Aprepitant micelle composition and preparation method thereof

Abstract

The invention belongs to the field of medicine, and provides an aprepitant micelle composition and a preparation method thereof, the aprepitant micelle composition is composed of an active component aprepitant and auxiliary materials such as phospholipid, cholic acid or a salt thereof, a nano-micelle stabilizer, a pH regulator and the like, the dosage form is a freeze-dried powder injection, and the solubility of the aprepitant is remarkably improved; the combination 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, and reduces the risk of hyperlipidemia. Ethanol is not contained, so that ethanol anaphylaxis is avoided, and the safety of clinical medication can be remarkably improved. After the freeze-dried powder injection is redissolved, a hot-pressing sterilization mode can be adopted, so that the sterile guarantee level is remarkably improved, and the clinical medication risk is reduced. The aprepitant micelle composition is prepared by adopting a tert-butyl alcohol-water freeze-drying method, the process is simple and convenient, large-scale production is easy, a common freeze-dried powder injection production line can be adopted, 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 present invention belongs to the field of medicine, and provides an aprepitant micelle composition 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, molecular formula: C 23 H 21 7F4N4O3, molecular weight: 534.427, and the chemical structural formula is as follows:

[0003]

[0004] Aprepitant is a weakly basic compound, with a pKa value of 9.7 within the pH range of 2 - 12. It is a white or slightly white crystal, slightly soluble in acetonitrile, soluble in ethanol, and poorly soluble in water (0.55 μg / mL, pH = 2 - 10), with relatively high lipophilicity [log P (pH7) = 4.8]. 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] As a neurokinin-1 (NK-1) receptor antagonist, aprepitant can selectively bind to the NK-1 receptor and block the action of the neurotransmitter substance P. Substance P is closely related to chemotherapy-induced nausea and vomiting (CINV). By blocking this pathway, aprepitant can not only act on the central nervous system but also exert an antiemetic effect in the peripheral nervous system, and has an inhibitory effect on both acute and delayed CINV. At the same time, it has good oral absorption, high bioavailability, high plasma protein binding rate, is metabolized by the liver, excreted in feces and urine, has a relatively long half-life, and can maintain an effective blood drug concentration.

[0006] Aprepitant is mainly used clinically to prevent chemotherapy-induced CINV, especially for highly emetogenic chemotherapy drugs such as cisplatin. Using it before chemotherapy can significantly reduce the incidence and severity of acute and delayed vomiting. It is often combined with 5-hydroxytryptamine 3 (5-HT3) receptor antagonists and glucocorticoids to form the standard triple antiemetic regimen for preventing CINV caused by highly emetogenic chemotherapy drugs. At the same time, it also has a certain effect on preventing postoperative nausea and vomiting (PONV) and can be used as an adjuvant drug for high-risk patients (such as women, non-smokers, those with a history of PONV or motion sickness, etc.). However, its application in this regard is relatively less, and more clinical studies are needed to further confirm its effectiveness and safety. When using it, the dosage and regimen need to be adjusted according to the specific situation of the patient. This drug generally has good tolerance and may cause mild adverse reactions such as headache and fatigue, and the symptoms usually can be relieved after stopping the drug.

[0007] The oral capsule of aprepitant developed by Merck & Co., Inc. in the United States was approved for marketing in 2003. Due to the low solubility and poor absorption of aprepitant, with a solubility in water of only 0.55 μg / mL, the aprepitant fat emulsion injection further developed by Heron Therapeutics in 2017 (with a specification of 18 mL: 130 mg), compared with the oral capsule, has the advantages of rapid absorption, high bioavailability, and good compliance, providing a more convenient way of use for clinical practice.

[0008] Domestically, in September 2022, the aprepitant injection of Qilu Pharmaceutical Co., Ltd. was approved for marketing by the National Medical Products Administration and was regarded as passing the consistency evaluation, becoming the first approved aprepitant submicron emulsion injection in China. On December 18, 2023, the aprepitant injection of Nanjing Entai Pharmaceutical Co., Ltd. was approved for marketing and was included in the 2023 national medical insurance negotiation. On September 9, 2024, the aprepitant injection developed by Shijiazhuang Pharmaceutical Group obtained the drug registration approval issued by the National Medical Products Administration; during the period from January 6 to January 12, 2025, the aprepitant injection developed by Sichuan Kelun Pharmaceutical Co., Ltd. was approved for marketing.

[0009] These domestic aprepitant injections from Qilu Pharmaceutical Co., Ltd., Enqi Hui, Shijiazhuang Pharmaceutical Group, and Kelun Pharmaceutical Co., Ltd. and the original research aprepitant injection all use submicron emulsion as the drug delivery system, encapsulating aprepitant in the oil phase such as soybean oil to make submicron emulsion preparations; in the preparation process, it is necessary to mix the oil phase and the water phase through an emulsification process to form a stable emulsion. There are still defects in the prescription design and process design.

[0010] Patent document CN111514099A discloses an aprepitant injection, which contains aprepitant, phospholipid, injection oil, and injection water. Ethanol is used as a co-emulsifier, and its dosage in the injection is 1-4 wt / wt%, and no measures are taken to remove ethanol.

[0011] Patent document CN109010269A discloses a fat emulsion injection of aprepitant, which includes aprepitant, phospholipid, injection oil, glycine, polyvinylpyrrolidone, and injection water, and does not include sucrose. Short-chain alcohols such as ethanol and propylene glycol are used as co-solvents. There are many clinical reports on the adverse reactions of propylene glycol in clinical practice, which limits its clinical application.

[0012] Both of the above two documents use ethanol as a co-solvent. Ethanol is irritating. After being injected into the human body, it may irritate local tissues, resulting in symptoms such as pain and redness at the injection site.

[0013] 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. Ethanol is removed through the reduced-pressure distillation operation of a rotary evaporator in the oil phase preparation stage; the coarse emulsion is homogenized multiple times through a microfluidizer; it causes certain difficulties in the later large-scale production.

[0014] Patent documents CN112535661A, CN110368363A, CN113952299A, and the above three documents all use injection oil, which can be selected from long-chain fatty acid triglycerides and / or medium-chain fatty acid triglycerides. The injection oil contains unsaturated fatty acids. Under the action of factors such as light, heat, and oxygen, the unsaturated bonds are prone 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 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, bringing challenges to the quality control of the injection.

[0015] The above six patents are all aprepitant emulsion injections for injection. As a special preparation, the distribution of the emulsion particle size is directly related to its pharmacokinetics in the body, 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 the patient.

[0016] Patent document CN110934829A provides an aprepitant nano-micelle preparation, which includes aprepitant, phospholipids, sucrose, ethanol and water for injection, wherein 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 concentrations of ethanol may cause adverse reactions such as pain at the injection site and neuritis; secondly, the uniformity and stability of operations such as mixing, shearing, and homogenization during large-scale production are difficult to control, and the amplification effect of the equipment may cause fluctuations in product quality, increase the difficulty and cost of process amplification, and hinder the industrial promotion of the product.

[0017] Patent document CN112168788A discloses a sterile lyophilized preparation of aprepitant micelles for intravenous injection and a preparation method thereof, wherein the sterile lyophilized preparation of aprepitant micelles for injection comprises aprepitant and methoxypolyethylene glycol-derivatized phospholipids, and a pharmaceutically acceptable lyophilization protective agent. The obtained micelle solution is sterilized by passing through a 0.22 μm microporous filter membrane, and then lyophilized to remove water to obtain a sterile lyophilized powder of aprepitant micelles. The preparation process uses a rotary evaporator and a large amount of ethanol, which is dangerous and not conducive to scale-up production.

[0018] The above two micelle patent documents both 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 poor stability, easy oxidative degradation, uneven micelle structure, short circulation time in the body, and poor efficacy.

