Pharmaceutical composition, aprepitant injection solution and freeze-dried powder injection

Abstract

The present invention discloses a pharmaceutical composition, an aprepitant injection solution and an aprepitant lyophilized powder injection solution. The pharmaceutical composition includes aprepitant, a primary stabilizer and a secondary stabilizer, the primary stabilizer includes sodium deoxycholate, and the secondary stabilizer includes povidone. The aprepitant injection solution provided by the present invention can be administered by injection, and the formulation can greatly reduce the amount of auxiliary agents used, and is less irritating to the injection site when administered to patients, less likely to cause allergic reactions, safer, has good formulation stability, and can be stored and transported at room temperature, greatly reducing production, storage and transport costs.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition, and further to an aprepitant injection solution and an aprepitant lyophilized powder injection solution. [Background technology]

[0002] Aprepitant is an NK1 receptor antagonist developed and marketed by MERCK, and was approved for sale in oral capsule form by the US FDA in 2003 under the trade name Emend. In clinical practice, it is mainly used to prevent acute and delayed nausea and vomiting that occurs during the initial and repeated treatment courses of highly emetogenic antitumor chemotherapy. Aprepitant is always used in combination with glucocorticoids and a type of 5-HT3 antagonist, and is applied to patients aged 6 months or older. It is used for 1. acute and delayed nausea and vomiting associated with the initial and repeated treatment courses of highly emetogenic antitumor chemotherapy (HEC), including large doses of cisplatin, and 2. nausea and vomiting associated with the initial and repeated treatment courses of moderately emetogenic antitumor chemotherapy (MEC). Its chemical structure is as follows: JPEG0007606633000001.jpg4572

[0003] Aprepitant is a selective, high-affinity antagonist of the human substance P neurokinin 1 (NK1) receptor. It has low or no affinity for 5-hydroxytryptamine receptor 3 (5-HT3), dopamine receptors, and glucocorticoid receptors, which are the action targets of other existing drugs to treat chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). Preclinical studies have shown that NK1 receptor antagonists can suppress emesis caused by cytotoxic chemotherapy drugs, such as cisplatin. Preclinical and human positron emission tomography (PET) studies of aprepitant have shown that aprepitant penetrates the blood-brain barrier and occupies NK1 receptors in the brain. Aprepitant suppresses acute and delayed emesis caused by cisplatin and enhances the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone against cisplatin-induced emesis.

[0004] Aprepitant drug substance is a white to off-white crystalline solid with a molecular weight of 534.43, and is poorly soluble in water. According to the Japan IF file information for Aprepitant capsules, the solubility of Aprepitant in water at room temperature is 0.00055 mg / mL, and it is slightly soluble in ethanol, isopropyl acetate, and acetonitrile. It belongs to the category of drugs with low solubility and low permeability, and is classified as Class IV in biopharmaceuticals. Due to its poor water solubility, the drug dissolution is slow and incomplete, resulting in low bioavailability. MSD has used nanocrystal technology to improve the bioavailability of drugs, but the absolute bioavailability of the developed oral capsules is only 60% to 65%, and the maximum blood concentration (C max ), which is disadvantageous for the rapid effect before or after chemotherapy in patients, and seriously limits the clinical application scenarios.

[0005] The injection has obvious clinical advantages when administered before chemotherapy, and its high bioavailability and rapid action after administration can benefit cancer chemotherapy patients to the maximum extent, and can further improve the therapeutic effect of the drug. However, aprepitant is hardly soluble in water (0.00055mg / mL), and it is difficult to develop a true solution type of injection, and its poor solubility is an obstacle that formulators find difficult to overcome.

[0006] Due to the poor solubility of aprepitant, many difficulties must be overcome in the development of the injection. After intensive research, in 2010, MERCK developed fosaprepitant meglumine as a prodrug for aprepitantone to improve solubility, and it was finally developed as a freeze-dried powder injection, with the product name EMEND (fosaprepitant meglumine for injection). However, the previous prodrug injection has many defects. 1) The stability of the prodrug is extremely poor and it is easily converted to aprepitant, so it is necessary to store the drug substance under -20°C conditions; 2) The stability of the freeze-dried fosaprepitant meglumine injection is still poor and needs to be stored at 2-8°C; 3) Fosaprepitant meglumine has poor stability, which results in higher costs for the production, storage, and transportation of the drug substance and the production, transportation, and storage of the formulation compared to injections produced and stored at normal room temperature, which increases the medication cost for patients. Both of these have resulted in a huge waste of medical resources; (4) the formulation of fosaprepitant meglumine injection contains a large amount of Tween 80 (58% of the active ingredient used), which often causes severe pain at the injection site for patients when used; and clinical data shows that the incidence of adverse reactions at the injection site of fosaprepitant meglumine (3.0%) is higher than that of the oral aprepitant control group (0.5%); (5) fosaprepitant meglumine is easily converted to aprepitant in water and prone to precipitation, raising safety concerns when used by patients.

