Aprepitant micellar injection and preparation method thereof

Abstract

The present 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 an active ingredient aprepitant, a phospholipid, bile acid or a salt thereof, a nano-micelle stabilizer, a pH regulator and water for injection. The above scheme selects a phospholipid and bile acid micelle system with good physiological compatibility and good safety for solubilization, thereby significantly improving the solubility of aprepitant; the combined use of the nano-micelle stabilizer can significantly improve the stability of the preparation; avoids the use of a large amount of soybean oil for solubilization, thereby reducing the risk of lipid metabolism; does not contain ethanol to avoid ethanol allergic reactions, thereby improving the safety of clinical medication; adopts a hot press sterilization method, thereby improving the sterility assurance level; the process is simple, easy to scale up for production, similar to the production process of ordinary injections, does not require special equipment such as a high-pressure homogenizer and a dedicated fat emulsion production line, and can significantly reduce production costs.

Description

Technical Field

[0001] The present 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 F7N4O3, molecular weight: 534.427, structural formula is as follows:

[0003] ;

[0004] Aprepitant is a weakly basic compound with a pKa value of 9.7 in the pH range of 2 to 12. It is a white or off-white crystal, 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.

[0005] Preclinical and human positron emission tomography (PET) studies of aprepitant have shown that it can cross the blood-brain barrier and exerts its effects primarily by binding to NK-1 receptors in the brain. Substance P is a key neurotransmitter in the nausea and vomiting reflex pathway induced by chemotherapy or surgery, activating the NK-1 receptor. Aprepitant competitively antagonizes the NK-1 receptor, thereby blocking the effects of substance P, effectively suppressing nausea and vomiting. It also enhances the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone against cisplatin-induced vomiting.

[0006] Aprepitant oral capsules developed by Merck & Co., Inc. 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.

[0007] Aprepitant fat emulsion injection CINVANTI ® There are also certain shortcomings. Domestic and foreign pharmaceutical companies or research institutions have conducted a lot of research on aprepitant fat emulsion injection.

[0008] Patent document CN117414334A provides an aprepitant emulsion pharmaceutical composition and a preparation method thereof, which contains aprepitant, ethanol, phospholipids, soybean oil, an isotonicity regulator and a pH regulator. Its core equipment is an online shearing machine and a high-pressure microfluidizer. Colostrum is prepared by online shearing and mixing of the oil phase and the aqueous phase. The equipment cost is high and it is difficult to achieve large-scale production expansion.

[0009] Patent document CN109010269A discloses an aprepitant fat emulsion injection, comprising aprepitant, phospholipids, injection oil, glycine, polyvinylpyrrolidone, and water for injection, but excluding sucrose. Short-chain alcohols such as ethanol and propylene glycol are used as cosolvents. However, numerous clinical reports of adverse reactions to propylene glycol have limited its clinical application.

[0010] Both patents mentioned above use high levels of ethanol, which can be harmful to alcoholics, those with impaired alcohol metabolism, and pregnant or breastfeeding women. Furthermore, high concentrations of ethanol may cause adverse reactions such as injection site pain and neuritis.

[0011] Patent document CN111388419A discloses a stable aprepitant emulsion formulation for injection, comprising aprepitant, an emulsifier, a co-emulsifier, an injection oil, a tonicity modifier, a pH adjuster, and water for injection. During the oil phase preparation stage, ethanol is removed by vacuum distillation using a rotary evaporator. The crude emulsion is homogenized multiple times using a microfluidizer, which presents certain challenges for subsequent scale-up production.

[0012] Patent document CN113952299A discloses a substantially ethanol-free aprepitant emulsion and its preparation method. The invention comprises aprepitant, an emulsifier, oil, polyethylene glycol, and water. Sterilization is performed using a membrane filter with a pore size of 0.2-0.22 μm. If impurities in the emulsion are difficult to filter, they may clog the filter membrane, affecting production efficiency and product quality. Furthermore, the selection and use of membrane filters require caution, as membranes of different materials and pore sizes may adsorb emulsion components, affecting drug content and emulsion stability.

[0013] Patent document CN110368363A discloses an aprepitant fat emulsion injection and a preparation method thereof. The aprepitant fat emulsion injection of the invention uses polyethylene glycol 15-hydroxystearic acid as an emulsifier and solubilizer, poloxamer and sodium oleate as co-emulsifiers, and soybean oil and polyoxyethylene castor oil in a mass ratio of 3:1 as the oil phase.

[0014] Patent document CN112535661A discloses an autoclavable aprepitant submicroemulsion injection and a preparation method thereof. The aprepitant injection comprises aprepitant, polyethylene glycol 15-hydroxystearate, phospholipids and injection oil.

[0015] All six patents cited above use soybean oil or other vegetable oils as the oil phase, and all are long-chain triglycerides (LCTs). LCTs contain unsaturated fatty acids. Under the influence of factors such as light, heat, and oxygen, the unsaturated bonds are susceptible to oxidation, producing 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 inflammation and cell damage. Without effective antioxidant measures during long-term storage or preparation, oxidation issues may become more prominent, posing challenges to the quality control of the injection solution.

[0016] As a special preparation, the distribution of aprepitant injectable emulsion particle size is directly related to its pharmacokinetics in the body, which in turn affects the efficacy. Since the diameter of human microvessels is approximately 4 to 9 μm and the diameter of pulmonary microvessels is approximately 5 μm, if a large number of emulsions are larger than 5 μm in diameter, it may cause pulmonary embolism, alveolar tissue damage, and even worse, the patient's death.

[0017] Patent document CN110934829A provides an aprepitant nanomicelle formulation comprising aprepitant, phospholipids, sucrose, ethanol, and water for injection, wherein the phospholipids include phosphatidylcholine and phosphatidylglycerol. First, a small amount of ethanol evaporates during the preparation process, but the mass of ethanol in the final micelle formulation is more than three times that of aprepitant. High ethanol concentrations 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. The scale-up effect of the equipment may lead to fluctuations in product quality, increasing the difficulty and cost of process scale-up and hindering the industrialization of the product.

[0018] Patent document CN112168788A discloses a sterile lyophilized micellar formulation of aprepitant for intravenous injection and its preparation method. The sterile lyophilized micellar formulation of aprepitant for injection comprises aprepitant, a phospholipid derivatized with methoxypolyethylene glycol, and a pharmaceutically acceptable lyoprotectant. The resulting micellar solution is sterilized by filtration through a 0.22 μm microporous membrane and lyophilized to remove water, thereby producing a sterile lyophilized micellar powder of aprepitant.

[0019] Both of the above-mentioned micelle patent documents use a membrane filter with a pore size of 0.22μm for sterilization, which is not conducive to the control of the sterility assurance level and has certain clinical drug use risks. In addition, there are also problems such as poor hydrophilicity of the nanomicelles, easy aggregation, resulting in unsatisfactory stability, short circulation time in the body, and poor efficacy.

[0020] Currently, the preparation of aprepitant injection requires the use of high-speed shearing equipment and homogenizing equipment, and requires high-speed stirring (up to 10,000 rpm) for a long time (>2 hours). This is highly dependent on the equipment and has high energy consumption. The prepared injection is difficult to sterilize under high pressure, and high-pressure sterilization has a significant adverse effect on stability, resulting in the injection being unable to achieve both stability and sterility reliability. In addition, the pH of the injection is alkaline (≥8.5), resulting in the problem of phospholipid hydrolysis at a higher pH during use, resulting in excessive hemolytic phospholipid content.

