Poloxamer-carboxylic acid drug conjugate and preparation method and application thereof

A technology of carboxylic acid drugs and poloxamers, which is applied in pharmaceutical formulations, medical preparations of non-active ingredients, powder delivery, etc., can solve the problems of fast degradation, lack of drug release effect, and difficult chemical reactions of polymers And other issues

Inactive Publication Date: 2011-03-30
CHINA PHARM UNIV
View PDF0 Cites 17 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Some polymer-drug conjugates are now in the research stage, but these conjugates still have the following defects: most synthetic polymers have more or less defects such as hemolysis, heat source reaction and permeability; biological macromolecules Various water-soluble proteins are easily hydrolyzed by proteases, and the degradation rate in the body

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Poloxamer-carboxylic acid drug conjugate and preparation method and application thereof
  • Poloxamer-carboxylic acid drug conjugate and preparation method and application thereof
  • Poloxamer-carboxylic acid drug conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0022] 1. Preparation of active intermediate ester

[0023] Dissolving carboxylic acid drugs in a suitable organic solvent, adding catalyst a and catalyst b, and performing condensation reaction under temperature control to obtain an active intermediate ester.

[0024] 2. Preparation of poloxamer-carboxylic acid drug conjugates

[0025] a. Dissolve a certain amount of poloxamer and catalyst c in an appropriate solvent, slowly add the organic solution of the above-mentioned intermediate ester into the poloxamer solution dropwise at 0-4°C, and control the temperature until the reaction is complete.

[0026] b. The above reaction solution is dialyzed in an appropriate organic solvent, the dialysate is constantly replaced, and the drug concentration in the external dialysate is detected at the same time, until the free drug is completely separated by dialysis, add 5 to 10 times the volume of water to the product in the dialysis bag, Continue dialysis in distilled water to remove ...

Embodiment 1

[0044] Example 1: Synthesis of Poloxamer-Methotrexate

[0045] Take 10mmol of methotrexate, 15mmol of dicyclohexylcarbodiimide (DCC), and 15mmol of hydroxysuccinimide (NHS), dissolve them in 30ml of N,N-dimethylformamide, protect them from light and nitrogen, React in an ice bath for 30 minutes, then rise to room temperature and react for 24 hours. After the reaction, centrifuge to remove the precipitate to obtain an organic solution of the intermediate ester; dissolve 10 mmol poloxamer and 15 mmol 4-lutidine (DMAP) in 20 ml N, N -In dimethylformamide, slowly drop the intermediate ester solution into the above solution, and react at 50°C for 24 hours; after the reaction, transfer the reaction solution to a dialysis bag, and dialyze in N,N-dimethylformamide, Remove free drugs and catalysts, and change the dialysate continuously until the presence of drugs is no longer detected in the dialysate; dilute the dialysate in the dialysis bag by 5 times, add it to another dialysis bag ...

Embodiment 2

[0046] Embodiment 2: the synthesis of poloxamer-all-trans retinoic acid

[0047] Take 10mmol all-trans retinoic acid, 20mmol dicyclohexylcarbodiimide (DCC), 20mmol hydroxysuccinimide (NHS), dissolve in 30ml N,N-dimethylformamide, protect from light and nitrogen , react in ice bath for 30min, then rise to room temperature and react for 24h. After the reaction is over, centrifuge to remove the precipitate to obtain an organic solution of intermediate ester; dissolve 5mmol poloxamer and 20mmol 4-lutidine (DMAP) in 20ml dichloro In the methane solution, the intermediate ester solution was slowly added dropwise to the above solution, and reacted at room temperature for 24 hours; after the reaction, the reaction solution was transferred to a dialysis bag, and dialyzed in N,N-dimethylformamide to remove free drugs and catalysts , and constantly change the dialysate until the presence of drugs is no longer detected in the dialysate; dilute the dialysate in the dialysis bag by 5 times,...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Particle sizeaaaaaaaaaa
Login to view more

Abstract

The invention discloses a poloxamer-carboxylic acid drug conjugate and a preparation method and application thereof. The conjugate is formed by directly linking the carboxyl of the carboxylic acid drug with the carboxyl of the poloxamer by the ester bond in the presence of a catalyst. The conjugate is the compound in the general formula (i) or (ii). Compared with the original carboxylic acid drugs, the conjugate has greatly improved drug solubility, enhanced pharmacological effects, reduced adverse reaction and higher safety. By utilizing the hydrophobic carboxylic acid drug, the conjugate can enhance the hydrophobicity of the poloxamer and greatly improve the amphipathy of the poloxamer, thus being capable of forming stable micellar structure under waterborne environment. As the drug carrier, the conjugate can complete further encapsulation of the drugs and can meet different release requirements by controlling the chemical grafted amount and the physical encapsulation amount or realize combined therapy of the drugs by physically embedding other pharmaceutically active drugs. The invention has simple preparation method, mature process and high yield and is suitable for industrialproduction.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a poloxamer-carboxylic acid drug conjugate with good physiological activity and biodegradability as a drug carrier or a polymer prodrug, and the invention also relates to the conjugate The preparation method and its application. Background technique [0002] In drug research, it is found that nearly 40% of drugs are insoluble in water, which easily leads to problems such as difficult preparation of preparations and low bioavailability. A hot and difficult point. [0003] In the preparation process, technologies such as microemulsion, liposome and solid dispersion are often used, or methods such as preparing the drug into a salt, adding a latent solvent, adding a co-solvent, and adding a surfactant are used to solubilize. However, as a drug carrier, liposomes still have disadvantages such as low encapsulation efficiency, unsatisfactory target distribution, and poor stabi...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): A61K47/48A61K47/34A61K9/19A61K47/10A61K47/60
Inventor 周建平姚静方正杰任瑾侯琳
Owner CHINA PHARM UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap