hydrochloric acid solution.

[0040] In some embodiments, the pH adjusting agent solution has a concentration of 0.1-5 mol / l.

[0041] In some embodiments, the pH of the liquid composition is about 6.0-7.4; preferably, the pH of the liquid composition is about 6.0-7.1. The pH can be about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, or 7.4. Preferably, the pH of the liquid composition is about 6.5-7.1. By controlling the pH of the liquid composition to be between 6.0-7.4 (preferably 6.0-7.1), the present application can better control the impurities produced by high temperature in the aqueous solution of the L-tartrate salt of the compound of Formula I, especially when the pH is > 6.5, the salt ionic strength is high, and the unknown impurities can be significantly reduced.

[0042] In some embodiments, the liquid composition described in the present application further comprises an osmotic pressure adjusting agent selected from at least one of mannitol, xylitol, sorbitol, sodium chloride, calcium chloride, potassium chloride, and glucose. Preferably, the osmotic pressure adjusting agent is sodium chloride or mannitol.

[0043] In some embodiments, the osmotic pressure adjusting agent described in the present application has a concentration of 1.0-15.0 mg / ml in the liquid composition, which can be selected from 1.0 mg / ml, 2.0 mg / ml, 3.0 mg / ml, 4.0 mg / ml, 5.0 mg / ml, 6.0 mg / ml, 7.0 mg / ml, 8.0 mg / ml, 9.0 mg / ml, 10.0 mg / ml, 11.0 mg / ml, 12.0 mg / ml, 13.0 mg / ml, 14.0 mg / ml, or 15.0 mg / ml.

[0044] In some embodiments, the osmolarity of the liquid composition described herein is about 240-340 mOsmol / kg, and can be selected from 240 mOsmol / kg, 250 mOsmol / kg, 260 mOsmol / kg, 270 mOsmol / kg, 280 mOsmol / kg, 281 mOsmol / kg, 282 mOsmol / kg, 283 mOsmol / kg, 284 mOsmol / kg, 285 mOsmol / kg, 286 mOsmol / kg, 287 mOsmol / kg, 288 mOsmol / kg, 289 mOsmol / kg, 290 mOsmol / kg, 291 mOsmol / kg, 292 mOsmol / kg, 293 mOsmol / kg, 294 mOsmol / kg, 295 mOsmol / kg, 296 mOsmol / kg, 297 mOsmol / kg, 298 mOsmol / kg, 299 mOsmol / kg, 300 mOsmol / kg, 301 mOsmol / kg, 302 mOsmol / kg, 303 mOsmol / kg, 304 mOsmol / kg, 305 mOsmol / kg, 306 mOsmol / kg, 307 mOsmol / kg, 308 mOsmol / kg, 309 mOsmol / kg, 310 mOsmol / kg, 311 mOsmol / kg, 312 mOsmol / kg, 313 mOsmol / kg, 314 mOsmol / kg, 315 mOsmol / kg, 316 mOsmol / kg, 317 mOsmol / kg, 318 mOsmol / kg, 319 mOsmol / kg, or 320 mOsmol / kg.

[0045] In some embodiments, the L-tartaric acid salt of the compound of Formula I is in Form II as a starting material for preparing an injection. As disclosed in WO2023284788A1, the X-ray powder diffractogram thereof includes at least peaks at diffraction angles 2 theta (°) values of 13.82±0.2, 14.87±0.2, 20.55±0.2, 23.15±0.2.

[0046] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form II further comprises one or more peaks at diffraction angle 2-theta (°) values selected from the group consisting of: 10.41 ± 0.2, 15.75 ± 0.2, 16.28 ± 0.2, 17.21 ± 0.2, 17.63 ± 0.2, 19.98 ± 0.2, 20.22 ± 0.2, 21.08 ± 0.2, 22.22 ± 0.2, 24.56 ± 0.2, 28.91 ± 0.2, 38.00 ± 0.2, 44.21 ± 0.2 in addition to peaks at diffraction angle 2-theta (°) values: 13.82 ± 0.2, 14.87 ± 0.2, 20.55 ± 0.2, 23.15 ± 0.2.

[0047] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form II comprises peaks at diffraction angle 2-theta (°) values: 10.41 ± 0.2, 13.82 ± 0.2, 14.87 ± 0.2, 15.75 ± 0.2, 16.28 ± 0.2, 17.21 ± 0.2, 17.63 ± 0.2, 19.98 ± 0.2, 20.22 ± 0.2, 20.55 ± 0.2, 21.08 ± 0.2, 22.22 ± 0.2, 23.15 ± 0.2, 24.56 ± 0.2, 28.91 ± 0.2.

[0048] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form II comprises peaks at diffraction angle 2-theta (°) values: 10.41 ± 0.2, 13.82 ± 0.2, 14.87 ± 0.2, 15.75 ± 0.2, 16.28 ± 0.2, 17.21 ± 0.2, 17.63 ± 0.2, 19.98 ± 0.2, 20.22 ± 0.2, 20.55 ± 0.2, 21.08 ± 0.2, 22.22 ± 0.2, 23.15 ± 0.2, 24.56 ± 0.2, 28.91 ± 0.2, 38.00 ± 0.2, 44.21 ± 0.2.

[0049] In some embodiments, the L-tartaric acid salt of the compound of Formula I is in the form of crystalline Form III as a starting material for preparing an injection, and the X-ray powder diffraction pattern of the crystalline Form III comprises at least peaks at diffraction angle 2-theta (°) values: 17.1 ± 0.2, 17.4 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2.

[0050] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form III comprises at least one or more peaks at diffraction angle 2-theta (°) values selected from the group consisting of: 7.2 ± 0.2, 10.0 ± 0.2, 13.1 ± 0.2, 17.1 ± 0.2, 17.4 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 24.3 ± 0.2.

[0051] In some embodiments, the X-ray powder diffraction pattern of the Form III comprises at least one peak selected from the group consisting of angles 2-theta (°) values at 7.2 ± 0.2, 10.0 ± 0.2, 10.4 ± 0.2, 11.1 ± 0.2, 13.1 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 17.4 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 24.3 ± 0.2, 25.7 ± 0.2.

[0052] In some embodiments, the X-ray powder diffraction pattern of the Form III comprises at least one peak selected from the group consisting of angles 2-theta (°) values at 3.7 ± 0.2, 7.2 ± 0.2, 10.0 ± 0.2, 10.4 ± 0.2, 11.1 ± 0.2, 12.0 ± 0.2, 13.1 ± 0.2, 14.4 ± 0.2, 14.8 ± 0.2, 15.4 ± 0.2, 15.8 ± 0.2, 17.1 ± 0.2, 17.4 ± 0.2, 18.6 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 22.2 ± 0.2, 24.3 ± 0.2, 25.7 ± 0.2, 26.2 ± 0.2, 27.1 ± 0.2, 28.7 ± 0.2, 29.3 ± 0.2, 29.9 ± 0.2, 30.4 ± 0.2, 31.4 ± 0.2, 33.0 ± 0.2, 34.7 ± 0.2, 36.0 ± 0.2, 37.0 ± 0.2, 37.8 ± 0.2, 39.2 ± 0.2.

[0053] In some embodiments, the X-ray powder diffraction pattern of the Form III is substantially as shown in Figure 1.

[0054] In some embodiments, the melting point of the Form III is 160-170 °C.

[0055] In some embodiments, the Form III has a peak temperature of 167.55 ± 2 °C in a differential scanning calorimetry profile.

[0056] In some embodiments, the Form III is prepared by the following method: heating and stirring an L-tartaric acid salt of a compound of Formula I in a solvent, filtering, and drying to obtain the Form III, wherein the solvent comprises ethyl acetate or methyl tert-butyl ether.

[0057] In some embodiments, the volume of the solvent is 10-20 times the amount of the L-tartaric acid salt of a compound of Formula I.

[0058] In some embodiments, the heating temperature is 40-80 °C, more preferably, the heating temperature is 50-65 °C. In some embodiments, the heating temperature is 40-80 °C, more preferably, the heating temperature is 50-65 °C.

[0059] In some embodiments, the liquid composition contains an injection solvent selected from at least one of water for injection, 0.9% sodium chloride solution, saline solution, oil for injection, ethanol, propylene glycol, ethylene glycol, t-butanol and polyethylene glycol. The polyethylene glycol includes polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600.

[0060] In some embodiments, the injection solvent is water for injection or 0.9% sodium chloride solution.

[0061] In some embodiments, the injection solvent is a mixture of any one of ethanol, propylene glycol, ethylene glycol, t-butanol and polyethylene glycol with water for injection or sodium chloride solution.

[0062] In some embodiments, the liquid composition described in the present application is an injection.

[0063] In some embodiments, the liquid composition described in the present application is an injection, which can include small volume injections (20 ml or less, such as 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, 20 ml) and large volume injections (50 ml or more, such as 50 ml, 60 ml, 70 ml, 75 ml, 80 ml, 90 ml, 100 ml, 250 ml, 500 ml, etc.).

[0064] In some embodiments, the injection described in the present application contains L-tartaric acid salt of the compound of Formula I, buffer salt, pH adjusting agent, osmotic pressure adjusting agent and injection solvent, and the pH of the injection is 6.0-7.4.

[0065] In some embodiments, the injection described in the present application contains L-tartaric acid salt of the compound of Formula I, buffer salt, pH adjusting agent, osmotic pressure adjusting agent and injection solvent, and the pH of the injection is 6.0-7.1.

[0066] In some embodiments, based on the volume of the injection, the concentration of L-tartaric acid salt of the compound of Formula I is 0.1-5.0 mg / ml as free base, the concentration of buffer salt is <6.8 mg / ml, the concentration of osmotic pressure adjusting agent is 1.0-15.0 mg / ml, and the pH of the injection is 6.0-7.4.

[0067] In some embodiments, the concentration of the L-tartaric acid salt of the compound of Formula I is 0.1-5.0 mg / ml as free base, the concentration of the buffer salt is < 6.8 mg / ml, the concentration of the osmotic pressure regulator is 1.0-15.0 mg / ml, the pH regulator is appropriate amount, the injection solvent is appropriate amount to make the injection volume 1-10 ml, and the pH of the injection is 6.0-7.1, wherein the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition as free base is < 3.4, based on the volume of the injection.

