Use of Polyethylene Glycol Derivatives-Small Molecule Drug Conjugate Polymer Micelle in Inflammation Targeted Drug Delivery System

A technology of drug conjugates and polyethylene glycol, which is applied in the field of medicine, can solve the problems of non-evaluable use, drug leakage, poor water solubility, etc., and achieve the effect of increasing accumulation and increasing concentration

Active Publication Date: 2020-03-27
SICHUAN UNIV
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Problems solved by technology

However, the biggest disadvantages of free glucocorticoids (GCs) drugs include: poor water solubility, repeated administration, lack of targeting, and severe systemic side effects after long-term use, so patients' compliance is poor
However, these nano-drug delivery systems also have the following problems: (1) liposomes and ordinary physically encapsulated micelles are unstable in the blood circulation in vivo, the main reasons are: firstly, they will be phagocytized by the reticuloendothelial system; secondly, It will interact with many components in plasma (albumin, lipoprotein, IgG, etc.); moreover, it is easy to cause early leakage of drugs after being diluted by blood; (2) due to the above-mentioned liposomes, nanoparticles and ordinary physical encapsulation Due to the uncontrollable drug release behavior of the micelles in the body, it is difficult to ensure the full play of its curative effect
(3) The drug loading capacity of ordinary nano-drug loading system is low, which limits its clinical application
[0006] In the prior art, CN201310756002.9 and CN2013755517.7 use hydrazone bonds to connect polyethylene glycol monomethyl ether-polylactic acid, curcumin with single-terminal phenolic hydroxyl carbonylation and curcumin with double-terminal phenolic hydroxyl carbonylation, respectively, to prepare pH-sensitive curcumin drug-loaded micelles (single-chain) and pH-sensitive curcumin drug-loaded micelles (double-chain), however, these two drug-loaded micelles have the following problems: ①PLA must be added to the chemical formula to However, my country’s FDA has not approved the use of polylactic acid (PLA) as an excipient for intravenous injection, and its use may cause unassessable risks; ②The drug loadings of the two drug-loaded micelles are different More than 15% and 5%, the clinical use value needs to be improved
According to research, when the molecular weight of macromolecular drugs is lower than 40,000, the clearance rate of the macromolecular drugs is very high, so it is difficult for such conjugates to achieve the purpose of tumor targeting
[0008] At present, there is no report on polymer micelles targeting inflammation using hydrazone-linked pH-sensitive polyethylene glycol derivatives-small molecule drug conjugates

Method used

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  • Use of Polyethylene Glycol Derivatives-Small Molecule Drug Conjugate Polymer Micelle in Inflammation Targeted Drug Delivery System
  • Use of Polyethylene Glycol Derivatives-Small Molecule Drug Conjugate Polymer Micelle in Inflammation Targeted Drug Delivery System
  • Use of Polyethylene Glycol Derivatives-Small Molecule Drug Conjugate Polymer Micelle in Inflammation Targeted Drug Delivery System

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] First, β-aminoethanol (7.37 g, 0.12 mol) was protected with BOC anhydride (32.72 g, 0.15 mol) to obtain BOC-aminoethanol. Next, BOC-aminoethanol (0.88 g, 5 mmol) was subjected to two-step ring-opening copolymerization with EO (100 mL, 1.98 mol) and AGE (30.1 g, 0.26 mol), respectively, to obtain BOC-N-(EO)n -(AGE)m. Then BOC-N-(EO)n-(AGE)m removes the BOC protecting group in trifluoroacetic acid / dichloromethane (v / v: 5 / 2) solution to obtain the product animo-(EO)n- (AGE)m. The above product animo-(EO)n-(AGE)m (6.72 g, 7.53 mmol C=C) was dissolved in THF, and further mixed with methyl thioglycolate under the catalysis of azobisisobutyronitrile (AIBN) in Reflux reaction under nitrogen protection for 5h, the product animo-(EO)n-(AGE)m-OCH was obtained after rotary evaporation 3 . Then all the above products were reacted with hydrazine hydrate (37.7g, 36.6 mL, 753 mmol) under reflux in THF solution for 7 h, and the product animo-(EO)n-(AGE)m-OCH was obtained by rotary e...

Embodiment 2

[0078] First, β-aminoethanol (7.37 g, 0.12 mol) was protected with BOC anhydride (32.72 g, 0.15 mol) to obtain BOC-aminoethanol. Next, BOC-aminoethanol (0.88 g, 5 mmol) was subjected to two-step ring-opening copolymerization with EO (100 mL, 1.98 mol) and AGE (30.1 g, 0.26 mol), respectively, to obtain BOC-N-(EO)n -(AGE)m. Then BOC-N-(EO)n-(AGE)m removes the BOC protecting group in trifluoroacetic acid / dichloromethane (v / v: 5 / 2) solution to obtain the product animo-(EO)n- (AGE)m. The above product animo-(EO)n-(AGE)m (6.72 g, 7.53 mmol C=C) was dissolved in THF, and further mixed with methyl thioglycolate under the catalysis of azobisisobutyronitrile (AIBN) in Reflux reaction under nitrogen protection for 5h, the product animo-(EO)n-(AGE)m-OCH was obtained after rotary evaporation 3 . Then all the above products were reacted with hydrazine hydrate (37.7g, 36.6 mL, 753 mmol) under reflux in THF solution for 7 h, and the product animo-(EO)n-(AGE)m-OCH was obtained by rotary e...

Embodiment 3

[0080] Accurately weigh 30 mg of the above two pH-sensitive polyethylene glycol derivatives-small molecule drug conjugates, dissolve them in 7.5 ml of double-distilled water, and then stir in the same direction at 25°C for 0.5 hours to obtain 4 Polymer micelles of mg / ml pH-sensitive polyethylene glycol derivative-small molecule drug conjugates.

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Abstract

The invention provides an application of pH (potential of hydrogen) sensitive polyethylene glycol derivative and small molecule drug conjugate in a formula (I) and polymer micelle thereof as an inflammatory targeting delivery system and a preparation method of the pH sensitive polyethylene glycol derivative and small molecule drug conjugate. A portion B includes a small molecule drug D with inflammatory disease treating activity, and a portion A includes a polyethylene glycol derivative carrier system. The pH sensitive polyethylene glycol derivative and small molecule drug conjugate polymer micelle has good inflammatory targeting property, the concentration of the drug in the portion B at a low-pH inflammatory site can be remarkably increased, or staying time of the drug at the low-pH inflammatory site can be prolonged, or the anti-inflammatory effect of the drug can be enhanced.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to the use of polymer micelles of pH-sensitive polyethylene glycol derivatives-small molecule drug conjugates linked by hydrazone bonds as an inflammation targeting delivery system. . Background technique [0002] Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting multiple joints in a symmetrical pattern, characterized by an inflammatory process in the synovium that culminates in destruction of articular cartilage, periarticular bone, and ultimately Altered joint function and integrity, in addition to joint symptoms, many patients also have systemic and extra-articular inflammation. In RA patients, disease-related disability usually occurs early, with approximately 35% of patients prematurely incapacitated within 10 years of being diagnosed with RA. In addition, studies have found that the life expectancy of RA patients is shorter than that of normal people. At present, t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K31/573A61K31/704A61P29/00A61P35/00
CPCA61K31/573A61K31/704
Inventor 孙逊李春红张志荣龚涛
Owner SICHUAN UNIV
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