Alfasal fat emulsion injection and its preparation method

Abstract

This invention discloses an alfasalol fat emulsion injection and its preparation method. The alfasalol fat emulsion injection comprises alfasalol and its pharmaceutically acceptable salts; an oil phase, an emulsifier, an osmotic pressure regulator, a stabilizer, a pH adjuster, and water for injection. The oil phase of this application is a 1:1 mixture of soybean oil and medium-chain oil, which can significantly reduce particle size and the occurrence of allergies, and has good stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology. Specifically, this invention relates to alfasalol fat emulsion injection and its preparation method. Background Technology

[0002] Alphaxalone possesses sedative, anesthetic, anticonvulsant, and neuroprotective properties by modulating GABA A receptors. As an effective neuroactive steroid anesthetic, alphaxalone lacks progestin, estrogen, mineralocorticoid, or thymolytic activity.

[0003] Althesin is an intravenous injection composed of alfasalone and alphadolone in a 3:1 ratio. Alfadolone is only half as potent as alfasalone, but it can increase the solubility of alfasalone by three times. Each milliliter of Althesin solution contains 9 mg of alfasalone and 3 mg of alphadolone. Althesin achieves rapid onset and counteracting of anesthetic effects, has minimal vascular irritation, and only mild cardiovascular and respiratory side effects.

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 Since 1984, althesin has been withdrawn from the market as a human intravenous anesthetic.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

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

[0006] Injectable emulsions must have very small droplet sizes. In order to prevent capillary blockage and embolism in the bloodstream, the Chinese Pharmacopoeia, Part IV, General Chapter 0102, requires that the average particle size of emulsion injections not exceed 0.5 micrometers.

[0007] Furthermore, although emulsions are thermodynamically unstable systems, they are expected to be physically and chemically stable during storage. The droplet size limits defined in General Chapter 0102 of the Chinese Pharmacopoeia (Part IV) apply to the entire specified storage period, typically extending to 2-3 years or longer for commercial pharmaceutical formulations. All true emulsions are thermodynamically unstable and may undergo processes that tend to increase droplet size over time. These include direct droplet coalescence, where two droplets collide to form a single new droplet, and aggregation, where droplets adhere together to form larger clumps. Aggregation can, in some cases, be a precursor to further coalescence into larger droplets. Ultimately, these processes can result in large aggregates of free oil visible on the emulsion surface or rising to the surface of the container, a phenomenon known as “emulsion creaming.” Measurement of droplet size, which measures the initial increase in size, allows for prediction of the physical stability of the emulsion early, before the formulation shows visible changes.

[0008] Additionally, drug components may degrade; for example, lipophilic drugs may separate into an oil phase, which provides a degree of protection, but hydrolytic degradation can still occur at the oil-water interface. Possible chemical degradation of parenteral fat emulsions includes the oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, as well as the hydrolysis of phospholipids, leading to the formation of free fatty acids (FFA) and lysophospholipids. These degradation products lower the pH, which may further promote degradation. Therefore, pH should be controlled during manufacturing, and parenteral emulsion formulations may include buffers to provide additional control. Any pH decrease within the specified shelf life can indicate chemical degradation.

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

[0010] The fat emulsion injection of the present invention requires a high-shear homogenization step to achieve a sufficiently small droplet size for sterilization and intravenous administration. To encapsulate alfasalam in the emulsion with a sufficiently small droplet size, enabling sterilization by filtration, and simultaneously meeting the requirements of the Chinese Pharmacopoeia throughout the specified shelf life, the inventors have conducted extensive research on its formulation and process.

[0011] Alphadolone has only half the potency of alfasalone, but it can increase the solubility of alfasalone by three times. The literature Mark S. Althesin-a new intravenous anaesthetic[J] Canda. Anaesth 1973(20):186-191 reports that alphadolone has a solubilizing effect on alfasalone. This invention aims to provide an emulsion containing only alfasalone. Without the solubilizing effect of alphadolone, the solubility of alfasalone will be even lower. Therefore, solubility is a pressing technical problem to be solved in the preparation of emulsions containing only high-potency alfasalone. Summary of the Invention

[0012] The present invention aims to at least partially solve one of the aforementioned technical problems or at least provide a useful commercial alternative. Therefore, one object of the present invention is to provide an alfasalone fat emulsion injection that is highly effective, has stable drug quality, is non-irritating to blood vessels, has high clinical safety, and good patient compliance.

[0013] One aspect of the present invention provides an alfasalin fat emulsion injection comprising alfasalin or a pharmaceutically acceptable salt thereof; an oil for injection; an emulsifier; an osmotic pressure regulator; a stabilizer; a pH adjuster; and water for injection.

[0014] In some specific embodiments, the injectable oil is soybean oil or a mixture of soybean oil and medium-chain triglycerides.

[0015] In some specific embodiments, the weight ratio of soybean oil to medium-chain triglycerides in the mixture of soybean oil and medium-chain triglycerides is 1-5:1-5, preferably 1:1.

[0016] In some specific embodiments, the weight ratio of the alfasalol or its pharmaceutically acceptable salt (calculated by weight in alfasalol) to the oil for injection is optionally 1-10:50-300, preferably 1-10:100-300, preferably 1-6:100-300, preferably 1-3:100-300, and even more preferably 1-3:100-200. In some specific embodiments, the amount of oil for injection in the alfasalol fat emulsion injection accounts for 10-30% of the mass concentration of the fat emulsion injection, preferably 10%-20%.

[0017] In some specific embodiments, the average particle size of the oil phase in the Alfasal fat emulsion injection is 0.2 to 0.4 μm, preferably 0.22 to 0.3 μm.

[0018] In some specific implementations, the alfasal fat emulsion injection uses alfasal or a pharmaceutically acceptable salt thereof with a purity greater than 95%, more preferably alfasal or a pharmaceutically acceptable salt thereof with a purity greater than 98%.

[0019] In some specific embodiments, the content of alfasal or its pharmaceutically acceptable salt in the alfasal fat emulsion injection is 1 to 10 mg / ml, preferably 2 to 8 mg / ml, and more preferably 2 to 4 mg / ml.

[0020] In some specific implementation schemes, the content of injectable oil in the alfasal fat emulsion injection is 100-300 mg / ml, preferably 100-200 mg / ml.

[0021] In some specific implementation schemes, the emulsifier content in the alfasal fat emulsion injection is 6-15 mg / ml, preferably 9-15 mg / ml.

[0022] In some specific implementation schemes, the stabilizer content in the alfasal fat emulsion injection is 0.05-0.3 mg / ml, preferably 0.06-0.3 mg / ml, and more preferably 0.1-0.3 mg / ml.

