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

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...

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 is relatively fast; the inherent difficulties in the chemical reaction of polymers make the synthesis conditions relatively harsh and the yield is low; the reaction usually needs to add complex linking arms, such as Amino acid or polypeptide; after chemical grafting, its release behavior is single, and the ideal drug release effect cannot be achieved, etc.

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