Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof

Abstract

The invention relates to a cholesterol-poloxamer-cholesterol triblock copolymer, a preparation method and application thereof. The triblock copolymer is obtained by taking poloxamer as the basic framework, and connecting cholesterol to both ends by carbonic ester bonds. The preparation method includes: placing poloxamer in a sealed container, adding an alkaline catalyst and an acid binding agent under a nitrogen condition, slowly adding a dichloromethane solution containing cholesteryl chloroformate dropwise, conducting stirring mixing in ice-water bath for 5-30min, then placing the mixture at room temperature to react for 1-72h, after the reaction, at the end of the reaction, reducing the pressure and removing the solvent so as to obtain a crude product; adding a proper amount of distilled water to the crude product, performing extraction with dichloromethane three times, then conducting washing three times with ice water, saturated sodium chloride and 100mM hydrochloric acid in order, and carrying out precipitation by ice ether to obtain a white wax matter; and subjecting the white wax matter to repeated precipitation refining by ice ether, thus obtaining the triblock copolymer. And the triblock copolymer has the advantages of low critical micelle concentration, large drug loading capacity, good dilution stability, simple synthetic process, low cost, and wide application range, etc. (structural formula).

Description

[0001] technical field [0002] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of a class of poloxamer derivatives and its application in a drug delivery system. [0003] Background technique [0004] Poloxamer is a multifunctional pharmaceutical excipient approved by the FDA. The block composition is an amphiphilic block copolymer. With the different numbers of hydrophilic EO chains and hydrophobic PO chains, they have different hydrophilic-lipophilic balance (HLB), critical micelle concentration (CMC) and oil-water partition coefficient (P). Poloxamer has a long history of research in the field of medicine due to its non-toxic, non-antigenic, non-irritating, non-sensitizing, non-hemolytic, and stable chemical properties. [0005] Poloxamers are usually used as emulsifiers, solubilizers, drug stabilizers, solid dispersion carriers, ointments and suppository bases, transdermal absorption enhancers, etc....

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Problems solved by technology

[0017] But this patent has the following defects: (1) Compared with poloxamer with bilateral grafted cholesterol, after unilaterally grafted cholesterol, poloxamer The decrease of the critical micelle concentration of the poloxamer is not obvious, and the drug loading capacity is not significantly improved; (2) Since both ends of the poloxamer contain hydroxyl groups, the synthesis and purification process of the polymer grafted on one side with cholesterol is more complicated and the yield is lower ; (3) Compared with the carbonate bond, the anhydride ester bond has a shorter circulation time in the body, which easily leads to the leakage of the encapsulated drug; (Xu, H., et al., Esterase-catalyzed dePEGylation of pH-sensitive vesicles modified with cleavable PEG-lipid derivatives. Journal of Controlled Release, 2008. 130(3): p. 238-245) (4) The patent did not confirm the structure of the obtained results, nor did it investigate the properties of the preparations in the examples

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