阅读说明：本技术 改善多囊卵巢综合征患者月经周期的制剂 (Preparation for improving menstrual cycle of patients with polycystic ovarian syndrome ) 是由 张春兰 孙淼 郝松莉 孟小钰 于 2021-11-01 设计创作，主要内容包括：本发明涉及改善多囊卵巢综合征患者月经周期的制剂用,本发明以特定的比例联合使用异白苏烯酮和盐酸小檗碱作为治疗活性成分制成口服制剂,通过实验证明两者合用具有协同增效的改善多囊卵巢综合征患者的月经周期,临床实验结果进一步证实了本发明的药物制剂可明显改善月经稀发或闭经的多囊卵巢综合征患者的月经周期,提高其妊娠率。(The invention relates to a preparation for improving the menstrual cycle of patients with polycystic ovarian syndrome, which is an oral preparation prepared by using isoalbonone and berberine hydrochloride as therapeutic active ingredients in a specific proportion in a combined way.)

1. A preparation for improving the menstrual cycle of patients with polycystic ovarian syndrome is characterized in that the preparation is an oral preparation and contains active ingredients of isoalbonone and berberine hydrochloride, wherein the mass ratio of the isoalbonone to the berberine hydrochloride is 2: 0.8-1.5.

2. The preparation according to claim 1, wherein the mass ratio of the isoalbonone to the berberine hydrochloride is 2: 0.8-1.2.

3. The formulation according to claim 1, which may or may not optionally contain other pharmaceutically active ingredients for the treatment of polycystic ovary syndrome in addition to isoalbonone and berberine hydrochloride.

4. The formulation of claim 3, further comprising one or more of clomiphene citrate, metformin, troglitazone, rosiglitazone and the like.

5. The formulation of any one of claims 1-4, further comprising a pharmaceutically acceptable carrier.

6. The formulation of claim 5, wherein the pharmaceutically acceptable carrier comprises one or more of lactose, glucose, powdered sugar, microcrystalline cellulose, starch, dextrin, mannitol, methylcellulose, hypromellose, carboxymethylcellulose, microcrystalline cellulose, povidone, starch slurry, mucilage, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, hydroxypropyl starch, magnesium stearate, calcium stearate, and talc.

7. The formulation according to any one of claims 1 to 4, which is a formulation comprising berberine hydrochloride, isoalbonone, microcrystalline cellulose, lactose, starch, talc and magnesium stearate.

8. Use of a formulation according to any one of claims 1 to 7 in the manufacture of a medicament for improving the menstrual cycle in a patient with polycystic ovarian syndrome.

9. The use according to claim 8, wherein the polycystic ovary syndrome patient is a patient with infrequent or closed menstruation.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation for improving the menstrual cycle of patients with polycystic ovarian syndrome and application thereof.

Background

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, accounting for 4% -12% of women of reproductive age. Clinically manifested as symptoms of infrequent or amenorrhea, obesity, hirsutism, infertility and increased polycystic ovarian capacity in both ovaries, typical endocrine features are hyperandrogenism, increased plasma Luteinizing Hormone (LH) levels, increased LH/FSH (follicle stimulating hormone) ratios, and increased estrone (E1). Hyperinsulinemia, peripheral insulin resistance and dyslipidemia are also associated. To date, the etiology of PCOS has not been understood. Current research indicates that PCOS is a syndrome characterized by genetic heterogeneity, possibly due to the interaction of multiple or a few major genes with environmental factors. PCOS severely affects the quality of life and reproductive health level of patients.

Polycystic ovary syndrome (PCOS) is a disease with hyperandrogenism and persistent anovulation as main pathological features, and is an endocrine dyscrasia syndrome related to abnormal reproduction and metabolism, and clinical symptoms comprise menstrual disorder, amenorrhea, infertility, hirsutism, acne and the like. The infertility caused by PCOS accounts for more than 60 percent of the anovulatory infertility of women of childbearing age, and the early abortion rate after pregnancy is up to 30 to 50 percent, which is the most main reason of the infertility of women of childbearing age. Aiming at the treatment of PCOS, Western medicine mostly uses ovulation-promoting drugs such as clomiphene and the like, reduces the secretion of luteinizing hormone, reduces the synthesis and release of androgen, increases the secretion of follicle-stimulating hormone and promotes the development of follicles by blocking the positive and negative feedback effects of estrogen. However, in addition to presenting with persistent anovulation, PCOS patients often suffer from impaired endometrial receptivity, manifested by decreased endometrial thickness, volume and subintimal blood flow, abnormalities in the endometrial stroma, and the like. Although the simple use of the ovulation-promoting drugs is helpful for relieving the persistent anovulation symptom caused by the polycystic ovarian syndrome and plays a certain role in treatment, the ovulation-promoting drugs have no treatment effect on the endometrial receptivity of the polycystic ovarian syndrome, and the low pregnancy rate and the high abortion rate after ovulation-promoting treatment are closely related to implantation disorder of fertilized eggs, so that the effect of the simple use of the ovulation-promoting drugs on infertility caused by PCOS is limited, the ovarian hyperstimulation syndrome is easy to occur after the long-term use of the ovulation-promoting drugs, the incidence rate of pregnancy complications is increased, and the polycystic ovarian syndrome cannot be effectively treated.

