Afacalone fat emulsion injection and preparation method thereof

Abstract

The invention relates to an alfasalone fat emulsion injection and a preparation method thereof. The alfasalone fat emulsion injection comprises alfasalone and pharmaceutically acceptable salts thereof, an oil phase, an emulsifier, a co-emulsifier, an osmotic pressure regulator, a stabilizer, a pH value regulator and water for injection.

Description

Alfaxalone fat emulsion injection and preparation method thereof Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular, relates to an alfaxalone fat emulsion injection and a preparation method thereof. Background Art

[0002] Alphaxalone has sedative, anesthetic, anticonvulsant, and neuroprotective properties by modulating GABA A receptors. As a potent neuroactive steroid anesthetic, alphaxalone lacks progestogenic, estrogenic, mineralocorticoid, or thymolytic activity.

[0003] Althesin is an intravenous injection consisting of alfaxalone and alphadolone in a 3:1 ratio. While alphadolone is only half as potent as the former, it triples its solubility. Each milliliter of Althesin solution contains 9 mg of alfaxalone and 3 mg of alphadolone. Althesin achieves rapid onset and offset of anesthetic effects, with minimal vascular irritation and only mild cardiovascular and respiratory side effects.

[0004] To improve the solubility of althesin, the polyethoxylated castor oil excipient Cremophor EL (CAS Reg. No. 61791-12-6) is often added to intravenous formulations. This drug was used in clinical anesthesia practice in many countries between 1972 and 1984 for induction and maintenance of anesthesia. Since 1984, althesin has been withdrawn from the market as an intravenous anesthetic in humans. Despite its high therapeutic index, althesin occasionally causes unpredictable but severe allergic reactions.

[0005] Chinese patent CN94190450.4 discloses an alfaxalone castor oil emulsion, in which Cremophor EL is a surfactant that forms micelles in aqueous solution when its concentration exceeds the critical micelle concentration. Cremophor EL is an excellent encapsulating polymer that can significantly increase the solubility of water-insoluble drugs. Because the micelles decompose when diluted below their critical micelle concentration, Cremophor EL formulations can effectively release alfaxalone and make it bioavailable for absorption by the central nervous system. Although Cremophor EL is a good solvent for dissolving neuroactive steroid anesthetics (such as alfaxalone), its biological activity has caused severe anaphylactic-like hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, red blood cell aggregation, and peripheral neuropathy.

[0006] Injectable emulsions must have very small droplet sizes. In order to avoid capillary blockage and embolism in the blood circulation, the Chinese Pharmacopoeia Part 4 General Chapter 0102 on emulsion injections stipulates that the average particle size cannot exceed 0.5 microns.

[0007] Furthermore, despite being thermodynamically unstable systems, emulsions are expected to be physically and chemically stable during storage. The droplet size limit requirements defined in General Chapter 0102 of Part IV of the Chinese Pharmacopoeia apply throughout the specified shelf life, which typically extends to 2-3 years or longer for commercial pharmaceutical formulations. All true emulsions are thermodynamically unstable and may undergo processes that tend to increase droplet size over time. These include direct droplet coalescence, where two droplets collide to form a single, new droplet, and aggregation, where droplets adhere to form larger clumps. Aggregation can, in some cases, be a precursor to further coalescence into larger droplets. Ultimately, these processes may result in free oil being visible on the surface of the emulsion, or large aggregates that rise to the surface of the container, a phenomenon known as "creaming." Droplet size measurements can measure the initial size increase and thus predict the physical stability of an emulsion at an early stage, before the formulation shows visible changes to the naked eye.

[0008] In addition, the drug components may degrade, for example, lipophilic drugs will separate into the oil phase, which will provide a certain degree of protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation of parenteral fat emulsions includes oxidation of unsaturated fatty acid residues present in triglycerides and lecithin and hydrolysis of phospholipids, which leads to the generation of free fatty acids (FFA) and lysophospholipids. These degradation products lower the pH value, which may further promote degradation. Therefore, the pH value should be controlled during the production process, and the parenteral emulsion formulation can include a buffer to provide additional control. Any drop in pH value within the specified storage period can indicate chemical degradation.

[0009] For example, in charge-stabilized emulsions, such as those using lecithin as an emulsifier, the stabilizing charge can vary depending on the pH. Therefore, changes in pH due to chemical degradation can also accelerate physical degradation. If the emulsion is sterically stabilized, for example, by poly(ethylene oxide) surfactants, changes in pH typically have little effect on emulsion stability.

[0010] The fat emulsion injection of the present invention requires a high shear homogenization step to achieve a droplet size small enough for sterilization and intravenous administration. In order to contain alfaxalone in the emulsion in a droplet size small enough to be sterilized by filtration while meeting the requirements of the Chinese Pharmacopoeia throughout the specified shelf life of the formulation, the inventors have conducted extensive research on its formulation and process.

[0011] Fat overload syndrome (FOS) is a syndrome characterized by elevated triglycerides caused by the infusion rate and / or dose of fat emulsion exceeding the body's fat clearance capacity. Clinical manifestations include hepatosplenomegaly, jaundice, hypoproteinemia, fever, acute respiratory distress syndrome (ARDS), metabolic acidosis, thrombocytopenia, bleeding, and diffuse intravascular hemorrhage (DIC). The main causes of FOS can be attributed to two factors: first, excessive use of FOS in patients with normal fat clearance capacity; second, regular use of FOS in patients with decreased fat clearance capacity.

[0012] The concentration of commercially available propofol is 10 mg / ml, and the potency of alfaxalone is 5 times that of propofol. Theoretically, 2 mg / ml of alfaxalone can achieve the anesthetic potency of 10 mg / ml of propofol. If alfaxalone can be prepared into 6 mg / ml, the intake of phospholipids and injectable oils will be reduced, which will be more beneficial for some obese and hyperlipidemia patients.

[0013] Alfadolone has only half the potency of alfaxalone, but it can triple the solubility of alfaxalone, and the document Mark S.Althesin-a new intravenous anaesthesia[J].Canda.Anaesth 1973(20):186-191 reports that alfadolone has a solubility-promoting effect on alfaxalone. The present application provides a fat emulsion injection containing only alfaxalone, but in the absence of the alfadolone cosolvent, the solubility of alfaxalone will be even lower. To prepare a fat emulsion injection containing only high potency and high drug loading of alfaxalone, solubility will be a technical problem that urgently needs to be solved.

[0014] Summary of the Invention

[0015] The present invention aims to at least partially solve one of the above-mentioned technical problems or at least provide a useful commercial option. To this end, one object of the present invention is to provide an alfaxalone fat emulsion injection with high potency, high drug loading, stable drug quality, no vascular irritation, high clinical safety, and good compliance.

[0016] One aspect of the present invention provides an alfaxalone fat emulsion injection, comprising alfaxalone or a pharmaceutically acceptable salt thereof, injection oil, an emulsifier, an emulsifier aid, an osmotic pressure regulator, a stabilizer, a pH regulator and water for injection.

[0017] In some specific embodiments, the injection oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides.

[0018] In some specific embodiments, the weight ratio of soybean oil to medium-chain triglycerides in the mixture of soybean oil and medium-chain triglycerides is 1-5:1-5, preferably 1:1.

[0019] In some specific embodiments, the weight ratio of the optional alfaxalone or a pharmaceutically acceptable salt thereof (calculated as alfaxalone) to the injection oil is 1-10:50-300, preferably 1-10:100-300, preferably 1-6:100-300, preferably 1-3:100-300, and preferably 1-3:100-200. In some specific embodiments, the amount of injection oil in the alfaxalone fat emulsion injection accounts for 10% to 30% of the mass concentration of the fat emulsion injection, preferably 10% to 20%.

[0020] In some specific embodiments, the average particle size of the oil phase in the alfaxalone fat emulsion injection is 0.15 to 0.4 μm, preferably 0.15 to 0.3 μm, more preferably 0.15 to 0.25 μm.

[0021] In some specific embodiments, the alfaxalone fat emulsion injection uses alfaxalone or a pharmaceutically acceptable salt thereof with a purity greater than 95%, more preferably alfaxalone or a pharmaceutically acceptable salt thereof with a purity greater than 98%.

[0022] In some specific embodiments, the content of alfaxalone or a pharmaceutically acceptable salt thereof in the alfaxalone fat emulsion injection is 1 to 10 mg / ml, preferably 2 to 8 mg / ml, and preferably 2 to 4 mg / ml.

