阅读说明：本技术 一种提高熊果酸水溶性的共无定型复合物及其制备工艺 (Co-amorphous compound for improving water solubility of ursolic acid and preparation process thereof ) 是由 洪燕萍 杨仲平 谢佩勲 邱丰艳 陈荣秦 于 2019-10-29 设计创作，主要内容包括：本发明公开了一种提高熊果酸水溶性的共无定型复合物及其制备工艺。将熊果酸和懈皮素分别加入无水乙醇中,水浴加热溶解得到熊果酸醇溶液和槲皮素醇溶液,然后按照熊果酸与槲皮素的质量比为1:0.02-0.2的比例,将槲皮素醇溶液倒入熊果酸醇溶中,混匀,旋转蒸发得到熊果酸-槲皮素共无定型复合物。本发明将两种具有活性的药物成分即熊果酸和槲皮素通过制备药物-药物无定型系统的方法,以槲皮素作为配体,利用槲皮素玻璃态形成能力,与熊果酸形成稳定的无定型复合物,增加熊果酸的水溶性,以提高熊果酸的口服吸收及药效。本发明的复合物解决了聚合物固体分散体中因大量聚合物的加入,增加最终剂型的体积,以及聚合物具有吸湿性会降低其稳定性的缺陷。(The invention discloses a co-amorphous compound for improving the water solubility of ursolic acid and a preparation process thereof. Adding ursolic acid and relaxin into absolute ethyl alcohol respectively, heating in a water bath for dissolving to obtain an ursolic acid alcohol solution and a quercetin alcohol solution, then pouring the quercetin alcohol solution into the ursolic acid alcohol solution according to the mass ratio of the ursolic acid to the quercetin of 1:0.02-0.2, uniformly mixing, and performing rotary evaporation to obtain the ursolic acid-quercetin co-amorphous compound. The invention uses two active medicinal components, namely ursolic acid and quercetin, as a method for preparing a medicament-medicament amorphous system, and uses quercetin as a ligand, and utilizes the glass state forming capability of the quercetin to form a stable amorphous compound with the ursolic acid, so as to increase the water solubility of the ursolic acid and improve the oral absorption and the medicinal effect of the ursolic acid. The compound of the invention overcomes the defects that the volume of the final dosage form is increased due to the addition of a large amount of polymer in a polymer solid dispersion, and the stability of the polymer is reduced due to the hygroscopicity of the polymer.)

1. A preparation process of a co-amorphous compound for improving the water solubility of ursolic acid is characterized by comprising the following steps: which comprises the following steps:

1) adding ursolic acid into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain ursolic acid alcoholic solution;

2) adding quercetin into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain quercetin alcoholic solution;

3) pouring the quercetin alcohol solution into the ursolic acid alcohol solution according to the mass ratio of the ursolic acid to the quercetin of 1:0.02-0.2, uniformly mixing, and performing rotary evaporation until the ethanol is completely volatilized, thus obtaining the ursolic acid-quercetin co-amorphous compound.

2. The process of claim 1, wherein the composition further comprises: the water bath heating in the step 1) is carried out at the temperature of 85-95 ℃ for 15-20 min.

3. The process of claim 1, wherein the composition further comprises: the concentration of the ursolic acid alcoholic solution in the step 1) is 1g/60 mL.

4. The process of claim 1, wherein the composition further comprises: the water bath heating temperature of the step 2) is 45-55 ℃, and the time is 20-25 min.

5. The process of claim 1, wherein the composition further comprises: the concentration of the lachrymarin alcoholic solution in the step 2) is 0.02-0.2g/140 mL.

6. The process of claim 1, wherein the composition further comprises: and 3) the mass ratio of the ursolic acid to the quercetin is 1: 0.05.

7. The ursolic acid-quercetin co-amorphous complex obtained according to any one of the preparation processes of claims 1-6.

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to a co-amorphous compound for improving the water solubility of ursolic acid and a preparation process thereof.

Background

In order to solve the problems of difficult water solubility and low dissolution rate of the medicine, a plurality of preparation technologies are applied, such as micronization, cyclodextrin inclusion, solid dispersion, cosolvent and solubilizer, new preparation forms such as microemulsion and liposome and the like are adopted, salt forming treatment is carried out on the medicine, and the like.

Generally, the amorphous state of a drug has higher solubility than the crystalline state, and can promote absorption and improve oral bioavailability, but the stability of a single amorphous drug is poor. The solid dispersion preparation can convert the medicine from a crystal state to an amorphous state, maintain a relatively stable amorphous state, increase the solubility and dissolution rate and improve the bioavailability. However, poor solubility of drug in polymer solid dispersions (PASD) often results in the addition of large amounts of polymer, increasing the volume of the final dosage form, and most polymers are hygroscopic, decreasing their stability.

Over the past few years, co-amorphous drug Systems (CAMs) have been proposed and rapidly developed as a potential drug delivery system (Rahul B Chavana et al, 2016). A medicine and a small molecular excipient (auxiliary material) or a binary co-amorphous system can be formed between the two medicines, and the CAM is used as a promising method for replacing PASD, particularly exists in a medicine-medicine CAM form, can be used as a combined treatment medicine, can improve the water solubility and the dissolution rate of two slightly soluble medicines, can also enhance the curative effect and reduce the toxic and side effect of the medicine, and part of the system even has the potential of synergistic medicine release.

