Application of salvianolic acid B in preparation of product for promoting uterus tissue injury repair

Abstract

The invention relates to the field of medicine and health care, in particular to novel application of a compound in preparation of a product for promoting uterus tissue injury repair. Experimental research proves that the salvianolic acid B is administered to mice with damaged uterine tissues through intraperitoneal injection, the administration dosage is 12.5-50 mg / kg / d, expression of epidermal growth factors (EGF) and fibroblast growth factors (FGF) in the damaged uterine tissues can be remarkably promoted, the damaged uterine tissues can be effectively repaired, the effect of the salvianolic acid B can be better than that of a positive drug estradiol, and the salvianolic acid B can be used for treating the uterine tissues. And toxic and side effects are greatly reduced. Therefore, the salvianolic acid B (or the salt thereof or the ester thereof) can be applied to preparation of products (medicines or health care products) for promoting uterine tissue repair.

Description

Technical Field

[0001] The present invention relates to the field of medicine and health care, and in particular to a new use of salvianolic acid B in preparing products (such as medicines or health products) for promoting the repair of uterine tissue damage. Background Art

[0002] Curettage (or curettage), hysteroscopy, and laparoscopy are common clinical operations in the field of gynecology, mainly used to terminate pregnancy, remove intrauterine residues, remove diseased tissues (such as uterine fibroids, intrauterine polyps), diagnose endometrial lesions, diagnose abdominal lesions, etc. However, these operations will inevitably cause mechanical damage to the uterine tissue, affect its normal physiological function, and may cause a series of complications, such as intrauterine adhesions (the incidence rate is as high as 25% to 30%), poor repair of uterine tissue, intrauterine fluid and fibrosis, uterine pathology leading to tubal fluid and fibrosis, abnormal menstruation and even infertility. In addition, women with low estrogen secretion, uterine polyps, uterine fibroids, etc. can damage uterine tissue, leading to infertility. These problems not only seriously affect women's reproductive health and quality of life, but also bring huge psychological and economic burdens to patients. Therefore, the repair of uterine damage is an important topic in gynecological clinics. The uterus is an important place for embryo implantation, and the integrity of its functional layer and basal layer is crucial to maintaining a normal menstrual cycle and fertility. However, currently commonly used treatment methods in clinical practice, such as estrogen therapy, biological barrier materials (such as amniotic membrane, hyaluronic acid), etc., although they can promote the repair of uterine tissue to a certain extent, have many limitations. For example, estrogen therapy may cause side effects such as thrombosis, and the stability and biological activity of biological barrier materials are insufficient to meet the needs of long-term repair. Therefore, the development of a safe and effective drug to promote the repair of uterine damage, such as the repair of the uterus after curettage, has become a problem that needs to be solved in the field of gynecology.

[0003] At present, the demand for the treatment of gynecological diseases continues to grow worldwide, especially in the field of infertility, where the market demand is particularly prominent. According to relevant statistics, the global infertility market has exceeded US$20 billion and is on an upward trend year by year. Therefore, the development of a drug that can effectively promote the repair of uterine damage can not only provide patients with more effective treatment options, but also fill the market gap and create significant economic benefits. In addition, uterine damage and the complications caused by it seriously affect women's reproductive health and quality of life. The development of this drug not only helps to reduce the incidence of infertility, but also reduces the pain and economic burden of patients, which has important social significance. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a new product for promoting the repair of uterine tissue damage and a new use of salvianolic acid B in the preparation of the product, that is, a new application of salvianolic acid B (including itself, its salt, or its ester) in the preparation of medicines or health products. The chemical structure of salvianolic acid B is as follows: Figure 1 shown.

[0005] One aspect of the present application provides a use of salvianolic acid B or a salt thereof in the preparation of a product that promotes the repair of uterine tissue damage.

[0006] Furthermore, the product is a medicine or a health product.

[0007] Furthermore, the uterine tissue includes endometrium and myometrium.

[0008] Furthermore, the uterine tissue is selected from endometrium.

[0009] Furthermore, the salt of salvianolic acid B is selected from an inorganic acid salt formed by the carboxyl group of salvianolic acid B and other cations, or an organic acid salt formed by the carboxyl group of salvianolic acid B and an organic base.

[0010] Furthermore, the inorganic acid salt includes but is not limited to lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, strontium salt, zinc salt, aluminum salt, barium salt, and ammonium salt; the organic acid salt includes but is not limited to choline salt, triethylamine salt, ethanolamine salt, acetate, citrate, salicylate, lactate, lysine salt, arginine salt, and ornithine salt.

