Aprepitant micelle injection and preparation method thereof

Abstract

The invention belongs to the field of medicine, and provides an aprepitant micelle injection and a preparation method thereof.The aprepitant micelle injection is composed of active ingredients of aprepitant, phospholipid, cholic acid or salt of cholic acid, a nano-micelle stabilizer, a pH regulator and water for injection. The solubility of the aprepitant is obviously improved; the stability of the preparation can be remarkably improved through combination of the nano-micelle stabilizer; the use of a large amount of soybean oil for solubilization is avoided, and the lipid metabolism risk is reduced; the injection does not contain ethanol so as to avoid ethanol anaphylaxis, the safety of clinical medication is improved, the sterile guarantee level is improved by adopting a hot-pressing sterilization mode, the process is simple and convenient, large-scale production is easy, the injection is similar to a production process of a common injection, special equipment such as a high-pressure homogenizer and a special fat emulsion production line are not needed, and the production cost can be remarkably reduced.

Description

Technical Field

[0001] The invention belongs to the field of medicine and provides an aprepitant micelle injection and a preparation method thereof. Background Art

[0002] The chemical name of Aprepitant is 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one, and its molecular formula is: C 23 H 21 F 7 N 4 O 3 , molecular weight: 534.427, structural formula is as follows: ; Aprepitant is a weakly alkaline compound with a pKa value of 9.7 in the pH range of 2 to 12. It is white or off-white crystals, slightly soluble in acetonitrile, soluble in ethanol, and poorly soluble in water (0.55 μg / mL, pH 2-10). It has a high lipophilicity (log P = 4.8, pH 7). In addition, the intermediate permeability of aprepitant in the Caco2 model is not high, only 7.85×10 -6 cm / s. Therefore, aprepitant is classified as a BCS class IV drug with limited bioavailability.

[0003] Preclinical and human positron emission tomography (PET) studies of aprepitant have shown that aprepitant can pass through the blood-brain barrier and exert its effects mainly by binding to NK-1 receptors in the brain. Substance P is an important neurotransmitter in the nausea and vomiting reflex pathway caused by chemotherapy drugs or surgery, which can activate NK-1 receptors. Aprepitant competitively antagonizes NK-1 receptors, thereby blocking the effects of substance P, effectively inhibiting the occurrence of nausea and vomiting, and enhancing 5-HT 3 Antiemetic activity of the receptor antagonist ondansetron and the glucocorticoid dexamethasone in cisplatin-induced vomiting.

[0004] Aprepitant oral capsules developed by Merck Pharmaceuticals in the United States were approved for marketing in 2003. Due to the low solubility and poor absorption of aprepitant, its solubility in water is only 0.55 μg / ml. In 2017, Heron Therapeutics further developed aprepitant fat emulsion injection CINVANTI ® (Specification: 18ml:130mg) Compared with oral capsules, CINVANTI ® It has the advantages of rapid absorption, high bioavailability and good compliance, providing a more convenient way of use in clinical practice.

[0005] Aprepitant Fat Emulsion Injection CINVANTI ® There are also certain disadvantages. Pharmaceutical companies and research institutions at home and abroad have conducted a large number of studies on aprepitant fat emulsion injections.

[0006] Patent document CN117414334A provides an aprepitant emulsion pharmaceutical composition and its preparation method, which includes aprepitant, ethanol, phospholipids, soybean oil, isotonic regulator and pH regulator. Its core equipment is an online shearer and a high-pressure microfluidizer. The primary emulsion is prepared by online shear mixing of the oil phase and the water phase. The equipment cost is high and it is difficult to achieve large-scale production expansion.

[0007] Patent document CN109010269A discloses a fat emulsion injection of aprepitant, which includes aprepitant, phospholipids, injection oil, glycine, polyvinylpyrrolidone, and injection water, and does not include sucrose. Short-chain alcohols such as ethanol and propylene glycol are used as cosolvents. There are many clinical reports on the adverse reactions of propylene glycol, which limits its clinical application.

[0008] Both of the above two patents use a large amount of ethanol, which is harmful to people with alcoholism or impaired alcohol metabolism, as well as pregnant or lactating women. In addition, high concentrations of ethanol may cause adverse reactions such as injection site pain and neuritis.

[0009] Patent document CN111388419A discloses a stable aprepitant emulsion preparation for injection, which includes: aprepitant, emulsifier, co-emulsifier, injection oil, tonicity regulator, pH regulator and injection water. In the oil phase preparation stage, ethanol is removed through the vacuum distillation operation of a rotary evaporator; the coarse emulsion is homogenized multiple times through a microfluidizer; it causes certain difficulties in the later large-scale production.

[0010] Patent document CN113952299A discloses an aprepitant emulsion substantially free of ethanol and its preparation method. The invention includes aprepitant, emulsifier, oil, polyethylene glycol and water. Sterilization is carried out using a membrane filter with a pore size of 0.2 - 0.22 μm. If there are impurities difficult to filter in the emulsion, it may clog the filter membrane, affecting production efficiency and product quality. And the selection and use of the membrane filter need to be cautious. Membrane filters with different materials and pore sizes may have an adsorption effect on the emulsion components, affecting the drug content and emulsion stability.

[0011] Patent document CN110368363A discloses an aprepitant fat emulsion injection and its preparation method. The aprepitant fat emulsion injection of this invention uses polyethylene glycol 15 hydroxystearic acid as an emulsifier and solubilizer, uses poloxamer and sodium oleate as co-emulsifiers, and uses soybean oil and polyoxyethylene castor oil with a mass ratio of 3:1 as the oil phase.

[0012] Patent document CN112535661A discloses a thermally sterilizable aprepitant submicron emulsion injection and its preparation method. The aprepitant injection contains aprepitant, polyethylene glycol 15-hydroxystearate, phospholipids and injection oil.

[0013] The above six patent documents all use soybean oil or other vegetable oils as the oil phase, which are all long-chain triglycerides (LCT). Long-chain triglycerides (LCT) contain unsaturated fatty acids. Under the action of factors such as light, heat, and oxygen, the unsaturated bonds are prone to oxidation, generating harmful substances such as peroxides, aldehydes, and ketones. These oxidation products not only affect the quality and stability of soybean oil, but may also have adverse effects on the human body, such as causing inflammatory reactions and cell damage. If effective antioxidant measures are not taken during long-term storage or preparation, the oxidation problem may be more prominent, posing challenges to the quality control of the injection.

[0014] As a special preparation, the particle size distribution of the aprepitant injectable emulsion is directly related to its pharmacokinetics in vivo, and thus affects the drug efficacy. Since the diameter of human microvessels is about 4-9 μm and the diameter of pulmonary microvessels is about 5 μm, if a large number of emulsion particles have a diameter greater than 5 μm, it may lead to pulmonary embolism and alveolar tissue damage, and even cause the death of patients in severe cases.

[0015] Patent document CN110934829A provides an aprepitant nanomicelle preparation. The micelle preparation includes aprepitant, phospholipids, sucrose, ethanol and injection water, and the phospholipids include phosphatidylcholine and phosphatidylglycerol. First, a small amount of ethanol is evaporated during the preparation process, but the mass of ethanol in the final micelle preparation is more than three times that of aprepitant. High-concentration ethanol may cause adverse reactions such as injection site pain and neuritis. Second, the uniformity and stability of operations such as mixing, shearing, and homogenization during large-scale production are difficult to control, and the scale-up effect of the equipment may lead to product quality fluctuations, increasing the difficulty and cost of process scale-up and hindering the industrial promotion of the product.

[0016] Patent document CN112168788A discloses an intravenous injection of aprepitant micelle sterile freeze-dried preparation and its preparation method. The injectable aprepitant micelle sterile freeze-dried preparation contains aprepitant and methoxypolyethylene glycol-derivatized phospholipids, as well as pharmaceutically acceptable freeze-drying protectants. The obtained micelle solution is sterilized by passing through a 0.22 μm microporous membrane filter, and water is removed by freeze-drying to obtain an aprepitant micelle sterile freeze-dried powder.

[0017] In the above two micelle patent documents, membrane filters with a pore size of 0.22 μm are used for sterilization, which is not conducive to the control of the aseptic assurance level and has a certain clinical medication risk. In addition, there are also problems such as poor hydrophilicity of the nanomicelles, easy aggregation resulting in unsatisfactory stability, short in vivo circulation time, and poor drug efficacy.

[0018] Currently, when preparing aprepitant injection, high-speed shearing equipment and homogenizing equipment are required. Under high-speed stirring (up to 10,000 rpm) for a long time (>2 h), it has a great dependence on equipment and high energy consumption. The prepared injection is difficult to be applicable to high-pressure sterilization. After high-pressure sterilization, it has a great adverse effect on stability, resulting in the injection being unable to balance stability and aseptic reliability. Moreover, the pH of the injection is alkaline (≥8.5), resulting in the problem that phospholipids hydrolyze at a higher pH during use, leading to the content of hemolytic phospholipids exceeding the standard.

