Use of beta-elemene or its derivatives in the preparation of a drug for preventing and / or treating polycystic ovary syndrome

Abstract

The application belongs to the technical field of biological medicine, and discloses application of beta-elemene acid or a derivative or a pharmaceutically acceptable salt thereof in preparation of a medicine for preventing and / or treating polycystic ovary syndrome (PCOS). The beta-elemene acid is screened from a medicinal and edible homology library, and experiments prove that the beta-elemene acid can significantly improve the ovary morphology and mature follicle quantity of PCOS, normalize the estrous cycle, significantly improve the serum hormone level, and also significantly improve the glucose tolerance, insulin tolerance and body weight of PCOS. The beta-elemene acid of the application is a compound based on medicinal and edible homology, which can be used as a medicine and also as a natural ingredient of food, has low toxicity, is safe in long-term use, has low cost of safety evaluation of a relatively new synthetic compound, and can be applied to development and preparation of a medicine for preventing and / or treating PCOS or a lead compound thereof.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and specifically relates to the use of β-elemene acid or its derivatives or pharmaceutically acceptable salts in the preparation of drugs for the prevention and / or treatment of polycystic ovary syndrome. Background Technology

[0002] Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women, characterized by hyperandrogenemia, ovulation abnormalities, and polycystic ovaries, often accompanied by insulin resistance, glucose tolerance, and obesity. PCOS seriously endangers the reproductive health of women of reproductive age and also affects the health of offspring during fetal development, childhood, reproductive years, and even middle and old age. However, due to the clinical heterogeneity and complexity of PCOS, its pathogenesis and pathophysiological mechanisms remain unclear, and currently there are no effective drugs for the treatment of PCOS, either domestically or internationally. Current clinical drug treatments and their limitations mainly include: 1. For adolescents and women of reproductive age who do not desire fertility, oral contraceptives are used to regulate the menstrual cycle. However, this method only creates an artificial menstrual cycle, protecting the endometrium from the effects of long-term anovulation caused by single estrogen stimulation and reducing acne and hirsutism caused by high androgen levels. It does not treat PCOS, and menstrual irregularities and amenorrhea can still occur after discontinuation. 2. For anti-androgen therapy when oral contraceptives are ineffective, spironolactone is often used. However, this drug has a long treatment cycle, and long-term use at high doses often causes side effects such as hypotension, hyperkalemia, headache, or polyuria. 3. For obese patients and those with glucose and lipid metabolism disorders, treatment guidelines recommend metformin or insulin sensitizers. Long-term use commonly causes gastrointestinal side effects, vitamin B12 deficiency, and exacerbation of liver and kidney damage. In summary, each existing drug class treats a single symptom, hormonal drugs have many complications, and other drugs have poor efficacy. Therefore, there is currently a lack of comprehensive drugs for effectively treating PCOS. Summary of the Invention

[0003] In order to overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide the use of β-elemeneic acid (β-EA) or its derivatives or pharmaceutically acceptable salts in the preparation of drugs for the prevention and / or treatment of polycystic ovary syndrome or their lead compounds.

[0004] This invention screened β-elemene acid from a library of food and medicine homologous compounds. Studies found that β-elemene acid can significantly improve ovarian morphology and the number of mature follicles in patients with PCOS, normalize disordered estrous cycles, and significantly improve serum hormone levels. Since compounds from food and medicine homologous compounds can be used as both drugs and natural food ingredients, these compounds have low toxicity, guaranteed long-term safety, and lower safety assessment costs compared to novel synthetic compounds. They can be used to develop and prepare drugs for the prevention and / or treatment of PCOS or their lead compounds.

[0005] The objective of this invention is achieved through the following solution:

[0006] The use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of drugs for the prevention and / or treatment of PCOS or their lead compounds.

[0007] The β-elemene acid has the structure shown in the following formula:

[0008]

[0009] Furthermore, one or more hydrogen atoms on the molecular chain of the β-elemeneic acid may be substituted with halogen atoms, C1-C20 straight-chain / branched / cyclic alkyl groups, C1-C20 haloalkyl groups, C2-C10 alkenyl groups, C2-C10 alkynyl groups, C1-C20 alkoxy groups, C1-C10 hydroxyalkyl groups, hydroxyl groups, C1-C20 carbonyl groups, carboxyl groups, cyano groups, nitro groups, amino groups, phenyl groups, C1-C20 ester groups, C6-C20 aryl groups, etc.