[0011] Furthermore, the uterine tissue damage includes uterine tissue damage or complications caused by uterine tissue damage.

[0012] Furthermore, the uterine tissue damage includes but is not limited to physical damage, damage caused by pathological factors, and damage caused by hormonal abnormalities.

[0013] Furthermore, the physical damage includes but is not limited to uterine tissue damage caused by the following situations: uterine tissue damage caused by one or more artificial abortions / curettages / hysteroscopy / laparoscopy, uterine tissue damage caused by the removal of intrauterine contraceptive devices, and uterine tissue damage caused by the delivery process.

[0014] Furthermore, the damage caused by the pathological factors includes, but is not limited to, uterine tissue damage caused by endometriosis, uterine tissue damage caused by uterine polyps, and uterine tissue damage caused by uterine fibroids.

[0015] Furthermore, the damage caused by hormonal abnormalities includes endometrial damage caused by endocrine disorders; the damage caused by endocrine disorders includes thinning, atrophy or shedding of the endometrium caused by estrogen deficiency or long-term use of contraceptives.

[0016] Furthermore, the uterine tissue damage is endometrial damage caused by curettage, hysteroscopy or laparoscopy.

[0017] Furthermore, the complications caused by uterine tissue damage include one or more of uterine adhesions, poor uterine tissue repair, uterine cavity effusion, uterine tissue fibrosis, hydrosalpinx and fibrosis caused by uterine pathology, abnormal menstruation, infertility, chronic pelvic pain, abnormal menstruation, recurrent miscarriage, abnormal placenta implantation, and premature birth.

[0018] Furthermore, the complication caused by the uterine tissue damage is intrauterine adhesion.

[0019] Furthermore, the complications caused by the uterine tissue damage are uterine cavity effusion and / or uterine tissue fibrosis.

[0020] Furthermore, the complications caused by the uterine tissue damage are hydrosalpinx and fibrosis caused by the ascending uterine pathology.

[0021] Furthermore, the promoting the repair of uterine tissue damage includes one or more of promoting the repair of pathological tissue, promoting the repair of damaged epithelial cells, reducing uterine cavity effusion, reducing uterine tissue fibrosis, increasing the level of epidermal growth factor in damaged tissue, and increasing the level of fibroblast growth factor in damaged tissue.

[0022] Furthermore, the medicine or health product also includes a pharmaceutically acceptable carrier (or excipient) or an excipient acceptable to a registered health food product, and is prepared into various preparations for use, including solid preparations, liquid preparations or semisolid preparations.

[0023] Furthermore, the preparation can be selected from preparations for injection, preparations for oral administration, preparations for topical vaginal administration, or preparations for topical anal administration.

[0024] Furthermore, the preparation is selected from injection, powder, granule, effervescent tablet, tablet, hard capsule, soft capsule, granule, granule, oral liquid, pill, suppository, gel, ointment, cream and paste.

[0025] Furthermore, the preparation is an injection, a tablet or a suppository.

[0026] Furthermore, the aforementioned salvianolic acid B or its salt is the only active ingredient of the medicine or health care product.

[0027] Furthermore, the medicine or health product also includes a second active ingredient known to promote the repair of uterine tissue damage.

[0028] Furthermore, the second active ingredient includes but is not limited to one or more of the following substances: estrogen, progesterone, levothyroxine sodium, vitamin E, vitamin C, Centella asiatica extract, angelica extract, Leonurus japonicus extract, epidermal growth factor, fibroblast growth factor, vascular endothelial growth factor, arginine, glutamine, hyaluronic acid or sodium hyaluronate, zinc, lactic acid bacteria, collagen, and sialic acid.

[0029] Furthermore, the second active ingredient is estrogen.

[0030] Furthermore, the estrogen is estradiol and / or estradiol valerate.

[0031] Furthermore, the unit dosage of the aforementioned salvianolic acid B or its salt in the medicine or health product is 20 mg-4 g.

[0032] Furthermore, the unit dose of the salvianolic acid B or its salt in the medicine or health product is selected from 50-500 mg, 100 mg-400 mg, 200-400 mg, and 350-400 mg.

[0033] Furthermore, the unit dose of the salvianolic acid B or its salt in the medicine or health product is selected from 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, and 400 mg.

[0034] Another aspect of the present invention relates to a pharmaceutical composition comprising salvianolic acid B or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers (or excipients).

[0035] Furthermore, the salvianolic acid B is the only active ingredient of the pharmaceutical composition.

[0036] Furthermore, the salvianolic acid B is used in combination with one or more other known second active ingredients for promoting the repair of uterine tissue damage, or the pharmaceutical composition is prepared in combination.

