WO2024012361A1 - 阿法沙龙脂肪乳注射液及其制备方法 - Google Patents

阿法沙龙脂肪乳注射液及其制备方法 Download PDF

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WO2024012361A1
WO2024012361A1 PCT/CN2023/106281 CN2023106281W WO2024012361A1 WO 2024012361 A1 WO2024012361 A1 WO 2024012361A1 CN 2023106281 W CN2023106281 W CN 2023106281W WO 2024012361 A1 WO2024012361 A1 WO 2024012361A1
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injection
alfaxalon
value
sodium
fat emulsion
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PCT/CN2023/106281
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English (en)
French (fr)
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徐祥清
韩玉峰
彭卫娟
胡书明
杨超
王董理
杨茜
程宁宁
陈建征
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江苏恩华药业股份有限公司
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Publication of WO2024012361A1 publication Critical patent/WO2024012361A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the present invention belongs to the technical field of pharmaceutical preparations. Specifically, the present invention relates to Alfaxalon fat emulsion injection and its preparation method.
  • Alphaxalone has sedative, anesthetic, anticonvulsant and neuroprotective properties through modulation of GABA A receptors.
  • Althesin is an intravenous injection consisting of alfaxalone and alphadolone in a ratio of 3:1. Alphadolone is only half as effective as the former, but alphadolone can reduce the effects of alfaxalone. Solubility increased threefold. Each milliliter of Althesin solution contains 9 mg of alfaxalon and 3 mg of alfaxalone. Althesin can achieve rapid onset and offset of anesthesia, has almost no stimulating effect on blood vessels, and has only mild cardiovascular and respiratory side effects.
  • Althesin To increase the solubility of Althesin, the polyethoxylated castor oil excipient Cremophor EL (CAS Reg. No. 61791-12-6) is often added to intravenous dosage forms. This drug was used in clinical anesthesia practice in many countries between 1972 and 1984 by inducing and maintaining anesthesia. Althesin has been withdrawn from the market as a human intravenous anesthetic since 1984. Despite its high therapeutic index, Althesin can occasionally cause unpredictable but serious allergic reactions.
  • Cisophor EL is a surfactant that will form micelles in an aqueous solution when it is higher than the critical micelle concentration. Cremophor EL is an excellent encapsulating polymer that can significantly improve the solubility of water-insoluble drugs. Because micelles disintegrate when diluted below their critical micelle concentration, Cremophor EL formulations effectively release alfaxalone and make it bioavailable for absorption by the central nervous system.
  • Cremophor EL is a good solvent for dissolving neuroactive steroid anesthetics such as alfaxalone, it is biologically active and its use has caused severe anaphylactoid hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, red blood cell aggregation and Peripheral neuropathy.
  • Injectable emulsions must have very small droplet sizes.
  • the provisions of General Chapter 0102 of Part 4 of the Chinese Pharmacopoeia on emulsion injections require that the average particle size should not exceed 0.5 microns.
  • emulsions are thermodynamically unstable systems, emulsions are expected to be physically and chemically stable during storage.
  • the droplet size limit requirements defined in Chinese Pharmacopoeia Part 4 General Chapter 0102 apply for the entire specified storage period, which is typically extended to 2-3 years or more for commercial pharmaceutical preparations. 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 with each other to form a single new droplet, and aggregation, where droplets adhere together to form larger clumps. Aggregation can in some cases serve as precursors for further coalescence into larger droplets.
  • parenteral fat emulsions include oxidation of unsaturated fatty acid residues present in triglycerides and lecithin and hydrolysis of phospholipids, resulting in the production of free fatty acids (FFA) and lysophospholipids.
  • FFA free fatty acids
  • parenteral emulsion formulations may include buffers to provide additional control. Any decrease in pH during the specified storage period can indicate chemical degradation.
  • the stabilized charge may vary due to differences in pH. Therefore, changes in pH due to chemical degradation may also accelerate physical degradation. If the emulsion is sterically stabilized, for example, by a poly(oxyethylene) surfactant, changes in pH usually have little effect on emulsion stability.
  • the lipid emulsion injections of the present invention require the use of a high-shear homogenization step to achieve droplet sizes small enough for sterilization and intravenous administration.
  • a high-shear homogenization step to achieve droplet sizes small enough for sterilization and intravenous administration.
  • the inventors developed their formulation and process. Numerous studies.
  • Fat overload syndrome is a syndrome characterized by an increase in triacylglycerol due to the infusion rate and/or dose of fat emulsion exceeding the body's fat clearance ability.
  • the clinical manifestations are: hepatosplenomegaly and jaundice. , hypoalbuminemia, fever, acute respiratory distress syndrome (ARDS), metabolic acidosis, thrombocytopenia, bleeding, diffuse intravascular hemorrhage (DIC), etc.
  • the main causes of fat overload syndrome can be attributed to two aspects: first, the patient's own fat clearing ability is normal, but the fat emulsion is used excessively; second, the fat emulsion is used regularly, but the patient's own fat clearing ability is reduced.
  • the concentration of commercially available propofol is 10mg/ml.
  • the potency of alfaxalone is 5 times that of propofol.
  • 2mg/ml of alfaxalone can achieve the anesthetic potency of 10mg/ml propofol. If possible Alfaxalone prepared at 6 mg/ml will reduce the intake of phospholipids and injection oils, which will be more beneficial for some patients with obesity and hyperlipidemia.
  • the present invention aims at solving one of the above technical problems at least to a certain extent or at least providing a useful commercial option.
  • one object of the present invention is to provide an Alfaxalon fat emulsion injection with high potency, high drug loading, stable drug quality, no irritation to blood vessels, high clinical drug safety, and good compliance.
  • One aspect of the invention provides an Alfaxalon fat emulsion injection, including Alfaxalon or its pharmaceutically acceptable salt, injection oil, emulsifier, co-emulsifier, osmotic pressure regulator, stabilizer, pH value regulator and water for injection.
  • the injectable oil is soybean oil or a mixture of soybean oil and medium chain triglycerides.
  • the weight ratio of soybean oil to medium-chain triglyceride in the mixture of soybean oil and medium-chain triglyceride is 1-5:1-5, preferably 1:1.
  • the weight ratio of alfaxalone or its pharmaceutically acceptable salt (weight calculated as alfaxalone) to the injection oil is 1-10:50-300, preferably 1-10:50-300. 10:100-300, preferably 1-6:100-300, preferably 1-3:100-300, preferably 1-3:100-200. In some specific embodiments, the amount of oil for injection in the Alfaxalon fat emulsion injection accounts for 10% to 30% of the mass concentration of the fat emulsion injection, preferably 10% to 20%.
  • the average particle size of the oil phase in Alfaxalon fat emulsion injection is 0.15 to 0.4 ⁇ m, preferably 0.15 to 0.3 ⁇ m, more preferably 0.15 to 0.25 ⁇ m.
  • alfaxalone with a purity greater than 95% or a pharmaceutically acceptable salt thereof is used in the alfaxalone fat emulsion injection.
  • Alfaxalone with a purity greater than 98% or a pharmaceutically acceptable salt thereof is more preferably used. Salt.
  • the content of alfaxalone or its pharmaceutically acceptable salt in the alfaxalone fat emulsion injection is 1 to 10 mg/ml, preferably 2 to 8 mg/ml, preferably 2 to 4 mg/ml. .
  • the content of injection oil in Alfaxalon fat emulsion injection is 100-300 mg/ml, preferably 100-200 mg/ml.
  • the content of the emulsifier in Alfaxalon fat emulsion injection is 6 to 15 mg/ml, preferably 9 to 15 mg/ml.
  • the content of co-emulsifier in Alfaxalon fat emulsion injection is 0.05-20 mg/ml, preferably 0.1-20 mg/ml, preferably 0.1-10 mg/ml, preferably 0.5-10 mg/ml. .
  • the content of the stabilizer in Alfaxalon fat emulsion injection is 0.1 to 0.3 mg/ml.
  • the content of the osmotic pressure regulator in Alfaxalon fat emulsion injection is 22-25 mg/ml, preferably 22.5-25 mg/ml.
  • the content of emulsifier in Alfaxalon fat emulsion injection is 0.6%-1.5% (wt), preferably 0.9%-1.5% (wt).
  • the content of co-emulsifier in Alfaxalon fat emulsion injection is 0.05%-1.0% (wt), preferably 0.2% (wt), 0.4% (wt), 0.6% (wt) or 0.8%(wt).
  • the zeta potential of Alfaxalon fat emulsion injection is 36 to 60 mV.
  • the pH value of Alfaxalon fat emulsion injection is 5.0 to 8.5, preferably 6.0 to 8.5.
  • the emulsifier of Alfaxalon fat emulsion injection is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, preferably It is a mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M with a weight ratio of 1:2.
  • the osmotic pressure regulator is glycerol.
  • the co-emulsifier is a cholic acid compound or a salt thereof, preferably glycocholic acid, cholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, At least one of glycochenodeoxycholic acid or taurochenodeoxycholic acid or a pharmaceutically acceptable salt thereof.
  • the salt of the cholic acid compound is sodium glycocholate, sodium cholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, chenodeoxycholic acid Sodium, sodium glycinchenodeoxycholate or sodium taurochenodeoxycholate.
  • the emulsifier of Alfaxalon fat emulsion injection is egg yolk lecithin, preferably at least one of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T, preferably A mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M with a weight ratio of 1:2, capable of adjusting the pH value to 5.0 to 8.5, preferably to 6.0 to 8.5; and
  • the osmotic pressure regulator is glycerin,
  • the co-emulsifier is a cholic acid compound or a salt thereof,
  • the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate,
  • the pH adjuster is sodium hydroxide
  • the emulsifier of Alfaxalon fat emulsion injection is at least one selected from the group consisting of egg yolk lecithin E-80, egg yolk lecithin PL-100M, and egg yolk lecithin PC-98T.
  • the weight ratio is A 1:2 mixture of egg yolk lecithin E-80 and egg yolk lecithin PL-100M, a pH regulator capable of adjusting the pH value to 6.0 to 8.5 in the required amount; and
  • the osmotic pressure regulator is glycerin
  • the co-emulsifier is a cholic acid compound or a salt thereof, preferably glycocholic acid, cholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, etc. At least one of deoxycholic acid or taurochenodeoxycholic acid or a pharmaceutically acceptable salt thereof.
  • the salt of the cholic acid compound is sodium glycocholate, sodium cholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, chenodeoxycholic acid sodium, sodium glycinchenodeoxycholate or sodium taurochenodeoxycholate;
  • the stabilizer is at least one selected from oleic acid and sodium oleate, preferably sodium oleate,
  • the pH adjuster is sodium hydroxide
  • Alfaxalon fat emulsion injection contains 0.05%-1.0% (w/v), preferably 0.2% (w/v), 0.4% (w/v), 0.6% (w/v) ) or 0.8% (w/v) co-emulsifier.
  • Alfaxalon fat emulsion injection contains 0.05%-1.0% (w/v), preferably 0.2% (w/v), 0.4% (w/v), 0.6% (w/v) ) or 0.8% (w/v) cholic acid compounds or salts thereof.
  • Alfaxalon fat emulsion injection contains 0.6%-1.5% (w/v), preferably 0.6% (w/v), 0.9% (w/v), 1.2% (w/v) ), 1.5% (w/v) emulsifier, more preferably 0.9% (w/v), 1.2% (w/v), 1.5% (w/v) emulsifier.
  • Alfaxalon fat emulsion injection contains 0.05%-1.0% (w/v), preferably 0.2% (w/v), 0.4% (w/v), 0.6% (w/v) ) or 0.8% (w/v) sodium glycocholate.
  • Alfaxalon fat emulsion injection contains 5%-15% (w/v), preferably 5% (w/v), 10% (w/v), 15% (w/v) ) of soybean oil.
  • Alfaxalon fat emulsion injection contains 5%-15% (w/v), preferably 5% (w/v), 10% (w/v), 15% (w/v) ) of medium chain triglycerides.
  • Alfaxalon fat emulsion injection contains 0.01%-0.03% (w/v), preferably 0.01% (w/v), 0.03% (w/v) sodium oleate.
  • Alfaxalon fat emulsion injection contains 2.25%-2.5% (w/v), preferably 2.25% (w/v), 2.5% (w/v) glycerol.
  • Alfaxalon fat emulsion injection contains 0.6%-1.5% (w/v), preferably 0.6% (w/v), 0.9% (w/v), 1.2% (w/v) ), 1.5% (w/v) egg yolk lecithin, more preferably 0.9% (w/v), 1.2% (w/v), 1.5% (w/v) egg yolk lecithin.
  • the Alfaxalon fat emulsion injection contains cholic acid compounds or salts thereof as co-emulsifiers, wherein the Alfaxalon fat emulsion injection contains 0.05%-1.0% (w/v), preferably It is 0.2% (w/v), 0.4% (w/v), 0.6% (w/v) or 0.8% (w/v) sodium glycocholate; and the oil in the Alfaxalon fat emulsion injection
  • the phase average particle size is 0.15 to 0.4 ⁇ m, preferably 0.15 to 0.3 ⁇ m, more preferably 0.15 to 0.25 ⁇ m.
  • the content of alfaxalone or its pharmaceutically acceptable salt in the alfaxalone fat emulsion injection is 2 to 4 mg/ml.
  • Alfaxalon fat emulsion injection contains 0.6%-1.5% (wt), preferably 0.9%-1.5% (wt) egg yolk lecithin as an emulsifier. Furthermore, the zeta potential of Alfaxalon fat emulsion injection is 36 to 60mV. Furthermore, the pH value of Alfaxalon fat emulsion injection is 5.0 to 8.5, preferably 6.0 to 8.5.
  • the pH value of Alfaxalon fat emulsion injection is 5.0-8.5, and each component includes, in parts by weight: Alfaxalon 1-10; soybean oil 50-200; medium chain triglyceride Ester 0-100; emulsifier 9-15; co-emulsifier 0.1-20; stabilizer 0.1-0.3; glycerol 22-25.
  • the pH value of Alfaxalon fat emulsion injection is 6.0-8.5, and each component includes, in parts by weight: Alfaxalon 1-10; Soybean oil 50-200; Medium-chain triglyceride Ester 0-100; emulsifier 9-15; co-emulsifier 0.1-20; stabilizer 0.1-0.3; glycerin 22-25.
  • the pH value of alfaxalone fat emulsion injection is 6.0 to 8.5, and each component includes, in parts by weight: alfaxalone 2 to 8; soybean oil 50 to 200; medium chain triglyceride Ester 0 ⁇ 100; emulsifier 9 ⁇ 12; co-emulsifier 0.1 ⁇ 10; stabilizer 0.1 ⁇ 0.3; glycerin 22 ⁇ 25.
