Etoricoxib emulsion for injection and preparation method thereof

Abstract

The invention provides an etoricoxib emulsion for injection, such as a large volume parenteral emulsion, which can relieve acute treatment of postoperative pain on one hand, and can provide parenteral nutrition for patients who cannot eat food after operation on the other hand. The emulsion for injection provided by the invention has good stability and has dual effects of nutrition and treatment.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an etoricoxib injection emulsion and its preparation method. Background Technology

[0002] Etoricoxib is a selective COX-2 inhibitor with anti-inflammatory, analgesic, and antipyretic effects. It is suitable for treating the symptoms and signs of acute and chronic osteoarthritis, and can also treat acute gouty arthritis. Currently, etoricoxib is only available in oral formulations. However, in clinical settings, it is difficult for patients to remain conscious during the perioperative period, especially under general anesthesia. Furthermore, factors such as fasting during surgery make oral medication and food intake difficult to achieve. Injectable formulations cannot contain flavorings, sweeteners, or preservatives. Additionally, to avoid allergies and injection irritation, the use and dosage of surfactants such as polyoxyethylene castor oil and its analogues are subject to strict requirements.

[0003] On the other hand, for patients with gastrointestinal dysfunction or failure such as intestinal dysfunction, short bowel syndrome, intestinal ischemia, high-flow fistula, abdominal compartment syndrome, intestinal obstruction, moderate to severe radiation enteritis, extensive intestinal necrosis, severe pancreatitis, severe diarrhea, vomiting, etc., patients with vital organ dysfunction, patients with advanced tumors (to improve malnutrition), patients in the perioperative period of major surgery or trauma, and patients whose nutritional needs cannot be met by oral and / or enteral routes, parenteral nutrition support is urgently needed. Therefore, there is an urgent need for a safe, stable, intravenously injectable preparation with the dual functions of postoperative analgesia and postoperative nutrition. Summary of the Invention

[0004] This invention provides an etoricoxib emulsion that meets the dual needs of patients requiring parenteral nutrition and analgesia. The emulsion comprises the following components:

[0005] Etocoxib or its pharmaceutically acceptable salts, injectable oils, injectable emulsifiers, additives, and injectable osmoregulators.

[0006] According to an embodiment of the present invention, the etoricoxib emulsion is an etoricoxib large-volume parenteral emulsion. According to an embodiment of the present invention, the volume of the etoricoxib large-volume parenteral emulsion is 100mL-5000mL, preferably 100mL-3000mL, for example 100mL, 150mL, 200mL, 250mL, 300mL, 350mL, 400mL, 500mL, 800mL, 1000mL, 1200mL, 1500mL, or 2000mL.

[0007] According to an embodiment of the present invention, the etoricoxib emulsion has a therapeutically effective amount of etoricoxib in a single-dose formulation, wherein the therapeutically effective amount is selected from 10 mg to 200 mg, for example 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg, and 200 mg.

[0008] According to embodiments of the present invention, the pharmaceutically acceptable salt of etoricoxib is selected from oxalate, succinate, fumarate, benzenesulfonate, hydrobromide, glutamate, aminosulfonate, benzoate, cinnamate, salicylate or toluenesulfonate of etoricoxib.

[0009] According to embodiments of the present invention, the percentage content of etoricoxib is 0.005%-1.0%, preferably 0.01%-0.8%, and more preferably 0.03%-0.5%. According to embodiments of the present invention, the percentage content of etoricoxib is 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.10%, 0.12%, 0.15%, 0.18%, 0.20%, 0.23%, 0.25%, 0.28%, 0.30%, and 0.40%.

[0010] According to embodiments of the present invention, the concentration of etoricoxib is 0.01 mg / mL to 2.0 mg / mL, preferably 0.05 mg / mL to 1.8 mg / mL, for example 1.5 mg / mL, 1.3 mg / mL, 1.2 mg / mL, 0.6 mg / mL, 0.5 mg / mL, 0.4 mg / mL, 0.3 mg / mL, 0.2 mg / mL, 0.15 mg / mL, 0.1 mg / mL, and 0.08 mg / mL.

[0011] According to an embodiment of the present invention, the oil for injection is selected from one, two or more of medium-chain triglycerides (MCT), ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil.

[0012] According to embodiments of the present invention, ω-3 polyunsaturated fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

[0013] According to an embodiment of the present invention, the oil for injection is a mixed oil.

[0014] According to an embodiment of the present invention, the injectable oil includes injectable oil-1 and injectable oil-2; injectable oil-1 is selected from medium-chain triglycerides (MCT); injectable oil-2 is selected from any one, two or more of olive oil, soybean oil, sesame oil, castor oil and peanut oil.

[0015] According to an embodiment of the present invention, the injectable oil is composed of injectable oil-1 and injectable oil-2; injectable oil-1 is selected from medium-chain triglycerides (MCT); injectable oil-2 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil.

[0016] According to an embodiment of the present invention, the mass ratio of injection oil-1 to injection oil-2 is 1:5-5:1, for example 1:4, 1:3, 1:2, 1:1.5 (2:3), 1:1, 1.5:1 (3:2, 12:8), 2:1, 3:1, 4:1.

[0017] According to embodiments of the present invention, the percentage content of injectable oil-1 (e.g., medium-chain triglycerides (MCT)) is 5%-30%, for example 8%, 10%, 12%, 15%, 18%, or 20%.

[0018] According to embodiments of the present invention, the percentage of injection oil-2 (e.g., soybean oil) is 1%-20%, preferably 3%-18%, for example 5%, 6%, 8%, 10%, 12%, or 15%.

[0019] For example, the injectable oil is composed of medium-chain triglycerides (MCTs) and soybean oil. For example, the volume ratio of medium-chain triglycerides (MCTs) to soybean oil is 3:2. For example, the percentage content of medium-chain triglycerides is 12%. For example, the percentage content of soybean oil is 8%.

[0020] According to an embodiment of the invention, the injectable oil is a single injectable oil. Preferably, the injectable oil is a medium-chain triglyceride (MCT). According to an embodiment of the invention, the content percentage of the injectable oil (e.g., medium-chain triglyceride (MCT)) is 5%-30%, for example, 8%, 10%, 12%, 15%, 18%, or 20%.

[0021] According to an embodiment of the present invention, the injectable oil does not contain medium-chain triglycerides. According to an embodiment of the present invention, the injectable oil includes injectable oil-3 and injectable oil-4; injectable oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injectable oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil.

[0022] According to an embodiment of the present invention, the volume ratio of injection oil-3 to injection oil-4 is 1:5-5:1, for example 1:4, 1:3, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 3:1, 4:1.

[0023] According to embodiments of the present invention, the percentage content of the oil for injection is 5%-30%, preferably 6%-28%, for example 8%, 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%.

[0024] According to an embodiment of the present invention, the injectable emulsifier is selected from one, two or more of egg yolk lecithin, hydrogenated soybean lecithin, soybean lecithin, polysorbate 80, and polyethylene glycol (15)-hydroxystearate; preferably, the injectable emulsifier is selected from one or two of egg yolk lecithin and hydrogenated soybean lecithin.

[0025] According to embodiments of the present invention, the percentage content of the injectable emulsifier is 0.1%-5%, preferably 0.6%-4%, for example 0.7%, 0.8%, 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, 2.2%, 2.5%, 3%.

[0026] According to embodiments of the present invention, the injectable osmotic pressure regulator is selected from glycerol, amino acids, inorganic salts, and sugars; for example, it is selected from glycerol.