[0023] In some specific embodiments, the content of injection oil in the alfaxalone fat emulsion injection is 100-300 mg / ml, preferably 100-200 mg / ml.

[0024] In some specific embodiments, the content of the emulsifier in the alfaxalone fat emulsion injection is 6 to 15 mg / ml, preferably 9 to 15 mg / ml.

[0025] In some specific embodiments, the content of the co-emulsifier in the alfaxalone fat emulsion injection is 0.05-20 mg / ml, preferably 0.1-20 mg / ml, preferably 0.1-10 mg / ml, and preferably 0.5-10 mg / ml.

[0026] In some specific embodiments, the content of the stabilizer in the alfaxalone fat emulsion injection is 0.1 to 0.3 mg / ml.

[0027] In some specific embodiments, the content of the osmotic pressure regulator in the alfaxalone fat emulsion injection is 22-25 mg / ml, preferably 22.5 to 25 mg / ml.

[0028] In some specific embodiments, the content of the emulsifier in the alfaxalone fat emulsion injection is 0.6%-1.5% (wt), preferably 0.9%-1.5% (wt).

[0029] In some specific embodiments, the content of the co-emulsifier in the alfaxalone fat emulsion injection is 0.05%-1.0% (wt), preferably 0.2% (wt), 0.4% (wt), 0.6% (wt) or 0.8% (wt).

[0030] In some specific embodiments, the zeta potential of the alfaxalone fat emulsion injection is 36 to 60 mV.

[0031] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 5.0 to 8.5, preferably 6.0 to 8.5.

[0032] In some specific embodiments, the emulsifier of the alfaxalone fat emulsion injection is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2.

[0033] In some specific embodiments, the osmotic pressure regulator is glycerol.

[0034] In some specific embodiments, the co-emulsifier is a bile acid compound or a salt thereof, preferably at least one of glycocholic acid, cholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, or taurochenodeoxycholic acid, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the salt of the bile acid compound is sodium glycocholate, sodium cholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium chenodeoxycholate, sodium glycochenodeoxycholate, or sodium taurochenodeoxycholate.

[0035] In some specific embodiments, the emulsifier of the alfaxalone fat emulsion injection is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2, and a pH regulator capable of adjusting the pH to 5.0 to 8.5, preferably 6.0 to 8.5; and

[0036] Optionally, the osmotic pressure regulator is glycerol,

[0037] Optionally, the co-emulsifier is a bile acid compound or a salt thereof,

[0038] Optionally, the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate,

[0039] Optionally, the pH regulator is sodium hydroxide,

[0040] and the balance water for injection.

[0041] In some specific embodiments, the emulsifier of the alfaxalone fat emulsion injection is at least one selected from egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2, and a pH regulator capable of adjusting the pH value to a required amount of 6.0 to 8.5; and

[0042] Optionally, the osmotic pressure regulator is glycerol;

[0043] Optionally, the co-emulsifier is a bile acid compound or a salt thereof, preferably at least one of glycocholic acid, cholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, or taurochenodeoxycholic acid, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the salt of the bile acid compound is sodium glycocholate, sodium cholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium chenodeoxycholate, sodium glycochenodeoxycholate, or sodium taurochenodeoxycholate;

[0044] Optionally, the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate,

[0045] Optionally, the pH regulator is sodium hydroxide,

[0046] And the remaining amount of water for injection.

[0047] In some specific embodiments, the alfaxalone fat emulsion injection contains 0.05%-1.0% (w / v), preferably 0.2% (w / v), 0.4% (w / v), 0.6% (w / v) or 0.8% (w / v) of an emulsifier.

[0048] In some specific embodiments, the alfaxalone fat emulsion injection contains 0.05%-1.0% (w / v), preferably 0.2% (w / v), 0.4% (w / v), 0.6% (w / v) or 0.8% (w / v) of bile acid compounds or salts thereof.

[0049] In some specific embodiments, the alfaxalone fat emulsion injection contains 0.6%-1.5% (w / v), preferably 0.6% (w / v), 0.9% (w / v), 1.2% (w / v), 1.5% (w / v) of emulsifier, and further preferably 0.9% (w / v), 1.2% (w / v), 1.5% (w / v) of emulsifier.

[0050] In some specific embodiments, the alfaxalone fat emulsion injection contains 0.05%-1.0% (w / v), preferably 0.2% (w / v), 0.4% (w / v), 0.6% (w / v) or 0.8% (w / v) sodium glycocholate.

[0051] In some specific embodiments, the alfaxalone fat emulsion injection contains 5%-15% (w / v), preferably 5% (w / v), 10% (w / v), 15% (w / v) soybean oil.

[0052] In some specific embodiments, the alfaxalone fat emulsion injection contains 5%-15% (w / v), preferably 5% (w / v), 10% (w / v), 15% (w / v) medium chain triglycerides.

[0053] In some specific embodiments, the alfaxalone fat emulsion injection contains 0.01%-0.03% (w / v), preferably 0.01% (w / v), 0.03% (w / v) of sodium oleate.

[0054] In some specific embodiments, the alfaxalone fat emulsion injection contains 2.25%-2.5% (w / v), preferably 2.25% (w / v), 2.5% (w / v) glycerol.

[0055] In some specific embodiments, the alfaxalone fat emulsion injection contains 0.6%-1.5% (w / v), preferably 0.6% (w / v), 0.9% (w / v), 1.2% (w / v), 1.5% (w / v) egg yolk lecithin, and further preferably 0.9% (w / v), 1.2% (w / v), 1.5% (w / v) egg yolk lecithin.

[0056] In some embodiments, the alfaxalone fat emulsion injection contains a bile acid compound or its salt as an emulsifier, wherein the alfaxalone fat emulsion injection contains 0.05%-1.0% (w / v), preferably 0.2% (w / v), 0.4% (w / v), 0.6% (w / v), or 0.8% (w / v) of sodium glycocholate; and the average particle size of the oil phase in the alfaxalone fat emulsion injection is 0.15 to 0.4 μm, preferably 0.15 to 0.3 μm, and more preferably 0.15 to 0.25 μm. Furthermore, the content of alfaxalone or its pharmaceutically acceptable salt in the alfaxalone fat emulsion injection is 2 to 4 mg / ml. Furthermore, the alfaxalone fat emulsion injection contains 0.6%-1.5% (wt), preferably 0.9%-1.5% (wt) of egg yolk lecithin as an emulsifier. Furthermore, the zeta potential of the alfaxalone fat emulsion injection is 36 to 60 mV. Furthermore, the pH value of the alfaxalone fat emulsion injection is 5.0 to 8.5, preferably 6.0 to 8.5.

[0057] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 5.0-8.5, and the components, calculated by weight, include: 1-10 parts of alfaxalone; 50-200 parts of soybean oil; 0-100 parts of medium-chain triglycerides; 9-15 parts of emulsifier; 0.1-20 parts of co-emulsifier; 0.1-0.3 parts of stabilizer; and 22-25 parts of glycerol.

[0058] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and the components, calculated by weight, include: 1-10 parts of alfaxalone; 50-200 parts of soybean oil; 0-100 parts of medium-chain triglycerides; 9-15 parts of emulsifier; 0.1-20 parts of co-emulsifier; 0.1-0.3 parts of stabilizer; and 22-25 parts of glycerol.

[0059] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and the components, calculated by weight, include: 2-8 parts of alfaxalone; 50-200 parts of soybean oil; 0-100 parts of medium-chain triglycerides; 9-12 parts of emulsifier; 0.1-10 parts of co-emulsifier; 0.1-0.3 parts of stabilizer; and 22-25 parts of glycerol.

[0060] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 50-100 mg of soybean oil; 50-100 mg of medium-chain triglycerides; 9-15 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate, the amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0061] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 100-200 mg of soybean oil; 9-15 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0062] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 50-100 mg of soybean oil; 50-100 mg of medium-chain triglycerides; 9-15 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; and 25 mg of glycerol.