  • the pH value of Alfaxalon fat emulsion injection is 6.0-8.5, and every 1 ml of Alfaxalon fat emulsion injection contains: 1-10 mg of Alfaxalon; 50-100 mg of soybean oil. mg; medium chain triglyceride 50 to 100 mg; egg yolk lecithin 9 to 15 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg, which can control the pH value of the injection to 6.0 to 8.5. dosage of sodium hydroxide; and the remaining amount of water for injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0 to 8.5, and every 1 ml of Alfaxalon fat emulsion injection contains: 1 to 10 mg of Alfaxalon; 100 to 200 mg of soybean oil. mg; egg yolk lecithin 9 to 15 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; the amount of sodium hydroxide required to control the pH of the injection to 6.0 to 8.5; and the remainder. Water for Injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0-8.5, and every 1 ml of Alfaxalon fat emulsion injection contains: 1-10 mg of Alfaxalon; 50-100 mg of soybean oil. mg; medium chain triglycerides 50 to 100 mg; egg yolk lecithin 9 to 15 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; glycerol 25 mg.
  • the pH value of Alfaxalon fat emulsion injection is 6.0 to 8.5, and every 1 ml of Alfaxalon fat emulsion injection contains: 1 to 10 mg of Alfaxalon; 100 to 200 mg of soybean oil. mg; egg yolk lecithin 9 to 15 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; glycerol 25 mg; the amount of sodium hydroxide required to control the pH of the injection to 6.0 to 8.5; and the balance of water for injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0 to 8.5, and each 1 ml of Alfaxalon fat emulsion injection contains: 1 to 10 mg of Alfaxalon; 100 mg of soybean oil; Medium chain triglyceride 100 mg; egg yolk lecithin 9 to 15 mg; glycocholic acid 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; 25 mg of glycerin, the amount required to control the pH value of the injection to 6.0 to 8.5 Sodium hydroxide; and the remaining water for injection;
  • the pH value is 6.0 to 8.5
  • each 1 ml of the Alfaxalon fat emulsion injection contains: 1 to 10 mg of Alfaxalon; 200 mg of soybean oil; 9 to 15 mg of egg yolk lecithin; and 0.1 to 10 cholic acid. mg; sodium oleate 0.1 to 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 6.0 to 8.5; and the remainder of water for injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0 to 8.5, and each 1 ml of Alfaxalon fat emulsion injection contains: 2 to 8 mg of Alfaxalon; 100 mg of soybean oil; Medium chain triglyceride 100 mg; egg yolk lecithin 9 to 12 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; glycerol 25 mg; required to control the pH of the injection to 6.0 to 8.5 The amount of sodium hydroxide; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: 2 to 8 mg of Alfaxalon; 200 mg of soybean oil; 9 to 12 mg of egg yolk lecithin; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; glycerol 25 mg; the amount of sodium hydroxide required to control the pH of the injection to 6.0 to 8.5; and the remainder of water for injection;
  • the pH value is 6.0-8.5
  • each 1 ml of the Alfaxalon fat emulsion injection contains: 2-8 mg of Alfaxalon; 100 mg of soybean oil; 50 mg of medium-chain triglycerides; 9-9 mg of egg yolk lecithin. 12 mg; sodium glycocholate 0.1 to 20 mg; sodium oleate 0.1 to 0.3 mg; glycerol 25 mg; the amount of sodium hydroxide required to control the pH of the injection to 6.0 to 8.5; and the remainder of water for injection;
  • the pH value is 6.0-8.5
  • each 1 ml of the Alfaxalon fat emulsion injection contains: 2-8 mg of Alfaxalon; 100 mg of soybean oil; 50 mg of medium-chain triglycerides; 9-9 mg of egg yolk lecithin. 12 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH of the injection to 6.0 to 8.5; and the remainder of water for injection;
  • the pH value is 6.0-8.5
  • each 1 ml of the Alfaxalon fat emulsion injection contains: 2-8 mg of Alfaxalon; 50 mg of soybean oil; 50 mg of medium-chain triglycerides; and 9-9 mg of egg yolk lecithin. 12 mg; sodium glycocholate 0.1 to 10 mg; sodium oleate 0.1 to 0.3 mg; 25 mg of glycerin; the amount of sodium hydroxide required to control the pH of the injection to 6.0 to 8.5; and the remainder of water for injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0-8.5, and every 1 ml of Alfaxalon fat emulsion injection contains: 1-10 mg of Alfaxalon; 50-200 mg of soybean oil. mg; medium chain triglyceride 50-100 mg; egg yolk lecithin 9-15 mg; sodium glycocholate 0.1-20 mg; sodium oleate 0.1-0.3 mg; glycerin 22.5-25 mg; able to control the pH of the injection The required amount of sodium hydroxide for 6.0 to 8.5; and the remaining amount of water for injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0-8.5, and every 1 ml of Alfaxalon fat emulsion injection contains: 1-10 mg of Alfaxalon; 50-200 mg of soybean oil. mg; medium chain triglyceride 50-100 mg; egg yolk lecithin 9-15 mg; sodium glycocholate 0.1-10 mg; sodium oleate 0.1-0.3 mg; glycerin 22.5-25 mg; able to control the pH of the injection The required amount of sodium hydroxide for 6.0 to 8.5; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 2 mg; soybean oil 50 mg; medium chain triglyceride 50 mg; egg yolk lecithin E-80 4 mg; Egg yolk lecithin PL-100M 8 mg; sodium glycocholate 3 mg; sodium oleate 0.3 mg; glycerol 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 3 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 12 mg; Sodium glycocholate 2 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 6.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 4 mg; soybean oil 50 mg; medium chain triglyceride 50 mg; egg yolk lecithin E-80 9 mg; Sodium glycocholate 4 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 4 mg; soybean oil 200 mg; egg yolk lecithin E-80 12 mg; sodium glycocholate 4 mg; Sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 4 mg; soybean oil 200 mg; egg yolk lecithin E-80 12 mg; sodium glycocholate 1 mg; Sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 2 mg; soybean oil 100 mg; egg yolk lecithin E-80 12 mg; sodium glycocholate 4 mg; Sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 4 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 15 mg; Sodium glycocholate 3 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 4 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 12 mg; Sodium glycocholate 1 mg; sodium oleate 0.3 mg; glycerol 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 4 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 15 mg; Sodium glycocholate 3 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 5 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 15 mg; Sodium glycocholate 3 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 7.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 5 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 12 mg; Sodium glycocholate 1 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of sodium hydroxide required to control the pH value of the injection to 7.0; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 6 mg; soybean oil 50 mg; medium chain triglycerides 50 mg; egg yolk lecithin E-80 12 mg; glycerin 2 mg of sodium amcholate; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection to 7.5; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 7 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin 12 mg; glycochol. 4 mg of sodium oleate; 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 8.0; and the remaining amount of water for injection;
  • the pH value is 7.5
  • each 1 ml of the Alfaxalon fat emulsion injection contains: Alfaxalon 7 mg;
  • Soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin 12 mg; sodium glycocholate 1 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of hydrogen required to control the pH value of the injection to 7.5 Sodium oxide; and the balance water for injection.
  • the pH value of Alfaxalon fat emulsion injection is 6.0-8.5, and every 1 ml of Alfaxalon fat emulsion injection consists of 1-10 mg of Alfaxalon; 50-200 mg of soybean oil. ; Medium chain triglyceride 50-100 mg; Egg yolk lecithin 9-15 mg; Sodium glycocholate 0.1-10 mg; Sodium oleate 0.1-0.3 mg; Glycerin 22.5-25 mg; Able to control the pH value of the injection. 6.0 ⁇ 8.5 required amount of sodium hydroxide; and the remaining amount of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of Alfaxalon 2 mg; soybean oil 50 mg; medium chain triglyceride 50 mg; egg yolk lecithin E-80 4 mg; egg yolk Lecithin PL-100M 8 mg; sodium glycocholate 3 mg; sodium oleate 0.3 mg; glycerol 25 mg; the amount of sodium hydroxide required to control the pH of the injection to 8.0; and the remainder of water for injection;
  • the pH value is 6.0
  • each 1 ml of the Alfaxalon fat emulsion injection consists of Alfaxalon 3 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 12 mg; glycerin It consists of 2 mg of sodium amcholate; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection to 6.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of Alfaxalon 4 mg; soybean oil 50 mg; medium chain triglyceride 50 mg; egg yolk lecithin E-80 9 mg; glycerin It consists of 4 mg of sodium amcholate; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection to 8.0; and the remainder of water for injection;
  • the pH value is 8.0
  • each 1 ml of the Alfaxalon fat emulsion injection consists of Alfaxalon 4 mg; soybean oil 200 mg; egg yolk lecithin E-80 12 mg; sodium glycocholate 4 mg; oil. It consists of 0.3 mg of sodium bisulfate; 25 mg of glycerin; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of 4 mg of Alfaxalon; 200 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 1 mg of sodium glycocholate; oil. It consists of 0.3 mg of sodium bisulfate; 25 mg of glycerin; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of 2 mg of Alfaxalon; 100 mg of soybean oil; 12 mg of egg yolk lecithin E-80; 4 mg of sodium glycocholate; oil. It consists of 0.3 mg of sodium bisulfate; 25 mg of glycerin; the amount of sodium hydroxide required to control the pH value of the injection to 8.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of 4 mg of Alfaxalon; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 15 mg of egg yolk lecithin E-80; glycerin It consists of 3 mg of sodium amcholate; 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 8.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of 4 mg of Alfaxalon; 100 mg of soybean oil; 100 mg of medium-chain triglycerides; 12 mg of egg yolk lecithin E-80; glycerin It consists of 1 mg of sodium amcholate; 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 8.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of 4 mg of Alfaxalon; 100 mg of soybean oil; 100 mg of medium chain triglycerides; 15 mg of egg yolk lecithin E-80; glycerin It consists of 3 mg of sodium amcholate; 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 8.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of Alfaxalon 5 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 15 mg; glycerin It consists of 3 mg of sodium amcholate; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection to 7.0; and the remainder of water for injection;
  • each 1 ml of the Alfaxalon fat emulsion injection consists of Alfaxalon 5 mg; soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin E-80 12 mg; glycerin It consists of 1 mg of sodium amcholate; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection to 7.0; and the remainder of water for injection;
  • the Alfaxalon fat emulsion injection with a pH value of 7.5 and per 1 ml consists of Alfaxalon 6 mg; soybean oil 50 mg; medium chain triglycerides 50 mg; egg yolk lecithin E-80 12 mg; glycine It consists of 2 mg of sodium cholate; 0.3 mg of sodium oleate; 25 mg of glycerol; the amount of sodium hydroxide required to control the pH of the injection to 7.5; and the remainder of water for injection;
  • the pH value is 8.0
  • each 1 ml of the Alfaxalon fat emulsion injection contains 7 mg of Alfaxalon; 100 mg of soybean oil; 100 mg of medium chain triglycerides; 12 mg of egg yolk lecithin; and glycocholic acid. It consists of 4 mg of sodium; 0.3 mg of sodium oleate; 25 mg of glycerin; the amount of sodium hydroxide required to control the pH of the injection to 8.0; and the remainder of water for injection;
  • the pH value is 7.5, and each 1 ml of the Alfaxalon fat emulsion injection contains 7 mg of Alfaxalon;
  • Soybean oil 100 mg; medium chain triglyceride 100 mg; egg yolk lecithin 12 mg; sodium glycocholate 1 mg; sodium oleate 0.3 mg; glycerin 25 mg; the amount of hydrogen required to control the pH value of the injection to 7.5 Sodium oxide; and the balance water for injection.
  • Another aspect of the present invention provides a method for preparing Alfaxalon fat emulsion injection, including:
  • the oil for injection is soybean oil or a mixture of soybean oil and medium-chain triglyceride; more preferably, the oil for injection is soybean oil and medium-chain triglyceride in a weight ratio of 1:1. mixture;
  • 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;
  • the co-emulsifier is glycine Sodium cholate
  • the stabilizer is sodium oleate
  • the osmotic pressure regulator is glycerin
  • Another aspect of the present invention provides a method for preparing Alfaxalon fat emulsion injection, including:
  • the oil for injection is soybean oil or a mixture of soybean oil and medium-chain triglyceride; more preferably, the oil for injection is soybean oil and medium-chain triglyceride in a weight ratio of 1:1. mixture;
  • 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;
  • the pH is 7 to 11.5.
  • the co-emulsifier is sodium glycocholate
  • the stabilizer is sodium oleate
  • the osmotic pressure regulator is glycerin
  • the pH adjuster The agent is sodium hydroxide
  • a pH adjuster to adjust the pH of the third mixture to 6.5 to 11.5, preferably 6.5 to 10.5, preferably 6.5 to 10, in order to obtain the fourth mixture; preferably, the pH value
  • the regulator is sodium hydroxide
  • shear mixing is performed at a rotation speed of 5,000 to 16,000 rpm for 5 to 25 minutes; preferably, the shear rotation speed during the mixing process is 10,000 rpm, and the shear rotation speed after mixing is completed is 15,000-16,000 rpm.
  • step (3) of the preparation method of Alfaxalon fat emulsion shear mixing is performed at a rotation speed of 5,000 to 16,000 rpm for 5 to 25 minutes.
  • the low-pressure homogenization in step (4) of the preparation method of Alfaxalon fat emulsion is homogenized under a pressure of 100/160 bar, and the high-pressure homogenization in step (5) is performed at 500-500 bar. Homogenize 5 to 8 times under a pressure of 1000 bar, and the high-pressure homogenization temperature is controlled at 30°C to 70°C.
  • isotonic means that it has an osmotic pressure equal to or similar to physiological fluids.
  • Body fluids typically have an osmotic pressure that is often described as corresponding to a 0.9% (weight/volume) aqueous sodium chloride solution.
  • This application uses glycerol to adjust isotonicity.
  • the amount of glycerol used in each 1 ml of the Alfaxalon fat emulsion injection contains 22 to 25 mg of glycerol, specifically 22 mg/ml, 22.5 mg/ml, 23 mg/ml, 23.5 mg/ml, 24 mg/ml, 24.5 mg/ml, specifically 25 mg/ml.
  • medium chain oil refers to medium chain triglycerides and medium chain triglycerides
  • long chain oil refers to soybean oil
