CN114225011A

CN114225011A - Compound preparation for preventing and treating GSM and application thereof

Info

Publication number: CN114225011A
Application number: CN202111669790.9A
Authority: CN
Inventors: 于普光; 李广永; 何瑞; 占学康
Original assignee: Ningxia Medical University; General Hospital of Ningxia Medical University
Current assignee: Ningxia Medical University; General Hospital of Ningxia Medical University
Priority date: 2021-12-31
Filing date: 2021-12-31
Publication date: 2022-03-25
Anticipated expiration: 2041-12-31
Also published as: CN114225011B

Abstract

The application provides a compound preparation which is applied to preventing and/or treating female perimenopausal urogenital syndrome and comprises the following main components: epidermal growth factor, sea buckthorn seed oil and glycerol. The application also provides a new application of the compound preparation, namely the application in preventing and/or treating the female perimenopausal urogenital syndrome and in products thereof; the use in the prevention and/or treatment of vaginal atrophy, maintenance of the state of the sexual organs and in the products thereof in women; the application in preventing and/or treating female perimenopausal urination dysfunction, frequent micturition, urgency, nocturia and other urination disorders and the product thereof, and the application in improving female perimenopausal sex hormone level, regulating and recovering female disordered menstrual cycle and the product thereof. The application provides a basis for directly utilizing the compound preparation to prevent and treat perimenopausal urogenital syndrome.

Description

Compound preparation for preventing and treating GSM and application thereof

Technical Field

The application relates to the technical field of preparation and application of a composite preparation, in particular to a composite preparation for preventing and treating GSM and application thereof.

Background

Perimenopausal urogenital syndrome (GSM) refers to vulvovaginal atrophy, dryness, dyspareunia and urinary symptoms caused by decreased endogenous estrogen levels, including frequency, urgency and incontinence. At present, 1.3 hundred million perimenopausal women exist in China, 2.8 million is predicted to be reached in 2030, and research shows that 40 percent of women suffering from dyspareunia and vaginal dryness in China have sexual disorder in the whole course of sexual life, 24 percent of women lack of sexual desire, 34 percent of women have difficulty in sexual arousal and 19 percent of women suffering from vulvovaginal symptoms. Therefore, GSM has a serious negative impact on the quality of life, and it is important to correctly recognize GSM and administer a targeted therapy.

The main cause of GSM is caused by a decrease in sex hormone levels. With age, the ovarian function gradually declines, the sex hormone level decreases, and the urogenital tract loses the nutritional effect of estrogen, thereby causing a series of symptoms of the reproductive system, the urinary system and the whole body. The health management of perimenopausal women is one of the important social concerns in the future, GSM is correctly known, effective prevention and treatment measures are explored, and the health management has important significance for improving the life quality and prognosis of patients. At present, the treatment aiming at the GSM in clinic is mainly based on the over-the-counter drugs represented by vaginal lubricant (humectant) and hormone drugs mainly based on estrogen. The lubricant type medicines have quick response and obvious effect, but can only improve the related symptoms caused by vaginal dryness, and treat the symptoms but not the root causes; hormone drugs mainly supplement exogenous estrogen and have good improvement effect on a plurality of symptoms of vulvar genitourinary tract caused by hormone decline, but because the hormone drugs have obvious complications and dependence of a cardiovascular system, the hormone drugs cannot be widely used clinically. Therefore, for GSM treatment, there is an urgent need to develop drugs with general applicability, exact therapeutic effect, and few side effects.

In earlier researches, the application searches out a new substance, namely the epidermal growth factor, for improving the GSM and a novel compound preparation for treating the GSM, which takes the epidermal growth factor as a main component and is supplemented with sea buckthorn seed oil and a plurality of flora formulas. To date, there is no report that epidermal growth factor and the compound preparation have preventive and therapeutic effects on GSM.