[0068] In some embodiments, the concentration of the L-tartaric acid salt of the compound of Formula I is 0.1-5.0 mg / ml as free base, the concentration of the buffer salt is < 6.8 mg / ml, the concentration of the osmotic pressure regulator is 1.0-15.0 mg / ml, the pH regulator is appropriate amount, the injection solvent is appropriate amount to make the injection volume 1-10 ml, and the pH of the injection is 6.0-7.4, wherein the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition as free base is < 0.8, based on the volume of the injection.

[0069] In some embodiments, the injection described herein has a volume, wherein the buffer salt is selected from at least one of sodium dihydrogen phosphate, sodium acetate, histidine and sodium citrate. The pH regulator can be selected from sodium hydroxide solution or hydrochloric acid solution. The buffer salt-pH regulator system selected herein has relatively good compatibility with the L-tartaric acid salt of the compound of Formula I under terminal sterilization conditions, and can inhibit the impurities generated by high temperature in the aqueous solution of the L-tartaric acid salt of the compound of Formula I.

[0070] In some embodiments, the concentration of the L-tartaric acid salt of the compound of Formula I is 0.1-5.0 mg / ml as free base, the concentration of the buffer salt is < 6.8 mg / ml, the concentration of the osmotic pressure regulator is 1.0-15.0 mg / ml, the pH regulator is appropriate amount, the injection solvent is appropriate amount to make the injection volume 1-10 ml, and the pH of the injection is 6.0-7.1, wherein the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition as free base is < 3.4, based on the volume of the injection.

[0071] The ratio of the concentration of the buffering salt to the concentration of the salt of the compound of Formula I in the liquid composition, based on the volume of the injection solution, can be selected from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, or 3.3.

[0072] In some embodiments, the L-tartaric acid salt of the compound of Formula I has a concentration of 1.0 mg / ml as free base, the buffering salt has a concentration of 0.8-2.0 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is present in an amount sufficient to adjust the pH of the injection solution to a pH of 6.0-7.1, the injection solvent is present in an amount sufficient to bring the injection solution to a volume of 1-10 ml, and the buffering salt is sodium phosphate dibasic.

[0073] In some embodiments, the L-tartaric acid salt of the compound of Formula I has a concentration of 1.0 mg / ml as free base, the buffering salt has a concentration of <0.6 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is present in an amount sufficient to adjust the pH of the injection solution to a pH of 6.0-7.4, the injection solvent is present in an amount sufficient to bring the injection solution to a volume of 1-10 ml, and the buffering salt is sodium phosphate dibasic.

[0074] In some embodiments, the L-tartaric acid salt of the compound of Formula I has a concentration of 1.0 mg / ml as free base, the buffering salt has a concentration of 0.1-0.4 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is present in an amount sufficient to adjust the pH of the injection solution to a pH of 6.0-7.4, the injection solvent is present in an amount sufficient to bring the injection solution to a volume of 1-10 ml, and the buffering salt is sodium phosphate dibasic.

[0075] In some embodiments, the L-tartaric acid salt of the compound of Formula I has a concentration of 2.0 mg / ml as free base, the buffering salt has a concentration of 1.0-3.5 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is present in an amount sufficient to adjust the pH of the injection solution to a pH of 6.0-7.1, the injection solvent is present in an amount sufficient to bring the injection solution to a volume of 1-10 ml, and the buffering salt is sodium phosphate dibasic.

[0076] In some embodiments, based on the volume of the injection, the L-tartrate salt of the compound of Formula I has a concentration of 1.0 mg / ml as free base, the buffer salt has a concentration of 0.1-3.0 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is in an appropriate amount, the injection solvent is added to the injection volume of 1-10 ml, the pH of the injection is 6.0-7.1, and the buffer salt is sodium citrate.

[0077] In some embodiments, based on the volume of the injection, the L-tartrate salt of the compound of Formula I has a concentration of 1.0 mg / ml as free base, the buffer salt has a concentration of 0.75-1.5 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is in an appropriate amount, the injection solvent is added to the injection volume of 1-10 ml, the pH of the injection is 6.5-7.1, and the buffer salt is sodium citrate.

[0078] In some embodiments, based on the volume of the injection, the salt of the compound of Formula I has a concentration of 1.0 mg / ml as free base, the buffer salt has a concentration of 0.7-3.2 mg / ml, the osmotic pressure adjusting agent has a concentration of 1.0-15.0 mg / ml, the pH adjusting agent is in an appropriate amount, the injection solvent is added to the injection volume of 1-10 ml, the pH of the injection is 6.0-7.4, and the buffer salt is sodium acetate.

[0079] The second aspect of the present application provides a preparation method of the above-mentioned liquid composition, which comprises mixing the salt of the compound of Formula I, the buffer salt, the pH adjusting agent, and the injection solvent (preferably injection water), and further comprises adding the osmotic pressure adjusting agent.

[0080] In some embodiments, the preparation method of the liquid composition of the present application further comprises at least one of the following steps: filling, nitrogen filling, and sterilization.

[0081] In some embodiments, the preparation method of the liquid composition of the present application comprises the steps of: mixing the salt of the compound of Formula I, the buffer salt, the pH adjusting agent, the osmotic pressure adjusting agent, and injection water; and at least one of the following steps: filling, nitrogen filling, or sterilization.

[0082] In some embodiments, the salt of the compound of Formula I is the L-tartrate salt of the compound of Formula I.

[0083] In some embodiments, the L-tartaric acid salt of the compound of Formula I is formulated into an injection using Form II as a starting material. As disclosed in WO2023284788A1, the X-ray powder diffractogram thereof includes at least peaks at diffraction angle 2 theta (°) values of 13.82±0.2, 14.87±0.2, 20.55±0.2, 23.15±0.2.

[0084] In some embodiments, the X-ray powder diffractogram of the Form II includes peaks at diffraction angle 2 theta (°) values of 10.41±0.2, 13.82±0.2, 14.87±0.2, 15.75±0.2, 16.28±0.2, 17.21±0.2, 17.63±0.2, 19.98±0.2, 20.22±0.2, 20.55±0.2, 21.08±0.2, 22.22±0.2, 23.15±0.2, 24.56±0.2, 28.91±0.2.

[0085] In some embodiments, the X-ray powder diffractogram of the Form II includes peaks at diffraction angle 2 theta (°) values of 10.41±0.2, 13.82±0.2, 14.87±0.2, 15.75±0.2, 16.28±0.2, 17.21±0.2, 17.63±0.2, 19.98±0.2, 20.22±0.2, 20.55±0.2, 21.08±0.2, 22.22±0.2, 23.15±0.2, 24.56±0.2, 28.91±0.2, 38.00±0.2, 44.21±0.2.

[0086] In some embodiments, the L-tartaric acid salt of the compound of Formula I is formulated into an injection using Form III as a starting material.

[0087] In some embodiments, the L-tartaric acid salt of the compound of Formula I is Form III, and the X-ray powder diffractogram of Form III includes at least peaks at diffraction angle 2 theta (°) values of 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2.

[0088] In some embodiments, the X-ray powder diffractogram of Form III includes at least peaks at diffraction angle 2 theta (°) values of 7.2±0.2, 10.0±0.2, 13.1±0.2, 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2, 24.3±0.2.

[0089] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form III comprises at least one peak selected from the group consisting of diffraction angle 2-theta (°) values at 7.2±0.2, 10.0±0.2, 10.4±0.2, 11.1±0.2, 13.1±0.2, 14.4±0.2, 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2, 21.2±0.2, 24.3±0.2, 25.7±0.2.

[0090] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form III comprises at least one peak selected from the group consisting of diffraction angle 2-theta (°) values at 3.7±0.2, 7.2±0.2, 10.0±0.2, 10.4±0.2, 11.1±0.2, 12.0±0.2, 13.1±0.2, 14.4±0.2, 14.8±0.2, 15.4±0.2, 15.8±0.2, 17.1±0.2, 17.4±0.2, 18.6±0.2, 19.5±0.2, 20.2±0.2, 21.2±0.2, 22.2±0.2, 24.3±0.2, 25.7±0.2, 26.2±0.2, 27.1±0.2, 28.7±0.2, 29.3±0.2, 29.9±0.2, 30.4±0.2, 31.4±0.2, 33.0±0.2, 34.7±0.2, 36.0±0.2, 37.0±0.2, 37.8±0.2, 39.2±0.2.

[0091] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form III is as shown in Figure 1.

[0092] In some embodiments, the sterilization is terminal sterilization, i.e. moist heat sterilization.

[0093] In some embodiments, the moist heat sterilization refers to a method of sterilization in saturated steam, boiling water or flow-through steam, for example, 115°C for 30-50 minutes, 121°C for 12-20 minutes, 126°C for 10-15 minutes, 134°C for 3-5 minutes.

[0094] In some embodiments, the filling is filling the liquid composition into an ampoule.

[0095] The third aspect of the present application provides a crystalline Form III of L-tartaric acid salt of the compound of Formula I.

[0096] In some embodiments, the L-tartaric acid salt of the compound of Formula I is Form III, and the X-ray powder diffraction pattern of Form III comprises at least peaks at diffraction angles 2-mu (°) values of 17.1 ± 0.2, 17.4 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2.

[0097] In some embodiments, the X-ray powder diffraction pattern of Form III comprises at least peaks at diffraction angles 2-mu (°) values of 7.2 ± 0.2, 10.0 ± 0.2, 13.1 ± 0.2, 17.1 ± 0.2, 17.4 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 24.3 ± 0.2.

[0098] In some embodiments, the X-ray powder diffraction pattern of Form III comprises at least peaks at diffraction angles 2-mu (°) values of 7.2 ± 0.2, 10.0 ± 0.2, 10.4 ± 0.2, 11.1 ± 0.2, 13.1 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 17.4 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 24.3 ± 0.2, 25.7 ± 0.2.

