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

A cholesterol and tri-block technology, which is applied in the field of preparation of poloxamer derivatives, can solve the complex synthesis and purification process of unilaterally grafted cholesterol, the insignificant reduction of critical micelle concentration, and the short cycle time of anhydride-ester bonds, etc. problem, to achieve the effect of improving drug loading capacity, low critical micelle concentration, and improving dilution stability

Active Publication Date: 2014-11-26
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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...

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Take 336 mg of F68 (0.04 mM) in a closed container, add 2.44 mg of 4-lutidine and 20 μL of triethylamine under nitrogen, slowly add a solution of cholesteryl chloromethyl ester (0.12 mM) in dichloromethane 8 mL, stirred and mixed in an ice-water bath for 30 min, then reacted at room temperature for 24 h, and removed the solvent under reduced pressure after the reaction was completed. A certain amount of distilled water was added to the obtained crude product, extracted three times with dichloromethane, washed three times with ice water, saturated sodium chloride and 100 mM hydrochloric acid, and precipitated with ice ether to obtain a white wax, which was further refined by repeated precipitation for 3 The CHMC-F68-CHMC three-block copolymer is obtained in one time.

[0057] During the reaction, silica gel thin-layer chromatography (TLC) was used to monitor the progress of the reaction and analyze the purity. Developing agent: chloroform: methanol: water: acetone: glac...

Embodiment 2

[0062] Take 504 mg F127 (0.04 mM) in a closed container, add 2.44 mg 4-lutidine and 20 μL triethylamine under nitrogen, slowly add a dichloromethane solution of cholesteryl chloromethyl ester (0.12 mM) dropwise8 mL, stirred and mixed in an ice-water bath for 30 min, then reacted at room temperature for 24 h, and removed the solvent under reduced pressure after the reaction was completed. Add a certain amount of distilled water to the obtained crude product, extract three times with dichloromethane, wash three times with ice water, saturated sodium chloride and 100 mM hydrochloric acid respectively, and precipitate a white waxy substance through ice ether precipitation, continue to repeatedly precipitate and refine Three times to get powdered CHMC-F127-CHMC tri-block copolymer.

[0063] During the reaction, silica gel thin-layer chromatography (TLC) was used to monitor the progress of the reaction and analyze the purity. Developing agent: chloroform: methanol: water: acetone: ...

Embodiment 3

[0068] Take 308 mg F87 (0.04 mM) and place it in a closed container, add 2.44 mg 4-lutidine and 20 μL triethylamine under nitrogen, slowly add cholesteryl chloromethyl ester (0.12 mM) in dichloromethane solution 8 mL, stirred and mixed in an ice-water bath for 30 min, then reacted at room temperature for 24 h, and removed the solvent under reduced pressure after the reaction was completed. Add a certain amount of distilled water to the obtained crude product, extract three times with dichloromethane, wash three times with ice water, saturated sodium chloride and 100 mM hydrochloric acid respectively, and precipitate a white waxy substance through ice ether precipitation, continue to repeatedly precipitate and refine Three times to get powdered CHMC-F87-CHMC tri-block copolymer.

[0069] Use IFS-55 Fourier Transform Infrared Spectrometer (Bruker Company, Switzerland) to carry out infrared analysis on the product obtained, and the test spectrum is shown in the accompanying drawi...

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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....

Claims

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Application Information

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IPC IPC(8): C08G65/00A61K47/34A61K45/00A61K47/28
Inventor 邓意辉宋艳志刘欣荣田清菁隋月蒋宫平佘振南程晓波
Owner SHENYANG PHARMA UNIVERSITY
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