[0010] Furthermore, the same or different drugs respectively include therapeutically effective amounts of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts thereof.

[0011] Furthermore, the same or different drugs can be prepared 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, powders, pills, elixirs, suspensions, tinctures, drops, and other oral dosage forms, as well as non-oral dosage forms such as injections.

[0012] Furthermore, the drugs, whether identical or different, may also contain one or more pharmaceutically acceptable carriers or excipients.

[0013] Furthermore, the carrier or excipient may include diluents, adhesives, surfactants, humectants, adsorbents, lubricants, fillers, disintegrants, preservatives, etc.

[0014] The present invention also provides a pharmaceutical composition for treating PCOS, comprising the β-elemene acid or a derivative thereof or a pharmaceutically acceptable salt thereof or other pharmaceutically acceptable components thereof.

[0015] This invention screens β-elemene acid from a library of food and medicine homologous substances. β-elemene acid or its derivatives or pharmaceutically acceptable salts can significantly improve ovarian morphology and the number of mature follicles in PCOS, normalize disordered estrous cycles, and significantly improve serum hyperandrogen levels. In addition, β-elemene acid or its derivatives or pharmaceutically acceptable salts can significantly improve glucose tolerance, insulin tolerance, and body weight in PCOS, and can be used in the development and preparation of drugs or lead compounds for the prevention and / or treatment of PCOS. Attached Figure Description

[0016] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 Results of H&E staining for ovarian morphology observation.

[0018] Figure 2 This is a statistical chart of the number of rat follicles.

[0019] Figure 3 This is a statistical graph of the estrous cycle in rats.

[0020] Figure 4 This represents the serum testosterone level in rats.

[0021] Figure 5 This represents the change in rat body weight.

[0022] Figure 6 The result is fasting blood glucose in rats.

[0023] Figure 7 This refers to the glucose tolerance test in rats.

[0024] Figure 8 This is for rat insulin tolerance.

[0025] Where * p<0.05, ** p<0.01, *** p<0.001; # p<0.05, ## p<0.01, ### p<0.001. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, all materials involved in the following embodiments are commercially available. Unless otherwise specified, all methods described are conventional methods.

[0027] In one embodiment, the use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of PCOS or their lead compounds.

[0028] In a specific embodiment of the present invention, the β-elemene acid has the structure shown in the following formula:

[0029]

[0030] In a specific embodiment of the present invention, one or more hydrogen atoms on the molecular chain of the β-elemeneic acid may be substituted by halogen atoms, C1-C20 straight-chain / branched / cyclic alkyl groups, C1-C20 haloalkyl groups, C2-C10 alkenyl groups, C2-C10 alkynyl groups, C1-C20 alkoxy groups, C1-C10 hydroxyalkyl groups, hydroxyl groups, C1-C20 carbonyl groups, carboxyl groups, cyano groups, nitro groups, amino groups, phenyl groups, C1-C20 ester groups, C6-C20 aryl groups, etc.

[0031] In specific embodiments of the present invention, the drugs, whether identical or different, include therapeutically effective amounts of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts thereof.

[0032] In another embodiment, a pharmaceutical composition for treating PCOS comprises the aforementioned β-elemeneic acid or a derivative thereof, or a pharmaceutically acceptable salt thereof, or other pharmaceutically acceptable components thereof.

[0033] In specific embodiments of the present invention, the dosage of the drug or pharmaceutical composition of the present invention can be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, condition, diet, administration time, route of administration, excretion rate and responsiveness. Skilled physicians can usually easily determine the prescription and the dosage that is effective for the desired treatment or prevention.

[0034] In specific embodiments of the present invention, the therapeutically effective amount refers to an amount that can produce a therapeutic effect on humans and / or animals and is acceptable to humans and / or animals. For example, a therapeutically or pharmaceutically effective amount refers to the amount of drug required to produce the desired therapeutic effect, which can be reflected by the results of clinical trials, animal model studies, and / or in vitro studies. A pharmaceutically effective amount depends on several factors, including but not limited to: the characteristics of the treatment subject (such as the height, weight, sex, age, and medication history of the treatment subject), and the severity of the disease.

[0035] 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 is acceptable to the patients.

[0036] In specific embodiments of the present invention, the administration methods of the drug or drug composition include, but are not limited to: oral administration, non-gastrointestinal administration, administration via inhalation spray, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, or administration via an implanted drug storage device. Oral administration or injection is preferred.

[0037] In specific embodiments of the present invention, any orally acceptable dosage form may 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.