[0021] Therefore, it is necessary to develop a new type of aprepitant injection, which should have the following characteristics: no soybean oil, no ethanol, good formulation stability, and can withstand hot pressing sterilization, so as to overcome the various shortcomings of the above-mentioned existing marketed emulsion injections and injections reported in the literature, and provide a safer and more stable aprepitant injection for clinical use. This has become a key technical problem that needs to be solved urgently in this field. Summary of the Invention

[0022] In response to the shortcomings of the above-mentioned current technologies, the present invention provides an aprepitant micelle injection that can withstand autoclaving and a preparation method thereof, which is composed of the active ingredient aprepitant and the excipients phospholipids, bile acid or its salt, nanomicelle stabilizer, pH adjuster and water for injection. Aprepitant micelle injection uses an innovative formula design to select phospholipids with good physiological compatibility and good safety and bile acid micelle system for solubilization, which significantly improves the solubility of aprepitant; the combined use of nanomicelle stabilizers can significantly improve the stability of the preparation. Compared with the original aprepitant fat emulsion injection, this innovative formula design avoids the use of large amounts of soybean oil for solubilization, thereby reducing the risk of lipid metabolism; it does not contain ethanol, thereby avoiding ethanol allergic reactions, and thus can significantly improve the safety of clinical use. Aprepitant micelle injection has good stability and can be autoclaved, which significantly improves the level of sterility assurance and reduces the risk of clinical use. Aprepitant micellar injection can adopt an innovative thin film dispersion process or blank micelle process. The process is simple and easy to scale up. It is similar to the production process of ordinary injections. It does not require special equipment such as high-pressure homogenizers and dedicated fat emulsion production lines, which can significantly reduce production costs.

[0023] The main inventive concept of the invention is to provide a more ideal carrier for aprepitant. Liver cells can autonomously secrete bile acids. Taurine or glycine combines with bile acids to form salts, namely bile salts. Bile salts contain hydrophilic hydroxyl and carboxyl groups, as well as hydrophobic methyl groups, and therefore have the ability to form micelles. They can solubilize poorly soluble drugs by reducing the surface tension between the lipid and aqueous phases, thereby increasing drug concentration, enhancing drug stability, and promoting drug absorption, thereby improving efficacy. Bile secreted by human liver cells is rich in bile salts and phospholipids, which play an important role in the absorption of fat-soluble substances such as lipid vitamins and are known as "physiological detergents." Both phospholipids and bile salts are inherent components of the body and therefore have good biocompatibility, making them an ideal carrier for aprepitant.

[0024] The addition of a nanomicelle stabilizer to the phospholipid bile salt carrier has multiple effects on the system. First, it improves the stability of the preparation: by modifying the hydrophilic polyethylene glycol long chain (polysorbate 80, poloxamer 188, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate), the hydrophilicity of the nanomicelle particles is increased, particle aggregation is avoided, and thus the stability of the preparation is improved; sodium oleate can increase the Zeta potential of the nanoparticles, and through the electrostatic repulsion effect, nanoparticle aggregation is avoided, thereby improving the stability of the preparation.

[0025] Secondly, nanoformulations can be stabilized in vivo: Nanomicelle particles are modified with long polyethylene glycol chains to increase their hydrophilicity. After intravenous administration, they can avoid recognition and phagocytosis by phagocytes, thereby prolonging the nanomicelles' in vivo circulation time, improving the efficiency of transmembrane transport across the blood-brain barrier, and enhancing targeting, thereby increasing drug efficacy. Furthermore, the addition of PVP (polyvinylpyrrolidone) can stabilize the micelle structure through steric hindrance, leveraging its hydrophilicity to increase the solubility of poorly soluble drugs and forming a diffusion barrier on the micelle surface, delaying drug release. PVP's biocompatibility can also reduce tissue irritation and protect drug activity through hydrogen bonding or van der Waals forces with drug molecules.

[0026] Sodium cholesterol sulfate was chosen because its rigid steroidal structure can be inserted into the phospholipid bilayer, forming a tighter molecular arrangement with phosphatidylcholine, thereby reducing the micelle surface energy. The polar head of the sulfate group can stably bind to the micelle interface, forming a stable ternary complex system with the bile salt. Particularly noteworthy is the strong negative charge of the sulfate group, which can increase the micelle surface potential to above -30mV. This high negative potential effectively inhibits the aggregation of micelle particles through charge repulsion, maintaining long-term particle size stability.

[0027] The present invention first provides an aprepitant micelle injection, which comprises the active ingredient aprepitant, phospholipids, bile acid or its salt, and a pH regulator. The solvent used is water for injection. The injection also contains a nano-micelle stabilizer; wherein the content of the nano-micelle stabilizer is 0.05-10 mg / mL.

[0028] Preferably, the mass ratio of aprepitant to the nanomicelle stabilizer is 1:(0.025-5).

[0029] More preferably, the mass ratio of aprepitant to the nanomicelle stabilizer is 1:(0.025-3).

[0030] In the above injection, the concentration of aprepitant is 1-10 mg / mL, the concentration of bile acid or its salt is 40-150 mg / mL, the mass ratio of phospholipid to bile acid or its salt is 1:(0.5-1.5), and the pH of the injection is adjusted to 6.0-7.5 by a pH regulator.

[0031] After being made into the finished product, the volume specification of the prepared aprepitant micelle injection is 1-10 mg / mL, pH is 6.0-7.5, particle size is 2-10 nm, Zeta potential is -20~-60 mV, and transmittance is greater than 90%; the volume specification is preferably 4.4 mL, which is placed in a penicillin bottle.

[0032] The phospholipids include but are not limited to natural phospholipids or synthetic phospholipids. The natural phospholipids are selected from one of soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, and hydrogenated egg yolk lecithin; the synthetic phospholipids are selected from one of dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, and dioleoylphosphatidylcholine; among which soybean lecithin is preferred.

[0033] The phospholipid is preferably injection-grade phospholipid, wherein the content of phosphatidylcholine (PC) is >94%, more preferably >97%.

[0034] The bile acid or its salt is bile acid, glycocholic acid, deoxycholic acid, glycodeoxycholic acid or a mixture of these salts, or a mixture of these salts; glycocholic acid or sodium glycocholate is preferred.

[0035] 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 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.

[0036] The nanomicelle stabilizer includes one or more of polyethylene glycol 15-hydroxystearate, polysorbate, poloxamer, phosphatidylethanolamine, polyoxyethylene castor oil, sodium oleate, PVP K12, PVP K17, and sodium cholesterol sulfate, preferably polysorbate.

[0037] The present invention further provides a method for preparing the aprepitant micelle injection, which is a thin film dispersion method and specifically comprises the following steps:

[0038] (1) Film preparation: Weigh the prescribed amount of aprepitant, phospholipid, bile acid or its salt and nanomicelle stabilizer, add an appropriate amount of organic solvent to dissolve, place on 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, glycocholic acid, deoxycholic acid and glycodeoxycholic acid;

[0039] (2) Preparation of drug solution: add an alkaline pH regulator in a molar ratio of 1:(0.8-1.2) to the bile acid or its salt added in step (1), and completely dissolve it with water for injection filled with protective gas accounting for 50-85% of the total volume of the injection solution prepared, transfer the resulting solution to the loose film of step (1), and after complete hydration, adjust the pH to 6.0-7.5 with a pH regulator to obtain a drug solution;

[0040] (3) Volume or weight determination: The liquid obtained in step (2) is volume or weight determined, filtered, and filled with protective gas. The filtration is performed using a 0.22 μm filter membrane;

[0041] (4) Stoppering, capping and sterilization: After filling the headspace with protective gas, stopper and cap are added, and then sterilized by autoclave at 121℃ for 15 minutes.

[0042] When the bile acid or its salt used in step (1) is one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, and sodium glycodeoxycholate, the inventors adjusted step (2) by directly transferring the solution to the loose film with water for injection filled with protective gas, which accounts for 50-85% of the total volume of the injection solution, and after complete hydration, adjusting the pH to 6.0-7.5 with a pH regulator to obtain a drug solution.

[0043] 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; the amount of the organic solvent is 5-15% of the total volume of the injection solution prepared; as a further preferred embodiment, the organic solvent is a mixed solvent of methanol and ethanol, and the volume ratio of methanol to ethanol is 2.5:1.

[0044] The protective gas is any one of nitrogen, helium, carbon dioxide and argon. The time of introducing the protective gas is 0.5-2 h, the residual dissolved oxygen range is 0-5 mg / L, and the residual oxygen content in the headspace is controlled at 0-5%.

