Application of beta-elemonic acid or derivative thereof in preparation of medicine for preventing and / or treating polycystic ovarian syndrome

Abstract

The invention belongs to the technical field of biological medicines, and discloses application of beta-elemonic acid or derivatives thereof or pharmaceutically acceptable salts thereof in preparation of medicines for preventing and / or treating polycystic ovarian syndrome (PCOS). The beta-elemonic acid is screened from a medicinal and edible library, and experiments prove that the beta-elemonic acid can remarkably improve the PCOS ovarian form and the number of mature follicles, normalize the disordered estrus cycle, remarkably improve the serum hormone level and further remarkably improve the sugar tolerance, insulin tolerance and weight of PCOS. The beta-elemonic acid disclosed by the invention is a compound based on homology of medicine and food, can be used as a medicine as well as a natural ingredient of food, is relatively low in toxicity, ensures the safety after long-term use, is relatively low in safety evaluation cost of a relatively brand-new synthetic compound, and can be applied to development and preparation of a medicine or a lead compound thereof for preventing and / or treating PCOS, or a health care product.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and particularly relates to the use of β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing and / or treating polycystic ovary syndrome. Background Art

[0002] Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women characterized by hyperandrogenism, ovulatory abnormalities, and polycystic ovaries, often accompanied by insulin resistance, glucose intolerance, and obesity. PCOS severely compromises the reproductive health of women of childbearing age and also affects the health of offspring during fetal development, childhood, childbearing years, and even into middle and old age. However, due to the clinical heterogeneity and complexity of PCOS, its etiology and pathophysiological mechanisms remain largely unexplained. Currently, no effective treatment for PCOS is available, either domestically or internationally. Current clinical drug treatments and their limitations include the following: 1. For adolescents and women of childbearing age who do not desire childbearing, oral contraceptives are used to regulate menstrual cycles. However, these methods only induce artificial "menstruation," protect the endometrium from prolonged anovulation, and reduce acne and hirsutism caused by hyperandrogenism. However, they do not cure PCOS, and menstrual irregularities and amenorrhea can still occur after discontinuation of the medication. 2. For anti-hyperandrogen therapy in patients with poor response to contraceptives, spironolactone is often used. However, this medication requires a long treatment cycle, and long-term use of high doses often causes side effects such as hypotension and hyperkalemia, headaches, or polyuria. 3. For patients with obesity and lipid disorders, diagnostic and treatment guidelines recommend the use of metformin or insulin sensitizers. However, long-term use is often associated with gastrointestinal side effects, vitamin B12 deficiency, and exacerbated liver and kidney damage. In summary, each existing drug class treats a single symptom, hormonal medications are prone to complications, and other medications are less effective. Consequently, there is currently a lack of effective comprehensive treatments for PCOS. Summary of the Invention

[0003] In order to overcome the above-mentioned shortcomings and deficiencies of the prior art, the primary object of the present invention is to provide the use of β-elemenic acid (β-EA) or its derivatives or pharmaceutically acceptable salts in the preparation of drugs or their lead compounds for preventing and / or treating polycystic ovary syndrome.

[0004] The present invention screened β-elemenic acid from a library of medicinal and edible compounds. Studies have shown that β-elemenic acid can significantly improve ovarian morphology and the number of mature follicles in PCOS, normalize disrupted estrous cycles, and significantly improve serum hormone levels. Based on the fact that compounds in this library can be used as both pharmaceuticals and natural food ingredients, these compounds have low toxicity, are safe for long-term use, and have lower safety assessment costs than newer synthetic compounds. These compounds can be used in the development and preparation of drugs or lead compounds for the prevention and / or treatment of PCOS.

[0005] Another object of the present invention is to provide a use of β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof in the preparation of health products for auxiliary prevention and / or auxiliary treatment of PCOS.

[0006] The purpose of the present invention is achieved through the following solutions:

[0007] Use of β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing and / or treating PCOS or their lead compounds.

