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A kind of lipid derivative containing sialic acid fragment and its application

A technology of lipid derivatives and sialic acid, which is applied in the field of preparation and modification of microparticle preparations, can solve the problems of easy disintegration, poor control, and difficult insertion of micelles, and achieve long tumor targeting, long internal circulation time, immune The effect of low originality

Active Publication Date: 2016-03-30
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this synthesis reaction has great randomness and poor controllability; and the fatty chains connected by PSA are short, the micelles are easy to disintegrate in vivo, and the targeted drug delivery ability is low; and the material is difficult to insert firmly into the surface of liposomes

Method used

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  • A kind of lipid derivative containing sialic acid fragment and its application
  • A kind of lipid derivative containing sialic acid fragment and its application
  • A kind of lipid derivative containing sialic acid fragment and its application

Examples

Experimental program
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Effect test

Embodiment 1

[0093] Example 1: poly Sialic acid octadecylamine derivatives ( ODA-PSA ) Synthesis

[0094]Freshly prepared 0.2M / L sodium metaperiodate (NaIO 4 ) mixed with PSA (average molecular weight 11.0kDa) solution and stirred in the dark for about 15 minutes; then added propylene glycol to the reaction system and stirred in the dark for 30 minutes (PSA:NaIO 4 : propylene glycol=1:6:2.5, mol / mol); add octadecylamine (ODA) ethanol solution (PSA:ODA=1:1, mol / mol) to this system and stir in the dark until the solution is clear and milky Light; Potassium borohydride (KBH) was gradually added dropwise to the reaction system 4 ) (KBH 4 : ODA=4:1, mol / mol), continue to react for about 4h. Use deionized water as the dialysis medium to dialyze the reaction solution for about 24 hours. The dialysis medium is about 100 times the volume of the reaction solution. The dialysis medium is replaced every 6 hours, a total of 4 times. Freeze-dry the reaction solution after dialysis to obtain wh...

Embodiment 2

[0098] Embodiment 2: the synthesis of DSPE-PSA :

[0099] Activation of PSA: freshly prepared 0.2M / L sodium metaperiodate (NaIO 4 ) mixed with PSA (average molecular weight 11.0kDa) solution (NaIO 4 : PSA=6:1, mol / mol), the reaction mixture was magnetically stirred for 15 min in the dark. Precipitate the oxidized PSA with 70% (final concentration) ethanol and centrifuge the mixture at 3000 g for 20 min, remove the supernatant, dissolve the pellet with a minimum amount of deionized water, and then precipitate the PSA with 70% ethanol, then Centrifuge at 12000 g. The pellet was dissolved with a minimum amount of water to obtain an activated PSA aqueous solution, which was lyophilized and stored at -20°C until use.

[0100] Connection of activated PSA and DSPE: Dissolve activated PSA and DSPE in ethanol (1:1, mol / mol), stir in the dark until the solution is clear and opalescent, and gradually add potassium borohydride (KBH 4 ) (KBH 4 : DSPE=4:1, mol / mol), continue to react...

Embodiment 3

[0103] Embodiment 3: the synthesis of ODA-SA

[0104] Mix 0.027g of sialic acid (SA), 2mL of 0.1mol / L sodium periodate aqueous solution and 4mL of ethylene glycol and stir for about 1 hour at 15-25°C in the dark; add 4mL of octadecylamine (ODA ) ethanol solution (containing ODA0.0151g) and continue to stir for about 15h; add sodium borohydride (NaBH 4 ) (NaBH 4 : ODA=4:1, mol / mol), continue to react for about 6 hours and then terminate the reaction, freeze-dry the solvent and redissolve the freeze-dried product with dichloromethane system, take the supernatant and concentrate after centrifugation, and the main components of the obtained product are Sialic acid octadecylamine derivatives (abbreviated as ODA-SA). ODA-SA was purified by silica gel column chromatography with a mixed solvent of chloroform and petroleum ether as a developing solvent.

[0105] Use BRUKERAVANCE-600MHz superconducting nuclear magnetic resonance (Switzerland Bruker Company) to carry out carbon spec...

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Abstract

The invention belongs to the field of pharmaceutical preparations, and provides a lipid derivative containing sialic acid fragments, its preparation method and application, especially for the preparation and modification of microparticle preparations. The sialic acid fragment contains at least one sialic acid unit, and the sialic acid units are connected by α-2,8-glycosidic bonds, and the lipid fragment and the 7th carbon of the non-reducing end sialic acid unit in the sialic acid fragment are connected by C-N key connection. Its general structural formula is as follows: the microparticle preparation modified or prepared by this compound has extremely low immunogenicity and excellent in vivo pharmacokinetic properties. Wherein SA represents a sialic acid unit, n represents an integer whose minimum value is 1; the R-HN segment comes from R-NH2, and R-NH2 is a compound containing a primary amino group.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a lipid derivative containing sialic acid fragments, its preparation method and application, especially for the preparation and modification of microparticle preparations. Background technique [0002] In the development history of drug delivery system (Drug Delivery System, DDS), the polymer modification of drug molecules and carriers can increase the stability of drug preparations, reduce the degradation of drug molecules in vivo, and change the pharmacokinetic behavior of drugs in vivo to improve drug treatment efficiency. . Among them, the PEGylated (PEGylated, also known as PEGylated) technology of carriers and drug molecules has the most development potential and practical value. For a long time, governments around the world have invested a lot of human, financial and material resources to carry out such as PEGylated small molecule drugs, PEGylated ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H7/027C07H1/00C08G81/00A61K47/36A61K47/34A61K47/24A61K9/107A61K9/127A61K9/14A61K9/10
Inventor 邓意辉佘振南张婷欧瀚杰
Owner SHENYANG PHARMA UNIVERSITY