[0007] HERON has attempted to develop aprepitant as a lipid emulsion injection, and after many years of efforts, it finally succeeded in the development, and was approved by the US FDA in 2017. Aprepitant lipid emulsion injection is on the market, with the trade name CINVANTI and a specification of 130 mg / 18 mL. This formulation contains lecithin 2.6 g, ethanol 0.5 g, sodium oleate 0.1 g, soybean oil 1.7 g, and sucrose 1 g. This injection still has many deficiencies. 1) The formula contains a large amount of soybean oil and lecithin, and the amount of adjuvants used in the preparation is 5.9g, which is 45 times the active ingredient. The large amount of adjuvants makes it easy for allergic reactions to occur after intravenous injection of the drug, which is harmful to the patient's health; 2) sodium oleate has a certain irritation and is prone to cause pain at the administration site after intravenous administration; 3) the emulsion is a thermodynamically unstable system, and the preparation still needs to be stored at 2-8°C; 4) the preparation also has a large volume of medicinal solution, which brings certain inconveniences to clinical use and is inconvenient for rapid use.

[0008] In order to address the deficiencies of currently available products, improve safety for patients, reduce production, storage and transportation costs, facilitate clinical use, and save medical costs, there is still a need to develop injectables that are safe (such as less irritation at the administration site and less likely to cause allergic reactions), have a small pharmaceutical volume, are convenient to use, and can be stored and transported at room temperature. Summary of the Invention

[0009] In response to the problems of the prior art, the present invention attempts to directly develop aprepitant into a suspension injection using nanocrystal formulation technology. The development of nanocrystal suspension injections is difficult, and the preparations that have been successfully marketed are often used in the development of long-acting drugs in the field of psychiatric disorders, for example, the already marketed drugs aripiprazole sustained release intramuscular injection and paliperidone palmitate injection are both intramuscular injection preparations. The development of nanocrystal suspension injections that can be injected intravenously is even more difficult, on the one hand, limited by the small number of surfactants for intravenous injection, on the other hand, limited by the physicochemical properties of the drug substance and the complicated formulation process, and in the third aspect, nanocrystal suspension injections have strict requirements for the particle size of the particles. In order to achieve the object of the present invention, the following measures are adopted.

[0010] In a first aspect, the present invention provides a pharmaceutical composition comprising aprepitant, a primary stabilizer, and a secondary stabilizer, the primary stabilizer comprising sodium deoxycholate, and the secondary stabilizer comprising povidone. The present invention employs a combination of sodium deoxycholate and povidone as stabilizers, thereby providing a nanocrystalline suspension having excellent stability and a small particle size, which can be used for injection.

[0011] In some embodiments, the mass ratio of the primary stabilizer to the secondary stabilizer is 1:1 to 8. In some embodiments, the mass ratio of the primary stabilizer to the secondary stabilizer is 1:1 to 7, preferably 1:2 to 7. In some examples, the mass ratio of the primary stabilizer to the secondary stabilizer is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5.5, 1:6, 1:6.5, or 1:7.

[0012] In some embodiments, the ratio of the mass of the sodium deoxycholate to the mass of the povidone is 1:1-8. In some embodiments, the ratio of the mass of the sodium deoxycholate to the mass of the povidone is 1:1-7, preferably 1:2-7. The inventors have found that when the mass ratio of the sodium deoxycholate to the povidone is within this range, a nanocrystal formulation with a small particle size can be obtained and the stability of the nanocrystal suspension can be significantly improved. In some embodiments, the ratio of the mass of the sodium deoxycholate to the mass of the povidone is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5.5, 1:6, 1:6.5, or 1:7.

[0013] In some embodiments, the ratio of the mass of the aprepitant to the total mass of the primary stabilizer and the secondary stabilizer is 1:0.05-3.7. In some embodiments, the ratio of the mass of the aprepitant to the total mass of the primary stabilizer and the secondary stabilizer is 1:0.1-2. In some embodiments, the ratio of the mass of aprepitant to the combined mass of the primary stabilizer and the secondary stabilizer is 1:0.065, 1:0.08, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, etc.

