An injectable pharmaceutical composition comprising aprepitant and a method of preparing the same

Abstract

The application discloses an injectable pharmaceutical composition, which comprises aprepitant, a surface stabilizer and an anti-flocculating agent, wherein the anti-flocculating agent is selected from one or more than two of citrate, tartrate, phosphate or carbonate. The pharmaceutical composition provided by the application can be injected for administration, the preparation has good stability, can be stored and transported at room temperature, can greatly reduce the production, storage and transportation costs, and the dosage of the auxiliary materials of the preparation is extremely small, the injection site has small irritation when used by patients, is not prone to hypersensitivity reaction, and is safer.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more specifically to an injectable pharmaceutical composition comprising aprepitant and a method for preparing the same. Background Technology

[0002] Aprepitant is an NK1 receptor antagonist developed and marketed by Merck Sharp & Dohme. 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). maxThis 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 required overcoming numerous difficulties. After arduous efforts, in 2010, Merck & Co. developed aprepitant into the prodrug fosapitant meglumine to improve solubility, and finally developed it into 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 under the brand name CINVANTI, with a specification of 18mL:130mg. 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 a large amount of soybean oil and lecithin, and the excipient dosage is 5.9g, which is 45 times the amount of the active ingredient. The large amount of excipients can easily cause hypersensitivity reactions after intravenous injection, endangering the patient's 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℃; 4) In addition, the large volume of this formulation brings certain inconvenience to clinical use and is not convenient for quick administration.

[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 aforementioned problems in the existing technology, this invention provides an aprepitant nanocrystal injection with good stability, low excipient dosage, minimal patient irritation, and enhanced safety, as well as its preparation method. This significantly reduces production, storage, and transportation costs, and promotes its clinical application.

[0011] To achieve the above objectives, a first aspect of the present invention provides an injectable pharmaceutical composition comprising aprepitant, a surface stabilizer, and an antiflocculator, wherein the antiflocculator is selected from one or more of citrate, tartrate, phosphate (such as sodium dihydrogen phosphate or disodium hydrogen phosphate), or carbonate.

[0012] Although adding surface stabilizers to aprepitant nanocrystalline injection compositions can improve the dispersibility and stability of aprepitant particles during preparation, nanocrystalline formulations are thermodynamically unstable liquid suspensions. During long-term storage, Oswald ripening occurs, leading to aggregation and sedimentation, which hinders their clinical application. This invention incorporates an anti-flocculator, which improves dispersibility and stability during preparation and inhibits sedimentation of aprepitant particles, thereby enhancing the stability of aprepitant nanocrystals during long-term storage.

[0013] According to some embodiments of the present invention, the mass ratio of aprepitant to the antiflocculator is 1:(0.001-1), preferably 1:(0.001-0.1), more preferably 1:(0.001-0.05), and most preferably 1:(0.001-0.01).

[0014] According to some embodiments of the present invention, the surface stabilizer comprises a primary surface stabilizer and a secondary surface stabilizer, wherein the primary surface stabilizer is selected from anionic surfactants, preferably sodium deoxycholate, sodium cholate, and sodium dodecyl sulfate, more preferably sodium deoxycholate and sodium cholate; the secondary surface stabilizer is selected from nonionic or amphoteric surfactants, preferably polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, Tween 80, poloxamer, polyethylene glycol 15-hydroxystearate, and lecithin; more preferably polyethylene glycol and poloxamer. The average molecular weight of the polyethylene glycol can be 200-7000, preferably 400-4000. In some embodiments, the polyethylene glycol is selected from one or more of polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, and polyethylene glycol 4000.

[0015] According to some embodiments of the present invention, the antiflocculator is selected from one or more of sodium citrate, sodium tartrate, sodium phosphate, sodium carbonate, potassium phosphate, and potassium carbonate, preferably sodium citrate and sodium tartrate.

[0016] According to some embodiments of the present invention, the mass ratio of aprepitant to the surface stabilizer is 1:(0.01-10), preferably 1:(0.05-5), more preferably 1:(0.1-4), and most preferably 1:(0.15-3.6).

[0017] According to some embodiments of the present invention, the mass ratio of aprepitant to the primary surface stabilizer is 1:(0.05-0.4), preferably 1:(0.06-0.36), and more preferably 1:(0.075-0.32).