Disclosure of Invention

In view of the above, the present application provides a composite preparation for preventing and treating GSM and an application thereof, so as to solve the problem that no epidermal growth factor and a composite preparation prepared from the epidermal growth factor, sea buckthorn seed oil, a bacterial flora and the like are applied to GSM.

In a first aspect, the present application provides a complex formulation for use in the prevention and/or treatment of perimenopausal urogenital syndrome in women, comprising the following main components: epidermal growth factor, sea buckthorn seed oil and glycerol.

Optionally, the compound preparation further comprises one or more of burkholderia, lactobacillus plantarum and propionibacterium freudenreichii.

In a second aspect, the present application provides a complex formulation for use in the prevention and/or treatment of perimenopausal urogenital syndrome in women, comprising the following components: 20-30% of epidermal growth factor, 1-3% of Burkholderia, 1-3% of lactobacillus plantarum, 1-3% of propionibacterium freudenreichii, 5-15% of seabuckthorn flavone and 41-72% of glycerol.

In a third aspect, the application provides a composite preparation for preventing and/or treating perimenopausal urogenital syndrome in women and application of the composite preparation in products thereof.

In a fourth aspect, the present application provides a use of a complex formulation for preventing and/or treating vaginal atrophy, maintaining the state of sexual organs in women and products thereof.

In a fifth aspect, the application provides a compound preparation for preventing and/or treating female urination dysfunction in perimenopause, frequent micturition, urgent micturition, nocturia and other urination disorders and an application of the compound preparation in products thereof.

In a sixth aspect, the present application provides a combination preparation for use in increasing the perimenopausal sex hormone level in women, regulating and restoring a disordered menstrual cycle in women and products thereof.

Optionally, the product comprises a pharmaceutical and a nutraceutical.

Optionally, the dosage form of the medicine comprises gel, soft capsule, dripping pill, emulsion, tablet, lotion, liniment, ointment or suppository and the like.

According to the technical scheme, the application provides a compound preparation which is applied to preventing and/or treating female perimenopausal urogenital syndrome and comprises the following main components: epidermal growth factor, sea buckthorn seed oil and glycerol. The application also provides a new application of the compound preparation, namely the application in preventing and/or treating the female perimenopausal urogenital syndrome and in products thereof; the use in the prevention and/or treatment of vaginal atrophy, maintenance of the state of the sexual organs and in the products thereof in women; the application in preventing and/or treating female perimenopausal urination dysfunction, frequent micturition, urgency, nocturia and other urination disorders and the product thereof, and the application in improving female perimenopausal sex hormone level, regulating and recovering female disordered menstrual cycle and the product thereof. The application provides a basis for directly utilizing the compound preparation to prevent and treat perimenopausal urogenital syndrome.

Drawings

In order to more clearly explain the technical solution of the present application, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious to those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a schematic diagram showing the variation of urination habits, i.e., urinary plaques, of mice in different dose groups;

FIG. 2 is a schematic diagram showing the variation of the estrus cycle of mice in different dose groups;

FIG. 3 is a schematic diagram of an experimental procedure provided herein;

FIG. 4 is a schematic illustration of the technical route provided by the present application;

FIG. 5A is an ex vivo view of vaginal tissue from different groups of mice;

FIG. 5B is a graph showing the weight of the vagina in different groups of mice;

FIG. 5C is a graph showing vaginal index of different groups of mice;

FIG. 5D is a graph showing the weight of the uterus of different groups of mice;

FIG. 5E is a graph showing the uterine index of the vagina in different groups of mice;

FIG. 6 is a graph showing the serum estrogen levels in different groups of mice;

FIG. 7 is a graph showing the androgen content in the serum of different groups of mice;

FIG. 8 is a graph of HE staining of four estrus cycles in mice;

FIG. 9 is a schematic diagram showing the variation of estrus cycle of mice in different groups;

FIG. 10 is a schematic diagram of the urine spot test of different groups of mice.

