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Phospholipid compound of hydrophilic drugs as well as pharmaceutical composition and application of phospholipid compound

A technology of phospholipid compounds and hydrophilic drugs, applied in the field of medicine, can solve problems such as poor lipophilicity and poor transmembrane ability

Active Publication Date: 2016-02-03
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Therefore, hydrophilic drugs have the following disadvantages in clinical use: poor lipophilicity and poor transmembrane ability
[0009] The common structural design method in the literature is to replace the hydrophilic head of the phospholipid with a hydrophilic drug, or connect it to the hydrophilic head of the phospholipid, so that the drug is chemically bonded to the phospholipid, and all or part of the tail fat chain of the phospholipid is retained. The lipophilicity of the drug is improved, but the prodrug molecule is not a phosphorylcholine structure because the hydrophilic head is not, and the surface structure of the assembled liposome is composed of hydrophilic drugs, which are compatible with the phosphorylcholine structure of the phospholipids on the cell membrane surface completely different

Method used

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  • Phospholipid compound of hydrophilic drugs as well as pharmaceutical composition and application of phospholipid compound
  • Phospholipid compound of hydrophilic drugs as well as pharmaceutical composition and application of phospholipid compound
  • Phospholipid compound of hydrophilic drugs as well as pharmaceutical composition and application of phospholipid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Synthesis of Gemcitabine Derivatives Protected by tert-Butoxycarbonyl (t-BOC)

[0132] Synthesize 4-N-BOC-3'-O-BOC-gemcitabine (4- N-3'-O-Bis(tert-Butoxycarbonyl) gemcitabine, 1), 3'-O-BOC-5'-O-BOC-gemcitabine (3', 5'-O-Bis(tert-Butoxycarbonyl) gemcitabine, 2), 4-N-BOC-5'-O-Boc-gemcitabine (4-N-5'-O-Bis(tert-Butoxycarbonyl) gemcitabine, 3).

Embodiment 2

[0134] Synthesis of two (gemcitabine-5'-succinate) phosphatidylcholine compounds (see the synthetic route figure 1 )

[0135] Dissolve 1g of 4-N-BOC-3′-O-BOC-gemcitabine in dichloromethane, add 1.5g of pyridine, 2g of succinic anhydride, react at 40°C for 8 hours, filter, remove the solvent by rotary evaporation, and obtain 4- N-BOC-3'-O-BOC-gemcitabine-5'-succinic acid monoester 0.85 g. Dissolve 0.8g of 4-N-BOC-3′-O-BOC-gemcitabine-5′-succinic acid monoester in dimethyl sulfoxide, add CDI0.5g, activate for 1h, add GPC0.4g and DBU0.5g, room temperature After 24 hours of reaction, a precipitate was precipitated in cold ether, and separated by column chromatography to obtain 0.66 g of bis(4-N-BOC-3'-O-BOC-gemcitabine-5'-succinate)phosphatidylcholine. Bis(4-N-BOC-3′-O-BOC-gemcitabine-5′-succinate) phosphatidylcholine was dispersed in chloroform, TFA was added dropwise at 0°C, raised to room temperature and reacted for 3 hours, desorption After removing the BOC protecting group...

Embodiment 3

[0139] Synthesis of two (gemcitabine-4-N-succinyl) phosphatidylcholine compounds (see the synthetic route figure 2 )

[0140] Dissolve 1 g of 3′-O-BOC-5′-O-BOC-gemcitabine in dichloromethane, add 1.5 g of pyridine and 2 g of succinic anhydride, react at 0°C for 8 hours, filter, remove the solvent by rotary evaporation, and separate by column chromatography to obtain 3 '-O-BOC-5'-O-BOC-gemcitabine-4-N-succinic acid 0.81 g. Dissolve 0.8g of 3′-O-BOC-5′-O-BOC-gemcitabine-4-N-succinic acid in dimethylsulfoxide, add 0.5g of CDI, activate for 1h, add 0.4g of GPC and 0.5g of DBU, and keep at room temperature After 24 hours of reaction, a precipitate was precipitated in cold ether, and separated by column chromatography to obtain 0.56 g of bis(3'-O-BOC-5'-O-BOC-gemcitabine-4-N-succinyl)phosphatidylcholine. Bis(3′-O-BOC-5′-O-BOC-gemcitabine-4-N-succinyl)phosphatidylcholine was dispersed in chloroform, and TFA was added dropwise at 0°C, raised to room temperature and reacted for 3 hour...

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Abstract

The invention discloses a phospholipid compound of hydrophilic drugs as well as a pharmaceutical composition and application of the phospholipid compound. The pharmaceutical composition of the phospholipid compound of the hydrophilic drugs or a combined pharmaceutical composition of the phospholipid compound of the hydrophilic drugs and a pharmacologically acceptable carrier; and the pharmaceutical composition is in the form of a liquid preparation, a solid preparation, a semisolid preparation, a capsule, granules, a gel or an injection. The pharmaceutical composition is in the form of liposome nanoparticles prepared from the phospholipid compound of the hydrophilic drugs or the phospholipid compound of the hydrophilic drugs and adjuvants, and the pharmaceutical composition is 10-1000nm in grain size. The phospholipid compound of the hydrophilic drugs and the liposome nanoparticles thereof can serve as a liquid preparation, a solid preparation, a semisolid preparation, a sterilized preparation and a sterile preparation; and the phospholipid compound of the hydrophilic drugs and the liposome nanoparticles thereof are low in toxicity, and are applicable to the efficient treatment of various tumors and the like.

Description

technical field [0001] The invention relates to a phospholipid compound of a hydrophilic drug with anti-tumor effects, its pharmaceutical composition and application, and relates to the technical field of medicine. Background technique [0002] Hydrophilic drugs can be formulated into solutions orally or administered by injection. However, due to their excellent hydrophilicity and poor lipophilicity, these drugs often cannot or are difficult to pass through the cell membrane and enter cells by passive diffusion, resulting in limited drug efficacy. Some or even most of the drug is excreted as the original drug. [0003] Nucleoside anti-metabolite anticancer drugs are water-soluble analogues of deoxycytidine. Due to their excellent water solubility and poor lipophilicity, they cannot pass through the cell membrane and enter cells by passive diffusion. Gemcitabine (2'-deoxy-2', 2'-difluorocytidine) is a pyrimidine nucleoside analogue developed by Eli Lilly and Company. Gemcit...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K9/127A61K9/14A61P35/00
Inventor 李新松徐晨杜亚伟凌龙兵侯永鹏
Owner SOUTHEAST UNIV
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