[0063] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 100-200 mg of soybean oil; 9-15 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0064] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 9-15 mg of egg yolk lecithin; 0.1-10 mg of glycocholic acid; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection;

[0065] Alternatively, the pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 200 mg of soybean oil; 9-15 mg of egg yolk lecithin; 0.1-10 mg of bile acid; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0066] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 2-8 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 9-12 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection;

[0067] Alternatively, the pH value is 6.0 to 8.5, and each ml of the alfaxalone fat emulsion injection contains: 2 to 8 mg of alfaxalone; 200 mg of soybean oil; 9 to 12 mg of egg yolk lecithin; 0.1 to 10 mg of sodium glycocholate; 0.1 to 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0 to 8.5; and the balance of water for injection;

[0068] Alternatively, the pH value is 6.0 to 8.5, and each ml of the alfaxalone fat emulsion injection contains: 2 to 8 mg of alfaxalone; 100 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 to 12 mg of egg yolk lecithin; 0.1 to 20 mg of sodium glycocholate; 0.1 to 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0 to 8.5; and the balance of water for injection;

[0069] Alternatively, the pH value is 6.0 to 8.5, and each ml of the alfaxalone fat emulsion injection contains: 2 to 8 mg of alfaxalone; 100 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 to 12 mg of egg yolk lecithin; 0.1 to 10 mg of sodium glycocholate; 0.1 to 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0 to 8.5; and the balance of water for injection;

[0070] Alternatively, the pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 2-8 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9-12 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0071] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 50-200 mg of soybean oil; 50-100 mg of medium-chain triglycerides; 9-15 mg of egg yolk lecithin; 0.1-20 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; 22.5-25 mg of glycerol; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0072] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: 1-10 mg of alfaxalone; 50-200 mg of soybean oil; 50-100 mg of medium-chain triglycerides; 9-15 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; 22.5-25 mg of glycerol; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection;

[0073] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 2 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 4 mg of egg yolk lecithin E-80; 8 mg of egg yolk lecithin PL-100M; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0074] Alternatively, the pH value is 6.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 3 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 2 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0; and the balance of water for injection;

[0075] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 4 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0076] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 4 mg of alfaxalone; 200 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0077] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 4 mg of alfaxalone; 200 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0078] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 2 mg of alfaxalone; 100 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0079] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 4 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0080] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 4 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0081] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 4 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0082] Alternatively, the pH value is 7.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 5 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 7.0; and the balance of water for injection;

[0083] Alternatively, the pH value is 7.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 5 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 7.0; and the balance of water for injection;

[0084] Alternatively, the pH value is 7.5 and each 1 ml of the alfaxalone fat emulsion injection contains: 6 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 2 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 7.5; and the balance of water for injection;

[0085] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: 7 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0086] Alternatively, the pH value is 7.5, and each 1 ml of the alfaxalone fat emulsion injection contains: alfaxalone 7 mg;

[0087] Soybean oil 100 mg; medium-chain triglycerides 100 mg; egg yolk lecithin 12 mg; sodium glycocholate 1 mg; sodium oleate 0.3 mg; glycerol 25 mg; sodium hydroxide in an amount sufficient to control the pH of the injection to 7.5; and the balance of water for injection.

[0088] In some specific embodiments, the pH value of the alfaxalone fat emulsion injection is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection is composed of 1-10 mg of alfaxalone; 50-200 mg of soybean oil; 50-100 mg of medium-chain triglycerides; 9-15 mg of egg yolk lecithin; 0.1-10 mg of sodium glycocholate; 0.1-0.3 mg of sodium oleate; 22.5-25 mg of glycerol; sodium hydroxide in an amount required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0089] Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection is composed of 2 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 4 mg of egg yolk lecithin E-80; 8 mg of egg yolk lecithin PL-100M; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0090] Alternatively, the pH value is 6.0, and each ml of the alfaxalone fat emulsion injection is composed of 3 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 2 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0; and the balance of water for injection;

[0091] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 4 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0092] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 4 mg of alfaxalone; 200 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0093] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 4 mg of alfaxalone; 200 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0094] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 2 mg of alfaxalone; 100 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0095] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 4 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0096] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 4 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0097] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection is composed of 4 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0098] Alternatively, the pH value is 7.0, and each ml of the alfaxalone fat emulsion injection is composed of 5 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 3 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 7.0; and the balance of water for injection;

[0099] Alternatively, the pH value is 7.0, and each ml of the alfaxalone fat emulsion injection is composed of 5 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 7.0; and the balance of water for injection;

[0100] Alternatively, the pH value is 7.5 and each ml of the alfaxalone fat emulsion injection is composed of 6 mg of alfaxalone; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 2 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 7.5; and the balance of water for injection;

[0101] Alternatively, the pH value is 8.0, and each ml of the alfaxalone fat emulsion injection comprises 7 mg of alfaxalone; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin; 4 mg of sodium glycocholate; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the balance of water for injection;

[0102] Alternatively, the pH value is 7.5, and each 1 ml of the alfaxalone fat emulsion injection contains 7 mg of alfaxalone;

[0103] Soybean oil 100 mg; medium chain triglycerides 100 mg; egg yolk lecithin 12 mg; sodium glycocholate 1 mg; sodium oleate 0.3 mg; glycerol 25 mg; sodium hydroxide in an amount sufficient to control the pH of the injection to 7.5; and the balance water for injection.

[0104] Another aspect of the present invention provides a method for preparing alfaxalone fat emulsion injection, comprising:

[0105] (1) Heat the injection oil to 50° C. to 75° C., then add the emulsifier and alfaxalone, mix, and shear until all the oil is dissolved and evenly dispersed, so as to obtain a first mixture containing an alfaxalone oil phase;

[0106] Preferably, the injection oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides; more preferably, the injection oil is a mixture of soybean oil and medium-chain triglycerides in a weight ratio of 1:1;

[0107] Preferably, the emulsifier is egg yolk lecithin; more preferably, the emulsifier is a mixture of egg yolk lecithin PL-100M and egg yolk lecithin E-80;

[0108] (2) heating water for injection to 50° C. to 75° C., then adding an emulsifier, a stabilizer, and an osmotic pressure regulator and stirring uniformly to obtain a second mixture forming an aqueous phase; preferably, the emulsifier is sodium glycocholate, the stabilizer is sodium oleate, and the osmotic pressure regulator is glycerol;

[0109] (3) mixing the first mixture and the second mixture while shearing to obtain a third mixture that forms colostrum;

[0110] (4) adjusting the pH of the third mixture to 6.5 to 11.5, preferably 6.5 to 10.5, and more preferably 6.5 to 10, with a pH adjuster to obtain a fourth mixture, and homogenizing once under low pressure to obtain a fifth mixture; preferably, the pH adjuster is sodium hydroxide;

[0111] (5) high-pressure homogenizing the fifth mixture for 3 or more times, preferably 4-8 times, more preferably 5-6 times, and during the homogenization process, nitrogen is injected below the liquid surface until the liquid is saturated with nitrogen, so as to obtain a sixth mixture;

[0112] (6) The sixth mixture is bottled, filled with nitrogen for protection, and sterilized with moist heat to obtain alfaxalone fat emulsion injection with a pH value of 6.0 to 8.5.

[0113] Another aspect of the present invention provides a method for preparing alfaxalone fat emulsion injection, comprising:

[0114] (1) Heat the injection oil to 50° C. to 75° C., then add the emulsifier and alfaxalone, mix, and shear until all the oil is dissolved and evenly dispersed, so as to obtain a first mixture containing an alfaxalone oil phase;

[0115] Preferably, the injection oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides; more preferably, the injection oil is a mixture of soybean oil and medium-chain triglycerides in a weight ratio of 1:1;

[0116] Preferably, the emulsifier is egg yolk lecithin; more preferably, the emulsifier is a mixture of egg yolk lecithin PL-100M and egg yolk lecithin E-80;

[0117] (2) heating water for injection to 50° C. to 75° C., then adding an emulsifier, a stabilizer, an osmotic pressure regulator, and a pH regulator and stirring uniformly to obtain a second mixture forming an aqueous phase; the pH is 7 to 11.5, preferably 7 to 10.5, and preferably 7 to 10. Preferably, the emulsifier is sodium glycocholate, the stabilizer is sodium oleate, the osmotic pressure regulator is glycerol, and the pH regulator is sodium hydroxide;

[0118] (3) mixing the first mixture and the second mixture while shearing to obtain a third mixture that forms colostrum;

[0119] (4) Optionally, adjusting the pH of the third mixture to 6.5 to 11.5, preferably 6.5 to 10.5, and preferably 6.5 to 10, with a pH adjuster to obtain a fourth mixture; preferably, the pH adjuster is sodium hydroxide;

[0120] (5) homogenizing the mixture obtained in (3) or (4) once at low pressure to obtain a fifth mixture; homogenizing the fifth mixture at high pressure for more than three times, preferably 4-8 times, more preferably 5-6 times, and filling the mixture with nitrogen below the liquid level during the homogenization process until the mixture is saturated with nitrogen, so as to obtain a sixth mixture;

[0121] (6) The sixth mixture is bottled, filled with nitrogen for protection, and sterilized with moist heat to obtain alfaxalone fat emulsion injection with a pH value of 6.0 to 8.5.