[0045] The present invention also provides another method for preparing the aprepitant micelle injection, which is a blank micelle method and specifically comprises the following steps:

[0046] (1) Preparation of bile salt solution: When the bile acid or its salt is selected from one or more of bile acid, glycocholic acid, deoxycholic acid, and glycodeoxycholic acid, 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;

[0047] (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;

[0048] (3) Preparation of drug solution: Weigh aprepitant according to the prescription and 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 translucent. After cooling to room temperature, adjust the pH to 6.0-7.5 with a pH adjuster.

[0049] (4) Volume or weight determination: The liquid obtained in step (3) is volume or weight determined, filtered, and filled with protective gas. The filtration is performed using a 0.22 μm filter membrane;

[0050] (5) Stoppering, capping and sterilization: After filling the headspace with protective gas, stopper and cap are added, and then sterilized by autoclave at 121℃ for 15 minutes.

[0051] When the bile acid or its salt used in step (1) is one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, and sodium glycodeoxycholate, the inventors adjusted the step (1) by directly dissolving the bile acid or its salt in water for injection filled with protective gas, and then adjusting the pH to 6.0-7.5 with a pH regulator to obtain a bile salt solution.

[0052] Preferably, the protective gas filled with water for injection, the protective gas filled after the liquid is fixed to volume, and the protective gas filled before stoppering and capping, is any one of nitrogen, helium, carbon dioxide and argon, the time for passing the protective gas is 0.5-2 h, the residual dissolved oxygen range is 0-5 mg / L, and the residual oxygen content in the headspace is controlled at 0-5%. As a further preference, the protective gas is nitrogen.

[0053] The aprepitant micellar injection provided herein can be used to treat or prevent symptoms such as, but not limited to, nausea and vomiting. It is particularly suitable for use in combination with steroids and 5-HT3 receptor antagonists to prevent acute and delayed nausea and vomiting in cancer patients undergoing initial and repeat treatment with highly emetogenic anti-tumor chemotherapy. Furthermore, aprepitant can also be used to prevent nausea and vomiting induced by radiotherapy and prior to surgery.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] (1) In this patented phospholipid bile salt micelle system, a nanomicelle stabilizer is added to improve the hydrophilicity of the nanomicelle particles through hydrophilic polyethylene glycol long chain modification, thereby preventing particle aggregation and improving the stability of the preparation; sodium oleate can increase the Zeta potential of the nanoparticles, prevent nanoparticle aggregation through electrostatic repulsion effect, and improve the stability of the preparation;

[0056] Secondly, improving the in vivo stability of nanoformulations: Nanomicelle particles are modified with long polyethylene glycol chains to increase hydrophilicity. After intravenous administration, they can avoid recognition and phagocytosis by phagocytes, thereby prolonging the in vivo circulation time of nanomicelles, increasing the efficiency of transmembrane transport across the blood-brain barrier, and improving targeting performance, thereby improving drug efficacy;

[0057] In addition, polyvinylpyrrolidone can stabilize the micelle structure through steric hindrance, utilize its hydrophilicity to improve the solubility of poorly soluble drugs, and form a diffusion barrier on the micelle surface to delay drug release. The biocompatibility of polyvinylpyrrolidone can also reduce tissue irritation and protect drug activity through hydrogen bonding or van der Waals forces with drug molecules.

[0058] The addition of sodium cholesterol sulfate is due to the fact that the rigid steroidal structure of cholesterol can be inserted into the phospholipid bilayer, forming a tighter molecular arrangement with phosphatidylcholine, thereby reducing the micelle surface energy. The polar head of the sulfate group can stably bind to the micelle interface, forming a stable ternary complex system with the bile salt. Particularly noteworthy is the strong negative charge of the sulfate group, which can increase the micelle surface potential to above -30mV. This high negative potential effectively inhibits the aggregation of micelle particles through charge repulsion, maintaining the long-term stability of the particle size.

[0059] (2) The original research emulsion injection is an O / W emulsion, also known as fat emulsion, which has the risk of droplet particle aggregation and the presence of large emulsion particles, which can easily lead to various adverse reactions, such as: large emulsion particles entering the human lungs and causing pulmonary granulomas; entering the capillaries and causing angiogranulomas, phlebitis and thrombosis. The aprepitant micellar injection prepared by the present invention is a sterile clear solution, which can strictly control visible foreign matter and insoluble particles. It is easier to observe visible foreign matter during clinical use, and can predict medication use in advance to reduce risks, thereby significantly improving medication safety.

[0060] (3) The original emulsion injection, due to its poor stability, can only be sterilized and filtered, with a low sterility assurance level and certain clinical drug risks. The aprepitant micellar injection prepared by the present invention significantly improves the stability of the preparation and can withstand hot pressure sterilization (121°C, 15 minutes). There is no significant change in the properties, pH, particle size, content, related substances and other indicators of the injection before and after sterilization, thereby greatly improving the sterility assurance.

[0061] (4) The original emulsion injection contains ethanol. The aprepitant micellar injection prepared by the present invention abandons ethanol as a solubilizer for phospholipids in the prescription and does not contain organic solvents. It avoids adverse reactions such as allergic reactions caused by ethanol, alcohol poisoning or impaired alcohol metabolism, injection pain and venous inflammation, and significantly improves the safety of clinical medication.

[0062] (5) The original emulsion injection formulation has poor stability: the storage condition is 2-8°C and it cannot be frozen. After being taken out and placed at room temperature, the shelf life is only 2 months. The aprepitant micellar injection of the present invention can withstand freeze-thaw cycles, significantly improving the stability of the formulation.

[0063] (6) Existing fat emulsions generally use an O / W primary emulsification-high-pressure homogenization-sterilization (sterile filtration) preparation process. This process is complex, quality control is difficult, and scale-up production is difficult. Special production equipment and production lines are required, resulting in high production costs. The preparation process described in the present invention uses an innovative thin film dispersion process or blank micelle process, which is similar to the production process of ordinary injections. It does not require special equipment and production lines, has a simple process, is easy to scale up, and can significantly reduce production costs.

[0064] (7) The final pH range of the injection of this patent is 6.0-7.5, which is physiological pH. It is administered intravenously with little vascular irritation. It is beneficial to the stability of phospholipids, controls the degradation products of hemolytic phospholipids, and improves the stability of the preparation.

[0065] (8) This solution avoids the problem of using high-pressure shearing methods in the existing technology to prepare injection solutions, which requires shearing for a long time (more than 2 hours) at a high speed (10,000 rpm), reduces production costs, overcomes the current problem of relying on special equipment for preparation, has low energy consumption, and does not cause obvious damage to the equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 This is a morphological diagram of the appearance of the aprepitant micelle injection prepared by the blank micelle method in Example 1;

[0067] Figure 2 The particle size distribution of aprepitant micelle injection prepared by the blank micelle method in Example 1 is shown in FIG. Figure 2 a is Figure 2 b shows the average particle size, polydispersity coefficient and intercept of the particle size distribution, Figure 2 b is the particle size distribution diagram;

[0068] Figure 3 This is the Zeta potential diagram of the aprepitant micelle injection prepared by the blank micelle method in Example 3, wherein Figure 3 a is Figure 3 b Zeta potential, Zeta potential standard deviation and conductivity of the Zeta potential distribution, Figure 3 b is the Zeta potential distribution diagram;

[0069] Figure 4 This is a HPLC chromatogram of related substance determination of Ari micelle injection prepared by the blank micelle method in Example 3 of Experimental Example 1;

[0070] Figure 5 This is the Zeta potential diagram of the freeze-thaw cycle test of the aprepitant micelle injection prepared by the thin film dispersion method in Example 5 of Experimental Example 4, where Figure 5 a is Figure 5 b Zeta potential, Zeta potential standard deviation and conductivity of the Zeta potential distribution, Figure 5 b is the Zeta potential distribution diagram;

[0071] Figure 6 This is the particle size distribution diagram of the aprepitant micelle injection prepared by the blank micelle method in Example 1 of Experimental Example 5 at an accelerated / 3-month interval, wherein Figure 6 a is Figure 6 b shows the average particle size, polydispersity coefficient and intercept of the particle size distribution, Figure 6 b is the particle size distribution diagram;

[0072] Figure 7 This is a graph showing the blood drug concentration-time curves of the aprepitant micelle injection and aprepitant emulsion injection prepared by the thin film dispersion method in Example 5 of Experimental Example 6 in rats;

[0073] Figure 8 This is the appearance of the aprepitant micelle injection prepared in Comparative Example 10 using a high shear dispersing emulsifier, which failed to form a clear solution. DETAILED DESCRIPTION

[0074] The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in the art or the product instructions were used.

