Phospholipid derivatives for branching polyethylene glycol, and lipid membrane structural body composed of same

A technology of polyethylene glycol and derivatives, applied in liposome delivery, drug combination, organic active ingredients, etc., can solve problems such as poor retention

Active Publication Date: 2014-06-25
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In traditional liposome preparations, when administered intravenously, they have poor retention in the blood and are easily captured by the reticuloendothelial system (hereinafter referred to as "RES") such as the liver and spleen. As a drug delivery system, there are difficulties in delivering drugs to organs other than the "RES" system or keeping reagents in the blood for a long time to control drug release

Method used

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  • Phospholipid derivatives for branching polyethylene glycol, and lipid membrane structural body composed of same
  • Phospholipid derivatives for branching polyethylene glycol, and lipid membrane structural body composed of same
  • Phospholipid derivatives for branching polyethylene glycol, and lipid membrane structural body composed of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0228] Example 1: L 4 Preparation of amide bonds in

[0229] A. Condensation method

[0230] L 4 Synthesis of compounds (A1-1) containing amide bonds in which L 1 = L 2 = L 3 =CH 2 , Y=CH, X 1 =X 2 =CH 3 , q=1, R is dilauroyl glyceride residue, polyethylene glycol molecular weight is about 2000.

[0231]

[0232] After adding 40g of branched polyethylene glycol acetic acid and DLPE (13.9g, 1.2 equivalents) into a dry and clean 1L round bottom flask, nitrogen protection, adding the solvent dichloromethane (500mL), stirring at room temperature for 10min, then adding 20mL Dichloromethane solution of triethylamine and 20g of dicyclohexanecarbodiimide (DCC), reacted at room temperature for 24 hours, filtered to remove insoluble matter, concentrated, and recrystallized from isopropanol to obtain the compound containing amide bond in L4 ( A1-1).

[0233] The hydrogen spectrum data of compound A1-1 are as follows:

[0234] 1 H NMR (CDCl 3 )δ (ppm): 0.95 (-CH 2 CH 3 ...

Embodiment 2

[0251] Example 2: L 4 Preparation of urethane linkages in

[0252] A, active ester synthesis method:

[0253] L 4 Synthesis of compounds containing carbamate bonds (A2-1) in which L 1 = L 2 =CH 2 CH 2 ,,L 3 =CH 2 CH 2 , X 1 =X 2 =CH 3 , Y is N, q=1, R is 1-stearyl-2-hydroxyglyceride residue, and the molecular weight of polyethylene glycol is about 1000.

[0254]

[0255] After adding branched polyethylene glycol succinimide carbonate active ester (20 g) and 1-stearyl-2-hydroxyglyceryl phosphatidylethanolamine (11.6 g, 1.2 equivalents) into a dry and clean 500 mL round bottom flask, Under nitrogen protection, add anhydrous dichloromethane (250mL), stir at room temperature for 10min, add 5mL triethylamine, react at room temperature for 24 hours, concentrate, and recrystallize from isopropanol to obtain the compound containing amino orthoester bond in L4 (A2-1).

[0256] The hydrogen spectrum data of compound A2-1 are as follows:

[0257] 1 H NMR (CDCl 3 )δ (p...

Embodiment 3

[0264] Example 3: L 4 Preparation of ester bond (-OCO-) in

[0265] A:L 4 Synthesis of compounds containing ester bonds (A3-1), where L 1 = L 2 = L 3 =CH 2 ,X 1 =X 2 =CH 3 , Y is CH, q=1, R is the residue of dimyristyl phosphatidylglyceride. The designed total molecular weight is about 1500.

[0266]

[0267] After adding branched polyethylene glycol acetic acid (30 g) and dimyristyl phosphatidylglycerol (66.6 g, 5 equivalents) into a dry and clean 1L round-bottomed flask, nitrogen protection was added, and the solvent dichloromethane (500 mL) was added and kept at room temperature After stirring for 10 minutes, add 20 mL of triethylamine and 20 g of dicyclohexanecarbodiimide (DCC) in dichloromethane in sequence, react at room temperature for 24 hours, filter to remove insoluble matter, concentrate, dissolve in water, filter, and dialyze. A compound (A3-1) containing an ester bond in L4 was obtained.

[0268] The hydrogen spectrum data of compound A3-1 are as fol...

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Abstract

The invention discloses phospholipid derivatives for branching polyethylene glycol, and a lipid membrane structural body composed of the same. The general formula of the phospholipid derivatives is as shown in the specification, wherein X1 and X2 are hydroxyl with 1-20 carbon atoms respectively and independently; n1 and n2 are integers ranging from 1 to 1000 respectively and independently, n3 is an integer ranging from 0 to 1000, and n1+n2+n3 is not less than 2 and not greater than 2000; Y is a branching centre with 1-20 carbon atoms, and connected with L1, L2 and L3 by a covalent bond; L1, L2 and L3 are linking groups for Y and polyethylene glycol units; q is 0 or 1; when n3=0, q is 0 and Y is not the polyamino acid residue of 2-10 amino acid residues; L4 is a linking group; M is hydrogen atom or cation; R is the residue of hydrophobic lipids. The lipid membrane structural body composed of the phospholipid derivatives for branching polyethylene glycol is used for wrapping a medicine and capable of effectively prolonging the cycle time of the medicine in a body.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a phospholipid derivative of branched polyethylene glycol and a lipid membrane structure composed of the same. Background technique [0002] Liposome is a closed vesicle formed by dispersing lipids (phospholipids and cholesterol) in water and encapsulating a part of the water phase. Its shape is spherical, spherical, oval, etc., and its diameter is about tens of nanometers to tens of microns. Liposome is a new type of drug carrier, and its stability in blood is the key to play the role of drug carrier. In traditional liposome preparations, when administered intravenously, they have poor retention in the blood and are easily captured by the reticuloendothelial system (hereinafter referred to as "RES") such as the liver and spleen. As a drug delivery system, there are difficulties in delivering drugs to organs other than the "RES" system or keeping reagents in the blood for a lon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/34A61K9/127A61K31/704A61P35/00
CPCA61K9/1271C08G65/3353C08G65/3356C08G65/3358
Inventor 翁文桂刘超廖金城闫策林毅
Owner XIAMEN SINOPEG BIOTECH
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