[0027] According to embodiments of the present invention, the percentage content of the injectable osmotic pressure regulator is 0.5%-8%, preferably 1%-5%, for example 1%, 1.5%, 2%, 2.25%, 2.5%, 3.0%, 3.5%, and 4.0%.

[0028] According to an embodiment of the present invention, the additive is beneficial to the stability of the emulsion.

[0029] According to an embodiment of the present invention, the additive is selected from one, two, or more of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine. For example, the additive is selected from sodium oleate.

[0030] According to embodiments of the present invention, the content percentage of the additive (e.g., sodium oleate) is 0.001%-1%, preferably 0.01%-0.5%, for example 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.1%, 0.2%, or 0.3%.

[0031] Alternatively, the additive may be an alkali, such as an organic or inorganic alkali, such as sodium hydroxide; and the pH of the etocoxib emulsion may be 7.0-7.5, such as 7.1, 7.2, 7.3, or 7.4.

[0032] According to an embodiment of the invention, the etocoxib emulsion optionally further comprises vitamins. The vitamins include both water-soluble and fat-soluble vitamins, which facilitates the integrity of parenteral nutrition in the emulsion.

[0033] According to an embodiment of the present invention, the vitamin is selected from one, two or more of vitamin B1, vitamin B2, vitamin B6, vitamin B12, carotene, vitamin C, vitamin E and vitamin D3.

[0034] According to an embodiment of the present invention, the vitamin content is 1mg-1000mg; for example, 2mg, 10mg, 30mg, 50mg, 80mg, 100mg, 125mg, 130mg, 140mg, 150mg, 180mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg.

[0035] According to an embodiment of the present invention, the concentration of the vitamin is 0.05 mg / mL to 5 mg / mL, preferably 0.1 mg / mL to 4 mg / mL, for example 0.1 mg / mL, 0.125 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 1 mg / mL, 1.2 mg / mL, 1.5 mg / mL, 1.8 mg / mL, 2 mg / mL, 2.2 mg / mL, 2.5 mg / mL, 2.8 mg / mL, 3 mg / mL, 3.5 mg / mL, 3.8 mg / mL, and 4.0 mg / mL.

[0036] According to an embodiment of the present invention, the etocoxib emulsion optionally further comprises sugars; preferably, the sugars are selected from one, two or more of sucrose, glucose, fructose and lactose.

[0037] According to an embodiment of the present invention, the concentration of the sugar is 5 mg / mL to 50 mg / mL, preferably 8 mg / mL to 40 mg / mL, for example 10 mg / mL, 12 mg / mL, 15 mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 32 mg / mL, 35 mg / mL, 38 mg / mL, or 40 mg / mL.

[0038] According to an embodiment of the present invention, the etocoxib emulsion optionally further comprises an amino acid; preferably, the amino acid is selected from one, two or more of lysine, leucine, methionine and phenylalanine.

[0039] According to an embodiment of the present invention, the concentration of the amino acid is 1 mg / mL to 40 mg / mL, preferably 2 mg / mL to 30 mg / mL, for example 2 mg / mL, 3 mg / mL, 3.3 mg / mL, 5 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 15 mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, and 30 mg / mL.

[0040] According to an embodiment of the present invention, the emulsion comprises the following components:

[0041] Etocoxib or its pharmaceutically acceptable salts, injectable oils, injectable emulsifiers, additives, and injectable osmoregulators;

[0042] Preferably, the etoricoxib emulsion is an etoricoxib large-volume parenteral emulsion;

[0043] Preferably, the volume of etoricoxib large-volume parenteral emulsion is 100mL-5000mL, more preferably 100mL-3000mL, for example 100mL, 150mL, 200mL, 250mL, 300mL, 350mL, 400mL, 500mL, 800mL, 1000mL, 1200mL, 1500mL, 2000mL;

[0044] Preferably, the percentage of etoricoxib content is 0.005%-1.0%, more preferably 0.01%-0.8%, and even more preferably 0.03%-0.5%; for example, the percentage of etoricoxib content is 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.10%, 0.12%, 0.15%, 0.18%, 0.20%, 0.23%, 0.25%, 0.28%, 0.30%, or 0.40%.

[0045] Preferably, the concentration of etoricoxib is 0.01 mg / mL to 2.0 mg / mL, more preferably 0.05 mg / mL to 1.8 mg / mL, for example 1.5 mg / mL, 1.3 mg / mL, 1.2 mg / mL, 0.6 mg / mL, 0.5 mg / mL, 0.4 mg / mL, 0.3 mg / mL, 0.2 mg / mL, 0.15 mg / mL, 0.1 mg / mL, 0.08 mg / mL.

[0046] Preferably, the oil for injection is selected from one, two or more of medium-chain triglycerides (MCT), ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil;

[0047] Preferably, the percentage of the oil for injection is 5%-30%, more preferably 6%-28%, for example 8%, 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%;

[0048] Preferably, the oil for injection is selected from any of the following:

[0049] (i) The oil for injection includes oil for injection-1 and oil for injection-2; oil for injection-1 is selected from medium-chain triglycerides (MCT); oil for injection-2 is selected from any one, two or more of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of oil for injection-1 to oil for injection-2 is 1:5-5:1, for example 1:4, 1:3, 1:2, 1:1.5 (2:3), 1:1, 1.5:1 (3:2, 12:8), 2:1, 3:1, 4:1; preferably, the content of oil for injection-1 (e.g., medium-chain triglycerides (MCT)) is... The percentage is 5%-30%, for example, 8%, 10%, 12%, 15%, 18%, 20%; preferably, the percentage of injection oil-2 (e.g., soybean oil) is 1%-20%, preferably 3%-18%, for example, 5%, 6%, 8%, 10%, 12%, 15%; exemplaryly, the injection oil is composed of medium-chain triglycerides (MCT) and soybean oil; exemplaryly, the volume ratio of medium-chain triglycerides (MCT) to soybean oil is 3:2; exemplaryly, the percentage of medium-chain triglycerides is 12%; exemplaryly, the percentage of soybean oil is 8%;

[0050] (ii) The injectable oil is a single injectable oil; preferably, the injectable oil is a medium-chain triglyceride (MCT); preferably, the percentage content of the injectable oil (e.g., medium-chain triglyceride (MCT)) is 5%-30%, for example, 8%, 10%, 12%, 15%, 18%, 20%;

[0051] (iii) The injectable oil does not contain medium-chain triglycerides; preferably, the injectable oil includes injectable oil-3 and injectable oil-4; injectable oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injectable oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the volume ratio of injectable oil-3 to injectable oil-4 is 1:5-5:1, for example, 1:4, 1:3, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 3:1, 4:1; preferably, the percentage content of the injectable oil is 5%-30%, preferably 6%-28%, for example, 8%, 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%;

[0052] Preferably, the injectable emulsifier is selected from one or both of egg yolk lecithin and hydrogenated soybean lecithin.

[0053] Preferably, the percentage content of the injectable emulsifier is 0.8%-3%, for example 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, 2.2%, 2.5%, or 3%.

[0054] Preferably, the injectable osmotic pressure regulator is selected from glycerin; preferably, the content percentage of the injectable osmotic pressure regulator is 0.5%-8%, more preferably 1%-5%, for example 1%, 1.5%, 2%, 2.25%, 2.5%, 3.0%, 3.5%, 4.0%;

[0055] Preferably, the additive is selected from one, two, or more of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine; preferably, the content percentage of the additive (e.g., sodium oleate) is 0.02%-0.5%, for example, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.1%, 0.2%, or 0.3%.