[0019] Currently, the preparation of aprepitant injection requires the use of high-speed shearing equipment and homogenizing equipment, which are stirred at high speed (up to 10,000 rpm) for a long time (>2h), are highly dependent on the equipment, and have high energy consumption; the prepared injection is difficult to be sterilized by high pressure, and has a significant adverse effect on stability after high pressure sterilization, resulting in the injection being unable to take into account both stability and sterility reliability; and the pH of the injection is alkaline (≥8.5), resulting in the problem of excessive hemolytic phospholipid content due to hydrolysis of phospholipids at a higher pH during use.

[0020] Therefore, it is necessary to develop a new type of aprepitant micelle composition, which has the following characteristics: no soybean oil, no ethanol, good formulation stability, tolerance to hot pressing sterilization, simple process, easy to scale up production and application. In order to overcome the above-mentioned shortcomings of the existing marketed emulsion injection and the injection reported in the literature, a safer and more stable aprepitant micelle composition is provided for clinical use, which has become a key technical problem to be solved in this field. Summary of the invention

[0021] The present invention belongs to the field of medicine and provides an aprepitant micelle composition and a preparation method thereof. The composition is composed of an active ingredient, aprepitant, and excipients such as phospholipids, bile acids or their salts, nano-micelle stabilizers, and pH regulators, and the dosage form is a freeze-dried powder for injection. Through innovative formulation design, the aprepitant micelle composition selects a phospholipid and bile acid micelle system with good physiological compatibility and safety to solubilize aprepitant, 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 the use of a large amount of soybean oil for solubilization, thereby reducing the risk of lipid metabolism; it does not contain ethanol, thus avoiding ethanol allergic reactions, and therefore can significantly improve the safety of clinical medication. The aprepitant micelle composition has good stability. After the freeze-dried powder for injection is reconstituted, it can be sterilized by heat pressing, thus significantly improving the level of sterility assurance and reducing the risk of clinical medication. The aprepitant micelle composition is prepared by the tert-butanol-water freeze-drying method. The process is simple and easy to scale up for production, 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.

[0022] The main inventive concept of the present invention is to provide a more ideal injection carrier for aprepitant. Hepatocytes can autonomously secrete bile acids, taurine or glycine, and the salts formed by combining with bile acids are bile salts. Bile salts contain hydrophilic hydroxyl and carboxyl groups, as well as hydrophobic methyl groups and other structures, so they have the ability to form micelles. They can solubilize poorly soluble drugs by reducing the surface tension between the oil phase and the aqueous phase, thereby increasing the drug concentration, enhancing the stability of the drug, and promoting drug absorption to improve the therapeutic effect. The bile secreted by human hepatocytes is rich in 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.

[0023] Adding nano-micelle stabilizers to the phospholipid bile salt carrier can significantly improve the system performance. Hydrophilic polyethylene glycol long-chain modified components (such as polysorbate 80) and sodium oleate can avoid particle aggregation and improve the stability of the preparation by enhancing particle hydrophilicity and increasing the Zeta potential, respectively; at the same time, polyethylene glycol modification can also help the nano-micelles avoid recognition by phagocytes, prolong the in vivo circulation time, enhance the transmembrane efficiency of the blood-brain barrier and the targeting property. In addition, adding polyvinylpyrrolidone (PVP) can stabilize the micelle structure through steric hindrance effects, improve the solubility of poorly soluble drugs by using its hydrophilicity, and form a diffusion barrier on the surface of the micelles 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] Sodium cholesteryl sulfate is selected because the rigid steroid structure of its cholesterol can insert into the phospholipid bilayer, form a closer molecular arrangement with lecithin, and thus reduce 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 micelle surface potential reach above -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 preparation of mixed micelles by the tert-butanol-water freeze-drying method shows multiple advantages compared with the existing blank micelle method and thin film method. First, this method can significantly improve the stability and drug loading efficiency of micelles. During the freeze-drying process, the porous structure formed by tert-butanol helps the uniform dispersion of micelles and the efficient encapsulation of drugs, while reducing the loss of drugs during freeze-drying. Second, the tert-butanol-water freeze-drying method can optimize the particle size distribution and morphological uniformity of micelles. Due to the low freezing point and high volatility of tert-butanol, the growth of ice crystals during the freeze-drying process is more controllable, thus forming a more uniform micelle structure and avoiding the common aggregation or non-uniformity phenomena in the blank micelle method and thin film method. In addition, this method can effectively protect the stability of drugs or active ingredients and reduce the degradation risk caused by solvent residues or high-temperature treatment, while the blank micelle method and thin film method may have certain limitations in these aspects. Finally, the tert-butanol-water freeze-drying method is more convenient to operate, more suitable for large-scale production, and has high process feasibility and economy.

[0026] The present invention first provides a preparation method of aprepitant micelle composition. Using the tert-butanol-water freeze-drying method, the dosage form is freeze-dried powder for injection, which specifically includes the following steps:

[0027] 1) Prepare a cholate solution and adjust the pH of the cholate solution to 6.0 - 7.5 with a pH regulator;

[0028] The cholate solution can be prepared by dissolving cholate with an alkaline sodium salt or directly dissolving cholate.

[0029] The cholate solution can be prepared by the following method: when using cholate for preparation, disperse cholate in water for injection, add an alkaline sodium salt or its solution, stir evenly, adjust the pH to 6.0 - 7.5, and fill with a protective gas to obtain it;

[0030] The cholate is selected from glycocholic acid and / or deoxycholic acid, preferably glycocholic acid, the alkaline sodium salt is selected from sodium hydroxide and / or sodium carbonate, and the molar ratio of cholate to alkaline sodium salt is 1:(0.95 - 1);

[0031] Alternatively, the cholate solution can also be prepared by the following method: when preparing with cholate, dissolve the cholate in water for injection, after stirring and dissolving, adjust the pH to 6.0 - 7.5, and then fill with a protective gas to obtain it; the cholate is selected from sodium glycocholate and / or sodium deoxycholate, preferably sodium glycocholate.

[0032] The volume of the cholate solution is 12.5 - 25% of the total volume after volume fixation in step 3).

[0033] The pH is adjusted using a pH regulator, and the pH regulator is selected from at least one of an acidic pH regulator and a basic pH regulator. Among them, the acidic pH regulator is selected from any one or a combination of any proportions of citric acid, hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, oxalic acid, and malic acid, and the basic pH regulator is selected from any one or a combination of any proportions of sodium hydroxide and sodium carbonate.

[0034] When the bile acid or its salt is dissolved and filled with a protective gas, the protective gas used is any one of nitrogen, helium, and argon, and the time for filling the protective gas is 0.5 - 2 hours; control the residual range of dissolved oxygen in the cholate solution to 0 - 5 mg / L, and control the residual headspace oxygen amount to 0 - 5%.

[0035] 2) Add aprepitant and phospholipids to tert-butanol, and at the same time add a nano-micelle stabilizer, and ultrasonically dissolve to obtain an aprepitant-phospholipid-tert-butanol solution.

[0036] The nano-micelle stabilizer is selected from one or more of polyethylene glycol 15-hydroxystearate, polysorbate, poloxamer, hydrogenated phosphatidylcholine, polyoxyethylene castor oil, sodium oleate, PVP K12, PVP K17, and sodium cholesteryl sulfate; in step 2), the mass ratio of the nano-micelle stabilizer to aprepitant is 0.05 - 0.5:1.

[0037] Preferably, in step 2), the ratio of aprepitant to the volume of volume fixation in step 3) is 1 - 10 mg:1 mL.

[0038] Preferably, in step 2), the mass ratio of aprepitant to phospholipids is 1:(10 - 15); in step 2), the mass ratio of phospholipids to the cholate in the cholate solution is 1:(0.5 - 1.5).

[0039] Preferably, in step 2), the volume of tert-butanol is 25 - 74% of the volume of volume fixation in step 3).

[0040] 3) While continuously stirring at 200 - 400 rpm, add the cholate solution obtained in step 1) to the aprepitant-phospholipid-tert-butanol solution obtained in step 2), after complete dissolution, fix the volume, and filter to obtain a mixed solution.

[0041] Preferably, the filtration diameter after constant volume is 0.22 μm.

[0042] 4) Aliquot the mixed solution obtained in step 3), semi-cork it, and then freeze-dry to obtain the aprepitant micelle composition.

