Posaconazole fatty acid ester, posaconazole fatty acid ester fat emulsion and preparation method of posaconazole fatty acid ester fat emulsion

Abstract

The invention discloses posaconazole fatty acid ester, posaconazole fatty acid ester fat emulsion and a preparation method of the posaconazole fatty acid ester fat emulsion, and belongs to the technical field of pharmaceutical preparations. The solubility of the posaconazole fatty acid ester provided by the invention in the oil for injection is remarkably improved, and the posaconazole fatty acid ester can be effectively applied to subsequent preparation of the posaconazole fatty acid ester fat emulsion. Meanwhile, by selecting components in a proper mass percentage range for mutual cooperation, the obtained posaconazole fatty acid ester fat emulsion is small in average particle size, and the pH value and the osmotic pressure are close to those of human plasma, so that the posaconazole fatty acid ester fat emulsion has excellent intravenous injection safety and can be effectively applied to preparation of antifungal injection. In addition, the preparation methods of the posaconazole fatty acid ester and the posaconazole fatty acid ester fat emulsion provided by the invention are simple to operate and beneficial to actual large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to posaconazole fatty acid ester, posaconazole fatty acid ester fat emulsion and a preparation method thereof. BACKGROUND

[0002] In recent years, with the application of antitumor drugs and broad-spectrum antibacterial drugs, and the increase of organ transplant patients and acquired immune deficiency syndrome patients, the risk of invasive fungal infection and patients in clinical practice have increased year by year. The commonly used anti-fungal infection drugs in clinical practice at present include itraconazole, fluconazole, voriconazole and posaconazole. For the prevention and treatment of invasive aspergillosis, posaconazole (structural formula as shown in formula II, molecular formula is C 37 H 42 F2N8O4, molecular weight is 700.8) is the most effective, and is widely used in clinical practice, which can significantly improve the population survival rate of patients. Posaconazole belongs to a new generation of triazole antifungal drugs, which was initially developed by Schering-Plough Corporation (which was acquired by American Merck Corporation in 2009). Its oral suspension (40 mg / mL, 105 mL), enteric-coated tablets (100 mg) and injection (300 mg / 16.7 mL) were approved for marketing in the United States in September 2006, November 2013 and March 2014, respectively, and the trade name is Noxafil. The above three dosage forms were approved for marketing in China in 2013, 2018 and 2021, respectively. Among them, the approved indications of posaconazole injection include: (1) treatment of invasive aspergillosis in adult patients; (2) patients aged 18 and above with increased risk of invasive aspergillosis and candida infection due to severe immunodeficiency, such as patients with graft-versus-host disease after receiving hematopoietic stem cell transplantation or patients with hematological malignancies with long-term neutropenia caused by chemotherapy;

[0003] According to Merck's patent in China (application number: 2017101692037), since the solubility of posaconazole in water or alkaline solution is less than 1 μg / mL, a large amount of sulfobutyl beta-cyclodextrin sodium is added to the injection formula as a solubilizer, with a concentration of up to 400 mg / mL, and the pH value of the injection is adjusted to 2.6 with hydrochloric acid. According to the instructions, this product has the following defects in clinical application: (1) When patients with moderate or severe renal insufficiency receive posaconazole injection, accumulation of the intravenous excipient sulfobutyl beta-cyclodextrin sodium is expected to occur, which poses a certain safety risk; (2) This product cannot be administered by intravenous push, but should be administered through a central venous access, including a central venous catheter or a peripherally inserted central catheter. Each dose should be slowly infused intravenously for more than 90 minutes, which is inconvenient for clinical use and has a higher risk than ordinary intravenous injection. Specifically, when Nocofi injection is administered intravenously, 6 out of 9 subjects experienced local reactions after infusion, manifested as erythema, induration and tenderness. One subject experienced extravasation and swelling of the arm. The initiator company believes that this local intolerance may have been caused by irritation caused by the low pH infusion solution administered slowly through a peripheral vein.