[0019] Therefore, it is necessary to develop a new type of aprepitant injection, which should have the following characteristics: free of soybean oil, free of ethanol, good preparation stability, and tolerable to autoclaving, so as to overcome the various disadvantages of the existing marketed emulsion injections and the injections reported in the literature, and provide a more safe and stable aprepitant injection for clinical use. This has become a key technical problem to be solved urgently in this field. Summary of the Invention

[0020] Aiming at the deficiencies of the above-mentioned technologies at present, the present invention provides an aprepitant micelle injection that can withstand autoclaving and its preparation method, which is composed of the active ingredient aprepitant and excipients phospholipids, bile acids or their salts, nano-micelle stabilizers, pH regulators and water for injection. Through innovative formulation design, the aprepitant micelle injection selects a phospholipid and bile acid micelle system with good physiological compatibility and safety for solubilization, significantly improving the solubility of aprepitant; the combined use of nano-micelle stabilizers can significantly improve the stability of the preparation. Compared with the original research aprepitant fat emulsion injection, this innovative formulation design avoids using a large amount of soybean oil for solubilization, thus reducing the risk of lipid metabolism; it is free of ethanol, thus avoiding ethanol allergic reactions, so it can significantly improve the safety of clinical medication. The aprepitant micelle injection has good stability and can adopt autoclaving, thus significantly improving the aseptic protection level and reducing the clinical medication risk. The aprepitant micelle injection can adopt an innovative thin-film dispersion process or blank micelle process. The process is simple and easy to scale up, similar to the production process of ordinary injections, without special equipment such as high-pressure homogenizers and dedicated fat emulsion production lines, and can significantly reduce production costs.

[0021] The main inventive concept of the invention lies in providing a more ideal carrier for aprepitant. Hepatocytes can secrete bile acids autonomously. The salts formed by the combination of taurine or glycine and bile acids, namely bile salts, contain hydrophilic hydroxyl and carboxyl groups, as well as hydrophobic methyl groups and other structures. Therefore, they have the ability to form micelles, can reduce the surface tension between the oil phase and the aqueous phase, play a role in solubilizing poorly soluble drugs, thereby increasing the drug concentration, enhancing the drug stability, promoting drug absorption and thus improving the curative effect. The bile secreted by human hepatocytes contains abundant bile salts and phospholipids, which play an important role in the absorption of fat-soluble substances such as fat-soluble vitamins and are called "physiological detergents". Both phospholipids and bile salts are inherent components in the body, so they have good biocompatibility and can be used as a more ideal carrier for aprepitant.

[0022] Adding a nano-micelle stabilizer to this phospholipid-bile salt carrier has multiple effects on this system. First, it improves the preparation stability: By modifying with hydrophilic polyethylene glycol long chains (polysorbate 80, poloxamer 188, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate), the hydrophilicity of nano-micelle particles is improved, avoiding particle aggregation, thus improving the preparation stability; while sodium oleate can increase the Zeta potential of nano-particles, and through the electrostatic repulsion effect, avoid nano-particle aggregation and improve the preparation stability.

[0023] Secondly, it improves the in-vivo stability of the nano-preparation: The nano-micelle particles are modified with polyethylene glycol long chains, which can improve the hydrophilicity. After intravenous injection, it can avoid recognition and phagocytosis by phagocytes, thereby prolonging the in-vivo circulation time of the nano-micelles, improving the transmembrane transport efficiency of the blood-brain barrier, enhancing the targeting performance, and thus improving the drug efficacy. In addition, adding PVP (polyvinylpyrrolidone) can also stabilize the micelle structure through the steric hindrance effect, utilize its hydrophilicity to increase the solubility of poorly soluble drugs, and form a diffusion barrier on the micelle surface to delay drug release. The biocompatibility of PVP can also reduce tissue irritation and protect the drug activity through hydrogen bonds or van der Waals forces with drug molecules.

[0024] The selection of sodium cholesteryl sulfate is because the rigid steroid structure of cholesterol can be inserted into the phospholipid bilayer, forming a closer molecular arrangement with lecithin, thereby reducing the surface energy of the micelle. The polar head of the sulfate group can stably bind to the micelle interface region and jointly construct a stable ternary composite system with bile salts. It is particularly worth noting that the sulfate group has a strong negative charge, which can make the micelle surface potential reach more than -30 mV. This high negative electrical potential can effectively inhibit the aggregation of micelle particles through the charge repulsion effect and maintain the long-term stability of the particle size.

[0025] The present invention first provides an aprepitant micelle injection, which contains the active ingredient aprepitant, phospholipids, bile acids or their salts, a pH regulator, and the solvent used is water for injection. The injection also contains a nano-micelle stabilizer; the content of the nano-micelle stabilizer is 0.05 - 10 mg / mL.

[0026] Preferably, the mass ratio of aprepitant to the nano-micelle stabilizer is 1:(0.025 - 5).

[0027] More preferably, the mass ratio of aprepitant to the nano-micelle stabilizer is 1:(0.025 - 3).

[0028] In the above injection, the content of aprepitant is 1 - 10 mg / mL, the content of bile acid or its salt is 40 - 150 mg / mL, the mass ratio of phospholipids to bile acid or its salt is 1:(0.5 - 1.5), and the pH regulator adjusts the pH of the injection to 6.0 - 7.5.

[0029] After being made into a finished product, the prepared aprepitant micelle injection has a volume specification of 1 - 10 mg / mL, a pH of 6.0 - 7.5, a particle size of 2 - 10 nm, a Zeta potential of -20 to -60 mV, and a light transmittance > 90%; the volume specification is preferably 4.4 mL and is placed in a vial.

[0030] The phospholipids include but are not limited to natural phospholipids or synthetic phospholipids. The natural phospholipids are selected from one of soybean phospholipids, egg yolk phospholipids, hydrogenated soybean phospholipids, and hydrogenated egg yolk phospholipids; the synthetic phospholipids are selected from one of dilauroyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, and dioleoyl phosphatidylcholine; preferably soybean phospholipids.

[0031] The phospholipids are preferably injection-grade phospholipids; the content of phosphatidylcholine (PC) is > 94%, and more preferably > 97%.

[0032] The bile acid or its salt is one or a mixture of several of bile acid, glycocholic acid, deoxycholic acid, glycochenodeoxycholic acid or their salts; preferably glycocholic acid or sodium glycocholate.

[0033] In the present invention, a pH regulator is added to adjust the pH of the injection to 6.0 - 7.5. The pH regulator includes at least one of an acidic pH regulator and a basic pH regulator; the acidic pH regulator includes one or more of citric acid, acetic acid, hydrochloric acid, and phosphoric acid, and the basic pH regulator is sodium hydroxide and / or sodium carbonate.

[0034] The nano micelle stabilizer includes one or more of polyethylene glycol 15-hydroxystearate, polysorbate, poloxamer, pegylated phosphatidylethanolamine, polyoxyethylene castor oil, sodium oleate, PVP K12, PVP K17, and sodium cholesteryl sulfate, and preferably polysorbate.

[0035] The present invention further provides a preparation method of the above aprepitant micelle injection. The preparation method is the thin film dispersion method, which specifically includes the following steps: (1) Thin film preparation: Weigh the prescribed amounts of aprepitant, phospholipid, bile acid or its salt, and nano micelle stabilizer, add an appropriate amount of organic solvent to dissolve, and place it on a rotary evaporator to obtain a loose thin film through rotary evaporation; the bile acid or its salt is one or more of bile acid, glycochenodeoxycholic acid, deoxycholic acid, and glycodeoxycholic acid; (2) Medicinal solution preparation: Add a basic pH regulator with a molar ratio of 1:(0.8 - 1.2) to the bile acid or its salt added in step (1), dissolve it completely with injection water filled with a protective gas and accounting for 50 - 85% of the total injection preparation volume, transfer the obtained solution to the loose thin film in step (1), after complete hydration, adjust the pH to 6.0 - 7.5 with a pH regulator to obtain a medicinal solution; (3) Volume or weight determination: Volume or weight determination, filtration, and filling with a protective gas of the medicinal solution obtained in step (2), and the filtration uses a 0.22 μm filter membrane; (4) Stoppering, capping, and sterilization: Subpackage, stopper and cap after filling the headspace with a protective gas, and perform autoclaving at 121 °C for 15 min.

[0036] When one or more of sodium cholate, sodium deoxycholate, sodium glycochenodeoxycholate, and sodium glycodeoxycholate are used as the bile acid or its salt in step (1), the inventor adjusts step (2) to directly transfer it to the loose thin film with injection water filled with a protective gas and accounting for 50 - 85% of the total injection preparation volume, perform complete hydration, and then adjust the pH to 6.0 - 7.5 with a pH regulator to obtain a medicinal solution.

[0037] The rotary evaporation parameters in step (1) are: water bath temperature 30 - 70 °C, time 2 - 6 h; the organic solvent in step (1) is one or more of methanol, ethanol, and isopropanol in any proportion combination; the dosage of the organic solvent is 5 - 15% of the total injection preparation volume; as a further preference, the organic solvent is a mixed solvent of methanol and ethanol, and the volume ratio of methanol to ethanol is 2.5:1.

[0038] The protective gas is any one of nitrogen, helium, carbon dioxide, and argon. The time for introducing the protective gas is 0.5 - 2 h, the residual range of dissolved oxygen is 0 - 5 mg / L, and the headspace residual oxygen content is controlled at 0 - 5%.