[0014] In some embodiments, the ratio of the mass of the aprepitant to the total mass of the sodium deoxycholate and povidone is 1:0.05-3.7. In some embodiments, the ratio of the mass of the aprepitant to the total mass of the sodium deoxycholate and povidone is 1:0.1-2. In some embodiments, the ratio of the weight of the aprepitant to the combined weight of the sodium deoxycholate and the povidone is 1:0.065, 1:0.08, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, etc.

[0015] In some embodiments, the povidone has a molecular weight of less than 45000, preferably a molecular weight of less than 40000, preferably a molecular weight of less than 35000, preferably a molecular weight of less than 30000, preferably a molecular weight of less than 25000, preferably a molecular weight of less than 20000, preferably a molecular weight of less than 15000, preferably a molecular weight of less than 10000, preferably a molecular weight of less than 8000, more preferably a molecular weight of less than 4000. In some embodiments, the povidone is one or more selected from povidone K30, povidone K18, povidone K17, povidone K15, and povidone K12.

[0016] In some embodiments, the primary stabilizer is sodium deoxycholate, hi other embodiments, the primary stabilizer further comprises one or two of Tween 80 and Tween 20.

[0017] In some embodiments, the secondary stabilizer is povidone.

[0018] In some embodiments, the pharmaceutical composition further comprises one or more of a pH adjusting agent, an osmolality adjusting agent, and a lyoprotectant. Preferably, the pH adjusting agent is one or more selected from hydrochloric acid, sodium hydroxide, citric acid, citrate salts, tartaric acid, tartrate salts, acetic acid, lactic acid, phosphoric acid, and phosphate salts (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.), preferably, the osmolality adjusting agent is one or more selected from sodium chloride, glucose, mannitol, and glycerin, and preferably, the lyoprotectant is one or more selected from sucrose, lactose, mannitol, sorbitol, polyethylene glycol, and trehalose.

[0019] In some embodiments, the pharmaceutical composition is in the form of a suspension. Preferably, the pH value of the suspension is 6.0-8.5, 6.0-8.0, or 6.5-8.0, preferably 6.5-8.0, most preferably 7.0-8.0. In some embodiments, the D50 of aprepitant in the suspension is less than 200 nm, preferably less than 120 nm, preferably less than 100 nm, for example less than 80 nm. A smaller particle size is advantageous for product stability and for improving dissolution rate.

[0020] In some embodiments, aprepitant is in a crystalline form, including crystalline form I, crystalline form II (crystalline form I, crystalline form II disclosed in CN98806703.X), amorphous, or a mixture thereof.

[0021] In some embodiments, the pharmaceutical composition comprises, by weight, 1 part aprepitant, 0.04 to 0.45 parts (e.g., 0.05, 0.06, 0.07, 0.08, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45) of a primary stabilizer, and 0.04 to 3.2 parts (e.g., 0.05, 0.06, 0.07, 0.08, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.5, 0.55, 0.6, 0.65) of a secondary stabilizer. , 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.) and 0.001 to 0.04 parts of a pH adjuster (for example, 0.001, 0.002, 0.003, 0.004, 0.005, 0.01, 0.012, 0.015, 0.02, 0.03, etc.), or consisting of these components.

[0022] In some embodiments, the pharmaceutical composition comprises, by weight, 1 part aprepitant, 0.04-0.45 (e.g., 0.05, 0.06, 0.07, 0.08, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45) parts of a primary stabilizer, and 0.04-3.2 (e.g., 0.05, 0.06, 0.07, 0.08, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.5, 0.55, 0.6, 0.65, 0.70) parts of a secondary stabilizer. , 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.) and 0.005 to 0.05 parts of an osmotic pressure adjuster (for example, 0.001, 0.002, 0.003, 0.004, 0.005, 0.01, 0.012, 0.015, 0.02, 0.03, 0.04, 0.05, etc.), or consisting of these components.

[0023] In some embodiments, the pharmaceutical composition comprises or consists of, by weight, 1 part aprepitant, 0.04 to 0.45 parts of a primary stabilizer, 0.04 to 3.2 parts of a secondary stabilizer, 0.001 to 0.04 parts of a pH adjuster, and 0.005 to 0.05 parts of an osmolality adjuster.

[0024] In some embodiments, the pharmaceutical composition further comprises water, preferably water for injection.

[0025] In some embodiments, the pharmaceutical composition comprises or consists of the following components, by weight: 1 part aprepitant, 0.04 to 0.45 parts of a primary stabilizer, 0.04 to 3.2 parts of a secondary stabilizer, 0.001 to 0.04 parts of a pH adjuster, 0.005 to 0.05 parts of an osmolality adjuster, and water.

