Pharmaceutical compositions and aripiprazole injection and lyophilized powder injection

Abstract

The application discloses a pharmaceutical composition, an aprepitant injection and an aprepitant freeze-dried powder injection. The pharmaceutical composition comprises aprepitant, a primary stabilizer and a secondary stabilizer, wherein the primary stabilizer comprises sodium deoxycholate, and the secondary stabilizer comprises povidone. The aprepitant injection provided by the application can be injected for administration, the dosage of auxiliary materials is greatly reduced, the injection site is less irritating when used by patients, and the aprepitant injection is less likely to cause hypersensitivity reaction and is safer; the preparation has good stability, can be stored and transported at room temperature, and greatly reduces the production, storage and transportation costs.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition, and also to an aprepitant injection and an aprepitant lyophilized powder injection. Background Technology

[0002] Aprepitant is an NK1 receptor antagonist developed and marketed by Merck. It was approved by the FDA in 2003 for oral capsule form under the brand name Emend. Clinically, it is primarily used to prevent acute and delayed nausea and vomiting during initial and repeated courses of highly emetogenic chemotherapy for cancer. Aprepitant is often used in combination with glucocorticoids and a 5-HT3 antagonist. It is indicated for patients older than 6 months for: 1. Acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic chemotherapy (HEC), including high-dose cisplatin; 2. Nausea and vomiting associated with initial and repeated courses of moderately emetogenic chemotherapy (MEC). Its chemical structure is:

[0003]

[0004] Aprepitant is a selective, high-affinity antagonist of the human substance P neurokinin 1 (NK1) receptor. It exhibits low or no affinity for the targets of other existing drugs used to treat chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV), namely serotonin receptor 3 (5-HT3), dopamine receptors, and glucocorticoid receptors. Preclinical studies have shown that NK1 receptor antagonists can inhibit vomiting induced by cytotoxic chemotherapy drugs such as cisplatin. Preclinical and human positron emission tomography (PET) studies of aprepitant have demonstrated that it can cross the blood-brain barrier and occupy NK1 receptors in the brain. Aprepitant inhibits both acute and delayed cisplatin-induced vomiting and enhances the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone against cisplatin-induced vomiting.

[0005] Aprepitant active pharmaceutical ingredient (API) is a white to off-white crystalline solid with a molecular weight of 534.43, and is poorly soluble in water. According to the Japanese IF document for aprepitant capsules, its solubility in water at room temperature is 0.00055 mg / mL, and it is slightly soluble in ethanol, isopropyl acetate, and acetonitrile. It is classified as a drug with low solubility and low permeability, belonging to category IV in biopharmaceutics. This poor water solubility results in slow and incomplete dissolution, leading to low bioavailability. Merck has used nanocrystal technology to improve bioavailability, but its oral capsules only have an absolute bioavailability of 60% to 65%, and it takes approximately 4 hours to reach maximum plasma concentration (C60). max This is not conducive to patients taking rapid action before or after chemotherapy, which severely limits its clinical application.

[0006] Injectable formulations offer significant clinical advantages when administered before chemotherapy. Their high bioavailability and rapid onset of action maximize benefits for cancer patients undergoing chemotherapy, potentially enhancing drug efficacy. However, aprepitant is virtually insoluble in water (0.00055 mg / mL), making it difficult to dissolve and develop into a true solution-type conventional injectable formulation. This poor solubility presents a formidable obstacle for pharmaceutical engineers.

[0007] Due to aprepitant's poor solubility, developing it into an injectable formulation presented numerous challenges. After arduous efforts, in 2010, MERCK developed aprepitant into the prodrug fosapitant meglumine to improve solubility, ultimately creating a lyophilized powder for injection, marketed as EMEND (fosapitant meglumine for injection). However, the previous injectable form of fosapitant had several drawbacks: 1) The prodrug had poor stability and was easily converted to aprepitant, requiring storage of the raw material at -20℃; 2) Even after freeze-drying, the fosapitant-meglumine injection still had poor stability and needed to be stored at 2-8℃; 3) The poor stability of fosapitant-meglumine resulted in higher costs for the production, storage, and transportation of the raw material and the preparation compared to ordinary injectables that could be produced and stored at room temperature, leading to increased medication costs for patients and a huge waste of social medical resources; 4) The fosapitant-meglumine injection formulation contained a large amount of Tween 80 (58% of the active ingredient), which often caused severe pain at the injection site. Clinical data showed that the incidence of adverse reactions at the injection site of fosapitant-meglumine (3.0%) was higher than that of the oral aprepitant control group (0.5%); 5) Fosapitant-meglumine was easily converted to aprepitant and precipitated in water, posing a safety risk to patients.