[0037] Furthermore, the second active ingredient is selected from any one or more of estrogen, progesterone, levothyroxine sodium, vitamin E, vitamin C, Centella asiatica extract, angelica extract, Leonurus japonicus extract, epidermal growth factor, fibroblast growth factor, vascular endothelial growth factor, arginine, glutamine, hyaluronic acid or sodium hyaluronate, zinc, lactic acid bacteria, collagen, and sialic acid.

[0038] Furthermore, the second active ingredient is estrogen.

[0039] Furthermore, the estrogen is estradiol and / or estradiol valerate.

[0040] Furthermore, the pharmaceutical composition may be in the form of a solid preparation, a liquid preparation or a semisolid preparation.

[0041] Furthermore, the pharmaceutical composition is prepared as an injectable preparation, an oral preparation, or a topical preparation for vaginal or anal administration.

[0042] Furthermore, the specific dosage forms of the preparation include, but are not limited to, injections, powders, effervescent tablets, tablets, hard capsules, soft capsules, granules, granules, oral liquids, pills, suppositories, gels, ointments, creams, and pastes.

[0043] Furthermore, the preparation is an injection, a tablet or a suppository.

[0044] Furthermore, the unit dosage of the aforementioned salvianolic acid B, its salt, or its ester in the pharmaceutical composition is 20 mg-4 g.

[0045] Furthermore, the unit dose of the salvianolic acid B, its salt, or its ester in the pharmaceutical composition is selected from 50-500 mg, 100 mg-400 mg, 200-400 mg, 350-400 mg.

[0046] Furthermore, the unit dose of the salvianolic acid B, its salt or ester in the pharmaceutical composition is selected from 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg.

[0047] Furthermore, the unit dosage of the salvianolic acid B, its salt, or its ester in the medicine or health product is 200 mg or 400 mg.

[0048] In the present invention, the dosage and method of use of the active ingredient salvianolic acid B, its salts, or its esters depend on many factors, including the patient's age, weight, health status, nutritional status, activity strength of the compound, time of administration, metabolic rate, severity of the disease, and subjective judgment of the treating physician.

[0049] In the present invention, the term "subject" may refer to a patient or other animal that receives the product or composition of the present invention to treat, prevent, alleviate and / or relieve the disease or condition described in the present invention, especially a mammal, such as a human, dog, monkey, cow, horse, etc.

[0050] In the present invention, the term "uterine tissue damage" refers to the damage of uterine tissue (including endometrium and myometrium) due to various reasons, resulting in abnormal structure or function. Uterine tissue damage can affect its normal function, leading to problems such as infertility and abnormal menstruation. Common causes include: 1. Physical damage, damage caused by artificial abortion / curettage / hysteroscopy or surgery / placement or removal of intrauterine contraceptive device, damage caused by childbirth (such as dystocia or postpartum curettage), etc.; 2. Damage caused by pathological factors, endometriosis in which endometrial tissue grows outside the uterus, uterine polyps or uterine fibroids that compress or destroy uterine tissue, and other pathological factors; 3. Damage caused by abnormal hormones: estrogen deficiency or long-term use of contraceptives causes thinning, atrophy or shedding of the endometrium; 4. Other factors: chemical damage caused by improper use of drugs or chemicals; damage caused by chronic diseases such as diabetes and autoimmune diseases. Common clinical manifestations include: pain (such as lower abdominal pain, dyspareunia), abnormal bleeding (such as abnormal menstruation, post-coital bleeding, postmenopausal bleeding), functional disorders (such as infertility, menstrual disorders), and structural changes (such as scar formation, adhesions, epithelial cell damage, shedding, and fibrosis).

[0051] In the present invention, the term "complications caused by uterine tissue damage" refers to functional abnormalities or health problems caused by untimely treatment of uterine tissue damage, including intrauterine adhesions, poor uterine tissue repair, intrauterine fluid, uterine tissue fibrosis, hydrosalpinx and fibrosis caused by uterine pathology, abnormal menstruation, infertility, chronic pelvic pain, abnormal menstruation, recurrent miscarriage, abnormal placenta implantation, premature birth, etc.

[0052] Advantageous Effects of the Invention

[0053] The experimental study of the present invention proves that the salvianolic acid B administered to mice with damaged uterine tissue by intraperitoneal injection at a dosage of 12.5-50 mg / kg / d can significantly promote the expression of epidermal growth factor (EGF) and fibroblast growth factor (FGF) in damaged uterine tissue, and can effectively repair uterine tissue damage, and its effect is better than that of the positive drug estradiol, while the toxic and side effects are greatly reduced. Therefore, the salvianolic acid B (or its salt or ester) of the present invention can be used in the preparation of products (medicines or health products) that promote uterine tissue repair. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 It is the chemical structural formula of salvianolic acid B.