[0056] Alternatively, the additive may be an alkali, such as an organic or inorganic alkali, such as sodium hydroxide; and the pH of the etocoxib emulsion may be 7.0-7.5, such as 7.1, 7.2, 7.3, or 7.4.

[0057] According to an embodiment of the present invention, the emulsion comprises the following components:

[0058] Etocoxib or its pharmaceutically acceptable salts, injectable oils, injectable emulsifiers, additives, and injectable osmoregulators;

[0059] Preferably, the etoricoxib emulsion is an etoricoxib large-volume parenteral emulsion;

[0060] Preferably, the volume of etoricoxib large-volume parenteral emulsion is 100mL-2000mL (e.g., 100mL, 150mL, 200mL, 250mL, 300mL, 350mL, 400mL, 500mL, 800mL, 1000mL, 1200mL, 1500mL, 2000mL);

[0061] Preferably, the percentage of etoricoxib is 0.03%-0.5% (e.g., 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.10%, 0.12%, 0.15%, 0.18%, 0.20%, 0.23%, 0.25%, 0.28%, 0.30%, 0.40%).

[0062] Preferably, the percentage content of the oil for injection is 5%-30% (e.g., 8%, 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%).

[0063] Preferably, the oil for injection is selected from one, two or more of medium-chain triglycerides (MCT), ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil;

[0064] Preferably, the injectable emulsifier is selected from one or both of egg yolk lecithin and hydrogenated soybean lecithin.

[0065] Preferably, the percentage content of the injectable emulsifier is 0.8%-3% (e.g., 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, 2.2%, 2.5%, 3%).

[0066] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0067] Preferably, the percentage of injectable osmotic pressure regulator is 1%-5% (e.g., 1%, 1.5%, 2%, 2.25%, 2.5%, 3.0%, 3.5%, 4.0%).

[0068] Preferably, the additive is selected from one, two, or more of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine; preferably, the content percentage of the additive (e.g., sodium oleate) is 0.02%-0.5% (e.g., 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.1%, 0.2%, 0.3%); or, the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide; the pH of the etocoxib emulsion is 7.0-7.5, such as 7.1, 7.2, 7.3, or 7.4.

[0069] Preferably, the oil for injection is selected from any of the following:

[0070] (i) The oil for injection includes oil for injection-1 and oil for injection-2; oil for injection-1 is selected from medium-chain triglycerides (MCT); oil for injection-2 is selected from any one, two or more of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of oil for injection-1 to oil for injection-2 is 1:5-5:1, for example 1:4, 1:3, 1:2, 1:1.5 (2:3), 1:1, 1.5:1 (3:2, 12:8), 2:1, 3:1, 4:1; preferably, the content of oil for injection-1 (e.g., medium-chain triglycerides (MCT)) is... The percentage is 5%-30%, for example, 8%, 10%, 12%, 15%, 18%, 20%; preferably, the percentage of injection oil-2 (e.g., soybean oil) is 1%-20%, preferably 3%-18%, for example, 5%, 6%, 8%, 10%, 12%, 15%; exemplaryly, the injection oil is composed of medium-chain triglycerides (MCT) and soybean oil; exemplaryly, the volume ratio of medium-chain triglycerides (MCT) to soybean oil is 3:2; exemplaryly, the percentage of medium-chain triglycerides is 12%; exemplaryly, the percentage of soybean oil is 8%;

[0071] (ii) The injectable oil is a single injectable oil; preferably, the injectable oil is a medium-chain triglyceride (MCT); preferably, the percentage content of the injectable oil (e.g., medium-chain triglyceride (MCT)) is 5%-30%, for example, 8%, 10%, 12%, 15%, 18%, 20%;

[0072] (iii) The injectable oil does not contain medium-chain triglycerides; preferably, the injectable oil includes injectable oil-3 and injectable oil-4; injectable oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injectable oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the volume ratio of injectable oil-3 to injectable oil-4 is 1:5-5:1, for example, 1:4, 1:3, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 3:1, 4:1; preferably, the percentage content of the injectable oil is 5%-30%, preferably 6%-28%, for example, 8%, 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%.

[0073] Preferably, the etocoxib emulsion optionally further comprises vitamins; preferably, the vitamins are selected from one, two or more of vitamin B1, vitamin B2, vitamin B6, vitamin B12, carotene, vitamin C, vitamin E, and vitamin D3.

[0074] Preferably, the concentration of the vitamin is 0.05 mg / mL to 5 mg / mL, more preferably 0.1 mg / mL to 4 mg / mL, for example 0.1 mg / mL, 0.125 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 1 mg / mL, 1.2 mg / mL, 1.5 mg / mL, 1.8 mg / mL, 2 mg / mL, 2.2 mg / mL, 2.5 mg / mL, 2.8 mg / mL, 3 mg / mL, 3.5 mg / mL, 3.8 mg / mL, 4.0 mg / mL;

[0075] Preferably, the etocoxib emulsion optionally further comprises sugars; preferably, the sugars are selected from one, two, or more of sucrose, glucose, fructose, and lactose; preferably, the concentration of the sugars is 5 mg / mL to 50 mg / mL, more preferably 8 mg / mL to 40 mg / mL, for example 10 mg / mL, 12 mg / mL, 15 mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 32 mg / mL, 35 mg / mL, 38 mg / mL, or 40 mg / mL;

[0076] Preferably, the etocoxib emulsion optionally further comprises an amino acid; preferably, the amino acid is selected from one, two or more of lysine, leucine, methionine, and phenylalanine; preferably, the concentration of the amino acid is 1 mg / mL-40 mg / mL, more preferably 2 mg / mL-30 mg / mL, for example 2 mg / mL, 3 mg / mL, 3.3 mg / mL, 5 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 15 mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, and 30 mg / mL.

[0077] According to an embodiment of the present invention, the single-dose formulation of the etoricoxib injection emulsion (100mL-5000mL, preferably 100mL-3000mL, for example 100mL, 150mL, 200mL, 250mL, 300mL, 350mL, 400mL, 500mL, 800mL, 1000mL, 1200mL, 1500mL, 2000mL) comprises the following components:

[0078]

[0079] The single-dose formulation also includes additives;

[0080] Preferably, the oil for injection is selected from one, two or more of medium-chain triglycerides (MCT), ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil;

[0081] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0082] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0083] Preferably, the additive is selected from sodium oleate;

[0084] Preferably, the additive is selected from any one of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine; preferably, the content of the additive is 0.02g-0.5g (e.g., 0.01g, 0.02g, 0.03g, 0.05g, 0.06g, 0.07g, 0.08g, 0.1g, 0.12g, 0.2g, 0.24g, 0.3g, 0.36g, 0.4g); or, the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide; the pH of the formulation is 7.0-7.5, for example, 7.1, 7.2, 7.3, or 7.4.

[0085] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0086]

[0087]

[0088] Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2; or, the injectable oil is selected from medium-chain triglycerides.

[0089] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0090] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0091] Preferably, the additive is selected from sodium oleate.

[0092] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0093]

[0094] Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2; or, the injectable oil is selected from medium-chain triglycerides.

[0095] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0096] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0097] Preferably, the additive is selected from sodium oleate.

[0098] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0099]

[0100]

[0101] Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2.