[0008] HERON Corporation attempted to develop aprepitant into a fat emulsion injection. After years of effort, they finally succeeded, and in 2017, the US FDA approved aprepitant fat emulsion injection for marketing under the brand name CINVANTI, with a strength of 130mg / 18mL. This formulation contains 2.6g of lecithin, 0.5g of ethanol, 0.1g of sodium oleate, 1.7g of soybean oil, and 1g of sucrose. This injection still has several drawbacks: 1) The formulation contains large amounts of soybean oil and lecithin, with excipients totaling 5.9g, 45 times the amount of the active ingredient. This large amount of excipients can easily cause hypersensitivity reactions after intravenous injection, endangering patient health; 2) Sodium oleate has a certain degree of irritation, and intravenous administration can easily cause symptoms such as pain at the administration site; 3) Emulsions are thermodynamically unstable systems, and this formulation still needs to be stored at 2–8°C; 4) In addition, the large volume of this formulation causes some inconvenience in clinical use, making it less convenient and quick to administer.

[0009] In response to the shortcomings of existing products, there is still a need to develop an injectable drug with good safety (low irritation at the administration site, low risk of hypersensitivity reactions, etc.), small size, convenient use, and room temperature storage and transportation, in order to improve patient safety, reduce production, storage and transportation costs, facilitate clinical use, and save medical costs. Summary of the Invention

[0010] To address the problems existing in current technologies, this invention attempts to directly develop aprepitant into a suspension injection using nanocrystalline formulation technology. Developing nanocrystalline suspension injections is challenging; most successfully marketed formulations are used for developing long-acting drugs for mental illnesses, such as the marketed long-acting intramuscular injection of aripiprazole and paliperidone palmitate injection, both of which are intramuscular injections. Developing an intravenously injectable nanocrystalline suspension injection is even more difficult, firstly due to the limited variety of surfactants suitable for intravenous injection, secondly due to the physicochemical properties of the active pharmaceutical ingredient and the complex formulation process, and thirdly due to the stringent requirements on particle size for nanocrystalline suspension injections. To achieve the objectives of this invention, the following technical solution is adopted.

[0011] In a first aspect, the present invention provides a pharmaceutical composition comprising aprepitant, a primary stabilizer, and a secondary stabilizer, wherein the primary stabilizer comprises sodium deoxycholate, and the secondary stabilizer comprises povidone. The present invention, by employing a combination of sodium deoxycholate and povidone as stabilizers, can produce a nanocrystalline suspension with good stability and small particle size suitable for injection.

[0012] 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 embodiments, 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.

[0013] In some embodiments, the mass ratio of sodium deoxycholate to povidone is 1:1 to 8. In some embodiments, the mass ratio of sodium deoxycholate to povidone is 1:1 to 7, preferably 1:2 to 7. The inventors have found that when the mass ratio of sodium deoxycholate to povidone is within this range, nanocrystalline formulations with smaller particle sizes can be prepared, and the stability of the nanocrystalline suspension can be greatly improved. In some embodiments, the mass ratio of sodium deoxycholate to 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.

[0014] In some embodiments, the mass ratio of aprepitant to the total mass of the primary stabilizer and the secondary stabilizer is 1:0.05 to 3.7. In some embodiments, the mass ratio of aprepitant to the total mass of the primary stabilizer and the secondary stabilizer is 1:0.1 to 2. In some embodiments, the mass ratio of aprepitant to the total 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.

[0015] In some embodiments, the mass ratio of aprepitant to the total mass of sodium deoxycholate and povidone is 1:0.05 to 3.7. In some embodiments, the mass ratio of aprepitant to the total mass of sodium deoxycholate and povidone is 1:0.1 to 2. In some embodiments, the mass ratio of aprepitant to the total mass of sodium deoxycholate and 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.

[0016] In some embodiments, the polyvinyl alcohol has a molecular weight of less than 45,000, preferably less than 40,000, more preferably less than 35,000, more preferably less than 30,000, more preferably less than 25,000, more preferably less than 20,000, more preferably less than 15,000, more preferably less than 10,000, more preferably less than 8,000, and even more preferably less than 4,000. In some embodiments, the polyvinyl alcohol is selected from one or more of polyvinyl alcohol K30, polyvinyl alcohol K18, polyvinyl alcohol K17, polyvinyl alcohol K15, and polyvinyl alcohol K12.