  • w/v refers to the mass content of the component per unit volume of the injection, and the unit is "g/ml”.
  • co-emulsifier generally plays a positive role in the stability of emulsions in emulsion systems.
  • the co-emulsifiers in this application are specifically cholic acid compounds or their salts, more specifically glycocholic acid and sodium glycocholate. , cholic acid, taurocholic acid, glycodeoxycholic acid or taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid or taurodeoxycholic acid, etc., which can improve the solubility of the drug, Improvement of the stability of lipid emulsions and drugs, etc.
  • AFSL Alfa Salon.
  • the solubility of alfaxalone in castor oil is higher than that of medium-chain oil and long-chain oil.
  • the optimal oil ratio for injection the use of medium-chain and long-chain oil for injection with poor solubility of alfaxalone
  • the optimal ratio, and the injection oil content should be within a certain appropriate range, can ensure that the emulsifier can completely emulsify the oil phase and the water phase.
  • the present invention can only be satisfied with the preparation of small specifications (2mg/ml), and the preparation of large specifications (4mg/ml) can only be prepared after being refrigerated for 10 days.
  • the raw materials may separate out, there may be oil droplets on the surface of the fat emulsion, the emulsion may be broken, etc., and the stability may be poor.
  • Sodium glycocholate is used to synergize with lecithin to improve the dissolution effect.
  • the average particle size prepared is lower than that of the group without sodium glycocholate.
  • the particle size uniformity is good.
  • the pH has been confirmed by the stability test and the pH is stable. A significant decrease occurs, indicating that the emulsion has good stability, is conducive to storage, and does not require strict storage conditions. It indicates that sodium glycocholate or glycocholic acid has both solubilizing and stabilizing effects and can increase the affinity between the drug and the oil phase. Thereby improving the stability of the formulation. Compared with castor oil preparations, the preparation has smaller particle size, is more stable, significantly reduces the occurrence of allergies, and is safer.
  • the drug loading capacity can be significantly increased, from 2 mg/ml to 6 mg/ml, and the drug loading capacity is increased three times.
  • the fat emulsion provided by this application has been confirmed by pharmacological experiments to have significantly lower allergenicity than the castor oil-containing emulsion prepared in accordance with CN94190450.4, the average particle size is significantly smaller than the castor oil emulsion group, and the encapsulation rate is higher than the castor oil preparation group.
  • the injection pain was less than that of the castor oil emulsion group, and all stability indicators were better than those of the castor oil emulsion group.
  • the Alfasalon fat emulsion injection of the present invention avoids the use of castor oil, cyclodextrin and other excipients that are easy to cause adverse reactions.
  • the present invention adopts an emulsion made of a new formula, and uses a weight ratio of 1:1 in the preparation. Soybean oil and medium chain triglycerides are used as injection oils, while sodium oleate is used as a stabilizer, egg yolk lecithin E-80 is used as an emulsifier, and sodium glycocholate or glycocholic acid is used as a co-emulsifier.
  • the quality of the prepared Alfaxalon fat emulsion injection sample is more stable.
  • the use of sodium glycocholate or glycocholic acid as a co-emulsifier greatly improves the stability of Alfaxalon fat emulsion injection, which can prevent the deterioration of the fat emulsion caused by changes in storage conditions during the placement of Alfaxalon preparations.
  • the formulation is unstable due to aggregation and merging of emulsion droplets, and is non-irritating to blood vessels, improving the safety and compliance of clinical medication.
  • Figure 1 is a layered diagram of 1.2% sodium glycocholate fat emulsion colostrum.
  • Figure 2 is a layered diagram of 1.4% sodium glycocholate fat emulsion colostrum.
  • Figure 3 is a layered diagram of 2.0% sodium glycocholate fat emulsion colostrum.
  • Figure 4 is a graph of API precipitation in 20 days after sterilization of samples without adding 4 mg/ml sodium glycocholate.
  • Figure 5 is a graph showing the measurement of histamine content in mouse plasma after intravenous administration.
  • Figure 6 is a diagram of the electromyographic stimulation test in rats.
  • Egg yolk lecithin E80, purchased from Lipoid GmbH, Germany; glycerin was purchased from Shantou Jiahe Biotechnology Co., Ltd.; sodium glycocholate was purchased from Hebei Zhentian Food Additive Co., Ltd.; soybean oil was purchased from Guangzhou Baiyunshan Hagging Modern Medicine Co., Ltd.; medium chain triglycerides (caprylic acid 57.1%, capric acid 42.8%) were purchased from Liaoning Xinxing Pharmaceutical Co., Ltd.; sodium oleate was purchased from Lipoid GmbH, Germany; alfasalone was purchased from Jiangsu Enhua Pharmaceutical Co., Ltd.
  • the company makes its own alfaxalone with a purity of more than 95%; Propofol (manufacturer: Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: BB200215); Cremophor EL (manufacturer: Sinopharm Chemical Reagent Co., Ltd., batch number: 20220104); Sulfobutyl- ⁇ -cyclodextrin/SBE- ⁇ -CD (manufacturer: Zibo Qianhui Biotechnology Co., Ltd., batch number: SB210911).
  • Example 1-4 Preparation method of emulsion without adding sodium glycocholate (batch is based on 1000ml)
  • Preparation of 0.1mol/L sodium hydroxide Weigh 0.4g sodium hydroxide, dissolve it in an appropriate amount of water, let it cool, then transfer it to a 100ml volumetric flask, adjust the volume to the mark and set aside.
  • Oil phase preparation Add 100g each of soybean oil and medium-chain triglycerides to a 500ml beaker and heat in a water bath at 70°C. Weigh the egg yolk lecithin and alfaxalone (AFSL) according to the preparation amount, add the oil phase at a speed of 10,000 rpm, and shear for 5 minutes to prepare the oil phase.
  • AFSL egg yolk lecithin and alfaxalone
  • Water phase preparation Weigh an appropriate amount of water for injection into a 2000ml beaker, heat it in a water bath, and control the water temperature at 70°C; add 0.3g sodium oleate and 25g glycerin to the water phase and stir evenly with a glass rod to prepare the water phase.
  • Colostrum preparation Add the oil phase to the water phase, add it while shearing (10000rpm), and control the colostrum temperature to 70°C; after adding the oil phase, adjust the shearing speed to 15400rpm, shear for 5 minutes, use 0.1mol /L sodium hydroxide to adjust the colostrum pH to 9.0 to prepare colostrum.
  • Comparative Example 1-2 prepared by referring to the method disclosed in Example 1 of CN94190450.4
  • Oil phase preparation Add a preparation amount of castor oil and soybean oil or castor oil to a 250 ml beaker, and heat in a water bath at 70°C. Weigh 2g of AFSL and add it to the oil phase at a speed of 10,000 rpm and shear for 2 minutes. Weigh 12g of egg yolk lecithin and add it to the oil phase at a speed of 10,000 rpm and shear for 5 minutes to prepare the oil phase.
  • Preparation of the water 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°C; add 22.5g of glycerin to the water phase and stir evenly with a glass rod to prepare the water phase.
  • Colostrum preparation Add the oil phase to the water phase, add it while shearing (10000rpm), and control the colostrum temperature to 70°C; after adding the oil phase, adjust the shearing speed to 15400rpm, shear for 5 minutes, use 0.1mol /L sodium hydroxide to adjust the colostrum pH to 9.0 to prepare colostrum.
  • Example 1 Refer to the test method of Example 1 to try the feasibility of preparing samples with different formulation compositions.
  • Samples prepared with different oil phases (soybean oil or a mixture of soybean oil and medium-chain triglycerides) with proportions (10%, 20%, 30%) have the properties, content, encapsulation rate, and pH of the samples. There is no significant difference in the value and Zeta potential, but the average particle size shows a gradually increasing trend as the proportion of oil phase increases.
  • the average particle size of the preparation containing 30% oil phase is greater than 0.4 ⁇ m, which is close to the limit.
  • their properties, encapsulation rate, pH, content, potential and other indicators are all within the qualified range, but the average particle size is greater than or close to 0.5 ⁇ m, and the particle size is significantly higher than that of preparations without castor oil. .
  • the type and proportion of injection oil should be selected within an appropriate range to ensure that the emulsifier can completely emulsify the oil phase and the water phase. Therefore, the preferred range of the proportion of oil phase in the present invention is 10%-20%; the preferred oil phase is soybean oil or a mixture of soybean oil and medium-chain triglycerides. The following examples were investigated with the oil phase accounting for 20% (the ratio of soybean oil and medium chain triglycerides being 1:1).
  • Example 16 Preparation method of emulsion (batch based on 1000ml) adding sodium glycocholate
  • Aqueous phase preparation :
  • Low pressure homogenization pressure 100bar/160bar, homogenization once.
  • High pressure homogenization pressure 100bar/600bar, homogenization six times. After homogenization, the samples were filled, filled with nitrogen, and sterilized (121°C, 15 min).
  • Examples 14, 15, and 17 were prepared according to the method of Example 16, except that different co-emulsifiers were replaced.
  • Example 16 Compared with the preparation of Example 16, the appearance of the preparation of Example 14 has the phenomenon of oil floating, and the appearance of Example 15 and Example 17 has the phenomenon of API precipitation, which indicates that Tween 80, Poloxamer 188, and HS15 cannot act.
  • the appearance and properties of the preparation of Example 16 meet the regulations, and the content, potential, particle size and other indicators are within the qualified range.
  • preparations containing sodium glycocholate can improve the stability of emulsion samples.
  • Example 18 has the phenomenon of oil drifting
  • Example 19 and Example 20 has the phenomenon of API precipitation. This shows that Tween 80, Poloxamer 188, and HS15 cannot achieve the purpose of promoting dissolution.
  • the visual properties of the samples in Examples 21-23 meet the regulations, and the content, potential, particle size and other indicators are within the qualified range.
  • the preparations containing cholic acid compounds or their salts can improve the stability of emulsion samples.
  • Aqueous phase preparation :
  • Low pressure homogenization pressure 100bar/160bar, homogenization once.
  • High pressure homogenization pressure 100bar/600bar, homogenization six times. After homogenization, the samples were filled, filled with nitrogen, and sterilized (121°C, 15 min).
  • Examples 38, 39 and 40 were prepared according to the method of Example 16, using glacial acetic acid to adjust the colostrum pH, and fine-tuning the contents of other preparation components.
  • Blank plasma Take blood directly from mice and centrifuge it.
  • Normal saline Inject normal saline with a volume of 5mL/kg.
  • Blank fat emulsion (20% medium and long chain fat emulsion): the administration volume is 5 mL/kg.
  • Alfaxalon fat emulsion (containing sodium glycocholate, batch sample of Example 26):
  • the dosage of alfaxalon fat emulsion (containing sodium glycocholate) is 7 mg/kg, and the ED50 of alfaxalon is about 3.5 mg/kg. kg, so the administered dose is 7mg/kg.
  • the specification of Alfaxalon fat emulsion (containing sodium glycocholate) is 5 mg/mL, use blank fat emulsion to dilute to 1.4 mg/mL, and the dosage volume is 5 mL/kg.
  • SBE- ⁇ -CD Preparation method: 0.7mL 13% SBE- ⁇ -CD+4.3mL physiological saline, administration volume is 5mL/kg.
  • the preparation of Suspension Bridge Company is alfaxalone dissolved in 13% SBE- ⁇ -CD, and the concentration after dissolution is 10 mg/mL, so this group of experiments refers to the preparation of Suspension Bridge Company to prepare the drug solution).
  • Cremophor EL 0.7mL Cremophor EL+4.3mL physiological saline, the concentration of Cremophor EL is 0.14mL/mL, the dosage is 5mL/kg, the dosage of Cremophor EL is 0.7mL/kg.
  • SBE- ⁇ -CD&Cremophor EL 0.7mL 13% SBE- ⁇ -CD+0.7mL Cremophor EL+3.6mL normal saline, the administration volume is 5mL/kg.
  • Alfaxalon@SBE- ⁇ -CD&Cremophor EL 0.7mL Alfaxalon@13% SBE- ⁇ -CD (10mg/mL)+0.7mL Cremophor EL+3.6mL normal saline, the administration volume is 5mL/kg.
  • the final concentration of alfaxalone is 1.4 mg/mL, so the final dose of alfaxalone is 7 mg/kg and the dose of Cremophor EL is 0.7 mL/kg.
  • mice in the Alfaxalon@(SBE- ⁇ -CD&Cremophor EL) group was significantly higher than that of the SBE- ⁇ -CD&Cremophor EL group, indicating that Alfaxalon dissolved in SBE- ⁇ -CD&Cremophor EL promotes the release of histamine in mice. Aggravated allergies.
  • Blank fat emulsion does not contain the main drug alfaxalone, and the others are the same as Example 1
  • Blank fat emulsion (containing sodium glycocholate): does not contain the main drug alfaxalone, other contents are the same as Example 33
  • Cremophor EL 1mL Cremophor EL+4mL normal saline.
  • SBE- ⁇ -CD&Cremophor EL 1mL 13% SBE- ⁇ -CD+1mL Cremophor EL+3mL normal saline.
  • Alfaxalon@(SBE- ⁇ -CD&Cremophor EL) 1mL Alfaxalon@13% SBE- ⁇ -CD (10mg/mL)+1mL Cremophor EL+3mL normal saline.
  • Rats were intraperitoneally injected with 20% urethane solution. After anesthesia, the rats were fixed on the operating board. The saphenous artery on one side of the hind limb was found and separated, the semitendinosus of the ipsilateral hind limb was found, and the electrode was inserted. A plastic cannula was inserted into the isolated saphenous artery, and drugs were injected through the plastic cannula. After each injection, the cannula was flushed with physiological saline.
  • Integrate the rat electromyography before and after injection calculate the ratio of the rat electromyography after injection and the baseline, and evaluate the electromyographic stimulation of rats by the solution.
  • the drug injection volume is 0.1 mL, and the plastic cannula is flushed with physiological saline after administration.
  • Blank fat emulsion containing sodium glycocholate
  • alfaxalon fat emulsion containing sodium glycocholate, Example 33
  • Cremophor EL SBE- ⁇ -CD&Cremophor EL
  • alfaxalon@( SBE- ⁇ -CD&Cremophor EL) had no significant effect on rat electromyography after administration. It is speculated that there is no injection irritation and no injection pain. See Figure 6.