[0075] The water for injection and the liquid medicine after volume adjustment used in the examples were filled with protective gas, and the dissolved oxygen was controlled within the range of 0-5 mg / L. The residual oxygen content in the headspace after packaging and before sealing was controlled within the range of 0-5%.

[0076] Example 1 An aprepitant micellar injection, the formulation of which is as follows:

[0077] Aprepitant 1.28 g, soybean lecithin 16.16 g, sodium glycocholate 20.20 g, polyoxyethylene 35 castor oil 64 mg, add water for injection to 200 mL.

[0078] The blank micelle method is adopted, and the preparation method includes the following steps:

[0079] (1) Weigh the prescribed amount of sodium glycocholate, add 160 mL of nitrogen-deoxygenated water for injection, stir for 20 minutes to dissolve, and adjust the pH to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0080] (2) Weigh the soybean lecithin and polyoxyethylene 35 castor oil in the prescription, add the solution prepared in step (1), heat in a water bath at 100°C, and stir at 400 rpm until the solution becomes clear to obtain a blank micelle solution;

[0081] (3) Weigh the prescribed amount of aprepitant and add it to the blank micelle solution prepared in step (2). Heat and stir in a water bath at 100°C until the solution is clear and translucent. Cool to room temperature and adjust the pH to 6.50.

[0082] (4) The solution from step (3) was made up to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0083] (5) Dispense the vial in 4.4 mL portions, fill the vial headspace with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0084] like Figure 1 As shown, the aprepitant micellar injection obtained in Example 1 is clear, transparent, light yellow-green, and has a pH of 6.55.

[0085] like Figure 2 As shown, the Z-Average of the mixed micelle solution is 2.891 nm, the PDI is 0.331, and the Zeta potential is -39.1 mV.

[0086] Example 2 An aprepitant micellar injection, the formulation of which is as follows:

[0087] Aprepitant 1.28 g, soybean lecithin 13.65 g, glycocholic acid 16.29 g, sodium hydroxide 1.21 g, polysorbate 80 64 mg, add water for injection to 200 mL.

[0088] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0089] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, glycocholic acid, and polysorbate 80, add 17 mL of methanol and 7 mL of anhydrous ethanol to dissolve completely, place in a rotary evaporator, and evaporation in a 60°C water bath for 3 h to obtain a loose film;

[0090] (2) After sodium hydroxide is completely dissolved in 160 mL of nitrogen-filled water for injection, transfer it to the obtained loose film and stir it in a water bath at 40°C at 400 rpm for 30 min to completely hydrate it. Adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0091] (3) After pH adjustment, the solution was diluted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0092] (4) Aliquot (4.4 mL / vial). Fill the vial with nitrogen, then stopper and cap. Sterilize by autoclaving at 121°C for 15 min.

[0093] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.995 nm, a PDI of 0.298, a Zeta potential of -42.3 mV, and a pH of 6.54.

[0094] Example 3 An aprepitant micellar injection, the formulation of which is as follows:

[0095] Aprepitant 1.28 g, egg yolk lecithin 11.52 g, glycocholic acid 13.76 g, sodium hydroxide 0.94 g, polysorbate 80 32 mg, add water for injection to 100 mL.

[0096] The blank micelle method is adopted, and the preparation method includes the following steps:

[0097] (1) Weigh the prescribed amount of glycocholic acid and sodium hydroxide, add 80 mL of nitrogen-deoxygenated water for injection, stir to dissolve, and adjust the pH to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0098] (2) Weigh the egg yolk phospholipids and polysorbate 80 in the prescription, add the solution prepared in step (1), heat in a water bath at 100°C, and stir at 400 rpm until the solution becomes clear to obtain a blank micelle solution;

[0099] (3) Weigh the prescribed amount of aprepitant and add it to the blank micelle solution prepared in step (2). Heat and stir in a water bath at 100°C until the solution is clear and translucent. Cool to room temperature and adjust the pH to 6.50.

[0100] (4) The volume of the solution prepared in step (3) was adjusted to 100 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0101] (5) Dispense the vial in 4.4 mL portions, fill the vial headspace with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0102] The obtained injection solution was clear, transparent and light yellow-green. The Z-Average of the mixed micelle solution was 2.876 nm, the PDI was 0.311, and the pH was 6.80; Figure 3 As shown, the zeta potential is -41.2 mV.

[0103] Example 4 An aprepitant micellar injection, the formulation of which is as follows:

[0104] Aprepitant 0.64 g, soybean lecithin 6.82 g, glycocholic acid 8.15 g, sodium hydroxide 0.61 g, phosphatidylethanolamine 32 mg, add water for injection to 100 mL.

[0105] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0106] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, glycocholic acid, and phosphatidylethanolamine, add 8 mL of methanol and 3 mL of anhydrous ethanol to dissolve completely, place in a rotary evaporator, water bath at 60°C, and evaporation for 3 h to obtain a loose film;

[0107] (2) Weigh the sodium hydroxide in the prescription, dissolve it in 80 mL of nitrogen-filled water for injection, and transfer it to the obtained loose film. Stir it in a water bath at 400 rpm and 40°C for 30 min to completely hydrate it. Adjust the pH value to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution.

[0108] (3) After pH adjustment, the solution was diluted to 100 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0109] (4) Aliquot (4.4 mL / vial). Fill the vial with nitrogen, then stopper and cap. Sterilize by autoclaving at 121°C for 15 min.

[0110] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.986 nm, a PDI of 0.293, a Zeta potential of -39.2 mV, and a pH of 6.49.

[0111] Example 5 An aprepitant micellar injection, the formulation of which is as follows:

[0112] Aprepitant 1.28 g, soybean lecithin 15.68 g, glycocholic acid 18.72 g, sodium hydroxide 1.59 g, polysorbate 80 32 mg, add water for injection to 200 mL.

[0113] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0114] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, glycocholic acid, and polysorbate 80, add 17 mL of methanol and 6 mL of anhydrous ethanol to dissolve completely, place in a rotary evaporator, and evaporation in a 60°C water bath for 3 h to obtain a loose film;

[0115] (2) Weigh the sodium hydroxide in the prescription, dissolve it in 160 mL of nitrogen-filled water for injection, transfer it to the obtained loose film, stir it in a water bath at 400 rpm and 40°C for 30 minutes 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;

[0116] (3) After pH adjustment, the solution was diluted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0117] (4) Aliquot (4.4 mL / vial). Fill the vial with nitrogen, then stopper and cap. Sterilize by autoclaving at 121°C for 15 min.

[0118] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.898 nm, a PDI of 0.301, a Zeta potential of -39.0 mV, and a pH of 6.85.

[0119] Example 6 An aprepitant micellar injection, the formulation of which is as follows:

[0120] Aprepitant 0.64 g, soybean lecithin 8.10 g, glycocholic acid 9.64 g, sodium hydroxide 0.82 g, polyethylene glycol 15-hydroxystearate 64 mg, add water for injection to 200 mL.

[0121] The blank micelle method is adopted, and the preparation method includes the following steps:

[0122] (1) Weigh the prescribed amount of glycocholic acid and sodium hydroxide, add 160 mL of nitrogen-deoxygenated water for injection, stir to dissolve, and adjust the pH to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0123] (2) Weigh the soybean lecithin 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 becomes clear to obtain a blank micelle solution;

[0124] (3) Weigh the prescribed amount of aprepitant and add it to the blank micelle solution prepared in step (2). Heat and stir in a water bath at 100°C until the solution is clear and translucent. Cool to room temperature and adjust the pH to 6.50.