[0039] The present invention also provides another preparation method of the aprepitant micelle injection, and the preparation method is a blank micelle method, which specifically includes the following steps: (1) Preparation of cholate solution: When the bile acid or its salt is selected from one or more of cholic acid, glycocholic acid, deoxycholic acid, and glycochenodeoxycholic acid, add the bile acid or its salt and a basic pH regulator, wherein the molar ratio of the bile acid or its salt to the basic pH regulator is 1:(0.8 - 1.2). Dissolve it completely with injection water filled with a protective gas accounting for 60 - 80% of the total injection preparation volume, and then adjust the pH of the solution to 6.0 - 7.5 with a pH regulator to obtain a cholate solution; (2) Preparation of blank micelle solution: Weigh the phospholipids and nano - micelle stabilizers in the prescription, add them to the cholate solution in step (1), and stir in a water bath at 90 - 100 °C until the solution becomes clear to obtain a blank micelle solution; (3) Preparation of drug solution: Weigh aprepitant according to the prescription, slowly add it to the blank micelle solution obtained in step (2), heat and stir in a water bath at 90 - 100 °C until the solution becomes clear and transparent. After cooling to room temperature, adjust the pH to 6.0 - 7.5 with a pH regulator; (4) Volume or weight determination: Volume - determine or weight - determine the drug solution obtained in step (3), filter, and fill with a protective gas. The filtration uses a 0.22 μm filter membrane; (5) Stoppering, capping, and sterilization: Sub - package, fill the headspace with a protective gas, then stopper and cap, and sterilize by autoclaving at 121 °C for 15 min.

[0040] When the bile acid or its salt used in step (1) is one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, and sodium glycochenodeoxycholate, the inventor adjusts the method in step (1) to directly dissolve the bile acid or its salt with injection water filled with a protective gas, and then adjust the pH to 6.0 - 7.5 with a pH regulator to obtain a cholate solution.

[0041] Preferably, in the injection water filled with a protective gas, the drug solution filled with a protective gas after volume determination, and the headspace filled with a protective gas before stoppering and capping, the protective gas is any one of nitrogen, helium, carbon dioxide, and argon. The time for introducing the protective gas is 0.5 - 2 h, the residual range of dissolved oxygen is 0 - 5 mg / L, and the residual headspace oxygen content is controlled at 0 - 5%. As a further preference, the protective gas is nitrogen.

[0042] The aprepitant micelle injection provided by the present invention above can be used for treating or preventing, such as but not limited to, nausea and vomiting, and is particularly suitable for cancer patients during the initial and repeated treatments of highly emetogenic anti - tumor chemotherapy, in combination with steroids and 5 - HT 3The receptor antagonists are used in combination to prevent acute and delayed nausea and vomiting. In addition, aprepitant can also be used for the prevention of nausea and vomiting caused by radiotherapy and preoperative nausea and vomiting.

[0043] Compared with the prior art, the present invention has the following beneficial effects: (1) In the phospholipid bile salt micelle system of this patent, a nano-micelle stabilizer is added. Through the modification of the hydrophilic polyethylene glycol long chain, the hydrophilicity of the nano-micelle particles is improved, and particle aggregation is avoided, thereby improving the stability of the preparation; while sodium oleate can increase the Zeta potential of the nanoparticles. Through the electrostatic repulsion effect, nanoparticle aggregation is avoided, and the stability of the preparation is improved; Secondly, the in vivo stability of the nano-preparation is improved: the nano-micelle particles are modified by the polyethylene glycol long chain, which can improve the hydrophilicity. After intravenous injection, it can avoid recognition and phagocytosis by phagocytes, thereby prolonging the in vivo circulation time of the nano-micelles, improving the transmembrane transport efficiency of the blood-brain barrier, improving the targeting performance, and thus improving the drug efficacy; In addition, when polyvinylpyrrolidone is selected, the micelle structure can be stabilized by the steric hindrance effect, the solubility of poorly soluble drugs can be increased by using its hydrophilicity, and a diffusion barrier is formed on the surface of the micelle to delay drug release. The biocompatibility of polyvinylpyrrolidone can also reduce tissue irritation and protect the drug activity through hydrogen bonds or van der Waals forces with drug molecules; The addition of sodium cholesteryl sulfate is due to the rigid steroid structure of its cholesterol, which can be inserted into the phospholipid bilayer to form a closer molecular arrangement with lecithin, thereby reducing the surface energy of the micelle. The polar head of the sulfate group can stably bind to the micelle interface region and jointly construct a stable ternary composite system with bile salts. It is particularly noteworthy that the sulfate group has a strong negative charge, which can make the surface potential of the micelle reach more than -30 mV. This high negative electrical potential can effectively inhibit the aggregation of micelle particles through the charge repulsion effect and maintain the long-term stability of the particle size.

[0044] (2) The original emulsion injection is an O / W type emulsion, also known as fat emulsion, which has the risk of aggregation of emulsion droplets. There are large emulsion particles in itself, which are likely to cause various adverse reactions, such as: large emulsion particles entering the human lungs causing pulmonary granulomas; entering capillaries causing vascular granulomas, phlebitis and thrombosis, etc. The aprepitant micelle injection prepared by the present invention is a sterilized clear solution, which can strictly control visible foreign matters and insoluble particles. It is easier to observe visible foreign matters during clinical medication, and can predict medication in advance to reduce risks, thereby significantly improving the safety of medication.

[0045] (3) The original research emulsion injection has poor preparation stability and can only adopt the aseptic filtration method, with a relatively low aseptic assurance level and certain clinical medication risks. The aprepitant micelle injection prepared by the present invention significantly improves the stability of the preparation, can withstand autoclaving (121 °C, 15 min), and there are no significant changes in indicators such as the appearance, pH, particle size, content, and related substances of the injection before and after sterilization, thus greatly improving the aseptic guarantee.

[0046] (4) The original research emulsion injection contains ethanol. In the aprepitant micelle injection prepared by the present invention, ethanol is abandoned as a solubilizer for phospholipids in the prescription, and it does not contain organic solvents, avoiding adverse reactions such as allergic reactions, alcohol poisoning or impaired alcohol metabolism, injection pain, and venous inflammation caused by ethanol, and significantly improving the safety of clinical medication.

[0047] (5) The original research emulsion injection has poor preparation stability: the storage condition is 2 - 8 °C and it cannot be frozen. After taking it out and placing it at room temperature, the validity period is only 2 months. The aprepitant micelle injection of the present invention can withstand freeze-thaw cycles and significantly improves the stability of the preparation.

[0048] (6) Existing fat emulsions generally adopt the preparation process of O / W primary emulsification - high-pressure homogenization - sterilization (aseptic filtration), which has a complex process, difficult quality control, difficult scale-up production, requires special production equipment and production lines, and has a high production cost. The preparation process described in the present invention adopts an innovative thin-film dispersion process or blank micelle process, which is similar to the production process of ordinary injections, does not require special equipment and production lines, has a simple process, is easy to scale up production, and can significantly reduce the production cost.

[0049] (7) The final pH range of the injection of this patent is 6.0 - 7.5, which belongs to the physiological pH. For intravenous injection, the vascular irritation is small; it is beneficial to the stability of phospholipids, controls the degradation products of hemolytic phospholipids, and improves the stability of the preparation.

[0050] (8) This solution avoids the problem in the prior art that the high-pressure shearing method is used to prepare the injection, which requires shearing at a high speed (10,000 rpm) for a long time (more than 2 h), reduces the production cost, overcomes the problem that the current preparation relies on special equipment, has low energy consumption, and has no obvious loss to the equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 It is the appearance morphology diagram of the aprepitant micelle injection prepared by the blank micelle method in Example 1; Figure 2 It is the particle size distribution diagram of the aprepitant micelle injection prepared by the blank micelle method in Example 1, where Figure 2 a is Figure 2 the average particle size, polydispersity coefficient, and intercept of the particle size distribution shown in b, Figure 2b is the particle size distribution diagram; Figure 3 is the Zeta potential diagram of aprepitant micelle injection prepared by the blank micelle method in Example 3, where Figure 3 a is Figure 3 the Zeta potential, Zeta potential standard deviation and conductivity of the Zeta potential distribution shown in b, Figure 3 b is the Zeta potential distribution diagram; Figure 4 is the high performance liquid chromatography diagram for the determination of related substances of aprepitant micelle injection prepared by the blank micelle method in Example 3 of Experimental Example 1; Figure 5 is the Zeta potential diagram of the freeze-thaw cycle test of aprepitant micelle injection prepared by the thin film dispersion method in Example 5 of Experimental Example 4, where Figure 5 a is Figure 5 the Zeta potential, Zeta potential standard deviation and conductivity of the Zeta potential distribution shown in b, Figure 5 b is the Zeta potential distribution diagram; Figure 6 is the particle size distribution diagram of aprepitant micelle injection prepared by the blank micelle method in Example 1 of Experimental Example 5 for acceleration / 3 months, where Figure 6 a is Figure 6 the average particle size, polydispersity coefficient and intercept of the particle size distribution shown in b, Figure 6 b is the particle size distribution diagram; Figure 7 is the blood drug concentration-time curve diagram of aprepitant micelle injection and aprepitant emulsion injection prepared by the thin film dispersion method in Example 5 of Experimental Example 6; Figure 8 is the appearance diagram of aprepitant micelle injection that fails to form a clear solution prepared by the high shear dispersion emulsification mechanism in Comparative Example 10. Detailed implementation mode

[0052] The following examples are used to illustrate the present invention, but are not used to limit the scope of the present invention. For those not specified in the examples for specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in the field or according to the product specifications.

