阅读说明：本技术 泽泻醇a的晶型及其制备方法和在医药上的应用 (Crystal form of alisol A, preparation method and medical application thereof ) 是由 程志红 宋定中 侯惠民 张贝贝 袁杰 赵静 王珂 于 2019-04-17 设计创作，主要内容包括：本发明公开了一种一种泽泻醇A的晶型及其制备方法和在医药上的应用,所述的泽泻醇A的晶型,X-射线衍射图谱在2θ值(±0.2)为7.281、10.579、12.213、13.736、14.721和17.464处具有特征峰。动物试验证明,本发明所述的泽泻醇A的晶型,可用于制备治疗高脂血症及动脉粥样硬化疾病的药物,其治疗效果优于无定型的泽泻醇A。本发明制备方法简单,溶解度大、溶解速率快、保存稳定性好的优点,可用于制备治疗高脂血症及动脉粥样硬化疾病的药物,其治疗效果优于无定型的泽泻醇A。(The invention discloses a crystal form of alisol A, a preparation method and medical application thereof, wherein the crystal form of alisol A has characteristic peaks at positions with 2 theta values (+ -0.2) of 7.281, 10.579, 12.213, 13.736, 14.721 and 17.464 in an X-ray diffraction pattern. Animal experiments prove that the crystal form of alisol A can be used for preparing medicines for treating hyperlipidemia and atherosclerosis, and the treatment effect of the crystal form is superior to that of amorphous alisol A. The invention has the advantages of simple preparation method, high solubility, high dissolution rate and good storage stability, can be used for preparing the medicine for treating hyperlipemia and atherosclerosis diseases, and has better treatment effect than amorphous alisol A.)

1. A crystalline form of alisol A characterised by an X-ray diffraction pattern having characteristic peaks at 2 θ values (+ -0.2) of 7.281, 10.579, 12.213, 13.736, 14.721 and 17.464.

2. The crystalline form of alisol a of claim 1, characterised in that the crystalline form has an X-ray diffraction pattern further comprising characteristic peaks at 2 Θ values (± 0.2) of 5.392, 10.899, 15.055, 15.686, 18.452, 19.891, 20.345, 20.823, 21.397, 22.026, 22.676, 23.364, 25.088, 25.814, 26.283, 27.942, 29.764, 31.300, 35.447, 36.492, 37.455, 42.424 and 42.980.

3. The crystalline form of alisol a according to claim 2, characterised in that the powder X-ray diffraction pattern of alisol crystalline form a is expressed in crystalline form with 2 Θ values, interplanar spacings d and relative intensities I (%) as follows:

4. use of the crystalline form of alisol a according to claim 1, 2 or 3 in the manufacture of a medicament for the treatment of hyperlipidemia and atherosclerotic disease.

5. A method of preparing the crystalline form of alisol a according to claim 1, 2 or 3, characterised in that it comprises the steps of:

(1) dissolving amorphous alisol A in an organic solvent, filtering, and collecting filtrate;

(2) standing for 20-28 hours at the temperature of 2-8 ℃, and collecting solids, namely the crystal form of alisol A.

6. The method according to claim 5, wherein the organic solvent is selected from the group consisting of 50 to 70 vol% ethanol solution, 50 to 70 vol% methanol aqueous solution, 40 to 60 vol% isopropanol aqueous solution, 50 to 70 vol% acetonitrile aqueous solution, and 25 to 35 vol% tetrahydrofuran solution.

7. The method according to claim 6, wherein in the step (1), the content of alisol A in the organic solvent is 10-50 g/L.

8. The method according to claim 5, wherein in the step (2), water is added, mixed, and left to stand at 2 to 8 ℃ for 20 to 28 hours, and the solid is collected.

9. The method according to claim 8, wherein the water is added in an amount of 0.2 to 2 times by volume based on the volume of the organic solvent.

Technical Field

The invention relates to a crystal form of alisol A and application thereof in medicine.