[0017] In some embodiments, the primary stabilizer is sodium deoxycholate. In other embodiments, the primary stabilizer further includes one or both of Tween 80 and Tween 20.

[0018] In some embodiments, the secondary stabilizer is povidone.

[0019] In some embodiments, the pharmaceutical composition further includes one or more of a pH adjuster, an osmotic pressure regulator, and a lyophilization protectant. Preferably, the pH adjuster is selected from one or more of hydrochloric acid, sodium hydroxide, citric acid, citrate, tartaric acid, tartrate, acetic acid, lactic acid, phosphoric acid, and phosphates (such as sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.); preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, mannitol, and glycerol; preferably, the lyophilization protectant is selected from one or more of sucrose, lactose, mannitol, sorbitol, polyethylene glycol, and trehalose.

[0020] In some embodiments, the pharmaceutical composition is in suspension form. Preferably, the pH of the suspension is 6.0–8.5, 6.0–8.0, or 6.5–8.0, more preferably 6.5–8.0, and 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, more preferably less than 100 nm, for example less than 80 nm. Smaller particle size is more conducive to product stability and also helps to improve the dissolution rate.

[0021] In some embodiments, aprepitant is in crystalline form, including crystal form I, crystal form II (crystal form I and crystal form II disclosed in CN98806703.X), amorphous form, or a mixture thereof.

[0022] In some embodiments, the pharmaceutical composition comprises or consists of the following components: 1 part by weight of 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) of a primary stabilizer. Secondary stabilizers in the amounts of 0.6, 0.65, 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.; pH adjusters in the amounts of 0.001 to 0.04 parts (e.g., 0.001, 0.002, 0.003, 0.004, 0.005, 0.01, 0.012, 0.015, 0.02, 0.03, etc.).

[0023] In some embodiments, the pharmaceutical composition comprises or consists of the following components: 1 part by weight of aprepitant; 0.04 to 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 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, ... Secondary stabilizers in amounts of 0.65, 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 osmotic pressure regulators in amounts of 0.005 to 0.05 parts (e.g., 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.).

[0024] In some embodiments, the pharmaceutical composition comprises or consists of the following components: 1 part by weight of aprepitant; 0.04 to 0.45 parts by weight of a primary stabilizer; 0.04 to 3.2 parts by weight of a secondary stabilizer; 0.001 to 0.04 parts by weight of a pH adjuster; and 0.005 to 0.05 parts by weight of an osmotic pressure adjuster.

[0025] In some embodiments, the pharmaceutical composition further includes water, preferably water for injection.

[0026] In some embodiments, the pharmaceutical composition comprises or consists of the following components: 1 part by weight of aprepitant; 0.04 to 0.45 parts by weight of a primary stabilizer; 0.04 to 3.2 parts by weight of a secondary stabilizer; 0.001 to 0.04 parts by weight of a pH adjuster; 0.005 to 0.05 parts by weight of an osmotic pressure adjuster; and water.

[0027] In some embodiments, the pharmaceutical composition comprises or consists of the following components: 1 part by weight of aprepitant; 0.04 to 0.42 parts by weight of a primary stabilizer; 0.08 to 2.9 parts by weight of a secondary stabilizer; 0.001 to 0.04 parts by weight of a pH adjuster; 0.005 to 0.05 parts by weight of an osmotic pressure adjuster; and water.

[0028] In some embodiments, the pharmaceutical composition comprises or consists of the following components: 1 part by weight of aprepitant; 0.05 to 0.40 parts by weight of a primary stabilizer; 0.1 to 2.8 parts by weight of a secondary stabilizer; 0.001 to 0.04 parts by weight of a pH adjuster; 0.005 to 0.5 parts by weight of an osmotic pressure adjuster; and water.

[0029] In some embodiments, the pharmaceutical composition comprises, by weight, 1 part aprepitant; 0.04 to 0.45 parts sodium deoxycholate; 0.04 to 3.2 parts povidone; 0.001 to 0.04 parts a pH adjuster; and 0.005 to 0.05 parts an osmotic pressure adjuster; and water.

[0030] In some embodiments, the pharmaceutical composition comprises, by weight, 1 part aprepitant; 0.05 to 0.38 parts sodium deoxycholate; 0.1 to 2.00 parts povidone; 0.001 to 0.04 parts a pH adjuster; and 0.005 to 0.05 parts an osmotic pressure adjuster.

[0031] In some embodiments, the pharmaceutical composition comprises, by weight, 1 part aprepitant; 0.06 to 0.37 parts sodium deoxycholate; 0.12 to 1.90 parts povidone; 0.001 to 0.04 parts a pH adjuster; and 0.005 to 0.05 parts an osmotic pressure adjuster.

