CN111281867B

CN111281867B - Medicine for treating polycystic ovarian syndrome and preparation method thereof

Info

Publication number: CN111281867B
Application number: CN202010194279.7A
Authority: CN
Inventors: 左冬冬; 张晓娟
Original assignee: Heilongjiang University of Chinese Medicine
Current assignee: Heilongjiang University of Chinese Medicine
Priority date: 2020-03-16
Filing date: 2020-03-16
Publication date: 2021-03-19
Anticipated expiration: 2040-03-16
Also published as: CN111281867A

Abstract

The invention relates to a medicine for treating polycystic ovarian syndrome and a preparation method thereof, belonging to the field of medicines. The invention firstly provides the application of marmin in preparing the medicine for treating polycystic ovarian syndrome (PCOS). Pharmaceutical compositions comprising marmin and related formulations are then further provided.

Description

Medicine for treating polycystic ovarian syndrome and preparation method thereof

Technical Field

The invention relates to a medicine for treating polycystic ovarian syndrome and a preparation method thereof, belonging to the field of medicines.

Background

Polycystic ovarian syndrome (PCOS) is a common gynecological endocrine disease with concurrent reproductive dysfunction and metabolic abnormalities, characterized by hyperandrogenism, ovulation failure, and ovarian polycystic state. The major clinical manifestations are irregular menstrual cycle, infertility, hirsutism and/or acne, the most common endocrine disorders in women. Patients with PCOS have enlarged ovaries, thickened leucocytes, follicles at various stages of development, and concomitant flavonization of granulosa cells.

Currently, medical treatment of PCOS has replaced surgical treatment as a first-line treatment, the purpose of which is primarily related to the fertility requirements of the patient. For example, hyperandrogenism in PCOS patients is controlled by oral contraceptives, glucocorticoids, ketoconazole, spironolactone, flutolanil, finasteride, and gonadotropin-releasing hormone analogues (GnRH-a). For another example, ovulation-promoting treatment is performed on a PCOS patient by using drugs such as clomiphene, gonadotropin, letrozole and the like to meet the fertility requirements of the patient. However, in recent years, it has been found that the ovulation-promoting drug therapy has a high ovulation rate but still has a low pregnancy rate, which may be related to the complex diversity of endocrine disorders in PCOS patients, and with the study of the pathogenesis of PCOS by researchers, the auxiliary ovulation-promoting drug of PCOS has been gaining more and more importance, such as metformin, which not only improves the ovulation-promoting effect of the above ovulation-promoting drug, increases the pregnancy rate, but also reduces the incidence of OHSS.

Although many scholars at home and abroad have conducted a lot of experiments and clinical related researches on PCOS in recent years, the cause of the disease is still not clear, so further exploring the pathogenesis of PCOS and trying to explore more effective treatment schemes and overcome the side effects of the existing drugs become the hot topic of the current PCOS research.

Disclosure of Invention

The invention provides the application of marmin in preparing medicine for treating polycystic ovary syndrome (PCOS).

The marmin is a coumarin compound, and the specific structural formula of the marmin is as follows:

the existing research shows that marmin has obvious activities of neuroprotection, anti-inflammation, free radical elimination and the like, but the activity of PCOS related diseases is not reported in documents.

In a second aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating polycystic ovary syndrome, comprising: marmin and metformin; the weight ratio of the marmin to the metformin is 0.01-2: 1.

In one embodiment, the weight ratio of marmin to metformin is from 0.05 to 0.5: 1.

In another embodiment, the weight ratio of marmin to metformin is 0.1: 1.

The third aspect of the invention provides the application of the pharmaceutical composition in preparing a medicine for treating or preventing polycystic ovary syndrome.

A fourth aspect of the invention provides a pharmaceutical formulation comprising said pharmaceutical composition, consisting of said pharmaceutical composition and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical formulation is an oral formulation and the pharmaceutically acceptable carrier comprises one or more of starch, microcrystalline cellulose, dextrin, lactose, glucose, magnesium stearate, stearic acid, aspartame, poloxamer, water, ethanol.

The invention discovers that the marmin can obviously regulate the sex hormone level, the ovarian mature follicle number and the ovarian index in a PCOS rat model induced by Dehydroepiandrosterone (DHEA), the treatment effect is further improved after the marmin and the metformin are used together, and the fact that the marmin and the metformin generate obvious synergistic effect in the treatment of the PCOS is suggested.

Detailed Description

The invention may be further understood by reference to the following examples, which illustrate some methods of making or using. However, it is to be understood that these examples do not limit the present invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the invention as described herein and claimed below.