[0023] In some specific implementation schemes, the content of osmotic pressure regulator in the alfasal fat emulsion injection is 22-25 mg / ml, preferably 22.5-25 mg / ml.

[0024] In some specific implementations, the content of emulsifier in the alfasal fat emulsion injection is 0.6%-1.5% (wt), preferably 0.9%-1.5% (wt).

[0025] In some specific implementations, the zeta potential of the alfasal fat emulsion injection is 36 to 60 mV.

[0026] In some specific implementation schemes, the pH value of the alfasal fat emulsion injection is 6.0 to 8.5.

[0027] In some specific embodiments, the alfasal fat emulsion injection contains 0.6%-1.5% (w / v), preferably 0.6% (w / v), 0.9% (w / v), 1.2% (w / v), or 1.5% (w / v) of an emulsifier, and more preferably 0.9% (w / v), 1.2% (w / v), or 1.5% (w / v) of an emulsifier.

[0028] In some specific embodiments, the alphasalam fat emulsion injection contains 5%-15% (w / v), preferably 5% (w / v), 10% (w / v), or 15% (w / v) of soybean oil.

[0029] In some specific embodiments, the alfasal fat emulsion injection contains 5%-15% (w / v), preferably 5% (w / v), 10% (w / v), or 15% (w / v) of medium-chain triglycerides.

[0030] In some specific embodiments, the alphasalam fat emulsion injection contains 0.01%-0.03% (w / v), preferably 0.01% (w / v), 0.02% (w / v), or 0.03% (w / v) of sodium oleate.

[0031] In some specific embodiments, the alfasal fat emulsion injection contains 2.25%-2.5% (w / v), preferably 2.25% (w / v), 2.5% (w / v) of glycerol.

[0032] In some specific embodiments, the Alfasal fat emulsion injection contains 0.6%-1.5% (w / v), preferably 0.6% (w / v), 0.9% (w / v), 1.2% (w / v), or 1.5% (w / v) of egg yolk lecithin, and more preferably 0.9% (w / v), 1.2% (w / v), or 1.5% (w / v) of egg yolk lecithin.

[0033] In some specific implementations, the emulsifier of the Alfasal fat emulsion injection is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, and preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2.

[0034] In some specific implementations, the osmotic pressure regulator is glycerol.

[0035] In some specific embodiments, the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate.

[0036] In some specific implementations, the pH adjuster is sodium hydroxide.

[0037] In some specific implementation schemes, the emulsifier of the Alfasal fat emulsion injection is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, and preferably a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:2.

[0038] A pH adjuster capable of controlling the pH of the injection solution within the required range of 6.0–8.5; and

[0039] Optionally, the osmotic pressure regulator is glycerol.

[0040] Optionally, the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate.

[0041] Optionally, the pH adjuster is sodium hydroxide.

[0042] And the remaining amount of water for injection.

[0043] In some specific implementation schemes, the pH value of the alfasalin fat emulsion injection is 6.0–8.5; the components, by mass concentration, include: alfasalin 0.1%–0.3%; soybean oil 5%–10%; medium-chain triglycerides 5%–10%; emulsifier 0.9%–1.5%; stabilizer 0.01%–0.03%; and glycerol 2.2%–2.5%.

[0044] In some specific implementation schemes, the pH value of the alfasalol fat emulsion injection is 6.0 to 8.5, and the components, by weight, include: 1 to 3 parts alfasalol; 50 to 100 parts soybean oil; 50 to 100 parts medium-chain triglycerides; 9 to 12 parts emulsifier; 0.1 to 0.3 parts stabilizer; and 22 to 25 parts glycerol.

[0045] In some specific implementation schemes, the pH value of the alfasalol fat emulsion injection is 6.0-8.5, and the components, by weight, include: alfasalol 1-3; soybean oil 100-200; emulsifier 9-15; stabilizer 0.1-0.3; and glycerin 22-25.

[0046] In some specific implementation schemes, the pH value of the alfasalofat emulsion injection is 6.0 to 8.5, and the components, by weight, include: 1 to 3 parts alfasalofat; 100 to 200 parts soybean oil; 9 to 12 parts emulsifier; and 0.1 to 0.3 parts stabilizer.

[0047] In some specific implementation schemes, the pH value of the alfasal fat emulsion injection is 6.0 to 8.5, and the components, by weight, include: 1 to 3 parts alfasal; 100 to 200 parts soybean oil; 9 to 12 parts emulsifier; 0.1 to 0.3 parts stabilizer; and 22 to 25 parts glycerin.

[0048] In some specific embodiments, the pH value of the alfasalofat emulsion injection is 6.0-8.5, and the components, by weight, include: 1-3 parts alfasalofat, 100-200 parts soybean oil, 9-15 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, and 22-25 parts glycerol; preferably, the components are: 1-3 parts alfasalofat, 100-200 parts soybean oil, 9-12 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, and 22.5 parts glycerol; more preferably, the components are: 1-3 parts alfasalofat, 100-200 parts soybean oil, 9-12 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, and 25 parts glycerol.

[0049] In some specific embodiments, the pH value of the alfasaloel fat emulsion injection is 6.0-8.5, and the components, by weight, include: 1-3 parts alfasaloel, 100 parts soybean oil, 100 parts medium-chain triglycerides, 9-15 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, 22.5-25 parts glycerol, and an appropriate amount of sodium hydroxide; preferably, the components are: 1-3 parts alfasaloel, 100 parts soybean oil, 100 parts medium-chain triglycerides, 9-12 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, and 22.5-25 parts glycerol; more preferably, the components are: 1-3 parts alfasaloel, 200 parts soybean oil, 9-15 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, and 22.5-25 parts glycerol; even more preferably, the components are: 1-3 parts alfasaloel, 200 parts soybean oil, 9-12 parts egg yolk lecithin, 0.1-0.3 parts sodium oleate, and 22.5-25 parts glycerol.

[0050] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasalam; 100-200 mg of soybean oil for injection; 9-12 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 22-25 mg of glycerol; the amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance being water for injection.

[0051] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0 to 8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1 to 3 mg of alfasal; 100 to 200 mg of soybean oil; 9 to 15 mg of emulsifier; 0.1 to 0.3 mg of stabilizer; 25 mg of glycerol; and the balance being water for injection.

[0052] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0 to 8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1 to 3 mg of alfasal; 100 to 200 mg of soybean oil; 9 to 12 mg of emulsifier; 0.1 to 0.3 mg of stabilizer; 22 mg of glycerol; and the balance being water for injection.

[0053] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasal; 100-200 mg of soybean oil; 9-15 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 22.5 mg of glycerol; the amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0054] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasal; 200 mg of soybean oil; 9-15 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 22.5 mg of glycerol; the amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance of water for injection.

