Glycyrrhetinic acid-modified lipid, liver targeting liposome, micelle and compound, and their preparation method

Abstract

The invention belongs to the medical field, and specifically, relates to a novel glycyrrhetinic acid-modified lipid, a liver targeting liposome, a micelle and a compound, and their preparation method. The novel glycyrrhetinic acid-modified lipid contains glycyrrhetinic acid as a liver targeting mediating material, and is utilized as a membrane material of a liposome or a micelle to enable the liposome or the micelle to have liver targeting activity. Specifically, the novel glycyrrhetinic acid-modified lipid is prepared from raw materials of glycyrrhetinic acid and a phosphatide or cholesterol by a reaction in a condensing agent-containing solvent. The invention also provides a liver targeting liposome carrier and a liver targeting micelle carrier mediated by glycyrrhetinic acid. The liver targeting liposome carrier is prepared from the novel glycyrrhetinic acid-modified lipid, cholesterol and a phosphatide. The liver targeting micelle carrier is prepared directly from the novel glycyrrhetinic acid-modified lipid. The invention also provides a liver targeting liposome compound or a liver targeting micelle compound comprising an encapsulation layer of the liver targeting liposome carrier and the liver targeting micelle carrier. Therefore, glycyrrhetinic acid mediation-related drugs can be targeted to hepatic cells; toxicity of the glycyrrhetinic acid mediation-related drugs on normal tissue is reduced; and drug effects of prevention and treatment of liver complaints are improved.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to glycyrrhetinic acid-modified lipids, liver-targeted liposomes, micelles and complexes and a preparation method. Background technique [0002] At present, liver diseases such as liver cancer and hepatitis are still one of the major diseases that endanger human health. A lot of work has been done in the vast scientific research work, but the prevention and treatment effect is still not satisfactory. Liver disease is still one of the powerful challenges facing the medical field. [0003] The treatment of hepatitis is mainly to use two or more antiviral drugs in combination. Since most patients with refractory hepatitis are in a state of immune tolerance, the curative effect of using only one drug is relatively poor. Different drugs are selected for different disease sites, so that the drugs can exert their efficacy at different sites at the same time. In addition, the body's own...

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Problems solved by technology

Due to the introduction of stearyl alcohol in liposomes, its biocompatibility is difficult to guarantee

[0009] 2. Glycyrrhetinic acid-modified liposomes recorded in the literature are easily phagocytized by the mononuclear macrophage system, and it is difficult to reach hepatic parenchymal cells in large quantities, so they cannot be used as excellent carriers for drugs based on hepatic parenchymal cell diseases

[0010] 3. In the glycyrrhetinic acid-modified liposomes recorded in the literature, the molar content of directing molecules incorporated is up to 10%. If the proportion of incorporation is further increased, the obtained liposomes are white turbid liquid, and a large amount of flocculation will appear in a short time. Precipitate, unable to produce stable liposomes with high glycyrrhetinic acid targeting ligand content

[0011] 4. The average particle size of glycyrrhetinic acid surface-modified liposomes is between 65-79nm, and the particle size range is narrow, which is difficult to meet the particle size requirements of different liver diseases

[0012] 5. The glycyrrhetinic acid surface-modified liposomes recorded in the literature, the phospholipid used in the prescription is soybean phospholipid, which is prepared by injection method, which cannot meet the high-efficiency entrapment of drugs with different properties such as hydrophilic drugs, gene proteins and other macromolecular drugs

The main reason why macromolecular drugs such as gene proteins cannot be efficiently entrapped is that macromolecules such as gene proteins often have positive charges, and soybean phospholipids are neutral phospholipids, which cannot be efficiently entrapped by electrostatic adsorption; in addition, the preparation of injection method The encapsulation efficiency of macromolecular drugs such as hydrophilic drugs and gene proteins is relatively low.

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