[0032] In some embodiments, the pharmaceutical composition comprises, by weight, 1 part aprepitant; 0.06 to 0.35 parts sodium deoxycholate; 0.12 to 1.75 parts povidone; 0.001 to 0.04 parts a pH adjuster; and 0.005 to 0.05 parts an osmotic pressure adjuster.

[0033] In a second aspect, the present invention provides a method for preparing a pharmaceutical composition (e.g., the pharmaceutical composition described in the first aspect of the present invention), the method comprising wet milling a primary stabilizer, a secondary stabilizer, optional components, and aprepitant, wherein the primary stabilizer comprises sodium deoxycholate, the secondary stabilizer comprises povidone, and the optional components comprise one or more of a pH adjuster and an osmotic pressure adjuster.

[0034] In some embodiments, the abrasive media for the wet grinding process are zirconia beads and / or polystyrene beads.

[0035] In some embodiments, the wet grinding is performed at a speed of 6.0 m / s to 17.0 m / s.

[0036] In some embodiments, the preparation method includes the following steps:

[0037] 1) Dissolve the primary stabilizer and the secondary stabilizer in water for injection, stir until completely dissolved, optionally add the pH adjuster, add aprepitant and disperse evenly to form an initial grinding suspension;

[0038] (2) Add the grinding media into the grinding chamber, add the initial grinding suspension into the grinding cylinder and start grinding at a speed of 6.0 m / s to 17.0 m / s; grind to obtain aprepitant nano suspension with D50 less than 200 nm;

[0039] (3) The aprepitant nano suspension is sterilized and filtered before being filled into vials or ampoules.

[0040] In a third aspect, the present invention provides an aprepitant injection comprising the pharmaceutical composition described in the first aspect of the present invention.

[0041] The aprepitant injection provided by this invention is suitable for intravenous injection. The aprepitant injection provided by this invention significantly reduces the amount of excipients required and exhibits good stability.

[0042] In a fourth aspect, the present invention provides an aprepitant lyophilized powder injection, comprising a lyophilized powder prepared by freeze-drying the pharmaceutical composition described in the first aspect of the present invention, preferably with the addition of a lyophilization protectant.

[0043] In some embodiments, aprepitant is 1 part by weight, and the lyophilization protectant is 0 to 3.5 parts by weight. In some embodiments, aprepitant is 1 part by weight, and the lyophilization protectant is 0.1 to 3, 0.15 to 2, 0.2 to 1.5, 0.2 to 1.0, or 0.1 to 0.5 parts by weight.

[0044] This invention innovatively prepares aprepitant into an intravenously injectable nanocrystalline suspension. This formulation significantly reduces the amount of excipients required. The developed formulation causes less irritation at the injection site and is less likely to cause hypersensitivity reactions, making it safer for patients. The drug is small in size and easy to use. The formulation has good stability and can be stored and transported at room temperature, which can significantly reduce production, storage and transportation costs. Detailed Implementation

[0045] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0046] Example 1: Effect of a single surfactant on grinding particle size

[0047] Aprepitant nanosuspension injection was prepared using different types of surfactants. An appropriate amount of water for injection was added to a container, followed by the surface stabilizers listed in Table 1, and stirred until completely dissolved. Then, the active pharmaceutical ingredient (aprepitant) was added and stirred until uniformly dispersed. Yttrium-stabilized zirconia beads (0.1–0.2 mm) were added to a wet mill, filling 80% of the milling chamber volume. Milling was carried out at approximately 12.1–12.3 m / s for 3 hours. The resulting suspension was examined using a Malvern laser particle size analyzer (Mastersizer 3000). 50 The particle size representing the 50% cumulative particle distribution is defined as the volume percentage of particles smaller than this size, which is 50% of all particles. The stability of the grinding suspension was also preliminarily investigated (the suspension was placed at 40℃ for 10 days to observe for flocculation, aggregation, or crystal growth). The results are shown in Table 1 below.

[0048] Table 1. Particle size of individual surface stabilizer suspensions

[0049]

[0050] Particle size analysis results showed that, except for poloxamer 188 in the formulation, all other surface stabilizers could reduce the average particle size of the nanocrystalline suspension to less than 200 nm. The solution containing sodium deoxycholate showed better grinding performance, resulting in the smallest average particle size of the nanocrystalline suspension; however, all of them exhibited poor stability. These results indicate that using surface stabilizers alone is ineffective for developing nanocrystalline suspension injections.