[0055] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0–8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1–3 mg of alfasaline; 200 mg of soybean oil; 9–12 mg of egg yolk lecithin; 0.1–0.3 mg of sodium oleate; 22.5 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0–8.5; and the balance being water for injection. Preferably, the following injection solutions are also available:

[0056] The pH of the injection solution is 6.0–8.5, and each 1 ml of the alfasalam fat emulsion injection solution contains: 1–3 mg of alfasalam; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 9–15 mg of egg yolk lecithin; 0.1–0.3 mg of sodium oleate; 22.5–25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection solution to 6.0–8.5; and the balance being water for injection.

[0057] Alternatively, the pH of the injection solution is 6.0–8.5, and each 1 ml of the alfasalol fat emulsion injection solution contains: 1–3 mg of alfasalol; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 9–12 mg of egg yolk lecithin; 0.1–0.3 mg of sodium oleate; 22.5–25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection solution to 6.0–8.5; and the balance being water for injection;

[0058] Alternatively, the pH of the injection solution is 6.0–8.5, and each 1 ml of the alfasalol fat emulsion injection solution contains: 1–3 mg of alfasalol; 200 mg of soybean oil; 9–15 mg of egg yolk lecithin; 0.1–0.3 mg of sodium oleate; 22.5–25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection solution to 6.0–8.5; and the balance being water for injection;

[0059] Alternatively, the pH of the injection solution is 6.0–8.5, and each 1 ml of the alfasalam fat emulsion injection solution contains: 1–3 mg of alfasalam; 200 mg of soybean oil; 9–12 mg of egg yolk lecithin; 0.1–0.3 mg of sodium oleate; 22.5–25 mg of glycerol; an amount of sodium hydroxide required to control the pH of the injection solution to 6.0–8.5; and the remainder of water for injection.

[0060] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasal; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 9-12 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 22.5 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance being water for injection.

[0061] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasal; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 9-12 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance being water for injection.

[0062] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasal; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9-12 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance being water for injection.

[0063] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection contains: 1-3 mg of alfasalam; 50-100 mg of soybean oil; 50-100 mg of medium-chain triglycerides; 9-12 mg of egg yolk lecithin; 0.1-0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5; and the balance being water for injection;

[0064] Alternatively, the injection solution has a pH of 8.0, and each 1 ml of the alfasalol fat emulsion injection contains 2 mg of alfasalol; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 mg of egg yolk lecithin E-80; 0.1 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH to 8.0; and the remainder of water for injection.

[0065] Alternatively, the injection solution has a pH of 8.0, and each 1 ml of the alfasalol fat emulsion injection contains: 2 mg of alfasalol; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH to 8.0; and the balance being water for injection;

[0066] Alternatively, the injection solution has a pH of 7.0, and each 1 ml of the alfasalol fat emulsion injection contains: 3 mg of alfasalol; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH to 7.0; and the remainder of water for injection;

[0067] Alternatively, the injection solution has a pH of 8.0, and each 1 ml of the alfasalol fat emulsion injection contains: 4 mg of alfasalol; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH to 8.0; and the balance being water for injection;

[0068] Alternatively, the injection solution has a pH of 7.0, and each 1 ml of the alfasalol fat emulsion injection contains: 3 mg of alfasalol; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH to 7.0; and the balance of water for injection;

[0069] Alternatively, the injection solution has a pH of 7.5, and each 1 ml of the alfasal fat emulsion injection contains: 2 mg of alfasalam; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to adjust the pH to 7.5; and the remainder of water for injection;

[0070] Alternatively, the injection solution has a pH of 8.0, and each 1 ml of the alfasal fat emulsion injection contains: 2 mg of alfasalam; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH to 8.0; and the remainder of water for injection.

[0071] In some specific embodiments, the pH value of the alfasal fat emulsion injection is 6.0-8.5, and each 1 ml of the alfasal fat emulsion injection consists of 1-3 mg of alfasal, 50-100 mg of soybean oil, 50-100 mg of medium-chain triglycerides, 9-12 mg of egg yolk lecithin, 0.1-0.3 mg of sodium oleate, 25 mg of glycerol, an amount of sodium hydroxide required to control the pH value of the injection to 6.0-8.5, and the remainder being water for injection.

[0072] Alternatively, the pH of the injection solution is 8.0, and each 1 ml of the alfasalol fat emulsion injection solution consists of 2 mg of alfasalol; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 mg of egg yolk lecithin E-80; 0.1 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH to 8.0; and the balance being water for injection.

[0073] Alternatively, the pH of the injection solution is 8.0, and each 1 ml of the alfasalam fat emulsion injection solution consists of 2 mg of alfasalam; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH to 8.0; and the balance being water for injection.

[0074] Alternatively, the injection solution has a pH of 7.0, and each 1 ml of the alfasal fat emulsion injection consists of 3 mg of alfasaline; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH to 7.0; and the balance being water for injection.

[0075] Alternatively, the pH of the injection solution is 8.0, and each 1 ml of the alfasal fat emulsion injection solution consists of 4 mg of alfasaline; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 9 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH to 8.0; and the balance being water for injection.

[0076] Alternatively, the pH of the injection solution is 7.0, and each 1 ml of the alfasal fat emulsion injection solution consists of 3 mg of alfasaline; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH to 7.0; and the balance being water for injection.

[0077] Alternatively, the pH of the injection solution is 7.5, and each 1 ml of the alfasal fat emulsion injection solution consists of 2 mg of alfasaline; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to adjust the pH to 7.5; and the balance being water for injection.

[0078] Alternatively, the pH of the injection solution is 8.0, and each 1 ml of the alfasal fat emulsion injection solution consists of 2 mg of alfasalam; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin; 0.3 mg of sodium oleate; 25 mg of glycerol; an amount of sodium hydroxide required to control the pH to 8.0; and the balance being water for injection.

[0079] Another aspect of the present invention provides a method for preparing an alfasalol fat emulsion injection, comprising:

[0080] (1) Heat the oil for injection to 50℃~75℃, then add the emulsifier and alfasal, mix, and shear until completely dissolved and evenly dispersed to obtain a first mixture containing the alfasal oil phase;

[0081] Preferably, the oil for injection is soybean oil or a mixture of soybean oil and medium-chain triglycerides; more preferably, the oil for injection is a mixture of soybean oil and medium-chain triglycerides in a weight ratio of 1:1.