[0008] The β-elemenic acid has a structure shown in the following formula:

[0009]

[0010] Furthermore, one or more hydrogen atoms on the molecular chain of the β-elemenic acid may be substituted by a halogen atom, a C1-C20 linear / branched / cyclic alkyl group, a C1-C20 haloalkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C20 alkoxy group, a C1-C10 hydroxyalkyl group, a hydroxyl group, a C1-C20 carbonyl group, a carboxyl group, a cyano group, a nitro group, an amino group, a phenyl group, a C1-C20 ester group, a C6-C20 aryl group, or the like.

[0011] Furthermore, the drugs are the same or different and respectively comprise a therapeutically effective amount of β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof.

[0012] Furthermore, the drugs, whether the same or different, can be made into various pharmaceutical dosage forms using conventional methods. These dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, electuary preparations, pills, pills, suspensions, alcohol preparations, tinctures, drops and other oral dosage forms, as well as injections and other non-oral dosage forms, such as injections.

[0013] Furthermore, the drugs, whether the same or different, may also contain one or more pharmaceutically acceptable carriers or excipients.

[0014] Further, the carrier or adjuvant can include diluents, binders, surface active agents, wetting agents, adsorptive carriers, lubricants, fillers, disintegrants, preservatives, etc.

[0015] The present application also provides a pharmaceutical composition for treating PCOS, comprising the β-elemene acid or its derivative or its pharmaceutically acceptable salt or other components thereof.

[0016] The present application also provides the use of β-elemene acid or its derivative or its pharmaceutically acceptable salt in the preparation of health care products for assisting in the prevention and / or treatment of PCOS.

[0017] The present application screens β-elemene acid from the medicinal and edible homologous library, and the β-elemene acid or its derivative or its pharmaceutically acceptable salt can significantly improve the ovary morphology and the number of mature follicles of PCOS, normalize the estrous cycle, and significantly improve the serum high androgen level; in addition, the β-elemene acid or its derivative or its pharmaceutically acceptable salt can significantly improve the glucose tolerance, insulin tolerance and body weight of PCOS, and can be applied to the development and preparation of a drug or a lead compound for preventing and / or treating PCOS, or a health care product. BRIEF DESCRIPTION OF DRAWINGS

[0018] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiments will be briefly introduced below, and it should be understood that the following drawings only show some of the embodiments of the present application, and therefore should not be regarded as a limitation on the scope, and for those skilled in the art, other related drawings can also be obtained without creative labor.

[0019] Figure 1 It is the observation result of H&E staining ovary morphology.

[0020] Figure 2 It is the statistical chart of rat follicle number.

[0021] Figure 3 It is the statistical chart of rat estrous cycle.

[0022] Figure 4 It is the testosterone level in rat serum.

[0023] Figure 5 It is the body weight change of rat.

[0024] Figure 6 It is the fasting blood glucose of rat.

[0025] Figure 7 It is the glucose tolerance of rat.

[0026] Figure 8 It is the insulin tolerance of rat.

[0027] Among them, *p<0.05, **p<0.01, ***p<0.001; #p<0.05, ##p<0.01, ###p<0.001. DETAILED DESCRIPTION

[0028] The present invention will be further described in detail below with reference to the examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the materials involved in the following examples can be obtained from commercial channels. The methods described are conventional methods unless otherwise specified.

[0029] In one embodiment, β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof are used in the preparation of a drug or its lead compound for preventing and / or treating PCOS.

[0030] In a specific embodiment of the present invention, the β-elemenic acid has a structure shown in the following formula:

[0031]

[0032] In a specific embodiment of the present invention, one or more hydrogen atoms on the molecular chain of the β-elemenic acid may be replaced by a halogen atom, a C1-C20 linear / branched / cyclic alkyl group, a C1-C20 haloalkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C20 alkoxy group, a C1-C10 hydroxyalkyl group, a hydroxyl group, a C1-C20 carbonyl group, a carboxyl group, a cyano group, a nitro group, an amino group, a phenyl group, a C1-C20 ester group, a C6-C20 aryl group, or the like.

[0033] In a specific embodiment of the present invention, the drugs are the same or different and respectively comprise a therapeutically effective amount of β-elemenic acid or a derivative thereof or a pharmaceutically acceptable salt thereof.

[0034] In another embodiment, a pharmaceutical composition for treating PCOS comprises the β-elemenic acid or its derivatives or pharmaceutically acceptable salts or other pharmaceutically acceptable components.