[0004] The patent (CN 118001239 A) provides a posaconazole phospholipid complex submicron emulsion and a preparation method thereof. However, the posaconazole phospholipid complex submicron emulsion provided by this technical solution contains Tween 80 (a nonionic surfactant and emulsifier) ​​and organic solvent residues. Tween 80 has a certain hemolytic effect after injection, and the residual organic solvents (such as ethanol and glycerol) also have certain toxic side effects after being injected into the blood. In view of the fact that removing surfactants such as Tween 80 and organic solvents from injections is already one of the ways to improve new drugs. For example, Beihai Bio announced in October 2024 that its independently developed improved new drug docetaxel BH009 (trade name: ) has been approved for marketing in the United States and is mainly used to treat breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, prostate cancer and gastric cancer. It is reported that the docetaxel products currently on the market all contain Tween 80, which can cause severe allergies, fluid retention and other serious toxic side effects during clinical use. Beihai Bio's BEIZRAY preparation does not contain Tween 80 at all. Clinical trial results show that BEIZRAY eliminates the severe allergic reactions caused by Tween 80 and significantly improves the clinical safety of docetaxel. Therefore, it is urgent to provide a posaconazole-like substance that can provide a good injection effect without adding substances with strong toxic side effects such as cyclodextrin and Tween 80. Summary of the Invention

[0005] The object of the present invention is to overcome the deficiencies of the above-mentioned prior art and to provide a posaconazole fatty acid ester, a posaconazole fatty acid ester fat emulsion and a preparation method thereof, which have high solubility in injectable oil, have a pH value and osmotic pressure close to those of human plasma when used in the preparation of a posaconazole fatty acid ester fat emulsion, do not contain components with significant toxic side effects such as cyclodextrin and Tween 80, and are safe for intravenous injection.

[0006] To achieve the above objectives, in a first aspect of the present invention, the present invention provides a posaconazole fatty acid ester, the structural formula of the posaconazole fatty acid ester is shown in Formula I: Wherein, R is selected from C12 to C22 saturated or unsaturated fatty acid acyl groups.

[0007] The posaconazole fatty acid ester provided by the present invention is prepared by introducing an R group through an esterification reaction at the free hydroxyl group at the terminal of posaconazole. The solubility of the obtained posaconazole fatty acid ester in injection oil is significantly improved, so that the posaconazole fatty acid ester can be effectively used in the subsequent preparation of posaconazole fatty acid ester fat emulsion, thereby improving the injection safety of the posaconazole fatty acid ester fat emulsion.

[0008] As a preferred embodiment of the posaconazole fatty acid ester of the present invention, the R is selected from any one of a C16 saturated or unsaturated fatty acid acyl group, a C18 saturated or unsaturated fatty acid acyl group, and a C22 saturated or unsaturated fatty acid acyl group.

[0009] The present invention has found that when R is further selected from any one of C16 saturated or unsaturated fatty acid acyl, C18 saturated or unsaturated fatty acid acyl, and C22 saturated or unsaturated fatty acid acyl, the solubility of the obtained posaconazole fatty acid ester in the injection oil is better, and the overall effect of the obtained product is also better.

[0010] For example, the R may be a palmitic acid acyl group, a palmitoleic acid acyl group, a behenic acid acyl group, or an eicosapentaenoic acid acyl group.

[0011] In a second aspect of the present invention, the present invention provides a method for preparing posaconazole fatty acid ester, the preparation method comprising the following steps: In an inert gas environment, a fatty acid chloride is added dropwise to an organic solution containing posaconazole and an organic base at -5 to 5°C. After the addition is completed, the temperature is raised to react. After the reaction is completed, water is added and the pH value is adjusted. The two phases are then separated, and the organic phase is collected and purified to obtain posaconazole fatty acid ester.

[0012] The preparation method provided by the present invention uses posaconazole as a raw material and reacts it with fatty acid chloride, so that a chlorine substitution reaction can effectively occur between the two to form posaconazole fatty acid ester.

[0013] As a preferred embodiment of the preparation method of the present application, the organic solvent comprises at least one of dichloromethane, tetrahydrofuran, acetone.

[0014] As a preferred embodiment of the preparation method of the present application, the organic base comprises at least one of pyridine, triethylamine, 4-dimethylaminopyridine.

[0015] As a preferred embodiment of the preparation method of the present application, the fatty acyl chloride comprises at least one of lauroyl chloride, tridecanoyl chloride, myristoyl chloride, pentadecanoyl chloride, palmitoyl chloride, pearl acyl chloride, stearoyl chloride, nonadecanoyl chloride, arachidoyl chloride, heneicosanoyl chloride, behenoyl chloride, oleoyl chloride, linoleoyl chloride, linolenoyl chloride, arachidonoyl chloride, eicosapentaenoyl chloride, docosahexaenoyl chloride.