[0099] In some embodiments, the X-ray powder diffraction pattern of Form III comprises at least peaks at diffraction angles 2-mu (°) values of 3.7 ± 0.2, 7.2 ± 0.2, 10.0 ± 0.2, 10.4 ± 0.2, 11.1 ± 0.2, 12.0 ± 0.2, 13.1 ± 0.2, 14.4 ± 0.2, 14.8 ± 0.2, 15.4 ± 0.2, 15.8 ± 0.2, 17.1 ± 0.2, 17.4 ± 0.2, 18.6 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 22.2 ± 0.2, 24.3 ± 0.2, 25.7 ± 0.2, 26.2 ± 0.2, 27.1 ± 0.2, 28.7 ± 0.2, 29.3 ± 0.2, 29.9 ± 0.2, 30.4 ± 0.2, 31.4 ± 0.2, 33.0 ± 0.2, 34.7 ± 0.2, 36.0 ± 0.2, 37.0 ± 0.2, 37.8 ± 0.2, 39.2 ± 0.2.

[0100] In some embodiments, the X-ray powder diffraction pattern of Form III is as shown in FIG. 1.

[0101] In some embodiments, the melting point of Form III is 160-170 °C.

[0102] In some embodiments, the Form III further has the differential scanning calorimetry pattern with a peak temperature at 167.55±2°C.

[0103] The fourth aspect of the present application provides a preparation method of the Form III of the L-tartaric acid salt of the compound of Formula I, which comprises the following method: taking the L-tartaric acid salt of the compound of Formula I, a solvent, heating and stirring, filtering, and drying to obtain the Form III, wherein the solvent comprises ethyl acetate or methyl tert-butyl ether.

[0104] In some embodiments, the volume of the solvent is 10-20 times the amount of the L-tartaric acid salt of the compound of Formula I.

[0105] In some embodiments, the heating temperature is 40-80°C, and more preferably, the heating temperature is 50-65°C.

[0106] The fifth aspect of the present application provides that the liquid composition can be used for preparing a medicine for preventing and / or treating a disease related to MOR receptor agonist, wherein the disease related to MOR receptor agonist is selected from pain, immune dysfunction, inflammation, esophageal reflux disease, neurological disease, mental disease, urological disease, reproductive disease, cardiovascular disease, and respiratory disease.

[0107] The pain is selected from postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, and inflammation-induced pain. The cancer in the cancer-induced pain is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia, and leukemia. The postoperative pain includes postoperative pain of abdominal surgery, preferably moderate to severe postoperative pain or acute pain of abdominal surgery.

[0108] The therapeutically effective amount of the liquid composition of the present application is about 0.1 mg / kg to about 5 g / kg (body weight).

[0109] As used herein, "therapeutically effective amount" means an amount that is functional or active and acceptable to a human and / or animal. As used herein, "patient" means an animal, preferably a mammal, and more preferably a human. The term "mammal" means a warm-blooded vertebrate animal, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.

[0110] As used herein, "treatment" means to alleviate, slow the progression of, attenuate, prevent, or maintain an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition. Beneficial effects:

[0111] The maleate salt, fumarate salt, L-tartrate salt or succinate salt of the compound of Formula I is selected as the API of the liquid composition in the present application, especially the L-tartrate salt, which has lower impurity types and total impurity content in the stability test, is safer and more suitable as the active ingredient of the injection.

[0112] The prescription of the liquid composition described in the present application is simple, and the specific buffer salt solution, its ratio and pH are selected to avoid discoloration, turbidity or precipitation during the preparation process or terminal sterilization. The liquid composition of the present application is a colorless and clear liquid without visible foreign matter in the terminal sterilization or stability test.

[0113] The buffer system (including buffer salt and pH adjuster) of the liquid composition described in the present application has relatively good compatibility with the L-tartrate salt of the compound of Formula I under terminal sterilization conditions. By finally controlling the pH to be between 6.0 and 7.4, the impurities generated by the L-tartrate salt of the compound of Formula I in aqueous solution due to high temperature can be better controlled, especially when the pH value is greater than 6.5, the salt ion strength is high, and the unknown impurities are significantly reduced.

[0114] The liquid composition described in the present application has good stability, and the total impurity is ≤3.0% under long-term, high-temperature or light irradiation, preferably, the total impurity is ≤1.5%, the impurity risk is controllable, and the risk of visible foreign matter and related substances is small.

[0115] The pH of the liquid composition described in the present application is not more than 8.0, which has less vascular irritation for intravenous injection and better safety.

[0116] The preparation process of the liquid composition described in the present application is simple, which can be completed by stirring uniformly at room temperature for a short time, and is easy to realize scale-up production. The terminal moist heat sterilization method is selected, which has low cost, high level of sterility assurance and better safety.

[0117] Terminology

[0118] The related substances described in the present application refer to isomers, intermediates, synthetic by-products, degradation product impurities and the like generated during the preparation process and storage process of the API. Generally, the safety and purity of the drug are investigated by the maximum single impurity content, total impurity content and impurity types or number in the related substances.

[0119] The RRT described in the present application is the relative retention time, and the peak time of the API (for example, the L-tartrate salt of the compound of Formula I) is taken as the reference peak. The ratio of the peak time of each related substance to the peak time of the API. The calculation formula is as follows:

[0120] The ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition as free base (the concentrations are mass-volume concentrations, such as mg / ml, g / L, g / ml, mg / L, mg / m 3 The ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I in the liquid composition as free base (the concentrations are mass-volume concentrations, such as mg / ml, g / L, g / ml, mg / L, mg / m

[0121] The visible foreign matter in the present application refers to insoluble substances that can be observed by visual observation under specified conditions, and the particle size or length is usually greater than 50 μm, which exist in injections, ophthalmic liquid preparations and sterile bulk drugs. According to the visible foreign matter inspection method in Pharmacopoeia 2020 edition volume IV general rules.

[0122] The appropriate amount of pH regulator in the present application refers to the amount of basic regulator and / or acidic regulator, which can be adjusted according to the pH value range of the injection, for example, the pH regulator is selected as sodium hydroxide solution or hydrochloric acid solution, and the pH value of the injection is adjusted to 6.0-7.4. BRIEF DESCRIPTION OF DRAWINGS

[0123] The drawings described herein are used to provide further understanding of the present application, and form a part of the present application. The schematic embodiments of the present application and their descriptions are used to explain the present application, and do not constitute improper limitations on the present application.

[0124] Figure 1 is the X-ray powder diffraction spectrum of the crystal form III of the L-tartaric acid salt of the compound of Formula I in the present application.

[0125] Figure 2 is the differential scanning calorimetric spectrum (DSC) of the crystal form III of the L-tartaric acid salt of the compound of Formula I in the present application.

[0126] Figure 3 is the X-ray powder diffraction spectrum of the fumaric acid salt crystal form of the compound of Formula I in the present application. DETAILED DESCRIPTION

[0127] The following examples will help to understand the present application, but are not intended to limit the scope of the present application. The following discloses some embodiments of the present application, and those skilled in the art can appropriately improve the process parameters according to the content herein. It is particularly pointed out that all similar replacements and changes are obvious to those skilled in the art, and they are considered to be included in the present application. The methods and applications of the present application have been described by the preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present application, in order to realize and apply the present application technology.

[0128] Unless otherwise specified, the raw materials, excipients and reagents used in the following examples are commercially available or can be prepared by known methods.

[0129] I. Preparation of maleate, L-tartrate, succinate and fumarate salts of the compound of formula I

[0130] [According to Rule 26, the maleate, L-tartrate and succinate salts of the compound of formula I in this application are: maleate, L-tartrate and succinate salts of (4S,6S)-6-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-amine. The preparation method can refer to the example of WO2023284788A1.

[0131] Preparation of fumarate salt of the compound of formula I: weigh YZJ-4729 free base into a vial, add acetone under magnetic stirring at 50°C, and stir until the compound is completely dissolved. Then slowly add the counterion (fumaric acid) to the reaction solution at a molar ratio of 1:1.05, and raise the temperature to 50°C within 30 min, maintain for 1 h, and then lower the temperature to room temperature within 2 h. Finally, magnetically stir the sample at room temperature overnight (about 20 hours).

[0132] After stirring overnight, if the sample in the vial is a suspension and the amount of solid is large, centrifugal filtration (6000 rpm, centrifugal for 10 min) is used to collect the solid; if the sample in the vial is a clear solution or the amount of solid is small, the solvent is concentrated by natural evaporation and the solid is collected. The collected solid is dried in an oven at 40°C overnight, and the dried solid is subjected to X-ray powder diffraction test. The X-ray powder diffraction spectrum of the fumarate salt of the compound of formula I is shown in Figure 3.

[0133] The testing instrument of the X-ray powder diffraction spectrum is the X-ray powder diffractometer of D2 PHASER of Bruker Company.

[0134] The determination conditions of the X-ray powder diffraction spectrum are as follows: Cu-Kα ray is used The working voltage is set to 30 kV, the current is set to 10 mA, the scanning range is 2θ: 3-60°, the step length is 0.02 sec / step, and the time is 0.5 s.

[0135] II. Quality standard of the injection of the salt of the compound of formula I

[0136] III. Content determination method of the salt of the compound of formula I

[0137] Content determination: refer to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 edition Part IV General Rules 0512).

[0138] Reference solution: accurately weigh the L-tartaric acid salt of the compound of formula I, dissolve in water and dilute quantitatively to prepare a salt solution of the compound of formula I.

[0139] Test solution: take an appropriate amount of the liquid composition of the product.

[0140] Chromatographic conditions:

[0141] Chromatographic column: octadecylsilane bonded silica gel as filler (4.6 mm x 150 mm, 3.5 μm) or a chromatographic column with equivalent performance;

[0142] Mobile phase: mobile phase A: containing phosphate buffer mobile phase, B: containing acetonitrile-methanol, A:B = 20-80%:80-20% elution;

[0143] Detection wavelength: 262 nm;

[0144] Flow rate: 1 ml / min;

[0145] Column temperature: 30℃;

[0146] Injection volume: 10 μl;

[0147] Run time: 15 min.

[0148] System suitability requirements: the theoretical plate number calculated according to the chromatographic peak of the compound of formula I should not be less than 2000, and the separation degree between the chromatographic peak of the compound of formula I and the adjacent impurity peak should meet the requirements.

[0149] Determination method: accurately measure the test solution and the reference solution, respectively inject into the liquid chromatograph, and record the chromatogram. Calculate by peak area according to the external standard method.

[0150] Four, determination method of related substances

[0151] Determination of related substances: determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512).

[0152] Test solution: take an appropriate amount of the product.

[0153] Reference solution: accurately measure an appropriate amount of the test solution, dissolve in the mobile phase and dilute quantitatively to prepare the reference solution.

