5-fluorouracil-sn2-phosphatidyl choline copolymer as well as preparation method and application thereof

A technology of phosphatidylcholine and fluorouracil, applied in the field of medicine, can solve the problems such as the preparation method and use of 5-fluorouracil-phosphatidylcholine copolymer, the application of drug-phosphatidylcholine copolymer, side effects and the like have not been found.

Inactive Publication Date: 2009-07-22
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] (3) Side effects
[0065] After literature search, so far, no application of drug-phosphatidylcholine copolymer in transdermal drug delivery system has been found, nor has 5-fluorouracil-sn 2 -Related reports on phosphatidylcholine copolymer and its preparation method and use

Method used

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  • 5-fluorouracil-sn2-phosphatidyl choline copolymer as well as preparation method and application thereof
  • 5-fluorouracil-sn2-phosphatidyl choline copolymer as well as preparation method and application thereof
  • 5-fluorouracil-sn2-phosphatidyl choline copolymer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example

[0201] Example: Take lysophosphatidylcholine containing palmitic acid residues as an example.

[0202] The carboxylic acid derivative of 5-fluorouracil - 1-acetic acid-5-fluorouracil, is condensed with 1-palmitoyloxy-sn-glycerol-phosphatidylcholine to obtain 5-fluorouracil-sn 2 - Phosphatidylcholine copolymer: 1-palmitoyloxy-2-(5-fluorouracil-1-acetoxy)-sn-glycerol-phosphatidylcholine.

[0203] Carboxylate derivatives of 5-fluorouracil——succinic acid mono[(5-fluoro-2,4-dioxo-3,-dihydro-2H-pyrimidin-1-yl)-methyl]ester, with 1 -palmitoyloxy-sn-glycerol-phosphatidylcholine condensation to give 5-fluorouracil-sn 2 - Phosphatidylcholine copolymer: 1-palmitoyloxy-2-{[(5-fluoro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-methoxycarbonyl ]-propionyloxy}-sn-glycerol-phosphatidylcholine.

[0204] Its chemical synthesis route is as follows:

[0205]

[0206] (2) 5-fluorouracil-sn 2 - Content control of phosphatidylcholine copolymer

[0207] The present invention adopts high perform...

Embodiment 1

[0245] The synthesis of embodiment 1,1-acetic acid-5-fluorouracil (1)

[0246] Weigh 0.03mol (3.9g) of 5-fluorouracil, 0.02mol potassium carbonate (1g), and 0.5g potassium iodide, put them into a 100ml reaction bottle, add 70ml dimethylsulfoxide (DMSO for short), and heat in an oil bath. Initially insoluble, it becomes cloudy after a period of heating. When the temperature rose to 70°C, 0.03 ethyl chloroacetate was added dropwise, and reacted overnight in an oil bath at 70°C. During the period, samples were taken at 10h, 12h, 14h, 16.5h, and 18.5h to spot the plate (TLC plate paved with GF254, with ethyl acetate:petroleum ether=3:1 as the developing solvent) to observe the 5- Formation of fluorouracil. When the reaction lasted for 18.5 hours, the reaction was terminated, and the reaction solution was evacuated at 90° C. with an oil pump, and DMSO was distilled off under reduced pressure. Dissolve the residue in 100ml of ethyl acetate (the residue is the dried product of a l...

Embodiment 2

[0248] Example 2, the synthesis of intermediate succinic acid mono[(5-fluoro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-methyl]ester (n=2)

[0249] Take 0.01mol 5-fluorouracil, 0.025mol 37% formaldehyde solution and stir at 60°C for reaction. After all the solids are dissolved, continue to stir for 1 hour. ), directly used in the next step of synthesis without purification.

[0250] Take 0.01 mol of intermediate (2), an appropriate amount of pyridine as a solvent, then add 0.01 mol of succinic anhydride, and stir at room temperature for reaction. After the reaction is completed, put the reaction mixture into an appropriate amount of water, extract with dichloromethane, wash with water, and dry over anhydrous sodium sulfate , filtered and concentrated to obtain a viscous liquid, purified by column chromatography to obtain intermediate succinic acid mono[(5-fluoro-2,-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) with different side chain lengths )-methyl]ester (3), mp 153-156°C. Molecula...

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Abstract

The invention relates to 5-fluorouracil-sn2-phosphatidylcholine copolymers and a preparation method and application thereof. The preparation method comprises: preparing 5-fluorouracil derivatives containing carboxyl groups, using a carboxylic group as a connecting group to covalently bond 5-fluorouracil on a sn2 site of phosphatidylcholine, and obtaining the copolymers. The copolymers have amphiphilic surface activity, can form liposome nano-capsules and a self-assembly delivery system, and can be taken as an intermediate preparation formulation and further prepared into a corresponding transdermal delivery preparation such as gel. The copolymers and the delivery system of the copolymers can effectively enter focuses, and can be subjected to enzymolysis through high-expression phospholipase A2 on the focuses to metabolize active skin cancer resistant medicines, namely the 5-fluorouracil, so that the copolymers and the delivery system have the advantage of skin-targeted medication of skin cancer, overcomes the defects that the water-soluble 5-fluorouracil is not suitable for transdermal administration and has low envelop rate of liposome, easy leakage and difficult acquisition of liposome with superior transdermal carrier performance, and provides a novel medicine source for clinical medicines.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to a new pharmaceutical composition and its preparation method and use, more specifically to a 5-fluorouracil-phospholipid copolymer and its preparation method and use, and more specifically Said to involve 5-fluorouracil-sn 2 - Phosphatidylcholine copolymer and its preparation method and use. Background technique [0002] (1) Research status of 5-fluorouracil [0003] 1 Overview [0004] [0005] 5-Fluorouracil is a pyrimidine fluoride, which belongs to anti-metabolism and anti-neoplastic drugs. It is a first-line anti-tumor and anti-viral drug with definite curative effect, especially for all phases of proliferative cell populations. Many studies have shown that 5-fluorouracil also has strong local anti-skin cancer activity in the treatment of skin diseases (van Ruth S, et al.Total bodytopical 5-fluorouracil for extensive non-melanoma skin cancer.Pharm World Sci, 20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/513A61K47/24A61K9/00A61P35/00A61K47/54
Inventor 张立超李玲孙青䶮张俊
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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