[0051] Example 2: Investigating a combination of two surfactants

[0052] Aprepitant nanosuspension injection was prepared using two surfactants. A combination of povidone K12, povidone K17, poloxamer 188, sodium oleate, and sodium deoxycholate was used as a surface stabilizer for grinding. According to the formulation and proportions in Table 2, an appropriate amount of water for injection was added to a container, followed by the addition of the two surface stabilizers, stirring until completely dissolved. Then, the active pharmaceutical ingredient (aprepitant) was added and stirred until uniformly dispersed. 0.1–0.2 mm yttrium-stabilized zirconia beads, occupying 80% of the grinding chamber volume, were added, and grinding was performed at a speed of approximately 12.1–12.3 m / s. The particle size distribution of the resulting suspension was examined using a Malvern laser particle size analyzer (Mastersizer 3000). D50 represents the particle size at which the cumulative distribution of particles reaches 50%, i.e., particles smaller than this size account for 50% of the total particle volume. The stability of the ground suspension was also preliminarily investigated (the suspension was placed at 40°C for 10 days to observe for flocculation, aggregation, or crystal growth). The results are shown in Table 2.

[0053] Table 2 Grinding particle size data for different surface stabilizer combinations

[0054]

[0055]

[0056] The experimental data above show that using povidone K17 and combinations of povidone K12 at different concentrations with sodium deoxycholate can achieve an average particle size of less than 200 nm in nanocrystalline suspensions. Unexpectedly, compared to using sodium deoxycholate alone or in combination with other stabilizers, the combination of sodium deoxycholate and povidone yields nanocrystalline suspensions with even smaller D50 values ​​(less than 150 nm, less than 120 nm, and even less than 100 nm), and the ground solution exhibits good stability. Further investigation revealed that a mass ratio of sodium deoxycholate to povidone of 1:2 to 7 can further improve solution stability. These results indicate that the stabilizer combination of sodium deoxycholate and povidone is suitable for developing nanocrystalline suspension injections.

[0057] Example 3:

[0058] Preparation of aprepitant suspension for injection (wet grinding method)

[0059] Prescription (100 vials)

[0060] Aprepitant 13g

[0061] Sodium deoxycholate 0.85g

[0062] Povidone K12 3.9g

[0063] Sodium chloride 0.25g

[0064] Add water for injection to 500 mL

[0065] Preparation process:

[0066] (1) Preparation of initial suspension: Dissolve 3.9g of povidone K12, 0.85g of sodium deoxycholate and 0.25g of sodium chloride in water for injection and stir until completely dissolved. Add 13g of aprepitant raw material and disperse evenly to obtain the initial suspension.

[0067] (2) Add 50ml of yttrium-stabilized grinding beads (grinding media) into the grinding chamber, add the initial suspension into the grinding cylinder to start grinding at a speed of 16m / s.

[0068] (3) After grinding for 3 hours, the average particle size of the suspension was tested and found to be less than 200 nm, thus obtaining aprepitant nano suspension.

[0069] (4) The nano-suspension is further diluted with water for injection to about 26 mg / mL, sterilized and filtered, and then filled into sterilized vials or ampoules to prepare aprepitant nano-suspension injection.

[0070] Example 4:

[0071] Preparation of aprepitant suspension for injection (wet grinding method)

[0072] Prescription (100 vials)

[0073] Aprepitant 13g

[0074] Sodium deoxycholate 1.7g

[0075] Povidone K12 5.85g

[0076] Adjust the pH to 6.5–7.5 using sodium citrate or sodium dihydrogen phosphate.

[0077] Add water for injection to 500 mL

[0078] Preparation process:

[0079] (1) Preparation of grinding suspension: Dissolve 5.85g of povidone K12 and 1.7g of sodium deoxycholate in water for injection and stir until completely dissolved. Add sodium citrate or sodium dihydrogen phosphate to adjust the pH of the solution to 6.5-7.5. Add 13g of aprepitant raw material and disperse evenly to obtain the initial grinding suspension.

[0080] (2) Add 50 mL of yttrium-stabilized grinding beads into the grinding chamber, add the initial grinding suspension into the grinding cylinder and start grinding at a speed of 16 m / s.

[0081] (3) After grinding for 3 hours, the average particle size of the suspension was tested and found to be less than 200 nm, thus obtaining aprepitant nano suspension.

[0082] (4) The nano-suspension is further diluted with water for injection to about 26 mg / mL, sterilized and filtered, and then filled into sterilized vials or ampoules to prepare aprepitant nano-suspension injection.