[0053] The water for injection and the liquid medicine after volume fixation used in the examples are filled with a protective gas, and the dissolved oxygen is controlled within the range of 0 - 5 mg / L. The headspace residual oxygen content before capping and sealing after dispensing is controlled within the range of 0 - 5%.

[0054] Example 1 An aprepitant micelle injection, the prescription thereof is as follows: Aprepitant 1.28 g, soybean phospholipid 16.16 g, sodium glycocholate 20.20 g, polyoxyethylene 35 castor oil 64 mg, add water for injection to 200 mL.

[0055] Using the blank micelle method, the preparation method includes the following steps: (1) Weigh the prescribed amount of sodium glycocholate, add 160 mL of nitrogen-purged and deoxygenated injection water, stir for 20 min to dissolve, and adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (2) Weigh the soybean phospholipid and polyoxyl 35 castor oil in the prescription, add them to the solution prepared in step (1), heat in a water bath at 100 °C and stir at 400 rpm until the solution is clear to obtain a blank micelle solution; (3) Weigh the prescribed amount of aprepitant, add it to the blank micelle solution prepared in step (2), heat in a water bath at 100 °C, heat and stir until the solution is clear and transparent, cool to room temperature and then adjust the pH value to 6.50; (4) Fix the liquid medicine in step (3) to 200 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen; (5) Dispense 4.4 mL per vial, fill the headspace of the vial with nitrogen, stopper and crimp, and sterilize by autoclaving at 121 °C for 15 min.

[0056] As Figure 1 shown, the aprepitant micelle injection obtained in Example 1 is clear, transparent, light yellowish green, and the pH is 6.55.

[0057] As Figure 2 shown, the Z-Average of the mixed micelle solution is 2.891 nm, the PDI is 0.331; the Zeta potential is -39.1 mV.

[0058] Example 2 An aprepitant micelle injection, the prescription is as follows: Aprepitant 1.28 g, soybean phospholipid 13.65 g, glycocholic acid 16.29 g, sodium hydroxide 1.21 g, polysorbate 80 64 mg, add injection water to 200 mL.

[0059] Using the thin film dispersion method, the preparation method includes the following steps: (1) Weigh the prescribed amount of aprepitant, soybean phospholipid, glycocholic acid, and polysorbate 80, dissolve them completely in 17 mL of methanol and 7 mL of absolute ethanol, place them on a rotary evaporator, and perform rotary evaporation in a 60 °C water bath for 3 h to obtain a loose thin film; (2) After completely dissolving sodium hydroxide in 160 mL of nitrogen-purged injection water, transfer it to the obtained loose thin film, stir at 400 rpm and in a 40 °C water bath for 30 min to completely hydrate it, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (3)After adjusting the pH, make up the volume of the medicinal solution to 200 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen. (4)Dispense (4.4 mL per vial), after filling the headspace of the vial with nitrogen, stopper and crimp the vial, and sterilize it by autoclaving at 121 °C for 15 min.

[0060] The injection is clear, transparent, light yellowish-green. The Z-Average of the mixed micelle solution is 2.995 nm, the PDI is 0.298, the Zeta potential is -42.3 mV, and the pH is 6.54.

[0061] Example 3 A aprepitant micelle injection, the prescription is as follows: Aprepitant 1.28 g, egg yolk phospholipid 11.52 g, glycocholic acid 13.76 g, sodium hydroxide 0.94 g, polysorbate 80 32 mg, add water for injection to 100 mL.

[0062] Using the blank micelle method, the preparation method includes the following steps: (1)Weigh the prescribed amount of glycocholic acid and sodium hydroxide, add 80 mL of nitrogen-filled and deoxygenated water for injection, stir to dissolve, and adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (2)Weigh the egg yolk phospholipid and polysorbate 80 in the prescription, add them to the solution prepared in step (1), heat in a water bath at 100 °C and stir at 400 rpm until the solution is clear to obtain a blank micelle solution; (3)Weigh the prescribed amount of aprepitant, add it to the blank micelle solution prepared in step (2), heat in a water bath at 100 °C, stir until the solution is clear and transparent, cool to room temperature, and then adjust the pH value to 6.50; (4)Make up the volume of the medicinal solution in step (3) to 100 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen; (5)Dispense 4.4 mL per vial, fill the headspace of the vial with nitrogen, stopper and crimp the vial, and sterilize it by autoclaving at 121 °C for 15 min.

[0063] The obtained injection is clear, transparent, light yellowish-green. The Z-Average of the mixed micelle solution is 2.876 nm, the PDI is 0.311, the pH is 6.80; as Figure 3 shown, the Zeta potential is -41.2 mV.

[0064] Example 4 A aprepitant micelle injection, the prescription is as follows: Aprepitant 0.64 g, soybean phospholipid 6.82 g, glycocholic acid 8.15 g, sodium hydroxide 0.61 g, pegylated phosphatidylethanolamine 32 mg, add water for injection to 100 mL.

[0065] The thin film dispersion method is adopted, and the preparation method includes the following steps: (1) Weigh the prescribed amounts of aprepitant, soybean phospholipid, glycocholic acid, and galactosylated phosphatidylethanolamine, add 8 mL of methanol and 3 mL of absolute ethanol, dissolve completely, place on a rotary evaporator, perform rotary evaporation in a 60 °C water bath for 3 h to obtain a loose film; (2) Weigh the sodium hydroxide in the prescription, dissolve it in 80 mL of nitrogen-filled injection water, transfer it to the obtained loose film, stir at a speed of 400 rpm in a 40 °C water bath for 30 min to complete hydration, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (3) After adjusting the pH, make up the volume of the medicinal liquid to 100 mL, filter through a 0.22 μm filter membrane, and fill with nitrogen; (4) Dispense (4.4 mL per vial), fill the headspace of the vial with nitrogen, stopper and crimp the vial, and sterilize by autoclaving at 121 °C for 15 min.

[0066] This injection is clear, transparent, and light yellowish green. The Z-Average of the mixed micelle solution is 2.986 nm, the PDI is 0.293, the Zeta potential is -39.2 mV, and the pH is 6.49.

[0067] Example 5 An aprepitant micelle injection, with the following prescription: Aprepitant 1.28 g, soybean phospholipid 15.68 g, glycocholic acid 18.72 g, sodium hydroxide 1.59 g, polysorbate 80 32 mg, add injection water to 200 mL.

[0068] The thin film dispersion method is adopted, and the preparation method includes the following steps: (1) Weigh the prescribed amounts of aprepitant, soybean phospholipid, glycocholic acid, and polysorbate 80, add 17 mL of methanol and 6 mL of absolute ethanol, dissolve completely, place on a rotary evaporator, perform rotary evaporation in a 60 °C water bath for 3 h to obtain a loose film; (2) Weigh the sodium hydroxide in the prescription, dissolve it in 160 mL of nitrogen-filled injection water, transfer it to the obtained loose film, stir at a speed of 400 rpm in a 40 °C water bath for 30 min to complete hydration, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (3) After adjusting the pH, make up the volume of the medicinal liquid to 200 mL, filter through a 0.22 μm filter membrane, and fill with nitrogen; (4) Dispense (4.4 mL per vial), fill the headspace of the vial with nitrogen, stopper and crimp the vial, and sterilize by autoclaving at 121 °C for 15 min.

[0069] The injection solution is clear, transparent, light yellowish-green. The Z-Average of the mixed micelle solution is 2.898 nm, the PDI is 0.301, the Zeta potential is -39.0 mV, and the pH is 6.85.

[0070] Example 6 A aprepitant micelle injection solution, with the following prescription: Aprepitant 0.64 g, soybean phospholipid 8.10 g, glycocholic acid 9.64 g, sodium hydroxide 0.82 g, polyethylene glycol 15-hydroxystearate 64 mg, add water for injection to make 200 mL.

[0071] Using the blank micelle method, the preparation method includes the following steps: (1) Weigh the prescribed amounts of glycocholic acid and sodium hydroxide, add 160 mL of nitrogen-filled and deoxygenated water for injection, stir to dissolve, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (2) Weigh the soybean phospholipid and polyethylene glycol 15-hydroxystearate in the prescription, add them to the solution prepared in step (1), heat in a water bath at 100 °C and stir at 400 rpm until the solution is clear to obtain a blank micelle solution; (3) Weigh the prescribed amount of aprepitant, add it to the blank micelle solution prepared in step (2), heat in a water bath at 100 °C, heat and stir until the solution is clear and transparent, and adjust the pH value to 6.50 after cooling to room temperature; (4) Fix the medicinal liquid in step (3) to 200 mL, filter through a 0.22 μm filter membrane, and fill with nitrogen; (5) Sub-pack 4.4 mL per vial, fill the headspace of the vial with nitrogen, add a stopper and crimp the cap, and sterilize by autoclaving at 121 °C for 15 min.

[0072] The injection solution is clear, transparent, light yellowish-green. The Z-Average of the mixed micelle solution is 2.925 nm, the PDI is 0.302, the Zeta potential is -40.3 mV, and the pH is 6.90.

[0073] Example 7 A aprepitant micelle injection solution, with the following prescription: Aprepitant 1.28 g, soybean phospholipid 15.68 g, glycocholic acid 18.72 g, sodium hydroxide 1.59 g, PVP K12 32 mg, add water for injection to make 200 mL.