[0102] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0103] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0104] Preferably, the additive is selected from sodium oleate.

[0105] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0106]

[0107] Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2.

[0108] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0109] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0110] Preferably, the additive is selected from sodium oleate.

[0111] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0112]

[0113]

[0114] Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2.

[0115] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0116] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0117] Preferably, the additive is selected from sodium oleate.

[0118] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0119]

[0120] Preferably, the oil for injection is selected from medium-chain triglycerides;

[0121] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0122] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0123] Preferably, the additive is selected from sodium oleate.

[0124] According to an embodiment of the present invention, the single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components:

[0125]

[0126] Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2.

[0127] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0128] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0129] Preferably, the additive is selected from sodium oleate.

[0130] According to an embodiment of the present invention, the single-dose formulation (200 mL) of the etoricoxib injection emulsion comprises the following components:

[0131]

[0132] Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:1.

[0133] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0134] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0135] Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate;

[0136] Preferably, the single-dose prescription optionally further comprises vitamins; preferably, the vitamin content is 1mg-1000mg (e.g., 2mg, 10mg, 30mg, 50mg, 80mg, 100mg, 125mg, 130mg, 140mg, 150mg, 180mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg). (g, 750mg, 800mg); preferably, the vitamins are selected from vitamin B1, vitamin B2, vitamin B6, vitamin B12, carotene, vitamin C, vitamin E, and vitamin D3; preferably, the single-dose prescription includes 130mg vitamin B1, 140mg vitamin B2, 125mg vitamin B6, 2mg vitamin B12, 400mg carotene, 200mg vitamin C, 100mg or 200mg vitamin E, or 2mg vitamin D3;

[0137] Preferably, the single-dose prescription optionally further includes carbohydrates; preferably, the carbohydrate content is 4000 mg; preferably, the carbohydrates are selected from sucrose, glucose, fructose, and lactose.

[0138] Preferably, the single-dose formulation optionally further comprises amino acids; preferably, the content of amino acids is 4000 mg; preferably, the amino acids are selected from lysine, leucine, methionine, and phenylalanine.

[0139] According to an embodiment of the present invention, the single-dose formulation (200 mL) of the etoricoxib injection emulsion comprises the following components:

[0140]

[0141] The single-dose formulation also includes an additive; the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide.

[0142] The pH of the single-dose formulation is 7.0-7.5, for example 7.1, 7.2, 7.3, 7.4;

[0143] Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:1.

[0144] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0145] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0146] Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate.

[0147] According to an embodiment of the present invention, the single-dose formulation (200 mL) of the etoricoxib injection emulsion comprises the following components:

[0148]

[0149] The single-dose formulation also includes an additive; the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide.

[0150] The pH of the single-dose formulation is 7.0-7.5, for example 7.1, 7.2, 7.3, 7.4;

[0151] Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:1.

[0152] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0153] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0154] Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate.

[0155] According to an embodiment of the present invention, the single-dose formulation (200 mL, 400 mL, 800 mL, or 1200 mL) of the etoricoxib injection emulsion comprises the following components:

[0156]

[0157] Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:1.

[0158] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0159] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0160] Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate.

[0161] According to an embodiment of the present invention, the single-dose formulation (200 mL, 400 mL, 800 mL, or 1200 mL) of the etoricoxib injection emulsion comprises the following components:

[0162]

[0163] Preferably, the single-dose formulation (200 mL) of the etoricoxib injection emulsion comprises the following components:

[0164]

[0165]

[0166] Preferably, the single-dose formulation (400 mL) of the etoricoxib injection emulsion comprises the following components:

[0167]

[0168] Preferably, the single-dose formulation (800 mL) of the etoricoxib injection emulsion comprises the following components:

[0169]

[0170] Preferably, the single-dose formulation (1200 mL) of the etoricoxib injection emulsion comprises the following components:

[0171]

[0172] Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:1.

[0173] Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin;

[0174] Preferably, the injectable osmotic pressure regulator is selected from glycerol;

[0175] Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate.

[0176] Preferably, the single-dose prescription optionally further comprises vitamins; preferably, the vitamin content is 1mg-1000mg (e.g., 2mg, 10mg, 30mg, 50mg, 80mg, 100mg, 125mg, 130mg, 140mg, 150mg, 180mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg); preferably, vitamins The ingredients are selected from vitamins B1, B2, B6, B12, carotene, C, E, and D3; preferably, the single-dose prescription includes 130 mg of vitamin B1, 140 mg of vitamin B2, 125 mg of vitamin B6, 2 mg of vitamin B12, 400 mg of carotene, 200 mg of vitamin C, 100 mg or 200 mg of vitamin E, or 2 mg of vitamin D3; preferably, the vitamins include vitamin E and carotene, for example, 200 mg of vitamin E and 400 mg of carotene.

[0177] Preferably, the single-dose prescription optionally further includes carbohydrates; preferably, the carbohydrate content is 4000mg-24000mg; preferably, the carbohydrates are selected from sucrose, glucose, fructose, and lactose.

[0178] Preferably, the single-dose formulation optionally further comprises amino acids; preferably, the content of amino acids is 4000 mg; preferably, the amino acids are selected from lysine, leucine, methionine, and phenylalanine.

[0179] It should be noted that when the volume of a single-dose prescription is increased by a corresponding multiple compared to 200mL, the amounts of injectable oil, injectable surfactant, injectable osmotic pressure regulator, additives, and sugars also increase by a corresponding multiple.

[0180] This invention also provides a method for preparing the above-mentioned etoricoxib injection emulsion, the method comprising the following steps:

[0181] (1) Preparation of oil phase: Weigh the oil for injection, add etoricoxib, dissolve and set aside;

[0182] (2) Preparation of aqueous phase: Weigh the injectable emulsifier, additive and injectable osmotic pressure regulator, add water, dissolve and set aside;

[0183] (3) Mix the aqueous phase in step (2) with the oil phase in step (1), and add water to obtain the emulsion.

[0184] According to an embodiment of the present invention, the preparation method includes the following steps:

[0185] (1) Preparation of oil phase: Weigh the oil for injection and the optional fat-soluble vitamin, add etoricoxib, dissolve and set aside;

[0186] (2) Preparation of aqueous phase: Weigh the injectable emulsifier, optional water-soluble vitamins, additives and injectable osmotic pressure regulator, add water, dissolve and set aside;

[0187] (3) Preparation of primary emulsion: The aqueous phase in step (2) and the oil phase in step (1) are mixed under high-speed shearing to obtain the primary emulsion;

[0188] (4) Final emulsion: Add water to the colostrum from step (3) to make up to a fixed volume, homogenize under high pressure, and filter to obtain the emulsion for etoricoxib injection.

[0189] According to an embodiment of the present invention, in step (1), the dissolution temperature is 60℃-80℃; preferably, the dissolution is carried out in a water bath.

[0190] According to an embodiment of the present invention, in step (3), the high-speed shearing speed is 3000rpm-8000rpm, for example 5000rpm.

[0191] According to an embodiment of the present invention, in step (4), the pressure of the high-pressure homogenization is 1000 bar to 1500 bar, for example 1300 bar.

[0192] According to an embodiment of the present invention, in step (4), a filtration operation is performed using a 0.22-micron filter membrane.

[0193] According to an embodiment of the present invention, step (4) may optionally include dispensing, sterilization and other steps after the filtration step.

[0194] The present invention also provides the use of the above-mentioned injectable emulsion in the preparation of medicaments for treating pain, fever, and inflammation.