[0016] It should be noted that lauroyl chloride, tridecanoyl chloride, myristoyl chloride, pentadecanoyl chloride, palmitoyl chloride, pearl acyl chloride, stearoyl chloride, nonadecanoyl chloride, arachidoyl chloride, heneicosanoyl chloride, behenoyl chloride, oleoyl chloride, linoleoyl chloride, linolenoyl chloride, arachidonoyl chloride, eicosapentaenoyl chloride, docosahexaenoyl chloride are respectively lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, pearl acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid chloride.

[0017] Preferably, the fatty acyl chloride comprises any one of palmitoyl chloride, oleoyl chloride.

[0018] As a preferred embodiment of the preparation method of the present application, the temperature of the temperature-increasing reaction is 20-30℃, and the time is 2-22h.

[0019] As a preferred embodiment of the preparation method of the present application, the pH value is adjusted to 4-5.

[0020] As a preferred embodiment of the preparation method of the present application, the molar ratio of posaconazole and fatty acyl chloride is 1:1-3.

[0021] As a preferred embodiment of the preparation method of the present application, the molar ratio of posaconazole and organic base is 1:1-6.

[0022] The present application researches and finds that when the parameters in the preparation process are further selected within the above range, the yield of the posaconazole fatty acid ester obtained is higher.

[0023] In the third aspect of the present application, the present application provides a posaconazole fatty acid ester fat emulsion, which comprises the following components in mass percentage: 0.01-1.0% of the posaconazole fatty acid ester of the present application, 5-75% of an injection oil, 0.05-3% of an emulsifier, 0.0-1.0% of a stabilizer, 0.1-6.0% of an isotonicity adjusting agent, 0-1% of a pH adjusting agent, and the balance of injection water.

[0024] The posaconazole fatty acid ester fat emulsion provided by the present application has small average particle size and good stability, and does not contain components such as cyclodextrin and Tween 80 which have obvious toxic and side effects, and the pH value and osmotic pressure of the prepared posaconazole fatty acid ester fat emulsion are close to those of human plasma, so that the posaconazole fatty acid ester fat emulsion has excellent safety for injection.

[0025] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the posaconazole fatty acid ester fat emulsion comprises the following components in mass percentage: 0.02-0.5% of the posaconazole fatty acid ester of the present application, 10-20% of an injection oil, 0.05-2% of an emulsifier, 0.0-1.0% of a stabilizer, 0.1-5.0% of an isotonicity adjusting agent, 0-1% of a pH adjusting agent, and the balance of injection water.

[0026] The present application researches and finds that when the mass percentage of the components is further selected within the above range, the comprehensive performance of the product is better.

[0027] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the injection oil comprises at least one of soybean oil, safflower oil, olive oil, sesame oil, coconut oil, fish oil, medium-chain fatty acid triglyceride, corn oil, tea oil, peanut oil, sunflower oil, castor oil, and flaxseed oil.

[0028] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the medium-chain fatty acid triglyceride comprises at least one of capryl capric acid glyceride, tricaprin, trilaurin, and trioctanoin.

[0029] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the emulsifier comprises at least one of injection yolk lecithin, soybean lecithin, hydrogenated soybean phospholipid, polyethylene glycol modified phospholipid, and polyethylene glycol stearate.

[0030] Exemplarily, the yolk lecithin can be PL-100M, LIPOID E80, PC-98T, etc.

[0031] Exemplarily, the polyethylene glycol stearate can be HS 15, etc.

[0032] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the stabilizer comprises at least one of oleic acid, sodium oleate, phosphatidylglycerol.

[0033] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the isotonicity regulator comprises at least one of glycerol, mannitol.

[0034] As a preferred embodiment of the posaconazole fatty acid ester fat emulsion of the present application, the pH regulator comprises at least one of sodium hydroxide, hydrochloric acid.

