Afacalone fat emulsion injection and preparation method thereof

Abstract

The invention discloses 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. The injection oil with the optimal proportion is used for dissolving the alfasalone, meanwhile, the medication safety is improved, meanwhile, sodium glycocholate or glycocholic acid is used as a co-emulsifier to form synergy with the emulsifier, the dissolving effect is improved, the drug loading capacity is obviously improved, and the purposes that the particle size uniformity is good, and the bioavailability is high are achieved. The stability of the alfasalone fat emulsion injection is greatly improved, and unstable preparation conditions such as fat emulsion droplet aggregation and combination caused by storage condition change in the storage process of an alfasalone preparation can be prevented.

Description

[0001] This application claims the priority of Chinese Patent Application No. 202311855530.X filed on December 29, 2023, and Chinese Patent Application No. 202410018881.3 filed on January 5, 2024. The contents of the above priority documents are incorporated into this application by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medicine, and particularly relates to an alphaxalone fat emulsion injection and a preparation method thereof. Background Art

[0003] Alphaxalone has sedative, anesthetic, anticonvulsant and neuroprotective properties by modulating the GABA A receptor. As an effective neuroactive steroid anesthetic, alphaxalone lacks progestogenic, estrogenic, mineralocorticoid or thymolytic activity.

[0004] Althesin is an intravenous injection composed of alphaxalone and alphadolone in a ratio of 3:1. The potency of alphadolone is only half of that of the former, but alphadolone can increase the solubility of alphaxalone by three times. For example, according to the literature Mark S. Althesin - a new intravenous anaesthetic [J]. Canda. Anaesth 1973(20):186 - 191, alphadolone has a solubilizing effect on alphaxalone. Each milliliter of Althesin solution contains 9 mg of alphaxalone and 3 mg of alphadolone. Althesin can achieve a rapid onset of anesthesia, has little irritation to blood vessels, and only has mild cardiovascular and respiratory side effects. In order to improve the solubility of the active ingredients in Althesin, the polyethoxylated castor oil excipient Cremophor EL (CAS registration number 61791 - 12 - 6) is usually added to the intravenous injection. Due to its good induction and maintenance of anesthesia characteristics, this drug was used for clinical anesthesia in many countries from 1972 to 1984. Since 1984, Althesin has been withdrawn from the market as a human intravenous anesthetic because, despite having a high therapeutic index, it occasionally causes unpredictable but severe allergic reactions.

[0005] Chinese Patent CN94190450.4 discloses an alfaxalone castor oil emulsion. Among them, Cremophor EL is a surfactant that forms micelles in aqueous solution when it is above the critical micelle concentration. Cremophor EL is a good encapsulating polymer that can significantly increase the solubility of water-insoluble drugs. Since micelles decompose when diluted below their critical micelle concentration, Cremophor EL formulations can effectively release alfaxalone and make it bioavailable, and distribute to the central nervous system to produce an anesthetic effect. Although Cremophor EL is a good solvent for dissolving neuroactive steroid anesthetics such as alfaxalone, it has biological activity and can cause severe anaphylactoid hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, erythrocyte aggregation, and peripheral neuropathy.

[0006] For injectable emulsions, on the one hand, they must have very small droplet sizes; otherwise, they are likely to cause capillary blockage and embolism in the blood circulation. The regulations in General Chapter 0102 of Part 4 of the Chinese Pharmacopoeia regarding injectable emulsions require that the average particle size does not exceed 0.5 micrometers. In addition, the emulsion must be physically stable. The droplet size limit defined in General Chapter 0102 of Part 4 of the Chinese Pharmacopoeia applies throughout the specified storage period, which typically extends to 2 - 3 years or longer for commercial drug 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 attach together to form larger agglomerates. Aggregation can, in some cases, be a precursor to further coalescence into larger droplets. Eventually, these processes may lead to visible free oil on the surface of the emulsion or rising to the surface of the container to form large aggregates, a phenomenon known as "creaming of the emulsion". Measuring the droplet size, especially the change in its size at the initial stage, can predict the physical stability of the emulsion at an early stage before the formulation shows visible changes to the naked eye.

[0007] On the other hand, the drug components may degrade. For example, although lipophilic drugs will be separated in the oil phase, which will provide a certain degree of protection, hydrolysis degradation of the drug components may still occur at the oil-water interface. Possible chemical degradations of parenteral fat emulsions include the oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, as well as the hydrolysis of phospholipids, which results in the formation of free fatty acids (FFAs) and lysophospholipids. These degradation products lower the pH value and may further promote the degradation of the drug components. Therefore, the pH value should be controlled during the production process, and parenteral emulsion preparations may include buffers to provide additional control. Any decrease in the pH value within the specified storage period may indicate chemical degradation. Take charge-stabilized emulsions as an example, such as those in which lecithin is used as an emulsifier, the stabilizing charge may vary due to different pH values. Therefore, the change in pH value due to chemical degradation may also accelerate physical degradation. If the emulsion is sterically stabilized, for example, by a surfactant of poly(oxyethylene), generally the change in pH value has little effect on the emulsion stability.

[0008] Fat overload syndrome is a syndrome characterized by elevated triglycerides due to the infusion rate and / or dose of fat emulsion exceeding the body's fat clearance capacity. The clinical manifestations include hepatosplenomegaly, jaundice, hypoproteinemia, fever, acute respiratory distress syndrome (ARDS), metabolic acidosis, thrombocytopenia, bleeding, disseminated intravascular hemorrhage (DIC), etc. The main causes of fat overload syndrome can be attributed to two aspects: firstly, the patient's own fat clearance capacity is normal, but the fat emulsion is used in excess; secondly, the fat emulsion is used at a constant amount, but the patient's own fat clearance capacity decreases.

[0009] As known in the prior art, the concentration of commercially available propofol is 10 mg / ml, and the potency of alfaxalone is 5 times that of propofol. In theory, 2 mg / ml of alfaxalone can achieve the anesthetic potency of 10 mg / ml of propofol. However, if an alfaxalone fat emulsion injection with a high drug loading above 2 mg / ml, such as 4 mg / ml or 6 mg / ml, can be prepared, it will be possible to reduce the intake of phospholipids and injection oil, which is in strong demand and more beneficial for especially some obese and hyperlipidemic patients.

[0010] In summary, although there is Althesin alfaxalone castor oil emulsion in the prior art, it has allergic reactions. The art still needs to develop an alfaxalone fat emulsion injection that avoids the use of castor oil, which has high potency, high drug loading, good solubility, physical and chemical stability, clinical medication safety, and low intake of injection oil and phospholipids. SUMMARY OF THE INVENTION

[0011] To overcome the technical problems existing in the prior art at least in some of the above aspects, preferably in all of the above aspects, the present inventors have conducted continuous and in-depth research. For example, in Chinese Patent Application No. 2023108299557 and PCT International Application No. PCT / CN2023 / 106281, an alfaxalone emulsion injection without glycocholic acid and an alfaxalone emulsion injection with glycocholic acid as a co-emulsifier are respectively described, and the entire content thereof is incorporated herein by reference.

[0012] One object of the present invention is to provide an alfaxalone fat emulsion injection having a high drug loading and high potency, while having stable drug quality, no irritation to blood vessels, high clinical drug safety, and good compliance.

[0013] On the one hand, the present invention provides an alfaxalone fat emulsion injection, comprising alfaxalone and its pharmaceutically acceptable salts, injection oil, emulsifier, co-emulsifier, osmotic pressure regulator, stabilizer, pH regulator and injection water, characterized in that the fat emulsion injection does not include alphadolone, and the co-emulsifier is a cholic acid compound or its salt, preferably glycocholic acid or its salt, preferably any one or two of glycocholic acid or sodium glycocholate, more preferably glycocholic acid.

[0014] On the other hand, for the above alfaxalone fat emulsion injection, the emulsifier is egg yolk lecithin, preferably one or more of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, more preferably egg yolk lecithin E-80.

[0015] On the other hand, for the above alfaxalone fat emulsion injection, in terms of the mass grams of the corresponding component in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), the content of the emulsifier is greater than 1.5% and below 3.0%, and the content of the co-emulsifier is 0.01 - 2.0%.

[0016] On the other hand, for the above alfaxalone fat emulsion injection, the injection oil is selected from one or two of soybean oil and medium-chain triglycerides, preferably a mixture of soybean oil and medium-chain triglycerides.

[0017] On the other hand, for the above alfaxalone fat emulsion injection, in terms of the mass grams of the corresponding component in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one or more of the following conditions:

[0018] (1) The content of the soybean oil is 5.0 - 20%, preferably 5 - 10%;

[0019] (2) The content of the medium-chain triglycerides is 0 - 10%, preferably 5 - 10%; and / or

[0020] (3) The mass ratio of the soybean oil to the medium-chain triglyceride is 1-5:1-5, preferably 1-3:1-3, and more preferably 1:1.

[0021] On the other hand, for the above alfaxalone fat emulsion injection, when calculated by the mass grams of the corresponding components in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one or more of the following conditions:

[0022] (1) The content of alfaxalone or its pharmaceutically acceptable salt is 0.1-1.0%, preferably 0.2-1.0%, more preferably 0.2-0.6%, and even more preferably 0.4-0.6%;

[0023] (2) The content of the injection oil is 5.0-30%, preferably 10-30%, and more preferably 10-20%;

[0024] (3) The content of the emulsifier is greater than 1.5% and not more than 3.0%, preferably greater than 1.5% and not more than 2.4%;

[0025] (4) The content of the co-emulsifier is 0.01-2.0%, preferably 0.05-1.0%.

[0026] On the other hand, for the above alfaxalone fat emulsion injection, when calculated by the mass grams of the corresponding components in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one or more of the following conditions:

[0027] (1) The content of alfaxalone or its pharmaceutically acceptable salt is 0.1-1.0%, preferably 0.2-1.0%, more preferably 0.2-0.6%, and even more preferably 0.4-0.6%;

[0028] (2) The content of the injection oil is 5.0-30%, preferably 10-30%, and more preferably 10-20%;

[0029] (3) The content of the emulsifier is greater than 1.5% and not more than 3.0%, preferably greater than 1.5% and not more than 2.4%;

[0030] (4) The content of the co-emulsifier is 0.01-2.0%, preferably 0.05-1.0%;

[0031] (5) The content of the osmotic pressure regulator is 2.2-2.5%;

[0032] (6) The content of the stabilizer is 0.01-0.08%, preferably 0.01%-0.03%.

[0033] On the other hand, the above-mentioned alfaxalone fat emulsion injection, wherein the purity of the alfaxalone or its pharmaceutically acceptable salt is greater than 95%, preferably greater than 98%.

[0034] On the other hand, the above-mentioned alfaxalone fat emulsion injection, wherein the pH regulator is sodium hydroxide, and the amount thereof is sufficient to adjust the pH value of the fat emulsion injection to 5.0-8.5; and / or the osmotic pressure regulator is glycerol; and / or the stabilizer is selected from at least one of oleic acid and sodium oleate.

[0035] On the other hand, the above-mentioned alfaxalone fat emulsion injection, wherein the pH regulator is sodium hydroxide, and the amount thereof is sufficient to adjust the pH value of the fat emulsion injection to 5.0-8.5; and / or the osmotic pressure regulator is glycerol; and / or the stabilizer is selected from at least one of oleic acid and sodium oleate, preferably sodium oleate.

[0036] In a preferred embodiment of the present invention, the above-mentioned alfaxalone fat emulsion injection, wherein in terms of the mass grams of the corresponding components in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one or more of the following conditions:

[0037] (1) The content of the alfaxalone or its pharmaceutically acceptable salt is 0.1-1.0%, preferably 0.2-1.0%, more preferably 0.2-0.6%, and even more preferably 0.4-0.6%;

[0038] (2) The content of the injection oil is 5.0-30%, preferably 10-30%, more preferably 10-20%;

[0039] (3) The content of the emulsifier is greater than 1.5% and below 3.0%, preferably greater than 1.5% and below 2.4%;

[0040] (4) The content of the co-emulsifier is 0.01-2.0%, preferably 0.05-1.0%;

[0041] (5) The content of the osmotic pressure regulator is 2.2-2.5%;

[0042] (6) The content of the stabilizer is 0.01-0.08%, preferably 0.01%-0.03%;

[0043] Wherein, the injection oil is selected from one or two of soybean oil and medium-chain triglycerides; the emulsifier is selected from one or more of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T; the co-emulsifier is selected from one or two of glycocholic acid and sodium glycocholate.

[0044] In a preferred embodiment of the present invention, the alfaxalone fat emulsion injection, calculated as the mass in grams of the corresponding component in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), comprises:

[0045] (1) The content of alfaxalone or its pharmaceutically acceptable salt is 0.2 - 0.6%, more preferably 0.4 - 0.6%;

[0046] (2) The content of the injection oil is 10 - 20%;

[0047] (3) The content of the emulsifier is greater than 1.5% and not more than 2.4%;

[0048] (4) The content of the co-emulsifier is 0.05 - 1.0%, preferably 0.05 - 0.4%;

[0049] Among them, the injection oil is selected from one or both of soybean oil and medium-chain triglycerides; the emulsifier is selected from one or more of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T; the co-emulsifier is selected from one or both of glycocholic acid and sodium glycocholate.

[0050] On the other hand, the above-mentioned alfaxalone fat emulsion injection is characterized in that, calculated as the mass in grams of the corresponding component in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one of the following conditions:

[0051] (1) The alfaxalone fat emulsion injection includes:

[0052] Alfaxalone 0.1 - 1.0%

[0053] Injection oil 5.0 - 30%

[0054] Emulsifier greater than 1.5% and not more than 3.0%

[0055] Co-emulsifier 0.01 - 2.0%

[0056] Osmotic pressure regulator 2.2 - 2.5%

[0057] Stabilizer 0.01 - 0.08%

[0058] pH regulator in an amount required to adjust the pH value of the injection to 5.0 - 8.0;

[0059] And an appropriate amount of injection water;

[0060] (2) The alfaxalone fat emulsion injection includes:

[0061] Alfaxalone 0.2 - 1.0%

[0062] 10 - 30% injection oil

[0063] Emulsifier greater than 1.5% and below 3.0%

[0064] Co - emulsifier 0.01 - 2.0%

[0065] Osmotic pressure regulator 2.2 - 2.5%

[0066] Stabilizer 0.01 - 0.03%

[0067] pH regulator in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0068] (3) The alfaxalone fat emulsion injection described above includes:

[0069] Alfaxalone 0.2 - 0.6%

[0070] 10 - 20% injection oil

[0071] Emulsifier greater than 1.5% and below 3.0%

[0072] Co - emulsifier 0.01 - 2.0%

[0073] Osmotic pressure regulator 2.2 - 2.5%

[0074] Stabilizer 0.01 - 0.03%

[0075] pH regulator in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0076] (4) The alfaxalone fat emulsion injection described above includes:

[0077] Alfaxalone 0.1 - 1.0%

[0078] 5.0 - 30% injection oil

[0079] Emulsifier greater than 1.5% and below 2.4%

[0080] Co - emulsifier 0.01 - 2.0%

[0081] Osmotic pressure regulator 2.2 - 2.5%

[0082] Stabilizer 0.01 - 0.03%

[0083] pH regulator in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0084] (5) The alfaxalone fat emulsion injection described above includes:

[0085] Alfaxalone 0.1 - 1.0%

[0086] Injection oil 5.0 - 30%

[0087] Emulsifier greater than 1.5% and not exceeding 3.0%

[0088] Co - emulsifier 0.05 - 1.0%

[0089] Osmotic pressure regulator 2.2 - 2.5%

[0090] Stabilizer 0.01 - 0.03%

[0091] pH regulator in an amount required to adjust the pH of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0092] (6) The alfaxalone fat emulsion injection described above includes:

[0093] Alfaxalone 0.1 - 1.0%

[0094] Injection oil 5.0 - 30%

[0095] Emulsifier greater than 1.5% and not exceeding 2.4%

[0096] Co - emulsifier 0.05 - 1.0%

[0097] Osmotic pressure regulator 2.2 - 2.5%

[0098] Stabilizer 0.01 - 0.03%

[0099] pH regulator in an amount required to adjust the pH of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0100] (7) The alfaxalone fat emulsion injection described above includes:

[0101] Alfaxalone 0.2 - 0.8%

[0102] Injection oil 10 - 20%

[0103] Emulsifier greater than 1.5% and not exceeding 2.4%

[0104] Co - emulsifier 0.05 - 1.0%

[0105] Osmotic pressure regulator 2.2 - 2.5%

[0106] Stabilizer 0.01 - 0.03%

[0107] pH regulator in an amount required to adjust the pH of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0108] (8) The alfaxalone fat emulsion injection described above includes:

[0109] Alfaxalone 0.2 - 0.6%

[0110] Injection oil 10 - 20%

[0111] Emulsifier greater than 1.5% and below 2.4%

[0112] Co - emulsifier 0.05 - 1.0%

[0113] Osmotic pressure regulator 2.2 - 2.5%

[0114] Stabilizer 0.01 - 0.03%

[0115] pH regulator in an amount required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of injection water;

[0116] (9) The alfaxalone fat emulsion injection described above includes:

[0117] Alfaxalone 0.4 - 0.6%

[0118] Injection oil 10 - 20%

[0119] Emulsifier greater than 1.5% and below 2.4%

[0120] Co - emulsifier 0.05 - 1.0%

[0121] Osmotic pressure regulator 2.2 - 2.5%

[0122] Stabilizer 0.01 - 0.03%

[0123] pH regulator in an amount required to adjust the pH value of the injection to 5.0 - 8.0;

[0124] And an appropriate amount of injection water;

[0125] (10) The alfaxalone fat emulsion injection described above includes:

[0126] Alfaxalone 0.4 - 1.0%

[0127] Injection oil 10 - 20%

[0128] Emulsifier greater than 1.5% and below 2.4%

[0129] Co - emulsifier 0.05 - 1.0%

[0130] Osmotic pressure regulator 2.2 - 2.5%

[0131] Stabilizer 0.01 - 0.03%

[0132] A pH regulator in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0133] And an appropriate amount of water for injection.

[0134] On the other hand, the above - mentioned alfaxalone fat emulsion injection is characterized in that, calculated by the mass grams of the corresponding components in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one of the following conditions:

[0135] (1) The said alfaxalone fat emulsion injection includes:

[0136] Alfaxalone 0.3 - 0.6%

[0137] Injection oil 10 - 20%

[0138] Emulsifier greater than 1.5% and not exceeding 2.4%

[0139] Co - emulsifier 0.05 - 1.0%

[0140] Osmotic pressure regulator 2.2 - 2.5%

[0141] Stabilizer 0.01 - 0.03%

[0142] A pH regulator in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0143] And an appropriate amount of water for injection;

[0144] (2) The said alfaxalone fat emulsion injection includes:

[0145] Alfaxalone 0.3 - 0.6%

[0146] Injection oil 10 - 20%

[0147] Emulsifier greater than 1.5% and not exceeding 2.4%

[0148] Co - emulsifier 0.05 - 0.4%

[0149] Osmotic pressure regulator 2.2 - 2.5%

[0150] Stabilizer 0.01 - 0.03%

[0151] A pH regulator in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0152] And an appropriate amount of water for injection;

[0153] (3) The said alfaxalone fat emulsion injection includes:

[0154] Alfaxalone 0.2 - 0.6%

[0155] Injection oil 10 - 20%

[0156] Emulsifier greater than 1.5% and below 2.4%

[0157] Co - emulsifier 0.05 - 0.4%

[0158] Osmotic pressure regulator 2.2 - 2.5%

[0159] Stabilizer 0.01 - 0.03%

[0160] pH regulator in an amount required to adjust the pH of the injection solution to 5.0 - 8.0;

[0161] And an appropriate amount of water for injection.

