CN102786573B - Glycyrrhetinic acid crystal B-type material and preparation method and apply in medicine and healthcare products - Google Patents

Abstract

The invention discloses a new crystal type B substance state of glycyrrhetinic acid represented by formula (I); a preparation method of a sample of glycyrrhetinic acid crystal type B; a product prepared by using glycyrrhetinic acid crystal type B substance as an active ingredient, The products include medicines and health care products, and the application of glycyrrhetinic acid crystal type B in disease prevention and health care.

Description

Glycyrrhetinic acid crystal type B substance, preparation method and application in medicine and health care products

technical field

The present invention relates to a new crystal type A substance state of glycyrrhetinic acid, a preparation method of glycyrrhetinic acid crystal type A sample, a product using glycyrrhetinic acid crystal type A substance as an active ingredient, and the use of glycyrrhetinic acid crystal type A, It belongs to the field of medical technology.

Background technique

Glycyrrhetinic acid, English name is Glycyrrhetinicacid, and molecular structure is as shown in formula (I)

In the Chinese patent CN101899081A (publication number), the "synthesis method of glycyrrhetinic acid ester derivatives and deoxyglycyrrhetinic acid ester compounds" invented by Zhang Aiming et al. ^[1] , which involves the preparation of glycyrrhetinic acid ester derivatives method. Glycyrrhetinic acid compounds are not involved.

In the Chinese patent CN1563073 (publication number), the "preparation method of glycyrrhetinic acid" invented by Fan Yunge et al. ^[2] is recorded, which involves the preparation of glycyrrhetinic acid by using glycyrrhizic acid as a raw material through acid hydrolysis method. The preparation method of this patent belongs to glycyrrhetinic acid compound is different from the preparation method of this patent application.

In the Chinese patent CN1846705 (publication number), it is recorded that "the application of glycyrrhizic acid or glycyrrhetinic acid in the preparation of drugs for treating inflammatory bowel disease" invented by Ding Hong of Wuhan University ^[3] , which involves the preparation of glycyrrhizic acid or glycyrrhetinic acid Use of anti-inflammatory bowel disease drugs. It belongs to the clinical application of glycyrrhetinic acid and does not involve the preparation of glycyrrhetinic acid crystal form.

In the Chinese patent CN101254308 (publication number), the "glycyrrhetinic acid-polyethylene glycol/chitosan liver targeting compound drug delivery system and preparation method" invented by Yuan Zhi et al. ^[4] involves a new Liver-targeted drug carrier-glycyrrhetinic acid-polyethylene glycol/chitosan or chitosan derivative liver-targeted compound drug delivery system. The patent relates to the preparation method of the compound of glycyrrhetinic acid, and does not involve the preparation of glycyrrhetinic acid crystal form.

In the Chinese patent CN101292952 (publication number), it is recorded that “Glycyrrhizic acid, glycyrrhetinic acid or its salt or its derivative temperature-sensitive gel and its preparation method and application” invented by Ding Hong et al. ^[5] , which involves glycyrrhizic acid, licorice Hypoacid or its salt or its derivative thermosensitive gel. The patent relates to the preparation method of glycyrrhetinic acid complex, not the crystal form preparation of glycyrrhetinic acid.

In the Chinese patent CN101919870A (publication number), it is recorded that "the application ^of glycyrrhetinic acid and glycyrrhizic acid in the preparation of drugs for the prevention or treatment of pulmonary fibrosis" invented by Zhang Lurong et al. Or the application in the treatment of pulmonary fibrosis medicine. It belongs to the clinical application of glycyrrhetinic acid and does not involve the preparation of glycyrrhetinic acid crystal form.

In the Chinese patent CN101920017A (publication number), it is recorded in the "composition for promoting the transdermal penetration of glycyrrhetinic acid" invented by Wang Qing et al. of Dalian University of Technology ^[7] , which involves a method for promoting the transdermal penetration of glycyrrhetinic acid. The composition for skin penetration belongs to the field of medicine, and the patent relates to the preparation method of glycyrrhetinic acid compound, and does not involve the crystal form preparation of glycyrrhetinic acid.

In the Chinese patent CN101926815A (publication number), Zhou Haibin et al. described "a composition of paeoniflorin and glycyrrhetinic acid and its preparation method and application" ^[8] , which involves the composition of paeoniflorin and glycyrrhetinic acid. The patent relates to the preparation method of glycyrrhetinic acid complex, not the crystal form preparation of glycyrrhetinic acid.