[0035] In the fourth aspect of the present application, the present application provides a preparation method of posaconazole fatty acid ester fat emulsion, which comprises the following steps: S1, preparation of oil phase: dissolving posaconazole fatty acid ester into injection oil, then adding emulsifier and stabilizer and uniformly dispersing to obtain oil phase; S2, preparation of water phase: adding isotonicity regulator into injection water and stirring uniformly to obtain water phase; S3, preparation of posaconazole fatty acid ester fat emulsion: dispersing oil phase into water phase, then adjusting pH value using pH regulator, then homogenizing and emulsifying, and finally sterilizing to obtain posaconazole fatty acid ester fat emulsion.

[0036] As a preferred embodiment of the preparation method of the present application, in the step S1, the temperature for dissolving and uniformly dispersing is 60-80℃, and the preparation of oil phase is operated in an inert gas protection environment.

[0037] As a preferred embodiment of the preparation method of the present application, in the step S2, the temperature for stirring uniformly is 60-80℃.

[0038] As a preferred embodiment of the preparation method of the present application, in the step S3, the dispersing is shear dispersion of emulsifier, and the dispersion temperature is 60-80℃.

[0039] As a preferred embodiment of the preparation method of the present application, in the step S3, the adjustment of pH value is adjusting pH value to 4.0-9.0.

[0040] As a preferred embodiment of the preparation method of the present application, in the step S3, the homogenizing and emulsifying comprises the following three stages: first stage: setting pressure of high-pressure homogenizer to 100-180 bar, controlling process temperature at 60-80℃, pre-emulsifying, circulating emulsifying 1-4 times, and adjusting pH to 4.0-9.0; The second stage: the high-pressure homogenizer is set to a pressure of 400-1000 bar, and the process control temperature is 60-80 DEG C, high-pressure emulsification is carried out, and the emulsification is cycled 5-10 times, and the pH is adjusted to 4.0-9.0; The third stage: the high-pressure homogenizer is set to a pressure of 100-180 bar, and the process control temperature is 30-50 DEG C, and the final emulsification is carried out.

[0041] As a preferred embodiment of the preparation method, in step S3, the sterilization temperature is 121±2 DEG C, and the time is 10-14 min.

[0042] In the fifth aspect of the present application, the present application provides the use of the posaconazole fatty acid ester fat emulsion in the preparation of an antifungal injection.

[0043] The present application researches and finds that the posaconazole fatty acid ester fat emulsion provided by the present application has a small particle size and a suitable zeta potential on the basis of not adding components such as cyclodextrin and Tween 80 which have obvious toxic side effects, and can also achieve a pH value and an osmotic pressure close to human blood plasma, thereby being effectively applied to the preparation of an antifungal injection, and the obtained injection can be directly intravenously injected, and has good safety and clinical compliance.

[0044] Compared with the prior art, the present application has the following beneficial effects: The posaconazole fatty acid ester provided by the present application is obtained by esterification reaction at the terminal free hydroxyl group of posaconazole, and the introduction of the R group significantly improves the solubility of the obtained posaconazole fatty acid ester in injection oil, thereby being effectively applied to the subsequent preparation of a posaconazole fatty acid ester fat emulsion. Meanwhile, the present application selects components with a suitable mass percentage range to cooperate with each other, and the obtained posaconazole fatty acid ester fat emulsion has a small average particle size and good stability, and does not contain components such as cyclodextrin and Tween 80 which have obvious toxic side effects. Meanwhile, the pH value and the osmotic pressure of the prepared posaconazole fatty acid ester fat emulsion are close to human blood plasma. Therefore, the posaconazole fatty acid ester fat emulsion provided by the present application has excellent intravenous injection safety, and can be effectively applied to the preparation of an antifungal injection. In addition, the preparation method of the posaconazole fatty acid ester and the posaconazole fatty acid ester fat emulsion provided by the present application is simple in operation, and is conducive to actual large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 It is a synthesis route schematic diagram of the posaconazole fatty acid ester in example 1; Figure 2 It is a synthesis route schematic diagram of the posaconazole fatty acid ester in example 2; Figure 3 It is a synthesis route schematic diagram of the posaconazole fatty acid ester in example 3; Figure 4 The synthesis route of the posaconazole fatty acid ester in Example 4 is shown. DETAILED DESCRIPTION

[0046] For the purpose of better illustrating the object, technical scheme and advantages of the present application, the present application will be further described in conjunction with specific examples.