[0035] In another embodiment, β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof are used in the preparation of health products for auxiliary prevention and / or auxiliary treatment of PCOS.

[0036] In a specific embodiment of the present invention, the dosage of the drug or pharmaceutical composition of the present invention can be prescribed in a variety of ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, morbidity, diet, administration time, administration route, excretion rate and reaction sensitivity. A skilled physician can usually easily determine the prescription and the dosage that is effective for the desired treatment or prevention.

[0037] In a specific embodiment of the present invention, the therapeutically effective amount refers to an amount that can produce a therapeutic effect on humans and / or animals and can be accepted by humans and / or animals. For example, a therapeutically or pharmaceutically effective amount refers to the amount of the drug required to produce the desired therapeutic effect, and the therapeutic effect can be reflected by the results of clinical trials, model animal studies and / or in vitro studies. The pharmaceutically effective amount depends on several factors, including but not limited to: characteristic factors of the subject to be treated (such as the subject's height, weight, gender, age and medication history, etc.), and the severity of the disease.

[0038] In a specific embodiment of the present invention, the therapeutically effective amount refers to an amount that can produce a therapeutic effect on PCOS patients and can be accepted by the patients.

[0039] In a specific embodiment of the present invention, the administration of the drug or pharmaceutical composition includes, but is not limited to, oral administration, parenteral administration, administration by inhalation spray, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, or administration via an implanted drug reservoir. Oral administration or injection is preferred.

[0040] In a specific embodiment of the present invention, any orally acceptable dosage form can be used, including but not limited to capsules (hard capsules, soft capsules), tablets (sugar-coated tablets, film-coated tablets, enteric-coated tablets), aqueous suspensions or solutions.

[0041] In specific embodiments of the invention, liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.

[0042] In a specific embodiment of the invention, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0043] In a specific embodiment of the present invention, the drug or pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients. The pharmaceutically acceptable carrier or excipient may contain an inert component that does not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier or excipient should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic or without other undesirable reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques can be used.

[0044] In a specific embodiment of the present invention, pharmaceutically acceptable carriers or excipients include, but are not limited to, diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers, disintegrants, preservatives, etc. These substances are used to help the stability of the formulation, or to help improve the activity or its biological effectiveness, or to produce an acceptable taste or smell in the case of oral administration. The preparations that can be used in such pharmaceutical compositions can be in the form of the original compound itself or optionally in the form of a pharmaceutically acceptable salt thereof. The pharmaceutical composition thus formulated can be administered by any appropriate method known to those skilled in the art as needed.

[0045] In a specific embodiment of the present invention, the diluent includes but is not limited to lactose, sodium chloride, glucose, urea, starch, water.

[0046] In a particular embodiment of the present invention, binders include, but are not limited to, starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, alginic acid and alginates, xanthan gum, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0047] In a specific embodiment of the present invention, the surfactant includes but is not limited to polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, and cetyl alcohol.

[0048] In a specific embodiment of the present invention, the humectant includes but is not limited to glycerin and starch.

[0049] In a specific embodiment of the present invention, the adsorption carrier includes, but is not limited to, starch, lactose, bentonite, silica gel, kaolin and bentonite.

[0050] In a specific embodiment of the present invention, lubricants include but are not limited to zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, and magnesium lauryl sulfate.

[0051] In a specific embodiment of the present invention, fillers include, but are not limited to, mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polymeric sugars, coupling sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, laminarin powder, agar powder, calcium carbonate, and sodium bicarbonate.

[0052] In a specific embodiment of the present invention, the disintegrant includes but is not limited to cross-linked vinyl pyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl methyl, cross-linked sodium carboxymethyl cellulose, and soybean polysaccharide.

[0053] In a specific embodiment of the present invention, the medicine or pharmaceutical composition further comprises other drugs for treating PCOS, that is, the β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof can be used in combination with other compounds that can be used to treat PCOS.