[0055] Figure 2 The damage degree and score of uterine tissue of mice in each group.

[0056] Figure 3 The expression of EGF and FGF in the uterine tissue of each group of mice. DETAILED DESCRIPTION

[0057] The present invention is further described according to the specific embodiments and the accompanying drawings so that those skilled in the art can better understand the technical solution of the present invention. In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art.

[0058] Example 1 (Effect Experiment)

[0059] 1. Repair effect of salvianolic acid B on mice with uterine tissue damage

[0060] Female mice treated with synchronized physiological cycles were induced with respiratory anesthesia using 2% isoflurane, and then maintained with 1.5% isoflurane. 4% phloroglucinol (0.02 mg / g) was injected intraperitoneally to relax the mouse cervix. A small curette was inserted from the mouse vagina, and after probing the relaxation of the cervix, it entered the uterus to a depth of about 1 cm. The curette was used to gently scrape the endometrium, and each side of the uterus was scraped 50 times, and the scraping force should be moderate. After the scraping was completed, the curette was slowly withdrawn, and the mouse was placed under a warm lamp for recovery, and penicillin 5 mg / kg was injected intraperitoneally to prevent infection. Sal B (12.5, 25, 50 mg / kg) and E2 (10 μg) of corresponding concentrations were injected intraperitoneally every night in the Sal B group and the positive drug estradiol (E2) group. The model group was given an equal amount of sterile saline for 7 consecutive days. After modeling and drug treatment, the mice in each group (10 mice in each group) were eyeballed and blood was collected on the 8th day and then killed by cervical dislocation. After dissection, the mouse uterus was taken out, one side was fixed in 4% paraformaldehyde, and the other side was used to detect the levels of EGF and FGF. The fixed part of the tissue was stained with H&E to detect the pathological morphological changes of the mouse uterine tissue, and the histological score was performed according to the degree of uterine damage (0-3 grades, representing from normal to severe, including normal, mild, moderate and severe). Figure 2 As shown in the figure (# indicates significant difference between the model group and the control group, * indicates significant difference between the drug administration group and the model group, 1 indicates p < 0.05, 2 indicates p < 0.01), the uterine tissue structure of the control group was normal, without obvious histopathological changes. Compared with the control group, the pathological changes of the uterine tissue in the model group were more serious and obvious, as shown by: damage and shedding of endometrial epithelial cells; uterine effusion; fibrosis of uterine tissue. The degree of uterine tissue damage in the Sal B group and the positive drug group was repaired to varying degrees, and Sal B promoted tissue repair in a dose-dependent manner. The degree of repair of the Sal B medium-dose group and the positive drug group was comparable, and the high-dose group was superior to the positive drug group.

[0061] 2. Effect of salvianolic acid B on the levels of epidermal growth factor (EGF) and fibroblast growth factor (FGF) in the uterine tissue of mice with damaged uterine tissue

[0062] EGF and FGF can promote tissue damage and repair. After washing the uterine tissue with PBS, add PBS, protease inhibitors and cell lysis buffer, and homogenize on ice. Take the homogenate and use the protein detection kit (Biyuntian, P0010), EGF ELISA detection kit (Xinbosheng, EMC126) and FGF ELISA detection kit (Boster, J25181) for detection. Figure 3 As shown in the figure (# indicates significant difference between the model group and the control group, * indicates significant difference between the drug administration group and the model group, 1 indicates p < 0.05, 2 indicates p < 0.01), Sal B significantly promoted the expression of EGF and FGF in damaged uterine tissue in a dose-dependent manner. The effect of medium dose of Sal B was equivalent to that of positive drug, and the high dose was superior to that of positive drug.

[0063] Conclusion: This study found that after the uterine tissue of mice was damaged, salvianolic acid B could significantly promote the repair of tissue damage. In addition, those skilled in the art will know that when the uterine tissue is repaired, the complications caused by uterine tissue damage can also be prevented and repaired accordingly. Therefore, comprehensive analysis shows that salvianolic acid B (usually, including its salts or esters) is an effective ingredient that promotes the repair of uterine tissue damage and its complications, and can be used to prepare various dosage forms of drugs or health products.