[0083] Example 5:

[0084] Preparation of aprepitant suspension lyophilized powder for injection (wet grinding method)

[0085] Prescription (100 vials)

[0086] Aprepitant 13g

[0087] Sodium deoxycholate 1.70g

[0088] Povidone K12 7.8g

[0089] Sodium citrate is used to adjust the pH to 6.5–7.5.

[0090] Mannitol 3.9g

[0091] Add water for injection to 500 mL

[0092] Preparation process:

[0093] (1) Preparation of grinding suspension: Dissolve 7.8g of povidone K12, 1.70g of sodium deoxycholate and 3.9g of mannitol in water for injection and stir until completely dissolved. Adjust the pH to 6.5-7.5 with sodium citrate, add 13g of aprepitant raw material and disperse evenly to obtain the initial grinding suspension.

[0094] (2) Add 50ml of yttrium-stabilized grinding beads into the grinding chamber, add the initial grinding suspension into the grinding cylinder and start grinding at a speed of 6m / s.

[0095] (3) After grinding for 2 hours, the average particle size of the suspension was tested and found to be less than 200 nm, thus obtaining aprepitant nano suspension.

[0096] (4) The above nano-suspension was further diluted with water for injection to approximately 26 mg / ml, sterilized and filtered, then filled into vials, and freeze-dried to obtain aprepitant lyophilized powder for injection. The freeze-drying process is as follows:

[0097]

[0098] The sample obtained after freeze-drying appears as a loose, porous white block that is easily resoluble. After resolvation, the particle size of the nano suspension remains unchanged from that before freeze-drying.

[0099] The suspension injection and lyophilized powder injection prepared using nanocrystal technology exhibit good stability, and both the active pharmaceutical ingredient (API) and the finished product can be stored and transported at room temperature, significantly reducing production, storage, and transportation costs. Fosapitam-Meglumine API requires storage at -20°C, while its finished product requires storage at 2–8°C. Therefore, the suspension injection and lyophilized powder injection of this invention have significant advantages over fosapitam-Meglumine. Aprepitam fat emulsion injection requires storage at 2–8°C; therefore, the suspension injection and lyophilized powder injection of this invention have better stability than aprepitam fat emulsion injection, saving on warehousing, transportation, and usage costs during drug production and distribution.

[0100] The suspension injection prepared using nanocrystal technology contains fewer excipients, with excipient dosage ranging from 0.05 to 0.35 g per vial. For example, the excipient dosage in Example 3 is 0.05 g per vial, and in Example 4 it is 0.14 g per vial. Compared to the already marketed aprepitant fat emulsion injection, this significantly reduces the amount of excipients required. As shown in Table 3, the excipient dosage for aprepitant fat emulsion injection is 5.9 g per vial.

[0101] Table 3. Formulation of marketed aprepitant fat emulsion injection (CINVANTI)

[0102]

[0103]

[0104] Example 6: Stability Test Results

[0105] The stability of the aprepitant nanosuspension injection prepared in Example 3 and the aprepitant lyophilized powder injection prepared in Example 5 were investigated, and both showed good physical and chemical stability.

[0106] 1) Stability study of aprepitant nanosuspension injection

[0107] The stability of aprepitant nanosuspension injection was investigated at accelerated temperature (40°C) for 6 months. The data are as follows:

[0108]

[0109] The stability of the aprepitant nanosuspension injection was investigated under accelerated conditions for 6 months. The results showed that the key quality attributes of the injection, such as appearance, particle size, insoluble particles, and related substances, remained unchanged, indicating that the nanosuspension injection has good stability and can be stored at room temperature.

[0110] 2) Aprepitant nano-lyophilized powder for injection

[0111] The stability of aprepitant nano-lyophilized powder for injection was investigated at accelerated temperature (60°C) for 5, 15, and 30 days. The data are as follows:

[0112]

[0113]

[0114] The stability of the above-mentioned aprepitant nano-lyophilized powder injection was investigated at a high temperature of 60°C for 30 days. The results showed that the key quality attributes, appearance, particle size, insoluble microparticles, and related substances, remained unchanged, indicating that the nano-injection solution has good stability and can be stored at room temperature.