Detailed Description

Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following examples do not represent all embodiments consistent with the present application. But merely as exemplifications of systems and methods consistent with certain aspects of the application, as recited in the claims.

The application provides a compound preparation which is applied to preventing and/or treating female perimenopausal urogenital syndrome and comprises the following main components: epidermal growth factor, sea buckthorn seed oil and glycerol. Wherein epidermal growth factor, oleum Hippophae and glycerol are used as main ingredients. Seabuckthorn seed oil extracts such as seabuckthorn flavone may also be used. Further, the compound preparation also comprises auxiliary components, wherein the auxiliary components comprise one or more of Burkholderia, Lactobacillus plantarum and Propionibacterium freudenreichii. The composite preparation may be composed of only the main component. The specific contents of the main component and the auxiliary component can be set and adjusted according to actual conditions.

The application provides a Chinese and western medicine combined compound preparation for preventing and/or treating female perimenopausal urogenital syndrome, which comprises the following substances in percentage by weight: 20-30% of epidermal growth factor, 1-3% of Burkholderia (Burkholderia), 1-3% of Lactobacillus plantarum (Lactobacillus plantarum), 1-3% of Propionibacterium freudenreichii ssp. shermanii), 5-15% of sea buckthorn seed oil and 41-72% of glycerol.

The preparation method of the compound preparation comprises mixing the above materials at a certain proportion to make into gel. The following screening process was performed: in the screening process, the compound preparation is divided into three dosage groups of low, medium and high according to the pharmacokinetic characteristics of various components in vivo to determine the optimal preparation proportion. Wherein the low dose group comprises the following substances in weight percent: epidermal growth factor 20%, Burkholderia (Burkholderia) 1%, Lactobacillus plantarum (Lactobacillus plantarum) 1%, Propionibacterium freudenreichii ssp.shermanii 1%, hippophae rhamnoides seed oil extract (hippophae rhamnoides flavone) 5%, glycerin 72%.

The medium dose group comprises the following substances in percentage by weight: epidermal growth factor 25%, Burkholderia (Burkholderia) 2%, Lactobacillus plantarum (Lactobacillus plantarum) 2%, Propionibacterium freudenreichii ssp.shermanii 2%, hippophae rhamnoides seed oil extract (hippophae rhamnoides flavone) 10%, glycerin 59%.

The high dose group included the following materials in weight percent: 30% of epidermal growth factor, 3% of Burkholderia (Burkholderia), 3% of Lactobacillus plantarum (Lactobacillus plantarum), 3% of Propionibacterium freudenreichii ssp.shermanii, 15% of sea buckthorn seed oil extract (sea buckthorn flavone) and 46% of glycerol.

Further, the present application divided 8-week-old C57 mice into 5 groups, i.e., a control group (NCD group), a model group (GSM group), a low dose group (LDG group), a medium dose group (MDG group), and a high dose group (HGD group). Mice were monitored for symptoms of urination (urospotting) and for changes in estrous cycles by administering each group for 48 consecutive days with a preset number of days. FIG. 1 is a graph showing the change in urination among mice in different dose groups, NCD-control group, GSM-model group, LDG-low dose group, MDG-medium dose group, and HDG-high dose group. As shown in fig. 1, the mice in the medium dose group urinated most closely to normal mice. FIG. 2 is a schematic diagram showing the variation of the estrous cycles of mice in different dose groups, in which the ordinate represents the percentage of each cycle, and the abscissa represents four estrous cycles, a promestrus-anteestrus phase, an Estrus-estrous phase, a Metstrus-postestrus phase, a Diestus-interval, an NCD-control group, a GSM-model group, an LDG-low dose group, an MDG-medium dose group, and an HDG-high dose group. As shown in fig. 2, in the estrus cycle, although three doses of treatment improved the disturbance of the estrus cycle in mice, the medium dose group of mice improved the most significantly, and maintained the longest. In summary, the present application provides a combination preparation with improved urination and estrous cycle. Further, the dosage of each component of the intermediate dosage group can be taken as the preferable dosage proportion of the compound preparation.