[0043] Specifically, aliquot the mixed solution from step (3) into freeze-drying vials, semi-cork them, and then freeze-dry to obtain a loose freeze-dried block, namely the aprepitant nano-micelle freeze-dried powder injection composition. When used clinically, add sterile water for injection to reconstitute it to obtain the aprepitant nano-micelle injection solution for intravenous injection.

[0044] Preferably, the phospholipid is selected from one of soybean phospholipid, egg yolk phospholipid, hydrogenated soybean phospholipid, and hydrogenated egg yolk phospholipid; among which, soybean phospholipid is preferred.

[0045] Preferably, the steps of freeze-drying are as follows:

[0046] (1) Pre-freezing: Put the semi-corked sample into the freeze-dryer, turn on the circulating pump and the baffle refrigeration, set the baffle temperature to reach -30°C to -50°C in 1 h, and keep it warm for 2 to 4 h.

[0047] (2) Sublimation drying: Evacuate the freeze-dryer and maintain a pressure of 10 to 30 Pa, heat the sample at a rate of 0.5°C / min to -20°C to -10°C, and keep it warm for 20 to 25 h.

[0048] (3) Desorption drying: Evacuate the freeze-dryer and maintain a pressure of 10 to 30 Pa, heat the sample at a rate of 0.5°C / min to 20°C to 30°C, and keep it warm for 2 to 4 h.

[0049] Each drug has its unique melting point and glass transition temperature, and these physical properties will affect the phase change behavior during freeze-drying. The melting point and glass transition temperature of aprepitant are different from those of other drugs. If directly applying the tert-butanol-water freeze-drying process of other drugs, it will cause an inappropriate ice crystal structure to be formed during the freezing stage, or phenomena such as collapse and shrinkage during the drying stage, affecting the appearance and quality of the product.

[0050] The present invention performs customized operations according to the material characteristics, etc. According to the characteristics of the material such as the freezing point and eutectic point, precisely set the temperatures of the pre-freezing, sublimation, and desorption drying stages, so that the water can sublimate and be removed in the best state at different stages, improving the drying efficiency and effect and shortening the drying time.

[0051] Through the above method, the aprepitant micelle composition can be prepared, and its dosage form is a freeze-dried powder injection composition.

[0052] The present invention further provides an aprepitant micelle composition injection solution, which is obtained by reconstituting the aprepitant micelle composition in the form of a lyophilized powder injection with water for injection. It contains the active ingredient aprepitant, phospholipids, bile acids or their salts, nano-micelle stabilizers, pH regulators and water for injection. The proportions of each component are as follows: the concentration of the active ingredient aprepitant is 1-10 mg / mL; the mass ratio of aprepitant to phospholipids is 1:(10-15), the mass ratio of phospholipids to bile acids or their salts is 1:(0.5-1.5), and the mass ratio of aprepitant to nano-micelle stabilizers is (0.05-0.5):1; its pH is 6.0-7.5.

[0053] Preferably, the total volume of the aprepitant micelle composition injection solution is 1 mL to 20 mL, the concentration of aprepitant is 1-10 mg / mL, the pH is 6.0-7.5, the average particle size of the micelles in the aprepitant micelle composition injection solution is 2-10 nm, the Zeta potential is -20 to -60 mV, and the light transmittance of the aprepitant micelle composition injection solution > 90%.

[0054] Preferably, after obtaining the aprepitant micelle composition by freeze-drying, the aprepitant micelle composition is reconstituted with water for injection and fixed in volume, then filled with a protective gas, sub-packed into vials, stoppered and crimped, and heat-sterilized at 121 °C for 15 min;

[0055] Among the protective gases filled after reconstitution and volume fixation, the protective gas used is any one of nitrogen, helium and argon, and the time for filling the protective gas is 0.5-2 hours; the residual range of dissolved oxygen in the bile salt solution is controlled at 0-5 mg / L, and the residual headspace oxygen content is controlled at 0-5%.

[0056] In addition, the inventor also provides a preparation method of an aprepitant nano-micelle composition injection solution, specifically: in step 4), the mixed solution in step 3) is transferred to a stainless steel freeze-drying tray, freeze-dried to obtain a loose freeze-dried block, taken out of the box, dissolved with water for injection, fixed in volume, filled with a protective gas, sub-packed into vials, stoppered (tetrafluoroethylene-coated bromobutyl rubber stopper) and crimped, and heat-sterilized at 121 °C for 15 min to obtain the aprepitant nano-micelle composition injection solution.

[0057] The aprepitant micelle injection solution 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 use in combination with steroids and 5-HT3 receptor antagonists during the initial and repeated treatments of cancer patients receiving highly emetogenic anti-tumor chemotherapy to prevent acute and delayed nausea and vomiting. In addition, aprepitant can also be used for preventing nausea and vomiting caused by radiotherapy and nausea and vomiting before surgery.

[0058] Compared with the prior art, the present invention has the following beneficial effects:

[0059] (1) The tert-butanol-water freeze-drying method is carried out at low temperature, effectively reducing the oxidation and degradation of phospholipids and bile salts, maintaining the structural integrity of the mixed micelles, and thus improving their stability. At the same time, this method can effectively encapsulate drug molecules during the freezing process, reduce drug leakage, significantly improve the drug encapsulation rate, and enhance the drug efficacy. This method simplifies the traditional complex preparation steps, only requiring mixing and freeze-drying, reducing the production cost and time cost.

[0060] (2) Existing fat emulsions generally adopt the preparation process of O / W primary emulsification - high-pressure homogenization - sterilization (sterile filtration). The process is complex, difficult to control quality, difficult to 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 the innovative tert-butanol-water freeze-drying process, which can use ordinary freeze-dried powder injection production lines or ordinary aqueous injection production lines, without special equipment such as high-pressure homogenizers and dedicated fat emulsion production lines, and can significantly reduce the production cost.

[0061] (3) In the phospholipid-bile salt micelle system of this patent, adding a nano-micelle stabilizer to the phospholipid-bile salt carrier can significantly improve the system performance. Hydrophilic polyethylene glycol long-chain modification components (such as polysorbate 80) and sodium oleate can avoid particle aggregation and improve the preparation stability by enhancing particle hydrophilicity and increasing the Zeta potential respectively;

[0062] At the same time, polyethylene glycol modification can also help the nano-micelles avoid recognition by phagocytes, prolong the in vivo circulation time, and enhance the transmembrane efficiency and targeting of the blood-brain barrier;

[0063] In addition, adding PVP (polyvinylpyrrolidone) can stabilize the micelle structure through steric hindrance effects, increase the solubility of poorly soluble drugs by using its hydrophilicity, and form a diffusion barrier on the micelle surface to delay drug release. The biocompatibility of PVP can also reduce tissue irritation and protect drug activity through hydrogen bonds or van der Waals forces with drug molecules;

[0064] Selecting sodium cholesteryl sulfate is because its rigid steroid structure of cholesterol can insert into the phospholipid bilayer, form a closer molecular arrangement with lecithin, and thus reduce the surface energy of the micelles. 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 above -30 mV. This high negative electrical potential can effectively inhibit the aggregation of micelle particles through charge repulsion effects and maintain the long-term stability of particle size.

[0065] (4) The original research emulsion injection is an O / W emulsion, also known as fat emulsion, which has the risk of aggregation of emulsion droplets. It has large emulsion particles itself and is prone to cause various adverse reactions. The reconstituted and reconstituted and sterilized freeze-dried powder injection of aprepitant micelle composition prepared by the present invention are both clear solutions, which can strictly control visible foreign matters and insoluble particles. Visible foreign matters are easier to observe during clinical medication, and the medication can be predicted in advance to reduce risks, thereby significantly improving the safety of medication.

[0066] (5) The soybean oil in the original research emulsion prescription contains 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. The freeze-dried powder injection of aprepitant micelle composition prepared by the present invention does not contain soybean oil, thereby reducing the risk of lipid metabolism.