[0154] Related substance positioning solution: take an appropriate amount of related substances, dissolve and dilute with mobile phase to prepare a solution with appropriate concentration as the positioning solution.

[0155] System suitability solution: take an appropriate amount of L-tartaric acid salt of the compound of formula I and related substances, dissolve in the mobile phase and dilute with the mobile phase to prepare a mixed solution with appropriate concentration as the system suitability solution.

[0156] Chromatographic conditions:

[0157] Column: Silica gel with octadecylsilane bonded (4.6 mm x 150 mm, 3.5 μm or equivalent performance of the column);

[0158] Mobile phase: mobile phase A: aqueous solution, mobile phase B: containing acetonitrile-methanol, elution gradient 90%-10%;

[0159] Detection wavelength: 262 nm and 210 nm;

[0160] Flow rate: 1 ml / min;

[0161] Column temperature: 30 °C;

[0162] Injection volume: 15 μl.

[0163] System suitability requirements: in the chromatogram of the system suitability solution, the related substance chromatographic peak and the main component API chromatographic peak are in turn eluted, and the separation degree between each component peak shall meet the requirements.

[0164] Determination method: accurately measure the positioning solution, test sample solution and control solution, respectively inject into the liquid chromatograph, record the chromatogram of the control solution at 262 nm wavelength, sample solution at 210 nm wavelength and 262 nm wavelength, and calculate the content of each impurity according to the self-dilution control method. The calculation formula is as follows:

[0165] Total impurities = ∑ impurities

[0166] In the formula: A impurity: the peak area of API at 210 nm of the sample solution,

[0167] The peak area of the related substance at 262 nm of the sample solution;

[0168] A control 262 nm: the main peak area at 262 nm of the control solution;

[0169] f: correction factor of impurity;

[0170] ∑ impurities: the total content of impurities not less than 0.05%.

[0171] Limit: in the chromatogram of the test sample solution, the maximum single impurity content of the related substance is ≤0.70%, and the total impurity is ≤3.0%. The chromatographic peak with a content less than 0.05% in the chromatogram of the test sample solution is ignored.

[0172] Five, the determination method of insoluble particles:

[0173] Take 4 parts of the liquid composition, and check according to the method (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0903), the number of particles of 10 μm and above in each test sample container (parts) should not exceed 6000, and the number of particles of 25 μm and above should not exceed 600.

[0174] The injection of the following Examples 1-46 and Comparative Examples 1-31 of the present application is prepared using L-tartrate salt Form II of the compound of Formula I as the starting material.

[0175] Formulation of Examples 1-5: see Table 1

[0176] Table 1: Injection with a specification of about 1 mg / ml Note: The mass of L-tartrate salt of the compound of Formula I is 6.85 (mg / branch), and the mass of free base is 5.0 (mg / branch).

[0177] Appropriate amount: adjust the pH value of the injection to 6.0-6.9 with sodium hydroxide solution.

[0178] Preparation process:

[0179] (1) Take 90% of the prescription amount of water for injection, add the prescription amount of sodium phosphate monohydrate, and stir until dissolved completely; add the prescription amount of L-tartrate salt of the compound of Formula I, and stir until dissolved completely;

[0180] (2) Prepare a 0.1 mol / L sodium hydroxide solution for pH adjustment;

[0181] (3) Add sodium chloride to adjust the osmotic pressure of the liquid, and add the remaining prescription amount of water, and stir for 10 min;

[0182] (4) Add an appropriate amount of pH adjuster to the pH value of the injection;

[0183] (5) Fill and seal;

[0184] (6) Sterilize the filled and sealed injection at 121°C for 12 min.

[0185] Formulation of Examples 6-11: see Table 2

[0186] Table 2: Injection with a specification of about 1 mg / ml Note: The mass of L-tartrate salt of the compound of Formula I is 6.85 (mg / branch), and the mass of free base is 5.0 (mg / branch).

[0187] Preparation process:

[0188] (1) Take 90% of the prescription amount of water for injection, add the prescription amount of sodium phosphate monobasic monohydrate, stir and dissolve completely; add the prescription amount of L-tartrate of the compound of formula I, stir and dissolve completely;

[0189] (2) Prepare a 0.1 mol / L sodium hydroxide solution to adjust the pH value;

[0190] (3) Add an appropriate amount of sodium chloride to adjust the osmotic pressure of the liquid, and make up the remaining prescription amount of water, stir for 10 min;

[0191] (4) Add an appropriate amount of pH adjuster to adjust the pH value of the injection;

[0192] (5) Fill and seal;

[0193] (6) The filled and sealed injection is sterilized at 121°C for 12 min.

[0194] Formulation of Examples 12-17: see Table 3

[0195] Table 3: Injection with a specification of about 1 mg / ml Note: The mass of L-tartrate of the compound of formula I is 6.85 (mg / branch), and the mass of free base is 5.0 (mg / branch).

[0196] Appropriate amount: adjust the pH value of the injection to 6.0-7.4 with sodium hydroxide solution.

[0197] Preparation process:

[0198] (1) Take 90% of the prescription amount of water for injection, add the prescription amount of sodium phosphate monobasic monohydrate, stir and dissolve completely; add the prescription amount of L-tartrate of the compound of formula I, stir and dissolve completely;

[0199] (2) Prepare a 0.1 mol / L sodium hydroxide solution to adjust the pH value;

[0200] (3) Add an appropriate amount of sodium chloride to adjust the osmotic pressure of the liquid, and make up the remaining prescription amount of water, stir for 10 min;

[0201] (4) Add an appropriate amount of pH adjuster to adjust the pH value of the injection;

[0202] (5) Fill and seal;

[0203] (6) The filled and sealed injection is sterilized at 121°C for 12 min.

[0204] Formulation of Examples 18-23: see Table 4

[0205] Table 4: Injection with a specification of about 2 mg / ml Note: L-tartaric acid salt of compound of formula I mass 13.7 (mg / branch), free base mass 10.0 (mg / branch).

[0206] Appropriate amount: adjust to injection pH value to 6.0-7.4 with sodium hydroxide solution.

[0207] Preparation process:

[0208] (1) take 90% of the prescription amount of water for injection, add the prescription amount of sodium dihydrogen phosphate monohydrate, stir to dissolve completely; add the prescription amount of L-tartaric acid salt of compound of formula I, stir to dissolve completely;

[0209] (2) prepare 0.1 mol / L of sodium hydroxide solution pH adjuster value;

[0210] (3) add an appropriate amount of sodium chloride to adjust the osmotic pressure of the liquid medicine, make up the remaining prescription amount of water, stir for 10 min;

[0211] (4) add an appropriate amount of pH adjuster value to the injection pH value;

[0212] (5) fill and seal;

[0213] (6) the filled and sealed injection is sterilized at 121°C for 12 min.

[0214] Examples 24-32 prescription: see table 5

[0215] Table 5 injection containing sodium citrate Note: L-tartaric acid salt of compound of formula I mass 13.7 (mg / branch), free base mass 10.0 (mg / branch).

[0216] Appropriate amount: adjust to injection pH value to 6.0-7.4 with sodium hydroxide solution.

[0217] Preparation process:

[0218] (1) take 90% of the prescription amount of water for injection, add the prescription amount of sodium citrate, stir to dissolve completely; add the prescription amount of L-tartaric acid salt of compound of formula I, stir to dissolve completely;

[0219] (2) prepare 0.1 mol / L of sodium hydroxide solution pH adjuster value;

[0220] (3) add an appropriate amount of sodium chloride to adjust the osmotic pressure of the liquid medicine, make up the remaining prescription amount of water, stir for 10 min;

[0221] (4) add an appropriate amount of pH adjuster value to the injection pH value;

[0222] (5) fill and seal;

[0223] (6) The filled injection is sterilized at 121 °C for 12 min.

[0224] Formulation of injection of other systems in Examples 33-36, 41: see Table 6

[0225] Table 6 Injection of other systems Note: The mass of L-tartaric acid salt of the compound of Formula I is 13.7 (mg / branch), and the mass of free base is 10.0 (mg / branch).

[0226] Appropriate amount: adjust the pH of the injection to 6.0-7.4 with sodium hydroxide solution.

[0227] Formulation process:

[0228] (1) Take 90% of the prescription amount of water for injection, add the prescription amount of buffer, stir to dissolve completely; add the prescription amount of L-tartaric acid salt of the compound of Formula I, stir to dissolve completely;

[0229] (2) Prepare 0.1 mol / L sodium hydroxide solution for pH adjustment;

[0230] (3) Add an appropriate amount of osmotic pressure regulator, make up the remaining prescription amount of water, stir for 10 min;

[0231] (4) Add an appropriate amount of pH adjuster to the pH of the injection;

[0232] (5) Fill and seal;

[0233] (6) The filled injection is sterilized at 121 °C for 12 min.

[0234] Formulation of Examples 37-40: see Table 7

[0235] Table 7 Formulation of different API salts Note: RRT is the relative retention time.

[0236] Formulation process:

[0237] (1) Take 90% of the prescription amount of water for injection, add the prescription amount of sodium dihydrogen phosphate monohydrate, stir to dissolve completely; add the prescription amount of API salt, stir to dissolve completely;

[0238] (2) Prepare the pH adjuster value: prepare 0.1 mol / L sodium hydroxide solution;

[0239] (3) Add an appropriate amount of sodium chloride to adjust the osmotic pressure of the liquid medicine, make up the remaining prescription amount of water, stir for 10 min;

[0240] (4) Adjust pH: add appropriate amount of pH adjuster to the pH of the injection;

[0241] (5) Filling and sealing;

[0242] (6) Sterilize the filled and sealed injection at 121°C for 12 minutes.

[0243] Conclusion: As shown in Table 7 above, the total impurities of the L-tartaric acid salt of the compound of Formula I are not more than 1%, and the number of impurity types is small. Other salt types show an increase in the number of impurity types and the total impurity content, which poses a safety hazard. The L-tartaric acid salt of the compound of Formula I is more suitable for preparation into an injection.

[0244] Examples 42-45 Formulation: See Table 8

[0245] Table 8 Note: The mass of the L-tartaric acid salt of the compound of Formula I is calculated based on the mass of the free base.