[0047] The reagents, methods and equipment used in the present application are all conventional reagents, methods and equipment in the art unless otherwise specified.

[0048] Example 1 The present application provides a posaconazole fatty acid ester (posaconazole palmitate), the synthesis route of which is shown in Figure 1 The preparation method comprises the following steps: Into a 250 mL three-necked flask, add posaconazole (14.0 g, 20 mmol), dichloromethane (100 mL) and pyridine (4.7 g, 60 mmol), protect with nitrogen, cool to 0 ℃, drop palmitoyl chloride (8.2 g, 30 mmol), after the drop is completed, warm to 25±2 ℃, incubate for 16 hours, monitor by TLC, after the reaction is completed, add water (50 mL), then add citric acid to adjust pH to 4-5, separate the phases, collect the organic phase and dry with anhydrous sodium sulfate, after drying, filter to collect the filtrate and concentrate, purify with 100-200 mesh silica gel, elute with ethyl acetate: petroleum ether = 3:1, collect the main component, concentrate, obtain white solid, which is posaconazole palmitate (11.2 g), the yield is 60%.

[0049] Characterization of posaconazole palmitate: MS (ESI, M + H): 939.6; 1H-NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.43-7.41 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.89-6.86 (m, 2H), 6.81 (d, J = 8.9 Hz, 2H), 5.28-5.24 (m, 1H), 4.61 (dd, J = 34, 14 Hz, 2H), 4.24 (m, 1H), 4.17 (t, J = 8.0 Hz, 1H), 3.83-3.65 (m, 3H), 3.40-3.26 (m, 8H), 2.61 (m, 2H), 2.28 (q, J = 7.6 Hz, 2H), 2.13-1.75 (m, 3H), 1.55 (m, 2H), 1.32 (m, 27H), 0.91 (m, 6H).

[0050] Example 2 The present application provides a posaconazole fatty acid ester (posaconazole oleate), the synthetic route of which is shown as Figure 2 The preparation method comprises the following steps: A 250 mL three-necked flask was charged with posaconazole (14.0 g, 20 mmol), dichloromethane (100 mL) and pyridine (4.7 g, 60 mmol), and protected by nitrogen. The mixture was cooled to 0 °C, and oleoyl chloride (9.08 g, 30 mmol) was added dropwise. After the addition was completed, the temperature was raised to 25 ± 2 °C, and the mixture was incubated for 16 hours. TLC monitoring showed that the reaction was complete. Water (50 mL) was added, followed by citric acid to adjust the pH to 4-5. The organic phase was separated and dried over anhydrous sodium sulfate. After drying, the filtrate was collected by filtration and concentrated, and purified on a 100-200 mesh silica gel column, eluted with ethyl acetate: petroleum ether = 3: 1, and the main component was collected and concentrated to obtain a white solid, which was posaconazole oleate (11.6 g), with a yield of 60%.

[0051] Characterization of posaconazole oleate: MS (ESI, M + H): 965.6; 1H-NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.43-7.42 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.96-6.87 (m, 4H), 6.81 (d, J = 8.4 Hz, 2H), 5.38-5.28 (m, 2H), 5.26-5.24 (m, 1H), 4.63 (dd, J = 34, 10 Hz, 2H), 4.24 (m, 1H), 4.15 (t, J = 7.6 Hz, 1H), 3.83-3.65 (m, 3H), 3.40-3.26 (m, 8H), 2.61 (m, 2H), 2.28 (q, J = 7.6 Hz, 2H), 2.14-1.75 (m, 7H), 1.55 (m, 2H), 1.32 (m, 23H), 0.91 (m, 6H).

[0052] Example 3 The present application provides a posaconazole fatty acid ester (posaconazole behenate), the synthetic route of which is shown as Figure 3 The preparation method comprises the following steps: Into a 250 mL three-necked flask, posaconazole (14.0 g, 20 mmol), dichloromethane (100 mL) and pyridine (4.7 g, 60 mmol) were added, and the mixture was cooled to 0 °C under nitrogen protection. Then, docosanoyl chloride (10.76 g, 30 mmol) was added dropwise. After the addition was completed, the mixture was warmed to 25 ± 2 °C and kept for 16 h. TLC monitoring showed that the reaction was completed. Water (50 mL) was added, followed by the addition of citric acid to adjust the pH to 4-5. The organic phase was collected and dried over anhydrous sodium sulfate. After drying, the filtrate was collected and concentrated. Purification was performed on silica gel (100-200 mesh) with ethyl acetate: petroleum ether = 3: 1 as the eluent. The main component was collected and concentrated to obtain a white solid, which was posaconazole docosanoate (11.3 g) with a yield of 59%.