[0162] On the other hand, the above - mentioned alfaxalone fat emulsion injection is characterized in that, calculated by the mass in grams of the corresponding components in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one of the following conditions:

[0163] (1) The alfaxalone fat emulsion injection comprises:

[0164] Alfaxalone 0.1 - 1.0%

[0165] Soybean oil + medium - chain triglycerides 5.0 - 30%

[0166] Egg yolk lecithin greater than 1.5% and below 3.0%

[0167] Glycocholic acid 0.01 - 2.0%

[0168] Glycerol 2.2 - 2.5%

[0169] Sodium oleate 0.01 - 0.08%

[0170] Sodium hydroxide in an amount required to adjust the pH of the injection solution to 5.0 - 8.0;

[0171] And an appropriate amount of water for injection;

[0172] (2) The alfaxalone fat emulsion injection comprises:

[0173] Alfaxalone 0.2 - 1.0%

[0174] Soybean oil + medium - chain triglycerides 10 - 30%

[0175] Egg yolk lecithin greater than 1.5% and below 3.0%

[0176] Glycocholic acid 0.01 - 2.0%

[0177] Glycerol 2.2 - 2.5%

[0178] Sodium oleate 0.01 - 0.03%

[0179] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0180] (3) The alfaxalone fat emulsion injection solution includes:

[0181] Alfaxalone 0.2 - 0.6%

[0182] Soybean oil + medium - chain triglycerides 10 - 20%

[0183] Egg yolk lecithin greater than 1.5% and below 3.0% Glycocholic acid 0.01 - 2.0%

[0184] Glycerol 2.2 - 2.5%

[0185] Sodium oleate 0.01 - 0.03%

[0186] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0187] (4) The alfaxalone fat emulsion injection solution includes:

[0188] Alfaxalone 0.1 - 1.0%

[0189] Soybean oil + medium - chain triglycerides 5 - 30%

[0190] Egg yolk lecithin greater than 1.5% and below 2.4% Glycocholic acid 0.01 - 2.0%

[0191] Glycerol 2.2 - 2.5%

[0192] Sodium oleate 0.01 - 0.03%

[0193] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0194] (5) The alfaxalone fat emulsion injection solution includes:

[0195] Alfaxalone 0.1 - 1.0%

[0196] Soybean oil + medium - chain triglycerides 5 - 30%

[0197] Egg yolk lecithin greater than 1.5% and below 3.0% Glycocholic acid 0.05 - 1.0%

[0198] Glycerol 2.2 - 2.5%

[0199] Sodium oleate 0.01 - 0.03%

[0200] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0201] (6) The alfaxalone fat emulsion injection solution includes:

[0202] Alfaxalone 0.1 - 1.0%

[0203] Soybean oil + medium-chain triglycerides 5.0 - 30%

[0204] Egg yolk lecithin greater than 1.5% and below 2.4% Glycocholic acid 0.05 - 1.0%

[0205] Glycerol 2.2 - 2.5%

[0206] Sodium oleate 0.01 - 0.03%

[0207] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0208] (7) The alfaxalone fat emulsion injection solution includes:

[0209] Alfaxalone 0.2 - 0.8%

[0210] Soybean oil + medium-chain triglycerides 10 - 20%

[0211] Egg yolk lecithin greater than 1.5% and below 2.4% Glycocholic acid 0.05 - 1.0%

[0212] Glycerol 2.2 - 2.5%

[0213] Sodium oleate 0.01 - 0.03%

[0214] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0215] (8) The alfaxalone fat emulsion injection solution includes:

[0216] Alfaxalone 0.2 - 0.6%

[0217] Soybean oil + medium-chain triglycerides 10 - 20%

[0218] Egg yolk lecithin greater than 1.5% and below 2.4% Glycocholic acid 0.05 - 1.0%

[0219] Glycerol 2.2 - 2.5%

[0220] Sodium oleate 0.01 - 0.03%

[0221] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection;

[0222] (9) The alfaxalone fat emulsion injection solution includes:

[0223] Alfaxalone 0.4 - 0.6%

[0224] Soybean oil + medium - chain triglycerides 10 - 20%

[0225] Egg yolk lecithin greater than 1.5% and below 2.4%

[0226] Glycocholic acid 0.05 - 1.0%

[0227] Glycerol 2.2 - 2.5%

[0228] Sodium oleate 0.01 - 0.03%

[0229] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0230] and an appropriate amount of water for injection;

[0231] (10) The alfaxalone fat emulsion injection solution includes:

[0232] Alfaxalone 0.4 - 1.0%,

[0233] Soybean oil + medium - chain triglycerides 10 - 20%

[0234] Egg yolk lecithin greater than 1.5% and below 2.4%

[0235] Glycocholic acid 0.05 - 1.0%

[0236] Glycerol 2.2 - 2.5%

[0237] Sodium oleate 0.01 - 0.03%

[0238] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0239] and an appropriate amount of water for injection.

[0240] On the other hand, the above - mentioned alfaxalone fat emulsion injection solution is characterized in that, based on the mass grams of the corresponding components in 1 ml of the fat emulsion injection solution (i.e., w / v, unit: g / ml), it satisfies one of the following conditions:

[0241] (1) The alfaxalone fat emulsion injection solution includes:

[0242] Alfaxalone 0.2 - 0.6%

[0243] Soybean oil + medium-chain triglycerides 10 - 20%

[0244] Egg yolk lecithin 1.6%

[0245] Glycocholic acid 0.05 - 1.0%

[0246] Glycerol 2.2 - 2.5%

[0247] Sodium oleate 0.01 - 0.03%

[0248] Sodium hydroxide in an amount required to adjust the pH of the injection solution to 5.0 - 8.0;

[0249] And an appropriate amount of water for injection.

[0250] (2) The alfaxalone fat emulsion injection solution described above includes:

[0251] Alfaxalone 0.2 - 0.6%

[0252] Soybean oil + medium-chain triglycerides 10 - 20%

[0253] Egg yolk lecithin 1.8%

[0254] Glycocholic acid 0.05 - 1.0%

[0255] Glycerol 2.2 - 2.5%

[0256] Sodium oleate 0.01 - 0.03%

[0257] Sodium hydroxide in an amount required to adjust the pH of the injection solution to 5.0 - 8.0; and an appropriate amount of water for injection.

[0258] (3) The alfaxalone fat emulsion injection solution described above includes:

[0259] Alfaxalone 0.2 - 0.6%

[0260] Soybean oil + medium-chain triglycerides 10 - 20%

[0261] Egg yolk lecithin 2.0%

[0262] Glycocholic acid 0.05 - 1.0%

[0263] Glycerol 2.2 - 2.5%

[0264] Sodium oleate 0.01 - 0.03%

[0265] Sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of water for injection.

[0266] (4) The alfaxalone fat emulsion injection described above includes:

[0267] Alfaxalone 0.2 - 0.6%

[0268] Soybean oil + medium-chain triglycerides 10 - 20%

[0269] Egg yolk lecithin 2.4%

[0270] Glycocholic acid 0.05 - 1.0%

[0271] Glycerol 2.2 - 2.5%

[0272] Sodium oleate 0.01 - 0.03%

[0273] Sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of water for injection;

[0274] (5) The alfaxalone fat emulsion injection described above includes:

[0275] Alfaxalone 0.2 - 0.6%

[0276] Soybean oil + medium-chain triglycerides 10 - 20%

[0277] Egg yolk lecithin greater than 1.5% and below 2.4% Glycocholic acid 0.05%

[0278] Glycerol 2.2 - 2.5%

[0279] Sodium oleate 0.01 - 0.03%

[0280] Sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of water for injection;

[0281] (6) The alfaxalone fat emulsion injection described above includes:

[0282] Alfaxalone 0.2 - 0.6%

[0283] Soybean oil + medium-chain triglycerides 10 - 20%

[0284] Egg yolk lecithin greater than 1.5% and below 2.4% Glycocholic acid 0.1%

[0285] Glycerol 2.2 - 2.5%

[0286] Sodium oleate 0.01 - 0.03%

[0287] The amount of sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of water for injection;

[0288] (7) The alfaxalone fat emulsion injection described above includes:

[0289] Alfaxalone 0.2 - 0.6%

[0290] Soybean oil + medium-chain triglycerides 10 - 20%

[0291] Egg yolk lecithin greater than 1.5% and below 2.4%, glycocholic acid 0.2%

[0292] Glycerol 2.2 - 2.5%

[0293] Sodium oleate 0.01 - 0.03%

[0294] The amount of sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of water for injection;

[0295] (8) The alfaxalone fat emulsion injection described above includes:

[0296] Alfaxalone 0.2 - 0.6%

[0297] Soybean oil + medium-chain triglycerides 10 - 20%

[0298] Egg yolk lecithin greater than 1.5% and below 2.4%, glycocholic acid 0.4%

[0299] Glycerol 2.2 - 2.5%

[0300] Sodium oleate 0.01 - 0.03%

[0301] The amount of sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0; and an appropriate amount of water for injection;

[0302] (9) The alfaxalone fat emulsion injection described above includes:

[0303] Alfaxalone 0.2 - 0.6%

[0304] Soybean oil + medium-chain triglycerides 10 - 20%

[0305] Egg yolk lecithin greater than 1.5% and below 2.4%

[0306] Glycocholic acid 0.8%

[0307] Glycerol 2.2 - 2.5%

[0308] Sodium oleate 0.01 - 0.03%

[0309] The amount of sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0;

[0310] and an appropriate amount of water for injection;

[0311] (10) The alfaxalone fat emulsion injection described above includes:

[0312] Alfaxalone 0.2 - 0.6%

[0313] Soybean oil + medium-chain triglycerides 10 - 20%

[0314] Egg yolk lecithin greater than 1.5% and below 2.4%

[0315] Glycocholic acid 1.0%

[0316] Glycerol 2.2 - 2.5%

[0317] Sodium oleate 0.01 - 0.03%

[0318] The amount of sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0;

[0319] and an appropriate amount of water for injection.

