Oligopeptide-based pH-sensitive amphoteric ion and application thereof in medicament

A drug and matrix technology, applied in the direction of medical preparations with non-active ingredients, medical preparations containing active ingredients, peptides, etc., can solve problems such as carrier damage and drug leakage, and achieve good blood compatibility.

Active Publication Date: 2012-07-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This pH-sensitive characteristic of causing membrane fusion can easily damage the carrier and cause the drug in it to leak out.

Method used

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  • Oligopeptide-based pH-sensitive amphoteric ion and application thereof in medicament
  • Oligopeptide-based pH-sensitive amphoteric ion and application thereof in medicament
  • Oligopeptide-based pH-sensitive amphoteric ion and application thereof in medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of 1,5-eicosanol-L-glutamic acid-histidine-succinic anhydride

[0045] Glutamic acid (11.8 g, 80.2 mmol) and p-toluenesulfonic acid (18.3 g, 96.2 mmol) were dissolved in 350 mL of toluene, and refluxed for 1 h. Add n-eicosanol (52.8g, 176.7mol) and reflux for 12h. 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 (100mL×2), washed with water (100mL×1), the organic layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from methanol to obtain a white powdery solid 1 , 5-Eicosanol-L-glutamic acid (EI 2 -Glu, 32 g, 56.2%). Boc-L-His(Tos)-OH (6.9g, 16.8mmol), N,N-dicyclohexylcarbodiimide (DCC, 10.3g, 49.9mmol) and N-hydroxysuccinimide (NHS , 2.9g, 25.2mmol) was dissolved in 100mL N, N-dimethylformamide (DMF), stirred at room temperature for 3h; EI 2 -Glu (12g, 16.9mmol) was added to the above ...

Embodiment 2

[0049] 1,5-n-octadecyl alcohol-L-glutamic acid-histidine-citrafuric anhydride (SA 2 -Glu-His-CTA) preparation

[0050] Glutamic acid (11.8 g, 80.2 mmol) and p-toluenesulfonic acid (18.3 g, 96.2 mmol) were dissolved in 350 mL of toluene, and refluxed for 1 h. Add octadecyl alcohol (47.8g, 176.7mol) and reflux for 12h. 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 (100mL×2), washed with water (100mL×1), the organic layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from methanol to obtain a white powdery solid 1 , 5-octadecyl-L-glutamic acid (SA 2 -Glu, 29 g, 55.4%). Boc-L-His(Tos)-OH (6.9g, 16.8mmol), DCC (10.3g, 49.9mmol) and NHS (2.9g, 25.2mmol) were dissolved in 100mLDMF, stirred at room temperature for 3h; 2 -Glu (11 g, 16.9 mmol) was added to the above mixed solution and stirred at room temperatu...

Embodiment 3

[0054] Preparation of 1,5-n-dodecyl alcohol-L-glutamic acid-histidine-hexahydrophthalic anhydride

[0055] Glutamic acid (11.8 g, 80.2 mmol) and p-toluenesulfonic acid (18.3 g, 96.2 mmol) were dissolved in 350 mL of toluene, and refluxed for 1 h. Add n-dodecyl alcohol (3.3g, 176.7mol) and reflux for 12h. 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 (100mL×2), washed with water (100mL×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-L-glutamic acid (DO 2 -Glu, 17 g, 44.1%). Boc-L-His(Tos)-OH (6.9g, 16.8mmol), DCC (10.3g, 49.9mmol) and NHS (2.9g, 25.2mmol) were dissolved in 100mLDMF, stirred at room temperature for 3h; 2 -Glu (8.1 g, 16.9 mmol) was added to the above mixed solution and stirred at room temperature for 12 h. ...

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Abstract

The invention relates to the field of accessories and preparations with medicinal functions, in particular to a kind of oligopeptide-based pH-sensitive amphoteric ion lipid (I) or (II). In the invention, the derivatives of the oligopeptide amphoteric ion lipid have different surface charges under different pH conditions and can take relatively strong negative charges in a physiological environment with pH near neutrality so that the lipid has good blood compatibility; when the lipid reaches a tumor part, the surface charges of the oligopeptide amphoteric ion lipid are reversed in an acidulous tumor environment, so that the original electronegativity is reversed into electropositivity; and a carrier with positive charges is easily combined with the surface of a tumor cell, and the tumor cell targeting can be effectively realized through an endocytosis path. In lysosome, a cationic carrier continuously realizes a function of proton sponge or a function of splitting lysosome membranes, and the two functions can ensure the integrity of the carrier, so that the carrier can safely escape to cytoplast or other organelles.

Description

technical field [0001] The invention relates to the field of pharmaceutical functional excipients and preparations. It specifically relates to a class of oligopeptide pH-sensitive zwitterionic lipids and a preparation method thereof, and also relates to its application in preparations as a drug carrier such as being assembled into a liposome or as a coating material for a cationic carrier. Background technique [0002] As a drug carrier, liposome has the advantages of targeting the drug to the reticuloendothelial system, prolonging drug efficacy, reducing drug toxicity, improving curative effect, avoiding tolerance, and changing the route of administration. However, as a drug carrier, liposomes still have disadvantages such as unsatisfactory targeting characteristics for some diseases, poor in vivo stability and storage stability, which limit the clinical application and industrial production of liposomes. In recent years, people have developed new liposomes such as long-ci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078A61K47/18A61K9/127A61K45/00
Inventor 张灿莫然孙琼崔烨李楠
Owner CHINA PHARM UNIV
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