[0246] Appropriate amount; adjust the pH of the injection to 6.5-7.1 with sodium hydroxide. If the pH of the injection is adjusted to >6.5-7.1 with sodium hydroxide, use hydrochloric acid to adjust the pH of the injection to 6.5-7.1.

[0247] Formulation process:

[0248] (1) Weigh 90% of the prescription amount of water for injection, add the prescription amount of sodium dihydrogen phosphate monohydrate, and stir until completely dissolved; add the prescription amount of L-tartaric acid salt of the compound of Formula I, and stir until completely dissolved;

[0249] (2) Prepare 0.1 mol / L sodium hydroxide solution and / or 0.1 mol / L hydrochloric acid solution;

[0250] (3) Add sodium chloride to adjust the osmotic pressure of the liquid, and add the remaining prescription amount of water, and stir for 10 minutes;

[0251] (4) Add an appropriate amount of sodium hydroxide solution and / or hydrochloric acid to the pH of the injection;

[0252] (5) Filling and sealing;

[0253] (6) Sterilize the filled and sealed injection at 121°C for 20 minutes or at 115°C for 50 minutes.

[0254] Examples 46-48 Stability

[0255] Example 46: Preparation of an injection using L-tartaric acid salt Form II of the compound of Formula I as the raw material

[0256] Examples 47-48: Preparation of an injection using L-tartaric acid salt Form III of the compound of Formula I as the raw material

[0257] Illumination condition: illuminance 4500±500lx, total illuminance no less than: 1.2x106lux·hr, near ultraviolet lamp energy no less than: 200W·hr / m 2 .

[0258] Results: as shown in Table 9

[0259] Table 9 Stability test of 10 days at 60℃ and under illumination condition

[0260] Examples 46-48 were prepared according to the method of Example 1.

[0261] Example 49 Preparation of Form III

[0262] Take 10 g of L-tartaric acid salt of the compound of Formula I, add 150 mL of ethyl acetate, stir at 65℃ for 24 h, filter, and dry the material at 60℃ under reduced pressure to obtain Form III.

[0263] Example 50 Preparation of Form III

[0264] Take 10 g of L-tartaric acid salt of the compound of Formula I, add 150 mL of methyl tert-butyl ether, stir at 50℃ for 12 h, filter, and dry the material at 60℃ under reduced pressure to obtain Form III.

[0265] Example 51 Structural characterization of Form III

[0266] D2 PHASER|Bruker X-ray powder diffraction analyzer was collected, and the XRPD parameters are shown in Table 10 below:

[0267] Table 10

[0268] In this application, the highest peak of the compound is defined as the base peak, and its relative intensity is 100%, which is I0, and the relative intensity of other peaks is the ratio of the peak height to the base peak, which is I / I0, only reflecting the approximate size of each position. The division of the relative intensity of each peak is defined as shown in Table 11 below.

[0269] Table 11

[0270] The X-ray powder diffraction spectrum of Form III is substantially characterized by Figure 1, and the related data is shown in Table 12. The differential scanning calorimetric spectrum (DSC) of Form III is substantially shown in Figure 2.

[0271] Table 12

[0272] Test Example 1 Selection of excipients for the formulation of the present application

[0273] Purpose of the experiment:

[0274] The compatibility of the L-tartrate of the compound of Formula I with various excipients was investigated for terminal sterilization, so as to select suitable excipients.

[0275] Experimental method:

[0276] Since the effect of the osmotic pressure regulator in the injection of the present application on the sterilization properties and the content change of the related substances was not significant, it was not a major factor, so in this test, the L-tartrate of the compound of Formula I was mixed with the excipients of the buffer system, respectively. The selected excipients were selected from sodium phosphate, sodium hydroxide, disodium hydrogen phosphate, acetic acid, sodium acetate, histidine, arginine, hydrochloric acid, phosphoric acid, cyclodextrin, etc. The composition and ratio of the excipients are shown in Table 13 (unit: mg / mL: mg / mL). Sterilization at 121°C for 20 min or at 115°C for 50 min, and the change of the properties, content and related substances of the sample solution before and after sterilization was investigated.

[0277] Experimental results:

[0278] As can be seen from Table 13, the sodium hydroxide, disodium hydrogen phosphate, sodium acetate, histidine, arginine of the single system, and the disodium hydrogen phosphate / sodium dihydrogen phosphate, citric acid / disodium hydrogen phosphate, tartaric acid / sodium hydroxide, cyclodextrin / sodium hydroxide, phosphoric acid / sodium hydroxide, histidine / hydrochloric acid of the binary system were used to adjust the pH value of the aqueous solution of the L-tartrate of the compound of Formula I, and the injection was prepared. After sterilization, it was found that the total impurity content of the injection increased or the injection had a turbidity phenomenon after sterilization, and the number of impurities of the injection after sterilization increased, which brought safety hazards. Although the pH value of the aqueous solution of the L-tartrate of the compound of Formula I was adjusted by the phosphoric acid / sodium hydroxide, histidine / hydrochloric acid system, the injection had no change in properties after sterilization, but the maximum single impurity content after sterilization exceeded 1.0%, which did not meet the quality standard and had safety hazards. Therefore, after the selection of the excipients of the present application, the buffer systems described in Table 13 cannot be used as the excipients of the L-tartrate injection of the compound of Formula I.

[0279] Test Example 2 Investigation of the amount and pH of the buffer system

[0280] Experimental method: The injection of the prescription of the comparative example shown in Table 14 was obtained according to the preparation method of Example 1.

[0281] Experimental results:

[0282] The pH value of sodium phosphate and sodium hydroxide as buffer system was investigated, as shown in Table 14. From the comparative examples 14-19, when the concentration of sodium phosphate was 3.4 mg / ml, i.e. the concentration ratio of sodium phosphate to the L-tartaric acid salt of the compound of Formula I was 3.4, no matter how to adjust the pH value from 6.0 to 7.2, visible foreign matter was generated after being placed at 80°C.

[0283] The investigation of reducing the pH value, in comparative examples 23 and 24, when the amount of sodium phosphate was about 3.46 mg / ml and the pH value was less than 6.0, although there was no solution turbidity during terminal sterilization, the amount of high-temperature impurities increased, which had a potential safety hazard, and the maximum single impurity was more than 1.0%.

[0284] The investigation of increasing the concentration of sodium phosphate, in comparative example 21, the concentration of sodium phosphate was 6.8 mg / ml, and the concentration ratio of sodium phosphate to the L-tartaric acid salt of the compound of Formula I was 3.4, during terminal sterilization, there was solution turbidity. In comparative example 22, the concentration of sodium phosphate was 12.5 mg / ml, and the concentration ratio of sodium phosphate to the L-tartaric acid salt of the compound of Formula I was 6.25, during terminal sterilization, there was solution turbidity.

[0285] The investigation of reducing the concentration of sodium phosphate, in comparative examples 19 and 20, at pH 7.2, the amount of sodium phosphate was reduced to 0.8 mg / ml, at pH 7.2, there was no visible foreign matter, but small oil droplets appeared during terminal sterilization, which had a high risk of unqualified properties. It can be seen that when the amount of sodium phosphate is reduced to 0.8 mg / ml, at pH 7.2, there is a high risk. Further reducing the concentration of sodium phosphate in comparative examples 32 and 33, still generated foreign matter, only when the concentration of sodium phosphate is reduced to 0.4 mg / ml or below, and the pH value reaches 7.4, the problem of oil droplets or particles during terminal sterilization can be overcome, and the content of visible foreign matter and impurities meets the requirements (see example 46).

[0286] The investigation of whether to add sodium phosphate, from comparative examples 30 and 31, it was found that without adding buffer salt in the prescription, and directly adding sodium hydroxide to adjust the pH value, indicated that without adding buffer salt in the prescription, there was no risk of visible foreign matter, but the risk of related substances increased, although the total impurity content did not exceed the limit, but it was much higher than the impurities of the injection with added sodium phosphate, and with the extension of time, the possibility of exceeding the limit of total impurity content was larger.

[0287] From the above analysis and examples 1-23, it can be seen that when the concentration ratio of sodium phosphate to the L-tartaric acid salt of the compound of Formula I is less than 3.4, and the pH value of the final injection is between 6.0 and 7.1, the impurities generated by high temperature in the aqueous solution of the L-tartaric acid salt of the compound of Formula I can be better controlled, there is no solution turbidity during terminal sterilization, and no foreign matter is generated after being placed at high temperature.

[0288] As can be seen from Comparative Examples 20, 32, 33 and Example 46, when the concentration of sodium dihydrogen phosphate is reduced to a sufficiently small value, for example, the concentration of sodium dihydrogen phosphate is < 0.6 mg / ml, the pH of the injection can be increased to 7.4, and the visible foreign matter, the risk of the properties during sterilization and the related substance can still be well controlled.

[0289] As can be seen from Comparative Examples 25 and 26, when the amount of sodium citrate is 3.4 mg / ml, the pH is 6.7-7.1 (compared with Examples 24-32), and the risk of unqualified properties during sterilization is greater; when the amount of citric acid is 1.5 mg / ml, the pH is > 7.1, and the risk of unqualified properties during sterilization is greater (see Comparative Examples 27-29). As can be seen from Examples 24-32, when the amount of citric acid is less than 3.4 mg / ml, the pH is controlled at 6.5-7.1, the properties during sterilization are qualified, the risk of related substances is controllable, and the total impurity content is less than 3.0%.

[0290] Table 15 Citrate-sodium hydroxide as a buffer system

[0291] Test Example Three Investigation of Sterilization Conditions

[0292] In order to ensure the sterile level of the product, the selection of the sterilization process should be carried out according to the sterilization decision tree in the Guiding Principles for Sterilization and Aseptic Process Research and Validation of Chemical Drug Injection (Trial Implementation). The excessive killing method and the residual probability method are the main terminal sterilization methods. The filtration killing method (F0≥12) and the residual probability method (12>F0≥8) are respectively developed. The samples (3 batches of samples prepared according to the prescription of Example 12) are sterilized. The sterilization conditions investigated by the residual probability method are: 1) 121 ℃, 8 min; 2) 115 ℃, 30 min; and 3) 110 ℃, 100 min. The key items of the samples before and after the above three sterilization conditions are detected, and the detection results are compared with those before sterilization. The specific results are shown in Table 16 below.