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Abstract

一种阿法沙龙脂肪乳注射液及其制备方法，阿法沙龙脂肪乳注射液包括阿法沙龙及其药学上可接受的盐，油相，乳化剂，助乳化剂，渗透压调节剂，稳定剂，pH值调节剂和注射用水。

Description

阿法沙龙脂肪乳注射液及其制备方法 技术领域
本发明属于药物制剂技术领域，具体的，本发明涉及阿法沙龙脂肪乳注射液及其制备方法。
背景技术
阿法沙龙(Alphaxalone)通过调节GABA A受体具有镇静、麻醉、抗惊厥和神经保护特性。作为一种有效的神经活性类固醇麻醉剂，阿法沙龙缺乏孕激素、雌激素、盐皮质激素或胸腺溶解活性。
Althesin是一种静脉注射剂，由阿法沙龙和阿法多龙(alphadolone)以3:1的比例组成，阿法多龙的效力仅有前者的一半，但阿法多龙可以使阿法沙龙的溶解度提高三倍。每毫升Althesin溶液含有9mg阿法沙龙和3mg阿法多龙。Althesin能够实现麻醉作用的快速起效和抵消，对血管几乎没有刺激作用，仅有轻微的心血管和呼吸系统副作用。
为了提高Althesin的溶解度，通常将聚乙氧基化蓖麻油赋形剂Cremophor EL(CAS登记号61791-12-6)添加到静脉注射剂中。通过诱导和维持麻醉，该药物于1972年至1984年期间在许多国家用于临床麻醉实践。自1984年以来，Althesin作为人体静脉麻醉剂从市场上撤出。尽管具有高的治疗指数，Althesin偶尔会引起不可预测但严重的过敏反应。
中国专利CN94190450.4公开了一种阿法沙龙蓖麻油乳剂，其中Cremophor EL是一种表面活性剂，当它高于临界胶束浓度时，它会在水溶液中形成胶束。Cremophor EL是一种很好的包封聚合物，可以显著提高水不溶性药物的溶解度。因为胶束在稀释到其临界胶束浓度以下时会分解，所以Cremophor EL制剂可以有效地释放阿法沙龙并使其生物可利用，供中枢神经系统吸收。虽然Cremophor EL是溶解神经活性类固醇麻醉剂(如阿法沙龙)的良好溶剂，但它具有生物活性，其使用已引起严重的过敏样超敏反应、高脂血症、异常脂蛋白模式、红细胞聚集和周围神经病变。
注射乳液必须具有非常小的液滴尺寸，为了使在血液循环中不造成毛细血管堵塞和栓塞，中国药典4部通则0102关于乳剂注射液的规定要求平均粒径不能超过0.5微米。
此外，尽管乳剂为热力学不稳定体系，但是期望乳剂在贮存期间是物理和化学稳定的。中国药典4部通则0102定义的液滴大小界限要求适用于整个指定贮存期限，对于商业药物制剂来说，典型地通常会延长至2-3年或更长的时间。所有真正的乳液是热力学不稳定的，可能会随着时间的推移经历倾向于增加液滴尺寸的过程。这些包括直接的液滴聚结，即两个液滴相互碰撞，形成一个单一的新的液滴，以及聚集，其中液滴附着在一起以形成较大的团块。聚集可以在某些情况下成为进一步聚结成较大液滴的前体。最终，这些过程可能会导致游离油在乳液表面上可见，或上升到容器的表面的大的聚集体，这种现象被称为“乳状液分层(creaming)”。液滴尺寸的测量，可以测量初始的大小增加，从而可以在早期即制剂显示肉眼可见的变化之前预测乳液的物理稳定性。
另外，药物成分可能会降解，例如，亲脂性药物将分离成油相，这将赋予一定程度的保护，但水解降解仍可能发生在油-水界面。肠胃外脂肪乳液的可能的化学降解包括存在于甘油三酯和卵磷脂中的不饱和脂肪酸残基的氧化以及和磷脂的水解，该水解导致游离脂肪酸(FFA)和溶血磷脂的生成。这些降解产物降低pH值，这可能会进一步促进降解。因此，在生产过程中应控制pH值，并且肠外乳液制剂可以包括缓冲剂以提供额外的控制。指定贮存期限内的任何pH值下降可以指示化学降解。
以电荷稳定的乳液为例，如那些其中以卵磷脂作为乳化剂的乳液，稳定化的电荷可能由于pH值的不同而有所差异。因此，由于化学降解产生的pH值的变化也可能加速物理降解。如果乳液是空间稳定的，例如，通过聚(氧乙烯)的表面活性剂，通常pH值的变化对乳液稳定性的影响不大。
本发明的脂肪乳注射液需要使用高剪切均质步骤，从而实现足够小的用于灭菌和静脉给药的液滴尺寸。为了将阿法沙龙以足够小的液滴尺寸包含于乳液中，从而能通过过滤进行灭菌，并且同时在整个指定的制剂贮存期限满足中国药典的要求，本发明人对其制剂和工艺进行了大量的研究。
脂肪超载综合征(fat overload syndrome)是由于脂肪乳剂输注速度和/或剂量超过机体的脂肪廓清能力，导致的以三酰甘油升高为特征的症候群，临床表现为：肝脾肿大、黄疸、低蛋白血症、发热、急性呼吸窘迫综合征(ARDS)、代谢性酸中毒、血小板减少、出血、弥漫性血管内出血(DIC)等。脂肪超载综合征的主要原因可归结为两个方面：其一，患者本身的脂肪廓清能力正常，而脂肪乳剂使用过量；其二，脂肪乳剂常量使用，但患者本身的脂肪廓清能力下降。
市售丙泊酚的浓度为10mg/ml，阿法沙龙的效价是丙泊酚的5倍，理论上2mg/ml的阿法沙龙可以达到10mg/ml丙泊酚的麻醉效价，如果可以制备成6mg/ml的阿法沙龙，将可以使磷脂、注射用油的摄入减少，对于一些肥胖、高脂血症患者，将更有利。
阿法多龙的效力只有阿法沙龙的一半，但阿法多龙可以使阿法沙龙的溶解度提高三倍，且文献Mark S.Althesin-a new intravenous anaesthetic[J].Canda.Anaesth1973(20):186-191报导阿法多龙对于阿法沙龙具有助溶解作用。本申请提供只含有阿法沙龙脂肪乳注射液，但在缺少阿法多龙助溶剂的作用下，阿法沙龙的溶解性将更低，制备只含有高效价、高载药量的阿法沙龙脂肪乳注射液，溶解性将是迫切需要解决的技术难题。
发明内容
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选择。为此，本发明的一个目的在于提供一种高效价，高载药量、药品质量稳定、对血管无刺激性、临床用药安全性高，顺应性好的阿法沙龙脂肪乳注射液。
本发明的一个方面提供了一种阿法沙龙脂肪乳注射液，包括阿法沙龙或其药学上可接受的盐，注射用油，乳化剂，助乳化剂，渗透压调节剂，稳定剂，pH值调节剂和注射用水。
在具体一些实施方案中，所述注射用油为大豆油或者大豆油和中链甘油三酯的混合物。
在具体一些实施方案中，所述大豆油和中链甘油三酯的混合物中大豆油与中链甘油三酯的重量比为1～5:1～5，优选为1：1。
在具体一些实施方案中，任选所述阿法沙龙或其药学上可接受的盐(重量以阿法沙龙计算)与注射用油的重量比为1-10:50-300，优选为1-10:100-300，优选为1-6:100-300，优选为1-3:100-300，优选为1-3:100-200。在具体一些实施方案中，阿法沙龙脂肪乳注射液中注射用油用量占脂肪乳注射液的质量浓度为10～30％，优选为10％～20％。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中油相平均粒径为0.15至0.4μm，优选0.15至0.3μm，更优选0.15至0.25μm。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中使用纯度大于95％的阿法沙龙或其药学上可接受的盐，更优选纯度大于98％的阿法沙龙或其药学上可接受的盐。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中阿法沙龙或其药学上可接受的盐的含量为1～10mg/ml，优选为2～8mg/ml，优选为2至4mg/ml。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中注射用油的含量为100～300mg/ml，优选为100～200mg/ml。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中乳化剂的含量为6～15mg/ml，优选为9～15mg/ml。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中助乳化剂的含量为0.05～20mg/ml，优选为0.1～20mg/ml，优选为0.1～10mg/ml，优选为0.5～10mg/ml。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中稳定剂的含量为0.1～0.3mg/ml。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中渗透压调节剂的含量为22-25mg/ml，优选为22.5～25mg/ml。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中乳化剂的含量为0.6％-1.5％(wt)，优选为0.9％-1.5％(wt)。
在具体一些实施方案中，阿法沙龙脂肪乳注射液中助乳化剂的含量为0.05％-1.0％(wt)，优选为0.2％(wt),0.4％(wt),0.6％(wt)或0.8％(wt)。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的Zeta电位为36至60mV。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为5.0至8.5，优选为6.0至8.5。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的乳化剂为蛋黄卵磷脂，优选蛋黄卵磷脂E-80、蛋黄卵磷脂PL-100M、蛋黄卵磷脂PC-98T中的至少一种，优选为重量比为1：2的蛋黄卵磷脂E-80和蛋黄卵磷脂PL-100M的混合物。
在具体一些实施方案中，所述渗透压调节剂为甘油。
在具体一些实施方案中，助乳化剂为胆酸类化合物或其盐，优选甘氨胆酸、胆酸、牛磺胆酸、甘氨脱氧胆酸、牛磺脱氧胆酸、鹅脱氧胆酸、甘氨鹅脱氧胆酸或牛磺鹅脱氧胆酸或其可药用盐中的至少一种。在具体一些实施方案中，所述胆酸类化合物的盐为甘氨胆酸钠、胆酸钠、牛磺胆酸钠、甘氨脱氧胆酸钠、牛磺脱氧胆酸钠、鹅脱氧胆酸钠、甘氨鹅脱氧胆酸钠或牛磺鹅脱氧胆酸钠。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的乳化剂为蛋黄卵磷脂，优选蛋黄卵磷脂E-80、蛋黄卵磷脂PL-100M、蛋黄卵磷脂PC-98T中的至少一种，优选为重量比为1：2的蛋黄卵磷脂E-80和蛋黄卵磷脂PL-100M的混合物，能够调节pH值至5.0～8.5，优选6.0～8.5所需量的pH值调节剂；以及
任选地，所述渗透压调节剂为甘油，
任选地，助乳化剂为胆酸类化合物或其盐，
任选地，所述稳定剂为选自油酸和油酸钠中的至少一种，优选油酸钠，
任选地，所述pH值调节剂为氢氧化钠，
及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的乳化剂为选自蛋黄卵磷脂E-80、蛋黄卵磷脂PL-100M、蛋黄卵磷脂PC-98T的至少一种，优选为重量比为1：2的蛋黄卵磷脂E-80和蛋黄卵磷脂PL-100M的混合物，能够调节pH值至6.0～8.5所需量的pH值调节剂；以及
任选地，所述渗透压调节剂为甘油；
任选地，助乳化剂为胆酸类化合物或其盐，优选甘氨胆酸、胆酸、牛磺胆酸、甘氨脱氧胆酸、牛磺脱氧胆酸、鹅脱氧胆酸、甘氨鹅脱氧胆酸或牛磺鹅脱氧胆酸或其可药用盐中的至少一种。在具体一些实施方案中，所述胆酸类化合物的盐为甘氨胆酸钠、胆酸钠、牛磺胆酸钠、甘氨脱氧胆酸钠、牛磺脱氧胆酸钠、鹅脱氧胆酸钠、甘氨鹅脱氧胆酸钠或牛磺鹅脱氧胆酸钠；
任选地，所述稳定剂为选自油酸和油酸钠中的至少一种，优选油酸钠，
任选地，所述pH值调节剂为氢氧化钠，
及余量的注射用水。。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有0.05％-1.0％(w/v)，优选为0.2％(w/v),0.4％(w/v),0.6％(w/v)或0.8％(w/v)的助乳化剂。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有0.05％-1.0％(w/v)，优选为0.2％(w/v),0.4％(w/v),0.6％(w/v)或0.8％(w/v)的胆酸类化合物或其盐。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有0.6％-1.5％(w/v)，优选为0.6％(w/v),0.9％(w/v),1.2％(w/v),1.5％(w/v)的乳化剂，进一步优选0.9％(w/v),1.2％(w/v),1.5％(w/v)的乳化剂。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有0.05％-1.0％(w/v)，优选为0.2％(w/v),0.4％(w/v),0.6％(w/v)或0.8％(w/v)的甘氨胆酸钠。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有5％-15％(w/v)，优选为5％(w/v),10％(w/v),15％(w/v)的大豆油。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有5％-15％(w/v)，优选为5％(w/v),10％(w/v),15％(w/v)的中链甘油三酯。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有0.01％-0.03％(w/v)，优选为0.01％(w/v),0.03％(w/v)的油酸钠。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有2.25％-2.5％(w/v)，优选为2.25％(w/v),2.5％(w/v)的甘油。
在具体一些实施方案中，阿法沙龙脂肪乳注射液含有0.6％-1.5％(w/v)，优选为0.6％(w/v),0.9％(w/v),1.2％(w/v),1.5％(w/v)的蛋黄卵磷脂，进一步优选0.9％(w/v),1.2％(w/v),1.5％(w/v)的蛋黄卵磷脂。
在一些实施方案中，所述阿法沙龙脂肪乳注射液含有作为助乳化剂的胆酸类化合物或其盐，其中阿法沙龙脂肪乳注射液含有0.05％-1.0％(w/v)，优选为0.2％(w/v),0.4％(w/v),0.6％(w/v)或0.8％(w/v)的甘氨胆酸钠；以及所述阿法沙龙脂肪乳注射液中油相平均粒径为0.15至0.4μm，优选0.15至0.3μm，更优选0.15至0.25μm。更进一步地，所述阿法沙龙脂肪乳注射液中阿法沙龙或其药学上可接受的盐的含量为2至4mg/ml。更进一步地，阿法沙龙脂肪乳注射液含有0.6％-1.5％(wt)，优选为0.9％-1.5％(wt)的蛋黄卵磷脂作为乳化剂。更进一步地，阿法沙龙脂肪乳注射液的Zeta电位为36至60mV。更进一步地，阿法沙龙脂肪乳注射液的pH值为5.0至8.5，优选为6.0至8.5。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为5.0～8.5，各组分按重量份数计，包含：阿法沙龙1-10；大豆油50～200；中链甘油三酯0～100；乳化剂9～15；助乳化剂0.1～20；稳定剂0.1～0.3；甘油22～25。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，各组分按重量份数计，包含：阿法沙龙1-10；大豆油50～200；中链甘油三酯0～100；乳化剂9～15；助乳化剂0.1～20；稳定剂0.1～0.3；甘油22～25。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，各组分按重量份数计，包含：阿法沙龙2～8；大豆油50～200；中链甘油三酯0～100；乳化剂9～12；助乳化剂0.1～10；稳定剂0.1～0.3；甘油22～25。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油50～100毫克；中链甘油三酯50～100毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克，能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油100～200毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油50～100毫克；中链甘油三酯50～100毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油100～200毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油200毫克；蛋黄卵磷脂9～15毫克；胆酸0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2～8毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂9～12毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2～8毫克；大豆油200毫克；蛋黄卵磷脂9～12毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2～8毫克；大豆油100毫克；中链甘油三酯50毫克；蛋黄卵磷脂9～12毫克；甘氨胆酸钠0.1～20毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2～8毫克；大豆油100毫克；中链甘油三酯50毫克；蛋黄卵磷脂9～12毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2～8毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂9～12毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油50-200毫克；中链甘油三酯50-100毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～20毫克；油酸钠0.1～0.3毫克；甘油22.5-25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙1～10毫克；大豆油50-200毫克；中链甘油三酯50-100毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油22.5-25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂E-80 4毫克；蛋黄卵磷脂PL-100M 8毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为6.