[0067] (6) For the original research emulsion injection, due to poor preparation stability, only the method of sterile filtration can be used, and the sterile assurance level is relatively low, with certain clinical medication risks. The aprepitant micelle composition prepared by the present invention significantly improves the stability of the preparation. After reconstitution, it can withstand autoclaving. Before and after sterilization after reconstitution, the injection properties, pH, particle size, content, related substances and other indicators have no significant changes, thereby greatly improving the sterile assurance.

[0068] (7) The original research emulsion injection contains ethanol. In the prescription of the aprepitant micelle composition prepared by the present invention, ethanol is abandoned as a solubilizer for phospholipids, 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.

[0069] (8) 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 reconstituted aprepitant micelle composition of the present invention can withstand freeze-thaw cycles, significantly improving the stability of the preparation. Description of the Drawings

[0070] Figure 1 Shows the appearance state of the freeze-dried powder injection of aprepitant micelle composition prepared by the tert-butanol-water freeze-drying method in Example 1;

[0071] Figure 2 Shows the particle size distribution diagram of the reconstituted freeze-dried powder injection of aprepitant micelle composition prepared by the tert-butanol-water freeze-drying method in Example 1;

[0072] Figure 3 Shows the Zeta potential diagram of the reconstituted freeze-dried powder injection of aprepitant micelle composition prepared by the tert-butanol-water freeze-drying method in Example 1;

[0073] Figure 4 Shows the high-performance liquid chromatography (HPLC) chromatogram of the content determination after reconstitution of the freeze-dried powder injection of aprepitant micelle composition prepared by the tert-butanol-water freeze-drying method in Example 1 Figure 4 A) and the HPLC chromatogram of the reference substance Figure 4 B);

[0074] Figure 5 Shows the appearance state of the aprepitant composition micelle injection prepared by the tert-butanol-water freeze-drying method in Example 11;

[0075] Figure 6 Shows the chromatogram of related substances of the aprepitant composition micelle injection prepared by the tert-butanol-water freeze-drying method in Example 11 after sterilization;

[0076] Figure 7 Shows the particle size diagram of the aprepitant composition micelle injection prepared by the tert-butanol-water freeze-drying method in Example 11 after 3 rounds of freeze-thaw cycles;

[0077] Figure 8 Shows the gas chromatogram of the reference substance solution for the determination method of residual solvent tert-butanol in Experimental Example 5;

[0078] Figure 9 Shows the gas chromatogram of the test solution for the determination method of residual solvent tert-butanol in Experimental Example 5;

[0079] Figure 10 Shows the appearance diagram of the non-clear aprepitant mixed micelle injection prepared by the high-shear dispersion emulsification mechanism in Comparative Example 2. Detailed implementation manners

[0080] 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 regarding 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.

[0081] In the following examples, for the filling of the protective gas, the protective gas is selected from any one of nitrogen, helium and argon, and the time for filling the protective gas is 0.5 - 2 hours; the residual range of dissolved oxygen in the cholate solution is controlled at 0 - 5 mg / L, and the residual headspace oxygen amount is controlled at 0 - 5%.

[0082] Example 1 Preparation of freeze-dried powder injection of aprepitant micelle composition

[0083] The formula of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 15.68 g of soybean phospholipid, 18.72 g of glycocholic acid, 1.59 g of sodium hydroxide, 130 mL of butanol, and made up to 400 mL with injection water.

[0084] Preparation process:

[0085] (1) Weigh sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh glycocholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the glycocholic acid solution, stir and dissolve until clear. Adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain the sodium glycocholate solution;

[0086] (2) Weigh aprepitant and soybean phospholipid in the prescription, add tert-butanol in the prescription, and dissolve them by ultrasonic wave to obtain the aprepitant-phospholipid-tert-butanol solution;

[0087] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycocholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with injection water, and filter with a 0.22 μm filter membrane to obtain the mixed solution;

[0088] (4) Fill the mixed solution in step (3) with nitrogen, sub-pack it into vials, half stopper it, freeze-dry, fill with nitrogen, stopper it, and crimp the cap.

[0089] The freeze-drying steps adopted are as follows:

[0090] (1) Pre-freezing: Put the semi-stoppered sample into the freeze-dryer, turn on the circulation pump and partition refrigeration, and set the partition temperature to reach -30°C to -50°C in 1 h, and keep warm for 2 to 4 h;

[0091] (2) Sublimation drying: Evacuate the freeze-dryer and maintain it at 10 to 30 Pa, heat the sample at 0.5°C / min to -20°C to -10°C, and keep warm for 20 to 25 h;

[0092] (3) Desorption drying: Evacuate the freeze-dryer and maintain it at 10 to 30 Pa, heat the sample at 0.5°C / min to 20°C to 30°C, and keep warm for 2 to 4 h.

[0093] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0094] The obtained freeze-dried powder injection of aprepitant micelle composition, the appearance properties are shown in Figure 1 ; then add 4.0 mL of injection water for reconstitution (in the ratio of 32 mg:4 mL), measure the particle size and potential distribution, and the results are shown in Figure 2 、 Figure 3 respectively.

[0095] It can be seen from Figure 1 that the appearance of this freeze-dried powder injection is a uniform and delicate freeze-dried block. After reconstitution, it is a clear and transparent solution, slightly light yellowish green, and from Figure 2It can be seen that the average particle size of the micelles is 2.655 nm, and the polydispersity index PDI is 0.296. This result indicates that the average particle size of the complex solution is small, similar to that of a true solution dispersion system. From Figure 3 It can be seen that the Zeta potential of the micelle particles is -37.4 mV. Generally, the stable Zeta potential range (absolute value) is 20 - 60 mV. Therefore, the stability of the micelle solution after reconstitution is good.

[0096] Preparation of the lyophilized powder injection of aprepitant micelle composition in Example 2

[0097] The formulation of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 15.68 g of soybean phospholipid, 18.47 g of deoxycholic acid, 1.88 g of sodium hydroxide, 130 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0098] Preparation process:

[0099] (1) Weigh the sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh the deoxycholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the deoxycholic acid solution. React until it becomes clear, and adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution. Fill with nitrogen to obtain the sodium deoxycholate solution;

[0100] (2) Weigh the aprepitant and soybean phospholipid in the prescription, add the tert-butanol in the prescription, and dissolve it by ultrasonic treatment to obtain the aprepitant-phospholipid-tert-butanol solution;

[0101] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium deoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer it to a graduated cylinder, make up the volume to 400 mL with injection water, and filter it through a 0.22 μm filter membrane to obtain the mixed solution;

[0102] (4) Dispense the mixed solution in step (3) into vials, half-cork them, perform freeze-drying, fill with nitrogen, stopper, and crimp the caps.

[0103] The freeze-drying steps adopted are the same as those in Example 1.

[0104] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0105] Preparation of the lyophilized powder injection of aprepitant micelle composition in Example 3

[0106] The formulation of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 15.68 g of soybean phospholipid, 18.47 g of sodium glycochenodeoxycholate, 130 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0107] Preparation process:

[0108] (1) Weigh sodium glycochenodeoxycholate in the prescription, dissolve it in 100 mL of water for injection, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain sodium glycochenodeoxycholate solution;

[0109] (2) Weigh aprepitant and soybean phospholipid in the prescription, add tert-butanol in the prescription, and dissolve it by ultrasonic to obtain aprepitant-phospholipid-tert-butanol solution;

[0110] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycochenodeoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve it completely, transfer it to a graduated cylinder, make up the volume to 400 mL with water for injection, and filter it through a 0.22 μm filter membrane to obtain a mixed solution;

[0111] (4) Subpackage the mixed solution in step (3) into vials, half stopper it, freeze-dry it, fill with nitrogen, stopper it, and crimp the cap.

[0112] The freeze-drying step adopted is the same as that in Example 1.

[0113] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0114] Preparation of freeze-dried powder injection of aprepitant micelle composition in Example 4

[0115] The formula of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 15.68 g of soybean phospholipid, 18.47 g of sodium deoxycholate, 130 mL of tert-butanol, and make up the volume to 400 mL with water for injection.