[0320] On the other hand, the above-mentioned alfaxalone fat emulsion injection is characterized in that, in terms of the mass grams of the corresponding components in 1 ml of the fat emulsion injection (i.e., w / v, unit: g / ml), it satisfies one of the following conditions:

[0321] (1) The alfaxalone fat emulsion injection described above includes:

[0322] Alfaxalone 0.3 - 0.6%

[0323] Soybean oil + medium-chain triglycerides 10 - 20%

[0324] Egg yolk lecithin greater than 1.5% and below 2.4%

[0325] Glycocholic acid 0.05 - 1.0%

[0326] Glycerol 2.2 - 2.5%

[0327] Sodium oleate 0.01 - 0.03%

[0328] The amount of sodium hydroxide required to adjust the pH value of the injection to 5.0 - 8.0;

[0329] and an appropriate amount of water for injection;

[0330] (2) The alfaxalone fat emulsion injection described above includes:

[0331] Alfaxalone 0.3 - 0.6%

[0332] Soybean oil + medium-chain triglycerides 10 - 20%

[0333] Egg yolk lecithin greater than 1.5% and below 2.4%

[0334] Glycocholic acid 0.05 - 0.4%

[0335] Glycerol 2.2 - 2.5%

[0336] Sodium oleate 0.01 - 0.03%

[0337] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0338] And an appropriate amount of water for injection;

[0339] (3) The alfaxalone fat emulsion injection described above comprises:

[0340] Alfaxalone 0.2 - 0.6%

[0341] Soybean oil + medium-chain triglycerides 10 - 20%

[0342] Egg yolk lecithin greater than 1.5% and below 2.4%

[0343] Glycocholic acid 0.05 - 0.4%

[0344] Glycerol 2.2 - 2.5%

[0345] Sodium oleate 0.01 - 0.03%

[0346] Sodium hydroxide in an amount required to adjust the pH value of the injection solution to 5.0 - 8.0;

[0347] And an appropriate amount of water for injection.

[0348] In addition, the present invention also provides a method for preparing the above-mentioned alfaxalone fat emulsion injection, comprising:

[0349] (1) Preparation of the oil phase: Take the injection oil and heat it, then add the emulsifier and alfaxalone, mix and shear to obtain a first mixture containing the alfaxalone oil phase;

[0350] (2) Preparation of the water phase: Take the water for injection and heat it, then add the co-emulsifier, stabilizer, osmotic pressure regulator, and pH value regulator to obtain a second mixture forming the water phase;

[0351] (3) Preparation of the primary emulsion: Mix the first mixture of the oil phase and the second mixture of the water phase, and shear while mixing to obtain a third mixture forming the primary emulsion;

[0352] (4) Preparation of the finished product: subject the sample to pressure homogenization, followed by filling, nitrogen filling, heat sealing, and sterilization of the sample.

[0353] In addition, the present invention also provides an alfaxalone fat emulsion injection, characterized in that the fat emulsion injection does not include alfadolone, and uses one or both of soybean oil and medium-chain triglycerides as the injection oil, uses egg yolk lecithin as the emulsifier, uses a cholic acid compound or its salt, preferably glycocholic acid or its salt, preferably glycocholic acid or sodium glycocholate, more preferably glycocholic acid as the co-emulsifier, and the injection has substantially no effect on the normal histamine level in the human body after administration.

[0354] Use of a cholic acid compound or its salt as a co-emulsifier in the preparation of an alfaxalone fat emulsion injection with a high drug loading, characterized in that the fat emulsion injection does not include alfadolone, and uses one or both of soybean oil and medium-chain triglycerides as the injection oil, uses egg yolk lecithin as the emulsifier, the cholic acid compound or its salt is glycocholic acid or sodium glycocholate, more preferably glycocholic acid; and / or calculated by the mass in grams per milliliter of the alfaxalone fat emulsion injection (i.e., w / v, unit g / ml), the content of the co-emulsifier is 0.01 - 2.0%, more preferably 0.05 - 1.0%.

[0355] The present invention also provides the use of an alfaxalone fat emulsion injection in the preparation of a drug that has substantially no effect on the normal histamine level in the human body after administration, characterized in that calculated by the mass in grams per milliliter of the alfaxalone fat emulsion injection (i.e., w / v, unit g / ml), the alfaxalone fat emulsion injection includes 0.1 - 1.0% of alfaxalone or its pharmaceutically acceptable salt, 10 - 20% of the injection oil, more than 1.5% and below 2.4% of the emulsifier, and 0.05 - 1.0% of glycocholic acid.

[0356] Preferably, the injection oil is selected from one or both of soybean oil and medium-chain triglycerides, preferably a mixture of soybean oil and medium-chain triglycerides; the emulsifier is egg yolk lecithin, preferably one or more of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T.

[0357] According to an embodiment of the present invention, calculated by the mass in grams per milliliter of the alfaxalone fat emulsion injection (i.e., w / v, unit g / ml) (the same hereinafter), the content of alfaxalone or its pharmaceutically acceptable salt in the alfaxalone fat emulsion injection is selected from 0.1 - 1.0%, for example, selected from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 (w / v, unit g / ml), or the range between any two of the foregoing values.

[0358] In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.1 - 1.0% (w / v, unit: g / ml); in some specific embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.1 - 0.9% (w / v, unit: g / ml), 0.1 - 0.8% (w / v, unit: g / ml), 0.1 - 0.7% (w / v, unit: g / ml), 0.1 - 0.6% (w / v, unit: g / ml), 0.1 - 0.5% (w / v, unit: g / ml), 0.1 - 0.4% (w / v, unit: g / ml), 0.1 - 0.3% (w / v, unit: g / ml), and 0.1 - 0.2% (w / v, unit: g / ml). In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 1.0% (w / v, unit: g / ml); in some specific embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 0.9% (w / v, unit: g / ml), 0.2 - 0.8% (w / v, unit: g / ml), 0.2 - 0.7% (w / v, unit: g / ml), 0.2 - 0.6% (w / v, unit: g / ml), 0.2 - 0.5% (w / v, unit: g / ml), 0.2 - 0.4% (w / v, unit: g / ml), and 0.2 - 0.3% (w / v, unit: g / ml). In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.3 - 1.0% (w / v, unit: g / ml); in some specific embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.3 - 0.9% (w / v, unit: g / ml), 0.3 - 0.8% (w / v, unit: g / ml), 0.3 - 0.7% (w / v, unit: g / ml), 0.3 - 0.6% (w / v, unit: g / ml), 0.3 - 0.5% (w / v, unit: g / ml), and 0.3 - 0.4% (w / v, unit: g / ml). In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.4 - 1.0% (w / v, unit: g / ml); in some specific embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.4 - 0.9% (w / v, unit: g / ml), 0.4 - 0.8% (w / v, unit: g / ml), 0.4 - 0.7% (w / v, unit: g / ml), 0.4 - 0.6% (w / v, unit: g / ml), and 0.4 - 0.5% (w / v, unit: g / ml).

[0359] In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.1 - 1.0% (w / v, unit: g / ml); preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 1.0% (w / v, unit: g / ml); more preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 0.6% (w / v, unit: g / ml); further preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.4 - 0.6% (w / v, unit: g / ml).

[0360] In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 1.0% (w / v, unit: g / ml); preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 0.8% (w / v, unit: g / ml); further preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.2 - 0.6% (w / v, unit: g / ml).

[0361] In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.3 - 1.0% (w / v, unit: g / ml); preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.3 - 0.8% (w / v, unit: g / ml); further preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.3 - 0.6% (w / v, unit: g / ml).

[0362] In some embodiments, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.4 - 1.0% (w / v, unit: g / ml); preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.4 - 0.8% (w / v, unit: g / ml); further preferably, the content of alfaxalone or its pharmaceutically acceptable salt is selected from 0.4 - 0.6% (w / v, unit: g / ml).

[0363] According to the embodiments of the present invention, the content of the injection oil in the alfaxalone fat emulsion injection is selected from 5.0% - 30% (w / v, unit: g / ml), such as selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (w / v, unit: g / ml), or the range between any two of the foregoing values. In some embodiments, the content of the injection oil is selected from 10 - 30% (w / v, unit: g / ml). Preferably, the content of the injection oil is selected from 10 - 20% (w / v, unit: g / ml).

[0364] According to an embodiment of the present invention, the content of the emulsifier in alfaxalone fat emulsion injection is greater than 1.5% (w / v, unit: g / ml) and not more than 3.0% (w / v, unit: g / ml), for example, selected from 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, and 3.0 (w / v, unit: g / ml), or a range between any two of the foregoing values. In some embodiments, the content of the emulsifier is greater than 1.5% (w / v, unit: g / ml) and not more than 2.4% (w / v, unit: g / ml).

[0365] According to an embodiment of the present invention, the content of the co-emulsifier in alfaxalone fat emulsion injection is selected from 0.01 - 2.0% (w / v, unit: g / ml), for example, selected from 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.0 (w / v, unit: g / ml), or the range between any two of the foregoing values.

[0366] In some embodiments, the content of the co-emulsifier is selected from 0.05 - 1.0% (w / v, unit: g / ml). In some embodiments, the content of the co-emulsifier is selected from 0.05 - 0.9% (w / v, unit: g / ml). In some embodiments, the content of the co-emulsifier is selected from 0.05 - 0.8% (w / v, unit: g / ml). In some embodiments, the content of the co-emulsifier is selected from 0.05 - 0.7% (w / v, unit: g / ml). In some embodiments, the content of the co-emulsifier is selected from 0.05 - 0.6% (w / v, unit: g / ml). In some embodiments, the content of the co-emulsifier is selected from 0.05 - 0.5% (w / v, unit: g / ml). In some embodiments, the content of the co-emulsifier is selected from 0.05 - 0.4% (w / v, unit: g / ml).

[0367] According to the embodiments of the present invention, the content of the osmotic pressure regulator in alfaxalone fat emulsion injection is selected from 2.2 - 2.5% (w / v, unit: g / ml), for example, selected from 2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.30, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.40, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.50 (w / v, unit: g / ml), or the range between any two of the foregoing values.

[0368] According to the embodiments of the present invention, the content of the stabilizer in alfaxalone fat emulsion injection is selected from 0.01 - 0.03% (w / v, unit: g / ml), for example, selected from 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.030 (w / v, unit: g / ml), or the range between any two of the foregoing values.

[0369] According to an embodiment of the present invention, the content of soybean oil in alfaxalone fat emulsion injection is selected from 5.0% - 20% (w / v, unit: g / ml), for example, selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, (w / v, unit: g / ml), or the range between any two of the foregoing values. In some embodiments, the content of the injection oil is selected from 5 - 10% (w / v, unit: g / ml).