[0018] According to some embodiments of the present invention, the mass ratio of aprepitant to the secondary surface stabilizer is 1:(0.1 to 3.2), preferably 1:(0.12 to 2.8), and more preferably 1:(0.15 to 2.5).

[0019] According to some embodiments of the present invention, the mass ratio of the primary surface stabilizer to the secondary surface stabilizer is 1:(2-10), preferably 1:(2-8).

[0020] According to some embodiments of the present invention, the surface stabilizer comprises sodium deoxycholate and polyethylene glycol. Preferably, the mass ratio of sodium deoxycholate to polyethylene glycol is 1:(2-10), more preferably, the mass ratio of sodium deoxycholate to polyethylene glycol is 1:(2-8).

[0021] According to some embodiments of the present invention, the mass ratio of aprepitant to sodium deoxycholate is 1:(0.05-0.4), preferably 1:(0.06-0.36), and more preferably 1:(0.075-0.32).

[0022] According to some embodiments of the present invention, the mass ratio of aprepitant to polyethylene glycol is 1:(0.1-3.2), preferably 1:(0.12-2.8), and more preferably 1:(0.15-2.5).

[0023] According to some embodiments of the present invention, the primary surface stabilizer is sodium deoxycholate, the secondary surface stabilizer is polyethylene glycol, and the antiflocculator is selected from sodium citrate, sodium tartrate, and phosphate, preferably sodium citrate.

[0024] According to some embodiments of the present invention, the pharmaceutical composition further comprises a liquid medium selected from water, vegetable oil, ethanol, tert-butanol and ethylene glycol, preferably water.

[0025] According to some embodiments of the present invention, the aprepitant is a nanocrystal. According to some embodiments of the present invention, the aprepitant nanocrystals have a D... 50 The particle size is less than 200 nm, preferably less than 120 nm, and even more preferably less than 100 nm. The small particle size of Repitan nanocrystals is more conducive to product stability and also helps to improve its dissolution rate.

[0026] According to some embodiments of the present invention, the pharmaceutical composition comprises, by weight, the following components:

[0027] 1 part aprepitant; 0.05 to 0.4 parts primary surface stabilizer; 0.1 to 3.2 parts secondary surface stabilizer; 0.001 to 1 part antiflocculator and water.

[0028] According to some embodiments of the present invention, the pharmaceutical composition comprises, by weight, the following components:

[0029] 1 part aprepitant; 0.05 to 0.4 parts sodium deoxycholate; 0.1 to 3.2 parts polyethylene glycol and 0.001 to 0.1 parts sodium citrate.

[0030] According to some embodiments of the present invention, the pharmaceutical composition comprises, by weight, the following components:

[0031] 1 part aprepitant; 0.06 to 0.36 parts sodium deoxycholate; 0.12 to 2.8 parts polyethylene glycol and 0.001 to 0.05 parts sodium citrate.

[0032] According to some embodiments of the present invention, the pharmaceutical composition comprises, by weight, the following components:

[0033] 1 part aprepitant; 0.075 to 0.32 parts sodium deoxycholate; 0.15 to 2.5 parts polyethylene glycol and 0.001 to 0.01 parts sodium citrate.

[0034] According to some embodiments of the present invention, the pharmaceutical composition comprises aprepitant, sodium deoxycholate, polyethylene glycol, an antiflocculator, and water.

[0035] The anti-flocculator is selected from one or more of sodium citrate, sodium tartrate, and phosphate, preferably sodium citrate; the aprepitant is a nanocrystal, and the aprepitant nanocrystal has a D... 50 The aprepitant is less than 200 nm, preferably less than 100 nm; the weight ratio of aprepitant to the anti-flocculating agent is 1:(0.001-0.05), preferably 1:(0.001-0.01); the weight ratio of aprepitant to sodium deoxycholate is 1:(0.06-0.36), preferably 1:(0.075-0.32); the weight ratio of aprepitant to polyethylene glycol is 1:(0.12-2.8), preferably 1:(0.15-2.5); the mass ratio of sodium deoxycholate to polyethylene glycol is 1:(2-10), preferably 1:(2-8).