[0116] Preparation process:

[0117] (1) Weigh sodium deoxycholate in the prescription, dissolve it in 100 mL of water for injection, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain sodium deoxycholate solution;

[0118] (2) Weigh aprepitant and soybean phospholipid in the prescription, add tert-butanol in the prescription, and dissolve it by ultrasonic to obtain aprepitant-phospholipid-tert-butanol solution;

[0119] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium deoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve it completely, transfer it to a graduated cylinder, make up the volume to 400 mL with water for injection, and filter it through a 0.22 μm filter membrane to obtain a mixed solution;

[0120] (4) Subpackage the mixed solution in step (3) into vials, half stopper it, freeze-dry it, fill with nitrogen, stopper it, and crimp the cap.

[0121] The lyophilization step adopted is the same as that in Example 1.

[0122] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0123] Preparation of freeze-dried powder injection of aprepitant micelle composition in Example 5

[0124] The formula of the mixed solution used for lyophilization is as follows: 1.28 g of aprepitant, 15.68 g of soybean phospholipid, 18.72 g of glycocholic acid, 1.59 g of sodium hydroxide, 260 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0125] Preparation process:

[0126] (1) Weigh sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh glycocholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the glycocholic acid solution. React until it becomes clear, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain sodium glycocholate solution;

[0127] Except for adjusting the ratio of tert-butanol to injection water, the other steps are the same as those in Example 1.

[0128] The lyophilization step adopted is the same as that in Example 1.

[0129] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0130] Preparation of freeze-dried powder injection of aprepitant micelle composition in Example 6

[0131] The formula of the mixed solution used for lyophilization is as follows: 1.28 g of aprepitant, 15.68 g of soybean phospholipid, 18.72 g of glycocholic acid, 1.59 g of sodium hydroxide, 200 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0132] Preparation process:

[0133] In Example 6, except for adjusting the ratio of tert-butanol to injection water, other experimental parameters and conditions are the same as those in Example 1.

[0134] The lyophilization step adopted is the same as that in Example 1.

[0135] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0136] Preparation of freeze-dried powder injection of aprepitant micelle composition in Example 7

[0137] The formulation of the mixed solution for lyophilization is as follows: aprepitant 1.30 g, soybean phospholipid 13.86 g, glycocholic acid 16.53 g, sodium hydroxide 1.42 g, polysorbate 80 64 mg, tert-butanol 130 mL, and the volume is made up to 400 mL with injection water.

[0138] Preparation process:

[0139] (1) Weigh the sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh the glycocholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the glycocholic acid solution, stir and dissolve until clear, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain the sodium glycocholate solution;

[0140] (2) Weigh the aprepitant, soybean phospholipid, and polysorbate 80 in the prescription, add the tert-butanol in the prescription, and dissolve them ultrasonically to obtain the aprepitant-phospholipid-tert-butanol solution;

[0141] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycocholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with injection water, and filter through a 0.22 μm filter membrane to obtain the mixed solution;

[0142] (4) Dispense the mixed solution in step (3) into vials, half-stopper, lyophilize, fill with nitrogen, stopper, and crimp the cap.

[0143] The lyophilization steps adopted are the same as those in Example 1.

[0144] Each vial contains 130 mg of aprepitant, and a total of 10 vials are prepared.

[0145] Preparation of the lyophilized powder injection of aprepitant micelle composition in Example 8

[0146] The formulation of the mixed solution for lyophilization is as follows: aprepitant 1.28 g, soybean phospholipid 14.01 g, deoxycholic acid 16.51 g, sodium hydroxide 1.68 g, hydrogenated phosphatidylcholine 64 mg, tert-butanol 130 mL, and the volume is made up to 400 mL with injection water.

[0147] Preparation process:

[0148] (1) Weigh the sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh the deoxycholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the deoxycholic acid solution, react until clear, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain the sodium deoxycholate solution;

[0149] (2) Weigh aprepitant, soybean phospholipid, and hydrogenated phosphatidylcholine in the prescription, add tert-butanol in the prescription, and dissolve them by ultrasonic treatment to obtain an aprepitant-phospholipid-tert-butanol solution.

[0150] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium deoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with water for injection, and filter through a 0.22-μm filter membrane to obtain a mixed solution.

[0151] (4) Dispense the mixed solution in step (3) into vials, half-stopper, freeze-dry, fill with nitrogen, stopper, and crimp.

[0152] The freeze-drying step adopted is the same as that in Example 1.

[0153] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0154] Preparation of freeze-dried powder injection of aprepitant micelle composition in Example 9

[0155] The formula of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 14.40 g of soybean phospholipid, 18 g of glycochenodeoxycholic acid, 64 mg of polyoxyl castor oil, 130 mL of tert-butanol, and make up the volume to 400 mL with water for injection.

[0156] Preparation process:

[0157] (1) Weigh glycochenodeoxycholic acid in the prescription, dissolve it with 100 mL of water for injection, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain a sodium glycochenodeoxycholate solution.

[0158] (2) Weigh aprepitant, soybean phospholipid, and polyoxyl castor oil in the prescription, add tert-butanol in the prescription, and dissolve them by ultrasonic treatment to obtain an aprepitant-phospholipid-tert-butanol solution.

[0159] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycochenodeoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with water for injection, and filter through a 0.22-μm filter membrane to obtain a mixed solution.

[0160] (4) Dispense the mixed solution in step (3) into vials, half-stopper, freeze-dry, fill with nitrogen, stopper, and crimp.

[0161] The freeze-drying step adopted is the same as that in Example 1.

[0162] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0163] Preparation of Freeze-dried Powder for Injection of Aprepitant Micelle Composition in Example 10

[0164] The formulation of the mixed solution used for freeze-drying is as follows: aprepitant 1.28 g, soybean phospholipid 14.40 g, sodium glycocholate 18 g, polyethylene glycol 15-hydroxystearate 64 mg, tert-butanol 130 mL, and the volume is made up to 400 mL with injection water.

[0165] Preparation process:

[0166] (1) Weigh sodium glycocholate in the prescription, dissolve it with 100 mL of injection water, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain sodium glycocholate solution.

[0167] (2) Weigh aprepitant, soybean phospholipid, and polyethylene glycol 15-hydroxystearate in the prescription, add tert-butanol in the prescription, and dissolve it by ultrasonic wave to obtain aprepitant-phospholipid-tert-butanol solution.

[0168] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycocholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve it completely, transfer it to a measuring cylinder, make up the volume to 400 mL with injection water, and filter it through a 0.22 μm filter membrane to obtain a mixed solution.

[0169] (4) Dispense the mixed solution in step (3) into vials, half stopper it, perform freeze-drying, fill with nitrogen, stopper it, and crimp the cap.

[0170] The freeze-drying step adopted is the same as that in Example 1.

[0171] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0172] Preparation of Aprepitant Micelle Composition Injection in Example 11

[0173] The formulation of the mixed solution used for freeze-drying is as follows: aprepitant 1.28 g, soybean phospholipid 13.65 g, glycocholic acid 16.29 g, sodium hydroxide 1.40 g, polysorbate 80 64 mg, tert-butanol 130 mL, and the volume is made up to 400 mL with injection water.

[0174] Preparation process:

[0175] (1) Weigh the sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh the glycochenodeoxycholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the glycochenodeoxycholic acid solution. React until it becomes clear, and adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution. Fill with nitrogen to obtain the sodium glycochenodeoxycholate solution;

[0176] (2) Weigh aprepitant, soybean phospholipid, and polysorbate 80 in the prescription, add tert-butanol in the prescription, and dissolve them by ultrasonic treatment to obtain the aprepitant-phospholipid-tert-butanol solution;

[0177] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycochenodeoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2). After complete dissolution, transfer it to a graduated cylinder, make up the volume to 400 mL with injection water, and filter it through a 0.22 μm filter membrane to obtain the mixed solution;

[0178] (4) Transfer the mixed solution in step (3) to a stainless-steel freeze-drying tray, perform freeze-drying to obtain a loose freeze-dried block. Take it out of the box, add 160 mL of injection water, dissolve it completely, transfer it to a graduated cylinder, make up the volume to 200 mL, filter it through a 0.22 μm filter membrane, fill with nitrogen, sub-pack it into vials, add stoppers (tetrafluoroethylene-coated bromobutyl rubber stoppers), crimp the caps, and sterilize it by autoclaving at 121 °C for 15 min.

[0179] The freeze-drying step adopted is the same as that in Example 1.

[0180] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0181] As Figure 5 shown, the aprepitant micellar injection obtained in Example 11 is clear and transparent, showing a light yellowish green color.

[0182] Preparation of aprepitant micellar composition injection in Example 12

[0183] The formula of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 14.01 g of soybean phospholipid, 16.51 g of deoxycholic acid, 1.68 g of sodium hydroxide, 64 mg of hydrogenated phosphatidylcholine, 130 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0184] Preparation process:

[0185] (1) Weigh the sodium hydroxide in the prescription and dissolve it in 50 mL of injection water; weigh the deoxycholic acid in the prescription, add 50 mL of injection water, and under magnetic stirring, add the sodium hydroxide solution to the deoxycholic acid solution. React until it becomes clear, and adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution. Fill with nitrogen to obtain the sodium deoxycholate solution;

[0186] (2) Weigh aprepitant, soybean phospholipid, and galactosylated phosphatidylcholine in the prescription, add tert-butanol in the prescription, and dissolve them by ultrasonic treatment to obtain an aprepitant-phospholipid-tert-butanol solution.

[0187] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium deoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with injection water, and filter through a 0.22 μm filter membrane to obtain a mixed solution.

[0188] (4) Transfer the mixed solution in step (3) to a stainless-steel freeze-drying tray, freeze-dry to obtain a porous freeze-dried block, take it out of the box, add 160 mL of injection water, dissolve completely, transfer to a graduated cylinder, make up the volume to 200 mL, filter through a 0.22 μm filter membrane, fill with nitrogen, sub-pack into vials, add stoppers (tetrafluoroethylene-coated bromobutyl rubber stoppers), crimp the caps, and sterilize by autoclaving at 121 °C for 15 min.

[0189] The freeze-drying step adopted is the same as that in Example 1.

[0190] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0191] Preparation of aprepitant micelle composition injection in Example 13

[0192] The formula of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 14.40 g of soybean phospholipid, 18 g of glycochenodeoxycholic acid, 64 mg of polyoxyl castor oil, 130 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0193] Preparation process:

[0194] (1) Weigh glycochenodeoxycholic acid in the prescription, dissolve it with 100 mL of injection water, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain a sodium glycochenodeoxycholate solution.

[0195] (2) Weigh aprepitant, soybean phospholipid, and polyoxyl castor oil in the prescription, add tert-butanol in the prescription, and dissolve them by ultrasonic treatment to obtain an aprepitant-phospholipid-tert-butanol solution.

[0196] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium glycochenodeoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with injection water, and filter through a 0.22 μm filter membrane to obtain a mixed solution.

[0197] (4) Transfer the mixed solution from step (3) to a stainless-steel freeze-drying tray, freeze-dry to obtain a porous freeze-dried block, take it out of the box, add 160 mL of injection water, dissolve completely, transfer to a graduated cylinder, make up the volume to 200 mL, filter through a 0.22-μm filter membrane, fill with nitrogen, sub-pack into vials, add stoppers (tetrafluoroethylene-coated bromobutyl rubber stoppers), crimp the caps, and sterilize by autoclaving at 121 °C for 15 min.

[0198] The freeze-drying step adopted is the same as that in Example 1.

[0199] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0200] Preparation of aprepitant micelle composition injection in Example 14

[0201] The formula of the mixed solution used for freeze-drying is as follows: 1.28 g of aprepitant, 14.40 g of soybean phospholipid, 18 g of sodium deoxycholate, 64 mg of PVP K12, 130 mL of tert-butanol, and the volume is made up to 400 mL with injection water.

[0202] Preparation process:

[0203] (1) Weigh sodium deoxycholate in the prescription, dissolve it in 100 mL of injection water, adjust the pH value to 6.5 with 0.5 mol / L citric acid solution and 1 mol / L sodium hydroxide solution, and fill with nitrogen to obtain a sodium deoxycholate solution.

[0204] (2) Weigh aprepitant, soybean phospholipid, and PVP K12 in the prescription, add tert-butanol in the prescription, and dissolve by ultrasonic treatment to obtain an aprepitant-phospholipid-tert-butanol solution.

[0205] (3) Under the condition of magnetic stirring at 400 rpm, add the sodium deoxycholate solution in step (1) to the aprepitant-phospholipid-tert-butanol solution in step (2), dissolve completely, transfer to a graduated cylinder, make up the volume to 400 mL with injection water, filter through a 0.22-μm filter membrane to obtain a mixed solution.

[0206] (4) Transfer the mixed solution from step (3) to a stainless-steel freeze-drying tray, freeze-dry to obtain a porous freeze-dried block, take it out of the box, add 160 mL of injection water, dissolve completely, transfer to a graduated cylinder, make up the volume to 200 mL, filter through a 0.22-μm filter membrane, fill with nitrogen, sub-pack into vials, add stoppers (tetrafluoroethylene-coated bromobutyl rubber stoppers), crimp the caps, and sterilize by autoclaving at 121 °C for 15 min.

[0207] The freeze-drying step adopted is the same as that in Example 1.

[0208] Each vial contains 32 mg of aprepitant, and a total of 40 vials are prepared.

[0209] For Comparative Example 1, referring to Example 1 described in CN117752596A, reduce its drug loading to 3%, and prepare aprepitant mixed micelle injection: 1.0 g of aprepitant, 18 g of glycocholic acid, 14 g of soybean phospholipid, 1.5 g of sodium hydroxide, and 85 g of water for injection.

[0210] Preparation method:

[0211] (1) Weigh 1.5 g of sodium hydroxide and add it to 85 g of water for injection. Under magnetic stirring, heat to 55 °C. After the sodium hydroxide is dissolved, add 18 g of glycocholic acid and continue stirring until completely dissolved. Carry out neutralization for 10 min to form a sodium glycocholate solution;

[0212] (2) Turn on the high-shear dispersion emulsifier, heat to 65 °C under the condition of high-speed shearing at 10000 rpm, add 14 g of soybean phospholipid to the sodium glycocholate solution, and emulsify for 120 min to form a mixed micelle solution;

[0213] (3) Continue under the condition of high-speed shearing at 10000 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;

[0214] (4) After adjusting the pH value of the aprepitant mixed micelle solution to 8.5 with 3 wt% hydrochloric acid solution, filter the obtained mixed micelles through a 0.22 μm filter membrane (PES), fill with nitrogen and control the residual oxygen content in the bottle headspace ≤ 5%, and sterilize by heat pressing (121 °C, 15 min) to obtain aprepitant mixed micelle injection.

[0215] For Comparative Example 2, prepare aprepitant mixed 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, and 845 g of water for injection.

[0216] Preparation method:

[0217] (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. Carry out neutralization for 10 min to form a sodium glycocholate solution;

[0218] (2) Turn on the high-shear dispersion emulsifier, heat to 65 °C under the condition of high-speed shearing at 10000 rpm, add 80.0 g of soybean phospholipid to the sodium glycocholate solution, and emulsify for 120 min to form a mixed micelle solution;

[0219] (3) Continue under the high-speed shearing condition of 10,000 rpm, maintaining the temperature at 65 °C, slowly add 10.0 g of aprepitant to the mixed micelle solution, and perform shearing dispersion for 120 min. A clear aprepitant mixed micelle injection solution could not be formed, and a large amount of aprepitant raw material was still not encapsulated into the mixed micelles, as Figure 10 shown.

[0220] Determination methods for drug loading, content, and related substances in Experimental Example 1

[0221] 1. Drug loading = mass of aprepitant dissolved in the prescription / mass of total excipients added × 100%, where the mass of total excipients added = phospholipid + bile salt + aprepitant.