[0054] Example 1: In vivo study on the improvement of PCOS by β-elemenic acid

[0055] (1) Establishment of PCOS model

[0056] Sprague Dawley rats were housed in the clean-grade laboratory animal facility of Guangzhou Medical University. This animal model was established using dehydroepiandrosterone (DHEA). Four-week-old female rats were subcutaneously injected with DHEA (60 mg / kg body weight) daily for 28 consecutive days. The successful establishment of the PCOS model was assessed by measuring serum testosterone levels, estrous cycles, and H&E staining of the ovaries and the number of mature follicles.

[0057] (2) Experimental groups and drug administration

[0058] This experiment involved five rats in each group: a normal control (Vehicle), a model (PCOS) group, a low-dose β-EA group (10 mg / kg), and a high-dose β-EA group (20 mg / kg). After successful model establishment, the Vehicle and PCOS groups were given an equal amount of PEG300 by oral gavage daily, while the low-dose and high-dose β-EA groups were given the corresponding dose (dissolved in 0.2 mL of PEG300) by oral gavage daily for 28 days.

[0059] (3) Experimental results testing and data collection

[0060] Starting on the 10th day of dosing, vaginal smears were obtained daily for observation of estrous cycles. Blood glucose and body weight were measured every 7 days after fasting. Glucose tolerance was tested on the 25th day after dosing, and insulin tolerance was tested and blood samples were collected on the 28th day. On the 25th day, after fasting for 12 hours, rats were intraperitoneally injected with glucose (2g / kg body weight), and blood glucose levels were measured at 0, 30, 60, 90, and 120 minutes. Three days later (to exclude the effect of glucose on insulin sensitivity), rats were fasted for 6 hours and injected with insulin (0.5U / kg body weight). Blood glucose levels were then measured at 0, 30, 60, 90, and 120 minutes. Ovarian tissue was then collected and paraffin-embedded and sectioned for HE staining to observe ovarian morphological changes. Serum samples were analyzed for testosterone levels by ELISA.

[0061] (4) Result analysis

[0062] ①β-EA significantly improves PCOS ovarian morphology and the number of mature follicles

[0063] The core feature of reproductive dysfunction in PCOS patients is follicular development disorder and a decrease in the number of mature follicles. Figure 1 The ovarian morphology of each group was observed under an H&E staining microscope. In the normal control group, ovarian follicles and corpora lutea at different stages of development were visible, and the granulosa cells were intact and neatly arranged. In the PCOS model group, the ovaries of rats increased in atresia, with fewer mature follicles, many of which contained no oocytes. The granulosa cells were loosely arranged, with thinner layers and some detached, and few corpora lutea were formed. In both the low- and high-dose β-EA groups, follicles at different stages of development were visible, with a restored number of mature follicles, denser arrangement of granulosa cells, and increased layers, with a morphology similar to that of the normal control group. Figure 2 The comparison of the number of mature follicles in the ovaries of rats in different groups shows that the number of mature follicles in the PCOS group is significantly reduced compared with the normal control group, while the number of mature follicles in the low-dose and high-dose β-EA groups of the present invention is significantly increased compared with the PCOS group.

[0064] ②β-EA significantly improves the disordered estrous cycle of PCOS rats

[0065] Figure 3 The figure is a statistical chart of the rat estrous cycle. Figure 3 It can be seen that the observation results from the 10th day after the successful administration of the PCOS model showed that the normal control group showed a regular 4-5 day estrous cycle (Proestrus: proestrus, Estrus: estrus, Metestrus: metestrus, Diestrus: diestrus); the estrous cycle of the PCOS model group was disordered and remained in the diestrus; the estrous cycles of the low-dose and high-dose β-EA groups of the present invention both returned to normal levels.

[0066] ③β-EA significantly improves serum high androgen levels in PCOS rats

[0067] One of the main clinical manifestations and detection indicators of PCOS is hyperandrogenism. Serum testosterone levels in each group were measured using ELISA according to the kit instructions (Finetest, Wuhan). Figure 4 The figure shows the changes in serum testosterone levels in each group of rats. As shown in the figure, the serum testosterone level in the normal control group was approximately 700 pg / mL; the serum testosterone level in the PCOS group was approximately 4500 pg / mL, significantly higher than the control group; and the serum testosterone levels in the low-dose and high-dose β-EA groups of the present invention were approximately 1000 pg / mL and 1200 pg / mL, respectively, significantly lower than the PCOS group and close to the control group.