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙3毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠2毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为6.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙4毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂E-80 9毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙4毫克；大豆油200毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙4毫克；大豆油200毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙2毫克；大豆油100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙4毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 15毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙4毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙4毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 15毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为7.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙5毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 15毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为7.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙5毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为7.5且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙6毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠2毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.5所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙7毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂12毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
或者，pH值为7.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：阿法沙龙7毫克；
大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.5所需用量的氢氧化钠；以及余量的注射用水。
在具体一些实施方案中，阿法沙龙脂肪乳注射液的pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙1～10毫克；大豆油50-200毫克；中链甘油三酯50-100毫克；蛋黄卵磷脂9～15毫克；甘氨胆酸钠0.1～10毫克；油酸钠0.1～0.3毫克；甘油22.5-25毫克；能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙2毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂E-80 4毫克；蛋黄卵磷脂PL-100M 8毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为6.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙3毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠2毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为6.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙4毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂E-80 9毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙4毫克；大豆油200毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙4毫克；大豆油200毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙2毫克；大豆油100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙4毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 15毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙4毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙4毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 15毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为7.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙5毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 15毫克；甘氨胆酸钠3毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为7.0，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙5毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为7.5且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙6毫克；大豆油50毫克；中链甘油三酯50毫克；蛋黄卵磷脂E-80 12毫克；甘氨胆酸钠2毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.5所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液有阿法沙龙7毫克；大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂12毫克；甘氨胆酸钠4毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水组成；
或者，pH值为7.5，且每1毫升所述阿法沙龙脂肪乳注射液由阿法沙龙7毫克；
大豆油100毫克；中链甘油三酯100毫克；蛋黄卵磷脂12毫克；甘氨胆酸钠1毫克；油酸钠0.3毫克；甘油25毫克；能够控制注射液pH值为7.5所需用量的氢氧化钠；以及余量的注射用水组成。
本发明的另一个方面，提供一种制备阿法沙龙脂肪乳注射液的方法，包括：
(1)取注射用油加热至50℃～75℃，然后加入乳化剂、阿法沙龙，混合，剪切至全部溶解分散均匀，以便获得含阿法沙龙油相的第一混合物；
优选地，所述的注射用油为大豆油或者大豆油与中链甘油三酯的混合物；更优选地，所述的注射用油为重量比为1：1的大豆油与中链甘油三酯混合物；
优选的，所述乳化剂为蛋黄卵磷脂；更优选地，所述乳化剂为蛋黄卵磷脂PL-100M和蛋黄卵磷脂E-80的混合物；
(2)取注射用水加热至50℃～75℃然后加入助乳化剂、稳定剂、渗透压调节剂搅拌均匀，以便获得形成水相的第二混合物；优选地，所述助乳化剂为甘氨胆酸钠，所述稳定剂为油酸钠，所述渗透压调节剂为甘油；
(3)将所述第一混合物和所述第二混合物混合，边混合边剪切，以便获得形成初乳的第三混合物；
(4)用pH值调节剂调节所述第三混合物的pH为6.5～11.5，优选为6.5～10.5，优选为6.5～10，以便获得第四混合物，低压均质一次获得第五混合物；优选地，所述pH值调节剂为氢氧化钠；
(5)将所述第五混合物进行高压均质3次以上，优选4-8次，更优选5-6次，且均质过程中均充入氮气到液面以下至氮气饱和，以便获得第六混合物；
(6)将所述第六混合物进行灌装，充入氮气保护，并进行湿热灭菌，以便获得阿法沙龙脂肪乳注射液，pH值为6.0～8.5。
本发明的另一个方面，提供一种制备阿法沙龙脂肪乳注射液的方法，包括：
(1)取注射用油加热至50℃～75℃，然后加入乳化剂、阿法沙龙，混合，剪切至全部溶解分散均匀，以便获得含阿法沙龙油相的第一混合物；
优选的，所述的注射用油为大豆油或者大豆油与中链甘油三酯的混合物；更优选地，所述的注射用油为重量比为1：1的大豆油与中链甘油三酯混合物；
优选地，所述乳化剂为蛋黄卵磷脂；更优选地，所述乳化剂为蛋黄卵磷脂PL-100M和蛋黄卵磷脂E-80的混合物；
(2)取注射用水加热至50℃～75℃然后加入助乳化剂、稳定剂、渗透压调节剂、pH值调节剂搅拌均匀，以便获得形成水相的第二混合物；pH为7～11.5，优选为7～10.5，优选为7～10，优选地，所述助乳化剂为甘氨胆酸钠，所述稳定剂为油酸钠，所述渗透压调节剂为甘油，所述pH值调节剂为氢氧化钠；
(3)将所述第一混合物和所述第二混合物混合，边混合边剪切，以便获得形成初乳的第三混合物；
(4)任选地，用pH值调节剂调节所述第三混合物的pH为6.5～11.5，优选为6.5～10.5，优选为6.5～10，以便获得第四混合物；优选地，所述pH值调节剂为氢氧化钠；
(5)将(3)或(4)所得混合物低压均质一次获得第五混合物；将所述第五混合物进行高压均质3次以上，优选4-8次，更优选5-6次，且均质过程中均充入氮气到液面以下至氮气饱和，以便获得第六混合物；
(6)将所述第六混合物进行灌装，充入氮气保护，并进行湿热灭菌，以便获得阿法沙龙脂肪乳注射液，pH值为6.0～8.5。
在在一些具体的实施方案中，剪切混合在5000～16000rpm的转速下进行5～25min；优选的，混合过程中剪切的转速为10000rpm，混合完成后剪切的转速为15000-16000rpm。
在一些具体的实施方案中，阿法沙龙脂肪乳的制备方法的步骤(3)中，在5000～16000rpm的转速下进行为5～25min剪切混合。
在一些具体的实施方案中，阿法沙龙脂肪乳的制备方法中的步骤(4)的低压均质是在100/160bar的压力下均质，步骤(5)所述高压均质是在500-1000bar的压力下均质5～8次，所述高压均质温度控制在30℃～70℃。
术语释义：
术语“等渗”是指其具有与生理体液相等的渗透压或者类似于生理体液。体液通常具有经常被描述为对应于0.9％(重量/体积)的氯化钠水溶液的渗透压。本申请使用甘油调节等渗，甘油的用量在每1毫升所述阿法沙龙脂肪乳注射液包含甘油22～25毫克，具体的为22毫克/毫升，22.5毫克/毫升，23毫克/毫升，23.5毫克/毫升，24毫克/毫升，24.5毫克/毫升，具体的为25毫克/毫升。
术语“中链油”为中链甘油三酯、中链甘油三酸酯；术语“长链油”为大豆油。
术语“w/v”是指单位体积注射液中组分的质量含量，单位为“g/ml”。
术语“助乳化剂”，一般乳液体系对乳液的稳定性起到积极作用，本申请的助乳化剂具体为胆酸类化合物或其盐，更具体的为甘氨胆酸和甘氨胆酸钠、胆酸、牛磺胆酸、甘氨脱氧胆酸或牛磺脱氧胆酸、鹅脱氧胆酸、甘氨鹅脱氧胆酸或牛磺鹅脱氧胆酸等，可以实现药物的溶解性的提高、脂肪乳剂和药物的稳定性的提高等。
术语“AFSL”为阿法沙龙。
本说明书中的“约”可以理解为在所述数值的10％、9％、8％、7％、6％、5％、4％、3％、2％、1％、0.5％、0.1％、0.05％或0.01％内。除非另外明确说明，本文提供的所有数值都由术语“约”修饰。
技术效果：
阿法沙龙在蓖麻油中的溶解度高于中链油和长链油，本发明通过摸索最佳的注射用油配比，发现使用对阿法沙龙溶解性较差的注射中链和长链油的最佳配比，且注射用油含量应在一定的合适范围，才能保证乳化剂能够将油相和水相完全乳化。
本发明与未加入甘氨胆酸钠制剂相比，未加入甘氨胆酸钠制剂只能满足于小规格(2mg/ml)的制备，大规格的制备(4mg/ml)在冷藏放置10天后出现原料析出的情况，脂肪乳表面有油滴，已破乳等现象，稳定性较差。
使用甘氨胆酸钠，与卵磷脂形成协同提高溶解效果，制备得到的平均粒径低于未加甘氨胆酸钠组，粒径均匀度好，pH经过稳定性试验确认，pH稳定，未发生明显的降低，表明乳剂稳定性好，有利于存储，对存储条件要求不苛刻，说明甘氨胆酸钠或甘氨胆酸兼具助溶与稳定作用，能够增加药物与油相的亲和力，从而改善制剂的稳定。与蓖麻油制剂相比，制剂粒径更小，更稳定，并且显著降低过敏的发生，更安全。
另外，在加入甘氨胆酸或甘氨胆酸钠制剂中，与未加入制剂相比，可以明显提高载药量，由2mg/ml提高到6mg/ml，载药量提高三倍。
本申请提供的脂肪乳剂，经药理实验证实，致敏性显著低于按照CN94190450.4制备的含有蓖麻油的乳剂，平均粒径显著小于蓖麻油乳剂组，包封率高于蓖麻油制剂组，且注射痛小于蓖麻油乳剂组，稳定性各项指标均好于蓖麻油乳剂组。
本发明所述的阿法沙龙脂肪乳注射液，避免使用蓖麻油、环糊精等易引起不良反应的辅料，本发明采用新配方制成的乳剂，在制剂中采用重量比为1：1的大豆油和中链甘油三酯作为注射用油，同时以油酸钠作为稳定剂、以蛋黄卵磷脂E-80作为乳化剂，以甘氨胆酸钠或甘氨胆酸为助乳化剂，其制备得到的阿法沙龙脂肪乳注射液样品的质量更稳定。利用甘氨胆酸钠或甘氨胆酸作为助乳化剂，大大提高了阿法沙龙脂肪乳注射液的稳定性，其可防止阿法沙龙制剂在放置过程中因贮存条件变化引起的脂肪乳的乳滴聚集、合并等制剂不稳定情况，对血管无刺激性、提高了临床用药的安全性和顺应性。
附图说明
图1是1.2％甘氨胆酸钠脂肪乳初乳分层图。
图2是1.4％甘氨胆酸钠脂肪乳初乳分层图。
图3是2.0％甘氨胆酸钠脂肪乳初乳分层图。
图4是未加入甘氨胆酸钠4mg/ml的灭菌后样品在20天出现API析出图。
图5是静脉注射给药后小鼠血浆内组胺含量测定图。
图6是大鼠肌电刺激性试验图。
具体实施方式
蛋黄卵磷脂：E80，购自德国Lipoid GmbH；甘油购自汕头市佳禾生物科技有限公司；甘氨胆酸钠购自河北贞田食品添加剂有限公司；大豆油购自广州白云山汉方现代药业有限公司；中链甘油三酸酯(辛酸57.1％，葵酸42.8％)购自辽宁新兴药业股份有限公司；油酸钠购自德国Lipoid GmbH；阿法沙龙为江苏恩华药业股份有限公司自制纯度95％以上的阿法沙龙；丙泊酚(生产厂家：江苏恩华药业股份有限公司，批号：BB200215)；Cremophor EL(生产厂家：国药集团化学试剂有限公司，批号：20220104)；磺丁基-β-环糊精/SBE-β-CD(生产厂家：淄博千汇生物科技有限公司，批号：SB210911)。
实施例1-4未加甘氨胆酸钠的乳剂(批量以1000ml计)制备方法
0.1mol/L氢氧化钠配制：称取0.4g氢氧化钠用适量水溶解放冷后转移至100ml容量瓶中，定容至刻度备用。
油相制备：向500ml烧杯中加入大豆油及中链甘油三酸酯各100g于70℃水浴加热。按制剂量称取蛋黄卵磷脂、阿法沙龙(AFSL)加入油相以速度为10000rpm，剪切5min，制得油相。
水相制备：称取适量注射用水至2000ml烧杯中，在水浴锅内升温，水温控制在70℃；向水相中加入油酸钠0.3g、甘油25g用玻璃棒搅拌均匀，制得水相。
初乳制备：向水相中加入油相，边剪切(10000rpm)边加入，控制初乳温度为70℃；加完油相后，将剪切速度调整至15400rpm，剪切5min，用0.1mol/L的氢氧化钠将初乳pH调至9.0，制得初乳。
成品制备：低压均质压力：100bar/160bar，均质一次。高压均质压力：100bar/600bar，均质六次。均质后对样品进行灌封，充氮，灭菌(121℃，15min)。
1.1制剂组成
1.2实验结果
1.3结论：4个规格样品的原料药均在油相中完全溶解，溶液呈澄清透明；4个批次在刚灭菌完，其成品外观性状、包封率、pH、粒径、Zeta电位均符合要求，但随着规格的增加含量有减小的趋势，特别是实施例4(5mg/ml)在刚灭完菌后，含量仅有94.16％。
1.4影响因素试验
对2mg/ml，3mg/ml，4mg/ml，5mg/ml规格样品进行高温(60℃、40℃)、低温(4℃)条件放样。于5天、10天、30天取样检测，结果见下表。
实施例1：(规格：2mg/ml)