[0222] 2. Content determination method (each ratio in the following mobile phase is by volume)

[0223] 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.

[0224] Reference solution: Weigh accurately 10.0 mg of aprepitant raw material, place it in a 100 mL volumetric flask, dissolve and make up to the mark with the mobile phase solution to prepare a reference solution of 100 μg / mL.

[0225] Test solution: Accurately measure 1 mL of the aprepitant-loaded micelle solution and place it in a 50 mL volumetric flask, add 2 mL of methanol to demulsify, 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.

[0226] 3. Related substances test method

[0227] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (Venusil XBP C18 specification: 250 × 4.6 mm, 5 μm); 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 use 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.

[0228] Table 1 Gradient elution table for related substances method of aprepitant micelle injection

[0229]

[0230] Related substances test solution: Accurately measure 1 mL of this product, place it in a 10 mL volumetric flask, dilute to the mark with methanol, and shake well.

[0231] Examples 1-14 were tested according to the above methods for drug loading, content, and related substances determination, and the results are shown in Tables 2 and 3.

[0232] From Figure 4 It can be seen that after the aprepitant micelle composition obtained in Example 1 was redissolved, the liquid chromatography peak had a symmetrical shape, good resolution, and appropriate retention time. Therefore, the high performance liquid chromatography method established in the present invention can meet the requirements for the content determination of the active pharmaceutical ingredient.

[0233] The chromatogram of related substances of the aprepitant composition micelle injection prepared in Example 11 after sterilization is as Figure 6 shown. The black line and the pink line in this figure are the chromatograms of related substances of the aprepitant injection and the blank excipient solution respectively. After comparison, the related substances of the aprepitant composition micelle injection after sterilization meet the quality requirements compared with those of the aprepitant active pharmaceutical ingredient. It can be seen from the results in Table 2 that compared with Examples 1-6, Examples 7-10 have higher drug loadings. It can be seen that adding a nano-micelle stabilizer to the formulation of the composition micelle freeze-dried powder injection can further increase the drug loading; there is no significant change in the content of the composition micelle injection prepared in Examples 11-14 before and after autoclaving sterilization.

[0234] Table 2 Detection results of drug loading, content, and related substances of the aprepitant micelle composition freeze-dried powder injection

[0235]

[0236]

[0237] Table 3 Detection results of drug loading, content, and related substances of the aprepitant micelle composition injection

[0238]

[0239] Experimental Example 2 Investigation of the redissolution stability of the samples

[0240] For the samples prepared in Examples 1-10, each was redissolved with 4 mL of water for injection and its stability was investigated under the conditions of temperature 25°C ± 2°C and relative humidity 60% ± 5%. The results are shown in Table 4.

[0241] Table 4 Redissolution stability of the aprepitant micelle composition freeze-dried powder injection

[0242]

[0243]

[0244] For the samples prepared in Examples 1-10, after redissolution with water for injection, their stability was investigated under the condition of temperature 5°C ± 3°C. The results are shown in Table 5.

[0245] Table 5 Reconstitution Stability of Aprepitant Micelle Composition Freeze-dried Powder for Injection

[0246]

[0247]

[0248]

[0249] As can be seen from Table 4 and Table 5, within 12 hours under the conditions of 25°C ± 2°C, relative humidity 60% ± 5% and 5°C ± 3°C after reconstitution of the aprepitant micelle composition injections in Examples 1-10, indicators such as the appearance of the reconstituted solution, pH, particle size, Zeta potential, labeled content, and total impurities did not change significantly. The results indicate that the freeze-dried powder injections of the aprepitant micelle compositions in Examples 1-10 have good dilution stability and meet the requirements of clinical drug use.

[0250] Experimental Example 3 Freeze-thaw Cycle Experiment

[0251] Take the aprepitant micelle composition injections prepared in Examples 11-14 and the aprepitant mixed micelle injection prepared in Comparative Example 1 for freeze-thaw tests. The tests should include 3 cycles. Each cycle is placed at -10 to -20°C for 2 days, and then at 25°C for 2 days. Samples are taken for testing after each round. The results are shown in Table 6 and Table 7.

[0252] After 3 rounds of cycles, as can be seen from the results in Table 6, for Examples 11-14 (all added with nano-micelle stabilizers), no crystals precipitated after 3 rounds of freeze-thaw cycles. While in Comparative Example 1 without adding nano-micelle stabilizers, precipitation occurred in the first round of freeze-thaw cycle. Therefore, nano-micelle stabilizers can increase the stability of the aprepitant micelle composition injection.

[0253] As can be seen from the results in Table 7, for the sample prepared in Example 11, 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 particle size diagram of the sample in Example 11 after three rounds of freeze-thaw is as Figure 7 shown. The above results indicate that the aprepitant micelle composition injection can withstand the freeze-thaw test.

[0254] Table 6 Results of Freeze-thaw Tests

[0255] Time (h) Round 1 Round 2 Round 3 Example 11 - - - Example 12 - - - Example 13 - - - Example 14 - - - Comparative Example 1 + + +

[0256] Note: "-" indicates "no crystal precipitation", and "+" indicates "crystal precipitation".

[0257] Table 7 Results of Freeze-thaw Tests for Example 11

[0258]

[0259]

[0260] Note: Information on the colorimetric solution used under the item of color: Name: Pharmacopoeia Standard Colorimetric Solution of 2020 Edition, Number: TM-2020-0901, Batch Number: C2011013, Manufacturer: Shanghai Tanmo Quality Inspection Technology Co., Ltd.;

[0261] The turbidity standard solution used for clarity was prepared with reference to the Chinese Pharmacopoeia 2020 Edition.

[0262] Experimental Example 4 Accelerated Test and Long-Term Test

[0263] The lyophilized powder injection of aprepitant micelle composition in Examples 7-10 and the injection of aprepitant micelle composition in Examples 11-14 were subjected to stability studies under the following conditions. Record the appearance, properties, pH, and particle size changes, and determine the aprepitant content and related substances according to Example 1 above. The results are shown in Tables 8 and 9.

[0264] Long-term test: 25°C ± 2°C / 60% RH ± 5%; Accelerated test: 40°C ± 2°C / 75% RH ± 5%.

[0265] Table 8 Results of Stability Investigation of Lyophilized Powder Injection of Aprepitant Micelle Composition

[0266]

[0267]

[0268] As can be seen from Table 8, the lyophilized powder injection of aprepitant micelle composition in Examples 7-10 was placed under the conditions of accelerated stability (40°C ± 2°C / 75% RH ± 5%) for 6 months. The indexes such as the appearance and properties of the sample, the reconstitution performance, the properties, pH, particle size, potential, labeled content, and total impurities of the reconstituted solution did not change significantly. The above results indicate that the lyophilized powder injection of aprepitant micelle composition in Examples 7-10 has good stability. The designed storage condition for the lyophilized powder injection of aprepitant micelle composition is 2-8°C. According to the results of the accelerated experiment, the tentative validity period of the lyophilized powder injection of aprepitant micelle composition is 2 years.

[0269] Table 9 Results of Stability Investigation of Injection of Aprepitant Micelle Composition

[0270]

[0271]

[0272] As can be seen from Table 9, when the aprepitant micelle composition injection of Examples 11 - 14 was placed for 6 months under accelerated stability conditions (40°C ± 2°C / 75% RH ± 5% RH), there were no obvious changes in the appearance properties, pH, particle size, potential, labeled content, total impurities and other indicators of the samples. The above results indicate that the aprepitant micelle composition injection of Examples 7 - 14 has good stability. The designed storage condition for the aprepitant micelle composition injection is 2 - 8°C. According to the results of the accelerated experiment, the tentative expiration date of the aprepitant composition injection is 2 years.