The preparation method and process variables of the co-amorphous compound affect the structural characteristics of the final product, and common preparation methods include a melt quenching method, a solvent volatilization method, a solvent-spray (freeze) drying method, a co-grinding method and the like. When preparing the co-amorphous drug, the preparation method, the component proportion and the temperature are selected according to the properties of the drug.

Ursolic acid is a pentacyclic triterpenoid, belongs to low-solubility and low-permeability medicines, and belongs to a fourth class of medicines in the biopharmaceutics classification system BCS (biopharmaceutics classification system). The ursolic acid with higher purity is white powder, is white needle-shaped crystal in ethanol, and has the problems of poor solubility, oral absorption and discharge, low bioavailability, high in-vivo metabolism speed and the like in biopharmaceutics. The reported preparation method for improving the water solubility of ursolic acid is mainly a polymer solid dispersion method, and a large amount of polymer is added while the water solubility and the dissolution rate are improved, so that the volume of the final preparation form is increased, and the stability of the final preparation form is reduced.

Disclosure of Invention

The invention aims to improve the water solubility of ursolic acid, overcome the defects that the volume of a final preparation form is increased due to the addition of a large amount of polymers in a polymer solid dispersion, and the stability of the polymer is reduced due to the hygroscopicity of the polymers, and provide a co-amorphous compound for improving the water solubility of the ursolic acid and a preparation process thereof by adopting a drug-drug co-amorphous system.

In order to achieve the purpose, the invention adopts the technical scheme that:

a preparation process of a co-amorphous compound for improving the water solubility of ursolic acid is characterized by comprising the following steps: which comprises the following steps:

1) adding ursolic acid into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain ursolic acid alcoholic solution;

2) adding quercetin into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain quercetin alcoholic solution;

3) pouring the quercetin alcohol solution into the ursolic acid alcohol solution according to the mass ratio of the ursolic acid to the quercetin of 1:0.02-0.2, uniformly mixing, performing rotary evaporation until the ethanol is completely volatilized, and then filling the product into a sealed bag for storage to obtain the co-amorphous compound.

The water bath heating in the step 1) is carried out at the temperature of 85-95 ℃ for 15-20 min;

the concentration of the ursolic acid alcoholic solution in the step 1) is 1g/60 mL.

The water bath heating in the step 2) is carried out at the temperature of 45-55 ℃ for 20-25 min;

the concentration of the lachrymarin alcoholic solution in the step 2) is 0.02-0.2g/140 mL.

And 3) the mass ratio of the ursolic acid to the quercetin is 1: 0.05.

The ursolic acid-quercetin co-amorphous compound prepared by the invention has stable property, and provides a new preparation process for improving the water solubility of pentacyclic triterpenoid compounds such as ursolic acid and the like. In the preparation method, a grinding method and a solvent method are tried, and the solvent method is selected for preparation because the grinding method has poor effect; in the aspect of solvent selection, the invention adopts methanol and ethanol for dissolution, the ethanol has almost no toxicity and better solubility to ursolic acid, so the ethanol is selected as the solvent; in the preparation proportion, different mass ratios of ursolic acid and quercetin are selected, and finally, the water solubility of the ursolic acid is improved to 8.36mg/L from 3.96 mg/L when the mass ratio of the ursolic acid to the quercetin is 20:1 by a solvent method, and the preparation is characterized and shown to be in an amorphous compound state through powder X-ray diffraction (PXRD) spectrum analysis and Fourier transform infrared spectroscopy (FTIR) analysis.

The invention has the beneficial effects that: the invention uses two active medicinal components, namely ursolic acid and quercetin, as a method for preparing a medicament-medicament amorphous system, and quercetin is used as a ligand (co-former), and a stable amorphous compound is formed with the ursolic acid by utilizing the glassy state forming capability of the quercetin, so that the water solubility of the ursolic acid is increased, and the oral absorption and the medicinal effect of the ursolic acid are improved. The method is simple and easy to implement, the prepared compound does not increase too many carrier components, the defects that the volume of the final preparation form is increased due to the addition of a large amount of polymers in the polymer solid dispersion, and the stability of the polymer is reduced due to the hygroscopicity of the polymers are overcome, and the water solubility of the ursolic acid is improved.

Drawings

FIG. 1 is a PXRD pattern of example 6, wherein A is ursolic acid monomer, B is quercetin monomer, C is ursolic acid-quercetin co-amorphous complex prepared by milling, and D is ursolic acid-quercetin complex prepared by solvent method;

FIG. 2 is FTIR chart of ursolic acid of example 6;

FIG. 3 is a graph of quercetin FTIR of example 6;

FIG. 4 is a FTIR chart of ursolic acid-quercetin co-amorphous complex (1: 0.05) prepared by the solvent method of example 6;

FIG. 5 is a graph of FTIR of ursolic acid-quercetin complex (1: 0.2) prepared by the milling method of example 6.

Detailed Description

The invention is described in further detail below with reference to the following figures and detailed description: