An external traditional Chinese medicine composition for treating thin endometrium

Abstract

The present application relates to the field of traditional Chinese medicine, and specifically relates to a kind of external use traditional Chinese medicine composition for treating thin endometrium, which is composed of the following raw medicinal materials: cinnamon 250-300g, fennel 250-300g, Corydalis 250-480g, Cnidium 250-400g, safflower 250-300g, Evodia 150-200g, mugwort leaf 250-300g, and ginger juice 500-600ml.The external use combined medicine of the present application can obviously improve the symptoms of dysmenorrhea, little menstrual flow, dark red menstrual color, and more menstrual blood clots, thicken the endometrial thickness during ovulation, and improve the clinical pregnancy rate of patients with thin endometrium.The external use traditional Chinese medicine is absorbed through skin, does not burden liver and kidney functions, achieves the purposes of warming meridians, activating blood and resolving stasis through the action of acupoint meridian, has little side effects, and is convenient for promotion.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine, specifically to a topical Chinese medicine composition for treating thin endometrium. Background Technology

[0002] Since the advent of in vitro fertilization (IVF), this technology has been widely used to treat infertility. With the current two-child policy, the demand for new life is gradually increasing. However, factors such as age, uterine cavity damage, and endocrine disorders can lead to a thin endometrium, posing a significant obstacle to embryo implantation. Studies have shown that the incidence of repeated frozen-thawed embryo transfer (FET) failures in IVF is as high as 10%-15%, with a thin endometrium accounting for 30% of these failures. A thin endometrium is a key factor limiting IVF success rates.

[0003] Currently, Western medicine treatments for thin endometrium mainly employ methods such as drug therapy, surgery, immunotherapy, and regenerative medicine. High-dose estrogen pulse therapy is the most common drug treatment, but its effectiveness is limited. It does not increase endometrial thickness but instead leads to glandular secretion and fluid accumulation in the uterine cavity, further reducing endometrial receptivity. Furthermore, high-dose estrogen therapy carries a high risk of thrombosis. Although newer adjunctive medications for improving thin endometrium, such as aspirin, sildenafil, and vitamin E, have emerged, their true efficacy remains questionable. Large-scale, multi-center studies are lacking to validate these treatments, and there is no expert consensus on these approaches. Adverse reactions such as headaches and hypotension caused by some medications also result in low patient compliance, hindering widespread clinical application. Endometrial minimally invasive surgery involves scraping the endometrium under hysteroscopy. This mechanical stimulation of the endometrium can have a positive effect to some extent, but the surgery itself carries the risk of intrauterine infection and an increased incidence of postoperative intrauterine adhesions. While immunotherapies such as platelet-rich plasma (PRP) and granulocyte colony-stimulating factor (GCS) have shown some improvement in thin endometrium caused by intrauterine adhesions, their specific clinical application lacks multi-center, large-sample studies. For example, there is no consensus domestically or internationally on the timing and dosage of intrauterine infusion. Currently, emerging regenerative therapies—stem cell therapy—show great potential in endometrial repair by promoting the regeneration of the endometrial basal layer, but due to limitations in research depth, the dosage and timing of stem cell infusion have not yet been determined. Therefore, there is an urgent clinical need to develop a non-invasive treatment with proven efficacy. Summary of the Invention

[0004] The purpose of this invention is to provide a topical traditional Chinese medicine composition for treating thin endometrium.

[0005] In a first aspect, the present invention provides a topical traditional Chinese medicine composition for treating thin endometrium, comprising the following raw materials: 250-300g cinnamon, 250-300g fennel, 250-480g corydalis, 250-400g cnidium, 250-300g safflower, 150-200g evodia, 250-300g mugwort, and 500-600ml ginger juice.

[0006] Furthermore, the external application traditional Chinese medicine composition consists of the following raw materials: 280-300g cinnamon, 280-300g fennel, 350-480g corydalis, 300-400g cnidium, 280-300g safflower, 180-200g evodia, 280-300g mugwort, and 500-550ml ginger juice.

[0007] Furthermore, the external application Chinese medicine composition consists of the following raw materials: 300g cinnamon, 300g fennel, 480g corydalis, 400g cnidium, 300g safflower, 200g evodia, 300g mugwort, and 500ml ginger juice.