[0115] Example 7: Study on the effect of different pH adjusters on particle size

[0116] The effects of different pH adjuster dosages on nanocrystal particle size and stability were investigated by particle size and property testing. The pH adjuster and dosage were varied according to the formulation in Example 4. The results are as follows:

[0117]

[0118] Experimental data show that using sodium citrate or sodium dihydrogen phosphate as pH adjusters can achieve an average particle size of less than 200 nm in the nanocrystalline suspension, and the solution after grinding exhibits good stability. Adding sodium dihydrogen phosphate as a pH adjuster yields D... 50 Smaller nanocrystal suspensions (less than 150 nm, less than 120 nm, and even less than 100 nm) were further investigated, and it was found that a weight ratio of aprepitant to pH adjuster of 1:0.001 to 0.04 could further improve solution stability.

[0119] Example 8: Conclusion of Animal PK Experiment

[0120] The in vivo pharmacokinetic (PK) results of the commercially available fosapitan meglumine lyophilized powder injection (EMEND) and the nano-suspension injection prepared in Example 4 were compared.

[0121] Experimental Methods: Two groups of male SD rats, six in each group (approximately 300g in weight), were used. Each rat was administered 0.5ml of fosapitan-meglumine lyophilized powder for injection and a self-made nano-suspension for injection, diluted to 1mg / ml. Blood samples were collected at 2, 10, 20, 30, and 40 minutes and 1, 1.5, 2, 3, 5, 12, and 18 hours after administration. The total aprepitan concentration in the blood samples was measured using LC-MS / MS. Animal pharmacokinetic (PK) studies showed that the nano-suspension for injection prepared in Example 4 was pharmacokinetic equivalent to fosapitan-meglumine lyophilized powder for injection in animals and could be an equivalent substitute for fosapitan-meglumine lyophilized powder for injection. Moreover, the injection site irritation was less than that of the commercially available fosapitan-meglumine injection and aprepitant fat emulsion injection, making it safer for patients.

[0122] Example 9: Comparison of Vascular Irritation

[0123] We compared the marketed fosapitan dimeglumine lyophilized powder for injection (EMEND) and aprepitant fat emulsion injection (CINVANTI).

[0124] A: Aprepitant suspension for injection prepared in Example 3;

[0125] B: Aprepitant lyophilized powder for injection prepared in Example 5;

[0126] C: Fosaspirant / Meglumine Lyophilized Powder for Injection (EMEND);

[0127] D: Aprepitant fat emulsion injection (CINVANTI).

[0128] Experimental method: Five rabbits weighing 2.3–2.8 kg were used in each group. The test drug was injected into the left ear vein, and an equal volume of physiological saline was injected into the right ear vein as a self-control. The drug administration volume was 1 ml / kg (the concentration of the test drug was 1 mg / ml). The stimulation at the administration site was observed and scored 1 hour and 24 hours after administration.

[0129] The day after euthanizing the animals, tissue samples (3-10 mm proximal and 20-30 mm distal) were excised from the injection site and fixed in 10% neutral buffered formalin (NBF) for microscopic evaluation. Tissue samples used for evaluation were embedded in paraffin blocks, cut into thin sections, and stained with hematoxylin and eosin for microscopic evaluation. All collected tissues underwent histopathological evaluation, assessing any findings such as venous endothelial cell loss and inflammatory cell infiltration.

[0130] Table 4 Grading Table of Vascular Irritation Tests

[0131] Score vascular wall irritation response Score vascular wall irritation response 0 No obvious reaction 3 Moderate to severe congestion, swelling, and drooping of the ear. 1 Mild congestion or erythema 4 Same as 3, and with mild to moderate necrosis. 2 Mild to moderate congestion and swelling 5 Same as 3, and with severe and extensive necrosis.

[0132] Table 5 Histopathological Scoring Table

[0133]

[0134]

[0135] Experimental results:

[0136] 1. Results of vascular irritation in rabbit ear marginal veins

[0137] The right ear, serving as the control group, showed no significant reaction after injection of saline solution; the irritation results of the left ear after injection of the test drug are shown in the table below:

[0138]

[0139] The results show that the overall self-developed groups A and B have low irritation, which is superior to the marketed products fosaspirant meglumine and aprepitant injection.

[0140] 2. Histopathological examination results

[0141]

[0142] The results of the above-mentioned rabbit ear marginal vein irritation and histopathological examination show that the nanocrystal injection prepared in this invention has lower irritation at the injection site than commercially available injections, and is safer for patients.

[0143] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions 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 is sodium deoxycholate, the secondary stabilizer is povidone, and the mass ratio of sodium deoxycholate to povidone is 1:1 to 7.

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

7.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The molecular weight of the polyvinylpyrrolidone is less than 45,000.

4. The pharmaceutical composition according to claim 1 or 2, wherein, The molecular weight of the polyvinylpyrrolidone is less than 30,000.