Background

Alisol A has a structure shown in formula I, wherein the name is as follows: alisol a, molecular formula: c₃₀H₅₀O₅. Pharmacological experiments prove that the product can obviously reduce the blood fat level and can be used for preparing the blood fat reducing medicine.

Chinese patent CN201210520817 discloses and describes application of alisol A in preparation of anti-atherosclerosis drugs, and animal experiments prove that alisol A is applied to ApoE^-/-The atherosclerosis model of the mouse which is fed by high fat feed and combined with the carotid artery injury operation has obvious treatment effect.

Chinese patent CN201210473789 discloses and describes application of alisol A in preparation of drugs for preventing and treating obesity, and animal experiments prove that alisol A has a remarkable treatment effect on obesity animal models established by high-fat feed feeding.

Chinese patent CN200510010827 discloses the application of compound alisol A as effective component in preparing anti-hepatitis B medicine and anti-hepatitis B inhibitor medicine.

Pharmacological research shows that different crystal forms have different solubilities, dissolution rates and storage stabilities, and some crystal forms even have obvious changes.

In order to further improve the clinical application value of alisol A, a new alisol A crystal form is researched and developed, and the alisol A crystal form has very important clinical application value.

Disclosure of Invention

The invention aims to provide a crystal form of alisol A, a preparation method thereof and application thereof in medicine, so as to meet the requirement of clinical application.

The crystal form of alisol A has characteristic peaks at positions with 2 theta values (+ -0.2) of 7.281, 10.579, 12.213, 13.736, 14.721 and 17.464 in an X-ray diffraction pattern.

Further, the X-ray diffraction pattern of the crystal form also comprises characteristic peaks at positions with 2 theta values (+ -0.2) of 5.392, 10.899, 15.055, 15.686, 18.452, 19.891, 20.345, 20.823, 21.397, 22.026, 22.676, 23.364, 25.088, 25.814, 26.283, 27.942, 29.764, 31.300, 35.447, 36.492, 37.455, 42.424 and 42.980.

Preferably, the powder X-ray diffraction pattern of alisol form a is expressed in crystal form with 2 θ values, interplanar spacings d and relative intensities I (%) as shown in table 1:

TABLE 1

The preparation method of the crystal form of alisol A comprises the following steps:

(1) dissolving amorphous alisol A with the weight content of 95% in an organic solvent, filtering, and collecting filtrate;

(2) standing for 20-28 hours at the temperature of 2-8 ℃, and collecting solids, namely the crystal form of alisol A;

the organic solvent is selected from an ethanol solution with the volume concentration of 50-70%, a methanol solution with the volume concentration of 50-70%, an isopropanol solution with the volume concentration of 40-60%, an acetonitrile solution with the volume concentration of 50-70% or a tetrahydrofuran solution with the volume concentration of 25-35%;

in the step (1), the content of alisol A in the organic solvent is 10-50 g/L;

preferably, in the step (2), adding water, mixing, standing for 20-28 hours at 2-8 ℃, and collecting solids;

the weight of the added water is 0.2-2 times of the volume of the organic solvent;

the amorphous alisol a can be prepared from chen.pharm.ball.18 (7): 1347-1353, or a commercial product.

Animal experiments prove that the crystal form of alisol A can be used for preparing medicines for treating hyperlipidemia and atherosclerosis, and the treatment effect of the crystal form is superior to that of amorphous alisol A.

The invention has the advantages of simple preparation method, high solubility, high dissolution rate and good storage stability, can be used for preparing the medicine for treating hyperlipemia and atherosclerosis diseases, and has better treatment effect than amorphous alisol A.

Drawings

FIG. 1 is an X-ray diffraction pattern of a crystalline form of alisol A.

FIG. 2 is a differential scanning calorimetry diagram of the crystal form.

FIG. 3 is a thermogravimetric analysis of the crystalline form.

FIG. 4 is a graph showing the elution profile

Detailed Description