[0008] In a second aspect, the present invention provides a pharmaceutical preparation in which the above-described topical Chinese medicine composition is used as an active ingredient.

[0009] Furthermore, the aforementioned pharmaceutical preparation is a traditional Chinese medicine acupoint patch.

[0010] Furthermore, the preparation and usage of the aforementioned traditional Chinese medicine acupoint patch:

[0011] Weigh the raw materials according to the prescribed ratio, make them into coin-sized pills, and apply them to the center of the external patch. When using, begin after the patient's previous menstrual period and apply to the Zigung (GB20) and Shenshu (BL23) acupoints (bilateral), 3 times a week, one patch per acupoint, 8 hours per application, continuously until the next menstrual period. Discontinue use during menstruation. Continue treatment after the end of the menstrual period in the embryo transfer cycle until the day of embryo transfer.

[0012] A third aspect of the present invention provides the use of the topical Chinese medicine composition as described above in the preparation of a medicament for treating thin endometrium.

[0013] A fourth aspect of the present invention provides the use of the pharmaceutical preparation described above in the preparation of a medicament for treating thin endometrium.

[0014] In the external application traditional Chinese medicine composition of this invention: Cinnamon, fennel, corydalis, and evodia are the principal herbs in Dang Gui Wen Shan Tang (Angelica Sinensis and Evodia Decoction). These herbs are all warm in nature and enter the liver, kidney, spleen, and stomach meridians. They have the effects of tonifying fire and guiding fire back to its source, dispelling cold and relieving pain, and promoting blood circulation and menstruation. They are used for gynecological diseases such as infertility due to uterine cold, amenorrhea, and dysmenorrhea. Cnidium monnieri and Artemisia argyi are the assistant herbs, assisting the principal herbs in warming the kidneys and strengthening yang, warming the meridians and dispelling cold. Safflower is warm in nature and pungent in taste, serving as an adjuvant herb, with the effects of promoting blood circulation, dispelling blood stasis and relieving pain, thus enhancing the blood-activating effect. Finally, ginger juice is used as the guiding herb. Because ginger is slightly warm in nature and pungent in taste, it can both warm the spleen and assist yang, and also relieve exterior cold, opening the pores and accelerating the penetration of the other herbs.

[0015] The advantages and beneficial effects of this invention are as follows:

[0016] 1. External application of traditional Chinese medicine is absorbed through the skin, without burdening liver and kidney function. It achieves the purpose of warming the meridians, promoting blood circulation, and removing blood stasis through the action of acupoints and meridians. It has few side effects and is easy to promote.

[0017] 2. The combination of drugs of the present invention can be applied externally to acupoints to treat symptoms such as dysmenorrhea, scanty menstruation, dark red menstrual blood, and excessive menstrual blood clots.

[0018] 3. The combination of drugs of the present invention applied externally to acupoints can significantly increase the thickness of the endometrium during ovulation, optimize the morphology of the endometrium, increase the blood supply to the endometrium, improve the receptivity of the endometrium, and increase the clinical pregnancy rate of patients with thin endometrium.

[0019] 4. The combination of drugs of the present invention can be applied externally to acupoints to prevent and improve the recurrence rate of intrauterine adhesions after hysteroscopy. By increasing the blood supply to the pelvic cavity, uterus and subendometrium, the microenvironment for endometrial growth is improved and endometrial epithelial cells are induced to secrete growth factors. Detailed Implementation

[0020] The specific implementation methods provided by the present invention will be described in detail below with reference to the embodiments.

[0021] Unless otherwise specified, experimental methods in the following examples are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise noted, the medicinal materials used in the embodiments of this invention can be obtained from Chinese medicinal herb sales companies. Unless otherwise noted, all obtained medicinal materials are processed Chinese medicinal herbs. These processed herbs can be obtained from sales companies or can be obtained through processing.

[0022] Example 1: Composition of the traditional Chinese medicine composition of the present invention

[0023] 250g cinnamon, 250g fennel seeds, 250g corydalis rhizome, 250g cnidium fruit, 250g safflower, 150g evodia fruit, 250g mugwort leaves, 500ml ginger juice.