实施例2：(规格：3mg/ml)
实施例3：(规格：4mg/ml)
实施例4：(规格：5mg/ml)
结论：2mg/ml样品放样30天外观、含量、电位。粒径等指标均在合格范围内，但4mg/ml的 样品含量在30天出现下降且成品外观在4℃放样10天及常温20天后有API析出(即活性成分析出)现象(见图4)。5mg/ml样品灭菌后0时含量偏低且有API析出现象。
一、考察油相不同种类及比例
对比例1-2，参考CN94190450.4实施例1公开的方法制备
油相制备：向250ml烧杯中加入制剂量的蓖麻油及大豆油或者蓖麻油，于70℃水浴加热。称取AFSL 2g加入油相以速度为10000rpm，剪切2min，称取蛋黄卵磷脂12g入油相以速度为10000rpm，剪切5min，制得油相。
水相制备：称取861.5g注射用水至2000ml烧杯中，在水浴锅内升温，水温控制在70℃；向水相中加入甘油22.5g用玻璃棒搅拌均匀，制得水相。
初乳制备：向水相中加入油相，边剪切(10000rpm)边加入，控制初乳温度为70℃；加完油相后，将剪切速度调整至15400rpm，剪切5min，用0.1mol/L的氢氧化钠将初乳pH调至9.0，制得初乳。
成品制备：低压均质压力：100bar/160bar，均质一次。高压均质压力：100bar/600bar，均质六次。均质后对样品进行灌封，充氮，灭菌(121℃，15min)。
实验结果
结论：从实验过程观察，10％蓖麻油可以完全溶解AFSL，含量、电位等指标在合格范围内，但乳剂样品粒径大于0.5μm，依据中国药典4部通则0102规定属于不合格范围。
参考实施例1的试验方法，尝试不同制剂组成制备样品的可行性。
制剂组成(实施例5-9，制备体积为1000ml)

实验结果
结论：采用不同油相(大豆油或大豆油与中链甘油三酯的混合物)占比(10％、20％、30％)所制备的样品，其样品的性状、含量、包封率、pH值、Zeta电位均无明显差异，但平均粒径随着油相比例的增加，出现逐渐升高的趋势，其中含30％油相制剂的平均粒径大于0.4μm，接近限度。采用含有蓖麻油制剂的样品，其性状、包封率、pH、含量、电位等指标均在合格范围内，但平均粒径均大于或接近0.5μm，粒径显著高于不含蓖麻油的制剂。
综上所述，表明注射用油的种类选择及占比选择应在合适范围，以保证乳化剂能够将油相和水相完全乳化。故本发明油相占比优选范围为10％-20％；优选油相为大豆油或大豆油与中链甘油三酯的混合物。以下实施例以油相占比为20％(大豆油和中链甘油三酸酯的比例为1:1)进行考察。
二、考察不同磷脂比例
2.1.1尝试在2mg/ml的规格下使用不同比例磷脂的制剂，考察样品的可行性，制备方法参考实施例1(批量以1000ml计)
2.1.2样品检测结果：
2.1.3结论：在0.6％-1.5％磷脂比例范围内，对含量、电位无明显区别，随着磷脂比例增加样品粒径有减小趋势，但在0.9％-1.5％范围内区别不大；含0.6％磷脂样品外观有少许飘油现象。
2.1.4影响因素结果：
实施例10批样品
实施例11批样品
实施例12批样品