[0082] 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;

[0083] (2) Heat water for injection to 50℃~75℃, then add stabilizer and osmotic pressure regulator and stir evenly to obtain a second mixture forming an aqueous phase; preferably, the stabilizer is sodium oleate; preferably, the osmotic pressure regulator is glycerol;

[0084] (3) Mix the first mixture and the second mixture while shearing to obtain a third mixture that forms the colostrum;

[0085] (4) The pH of the third mixture is adjusted to 6.5-11.5, preferably 6.5-10.5, preferably 6.5-10, using a pH adjuster to obtain a fourth mixture, and a fifth mixture is obtained by low-pressure homogenization in one step; preferably, the pH adjuster is sodium hydroxide;

[0086] (5) The fifth mixture is subjected to high pressure homogenization 3 times or more, preferably 4-8 times, more preferably 5-6 times, and nitrogen gas is introduced into the liquid below the liquid surface until nitrogen saturation is achieved during the homogenization process in order to obtain the sixth mixture;

[0087] (6) The sixth mixture is filled, protected with nitrogen, and sterilized by moist heat to obtain alfasal fat emulsion injection with a pH value of 6.0 to 8.5.

[0088] Another aspect of the present invention provides a method for preparing an alfasalol fat emulsion injection, comprising: (1) heating an injection oil to 50°C to 75°C, then adding an emulsifier and alfasalol, mixing, and shearing until completely dissolved and evenly dispersed, so as to obtain a first mixture containing an alfasalol oil phase;

[0089] Preferably, the oil for injection is soybean oil or a mixture of soybean oil and medium-chain triglycerides; more preferably, the oil for injection is a mixture of soybean oil and medium-chain triglycerides in a weight ratio of 1:1.

[0090] 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.

[0091] (2) Take water for injection and heat it to 50℃~75℃, then add a stabilizer, an osmotic pressure regulator and a pH value regulator and stir evenly to obtain a second mixture forming an aqueous phase with a pH of 7~11.5, preferably 7~10.5, preferably 7~10; preferably, the stabilizer is sodium oleate; preferably, the osmotic pressure regulator is glycerol and the pH value regulator is sodium hydroxide;

[0092] (3) Mix the first mixture and the second mixture while shearing to obtain a third mixture that forms the colostrum;

[0093] (4) Optionally, the pH of the third mixture is adjusted to 6.5 to 11.5, preferably 6.5 to 10.5, and more preferably 6.5 to 10, using a pH adjuster to obtain a fourth mixture; preferably, the pH adjuster is sodium hydroxide;

[0094] (5) The mixture obtained in (3) or (4) is homogenized under low pressure once to obtain a fifth mixture; the fifth mixture is homogenized under high pressure 3 times or more, preferably 4-8 times, more preferably 5-6 times, and nitrogen is introduced into the mixture below the liquid surface until nitrogen saturation is achieved during the homogenization process in order to obtain a sixth mixture;

[0095] (6) The sixth mixture is filled with nitrogen for protection and then subjected to moist heat sterilization to obtain alfasal fat emulsion injection with a pH of 6.0 to 8.5.

[0096] In some specific implementations, shear mixing is carried out at a speed of 5000-16000 rpm for 5-25 minutes; preferably, the shearing speed during mixing is 10000 rpm, and the shearing speed after mixing is 15000-16000 rpm.

[0097] Terminology definition:

[0098] The term "isotonic" refers to a fluid having an osmotic pressure equal to or similar to that of physiological body fluids. Body fluids typically have an osmotic pressure often described as corresponding to a 0.9% (w / v) aqueous solution of sodium chloride. This application uses glycerol to adjust for isotonicity, with the amount of glycerol used being 22-25 mg per 1 ml of the described alfasalol fat emulsion injection, specifically 22 mg / ml, 22.5 mg / ml, 23 mg / ml, 23.5 mg / ml, 24 mg / ml, 24.5 mg / ml, and specifically 25 mg / ml.

[0099] The term "w / v" refers to the mass content of a component in a unit volume of injection solution, expressed in "g / ml".

[0100] The term "medium-chain oil" refers to medium-chain triglycerides; the term "long-chain oil" refers to soybean oil.

[0101] The term "AFSL" stands for Alpha Salon.

[0102] In this specification, “about” can be understood as being within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise expressly stated, all values ​​provided herein are modified by the term “about”.

[0103] Technical effects:

[0104] This invention confirms that alfasal can only achieve complete emulsification of the oil and aqueous phases when the appropriate injectable oil and its content are within a suitable range. The emulsion prepared by this invention has good particle size uniformity, and its pH is stable as confirmed by stability tests, without significant decrease, indicating good emulsion stability, which is beneficial for storage and does not have stringent requirements for storage conditions.

[0105] The fat emulsion provided in this application has been pharmacologically proven to have significantly lower sensitization than the castor oil-containing emulsion prepared according to CN94190450.4, significantly smaller average particle size than the castor oil emulsion group, higher encapsulation efficiency than the castor oil preparation group, less injection pain than the castor oil emulsion group, and better stability in all aspects than the castor oil emulsion group, making it safer.

[0106] Alphasalam has higher solubility in castor oil than medium-chain triglycerides and soybean oil. This invention, through exploration of the optimal ratio of injectable oils, found that the best ratio of injectable medium-chain triglycerides and soybean oil, which have poor solubility in alphasalam, is used. In addition, the content of injectable oils should be within a certain appropriate range to ensure that the emulsifier can completely emulsify the oil phase and the aqueous phase.

[0107] The fat emulsion provided in this application, as confirmed by pharmacological experiments, exhibits significantly lower sensitization than the castor oil-containing emulsion prepared according to CN94190450.4, a significantly smaller average particle size than the castor oil emulsion group, a higher encapsulation efficiency than the castor oil formulation group, less injection pain than the castor oil emulsion group, and better stability in all indicators compared to the castor oil emulsion group. This invention uses a novel formulation to prepare the emulsion, employing soybean oil and medium-chain triglycerides in a 1:1 weight ratio as the injection oil, and sodium oleate as a stabilizer. The resulting alfasalone fat emulsion injection sample demonstrates greater stability.

[0108] The sample prepared by the method described in this invention showed no change in appearance or properties at 4°C, with no stratification or flocculation observed. The drug content, impurity levels, and particle size remained largely unchanged, indicating that the alfasalol fat emulsion injection and its preparation method described in this invention possess excellent drug stability, effectively meeting the stability requirements for clinical use. The alfasalol fat emulsion injection obtained using the formulation and preparation method described in this invention features a simple preparation process, stable formulation quality, no vascular irritation, high clinical safety, and good patient compliance. Attached Figure Description

[0109] Figure 1 This is a graph showing the histamine content in mouse plasma after intravenous administration. Detailed Implementation

[0110] Egg yolk lecithin E80 was purchased from Lipoid GmbH, Germany; glycerol was purchased from Shantou Jiahe Biotechnology Co., Ltd.; soybean oil was purchased from Guangzhou Baiyunshan Hanfang Modern Pharmaceutical Co., Ltd.; medium-chain triglycerides, also known as medium-chain triglycerides (caprylic acid 57.1%, caprylic acid 42.8%), were purchased from Liaoning Xinxing Pharmaceutical Co., Ltd.; sodium oleate was purchased from Lipoid GmbH, Germany; alfasalone was self-made by Jiangsu Enhua Pharmaceutical Co., Ltd. with a purity of over 95%; 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).