[0122] In some specific embodiments, the shear mixing is performed at a rotation speed of 5000-16000 rpm for 5-25 min; preferably, the shear rotation speed during the mixing process is 10000 rpm, and the shear rotation speed after the mixing is completed is 15000-16000 rpm.

[0123] In some specific embodiments, in step (3) of the method for preparing alfaxalone fat emulsion, shear mixing is performed at a rotation speed of 5000 to 16000 rpm for 5 to 25 minutes.

[0124] In some specific embodiments, the low-pressure homogenization in step (4) of the method for preparing alfaxalone fat emulsion is performed at a pressure of 100 / 160 bar, and the high-pressure homogenization in step (5) is performed at a pressure of 500-1000 bar for 5 to 8 times, and the high-pressure homogenization temperature is controlled at 30° C. to 70° C.

[0125] Definition of terms:

[0126] The term "isotonic" means that it has an osmotic pressure equal to or similar to that of physiological body fluids. Body fluids generally have an osmotic pressure that is often described as corresponding to a 0.9% (weight / volume) sodium chloride aqueous solution. The present application uses glycerol to adjust isotonicity, and the amount of glycerol used in each 1 ml of the alfaxalone fat emulsion injection contains 22 to 25 mg of glycerol, specifically 22 mg / ml, 22.5 mg / ml, 23 mg / ml, 23.5 mg / ml, 24 mg / ml, 24.5 mg / ml, and specifically 25 mg / ml.

[0127] The term "medium-chain oil" refers to medium-chain triglycerides and medium-chain triglycerides; the term "long-chain oil" refers to soybean oil.

[0128] The term "w / v" refers to the mass content of a component per unit volume of injection, and the unit is "g / ml".

[0129] The term "co-emulsifier" generally plays a positive role in the stability of the emulsion system. The co-emulsifier of the present application is specifically a bile acid compound or its salt, more specifically glycocholic acid and sodium glycocholate, cholic acid, taurocholic acid, glycodeoxycholic acid or taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid or taurochenodeoxycholic acid, etc., which can improve the solubility of the drug, improve the stability of the fat emulsion and the drug, etc.

[0130] The term "AFSL" stands for alfaxalone.

[0131] "About" in this specification can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the numerical value. Unless otherwise expressly stated, all numerical values ​​provided herein are modified by the term "about".

[0132] Technical effect:

[0133] The solubility of alfaxalone in castor oil is higher than that of medium-chain oil and long-chain oil. By exploring the optimal ratio of injection oil, the present invention found that the optimal ratio of injection medium-chain and long-chain oils with poor solubility in alfaxalone is used, and the injection oil content should be within a certain appropriate range to ensure that the emulsifier can completely emulsify the oil phase and the water phase.

[0134] Compared with the preparation without sodium glycocholate, the preparation of the present invention can only meet the preparation of small specifications (2 mg / ml). The preparation of large specifications (4 mg / ml) will cause the raw materials to precipitate after refrigeration for 10 days, and there will be oil droplets on the surface of the fat emulsion, and the emulsion will be broken, and the stability is poor.

[0135] Sodium glycocholate synergistically enhances dissolution with lecithin, resulting in a lower average particle size than the group without sodium glycocholate. Particle size uniformity is also good, and stability testing confirms that the pH is stable, with no significant decrease. This indicates that the emulsion is stable and conducive to storage, with no demanding storage conditions. This suggests that sodium glycocholate or glycocholic acid has both solubilizing and stabilizing effects, increasing the affinity between the drug and the oil phase, thereby improving the stability of the formulation. Compared to castor oil formulations, the formulations exhibit smaller particle size, greater stability, significantly reduced allergic reactions, and greater safety.

[0136] In addition, when glycocholic acid or sodium glycocholate is added to the preparation, the drug loading capacity can be significantly increased from 2 mg / ml to 6 mg / ml, and the drug loading capacity is increased three times compared with the preparation without addition.

[0137] The fat emulsion provided in this application has been confirmed by pharmacological experiments to be significantly lower in sensitization than the emulsion containing castor oil prepared according to CN94190450.4, with a significantly smaller average particle size than the castor oil emulsion group, a higher encapsulation rate than the castor oil preparation group, and less injection pain than the castor oil emulsion group. All stability indicators are better than those of the castor oil emulsion group.

[0138] The alfaxalone fat emulsion injection described herein avoids the use of excipients such as castor oil and cyclodextrin, which are prone to causing adverse reactions. The emulsion is formulated using a novel formula, employing soybean oil and medium-chain triglycerides in a 1:1 weight ratio as the injection oil. Sodium oleate is also used as a stabilizer, egg yolk lecithin E-80 as an emulsifier, and sodium glycocholate or glycocholic acid as a co-emulsifier. The resulting alfaxalone fat emulsion injection sample has more stable quality. The use of sodium glycocholate or glycocholic acid as a co-emulsifier significantly improves the stability of the alfaxalone fat emulsion injection, preventing instability in the formulation, such as aggregation and merging of fat emulsion droplets, caused by changes in storage conditions during storage. The formulation is non-irritating to blood vessels, improving safety and compliance in clinical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0139] FIG1 is a diagram showing the colostrum layers of 1.2% sodium glycocholate fat emulsion.

[0140] FIG2 is a diagram showing the colostrum layers of 1.4% sodium glycocholate fat emulsion.

[0141] FIG3 is a diagram showing the colostrum layers of 2.0% sodium glycocholate fat emulsion.

[0142] FIG4 is a graph showing the precipitation of API in a sterilized sample without the addition of 4 mg / ml sodium glycocholate after 20 days.

[0143] FIG5 is a graph showing the determination of histamine content in mouse plasma after intravenous injection.

[0144] FIG6 is a diagram of the rat myoelectric stimulation test. DETAILED DESCRIPTION

[0145] Egg yolk lecithin: E80, purchased from Lipoid GmbH, Germany; glycerol was purchased from Shantou Jiahe Biotechnology Co., Ltd.; sodium glycocholate was purchased from Hebei Zhentian Food Additive Co., Ltd.; soybean oil was purchased from Guangzhou Baiyunshan Hanfang Modern Pharmaceutical Co., Ltd.; medium-chain triglycerides (57.1% caprylic acid, 42.8% capric acid) were purchased from Liaoning Xinxing Pharmaceutical Co., Ltd.; sodium oleate was purchased from Lipoid GmbH, Germany; alfaxalone was prepared by Jiangsu Enhua Pharmaceutical Co., Ltd. with a purity of more than 95%; propofol (manufacturer: Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: BB200215); Cremophor EL (manufacturer: Sinopharm Chemical Reagent Co., Ltd., batch number: 20220104); sulfobutyl-β-cyclodextrin / SBE-β-CD (manufacturer: Zibo Qianhui Biotechnology Co., Ltd., batch number: SB210911).

[0146] Example 1-4 Preparation of Emulsion Without Sodium Glycocholate (Batch Size 1000 ml)

[0147] Preparation of 0.1mol / L sodium hydroxide: Weigh 0.4g of sodium hydroxide, dissolve it in appropriate amount of water, let it cool, transfer it to a 100ml volumetric flask, and dilute to the scale for later use.

[0148] Oil phase preparation: Add 100 g each of soybean oil and medium-chain triglycerides to a 500 ml beaker and heat in a 70°C water bath. Weigh egg yolk lecithin and alfaxalone (AFSL) according to the preparation amount and add to the oil phase at 10,000 rpm for 5 minutes to prepare the oil phase.

[0149] Preparation of aqueous phase: Weigh an appropriate amount of water for injection into a 2000 ml beaker and heat it in a water bath to control the water temperature at 70°C; add 0.3 g of sodium oleate and 25 g of glycerol to the aqueous phase and stir evenly with a glass rod to prepare the aqueous phase.

[0150] Colostrum preparation: The oil phase was added to the aqueous phase while shearing (10,000 rpm) and the colostrum temperature was controlled at 70°C. After the addition of the oil phase, the shear rate was adjusted to 15,400 rpm and sheared for 5 minutes. The pH of the colostrum was adjusted to 9.0 with 0.1 mol / L sodium hydroxide to prepare colostrum.