实施例13批样品
2.1.5结论：与0天相比，含0.9％-1.5％磷脂样品在各影响因素30天的结果稳定，含量、粒径、电位等指标无明显变化。但含0.6％磷脂的样品，影响因素结果显示样品平均粒径出现增大，有聚集的趋势。表明乳剂样品不稳定。
三、不同乳化剂考察
3.1因以未加入甘氨胆酸钠制剂制备的4mg/ml、5mg/ml规格的乳剂样品在稳定性放样过程中有API析出现象，故尝试加入不同助乳化剂(泊洛沙姆188、甘氨胆酸钠、吐温80或15羟基硬脂酸聚乙二醇酯(HS15))与磷脂作为复合乳化剂，考察5mg/ml乳剂样品的可行性。
实施例16:加入甘氨胆酸钠的乳剂(批量以1000ml计)的制备方法
油相制备：
分别称取制剂量的大豆油、中链甘油三酸酯于60℃水浴加热。称取制剂量的蛋黄卵磷脂加入油相中，再称取AFSL于油相中，并以10000rpm速度，剪切5min。
水相制备：
称取适量的注射用水至2000ml烧杯中，在水浴锅内升温，水温控制在60℃，称取制剂量的甘氨胆酸钠、油酸钠、甘油于水相中并搅拌均匀，制得水相。
初乳制备：
向水相中加入油相，边剪切(10000rpm)边加入，控制初乳温度为60℃；加完油相后，将剪切速度调整至15400rpm，剪切5min。用0.5mol/L氢氧化钠将初乳调至pH 9左右。
成品制备：
低压均质压力：100bar/160bar，均质一次。高压均质压力：100bar/600bar，均质六次。均质后对样品进行灌封，充氮，灭菌(121℃，15min)。
实施例14、15、17参照实施例16的方法制备，仅替换不同的助乳化剂。

3.2实验结果：
3.3结论：与实施例16制剂相比，实施例14的制剂外观有飘油现象，实施例15及实施例17外观有API析出现象，这表明吐温80、泊洛沙姆188、HS15无法起到助乳化的目的，实施例16的制剂外观性状符合规定，且含量、电位、粒径等指标在合格范围内。综上所述，含甘氨胆酸钠的制剂可以提高乳剂样品稳定性。
3.4制剂组成(规格：4mg/ml)


3.5样品检测结果：
3.6.结论：实施例18的样品外观有飘油现象，实施例19及实施例20外观有API析出现象，这表明吐温80、泊洛沙姆188、HS15无法起到助溶的目的，实施例21-23的样品观性状符合规定，且含量、电位、粒径等指标在合格范围内，综上，所述含胆酸类化合物或其盐的制剂可以提高乳剂样品稳定性。
四、甘氨胆酸钠的作用确认
4.1未加甘氨胆酸钠与添加甘氨胆酸钠的比较(批量以1000ml计)
4.2样品检验结果
4.3结论：两个制剂样品的含量、电位、包封率等指标无明显区别，加入甘氨胆酸钠制剂的样品平均粒径小于常规制剂。
4.4稳定性数据
实施例24批样品：
实施例25批样品：
4.5结论：从稳定性数据看，含甘氨胆酸钠制剂的含量、电位、平均粒径等指标在放样30天与0时相比无明显变化，未加入甘氨胆酸钠制剂的样品在低温10天含量出现偏低，而且样品外观有API析出现象。这说明甘氨胆酸钠的加入有助于乳剂样品的稳定性。
五、考察制备更大规格制剂(含甘氨胆酸)的可行性
制备方法
油相制备：
分别称取制剂量的大豆油、中链甘油三酸酯于60℃水浴加热。称取制剂量的蛋黄卵磷脂加入油相中，再分别称取AFSL于油相中，并以10000rpm速度，剪切5min。
水相制备：
称取制剂量的注射用水至2000ml烧杯中，在水浴锅内升温，水温控制在60℃，称取制剂量的甘氨胆酸于注射用水中用0.5mol/L氢氧化钠调节至水相澄清，再称取制剂量的油酸钠、甘油于水相中并搅拌均匀，制得水相。
初乳制备：
向水相中加入油相，边剪切(10000rpm)边加入，控制初乳温度为60℃；加完油相后，将剪切速度调整至15400rpm，剪切5min。用0.5mol/L氢氧化钠将初乳调至pH 9左右。
成品制备：
低压均质压力：100bar/160bar，均质一次。高压均质压力：100bar/600bar，均质六次。均质后对样品进行灌封，充氮，灭菌(121℃，15min)。
5.1批量以1000ml计
5.2样品检测结果：
5.3结论：5mg/ml、6mg/ml的样品含量、外观性状、电位、粒径等指标均符合要求。
六、甘氨胆酸钠用量考察
6.1在规格4mg/ml的情况下考察不同比例甘氨胆酸钠对样品稳定性影响(批量以1000ml计)

6.2样品检测结果：
6.3结论：随着甘氨胆酸钠含量的增加，乳剂样品的含量、电位等指标无明显区别，而样品平均粒径有逐渐减小的趋势，在每毫升阿法沙龙脂肪乳注射液包含甘氨胆酸钠含量在例如12毫克,14毫克,20毫克时样品初乳出现分层(见图1、图2、图3)，而每毫升阿法沙龙脂肪乳注射液中甘氨胆酸钠含量在0.5-10毫克之间时样品初乳外观性状以及其它特性均较好。对每毫升阿法沙龙脂肪乳注射液中甘氨胆酸钠含量在0.5-10毫克之间的乳剂样品进行稳定性实验。
6.4稳定性数据
实施例28批样品(0.05％)

实施例29批样品(0.1％)
实施例30批样品(0.14％)
实施例31批样品(0.2％)

实施例32批样品(0.4％)
实施例33批样品(0.8％)
实施例34批样品(1.0％)
6.5结论：通过稳定性数据可以看出甘氨胆酸钠含量在0.05％-1.0％的乳剂样品在放样30天时其含量、电位及平均粒径等指标与0时相比均无明显变化，表明样品稳定。
七、样品低pH的可行性考察
实施例38、39和40参照实施例16的方法制备，用冰乙酸调节初乳PH，其它制剂组分含量微调。
7.1制剂组成(规格：2mg/ml)
7.2样品检测结果
7.3结论：样品在pH5.0以上时其外观、含量、粒径及电位等指标均合格，当pH低于5.0时出现飘油现象，粒径偏大，有不稳定趋势。
7.4稳定性数据
实施例38
实施例39
7.5结论：样品pH大于5时，其外观、含量、Zeta电位及粒径等指标在40℃、60℃放样30天情况下均合格，pH下降在可控范围内。
八、阿法沙龙在蓖麻油、长链油(大豆油)、中链油(中链甘油三酸酯)中的溶解性试验
1、实验目的：考察阿法沙龙在蓖麻油中的溶解度
实验过程：称取10mg阿法沙龙加入到70℃的100g蓖麻油中，10000rpm剪切5min后体系澄清。再次称取10mg阿法沙龙到体系中，10000rpm剪切3min后体系澄清。再次称取30mg阿法沙龙到体系中，10000rpm剪切3min后体系澄清。多次称取阿法沙龙直到其总量在2g时体系依然澄清。
实验结论：阿发沙龙在蓖麻油中的溶解度在2g以上。
2、实验目的：考察阿法沙龙在大豆油中的溶解度
实验过程：称取10mg阿法沙龙加入到70℃的100g大豆油中，10000rpm剪切5min后体系浑浊。
实验结论：阿法沙龙在100g大豆油溶解度小于10mg。
3、实验目的：考察阿法沙龙在中链油中的溶解度
实验过程：称取10mg阿法沙龙加入到70℃的100g中链油中，10000rpm剪切5min后体系澄清。再次称取10mg阿法沙龙到体系中，10000rpm剪切3min后体系澄清。再次称取30mg阿法沙龙到体系中，10000rpm剪切3min后体系略微浑浊。
实验结论：100g中链油可溶解阿发沙龙在40mg以下。
九、小鼠组胺释放数据汇总
总体试验方法：配制相应的溶液或制剂，静脉注射给药，给药后30min采血，EDTA抗凝后离心取血浆，ELISA试剂盒测定小鼠血浆内组胺含量。
空白血浆：小鼠直接取血后离心。
生理盐水：注射生理盐水，给药体积为5mL/kg。
空白脂肪乳(20％中长链脂肪乳)：给药体积为5mL/kg。
阿法沙龙脂肪乳(含甘氨胆酸钠，实施例26批样品)：阿法沙龙脂肪乳(含甘氨胆酸钠)给药剂量为7mg/kg，阿法沙龙ED50约为3.5mg/kg，因此给药剂量为7mg/kg。阿法沙龙脂肪乳(含甘氨胆酸钠)规格为5mg/mL，使用空白脂肪乳稀释至1.4mg/mL，给药体积为5mL/kg。
SBE-β-CD：配制方式：0.7mL 13％SBE-β-CD+4.3mL生理盐水，给药体积为5mL/kg。(吊桥公司的制剂为13％SBE-β-CD溶解阿法沙龙，溶解后浓度为10mg/mL，因此本组试验参考吊桥公司制剂进行配制药物溶液)。
Cremophor EL：0.7mL Cremophor EL+4.3mL生理盐水，Cremophor EL浓度为0.14mL/mL，给药剂量为5mL/kg，Cremophor EL的给药剂量为0.7mL/kg。
SBE-β-CD&Cremophor EL：0.7mL 13％SBE-β-CD+0.7mL Cremophor EL+3.6mL生理盐水，给药体积为5mL/kg。
阿法沙龙@SBE-β-CD&Cremophor EL：0.7mL阿法沙龙@13％SBE-β-CD(10mg/mL)+0.7mL Cremophor EL+3.6mL生理盐水，给药体积为5mL/kg。阿法沙龙终浓度为1.4mg/mL，因此最终阿法沙龙剂量为7mg/kg，Cremophor EL的剂量为0.7mL/kg。
阿法沙龙@蓖麻油(10％)脂肪乳(2mg/mL)：给药体积3.5mL/kg，剂量7mg/kg；蓖麻油给药量为0.35mL/kg。
阿法沙龙@蓖麻油(7％)脂肪乳(2mg/mL)：该对比例参考CN94190450.4实施例1的方法制备的，给药体积3.5mL/kg，剂量7mg/kg；蓖麻油给药量为0.245mL/kg。
阿法沙龙脂肪乳注射液(含甘氨胆酸钠数据)

结果描述：静脉注射后，生理盐水、空白脂肪乳(20％中长链脂肪乳)、阿法沙龙脂肪乳注射液(含甘氨胆酸钠，实施例26)、磺丁基-β-环糊精(SBE-β-CD)小鼠血浆组胺浓度与空白血浆无显著性差异，未引起小鼠组胺过量释放；Cremophor EL、SBE-β-CD&Cremophor EL、阿法沙龙@(SBE-β-CD&Cremophor EL)、阿法沙龙@蓖麻油(7％)脂肪乳、阿法沙龙@蓖麻油(10％)脂肪乳小鼠血浆组胺浓度显著高于溶媒组，引起小鼠组胺过量释放，推测可能引起过敏反应。阿法沙龙@(SBE-β-CD&Cremophor EL)组小鼠组胺血浆浓度显著高于SBE-β-CD&Cremophor EL组，表明阿法沙龙溶于SBE-β-CD&Cremophor EL后促进小鼠组胺释放，加重了过敏程度。
以上结果表明制剂中含有Cremophor EL和蓖麻油的阿法沙龙制剂静脉注射后会引起小鼠组胺过量释放，推测可能引起过敏反应；而阿法沙龙脂肪乳注射液(含甘氨胆酸钠)不引起过敏反应，见图5。
十、阿法沙龙不同制剂对大鼠肌电的影响
生理盐水：生理盐水
空白脂肪乳(普通制剂)：不含主药阿法沙龙，其他同实施例1
阿法沙龙脂肪乳(2mg/mL)：实施例1
阿法沙龙脂肪乳(10％蓖麻油)(2mg/mL)：对比例1
丙泊酚脂肪乳(10mg/mL)：江苏恩华药业股份有限公司生产，批号：BB200215
空白脂肪乳(含甘氨胆酸钠)：不含主药阿法沙龙，其他同实施例33
阿法沙龙脂肪乳(含甘氨胆酸钠)(4mg/mL阿法沙龙)：实施例33
Cremophor EL：1mL Cremophor EL+4mL生理盐水。
SBE-β-CD&Cremophor EL：1mL 13％SBE-β-CD+1mL Cremophor EL+3mL生理盐水。
阿法沙龙@(SBE-β-CD&Cremophor EL)：1mL阿法沙龙@13％SBE-β-CD(10mg/mL)+1mL Cremophor EL+3mL生理盐水。
试验方法：
大鼠腹腔注射20％乌拉坦溶液，麻醉后，固定于操作板上，找到并分离后肢一侧的隐动脉，找到同侧后肢的半腱肌，插入电极。在分离的隐动脉中插入塑料套管，经由塑料套管进行药物注射，每次注射结束后用生理盐水冲洗套管。
对注射前后的大鼠肌电进行积分，计算注射后大鼠肌电与基线的比值，评价溶液对大鼠肌电刺激。
药物注射体积为0.1mL，给药后生理盐水冲洗塑料套管。
试验结果：
数据表明，与生理盐水相比，空白脂肪乳、阿法沙龙脂肪乳(2mg/mL，实施例1)、阿法沙龙脂肪乳(10％蓖麻油)(2mg/mL)、丙泊酚脂肪乳(生产厂家：江苏恩华药业股份有限公司，批号：BB200215，10mg/mL)给药后大鼠肌电显著增大，实际使用中可能引起注射刺激性和注射疼痛。空白脂肪乳(含甘氨胆酸钠)、阿法沙龙脂肪乳(含甘氨胆酸钠，实施例33)(4mg/mL)、Cremophor EL、SBE-β-CD&Cremophor EL、阿法沙龙@(SBE-β-CD&Cremophor EL)给药后对大鼠肌电无显著影响，推测无注射刺激性、不会引起注射疼痛，见图6。
备注：表格中Dunnett检验的显著性均为与生理盐水组比较的结果。