In the Chinese patent CN101838303A (publication number), the "preparation method of glycyrrhetinic acid" invented by Pan Xuejun of Kunming University of Science and Technology ^[9] is recorded, which involves the refining method of glycyrrhetinic acid. It involves the preparation method of glycyrrhetinic acid by microwave technology, and does not involve the crystal form preparation of glycyrrhetinic acid.

In the Chinese patent CN101817867A (publication number), "a preparation method of glycyrrhetinic acid" invented by Gao Ying et al. ^[10] is recorded, which involves the purification method of glycyrrhetinic acid, that is, by dissolving glycyrrhetinic acid powder with an organic solvent Extract and concentrate to obtain the extract, in acetic acid, use mineral acid to catalyze hydrolysis and acetylation to obtain acetylglycyrrhetinic acid; then add water or alcohol to acetylglycyrrhetinic acid, hydrolyze under alkali catalysis to obtain crude glycyrrhetinic acid, add activated carbon Reflux for decolorization and crystallization to obtain glycyrrhetinic acid. The method for removing and decolorizing the inorganic salt of glycyrrhetinic acid is different from the crystal form preparation method of this patent application.

After domestic and foreign patent and literature search, it was found that there were literature reports on the research progress of glycyrrhetinic acid ^{[11, 12]} , extraction process ^[13] , detection method ^[14] and dosage form ^{[15, 16, 17]} , but no Research on crystal forms of glycyrrhetinic acid and patents or literature reports on crystal forms.

The present invention discovers the discovery, sample preparation and use of a new crystal form of glycyrrhetinic acid, which is different from the content of the above-mentioned patents or literature research reports. The research purpose of the present invention is to start from the study of glycyrrhetinic acid crystal form solid matter, through crystal form screening technology and crystal form biological activity evaluation technology, to find, discover and develop the best clinical curative effect on the level of different crystal form states of the same effective substance The dominant crystal form substance state of glycyrrhetinic acid that acts with health care products provides scientific data for applying for national or international intellectual property invention patent protection on the basis of glycyrrhetinic acid crystal form substances.

Contents of the invention

The technical problem to be solved in the present invention is to provide a new crystal form of glycyrrhetinic acid shown in formula (I), i.e. crystal type B

Another technical problem to be solved by the present invention is to provide a preparation method of glycyrrhetinic acid crystal type B substance.

Another technical problem to be solved by the present invention is to provide a product in which glycyrrhetinic acid crystal type B is used as an active ingredient.

Another technical problem to be solved by the present invention is to provide the application of glycyrrhetinic acid crystal type B.

Specifically, in order to solve the technical problem, the following technical solutions are adopted:

1. Morphological characteristics of the crystal type B sample of glycyrrhetinic acid:

1.1 Glycyrrhetinic acid crystal type B solid substance, when analyzed by powder X-ray diffraction (CuK _α radiation), shows that there is one diffraction peak with Height%=100 at 2-Theta=14.9°±0.2° or location. Accompanying drawing 1 provides the powder X-ray diffraction pattern of glycyrrhetinic acid crystal type B sample.

1.2 Glycyrrhetinic acid crystal type B solid substance, its infrared absorption spectrum (Figure 2) is at 3433, 2928, 2867, 2089, 1701, 1652, 1454, 1386, 1361, 1326, 1312, 1280, 1257, 1209, 1173, The absorption peaks at 1136, 1101, 1085, 1036, 992, 959, 947, 919, 880, 868, 818, 751, 700, 684, 666cm ^-1 ± 2cm ^-1 are the solid substances of glycyrrhetinic acid crystal type B. The positions of characteristic peaks in infrared spectra. Accompanying drawing 2 provides the infrared absorption spectrogram of glycyrrhetinic acid crystal type B sample.

1.3 Glycyrrhetinic acid crystal type B solid substance, its DSC spectrum (Figure 3) contains three Peak endothermic peaks at 78°C±3°C, 105°C±3°C, 297°C when the heating rate is 10°C per minute. ℃±3℃ position.