[0195] According to embodiments of the present invention, the inflammation includes osteoarthritis, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, such as the acute phase and chronic phase of osteoarthritis.

[0196] According to an embodiment of the present invention, the pain includes orthopedic pain and postoperative pain (perioperative analgesia; including mild postoperative pain, moderate postoperative pain, and severe postoperative pain).

[0197] According to embodiments of the present invention, the above-mentioned injectable emulsion can be used to relieve pain symptoms, including but not limited to nociceptive pain, neuropathic pain, postoperative pain (mild, moderate, severe), lower back pain, cluster headache, herpetic neuralgia, phantom limb pain, central pain, toothache, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during childbirth and delivery, pain caused by burns (including sunburn), postpartum pain, migraine and genitourinary pain (including cystitis), chronic low back pain, and primary dysmenorrhea.

[0198] According to embodiments of the present invention, the above-mentioned injectable emulsion can be used to reduce fever, including but not limited to fever caused by infection, drug reaction, allergic reaction, transfusion reaction, stroke, surgery, heatstroke, rheumatic disease, cancer, or fever of unknown cause.

[0199] According to an embodiment of the present invention, the above-mentioned injectable emulsion is administered once every 0.5 to 2 days, for example, once daily.

[0200] The present invention also provides a method for treating pain, fever, or inflammation in a subject, the method comprising administering a therapeutically effective amount of the above-mentioned injectable emulsion to the subject parenterally. Preferably, it is administered to the subject intravenously.

[0201] According to embodiments of the present invention, the inflammation includes osteoarthritis, acute gouty arthritis, such as the acute phase of osteoarthritis and the chronic phase of osteoarthritis.

[0202] According to an embodiment of the present invention, the pain includes orthopedic pain and postoperative pain (perioperative analgesia; including mild postoperative pain, moderate postoperative pain, and severe postoperative pain).

[0203] According to embodiments of the present invention, the above-mentioned injectable emulsion can be used to relieve pain symptoms, including but not limited to nociceptive pain, neuropathic pain, postoperative pain, lower back pain, cluster headache, herpetic neuralgia, phantom limb pain, central pain, toothache, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during childbirth and delivery, pain caused by burns (including sunburn), postpartum pain, migraine, and genitourinary pain (including cystitis).

[0204] According to embodiments of the present invention, the above-mentioned injectable emulsion can be used to reduce fever, including but not limited to fever caused by infection, drug reaction, allergic reaction, transfusion reaction, stroke, surgery, heatstroke, rheumatic disease, cancer, or fever of unknown cause.

[0205] According to an embodiment of the present invention, the above-mentioned injectable emulsion is administered once every 0.5 to 2 days, for example, once daily.

[0206] Beneficial effects

[0207] This invention provides an emulsion for etoricoxib injection, such as a large-volume infusion emulsion, which can relieve acute postoperative pain and provide parenteral nutrition for patients who are unable to eat after surgery. The emulsion for injection provided by this invention has good stability and provides both nutritional and therapeutic effects. Attached Figure Description

[0208] Figure 1 The pharmacokinetic diagrams are for the prescription and commercially available drugs in Example 6. Detailed Implementation

[0209] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0210] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0211] Example 1

[0212] The solubility of etoricoxib in the oil phase for injection at room temperature was investigated, and the results are shown in Table 1.

[0213] Table 1. Solubility of etoricoxib in different injectable oils

[0214] Serial Number Oil for injection Solubility (mg / g) 1 medium-chain triglycerides 9.39 2 soybean oil 4.19 3 olive oil 3.49 4 Sesame oil 3.77 5 Peanut oil 3.66 6 castor oil 3.88

[0215] As shown in Table 1, etoricoxib has the highest solubility in medium-chain triglycerides, followed by soybean oil, castor oil, sesame oil, and peanut oil, while olive oil has the lowest solubility.

[0216] Example 2

[0217] Following the method of Example 1, the solubility of etoricoxib in the mixed oil phase was investigated, and the results are shown in Table 2.

[0218] Table 2 Solubility of etoricoxib in mixed oil phase

[0219] Serial Number Oil for injection Ratio (mass ratio) Solubility (mg / g) 1 Medium-chain triglycerides: olive oil 3：2 7.07 2 Medium-chain triglycerides: Sesame oil 3：2 6.59 3 Medium-chain triglycerides: soybean oil 3：2 7.31

[0220] The results in Table 2 show that the solubility of etoricoxib was not significantly reduced by mixing different oil phases, and the mixed oil phases could also enrich the nutritional components in large-volume parenteral emulsions.

[0221] Example 3

[0222] Following the method in Example 1, the solubility of etoricoxib in oil mixtures with different oil phase ratios was investigated, and the results are shown in Table 3. The solubility of etoricoxib increased with increasing proportion of medium-chain triglycerides.

[0223] Table 3. Solubility of etoricoxib in oil mixtures with different oil phase ratios

[0224] Serial Number Oil for injection Ratio (mass ratio) Solubility (mg / g) 1 Medium-chain triglycerides: soybean oil 1：4 4.85 2 Medium-chain triglycerides: soybean oil 2：3 6.11 2 Medium-chain triglycerides: soybean oil 3：2 7.31 4 Medium-chain triglycerides: soybean oil 4：1 7.90

[0225] Example 4

[0226] (1) Preliminary investigation of emulsifier types using medium-chain triglycerides combined with injectable oils

[0227] According to the etoricoxib formulation in Table 4-1, etoricoxib large-volume parenteral emulsion was prepared. The preparation process is as follows:

[0228] 1. Weigh 12g of medium-chain triglycerides and 8g of soybean oil, mix them evenly, add 120mg of etoricoxib, and dissolve them in a water bath at 60℃-80℃ to obtain the oil phase;

[0229] 2. Weigh out 1.2g of emulsifier (egg yolk lecithin, hydrogenated soybean lecithin, soybean lecithin, polysorbate 80, polyethylene glycol (15)-hydroxystearate, or polyoxyethylene hydrogenated castor oil), 0.03g of sodium oleate and 2.25g of glycerin according to the prescription, and dissolve them in 30mL of purified water to obtain the aqueous phase;

[0230] 3. The oil phase and aqueous phase prepared in the above steps are mixed together and mixed at 5000 rpm using a high-speed shearing machine to obtain the primary emulsion;

[0231] 4. Add water to the colostrum from step 3 to bring the volume to 100 mL, homogenize at 1300 bar for 6 times, filter the collected material through a 0.22 micron filter membrane, dispense into vials, and sterilize at 121°C for 30 minutes.

[0232] The appearance of the prescription large-volume parenteral solution emulsion was observed, and the particle size of the emulsion was detected using Malvern 3000. The results are shown in Table 4-1.

[0233] Table 4-1 Etocorxib formulation composition, emulsion appearance, and average particle size composition

[0234]

[0235]

[0236] In emulsions with MCT and soybean oil as the oil phase, the addition of polysorbate 80 caused emulsion aggregation and stratification. Emulsions containing soybean lecithin, polyethylene glycol (15)-hydroxystearate, and polyoxyethylene hydrogenated castor oil showed stratification or slight stratification after storage at 25°C for two months. Emulsions containing egg yolk lecithin and hydrogenated soybean lecithin, however, were homogeneous emulsions, showing no aggregation, flocculation, or precipitation, and remained unchanged after storage at 25°C for two months, demonstrating excellent stability.

