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PSA-TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) conjugate and application thereof

A technology of conjugates and drugs, applied in PSA‑TPGS conjugates and its application fields, can solve the problems of large differences in TPGS purity, adverse effects of preparations, and uneven purity

Active Publication Date: 2016-11-09
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More importantly, the purity of TPGS varies greatly between different batches, which not only cannot guarantee the reproducibility of the preparation, but also adversely affects the efficacy of the preparation
In addition to the limitations of low-purity TPGS in intravenous injection, due to the uneven purity, when it is used as a synthetic raw material, the impurity PEG1000 may participate in the reaction and produce by-products, which will interfere with the experimental results and cannot be accurate. judge
In addition, di-TPGS and PEG1000 in commercially available TPGS have poor antitumor activity and MDR reversal effect, which weakens the efficacy of the preparation
[0008] In addition, the critical micelle concentration (CMC) of TPGS is relatively high (0.02%, w / v), and when used as a drug carrier, there are problems such as low drug loading and poor dilution stability, so it needs to be structurally modified , reduce the CMC value

Method used

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  • PSA-TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) conjugate and application thereof
  • PSA-TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) conjugate and application thereof
  • PSA-TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) conjugate and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The synthesis of embodiment 1PSA-TPGS derivative

[0043] 1.1 The preparation method is as follows

[0044] Dissolve PSA (100mg, 0.33mmol SA monomer) in 5mL formamide by heating in a water bath at 60°C. After the system cools down to room temperature, add 80mg N-hydroxysuccinimide (0.68mmol) and 128mg 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.68mmol), after stirring for 30min under ice-water bath conditions, TPGS (100mg, 0.066mmol) dissolved in 5mL of formamide was added to the reaction system , filled with nitrogen protection, sealed, and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was diluted 2 times with distilled water, and placed in a dialysis bag (molecular weight cut off 10 kDa). The dialysis medium was water system, and the dialysis volume was 3 L. The dialysis medium was changed every 4 hours for 12 hours. After the water dialysis, the dialysis was continued with absolute ethanol, the...

Embodiment 2

[0077] Embodiment 2 film hydration method:

[0078] Accurately weigh 150mg of PSA-TPGS and 5mg of DTX in a round bottom flask, add an appropriate amount of dichloromethane, mix thoroughly by ultrasonication for 10min, remove the organic solvent by rotary evaporation under reduced pressure, and dry in vacuum overnight to remove the residual solvent to obtain dry and transparent drug film. Heat the water bath to 60°C to melt the solid skeleton, add 10 mL of water at the same temperature, and stir for 30 minutes to hydrate. Cool to room temperature and pass through a 0.22 μm filter membrane to obtain a transparent drug-loaded micellar solution. The degree of polymerization of PSA is 100, the molecular weight of PEG in TPGS is 1000, and the encapsulation efficiency is 90%.

Embodiment 3

[0079] Embodiment 3 emulsification solvent volatilization method

[0080] Accurately weigh 150 mg of PSA-TPGS into a vial, add 10 mL of water to dissolve. Dissolve 5mg of DTX in acetone, add it dropwise into the vial quickly under the condition of heating and stirring in a water bath at 40°C, and continue stirring for 10 minutes until the acetone is completely evaporated. Cool to room temperature and pass through a 0.22 μm filter membrane to obtain a transparent drug-loaded micellar solution. The degree of polymerization of PSA is 100, the molecular weight of PEG in TPGS is 1000, and the encapsulation efficiency is 92%.

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Abstract

PSA is modified on high-purity TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate), so that the CMC (critical micelle concentration) value and the hemolysis of the TPGS can be reduced; the antitumor activity can also be improved; the TPGS and lipophilic substances are jointly prepared into mixed micelle. The mixed micelle can simultaneously have the respective advantages of PSA and TPGS; firstly, the character of the necessary nutrient element of tumor of the PSA is used for actively targeting to the tumor position; then, the anti-tumor character of the TPGS is used for synergistically killing tumor cells together with medicine; the original advantages of the TPGS are maintained; meanwhile, the CMC value of the TPGS is also reduced. More importantly, the ABC (accelerated blood clearance) phenomenon of PEG carrier crossed injection can also be eliminated.

Description

technical field [0001] The invention relates to a preparation method of a PSA-TPGS conjugate and its application in treating tumors. Background technique [0002] Polyethylene glycol 1000 vitamin E succinate (TPGS) is a water-soluble derivative of vitamin E. It is formed by linking lipophilic vitamin E succinate and hydrophilic polyethylene glycol 1000 through ester bonds. The structural formula is as follows shown. [0003] [0004] In addition to being used as a pharmaceutical excipient, studies in recent years have confirmed that TPGS also has certain biological activities. In vivo and in vitro results have proved that TPGS can selectively kill tumor cells, including pancreatic cancer, breast cancer and prostate cancer, and has no effect on normal cells. . [0005] Although TPGS has strong emulsifying and solubilizing ability, synergistic anti-tumor and other advantages, the purity of TPGS currently available on the market is low, and there are still many problems in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/107A61K31/337A61K31/122A61K38/08A61P35/00
CPCA61K9/1075A61K31/122A61K31/337A61K38/08
Inventor 邓意辉宋艳志田清菁刘欣荣王旭玲苏钰清全晶晶李博群
Owner SHENYANG PHARMA UNIVERSITY
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