[0036] A second aspect of the present invention provides a method for preparing the pharmaceutical composition described in the first aspect of the present invention, comprising the following steps:

[0037] (1) The surface stabilizer is mixed with the solvent, and the anti-flocculation agent is added to obtain a mixture. Preferably, the solvent is water for injection.

[0038] (2) Add aprepitant to the mixture described in step (1) to obtain the initial grinding solution;

[0039] (3) The initial grinding solution described in step (2) is ground to obtain a drug composition containing the drug.

[0040] According to some embodiments of the present invention, the grinding speed in step (3) is 2000 to 3800 RPM, and the grinding media is zirconia beads and / or polystyrene beads.

[0041] A third aspect of the present invention provides an aprepitant suspension injection comprising the pharmaceutical composition described in the first aspect of the present invention or the pharmaceutical composition prepared by the method described in the second aspect of the present invention.

[0042] A fourth aspect of the present invention provides an aprepitant lyophilized powder for injection, comprising:

[0043] (1) The pharmaceutical composition described in the first aspect of the present invention or the pharmaceutical composition prepared by the method described in the second aspect of the present invention, and

[0044] (2) Lyophilization protectant,

[0045] Preferably, the freeze-drying protectant is selected from one or more of sucrose, lactose, mannitol, sorbitol, polyethylene glycol, or trehalose.

[0046] According to some embodiments of the present invention, the lyophilized powder is prepared by freeze-drying the pharmaceutical composition described in the first aspect of the present invention with the addition of a lyophilization protectant.

[0047] According to some embodiments of the present invention, the weight ratio of aprepitant to the lyophilization protectant is 1:(0-5.0), preferably 1:(0.01-3.0).

[0048] A fifth aspect of the invention provides the use of the pharmaceutical composition described in the first aspect of the invention or the pharmaceutical composition prepared by the method described in the second aspect of the invention in the preparation of a medicament for the prevention and / or treatment of chemotherapy-induced nausea and vomiting, and / or postoperative nausea and vomiting.

[0049] Compared with the prior art, the present invention has the following beneficial effects: By selecting specific surface stabilizers and anti-flocculating agents, the present invention prepares aprepitant into an injectable nano-suspension injection, which greatly improves its stability, allows for storage and transportation at room temperature, and significantly reduces the amount of excipients used, thereby greatly reducing production, storage and transportation costs; in addition, the formulation developed by the present invention causes less irritation at the injection site and is less likely to cause hypersensitivity reactions when used by patients, making it safer; the drug is small in size and convenient to use. Detailed Implementation

[0050] The present invention will be further described in detail through the following embodiments and experimental examples. These embodiments and experimental examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0051] Example 1

[0052] Aprepitant nanocrystal suspension injection was prepared using sodium deoxycholate as the primary surface stabilizer, polyethylene glycol 4000 as the secondary surface stabilizer, and sodium citrate as the anti-flocculating agent. The specific formulation and dosage are as follows:

[0053] Prescription (100 vials)

[0054] Aprepitant 13g

[0055] Sodium deoxycholate 0.98g

[0056] Polyethylene glycol 4000 3.9g

[0057] Sodium citrate 0.04g

[0058] Add water for injection to 500 mL

[0059] Preparation process:

[0060] (1) Preparation of initial grinding solution: Dissolve 3.9g polyethylene glycol 4000, 0.98g sodium deoxycholate and 0.04g monosodium citrate in water for injection and stir until completely dissolved. Add 13g aprepitant raw material and disperse evenly to obtain the initial grinding solution.

[0061] (2) Add 50ml of yttrium-stabilized grinding beads (grinding media) to the grinding chamber, add the initial grinding liquid to the grinding cylinder and start grinding at a speed of 3800RPM.

[0062] (3) After grinding for 4 hours, the average particle size of the suspension was tested and found to be less than 200 nm, thus obtaining aprepitant nano suspension.

[0063] (4) The nano-suspension was further diluted with water for injection to about 26 mg / mL to prepare aprepitant nano-suspension injection.

[0064] After the above-mentioned nano-suspension injection was placed at 40°C for 10 days, its particle size, pH value, insoluble microparticles and related substances were examined. The test results are shown in Table 1.