[0370] The content of medium-chain triglycerides in alfaxalone fat emulsion injection is selected from 0% - 10% (w / v, unit: g / ml), for example, selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, (w / v, unit: g / ml), or the range between any two of the foregoing values. In some embodiments, the content of the injection oil is selected from 5 - 10% (w / v, unit: g / ml).

[0371] According to an embodiment of the present invention, the total content of soybean oil and medium-chain triglycerides in alfaxalone fat emulsion injection is selected from 5.0% - 30% (w / v, unit: g / ml), for example, selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (w / v, unit: g / ml), or the range between any two of the foregoing values. In some embodiments, the total content of soybean oil and medium-chain triglycerides is selected from 10 - 30% (w / v, unit: g / ml). Preferably, the total content of soybean oil and medium-chain triglycerides is selected from 10 - 20% (w / v, unit: g / ml).

[0372] Another aspect of the present invention provides a method for preparing the above-mentioned alfaxalone fat emulsion injection, including:

[0373] (1) Preparation of the oil phase: Heat the injection oil, then add an emulsifier and alfaxalone, mix and shear to obtain a first mixture containing the alfaxalone oil phase;

[0374] (2) Preparation of the water phase: Heat the injection water, then add a co-emulsifier, a stabilizer, an osmotic pressure regulator, and a pH regulator to obtain a second mixture forming the water phase;

[0375] (3) Preparation of the primary emulsion: Mix the first mixture of the oil phase and the second mixture of the water phase, and shear while mixing to obtain a third mixture forming the primary emulsion;

[0376] (4) Preparation of the finished product: Subject the sample to pressure homogenization, then fill the sample, charge with nitrogen, seal by melting, and sterilize.

[0377] Further, a method for preparing alfaxalone fat emulsion injection is provided, including:

[0378] (1) Preparation of the oil phase: Heat the injection oil to 50°C to 75°C, then add the emulsifier and alfaxalone, mix, and shear until completely dissolved and uniformly dispersed to obtain a first mixture containing the alfaxalone oil phase;

[0379] 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 with a weight ratio of 1:1;

[0380] 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;

[0381] (2) Preparation of the aqueous phase: Heat the injection water to 50°C to 75°C, then add the co-emulsifier, stabilizer, osmotic pressure regulator, and pH regulator, and stir evenly to obtain a second mixture forming the aqueous phase;

[0382] Preferably, the pH is 7 - 11.5. Preferably, the co-emulsifier is glycocholic acid, the stabilizer is sodium oleate, the osmotic pressure regulator is glycerol, and the pH regulator is sodium hydroxide;

[0383] (3) Preparation of the primary emulsion: Mix the first mixture and the second mixture, and shear while mixing to obtain a third mixture forming the primary emulsion;

[0384] Optionally, adjust the pH of the third mixture to 5.0 - 11.5 with a pH regulator to obtain a fourth mixture; preferably, the pH regulator is sodium hydroxide;

[0385] Homogenize the obtained mixture at low pressure once to obtain a fifth mixture; subject the fifth mixture to high-pressure homogenization more than 3 times, preferably 4 - 8 times, more preferably 5 - 6 times, and nitrogen is filled below the liquid surface to nitrogen saturation during the homogenization process to obtain a sixth mixture;

[0386] Fill the sixth mixture into a container, fill with nitrogen for protection, and perform moist heat sterilization to obtain alfaxalone fat emulsion injection with a pH value of 5.0 - 8.5.

[0387] In some specific embodiments, the shear mixing is carried out at a rotational speed of 5000 - 16000 rpm for 5 - 25 min; preferably, the rotational speed of shear during the mixing process is 10000 rpm, and the rotational speed of shear after the mixing is completed is 15000 - 16000 rpm.

[0388] In some specific embodiments, in step (3) of the preparation method of alfaxalone fat emulsion, shear mixing is carried out at a rotation speed of 5000 - 16000 rpm for 5 - 25 min.

[0389] In some specific embodiments, the low-pressure homogenization in step (4) of the preparation method of alfaxalone fat emulsion is carried out at a pressure of 100 / 160 bar, and the high-pressure homogenization in step (5) is carried out at a pressure of 500 - 1000 bar for 5 - 8 times, and the temperature of the high-pressure homogenization is controlled at 30℃ - 70℃.

[0390] Term Interpretation

[0391] Unless otherwise specified, the relevant terms used in the present invention have the following meanings.

[0392] The term "isotonic" means having the same osmotic pressure as physiological body fluids or being similar to physiological body fluids. Body fluids usually have an osmotic pressure often described as corresponding to a 0.9% (weight / volume) aqueous sodium chloride solution. In this application, glycerol is used to adjust isotonicity, and the content of glycerol in each 1 ml of the alfaxalone fat emulsion injection is 22 - 25 mg, specifically 22 mg / ml, 22.5 mg / ml, 23 mg / ml, 23.5 mg / ml, 24 mg / ml, 24.5 mg / ml, specifically 25 mg / ml.

[0393] The term w / v refers to the mass content of a component in a unit volume of injection. Unless otherwise specified, the content of each component in the injection of the present invention is calculated as the mass in grams of the corresponding component in 1 ml of the fat emulsion injection, with the unit g / ml.

[0394] The term "medium-chain oil" refers to medium-chain triglycerides and medium-chain triacylglycerols; the term "long-chain oil" refers to soybean oil.

[0395] The term "co-emulsifier" refers to an emulsion system that is beneficial to the stability of the fat emulsion injection and / or can improve the drug solubility. The co-emulsifier of the present invention is specifically a cholic acid compound or its salt, more specifically glycochenodeoxycholic acid or its salt, especially sodium glycochenodeoxycholate, as well as cholic acid, taurocholic acid, glycoursodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid or taurochenodeoxycholic acid, etc.

[0396] When describing the upper or lower limit values of the content of each component in the fat emulsion injection of the present invention, X - Y%, includes the X and Y numerical values themselves, for example, 0.2 - 1.0%, includes the 0.2 and 1.0 numerical values themselves; the used "greater than", "less than" do not include the numerical value itself, for example, "greater than 1.5%", does not include 1.5% itself; the used "above", "below" include the numerical value itself, for example, "2.4% or less", includes 2.4% itself, and is included within the scope of the present invention.

[0397] In the present invention, the co-emulsifier "glycocholic acid or sodium glycocholate" refers to different chemical forms of glycocholic acid. During the preparation of alfaxalone fat emulsion injection of the present invention, either one or both of glycocholic acid itself and sodium glycocholate can be used. The "glycocholic acid" in the prescription of alfaxalone fat emulsion injection in the present invention is the acid radical of glycocholic acid or / and sodium glycocholate used during the preparation process. The mass-volume ratio of "glycocholic acid" is the mass-volume ratio (w / v, unit: g / ml) of the acid radical of glycocholic acid or / and sodium glycocholate used during the preparation process in the alfaxalone fat emulsion injection.

[0398] In the present invention, the co-stabilizer "oleic acid or sodium oleate" refers to different chemical forms of oleic acid. During the preparation of the alfaxalone fat emulsion injection of the present invention, either one or both of oleic acid and sodium oleate can be used. The sodium oleate in the alfaxalone fat emulsion injection in the present invention is directly added sodium oleate during the preparation of the emulsion, or is the sodium oleate generated by the reaction of added oleic acid with sodium hydroxide.

[0399] The term "AFSL" refers to alfaxalone.

[0400] The term "high drug loading" means that the drug loading of alfaxalone in the fat emulsion injection is 2 times or more than 2 times of 1 mg / ml, including drug loadings of 2 - 10 mg / ml, especially 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, or 10 mg / ml.

[0401] Beneficial effects

[0402] By adopting the technical solution of the present invention, the following beneficial technical effects can be achieved:

[0403] 1. By using injection oil instead of castor oil with good solubility for alfaxalone in the present invention, it is possible to completely emulsify the oil phase and the water phase, which not only meets the dissolution requirements but also avoids the risk of adverse reactions such as allergies caused by the use of castor oil, and improves the drug use safety.

[0404] 2. In the present invention, sodium glycocholate or glycocholic acid forms a synergy with the emulsifier, which not only improves the dissolution effect, but also significantly increases the drug loading amount. At the same time, the prepared average particle size is lower than that of the group without sodium glycocholate, and the particle size uniformity is good. After the pH stability test, the pH is stable and there is no obvious decrease, indicating that the emulsion has good stability, is conducive to storage, has less demanding storage conditions, and greatly improves the stability of alfaxalone fat emulsion injection. The present invention can prevent the instability of the alfaxalone preparation such as the aggregation and coalescence of fat emulsion droplets caused by changes in storage conditions during storage. Especially at low temperatures, it still remains stable. Compared with the castor oil formulation, the preparation has a smaller particle size, better stability, and significantly reduces the occurrence of allergies, has no irritation to blood vessels, and improves the safety and compliance of clinical medication.

[0405] 3. The preferred mass-volume ratio of sodium glycocholate or glycocholic acid to the emulsifier in the present invention plays a key role in the stability of alfaxalone fat emulsion injection in a low-temperature storage environment. It can not only meet the stability requirements at 4 °C, but also meet the storage stability in a more demanding low-temperature environment of 1 °C, and can adapt to the temporary storage environment during drug transportation in low temperatures or even in cold winters, greatly ensuring the safety of medication. Detailed implementation manners

[0406] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only for illustrative and explanatory purposes of the present invention, and should not be construed as limiting the protection scope of the present invention. All technical solutions implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0407] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0408] Egg yolk lecithin: E80, purchased from Lipoid GmbH, Germany; glycerol was purchased from Shantou Jiahe Biotechnology Co., Ltd.; glycocholic acid was purchased from Jiangsu Southeast Nano Materials 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 self-made by Jiangsu Enhua Pharmaceutical Co., Ltd. with a purity of over 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).