The applicant of the present application has conducted continuous research on PCOS, and related research results are disclosed in the form of papers and patent applications. For example, chinese granted patent CN111281867B provides an application of marmin in preparing a medicine for treating polycystic ovary syndrome (PCOS). Chinese granted patent CN111592581B relates to a polypeptide compound for treating polycystic ovarian syndrome and application thereof, the polypeptide can improve polycystic ovarian syndrome, is particularly suitable for regulating the sexual cycle disorder caused by polycystic ovarian syndrome, and can effectively reverse insulin resistance. The Chinese granted patent CN112174979B discloses a medicine for treating polycystic ovarian syndrome and a preparation method thereof, the medicine can effectively improve the serum sex hormone level of patients with polycystic ovarian syndrome, reduce serum testosterone and luteinizing hormone, increase follicle-stimulating growth hormone, and remarkably improve the form of ovaries of the patients, so that the medicine can be used for treating polycystic ovarian syndrome. Chinese patent application CN113304157A relates to an active composition for the treatment of polycystic ovary syndrome (PCOS). The active composition of the invention comprises the following raw material components in percentage by weight: 30-50% of dexamethasone, 30-50% of pioglitazone and 10-30% of crocetin. The active composition consisting of dexamethasone, pioglitazone and crocetin in a specific proportion is adopted to treat patients with polycystic ovarian syndrome, and the results show that the combined drug administration group has more remarkable clinical curative effect on the polycystic ovarian syndrome, can adjust the reproductive hormone level in the bodies of the patients, promotes the gonadal hormone and androgen of the patients to recover normal levels, improves the ovulation rate, and can reduce the recurrence rate while ensuring the use safety. The invention provides a foundation for providing the pharmaceutical composition for treating polycystic ovarian syndrome with remarkable curative effect. In the previous research of the inventor of the application, the treatment effect of berberine hydrochloride on PCOS is also researched, and in the subsequent research, the berberine hydrochloride alone is found to be less helpful for improving the menstrual cycle of patients with polycystic ovarian syndrome.

However, the focus of the above patents or patent applications is primarily on PCOS itself, and no study has been specifically made for the menstrual cycle caused by PCOS. The application aims at improving the menstrual cycle of patients with polycystic ovarian syndrome, and provides a novel medicinal preparation which is clinically used and confirmed to be capable of improving the menstrual cycle of patients with polycystic ovarian syndrome.

Disclosure of Invention

Based on the reasons, the invention provides an agent for improving the menstrual cycle of patients with polycystic ovarian syndrome and application thereof. Specifically, in order to achieve the purpose of the present invention, the following technical solutions are proposed:

the invention relates to a preparation for improving the menstrual cycle of patients with polycystic ovarian syndrome, which is characterized in that the preparation is an oral preparation and contains active ingredients of isoalbonone and berberine hydrochloride, wherein the mass ratio of the isoalbonone to the berberine hydrochloride is 2: 0.8-1.5. The invention is beneficial to improving the menstrual cycle of patients with polycystic ovarian syndrome by using the isoalbonone and the berberine hydrochloride together according to a specific proportion.

In a preferred embodiment of the present invention, the mass ratio of the isoalbonone to the berberine hydrochloride is 2: 0.8-1.2. Based on the preferable mass ratio range, the menstrual cycle of patients with polycystic ovarian syndrome is further improved.