[0024] Example 2: Composition of the traditional Chinese medicine composition of the present invention

[0025] 260g cinnamon, 260g fennel seeds, 280g corydalis rhizome, 280g cnidium fruit, 260g safflower, 160g evodia fruit, 260g mugwort leaves, 520ml ginger juice.

[0026] Example 3: Composition of the traditional Chinese medicine composition of the present invention

[0027] 270g cinnamon, 270g fennel seeds, 320g corydalis rhizome, 300g cnidium fruit, 270g safflower, 170g evodia fruit, 270g mugwort leaves, 540ml ginger juice.

[0028] Example 4: Composition of the traditional Chinese medicine composition of the present invention

[0029] 280g cinnamon, 280g fennel seeds, 350g corydalis rhizome, 320g cnidium fruit, 280g safflower, 180g evodia fruit, 280g mugwort leaves, 560ml ginger juice.

[0030] Example 5: Composition of the traditional Chinese medicine composition of the present invention

[0031] 290g cinnamon, 290g fennel seeds, 400g corydalis rhizome, 360g cnidium fruit, 290g safflower, 190g evodia fruit, 290g mugwort leaves, 580ml ginger juice.

[0032] Example 6: Composition of the traditional Chinese medicine composition of the present invention

[0033] 300g cinnamon, 300g fennel seeds, 450g corydalis rhizome, 380g cnidium fruit, 300g safflower, 200g evodia fruit, 300g mugwort leaves, 600ml ginger juice.

[0034] Example 7: Composition of the traditional Chinese medicine composition of the present invention

[0035] 300g cinnamon, 300g fennel seeds, 480g corydalis rhizome, 400g cnidium fruit, 300g safflower, 200g evodia fruit, 300g mugwort leaves, 500ml ginger juice.

[0036] Example 8: Preparation and use of the herbal poultice of the present invention

[0037] Weigh the raw materials according to the composition and proportions described in any of Examples 1-4, make them into coin-sized pills, and apply them to the center of the external patch. When using, begin after the patient's previous menstrual period by applying the patch to the Zigung (bilateral) and Shenshu (bilateral) acupoints, 3 times a week, one patch per acupoint, for 8 hours each time, continuously until the next menstrual period. Discontinue use during menstruation. Continue treatment after the end of the menstrual cycle during the transplantation cycle until the day of transplantation.

[0038] Example 9: Clinical Trial

[0039] 1. Study subjects: Cases were obtained from infertile female patients who underwent in vitro fertilization and frozen embryo transfer at the Department of Reproductive Medicine of Shanghai First Maternity and Infant Hospital from May 2019 to May 2020.

[0040] 2. Diagnostic criteria

[0041] (1) The diagnostic criteria for female infertility are based on Obstetrics and Gynecology. That is, women who have not used contraception after marriage, have regular sexual intercourse, and have lived together for one year without conceiving.

[0042] (2) Diagnostic criteria for thin endometrium: When the diameter of the largest follicle is greater than 18 mm and the endometrial thickness is less than 7 mm, as monitored by vaginal ultrasound during the follicular phase for two consecutive menstrual cycles.

[0043] (3) Diagnostic criteria for kidney deficiency and blood stasis syndrome: formulated with reference to "Traditional Chinese Medicine Gynecology" and "Guiding Principles for Clinical Research of New Chinese Medicine Drugs".

[0044] 1) Main symptom: Infertility after prolonged marriage;

[0045] 2) Concurrent symptoms: (1) Lower back and abdominal pain during menstruation, which worsens in the later stages, and a feeling of emptiness in the vulva; (2) Dizziness, insomnia, and decreased libido; (3) Scanty menstruation, dark color, and thin consistency; (4) Pale and dark tongue with a swollen body, or petechiae on the sides; The main symptoms are required, and 2 out of the 4 concurrent symptoms must be met.

[0046] 3. Inclusion criteria:

[0047] (1) Meets the diagnostic criteria for infertility and thin endometrium and is diagnosed with kidney deficiency and blood stasis syndrome in traditional Chinese medicine;

[0048] (2) Age 25-42 years old;

[0049] (3) Body mass index (BMI) is 18.5–28;

[0050] (4) Those who have registered at our reproductive center and have ≥2 high-quality cleavage-stage embryos or ≥1 high-quality blastocyst.

