Medicine for treating endometriosis and preparation process

Abstract

The invention belongs to the technical field of medical preparations, and particularly relates to a medicine for treating endometriosis and a preparation process. The medicine for treating endometriosis is prepared from the following raw materials: cinnamyl aldehyde, isoengeletin and the like. The medicine disclosed by the invention not only can effectively relieve clinical symptoms such as abdominal pain and / or abnormal menstruation caused by endometriosis, but also can remarkably reduce the volume of ovary chocolate cyst and promote absorption and repair of diseased tissues.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical preparations, and particularly relates to a medicine for treating endometriosis and a preparation process. BACKGROUND

[0002] Endometriosis (EMs) is a common gynecological disease, mainly occurring in women of childbearing age. The disease is characterized by the presence of endometrial tissue outside the uterus, such as the ovaries, fallopian tubes, and pelvic cavity, which causes patients to experience chronic pain, menstrual irregularities, infertility, and other symptoms. In traditional Chinese medicine theory, endometriosis is classified as "blood stasis syndrome".

[0003] Currently, the treatment of endometriosis mainly includes surgery and drug therapy. Surgical treatment mainly involves the removal of diseased tissue for patients with severe symptoms or infertility, but the recurrence rate is high. Drug therapy mostly uses hormone therapy, including oral contraceptives, progestin drugs, gonadotropin-releasing hormone agonists (GnRH-a), etc., aiming to suppress ovulation and reduce estrogen levels to alleviate symptoms. However, these methods often come with side effects such as osteoporosis, mood swings, and dependency issues with long-term use, and the efficacy is not ideal for some patients.

[0004] Chinese patent CN 113855689 B discloses the use of amurin or its isomer in the preparation of a medicine for treating endometriosis. Animal experiment results show that amurin or its isomer can significantly improve the symptoms of endometriosis in experimental animals, and the combination of a small dose of prebiotics with amurin or its isomer can significantly enhance the therapeutic effect of amurin or its isomer in treating endometriosis.

[0005] The existing technology of traditional Chinese medicine drugs containing amurin or its isomer has a slow effect on treating pain and menstrual irregularities caused by endometriosis, and has poor therapeutic effect on chocolate cysts. SUMMARY

[0006] The purpose of the present application is to provide a medicine for treating endometriosis and a preparation process.

[0007] To achieve the above purpose, the present application provides the following technical solutions: A medicine for treating endometriosis, comprising the following components: cinnamyl aldehyde, isoamurin.

[0008] Preferably, the mass ratio of cinnamyl aldehyde to isoamurin is (1-5):(1-5). Preferably, the medicine further comprises a traditional Chinese medicine extract, and the raw material of the traditional Chinese medicine extract is angelica, cortex moutan, red peony root, and soapberry spine.​

[0009] Preferably, the mass ratio of cinnamyl aldehyde, isofraxidin and traditional Chinese medicine extract is (1-5):(1-5):(10-15).

[0010] Preferably, the mass ratio of traditional Chinese medicine extract, cinnamyl aldehyde and isofraxidin is (10-13):(4-7).

[0011] Preferably, the traditional Chinese medicine extract is prepared by fermenting and extracting angelica sinensis, cortex moutan, red peony root and saponin.

[0012] Preferably, the preparation method of the traditional Chinese medicine extract comprises the following steps: (1) mixing angelica sinensis, cortex moutan, red peony root and saponin, crushing, adding water, sterilizing to obtain fermentation raw materials; (2) adding strains to the fermentation raw materials, fermenting, sterilizing after the end to obtain fermentation products; (3) filtering the fermentation products, taking the filtrate, concentrating, freeze-drying to obtain the traditional Chinese medicine extract.

[0013] Preferably, the mass ratio of angelica sinensis, cortex moutan, red peony root and saponin is 10:(2-5):(12-14):(5-8).

[0014] Preferably, the fermentation conditions are aerobic fermentation at 30-35 DEG C for 3-5 days.

[0015] Preferably, the strains include clostridium, saccharomyces cerevisiae and candida utilis.

[0016] Preferably, the viable bacteria ratio of clostridium, saccharomyces cerevisiae and candida utilis in the strains is 1:(1.3-1.5):(0.5-0.8).