[0026] In some embodiments, the pharmaceutical composition comprises or consists of, by weight, 1 part aprepitant, 0.04-0.42 parts of a primary stabilizer, 0.08-2.9 parts of a secondary stabilizer, 0.001-0.04 parts of a pH adjuster, 0.005-0.05 parts of an osmolality adjuster, and water.

[0027] In some embodiments, the pharmaceutical composition comprises or consists of, by weight, 1 part aprepitant, 0.05-0.40 parts of a primary stabilizer, 0.1-2.8 parts of a secondary stabilizer, 0.001-0.04 parts of a pH adjuster, 0.005-0.5 parts of an osmolality adjuster, and water.

[0028] In some embodiments, the pharmaceutical composition contains, by weight, 1 part aprepitant, 0.04-0.45 parts sodium deoxycholate, 0.04-3.2 parts povidone, 0.001-0.04 parts pH adjuster, 0.005-0.05 parts osmolality adjuster, and water.

[0029] In some embodiments, the pharmaceutical composition contains, by weight, 1 part of aprepitant, 0.05-0.38 parts of sodium deoxycholate, 0.1-2.00 parts of povidone, 0.001-0.04 parts of a pH adjuster, and 0.005-0.05 parts of an osmolality adjuster.

[0030] In some embodiments, the pharmaceutical composition contains, by weight, 1 part of aprepitant, 0.06-0.37 parts of sodium deoxycholate, 0.12-1.90 parts of povidone, 0.001-0.04 parts of a pH adjuster, and 0.005-0.05 parts of an osmolality adjuster.

[0031] In some embodiments, the pharmaceutical composition contains, by weight, 1 part aprepitant, 0.06-0.35 parts sodium deoxycholate, 0.12-1.75 parts povidone, 0.001-0.04 parts pH adjuster, and 0.005-0.05 parts osmolality adjuster.

[0032] In a second aspect, the present invention provides a method for preparing a pharmaceutical composition (e.g., a pharmaceutical composition according to the first aspect of the present invention), comprising wet-grinding a primary stabilizer, a secondary stabilizer, optional ingredients and aprepitant, wherein the primary stabilizer comprises sodium deoxycholate, the secondary stabilizer comprises povidone, and the optional ingredients comprise one or more of a pH adjuster and an osmolality adjuster.

[0033] In some embodiments, the polishing media for the wet polishing is zirconia beads and / or polystyrene beads.

[0034] In some embodiments, the wet polishing is performed at a speed of 6.0 m / s to 17.0 m / s.

[0035] In some embodiments, the preparation method comprises: 1) dissolving the first stabilizer and the second stabilizer in water for injection, stirring until completely dissolved, optionally adding the pH adjuster, and adding and dispersing aprepitant uniformly to obtain an initial polishing suspension; (2) putting the polishing medium into the polishing chamber, and putting the initial polishing suspension into the polishing barrel to start polishing at a speed of 6.0 m / s to 17.0 m / s to obtain an aprepitant nanosuspension with a D50 of less than 200 nm; (3) sterile filtering the aprepitant nanosuspension and filling it, preferably into vials or ampoules.

[0036] In a third aspect, the present invention provides an aprepitant injection comprising the pharmaceutical composition according to the first aspect of the present invention.

[0037] The aprepitant injection provided by the present invention is applicable to intravenous injection. The aprepitant injection provided by the present invention significantly reduces the amount of auxiliary agents used and has excellent stability.

[0038] In a fourth aspect, the present invention provides a lyophilized powder injection of aprepitant, comprising a lyophilized powder prepared by lyophilizing the pharmaceutical composition according to the first aspect of the present invention, preferably with the addition of a lyophilization protection agent.

[0039] In some embodiments, by weight, aprepitant is 1 part and the lyoprotectant is 0-3.5 parts. In some embodiments, by weight, aprepitant is 1 part and the lyoprotectant is 0.1-3, 0.15-2, 0.2-1.5, 0.2-1.0, or 0.1-0.5 parts.

[0040] The advancement of the present invention is that aprepitant is formulated into a nanocrystalline suspension injection that can be injected intravenously, which greatly reduces the amount of adjuvant used. The developed formulation is safer, causes less irritation at the injection site when administered to patients, is less likely to cause allergic reactions, has a small pharmaceutical volume, is convenient to use, has good formulation stability, and can be stored and transported at room temperature, significantly reducing production, storage and transportation costs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] In order to clarify the objectives, technical solutions and advantages of the present invention, the present invention will be described in more detail with reference to the following examples. The specific examples described herein are for the purpose of illustrating the present invention, but are not intended to limit the present invention.