[0409] Preparation method of emulsion without glycocholic acid or sodium glycocholate (batch size: 1000 ml) (Examples 1 - 6)

[0410] Preparation of oil phase: Add the prescribed amounts of soybean oil and medium-chain triglycerides to a 500-ml beaker and heat in a water bath at 70°C. Weigh the egg yolk lecithin and alfaxalone (AFSL) according to the dosage and add them to the oil phase. Shear at a speed of 10000 rpm for 5 minutes to obtain the oil phase.

[0411] Preparation of aqueous phase: Weigh an appropriate amount of water for injection into a 2000-ml beaker and heat it in a water bath. Control the water temperature at 70°C. Add the prescribed amounts of sodium oleate and glycerol to the aqueous phase and stir evenly with a glass rod to obtain the aqueous phase.

[0412] Preparation of primary emulsion: Add the oil phase to the aqueous phase while shearing (10000 rpm) and control the temperature of the primary emulsion at 70°C. After adding the oil phase, adjust the shearing speed to 15400 rpm and shear for 5 minutes. Adjust the pH value of the primary emulsion with sodium hydroxide to obtain the primary emulsion.

[0413] Preparation of finished product: Low-pressure homogenization pressure: 100 bar / 160 bar, homogenize once. High-pressure homogenization pressure: 100 bar / 600 bar, homogenize six times. After homogenization, seal the sample, fill it with nitrogen, and sterilize it (121°C, 15 minutes).

[0414] Preparation method of emulsion with glycocholic acid or sodium glycocholate (batch size: 1000 ml):

[0415] Preparation of oil phase:

[0416] Weigh the prescribed amounts of soybean oil and medium-chain triglycerides separately and heat them in a water bath at 60°C. Weigh the prescribed amount of AFSL and add it to the oil phase. Then weigh the prescribed amount of egg yolk lecithin and add it to the oil phase, and shear at a speed of 10000 rpm for 10 minutes to obtain the oil phase.

[0417] Preparation of aqueous phase 1 (adding glycocholic acid):

[0418] Weigh the prescribed amount of water for injection into a beaker and heat it in a water bath. Control the water temperature at 60°C. Weigh the prescribed amounts of glycocholic acid, sodium hydroxide, sodium oleate, and glycerol and add them to the beaker and stir evenly to obtain the aqueous phase.

[0419] Preparation of aqueous phase 2 (adding sodium glycocholate):

[0420] Weigh the prescribed amount of water for injection into a beaker and heat it in a water bath. Control the water temperature at 60°C. Weigh the prescribed amounts of sodium glycocholate, sodium oleate, and glycerol and add them to the beaker and stir evenly to obtain the aqueous phase.

[0421] Preparation of primary emulsion:

[0422] Add the oil phase to the aqueous phase while shearing (at 10,000 rpm), and control the temperature of the primary emulsion to 60 °C; after adding the oil phase, adjust the shearing speed to 15,400 rpm and shear for 5 min, and adjust the pH value of the primary emulsion with sodium hydroxide to obtain the primary emulsion.

[0423] Finished product preparation:

[0424] Homogenize the sample once under low pressure, with the homogenization pressure: 100 bar / 160 bar. Homogenize six times under high pressure, with the homogenization pressure: 100 bar / 560 bar. After homogenization, fill the sample, fill it with nitrogen, seal it by melting, and sterilize it (at 121 °C for 15 min).

[0425] I. Investigation on different dosages of emulsifiers

[0426] 1.1 On the basis of the alfaxalone specification of 4 mg / ml (i.e., the content is 0.4%), investigate the influence of different dosages of phospholipids (15 g, 16 g, 18 g, 20 g, 24 g, and 28 g) on the formulation (the batch is calculated as 1000 ml).

[0427]

[0428]

[0429] 1.2 Sample determination results

[0430]

[0431] 1.3 Conclusion: When the dosage of egg yolk lecithin in the formulation is 15 g, 16 g, 18 g, 20 g, and 24 g, the indicators such as the properties, content, potential, related substances, and pH of the first 5 examples (Examples 1 - 5) have no obvious difference and are all within the qualified range. However, the particle sizes of the samples in Examples 4 and 5 increase before and after sterilization. The particle size of the sample in Example 4 increases from 0.176 μm to 0.325 μm before and after sterilization; the particle size of the sample in Example 5 increases from 0.130 μm to 0.487 μm before and after sterilization, and both are close to the limit of the qualified range; the particle sizes of the samples in Examples 1 - 3 hardly change before and after sterilization, and the particle size of the sample in Example 6 increases from 0.227 μm to 0.519 μm before and after sterilization, and there is an oil floating phenomenon in the appearance, which is unqualified.

[0432] 1.4 Sample stability data

[0433] Conduct stability sampling for Examples 1 - 5:

[0434] Example 1

[0435]

[0436] Example 2

[0437]

[0438] Example 3

[0439]

[0440] Example 4

[0441]

[0442] Example 5

[0443]

[0444] 1.5 Sample stability conclusion:

[0445] For Examples 1 - 3, when placed at 40 °C for 30 days, the indicators such as properties, content, potential, related substances, etc. showed no obvious changes compared with day 0. The pH decreased slightly but was within the qualified range. However, API crystallization was likely to occur at 4 °C, indicating that the sample was unstable. For Examples 4 - 5, when the sample was placed at low temperature of 4 °C, the particle size was greater than 0.5 μm, indicating that the sample was prone to aggregation and unstable at low temperature. It can be seen that if only containing emulsifiers, the stability of the injection solution is not good enough, and this problem needs to be solved by adding new excipients.

[0446] II. Investigation of different types of emulsifiers

[0447] 2.1 Investigate the feasibility of adding common emulsifiers (poloxamer 188, glycocholic acid, tween 80 or polyethylene glycol 15 - hydroxystearate (HS15)) and phospholipids as composite emulsifiers under the condition of a 4 mg / ml sample.

[0448] (Batch size is calculated as 1000 ml)

[0449] Prescription Composition Example 7 Example 8 Example 9 Function AFSL 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g Oil Phase Egg Yolk Lecithin 18g 18g 18g Emulsifier Poloxamer 188 6g / / Co-emulsifier Glycocholic Acid / 6g / Co-emulsifier Tween 80 / / 6g Co-emulsifier HS15 / / / Co-emulsifier Sodium Hydroxide / 0.51g / pH Regulator Glycerol 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g Stabilizer Water for Injection 776g 776g 776g Water Phase Prescription Composition Example 10 Example 11 Example 12 Function AFSL 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g Oil Phase Egg Yolk Lecithin 18g 18g 18g Emulsifier Poloxamer 188 / 3g / Co-emulsifier Glycocholic Acid / / / Co-emulsifier Tween 80 / / 3g Co-emulsifier HS15 6g 3g 3g Co-emulsifier Glycerol 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g Stabilizer Water for Injection 776g 776g 776g Water Phase

[0450] 2.2 Sample results

[0451]

[0452]

[0453] 2.3 Conclusion: For the 6 groups of examples, the indicators such as content, potential, particle size, pH and related substances showed no obvious differences and were within the qualified range. However, there was some oil floating in the appearance of the samples in Examples 7 and 11, API crystallization precipitated in Examples 9, 10 and 12, and the appearance of Example 8 met the requirements. The above results indicate that the inclusion of glycocholic acid in the formulation can improve the sample stability.

[0454] III. Investigate the feasibility of preparing larger - scale samples

[0455] 3.1 Investigate the feasibility of preparing samples with AFSL specifications of 5 and 6 mg / ml. (Batch size is 1000 ml)

[0456] Prescription Composition Example 13 Example 14 Example 15 Example 16 Function AFSL 5g 5g 6g 6g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 18g 20g 18g 20g Emulsifier Glycocholic Acid 1g 1g 1g 1g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.085g 0.085g 0.085g 0.085g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase

[0457] 3.2 Sample results

[0458]

[0459] 3.3 Conclusion: The appearance properties, content, related substances, particle size, potential, pH, etc. of Examples 13 - 16 are all within the qualified range.

[0460] IV. Compare the prescriptions with different amounts of glycocholic acid when the phospholipid dosage is 15 g

[0461] 4.1 Comparison of prescriptions with different amounts of glycocholic acid (Batch size is 1000 ml)

[0462] Prescription Composition Example 17 Example 18 Example 19 Example 20 Function AFSL 4g 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 15g 15g 15g 15g Emulsifier Glycocholic Acid 0.5g 1g 2g 4g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.0425g 0.085g 0.17g 0.34g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase Prescription Composition Example 21 Example 22 Example 23 Example 24 Function AFSL 4g 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 15g 15g 15g 15g Emulsifier Glycocholic Acid 8g 10g 12g 20g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.68g 0.85g 1.02g 1.7g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase

[0463] 4.2 Sample test results

[0464]

[0465]

[0466] 4.3 Conclusion: When the dosage of egg yolk lecithin in the prescription is 15 g, as can be seen from Examples 17 - 22, as the amount of glycocholic acid in the sample increases, the overall particle size of the sample shows a decreasing trend. When the amount of glycocholic acid in the prescription is 12 g or more (Examples 23 - 24), stratification occurs during the preparation of the primary emulsion, which does not belong to the emulsion injection dosage form, so the preparation is not continued. There are no obvious differences in the properties, content, potential, related substances, pH, etc. of Examples 17 - 22, and they are all within the qualified range.

[0467] V. Compare the prescriptions with different amounts of glycocholic acid when the phospholipid dosage is 16 g

[0468] 5.1 Comparison of prescriptions with different amounts of glycocholic acid (Batch size is 1000 ml)

[0469] Prescription Composition Example 25 Example 26 Example 27 Example 28 Function AFSL 4g 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 16g 16g 16g 16g Emulsifier Glycocholic Acid 0.5g 1g 2g 4g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.0425g 0.085g 0.17g 0.34g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase Prescription Composition Example 29 Example 30 Example 31 Example 32 Function AFSL 4g 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 16g 16g 16g 16g Emulsifier Glycocholic Acid 8g 10g 12g 20g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.68g 0.85g 1.02g 1.7g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase

[0470] 5.2 Sample test results

[0471]

[0472]

[0473] 5.3 Conclusion: When the dosage of egg yolk lecithin in the prescription is 16 g, it can be seen from Examples 25 - 30 that as the dosage of glycocholic acid in the sample increases, the overall particle size of the sample shows a decreasing trend. When the dosage of glycocholic acid in the prescription is 12 g (Example 31) and 20 g (Example 32), stratification occurs during the preparation of the primary emulsion, which does not belong to the emulsion injection dosage form, so the preparation is not continued. There are no obvious differences in the properties, content, potential, related substances, pH, etc. of Examples 25 - 30, and they are all within the qualified range.

