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Artesunate heparin derivative as well as pharmaceutical composition and application thereof

A technology of succinate heparin and artesunate, which is applied in drug combinations, anti-infective drugs, pharmaceutical formulations, etc., can solve the problems of short half-life, poor water solubility of artemisinin and dihydroartemisinin, and low bioavailability , to achieve the effect of low toxicity, easy entry into the cell, and prolonging the half-life of the drug

Inactive Publication Date: 2019-03-19
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After the mid-20th century, some new drugs appeared. Artemisinin and dihydroartemisinin developed by Chinese scientists have good anti-malarial effects and have been widely used. However, artemisinin, dihydroartemisinin, and artemisinin The water solubility of artesunate is very poor, the half-life in vivo is short, and the bioavailability is low
In addition, the problem of artemisinin resistance is becoming more and more serious in parts of Southeast Asia

Method used

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  • Artesunate heparin derivative as well as pharmaceutical composition and application thereof
  • Artesunate heparin derivative as well as pharmaceutical composition and application thereof
  • Artesunate heparin derivative as well as pharmaceutical composition and application thereof

Examples

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preparation example Construction

[0052] The preparation method of the artesunate heparin derivative of the present invention: the carboxyl group of the artesunate is activated and then reacted with heparin to connect them through an ester bond to obtain an amphiphilic artesunate heparin derivative. The amount of artesunate bound to the heparin molecule was measured using UV spectroscopy. The mass content of artesunate in the artesunate heparin derivative is 5%-50%.

[0053] The preparation method of artesunate heparin derivatives and pharmaceutical composition nanoparticles: from the mixture of artesunate heparin derivatives and auxiliary agents or synergists of the present invention, through film dispersion method, reverse phase evaporation method, ultrasonic dispersion method, spray drying method or high pressure homogenization method and other methods.

[0054] The artesunate heparin derivative of the present invention has amphiphilicity, and the mixture of the artesunate heparin derivative of the present...

Embodiment 1

[0057] Synthesis of artesunate heparin derivatives (synthetic route see figure 1 )

[0058] Add 150 mg of heparin sodium (HEP) into 10 ml of dimethylacetamide (DMAc), heat to 50°C, stir for 3 hours, and dissolve for later use. 0.768 g (2 mmol) of artesunate (ART) was dissolved in 10 ml of dimethylacetamide, 0.324 g (2 mmol) of N,N'-carbonyldiimidazole (CDI) was added, and activated at room temperature for 2 hours. Then, the activated artesunate solution was added dropwise to the heparin solution, 0.122 g (1 mmol) of 4-dimethylaminopyridine (DMAP) was added, and the reaction was stirred at 30° C. for 48 hours. Add KH to the reaction liquid 2 PO 4 The solution was neutralized and dialyzed with distilled water (MWCO: 3500) for 24 hours to remove small molecule impurities. The white solid product of artesunate heparin derivative was obtained by freeze-drying, which was characterized by infrared spectrum and nuclear magnetic resonance spectrum. The mass percent content of arte...

Embodiment 2

[0060] Synthesis of Artesunate Heparin Derivatives

[0061] The molar ratio of reagents in this experiment was set as ART:CDI:DMAP=2:2:1. Add 30, 90, 180, and 270 mg of heparin sodium (HEP) into dimethylacetamide (DMAc), heat to 50°C, stir for 3 hours, and dissolve for later use. An appropriate amount of artesunate (ART) was dissolved in dimethylacetamide, and the corresponding molar amount of CDI was added, and activated at room temperature for 2 hours. Then, the activated artesunate solution was added dropwise to the heparin solution, an appropriate amount of DMAP was added, and the reaction was stirred at 30° C. for 48 hours. Add KH to the reaction liquid 2 PO 4 The solution was neutralized and dialyzed with distilled water (MWCO: 3500) for 24 hours to remove small molecule impurities. Freeze-drying obtained four white solid products of artesunate heparin derivatives, wherein the mass percentages of artesunate were 5.1%, 18.5%, 35.3%, and 49.6%, respectively.

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Abstract

The invention discloses an artesunate heparin derivative as well as a pharmaceutical composition and an application thereof. The derivative is pharmaceutically acceptable salt having a high molecularcompound shown in a general formula (1) or a compound shown in the general formula (1): the formula (1) is shown in the description, in the formula (1), artesunate is bonded with heparin through esterbonds. In the artesunate heparin derivative, the content of the artesunate is 5 percent by mass to 50 percent by mass. The pharmaceutical composition of the artesunate heparin derivative comprises the artesunate heparin derivative or a mixture of the artesunate heparin derivative and a synergist. The derivative is characterized in that the artesunate is bonded with the heparin through the ester bonds, the pharmaceutical composition can be nano-particles which are self-assembled by the artesunate heparin derivative and have the particle size of 10 nanometers to 1000 nanometers, or nano-particles loaded with antimalarial medicines, and is used for preparing medicines for treating or preventing malaria caused by plasmodium.

Description

technical field [0001] The invention relates to an artesunate-heparin derivative and its pharmaceutical composition and application in pharmacy, belonging to the technical field of pharmaceutical manufacturing. Background technique [0002] Parasitic diseases are diseases caused by parasites invading the human body. The pathological changes and clinical manifestations caused by different insect species and parasitic sites are different. This type of disease is widely distributed and can be seen all over the world. It is more common in poor and backward areas with poor sanitation, and more in tropical and subtropical areas. The infected people are mainly working people who have more contact with the source of the epidemic and those with low immunity. child. [0003] Malaria is the most important parasitic disease in tropical areas, and it is also an infectious disease caused by Plasmodium parasites in humans. Patients are infected by the bite of an Anopheles mosquito or th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K31/357A61K45/06A61P33/06A61P33/12A61P33/02A61P33/10
CPCA61K45/06A61K47/61A61P33/02A61P33/06A61P33/10A61P33/12A61K31/357Y02A50/30
Inventor 李新松司马
Owner SOUTHEAST UNIV
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