[0042] Example 1: Effect of a single surfactant on abrasive particle size

[0043] Aprepitant nanosuspension injections were prepared using different types of surfactants. An appropriate amount of water for injection was added to the container, and the surface stabilizers in Table 1 were added and completely dissolved. Then, the drug substance (aprepitant) was added and stirred until it was uniformly dispersed. In a wet polishing machine, 0.1-0.2 mm yttrium-stabilized zirconia beads, which occupy 80% of the volume of the polishing chamber, were added, and the polishing speed was about 12.1-12.3 m / s. Polishing was performed for 3 h to obtain a polishing suspension. After that, the particle size distribution was examined using a Malvern laser particle size analyzer (Mastersizer 3000), and the D 50 represents the particle size at which the cumulative distribution of particles is 50%, i.e., the volume content of particles smaller than this particle size accounts for 50% of the total particles. The stability of the polishing suspension was initially examined (left at 40°C for 10 days and observed to see whether caking, aggregation or crystal growth occurred in the suspension). The result data is shown in Table 1 below.

[0044] JPEG0007606633000002.jpg120152

[0045] The particle size measurement results show that, except for the formulation containing poloxamer 188, the remaining surface stabilizers can all make the average particle size of the nanocrystal suspension less than 200 nm, among which the solution containing sodium deoxycholate in the formulation has a better polishing effect and the average particle size of the resulting nanosuspension is the smallest, but all of them have the defect of poor stability. The results show that the above surface stabilizers are not effective when used alone in the development of nanocrystal suspension injections.

[0046] Example 2: Considerations regarding the combination of two types of surfactants

[0047] Aprepitant nanosuspension injection was prepared using two kinds of surfactants. As surface stabilizers, povidone K12, povidone K17, poloxamer 188, and sodium oleate were used and polished in combination with sodium deoxycholate. Based on the prescription composition and mixing ratio in Table 2, an appropriate amount of water for injection was added to the container, and the two types of surface stabilizers were added in sequence and stirred until completely dissolved, then the drug substance (aprepitant) was added and stirred until uniformly dispersed, and 0.1-0.2 mm yttrium-stabilized zirconia beads, which occupy 80% of the volume of the polishing chamber, were added, and the polishing speed was about 12.1-12.3 m / s. The particle size distribution of the suspension injection obtained by polishing was examined, and the particle size distribution was examined using a Malvern laser particle size distribution analyzer (Mastersizer 3000), and the D 50 indicates the particle size at which the cumulative distribution of particles is 50%, i.e., the volume content of particles smaller than this particle size accounts for 50% of the total particles. The stability of the polishing suspension was initially examined (left at 40°C for 10 days and observed to see whether caking, aggregation or crystal growth occurred in the suspension). The research results are shown in Table 2.

[0048] JPEG0007606633000003.jpg223138 JPEG0007606633000004.jpg103140

[0049] The above experimental data shows that the average particle size of nanocrystal suspension can be less than 200 nm by using povidone K17 and different concentrations of povidone K12 in combination with sodium deoxycholate. Surprisingly, compared with single sodium deoxycholate and the combination of sodium deoxycholate with other stabilizers, the combination of sodium deoxycholate and povidone can obtain nanosuspension with smaller D50 (less than 150 nm, less than 120 nm, or even less than 100 nm) and good solution stability after grinding. Furthermore, it was found that the solution stability can be further improved when the mass ratio of sodium deoxycholate to povidone is within the range of 1:2-7. As a result, it is shown that the combination of sodium deoxycholate and povidone stabilizers is suitable for the development of nanocrystal suspension injections.

[0050] Example 3: Preparation of aprepitant suspension (wet grinding method)

[0051] Prescription (100 bottles) Aprepitant 13g Sodium deoxycholate 0.85g Povidone K12 3.9g Sodium chloride 0.25g Add water for injection to 500 mL.

[0052] Preparation process: (1) Preparation of initial suspension: 3.9 g of povidone K12, 0.85 g of sodium deoxycholate, and 0.25 g of sodium chloride were dissolved in water for injection and stirred until completely dissolved. 13 g of aprepitant drug substance was added and uniformly dispersed to prepare an initial suspension. (2) 50 ml of yttrium-stabilized polishing beads (polishing media) were placed into the polishing chamber, and the initial suspension was placed into the polishing barrel to start polishing, with a speed of 16 m / s. (3) After polishing for 3 hours, a sample was taken and the average particle size of the suspension was measured to be less than 200 nm, obtaining an aprepitant nanosuspension. (4) The nanosuspension was further diluted with water for injection to approximately 26 mg / mL, sterilized by filtration, and then filled into sterilized vials or ampoules to prepare aprepitant nanosuspension injections.