[0017] The application provides a preparation process of the medicine for treating endometriosis, which comprises the following steps: uniformly mixing cinnamyl aldehyde, isofraxidin and traditional Chinese medicine extract.

[0018] Compared with the prior art, the application has the following advantages and beneficial effects: 1. Although the use of isofraxidin or its isomer in preparing a medicine for treating endometriosis is disclosed in the prior art, the curative effect is limited and it is difficult to meet the clinical requirements. On the basis of the prior art, the application innovatively improves the medicine by scientifically compounding isofraxidin, cinnamyl aldehyde and various traditional Chinese medicine extracts, so that the anti-inflammatory, blood-activating and stasis-removing, immune-regulating and endometriosis lesion growth inhibiting abilities of the medicine are significantly enhanced through multi-component synergistic effect. The medicine prepared by the application has more excellent curative effect in improving the symptoms related to endometriosis, and is obviously superior to single-component or other conventional treatment medicines, and has higher clinical application value.

[0019] 2、The medicine of the present application can not only effectively relieve the clinical symptoms such as abdominal pain and / or menstrual abnormalities caused by endometriosis, but also significantly reduce the volume of ovarian chocolate cysts, promote the absorption and repair of diseased tissues. After systematic treatment, the disease recurrence rate is significantly reduced during the drug withdrawal observation period, indicating that the medicine has good long-term efficacy and stability, which helps to achieve long-term control or even cure of the disease. This feature overcomes the problem of easy recurrence after stopping the current many treatment methods, providing a safe, effective and long-lasting new treatment option for patients with endometriosis. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0021] The raw materials used in the following embodiments of the present application are all commercially available: Clostridium sphenoides, strain number: HZB224142, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0022] Saccharomyces cerevisiae, strain number: HZB119840, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0023] Candida utilis, strain number: HZB226747, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0024] Neocallimastix patricium, number HZB229424, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0025] Lactobacillus plantarum, strain number: HZB220201, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0026] Cinnamyl aldehyde, CAS number: 104-55-2.

[0027] Isoquercitrin, CAS number: 30987-58-7.

[0028] Yeast extract, Xuzhou Saifu Biotechnology Co., Ltd. EMBODIMENT

[0029] The present embodiment provides a medicine for treating endometriosis, which comprises cinnamyl aldehyde, isoquercitrin and traditional Chinese medicine extract in a mass ratio of 2:3:12.

[0030] The preparation method of the traditional Chinese medicine extract comprises the following steps: (1) Angelica sinensis, Cortex Moutan, Red Paeonia, Semen Zaojia were mixed according to the mass ratio of 10:3:13:7, and were crushed to less than 40 mesh to obtain a mixed powder, 12 times the mass of water was added, sterilized to obtain a fermentation raw material; (2) Sucrose, yeast extract and strains were added to the fermentation raw material; the concentration of sucrose in the fermentation raw material was 20 g / L, the concentration of yeast extract in the fermentation raw material was 5 g / L, and the strains included Clostridium, Saccharomyces cerevisiae and Candida utilis. The viable bacteria ratio of Clostridium, Saccharomyces cerevisiae and Candida utilis in the strains was 1:1.4:0.6; the strain dosage was 10 6 CFU / mL of fermentation raw material, aerobic fermentation, air flow rate 0.4 vvm, air was introduced, 32°C, fermentation for 4 days, sterilization to obtain a fermentation product; (3) The fermentation product was filtered using a 0.45 μm filter membrane, the filtrate was taken, concentrated, and freeze-dried to a water content of 5 wt% to obtain a traditional Chinese medicine extract.

[0031] The preparation process of the medicine for treating endometriosis comprises the following steps: uniformly mixing cinnamyl aldehyde, isoflavonoid and traditional Chinese medicine extract, and obtaining the product. Embodiment