[0053] Characterization of posaconazole docosanoate: MS (ESI, M + H): 1023.7; 1H-NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.43-7.41 (m, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.97-6.86 (m, 4H), 6.83 (d, J = 8.9 Hz, 2H), 5.28-5.24 (m, 1H), 4.61 (dd, J = 34, 14 Hz, 2H), 4.24 (m, 1H), 4.17 (t, J = 8.0 Hz, 1H), 3.83-3.65 (m, 3H), 3.40-3.26 (m, 8H), 2.65-2.57 (m, 2H), 2.27 (q, J = 7.6 Hz, 2H), 2.14-1.82 (m, 3H), 1.56 (m, 2H), 1.32 (m, 39H), 0.91 (m, 6H).

[0054] Example 4 The present application provides a posaconazole fatty acid ester (posaconazole eicosapentaenoate), the synthesis route of which is shown in Figure 4 The preparation method comprises the following steps: Into a 250 mL three-necked flask, posaconazole (14.0 g, 20 mmol), dichloromethane (100 mL) and pyridine (4.7 g, 60 mmol) were added, and the mixture was cooled to 0 °C under nitrogen protection. Then eicosapentaenoyl chloride (9.62 g, 30 mmol) was added dropwise. After the addition was completed, the temperature was increased to 25 ± 2 °C, and the mixture was incubated for 16 h. TLC monitoring showed that the reaction was completed. Then water (50 mL) was added, followed by the addition of citric acid to adjust the pH to 4-5. The organic phase was separated and dried over anhydrous sodium sulfate. After drying, the filtrate was collected and concentrated. The product was purified by silica gel chromatography (100-200 mesh) using ethyl acetate: petroleum ether = 3:1 as the eluent. The main component was collected and concentrated to obtain a white solid, which was posaconazole eicosapentaenoate (11.8 g) with a yield of 60%.

[0055] Characterization of posaconazole eicosapentaenoate: MS (ESI, M + H): 985.6; 1H-NMR (500 MHz, CDCl3) δ: 8.13 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.45 (d, J = 9.0 Hz, 2H), 7.42-7.40 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.96-6.80 (m, 6H), 5.39-5.31 (m, 10H), 5.25 (m, 1H), 4.63 (dd, J = 70, 14.5 Hz, 2H), 4.22 (m, 1H), 4.14 (t, J = 7.6 Hz, 1H), 3.83-3.63 (m, 3H), 3.40-3.29 (m, 8H), 2.79 (m, 8H), 2.61 (m, 2H), 2.25 (m, 2H), 2.08-1.80 (m, 7H), 1.55 (m, 2H), 1.32 (m, 3H), 0.88 (m, 6H).

[0056] Examples 1-5 The application examples of the present application provide a posaconazole fatty acid ester fat emulsion, and the components (mass percentage) of the posaconazole fatty acid ester fat emulsion are shown in Table 1. Table 1 The preparation method of the posaconazole fatty acid ester fat emulsion provided in Example 1 comprises the following steps: S1, preparation of an oil phase: posaconazole fatty acid ester is added to an injection oil and stirred to dissolve, followed by the addition of emulsifiers and stabilizers to disperse uniformly, thereby obtaining an oil phase; wherein the preparation process of the oil phase is carried out at a temperature of 70 ± 2 °C under a nitrogen environment; S2, preparation of an aqueous phase: an isotonicity adjusting agent is added to injection water and stirred uniformly, thereby obtaining an aqueous phase; wherein the preparation process of the aqueous phase is carried out at a temperature of 70 ± 2 °C. S3, preparation of the primary emulsion: the oil phase is added to the water phase, stirred uniformly, and then sheared for 10 min at a rotation speed of 10000 rpm using a high-shear dispersion emulsifier, the process temperature is maintained at 70±2℃, and nitrogen protection is used, to obtain a primary emulsion, and a pH regulator is used to adjust the pH to 8.5-9.0; S4, homogenization and emulsification: performed in three stages: First stage: the high-pressure homogenizer is set to a pressure of 140 bar, the process control temperature is 70±2℃, pre-emulsification is performed, and the pH is adjusted to 8.5-9.0 using a pH regulator; Second stage: the high-pressure homogenizer is set to a pressure of 600 bar, the process control temperature is 70±2℃, high-pressure emulsification is performed, and the pH is adjusted to 8.5-9.0 using a pH regulator, and the emulsion is circulated 6 times; Third stage: the high-pressure homogenizer is set to a pressure of 140 bar, and the emulsion is circulated for 10 min, the process control temperature is 40±2℃, and final emulsification is performed; S5, filling and sterilization The product after final emulsification is filled and sterilized at 121℃ for 12 min, to obtain a posaconazole fatty acid ester fat emulsion.

