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Oligopeptide-based cationic lipid derivative and application thereof in pharmaceutical preparation

A technology of lipid derivatives and cations, which is applied in the direction of liposome delivery, non-effective ingredients of polymer compounds, peptides, etc., and can solve problems such as difficult control, large particle size, and blood toxicity

Inactive Publication Date: 2012-07-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, cationic polymers mainly include polyethyleneimine (PEI), poly-L-lysine (PLL), chitosan and its derivatives, polyurethane, polyamidine and dendrimer polyamidoamine (PAMAM), etc. However, the surface of cationic polymers often has excessive positive charges, and the particle size is large and difficult to control. When it enters the blood system, it will combine with negatively charged serum proteins, resulting in blood toxicity.

Method used

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  • Oligopeptide-based cationic lipid derivative and application thereof in pharmaceutical preparation
  • Oligopeptide-based cationic lipid derivative and application thereof in pharmaceutical preparation
  • Oligopeptide-based cationic lipid derivative and application thereof in pharmaceutical preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of 1,5-n-octanol-glutamic acid-lysine

[0041] Glutamic acid (2.9 g, 19.7 mmol) and p-toluenesulfonic acid (4.1 g, 23.7 mmol) were dissolved in 60 mL of toluene and refluxed for 1 h. Add n-octanol (5.1 g, 39.4 mmol) and reflux for 12 h. After the reaction, the toluene was distilled off under reduced pressure. The concentrate was dissolved in an appropriate amount of dichloromethane, washed with 5% sodium bicarbonate solution (10mL×2), washed with water (10mL×1), the organic layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from methanol to obtain a white powdery solid 1 , 5-n-octanol-glutamic acid (OC 2 -Glu). Boc-L-Lys(Boc)-OH (2.9g, 8.4mmol), N,N-dicyclohexylcarbodiimide (DCC, 5.1g, 25mmol) and N-hydroxysuccinimide (NHS, 1.5g, 12.6mmol) was dissolved in 100mLDMF, stirred at room temperature for 3h; OC 2 -Glu (3.1 g, 8.4 mmol) was added to the above mixed solution and stirred at room temperature for 12 h. Filter off DCU, ...

Embodiment 2

[0045] Preparation of 1,5-n-decyl alcohol-glutamic acid-lysine

[0046] Glutamic acid (2.9 g, 19.7 mmol) and p-toluenesulfonic acid (4.1 g, 23.7 mmol) were dissolved in 60 mL of toluene and refluxed for 1 h. Add n-decyl alcohol (6.2 g, 39.4 mmol) and reflux for 12 h. After the reaction, the toluene was distilled off under reduced pressure. The concentrate was dissolved in an appropriate amount of dichloromethane, washed with 5% sodium bicarbonate solution (10mL×2), washed with water (10mL×1), the organic layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from methanol to obtain a white powdery solid 1 , 5-n-decyl-glutamic acid (DA 2 -Glu). Boc-L-Lys(Boc)-OH (2.9g, 8.4mmol), DCC (5.1g, 25mmol) and NHS (1.5g, 12.6mmol) were dissolved in 100mL DMF, stirred at room temperature for 3h; DA 2 -Glu (3.6g, 8.4mmol) was added to the above mixed solution and stirred at room temperature for 12h. Filter off DCU, add 100 mL of dichloromethane, wash with wat...

Embodiment 3

[0050] Preparation of 1,5-n-dodecyl-glutamic acid-lysine

[0051] Glutamic acid (2.9 g, 19.7 mmol) and p-toluenesulfonic acid (4.1 g, 23.7 mmol) were dissolved in 60 mL of toluene and refluxed for 1 h. Add n-dodecyl alcohol (7.3 g, 39.4 mmol) and reflux for 12 h. After the reaction, the toluene was distilled off under reduced pressure. The concentrate was dissolved in an appropriate amount of dichloromethane, washed with 5% sodium bicarbonate solution (10mL×2), washed with water (10mL×1), the organic layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from methanol to obtain a white powdery solid 1 , 5-n-dodecyl-glutamic acid (DO 2 -Glu). Boc-L-Lys(Boc)-OH (2.9g, 8.4mmol), DCC (5.1g, 25mmol) and NHS (1.5g, 12.6mmol) were dissolved in 100mLDMF, stirred at room temperature for 3h; 2 -Glu (4.1 g, 8.4 mmol) was added to the above mixed solution and stirred at room temperature for 12 h. Filter off DCU, add 100 mL of dichloromethane, wash with water ...

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Abstract

The invention relates to the field of pharmaceutical excipients and preparations, in particular to an oligopeptide cationic lipid derivative (I) or (II), a preparation method thereof and application thereof as a drug carrier in preparations such as lipids and micelles. The cationic lipids has high buffering capabiity, can generate the effects of proton sponge in acidic lysosomes, and can be compounded with plasmid DNA (Deoxyribonucleic Acid), oligonucleotides and small interfering substances (siRNA) into nanoparticle compounds.

Description

technical field [0001] The invention relates to the field of pharmaceutical excipients and preparations. It specifically relates to a class of oligopeptide cationic lipid derivatives and a preparation method thereof, and also relates to its application as a drug carrier in preparations such as assembling into liposomes and micelles. Background technique [0002] With the development of molecular biology, especially the establishment of human gene pools and the elucidation of human disease-related genes, gene therapy for diseases has emerged as the times require. At present, gene therapy has developed into a new research field in contemporary medicine and biology. Since the targets of most gene drugs are located in the cytoplasm, organelles or nuclei of tumor cells, how to introduce therapeutic gene drugs into the human body and even lesion sites has become a research hotspot in the fields of medicine, biology and pharmacy. [0003] Gene drugs are generally plasmid DNA, oli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/068A61K47/42A61K48/00A61K9/127A61K9/00
Inventor 张灿孙琼莫然崔烨李楠
Owner CHINA PHARM UNIV
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