[0293] Table 16

[0294] Conclusion: According to the change of impurities before and after sterilization, the impurities of the small test sample after sterilization at 110 ℃ for 100 min change greatly. Considering the change of impurities before and after sterilization and the production efficiency, the sterilization condition of 110 ℃ for 100 min is not selected.

[0295] Test Example Four Stability Test

[0296] Sample: The prescription of Example 12 is scaled up, and the stability of the sample is investigated according to the investigation conditions in Table 17.

[0297] The prescription of Example 26 was amplified and the stability of the sample was investigated according to the investigation conditions in Table 18.

[0298] Results: As shown in Table 17, the stability test proved that the maximum single impurity and total impurity of the prescription containing sodium dihydrogen phosphate did not increase, the property did not change, and the insoluble particles met the requirements under high temperature and high humidity environment. As shown in Table 18, the stability test proved that the maximum single impurity and total impurity of the prescription containing sodium citrate did not increase, the property did not change, and the insoluble particles met the requirements under high temperature and high humidity environment.

[0299] Table 17 Stability test of Example 12

[0300] Table 18 Stability test of Example 26

[0301] Test Example 5 Effectiveness experiment of L-tartaric acid salt injection of the compound shown in Formula I for postoperative analgesia of abdominal surgery

[0302] Main purpose of the test: To preliminarily explore the effectiveness of YZJ-4729 tartaric acid salt injection for postoperative analgesia of abdominal surgery compared with placebo;

[0303] Secondary purpose: To explore the safety of YZJ-4729 tartaric acid salt injection for postoperative analgesia of abdominal surgery compared with placebo and morphine.

[0304] Inclusion criteria:

[0305] 18 years old≤age≤75 years old, gender unrestricted;

[0306] 18.0 kg / m 2 ≤Body Mass Index (BMI)≤28.0 kg / m 2 ;

[0307] American Society of Anesthesiologists (ASA) classification grade I-Ⅱ;

[0308] Patients undergoing abdominal surgery under general anesthesia, 1 h≤predicted duration of surgery≤6 h;

[0309] The researcher judged that the patient had recovered from anesthesia to be awake enough to accurately complete the protocol questionnaire, and the intensity of postoperative pain was moderate to severe pain, i.e. the NRS pain score was≥4 points in the resting state within 4 h after extubation;

[0310] Fully understand, voluntarily participate in this study, understand and can cooperate with the process of the test, and sign the informed consent form.

[0311] Test drug:

[0312] Test drug: Injection of Example 12 (hereinafter referred to as tartrate injection) specification 5 mL: 5 mg, batch number: 23110221; storage condition: avoid light, airtight, stored at no more than 30 ℃; produced by Yangtze River Pharmaceutical Group Co., Ltd., provided by Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

[0313] Placebo: 0.9% sodium chloride injection, specification 5 mL, batch number: 23102621; storage condition: avoid light, airtight, stored at no more than 30 ℃; produced by Yangtze River Pharmaceutical Group Co., Ltd., provided by Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

[0314] Positive drug: Morphine hydrochloride injection, specification 1 mL: 10 mg, batch number: 230306; storage condition: light shielding, airtight storage; produced by Northeast Pharmaceutical Group Shenyang First Pharmaceutical Co., Ltd., provided by Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

[0315] Treatment plan of test drug:

[0316] The test drug 5 mL was given for a long time of 2 min. The test drug was started to be infused 10 min (±2 min) after the start of the loading dose, and the PCA pump containing the test drug was started. The volume of the test drug that the subject could accept by single effective pressing of the PCA pump was 1 mL, and the lockout time was 6 min. The subject continued to use the PCA pump until 24 h (±5 min) after the start of the loading dose.

[0317] Test group 1: tartrate injection loading dose 1.5 mg (5 mL), PCA single dose 0.2 mg (1 mL), lockout time 6 min.

[0318] Test group 2: tartrate injection loading dose 1.5 mg (5 mL), PCA single dose 0.35 mg (1 mL), lockout time 6 min.

[0319] Test group 3: tartrate injection loading dose 1.5 mg (5 mL), PCA single dose 0.5 mg (1 mL), lockout time 6 min.

[0320] Test group 4: tartrate injection loading dose 2 mg (5 mL), PCA single dose 0.35 mg (1 mL), lockout time 6 min.

[0321] Placebo group: 0.9% sodium chloride injection loading dose volume 5 mL, PCA single dose volume 1 mL, lockout time 6 min.

[0322] Positive drug group: Morphine hydrochloride injection loading dose 3 mg (5 mL), PCA single dose 1 mg (1 mL), lock time 6 min.

[0323] Rescue analgesic treatment plan:

[0324] Before rescue analgesia: The subject was guided by the investigator to use the NRS scale to evaluate the intensity of pain in the resting state and the pain relief score (the degree of pain relief compared with baseline).

[0325] During the period from the end of the loading dose test drug infusion to the end of the test drug treatment, the subject complained of pain after test drug treatment, and the investigator determined that the test drug could not meet the subject's analgesic needs (resting NRS ≥ 4 points). Rescue analgesia can be performed.

[0326] Primary efficacy index:

[0327] Sum of pain intensity difference (SPID24) in resting state within 24 hours.

[0328] Secondary efficacy index:

[0329] (1) The proportion of subjects who did not use rescue analgesic drugs within 0-24 hours;

[0330] (2) The sum of pain intensity difference (SPID) in resting state at each NRS evaluation time point.

[0331] Exploratory efficacy index:

[0332] (1) The number of times and cumulative amount of rescue analgesic drug use within 0-24 hours;

[0333] (2) The time of first use of rescue analgesic drug.

[0334] Safety evaluation index:

[0335] Vital signs, physical examination, 12-lead electrocardiogram examination, blood oxygen saturation, laboratory examination, addiction assessment (OWS, drug preference VAS scale), Ramsay sedation scale score, nausea VAS score and adverse events.

[0336] Study results

[0337] The primary efficacy index of this trial was the time-weighted sum of pain intensity differences (SPID24) in resting state within 24 hours. Because of the unbalanced baseline resting state NRS pain intensity score, the covariance analysis model was used, with the baseline resting state NRS pain intensity score as a covariant, to estimate the corrected mean and standard deviation of SPID24 of each treatment group. In the FAS population, the corrected mean (standard error) of trial group 1 was 84.028 (5.704), that of trial group 2 was 86.016 (5.689), that of trial group 3 was 84.961 (5.782), that of trial group 4 was 86.324 (5.686), that of the positive drug group was 94.580 (5.717), and that of the placebo group was 74.002 (5.693). Compared with the placebo group, each trial group showed a more obvious pain relief trend.

[0338] Compared with the positive drug group, the resting NRS mean of each trial group decreased to below 4 points immediately after the end of the loading dose infusion, indicating that the trial drug had a faster onset of action than the positive drug.

[0339] Evaluation results of secondary efficacy indexes

[0340] (1) The proportion of subjects who did not use rescue analgesics within 0-24 hours: In the FAS population, trial group 1 was 66.7%, trial group 2 was 76.7%, trial group 3 was 72.4%, trial group 4 was 70.0%, the positive drug group was 76.7%, and the placebo group was 53.3%. In the FAS population, compared with the placebo group, each trial group and the positive drug group showed a trend of being superior to the placebo.

[0341] (2) SPID at each NRS evaluation time point: In the FAS population, the corrected mean (standard error) of SPID6 of trial group 1 was 18.370 (1.503), that of trial group 2 was 19.782 (1.499), that of trial group 3 was 18.598 (1.523), that of trial group 4 was 20.339 (1.498), that of the positive drug group was 19.630 (1.506), and that of the placebo group was 15.181 (1.500). Compared with the placebo group, trial group 2, trial group 4, and the positive drug group could significantly relieve postoperative pain in subjects within 6 hours, and the difference was statistically significant (p values were 0.032, 0.016, and 0.038, respectively).

[0342] Key exploratory indexes (related to rescue analgesia)

[0343] (1) Rescue analgesic drug use frequency and cumulative amount: the use frequency and cumulative amount of rescue analgesic drugs in each test group within 0-24h were less than those in the placebo group, among which the test group 3 and the test group 4 were significantly less than the placebo group, and the difference was clinically significant (p values were 0.014 and 0.036, respectively). Compared with the placebo group, the number of subjects receiving rescue analgesic drug treatment within 0-2h after the start of the loading dose infusion was significantly reduced in each test group and the positive drug group; within 2-24h after the start of the loading dose infusion, the number of subjects receiving rescue analgesic drug treatment in the test group 2, the test group 3, the test group 4 and the positive drug group showed a downward trend.

[0344] (2) Time of first use of rescue analgesic drugs: among the subjects using rescue analgesic drugs, the time of first use of rescue analgesic drugs (25% percentile, median, 75% percentile, mean) in each test group was longer, which was better than that in the placebo group, and the trend was more obvious in the test group 2, the test group 3 and the test group 4.

[0345] Research conclusion

[0346] The results of the clinical trial of tartrate injection (biased μ opioid receptor agonist) for postoperative analgesia in abdominal surgery showed that it had good postoperative analgesic effect and safety.

[0347] Effectiveness: ① The main efficacy index SPID24: compared with the placebo group, each test group showed a better analgesic effect trend, and the analgesic effect of the PCA 0.35mg and 0.5mg groups (test groups 2-4) was more obvious than that of the PCA 0.2mg group (test group 1); key secondary efficacy index: compared with the placebo group, the proportion, frequency and cumulative amount of rescue analgesic treatment within 24h in each test group were significantly reduced, and the first rescue analgesic treatment time after surgery in each test group was significantly longer than that in the placebo group and the positive drug group; ② The results of PK / PD simulation analysis showed that after the start of the infusion of the loading dose of 1.5mg and 2.0mg, the resting NRS score rapidly decreased, and the decrease in the resting NRS score was more obvious with the loading dose of 2.0mg.

[0348] Safety: the adverse events related to the test drug were mild and moderate, and the prognosis was recovery, which showed that tartrate injection had good safety and tolerability.

[0349] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. [Amended according to Rule 26 16.01.2026] A liquid composition of a MOR receptor agonist comprising a compound represented by Formula I or a salt thereof, a buffer salt, and a pH adjustor, the liquid composition having a pH of 6.0-7.4, Preferably, the pH value of the liquid composition is 6.0-7.