[0051] 4. Exclusion criteria:

[0052] (1) Combination with uterine malformation, submucosal uterine fibroids, intramural uterine fibroids >4cm or larger, severe intrauterine adhesions, adenomyosis or endometriosis, endometrial polyps, endometrial tuberculosis, or hydrosalpinx.

[0053] (2) Individuals with coexisting autoimmune diseases;

[0054] (3) Thyroid dysfunction;

[0055] (4) Allergy to the test drug or a known drug ingredient;

[0056] (5) History of malignant tumors of the reproductive system.

[0057] 5. Treatment methods

[0058] Endometrial preparation protocol: (1) Natural cycle protocol: The subject underwent vaginal ultrasound monitoring on days 10-12 of the menstrual cycle. When the diameter of the primary follicle was >17mm, the endometrium was >7mm, and E2 was >150Pg / mL and P was <1ng / mL, ovulation was induced by intramuscular injection of 5000IU of human chorionic gonadotropin (HCG, 5000IU, Lizhu Pharmaceutical Factory) 21h on the same day. Three days after the HCG injection, two capsules of progesterone soft capsules (Angitan, 0.1g, Besen Belgium Pharmaceutical Factory) were administered vaginally twice a day. Five days after ovulation induction, 1-2 cleavage-stage embryos were transferred, or 1-2 blastocyst-stage embryos were transferred seven days later. After the transfer, two capsules of progesterone were administered vaginally twice a day for luteal support. (2) Letrozole ovulation induction protocol: Starting from day 3 of the menstrual cycle, take letrozole (Furex, 2.5mg, Jiangsu Hengrui Medicine Co., Ltd.) 2.5mg / qd orally for 5 days. Monitor follicles on day 10 of the menstrual cycle. If the primary follicle is ≥8mm, monitor every 2 days until ovulation is induced. If the primary follicle is <14mm, administer 75IU of urinary gonadotropin (Lebode, 75IU, Lizhu Pharmaceutical Factory) daily to promote follicle growth. The timing of ovulation induction, FET arrangement, and luteal support is the same as in the natural cycle described above. (3) Hormone Replacement Cycle Protocol: Subjects started the cycle on day 2-3 of their menstrual cycle. After the first ultrasound to rule out ovarian cysts, they were given estradiol valerate (Femoston Red Tablets, 2mg, Abbott Laboratories, Netherlands), 2 tablets, twice daily, for 12 consecutive days. A second ultrasound was then performed to monitor endometrial thickness. If the endometrial thickness was ≥8mm and the serum E2 value was >200Pg / ml on that day, dydrogesterone (Femoston Yellow Tablets, 10mg, Abbott Laboratories, Netherlands), 2 tablets, twice daily, for 3 consecutive days to induce endometrial transformation. Three days after transformation, 1-2 cleavage-stage embryos could be transferred, or five days later, 1-2 blastocyst-stage embryos could be transferred. After transfer, dydrogesterone 2 tablets, twice daily, orally, and progesterone capsules 2 tablets, twice daily, were administered vaginally for luteal support.

[0059] Treatment group: After the subjects' previous menstrual period ended, they were given warming patches applied to the uterus acupoints (bilateral) and kidney acupoints (bilateral) 3 times a week, 1 patch per acupoint, 8 hours each time, continuously until the next menstrual period, and discontinued during menstruation. After the menstrual period ended in the transplant cycle, the treatment continued until the day of transplantation.

[0060] Control group: Subjects began receiving regular heat patches at the Zigung (GB20) and Shenshu (BL23) acupoints after their previous menstrual period, three times a week, one patch per acupoint, for 8 hours each time, continuously until the next menstrual period, discontinuing during menstruation. Treatment continued after menstruation ended during the transplant cycle until the day of transplantation.