[0125] (4) The solution from step (3) was adjusted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0126] (5) Dispense the vial in 4.4 mL portions, fill the vial headspace with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0127] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.925 nm, a PDI of 0.302, a Zeta potential of -40.3 mV, and a pH of 6.90.

[0128] Example 7 An aprepitant micellar injection, the formulation of which is as follows:

[0129] Aprepitant 1.28 g, soybean lecithin 15.68 g, glycocholic acid 18.72 g, sodium hydroxide 1.59 g, PVP K1232 mg, add water for injection to 200 mL.

[0130] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0131] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, glycocholic acid, and PVP K12, add 17 mL of methanol and 6 mL of anhydrous ethanol to dissolve completely, place in a rotary evaporator, and evaporation in a 60°C water bath for 3 h to obtain a loose film;

[0132] (2) Weigh the sodium hydroxide in the prescription, dissolve it in 160 mL of nitrogen-filled water for injection, transfer it to the obtained loose film, stir it in a water bath at 400 rpm and 40°C for 30 minutes 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;

[0133] (3) After pH adjustment, the solution was diluted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0134] (4) Aliquot (4.4 mL / vial). Fill the vial with nitrogen, then stopper and cap. Sterilize by autoclaving at 121°C for 15 min.

[0135] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.999 nm, a PDI of 0.305, a Zeta potential of -39.8 mV, and a pH of 6.83.

[0136] Example 8 An aprepitant micellar injection, the formulation of which is as follows:

[0137] Aprepitant 0.64 g, soybean lecithin 8.10 g, glycocholic acid 9.64 g, sodium hydroxide 0.82 g, PVP K 1764 mg, add water for injection to 200 mL.

[0138] The blank micelle method is adopted, and the preparation method includes the following steps:

[0139] (1) Weigh the prescribed amount of glycocholic acid and sodium hydroxide, add 160 mL of nitrogen-deoxygenated water for injection, stir to dissolve, and adjust the pH to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0140] (2) Weigh the soybean lecithin and PVP K17 in the prescription, add the solution prepared in step (1), heat in a water bath at 100°C, and stir at 400 rpm until the solution becomes clear to obtain a blank micelle solution;

[0141] (3) Weigh the prescribed amount of aprepitant and add it to the blank micelle solution prepared in step (2). Heat and stir in a water bath at 100°C until the solution is clear and translucent. Cool to room temperature and adjust the pH to 6.50.

[0142] (4) The solution from step (3) was adjusted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0143] (5) Dispense the vial in 4.4 mL portions, fill the vial headspace with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0144] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.985 nm, a PDI of 0.307, a Zeta potential of -40.2 mV, and a pH of 6.87.

[0145] Example 9 An aprepitant micellar injection, the formulation of which is as follows:

[0146] Aprepitant 1.28 g, soybean lecithin 15.68 g, glycocholic acid 18.72 g, sodium hydroxide 1.59 g, sodium cholesterol sulfate 16 mg, add water for injection to 200 mL.

[0147] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0148] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, glycocholic acid, and sodium cholesterol sulfate, add 17 mL of methanol and 6 mL of anhydrous ethanol to dissolve completely, place in a rotary evaporator, and evaporation in a 60°C water bath for 3 h to obtain a loose film;

[0149] (2) Weigh the sodium hydroxide in the prescription, dissolve it in 160 mL of nitrogen-filled water for injection, transfer it to the obtained loose film, stir it in a water bath at 400 rpm and 40°C for 30 minutes 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;

[0150] (3) After pH adjustment, the solution was diluted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0151] (4) Aliquot (4.4 mL / vial). Fill the vial with nitrogen, then stopper and cap. Sterilize by autoclaving at 121°C for 15 min.

[0152] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.979 nm, a PDI of 0.296, a Zeta potential of -39.9 mV, and a pH of 6.82.

[0153] Comparative Example 1 An aprepitant micellar injection, the formulation of which is as follows:

[0154] Aprepitant 1.28 g, soybean lecithin 16.16 g, glycocholic acid 19.30 g, sodium hydroxide 1.60 g, add water for injection to 200 mL.

[0155] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0156] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, and glycocholic acid, add 17 mL of methanol and 7 mL of anhydrous ethanol to dissolve completely, and rotary evaporate in a 60°C water bath for 4 h to obtain a loose film;

[0157] (2) Take the prescribed amount of sodium hydroxide, add 160 mL of nitrogen-filled water for injection, stir to dissolve, transfer to the loose film obtained in step (1), stir at 400 rpm in a 40°C water bath for 30 min, stir to completely hydrate, and adjust the pH to 6.5 with 1 mol / L sodium hydroxide solution and 0.5 mol / L citric acid solution;

[0158] (3) The solution obtained in (2) was diluted to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0159] (4) Fill the vial with nitrogen, divide the vial into 4.4 mL / vial, add stoppers and caps, and sterilize by autoclaving at 121°C for 15 min.

[0160] The micelle injection is clear and transparent with a light yellow-green color. The Z-Average of the mixed micelle solution is 2.976 nm, the PDI is 0.293, the Zeta potential is -41.5 mV, and the pH is 6.65.

[0161] Comparative Example 2 An aprepitant micellar injection, the formulation of which is as follows:

[0162] Aprepitant 1.28 g, soybean lecithin 16.93 g, deoxycholic acid 19.94 g, sodium hydroxide 2.03 g, add water for injection to 200 mL.

[0163] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0164] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, and deoxycholic acid, add 17 mL of methanol and 7 mL of anhydrous ethanol, dissolve completely, place on a rotary evaporator, and evaporate in a water bath at 60°C for 4 h to obtain a loose film;

[0165] (2) Weigh the prescribed amount of sodium hydroxide, add 160 mL of nitrogen-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 to completely hydrate, and adjust the pH to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0166] (3) The solution obtained in (2) was diluted to 200 mL, filtered through a 0.22 μm pore size filter membrane, and filled with nitrogen;

[0167] Step (4) is the same as that in Comparative Example 1.

[0168] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.901 nm, a PDI of 0.315, a Zeta potential of -38.6 mV, and a pH of 6.72.

[0169] Comparative Example 3 An aprepitant micellar injection, the formulation of which is as follows:

[0170] Aprepitant 1.28 g, soybean lecithin 17.00 g, sodium glycocholate 21.16 g, and water for injection were added to 200 mL.

[0171] The blank micelle method is adopted, and the preparation method includes the following steps:

[0172] (1) Weigh the prescribed amount of sodium glycocholate, add 160 mL of nitrogen-deoxygenated water for injection, stir for 15 minutes to dissolve, and adjust the pH to 7.00 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0173] (2) Weigh the soybean lecithin in the prescription and add it to the solution in step (1). Heat it in a water bath at 100°C and stir it at 400 rpm for 1 hour. The solution is clarified to obtain a blank micelle solution.

[0174] (3) Weigh the prescribed amount of aprepitant and add it to the blank micellar solution obtained in step (2). Heat and stir in a water bath at 100°C until the active pharmaceutical ingredient (API) is completely dissolved and the solution is clear. Cool to room temperature and adjust the pH to 7.00 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution.

[0175] (4) The solution from step (3) was made up to 200 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0176] (5) Aliquot (4.4 mL / vial), fill the vial with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0177] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.938 nm, a PDI of 0.299, a Zeta potential of -40.2 mV, and a pH of 6.95.

[0178] Comparative Example 4 An aprepitant micellar injection, the formulation of which is as follows:

[0179] Aprepitant 0.64 g, soybean lecithin 9.19 g, sodium glycocholate 11.49 g, and water for injection are added to 100 mL.

[0180] The blank micelle method is adopted, and the preparation method includes the following steps:

[0181] (1) Weigh the prescribed amount of sodium glycocholate, add 80 mL of nitrogen-deoxygenated water for injection, stir for 15 minutes to dissolve, and adjust the pH to 7.00 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0182] Steps (2) and (3) were carried out in the same manner as described in Comparative Example 3;

[0183] (4) The volume of the solution prepared in step (3) was adjusted to 100 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0184] (5) Aliquot (4.4 mL / vial), fill the vial with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0185] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.924 nm, a PDI of 0.332, a Zeta potential of -39.5 mV, and a pH of 7.01.