1.4 Glycyrrhetinic acid crystal type B solid matter, its melting point is 293°C±2°C.

2. Characteristics of the preparation method of glycyrrhetinic acid crystal type B sample:

2.1 The present invention provides a preparation method of glycyrrhetinic acid crystal type B sample, which is characterized in that the glycyrrhetinic acid sample is completely dissolved at room temperature or high temperature using a single solvent of chloroform and subjected to ambient temperature of 4°C to 80°C, ambient humidity Glycyrrhetinic acid crystal type B solid sample prepared directly or indirectly at 10% to 75% under normal or vacuum pressure conditions.

2.2 The present invention provides another preparation method of glycyrrhetinic acid crystal type B sample, which is characterized in that any two or more of chloroform, n-hexane, cyclohexane, and water are used in different solvents and combined in different proportions The prepared mixed solvent system completely dissolves the glycyrrhetinic acid sample at normal temperature or high temperature, and directly or indirectly prepares the glycyrrhetinic acid sample under the conditions of ambient temperature 4°C-80°C, ambient humidity 10%-75%, and normal pressure or vacuum pressure. Acid crystal type B solid sample.

3. The dosage and use characteristics of the crystal type B of glycyrrhetinic acid as an active substance:

3.1 The present invention also provides a product that uses glycyrrhetinic acid crystal type B as the active ingredient and contains other auxiliary materials. Products described in the present invention include medicines and health care products.

The purity of glycyrrhetinic acid crystal type B in the product is 1%-100%.

The dosage form of the product is selected from tablet, capsule, pill, injection, slow release or controlled release agent, powder.

3.2 The present invention provides various products developed using glycyrrhetinic acid crystal type B as active ingredients, including medicines and health care products, characterized in that the daily intake dose of glycyrrhetinic acid crystal type B is in the range of 1 mg to 40 g.

3.3 The present invention provides various products developed using glycyrrhetinic acid crystal type B as the active ingredient, including medicines and health care products. It is characterized in that the use of glycyrrhetinic acid crystal type B as the active The absorption characteristics, effective bioavailability, effective blood drug concentration, and stable duration in the body can achieve the prevention, treatment, health care and application of the advantages.

4. Oral administration absorption characteristics of Glycyrrhetinic acid new crystal type B:

The invention provides various products developed using glycyrrhetinic acid crystal type B as active ingredients, including medicines and health care products, and the bioabsorption after oral administration, which is characterized in that glycyrrhetinic acid crystal type B can be used as an active ingredient. Through the gastrointestinal tract, it acts rapidly in 15 minutes, reaches the maximum concentration in the blood in 1 hour, and maintains the activity characteristics of the plateau cycle in 12 hours. Figure 4 shows the blood concentration curve of glycyrrhetinic acid crystal type B samples after oral administration in rats.

5. Application of glycyrrhetinic acid crystal type B in pharmaceuticals.

The invention provides the application of glycyrrhetinic acid crystal type B in the preparation of medicines for treating Addison's disease, anti-inflammatory bowel disease and preventing or treating pulmonary fibrosis.

Description of drawings

The powder X-ray diffraction pattern of Fig. 1 glycyrrhetinic acid crystal type B sample

The infrared absorption spectrum figure of Fig. 2 glycyrrhetinic acid crystal type B sample

Figure 3 DSC spectrum of glycyrrhetinic acid crystal type B sample

Figure 4 Glycyrrhetinic acid crystal type B sample after oral administration of the rat plasma concentration curve

detailed description

In order to better illustrate the technical solutions of the present invention, the following examples are given, but the present invention is not limited thereto.

Example 1

The direct preparation method of glycyrrhetinic acid crystal type B sample:

The preparation method of the crystal type B sample of glycyrrhetinic acid is characterized in that 20ml of chloroform solvent is used to completely dissolve the glycyrrhetinic acid sample at room temperature, and then the solvent is dried under vacuum conditions at a temperature of 45°C to prepare glycyrrhetinic acid. Crystal samples.

The powder X-ray diffraction pattern of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 1

The infrared absorption spectrogram of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 2

The DSC collection of illustrative plates of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 3

The results of the above spectrum data show that the crystal form of the crystal obtained in this example is glycyrrhetinic acid crystal type B.

Example 2

The direct preparation method of glycyrrhetinic acid crystal type B sample:

The crystal type B sample preparation method of glycyrrhetinic acid is characterized in that 20ml of chloroform is used to prepare a supersaturated glycyrrhetinic acid chloroform solution under the condition of 45°C water bath, and then placed at a constant temperature of 10°C to precipitate solids and then vacuum filtered and dried to prepare A sample of glycyrrhetinic acid crystal form was obtained.