[0237] (2) Further screening of the dosage of egg yolk lecithin emulsifier

[0238] According to the etoricoxib formulation in Table 4-2, the prescribed amounts of medium-chain triglycerides and soybean oil were mixed, and 120 mg of etoricoxib was added. The mixture was dissolved in a water bath at 60℃-80℃ to obtain the oil phase. Different masses of emulsifier egg yolk lecithin and other excipients were weighed and suspended in 30 mL of purified water to obtain the aqueous phase. The oil phase and aqueous phase prepared in the above steps were mixed together and mixed under high-speed shearing at 5000 rpm to obtain the pre-emulsion. The pre-emulsion was diluted with water to 100 mL, homogenized 6 times at 1300 bar, filtered through a 0.22 micron filter membrane, dispensed, and sterilized at 121℃ for 30 minutes to obtain etoricoxib large-volume parenteral emulsion.

[0239] The appearance of the prescription large-volume parenteral solution emulsion was observed, and its average particle size and viscosity were measured. The results are shown in Table 4-2. The results show that when the amount of egg yolk lecithin emulsifier is 1.2g, the emulsion is a homogeneous emulsion, without agglomeration, flocculation, precipitation, or bubbles.

[0240] Table 4-2 Etocorxib formulation composition, emulsion appearance, average particle size, and viscosity.

[0241]

[0242]

[0243] (3) Screening of sodium oleate additive dosage and glycerin dosage

[0244] According to the etoricoxib formulation in Table 4-3, the prescribed amount of medium-chain triglycerides and optional soybean oil were mixed, and 120 mg of etoricoxib was added. The mixture was dissolved at 60℃-80℃ and set aside. The emulsifier, egg yolk lecithin, and other excipients were weighed, and water was added and mixed at 5000 rpm to obtain the colostrum. The colostrum was then diluted with water to 100 mL, homogenized 6 times at 1300 bar, filtered through a 0.22-micron filter membrane, dispensed, and sterilized at 121℃ for 30 minutes to obtain etoricoxib large-volume parenteral emulsion.

[0245] The appearance of the prescription emulsion was observed and its osmotic pressure was measured. The results are shown in Table 4-3.

[0246] Table 4-3 Etocorxib formulation composition, emulsion appearance, and osmotic pressure

[0247]

[0248] Table 4-3 shows that the oil phase composition in the emulsion does not affect the stability of the emulsion. The emulsion is unstable when the amount of sodium oleate is small, and the emulsion is unstable when glycerol is not used.

[0249] Example 5: Emulsion Study Without Medium-Chain Triglycerides as the Oil Phase

[0250] (1) The mixed oil phase was investigated using 200 mL of emulsion.

[0251] Based on the solubility of etoricoxib in different oil phases, at least 40g of injectable oil is required to completely dissolve 120mg etoricoxib. Initially, injectable oils other than medium-chain triglycerides were used to prepare large-volume emulsions, and the preparation effect of emulsions with different mixed oil phases was investigated.

[0252] Referring to the etoricoxib formulations in Tables 5-1 to 5-3, etoricoxib large-volume parenteral emulsions were prepared. The preparation process is as follows:

[0253] 1. Weigh different injectable oils, mix them evenly, add 120 mg of etoricoxib, and dissolve them in a water bath at 60℃-80℃ to obtain the oil phase;

[0254] 2. Weigh 0.06g of sodium oleate and 4.5g of glycerol according to the prescription, and dissolve them in 60mL of purified water to obtain the aqueous phase;

[0255] 3. The oil phase and aqueous phase prepared in the above steps are mixed together and mixed at 5000 rpm using a high-speed shearing machine to obtain the primary emulsion;

[0256] 4. Add water to the colostrum from step 3 to a final volume of 200 mL, homogenize at 1300 bar for 6 cycles, collect the material, filter it through a 0.22 micron filter membrane, dispense it into vials, and sterilize at 121°C for 30 minutes.

[0257] The appearance of the prescription large-volume parenteral solution emulsion was observed, and the particle size of the emulsion was detected using Malvern 3000.

[0258] Table 5-1 Formulations and stability results of different oil phase mixtures

[0259]

[0260] Table 5-2 Formulations and stability results of different oil phase mixtures

[0261]

[0262] Table 5-3 Formulations and stability results of different oil phase mixtures

[0263]

[0264]

[0265] According to preliminary formulation screening, when preparing emulsions with 120 mg etoricoxib, the emulsions prepared with a mixed oil content of 40 g or more showed no abnormal precipitation, indicating that the amount of oil phase was sufficient to produce good emulsions with good stability, and the difference in oil phase had no significant impact on the emulsion.

[0266] (2) Screening emulsifiers using 200mL of mixed oil emulsion.

[0267] Referring to the etoricoxib formulation in Table 5-4, etoricoxib large-volume parenteral emulsion was prepared. The preparation process is as follows:

[0268] 1. Weigh out the oil for injection, mix it evenly, add 120 mg of etoricoxib, and dissolve it in a water bath at 60℃-80℃ to obtain the oil phase;

[0269] 2. Weigh out 2.4g of emulsifier, 0.06g of sodium oleate and 4.5g of glycerol according to the prescription, and dissolve them in 60mL of purified water to obtain the aqueous phase;

[0270] 3. The oil phase and aqueous phase prepared in the above steps are mixed together and mixed at 5000 rpm using a high-speed shearing machine to obtain the primary emulsion;

[0271] 4. Add water to the colostrum from step 3 to a final volume of 200 mL, homogenize at 1300 bar for 6 cycles, collect the material, filter it through a 0.22 micron filter membrane, dispense it into vials, and sterilize at 121°C for 30 minutes.

[0272] The appearance of the prescription large-volume parenteral solution emulsion was observed, and the particle size of the emulsion was detected using Malvern 3000.

[0273] Table 5-4 contains formulations and stability results for different emulsifiers.

[0274]

[0275]

[0276] Preliminary screening of emulsions using mixed oils revealed that the addition of polysorbate 80 caused emulsion aggregation and stratification. Emulsions containing polyethylene glycol (15)-hydroxystearate and polyoxyethylene hydrogenated castor oil showed slight stratification and increased particle size after storage at 25°C for two months. Emulsions containing egg yolk lecithin, hydrogenated soybean lecithin, and soybean lecithin were homogeneous emulsions, exhibiting no aggregation, flocculation, or precipitation, and remained unchanged after storage at 25°C for two months, demonstrating excellent stability.

[0277] (3) Use 200mL of mixed oil emulsion to screen additives

[0278] Referring to the etoricoxib formulation in Table 5-5, etoricoxib large-volume parenteral emulsion was prepared. The preparation process is as follows:

[0279] 1. Weigh out the oil for injection, mix it evenly, add 120 mg of etoricoxib, and dissolve it in a water bath at 60℃-80℃ to obtain the oil phase;

[0280] 2. Weigh out 2.4g of emulsifier egg yolk lecithin, 0.06g of additives (vitamins, sugars or amino acids) and 4.5g of glycerol according to the prescription, and dissolve them in 60mL of purified water to obtain the aqueous phase;

[0281] 3. The oil phase and aqueous phase prepared in the above steps are mixed together and mixed at 5000 rpm using a high-speed shearing machine to obtain the primary emulsion;

[0282] 4. Add water to the colostrum from step 3 to a final volume of 200 mL, homogenize at 1300 bar for 6 cycles, collect the material, filter it through a 0.22 micron filter membrane, dispense it into vials, and sterilize at 121°C for 30 minutes.