The application proves for the first time that the compound preparation taking the epidermal growth factor as the main component has new functions completely different from the prior art: (1) can effectively prevent and treat various symptoms of the female perimenopausal urogenital syndrome; (2) can be used for preventing and treating vaginal atrophy due to menopause; (3) can prevent and treat dysuria such as frequent micturition and urgent micturition (4) increase sexual hormone level; (5) regulating estrus cycle, and improving disorder of estrus cycle. The application provides basis for preventing and treating GSM by directly utilizing the compound preparation.

The application discloses a new application of a compound preparation taking epidermal growth factor as a main component, which comprises the application in preventing and/or treating female perimenopausal urogenital syndrome and products thereof; the use in the prevention and/or treatment of vaginal atrophy, maintenance of the state of the sexual organs and in the products thereof in women; the application in preventing and/or treating female perimenopausal urination dysfunction, frequent micturition, urgency, nocturia and other urination disorders and the product thereof, and the application in improving female perimenopausal sex hormone level, regulating and recovering female disordered menstrual cycle and the product thereof. Meanwhile, the application provides a basis for directly utilizing the compound preparation to prevent and treat perimenopausal urogenital syndrome.

In order to confirm that the complex formulation has the above-mentioned novel use, the following experiments were carried out.

1. Technical scheme

(1) Establishing a mouse model of GSM:

figure 3 is a schematic experimental flow chart provided by the present application, see figure 3, which simulates the clinical GSM mouse model by ovariectomy. The effect of the composite preparation of the application is verified by vaginal administration after successfully establishing a GSM mouse model after feeding for one month through bilateral ovariectomy.

(2) Technical route

Fig. 4 is a schematic diagram of the technical route provided by the present application, referring to fig. 4, the present application uses 8-week-old female C57 mice, which are divided into 5 groups, i.e., a control group (NCD group), a model group (GSM group), a positive control group (PCG group), an epidermal growth factor treatment group (EGF group), and a composite preparation group (CDP group). Wherein, the NCD group is a simple control group, and the mouse only needs to open the abdominal cavity and then is sutured by silk thread. The GSM group is a female perimenopausal urogenital syndrome model group, i.e. mice were oophorectomized. The NCD group and the GSM group were given the same dose of glycerin per day by vaginal smear. The PCD group used estrogen ointment for treating perimenopausal urogenital syndrome in clinic as a positive control, was administered with 0.1g of estrogen ointment (estrogen content is 97.5 mug) per day, and the drug was delivered to the proximal vaginal end 1/3 of the mouse by a dispenser according to the determined dosage for 28 consecutive days. The EGF group was the EGF treatment group, recombinant human EGF was administered at 0.2 g/day (containing 2550. mu.g of EGF), and the drug was delivered to the proximal vaginal end 1/3 of mice after the dose was determined by the administration device, and the administration was continued for 28 days. CDP is the combination treatment group, and 0.5 g/day of the combination is given. Wherein the compound preparation comprises the following substances in percentage by weight: epidermal growth factor 25%, Burkholderia (Burkholderia) 2%, Lactobacillus plantarum (Lactobacillus plantarum) 2%, Propionibacterium freudenreichii ssp.shermanii 2%, hippophae rhamnoides seed oil extract (hippophae rhamnoides) 10%, glycerin 59%. It should be noted that the present application does not specifically limit the content of the components of the composite preparation, and this example adopts a preferable embodiment. The content of the components can be selected according to the actual situation, and only the content is within the range limited by the application.

All groups of mice were harvested on day 29 and subjected to the following procedures: (1) observing the variation of the estrus cycle of the mice in different treatment groups; (2) observing the change of the urination habits of the mice in different treatment groups (3) weighing the uterus and the vagina after the materials are taken, and calculating the organ index; (4) and detecting the content of estrogen and androgen in the serum.