[0053] Example 4: Preparation of aprepitant suspension for injection (wet grinding method)

[0054] Prescription (100 bottles) Aprepitant 13g Sodium deoxycholate 1.7g Povidone K12 5.85g Adjust the pH to 6.5-7.5 with monosodium citrate or sodium dihydrogen phosphate. Add water for injection to 500 mL.

[0055] Preparation process: (1) Preparation of the polishing suspension: 5.85 g of povidone K12 and 1.7 g of sodium deoxycholate were dissolved in water for injection and stirred until completely dissolved, and the pH value of the solution was adjusted to 6.5-7.5 by adding monosodium citrate or sodium dihydrogen phosphate. 13 g of aprepitant drug substance was added and uniformly dispersed, and then the initial polishing suspension was prepared. (2) 50 mL of yttrium-stabilized polishing beads were placed into the polishing chamber, and the initial polishing suspension was placed into the polishing barrel to start polishing, with a speed of 16 m / s. (3) After polishing for 3 hours, a sample was taken and the average particle size of the suspension was measured to be less than 200 nm, obtaining an aprepitant nanosuspension. (4) The nanosuspension was further diluted with water for injection to approximately 26 mg / mL, sterilized by filtration, and then filled into sterilized vials or ampoules to prepare aprepitant nanosuspension injections.

[0056] Example 5: Preparation of aprepitant suspension freeze-dried powder for injection (wet grinding method)

[0057] Prescription (100 bottles) Aprepitant 13g Sodium deoxycholate 1.70g Povidone K12 7.8g Adjust the pH value to 6.5-7.5 with monosodium citrate. Mannitol 3.9g Add water for injection to 500 mL.

[0058] Preparation process: (1) Preparation of the polishing suspension: 7.8 g of povidone K12, 1.70 g of sodium deoxycholate, and 3.9 g of mannitol were dissolved in water for injection and stirred until completely dissolved. The pH value was adjusted to 6.5-7.5 with monosodium citrate, and 13 g of aprepitant drug substance was added and uniformly dispersed to prepare the initial polishing suspension. (2) 50 ml of yttrium-stabilized polishing beads were placed into the polishing chamber, and the initial polishing suspension was placed into the polishing barrel to start polishing, and the rotation speed was 6 m / s. (3) After polishing for 2 hours, a sample was taken and the average particle size of the suspension was measured to be less than 200 nm, obtaining an aprepitant nanosuspension. (4) The above nanosuspension was further diluted with water for injection to about 26 mg / ml, sterilized and filtered, then filled into a vial, and freeze-dried to obtain aprepitant freeze-dried powder injection. The freeze-drying process is as follows: JPEG0007606633000005.jpg42147

[0059] The appearance of the sample obtained after freeze-drying was a porous white mass that was highly susceptible to redissolution, and the particle size of the nanosuspension after redissolution was unchanged from that before freeze-drying.

[0060] The suspension injection and freeze-dried powder injection prepared using nanocrystal technology have excellent stability, and both the drug substance and the finished product can be stored and transported at room temperature, which can greatly reduce production, storage and transportation costs. Fosaprepitant meglumine drug substance needs to be stored at -20°C, and its finished product needs to be stored at 2-8°C. Therefore, the suspension injection and freeze-dried powder injection of the present invention have a great advantage over fosaprepitant meglumine. Since the finished product of aprepitant fat emulsion injection needs to be stored at 2-8°C, the suspension injection and freeze-dried powder injection of the present invention have better stability than aprepitant fat emulsion injection, which saves warehouse storage, transportation and usage costs in the drug production and distribution process.

[0061] The suspension injection prepared using nanocrystal technology contains less auxiliary agents, and the amount of auxiliary agents used may be 0.05-0.35g / bottle, for example, the amount of auxiliary agents used in Example 3 is 0.05g / bottle, and the amount of auxiliary agents used in Example 4 is 0.14g / bottle. Compared with commercially available aprepitant fat emulsion injections, the amount of auxiliary agents used can be significantly reduced. As shown in Table 3, the amount of auxiliary agents used in the aprepitant fat emulsion injection is 5.9g / bottle.

[0062] JPEG0007606633000006.jpg75152

[0063] Example 6: Stability Observation Results

[0064] The stability of the aprepitant nanosuspension injection prepared in Example 3 and the aprepitant lyophilized powder injection prepared in Example 5 was examined, and both had good physical and chemical stability.