[0111] Examples 1-3: Preparation methods (batch size: 1000ml)

[0112] Preparation of 0.1 mol / L sodium hydroxide: Weigh 0.4 g of sodium hydroxide, dissolve it in an appropriate amount of water, let it cool, transfer it to a 100 ml volumetric flask, and dilute to the mark for later use.

[0113] Oil phase preparation: Add the required amount of soybean oil and medium-chain triglycerides to a 500 ml beaker and heat in a 70°C water bath. Weigh out egg yolk lecithin and alfasalol (AFSL) according to the required dosage, add them to the oil phase, and shear at 10,000 rpm for 5 minutes to obtain the oil phase.

[0114] Preparation of aqueous phase: Weigh the water for injection into a 2000ml beaker, heat it in a water bath, and control the water temperature at 70℃; add the dosage amount of sodium oleate and glycerol to the aqueous phase and stir evenly with a glass rod to obtain the aqueous phase.

[0115] Preparation of colostrum: Add the oil phase to the aqueous phase while shearing (10000 rpm) and control the temperature of the colostrum at 70℃. After the oil phase is added, adjust the shearing speed to 15400 rpm and shear for 5 min. Adjust the pH of the colostrum to 9.0 with 0.1 mol / L sodium hydroxide to obtain the colostrum.

[0116] The finished product was prepared using a two-step homogenization method: low-pressure homogenization at 100 bar / 160 bar, once; and high-pressure homogenization at 100 bar / 600 bar, six times. After homogenization, the samples were filled, nitrogen-filled, and sterilized (121℃, 15 min).

[0117] 1.1 Formulation composition:

[0118]

[0119] 1.2 Experimental Results

[0120]

[0121]

[0122] 1.3 Conclusion: Immediately after sterilization, the appearance, encapsulation efficiency, pH, particle size, and zeta potential of the finished product all met the requirements.

[0123] 1.4 Influencing Factors Experiment

[0124] Samples from Example 2 were subjected to high-temperature (60℃, 40℃) and low-temperature (4℃) conditions. Samples were taken and tested at 5 days, 10 days, and 30 days. The results are shown in the table below.

[0125]

[0126] Conclusion: After 30 days of storage, the appearance, content, potential, and particle size of the 2 mg / ml sample were all within the acceptable range.

[0127] I. Investigate the different types and proportions of oil phases

[0128] Comparative Examples 1-2 were prepared according to the method disclosed in Example 1 of CN94190450.4.

[0129] Oil phase preparation: Add the required amount of castor oil or soybean oil / castor oil to a 250ml beaker and heat in a 70℃ water bath. Weigh 2g of AFSL and add it to the oil phase, shear at 10000rpm for 2min. Weigh 12g of egg yolk lecithin and add it to the oil phase, shear at 10000rpm for 5min to obtain the oil phase.

[0130] Preparation of aqueous phase: Weigh 861.5g of water for injection into a 2000ml beaker, heat it in a water bath, and control the water temperature at 70℃; add 22.5g of glycerol to the aqueous phase and stir evenly with a glass rod to obtain the aqueous phase.

[0131] Preparation of colostrum: Add the oil phase to the aqueous phase while shearing (10000 rpm) and control the temperature of the colostrum at 70℃. After the oil phase is added, adjust the shearing speed to 15400 rpm and shear for 5 min. Adjust the pH of the colostrum to 9.0 with 0.1 mol / L sodium hydroxide to obtain the colostrum.

[0132] Product preparation: Low-pressure homogenization: 100 bar / 160 bar, homogenization once. High-pressure homogenization: 100 bar / 600 bar, homogenization six times. After homogenization, the sample is filled, nitrogen-filled, and sterilized (121℃, 15 min).

[0133] 1.1.1 Dosage

[0134]

[0135] 1.1.2 Experimental Results

[0136] project Comparative Example 1 Comparative Example 2 Content (i.e., the content of the active pharmaceutical ingredient in the finished emulsion, %) 100.56 101.29 Encapsulation efficiency (%) 91.2 89.03 pH 7.54 7.45 Particle size (μm) 0.548 0.459 Zeta potential (mV) 41.4 39.6

[0137] 1.1.3 Conclusion: Based on the experimental process, 10% castor oil can completely dissolve AFSL, and the content, potential and other indicators are within the qualified range. However, the particle size of the emulsion sample is greater than 0.5μm, which is within the unqualified range according to the provisions of General Chapter 0102 of Part IV of the Chinese Pharmacopoeia.

[0138] Referring to the experimental method in Example 1, we explored the feasibility of preparing samples with different formulation compositions.

[0139] 1.2.1 Formulation composition (batch size: 1000ml)

[0140]

[0141]

[0142] 1.2.2 Experimental Results

[0143]

[0144] 1.2.3 Conclusion: Samples prepared with different proportions of oil phase (soybean oil or a mixture of soybean oil and medium-chain triglycerides) (10%, 20%, 30%) showed no significant differences in appearance, content, encapsulation efficiency, pH value, and zeta potential. However, the average particle size gradually increased with the increase of the oil phase proportion, with the average particle size of the preparation containing 30% oil phase being greater than 0.4 μm, close to the limit. Samples containing castor oil showed that their appearance, encapsulation efficiency, pH, content, and zeta potential were all within acceptable ranges, but the average particle size was greater than or close to 0.5 μm, significantly higher than that of the preparation without castor oil.

[0145] In summary, the selection of the type and proportion of oil for injection should be within an appropriate range to ensure that the emulsifier can completely emulsify the oil and water phases. Therefore, the preferred range for the oil phase proportion in this invention is 10%-20%; the oil phase is soybean oil or a mixture of soybean oil and medium-chain triglycerides.

[0146] The following examples were conducted with an oil phase content of 20% (the ratio of soybean oil to medium-chain triglycerides was 1:1).

[0147] II. Experiment on the optimal amount of phospholipid

[0148] 2.1 Experiment with formulations using different proportions of phospholipids at a concentration of 2 mg / ml to assess the feasibility of the samples. The preparation method is the same as in Example 1 (batch size is 1000 ml).