2. Main techniques

Referring to fig. 4, the following tests were performed:

1) establishing a GSM mouse model

Anesthetizing a mouse with 10g/0.1ml of 5% chloral hydrate, fixing on an animal operating table after anesthetization, making a 2cm incision in the middle of the upper part of the pubic symphysis, fully exposing the uterine horn, tracking the ovary upwards along the uterine horns on two sides, and removing the ovary after ligating an ovarian blood vessel.

2) Mouse vagina and uterus weight weighing

The material was drawn by finding the uterus and vagina of the mice, separating the surrounding excess fat and other tissue, and weighing on an analytical scale.

3) Examination of estrus cycle by smear method of vaginal cast-off cell flushing fluid

Sucking a proper amount of normal saline by a dropper, washing and sucking vaginal secretion on a glass slide at the same time point every 4 days, rapidly observing cell morphology under a microscope, and judging estrus cycle.

4) Mouse urination habit detection

A plastic cage similar to the size of a mouse cage is prepared, a 540-grade acid-hard filter paper is pasted on the bottom of the plastic cage in a flat mode, the paper is cut into a proper size, each mouse is slightly removed from the plastic cage and placed in an experimental plastic cage, and early urination caused by frightening of the mouse is avoided. (mice were allowed free access to water until they were housed in their cages for testing). The rat cage was placed in a quiet environment for 4 hours. When the mouse is in the cage, the room lights can be turned on or off depending on the time, but the room doors must be closed and no equipment is in operation to ensure the quiet environment of the experiment until the end of the 4 hour test period, a person is allowed to enter. During this time, the mice can eat regular food, but cannot drink water. The mouse was gently removed, returned to the mouse cage, carefully collected filter paper to avoid damage, the filter paper was air dried, the filter paper was observed under irradiation of ultraviolet light to reveal urine spots, and an image of the filter paper was electronically captured.

5) Serum estrogen and androgen level detection

Taking blood from heart when taking materials, centrifuging whole blood at 12000r/min for 10min, separating serum, adding each group of serum to be detected into reaction holes by using an ELISA detection kit, adding 100 mu L of serum to be detected into each hole, respectively arranging 4 compound holes in each group, incubating at 37 ℃ for 90min, discarding liquid in the holes, adding 100 mu L of biotinylated antibody working solution, incubating at 37 ℃ for 60min, discarding liquid in the holes, washing for 3 times, then adding 100 mu L of enzyme conjugate working solution, incubating at 37 ℃ for 30min, discarding liquid in the holes, washing for 5 times, adding 90 mu L of substrate solution into each hole, incubating at 37 ℃ for 15min, adding 50 mu L of stop solution, detecting at the wavelength of 450nm, and calculating the T, E2 content in the serum of each group of rats according to a standard curve.

3. Results of the experiment

3.1 the compound preparation of the application can increase the weight of vagina and uterus of mice and prevent and improve the atrophy of sexual organs

Vulvovaginal atrophy and atrophic vaginitis have been considered as the changes in the signs of major symptoms of the vulva, vagina and lower urinary tract corresponding to estrogen deficiency in the perimenopause, vaginal atrophy often causes vaginal dryness and dyspareunia, and frequent urination, urgent urination, painful urination, urinary incontinence, recurrent urinary tract infection and the like are more likely to occur due to vaginal and urinary tract atrophy. According to the application, different groups of treatments find that the estrogen, the epidermal growth factor and the compound preparation have good protection effect on terminal organs such as tissues of vagina, uterus and the like, and can effectively improve atrophy of vagina and uterus, and fig. 5A is an isolated diagram of vaginal tissues of mice of different groups, wherein the diagram shows an NCD (negative center for differentiation) -control group, a GSM (global system for mobile communications) -model group, a PCD-estrogen treatment group, an EGF-epidermal growth factor treatment group and a CDP-compound preparation group. As shown in FIG. 5A, the vagina of the model group (GSM group) mice was significantly atrophied, the volume was reduced, and the feeling to touch was hard, as compared with the control group (NCD group). After being treated by estrogen, epidermal growth factor and the compound preparation, the appearance structure of the vagina is improved compared with that of the GSM group, the vagina tissue is full, the volume is increased, and the compound preparation group (CDP group) is changed to be most remarkable. The same trend was obtained by further weighing the dissected vagina and uterus in vitro and calculating the organ ratio, as shown in fig. 5B, 5C, 5D, 5E, and the mice in the GSM group had significantly reduced vaginal and uterine weight, and increased weight in both organs after treatment with three different drugs, with the CDP group being the most significant.

