PH-sensitive hyaluronic acid nano drug-loading particles targeting atherosclerosis and preparation method thereof

A technology for atherosclerosis and hyaluronic acid, which is applied in pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc., can solve the problem of low carboxyl group, all-trans retinoic acid accompanied by inflammatory reaction and other problems to avoid accumulation, improve intracellular internalization, and achieve good reproducibility.

Inactive Publication Date: 2019-10-22
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Due to the irritating carboxyl group and its low water solubility, the subcutaneous administration of ATRA is often accompanied by an inflammatory response, which poses a challenge for intravenous administration, so designing an effective ATRA delivery system appears to be a challenge. It is necessary to design formulations that enhance the efficacy of anti-atherosclerotic treatments

Method used

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  • PH-sensitive hyaluronic acid nano drug-loading particles targeting atherosclerosis and preparation method thereof
  • PH-sensitive hyaluronic acid nano drug-loading particles targeting atherosclerosis and preparation method thereof
  • PH-sensitive hyaluronic acid nano drug-loading particles targeting atherosclerosis and preparation method thereof

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preparation example Construction

[0037] A preparation method for pH-sensitive hyaluronic acid nano drug-loaded particles targeting atherosclerosis, comprising the following steps:

[0038] 1) A linker having a terminal hydrazine group is covalently bonded to hyaluronic acid to obtain a hyaluronic acid derivative;

[0039] 2) Based on the hyaluronic acid derivative, the aldehyde compound containing the hydrophobic chain is grafted to the hyaluronic acid derivative through the terminal hydrazine group to obtain a pH-sensitive hyaluronic acid copolymer containing a hydrazone bond;

[0040] 3) Encapsulate the hydrophobic anti-atherosclerotic drug into the hydrophobic core of the pH-sensitive hyaluronic acid copolymer to obtain the pH-sensitive hyaluronic acid nano drug-loaded particles targeting atherosclerosis.

[0041] In step 1), the linker with a terminal hydrazine group is dihydrazide; in step 3), the hydrophobic drug can be selected from anti-atherosclerotic drugs, statin drugs, and anti-inflammatory drugs....

Embodiment 1

[0053] Using low molecular weight hyaluronic acid (about 10000Da) as raw material, a pH-sensitive hyaluronic acid copolymer HR (substitution degree of all-trans retinal is 7%) was synthesized.

[0054] 1) Synthesis of hyaluronic acid-modified adipic dihydrazide derivatives: 200 mg of hyaluronic acid (HA, molar mass about 10,000 Da) was dissolved in 50 mL of deionized water to obtain hyaluronic acid with a concentration of 4 mg / mL. 10 times mole of adipic hydrazide (ADH) was added to the solution, stirred at room temperature (250 rpm) for 30 min, and 0.1N HCl was added to adjust the pH value of the reaction mixture to 4.75. Then 96 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) in solid form was added to the mixture to start the reaction. Stir at room temperature for 1 h, and add 0.1M HCl in time to maintain the pH at 4.75. Finally, an appropriate amount of 0.1M sodium hydroxide solution was added to adjust the pH value to 7.0 to terminate the reac...

Embodiment 2

[0059] Using low molecular weight hyaluronic acid (about 10000Da) as raw material, a pH-sensitive HR polymer (substitution degree of all-trans retinal is 8%) was synthesized.

[0060] 1) Synthesis of hyaluronic acid-modified adipic dihydrazide derivatives: 200 mg of hyaluronic acid (HA, molar mass about 10,000 Da) was dissolved in 50 mL of deionized water to obtain hyaluronic acid with a concentration of 4 mg / mL. 10 times mole of adipic hydrazide (ADH) was added to the solution, stirred at room temperature (250 rpm) for 30 min, and 0.1N HCl was added to adjust the pH value of the reaction mixture to 4.75. Then 96 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) in solid form was added to the mixture to start the reaction. Stir at room temperature for 1 h, and add 0.1M HCl in time to maintain the pH at 4.75. Finally, an appropriate amount of 0.1M sodium hydroxide solution was added to adjust the pH value to 7.0 to terminate the reaction. The resulti...

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Abstract

The invention discloses a preparation method of pH-sensitive hyaluronic acid nano drug-loading particles targeting atherosclerosis, and belongs to the technical field of new drug preparations. The preparation method comprises the following steps: 1) covalent bonding of a bridging agent having terminal hydrazine groups to hyaluronic acid is carried out to obtain a hyaluronic acid derivative; 2) analdehyde compound containing a hydrophobic chain is grafted to the hyaluronic acid derivative through a terminal hydrazine group to obtain a pH-sensitive hyaluronic acid copolymer containing a hydrazone bond; and 3) a hydrophobic anti-atherosclerosis drug is encapsulated into the hydrophobic core of the pH-sensitive hyaluronic acid copolymer. The invention also discloses pharmaceutical particles thereof. Biodegradable and biocompatible materials are used in the invention, and are metabolized and excreted through normal physiological pathways. The vector has multi-targeting property. By specific binding of Hyaluronic acid to CD44 and Stabilin-2 receptors overexpressed on the atherosclerotic plaque cell surface, the carrier can respond to an acidic inflammatory environment to release the drug and achieve the combined treatment of anti-oxidant drugs and anti-atherosclerosis drugs.

Description

technical field [0001] The invention belongs to the technical field of new drug preparations, and in particular relates to pH-sensitive hyaluronic acid nano drug-loaded particles targeting atherosclerosis and a preparation method thereof. Background technique [0002] Atherosclerosis (AS) is a chronic inflammatory disease that is still the leading cause of death in the elderly worldwide. The initial lesion is the oxidation of low-density lipoprotein (LDL) in the intima by reactive oxygen species (ROS), leading to inflammation and endothelial dysfunction. Thus, oxidative stress appears to accelerate atherosclerosis-leading inflammation by participating in the initiation of lipid peroxidation (oxLDL) in the delivery of inflammatory signals. Recent studies have shown that inflammation and oxidative stress are key factors in halting the progression of atherosclerosis and preventing cardiovascular complications and should be controlled. [0003] The traditional treatment for at...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/36A61K45/00A61P9/10
CPCA61K9/5161A61K45/00A61P9/10
Inventor 黄宁平倪哈孙宁聪
Owner SOUTHEAST UNIV
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