[0283] The appearance of the prescription large-volume parenteral solution emulsion was observed, and the particle size of the emulsion was detected using Malvern 3000.

[0284] Table 5-5 contains formulations with different additives and their stability results.

[0285]

[0286]

[0287] Table 5-6 shows prescriptions containing different vitamins and their stability results.

[0288]

[0289]

[0290] Table 5-7 contains formulations containing different sugars and their stability results.

[0291]

[0292] Table 5-8 Formulations containing different amino acids and their stability results

[0293]

[0294]

[0295] Table 5-9 Formulations and stability results of emulsions at different volume specifications

[0296]

[0297] Table 5-5 shows that when the emulsion does not contain the emulsifier egg yolk lecithin and the additive sodium oleate, the emulsion exhibits stratification and poor stability. Without the additive sodium oleate, the particle size of the emulsion increases after storage at 25°C for two months. However, when emulsifiers and additives (including sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, and sodium glycocholate) are added, the emulsion is homogeneous, without agglomeration, flocculation, or precipitation, and shows no change after storage at 25°C for two months, demonstrating excellent stability.

[0298] Table 5-6 shows that the appearance and stability of the emulsion were not affected when different vitamins were added.

[0299] Table 5-7 shows that the appearance and stability of the emulsion were not affected when different types of sugar were added.

[0300] Table 5-8 shows that the appearance and stability of the emulsion are not affected when different types of amino acids are added.

[0301] Table 5-9 shows that the appearance and stability of the emulsion remained unchanged after the scale-up was achieved.

[0302] Example 6

[0303] Pharmacokinetic studies were conducted on formulation 35 in Example 5 and commercially available tablet Ankangxin (120mg / tablet, manufacturer: NVOrganon). The experimental animals were male SD rats, 200-250g.

[0304] Experimental methods: SD rats were administered the drug via intravenous injection (commercially available tablets were administered via gavage). Plasma samples were collected at different time points and analyzed by LC-MS / MS to obtain the blood drug concentration data and pharmacokinetic parameters of different formulations in SD rats. The experimental results are shown in Table 6. Figure 1 .

[0305] Table 6 Pharmacokinetic parameters of prescription 35

[0306] batch Prescription 35 Commercially available products <![CDATA[Half-life t 1 / 2 (h)]]> 2.41 2.14 <![CDATA[T max (h)]]> 0.083 1.00 <![CDATA[C max (ng / mL)]]> 13006.08 2801.49 <![CDATA[AUC last (mg / mL)]]> 30427.12 18649.22 <![CDATA[AUC last_D (h*kg*ng / mL / mg)]]> 2543.80 1503.97 <![CDATA[AUC INF (mg / mL)]]> 31198.51 18893.42 Cl (mL / h / kg) 407.46 2029.38 <![CDATA[MRT INF (h)]]> 3.06 656.87 <![CDATA[V ss (mL / kg)]]> 1222.38 4.44

[0307] The results above show that, compared to commercially available etoricoxib tablets, the etoricoxib intravenous emulsion prepared in this application has a shorter onset time and can maintain a high blood drug concentration for several hours after intravenous injection. When using the intravenous emulsion, patients can not only receive parenteral nutrition but also receive analgesia, and continuous infusion maintains a longer therapeutic effect.

[0308] Comparative Example 1

[0309] According to the etoricoxib formulation in Table 7, the prescribed amount of etoricoxib was added to the medium-chain triglycerides and dissolved at 60°C for later use. Polyoxyethylene hydrogenated castor oil and glycerin were weighed and added to the dissolved etoricoxib oil phase, stirred until homogeneous, and then 30% water was added. The mixture was homogenized several times at 1200 bar under high pressure to obtain the pre-emulsion. The pre-emulsion was then diluted to 150 mL with water and homogenized 6 times at 1300 bar. Observation of the prepared formulation revealed that a large number of crystals precipitated at the bottom, indicating instability.

[0310] Table 7. Composition of Etocorxib prescriptions

[0311]

[0312]

[0313] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An etoricoxib emulsion, said emulsion comprising the following components: Etocoxib or its pharmaceutically acceptable salts, injectable oils, injectable emulsifiers, additives, and injectable osmoregulators; The injectable emulsifier is selected from one, two or more of egg yolk lecithin, hydrogenated soybean lecithin, soybean lecithin, polysorbate 80, and polyethylene glycol (15)-hydroxystearate.

2. The emulsion according to claim 1, characterized in that, The injectable emulsifier is selected from one or both of egg yolk lecithin and hydrogenated soybean lecithin. Preferably, the percentage of injectable emulsifier is 0.1%-5%, more preferably 0.6%-4%; Preferably, the injectable osmotic pressure regulator is selected from glycerol, amino acids, inorganic salts, and sugars; for example, it is selected from glycerol. Preferably, the percentage of injectable osmotic pressure regulator is 0.5%-8%, more preferably 1%-5%; Preferably, the additive is selected from one, two or more of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine; preferably, the content percentage of the additive is 0.001%-1%, more preferably 0.01%-0.5%; Alternatively, the additive may be a base, such as an organic or inorganic base; the pH of the etoricoxib emulsion may be 7.0-7.

5.

3. The emulsion according to claim 1 or 2, characterized in that, The etoricoxib emulsion is an etoricoxib large-volume parenteral emulsion; Preferably, the volume of etoricoxib large-volume parenteral emulsion is 100mL-5000mL, more preferably 100mL-3000mL; Preferably, in the etoricoxib emulsion, the etoricoxib emulsion has a therapeutically effective amount of etoricoxib in a single-dose formulation, wherein the therapeutically effective amount is selected from 10 mg to 200 mg; Preferably, the percentage of etoricoxib is 0.005%-1.0%, more preferably 0.01%-0.8%; Preferably, the concentration of etoricoxib is 0.01 mg / mL-2.0 mg / mL, and more preferably 0.05 mg / mL-1.8 mg / mL; Preferably, the oil for injection is selected from one, two or more of the following: medium-chain triglycerides, ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil. Preferably, the percentage of the oil for injection is 5%-30%, more preferably 6%-28%; Preferably, the oil for injection is a mixture of oils; preferably, the oil for injection includes oil for injection-1 and oil for injection-2; oil for injection-1 is selected from medium-chain triglycerides; oil for injection-2 is selected from any one, two or more of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of oil for injection-1 to oil for injection-2 is 1:5 to 5:

1. Preferably, the injectable oil is a single injectable oil; preferably, the injectable oil is a medium-chain triglyceride. Preferably, the oil for injection includes oil for injection-3 and oil for injection-4; oil for injection-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; oil for injection-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; the volume ratio of oil for injection-3 to oil for injection-4 is 1:5 to 5:

1.