The pharmaceutical composition according to the present invention may optionally contain or not contain other pharmaceutically active ingredients for treating polycystic ovary syndrome in addition to isoalbonone and berberine hydrochloride. The invention is not particularly limited with respect to the kind of the other pharmaceutically active ingredients for treating polycystic ovary syndrome. In one embodiment, the further pharmaceutically active ingredient for the treatment of polycystic ovary syndrome is selected from one or more of glucocorticoids such as dexamethasone and prednisone, ovulation-promoting drugs such as clomiphene citrate, insulin sensitising drugs such as metformin, troglitazone, rosiglitazone and the like.

The medicine also comprises a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a carrier suitable for formulation with an active ingredient into a pharmaceutical composition for administration to a subject without causing unacceptable toxicity to the subject. For the preparation of the pharmaceutical composition, any pharmaceutically acceptable carrier commonly used in the art may be employed. For example, to prepare solid dosage forms for oral administration, solid carriers known in the art may be used. Examples of solid carriers are fillers such as lactose, glucose, powdered sugar, microcrystalline cellulose, starch, dextrin, mannitol, etc.; binders such as methylcellulose, hypromellose, carboxymethylcellulose, microcrystalline cellulose, povidone, starch slurry, mucilage, and the like; disintegrants such as croscarmellose sodium, sodium carboxymethyl starch, crospovidone, hydroxypropyl starch, etc.; lubricants such as magnesium stearate, calcium stearate, talc, and the like. In addition, coloring agents, sweetening agents, flavoring agents, preservatives and the like may also be used as long as they are compatible with the active ingredient already used. The pharmaceutical composition of the present invention can be prepared in the form of, for example, tablets, capsules, powders, granules, pills, etc., using the above-mentioned solid carriers.

In a preferred embodiment of the invention, the formulation is a tablet comprising berberine hydrochloride, isoalbonone, microcrystalline cellulose, lactose, starch, talc and magnesium stearate.

In another aspect, the invention also relates to the use of the pharmaceutical preparation described above for the preparation of a medicament for improving the menstrual cycle in patients with polycystic ovarian syndrome.

In a preferred embodiment of the present invention, the polycystic ovary syndrome patient is a patient with infrequent menstruation or amenorrhea.

Advantageous effects

According to the invention, the isoalbonone and the berberine hydrochloride are jointly used as therapeutic active ingredients in a specific proportion to prepare an oral preparation, experiments prove that the isoalbonone and the berberine hydrochloride are jointly used to improve the menstrual cycle of patients with polycystic ovarian syndrome with synergistic effect, and clinical experiment results further prove that the pharmaceutical preparation can obviously improve the menstrual cycle of patients with polycystic ovarian syndrome with thin menstruation or amenorrhea and improve the pregnancy rate of the patients.

Detailed Description

In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available. The isoalbonone used in the embodiment of the present invention is extracted from perilla leaves, and the structural formula thereof is shown as the following formula:

example 1: tablet composition

Isoalbonone 2g

Berberine hydrochloride 1g

Microcrystalline cellulose 20g

Lactose 20g

Starch 6g

Talcum powder 1.5g

Magnesium stearate 0.5g

The preparation method comprises the following steps: the berberine hydrochloride, the isoalbonone, the microcrystalline cellulose and the lactose with the formula amount are mixed evenly and granulated by 10mg/ml gelatin solution, then the wet granules are screened and dried, and then mixed with starch, talcum powder and magnesium stearate, screened and pressed into tablets, each tablet contains 0.01g of berberine hydrochloride.

Example 2: tablet composition

Isoalbonone 2g

Berberine hydrochloride 1.5g

Microcrystalline cellulose 20g

Lactose 20g

Starch 6g

Talcum powder 1.5g

Magnesium stearate 0.5g

The preparation method comprises the following steps: the berberine hydrochloride, the isoalbonone, the microcrystalline cellulose and the lactose with the formula amount are mixed evenly and granulated by 10mg/ml gelatin solution, then the wet granules are screened and dried, and then mixed with starch, talcum powder and magnesium stearate, screened and pressed into tablets, each tablet contains 0.015g of berberine hydrochloride.

Comparative example 1: tablet composition

Berberine hydrochloride 3g

Microcrystalline cellulose 20g

Lactose 20g

Starch 6g

Talcum powder 1.5g

Magnesium stearate 0.5g

The preparation method comprises the following steps: the berberine hydrochloride, the isoalbonone, the microcrystalline cellulose and the lactose with the formula amount are mixed evenly and granulated by 10mg/ml gelatin solution, then the wet granules are screened and dried, and then mixed with starch, talcum powder and magnesium stearate, screened and pressed into tablets, each tablet contains 0.03g of the berberine hydrochloride.

