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Galactose ligands and their application in liver-targeted liposomes

A technology of galactose ligand and phospholipid, which is applied in the field of medicine, can solve the problems of lowering liposome zeta potential, liposome instability, and many steps in chemical synthesis, and achieves good biodegradability and good biocompatibility The effect of simple synthesis steps

Inactive Publication Date: 2017-12-29
程怡
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 1. The preparation methods of galactose ligand molecules recorded in the literature are all chemical methods. The reagents and reaction media used are mostly toxic, and it is difficult to remove them after the reaction. It is difficult for the product to meet the quality requirements of injection preparations
[0009] 2. There are many steps in the chemical synthesis method, and there are many by-products, and the purification of the product is difficult, which can only meet the requirements of a small amount of preparation in the laboratory, and is not suitable for industrial production
[0010] 3. The synthesis yield is low, and the highest yield of the chemical synthesis method is only about 10% at present
[0011] 4. The reagents used in the chemical synthesis method and the by-products produced by the reaction are generally difficult to recycle and reuse, causing certain pollution to the environment
Therefore, it is difficult for ligand molecules synthesized by existing methods to adjust the ability to be recognized by ASGPR
At the same time, the galactose ligand molecule mentioned in the background technology is positively charged, and when it is coupled with negatively charged phospholipids to prepare liposomes, it will reduce the ZETA potential of liposomes, resulting in unstable liposomes, making the preparation of liver target When applied to liposomes, the yield is low

Method used

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  • Galactose ligands and their application in liver-targeted liposomes
  • Galactose ligands and their application in liver-targeted liposomes
  • Galactose ligands and their application in liver-targeted liposomes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Embodiment 1: Reaction raw material: cholesterol, divinyl sebacate, lactitol

[0070] Step 1: Take a 10mL Erlenmeyer flask with a stopper, add 0.224mmol of divinyl sebacate and 0.025mmol of cholesterol, dissolve it with 5mL of dehydrated isooctane ultrasonically, shake it in an air bath constant temperature oscillator for 30min, and add 7.7mg of enzyme RCL / mL reaction system, start the reaction, the reaction temperature is 35°C, after the reaction for 11.47h, the enzyme is recovered by filtration, the filtrate is low-temperature vacuum to remove isooctane, and then ultrasonically dissolved with 20 times the amount of methanol, and placed at 0°C for 24h. When a large amount of crystals were precipitated, low-temperature rapid suction filtration was performed to obtain the intermediate product (II) as a white powdery solid with a yield of 92%. The reaction process is shown below:

[0071]

[0072] Structural characterization of intermediate product (II):

[0073] MS...

Embodiment 2

[0081] Embodiment 2: fully according to the method of embodiment 1, just change the divinyl sebacate used into H 2 C=CH-OOC-(CH2) 11 -COO-CH=CH 2 , the enzyme in step 1 was changed to Chirazyme L-2 lipase, with an amount of about 5 mg / mL, and the solvent was changed to acetone; and the enzyme in step 2 was changed to adopt commercial immobilized enzyme Novozym435, with an amount of about 30 mg, and the solvent was acetone: Pyridine 1:5; The product obtained is in the form of a white waxy solid with a total yield of 83.26%, and the structure is:

[0082]

[0083] The structure of the target product is characterized by:

[0084] MS: [M+Na]+: 961.3; 13 C NMR (101MHz, Pyridine-d5) δ173.06, 172.40, 139.40, 122.16, 105.88, 84.38, 79.08, 76.42, 74.57, 73.21, 72.35, 72.28, 71.08, 69.76, 69.23, 65.11, 61.205, 66 ,49.62,41.85,39.31,39.09,37.97,36.61,36.19,35.85,35.39,34.15,33.75,31.50,31.40,29.14,29.05,28.90,28.74,27.85,27.58,24.77,24.59,23.85,23.51,22.29,22.05 , 20.64, 18.74, 1...

Embodiment 3

[0085] Embodiment 3: completely according to the method and condition of embodiment 1, just change the divinyl sebacate used into H 2 C=CH-OOC-(CH 2 ) 13 -COO-CH=CH 2 , the enzyme in step 1 was changed to Lipase QLM (Lipase QLM, a kind of lipase), the dosage was about 10 mg / mL, and the solvent was changed to petroleum ether; and the enzyme in step 2 was changed to commercial immobilized enzyme Novozym435 , the dosage is about 35 mg, and the solvent is pyridine+THF (1:1); the obtained product is in the form of a white waxy solid, with a total yield of 80.59%, and the structure is:

[0086]

[0087] Structural characterization of the target product:

[0088] MS: [M+Na]+ peak: 990.1; 13 C NMR (101MHz, Pyridine-d5) δ173.09, 172.43, 139.40, 122.17, 105.88, 84.36, 76.44, 74.59, 73.22, 72.37, 71.10, 69.77, 69.24, 66.13, 63.26, 61.21, 56.14, 4.95 ,39.30,39.09,37.97,36.60,36.19,35.85,35.38,34.16,33.76,31.50,31.40,29.23,29.10,28.93,28.75,27.85,27.57,24.78,24.60,23.84,23.50,22.28...

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Abstract

The invention relates to a galactose ligand molecule and its application in liver targeting liposome. The galactose ligand molecule is brand new, and can be used to modify liposome as a liver targeting mediated substance in order to make the liposome prepared by using the molecule have liver targeting. The galactose ligand molecule is obtained through esterification of galactosyl groups, steroidal groups and diethyl diester groups. The invention also provides a galactose ligand molecule modified liposome carrier, and a drug coating liver targeting liposome compound. The galactose ligand molecule mediation related drugs target at hepatocytes to reduce the toxicity to normal tissues and improve the hepatopathy prevention and treatment effects of drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a small-molecular-weight galactose ligand, a synthesis method thereof, and a liver-targeted liposome and a liver-targeted drug prepared by using the galactose ligand. Background technique [0002] In the development of new drugs, how to effectively target active ingredients to target cells or tissues is one of the important research topics. For example, no matter how good the pharmacological effect of a certain drug is, if it cannot reach the tissue to be treated, such as the lesion, the desired pharmacological effect cannot be achieved. In addition to local administration methods, generally, active pharmaceutical ingredients (drugs) need to be administered orally or by injection, and the drugs exert their pharmacological effects after being transported through the blood to the site of action. If the drug cannot effectively reach the treatment tissue, it is necessar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J17/00C12P33/20A61K31/7032A61K31/7024A61K9/127A61P1/16
CPCA61K47/554A61K47/555A61K47/6911C07J17/00C12P33/00
Inventor 程怡高幼衡陈宇潮郑品劲
Owner 程怡
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