[0032] The embodiment provides a medicine for treating endometriosis, which comprises cinnamyl aldehyde, isoflavonoid and traditional Chinese medicine extract at a mass ratio of 3:4:13, The preparation method of the traditional Chinese medicine extract comprises the following steps: (1) Angelica sinensis, Cortex Moutan, Red Paeonia, Semen Zaojia were mixed according to the mass ratio of 10:2:14:8, and were crushed to less than 40 mesh to obtain a mixed powder, 15 times the mass of water was added, sterilized to obtain a fermentation raw material; (2) Sucrose, yeast extract and strains were added to the fermentation raw material; the concentration of sucrose in the fermentation raw material was 20 g / L, the concentration of yeast extract in the fermentation raw material was 5 g / L, and the strains included Clostridium, Saccharomyces cerevisiae and Candida utilis. The viable bacteria ratio of Clostridium, Saccharomyces cerevisiae and Candida utilis in the strains was 1:1.3:0.5; the strain dosage was 10 7 CFU / mL of fermentation raw material, aerobic fermentation, air flow rate 0.4 vvm, air was introduced, 32°C, fermentation for 4 days, sterilization to obtain a fermentation product; (3) The fermentation product was filtered using a 0.45 μm filter membrane, the filtrate was taken, concentrated, and freeze-dried to a water content of 5 wt% to obtain a traditional Chinese medicine extract.

[0033] The preparation process of the medicine for treating endometriosis comprises the following steps: uniformly mixing cinnamyl aldehyde, isoflavonoid and traditional Chinese medicine extract, and obtaining the product. Embodiment

[0034] The embodiment provides a medicine for treating endometriosis, which comprises cinnamyl aldehyde, isofraxidin and a traditional Chinese medicine extract in a mass ratio of 1:3:10, The preparation method of the traditional Chinese medicine extract comprises the following steps: (1) mixed angelica, peony root, red peony root and kadsura agailaris according to a mass ratio of 10:5:12:5, crushed to less than 40 meshes to obtain a mixed powder, added with 10 times the mass of water, sterilized to obtain fermentation raw materials; (2) added sucrose, yeast extract and strains into the fermentation raw materials; the concentration of sucrose in the fermentation raw materials is 20 g / L, the concentration of yeast extract in the fermentation raw materials is 5 g / L, and the strains comprise clostridium, saccharomyces cerevisiae and candida utilis; the viable bacteria ratio of clostridium, saccharomyces cerevisiae and candida utilis in the strains is 1:1.5:0.8; the strain is used in an amount of 10 6 CFU / mL of the fermentation raw materials, aerobically fermented, ventilated at a ventilation volume of 0.4 vvm, air is introduced, 35 DEG C, fermented for 3 days, sterilized to obtain fermentation products (3) filtered the fermentation products by using a 0.45 mu m filter membrane, took the filtrate, concentrated, freeze-dried to obtain the traditional Chinese medicine extract with a water content of 5 wt%.

[0035] The preparation process of the medicine for treating endometriosis comprises the following steps: uniformly mixing cinnamyl aldehyde, isofraxidin and the traditional Chinese medicine extract to obtain the medicine.

[0036] Comparative Example 1 The difference between the comparative example and the embodiment 1 is that the medicine for treating endometriosis comprises cinnamyl aldehyde, isofraxidin and a traditional Chinese medicine extract in a mass ratio of 2:3:8.

[0037] Comparative Example 2 The difference between the comparative example and the embodiment 1 is that the medicine for treating endometriosis comprises cinnamyl aldehyde, isofraxidin and a traditional Chinese medicine extract in a mass ratio of 2:3:17.

[0038] Comparative Example 3 The difference between the comparative example and the embodiment 1 is that the medicine for treating endometriosis comprises cinnamyl aldehyde, isofraxidin and a traditional Chinese medicine extract in a mass ratio of 5:4:12.

[0039] Comparative Example 4 The difference between the comparative example and the embodiment 1 is that the medicine for treating endometriosis comprises cinnamyl aldehyde, isofraxidin and a traditional Chinese medicine extract in a mass ratio of 1:1:12.

[0040] Comparative Example 5 The difference between the comparative example and the embodiment 1 is that red peony root is replaced by salvia miltiorrhiza.

[0041] Comparative Example 6 The difference between this comparative example and Example 1 is that Angelica sinensis is replaced by Patrinia.

[0042] Comparative Example 7 The difference between this comparative example and Example 1 is that the bacterial strain includes Saccharomyces cerevisiae and Candida utilis. The ratio of viable bacteria of Saccharomyces cerevisiae and Candida utilis in the bacterial strain is 1.4:0.6.

