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Application of N-oxidized tertiary amine containing polymer as medicine or carrier

A technology for oxidizing tertiary amine groups and polymers, applied in the field of medicine, can solve the problems of difficulty in entering cells to exert drug efficacy and weak interaction

Active Publication Date: 2017-12-29
HAINAN PULIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while this ability endows it with the ability to hide, it also brings a serious disadvantage: after the drug or carrier molecule is linked to PEG or PHPMA, the interaction with the cell is very weak, so it is difficult to enter even after reaching the diseased site such as tumor tissue. Cells exert drug effects (Zahr, A.S.; Davis, C.A.; Pishko, M.V., Macrophage uptake of core-shell nanoparticle surface modified with poly(ethylene glycol). Langmuir 2006, 22 (19), 8178-8185.)
Therefore, there is a contradiction between the blood concealment ability of current drug carriers and the rapid entry into cells

Method used

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  • Application of N-oxidized tertiary amine containing polymer as medicine or carrier
  • Application of N-oxidized tertiary amine containing polymer as medicine or carrier
  • Application of N-oxidized tertiary amine containing polymer as medicine or carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1: Synthesis of PODEAEMA-SN38 Bonds

[0093] The application of the N-oxidized tertiary amine-based polymer as a drug carrier in the present application, one embodiment of which includes bonding chemotherapeutic drugs. More specifically, in one embodiment, the loaded drug is 7-ethyl-10-hydroxycamptothecin (SN38), which is synthesized as follows.

[0094]

[0095] Where x=0.8~0.95, n=3~300

[0096] (1) Synthesis of PODEAEMA-NHS.

[0097] 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA, 5.37g) and tert-butyl methacrylate (0.37g), 0.0041g ethyl 2-isobromobutyrate, 2,2 After putting 0.085 g of '-bipyridine, 0.038 g of cuprous bromide and 2 mL of methanol into the polymerization bottle, nitrogen gas was continuously fed for 30 minutes to remove oxygen. Then seal and react at 30°C for 6 hours. After the reaction is finished, the catalyst is removed through an aluminum oxide column, the obtained solution is concentrated and added to n-hexane for precipitation, an...

Embodiment 2

[0108] Embodiment 2: Preparation of PODEAEMA-b-polySN38 block copolymer

[0109] The application of the N-oxidized tertiary amine polymer as a drug carrier of the present application, one embodiment is to use the hydrophilic N-oxidized tertiary amine polymer as a long chain and connect it to the drug molecule or its polymer , to form amphiphilic bonded drugs that form nanoparticles or micelles through their assembly in aqueous solution. More specifically, in one embodiment, the loaded drug is 7-ethyl-10-hydroxycamptothecin (SN38), which is synthesized as follows.

[0110]

[0111] Wherein, m=3-200, n=3-300.

[0112] Add 240mg of 2-(N,N-diethylamino)ethyl methacrylate, 3.9mg of ethyl 2-isobromobutyrate, 40mg of pentamethyldiethylenetriamine, 10mg of cuprous bromide, and 1mL of DMF After entering the polymerization bottle, nitrogen gas was continuously passed through for 30 minutes to remove oxygen. Then seal and react at 40°C for 4 hours. Under the protection of argon, d...

Embodiment 3

[0115] An embodiment of the application of the N-oxide-based tertiary amine polymer as a macromolecular drug includes synthesizing the macromolecular drug itself as a macromolecular backbone structure. More specifically, in one embodiment, a nitrogen mustard polymer macromolecular drug of N-oxide polyethyleneimine (OPEI) (OPEI-Cl) is obtained.

[0116] Take 1.16 g of branched polyethyleneimine (Aldrich) with a weight average molecular weight of 25000 g / mol and dissolve it in 10 mL of formamide, and add 2.5 mL of propylene oxide in an ice-water bath. Stirring was continued overnight at 0°C, the resulting solution was dialyzed in water, and the dialysate was freeze-dried to obtain:

[0117]

[0118] Add 0.14g of the above product to 3mL of 30% hydrogen peroxide aqueous solution, stir at room temperature for 6 hours, then dialyze the water phase, and freeze-dry the dialyzate to obtain the N-oxidized product:

[0119]

[0120] Take 0.1 g of the above product, add 2 mL of fo...

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Abstract

The invention discloses application of an N-oxidized tertiary amine containing polymer as a medicine or a carrier. The invention discloses application of the N-oxidized tertiary amine containing polymer as an anti-tumor medicine, an anti-tumor medicine carrier or a gene delivery carrier. The polymer has a structural frame as shown in the specification, in the formula, A1 is a fragment with an N-oxide structural unit; A2 is a fragment for connecting medicine molecules, a fragment with the N-oxide structural unit, or a fragment connected with medicine molecules; x=0-1, n0=3-300, m=3-300, and n=3-300. The N-oxidized tertiary amine containing polymer disclosed by the invention is good in both water solubility, biocompatibility and blood shielding property, can be rapidly taken into cells and can be fed into a tumor anoxia area, and thus by adopting the polymer as a carrier, medicines can be effectively delivered to the tumor anoxia area, and efficient anti-tumor functions can be brought into play. The N-oxidized tertiary amine containing polymer is an excellent medicine delivery carrier material.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of a polymer containing an N-oxidized tertiary amine structure as a drug or a carrier. Background technique [0002] Many drug molecules are poorly soluble in water, making direct injection difficult. Drug delivery using hydrophilic polymers as delivery carriers can increase the water solubility of insoluble drugs, reduce the toxic and side effects of drug molecules, improve the bioavailability of drugs and improve the efficacy. This polymer carrier needs to have high hydrophilicity itself or be modified with a hydrophilic group to avoid immune system clearance in the body and prolong the half-life of the blood, so that it can be absorbed through the super-permeability and accumulation of tumor tissue (EPR effect). Enriched in the tumor to achieve better curative effect and lower side effects. [0003] Poly(2-hydroxypropyl(meth)acrylamide) (PHPMA) and polyethyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/58A61K48/00C12N15/87A61K31/704A61K31/4745A61K31/12A61K31/519A61K31/4375A61K31/337
CPCA61K31/12A61K31/337A61K31/4375A61K31/4745A61K31/519A61K31/704A61K48/0041C12N15/87
Inventor 申有青钟寅
Owner HAINAN PULIN PHARMA
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