[0061] 6. Testing indicators and testing methods:

[0062] 6.1 Pregnancy outcome: (1) Clinical pregnancy rate = number of patients with clinical pregnancy / total number of patients treated (clinical pregnancy is defined as the presence of a gestational sac and fetal heartbeat in the uterus on vaginal ultrasound examination 28 days after embryo transfer); (2) Implantation rate = number of patients with successful implantation / total number of patients treated (patients with positive urine HCG test strips or elevated serum HCG 14 days after embryo transfer); (3) Early miscarriage rate = number of patients with miscarriage / number of patients with clinical pregnancy (miscarriage refers to miscarriage occurring within 12 weeks of pregnancy).

[0063] 6.2 Endometrial receptivity indicators: (1) Endometrial thickness on the day of endometrial transformation; (2) Endometrial type (Type A: typical tri-line type, with strong echoes at the junction of the endometrium and myometrium and the central endometrial line, and low echoes in the area between the outer line and the central line; Type B: weak tri-line type, with an indistinct or discontinuous midline of the strong echo in the uterine cavity; Type C: homogeneous strong echoes, with no strong echoes in the midline of the uterine cavity); (3) Endometrial blood flow (Type I: no obvious blood flow signal in the endometrial area, with 0 blood flow branches; Type II: sparse blood flow signal in the endometrial area, with ≤2 blood flow branches; Type III: more blood flow signal in the endometrial area, with ≥2 and ≤4 blood flow branches; Type IV: abundant blood flow signal in the endometrial area, with ≥5 blood flow branches). (4) Serum E2 and P were detected by chemiluminescence on the day of transplantation.

[0064] 6.3 Comparison of TCM syndrome scores in reproductive quality assessment: (1) TCM syndrome scores: The TCM syndrome scoring method in the "Guiding Principles for Clinical Research of New Drugs (Traditional Chinese Medicine)" was adopted: Severe: Symptoms are significant or persistent, 6 points; Moderate: Symptoms are sometimes mild and sometimes severe or appear intermittently, 4 points; Mild: Symptoms are mild or appear occasionally, 2 points; None: No symptoms appear, 0 points. During the analysis, the tongue and pulse of patients who were greatly affected by subjective factors were excluded. The reproductive quality assessment used FertiQOL (Chinese version) developed by Professor Jacky Boivin. The reproductive quality scale has 36 items, of which 2 items are not included in the total score. The remaining 34 items consist of two parts: the central module and the treatment module. The central module evaluates the emotions, marital relationship, social relationship and mental / physical factors of infertile patients, including 4 dimensions and 24 items; the treatment module mainly evaluates the patient's compliance with treatment, tolerance and treatment environment, with a total of 10 items. The entire scale uses a 5-point rating system (0-4 points), with a total score of 100 points. Higher scores indicate higher quality of life.

[0065] 6.4 Safety indicators: Record adverse reactions, adverse events or side effects that occur in patients within 3 months from the start of the clinical trial to the end of the trial, and describe in detail the time of occurrence, symptoms, signs, subsequent treatment and time to relief of adverse events.

[0066] 6.5 Statistical Methods: SPSS 21.0 software was used for statistical analysis. For continuous data that satisfies a normal distribution, [the following methods were used]. For data description, t-tests were used for comparisons between groups. For data not conforming to a normal distribution, the median (interquartile range) was used. Wilcoxon rank-sum tests were used for comparisons between groups. Count data were described using frequencies (proportions), and chi-square tests were used for comparisons between groups.

[0067] 7. Results

[0068] 7.1 Baseline Data Comparison

[0069] There were no significant differences between the two groups in age, BMI, duration of infertility, cause of infertility, serum AMH, endometrial preparation protocol, embryo stage and number of embryos transferred (P>0.05), as shown in Table 1.

[0070] Table 1 Comparison of general information of patients in each group [ / M(Q)]

[0071]

[0072] 7.2 Comparison of pregnancy outcomes among groups

[0073] The clinical pregnancy rate and implantation rate were higher in the treatment group than in the control group, but the difference was not statistically significant (P>0.05). After stratifying the patients by age, the clinical pregnancy rate in the treatment group was significantly higher than that in the control group in patients ≤35 years old (P<0.05), while there was no statistically significant difference between the two groups in patients >35 years old (P>0.05). See Table 2-4.