3.2 the compound preparation can increase the level of serum neutral hormone

The main cause of GSM is the decline of estrogen levels in the body which causes the connective tissue to relax, which in turn causes internal sphincter dysfunction, causing changes in the urogenital system.

FIG. 6 is a graph showing the amount of estrogen in the serum of mice in different groups, wherein the ordinate represents the amount in ng/L. Referring to fig. 6, the present application finds that the serum neutral hormone level of mice in the GSM group is significantly lower than that of the NCD group, and the estrogen E2 content in the serum of the mice in the GSM group is increased after the treatment with estrogen, epidermal growth factor and the combination preparation respectively, and is close to that in the normal group, wherein the increasing effect of the combination preparation group (CDP group) on estrogen is most significant.

FIG. 7 is a graph showing the androgen content in the serum of mice of different groups, wherein the ordinate represents the content in ng/L. Referring to fig. 7, the present application finds, through the measurement of the serum neutral hormone level of each group of mice, that the androgen content in the serum of the mice in the GSM group is significantly reduced compared to that in the NCD group, and the androgen content is not significantly increased after estrogen treatment in the E2 group, which indicates that estrogen has no promotion effect on the production of androgen; in contrast, the EGF group treated with EGF and the CDP group treated with the combination formulation showed a significant increase in androgen levels, and the CDP group showed a more significant increase.

3.3 the compound preparation can regulate the disturbance of the estrus cycle of mice and establish the normal estrus cycle

The estrus cycle of mice is similar to the menstrual cycle of humans and is the basis for normal sexual response. FIG. 8 is a graph of HE staining of four estrus cycles in mice. Wherein, A is in prophase of estrus, and can be seen as fusiform epithelial cells which are in groups or appear independently, and the number of leucocytes is less; b is estrus, a large number of squamous epithelial cells are seen, the shape is large and irregular, no nucleus is formed, and white blood cells disappear; c is anagen, which can be seen in various cell types, leucocytes, anucleate epithelial cells and fusiform epithelial cells; d is interphase visible large amount of white blood cells, and very small amount of fusiform epithelial cells. FIG. 9 is a schematic diagram showing the variation of Estrus cycles of mice in different groups, wherein the abscissa represents four Estrus cycles, a promestrus-ante-Estrus cycle, an Estrus-Estrus cycle, a Metstrus-post-Estrus cycle, a disestrus-interval, and the ordinate represents the percentage of each cycle, a CDP-complex formulation group, a Model-Estrus cycle disorder Model group, and an NCD-normal control group. Referring to fig. 9, to verify the effect of the compound preparation on the estrus cycle of mice, the application establishes a model mouse of estrus cycle disorder by injecting letrozole (an aromatase inhibitor which can inhibit the conversion of androgen into estrogen, causing hyperhormonal anemia, resulting in estrus cycle disorder). After treatment with the combination formulation we found: the mice have the disturbance of the estrus cycle after molding, more continuous estrus intervals can be seen, the expression of other estrus cycles is less, no ovulation is prompted, after the compound preparation is used for treating for 21 days, other three estrus cycles gradually appear, and the regular estrus cycle appears in the later treatment period, so that the compound preparation has a good recovery effect on the disturbance of the estrus cycle of the mice.