[0149]

[0150] 2.2 Sample test results:

[0151] project Example 8 Example 9 Example 10 Example 11 Appearance Oil drift Uniform milky white Uniform milky white Uniform milky white content 102.56 100.53 102.35 99.92 Encapsulation rate 88.00 87.71 85.76 86.57 pH 7.40 7.75 7.70 7.62 Particle size (μm) 0.360 0.261 0.262 0.248 Zeta potential (mV) 40.2 38.6 33.3 38.2

[0152] 2.3 Conclusion: Within the phospholipid ratio range of 0.6%-1.5%, there was no significant difference in content and potential. As the phospholipid ratio increased, the sample particle size tended to decrease, but the difference was not significant within the range of 0.9%-1.5%. The sample containing 0.6% phospholipid showed a slight oil floating phenomenon in appearance.

[0153] 2.4 Results of Influencing Factors:

[0154] Example 8

[0155]

[0156]

[0157] Example 9

[0158] content(%) pH Particle size (μm) Zeta potential (mV) After sterilization 100.53 7.75 0.261 38.6 Low temperature 4℃-5d 100.41 7.66 0.269 40.9 High temperature 40℃ - 5 days 101.48 7.44 0.263 36.4 High temperature 60℃ - 5 days 101.47 7.25 0.258 40.6 Low temperature 4℃-10d 101.71 7.40 0.265 39.6 High temperature 40℃ - 10 days 100.42 7.26 0.265 40.3 High temperature 60℃-10d 101.23 7.09 0.258 40.6 Low temperature 4℃-30d 101.26 6.86 0.265 39.6 High temperature 40℃-30d 102.02 6.75 0.261 38.5 High temperature 60℃-30d 100.02 6.60 0.262 40.2

[0159] Example 10

[0160]

[0161]

[0162] Example 11

[0163] content(%) pH Particle size (μm) Zeta potential (mV) After sterilization 99.92 7.62 0.248 38.2 Low temperature 4℃-5d 99.93 7.62 0.244 35.2 High temperature 40℃ - 5 days 99.76 7.53 0.244 35.2 High temperature 60℃ - 5 days 100.86 7.21 0.246 34.4 Low temperature 4℃-10d 101.71 7.70 0.248 38.3 High temperature 40℃ - 10 days 100.48 7.37 0.248 36.6 High temperature 60℃-10d 101.60 7.18 0.256 37.4 Low temperature 4℃-30d 101.02 6.85 0.245 39.2 High temperature 40℃-30d 99.98 6.67 0.249 37.5 High temperature 60℃-30d 101.52 6.40 0.251 39.5

[0164] Conclusion: Compared with day 0, the results of samples containing 0.9%-1.5% phospholipids remained stable under various influencing factors over 30 days, with no significant changes in content, particle size, and potential. However, for samples containing 0.6% phospholipids, the results of influencing factors showed an increase in average particle size and a tendency to aggregate. This indicates that emulsion samples containing 0.6% phospholipids are unstable; therefore, the preferred phospholipid range is 0.9%-1.5%.

[0165] III. Solubility test of alfasalol in castor oil, long-chain oil (soybean oil), and medium-chain oil (medium-chain triglycerides)

[0166] 1. Experimental objective: To investigate the solubility of alfasalol in castor oil.

[0167] Experimental procedure: 10 mg of alfasalamine was weighed and added to 100 g of castor oil at 70 °C. After shearing at 10,000 rpm for 5 min, the system became clear. Another 10 mg of alfasalamine was weighed and added to the system. After shearing at 10,000 rpm for 3 min, the system became clear. Another 30 mg of alfasalamine was weighed and added to the system. After shearing at 10,000 rpm for 3 min, the system became clear. This process of weighing alfasalamine was repeated until the total amount reached 2 g, at which point the system remained clear.

[0168] Experimental conclusion: The solubility of afasalam in castor oil is above 2g.

[0169] 2. Experimental objective: To investigate the solubility of alfasalin in soybean oil.

[0170] Experimental procedure: 10 mg of alfasalam was weighed and added to 100 g of soybean oil at 70 °C. After shearing at 10,000 rpm for 5 min, the system became turbid.

[0171] Experimental conclusion: Alphasalam has a solubility of less than 10 mg in 100 g soybean oil.

[0172] 3. Experimental objective: To investigate the solubility of alfasalin in medium-chain oils.

[0173] Experimental procedure: 10 mg of alfasalamine was weighed and added to 100 g of medium-chain oil at 70 °C. After shearing at 10,000 rpm for 5 min, the system became clear. Another 10 mg of alfasalamine was weighed into the system, and after shearing at 10,000 rpm for 3 min, the system became clear. Another 30 mg of alfasalamine was weighed into the system, and after shearing at 10,000 rpm for 3 min, the system became slightly turbid.

[0174] Experimental conclusion: 100g of medium-chain oil can dissolve less than 40mg of afasalam.

[0175] IV. Pharmacological Experiments

[0176] Experimental method v: Prepare the appropriate solution or preparation, administer intravenously, collect blood 30 min after administration, centrifuge after EDTA anticoagulation, and determine the histamine content in mouse plasma using an ELISA kit.

[0177] Blank plasma: Blood was collected directly from mice and centrifuged.

[0178] Physiological saline: Inject physiological saline at a volume of 5 mL / kg.

[0179] Blank fat emulsion: The administration volume is 5 mL / kg.

[0180] Alfasal fat emulsion (Example 2): The dosage of alfasal fat emulsion was 7 mg / kg.

[0181] Alfasal ED50 is approximately 3.5 mg / kg, therefore the dosage is 7 mg / kg. Alfasal fat emulsion is available in 2 mg / mL form, diluted to 1.4 mg / mL using a blank fat emulsion, with a dosage volume of 5 mL / kg.

[0182] SBE-β-CD: Preparation method: 0.7 mL 13% SBE-β-CD + 4.3 mL physiological saline, with a dosing volume of 5 mL / kg. (The formulation from Suspension Bridge Company is 13% SBE-β-CD dissolved in alfasalol, with a concentration of 10 mg / mL after dissolution. Therefore, this group of experiments referred to the formulation from Suspension Bridge Company for drug solution preparation).

[0183] CremophorEL: 0.7 mL Cremophor EL + 4.3 mL physiological saline, Cremophor EL concentration is 0.14 mL / mL, dosage is 5 mL / kg, and Cremophor EL dosage is 0.7 mL / kg.

[0184] SBE-β-CD & Cremophor EL: 0.7 mL 13% SBE-β-CD + 0.7 mL Cremophor EL + 3.6 mL physiological saline, with a dosing volume of 5 mL / kg.

[0185] Alfasalam@SBE-β-CD & Cremophor EL: 0.7 mL alfasalam@13% SBE-β-CD (10 mg / mL) + 0.7 mL Cremophor EL + 3.6 mL normal saline, with a dosing volume of 5 mL / kg. The final concentration of alfasalam is 1.4 mg / mL, therefore the final dose of alfasalam is 7 mg / kg, and the dose of Cremophor EL is 0.7 mL / kg.