The powder X-ray diffraction pattern of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 1

The infrared absorption spectrogram of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 2

The DSC collection of illustrative plates of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 3

The results of the above spectrum data show that the crystal form of the crystal obtained in this example is glycyrrhetinic acid crystal type B.

Example 3

The direct preparation method of glycyrrhetinic acid crystal type B sample:

The preparation method of the crystal type B sample of glycyrrhetinic acid is characterized in that the glycyrrhetinic acid sample is completely dissolved by adding 20ml chloroform to 20ml~40ml n-hexane mixed solvent at a temperature of 40°C, and then the solid is precipitated at room temperature or low temperature, and then vacuum filtered Dry to prepare a sample of glycyrrhetinic acid crystal form.

The powder X-ray diffraction pattern of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 1

The infrared absorption spectrogram of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 2

The DSC collection of illustrative plates of gained glycyrrhetinic acid crystal form sample is as shown in accompanying drawing 3

The results of the above spectrum data show that the crystal form of the crystal obtained in this example is glycyrrhetinic acid crystal type B.

Example 4

Glycyrrhetinic acid crystal type B absorption characteristics and blood concentration characteristics in rats:

SD rats with a body weight of 230±5g were reared under conventional feeding conditions, free to drink water, and after fasting for 12 hours, the drug was given by intragastric administration at 200 mg/kg. , 3, 4, 6, 8, 12, 24(h). About 0.4ml of blood was collected from the orbit, centrifuged at 4,000rpm for 15min to prepare plasma. Take 150μl of plasma, add 200μl of methanol, vortex for 1min, centrifuge at 13,400rpm for 15min, absorb the supernatant and filter it through a 0.45μm microporous membrane, take 20μl for HPLC detection, AligentXDB-C ₁₈ (150×4.6mm, 5μm), mobile phase : Methanol:0.4% acetic acid aqueous solution=90:10, flow rate: 1ml/min, detection wavelength: 254nm. The results show that the active ingredient of glycyrrhetinic acid can be detected in the blood after oral administration of glycyrrhetinic acid crystal type B solid raw material, and it takes effect quickly through the gastrointestinal tract in 15 minutes, the blood reaches the maximum concentration in 1 hour, and maintains the activity of the plateau cycle in 12 hours feature.

Blood concentration data of glycyrrhetinic acid crystal type B

Example 5

Glycyrrhetinic acid crystal type B sample is used as the dosage of pharmaceutical active ingredients:

Use crystal type B glycyrrhetinic acid substance as the active ingredient of medicine to prepare and develop pharmaceutical tablets or other preparations, which are characterized in that it contains glycyrrhetinic acid crystal type B as the active ingredient of medicine, and the daily dosage is 300 mg, which can be prepared respectively as One 100mg ordinary tablet 3 times a day/each time, 1 150mg ordinary tablet 2 times a day/each time or 1 300mg tablet type once a day/each time.

Problems to be clarified: the pharmaceutical composition of glycyrrhetinic acid crystal form involved in the present invention is affected by many factors on the dosage of the active ingredients, for example: different uses for prevention and treatment result in different daily dosages; Differences in the nature and severity of the disease lead to differences in the daily dosage; differences in the gender, age, body surface area, route of administration, frequency of administration, and purpose of treatment result in differences in the daily dosage of the drug; in addition, The differences in absorption and blood drug concentration among crystal samples also lead to the suitable daily dose range of glycyrrhetinic acid crystal B component in the present invention being 0.01-150 mg/kg body weight, preferably 1-100 mg/kg body weight. When in use, different total dosage regimens of the active ingredients of glycyrrhetinic acid crystal type B should be formulated according to the actual needs of different prevention and treatment situations, and can be divided into single or multiple administration methods.