[0074] Using the thin film dispersion method, the preparation method includes the following steps: (1) Weigh the prescribed amounts of aprepitant, soybean phospholipid, glycocholic acid, and PVP K12, dissolve them completely in 17 mL of methanol and 6 mL of absolute ethanol, place them on a rotary evaporator, and perform rotary evaporation in a 60 °C water bath for 3 h to obtain a loose thin film; (2) Weigh the sodium hydroxide in the prescription, dissolve it in 160 mL of nitrogen-filled injection water, transfer it to the obtained loose film, stir at 400 rpm and 40 °C in a water bath for 30 min to complete its hydration, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (3) After adjusting the pH, make up the volume of the liquid medicine to 200 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen; (4) Dispense (4.4 mL per vial), fill the headspace of the vial with nitrogen, stopper and crimp, and sterilize by autoclaving at 121 °C for 15 min.

[0075] This injection solution is clear, transparent, light yellowish green. The Z-Average of the mixed micelle solution is 2.999 nm, the PDI is 0.305, the Zeta potential is -39.8 mV, and the pH is 6.83.

[0076] Example 8 An aprepitant micelle injection solution, the prescription of which is as follows: Aprepitant 0.64 g, soybean phospholipid 8.10 g, glycocholic acid 9.64 g, sodium hydroxide 0.82 g, PVP K17 64 mg, add injection water to make up 200 mL.

[0077] Using the blank micelle method, the preparation method includes the following steps: (1) Weigh the glycocholic acid and sodium hydroxide in the prescription, add 160 mL of nitrogen-filled and deoxygenated injection water, stir to dissolve, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (2) Weigh the soybean phospholipid and PVP K17 in the prescription, add them to the solution prepared in step (1), heat in a water bath at 100 °C and stir at 400 rpm until the solution is clear to obtain a blank micelle solution; (3) Weigh the prescribed amount of aprepitant, add it to the blank micelle solution prepared in step (2), heat in a water bath at 100 °C, stir until the solution is clear and transparent, cool to room temperature, and then adjust the pH value to 6.50; (4) Make up the volume of the liquid medicine in step (3) to 200 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen; (5) Dispense 4.4 mL per vial, fill the headspace of the vial with nitrogen, stopper and crimp, and sterilize by autoclaving at 121 °C for 15 min.

[0078] This injection solution is clear, transparent, light yellowish green. The Z-Average of the mixed micelle solution is 2.985 nm, the PDI is 0.307, the Zeta potential is -40.2 mV, and the pH is 6.87.

[0079] Example 9 An aprepitant micelle injection solution, the prescription of which is as follows: Aprepitant 1.28 g, soybean phospholipid 15.68 g, glycocholic acid 18.72 g, sodium hydroxide 1.59 g, sodium cholesteryl sulfate 16 mg, add injection water to make up to 200 mL.

[0080] Adopt the thin film dispersion method, and the preparation method includes the following steps: (1) Weigh the prescribed amounts of aprepitant, soybean phospholipid, glycocholic acid, and sodium cholesteryl sulfate, add 17 mL of methanol and 6 mL of absolute ethanol to dissolve completely, place on a rotary evaporator, and perform rotary evaporation in a water bath at 60 °C for 3 h to obtain a loose film; (2) Weigh the sodium hydroxide in the prescription, dissolve it in 160 mL of nitrogen-filled injection water, transfer it to the obtained loose film, stir at a speed of 400 rpm in a water bath at 40 °C for 30 min to make it completely hydrated, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (3) After adjusting the pH, make up the volume of the medicinal liquid to 200 mL, filter it through a 0.22 μm filter membrane, and fill with nitrogen; (4) Subpackage (4.4 mL per vial), fill the headspace of the vial with nitrogen, then stopper and crimp the cap, and sterilize by autoclaving at 121 °C for 15 min.

[0081] This injection is clear, transparent, and light yellowish green. The Z-Average of the mixed micelle solution is 2.979 nm, the PDI is 0.296, the Zeta potential is -39.9 mV, and the pH is 6.82.

[0082] Comparative Example 1 An aprepitant micelle injection, and its prescription is as follows: Aprepitant 1.28 g, soybean phospholipid 16.16 g, glycocholic acid 19.30 g, sodium hydroxide 1.60 g, add injection water to make up to 200 mL.

[0083] Adopt the thin film dispersion method, and the preparation method includes the following steps: (1) Weigh the prescribed amounts of aprepitant, soybean phospholipid, and glycocholic acid, add 17 mL of methanol and 7 mL of absolute ethanol to dissolve completely, and perform rotary evaporation in a water bath at 60 °C for 4 h to obtain a loose film; (2) Take the prescribed amount of sodium hydroxide, add 160 mL of nitrogen-filled injection water, stir to dissolve it, transfer it to the loose film obtained in step (1), stir at a speed of 400 rpm in a water bath at 40 °C for 30 min, stir to make it completely hydrated, and adjust the pH value to 6.5 with 1 mol / L sodium hydroxide solution and 0.5 mol / L citric acid solution; (3) Make up the volume of the medicinal liquid obtained in (2) to 200 mL, filter it through a 0.22 μm filter membrane, and fill with nitrogen; (4)Fill the vials with nitrogen, dispense (4.4 mL / vial), stopper and crimp the caps, and sterilize by autoclaving at 121 °C for 15 min.

[0084] The micellar injection is clear and transparent, light yellowish green in color. The Z-Average of the mixed micellar solution is 2.976 nm, the PDI is 0.293, the Zeta potential is -41.5 mV, and the pH is 6.65.

[0085] Comparative Example 2 An aprepitant micellar injection, with the following formulation: Aprepitant 1.28 g, soybean phospholipid 16.93 g, deoxycholic acid 19.94 g, sodium hydroxide 2.03 g, add water for injection to make 200 mL.

[0086] Using the thin film dispersion method, the preparation method includes the following steps: (1)Weigh the prescribed amounts of aprepitant, soybean phospholipid, and deoxycholic acid, add 17 mL of methanol and 7 mL of absolute ethanol, dissolve completely, place on a rotary evaporator, and rotary evaporate at 60 °C in a water bath for 4 h to obtain a loose film; (2)Weigh the prescribed amount of sodium hydroxide, add 160 mL of nitrogen-purged and deoxygenated water for injection, stir until completely dissolved, transfer to the film obtained in (1), stir at 400 rpm in a 40 °C water bath for 30 min, stir until completely hydrated, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (3)Dilute the solution obtained in (2) to 200 mL, filter through a 0.22 μm pore size filter membrane, and fill with nitrogen; Step (4) is the same as in Comparative Example 1.

[0087] This injection is clear, transparent, and light yellowish green. The Z-Average of the mixed micellar solution is 2.901 nm, the PDI is 0.315, the Zeta potential is -38.6 mV, and the pH is 6.72.

[0088] Comparative Example 3 An aprepitant micellar injection, with the following formulation: Aprepitant 1.28 g, soybean phospholipid 17.00 g, sodium glycochenodeoxycholate 21.16 g, add water for injection to make 200 mL.

[0089] Using the blank micelle method, the preparation method includes the following steps: (1)Weigh the prescribed amount of sodium glycochenodeoxycholate, add 160 mL of nitrogen-purged and deoxygenated water for injection, stir for 15 min to dissolve, and adjust the pH value to 7.00 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (2) Weigh the soybean phospholipid in the prescription and add it to the solution in step (1). Heat it in a water bath at 100 °C and stir at a speed of 400 rpm for 1 h until the solution becomes clear, obtaining a blank micelle solution. (3) Weigh the prescribed amount of aprepitant and add it to the blank micelle solution obtained in step (2). Heat it in a water bath at 100 °C, heat and stir until the active pharmaceutical ingredient (API) is completely dissolved and the solution is clear. Let it cool to room temperature, and adjust the pH value to 7.00 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution. (4) Make the solution in step (3) up to 200 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen. (5) Dispense (4.4 mL per vial), fill the headspace of the vial with nitrogen, stopper and crimp the vial, and sterilize it by autoclaving at 121 °C for 15 min.

[0090] This injection solution is clear, transparent, light yellowish green. The Z-Average of the mixed micelle solution is 2.938 nm, the PDI is 0.299, the Zeta potential is -40.2 mV, and the pH is 6.95.

[0091] Comparative Example 4 An aprepitant micelle injection solution, with the following prescription: Aprepitant 0.64 g, soybean phospholipid 9.19 g, sodium glycochenodeoxycholate 11.49 g, add injection water to 100 mL.

[0092] Using the blank micelle method, the preparation method includes the following steps: (1) Weigh the prescribed amount of sodium glycochenodeoxycholate, add 80 mL of nitrogen-purged and oxygen-removed injection water, stir for 15 min to dissolve it, and adjust the pH value to 7.00 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution. Steps (2) and (3) are carried out in the same manner as described in Comparative Example 3. (4) Make the solution in step (3) up to 100 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen. (5) Dispense (4.4 mL per vial), fill the headspace of the vial with nitrogen, stopper and crimp the vial, and sterilize it by autoclaving at 121 °C for 15 min.

[0093] This injection solution is clear, transparent, light yellowish green. The Z-Average of the mixed micelle solution is 2.924 nm, the PDI is 0.332, the Zeta potential is -39.5 mV, and the pH is 7.01.