[0065] Table 1

[0066]

[0067] The results showed that the injection solution prepared using sodium deoxycholate and polyethylene glycol 4000 as stabilizers and sodium citrate as anti-flocculator did not show significant changes in particle size, pH value, insoluble particles and related substances after being placed at 40℃ for 10 days, which preliminarily indicates that the sample has good stability.

[0068] Example 2

[0069] Aprepitant nanocrystal suspension injection was prepared using sodium deoxycholate as the primary surface stabilizer, polyethylene glycol 400 as the secondary surface stabilizer, and sodium citrate as the anti-flocculating agent. The specific formulation and dosage are as follows:

[0070] Prescription (100 vials)

[0071] Aprepitant 13g

[0072] Sodium deoxycholate 0.98g

[0073] Polyethylene glycol 400 1.95g

[0074] Sodium citrate 0.04g

[0075] Add water for injection to 500 mL

[0076] Preparation process:

[0077] (1) Preparation of initial grinding solution: Dissolve 1.95g polyethylene glycol 4000, 0.98g sodium deoxycholate and 0.04g monosodium citrate in water for injection and stir until completely dissolved. Add 13g aprepitant raw material and disperse evenly to obtain the initial grinding solution.

[0078] (2) Add 50ml of yttrium-stabilized grinding beads (grinding media) to the grinding chamber, add the initial grinding liquid to the grinding cylinder and start grinding at a speed of 3800RPM.

[0079] (3) After grinding for 4 hours, the average particle size of the suspension was tested and found to be less than 200 nm, thus obtaining aprepitant nano suspension.

[0080] (4) The nano-suspension was further diluted with water for injection to about 26 mg / mL to prepare aprepitant nano-suspension injection.

[0081] After the above-mentioned nano-suspension injection was placed at 40°C for 10 days, its particle size, pH value, insoluble microparticles and related substances were examined. The test results are shown in Table 2.

[0082] Table 2

[0083]

[0084] The results showed that the injection solution prepared using sodium deoxycholate and polyethylene glycol 400 as stabilizers and sodium citrate as an anti-flocculator did not show significant changes in particle size, pH value, insoluble particles and related substances after being placed at 40℃ for 10 days, which preliminarily indicates that the sample has good stability.

[0085] Example 3

[0086] The type and amount of surface stabilizer can affect the particle size and stability of the final sample. The formulation of Example 2 was used to investigate different types and proportions of stabilizers, and the test results are shown in Table 3.

[0087] Table 3

[0088]

[0089]

[0090]

[0091] The experimental data above show that using polyethylene glycol 4000 and combinations of polyethylene glycol 400 at different concentrations with sodium deoxycholate can achieve an average particle size of less than 200 nm in the nanocrystalline suspension. Unexpectedly, compared to combinations of sodium deoxycholate with other stabilizers, using a combination of sodium deoxycholate and polyethylene glycol yields D... 50 Smaller nanocrystalline suspensions (less than 150 nm, less than 120 nm, and even less than 100 nm) were obtained, and the solutions exhibited good stability after grinding. Further investigation revealed that the solution stability could be further improved when the mass ratio of sodium deoxycholate to polyethylene glycol was in the range of 1:2–8. These results indicate that the stabilizer combination of sodium deoxycholate and polyethylene glycol is suitable for the development of nanocrystalline suspension injections.

[0092] Example 4

[0093] The dispersion ability of different amounts of antiflocculators on nanocrystals was investigated by particle size and property testing. The test was conducted according to the minimum particle size formulation in Example 3, and the test results are shown in Table 4 below.

[0094] Table 4

[0095]

[0096]

[0097] Experimental data show that without the addition of anti-flocculation agent, the grinding particle size D 50 The particle size is relatively large, and the stability of the solution after grinding is poor. Using sodium citrate or sodium tartrate as deflocculators can reduce the average particle size of the nanocrystalline suspension to less than 200 nm, and the stability of the solution after grinding is good. Adding sodium citrate as a deflocculator can yield D... 50 Smaller (less than 150 nm, less than 120 nm, even less than 100 nm) nanocrystalline suspensions were found, and it was further discovered that the weight ratio of aprepitant to anti-flocculator of 1:0.001 to 0.01 can further improve the stability of the solution.

[0098] Example 5

[0099] Preparation of aprepitant suspension lyophilized powder for injection (wet grinding method)

[0100] Prescription (100 vials)

[0101] Aprepitant 13g

[0102] Sodium deoxycholate 2.54g

[0103] Polyethylene glycol 400 14.95g

[0104] Sodium citrate 0.08g

[0105] 15g of sucrose

[0106] Add water for injection to 500 mL

[0107] Preparation process:

[0108] (1) Preparation of grinding media: Dissolve 14.95g polyethylene glycol 400, 2.54g sodium deoxycholate and 0.08g monosodium citrate in water for injection and stir until completely dissolved. Add 13g aprepitant raw material and disperse evenly to form the initial grinding solution.

[0109] (2) Add 50ml of yttrium-stabilized grinding beads into the grinding chamber, add the initial grinding liquid into the grinding cylinder and start grinding at a speed of 3800RPM.

[0110] (3) After grinding for 4 hours, the average particle size of the suspension was tested and found to be less than 200 nm, thus obtaining aprepitant nano suspension.

[0111] (4) Dissolve sucrose (30%) and add it to the above nano-suspension, then further dilute with water for injection to approximately 26 mg / ml. After sterile filtration, fill the solution into vials and freeze-dry to obtain aprepitant lyophilized powder for injection. The freeze-drying process conditions are shown in Table 5.

[0112] Table 5

[0113]

[0114] The freeze-dried sample appeared as a loose, porous white block that was easily resoluble. The particle size of the nano-suspension after resolvation was unchanged from that before freeze-drying. The stability of the freeze-dried sample at 40°C for 6 months was investigated, and the results are shown in Table 6.

[0115] Table 6

[0116]

[0117] The results showed that the stability of aprepitant nano-suspension lyophilized powder for injection was investigated at a high temperature of 60℃ for 30 days. The results showed that the key quality attributes, appearance, particle size, insoluble microparticles, and related substances, remained unchanged, indicating that this nano-suspension injection has good stability and can be stored at room temperature.

[0118] The suspension injections and lyophilized powder injections prepared using nanocrystal technology with sodium deoxycholate, polyethylene glycol, and the anti-flocculating agent sodium citrate exhibit good stability. 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. This is a significant advantage compared to fosapitan meglumine, which requires storage at -20°C for the API and 2–8°C for the finished product. Furthermore, it demonstrates better stability than aprepitant fat emulsion injection, which requires storage at 2–8°C, further reducing warehousing, transportation, and usage costs during drug production and distribution.

[0119] The suspension injection prepared using nanocrystal technology contains fewer excipients, with excipient dosage ranging from 0.02 to 0.45 g per vial. For example, the excipient dosage in Example 2 is 0.03 g per vial, and in Example 5 it is 0.33 g per vial. This significantly reduces the amount of excipients compared to the already marketed aprepitant fat emulsion injection. As shown in Table 7, the excipient dosage for aprepitant fat emulsion injection is 5.9 g per vial.

[0120] Table 7. Formulation of Marketed Aprepitant Fat Emulsion Injection (CINVANTI)

[0121] Component Name Dosage (g / vial) effect Aripitan 0.13 Active ingredients Egg yolk lecithin 2.6 surfactants soybean oil 1.7 oil phase Sodium oleate 0.1 surfactants ethanol 0.5 Cosolvent sucrose 1 Osmotic pressure regulator Water for Injection 12 solvent

[0122] 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. An injectable pharmaceutical composition comprising aprepitant, a surface stabilizer, and an antiflocculator. in, The mass ratio of aprepitant to the surface stabilizer is 1:(0.01~10). The surface stabilizer includes a primary surface stabilizer and a secondary surface stabilizer, wherein the primary surface stabilizer is selected from sodium deoxycholate; the secondary surface stabilizer is selected from polyethylene glycol; and the mass ratio of the primary surface stabilizer to the secondary surface stabilizer is 1:(2~10). The polyethylene glycol is selected from one or more of polyethylene glycol 400 and polyethylene glycol 4000; The anti-flocculating agent is selected from one or two of citrate and tartrate. The mass ratio of aprepitant to the antiflocculator is 1:(0.001~0.01).

2. The pharmaceutical composition of claim 1, wherein, The antiflocculator is selected from sodium citrate and sodium tartrate.

3. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the surface stabilizer is 1:(0.05~5).

4. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the surface stabilizer is 1:(0.1~4).

5. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the surface stabilizer is 1:(0.15~3.6).

6. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the primary surface stabilizer is 1:(0.05~0.4).

7. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of aprepitant to the primary surface stabilizer is 1:(0.06~0.36).

8. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the primary surface stabilizer is 1:(0.075~0.32).

9. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the secondary surface stabilizer is 1:(0.1~3.2).

10. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the secondary surface stabilizer is 1:(0.12~2.8).

11. The pharmaceutical composition of claim 1, wherein, The mass ratio of aprepitant to the secondary surface stabilizer is 1:(0.15~2.5).

12. The pharmaceutical composition of claim 1, wherein, The mass ratio of sodium deoxycholate to polyethylene glycol is 1:(2~8).

13. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further comprises a liquid medium selected from water, vegetable oil, ethanol, tert-butanol, and ethylene glycol.

14. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further comprises a liquid medium selected from water.

15. The pharmaceutical composition according to claim 1, characterized in that, The aripiprazole is nanocrystalline, the D 50 less than 200 nm.

16. The pharmaceutical composition of claim 1, wherein, The aripiprazole is nanocrystalline, the D 50 less than 120 nm.

17. The pharmaceutical composition of claim 1, wherein, The aripiprazole is nanocrystalline, the D 50 less than 100 nm.

18. The pharmaceutical composition according to claim 1, comprising, by weight: 1 part aprepitant; 0.05 to 0.4 parts primary surface stabilizer; 0.1 to 3.2 parts of secondary surface stabilizer; 0.001 to 0.01 parts of antiflocculator and water.

19. The pharmaceutical composition according to claim 1, comprising, by weight: 1 part aprepitant; 0.05-0.4 parts sodium deoxycholate; 0.1 to 3.2 parts of polyethylene glycol and 0.001 to 0.01 parts of sodium citrate; or 1 part aprepitant; 0.06~0.36 parts sodium deoxycholate; 0.12 to 2.8 parts of polyethylene glycol and 0.001 to 0.01 parts of sodium citrate; or 1 part aprepitant; 0.075~0.32 parts sodium deoxycholate; 0.15 to 2.5 parts of polyethylene glycol and 0.001 to 0.01 parts of sodium citrate.

20. A method for preparing the pharmaceutical composition according to any one of claims 1 to 19, comprising the following steps: (1) Mix the surface stabilizer with the solvent, add the anti-flocculation agent, and obtain a mixture; (2) Add aprepitant to the mixture in step (1) to obtain the initial grinding solution; (3) The initial grinding solution described in step (2) is ground to obtain a drug composition containing the drug.

21. The method of claim 20, wherein, The solvent is water for injection.

22. The method according to claim 20, characterized in that, The grinding speed in step (3) is 2000~3800 RPM, and the grinding media are zirconia beads and / or polystyrene beads.

23. An aprepitant suspension injection comprising the pharmaceutical composition according to any one of claims 1 to 19 or the pharmaceutical composition prepared by the method according to any one of claims 20 to 22.

24. An aprepitant lyophilized powder for injection, comprising: (1) The pharmaceutical composition according to any one of claims 1 to 19 or the pharmaceutical composition prepared by the method according to any one of claims 20 to 22, and (2) Freeze-drying protectant.

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

26. The aprepitant lyophilized powder for injection according to claim 24, characterized in that, The weight ratio of aprepitant to the lyophilization protectant is 1:(0~5.0).

27. The aprepitant lyophilized powder for injection according to claim 24, characterized in that, The weight ratio of aprepitant to the lyophilization protectant is 1:(0.01~3.0).

28. The use of the pharmaceutical composition according to any one of claims 1 to 19 or the pharmaceutical composition prepared by the method according to any one of claims 20 to 22 in the preparation of a medicament for the prevention and / or treatment of chemotherapy-induced nausea and vomiting.

29. The use of the pharmaceutical composition according to any one of claims 1 to 19 or the pharmaceutical composition prepared by the method according to any one of claims 20 to 22 in the preparation of a medicament for the prevention and / or treatment of postoperative nausea and vomiting.