Example 6

Glycyrrhetinic acid crystal type B sample is used as the health care product dose of the active ingredient of the medicine:

A functional health product prepared and developed by using crystal B-type glycyrrhetinic acid as an active ingredient, characterized in that the health product contains glycyrrhetinic acid crystal B as a health-care active ingredient, and its dosage ranges from 1 mg to 40 g.

references

1. Chinese patent, publication number CN101899081C.

2. Chinese patent, publication number CN1563073.

3. Chinese patent, publication number CN1846705.

4. Chinese patent, publication number CN101254308.

5. Chinese patent, publication number CN101292952.

6. Chinese patent, publication number CN101919870C.

7. Chinese patent, publication number CN101920017C.

8. Chinese patent, publication number CN101926815C.

9. Chinese patent, publication number CN101838303C.

10. Chinese patent, publication number CN101817867C.

11. Xie Shirong, Zhao Jie, etc. Research and prospect of glycyrrhetinic acid. Journal of Dalian University, 2005, 26(4): 85-88

12. Yu Fang, Gao Jianpei, etc. Research progress on the preparation of glycyrrhetinic acid by extracting glycyrrhizic acid from licorice. Jiangxi Agricultural Journal, 2008, 20(8): 91-94.

13. Zeng Qihua. Study on the technology of extracting glycyrrhizic acid and glycyrrhetinic acid from licorice. 2006, 8(1): 62-64

14. Wang Shuping, Cao Bo, etc. Study on the determination method of glycyrrhetinic acid concentration in rat plasma. Journal of Armed Police Medical College, 2008, 17(3): 201-203.

15. Zhu Ling, Fang Haiyan, etc. Preparation and lipolysis of glycyrrhetinic acid cream. Modern Food Science and Technology, 2009, 25(11): 1335-1337.

16. Wang Jun, Zhang Jian et al. Preparation and Properties of Glycyrrhetinic Acid Polylactic Acid Microspheres. Shi Zhen Guo Yi Guo Yao, 2009, 20(4): 1002-1003.

17. Guo Bohong, Cheng Yi, etc. Preparation of glycyrrhetinic acid liposome and study on its pharmaceutical properties. Chinese Herbal Medicine, 2010, 41(3): 380-383.

Claims (12)

1. the crystal B type solid matter of glycyrrhetinic acid shown in formula (I), It is characterized in that when using powder _X -ray diffraction analysis, it shows that there is a diffraction peak position of Height%=100 at 2-Theta=14.9°±0.2° or location. 2. The preparation method of the glycyrrhetinic acid crystal B-type solid substance described in claim 1 is characterized in that, the glycyrrhetinic acid sample is completely dissolved at room temperature using a single solvent of chloroform first and then subjected to ambient temperature of 4° C. to 80° C. and ambient humidity. Glycyrrhetinic acid crystal type B solid matter is directly or indirectly prepared under normal pressure or vacuum pressure conditions of 10% to 75%. 3. the preparation method of glycyrrhetinic acid crystal B-type solid substance described in claim 1 is characterized in that, first use chloroform and normal hexane or hexanaphthene through the mixed solvent system that different proportions are combined to make glycyrrhetinic acid crystal The acid sample is completely dissolved, and the glycyrrhetinic acid crystal type B solid substance is directly or indirectly prepared under the conditions of ambient temperature 4°C-80°C, ambient humidity 10%-75%, normal pressure or vacuum pressure. 4. A medicine, characterized in that, the glycyrrhetinic acid crystal type B solid substance according to claim 1 is used as an active ingredient, and contains other auxiliary materials. 5. The medicine according to claim 4, characterized in that the crystal form purity of said glycyrrhetinic acid crystal type B solid substance is 1%-100%. 6. according to the medicine of claim 4, the dosage form of described medicine is selected from tablet, capsule, pill, injection, sustained-release or controlled-release preparation, powder. 7. A health care product, characterized in that, the glycyrrhetinic acid crystal type B solid substance according to claim 1 is used as an active ingredient and contains other auxiliary materials. 8. The health care product according to claim 7, characterized in that the crystal form purity of the glycyrrhetinic acid crystal type B solid substance is 1%-100%. 9. The health product according to claim 7, wherein the dosage form of the health product is selected from tablet, capsule, pill, injection, slow-release or controlled-release agent, powder. 10. The application of the glycyrrhetinic acid crystal type B solid substance according to claim 1 in the preparation of a medicament for treating Addison's disease. 11. The application of the glycyrrhetinic acid crystal type B solid substance according to claim 1 in the preparation of anti-inflammatory bowel disease medicaments. 12. The application of the glycyrrhetinic acid crystal type B solid substance according to claim 1 in the preparation of medicines for preventing or treating pulmonary fibrosis.