[0094] Comparative Example 5 An aprepitant micelle injection solution, with the following prescription: Aprepitant 0.64 g, soybean phospholipid 8.33 g, glycocholic acid 9.95 g, sodium hydroxide 0.85 g, add injection water to 100 mL.

[0095] Using the thin film dispersion method, the preparation method includes the following steps: (1) Weigh the prescribed amounts of aprepitant, soybean phospholipid, and glycocholic acid, dissolve them completely in 8 mL of methanol and 3 mL of absolute ethanol, and rotary evaporate at 60 °C in a water bath for 4 h to obtain a loose film; (2) Take the prescribed amount of sodium hydroxide, add 80 mL of nitrogen-filled injection water, stir to dissolve, transfer it to the loose film obtained in step (1), stir at 400 rpm and 40 °C in a water bath for 30 min to complete hydration, and adjust the pH value to 6.5 with 1 mol / L sodium hydroxide solution and 0.5 mol / L citric acid solution; (3) Dilute the medicinal liquid obtained in (2) to 100 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen; (4) Fill the vials with nitrogen, dispense (4.4 mL / vial), stopper and crimp the caps, and autoclave at 121 °C for 15 min.

[0096] This injection is clear, transparent, and light yellowish-green. The Z-Average of the mixed micelle solution is 2.854 nm, the PDI is 0.203, the Zeta potential is -38.7 mV, and the pH is 6.52.

[0097] Comparative Example 6 An aprepitant micelle injection, with the following prescription: Aprepitant 0.32 g, soybean phospholipid 4.59 g, glycocholic acid 5.49 g, sodium hydroxide 0.47 g, add injection water to 50 mL.

[0098] Using the blank micelle method, the preparation method includes the following steps: (1) Weigh the prescribed amounts of glycocholic acid and sodium hydroxide, add 40 mL of nitrogen-filled and deoxygenated injection water, stir to dissolve, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (2) Weigh the soybean phospholipid in the prescription, add it to the solution in step (1), heat in a water bath at 100 °C, and stir at 400 rpm until the solution is clear to obtain a blank micelle solution; (3) Weigh the prescribed amount of aprepitant, add it to the blank micelle solution in step (2), heat in a water bath at 100 °C, stir until the API is completely dissolved and the solution is clear, cool to room temperature, and adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution; (4) Dilute the medicinal liquid in step (3) to 50 mL, filter it through a 0.22 μm filter membrane, and fill it with nitrogen; (5) Dispense (4.4 mL / vial), fill the headspace of the vials with nitrogen, stopper and crimp the caps, and autoclave at 121 °C for 15 min.

[0099] The injection solution is clear, transparent, light yellowish-green. The Z-Average of the mixed micelle solution is 2.751 nm, the PDI is 0.302, the Zeta potential is -41.4 mV, and the pH is 6.68.

[0100] Comparative Example 7: According to Example 4 of CN110934829A, aprepitant nano-micelle injection solution was prepared, and its composition is as follows: Aprepitant 1 g, phosphatidylcholine 20 g, phosphatidylglycerol 1.5 g, ethanol 4 g, sucrose 7.69 g, sodium oleate 0.775 g, purified water 105 mL.

[0101] Preparation method: (1) Aprepitant, phosphatidylcholine, phosphatidylglycerol and ethanol were heated and mixed with stirring for 15 minutes to dissolve them in excess ethanol to prepare an ethanol solution; (2) Sucrose, sodium oleate and water for injection were stirred and mixed at room temperature for 25 minutes to prepare an aqueous phase; (3) The aqueous phase and the ethanol solution were subjected to high-speed shearing at over 10,000 rpm, and then homogenized by a high-pressure homogenizer at 1500 bar to form nano-micelles. After filtration through a 0.22 μm filter, the nano-micelle injection solution was obtained; The injection solution is clear, transparent, and a yellow to brown solution. The Z-Average of the mixed micelle solution is 42.0 nm, the PDI is 0.313, the Zeta potential is -42.9 mV, and the pH is 8.30; (4) To investigate the heat-pressure sterilization stability of this aprepitant micelle injection solution, the injection solution was filled with nitrogen and sub-packed into 10 mL vials. After sub-packing, the specification of the injection solution and aprepitant was 4.4 mL: 32 mg. The headspace was filled with nitrogen and heat-pressure sterilized at 121 °C for 15 min, and the appearance, content, and related substances were investigated.

[0102] The results showed that particle aggregation occurred in the injection solution after sterilization, the clarity decreased, and crystal precipitation occurred, indicating that the injection solution could not tolerate heat-pressure sterilization. The results of content determination and related substance inspection are shown in Table 2.

[0103] Comparative Example 8: Aprepitant nano-micelles were prepared according to Example 3 described in CN110934829A, and its composition is as follows: Aprepitant 1 g, phosphatidylcholine 20 g, phosphatidylglycerol 1 g, ethanol 12 g, sucrose 7.69 g, purified water 105 mL.

[0104] Preparation method: (1) Aprepitant, phosphatidylcholine, phosphatidylglycerol and ethanol were heated and mixed with stirring for 15 minutes to dissolve them in excess ethanol to prepare an ethanol solution; (2) Sucrose and water for injection were stirred and mixed at room temperature for 25 minutes to prepare an aqueous phase; (3) The aqueous phase and the ethanol solution were subjected to high-speed shearing at over 10,000 rpm, and then homogenized by a high-pressure homogenizer at 1500 bar to form nano micelles. After filtration through a 0.22 μm filter, the nano micelle injection solution was obtained; This injection solution is clear, transparent, and a yellow to brown solution. The Z-Average of the mixed micelle solution is 46.7 nm, the PDI is 0.283, the Zeta potential is -43.3 mV, and the pH is 8.15; (4) To investigate the heat-pressure sterilization stability of this aprepitant micelle injection solution, the injection solution was filled with nitrogen and dispensed into 10 mL vials. After dispensing, the specification of the injection solution and aprepitant is 4.4 mL: 32 mg. The headspace was filled with nitrogen and heat-pressure sterilized at 121 °C for 15 min. The appearance, content, and related substances were investigated.

[0105] The results showed that particle aggregation, decreased clarity, and crystal precipitation occurred in this injection solution after sterilization, indicating that this injection solution cannot withstand heat-pressure sterilization. The results of the content determination and related substance inspection are shown in Table 2.

[0106] Comparative Example 9 Reduced its drug loading amount according to the technical solution of CN117752596A to prepare an aprepitant micelle injection solution: Aprepitant 1 g, glycocholic acid 18 g, soybean phospholipid 14 g, sodium hydroxide 1.5 g, water for injection 85 g.

[0107] Preparation method: (1) Weigh 1.5 g of sodium hydroxide and add it to 85 g of water for injection. Under magnetic stirring, heat it to 55 °C. After the sodium hydroxide is dissolved, add 18 g of glycocholic acid and continue stirring until completely dissolved, and carry out neutralization for 10 min to form a sodium glycocholate solution; (2) Start the high-shear dispersion emulsifier, heat to 65 °C under the condition of high-speed shearing at 10,000 rpm, add 14 g of soybean phospholipid to the sodium glycocholate solution, and emulsify for 120 min to form a mixed micelle solution; (3) Continue under the condition of high-speed shearing at 10,000 rpm, maintain the temperature at 65 °C, slowly add 1.0 g of aprepitant to the mixed micelle solution, and carry out shear dispersion for a total of 150 min to form an aprepitant mixed micelle solution; (4) After adjusting the pH value of the aprepitant mixed micelle solution to 8.5 with 3 wt% hydrochloric acid solution, the obtained mixed micelles were filtered through a 0.22 μm filter membrane (PES), filled with nitrogen and bottled, controlling the residual oxygen content in the headspace of the bottle ≤ 5%, and heat-pressure sterilized (121 °C, 15 min) to obtain an aprepitant micelle injection solution.

[0108] Comparative Example 10: Prepare aprepitant micelle injection according to Example 1 described in CN117752596A: 10 g of aprepitant, 60 g of glycocholic acid, 80 g of soybean phospholipid, 5 g of sodium hydroxide, 845 g of water for injection.

[0109] Preparation method: (1) Weigh 5.0 g of sodium hydroxide and add it to 845 g of water for injection. Under magnetic stirring, heat to 55 °C. After the sodium hydroxide is dissolved, add 60.0 g of glycocholic acid and continue stirring until completely dissolved. Then carry out neutralization for 10 min to form a sodium glycocholate solution; (2) Turn on the high-shear dispersion emulsifier. Under the condition of high-speed shearing at 10000 rpm, heat to 65 °C, add 80.0 g of soybean phospholipid to the sodium glycocholate solution, and emulsify for 150 min to form a mixed micelle solution; (3) Continue under the condition of high-speed shearing at 10000 rpm, maintain the temperature at 65 °C, slowly add 10.0 g of aprepitant to the mixed micelle solution, and carry out shear dispersion for 120 min. A clear aprepitant micelle injection could not be formed, and a large amount of aprepitant raw material was still not encapsulated into the mixed micelles. As Figure 8 shown, subsequent verification tests could not be carried out.

[0110] Experimental Example 1 Determination methods for drug loading, content, related substances, and residual solvents 1. Drug loading = mass of aprepitant dissolved in the formulation / (sum of the mass of aprepitant and the total excipients added) × 100%, where the total excipients added include aprepitant, phospholipid, bile salt (for Comparative Examples 7 and 8, include aprepitant, phosphatidylcholine, phosphatidylglycerol, and sucrose).

[0111] 2. Content determination method (the following ratios in the mobile phase are all volume ratios) Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler; use 90% acetonitrile - 0.1% phosphoric acid solution (70:30) as the mobile phase; the detection wavelength is 210 nm; the injection volume is 20 μl, and the column temperature is 35 °C.

[0112] Reference solution: Weigh 10.0 mg of aprepitant raw material precisely, place it in a 100 mL volumetric flask, dissolve and make up the volume with the mobile phase solution to prepare a reference solution of 100 μg / ml.

[0113] Test solution: Precisely pipette 1 ml of aprepitant micelle injection into a 50 mL volumetric flask, add 2 ml of methanol to break the emulsion, add the mobile phase solution to two-thirds of the volume of the volumetric flask, make up the volume with methanol, shake well, and the solution is clear, then it is obtained.

[0114] 3. Related Substances Test Method Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Venusil XBP C18 specification: 250×4.6mm, 5μm); Use 0.1% phosphoric acid solution (take 1 ml of phosphoric acid, add 1000 mL of water, mix well)-acetonitrile-methanol (80∶10∶10) as mobile phase A, and 0.1% phosphoric acid solution-acetonitrile-methanol (10∶80∶10) as mobile phase B; The detection wavelength is 210 nm; The injection volume is 20 μl. Perform gradient elution according to Table 1.

[0115] Table 1 Gradient Elution Table for Related Substances of Aprepitant Micelle Injection Test solution for related substances: Accurately measure 1 mL of this product, place it in a 10 mL volumetric flask, dilute it to the mark with methanol, and shake well.

[0116] 4. Residual Solvents Determination Method: (1) Chromatographic conditions: A capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as the stationary liquid (it is recommended to use Agilent DB-624, 0.53mm×30m, 3μm or a chromatographic column with equivalent efficiency); The initial temperature is 50℃, maintain for 10 minutes, increase the temperature to 150℃ at a rate of 50℃ per minute, and maintain for 5 min; The inlet temperature is 200℃; The detector is a flame ionization detector, and the detector temperature is 300℃; The column flow rate is 2 mL per minute; The split ratio is 20:1; The headspace equilibrium temperature is 80℃; The quantitative loop temperature is 90℃; The equilibrium time is 30 minutes; System suitability requirements: In the chromatogram of the reference solution, methanol and ethanol elute in sequence, and the resolution between each chromatographic peak should meet the requirements.

[0117] (2) Preparation of solutions Test solution: Accurately measure 2 mL of this product, place it in a 20 mL headspace vial, stopper and seal it.

[0118] Reference solution: Weigh appropriate amounts of methanol and ethanol respectively, accurately weigh them, quantitatively dilute them with ultrapure water to prepare a mixed solution containing approximately 3 mg of methanol and 5 mg of ethanol per 1 mL. Accurately measure 2 mL of this solution, place it in a 20 mL headspace vial, stopper and seal it.

[0119] Detect Examples 1-9 and Comparative Examples 1-9 according to the above methods for drug loading, content, related substances, and residual solvents determination. The results are shown in Table 2; The chromatogram of related substances of the micelle injection prepared in Example 3 after sterilization is as Figure 4As shown. From the results in Table 2, it can be seen that compared with Comparative Examples 1-6, the drug loading amounts of Examples 1-9 are all higher. It can be seen that adding a nano-micelle stabilizer to the micelle injection formulation can further increase the drug loading amount. There is no obvious change in the content of the micelle injection prepared in the Examples before and after heat-pressure sterilization. The ethanol residue amounts of Comparative Examples 7-8 are high. After sterilization, particle aggregation occurs in this injection, the clarity decreases, crystal precipitation appears, and the impurity content is relatively large. Therefore, it may cause adverse reactions such as nervous system depression and vascular irritation, and in severe cases, it may lead to adverse reactions such as metabolic acidosis or respiratory failure.

[0120] Table 2 Detection Results of Drug Loading Amount, Content, Related Substances, etc. of Aprepitant Micelle Injection 。

[0121] Experimental Example 2 Investigating the Influence of Adding a Nano-Micelle Stabilizer For the aprepitant micelle injection prepared in the present invention, adding a nano-micelle stabilizer such as polysorbate 80 to the formulation can shorten the dissolution time of aprepitant in the blank micelle preparation process and improve the physical and chemical stability of the mixed micelles.

[0122] By comparing Comparative Example 4, Comparative Example 5, Comparative Example 6, Comparative Example 9, and Example 5 (adding a nano-micelle stabilizer), after the filtered liquid medicine is placed at room temperature, the physical stability is evaluated by observing whether crystals precipitate, and the dissolution time of aprepitant is compared. The results are shown in Table 3 and Table 4 below. The liquid medicine of Comparative Example 4 precipitated after being placed at room temperature for 10 h; while a small amount precipitated in Comparative Example 6 after being placed for 14 h. A small amount precipitated in Comparative Example 9 after heat-pressure sterilization at 121 °C for 15 min and then being placed at room temperature for 20 h, while no precipitation occurred in Comparative Example 9 without heat-pressure sterilization, indicating that heat-pressure sterilization at 121 °C for 15 min reduced the micelle stability of Comparative Example 9. In use, the heat-pressure sterilization parameters of Comparative Example 9 can be adjusted to avoid the problem of poor micelle stability, but if the heat-pressure sterilization parameters are adjusted, there will be a problem of poor sterility reliability. Therefore, the scheme of Comparative Example 9 cannot balance sterility reliability and micelle stability. No precipitation occurred in Example 5 after being placed for 24 h. Therefore, adding a nano-micelle stabilizer is beneficial to increasing the stability of the micelle system. Compared with Comparative Example 4, Comparative Example 5, and Comparative Example 6, the dissolution time of aprepitant in Example 5 is short, and the time-consuming of the blank micelle preparation process can be reduced.

[0123] Table 3 Investigation Results of Physical Stability Note: “-” means “no crystal precipitation”, “+” means “crystal precipitation”, and “N / A” means “not applicable”.

[0124] Table 4 Investigation Results of Aprepitant Dissolution Time 。

[0125] Experimental Example 3 Low-temperature Cycle Test Take the aprepitant micelle injection prepared in Example 5 for the low-temperature cycle test. The test should include 3 cycles. Each cycle is placed at 2 - 8°C for 2 days, and then placed at 25°C for 2 days. Samples are taken for testing after each round. The results are shown in Table 5.

[0126] It can be seen from the results in Table 5 that after 3 rounds, there is no precipitation phenomenon; compared with day 0, there are no significant changes in pH value, clarity and color, particle size, potential, content, related substances, etc., indicating that the prepared aprepitant micelle injection can withstand the low-temperature cycle test and has good low-temperature tolerance.

[0127] Note: Information on the color comparison solution used under the item of color: Name: Standard Color Comparison Solution of Chinese Pharmacopoeia 2020 Edition, Number: TM - 2020 - 0901, Batch Number: C2011013, Manufacturer: Tanmo Quality Inspection Technology Co., Ltd.; The turbidity standard solution used for clarity is prepared with reference to the Chinese Pharmacopoeia 2020 Edition.

[0128] Table 5 Results of the low-temperature cycle test of the aprepitant micelle injection in Example 5 。

[0129] Experimental Example 4 Freeze-thaw Cycle Test Take the aprepitant micelle injections prepared in Comparative Example 1, Comparative Example 5, Comparative Examples 7 - 9 (without adding nano-micelle stabilizer) and Examples 1 - 9 for the freeze-thaw test. The test should include 3 cycles. Each cycle is placed at -10~-20°C for 2 days, and then placed at 25°C for 2 days. Samples are taken for testing after each round. The results are shown in Table 6 and Table 7.

[0130] After 3 rounds of cycles, it can be seen from the results in Table 6 that precipitations occurred in Comparative Examples 7 - 9 during the first round of freeze-thaw cycle; in Comparative Example 1 and Comparative Example 5, without adding nano-micelle stabilizer, crystals had precipitated during the 3rd round of freeze-thaw cycle; with a certain amount of nano-micelle stabilizer added to the prescription composition (Examples 1 - 9), no crystals precipitated in all 3 rounds. It can be seen that the nano-micelle stabilizer can improve the freeze-thaw stability of the injection.

[0131] It can be seen from the results in Table 7 that for the sample prepared in Example 5, no crystals precipitated; compared with day 0, there were no significant changes in pH value, clarity and color, particle size, potential, content, related substances, etc. The Zeta potential diagram of Example 5 after 3 rounds of freeze-thaw is as Figure 5 shown. The above results indicate that the aprepitant micelle injection can withstand the freeze-thaw test.

[0132] Table 6 Results of the freeze-thaw cycle test Note: "-" indicates "no crystal precipitation", and "+" indicates "crystal precipitation".

[0133] Table 7 Results of freeze-thaw cycle test of Example 5 。

[0134] Experimental Example 5 Accelerated test and long-term test The aprepitant micellar injection in Examples 1-9 was subjected to stability studies under the following conditions, and the changes in appearance, properties, pH and Zeta potential were recorded. The aprepitant content and related substances were determined according to Experimental Example 1 above. The results are shown in Table 8;

[0135] Long-term test: 5°C ± 3°C; Accelerated test: 25°C ± 2°C / 60% RH ± 5% RH.