[0151] Finished product preparation: Low-pressure homogenization: 100 bar / 160 bar, homogenize once. High-pressure homogenization: 100 bar / 600 bar, homogenize six times. After homogenization, the sample is sealed, filled with nitrogen, and sterilized (121°C, 15 minutes).

[0152] 1.1 Preparation composition

[0153] 1.2 Experimental Results

[0154] 1.3 Conclusion: The APIs of all four specifications were completely dissolved in the oil phase, and the solutions were clear and transparent. The appearance, encapsulation efficiency, pH, particle size, and Zeta potential of the finished products of the four batches met the requirements immediately after sterilization. However, the content tended to decrease with increasing specifications, especially in Example 4 (5 mg / ml), where the content was only 94.16% immediately after sterilization.

[0155] 1.4 Influencing factors test

[0156] Samples of 2mg / ml, 3mg / ml, 4mg / ml, and 5mg / ml were placed under high temperature (60°C, 40°C) and low temperature (4°C) conditions. Samples were taken and tested after 5 days, 10 days, and 30 days. The results are shown in the table below.

[0157] Example 1: (Specification: 2 mg / ml)

[0158] Example 2: (Specification: 3 mg / ml)

[0159] Example 3: (Specification: 4 mg / ml)

[0160] Example 4: (Specification: 5 mg / ml)

[0161] Conclusion: The appearance, content, potential, and particle size of the 2 mg / ml sample were all within acceptable limits after 30 days of storage. However, the content of the 4 mg / ml sample decreased after 30 days, and the finished product showed precipitation of the API (i.e., active ingredient release) after 10 days of storage at 4°C and 20 days at room temperature (see Figure 4). The content of the 5 mg / ml sample was low at 0°C after sterilization, and there was also precipitation of the API.

[0162] 1. Investigate different types and proportions of oil phase

[0163] Comparative Examples 1-2 were prepared with reference to the method disclosed in Example 1 of CN94190450.4

[0164] Oil Phase Preparation: Add the formulated amount of castor oil and soybean oil or castor oil to a 250 ml beaker and heat in a 70°C water bath. Weigh 2 g of AFSL and add it to the oil phase at 10,000 rpm for 2 minutes. Weigh 12 g of egg yolk lecithin and add it to the oil phase at 10,000 rpm for 5 minutes to prepare the oil phase.

[0165] Preparation of aqueous phase: Weigh 861.5 g of water for injection into a 2000 ml beaker and heat in a water bath to control the water temperature at 70°C; add 22.5 g of glycerol to the aqueous phase and stir evenly with a glass rod to prepare the aqueous phase.

[0166] Colostrum preparation: The oil phase was added to the aqueous phase while shearing (10,000 rpm) and the colostrum temperature was controlled at 70°C. After the addition of the oil phase, the shear rate was adjusted to 15,400 rpm and sheared for 5 minutes. The pH of the colostrum was adjusted to 9.0 with 0.1 mol / L sodium hydroxide to prepare colostrum.

[0167] Finished product preparation: Low-pressure homogenization: 100 bar / 160 bar, homogenize once. High-pressure homogenization: 100 bar / 600 bar, homogenize six times. After homogenization, the sample is sealed, filled with nitrogen, and sterilized (121°C, 15 minutes).

[0168] Experimental results

[0169] Conclusion: From the experimental observation, 10% castor oil can completely dissolve AFSL, and the content, potential and other indicators are within the qualified range. However, the particle size of the emulsion sample is greater than 0.5μm, which is unqualified according to the provisions of General Chapter 0102 of Part 4 of the Chinese Pharmacopoeia.

[0170] With reference to the test method of Example 1, the feasibility of preparing samples with different formulation compositions was attempted.

[0171] Preparation composition (Examples 5-9, preparation volume is 1000ml)

[0172] Experimental results

[0173] Conclusion: There were no significant differences in properties, content, encapsulation efficiency, pH value, and zeta potential among samples prepared with different oil phase ratios (soybean oil or a mixture of soybean oil and medium-chain triglycerides) (10%, 20%, and 30%). However, the average particle size showed a gradual increase with increasing oil phase ratio. The average particle size of the preparation containing 30% oil phase was greater than 0.4 μm, approaching the limit. The properties, encapsulation efficiency, pH value, content, and potential of the samples containing castor oil were all within the acceptable range, but the average particle size was greater than or close to 0.5 μm, which was significantly higher than that of the preparation without castor oil.

[0174] In summary, the type and proportion of the injection oil should be selected within an appropriate range to ensure that the emulsifier can completely emulsify the oil and aqueous phases. Therefore, the preferred range for the oil phase in the present invention is 10%-20%, and the preferred oil phase is soybean oil or a mixture of soybean oil and medium-chain triglycerides. The following examples are based on an oil phase ratio of 20% (a 1:1 ratio of soybean oil to medium-chain triglycerides).

[0175] 2. Investigating different phospholipid ratios

[0176] 2.1.1 Try using different proportions of phospholipids at a specification of 2 mg / ml to investigate the feasibility of the sample. The preparation method refers to Example 1 (batch size is 1000 ml)

[0177] 2.1.2 Sample test results:

[0178] 2.1.3 Conclusion: Within the phospholipid ratio range of 0.6%-1.5%, there is no obvious difference in content and potential. As the phospholipid ratio increases, the sample particle size tends to decrease, but there is little difference within the range of 0.9%-1.5%. The sample containing 0.6% phospholipid has a slight oily appearance.

[0179] 2.1.4 Results of influencing factors:

[0180] Example 10 batch of samples

[0181] Example 11 Batch of samples

[0182] Example 12 Batch of Samples

[0183] Example 13 batch of samples

[0184] 2.1.5 Conclusion: Compared to day 0, the results for samples containing 0.9%-1.5% phospholipids at 30 days were stable across all influencing factors, with no significant changes in content, particle size, or potential. However, for samples containing 0.6% phospholipids, the influencing factors showed an increase in average particle size and a tendency toward aggregation, indicating that the emulsion sample was unstable.

[0185] 3. Investigation of different emulsifiers

[0186] 3.1 Because API precipitation occurred during stability testing in the 4 mg / ml and 5 mg / ml emulsion samples prepared without the addition of sodium glycocholate, we attempted to add different co-emulsifiers (poloxamer 188, sodium glycocholate, Tween 80, or polyethylene glycol 15-hydroxystearate (HS15)) and phospholipids as composite emulsifiers to investigate the feasibility of preparing a 5 mg / ml emulsion sample.

[0187] Example 16: Preparation of an emulsion containing sodium glycocholate (1000 ml batch size)

[0188] Oil phase preparation:

[0189] Weigh the prepared amount of soybean oil and medium-chain triglycerides separately and heat them in a water bath at 60°C. Weigh the prepared amount of egg yolk lecithin and add it to the oil phase. Then weigh AFSL into the oil phase and shear at 10,000 rpm for 5 minutes.

[0190] Aqueous phase preparation:

[0191] Weigh an appropriate amount of water for injection into a 2000 ml beaker, heat it in a water bath, and control the water temperature at 60°C. Weigh the preparation amount of sodium glycocholate, sodium oleate, and glycerol into the aqueous phase and stir evenly to prepare the aqueous phase.

[0192] Colostrum preparation:

[0193] Add the oil phase to the aqueous phase while shearing (10,000 rpm) and maintain the colostrum temperature at 60°C. After the oil phase is added, adjust the shear rate to 15,400 rpm and shear for 5 minutes. Adjust the colostrum to a pH of approximately 9 with 0.5 mol / L sodium hydroxide.

[0194] Finished product preparation:

[0195] Low-pressure homogenization pressure: 100bar / 160bar, homogenize once. High-pressure homogenization pressure: 100bar / 600bar, homogenize six times. After homogenization, the sample is sealed, filled with nitrogen, and sterilized (121℃, 15min).

[0196] Examples 14, 15, and 17 were prepared by referring to the method of Example 16, except that different co-emulsifiers were replaced.

[0197] 3.2 Experimental results:

[0198] 3.3 Conclusion: Compared with the formulation in Example 16, the formulation in Example 14 exhibited oily appearance, while the formulations in Examples 15 and 17 showed precipitation of the API. This indicates that Tween 80, Poloxamer 188, and HS15 failed to enhance emulsification. The formulation in Example 16 met the required appearance, and parameters such as content, potential, and particle size were within acceptable limits. In summary, formulations containing sodium glycocholate can improve the stability of emulsion samples.