Example 3 animal pharmacodynamic experiments

1 animal model construction and administration

A70-day-old healthy and clean female Spragudarey (SD) rat is selected, a polycystic ovary syndrome (PCOS) rat model is established according to a Poretsky method, chorionic gonadotropin (HCG) is injected 3.0U/d subcutaneously 2 times a day, effective insulin is injected from 0.5U/d to 6.0U/d gradually from day 1 to day 10, injection is performed at the dosage every day, after 22 days, the increase of the blood testosterone and insulin levels of the rat is detected, and the condition that the vaginal smear continuously presents keratinocytes accords with the PCOS model is detected.

After the modeling is successful, 80 female rats with the modeling results are divided into 4 groups, and each group comprises 20 female rats, namely an experimental group 1, an experimental group 2, a comparative group 1 and a control group; 20 female rats, which were not molded, were used as a blank group.

Experimental group 1, experimental group 2, and comparative group 1 were each gavaged every other day for 1 tablet composition prepared in example 1, example 2, and comparative example 1, and each rat was administered 5 times in total before discontinuation.

Control and blank groups: gavage every other day with the same dose of placebo made from starch.

2 statistics

After the gavage is finished, the recovery periodic change condition of the vaginal epithelial cells of each group of rats is determined by observing the state of the vaginal epithelial cells, and the specific experimental results are shown in table 1.

3 results of the experiment

Table 1: results of animal pharmacodynamics experiments

Group of	Sample size (only)	Vaginal epithelial cell recovery periodicity (only)	Recovery ratio (%)
				Blank group	20	19	95
Control group	20	6	30
				Experimental group 1	20	19	95
Experimental group 2	20	18	90
				Comparative example group 1	20	9	45

The experimental results in table 1 show that the number of the recurrent cycles of the vaginal epithelial cells of the rats in the model group is obviously reduced relative to that of the blank group, which indicates that the recurrent cycles of the vaginal epithelial cells of the rats are damaged by subcutaneous injection of chorionic gonadotropin, while the number of the recurrent cycles of the vaginal epithelial cells of the female rats in the example 1 group is obviously increased relative to that of the model group and the control group after the tablets of the invention in the example 1 and the example 2 are intragastrically injected, which indicates that the pharmaceutical composition of the invention has an obvious improvement effect on the recovery of the recurrent cycles of the vaginal epithelial cells caused by chorionic gonadotropin, particularly, the pharmaceutical composition in the example 1 has a more obvious improvement effect on the recovery of the recurrent cycles of the vaginal epithelial cells caused by chorionic gonadotropin.

Example 4: clinical pharmacodynamics experiment

The experimental study showed that 20 patients with overweight/obese polycystic ovarian syndrome (body weight index is more than or equal to 23), all of which showed ovarian ovulation failure, specifically manifested as premature menstruation or amenorrhea, were brought in 6 months to 12 months in 2020 and all come from the gynecological outpatient of the first hospital affiliated to Heilongjiang university of traditional Chinese medicine. All subjects were 15-35 years of age and had no hormonal drugs and no endocrine disease for nearly 3 months. The study was approved by the ethical committee of the first hospital institution affiliated to the university of traditional Chinese medicine, Heilongjiang, and was in accordance with the declaration of Helsinki. All subjects signed an informed consent.

20 patients with PCOS were divided into 2 groups of 10 patients each. One group of berberine hydrochloride medicaments prepared in comparative example 1 are orally taken for 3 times per day and 0.5 g/time for 3 times per month; another group of the preparations prepared in example 1 were orally administered, the amounts of the active ingredients isoalbonone and berberine hydrochloride were 0.5 g/time, 3 times/day for 3 months. Improvement in menstrual cycle is reported by the patient after withdrawal, where improvement means more menstrual flow than before treatment and significant improvement means a significant increase in menstrual flow than before treatment (days of the period of at least 4 or more). The results of the experiment are shown in table 2.

Table 2: results of clinical pharmacodynamics experiments

Group of	Sample size (size)	Without improvement	Improvements in or relating to	Obviously improve
					Experimental group	10	2	4	4
Control group	10	4	5	1

From the experimental results shown in table 2 above, it was confirmed that the preparation of the present invention is further effective in improving the menstrual cycle of patients with polycystic ovarian syndrome, compared to berberine hydrochloride alone.

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.