[0065] 1) Stability study of aprepitant nanosuspension injection The stability of aprepitant nanosuspension injection at an accelerated temperature of 40°C for 6 months was investigated and the data are as follows: JPEG0007606633000007.jpg65160

[0066] The stability of the above aprepitant nanosuspension for injection was examined under accelerated conditions for six months. As a result, there was no change in the appearance, particle size, insoluble fine particles, and related substances, which are considered to be important quality attributes of the injection, indicating that the nanosuspension for injection has good stability and can be stored at room temperature.

[0067] 2) Aprepitant nano lyophilized powder for injection The stability of aprepitant nano lyophilized powder injection at accelerated temperature of 60℃ for 5 days, 15 days and 30 days was investigated, and the data are as follows: JPEG0007606633000008.jpg69163

[0068] The stability of the aprepitant nano freeze-dried powder injection was examined at a high temperature of 60°C for 30 days, and the important quality attributes of appearance, particle size, insoluble fine particles, and related substances all remained unchanged, indicating that the nano injection has good stability and can be stored at room temperature.

[0069] Example 7: Study of the effect of different pH adjusters on particle size

[0070] By measuring particle size and properties, the effect of different amounts of pH adjuster on nanocrystal particle size and stability was investigated. The pH adjuster and amount used were changed based on the formulation of Example 4, and the measurement results are as follows: JPEG0007606633000009.jpg117153

[0071] Experimental data showed that by using monosodium citrate or sodium dihydrogen phosphate as pH adjuster, the average particle size of the nanocrystal suspension can be made less than 200 nm, and the solution stability after polishing is good. By adding sodium dihydrogen phosphate as pH adjuster, D 50It has been found that a nanocrystal suspension having a smaller particle size (less than 150 nm, less than 120 nm, or even less than 100 nm) can be obtained, and further, when the weight ratio of aprepitant to a pH adjuster is 1:0.001-0.04, the solution stability can be further improved.

[0072] Example 8: Conclusions of Animal PK Studies

[0073] The in vivo PK of the commercially available fosaprepitant meglumine lyophilized powder injection (EMEND) and the nanosuspension injection prepared in Example 4 were compared.

[0074] Test method: Two groups of male SD rats, 6 rats per group (body weight about 300g) were used. Each rat was administered 0.5ml. The concentrations of fosaprepitant meglumine lyophilized powder injection and the prepared nanosuspension injection were diluted to 1mg / ml. After administration, blood samples were taken at 2, 10, 20, 30, and 40 minutes, and 1, 1.5, 2, 3, 5, 12, and 18 hours, respectively, and the total aprepitant concentration in the blood samples was measured using LC-MS / MS. The results of the animal PK study showed that the nanosuspension injection prepared in Example 4 is equivalent to fosaprepitant meglumine lyophilized powder injection in animal in vivo PK, can equivalently replace fosaprepitant meglumine lyophilized powder injection, and has less irritation at the injection site than the commercially available fosaprepitant meglumine injection and aprepitant fat emulsion injection, making it safer for use in patients.

[0075] Example 9: Comparison of vascular irritation

[0076] We compared commercially available fosaprepitant meglumine lyophilized powder injection (EMEND) with aprepitant lipid emulsion injection (CINVANTI). A: Aprepitant suspension injection prepared in Example 3 B: Aprepitant freeze-dried powder injection prepared in Example 5 C: Fosaprepitant meglumine lyophilized powder for injection (EMEND) D: Aprepitant lipid emulsion injection (CINVANTI)

[0077] Test method: Each group consisted of 5 rabbits, weighing 2.3-2.8 kg. The test drug was intravenously injected into the left ear, and an equal amount of saline was intravenously injected into the right ear as a self-control, with an administration volume of 1 ml / kg (test drug concentration 1 mg / ml). One hour and 24 hours after administration, the irritation at the administration site was observed and scored.

[0078] The next day, the animals were sacrificed, and tissue samples (3-10 mm proximal end and 20-30 mm distal end) were excised from the injection site, fixed in 10% neutral buffered formalin (NBF), and evaluated under a microscope. The tissues were embedded in paraffin blocks, sliced, stained with hematoxylin and eosin, and evaluated under a microscope. Histopathological evaluation was performed on all collected tissues to evaluate the venous endothelial cell loss, inflammatory cell infiltration, etc.

[0079] JPEG0007606633000010.jpg54146

[0080] JPEG0007606633000011.jpg67141

[0081] Test results: 1. Rabbit ear vein vascular irritation results The right ear, as the control group, had no significant reaction after saline injection, and the left ear was injected with the test drug, and the irritation results are shown in the table below. JPEG0007606633000012.jpg50143The above results showed that the self-study groups A and B had low irritation and were superior to the commercially available products fosaprepitant meglumine and aprepitant injection.