[0199] 3.4 Preparation composition (Specification: 4 mg / ml)

[0200] 3.5 Sample test results:

[0201] 3.6. Conclusion: The sample in Example 18 showed oily appearance, while the sample in Examples 19 and 20 showed API precipitation. This indicates that Tween 80, Poloxamer 188, and HS15 were ineffective in promoting solubilization. The visual properties of the samples in Examples 21-23 met the requirements, and indicators such as content, potential, and particle size were within the acceptable range. In summary, the preparations containing bile acid compounds or their salts can improve the stability of emulsion samples.

[0202] 4. Confirmation of the effect of sodium glycocholate

[0203] 4.1 Comparison of the solution without and with sodium glycocholate (batch size 1000 ml)

[0204] 4.2 Sample inspection results

[0205] 4.3 Conclusion: There is no significant difference in the content, potential, encapsulation efficiency and other indicators of the two preparation samples. The average particle size of the sample with sodium glycocholate preparation is smaller than that of the conventional preparation.

[0206] 4.4 Stability data

[0207] Example 24 batch of samples:

[0208] Example 25 batch of samples:

[0209] 4.5 Conclusion: Based on the stability data, the content, potential, average particle size, and other indicators of the sodium glycocholate preparation did not change significantly after 30 days of staking compared to time 0. However, the sample without sodium glycocholate showed a lower content after 10 days at low temperature, and the sample showed precipitation of the API. This suggests that the addition of sodium glycocholate improves the stability of the emulsion sample.

[0210] 5. Investigate the feasibility of preparing a larger formulation (containing glycocholic acid)

[0211] Preparation method

[0212] Oil phase preparation:

[0213] Weigh the prepared amount of soybean oil and medium-chain triglycerides separately and heat them in a water bath at 60°C. Weigh the prepared amount of egg yolk lecithin and add it to the oil phase. Then weigh AFSL separately into the oil phase and shear at 10,000 rpm for 5 minutes.

[0214] Aqueous phase preparation:

[0215] Weigh the preparation amount of water for injection into a 2000ml beaker, heat it in a water bath and control the water temperature at 60°C. Weigh the preparation amount of glycocholic acid in the water for injection and adjust it with 0.5mol / L sodium hydroxide until the aqueous phase is clear. Then weigh the preparation amount of sodium oleate and glycerol into the aqueous phase and stir evenly to prepare the aqueous phase.

[0216] Colostrum preparation:

[0217] Add the oil phase to the aqueous phase while shearing (10,000 rpm) and maintain the colostrum temperature at 60°C. After the oil phase is added, adjust the shear rate to 15,400 rpm and shear for 5 minutes. Adjust the colostrum to a pH of approximately 9 with 0.5 mol / L sodium hydroxide.

[0218] Finished product preparation:

[0219] Low-pressure homogenization pressure: 100bar / 160bar, homogenize once. High-pressure homogenization pressure: 100bar / 600bar, homogenize six times. After homogenization, the sample is sealed, filled with nitrogen, and sterilized (121℃, 15min).

[0220] 5.1 Batch size is 1000ml

[0221] 5.2 Sample test results:

[0222] 5.3 Conclusion: The content, appearance, potential, particle size and other indicators of the 5mg / ml and 6mg / ml samples meet the requirements.

[0223] 6. Investigation of the dosage of sodium glycocholate

[0224] 6.1 Investigating the Effects of Different Ratios of Sodium Glycocholate on Sample Stability at 4 mg / ml (Batch Size: 1000 ml)

[0225] 6.2 Sample test results:

[0226] 6.3 Conclusion: As the sodium glycocholate content increased, there was no significant difference in the content, potential, and other indicators of the emulsion samples, while the average particle size of the samples showed a gradual decrease. When the sodium glycocholate content of the alfaxalone fat emulsion injection was 12 mg, 14 mg, and 20 mg / mL, the colostrum samples showed stratification (see Figures 1, 2, and 3). However, when the sodium glycocholate content of the alfaxalone fat emulsion injection was between 0.5 and 10 mg / mL, the colostrum samples showed better appearance and other properties. Stability experiments were conducted on emulsion samples containing sodium glycocholate between 0.5 and 10 mg / mL of alfaxalone fat emulsion injection.

[0227] 6.4 Stability data

[0228] Example 28 batch sample (0.05%)

[0229] Example 29 batch sample (0.1%)

[0230] Example 30 batch sample (0.14%)

[0231] Example 31 batch sample (0.2%)

[0232] Example 32 batch sample (0.4%)

[0233] Example 33 batch sample (0.8%)

[0234] Example 34 batch sample (1.0%)

[0235] 6.5 Conclusion: The stability data show that the content, potential and average particle size of the emulsion sample with sodium glycocholate content between 0.05% and 1.0% have no significant changes compared with those at 0 days after staking out for 30 days, indicating that the sample is stable.

[0236] VII. Feasibility Study of Low pH Samples

[0237] Examples 38, 39 and 40 were prepared according to the method of Example 16, with glacial acetic acid used to adjust the pH of the colostrum and the contents of other formulation components were slightly adjusted.

[0238] 7.1 Preparation composition (Specification: 2 mg / ml)

[0239] 7.2 Sample test results

[0240] 7.3 Conclusion: When the sample pH is above 5.0, its appearance, content, particle size and potential are all qualified. When the pH is lower than 5.0, oil floating phenomenon occurs, the particle size is large, and there is a trend of instability.

[0241] 7.4 Stability Data

[0242] Example 38

[0243] Example 39

[0244] 7.5 Conclusion: When the sample pH is greater than 5, its appearance, content, Zeta potential and particle size are all qualified when stored at 40℃ and 60℃ for 30 days, and the pH drop is within a controllable range.

[0245] 8. Solubility test of alfaxalone in castor oil, long-chain oil (soybean oil), and medium-chain oil (medium-chain triglycerides)

[0246] 1. Experimental purpose: To investigate the solubility of alfaxalone in castor oil

[0247] Experimental procedure: Weigh 10 mg of alfaxalone into 100 g of castor oil at 70°C. Shear at 10,000 rpm for 5 minutes. The solution becomes clear. Weigh another 10 mg of alfaxalone into the solution and shear at 10,000 rpm for 3 minutes. Weigh another 30 mg of alfaxalone into the solution and shear at 10,000 rpm for 3 minutes. The solution also becomes clear. Repeat the addition of alfaxalone until the total amount reaches 2 g and the solution remains clear.

[0248] Experimental conclusion: The solubility of afasalin in castor oil is above 2g.

[0249] 2. Experimental purpose: To investigate the solubility of alfaxalone in soybean oil

[0250] Experimental procedure: 10 mg of alfaxalone was weighed and added to 100 g of soybean oil at 70°C. After shearing at 10,000 rpm for 5 minutes, the system became turbid.

[0251] Experimental conclusion: The solubility of alfaxalone in 100g soybean oil is less than 10mg.

[0252] 3. Experimental purpose: To investigate the solubility of alfaxalone in medium chain oil

[0253] Experimental procedure: 10 mg of alfaxalone was added to 100 g of medium-chain oil at 70°C. After shearing at 10,000 rpm for 5 minutes, the system became clear. Another 10 mg of alfaxalone was added to the system and sheared at 10,000 rpm for 3 minutes. The system became clear. Another 30 mg of alfaxalone was added to the system and sheared at 10,000 rpm for 3 minutes. The system became slightly turbid.

[0254] Experimental conclusion: 100g of medium-chain oil can dissolve less than 40mg of alpha-salon.

[0255] IX. Summary of Mouse Histamine Release Data

[0256] Overall experimental method: prepare the corresponding solution or preparation, administer the drug intravenously, collect blood 30 minutes after administration, collect plasma after EDTA anticoagulation and centrifugation, and determine the histamine content in mouse plasma with an ELISA kit.

[0257] Blank plasma: Blood was directly taken from mice and then centrifuged.

[0258] Normal saline: Inject normal saline at a volume of 5 mL / kg.

[0259] Blank fat emulsion (20% medium-chain fat emulsion): the administration volume is 5 mL / kg.