[0074] Table 2 Comparison of pregnancy outcomes across all age groups in each group [n(%)]

[0075]

[0076] Table 3 Comparison of pregnancy outcomes in patients ≤35 years old [n(%)]

[0077]

[0078] Table 4 Comparison of pregnancy outcomes between the two groups of patients >35 years old [n(%)]

[0079]

[0080] Note: Compared with the control group, * P < 0.05

[0081] 7.3 Comparison of endometrial receptivity indicators

[0082] The endometrium in the treatment group was significantly thicker than that in the control group (P<0.05). Regarding endometrial type, the proportion of type A endometrium was higher in the treatment group than in the control group, but the difference was not statistically significant (P>0.05). The proportion of type III and IV endometrium was significantly higher in the treatment group than in the control group (P<0.05). There were no statistically significant differences in serum E2 and P levels between the two groups on the day of transplantation (P>0.05) (see Table 5).

[0083] Table 5 Comparison of endometrial receptivity indices among different groups of patients [ / M(Q), example(%)]

[0084]

[0085] Note: Compared with the control group, * P < 0.05.

[0086] 7.4 Comparison of Reproductive Quality Score and Traditional Chinese Medicine Syndrome Score

[0087] Before treatment, there were no statistically significant differences in reproductive quality scores and TCM syndrome scores between the two groups (P>0.05). The difference in reproductive quality scores before and after treatment in the treatment group was higher than that in the control group (P<0.05), and the difference in TCM syndrome scores was also higher in the treatment group than in the control group (P<0.05). See Table 6.

[0088] Table 6 Comparison of reproductive quality scores and TCM syndrome scores before and after treatment in each group of patients [score, / M(Q)]

[0089]

[0090] Note: Compared with the control group, * P < 0.05.

[0091] 7.5 Security Assessment

[0092] No serious adverse reactions occurred in any of the four groups of patients during treatment. One patient in the traditional Chinese medicine group experienced diarrhea, which resolved spontaneously without special treatment. Blood pressure, heart rate, respiration, and body temperature were not significantly abnormal in any group before and after treatment. Complete blood count, urinalysis, electrocardiogram, liver function, and kidney function tests were all within normal ranges. There were no significant differences (p>0.05) in the main liver and kidney function indicators, namely alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), creatinine (Cr), and blood urea nitrogen (BUN), before and after treatment. See Table 7.

[0093] Table 7 Comparison of liver and kidney function before and after treatment in each group [ M(Q)]

[0094]

[0095]

[0096] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.

Claims

1. A topical traditional Chinese medicine composition for treating thin endometrium, characterized in that, It is composed of the following raw materials: 250-300g cinnamon, 250-300g fennel, 250-480g corydalis, 250-400g cnidium, 250-300g safflower, 150-200g evodia, 250-300g mugwort, and 500-600ml ginger juice.

2. The topical traditional Chinese medicine composition for treating thin endometrium according to claim 1, characterized in that, From the following raw materials Ingredients: 280-300g cinnamon, 280-300g fennel seeds, 350-480g corydalis rhizome, 300-400g cnidium fruit, 280-300g safflower, 180-200g evodia fruit, 280-300g mugwort leaves, and 500-550ml ginger juice.

3. The topical traditional Chinese medicine composition for treating thin endometrium according to claim 1, characterized in that, It is composed of the following raw materials: 300g cinnamon, 300g fennel, 480g corydalis, 400g cnidium, 300g safflower, 200g evodia, 300g mugwort, and 500ml ginger juice.

4. A pharmaceutical preparation in which the topical Chinese medicine composition as described in any one of claims 1-3 is used as the active ingredient.

5. The pharmaceutical preparation according to claim 4, characterized in that, The aforementioned drug preparation is a traditional Chinese medicine acupoint patch.

6. The pharmaceutical preparation according to claim 5, characterized in that, The preparation method of the traditional Chinese medicine acupoint patch is as follows: weigh the raw materials according to the ratio, make them into pills the size of a coin, and apply them to the center of the external patch.

7. The use of a topical traditional Chinese medicine composition as described in any one of claims 1-3 in the preparation of a medicament for treating thin endometrium.

8. The use of a pharmaceutical preparation as described in any one of claims 4-6 in the preparation of a medicament for treating thin endometrium.

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