Propofol liposome freeze-drying preparation and preparation method thereof

Abstract

The invention discloses a propofol liposome freeze-drying preparation and its preparation method. The preparation is prepared from propofol, artificial synthetic phosphatide, cholesterol and a freeze-drying protectant. According to the preparation, artificial synthetic phosphatide is adopted to replace natural lecithin so as to avoid the hypersensitivity phenomenon which is easily caused by microprotein in natural lecithin. In addition, the preparation contains no auxiliary materials such as tween-80, EDTA-2Na, sulfite, thiosulfate and the like which are commonly used in a fat emulsion preparation, so as to further avoid the hypersensitivity phenomenon. The average particle size of the propofol liposome freeze-drying preparation is less than 100 nm such that injection pain caused by large particle size of a traditional propofol fat emulsion is avoided.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a non-irritating and painless propofol liposome freeze-dried preparation and a preparation method thereof. Background technique [0002] Propofol (Propofol), also known as dipofol, propofol, 2,6-diisopropylphenol, molecular formula: C 12 h 18 O, molecular weight: 178.3, see its chemical structure figure 1 . [0003] Propofol is a low-molecular phenol derivative. It is an injectable anesthetic that can induce and maintain general anesthesia. It has the advantages of fast onset, rapid elimination, and high safety. Endoscopic examination, induced abortion and other painless treatments. [0004] Due to the strong lipophilicity of propofol, it is difficult to dissolve in water, so the currently marketed products are mainly propofol fat emulsions, and the excipients used include soybean oil, medium-chain triglycerides, lecithin, oleic acid, glycerin and water for i...

AI Technical Summary

Problems solved by technology

[0005] ①This emulsion is a heterogeneous liquid preparation, which is a thermodynamically and kinetically unstable system. Therefore, when the emulsion is placed for a long time, the emulsion droplet particles are easy to merge to increase the particle size, or cause instability such as oil floating and layering of the emulsion;

[0007] ③ During the high temperature treatment in the preparation process and the long-term storage process of this emulsion, the drugs, soybean oil and lecithin in the emulsion are easily oxidized and degraded, thus causing allergies and other side effects: there are phenolic hydroxyl groups in the structure of propofol, which are easily destroyed Oxidation to generate 2,6-diisopropyl-1,4-benzoquinone or polymerization to generate 3,3,5,5'-tetraisopropyl biphenol (see chemical structure figure 2 ), these two impurities have greater toxicity;

[0008] ④ In order to prevent propofol from being oxidized, auxiliary materials such as EDTA-2Na, sulfite, and thiosulfate are often added to the preparation, but these auxiliary materials are also likely to cause allergic reactions, especially for patients with idiopathic asthma;

[0009] ⑤ The fat, phospholipids and other substances in this preparation are good substrates for microbial production in a liquid environment, so there is a risk of bacterial and fungal infection during storage and use, and if used improperly, it is easy to cause consequences such as infection;

[0010] ⑥ The incidence of pain at the injection site of this preparation is as high as 28% to 90%, which has seriously affected the patients;

[0011] ⑦ This emulsion is likely to cause hypertriglyceridemia after intravenous administration, especially for patients who receive long-term infusion;

[0012] ⑧ This preparation should avoid high and low temperature storage, and at the same time, it should not be shaken violently, so this product is not convenient for transportation and storage

[0014] The patent application No. 201510021939.0 prepared propofol fat emulsion injection, which overcomes the defects of excessive particle size deviation of colostrum, easy emulsion breaking, and excessive particle size deviation of emulsion after high-pressure homogenization, but it uses natural Egg yolk lecithin and soybean oil are used as excipients, which can easily cause allergic reactions

[0015] The patent application number is 201410819727.2 prepared propofol fat emulsion injection, which does not contain preservative disodium edetate, which reduces the toxic and side effects of the preparation, but the natural egg yolk lecithin and soybean oil it uses still cause allergies Phenomenon

[0016] The patent with authorized notification number CN101006992B prepares propofol freeze-dried milk, which increases the stability of the emulsion, but it uses natural egg yolk lecithin and soybean oil as auxiliary materials, which can easily cause allergic reactions

[0017] The patent application No. 201410130319.6 prepared propofol liposomes, which have the advantages of high encapsulation efficiency, high drug loading, and small particle size, but it uses emulsifier Tween-80 and natural egg yolk lecithin, which is easy to allergic reaction

[0018] The patent with authorized announcement number CN102805728B prepared a kind of propofol fat emulsion injection, which solved the problem of large particle size and easy demulsification of propofol fat emulsion, and at the same time alleviated the pain of injection, but it uses Tween-80 and Natural egg yolk lecithin and soybean oil, prone to allergic reactions

[0019] The patent application No. 201210419120.6 has prepared a stable and efficient propofol medium / long-chain fat emulsion injection, which is more stable than ordinary propofol fat emulsion, and at the same time, can significantly reduce the incidence of injection pain and improve Improve patient compliance, but the natural egg yolk lecithin it contains is prone to allergic reactions

[0020] The patent with authorized notification number CN102552136B has prepared a medium / long chain injection of propofol, which does not contain preservative disodium edetate, which reduces the irritation of the preparation, but it uses natural egg yolk lecithin and large Soybean oil can still cause allergies

[0021] The patent application number is CN104288130A has prepared a kind of propofol composition for injection, and it increases propofol in preparation by adding cosolvent propylene glycol, nonionic surfactant Tween 20, Tween 80, polyoxyethylene castor oil etc. The encapsulation rate in the medium reduces the injection pain caused by free propofol, but the excipients it adds will produce allergic irritation

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