5. The pharmaceutical composition according to claim 1 or 2, wherein, The molecular weight of the povidone is less than 15,000.

6. The pharmaceutical composition according to claim 1 or 2, wherein, The molecular weight of the polyvinylpyrrolidone is less than 10,000.

7. The pharmaceutical composition according to claim 1 or 2, wherein, The molecular weight of the polyvinylpyrrolidone is less than 4000.

8. The pharmaceutical composition according to claim 1 or 2, wherein, The povidone is selected from one or more of povidone K30, povidone K18, povidone K17, povidone K15 and povidone K12.

9. The pharmaceutical composition according to claim 1 or 2, wherein, The pharmaceutical composition also includes one or more of a pH adjuster and an osmotic pressure adjuster.

10. The pharmaceutical composition according to claim 9, wherein, The pH adjuster is selected from one or more of hydrochloric acid, sodium hydroxide, citric acid, citrate, tartaric acid, tartrate, acetic acid, lactic acid, phosphoric acid, and phosphates.

11. The pharmaceutical composition according to claim 9, wherein, The osmotic pressure regulator is selected from one or more of sodium chloride, glucose, mannitol, and glycerol.

12. The pharmaceutical composition according to claim 1 or 2, wherein, The pharmaceutical composition is in suspension form; and the D of aprepitant in the suspension 50 Less than 200nm.

13. The pharmaceutical composition according to claim 12, wherein, The pH value of the suspension is 6.0~8.

5.

14. The pharmaceutical composition according to claim 12, wherein, The pH value of the suspension is 6.5~8.

0.

15. The pharmaceutical composition according to claim 12, wherein, The pH value of the suspension is 7.0~8.

0.

16. The pharmaceutical composition according to claim 12, wherein, The D of aprepitant in the suspension 50 Less than 120nm.

17. The pharmaceutical composition according to claim 12, wherein, The D of aprepitant in the suspension 50 Less than 100nm.

18. The pharmaceutical composition according to claim 1 or 2, comprising: One part aprepitant by weight; 0.04~0.45 parts of primary stabilizer; 0.04 to 3.2 parts of secondary stabilizer; 0.001 to 0.04 parts of pH adjuster; 0.005 to 0.05 parts of osmotic pressure adjuster; and water.

19. The pharmaceutical composition according to claim 1 or 2, comprising: One part aprepitant by weight; 0.04~0.45 parts of sodium deoxycholate; 0.04–3.2 parts of povidone; 0.001–0.04 parts of pH adjuster; and 0.005–0.05 parts of osmotic pressure adjuster; or By weight, 1 part aprepitant; 0.05 to 0.38 parts sodium deoxycholate; 0.1 to 2.00 parts of povidone; 0.001 to 0.04 parts of pH adjuster; and 0.005 to 0.05 parts of osmotic pressure adjuster; or By weight, 1 part aprepitant; 0.06 to 0.37 parts sodium deoxycholate; 0.12–1.90 parts of povidone; 0.001–0.04 parts of pH adjuster; and 0.005–0.05 parts of osmotic pressure adjuster; or By weight, 1 part aprepitant; 0.06 to 0.35 parts sodium deoxycholate; 0.12 to 1.75 parts of povidone; 0.001 to 0.04 parts of pH adjuster; and 0.005 to 0.05 parts of osmotic pressure adjuster.

20. An aprepitant injection comprising the pharmaceutical composition according to any one of claims 1 to 19.

21. A method for preparing a pharmaceutical composition comprising any one of claims 1 to 19, comprising: (1) Dissolve the primary stabilizer and the secondary stabilizer in water for injection, stir until completely dissolved, optionally add a pH adjuster, add aprepitant and disperse evenly, and use as the initial grinding suspension; (2) Add the grinding media into the grinding chamber, add the initial grinding suspension into the grinding cylinder and start grinding at a speed of 6.0 m / s to 17.0 m / s to obtain D. 50 Aprepitant nanoparticle suspension smaller than 200nm; (3) The aprepitant nano suspension is sterilized and filtered before being filled into vials or ampoules.

22. The preparation method according to claim 21, characterized in that, The grinding media are zirconia beads and / or polystyrene beads.

23. An aprepitant lyophilized powder injection, comprising lyophilized powder obtained by adding a lyophilization protectant to the pharmaceutical composition according to any one of claims 1 to 19 and then freeze-drying it.

24. The aprepitant lyophilized powder for injection according to claim 23, characterized in that, The freeze-drying protectant is selected from one or more of sucrose, lactose, mannitol, sorbitol, polyethylene glycol, and trehalose.

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