[0186] Alfa Salon@castor oil (10%) fat emulsion (2 mg / mL): administration volume 3.5 mL / kg, dose 7 mg / kg; castor oil administration volume 0.35 mL / kg.

[0187] Alfa Salon@ Castor Oil (7%) Fat Emulsion (2 mg / mL): Dosage volume 3.5 mL / kg, dose 7 mg / kg; castor oil dosage 0.245 mL / kg.

[0188]

[0189] Results: After intravenous injection, the plasma histamine concentrations in mice treated with saline, 20% medium- and long-chain fat emulsions, alfasalol fat emulsion injection (Example 2), and sulfobutyl-β-cyclodextrin (SBE-β-CD) showed no significant difference compared to blank plasma, and no excessive histamine release was observed. However, the plasma histamine concentrations in mice treated with Cremophor EL, SBE-β-CD & Cremophor EL, alfasalol@(SBE-β-CD & Cremophor EL), alfasalol@caster oil (7%) fat emulsion, and alfasalol@caster oil (10%) fat emulsion were significantly higher than those in the solvent group, indicating excessive histamine release and potentially allergic reactions. The plasma histamine concentration in the alfasalol@(SBE-β-CD & Cremophor EL) group was significantly higher than that in the SBE-β-CD & Cremophor EL group, suggesting that alfasalol dissolved in SBE-β-CD & Cremophor EL promoted histamine release and exacerbated the allergic reaction.

[0190] The above results indicate that intravenous injection of alfasal formulations containing Cremophor EL and castor oil caused excessive histamine release in mice, suggesting a possible allergic reaction; however, the alfasal fat emulsion injection of this invention (Example 2) did not cause an allergic reaction (see attached). Figure 1 .

Claims

1. An alfasal fat emulsion injection, characterized in that, Including alfasalam or its pharmaceutically acceptable salts, oils for injection, emulsifiers, osmotic regulators, stabilizers, pH adjusters and water for injection; The oil for injection is soybean oil or a mixture of soybean oil and medium-chain triglycerides; The emulsifier is egg yolk lecithin; The stabilizer is sodium oleate; The components, based on their mass concentration relative to the fat emulsion injection, are: 0.1% to 0.3% of the alfasalol or its pharmaceutically acceptable salts, 10% to 30% of the oil for injection, and 0.9% to 1.5% of the emulsifier.

2. The alfasalol fat emulsion injection according to claim 1, characterized in that, Based on the mass concentration of the fat emulsion injection, the oil for injection is 10% to 20%.

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

4. The alfasalol fat emulsion injection according to claim 3, characterized in that, The soybean oil and medium-chain triglycerides mixture has a weight ratio of soybean oil to medium-chain triglycerides of 1:

1.

5. The alfasalol fat emulsion injection according to claim 1, characterized in that, The weight ratio of the alfasalol or its pharmaceutically acceptable salt to the injectable oil is 1-3:100-300.

6. The alfasalol fat emulsion injection according to claim 5, characterized in that, The weight ratio of the alfasal or its pharmaceutically acceptable salt to the injectable oil is 1-3:100-200.

7. The alfasalol fat emulsion injection according to claim 1, characterized in that, The purity of the alfasal or its pharmaceutically acceptable salt is greater than 95%.

8. The alfasal fat emulsion injection according to claim 1, characterized in that, The egg yolk lecithin is selected from at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T; the amount of pH adjuster used is the amount required to control the pH of the injection solution within the range of 6.0 to 8.

5.

9. The alfasalol fat emulsion injection according to claim 8, characterized in that, Egg yolk lecithin is selected from a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M in a weight ratio of 1:

2.

10. The alfasalol fat emulsion injection according to claim 1, characterized in that, The osmotic pressure regulator is glycerol.

11. The alfasalol fat emulsion injection according to claim 1, characterized in that, The pH adjuster is sodium hydroxide.

12. The alfasalol fat emulsion injection according to any one of claims 1-11, characterized in that, The pH value of the injection solution is 6.0~8.5; the components, based on their mass concentration in the fat emulsion injection solution, include: alfasalamine 0.1%~0.3%; soybean oil 5%~10%; medium-chain triglycerides 5%~10%; emulsifier 0.9%~1.5%; stabilizer 0.01%~0.03%; glycerol 2.2%~2.5%.

13. The alfasalol fat emulsion injection according to any one of claims 1-11, characterized in that, The pH value of the injection solution is 6.0~8.5; the components, by weight, include: alfasalamine 1~3; soybean oil 50~100; medium-chain triglycerides 50~100; emulsifier 9~12; stabilizer 0.1~0.3; glycerol 22~25.

14. The alfasalol fat emulsion injection according to any one of claims 1-11, characterized in that, The pH value of the injection solution is 6.0~8.5; the components, by weight, include: alfasalamine 1~3; soybean oil 100~200; emulsifier 9~15; stabilizer 0.1~0.3; glycerin 22~25.

15. The alfasalol fat emulsion injection according to claim 1, characterized in that, The pH value of the injection solution is 6.0~8.5; the components, by weight, include: alfasalamine 1~3, soybean oil 100~200; egg yolk lecithin 9~15; sodium oleate 0.1~0.3; glycerol 22~25.

16. The alfasalol fat emulsion injection according to claim 1, characterized in that, The pH value of the injection solution is 6.0~8.

5. The components, by weight, include: alfasalamine 1~3; soybean oil 100~200; emulsifier 9~12; stabilizer 0.1~0.3; glycerin 22~25.

17. The alfasal fat emulsion injection according to claim 1, characterized in that, The pH of the injection solution is 6.0~8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 100-200 mg of soybean oil; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22-25 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining amount of water for injection.

18. The alfasalol fat emulsion injection according to claim 1, characterized in that, The pH of the injection solution is 6.0~8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 100-200 mg of soybean oil; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 25 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining water for injection; Alternatively, the pH of the injection solution is 6.0 to 8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 50-100 mg of soybean oil; Medium-chain triglycerides 50-100 mg; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5 mg; Sodium hydroxide that can adjust the pH value to the required amount of 6.0~8.5; And the remaining amount of water for injection.

19. The alfasalol fat emulsion injection according to claim 1, characterized in that, The pH of the injection solution is 6.0~8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 100 mg of soybean oil; Medium-chain triglycerides 100 mg; Egg yolk lecithin 9-15 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5~25 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining water for injection; Alternatively, the pH of the injection solution is 6.0 to 8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 200 mg of soybean oil; Egg yolk lecithin 9-15 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5~25 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining amount of water for injection.