[0038] In specific embodiments of the present invention, liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.

[0039] In specific embodiments of the present invention, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0040] In specific embodiments of the invention, the drug or pharmaceutical composition further includes one or more pharmaceutically acceptable carriers or excipients. The pharmaceutically acceptable carriers or excipients may contain inert components that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carriers or excipients should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or free from other undesirable reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques can be used.

[0041] In specific embodiments of the invention, pharmaceutically acceptable carriers or excipients include, but are not limited to, diluents, binders, surfactants, humectants, adsorbents, lubricants, fillers, disintegrants, preservatives, etc. These substances are used as needed to aid in the stability of the formulation or to contribute to its activity or bioavailability, or to produce an acceptable taste or odor when taken orally. Formulations that can be used in such pharmaceutical compositions may be in the form of the original compound itself or optionally in the form of its pharmaceutically acceptable salts. Such formulated pharmaceutical compositions may be administered in any suitable manner known to those skilled in the art as needed.

[0042] In specific embodiments of the present invention, the diluent includes, but is not limited to, lactose, sodium chloride, glucose, urea, starch, and water.

[0043] In specific embodiments of the present invention, the adhesive includes, but is not limited to, starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, alginate and alginates, xanthan gum, hydroxypropylcellulose and hydroxypropylmethylcellulose.

[0044] In specific embodiments of the present invention, the surfactants include, but are not limited to, polyethylene oxide sorbitan fatty acid ester, sodium lauryl sulfate, glyceryl monostearate, and hexadecyl alcohol.

[0045] In specific embodiments of the present invention, the humectant includes, but is not limited to, glycerin and starch.

[0046] In specific embodiments of the present invention, the adsorption carrier includes, but is not limited to, starch, lactose, bentonite, silica gel, kaolin, and soap clay.

[0047] In specific embodiments of the present invention, the lubricant includes, but is not limited to, zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearate fumarate, polyoxyethylene monostearate, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, and magnesium dodecyl sulfate.

[0048] In specific embodiments of the present invention, the fillers include, but are not limited to, mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polysaccharides, coupled sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, kelp polysaccharide powder, agar powder, calcium carbonate, and sodium bicarbonate.

[0049] In specific embodiments of the present invention, the disintegrants include, but are not limited to, crosylvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylmethyl, crosylcarboxymethyl cellulose sodium, and soybean polysaccharides.

[0050] In a specific embodiment of the present invention, the drug or drug composition further includes other drugs for treating PCOS, namely, the β-elemene acid or its derivatives or pharmaceutically acceptable salts thereof may be used in combination with other compounds that can be used to treat PCOS.

[0051] Example 1: In vivo study of β-elemene acid improving PCOS

[0052] (1) Establishment of the PCOS model

[0053] 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. Successful establishment of the PCOS model was assessed by detecting serum testosterone levels, estrous cycles, H&E staining of the ovaries, and the number of mature follicles.

[0054] (2) Experimental grouping and drug administration

[0055] This experiment was divided into a normal control group (Vehicle), a model group (PCOS), a low-dose β-EA group (10 mg / kg), and a high-dose β-EA group (20 mg / kg); each group consisted of 5 rats. After successful modeling, the Vehicle and PCOS groups were administered an equal amount of PEG300 by gavage daily, while the low-dose and high-dose β-EA groups were administered the corresponding doses (dissolved in 0.2 mL of PEG300) by gavage daily for 28 days.

[0056] (3) Experimental results detection and data collection

[0057] Starting from day 10 of drug administration, vaginal smears were collected daily for staining to observe the estrous cycle. Blood glucose and body weight were measured every 7 days after fasting. Glucose tolerance was tested on day 25 after drug administration, and insulin tolerance was tested and samples were collected on day 28. On day 25, after fasting for 12 hours, glucose (2 g / kg body weight) was injected intraperitoneally, and blood glucose levels were measured at 0, 30, 60, 90, and 120 minutes. Three days later (excluding the influence of glucose tolerance testing on insulin sensitivity), after fasting for 6 hours, insulin (0.5 U / kg body weight) was injected, and blood glucose levels were measured at 0, 30, 60, 90, and 120 minutes. Then, samples were collected. Ovarian tissue was embedded in paraffin and stained with hematoxylin and eosin (HE) to observe ovarian morphological changes. Serum samples were used to detect testosterone levels by ELISA.

[0058] (4) Results Analysis

[0059] ①β-EA significantly improves ovarian morphology and the number of mature follicles in PCOS.