[0043] Comparative Example 8 The difference between this comparative example and Example 1 is that the bacterial strain includes Sporolactobacillus alimentarius, Saccharomyces cerevisiae and Candida utilis. The ratio of viable bacteria of Sporolactobacillus alimentarius, Saccharomyces cerevisiae and Candida utilis in the bacterial strain is 1:1.4:0.6. Sporolactobacillus alimentarius, No. HZB229424, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0044] Comparative Example 9 The difference between this comparative example and Example 1 is that the bacterial strain includes Lactobacillus plantarum, Saccharomyces cerevisiae and Candida utilis. The ratio of viable bacteria of Lactobacillus plantarum, Saccharomyces cerevisiae and Candida utilis in the bacterial strain is 1:1.4:0.6. Lactobacillus plantarum, strain No. HZB220201, Zhengzhou Fangjue Biotechnology Co., Ltd.

[0045] Performance test The drugs prepared in Examples 1-3 and Comparative Examples 1-9 were subjected to performance test, specifically referring to the method in CN 113855689 B: an endometriosis animal model was established. Female mature SPF level SD rats were selected to establish an endometriosis model, and the successfully modeled rats were randomly divided into 14 groups, 6 rats in each group.

[0046] Model control group: intragastrically administered with normal saline, 1 mL / kg per day.

[0047] Positive control group: intragastrically administered with the drug combination in Chinese patent CN 113855689 B: isoflavonoids, 90 mg / kg per day, and xylo-oligosaccharide, 10 mg / kg per day.

[0048] Experimental group: intragastrically administered with the drugs in Examples 1-3 and Comparative Examples 1-9, respectively, 80 mg / kg per day.

[0049] After 30 days of continuous administration, laparotomy was performed, and the ectopic endometrial tissue of the corresponding part was taken and placed in a formalin solution, paraffin-embedded, and then HE stained after slicing. The endometrial morphology was observed under a microscope, and the specific standards are as follows: 0 points: good growth state, more interstitium, and visible multiple glands (best morphology).

[0050] 1 point: Poor growth status, interstitium significantly reduced, 1-2 expanded glandular cavities (morphology good but poor).

[0051] 2 points: Atrophic state, interstitium is little, only 1 expanded glandular cavity (poor morphology).

[0052] 3 points: No obvious endometrial tissue, glandular body disappears (worst morphology).

[0053] The score results of each group are counted, and the results are shown in Table 1.

[0054] Score Model control group 2.35±0.64 Positive control group 0.87±0.32 Example 1 0.69±0.25 Example 2 0.72±0.21 Example 3 0.71±0.37 Comparative Example 1 1.21±0.53 Comparative Example 2 1.17±0.40 Comparative Example 3 1.15±0.36 Comparative Example 4 1.23±0.29 Comparative Example 5 0.83±0.27 Comparative Example 6 0.85±0.43 Comparative Example 7 1.07±0.51 Comparative Example 8 0.91±0.28 Comparative Example 9 0.94±0.24

[0055] It can be known from the results that the drugs of the embodiments 1-3 of the application have obvious therapeutic effect on endometriosis, which is better than the combined effect of isofraxidin and xylo-oligosaccharide in the prior art.

[0056] It can be known from the comparative examples 1-4 that the ratio of cinnamyl aldehyde, isofraxidin and traditional Chinese medicine extract has important influence on the therapeutic effect on endometriosis.

[0057] It can be known from the comparative examples 5 and 6 that replacing red peony root or angelica with other important raw materials will affect the therapeutic effect of the drug on endometriosis. It is analyzed that there is a complex interaction relationship between each medicinal material in the traditional Chinese medicine compound of the application, and red peony root and angelica can produce better therapeutic effect when used together than when used alone. The selection of red peony root and angelica is based on their effective intervention ability on the above pathological process, if other medicinal materials are used, even if the medicinal material also has certain anti-inflammatory or blood-activating and stasis-removing effect, but it cannot accurately correspond to the specific pathological characteristics of endometriosis like red peony root and angelica used together, and then affect the therapeutic effect.

[0058] It can be known from the comparative examples 7-9 that the strain used for fermentation of traditional Chinese medicine extract has important influence on the effect of the drug. The fermentation effect is not ideal when common saccharomyces cerevisiae and candida utilis are used, the inventors add bacillus fusiformis for co-fermentation on this basis, and the extract prepared has higher auxiliary synergistic effect on the other two traditional Chinese medicine monomers. It is analyzed that using different microbial strains in the fermentation process can significantly affect the chemical composition and biological activity of the final product, the fermentation of the specific strain used in the application can convert the components in the original medicinal material through metabolic action, generate new active substances, and at the same time improve the content of certain effective components, thereby enhancing the effect of the drug, when the three strains (saccharomyces cerevisiae, candida utilis and bacillus fusiformis) are co-fermented, a stronger synergistic effect is produced, and the overall fermentation efficiency and product quality are improved.