1.

2. The liquid composition according to claim 1, characterized in that, It comprises a salt of the compound of Formula I, a buffer salt and a pH adjusting agent, wherein the salt comprises a maleate salt, a fumarate salt, an L-tartrate salt or a succinate salt; preferably, the salt is an L-tartrate salt.

3. The liquid composition according to claim 1 or 2, characterized in that, The buffer salt comprises at least one of a phosphate salt, an acetate salt, a histidine, a citrate salt, a borate salt, an oxalate salt, a formate salt, a succinate salt, a lactate salt, a tartrate salt and a fumarate salt; preferably, the buffer salt is selected from at least one of a phosphate salt, an acetate salt, a histidine and a citrate salt; preferably, the phosphate salt is selected from at least one of sodium phosphate dibasic, sodium phosphate monobasic, potassium phosphate, potassium phosphate dibasic and potassium phosphate monobasic; preferably, the acetate salt is selected from at least one of sodium acetate, ammonium acetate, lithium acetate and potassium acetate; preferably, the citrate salt is selected from at least one of monosodium citrate, disodium citrate, sodium citrate and magnesium citrate; more preferably, the buffer salt is selected from at least one of sodium phosphate dibasic, sodium acetate, histidine and sodium citrate; further more preferably, the buffer salt is sodium phosphate dibasic and / or sodium citrate.

4. The liquid composition according to any one of claims 1 to 3, characterized in that, The concentration of the buffer salt in the liquid composition is less than 3.4 times the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base; preferably, the concentration of the buffer salt in the liquid composition is 0.1-2.0 times the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base; more preferably, the concentration of the buffer salt in the liquid composition is 0.2-1.7 times the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base; further more preferably, the concentration of the buffer salt in the liquid composition is 0.4-1.7 times the concentration of the salt of the compound of Formula I in the liquid composition in terms of free base.

5. The liquid composition according to any one of claims 1 to 4, characterized in that, The concentration of the buffer salt in the liquid composition is less than 6.8 mg / ml; preferably, the concentration of the buffer salt in the liquid composition is less than 3.4 mg / ml; further preferably, the concentration of the buffer salt in the liquid composition is 0.1-2.0 mg / ml; more preferably, the concentration of the buffer salt in the liquid composition is 0.2-1.7 mg / ml; further more preferably, the concentration of the buffer salt in the liquid composition is 0.4-1.7 mg / ml.

6. The liquid composition according to any one of claims 1 to 5, characterized in that, The pH adjusting agent is selected from at least one of a basic pH adjusting agent and / or an acidic pH adjusting agent; preferably, the basic pH adjusting agent is selected from at least one of a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate solution, a sodium bicarbonate solution, a sodium acetate solution, a triethylamine solution, a diethanolamine solution, a sodium phosphate solution and a tris solution; The acidic pH adjusting agent is selected from at least one of an ascorbic acid solution, a lactic acid solution, a malic acid solution, a fumaric acid solution, a citric acid solution, a tartaric acid solution, a succinic acid solution, a sulfuric acid solution, a hydrochloric acid solution, a histidine solution, a phosphoric acid solution and an acetic acid solution; Preferably, the pH adjusting agent comprises at least one of sodium hydroxide solution, acetic acid solution, sodium acetate solution, potassium hydroxide solution, hydrochloric acid solution and sulfuric acid solution; Preferably, the pH adjusting agent is sodium hydroxide solution and / or hydrochloric acid solution; Preferably, the solution concentration of the pH adjusting agent is 0.1-5 mol / l.

7. The liquid composition according to any one of claims 1 to 5, wherein The concentration of the salt of the compound of formula I in the liquid composition is 0.1-5.0 mg / ml as free base; Preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0-5.0 mg / ml as free base; more preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0 mg / ml or 2.0 mg / ml as free base.

8. The liquid composition according to claim 7, characterized in that, When the concentration of the salt of the compound of formula I in the liquid composition is 1.0-2.0 mg / ml as free base, the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of formula I in the liquid composition as free base is <3.4, and the buffer salt is sodium dihydrogen phosphate or sodium citrate; Preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0 mg / ml as free base, and the concentration of the buffer salt in the liquid composition is <3.4 mg / ml, and the buffer salt is sodium dihydrogen phosphate or sodium citrate; preferably, the concentration of the buffer salt in the liquid composition is 0.1-2.0 mg / ml, and the buffer salt is sodium dihydrogen phosphate or sodium citrate; preferably, the concentration of the buffer salt in the liquid composition is 0.2-1.7 mg / ml, and the buffer salt is sodium dihydrogen phosphate or sodium citrate; more preferably, the concentration of the buffer salt in the liquid composition is 0.4-1.7 mg / ml, and the buffer salt is sodium dihydrogen phosphate or sodium citrate; Preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0 mg / ml as free base, the concentration of the buffer salt in the liquid composition is 0.8-2.0 mg / ml, and the pH value of the liquid composition is 6.0-7.1, and the buffer salt is sodium dihydrogen phosphate; Preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0 mg / ml as free base, the concentration of the buffer salt in the liquid composition is <0.6 mg / ml, and the pH value of the liquid composition is 6.0-7.4, and the buffer salt is sodium dihydrogen phosphate; Preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0 mg / ml as free base, the concentration of the buffer salt in the liquid composition is 0.1-0.4 mg / ml, and the pH value of the liquid composition is 6.0-7.4, and the buffer salt is sodium dihydrogen phosphate; Preferably, the concentration of the salt of the compound of formula I in the liquid composition is 1.0 mg / ml as free base, the concentration of the buffer salt in the liquid composition is <3.0 mg / ml, and the pH value of the liquid composition is 6.0-7.1, and the buffer salt is sodium citrate; more preferably, the concentration of the buffer salt in the liquid composition is 0.75-1.5 mg / ml, and the buffer salt is sodium citrate. Preferably, the salt of the compound of Formula I is present in the liquid composition at a concentration of 2.0 mg / ml as free base, and the buffer salt is sodium phosphate dibasic, which is present in the liquid composition at a concentration of < 6.8 mg / ml; preferably, the buffer salt is sodium phosphate dibasic, which is present in the liquid composition at a concentration of 1.0-3.5 mg / ml, preferably 1.7-3.4 mg / ml; Preferably, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0-2.0 mg / ml as free base, and the buffer salt is sodium acetate, which is present in the liquid composition at a concentration of 0.7-3.2 mg / ml, preferably 0.7-2.3 mg / ml; Preferably, the salt of the compound of Formula I is present in the liquid composition at a concentration of 1.0-2.0 mg / ml as free base, and the buffer salt is histidine, which is present in the liquid composition at a concentration of 3.0-6.5 mg / ml.

9. The liquid composition according to any one of claims 1 to 8, characterized in that, The liquid composition contains an osmotic pressure regulator and / or an injection solvent; Preferably, the osmotic pressure regulator is at least one selected from the group consisting of mannitol, xylitol, sorbitol, sodium chloride, calcium chloride, potassium chloride, and glucose; preferably, the osmotic pressure regulator is sodium chloride or mannitol; Preferably, the osmotic pressure regulator is present in the liquid composition at a concentration of 1.0-15.0 mg / ml; Preferably, the osmotic pressure of the liquid composition is 240-340 mOsmol / kg; Preferably, the injection solvent is at least one selected from the group consisting of water for injection, 0.9% sodium chloride solution, saline solution, oil for injection, ethanol, propylene glycol, ethylene glycol, tert-butyl alcohol, and polyethylene glycol; more preferably, the injection solvent is water for injection.

10. The liquid composition according to any one of claims 1 to 9, characterized in that, The L-tartaric acid salt of the compound of Formula I is in the form of crystalline Form II, and the X-ray powder diffractogram of the Form II includes at least peaks at diffraction angles 2θ (°) values of 13.82±0.2, 14.87±0.2, 20.55±0.2, 23.15±0.2; Preferably, the X-ray powder diffractogram of the Form II further includes one or more peaks at diffraction angles 2θ (°) values selected from the group consisting of 10.41±0.2, 15.75±0.2, 16.28±0.2, 17.21±0.2, 17.63±0.2, 19.98±0.2, 20.22±0.2, 21.08±0.2, 22.22±0.2, 24.56±0.2, 28.91±0.2, 38.00±0.2, 44.21±0.2; Preferably, the X-ray powder diffraction pattern of said crystalline Form II has peaks at diffraction angles 2Q (°) values of the following groups: 10.41±0.2, 13.82±0.2, 14.87±0.2, 15.75±0.2, 16.28±0.2, 17.21±0.2, 17.63±0.2, 19.98±0.2, 20.22±0.2, 20.55±0.2, 21.08±0.2, 22.22±0.2, 23.15±0.2, 24.56±0.2, 28.91±0.2; Preferably, the X-ray powder diffraction pattern of said crystalline Form II has peaks at diffraction angles 2Q (°) values of the following groups: 10.41±0.2, 13.82±0.2, 14.87±0.2, 15.75±0.2, 16.28±0.2, 17.21±0.2, 17.63±0.2, 19.98±0.2, 20.22±0.2, 20.55±0.2, 21.08±0.2, 22.22±0.2, 23.15±0.2, 24.56±0.2, 28.91±0.2, 38.00±0.2, 44.21±0.2; or the L-tartaric acid salt of said compound of Formula I is in the crystalline Form III, which has an X-ray powder diffraction pattern comprising at least the following peaks at diffraction angles 2Q (°) values: 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2; Preferably, the X-ray powder diffraction pattern of said crystalline Form III comprises at least one peak at a diffraction angle 2Q (°) value selected from the group consisting of: 7.2±0.2, 10.0±0.2, 13.1±0.2, 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2, 24.3±0.2; Preferably, the X-ray powder diffraction pattern of said crystalline Form III comprises at least one peak at a diffraction angle 2Q (°) value selected from the group consisting of: 7.2±0.2, 10.0±0.2, 10.4±0.2, 11.1±0.2, 13.1±0.2, 14.4±0.2, 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2, 21.2±0.2, 24.3±0.2, 25.7±0.2; Preferably, the X-ray powder diffraction pattern of said Form III comprises at least one peak at a diffraction angle 2-theta (°) value selected from the group consisting of 3.7±0.2, 7.2±0.2, 10.0±0.2, 10.4±0.2, 11.1±0.2, 12.0±0.2, 13.1±0.2, 14.4±0.2, 14.8±0.2, 15.4±0.2, 15.8±0.2, 17.1±0.2, 17.4±0.2, 18.6±0.2, 19.5±0.2, 20.2±0.2, 21.2±0.2, 22.2±0.2, 24.3±0.2, 25.7±0.2, 26.2±0.2, 27.1±0.2, 28.7±0.2, 29.3±0.2, 29.9±0.2, 30.4±0.2, 31.4±0.2, 33.0±0.2, 34.7±0.2, 36±0.2, 37.0±0.2, 37.8±0.2, 39.2±0.

