A kind of temsirolimus liposome and preparation method thereof

Abstract

The invention relates to a temsirolimus liposome and a preparation method thereof. The formula of the invention is temsirolimus, phospholipids, and PEGylated phospholipids, and may further contain cholesterol, a stabilizer, and a freeze-drying protective agent. Aiming at the unique physical and chemical properties of temsirolimus, the invention carried out matching research on the composition of the prescription and the preparation process, and developed a temsirolimus liposome that is safe, stable in quality, simple in the preparation process, and can be produced industrially. Preferably it is a freeze-dried powder injection, which overcomes the shortcomings of existing preparations such as poor safety and stability, and lays a solid foundation for further research and application of temsirolimus in the field of antitumor.

Description

Technical field: [0001] The invention relates to the technical field of medicine, in particular to a temsirolimus liposome and a preparation method thereof. Background technique [0002] Temsirolimus (English name, Temsirolimus) is the 42-dimethylol propionate of sirolimus, and its structural formula is as follows. Tesirolimus is almost insoluble in water and is non-electrolyte, and its solubility cannot be increased by pH adjustment, salt formation, etc. Although it has good solubility in some pharmaceutically acceptable organic solvents (such as ethanol, propylene glycol, polyethylene glycol, etc.), almost all of them have chemical stability problems such as easy oxidative degradation and lactone ring cleavage; on the other hand, The temsirolimus is dissolved in the above organic solvent, and it cannot be directly diluted with aqueous solutions such as 0.9% sodium chloride solution, 5% glucose solution, etc. in clinical use, otherwise precipitation will be precipitated, w...

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Problems solved by technology

However, this preparation also has many disadvantages: ① the preparation contains a large amount of organic solvents, which is highly irritating for intravenous administration; ② the preparation contains Tween 80, which may cause allergic reactions. Antihistamines must be given; ③The preparation has poor compatibility with infusion equipment, because it contains Tween 80, which can dissolve the plasticizer (phthalate di(2) -ethyl)hexyl ester); ④ this preparation is a two-bottle preparation, which must first be diluted with a special diluent and then diluted with normal saline, otherwise precipitation will occur. This two-step dilution method is cumbersome to operate and increases secondary pollution risks of

Patent CN201210460639.9 discloses a kind of temsirolimus freeze-dried preparation, by adding cosolvent polyethylene glycol stearate 15, it can be directly prepared and used by water for injection or physiological saline, which solves the problem of And the patent CN200480021450.3 disclosed preparation needs two bottles, must use specific diluent to dilute first, then dilute through physiological saline, the operation is loaded down with trivial details, easily cause problems such as secondary pollution

But this preparation has used a large amount of surfactant macrogol stearate 15 to solubilize, there are literature (Zhang Jia, Li Yikui, Li Lianda, etc. 4 kinds of solubilizers such as polysorbate-80 and poloxamer 188 Acute toxicity to mice, Chinese Journal of New Drugs, 2008, 17(17): 1491-1493) reported that the surfactant was injected into the tail vein of mice with greater acute toxicity, even greater than Tween 80, showing its safety issues still to be discussed

Literature (Ma Haixia, Zou Xiang. Optimizing the prescription process of temsirolimus liposome by response surface methodology, National Antibiotic Academic Conference, 2013) prepared a kind of temsirolimus liposome, but its encapsulation efficiency is only About 83%; literature (Ran Mo, Qiong Sun, Nan Li, et al.Intracellular delivery and antitumor effects of pH-sensitive liposomes based on zwitterionic oligopeptide lipids, Biomaterials, 2013,34(11):2773-2786.) through lipid An amphipathic oligopeptide HHG2C18 was added to the body membrane material to prepare a temsirolimus pH-sensitive liposome. First, the literature research results showed that when HHG2C18 or PEGHG2C18 was added to the liposome membrane material , the particle size of the prepared blank liposomes and drug-loaded liposomes was significantly increased, especially after adding PEGHG2C18, the loading capacity of the drug temsirolimus was also significantly reduced, which shows that this component has a significant effect on the druggability of liposomes. A certain impact may affect the stability of liposome and the encapsulation of medicine, and according to the structure of the composition, its hydrophobic part is two stearyl alkane chains, and its affinity with phospholipids is obviously not as good as that of PEGylated phospholipids (i.e. Polyethylene glycol modified phospholipids), if used as a liposome membrane material component, is likely to be unfavorable for the formation of liposomes and the encapsulation of drugs; secondly, literature (Fang Chao, Shi Bin, Hong Ming, etc. Effects of particle size and relative molecular weight of MePEG on macrophage phagocytosis of stealth nanoparticles and long circulation in rats, 80nm, 170nm and 240nm particles were compared in Acta Pharmaceutica Sinica, 2006,41(4):305-312. The effect of particle size on macrophage phagocytosis in vitro and long circulation in rats. The results showed that with the decrease of particle size, the phagocytosis of macrophages decreased, and the half-life of rat plasma prolonged. It can be seen that the liposome membrane material in the After adding PEGHG2C18, the particle size of liposomes increased from 100nm to 150nm, which may have adverse effects on macrophage phagocytosis and circulation time in vivo.

[0007] Therefore, in view of the shortcomings of the existing temsirolimus preparations, we aim at temsirolimus, some commonly used dosage forms with better safety, such as sulfobutyl ether-β-cyclodextrin inclusion complex , liposome, and fat emulsion were screened, expecting to find a dosage form matched with temsirolimus (see Example 1), the results showed that sulfobutyl ether-β-cyclodextrin, fat emulsion were effective for temsirolimus As far as rolimus is concerned, the possibility of becoming a drug is extremely low, which is mainly reflected in: (1) up to 50% sulfobutyl ether-β-cyclodextrin still cannot realize the inclusion of 1mg / ml temsirolimus; ( 2) The solubility of temsirolimus in commonly used injection oils (medium chain oil, soybean oil) is too low to meet the requirements of formulations

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