Claims (19)

  1. 一种阿法沙龙脂肪乳注射液，其特征在于，包括阿法沙龙或其药学上可接受的盐，注射用油，乳化剂，助乳化剂，渗透压调节剂，稳定剂，pH值调节剂和注射用水。
  2. 根据权利要求1所述的阿法沙龙脂肪乳注射液，其特征在于，所述注射用油为大豆油或者大豆油和中链甘油三酯的混合物。
  3. 根据权利要求2所述的阿法沙龙脂肪乳注射液，其特征在于，所述大豆油和中链甘油三酯的混合物中大豆油与中链甘油三酯的重量比为1～5:1～5，优选为1：1。
  4. 根据权利要求1所述的阿法沙龙脂肪乳注射液，其特征在于，所述阿法沙龙或其药学上可接受的盐与注射用油的重量比为1-10:50-300，优选为1-10:100-300，优选为1-6:100-300，优选为1-3:100-300，优选为1-3:100-200；或者所述注射用油用量占脂肪乳注射液的质量浓度为10～30％，优选为10％～20％。
  5. 根据权利要求1-4任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，所述阿法沙龙或其药学上可接受的盐纯度大于95％。
  6. 根据权利要求1-5任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，所述乳化剂为蛋黄卵磷脂，优选蛋黄卵磷脂E-80、蛋黄卵磷脂PL-100M、蛋黄卵磷脂PC-98T的至少一种，更优选为重量比为1：2的蛋黄卵磷脂E-80和蛋黄卵磷脂PL-100M的混合物；pH值调节剂的用量控制注射液pH值为5.0～8.5所需的用量；
    任选地，所述渗透压调节剂为甘油，
    任选地，所述稳定剂为选自油酸和油酸钠中的至少一种，优选油酸钠，
    任选地，助乳化剂为胆酸类化合物或其盐，
    任选地，所述pH值调节剂为氢氧化钠。
  7. 根据权利要求1-6任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，所述乳化剂为蛋黄卵磷脂，优选蛋黄卵磷脂E-80、蛋黄卵磷脂PL-100M、蛋黄卵磷脂PC-98T的至少一种，更优选为重量比为1：2的蛋黄卵磷脂E-80和蛋黄卵磷脂PL-100M的混合物；pH值调节剂的用量控制注射液pH值为6.0～8.5所需的用量；
    任选地，所述渗透压调节剂为甘油，
    任选地，所述稳定剂为选自油酸和油酸钠中的至少一种，优选油酸钠，
    任选地，助乳化剂为胆酸类化合物或其盐，
    任选地，所述pH值调节剂为氢氧化钠。
  8. 根据权利要求6或7所述的阿法沙龙脂肪乳注射液，其特征在于，所述胆酸类化合物或其盐为甘氨胆酸、胆酸、牛磺胆酸、甘氨脱氧胆酸、牛磺脱氧胆酸、鹅脱氧胆酸、甘氨鹅脱氧胆酸、牛磺鹅脱氧胆酸或其钠盐中的至少一种，优选甘氨胆酸和/或甘氨胆酸钠。
  9. 根据权利要求1-8任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，注射液pH值为5.0～8.5；各组分按重量份数计，包含：
    阿法沙龙1-10；
    大豆油50～200；
    中链甘油三酯0～100；
    乳化剂9～15；
    助乳化剂0.1～20；
    稳定剂0.1～0.3；
    甘油22～25。
  10. 根据权利要求1-9任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，注射液pH值为6.0～8.5；各组分按重量份数计，包含：
    阿法沙龙1-10；
    大豆油50～200；
    中链甘油三酯0～100；
    乳化剂9～15；
    助乳化剂0.1～20；
    稳定剂0.1～0.3；
    甘油22～25。
  11. 根据权利要求8-10任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，注射液pH值为6.0～8.5；各组分按重量份数计，包含：
    阿法沙龙2～8；
    大豆油50～200；
    中链甘油三酯0～100；
    乳化剂9～12；
    助乳化剂0.1～10；
    稳定剂0.1～0.3；
    甘油22～25。
  12. 根据权利要求1～8任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油50～100毫克；
    中链甘油三酯50～100毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油100～200毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
  13. 根据权利要求8或12所述的阿法沙龙脂肪乳注射液，其特征在于，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油50～100毫克；
    中链甘油三酯50～100毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油100～200毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
  14. 根据权利要求1-10、12-13任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油200毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
  15. 根据权利要求1-13任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙2～8毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂9～12毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙2～8毫克；
    大豆油200毫克；
    蛋黄卵磷脂9～12毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙2～8毫克；
    大豆油100毫克；
    中链甘油三酯50毫克；
    蛋黄卵磷脂9～12毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙2～8毫克；
    大豆油50毫克；
    中链甘油三酯50毫克；
    蛋黄卵磷脂9～12毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水。
  16. 根据权利要求1-10任意一项所述的阿法沙龙脂肪乳注射液，其特征在于，pH值为6.0～8.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙1～10毫克；
    大豆油50-200毫克；
    中链甘油三酯50-100毫克；
    蛋黄卵磷脂9～15毫克；
    甘氨胆酸钠0.1～10毫克；
    油酸钠0.1～0.3毫克；
    甘油22.5-25毫克；
    能够控制注射液pH值为6.0～8.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙2毫克；
    大豆油50毫克；
    中链甘油三酯50毫克；
    蛋黄卵磷脂E-80 4毫克；
    蛋黄卵磷脂PL-100M 8毫克；
    甘氨胆酸钠3毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为6.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙3毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠2毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为6.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙4毫克；大豆油50毫克；
    中链甘油三酯50毫克；
    蛋黄卵磷脂E-80 9毫克；
    甘氨胆酸钠4毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙4毫克；
    大豆油200毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠4毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙4毫克；
    大豆油200毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠1毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙2毫克；
    大豆油100毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠4毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙4毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂E-80 15毫克；
    甘氨胆酸钠3毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙4毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠1毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙4毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂E-80 15毫克；
    甘氨胆酸钠3毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为7.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙5毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂E-80 15毫克；
    甘氨胆酸钠3毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为7.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为7.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙5毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠1毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为7.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为7.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙6毫克；
    大豆油50毫克；
    中链甘油三酯50毫克；
    蛋黄卵磷脂E-80 12毫克；
    甘氨胆酸钠2毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为7.5所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为8.0，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙7毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂12毫克；
    甘氨胆酸钠4毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为8.0所需用量的氢氧化钠；以及余量的注射用水；
    或者，pH值为7.5，且每1毫升所述阿法沙龙脂肪乳注射液包含：
    阿法沙龙7毫克；
    大豆油100毫克；
    中链甘油三酯100毫克；
    蛋黄卵磷脂12毫克；
    甘氨胆酸钠1毫克；
    油酸钠0.3毫克；
    甘油25毫克；
    能够控制注射液pH值为7.5所需用量的氢氧化钠；以及余量的注射用水。
  17. 一种制备权利要求1-16任一项所述的阿法沙龙脂肪乳注射液的方法，其特征在于，包括：
    (1)取注射用油加热至50℃～75℃，然后加入乳化剂、阿法沙龙，混合，剪切至全部溶解分散均匀，以便获得含阿法沙龙油相的第一混合物；
    优选地，所述的注射用油为大豆油或者大豆油与中链甘油三酯的混合物；更优选地，所述的注射用油为重量比为1：1的大豆油与中链甘油三酯混合物；
    优选地，所述乳化剂为蛋黄卵磷脂，更优选地，所述乳化剂为蛋黄卵磷脂PL-100M和蛋黄卵磷脂E-80的混合物；
    (2)取注射用水加热至50℃～75℃然后加入助乳化剂、稳定剂、渗透压调节剂搅拌均匀，以便获得形成水相的第二混合物；优选地，所述助乳化剂为甘氨胆酸钠，所述稳定剂为油酸钠，所述渗透压调节剂为甘油；
    (3)将所述第一混合物和所述第二混合物混合，边混合边剪切，以便获得形成初乳的第三混合物；
    (4)用pH值调节剂调节所述第三混合物的PH，以便获得第四混合物，低压均质一次获得第五混合物；优选地，所述pH值调节剂为氢氧化钠；
    (5)将所述第五混合物进行高压均质3次以上，优选4-8次，更优选5-6次，且均质过程中均充入氮气到液面以下至氮气饱和，以便获得第六混合物；
    (6)将所述第六混合物进行灌装，充入氮气保护，并进行湿热灭菌，以便获得阿法沙龙脂肪乳注射液，pH值为5.0～8.5，优选地，pH值为6.0～8.5。
  18. 一种制备权利要求1-16任一项所述的阿法沙龙脂肪乳注射液的方法，其特征在于，包括：
    (1)取注射用油加热至50℃～75℃，然后加入乳化剂、阿法沙龙，混合，剪切至全部溶解分散均匀，以便获得含阿法沙龙油相的第一混合物；
    优选地，所述的注射用油为大豆油或者大豆油与中链甘油三酯的混合物；更优选地，所述的注射用油为重量比为1：1的大豆油与中链甘油三酯混合物；
    优选地，所述乳化剂为蛋黄卵磷脂，更优选地，所述乳化剂为蛋黄卵磷脂PL-100M和蛋黄卵磷脂E-80的混合物；
    (2)取注射用水加热至50℃～75℃然后加入助乳化剂、稳定剂、渗透压调节剂、pH值调节剂搅拌均匀，以便获得形成水相的第二混合物；优选地，所述助乳化剂为甘氨胆酸钠，所述稳定剂为油酸钠，所述渗透压调节剂为甘油，所述pH值调节剂为氢氧化钠；
    (3)将所述第一混合物和所述第二混合物混合，边混合边剪切，以便获得形成初乳的第三混合物；
    (4)任选地，用pH值调节剂调节所述第三混合物的pH，以便获得第四混合物；优选地，所述pH值调节剂为氢氧化钠；
    (5)将步骤(3)或(4)所得混合物低压均质一次获得第五混合物；将所述第五混合物进行高压均质3次以上，优选4-8次，更优选5-6次，且均质过程中均充入氮气到液面以下至氮气饱和，以便获得第六混合物；
    (6)将所述第六混合物进行灌装，充入氮气保护，并进行湿热灭菌，以便获得阿法沙龙脂肪乳注射液，pH值为5.0～8.5，优选地，pH值为6.0～8.5。
  19. 根据权利要求17或18所述的方法，其特征在于，剪切混合在5000～16000rpm的转速下进行5～25min；优选地，混合过程中剪切的转速为10000rpm，混合完成后剪切的转速为15000-16000rpm。
PCT/CN2023/106281 2022-07-11 2023-07-07 阿法沙龙脂肪乳注射液及其制备方法 WO2024012361A1 (zh)

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WO1995001162A1 (en) * 1993-07-02 1995-01-12 Pharmacia Ab Pharmaceutical emulsions containing bioactive steroids
CN1402629A (zh) * 1999-12-23 2003-03-12 辉瑞产品公司 提供提高的药物浓度的药物组合物
CN104039311A (zh) * 2011-11-17 2014-09-10 迈兰公司 充液硬胶囊药物制剂
CN106137963A (zh) * 2016-07-27 2016-11-23 武汉科福新药有限责任公司 抗心律失常药物脂肪乳注射液及其制备方法
CN109966502A (zh) * 2017-12-26 2019-07-05 财团法人工业技术研究院 用于改善难溶物的溶解度的组合物、其用途与含其的复合制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001162A1 (en) * 1993-07-02 1995-01-12 Pharmacia Ab Pharmaceutical emulsions containing bioactive steroids
CN1402629A (zh) * 1999-12-23 2003-03-12 辉瑞产品公司 提供提高的药物浓度的药物组合物
CN104039311A (zh) * 2011-11-17 2014-09-10 迈兰公司 充液硬胶囊药物制剂
CN106137963A (zh) * 2016-07-27 2016-11-23 武汉科福新药有限责任公司 抗心律失常药物脂肪乳注射液及其制备方法
CN109966502A (zh) * 2017-12-26 2019-07-05 财团法人工业技术研究院 用于改善难溶物的溶解度的组合物、其用途与含其的复合制剂

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