4. The emulsion according to any one of claims 1-3, characterized in that, The emulsion comprises the following components: Etocoxib or its pharmaceutically acceptable salts, injectable oils, injectable emulsifiers, additives, and injectable osmoregulators; The injectable emulsifier is selected from one or both of egg yolk lecithin and hydrogenated soybean lecithin. The percentage of injectable emulsifier is 0.8%-3%; The additive is selected from one, two, or more of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine; the additive content percentage is 0.02%-0.5%; or, the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide; the pH of the emulsion is 7.0-7.5; The injectable osmotic pressure regulator is selected from glycerin; the content percentage of the injectable osmotic pressure regulator is 0.5%-8%, preferably 1%-5%; The percentage of oil for injection is 5%-30%, preferably 6%-28%; Preferably, the oil for injection is selected from one, two or more of the following: medium-chain triglycerides, ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil. Preferably, the etoricoxib emulsion is an etoricoxib large-volume parenteral emulsion; Preferably, the volume of etoricoxib large-volume parenteral emulsion is 100mL-5000mL, more preferably 100mL-3000mL; Preferably, the percentage of etoricoxib is 0.005%-1.0%, more preferably 0.01%-0.8%; Preferably, the concentration of etoricoxib is 0.01 mg / mL-2.0 mg / mL, and more preferably 0.05 mg / mL-1.8 mg / mL. Preferably, the oil for injection is selected from any of the following: (i) The oil for injection includes oil for injection-1 and oil for injection-2; oil for injection-1 is selected from medium-chain triglycerides; oil for injection-2 is selected from any one, two or more of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of oil for injection-1 to oil for injection-2 is 1:5-5:1; preferably, the content percentage of oil for injection-1 is 5%-30%; preferably, the content percentage of oil for injection-2 is 1%-20%; (ii) The injectable oil is a single injectable oil; preferably, the injectable oil is a medium-chain triglyceride; preferably, the content percentage of the injectable oil is 5%-30%; (iii) The injectable oil does not contain medium-chain triglycerides; preferably, the injectable oil includes injectable oil-3 and injectable oil-4; injectable oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injectable oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the volume ratio of injectable oil-3 to injectable oil-4 is 1:5 to 5:1; preferably, the percentage content of the injectable oil is 5% to 30%, more preferably 6% to 28%.

5. The emulsion according to any one of claims 1-4, characterized in that, The etoricoxib emulsion optionally further comprises vitamins; preferably, the vitamins are selected from one, two or more of vitamin B1, vitamin B2, vitamin B6, vitamin B12, carotene, vitamin C, vitamin E, and vitamin D3; preferably, the concentration of the vitamins is 0.05 mg / mL to 5 mg / mL, more preferably 0.1 mg / mL to 4 mg / mL; Preferably, the etocoxib emulsion optionally further comprises sugars; preferably, the sugars are selected from one, two or more of sucrose, glucose, fructose, and lactose; preferably, the concentration of the sugars is 5 mg / mL-50 mg / mL, more preferably 8 mg / mL-40 mg / mL; Preferably, the etocoxib emulsion optionally further comprises an amino acid; preferably, the amino acid is selected from one, two or more of lysine, leucine, methionine, and phenylalanine; preferably, the concentration of the amino acid is 1 mg / mL-40 mg / mL, more preferably 2 mg / mL-30 mg / mL.

6. The emulsion according to any one of claims 1-5, characterized in that, The single-dose formulation (100mL-5000mL) of the etoricoxib injection emulsion comprises the following components: The single-dose formulation also includes additives; Preferably, the oil for injection is selected from one, two or more of medium-chain triglycerides (MCT), ω-3 polyunsaturated fatty acids, ω-3 fatty acid triglycerides, olive oil, soybean oil, sesame oil, peanut oil, and castor oil; Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Preferably, the additive is selected from any one of sodium oleate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, folic acid, pantothenic acid, niacin, and taurine; preferably, the content of the additive is 0.02g-0.5g; or, the additive is a base, such as an organic base or an inorganic base; the pH of the formulation is 7.0-7.

5.

7. The emulsion according to any one of claims 1-6, characterized in that, The single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components: Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2; or, the injectable oil is selected from medium-chain triglycerides. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Alternatively, the single-dose formulation (100 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:

2. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Alternatively, the single-dose formulation (100 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the oil for injection is selected from medium-chain triglycerides; Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Alternatively, the single-dose formulation (200 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:

1. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate; Alternatively, the single-dose formulation (200 mL) of the etoricoxib injection emulsion may comprise the following components: The single-dose formulation also includes an additive; the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide. The pH of the single-dose formulation is 7.0-7.5; Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:

1. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate; Alternatively, a single-dose formulation (200 mL, 400 mL, 800 mL, or 1200 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:

1. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate.

8. The emulsion according to any one of claims 1-7, characterized in that, The single-dose formulation (100 mL) of the etoricoxib injection emulsion comprises the following components: Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:2; or, the injectable oil is selected from medium-chain triglycerides. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Alternatively, the single-dose formulation (100 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the injectable oil comprises medium-chain triglycerides and soybean oil; preferably, the mass ratio of medium-chain triglycerides to soybean oil is 3:

2. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Alternatively, the single-dose formulation (100 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the oil for injection is selected from medium-chain triglycerides; Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate; Alternatively, the single-dose formulation (200 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:

1. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate; Alternatively, the single-dose formulation (200 mL) of the etoricoxib injection emulsion may comprise the following components: The single-dose formulation also includes an additive; the additive is a base, such as an organic base or an inorganic base, such as sodium hydroxide. The pH of the single-dose formulation is 7.0-7.5, for example 7.1, 7.2, 7.3, 7.4; Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:

1. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate; Alternatively, a single-dose formulation (200 mL, 400 mL, 800 mL, or 1200 mL) of the etoricoxib injection emulsion may comprise the following components: Preferably, the injection oil includes injection oil-3 and injection oil-4; injection oil-3 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; injection oil-4 is selected from any one of olive oil, soybean oil, sesame oil, castor oil, and peanut oil; preferably, the mass ratio of injection oil-3 to injection oil-4 is 1:4 to 4:

1. Preferably, the injectable surfactant is selected from egg yolk lecithin or hydrogenated soybean lecithin; Preferably, the injectable osmotic pressure regulator is selected from glycerol; Preferably, the additive is selected from sodium oleate, sodium cholate, sodium taurocholate, sodium deoxycholate, or sodium glycocholate; Preferably, the single-dose prescription optionally further includes vitamins; preferably, the vitamin content is 1mg-1000mg; preferably, the vitamins are selected from vitamin B1, vitamin B2, vitamin B6, vitamin B12, carotene, vitamin C, vitamin E, and vitamin D3. Preferably, the single-dose formulation optionally further includes carbohydrates; preferably, the carbohydrate content is 4000mg-24000mg; preferably, the carbohydrates are selected from sucrose, glucose, fructose, and lactose. Preferably, the single-dose formulation optionally further comprises amino acids; preferably, the content of amino acids is 4000 mg; preferably, the amino acids are selected from lysine, leucine, methionine, and phenylalanine.

9. A method for preparing the emulsion according to any one of claims 1-8, the method comprising the following steps: (1) Preparation of oil phase: Weigh the oil for injection, add etoricoxib, dissolve and set aside; (2) Preparation of aqueous phase: Weigh the injectable emulsifier, additive and injectable osmotic pressure regulator, add water, dissolve and set aside; (3) Mix the aqueous phase in step (2) with the oil phase in step (1), and add water to obtain the emulsion.

10. The use of the emulsion according to any one of claims 1-8 in the preparation of a medicament for treating pain, fever, and inflammation; Preferably, the inflammation includes osteoarthritis, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, such as the acute phase and chronic phase of osteoarthritis; Preferably, the pain includes orthopedic pain and postoperative pain; Preferably, the fever includes fever caused by infection, drug reaction, allergic reaction, transfusion reaction, stroke, surgery, heatstroke, rheumatic disease, cancer, or fever of unknown cause.

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