[0186] Comparative Example 5 An aprepitant micellar injection, the formulation of which is as follows:

[0187] Aprepitant 0.64 g, soybean lecithin 8.33 g, glycocholic acid 9.95 g, sodium hydroxide 0.85 g, add water for injection to 100 mL.

[0188] The thin film dispersion method is adopted, and the preparation method includes the following steps:

[0189] (1) Weigh the prescribed amount of aprepitant, soybean lecithin, and glycocholic acid, add 8 mL of methanol and 3 mL of anhydrous ethanol to dissolve completely, and rotary evaporate in a 60°C water bath for 4 h to obtain a loose film;

[0190] (2) Take the prescribed amount of sodium hydroxide, add 80 mL of nitrogen-filled water for injection, stir to dissolve, transfer to the loose film obtained in step (1), stir in a water bath at 400 rpm and 40°C for 30 min to completely hydrate it, and adjust the pH value to 6.5 with 1 mol / L sodium hydroxide solution and 0.5 mol / L citric acid solution;

[0191] (3) The solution obtained in (2) was diluted to 100 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0192] (4) Fill the vial with nitrogen, divide the vial into 4.4 mL / vial, add stoppers and caps, and sterilize by autoclaving at 121°C for 15 min.

[0193] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.854 nm, a PDI of 0.203, a Zeta potential of -38.7 mV, and a pH of 6.52.

[0194] Comparative Example 6 An aprepitant micellar injection, the formulation of which is as follows:

[0195] Aprepitant 0.32 g, soybean lecithin 4.59 g, glycocholic acid 5.49 g, sodium hydroxide 0.47 g, add water for injection to 50 mL.

[0196] The blank micelle method is adopted, and the preparation method includes the following steps:

[0197] (1) Weigh the prescribed amount of glycocholic acid and sodium hydroxide, add 40 mL of nitrogen-deoxygenated water for injection, stir to dissolve, and adjust the pH to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution;

[0198] (2) Weigh the soybean lecithin in the prescription and add it to the solution in step (1). Heat in a water bath at 100°C and stir at 400 rpm until the solution becomes clear to obtain a blank micelle solution.

[0199] (3) Weigh the prescribed amount of aprepitant and add it to the blank micellar solution in step (2). Heat and stir in a water bath at 100°C until the API is completely dissolved and the solution is clear. Cool to room temperature and adjust the pH to 6.50 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution.

[0200] (4) The solution from step (3) was diluted to 50 mL, filtered through a 0.22 μm filter membrane, and filled with nitrogen;

[0201] (5) Aliquot (4.4 mL / vial), fill the vial with nitrogen, stopper and cap, and sterilize by autoclave at 121°C for 15 min.

[0202] The injection is clear, transparent, and pale yellow-green. The mixed micelle solution has a Z-Average of 2.751 nm, a PDI of 0.302, a Zeta potential of -41.4 mV, and a pH of 6.68.

[0203] Comparative Example 7 According to Example 4 of CN110934829A, aprepitant nanomicelle injection was prepared, and its composition was as follows:

[0204] Aprepitant 1g, phosphatidylcholine 20g, phosphatidylglycerol 1.5g, ethanol 4g, sucrose 7.69g, sodium oleate 0.775g, purified water 105mL.

[0205] Preparation method:

[0206] (1) Aprepitant, phosphatidylcholine, phosphatidylglycerol, and ethanol were heated and mixed and stirred for 15 minutes to dissolve them in excess ethanol to prepare an ethanol solution;

[0207] (2) Sucrose, sodium oleate, and water for injection were stirred and mixed at room temperature for 25 minutes to prepare an aqueous phase;

[0208] (3) The aqueous phase and ethanol solution were sheared at a high speed of more than 10,000 rpm and then homogenized in a high-pressure homogenizer at 1,500 bar to form nanomicelles. After filtration through 0.22 μm, the nanomicelle injection solution was obtained.

[0209] The injection is a clear, yellow to brown solution. The mixed micellar solution has a Z-Average of 42.0 nm, a PDI of 0.313, a Zeta potential of -42.9 mV, and a pH of 8.30.

[0210] (4) To investigate the autoclave stability of the aprepitant micellar injection, the injection was filled with nitrogen and dispensed into 10 mL vials. The injection and aprepitant were divided into 4.4 mL:32 mg vials after subpackaging. The headspace was filled with nitrogen and autoclaved at 121°C for 15 min to investigate the appearance, content, and related substances.

[0211] The results showed that after sterilization, the injection solution underwent particle aggregation, decreased clarity, and crystallization, indicating that the injection solution could not withstand hot pressure sterilization. The results of content determination and related substance inspection are shown in Table 2.

[0212] Comparative Example 8 Aprepitant nanomicelles were prepared according to Example 3 described in CN110934829A, and the composition thereof was as follows:

[0213] Aprepitant 1g, phosphatidylcholine 20g, phosphatidylglycerol 1g, ethanol 12g, sucrose 7.69g, purified water 105mL.

[0214] Preparation method:

[0215] (1) Aprepitant, phosphatidylcholine, phosphatidylglycerol, and ethanol were heated and mixed and stirred for 15 minutes to dissolve them in excess ethanol to prepare an ethanol solution;

[0216] (2) Sucrose and water for injection were stirred and mixed at room temperature for 25 minutes to prepare an aqueous phase;

[0217] (3) The aqueous phase and ethanol solution were sheared at a high speed of more than 10,000 rpm and then homogenized in a high-pressure homogenizer at 1,500 bar to form nanomicelles. After filtering through a 0.22 μm filter, the nanomicelle injection solution was obtained.

[0218] The injection is a clear, yellow to brown solution. The mixed micellar solution has a Z-Average of 46.7 nm, a PDI of 0.283, a Zeta potential of -43.3 mV, and a pH of 8.15.

[0219] (4) To investigate the autoclave stability of the aprepitant micellar injection, the injection was nitrogen-filled and dispensed into 10 mL vials. The ratio of injection to aprepitant was 4.4 mL:32 mg. The headspace was filled with nitrogen and autoclaved at 121°C for 15 min. The appearance, content, and related substances were investigated.

[0220] The results showed that after sterilization, the injection solution underwent particle aggregation, decreased clarity, and crystal precipitation, indicating that the injection solution could not withstand hot pressure sterilization. The results of content determination and related substance inspection are shown in Table 2.

[0221] Comparative Example 9 Aprepitant micellar injection was prepared by reducing the drug loading according to the technical solution of CN117752596A:

[0222] Aprepitant 1g, glycocholic acid 18g, soybean lecithin 14g, sodium hydroxide 1.5g, water for injection 85g.

[0223] Preparation method:

[0224] (1) Weigh 1.5 g of sodium hydroxide and add it to 85 g of water for injection. Heat to 55 °C under magnetic stirring. After the sodium hydroxide is dissolved, add 18 g of glycocholic acid and continue stirring until it is completely dissolved. Neutralize for 10 minutes to form a sodium glycocholate solution.

[0225] (2) Turn on the high shear dispersing emulsifier, heat to 65 °C under high shear conditions of 10,000 rpm, add 14 g of soybean lecithin to the glycocholate solution, and emulsify for 120 min to form a mixed micelle solution;

[0226] (3) Continuing to maintain the temperature at 65°C under high-speed shear conditions of 10,000 rpm, 1.0 g of aprepitant was slowly added to the mixed micelle solution and sheared for 150 min to form an aprepitant mixed micelle solution;

[0227] (4) After adjusting the pH value of the aprepitant mixed micelle solution to 8.5 with a 3 wt % hydrochloric acid solution, the obtained mixed micelles were filtered through a 0.22 μm filter membrane (PES), filled with nitrogen, and the residual oxygen content in the headspace of the bottle was controlled to be ≤5%. The solution was sterilized by autoclaving (121°C, 15 min) to obtain an aprepitant micelle injection.

[0228] Comparative Example 10 According to Example 1 described in CN117752596A, aprepitant micellar injection was prepared:

[0229] Aprepitant 10g, glycocholic acid 60g, soybean lecithin 80g, sodium hydroxide 5g, water for injection 845g.