3.4 the compound preparation can improve the urination disturbance of the vagina of mice

When a woman is in a perimenopause period, a series of symptoms caused by atrophy of bladder and urethral mucous membranes, such as atrophic cystitis, urethritis, urethral orifice eversion, caruncle, stress urinary incontinence and the like, are easily caused by estrogen deficiency, and symptoms such as frequent micturition, urgent micturition, nocturia and the like appear. FIG. 10 is a urine spot test for detecting changes in urination habits of different groups of mice. Under normal conditions, when a mouse urinates, four corners of the cage are selected to urinate intensively, and the urine spot is moderate and regular in size, which is related to the habit of the mouse; however, when urination dysfunction such as frequent, urgent and increased nocturia occurs, the mouse cannot control the urination and will urinate anywhere in the cage, often in the form of "dribbles". As shown in fig. 10, when the urination behavior of the normal group of mice is not damaged, the urine spots are moderate in size and regularly distributed at four corners, but the GSM group of mice is obviously abnormal, the urine spots are irregular in shape, mainly the urine spots are distributed at all places of the cage, which indicates that the mice have urination dysfunction, and urine leakage occurs when the mice fail to wait for the mice to go to the place suitable for urination; after the treatment of the three treatment groups, the urination behavior of the mice is obviously improved, the small urinary spot accounts for a small amount and gradually approaches to the urination of four corners, wherein the improvement of the compound preparation group is most obvious and is closest to the normal group. It is fully demonstrated that the compound preparation can improve the urination dysfunction of mice, namely remarkably relieve the symptoms of frequent micturition, urgent micturition, nocturia and the like.

From the above experimental results, it can be seen that:

1. the compound preparation provided by the application can prevent and treat the atrophy process of perimenopausal sexual organs and maintain the youthfulness of vagina and uterus;

2. the compound preparation provided by the application can improve the sex hormone level of mice in the perimenopausal period;

3. the compound preparation provided by the application is beneficial to recovering disordered estrus cycles of perimenopausal mice;

4. the compound preparation provided by the application can improve the urination habit of mice and relieve the symptoms of frequent micturition, urgent micturition, nocturia and the like.

The embodiments provided in the present application are only a few examples of the general concept of the present application, and do not limit the scope of the present application. Any other embodiments extended according to the scheme of the present application without inventive efforts will be within the scope of protection of the present application for a person skilled in the art.

Claims

1. A composite preparation for preventing and/or treating female perimenopausal urogenital syndrome is characterized by comprising the following main components: epidermal growth factor, sea buckthorn seed oil and glycerol.

2. The complex formulation according to claim 1, wherein the complex formulation further comprises one or more of Burkholderia, Lactobacillus plantarum, Propionibacterium freudenreichii.

3. A composite preparation for preventing and/or treating female perimenopausal urogenital syndrome is characterized by comprising the following components: 20-30% of epidermal growth factor, 1-3% of Burkholderia, 1-3% of lactobacillus plantarum, 1-3% of propionibacterium freudenreichii, 5-15% of seabuckthorn flavone and 41-72% of glycerol.

4. Application of a compound preparation in preventing and/or treating female perimenopausal urogenital syndrome and products thereof.

5. Use of a complex formulation in the prevention and/or treatment of vaginal atrophy, maintenance of the state of the sexual organs in women and in the production thereof.

6. A compound preparation is used for preventing and/or treating female perimenopausal dysuresia, pollakisuria, urgent micturition, nocturia, etc. dysuresia and its application in product.

7. A compound preparation is used for increasing female perimenopausal sex hormone level, regulating and recovering female disordered menstrual cycle and its application in product.

8. Use according to any one of claims 4 to 7, wherein the product comprises a pharmaceutical or nutraceutical product.

9. The use of claim 8, wherein the pharmaceutical dosage form comprises gel, soft capsule, dripping pill, emulsion, tablet, lotion, liniment, ointment, suppository, etc.