[0474] 5.4 Sampling results of sample stability

[0475] Example 25

[0476]

[0477] Example 26

[0478]

[0479] Example 27

[0480]

[0481]

[0482] Example 28

[0483]

[0484] Example 29

[0485]

[0486] Example 30

[0487]

[0488] 5.5 Conclusion on sample stability:

[0489] For Examples 25 - 30, when sampled at 4℃ and 40℃ for 60 days, there are no obvious changes in the properties, content, potential, related substances, etc. compared with day 0. The pH decreases slightly but is within the qualified range. The related substances (total impurities) change little at 4℃, and show an increasing trend at 40℃ but are within the qualified range. However, the growth rate of the related substances (total impurities) content in Examples 29 and 30 is greater than that in Examples 25 - 28, indicating that when the dosage of glycocholic acid is above 8 g, the related substances (total impurities) also increase. VI. Comparison of prescriptions with different dosages of glycocholic acid when the phospholipid dosage is 18 g

[0490] 6.1 Comparison of prescriptions with different dosages of glycocholic acid (batch size is 1000 ml)

[0491] Prescription Composition Example 33 Example 34 Example 35 Example 36 Function AFSL 4g 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 18g 18g 18g 18g Emulsifier Glycocholic Acid 0.5g 1g 2g 4g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.0425g 0.085g 0.17g 0.34g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase Prescription Composition Example 37 Example 38 Example 39 Example 40 Function AFSL 4g 4g 4g 4g Active Ingredient Soybean Oil 100g 100g 100g 100g Oil Phase Medium Chain Triglyceride 100g 100g 100g 100g Oil Phase Egg Yolk Lecithin 18g 18g 18g 18g Emulsifier Glycocholic Acid 8g 10g 12g 20g Co-emulsifier Glycerol 25g 25g 25g 25g Osmotic Pressure Regulator Sodium Oleate 0.3g 0.3g 0.3g 0.3g Stabilizer Sodium Hydroxide 0.68g 0.85g 1.02g 1.7g pH Regulator Water for Injection 776g 776g 776g 776g Water Phase

[0492] 6.2 Sample inspection results

[0493]

[0494] 6.3 Conclusion: When the dosage of egg yolk lecithin in the prescription is 18 g, as can be seen from Examples 33 - 38, with the increase in the dosage of glycocholic acid in the sample, the overall particle size of the sample shows a decreasing trend. When the dosage of glycocholic acid in the prescription is 12 g (Example 39) and 20 g (Example 40), stratification occurs during the preparation of the primary emulsion, and it is a non-uniform system, so the preparation is not continued. There are no obvious differences in the properties, content, potential, related substances, pH, etc. of Examples 33 - 38, and they are all within the qualified range.

[0495] 6.4 Sample stability sampling results

[0496] Example 33

[0497]

[0498] Example 34

[0499]

[0500] Example 35

[0501]

[0502] Example 36

[0503]

[0504]

[0505] Example 37

[0506]

[0507] Example 38

[0508]

[0509] 6.5 Sample stability conclusion:

[0510] For Examples 33 - 38, when sampled at 4°C and 40°C for 60 days, there are no obvious changes in the properties, content, potential, related substances, etc. compared with day 0. The pH decreases slightly but is within the qualified range. The related substances (total impurities) change little at 4°C, and show an increasing trend at 40°C but are within the qualified range.

[0511] VII. Comparison of Prescriptions with Different Glycocholic Acid Dosages when the Phospholipid Dosage is 20 g

[0512] 7.1 Comparison of Samples with Different Glycocholic Acid in the Prescription (Batch Calculated as 1000 ml)

[0513]

[0514]

[0515] 7.2 Sample Test Results:

[0516]

[0517] 7.3 Conclusion: When the egg yolk lecithin dosage in the prescription is 2.0%, as can be seen from Examples 41 - 46, as the glycocholic acid dosage in the sample increases, the overall particle size of the sample shows a decreasing trend. When the glycocholic acid content in the prescription is 12 g (Example 47) and 20 g (Example 48), stratification occurs during the preparation of the primary emulsion, and it is a non-uniform system, so the preparation is not continued. There are no obvious differences in the properties, contents, potentials, related substances, pH, etc. of Examples 41 - 46, and they are all within the qualified range.

[0518] 7.4 Sample Stability Sampling Results

[0519] Example 41

[0520]

[0521] Example 42

[0522]

[0523] Example 43

[0524]

[0525] Example 44

[0526]

[0527] Example 45

[0528]

[0529] Example 46

[0530]

[0531] 7.5 Sample Stability Conclusion:

[0532] For Examples 41 - 46, there were no significant changes in properties, content, and potential indicators compared to day 0 after being sampled for 60 days at 4°C and 40°C. The pH decreased slightly but remained within the qualified range. The related substances (total impurities) increased slowly at 4°C and had an increasing trend at 40°C but were still within the qualified range.

[0533] VIII. Comparison of Prescriptions with Different Glycocholic Acid Dosages when the Phospholipid Dosage is 24 g

[0534] 8.1 Comparison of Samples with Different Contents of Glycocholic Acid in the Prescription (Batch size is calculated as 1000 ml)

[0535]

[0536]

[0537] 8.2 Test Results of Samples:

[0538]

[0539] 8.3 Conclusion: When the dosage of egg yolk lecithin in the prescription is 2.4%, as can be seen from Examples 49 - 54, with the increase in the dosage of glycocholic acid in the sample, the overall particle size of the sample shows a decreasing trend and tends to be stable. When the content of glycocholic acid in the prescription is 12 g (Example 55) and 20 g (Example 56), stratification occurs during the preparation of the primary emulsion, and it is a non - homogeneous system, so the preparation is not continued. There are no significant differences in the properties, content, potential, related substances, pH, etc. of Examples 49 - 54, and they are all within the qualified range.

[0540] 8.4 Results of Sample Stability Sampling

[0541] Example 49

[0542]

[0543]

[0544] Example 50

[0545]

[0546] Example 51

[0547]

[0548] Example 52

[0549]

[0550] Example 53

[0551]

[0552]

[0553] Example 54

[0554]

[0555] 8.5 Sample stability conclusion:

[0556] For Examples 49 - 54, when placed at 4°C and 40°C for 60 days, there are no obvious changes in indicators such as properties, content, and potential compared with day 0. The related substances (total impurities) of the sample increase with the increase in temperature, and the pH drops rapidly, which is not conducive to the later stability of the sample. It is speculated that it may be related to the amount of phospholipids added. Therefore, the amount of phospholipids added in the prescription should not exceed 20 g.

[0557] IX. Solubility test of alfaxalone in castor oil, long-chain oil (soybean oil), and medium-chain oil (medium-chain triglyceride)

[0558] 1. Experimental purpose: To investigate the solubility of alfaxalone in castor oil

[0559] Experimental process: Weigh 10 mg of alfaxalone and add it to 100 g of castor oil at 70°C. After shearing at 10000 rpm for 5 min, the system becomes clear. Weigh another 10 mg of alfaxalone and add it to the system. After shearing at 10000 rpm for 3 min, the system remains clear. Weigh another 30 mg of alfaxalone and add it to the system. After shearing at 10000 rpm for 3 min, the system remains clear. Weigh alfaxalone multiple times until the total amount reaches 2 g and the system is still clear.

[0560] Experimental conclusion: The solubility of alfaxalone in castor oil is above 2 g.

[0561] 2. Experimental purpose: To investigate the solubility of alfaxalone in soybean oil

[0562] Experimental process: Weigh 10 mg of alfaxalone and add it to 100 g of soybean oil at 70°C. After shearing at 10000 rpm for 5 min, the system becomes turbid.

[0563] Experimental conclusion: The solubility of alfaxalone in 100 g of soybean oil is less than 10 mg.

[0564] 3. Experimental purpose: To investigate the solubility of alfaxalone in medium-chain oil

[0565] Experimental process: Weigh 10 mg of alfaxalone and add it to 100 g of medium-chain oil at 70°C. After shearing at 10000 rpm for 5 min, the system becomes clear. Weigh another 10 mg of alfaxalone and add it to the system. After shearing at 10000 rpm for 3 min, the system remains clear. Weigh another 30 mg of alfaxalone and add it to the system. After shearing at 10000 rpm for 3 min, the system becomes slightly turbid.

[0566] Experimental conclusion: In 100 g of medium-chain oil, alphaxalone can be dissolved at a level below 40 mg.

[0567] X. Detection of Histamine Content in Mouse Serum

[0568] 1. Prescription of Example 34

[0569]

[0570] 2. Test method:

[0571] Randomly divide ICR mice into two groups, namely the normal saline group and the alphaxalone emulsion injection group, with 6 male and 6 female mice in each group. Intravenously administer normal saline or alphaxalone emulsion injection respectively. Blood is collected 5 minutes after administration. After the blood naturally coagulates at room temperature, centrifuge at 1000 g for 20 minutes at 4°C, and take the supernatant. Detect the histamine content in the serum according to the steps of the histamine (HIS) ELISA kit instructions. The administration volume of alphaxalone emulsion injection is 5 mg / mL, and the administration dose is 20 mg / kg. The administration volume of normal saline is 5 mg / mL.

[0572] III. Test results:

[0573] Table 1 Histamine content in the serum of ICR mice after administration of normal saline and alphaxalone emulsion injection (ng / mL)

[0574]

[0575]

[0576] Conclusion: The histamine content in the serum of ICR mice after administration of normal saline and alphaxalone emulsion injection is shown in Table 1. After administration of alphaxalone emulsion injection, the histamine content in the serum is comparable to that of the normal saline group in both male and female animals. Therefore, administration of alphaxalone emulsion injection does not cause an increase in the histamine content in the mouse serum.