[0260] Alfaxalone fat emulsion (containing sodium glycocholate, Example 26 batch sample): The dosage of alfaxalone fat emulsion (containing sodium glycocholate) was 7 mg / kg. The ED50 of alfaxalone was approximately 3.5 mg / kg, so the dosage was 7 mg / kg. The specification of alfaxalone fat emulsion (containing sodium glycocholate) was 5 mg / mL. It was diluted to 1.4 mg / mL using blank fat emulsion, and the administration volume was 5 mL / kg.

[0261] SBE-β-CD: Preparation: 0.7 mL of 13% SBE-β-CD + 4.3 mL of normal saline, dosing volume 5 mL / kg. (The Suspension Bridge Company formulation uses 13% SBE-β-CD dissolved in alfaxalone, resulting in a 10 mg / mL concentration. Therefore, the drug solution in this study was prepared based on the Suspension Bridge Company formulation.)

[0262] Cremophor EL: 0.7 mL Cremophor EL + 4.3 mL normal saline, Cremophor EL concentration is 0.14 mL / mL, the administration dose is 5 mL / kg, and the administration dose of Cremophor EL is 0.7 mL / kg.

[0263] SBE-β-CD & Cremophor EL: 0.7 mL 13% SBE-β-CD + 0.7 mL Cremophor EL + 3.6 mL normal saline, the administration volume is 5 mL / kg.

[0264] Alfaxalone with SBE-β-CD & Cremophor EL: 0.7 mL of alfaxalone with 13% SBE-β-CD (10 mg / mL) + 0.7 mL of Cremophor EL + 3.6 mL of normal saline, for a dosing volume of 5 mL / kg. The final concentration of alfaxalone is 1.4 mg / mL, resulting in a final dose of 7 mg / kg of alfaxalone and 0.7 mL / kg of Cremophor EL.

[0265] Alfaxalone@castor oil (10%) fat emulsion (2 mg / mL): administration volume 3.5 mL / kg, dose 7 mg / kg; castor oil administration volume is 0.35 mL / kg.

[0266] Alfaxalone@castor oil (7%) fat emulsion (2 mg / mL): This comparative example was prepared according to the method of Example 1 of CN94190450.4, with a dosage of 3.5 mL / kg and 7 mg / kg; the amount of castor oil administered was 0.245 mL / kg.

[0267] Alfaxalone fat emulsion injection (containing sodium glycocholate data)

[0268] Description of results: After intravenous injection, the plasma histamine concentrations of mice injected with normal saline, blank fat emulsion (20% medium-chain fat emulsion), alfaxalone fat emulsion injection (containing sodium glycocholate, Example 26), and sulfobutyl-β-cyclodextrin (SBE-β-CD) were not significantly different from those in blank plasma, and did not cause excessive histamine release in mice; the plasma histamine concentrations of mice injected with Cremophor EL, SBE-β-CD & Cremophor EL, alfaxalone @ (SBE-β-CD & Cremophor EL), alfaxalone @ castor oil (7%) fat emulsion, and alfaxalone @ castor oil (10%) fat emulsion were significantly higher than those in the vehicle group, causing excessive histamine release in mice, which may be a possible allergic reaction. The plasma histamine concentration of mice in the alfaxalone@(SBE-β-CD&Cremophor EL) group was significantly higher than that in the SBE-β-CD&Cremophor EL group, indicating that alfaxalone dissolved in SBE-β-CD&Cremophor EL promoted the release of histamine in mice and aggravated the degree of allergy.

[0269] The above results indicate that intravenous injection of alfaxalone preparation containing Cremophor EL and castor oil can cause excessive release of histamine in mice, which may lead to an allergic reaction; whereas alfaxalone fat emulsion injection (containing sodium glycocholate) does not cause an allergic reaction, as shown in Figure 5.

[0270] 10. Effects of different preparations of alfaxalone on rat myoelectricity

[0271] Normal saline: normal saline

[0272] Blank fat emulsion (common preparation): does not contain the main drug alfaxalone, and the rest is the same as Example 1

[0273] Alfaxalone fat emulsion (2 mg / mL): Example 1

[0274] Alfaxalone fat emulsion (10% castor oil) (2 mg / mL): Comparative Example 1

[0275] Propofol fat emulsion (10 mg / mL): produced by Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: BB200215

[0276] Blank fat emulsion (containing sodium glycocholate): does not contain the main drug alfaxalone, and the rest is the same as Example 33

[0277] Alfaxalone fat emulsion (containing sodium glycocholate) (4 mg / mL alfaxalone): Example 33

[0278] Cremophor EL: 1 mL Cremophor EL + 4 mL normal saline.

[0279] SBE-β-CD & Cremophor EL: 1 mL 13% SBE-β-CD + 1 mL Cremophor EL + 3 mL normal saline.

[0280] Alfaxalone@(SBE-β-CD & Cremophor EL): 1 mL of Alfaxalone@13% SBE-β-CD (10 mg / mL) + 1 mL of Cremophor EL + 3 mL of normal saline.

[0281] Test method:

[0282] Rats were anesthetized by intraperitoneal injection of 20% urethane solution and secured to an operating table. The saphenous artery on one hind limb was located and isolated. The semitendinosus muscle of the ipsilateral hind limb was located and electrodes were inserted. A plastic cannula was inserted into the isolated saphenous artery, and drug injections were performed through the cannula. The cannula was flushed with saline after each injection.

[0283] The myoelectricity of the rats before and after injection was integrated, and the ratio of the myoelectricity of the rats after injection to the baseline was calculated to evaluate the myoelectric stimulation of the solution on the rats.

[0284] The drug injection volume was 0.1 mL, and the plastic cannula was flushed with normal saline after administration.

[0285] Test results:

[0286] The data showed that compared with normal saline, administration of blank fat emulsion, alfaxalone fat emulsion (2 mg / mL, Example 1), alfaxalone fat emulsion (10% castor oil) (2 mg / mL), and propofol fat emulsion (manufacturer: Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: BB200215, 10 mg / mL) significantly increased rat myoelectricity, which may cause injection irritation and pain in actual use. Administration of blank fat emulsion (containing sodium glycocholate), alfaxalone fat emulsion (containing sodium glycocholate, Example 33) (4 mg / mL), Cremophor EL, SBE-β-CD & Cremophor EL, and alfaxalone@(SBE-β-CD & Cremophor EL) had no significant effect on rat myoelectricity, suggesting no injection irritation or pain (see Figure 6).

[0287] Note: The significance of Dunnett's test in the table is the result of comparison with the normal saline group.

Claims

1. An alfaxalone fat emulsion injection, characterized in that: The invention comprises alfaxalone or a pharmaceutically acceptable salt thereof, oil for injection, an emulsifier, an auxiliary emulsifier, an osmotic pressure regulator, a stabilizer, a pH regulator and water for injection.

2. The alfaxalone fat emulsion injection according to claim 1, characterized in that The injection oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides.

3. The alfaxalone fat emulsion injection according to claim 2, characterized in that The weight ratio of soybean oil to medium-chain triglycerides in the mixture of soybean oil and medium-chain triglycerides is 1-5:1-5, preferably 1:

1.

4. The alfaxalone fat emulsion injection according to claim 1, characterized in that The weight ratio of alfaxalone or a pharmaceutically acceptable salt thereof to the injection oil is 1-10:50-300, preferably 1-10:100-300, preferably 1-6:100-300, preferably 1-3:100-300, preferably 1-3:100-200; or the amount of the injection oil accounts for 10% to 30% of the mass concentration of the fat emulsion injection, preferably 10% to 20%.

5. The alfaxalone fat emulsion injection according to any one of claims 1 to 4, characterized in that The purity of the alfaxalone or its pharmaceutically acceptable salt is greater than 95%.

6. The alfaxalone fat emulsion injection according to any one of claims 1 to 5, characterized in that The emulsifier is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, more preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2; the amount of the pH regulator is the amount required to control the pH value of the injection solution to 5.0-8.5; Optionally, the osmotic pressure regulator is glycerol, Optionally, the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate, Optionally, the co-emulsifier is a bile acid compound or a salt thereof, Optionally, the pH adjuster is sodium hydroxide.

7. The alfaxalone fat emulsion injection according to any one of claims 1 to 6, characterized in that The emulsifier is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, more preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2; the amount of the pH regulator is the amount required to control the pH value of the injection solution to 6.0-8.5; Optionally, the osmotic pressure regulator is glycerol, Optionally, the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate, Optionally, the co-emulsifier is a bile acid compound or a salt thereof, Optionally, the pH adjuster is sodium hydroxide.