[0064] Example 2 (Preparation of Salvianolic Acid B for Injection)

[0065] Weigh 5-20g of the salvianolic acid B compound and add it to 4 / 5 of the water for injection, stir and dissolve; add 10g of mannitol, stir and dissolve, and then add water for injection to 100mL; sterile filter through a 0.22μm microporous membrane, test the content of salvianolic acid B, pH, visible foreign matter, etc. of the solution, calculate the filling amount based on 100 bottles, and fill it into a cleaned, dried and sterilized tube bottle; after filling, freeze-dry according to freeze-drying conditions. After completion, pass dry sterile filtered nitrogen, cover with a rubber stopper, and roll an aluminum cap to obtain the product.

[0066] Example 3 (Preparation method of salvianolic acid B tablets)

[0067] Using a direct tableting method, 5-20 g of salvianolic acid B compound, 0.3 g of hydroxypropyl methylcellulose, 50-100 g of lactose monohydrate, 3 g of medicinal starch, 0.5 g of magnesium stearate, and 25-50 mg of microcrystalline cellulose are weighed, ground, passed through an 80-mesh sieve, and mixed evenly. The obtained powder is directly tableted using a rotary tablet press to obtain the product.

[0068] Example 4 (Preparation of Salvianolic Acid B Suppository)

[0069] Take semi-synthetic fatty acid glyceride, heat it in a water bath to melt it, reduce the temperature to about 50°C, add 5-20g of crushed and sieved salvianolic acid B compound, stir evenly, take samples for inspection, and after passing the inspection, inject them into the plug film, place it in a freezer, solidify it into shape, cut off the overflow part, and demould it to obtain the product.

[0070] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. Use of salvianolic acid B or its salt in the preparation of a medicine or health product for promoting the repair of uterine tissue damage, wherein: The uterine tissue includes endometrium and myometrium.

2. The use according to claim 1, wherein: The salt is a pharmaceutically acceptable salt selected from any one or more of lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, strontium salts, zinc salts, aluminum salts, barium salts, ammonium salts, choline salts, triethylamine salts, ethanolamine salts, acetates, citrates, salicylates, lactates, lysine salts, arginine salts, and ornithine salts.

3. The use according to claim 1 or 2, wherein: The uterine tissue damage includes uterine tissue damage and / or complications caused by uterine tissue damage.

4. The use according to claim 3, wherein: The uterine tissue damage includes physical damage, damage caused by pathological factors, and damage caused by abnormal hormones; preferably, the physical damage includes uterine tissue damage caused by curettage, uterine tissue damage caused by hysteroscopic surgery, uterine tissue damage caused by laparoscopic surgery, uterine tissue damage caused by the removal of intrauterine contraceptive devices, and uterine tissue damage caused by the delivery process; The damage caused by the pathological factors includes uterine tissue damage caused by endometriosis, uterine tissue damage caused by uterine polyps, and uterine tissue damage caused by uterine fibroids; the damage caused by hormonal abnormalities includes uterine tissue damage caused by endocrine disorders.

5. The use according to claim 3, wherein: The complications caused by uterine tissue damage include one or more of uterine adhesions, poor uterine tissue repair, uterine cavity effusion, uterine tissue fibrosis, hydrosalpinx and fibrosis caused by uterine pathology, abnormal menstruation, infertility, chronic pelvic pain, abnormal menstruation, recurrent miscarriage, abnormal placenta implantation, and premature birth.

6. The use according to claim 1, wherein: The promoting the repair of uterine tissue damage includes promoting the repair of pathological tissue, promoting the repair of damaged epithelial cells, reducing uterine cavity effusion, reducing uterine fibrosis, increasing the level of epidermal growth factor in damaged tissue, and increasing the level of fibroblast growth factor in damaged tissue.

7. The use according to any one of claims 1-2, 4-6, characterized in that: The medicine or health product also includes pharmaceutically acceptable excipients or excipients acceptable for registered health food products, and is prepared as a preparation for use. The preparation includes a solid preparation, a liquid preparation or a semisolid preparation; preferably, the preparation is an injectable preparation, an oral preparation, a topical preparation for vaginal use, or a topical preparation for anal use.

8. The use according to claim 7, wherein: The preparation is selected from injection, powder, granule, effervescent tablet, tablet, hard capsule, soft capsule, granule, granule, oral solution, pill, suppository, gel, ointment, cream, paste; preferably, the preparation is injection, tablet or suppository.

9. The use according to claim 8, characterized in that: The medicine or health product further comprises a second active ingredient.

10. The use according to any one of claims 1-2, 4-6, 8-9, characterized in that: The unit dosage of the salvianolic acid B or its salt in the medicine or health product is 20 mg-4 g, preferably 100 mg-400 mg, more preferably 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg.

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