[0057] The preparation method of the posaconazole fatty acid ester fat emulsion provided in application examples 2-5 is consistent with that of application example 1.

[0058] Application Example 6 The application example of the present application provides a posaconazole fatty acid ester fat emulsion, and the only difference between the posaconazole fatty acid ester fat emulsion and application example 1 is that the injection oil is medium-chain triglyceride (Miglyol 812N).

[0059] Application Example 7 The application example of the present application provides a posaconazole fatty acid ester fat emulsion, and the only difference between the posaconazole fatty acid ester fat emulsion and application example 1 is that the injection oil is olive oil.

[0060] Application Example 8 The application example of the present application provides a posaconazole fatty acid ester fat emulsion, and the only difference between the posaconazole fatty acid ester fat emulsion and application example 1 is that the injection oil is coconut oil.

[0061] Application Example 9 The application example of the present application provides a posaconazole fatty acid ester fat emulsion, and the only difference between the posaconazole fatty acid ester fat emulsion and application example 1 is that the stabilizer is phosphatidylglycerol.

[0062] Application Example 10 The application example provides a posaconazole fatty acid ester fat emulsion, the only difference between the posaconazole fatty acid ester fat emulsion and the application example 1 is that the emulsifier is soybean lecithin.

[0063] Application Example 11 The application example provides a posaconazole fatty acid ester fat emulsion, the only difference between the posaconazole fatty acid ester fat emulsion and the application example 1 is that the emulsifier is hydrogenated soybean phospholipid.

[0064] Application Example 12 The application example provides a posaconazole fatty acid ester fat emulsion, the only difference between the posaconazole fatty acid ester fat emulsion and the application example 1 is that the emulsifier is polyethylene glycol modified phospholipid (DSPE-PEG2000).

[0065] Application Example 13 The application example provides a posaconazole fatty acid ester fat emulsion, the only difference between the posaconazole fatty acid ester fat emulsion and the application example 1 is that the posaconazole fatty acid ester is posaconazole palmitate.

[0066] Application Example 14 The application example provides a posaconazole fatty acid ester fat emulsion, the only difference between the posaconazole fatty acid ester fat emulsion and the application example 1 is that the posaconazole fatty acid ester is posaconazole behenate.

[0067] Application Example 15 The application example provides a posaconazole fatty acid ester fat emulsion, the only difference between the posaconazole fatty acid ester fat emulsion and the application example 1 is that the posaconazole fatty acid ester is posaconazole eicosapentaenoate.

[0068] Effect Example 1 The effect example verifies the solubility of the posaconazole fatty acid ester prepared in the examples 1-4 in water and soybean oil, the test method is direct observation method, and the obtained solubility data is shown in Table 2. Table 2 As can be seen from Table 2, when the posaconazole is derivatized with a fatty acid ester, the solubility of the obtained posaconazole fatty acid ester in soybean oil is significantly improved.

[0069] Finally, it should be noted that the above examples are used to illustrate the technical solutions of the present application, but not to limit the protection scope of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced equivalently without departing from the essence and scope of the technical solutions of the present application.

Claims

1. A posaconazole fatty acid ester, characterized in that The structural formula of the posaconazole fatty acid ester is shown in Formula I: Wherein, R is selected from C12 to C22 saturated or unsaturated fatty acid acyl groups.