[0273] Determination Method for Residual Solvent tert-Butanol in Experimental Example 5

[0274] (1) Chromatographic conditions: A capillary column with 6% cyanopropylphenyl - 94% dimethylpolysiloxane (or similar polarity) as the stationary phase (Agilent DB - 624, 30m × 0.32mm, 1.8μm or a chromatographic column with equivalent efficiency is recommended); the initial temperature is 45°C, maintained for 15 minutes, then heated at a rate of 40°C per minute to 165°C and maintained for 8 minutes; the injection port temperature is 200°C; the detector is a flame ionization detector, and the detector temperature is 300°C; the column flow rate is 3 mL per minute; the split ratio is 20:1; the headspace equilibrium temperature is 80°C; the quantitative loop temperature is 90°C; the transfer line temperature is 110°C; the equilibrium time is 30 minutes.

[0275] (2) Preparation of solutions

[0276] Reference solution: Take an appropriate amount of tert-butanol, accurately weigh it, quantitatively dilute it with ultrapure water to prepare a mixed solution containing 5 mg of tert-butanol per 1 mL. Accurately measure 2 mL of this solution and place it in a 20 mL headspace vial, then stopper and seal it.

[0277] Test solution: Take 1 vial of the freeze-dried product of Example 1, add 5 mL of sterilized injection water, shake to dissolve; accurately measure 2 mL and place it in a 20 mL headspace vial, then stopper and seal it.

[0278] Determination results: The gas chromatograms of the reference solution and the test solution are shown in Figure 8 , Figure 9 . Using the peak area of the reference as a reference, the results show that the residual amount of tert-butanol is 0.007%, which meets the residual solvent limit requirements of the Chinese Pharmacopoeia 2020 Edition.

[0279] 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-substantial improvements are made using 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. A preparation method of aprepitant micelle composition, characterized in that, The tert-butanol-water freeze-drying method is adopted to prepare a freeze-dried powder injection dosage form, which specifically includes the following steps: 1) Prepare a cholate solution and adjust the pH of the cholate solution to 6.0 - 7.5 with a pH regulator; 2) Add aprepitant and phospholipids to tert-butanol, and at the same time add a nano-micelle stabilizer, and dissolve by ultrasonic wave to obtain an aprepitant-phospholipid-tert-butanol solution; in step 2), the mass ratio of the nano-micelle stabilizer to aprepitant is 0.05 - 0.5:1; in step 2), the volume of tert-butanol is 25 - 74% of the final volume in step 3); 3) Add the cholate solution obtained in step 1) to the aprepitant-phospholipid-tert-butanol solution obtained in step 2) under continuous stirring, make it dissolve completely, then make up the volume, and obtain a mixed solution after filtration; 4) Sub-pack the mixed solution obtained in step 3), half-cork it, and then freeze-dry to obtain an aprepitant micelle composition.

2. The preparation method of the aprepitant micelle composition according to claim 1, characterized in that In step 2), the nano-micelle stabilizer is selected from one or more of polyethylene glycol 15-hydroxystearate, polysorbate, poloxamer, pegylated phosphatidylcholine, polyoxyethylene castor oil, sodium oleate, PVP K12, PVP K17, sodium cholesteryl sulfate.

3. The preparation method of the aprepitant micelle composition according to claim 1, wherein, The cholate solution in step 1) is prepared by the following method: when the bile acid or its salt is bile acid, disperse the bile acid in water for injection, add an alkaline sodium salt or its solution, stir evenly, then adjust the pH to 6.0 - 7.5, and fill with a protective gas to obtain it; The bile acid is selected from glycocholic acid and / or deoxycholic acid; the alkaline sodium salt is selected from sodium hydroxide and / or sodium carbonate, and the molar ratio of the bile acid or its salt to the alkaline sodium salt is 1:0.95 - 1; The volume of the cholate solution is 12.5 - 25% of the total volume after volume adjustment in step 3); The pH is adjusted with a pH regulator, and the pH regulator is selected from at least one of an acidic pH regulator and a basic pH regulator. Among them, the acidic pH regulator is selected from any one or more of citric acid, hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, oxalic acid, malic acid in any proportion combination, and the basic pH regulator is selected from any one or more of sodium hydroxide, sodium carbonate in any proportion combination; When the bile acid or its salt is dissolved and filled with a protective gas, the protective gas used is any one of nitrogen, helium and argon, and the time for filling the protective gas is 0.5 - 2 hours; control the residual range of dissolved oxygen in the cholate solution to be 0 - 5 mg / L, and the residual amount of headspace oxygen to be controlled at 0 - 5%; 4. The preparation method of the aprepitant micelle composition according to claim 1, characterized in that, The cholate solution in step 1) is prepared by the following method: when the bile acid or its salt is cholate, dissolve the cholate in water for injection, stir and dissolve it, then adjust the pH to 6.0 - 7.5, and fill with a protective gas to obtain it; The cholate is selected from sodium glycocholate and / or sodium deoxycholate; The volume of the cholate solution is 12.5 - 25% of the total volume after volume adjustment in step 3); The pH is adjusted using a pH regulator, which is selected from at least one of acidic pH regulators and basic pH regulators. Among them, the acidic pH regulator is selected from any one or more of citric acid, hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, oxalic acid, and malic acid in any proportion combination, and the basic pH regulator is selected from any one or more of sodium hydroxide and sodium carbonate in any proportion combination; After dissolving cholic acid or its salt, it is placed in a protective gas. The protective gas used is any one of nitrogen, helium, and argon. The time for filling the protective gas is 0.5 - 2 hours; the dissolved oxygen residue range of the cholate solution is controlled at 0 - 5 mg / L, and the residual headspace oxygen content is controlled at 0 - 5%.

5. The preparation method of the aprepitant micelle composition according to any one of claims 1-4, characterized in that, The phospholipid is selected from one of soybean phospholipid, egg yolk phospholipid, hydrogenated soybean phospholipid, and hydrogenated egg yolk phospholipid; In step 2), the volume ratio of aprepitant to the final volume in step 3) is 1 - 10 mg:1 mL; In step 2), the mass ratio of aprepitant to phospholipid is 1:10 - 15; in step 2), the mass ratio of phospholipid to cholate in the cholate solution is 1:0.5 - 1.5; In step 3), the stirring rate is 200 - 400 rpm, and the filtration pore size is 0.22 μm.

6. The preparation method of the aprepitant micelle composition according to claim 5, characterized in that, The steps of freeze - drying are as follows: (1) Pre - freezing: The semi - stoppered sample is placed in a freeze - dryer, the circulating pump partition is turned on for refrigeration, and it is set that the partition temperature reaches - 30°C to - 50°C in 1 h and is kept warm for 2 - 4 h; (2) Sublimation drying: The inside of the freeze - dryer is evacuated and maintained at 10 - 30 Pa, and the sample is heated to - 20°C to - 10°C at a rate of 0.5°C / min and kept warm for 20 - 25 h; (3) Desorption drying: The inside of the freeze - dryer is evacuated and maintained at 10 - 30 Pa, and the sample is heated to 20°C to 30°C at a rate of 0.5°C / min and kept warm for 2 - 4 h.

7. An aprepitant micelle composition obtained by the preparation method according to any one of claims 1 - 6.

8. An aprepitant micelle composition injection solution obtained by re - dissolving the aprepitant micelle composition according to claim 7 with water for injection.

9. The aprepitant micelle composition injection according to claim 8, wherein The total volume of the aprepitant micelle composition injection solution is 1 mL to 20 mL, the concentration of aprepitant is 1 - 10 mg / mL, the pH is 6.0 - 7.5, the average particle size of the micelles in the aprepitant micelle composition injection solution is 2 - 10 nm, the Zeta potential is - 20 to - 60 mV, and the light transmittance of the aprepitant micelle composition injection solution is > 90%.

10. The aprepitant micelle composition injection according to claim 8, wherein After re - dissolving and making up the volume of the aprepitant micelle composition with water for injection, a protective gas is filled, it is sub - packed into vials, stoppered and crimped, and heat - sterilized at 121°C for 15 min; After re - dissolving and making up the volume and filling with a protective gas, the protective gas used is any one of nitrogen, helium, and argon. The time for filling the protective gas is 0.5 - 2 hours; the dissolved oxygen residue range of the cholate solution is controlled at 0 - 5 mg / L, and the residual headspace oxygen content is controlled at 0 - 5%.

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