[0060] The core characteristic of reproductive dysfunction in patients with PCOS is impaired follicular development, resulting in a reduced number of mature follicles. Figure 1The ovarian morphology of each group was observed under a microscope after H&E staining. In the normal control group, follicles and corpora lutea at different developmental stages were visible in the ovaries of rats, with intact granulosa cells and neat arrangement. In the PCOS model group, ovarian atresia increased, mature follicles decreased, many follicles did not contain oocytes, granulosa cells were loosely arranged, the number of layers decreased, some detached, and corpus luteum formation was reduced. In contrast, in the low-dose and high-dose β-EA groups of this invention, follicles at different developmental stages were visible, the number of mature follicles recovered, granulosa cells were more tightly arranged, the number of layers increased, and the morphology was close to that of the normal control group. Figure 2 Comparison of the number of mature follicles in the ovaries of rats in different groups showed that the number of mature follicles in the PCOS group was 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 this invention was significantly increased compared with the PCOS group.

[0061] ②β-EA significantly improved the disordered estrous cycle in PCOS rats.

[0062] Figure 3 This is a statistical graph of the estrous cycle in rats. Figure 3 As can be seen, the observation results from the 10th day after successful PCOS modeling showed that the normal control group exhibited a regular 4-5 day estrous cycle (Proestrus: proestrus, Estrus: estrus, Metestrus: metestrus, Diestrus: diestrus); the PCOS model group had disordered estrous cycles, remaining in the diestrus phase; and the estrous cycles of both the low-dose and high-dose β-EA groups of this invention returned to normal levels.

[0063] ③β-EA significantly improved serum hyperandrogen levels in PCOS rats

[0064] One of the main clinical manifestations and diagnostic indicators of PCOS is hyperandrogenemia. Serum testosterone levels in each group were measured using ELISA, following 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, which was significantly higher than that in the control group; the serum testosterone levels in the low-dose and high-dose β-EA groups of this invention were approximately 1000 pg / mL and 1200 pg / mL, respectively, which were significantly lower than those in the PCOS group and close to those in the control group.

[0065] ④β-EA significantly improved the body weight of PCOS rats

[0066] PCOS accompanied by hyperandrogenemia often affects appetite and metabolism, leading to overeating and weight gain. In addition, PCOS rats usually exhibit insulin resistance, which weakens the effect of insulin in the body and makes it unable to effectively regulate glucose and fat metabolism, thereby promoting fat accumulation and weight gain. Figure 5 The figure shows the changes in body weight of rats in each group. As shown in the figure, over time, the body weight of the PCOS group increased significantly compared to the normal group, while the body weight of the β-EA group of this invention decreased significantly, and the body weight of the high-dose group decreased to near that of the control group.

[0067] ⑤β-EA significantly improved blood glucose, glucose tolerance, and insulin sensitivity in PCOS rats.

[0068] PCOS rats often exhibit insulin resistance, which means that the body's response to insulin is reduced, resulting in insulin's inability to effectively promote the uptake of glucose by cells, thereby causing elevated blood glucose levels and decreased insulin sensitivity. Figure 6 The fasting blood glucose level in rats was measured. Fasting blood glucose levels in the PCOS group were significantly higher than in the normal group. The low-dose and high-dose β-EA groups of this invention significantly reduced fasting blood glucose levels in PCOS rats. Figure 7 In the glucose tolerance test, PCOS rats showed a significant increase in blood glucose, indicating a decline in glucose tolerance. The low-dose and high-dose β-EA groups of this invention can significantly reduce blood glucose levels in PCOS rats, indicating a recovery in glucose tolerance. Figure 8 In terms of insulin tolerance in rats, the insulin secretion function of PCOS rats is affected under insulin stimulation, resulting in elevated insulin levels but still failing to effectively control blood glucose. The low-dose and high-dose β-EA groups of this invention can significantly reduce blood glucose in PCOS rats under insulin stimulation and improve insulin tolerance.

[0069] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of β-elemeneic acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating polycystic ovary syndrome, characterized in that... The β-elemene acid has the structure shown in the following formula: 。 2. The application according to claim 1, characterized in that: The drug also contains one or more pharmaceutically acceptable carriers or excipients.

3. The application according to claim 2, characterized in that: The carrier or excipient includes at least one of diluent, adhesive, surfactant, humectant, adsorbent carrier, lubricant, filler, disintegrant and preservative.

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