8. The alfaxalone fat emulsion injection according to claim 6 or 7, characterized in that The bile acid compound or its salt is at least one of glycocholic acid, cholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid or their sodium salts, preferably glycocholic acid and / or sodium glycocholate.

9. The alfaxalone fat emulsion injection according to any one of claims 1 to 8, characterized in that The injection has a pH value of 5.0 to 8.5; the components, calculated by weight, include: Alphasalon 1-10; Soybean oil 50-200; Medium chain triglycerides 0-100; Emulsifier 9-15; Co-emulsifier 0.1~20; Stabilizer 0.1~0.3; Glycerol 22~25.

10. The alfaxalone fat emulsion injection according to any one of claims 1 to 9, characterized in that The injection has a pH value of 6.0 to 8.5; the components, calculated by weight, include: Alphasalon 1-10; Soybean oil 50-200; Medium chain triglycerides 0-100; Emulsifier 9-15; Co-emulsifier 0.1~20; Stabilizer 0.1~0.3; Glycerol 22~25.

11. The alfaxalone fat emulsion injection according to any one of claims 8 to 10, characterized in that The injection has a pH value of 6.0 to 8.5; the components, calculated by weight, include: Alphaxalone 2-8; Soybean oil 50-200; Medium chain triglycerides 0-100; Emulsifier 9-12; Co-emulsifier 0.1~10; Stabilizer 0.1~0.3; Glycerol 22~25.

12. The alfaxalone fat emulsion injection according to any one of claims 1 to 8, characterized in that: The pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 50-100 mg; Medium chain triglycerides 50-100 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 6.0 to 8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 100-200 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection.

13. The alfaxalone fat emulsion injection according to claim 8 or 12, characterized in that: The pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 50-100 mg; Medium chain triglycerides 50-100 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 6.0 to 8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 100-200 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection.

14. The alfaxalone fat emulsion injection according to any one of claims 1-10, 12-13, characterized in that The pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 6.0 to 8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 200 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection.

15. The alfaxalone fat emulsion injection according to any one of claims 1 to 13, characterized in that The pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 2-8 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin 9-12 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 6.0 to 8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 2-8 mg; Soybean oil 200 mg; Egg yolk lecithin 9-12 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 6.0 to 8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 2-8 mg; Soybean oil 100 mg; Medium chain triglycerides 50 mg; Egg yolk lecithin 9-12 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 6.0 to 8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 2-8 mg; Soybean oil 50 mg; Medium chain triglycerides 50 mg; Egg yolk lecithin 9-12 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection.

16. The alfaxalone fat emulsion injection according to any one of claims 1 to 10, characterized in that: The pH value is 6.0-8.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 1-10 mg; Soybean oil 50-200 mg; Medium chain triglycerides 50-100 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerol 22.5-25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0-8.5; and the remaining amount of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 2 mg; Soybean oil 50 mg; Medium chain triglycerides 50 mg; Egg yolk lecithin E-80 4 mg; Egg yolk lecithin PL-100M 8 mg; Sodium glycocholate 3 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 6.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 3 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 2 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 6.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 4 mg; soybean oil 50 mg; Medium chain triglycerides 50 mg; Egg yolk lecithin E-80 9 mg; Sodium glycocholate 4 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 4 mg; Soybean oil 200 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 4 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 4 mg; Soybean oil 200 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 1 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 2 mg; Soybean oil 100 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 4 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 4 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin E-80 15 mg; Sodium glycocholate 3 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 4 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 1 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 4 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin E-80 15 mg; Sodium glycocholate 3 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 7.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 5 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin E-80 15 mg; Sodium glycocholate 3 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH of the injection to 7.0; and the balance of water for injection; Alternatively, the pH value is 7.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 5 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 1 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH of the injection to 7.0; and the balance of water for injection; Alternatively, the pH value is 7.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 6 mg; Soybean oil 50 mg; Medium chain triglycerides 50 mg; Egg yolk lecithin E-80 12 mg; Sodium glycocholate 2 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection to 7.5; and the balance of water for injection; Alternatively, the pH value is 8.0, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 7 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin 12 mg; Sodium glycocholate 4 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection solution to 8.0; and the balance of water for injection; Alternatively, the pH value is 7.5, and each 1 ml of the alfaxalone fat emulsion injection contains: Alfaxalone 7 mg; Soybean oil 100 mg; Medium chain triglycerides 100 mg; Egg yolk lecithin 12 mg; Sodium glycocholate 1 mg; Sodium oleate 0.3 mg; Glycerol 25 mg; The amount of sodium hydroxide required to control the pH value of the injection to 7.5; and the balance of water for injection.

17. A method for preparing the alfaxalone fat emulsion injection according to any one of claims 1 to 16, characterized in that: include: (1) Heat the injection oil to 50° C. to 75° C., then add the emulsifier and alfaxalone, mix, and shear until all the oil is dissolved and evenly dispersed, so as to obtain a first mixture containing an alfaxalone oil phase; Preferably, the injection oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides; more preferably, the injection oil is a mixture of soybean oil and medium-chain triglycerides in a weight ratio of 1:1; Preferably, the emulsifier is egg yolk lecithin, more preferably, the emulsifier is a mixture of egg yolk lecithin PL-100M and egg yolk lecithin E-80; (2) heating water for injection to 50° C. to 75° C., then adding an emulsifier, a stabilizer, and an osmotic pressure regulator and stirring uniformly to obtain a second mixture forming an aqueous phase; preferably, the emulsifier is sodium glycocholate, the stabilizer is sodium oleate, and the osmotic pressure regulator is glycerol; (3) mixing the first mixture and the second mixture while shearing to obtain a third mixture that forms colostrum; (4) adjusting the pH of the third mixture with a pH regulator to obtain a fourth mixture, and homogenizing once under low pressure to obtain a fifth mixture; preferably, the pH regulator is sodium hydroxide; (5) high-pressure homogenizing the fifth mixture for 3 or more times, preferably 4-8 times, more preferably 5-6 times, and during the homogenization process, nitrogen is injected below the liquid surface until the liquid is saturated with nitrogen, so as to obtain a sixth mixture; (6) The sixth mixture is bottled, filled with nitrogen for protection, and sterilized with moist heat to obtain an alfaxalone fat emulsion injection having a pH value of 5.0 to 8.5, preferably a pH value of 6.0 to 8.

5.

18. A method for preparing the alfaxalone fat emulsion injection according to any one of claims 1 to 16, characterized in that: include: (1) Heat the injection oil to 50° C. to 75° C., then add the emulsifier and alfaxalone, mix, and shear until all the oil is dissolved and evenly dispersed, so as to obtain a first mixture containing an alfaxalone oil phase; Preferably, the injection oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides; more preferably, the injection oil is a mixture of soybean oil and medium-chain triglycerides in a weight ratio of 1:1; Preferably, the emulsifier is egg yolk lecithin, more preferably, the emulsifier is a mixture of egg yolk lecithin PL-100M and egg yolk lecithin E-80; (2) heating water for injection to 50° C. to 75° C., then adding an emulsifier, a stabilizer, an osmotic pressure regulator, and a pH regulator and stirring uniformly to obtain a second mixture forming an aqueous phase; preferably, the emulsifier is sodium glycocholate, the stabilizer is sodium oleate, the osmotic pressure regulator is glycerol, and the pH regulator is sodium hydroxide; (3) mixing the first mixture and the second mixture while shearing to obtain a third mixture that forms colostrum; (4) Optionally, adjusting the pH of the third mixture with a pH adjuster to obtain a fourth mixture; preferably, the pH adjuster is sodium hydroxide; (5) homogenizing the mixture obtained in step (3) or (4) once at low pressure to obtain a fifth mixture; homogenizing the fifth mixture at high pressure for more than three times, preferably 4-8 times, more preferably 5-6 times, and filling the mixture with nitrogen below the liquid level during the homogenization process until the mixture is saturated with nitrogen, so as to obtain a sixth mixture; (6) The sixth mixture is bottled, filled with nitrogen for protection, and sterilized with moist heat to obtain an alfaxalone fat emulsion injection having a pH value of 5.0 to 8.5, preferably a pH value of 6.0 to 8.

5.

19. The method according to claim 17 or 18, characterized in that The shear mixing is performed at a rotation speed of 5000 to 16000 rpm for 5 to 25 minutes; preferably, the shear rotation speed during the mixing process is 10000 rpm, and the shear rotation speed after the mixing is completed is 15000-16000 rpm.

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