2. The posaconazole fatty acid ester according to claim 1, wherein The R is selected from any one of a C16 saturated or unsaturated fatty acid acyl group, a C18 saturated or unsaturated fatty acid acyl group, and a C22 saturated or unsaturated fatty acid acyl group.

3. The method for preparing posaconazole fatty acid ester according to claim 1 or 2, wherein: The preparation method comprises the following steps: In an inert gas environment, a fatty acid chloride is added dropwise to an organic solution containing posaconazole and an organic base at -5 to 5°C. After the addition is completed, the temperature is raised to react. After the reaction is completed, water is added and the pH value is adjusted. The two phases are then separated, and the organic phase is collected and purified to obtain posaconazole fatty acid ester.

4. The preparation method according to claim 3, characterized in that The organic solvent includes at least one of dichloromethane, tetrahydrofuran, and acetone; and / or, the organic base comprises at least one of pyridine, triethylamine, and 4-dimethylaminopyridine; And / or, the fatty acid chloride includes at least one of lauroyl chloride, tridecanoyl chloride, myristoyl chloride, pentadecanoyl chloride, palmitoyl chloride, perillayl chloride, stearoyl chloride, nonadecanoyl chloride, arachidoyl chloride, heneicosanoyl chloride, behenoyl chloride, oleoyl chloride, linoleoyl chloride, linolenoyl chloride, arachidonic acid chloride, eicosapentaenoyl chloride, and docosahexaenoyl chloride.

5. A posaconazole fatty acid ester fat emulsion, characterized in that: The posaconazole fatty acid ester fat emulsion comprises the following components in percentage by mass: 0.01-1.0% of posaconazole fatty acid ester according to claim 1 or 2, 5-75% of injection oil, 0.05-3% of emulsifier, 0.0-1.0% of stabilizer, 0.1-6.0% of isotonicity regulator, 0-1% of pH regulator, and the balance of water for injection.

6. The posaconazole fatty acid ester fat emulsion according to claim 5, characterized in that The posaconazole fatty acid ester fat emulsion comprises the following components in percentage by mass: 0.02-0.5% of posaconazole fatty acid ester according to claim 1 or 2, 10-20% of injection oil, 0.05-2% of emulsifier, 0.0-1.0% of stabilizer, 0.1-5.0% of isotonicity regulator, 0-1% of pH regulator, and the balance of water for injection.

7. The posaconazole fatty acid ester fat emulsion according to claim 5, characterized in that At least one of the following is met: (1) The injection oil includes at least one of soybean oil, safflower oil, olive oil, sesame oil, coconut oil, fish oil, medium-chain fatty acid triglycerides, corn oil, tea oil, peanut oil, sunflower oil, castor oil, and linseed oil; (2) The emulsifier includes at least one of egg yolk phosphophosphate for injection, soybean lecithin, hydrogenated soybean lecithin, polyethylene glycol-modified phospholipids, and polyethylene glycol stearate; (3) The stabilizer includes at least one of oleic acid, sodium oleate, and phosphatidylglycerol; (4) The isotonicity adjusting agent includes at least one of glycerol and mannitol; (5) The pH adjuster includes at least one of sodium hydroxide and hydrochloric acid.

8. The posaconazole fatty acid ester fat emulsion according to claim 7, characterized in that The medium-chain fatty acid triglyceride includes at least one of caprylic acid glyceryl, tricapric acid glyceryl, trilauric acid glyceryl, and tricaprylic acid glyceryl.

9. The method for preparing posaconazole fatty acid ester fat emulsion according to any one of claims 5 to 8, characterized in that: The preparation method comprises the following steps: S1. Preparation of oil phase: adding posaconazole fatty acid ester to injection oil to dissolve, then adding emulsifier and stabilizer to disperse uniformly to obtain oil phase; S2. Preparation of aqueous phase: adding an isotonicity adjusting agent to water for injection and stirring uniformly to obtain an aqueous phase; S3. Preparation of posaconazole fatty acid ester fat emulsion: adding the oil phase to the aqueous phase for dispersion, then adjusting the pH value with a pH regulator, followed by homogenization and emulsification, and finally sterilization to obtain the posaconazole fatty acid ester fat emulsion.

10. Use of the posaconazole fatty acid ester fat emulsion according to any one of claims 5 to 8 in the preparation of antifungal injection.

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