[0059] Application example 3 volunteers with endometriosis, varying degrees of dysmenorrhea, B ultrasound examination of ovarian chocolate cysts, were diagnosed by laparoscopy.

[0060] Huang, B ultrasound examination of ovarian chocolate cysts in 6cm x 7cm, 5 years of disease, accompanied by dysmenorrhea, irregular menstruation. Take the preparation of the drug of example 1, 500mg daily. Course of treatment 6 months. 6 months later, ovarian chocolate cysts regression 65%, dysmenorrhea significantly relieved, no impact on normal life, irregular menstruation improved significantly, menstrual cycle regular. 6 months after stopping drug, ovarian chocolate cysts did not grow again.

[0061] Zhang, B ultrasound examination of ovarian chocolate cysts in 5cm x 6cm, 3 years of disease, accompanied by dysmenorrhea, irregular menstruation. Take the preparation of the drug of example 1, 500mg daily. Course of treatment 6 months. 6 months later, ovarian chocolate cysts regression 71%, dysmenorrhea significantly relieved, no impact on normal life, irregular menstruation improved significantly, menstrual cycle regular. 6 months after stopping drug, ovarian chocolate cysts did not grow again.

[0062] Wang, B ultrasound examination of ovarian chocolate cysts in 5cm x 6cm, 4 years of disease, accompanied by dysmenorrhea, irregular menstruation. Take the preparation of the drug of example 1, 500mg daily. Course of treatment 6 months. 6 months later, ovarian chocolate cysts regression 61%, dysmenorrhea significantly relieved, no impact on normal life, irregular menstruation improved significantly, menstrual cycle regular. 6 months after stopping drug, ovarian chocolate cysts did not grow again.

[0063] The above is the preferred embodiment of the present application, it should be noted that for those skilled in the art, without departing from the principles of the present invention, can also make a number of improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A drug for treating endometriosis, characterized in that: Including cinnamaldehyde and isoflavone glycosides.

2. The drug for treating endometriosis according to claim 1, characterized in that The mass ratio of cinnamaldehyde to isoflavone glycoside is (1~5): (1-5).

3. The drug for treating endometriosis according to claim 2, characterized in that: The medicine also includes Chinese herbal medicine extracts.

4. The drug for treating endometriosis according to claim 3, characterized in that: The raw materials of Chinese herbal medicine extract are angelica, peony bark, red peony root and soapberry thorn.

5. The drug for treating endometriosis according to claim 4, characterized in that: The mass ratio of Chinese herbal medicine extract: the sum of cinnamaldehyde and isoflavone glycosides is (10~13): (4~7).

6. The drug for treating endometriosis according to claim 3, characterized in that: The traditional Chinese medicine extract is prepared by mixing angelica sinensis, peony bark, red peony root and sapodilla thorn and then fermenting the mixture.

7. The drug for treating endometriosis according to claim 6, characterized in that: The preparation method of the Chinese medicine extract comprises the following steps: (1) Mix angelica sinensis, peony bark, red peony root, and sapodilla thorn, grind them, add water, and sterilize them to obtain a fermentation raw material; (2) Add the strain to the fermentation raw material, carry out fermentation, and sterilize them after completion to obtain a fermentation product; (3) Filter the fermentation product, collect the filtrate, concentrate it, and freeze-dry it to obtain a Chinese medicine extract.

8. The drug for treating endometriosis according to claim 6, characterized in that: The mass ratio of angelica sinensis, peony bark, red peony root and sapodilla thorn is 10: (2-5): (12-14): (5-8).

9. The drug for treating endometriosis according to claim 6, characterized in that: The bacterial species include Clostridium, Saccharomyces cerevisiae and Candida utilis.

10. A process for preparing the drug for treating endometriosis according to any one of claims 1 to 9, characterized in that: The following steps are involved: The product is obtained by uniformly mixing cinnamaldehyde, isoflavone glycoside and Chinese herbal medicine extract.