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A clathrate of an artemisinin type medicine and ring-opened cucurbituril and a preparation method thereof

A technology of artemisinin and cucurbitacil, which is applied in the direction of drug combination, pharmaceutical formula, medical preparations of non-active ingredients, etc., can solve the problem of cyclodextrin and its derivatives not being resistant to strong acid and strong alkali, low bioavailability, and containing The problem of compound instability and other problems can be overcome, and the effect of overcoming low bioavailability, improving solubility, and simple and easy preparation method

Inactive Publication Date: 2018-11-09
KUNMING UNIV OF SCI & TECH
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  • Abstract
  • Description
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Problems solved by technology

However, artemisinin drugs are more sensitive to high temperature. When the temperature is higher than 60°C, artemisinin will be completely decomposed, and the water solubility is poor, and the bioavailability is low, so that it cannot be well transported to the lesion. Therefore, the development of a The artemisinin series with good water solubility and high bioavailability has important practical significance
[0004] Dihydroartemisinin and other people have used cyclodextrin and its derivatives for inclusion, and its inclusion constant is only 200-300, the binding rate is low and the inclusion is not tight; at the same time, cyclodextrin and its derivatives are not Strong acid and alkali resistance, easy to decompose in the strong acidic environment of the human body, such as gastric acid, resulting in instability of inclusion complexes; therefore, the stability of supramolecular carriers for inclusion artemisinin drugs still needs to be improved

Method used

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  • A clathrate of an artemisinin type medicine and ring-opened cucurbituril and a preparation method thereof
  • A clathrate of an artemisinin type medicine and ring-opened cucurbituril and a preparation method thereof
  • A clathrate of an artemisinin type medicine and ring-opened cucurbituril and a preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the synthetic preparation of tetramer

[0026] Carry out with reference to the method in literature Ma D, et al.Nature Chemistry, 2012,4(6):503:

[0027] (1) Synthesis of dimer: mix glycoluril (500g, 3.51mol) and paraformaldehyde (105g, 3.51mol) evenly, add to HCl solution (8M, 700mL), and heat the reaction solution at 50°C for 48h; After the reaction, the reaction solution was cooled and vacuum filtered to obtain the crude product; the crude product was washed with water (500 mL), and then recrystallized with TFA (1.5 L) to obtain a dimer as a white solid (334 g, 62%) ;

[0028]

[0029] (2) Synthesis of tetramer: dimer (304g, 1.20mol) was added to anhydrous MeSO 3 In H (600mL), after the dimer is completely dissolved, the solution becomes transparent, then etherified methyl glycoluril (84g, 0.27mol) is added; the reaction solution is reacted at 50°C for 3h; The solution was poured into water (6.0L); after vacuum filtration, the crude product was dr...

Embodiment 2

[0037] Example 2: Preparation of inclusion compound of dihydroartemisinin and two kinds of open-ring cucurbituril

[0038] (1) Preparation of inclusion compound of dihydroartemisinin and secocucurbituril 1

[0039] Weigh 0.172g (0.1mmol) of ring-opening cucurbituril and dissolve it in 15mL of distilled water, stir until dissolved at 25°C, dissolve 0.116g (0.3mmol) of dihydroartemisinin in 10mL of ethanol solution, and Mix the two solutions under the same conditions, and stir for 72 hours in the dark, then filter with filter paper and microporous membrane to remove insoluble matter, filter and evaporate to dryness to obtain dihydroartemisinin inclusion compound; image 3 Visible, in D 2 The peak of dihydroartemisinin appeared at Oδ0-1ppm, which proved that dihydroartemisinin had been encapsulated into the cavity by ring-opening cucurbitacin 1.

[0040] (2) Preparation of inclusion compound of dihydroartemisinin and secocucurbituril 2

[0041] Weigh 0.1868g (0.1mmol) of ring-...

Embodiment 3

[0042] Example 3: Preparation of clathrates of artemisinin and two kinds of split cucurbituril

[0043] (1): Preparation of inclusion compound of artemisinin and secocucurbituril 1

[0044] Weigh 0.1 mmol of ring-opening cucurbituril and dissolve it in 15 mL of distilled water, stir until dissolved at 30°C, weigh 0.5 mmol of artemisinin and dissolve it in 10 mL of acetone solution, mix the two solutions under stirring conditions, avoid After light stirring for 36 hours, filter with filter paper and microporous membrane to remove insoluble matter, filter and evaporate to dryness to obtain artemisinin inclusion compound; Figure 5 Visible, in D 2 The peak of artemisinin appeared at Oδ0-1.25ppm, which proved that artemisinin had been encapsulated into the cavity by split-ring cucurbitacin 1.

[0045] (2) Preparation of inclusion compound of artemisinin and secocucurbituril 2

[0046] Weigh 0.1 mmol of ring-opening cucurbituril and dissolve it in 15 mL of distilled water, stir ...

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Abstract

A clathrate of an artemisinin type medicine and ring-opened cucurbituril is provided. The clathrate contains the artemisinin type medicine and the ring-opened cucurbituril in a mole ratio of 2:1-8:1,and is prepared by a solvent inclusion process. A flexible molecule cavity of the ring-opened cucurbituril is utilized to match the artemisinin type medicine well, and good water solubility of the ring-opened cucurbituril is utilized to greatly improve water solubility of the artemisinin type medicine, thus facilitating formation of an artemisinin type medicine liquid preparation. The clathrate prepared by the preparation method has good water solubility and high stability. The preparation method is simple, mild in condition and easy to operate, and is applied for development of novel artemisinin type preparations. The clathrate has potential practical application value.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to an inclusion compound of artemisinin drugs and split-ring cucurbituril and a preparation method thereof. Background technique [0002] Studies in recent years have found that artemisinin series can better kill cancer. Statistics in recent years show that nearly 3 million people die of malaria in the world every year, especially in Africa, where the incidence rate is extremely high, so the demand for artemisinin The amount is large. At present, medicinal artemisinin is isolated from the traditional Chinese medicine Artemisia annua. Experimental measurements reveal that the artemisinin molecule contains an endoperoxide group, which is necessary for killing malaria parasites. In 1973, dihydroartemisinin was produced through the chemical modification of artemisinin. This derivative is relatively stable and has stronger curative effect. Ether, artether and artesunate ar...

Claims

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Application Information

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IPC IPC(8): A61K31/366A61K47/69A61K47/22A61P35/00A61P33/06
CPCA61K47/22A61K47/6949A61P33/06A61P35/00A61K31/366
Inventor 杨波梁婧刘满朔廖荣强秦琪吕品廖霞俐高传柱赵榆林
Owner KUNMING UNIV OF SCI & TECH
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