2. Preferably, the X-ray powder diffraction pattern of said Form III is as shown in Figure 1.

11. The liquid composition according to claim 10, characterized in that, The melting point of said Form III is 160-170°C.

12. The liquid composition of claim 10, wherein, Said Form III further has the following characteristic: the peak temperature in the differential scanning calorimetry pattern is 167.55±2°C.

13. The liquid composition of claim 10, wherein, Said Form III is prepared by the following method: taking the L-tartaric acid salt of the compound of Formula I, a solvent, heating and stirring, filtering, and drying to obtain Form III, wherein the solvent comprises ethyl acetate or methyl tert-butyl ether. Preferably, the volume of said solvent is 10-20 times the amount of the L-tartaric acid salt of the compound of Formula I. Preferably, the heating temperature is 40-80°C, more preferably, the heating temperature is 50-65°C.

14. A crystalline Form III of an L-tartrate salt of a compound of Formula I: ###0002### characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 1. The X-ray powder diffraction pattern of the crystal form III comprises at least peaks at diffraction angle 2 theta (°) values of 17.1±0.2, 17.4±0.2, 19.5±0.2, 20.2±0.2; preferably, the X-ray powder diffraction pattern of the crystal form III further comprises at least one peak at a diffraction angle 2 theta (°) value selected from the group consisting of 7.2±0.2, 10.0±0.2, 13.1±0.2, 24.3±0.2; preferably, the X-ray powder diffraction pattern of the crystal form III further comprises at least one peak at a diffraction angle 2 theta (°) value selected from the group consisting of 10.4±0.2, 11.1±0.2, 14.4±0.2, 21.2±0.2, 25.7±0.2; preferably, the X-ray powder diffraction pattern of the crystal form III comprises at least one peak at a diffraction angle 2 theta (°) value selected from the group consisting of 3.7±0.2, 12.0±0.2, 14.8±0.2, 15.4±0.2, 15.8±0.2, 18.6±0.2, 22.2±0.2, 26.2±0.2, 27.1±0.2, 28.7±0.2, 29.3±0.2, 29.9±0.2, 30.4±0.2, 31.4±0.2, 33.0±0.2, 34.7±0.2, 36.0±0.2, 37.0±0.2, 37.8±0.2, 39.2±0.2; Preferably, the X-ray powder diffraction pattern of the crystal form III is shown in Figure 1.

15. The Form III of claim 14, characterized by: The melting point of the crystal form III is 160-170℃.

16. The Form III of claim 14, characterized by: The crystal form III further has the following characteristic: the peak temperature in the differential scanning calorimetry pattern is 167.55±2℃.

17. A method for preparing crystal form III of the L-tartrate salt of the compound shown in Formula I, characterized in that, The crystal form III is prepared by the following method: taking the L-tartaric acid salt of the compound of formula I, a solvent, heating and stirring, filtering, and drying to obtain the crystal form III, wherein the solvent comprises ethyl acetate or methyl tert-butyl ether; Preferably, the volume of the solvent is 10-20 times the amount of the L-tartaric acid salt of the compound of formula I. Preferably, the heating temperature is 40-80℃, more preferably, the heating temperature is 50-65℃.

18. The liquid composition according to any one of claims 1 to 13, wherein, The liquid composition is an injection; preferably, the injection has a volume of 20ml or less; preferably, the injection has a volume of 1-10ml.

19. The liquid composition of claim 18, wherein, The liquid composition is an injection comprising the L-tartaric acid salt of the compound of formula I, a buffer salt, and a pH adjusting agent, wherein the pH of the injection is 6.0-7.4, preferably, the pH of the injection is 6.0-7.1; Preferably, the injection comprises the L-tartaric acid salt of the compound of formula I, a buffer salt, a pH adjusting agent, an osmotic pressure adjusting agent, and an injection solvent, wherein the pH of the injection is 6.0-7.4; more preferably, the pH of the injection is 6.0-7.1; Preferably, the injection agent comprises L-tartaric acid salt of the compound of Formula I at a concentration of 0.1-5.0 mg / ml as free base; a buffer salt at a concentration of < 6.8 mg / ml in the liquid composition; an osmotic pressure regulator at a concentration of 1.0-15.0 mg / ml in the liquid composition; a pH regulator in an appropriate amount; the pH of the injection agent is 6.0-7.4; more preferably, the pH of the injection agent is 6.0-7.

1.

20. The liquid composition of claim 19, wherein, The injection agent comprises L-tartaric acid salt of the compound of Formula I at a concentration of 1.0-5.0 mg / ml as free base; a buffer salt at a concentration of < 6.8 mg / ml in the liquid composition; an osmotic pressure regulator at a concentration of 1.0-15.0 mg / ml in the liquid composition; a pH regulator in an appropriate amount; an injection solvent to a injection liquid volume of 1-10 ml; the pH of the injection agent is 6.0-7.1, wherein the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I as free base in the liquid composition is < 3.4; Preferably, the injection agent comprises L-tartaric acid salt of the compound of Formula I at a concentration of 1.0-2.0 mg / ml as free base; a buffer salt at a concentration of < 6.8 mg / ml in the liquid composition; an osmotic pressure regulator at a concentration of 1.0-15.0 mg / ml in the liquid composition; a pH regulator in an appropriate amount; an injection solvent to a injection liquid volume of 1-10 ml; the pH of the injection agent is 6.0-7.1, wherein the buffer salt is sodium dihydrogen phosphate or sodium citrate, and the ratio of the concentration of the buffer salt in the liquid composition to the concentration of the salt of the compound of Formula I as free base in the liquid composition is < 3.4; Preferably, the injection agent comprises L-tartaric acid salt of the compound of Formula I at a concentration of 1.0 mg / ml as free base; a buffer salt at a concentration of 0.8-2.0 mg / ml; an osmotic pressure regulator at a concentration of 1.0-15.0 mg / ml; a pH regulator in an appropriate amount; an injection solvent to a injection liquid volume of 1-10 ml, and the pH of the injection agent is 6.0-7.1, wherein the buffer salt is sodium dihydrogen phosphate; Preferably, the injection agent comprises L-tartaric acid salt of the compound of Formula I at a concentration of 1.0 mg / ml as free base; a buffer salt at a concentration of < 0.6 mg / ml; an osmotic pressure regulator at a concentration of 1.0-15.0 mg / ml; a pH regulator in an appropriate amount; an injection solvent to a injection liquid volume of 1-10 ml, and the pH of the injection agent is 6.0-7.4, wherein the buffer salt is sodium dihydrogen phosphate; Preferably, the injection agent comprises L-tartaric acid salt of the compound of Formula I at a concentration of 1.0 mg / ml as free base; a buffer salt at a concentration of < 0.6 mg / ml; an osmotic pressure regulator at a concentration of 1.0-15.0 mg / ml; a pH regulator in an appropriate amount; an injection solvent to a injection liquid volume of 1-10 ml, and the pH of the injection agent is 6.0-7.4, wherein the buffer salt is sodium dihydrogen phosphate; Preferably, the injection comprises L-tartrate salt of the compound of Formula I, 1.0 mg / ml in free base; a buffer salt, 0.1-0.4 mg / ml; an osmotic pressure regulator, 1.0-15.0 mg / ml; a pH regulator, in an appropriate amount; a solvent for injection, to 1-10 ml of the injection; the pH of the injection is 6.0-7.4, and the buffer salt is sodium phosphate; Preferably, the injection comprises L-tartrate salt of the compound of Formula I, 1.0 mg / ml in free base; a buffer salt, 0.1-0.4 mg / ml; an osmotic pressure regulator, 1.0-15.0 mg / ml; a pH regulator, in an appropriate amount; a solvent for injection, to 1-10 ml of the injection; the pH of the injection is 6.0-7.4, and the buffer salt is sodium phosphate; Preferably, the injection comprises L-tartrate salt of the compound of Formula I, 1.0 mg / ml in free base; a buffer salt, 0.1-0.4 mg / ml; an osmotic pressure regulator, 1.0-15.0 mg / ml; a pH regulator, in an appropriate amount; a solvent for injection, to 1-10 ml of the injection; the pH of the injection is 6.0-7.4, and the buffer salt is sodium phosphate; 21. A method of preparing a liquid composition according to any one of claims 1-13, 18-20, wherein, Preferably, the injection comprises L-tartrate salt of the compound of Formula I, 1.0 mg / ml in free base; a buffer salt, 0.1-0.4 mg / ml; an osmotic pressure regulator, 1.0-15.0 mg / ml; a pH regulator, in an appropriate amount; a solvent for injection, to 1-10 ml of the injection; the pH of the injection is 6.0-7.4, and the buffer salt is sodium phosphate; Preferably, the sterilization is terminal sterilization, i.e. moist heat sterilization. Preferably, the sterilization condition is 121°C, 8-30 min or 115°C, 30-60 min. Preferably, the salt of the compound of Formula I is L-tartrate salt of the compound of Formula I; preferably, the L-tartrate salt of the compound of Formula I is in the form of crystal form II or crystal form III.

22. Use of the liquid composition according to any one of claims 1-13, 18-20 in the preparation of a medicament for preventing and / or treating a disease mediated by MOR receptor agonist; preferably, the disease mediated by MOR receptor agonist is at least one selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux disease, neurological disease, mental disease, urological disease, reproductive disease, cardiovascular disease and respiratory disease; preferably, the pain is at least one selected from the group consisting of postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain and inflammation-induced pain; preferably, the cancer in the cancer-induced pain is at least one selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia; the postoperative pain includes abdominal surgery postoperative pain, preferably moderate to severe pain or acute pain.

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