[0577] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the limitations of the above embodiments. What is described in the above embodiments and the specification is only to illustrate the principle of the present invention.

[0578] Without departing from the concept of the present invention, those skilled in the art will also make various non-substantive changes and improvements to the present invention, and all of these fall within the scope of protection required by the present invention.

Claims

1. An alfaxalone fat emulsion injection, comprising alfaxalone and 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, characterized in that: The fat emulsion injection does not include alfadolone, and the co-emulsifier is a bile acid compound or a salt thereof, preferably glycocholic acid or a salt thereof, preferably any one or both of glycocholic acid or sodium glycocholate, more preferably glycocholic acid; wherein the content of the emulsifier is greater than 1.5% and less than 3.0% based on the mass grams of the corresponding components in 1 ml of fat emulsion injection (i.e. w / v, unit g / ml), and the content of the co-emulsifier is 0.01-2.0%.

2. The alfaxalone fat emulsion injection according to claim 1, characterized in that: The emulsifier is egg yolk lecithin, preferably one or more of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, more preferably egg yolk lecithin E-80.

3. The alfaxalone fat emulsion injection according to claim 1, characterized in that: Calculated by the mass grams (ie w / v, unit: g / ml) of the corresponding components in 1 ml of fat emulsion injection, the content of the emulsifier is greater than 1.5% and less than 2.4%; the content of the auxiliary emulsifier is 0.05-1.0%.

4. The alfaxalone fat emulsion injection according to any one of claims 1 to 3, characterized in that: The injection oil is selected from one or both of soybean oil and medium-chain triglycerides, and is preferably a mixture of soybean oil and medium-chain triglycerides.

5. The alfaxalone fat emulsion injection according to claim 4, characterized in that: Calculated by the mass grams (i.e. w / v, unit: g / ml) of the corresponding component in 1 ml of fat emulsion injection, it meets one or more of the following conditions: (1) The soybean oil content is 5.0-20%, preferably 5-10%; (2) the content of medium chain triglycerides is 0-10%, preferably 5-10%; and / or (3) The mass ratio of the soybean oil to the medium-chain triglycerides is 1-5:1-5, preferably 1-3:1-3, and more preferably 1:

1.

6. The alfaxalone fat emulsion injection according to any one of claims 1 to 5, characterized in that: Calculated by the mass grams (i.e. w / v, unit: g / ml) of the corresponding component in 1 ml of fat emulsion injection, it meets one or more of the following conditions: (1) The content of alfaxalone or a pharmaceutically acceptable salt thereof is 0.1-1.0%, preferably 0.2-1.0%, more preferably 0.2-0.6%, more preferably 0.4-0.6%; (2) The content of the injection oil is 5.0-30%, preferably 10-30%, more preferably 10-20%; (3) The content of the emulsifier is greater than 1.5% and less than 3.0%, preferably greater than 1.5% and less than 2.4%; (4) The content of the co-emulsifier is 0.01-2.0%, preferably 0.05-1.0%; (5) The content of the osmotic pressure regulator is 2.2-2.5%; (6) The content of the stabilizer is 0.01-0.08%, preferably 0.01%-0.03%.

7. The alfaxalone fat emulsion injection according to any one of claims 1 to 6, characterized in that: The purity of the alfaxalone or its pharmaceutically acceptable salt is greater than 95%, preferably greater than 98%.

8. The alfaxalone fat emulsion injection according to any one of claims 1 to 7, characterized in that: The pH regulator is sodium hydroxide, and its amount is sufficient to adjust the pH value of the fat emulsion injection to 5.0-8.5; and / or the osmotic pressure regulator is glycerol; and / or the stabilizer is selected from at least one of oleic acid and sodium oleate.

9. The Alfaxalone fat emulsion injection according to any one of claims 1 to 8, characterized in that: Calculated by the mass grams (i.e. w / v, unit: g / ml) of the corresponding component in 1 ml of fat emulsion injection, it meets one of the following conditions: (1) The alfaxalone fat emulsion injection comprises: Alphasalone 0.1-1.0% Injection oil 5.0-30% Emulsifier greater than 1.5% and less than 3.0% Emulsifier 0.01--2.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.08% A pH regulator in an amount required to adjust the pH value of the injection solution to 5.0-8.0; And an appropriate amount of water for injection; (2) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-1.0% Injection oil 10-30% Emulsifier greater than 1.5% and less than 3.0% Emulsifier 0.01-2.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% A pH regulator in an amount required to adjust the pH value of the injection solution to 5.0-8.0; And an appropriate amount of water for injection; (3) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-0.6% Injection oil 10-20% Emulsifier greater than 1.5% and less than 3.0% Emulsifier 0.01-2.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (4) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Oil for injection 5.0-30% Emulsifier greater than 1.5% and less than 2.4% Emulsifier 0.01-2.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (5) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Oil for injection 5.0-30% Emulsifier greater than 1.5% and less than 3.0% Emulsifier 0.05-1.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (6) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Oil for injection 5.0-30% Emulsifier greater than 1.5% and less than 2.4% Emulsifier 0.05-1.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (7) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-0.8% Injection oil 10-20% Emulsifier greater than 1.5% and less than 2.4% Emulsifier 0.05-1.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (8) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-0.6% Injection oil 10-20% Emulsifier greater than 1.5% and less than 2.4% Emulsifier 0.05-1.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (9) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.4-0.6% Injection oil 10-20% Emulsifier greater than 1.5% and less than 2.4% Emulsifier 0.05-1.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% The amount of pH adjuster required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (10) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.4-1.0% Injection oil 10-20% Emulsifier greater than 1.5% and less than 2.4% Emulsifier 0.05-1.0% Osmotic pressure regulator 2.2-2.5% Stabilizer 0.01-0.03% A pH regulator in an amount required to adjust the pH value of the injection solution to 5.0-8.0; And an appropriate amount of water for injection.

10. The alfaxalone fat emulsion injection according to any one of claims 1 to 9, characterized in that: Calculated by the mass grams (i.e. w / v, unit: g / ml) of the corresponding component in 1 ml of fat emulsion injection, it meets one of the following conditions: (1) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Soybean Oil + Medium Chain Triglycerides 5.0-30% Egg yolk lecithin greater than 1.5% and less than 3.0% Glycocholic acid 0.01-2.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.08% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; And an appropriate amount of water for injection; (2) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-1.0% Soybean Oil + Medium Chain Triglycerides 10-30% Egg yolk lecithin greater than 1.5% and less than 3.0% Glycocholic acid 0.01-2.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; And an appropriate amount of water for injection; (3) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-0.6% Soybean Oil + Medium Chain Triglycerides 10-20% Egg yolk lecithin greater than 1.5% and less than 3.0% Glycocholic acid 0.01-2.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (4) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Soybean Oil + Medium Chain Triglycerides 5-30% Egg yolk lecithin greater than 1.5% and less than 2.4% Glycocholic acid 0.01-2.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (5) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Soybean Oil + Medium Chain Triglycerides 5-30% Egg yolk lecithin greater than 1.5% and less than 3.0% Glycocholic acid 0.05-1.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (6) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.1-1.0% Soybean Oil + Medium Chain Triglycerides 5.0-30% Egg yolk lecithin greater than 1.5% and less than 2.4% Glycocholic acid 0.05-1.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (7) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-0.8% Soybean Oil + Medium Chain Triglycerides 10-20% Egg yolk lecithin greater than 1.5% and less than 2.4% Glycocholic acid 0.05-1.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (8) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.2-0.6% Soybean Oil + Medium Chain Triglycerides 10-20% Egg yolk lecithin greater than 1.5% and less than 2.4% Glycocholic acid 0.05-1.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (9) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.4-0.6% Soybean Oil + Medium Chain Triglycerides 10-20% Egg yolk lecithin greater than 1.5% and less than 2.4% Glycocholic acid 0.05-1.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; and an appropriate amount of water for injection; (10) The alfaxalone fat emulsion injection comprises: Alfaxalone 0.4-1.0%, soybean oil + medium chain triglycerides 10-20% Egg yolk lecithin greater than 1.5% and less than 2.4% Glycocholic acid 0.05-1.0% Glycerol 2.2-2.5% Sodium oleate 0.01-0.03% The amount of sodium hydroxide required to adjust the pH value of the injection solution to 5.0-8.0; And an appropriate amount of water for injection.

11. A method for preparing the alfaxalone fat emulsion injection according to any one of claims 1 to 10, comprising: (1) Preparation of oil phase: heating the injection oil, adding the emulsifier and alfaxalone, mixing, and shearing to obtain a first mixture containing the alfaxalone oil phase; (2) Preparation of aqueous phase: heating water for injection, and then adding an emulsifier, a stabilizer, an osmotic pressure regulator, and a pH regulator to obtain a second mixture forming an aqueous phase; (3) Preparation of colostrum: mixing the first oil phase mixture and the second water phase mixture, and shearing while mixing to obtain a third mixture that forms colostrum; (4) Finished product preparation: The sample is pressure homogenized, and after homogenization, the sample is filled, nitrogen-filled, sealed, and sterilized.

12. An alfaxalone fat emulsion injection, characterized in that: The fat emulsion injection does not include alfadolone, and uses one or two of soybean oil and medium-chain triglycerides as injection oil, uses egg yolk lecithin as an emulsifier, and uses bile acid compounds or salts thereof, preferably glycocholic acid or its salts, preferably glycocholic acid or sodium glycocholate, and more preferably glycocholic acid as an auxiliary emulsifier. After administration, the injection has substantially no effect on the normal histamine level of the human body.

13. Use of a bile acid compound or a salt thereof as an emulsifier in the preparation of a high-drug-loaded alfaxalone fat emulsion injection, characterized in that: The fat emulsion injection does not include alfalone, and uses one or two of soybean oil and medium-chain triglycerides as injection oils, uses egg yolk lecithin as an emulsifier, and the bile acid compound or its salt is glycocholic acid or its salt, more preferably glycocholic acid or sodium glycocholate; and / or the content of the co-emulsifier is 0.01-2.0%, more preferably 0.05-1.0%, measured in grams by mass (i.e. w / v, unit g / ml) in 1 ml of alfalone fat emulsion injection.

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