[0082] JPEG0007606633000013.jpg52144The above rabbit ear marginal vein vascular irritation results and histopathological test results showed that the nanocrystal injection prepared in the present invention has lower irritation to the injection site than commercially available injections, and is safer for patients to use.

[0083] The technical solution of the present invention is not limited to the above specific embodiments, and any technical modifications made by the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition comprising aprepitant, a primary stabilizer, and a secondary stabilizer, wherein the primary stabilizer comprises sodium deoxycholate, the secondary stabilizer comprises povidone, and the mass ratio of the primary stabilizer to the secondary stabilizer is 1:1-7.

2. The pharmaceutical composition according to claim 1, wherein the mass ratio of the primary stabilizer to the secondary stabilizer is 1:2-7.

3. 2. The pharmaceutical composition of claim 1, wherein a mass ratio of the sodium deoxycholate to the povidone is 1:1-7, and / or a mass ratio of the aprepitant to the total mass of the sodium deoxycholate and povidone is 1:0.05-3.

7.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the molecular weight of the povidone is less than 45,000.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the povidone is one or more types selected from povidone K30, povidone K18, povidone K17, povidone K15 and povidone K12.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the primary stabilizer further comprises one or two of Tween 80 and Tween 20.

7. The pharmaceutical composition of any one of claims 1 to 3, further comprising one or more of a pH adjusting agent and an osmolality adjusting agent.

8. The pH adjuster is one or more selected from hydrochloric acid, sodium hydroxide, citric acid, citrates, tartaric acid, tartrates, acetic acid, lactic acid, phosphoric acid, and phosphates; The pharmaceutical composition according to claim 7, wherein the osmotic pressure adjusting agent is one or more selected from sodium chloride, glucose, mannitol and glycerin.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is in the form of a suspension.

10. The pharmaceutical composition according to claim 9, wherein the pH value of the suspension is 6.0-8.5, and / or the D 50 of aprepitant in the suspension is less than 200 nm.

11. 8. The pharmaceutical composition of claim 7 comprising, in parts by weight, 1 part of aprepitant, 0.04-0.45 parts of a primary stabilizer, 0.04-3.2 parts of a secondary stabilizer, 0.001-0.04 parts of a pH adjuster, 0.005-0.05 parts of an osmolality adjuster, and water.

12. In parts by weight, 1 part of aprepitant, 0.04 to 0.45 parts of sodium deoxycholate, 0.04 to 3.2 parts of povidone, 0.001 to 0.04 parts of a pH adjuster, and 0.005 to 0.05 parts of an osmotic pressure adjuster; or In parts by weight, 1 part of aprepitant, 0.05 to 0.38 parts of sodium deoxycholate, 0.1 to 2.00 parts of povidone, 0.001 to 0.04 parts of a pH adjuster, and 0.005 to 0.05 parts of an osmotic pressure adjuster; or In parts by weight, 1 part of aprepitant, 0.06-0.37 parts of sodium deoxycholate, 0.12-1.90 parts of povidone, 0.001-0.04 parts of a pH adjuster, and 0.005-0.05 parts of an osmotic pressure adjuster; or 8. The pharmaceutical composition of claim 7 comprising, in parts by weight, 1 part of aprepitant, 0.06-0.35 parts of sodium deoxycholate, 0.12-1.75 parts of povidone, 0.001-0.04 parts of a pH adjuster, and 0.005-0.05 parts of an osmotic pressure adjuster.

13. An aprepitant injection comprising the pharmaceutical composition according to any one of claims 1 to 3.

14. (1) dissolving the first stabilizer and the second stabilizer in water for injection, stirring until completely dissolved, optionally adding a pH adjuster, and adding aprepitant and dispersing it uniformly to obtain an initial polishing suspension; (2) Put the polishing medium into the polishing chamber, put the initial polishing suspension into the polishing barrel, and start polishing at a speed of 6.0 m / s to 17.0 m / s. 50 obtaining an aprepitant nanosuspension having a particle size of less than 200 nm; (3) filtering the aprepitant nanosuspension by sterilization and then filling the suspension into vials or ampoules.

15. 15. The method of claim 14, wherein the polishing media is zirconia beads and / or polystyrene beads.

16. An aprepitant lyophilized powder injection preparation comprising a lyophilized powder prepared by adding a lyophilization protective agent to the pharmaceutical composition according to any one of claims 1 to 3 and lyophilizing the composition.

17. The aprepitant lyophilized powder injection of claim 16, wherein the lyoprotectant is one or more selected from the group consisting of sucrose, lactose, mannitol, sorbitol, polyethylene glycol, and trehalose.

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