Example 1 Effect of Marmin and pharmaceutical compositions on the PCOS rat model

The marmin and metformin standards were purchased from shanghai allimai bioengineering ltd; dehydroepiandrosterone (DHEA) was purchased from wuhanjianw biomedical ltd.

The molding method comprises the following steps: 4-week-old female SD rats are taken and adaptively fed for one week, then are randomly numbered and grouped into groups, 10 rats in each group, except a control group, rats in each group are injected with 6mg/100g of DHEA at the back of the neck, are injected once a day for 20 days continuously, and the control group is injected with physiological saline with the same amount.

The administration method comprises the following steps: after the model building is successful, different medicines are simultaneously administered to each administration group for treatment, and the administration mode is intragastric administration, wherein the marmin group is administered with 1, 5 and 10mg/kg of marmin; the metformin group is administered with 10mg/kg of metformin, and the combined administration group is administered with 1mg/kg of marmin and 10mg/kg of metformin; the control group and the model group were given an equal amount of physiological saline, and each group was given once daily for 15 consecutive days.

Detection indexes are as follows:

after 4h of the last administration, the rats were sacrificed under anesthesia and the ovarian tissues of the rats were harvested for relevant testing after the abdominal aorta blood was taken.

1. Weight of ovary: weighing and counting the ovary tissue peripheral blood after absorbing the ovary tissue peripheral blood by using filter paper

2. And (3) counting the number of mature follicles: and (3) taking ovarian tissues, carrying out section by a freezing microtome after paraffin embedding, carrying out HE staining, and selecting 5 sections to count the number of mature follicles under a microscope. Mature follicles: the cumulus is obvious, the follicular chamber is large, the follicular intimal cell is close to the follicular granular layer, a basement membrane is arranged between the follicular intimal cell and the granular layer for separation, the cytoplasm is clear, the nucleus is circular, and the adventitial cell is positioned at the outer layer.

3. Serum LH, FSH, testosterone and leptin levels: serum of rats in each group is taken, and the levels of LH, FSH, testosterone and leptin in the serum are measured by an ELISA method, and the steps refer to the kit instruction.

Statistical analysis: SPSS software is adopted for analysis, and the comparison among multiple groups is checked by adopting an Oneway-ANOVA method.

As a result:

1. effects of marmin, metformin and pharmaceutical compositions on ovarian weight

	Ovarian weight (mg)
		Control group	209.7±9.6
Model set	351.1±18.7^##
		Metformin hydrochloride	281.6±8.3**
Marmin group (1mg)	326.9±15.7
		Marmin group (5mg)	287.3±8.6**
Marmin group (10mg)	275.4±9.1**
		Combination administration set	243.6±5.3**

2. Effect of marmin, metformin and pharmaceutical composition on number of mature follicles

3. Effects of marmin, metformin and pharmaceutical compositions on serum LH, FSH, testosterone and leptin levels

The pathogenesis of polycystic ovarian syndrome is complex, clinically, symptoms such as hyperandrogenism, continuous anovulation, ovarian polycystic change, combined high LH blood disease, abnormal steroid hormone generation and the like are shown, the results show that DHEA better simulates relevant symptoms of PCOS in female rats, and a marmin medium-dose group, a marmin high-dose group, metformin and a combined drug group can better inhibit the relevant clinical manifestations, wherein the effect of the combined drug group is the best.

This summary merely illustrates some embodiments which are claimed, wherein one or more of the features recited in the claims can be combined with any one or more of the embodiments, and such combined embodiments are also within the scope of the present disclosure as if they were specifically recited in the disclosure.

Claims

1. Application of marmin in preparing medicine for treating polycystic ovarian syndrome is provided.

2. A pharmaceutical composition for preventing or treating polycystic ovary syndrome, comprising: marmin and metformin; the weight ratio of the marmin to the metformin is 0.01-2: 1.

3. The pharmaceutical composition of claim 2, wherein the weight ratio of marmin to metformin is 0.05-0.5: 1.

4. The pharmaceutical composition of claim 3, wherein the weight ratio of marmin to metformin is 0.1: 1.

5. Use of a pharmaceutical composition according to claims 2-4 for the manufacture of a medicament for the treatment or prevention of polycystic ovary syndrome.

6. A pharmaceutical formulation comprising the pharmaceutical composition of claims 2-4, consisting of the pharmaceutical composition and a pharmaceutically acceptable carrier.

7. The pharmaceutical formulation of claim 6, wherein the pharmaceutical formulation is an oral formulation.

8. The pharmaceutical formulation of claim 7, wherein the pharmaceutically acceptable carrier comprises one or more of starch, microcrystalline cellulose, dextrin, lactose, glucose, magnesium stearate, stearic acid, aspartame, poloxamer, water, and ethanol.