[0068] ④β-EA significantly improved the body weight of PCOS rats

[0069] PCOS is accompanied by hyperandrogenism, which often affects appetite and metabolism, leading to excessive eating and weight gain. In addition, PCOS rats usually show insulin resistance, which weakens the effect of insulin in the body and cannot effectively regulate glucose and fat metabolism, thereby promoting fat accumulation and weight gain. Figure 5 As shown in the figure, the weight of the PCOS group increased significantly over time compared with the normal group, while the weight of the β-EA group of the present invention decreased significantly, and the weight of the high-dose group decreased to a level close to that of the control group.

[0070] ⑤β-EA significantly improved blood glucose, glucose tolerance and insulin sensitivity in PCOS rats

[0071] PCOS rats often exhibit insulin resistance, which means the body's response to insulin is reduced, resulting in the inability of insulin to effectively promote glucose absorption by cells, leading to increased blood sugar levels and decreased insulin sensitivity. Figure 6 The fasting blood glucose level of the PCOS group was significantly higher than that of the normal group, while the low-dose and high-dose β-EA groups of the present invention significantly reduced the fasting blood glucose level of the PCOS group. Figure 7 The low-dose and high-dose β-EA groups of the present invention can significantly reduce the blood sugar levels of PCOS rats, indicating that their glucose tolerance has been restored. Figure 8 The insulin tolerance of PCOS rats is affected, and the insulin secretion function of PCOS rats under insulin stimulation is affected, resulting in increased insulin levels but still unable to effectively control blood sugar; the low-dose and high-dose β-EA groups of the present invention can significantly reduce the blood sugar of PCOS rats under insulin stimulation and improve insulin tolerance.

[0072] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Use of β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof in the preparation of a drug or its lead compound for preventing and / or treating polycystic ovary syndrome.

2. The use according to claim 1, characterized in that The β-elemenic acid has a structure shown in the following formula:

3. The use according to claim 1, characterized in that One or more hydrogen atoms on the molecular chain of the β-elemenic acid are replaced by a halogen atom, a C1-C20 linear / branched / cyclic alkyl group, a C1-C20 haloalkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C20 alkoxy group, a C1-C10 hydroxyalkyl group, a hydroxyl group, a C1-C20 carbonyl group, a carboxyl group, a cyano group, a nitro group, an amino group, a phenyl group, a C1-C20 ester group or a C6-C20 aryl group.

4. The use according to claim 1, characterized in that: The medicine comprises a therapeutically effective amount of β-elemenic acid or a derivative thereof or a pharmaceutically acceptable salt thereof.

5. The use according to claim 1, characterized in that: The drugs are the same or different and are prepared into various pharmaceutical dosage forms by conventional methods. These dosage forms include: tablets, capsules, oral liquids, lozenges, granules, granules, pills, pills, suspensions, wines, tinctures, drops for oral administration and injection dosage forms.

6. The use according to claim 1, characterized in that: The drugs are the same or different and are made into various pharmaceutical dosage forms by conventional methods. These dosage forms include: sugar-coated tablets, film-coated tablets, enteric-coated tablets, hard capsules, soft capsules, oral liquids, lozenges, granules, electuary preparations, pills, pills, suspensions, wine preparations, tinctures, oral dosage forms of drops and injections.

7. The use according to claim 1, characterized in that: The medicine further contains one or more pharmaceutically acceptable carriers or excipients.

8. The use according to claim 7, characterized in that: The carrier or auxiliary material includes at least one of a diluent, a binder, a surfactant, a wetting agent, an adsorption carrier, a lubricant, a filler, a disintegrant and a preservative.

9. A pharmaceutical composition for treating polycystic ovary syndrome, characterized in that The invention comprises the beta-elemenic acid or its derivative or its pharmaceutically acceptable salt or other pharmaceutically acceptable components.

10. Use of β-elemenic acid or its derivatives or pharmaceutically acceptable salts thereof in the preparation of health products for auxiliary prevention and / or auxiliary treatment of polycystic ovary syndrome.

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