[0136] Table 8 Results of stability investigation of accelerated test and long-term test Figure 6 The particle size distribution map of the aprepitant micellar injection prepared in Example 1 under accelerated conditions for 3 months is shown, indicating that there is no significant change in the particle size of the prepared micellar injection after being placed under accelerated conditions for 3 months compared with that at day 0.

[0137] As can be seen from the above table, when the aprepitant micellar injections in Examples 1-9 were placed for 6 months under the conditions of long-term stability and accelerated stability, there were no significant changes in indicators such as appearance, pH, potential, content, and related substances. The above results indicate that the aprepitant micellar injections in Examples 1-9 have good stability. The designed storage condition of the aprepitant micellar injection is to be stored at 2-8°C. According to the results of the accelerated stability experiment, the tentative expiration date of the aprepitant micellar injection is 2 years.

[0138] Experimental Example 6 Pharmacokinetic study Twelve SD rats were randomly divided into 2 groups, with 6 rats in each group. They were fasted for 12 hours before dosing and allowed free access to water. One group was injected with the aprepitant micellar injection prepared in Example 5 via the tail vein at a dose of 5 mg / kg, and the other group was injected with a commercially available aprepitant emulsion (trade name CINVANTI) at the same dose. ®), Glucose injection was used as the solvent for both groups, and the preparations were dissolved and diluted respectively. Blood samples of rats were collected at 0.033, 0.167, 0.5, 1, 2, 4, 8 and 24 hours after administration. The samples were immediately centrifuged at 13125×g for 10 min to separate plasma. The plasma samples were treated with acetonitrile to precipitate proteins, separated by a Cortex C18+ chromatographic column, with methanol-10 mmol / L ammonium acetate as the mobile phase, using an electrospray ionization source. The stable isotope-labeled internal standard d4-aprepitant was used as the internal standard for aprepitant respectively, and the concentration of aprepitant in plasma was analyzed by LC-MS / MS. The results are as Figure 7 shown.

[0139] Figure 7 It shows that the aprepitant micellar injection of Example 5 has a similar peak concentration to the commercially available aprepitant emulsion (trade name CINVANTI ® ), and the ratio of their AUC (area under the curve) is between 80% and 125%, which can be considered bioequivalent.

[0140] The above results indicate that by adding a nanomicelle stabilizer, the present invention can improve the micelle stability and preparation stability, avoid the adverse effects of large milk particles, and balance the aseptic reliability and micelle stability on the basis of maintaining the therapeutic effect and drug absorption effect.

[0141] For those of ordinary skill in the art, the specific embodiments only exemplarily describe the present invention. Obviously, the specific implementation of the present invention is not limited by the above methods. As long as various non-substantive improvements are made by adopting the method concept and technical solution of the present invention, or the concept and technical solution of the present invention are directly applied to other occasions without improvement, they are all within the protection scope of the present invention.

Claims

1. An aprepitant micellar injection, wherein the raw materials include aprepitant, phospholipids, bile acid or its salt, a pH regulator and water for injection, characterized in that: The injection also contains a nano-micelle stabilizer; the content of the nano-micelle stabilizer is 0.05-10 mg / mL, and the mass ratio of aprepitant to the nano-micelle stabilizer is 1:0.025-5.

2. The aprepitant micellar injection according to claim 1, characterized in that: The mass ratio of aprepitant to the nanomicelle stabilizer is 1:0.025-3.

3. The aprepitant micellar injection according to claim 1 or 2, characterized in that: The injection solution contains 1-10 mg / mL of aprepitant, 40-150 mg / mL of bile acid or its salt, the mass ratio of phospholipid to bile acid or its salt is 1:0.5-1.5, and the pH of the injection solution is adjusted to 6.0-7.5 by a pH adjuster.

4. The aprepitant micellar injection according to claim 1 or 2, characterized in that: The specifications of aprepitant micellar injection are 1-10 mg / mL, pH 6.0-7.5, particle size 2-10 nm, Zeta potential -20~-60 mV, and transmittance >90%.

5. The aprepitant micellar injection according to claim 1 or 2, characterized in that: The phospholipid is selected from natural phospholipids or synthetic phospholipids; the natural phospholipids include one of soybean phospholipids, egg yolk phospholipids, hydrogenated soybean phospholipids, and hydrogenated egg yolk phospholipids; the synthetic phospholipids include one of dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, and dioleoylphosphatidylcholine; The bile acid or its salt is one or a mixture of bile acid, glycocholic acid, deoxycholic acid, glycodeoxycholic acid or their salts; The pH regulator includes at least one of an acidic pH regulator and an alkaline pH regulator; the acidic pH regulator includes one or more of citric acid, acetic acid, hydrochloric acid, and phosphoric acid, and the alkaline pH regulator is sodium hydroxide and / or sodium carbonate.

6. The aprepitant micellar injection according to claim 1 or 2, characterized in that: The nano micelle stabilizer is selected from one or more of polyethylene glycol 15-hydroxystearate, polysorbate, poloxamer, phosphatidylethanolamine, polyoxyethylene castor oil, sodium oleate, PVP K12, PVP K17, and sodium cholesterol sulfate.

7. The method for preparing the aprepitant micellar injection according to any one of claims 1 to 6, characterized in that: The preparation method is a thin film dispersion method, which specifically comprises the following steps: (1) Film preparation: weigh a prescribed amount of aprepitant, phospholipid, bile acid or its salt and nanomicelle stabilizer, add an appropriate amount of organic solvent to dissolve, place in a rotary evaporator and perform rotary evaporation to obtain a loose film; the bile acid or its salt is one or more of bile acid, deoxycholic acid, glycocholic acid and glycodeoxycholic acid; (2) Preparation of drug solution: adding an alkaline pH regulator in a molar ratio of 1:0.8-1.2 to the bile acid added in step (1), dissolving it completely with water for injection filled with protective gas accounting for 50-85% of the total volume of the injection solution, transferring the resulting solution to the loose film in step (1), and after complete hydration, adjusting the pH to 6.0-7.5 with a pH regulator to obtain a drug solution; (3) Volume or weight determination: the drug solution obtained in step (2) is volume or weight determined, filtered, and filled with protective gas, and the filtration is performed using a 0.22 μm filter membrane; (4) Stoppering, capping and sterilization: Pack the tubes separately, fill the headspace with protective gas, then stopper and cap the tubes, and sterilize by autoclave at 121°C for 15 min.

8. The method for preparing aprepitant micellar injection according to claim 7, characterized in that: If the bile acid or salt thereof used in step (1) is one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, and sodium glycodeoxycholate, in step (2), water for injection filled with protective gas accounting for 50-85% of the total injection preparation volume is directly transferred to the loose film, and after complete hydration, the pH is adjusted to 6.0-7.5 with a pH adjuster to obtain a drug solution; The rotary evaporation parameters in step (1) are: water bath temperature 30-70°C, time 2-6h; the organic solvent in step (1) is one or more of methanol, ethanol, and isopropanol in any proportion; the amount of the organic solvent is 5-15% of the total injection preparation volume; the protective gas is any one of nitrogen, helium, carbon dioxide and argon, the time for passing the protective gas is 0.5-2h, the dissolved oxygen residual range is 0-5 mg / L, and the headspace residual oxygen content is controlled at 0-5%.

9. The method for preparing the aprepitant micellar injection according to any one of claims 1 to 6, characterized in that: The preparation method is a blank micelle method, which specifically comprises the following steps: (1) Preparation of bile salt solution: The bile acid or its salt is selected from one or more of bile acid, deoxycholic acid, glycocholic acid, and glycodeoxycholic acid, and the bile acid or its salt and an alkaline pH regulator are added, wherein the molar ratio of bile acid or its salt to the alkaline pH regulator is 1:0.8-1.2, and the bile acid or its salt is completely dissolved in water for injection filled with protective gas accounting for 60-80% of the total volume of the injection solution, and then the pH of the solution is adjusted to 6.0-7.5 with the pH regulator to obtain a bile salt solution; (2) Preparation of blank micelle solution: weigh the phospholipid and nanomicelle stabilizer in the prescription, add the bile salt solution in step (1), and stir in a 90-100° C. water bath until the solution is clear to obtain a blank micelle solution; (3) Preparation of drug solution: Weigh aprepitant according to the prescription, slowly add it to the blank micelle solution obtained in step (2), heat and stir in a 90-100°C water bath until the solution is clear and transparent, cool to room temperature, and adjust the pH to 6.0-7.5 with a pH adjuster; (4) Volume or weight determination: the drug solution obtained in step (3) is volume or weight determined, filtered, and filled with protective gas, and the filtration is performed using a 0.22 μm filter membrane; (5) Stoppering, capping and sterilization: After packaging, fill the headspace with protective gas, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

10. The method for preparing aprepitant micellar injection according to claim 9, characterized in that: If the bile acid or salt thereof used in step (1) is one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, and sodium glycodeoxycholate, in step (1), the bile acid or salt thereof is directly dissolved in water for injection filled with protective gas, and then the pH is adjusted to 6.0-7.5 with a pH adjuster to obtain a bile salt solution; The protective gas is any one of nitrogen, carbon dioxide, helium and argon. The time of introducing the protective gas is 0.5-2 h, the residual range of dissolved oxygen is 0-5 mg / L, and the residual oxygen content in the headspace is controlled at 0-5%.

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