[0230] Preparation method:

[0231] (1) Weigh 5.0 g of sodium hydroxide and add it to 845 g of water for injection. Heat to 55°C under magnetic stirring. After the sodium hydroxide is dissolved, add 60.0 g of glycocholic acid and continue stirring until it is completely dissolved. Neutralize for 10 minutes to form a sodium glycocholate solution.

[0232] (2) Turn on the high shear dispersing emulsifier, heat to 65 °C under high shear conditions of 10,000 rpm, add 80.0 g of soybean lecithin to the sodium glycocholate solution, and emulsify for 150 min to form a mixed micelle solution;

[0233] (3) Continuing to maintain the temperature at 65°C under high-speed shear conditions of 10,000 rpm, 10.0 g of aprepitant was slowly added to the mixed micelle solution and sheared and dispersed for 120 min. No clear aprepitant micelle injection solution was formed, and a large amount of aprepitant API was still not included in the mixed micelles. Figure 8 Therefore, subsequent verification tests could not be performed.

[0234] Experimental Example 1 Determination of drug loading, content, related substances, and residual solvents

[0235] 1. Drug loading = mass of aprepitant dissolved in the formulation / (the sum of the mass of aprepitant and total added excipients) × 100%, where the total added excipients include aprepitant, phospholipids, and bile salts (for Comparative Examples 7 and 8, the total added excipients include aprepitant, phosphatidylcholine, phosphatidylglycerol, and sucrose).

[0236] 2. Content determination method (the proportions mentioned in the following mobile phase are all volume ratios)

[0237] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler; 90% acetonitrile-0.1% phosphoric acid solution (70:30) was used as the mobile phase; the detection wavelength was 210 nm; the injection volume was 20 μl, and the column temperature was 35°C.

[0238] Reference solution: Accurately weigh 10.0 mg of aprepitant API into a 100 mL volumetric flask, dissolve and dilute to volume with mobile phase solution to prepare a 100 μg / mL reference solution.

[0239] Test solution: Accurately pipette 1 ml of aprepitant micellar injection into a 50 ml volumetric flask, add 2 ml of methanol to break the emulsion, add mobile phase solution to two-thirds of the volume of the volumetric flask, add methanol to make up to the volume, shake well, and the solution is clear.

[0240] 3. Testing methods for related substances

[0241] Chromatographic conditions: Octadecylsilane bonded silica gel (Venusil XBP C18, specifications: 250 × 4.6 mm, 5 μm) was used as the packing material; mobile phase A consisted of 0.1% phosphoric acid solution (1 mL of phosphoric acid was added to 1000 mL of water and mixed thoroughly)-acetonitrile-methanol (80:10:10); mobile phase B consisted of 0.1% phosphoric acid solution-acetonitrile-methanol (10:80:10); detection wavelength was 210 nm, and the injection volume was 20 μl. Gradient elution was performed according to Table 1.

[0242] Table 1 Related substances of aprepitant micellar injection (gradient elution method)

[0243]

[0244] Related substance test solution: Accurately measure 1 mL of the product, place it in a 10 mL volumetric flask, dilute to the mark with methanol, and shake well.

[0245] 4. Residual solvent determination method:

[0246] (1) Chromatographic conditions: capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as stationary phase (Agilent DB-624, 0.53 mm × 30 m, 3 μm or equivalent performance column is recommended); starting temperature is 50 °C, maintained for 10 min, then heated to 150 °C at a rate of 50 °C per minute and maintained for 5 min; injection port temperature is 200 °C; detector is flame ionization detector, detector temperature is 300 °C; column flow rate is 2 mL per minute; split ratio is 20:1; headspace equilibrium temperature is 80 °C; quantitative loop temperature is 90 °C; equilibration time is 30 min;

[0247] System suitability requirements: In the chromatogram of the reference solution, methanol and ethanol appear in sequence, and the separation between each chromatographic peak should meet the requirements.

[0248] (2) Solution preparation

[0249] Test solution: Accurately measure 2 mL of the product, place it in a 20 mL headspace bottle, and seal it with a stopper.

[0250] Reference solution: Take appropriate amounts of methanol and ethanol, accurately weigh them, and quantitatively dilute them with ultrapure water to make 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 bottle, and seal it with a stopper.

[0251] According to the above-mentioned drug loading, content, related substances, and residual solvent determination methods, Examples 1-9 and Comparative Examples 1-9 were tested, and the results are shown in Table 2; the chromatogram of the related substances of the micelle injection prepared in Example 3 after sterilization is shown in Table 2. Figure 4 As shown in Table 2, the drug loading of Examples 1-9 is higher than that of Comparative Examples 1-6, indicating that the addition of a nanomicelle stabilizer to the micelle injection formulation can further increase the drug loading. The micelle injections prepared in the Examples showed no significant change in content before and after autoclaving. However, the ethanol residue in Comparative Examples 7-8 was high, and after sterilization, the injections experienced particle aggregation, decreased clarity, and crystallization. The impurity content was high, which may cause nervous system depression and vascular irritation reactions, and in severe cases, may lead to adverse reactions such as metabolic acidosis or respiratory failure.

[0252] Table 2 Test results of drug loading, content, related substances, etc. of aprepitant micellar injection

[0253] .

[0254] Experimental Example 2: Investigating the effect of adding nanomicelle stabilizer

[0255] The aprepitant micelle injection prepared by the present invention has a nano-micelle stabilizer such as polysorbate 80 added to the formulation, which can shorten the dissolution time of aprepitant in the blank micelle preparation process and improve the physical and chemical stability of the mixed micelles.

[0256] Comparative Examples 4, 5, 6, and 9 were compared with Example 5 (which added a nanomicelle stabilizer). After filtration, the drug solutions were left at room temperature to observe for crystal precipitation and assess physical stability. The dissolution time of aprepitant was also compared. The results are shown in Tables 3 and 4 below. The drug solution in Comparative Example 4 precipitated after 10 hours at room temperature, while Comparative Example 6 exhibited a small amount of precipitation after 14 hours. Comparative Example 9, sterilized by autoclaving at 121°C for 15 minutes and then left at room temperature for 20 hours, exhibited a small amount of precipitation. However, no precipitation occurred in Comparative Example 9 without autoclaving. This indicates that autoclaving at 121°C for 15 minutes reduced the micelle stability of Comparative Example 9. During use, the poor micelle stability of Comparative Example 9 can be avoided by adjusting the autoclaving parameters. However, adjusting the autoclaving parameters can lead to poor sterility reliability. Therefore, the solution in Comparative Example 9 cannot achieve both sterility reliability and micelle stability. No precipitation occurred in Example 5 after 24 hours. Therefore, adding a nanomicelle stabilizer can improve the stability of the micelle system. Compared with Comparative Examples 4, 5, and 6, the dissolution time of aprepitant in Example 5 is short, which can reduce the time consumption of the blank micelle preparation process.

[0257] Table 3 Physical stability test results

[0258]

[0259] Note: “-” means “no crystals precipitated”, “+” means “crystals precipitated”, and “N / A” means “not applicable”.

[0260] Table 4 Results of investigation on the dissolution time of aprepitant

[0261] .

[0262] Experimental Example 3 Low Temperature Cycle Test

[0263] The aprepitant micellar injection prepared in Example 5 was subjected to a low-temperature cycling test. The test should include 3 cycles, each cycle of placing at 2-8°C for 2 days and then placing at 25°C for 2 days. Samples were taken and tested after each cycle. The results are shown in Table 5.

[0264] As shown in Table 5, no precipitation was observed after the third cycle. Compared with day 0, there were no significant changes in pH, clarity, color, particle size, potential, content, and related substances. This indicates that the prepared aprepitant micelle injection can withstand the low-temperature cycle test and has good low-temperature tolerance.

[0265] Note: Information on the colorimetric solution used under the color item: Name: Standard colorimetric solution of the Pharmacopoeia of the People's Republic of China 2020 edition, No.: TM-2020-0901, Batch No.: C2011013, Manufacturer: Tanmo Quality Inspection Technology Co., Ltd.