20. The alfasalol fat emulsion injection according to claim 1, characterized in that, The pH of the injection solution is 6.0~8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 100 mg of soybean oil; Medium-chain triglycerides 100 mg; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5~25 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining water for injection; Alternatively, the pH of the injection solution is 6.0 to 8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 200 mg of soybean oil; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5~25 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining amount of water for injection.

21. The alfasal fat emulsion injection according to claim 1, characterized in that, The pH of the injection solution is 6.0~8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 50 mg of soybean oil; Medium-chain triglycerides 50 mg; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining water for injection; Alternatively, the pH of the injection solution is 6.0 to 8.5, and each 1 ml of the alfasal fat emulsion injection solution contains: Alfasal 1-3 mg; 100 mg of soybean oil; Medium-chain triglycerides 100 mg; Egg yolk lecithin 9-12 mg; Sodium oleate 0.1~0.3 mg; Glycerin 22.5 mg; Sodium hydroxide can be used to control the pH of the injection solution to 6.0~8.

5. And the remaining amount of water for injection.

22. The alfasal fat emulsion injection according to claim 1, characterized in that, The injection solution has a pH of 8.0, and each 1 ml of the alfasal fat emulsion injection contains: Alfasal 2 mg; 100 mg of soybean oil; Medium-chain triglycerides 100 mg; Egg yolk lecithin 12 mg; Sodium oleate 0.3 mg; Glycerin 22.5 mg; It can control the amount of sodium hydroxide required to achieve a pH value of 8.0; And the remaining amount of water for injection.

23. The alfasal fat emulsion injection according to claim 1, characterized in that, The injection solution has a pH of 8.0, and each 1 ml of the alfasal fat emulsion injection contains: Alfasal 2 mg; 50 mg of soybean oil; Medium-chain triglycerides 50 mg; Egg yolk lecithin E-80 9 mg; Sodium oleate 0.1 mg; Glycerin 22.5 mg; It can control the amount of sodium hydroxide required to achieve a pH value of 8.0; And the remaining water for injection; Alternatively, the injection solution has a pH of 8.0, and each 1 ml of the alfasal fat emulsion injection contains: Alfasal 2 mg; 100 mg of soybean oil; Medium-chain triglycerides 100 mg; Egg yolk lecithin E-80 12 mg; Sodium oleate 0.3 mg; Glycerin 22.5 mg; It can control the amount of sodium hydroxide required to achieve a pH value of 8.0; And the remaining water for injection; Alternatively, the injection solution has a pH of 7.0, and each 1 ml of the alfasal fat emulsion injection contains: Alfasal 3 mg; 100 mg of soybean oil; Medium-chain triglycerides 100 mg; Egg yolk lecithin E-80 12 mg; Sodium oleate 0.3 mg; Glycerin 22.5 mg; The amount of sodium hydroxide required to control the pH value to 7.0; And the remaining water for injection; Alternatively, the injection solution has a pH of 7.0, and each 1 ml of the alfasal fat emulsion injection contains: Alfasal 3 mg; 50 mg of soybean oil; Medium-chain triglycerides 50 mg; Egg yolk lecithin E-80 15 mg; Sodium oleate 0.3 mg; Glycerin 22.5 mg; The amount of sodium hydroxide required to control the pH value to 7.0; And the remaining water for injection; Alternatively, the injection solution has a pH of 7.5, and each 1 ml of the said alfasal fat emulsion injection contains: Alfasal 2 mg; 50 mg of soybean oil; Medium-chain triglycerides 50 mg; Egg yolk lecithin E-80 12 mg; Sodium oleate 0.3 mg; Glycerin 22.5 mg; The amount of sodium hydroxide required to adjust the pH to 7.5; And the remaining amount of water for injection.

24. A method for preparing the alfasalone fat emulsion injection according to any one of claims 1-23, characterized in that, include: (1) Heat the oil for injection to 50℃~75℃, then add emulsifier and alfasal, mix, and shear until completely dissolved and evenly dispersed to obtain the first mixture containing the alfasal oil phase; (2) Heat water for injection to 50℃~75℃, then add stabilizer and osmotic pressure regulator and stir evenly to obtain a second mixture that forms an aqueous phase; (3) Mix the first mixture and the second mixture, and shear while mixing to obtain a third mixture that forms the colostrum; (4) Adjust the pH of the third mixture with a pH adjuster to obtain a fourth mixture, and homogenize under low pressure once to obtain a fifth mixture; (5) The fifth mixture is subjected to high-pressure homogenization more than 3 times, and nitrogen is introduced into the liquid to the level below the liquid surface until the nitrogen is saturated during the homogenization process to obtain the sixth mixture; (6) The sixth mixture is filled into a container, protected with nitrogen, and sterilized by moist heat to obtain an alfasal fat emulsion injection with a pH of 6.0 to 8.

5.

25. The method according to claim 24, characterized in that, The fifth mixture is subjected to high-pressure homogenization 4-8 times.

26. The method according to claim 25, characterized in that, The fifth mixture is subjected to high-pressure homogenization 5-6 times.

27. A method for preparing the alfasalone fat emulsion injection according to any one of claims 1-23, characterized in that, include: (1) Heat the oil for injection to 50℃~75℃, then add emulsifier and alfasal, mix, and shear until completely dissolved and evenly dispersed to obtain the first mixture containing the alfasal oil phase; (2) Heat water for injection to 50℃~75℃, then add stabilizer, osmotic pressure regulator and pH value regulator and stir evenly to obtain a second mixture that forms an aqueous phase, and control the pH to 6.0~9.5; (3) Mix the first mixture and the second mixture while shearing to obtain a third mixture that forms the colostrum; (4) Adjust the pH of the third mixture with a pH adjuster to obtain a fourth mixture; (5) The mixture obtained in (3) or (4) is homogenized under low pressure once to obtain a fifth mixture; the fifth mixture is homogenized under high pressure more than 3 times, and nitrogen is introduced into the mixture below the liquid surface until nitrogen saturation is achieved during the homogenization process, so as to obtain a sixth mixture; (6) The sixth mixture is filled, nitrogen is introduced for protection, and moist heat sterilization is performed to obtain an alfasal fat emulsion injection with a pH value of 6.0~8.

5.

28. The method according to claim 27, characterized in that, The fifth mixture is subjected to high-pressure homogenization 4-8 times.

29. The method according to claim 28, characterized in that, The fifth mixture is subjected to high-pressure homogenization 5-6 times.

30. The method according to claim 24 or 27, characterized in that, Shear mixing was performed at 5000~16000 rpm for 5~25 min.

31. The method according to claim 30, characterized in that, The shearing speed during the mixing process is 10,000 rpm, and the shearing speed after mixing is completed is 15,000~16,000 rpm.

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