[0266] The turbidity standard solution used for clarity was prepared with reference to the Pharmacopoeia of the People's Republic of China 2020 edition.

[0267] Table 5 Results of low temperature cycling test of aprepitant micelle injection of Example 5

[0268] .

[0269] Experimental Example 4 Freeze-thaw cycle test

[0270] Aprepitant micelle injection prepared in Comparative Example 1, Comparative Example 5, Comparative Examples 7-9 (no nanomicelle stabilizer added) and Examples 1-9 was subjected to a freeze-thaw test. The test should include 3 cycles, each cycle was placed at -10~-20°C for 2 days, and then placed at 25°C for 2 days. Samples were taken after each cycle for testing. The results are shown in Tables 6 and 7.

[0271] After the completion of the three cycles, it can be seen from the results in Table 6 that Comparative Examples 7-9 all precipitated in the first freeze-thaw cycle; Comparative Example 1 and Comparative Example 5 did not add the nanomicelle stabilizer, and crystals were precipitated in the third freeze-thaw cycle; a certain amount of nanomicelle stabilizer was added to the formulation (Examples 1-9), and no crystals were precipitated in the three cycles, indicating that the nanomicelle stabilizer can improve the freeze-thaw stability of the injection.

[0272] As shown in Table 7, the sample prepared in Example 5 had no precipitated crystals. Compared with day 0, there were no significant changes in pH value, clarity, color, particle size, potential, content, and related substances. The Zeta potential diagram of Example 5 after 3 cycles of freeze-thaw was as follows: Figure 5 As shown, the above results indicate that aprepitant micelle injection can withstand freeze-thaw test.

[0273] Table 6 Freeze-thaw cycle test results

[0274]

[0275] Note: “-” means “no crystals precipitated”, and “+” means “crystals precipitated”.

[0276] Table 7 Freeze-thaw cycle test results of Example 5

[0277] .

[0278] Experimental Example 5 Accelerated test and long-term test

[0279] The stability of the aprepitant micellar injection in Examples 1-9 was studied 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;

[0280] Long-term test: 5℃±3℃; accelerated test: 25℃±2℃ / 60%RH±5%RH.

[0281] Table 8 Stability results of accelerated test and long-term test

[0282]

[0283]

[0284]

[0285] Figure 6 The figure shows the particle size distribution of the aprepitant micelle injection prepared in Example 1 at an accelerated temperature of 3 months, indicating that the particle size of the micelle injection prepared under accelerated conditions for 3 months did not change significantly compared with that at day 0.

[0286] As shown in the table above, the aprepitant micellar injections of Examples 1-9 showed no significant changes in appearance, pH, potential, content, or related substances after six months of storage under long-term and accelerated stability conditions. These results demonstrate that the aprepitant micellar injections of Examples 1-9 exhibit good stability. Aprepitant micellar injections are designed to be stored at 2-8°C. Based on the results of the accelerated stability test, the shelf life of aprepitant micellar injection is tentatively set at two years.

[0287] Experimental Example 6 Pharmacokinetic Test

[0288] Twelve SD rats were randomly divided into two groups, each with 6 rats. The rats were fasted for 12 hours before administration and had free access to water. One group was injected with the aprepitant micelle injection prepared in Example 5 at a dose of 5 mg / kg via the tail vein, while the other group was injected with the same dose of aprepitant emulsion (trade name CINVANTI ®), both groups used glucose injection as the solvent to dissolve and dilute the preparations. Blood was collected from rats 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 minutes to separate the plasma. The plasma samples were treated with acetonitrile to precipitate proteins and separated by a Cortex C18+ column. The mobile phase was methanol-10mmol / L ammonium acetate. An electrospray ionization source was used. The stable isotope-labeled internal standard d4-aprepitant was used as the internal standard of aprepitant. The concentration of aprepitant in plasma was analyzed by LC-MS / MS. The results are shown in the following table. Figure 7 shown.

[0289] Figure 7 The comparison between the micelle injection of aprepitant in Example 5 and the commercially available aprepitant emulsion (trade name CINVANTI ® ) have similar peak concentrations, and their AUC (area under the curve) ratio is between 80% and 125%, which can be considered as bioequivalence.

[0290] The above results show that the present invention can improve micelle stability and formulation stability, avoid the adverse effects of large emulsion particles, and take into account both sterility reliability and micelle stability by adding nanomicelle stabilizers while maintaining therapeutic effects and drug absorption effects.

[0291] For ordinary technicians in this field, the specific embodiments are only illustrative descriptions of the present invention. It is obvious that the specific implementation of the present invention is not limited to the above-mentioned methods. As long as various non-substantial improvements are made using the method concepts and technical solutions of the present invention, or the concepts and technical solutions of the present invention are directly applied to other occasions without improvement, they are all within the scope of protection of the present invention.

Claims

1. An aprepitant micellar injection, wherein the raw materials include aprepitant, phospholipid, bile acid or its salt, pH regulator and water for injection, characterized in that: The injection solution 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 1:0.025-3; The injection contains 1-10 mg / mL of aprepitant and 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. The pH of the injection is adjusted to 6.0-6.5 with a pH adjuster. The specifications of the aprepitant micellar injection are 1-10 mg / mL, a particle size of 2-10 nm, a zeta potential of -20 to -60 mV, and a transmittance of >90%. The nano-micelle stabilizer is selected from one or more of phosphatidylethanolamine, PVP K12, PVP K17, and sodium cholesterol sulfate.

2. The aprepitant micellar injection according to claim 1, characterized in that The phospholipid is selected from natural phospholipids or synthetic phospholipids; the natural phospholipid is one of soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, and hydrogenated egg yolk lecithin; the synthetic phospholipid is 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 is at least one of an acidic pH regulator and an alkaline pH regulator; the acidic pH regulator is 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.

3. The method for preparing the aprepitant micellar injection according to claim 1 or 2, characterized in that: The preparation method is a thin film dispersion method, which specifically includes the following steps: (1) Film preparation: Weigh the prescribed amount of aprepitant, phospholipid, bile acid or its salt, and nanomicelle stabilizer, add an appropriate amount of organic solvent to dissolve, place on 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: add an alkaline pH regulator in a molar ratio of 1:0.8-1.2 to the bile acid added in step (1), and completely dissolve it with water for injection filled with protective gas accounting for 50-85% of the total volume of the injection solution prepared, transfer the resulting solution to the loose film in step (1), and after complete hydration, adjust the pH to 6.0-6.5 with a pH regulator to obtain a drug solution; (3) Volume or weight determination: The liquid obtained in step (2) is volume or weight determined, filtered, and filled with protective gas. The filtration is performed using a 0.22 μm filter membrane; (4) Stoppering, capping and sterilization: After filling the headspace with protective gas, stopper and cap the tubes, and sterilize by autoclave at 121°C for 15 min.

4. The method for preparing aprepitant micellar injection according to claim 3, wherein: If the bile acid or its salt 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 volume of the injection solution is directly transferred to the loose film, and after complete hydration, the pH is adjusted to 6.0-6.5 with a pH regulator to obtain a drug solution; The rotary evaporation parameters in step (1) are: water bath temperature 30-70°C, time 2-6 hours; 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 0.5-2 hours, the dissolved oxygen residual range is 0-5 mg / L, and the headspace residual oxygen content is controlled at 0-5%.

5. The method for preparing the aprepitant micellar injection according to claim 1 or 2, 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 and 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 translucent. After cooling to room temperature, adjust the pH to 6.0-6.5 with a pH adjuster. (4) Volume or weight determination: The liquid obtained in step (3) is volume or weight determined, filtered, and filled with protective gas. The filtration is performed using a 0.22 μm filter membrane; (5) Stoppering, capping and sterilization: After filling the headspace with protective gas, stopper and cap the tubes, and sterilize by autoclave at 121°C for 15 min.

6. The method for preparing aprepitant micellar injection according to claim 5, wherein: If the bile acid or its salt 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 its salt 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 regulator 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 dissolved oxygen range is 0-5 mg / L, and the residual oxygen content in the headspace is controlled at 0-5%.

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