A traditional Chinese medicine composition for promoting cervical ripening of term pregnancy, and a preparation method and use thereof

Abstract

This invention provides the use of ginseng extract and astragalus extract in combination in the preparation of a drug to promote cervical ripening in full-term pregnancy. This invention also provides a traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancy, prepared from the following raw materials in the indicated weight ratios: 0.8-1.2 parts ginseng extract and 0.8-1.2 parts astragalus extract. This invention also provides a method for preparing this traditional Chinese medicine composition and its uses. The traditional Chinese medicine granules for promoting cervical ripening in full-term pregnancy utilize ginseng to replenish vital energy and astragalus to replenish qi and raise yang; the two work synergistically to achieve the effects of replenishing qi, consolidating the body, supporting the body's resistance, and stabilizing the pregnancy. The formula is concise (only two herbs), significantly simplified compared to existing compound traditional Chinese medicines for promoting cervical ripening, with clearly defined active ingredients, facilitating standardized production and quality control. It is non-addictive, has low side effects, good patient compliance, and is inexpensive, making it suitable for promotion and application in primary healthcare institutions. It aligns with the national policy goal of reducing the cesarean section rate and has significant clinical and social value.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancies, its preparation method, and its uses. Background Technology

[0002] Cervical ripening refers to a series of histological and biochemical changes that occur in the cervix before labor, including collagen fiber degradation and rearrangement, increased matrix components, inflammatory cell infiltration, and increased tissue water content. These changes cause the cervix to gradually become softer, shorter, recede, and dilate from tough connective tissue. It is an essential condition for the initiation of normal labor and a key prerequisite for successful labor induction.

[0003] Clinically, the Bishop score is the gold standard for assessing cervical maturity. A Bishop score <6 is generally considered to indicate cervical immaturity. Direct induction of labor or waiting for spontaneous labor in women with immature cervixes often leads to prolonged latent period, labor arrest, fetal distress, and a significantly increased risk of cesarean section. Studies show that the cesarean section rate after failed induction of labor in immature cervixes can reach 50%. The National Health Commission has listed "reducing the rate of non-medical indication cesarean sections" as a national goal for improving obstetric medical quality and safety for many consecutive years. Statistics show that the cesarean section rate for primiparous women in my country increased from 37.69% in 2018 to 50.62% in 2024. Hasty management of labor in cases of cervical immaturity is one of the important reasons for non-medical indication cesarean sections. Therefore, developing safe and effective drugs to promote cervical ripening is not only of significant clinical value but also an important measure to implement the national policy goal of reducing the cesarean section rate.

[0004] Currently, commonly used methods for cervical ripening in clinical practice mainly include pharmacological and mechanical methods. Drug methods, primarily using prostaglandin preparations (such as dinoprostone and misoprostol), are the most common, but can induce adverse reactions such as uterine hyperstimulation, fetal distress, nausea, and vomiting, and are relatively expensive. While estrogen can improve Bishop scores, it can reduce postpartum milk production. Mechanical methods, such as Foley balloons and double-balloon catheters, are invasive procedures, increasing the risk of infection and premature rupture of membranes, and resulting in a poor experience for the pregnant woman. Therefore, exploring a safe, effective, and non-invasive method for cervical ripening has always been a research focus in the field of obstetrics.

[0005] Traditional Chinese medicine has long offered insightful discussions on the physiology of childbirth. The *Jingyue Quanshu* (Complete Works of Jingyue) states, "The ease or difficulty of childbirth depends entirely on the deficiency or excess of Qi and blood." The *Nüke Jinglun* (Classic of Gynecology) also says, "The signs of labor depend entirely on Qi and blood." Normal childbirth relies on abundant and unobstructed Qi and blood. The cervix ("the gate of the womb," "the gate of the uterus") is the gateway for the delivery of the fetus. If Qi and blood are deficient, the womb will not be nourished and will be obstructed from opening; if Qi stagnates and blood stasis occurs, the womb will be tightly closed and difficult to open and close. Therefore, treating the condition from the perspective of Qi and blood, using tonifying Qi and nourishing blood as the basic treatment method to promote cervical ripening, is a fundamental strategy consistent with the theories of traditional Chinese medicine obstetrics and gynecology.

[0006] In recent years, traditional Chinese medicine (TCM) has made beneficial explorations in promoting cervical ripening. Reports indicate that "Cuichan Zhusheng Tang" (a TCM formula for promoting cervical ripening) can reduce cervical tension and promote cervical ripening by increasing PGE2α, IL-8, and ET-1 levels. Other TCM formulas, such as "Jiawei Bazhen Tang" (a modified version of Bazhen Tang) combined with Zhuang medicine acupressure, "Baochan Wuyou San" (a TCM formula for ensuring safe childbirth), "Jiuwei Zhusheng Tang" (a TCM formula for promoting childbirth), and "Fufang Honghua Heji" (a compound safflower compound), have also been reported for promoting cervical ripening. However, analysis of existing TCM compound formulas for promoting cervical ripening reveals two common problems: First, the formulas are complex, leading to poor quality control. These formulas often consist of five or more herbs, resulting in unclear active ingredients, significant batch-to-batch quality variations, and failure to meet modern TCM quality control requirements, while also increasing the risk of potential adverse reactions. Second, the treatment methods are often unbalanced, potentially depleting qi and blood. Current formulations of compound formulas for promoting cervical ripening largely follow the traditional approach of formulas like "Kai Gu San" from *Fu Qingzhu's Gynecology*, which focuses on invigorating blood circulation, removing blood stasis, and promoting qi flow. These formulas often contain herbs such as Angelica sinensis, Ligusticum chuanxiong, Carthamus tinctorius, Achyranthes bidentata, and Leonurus japonicus, which promote blood circulation and have a more aggressive rather than tonifying effect. However, a significant proportion of women requiring cervical ripening in clinical practice are those with insufficient qi and blood or weak constitutions (such as those experiencing prolonged labor, fatigue, or significant physical exertion). Using blood-activating and purging agents on these women could deplete their qi and blood, hindering the smooth progress of labor. This contradicts the traditional Chinese medicine principle of "preserving even a small amount of qi and blood ensures survival" in postpartum care. Summary of the Invention

[0007] This invention provides a traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancies, its preparation method, and its uses.

[0008] This invention provides the use of ginseng extract and astragalus extract in combination in the preparation of a drug that promotes cervical ripening in full-term pregnancy.

[0009] The weight ratio of ginseng extract to astragalus extract is (0.8-1.2):(0.8-1.2); the ginseng extract is a water extract of ginseng; and the astragalus extract is a water extract of astragalus.

[0010] The weight ratio of the ginseng extract to the astragalus extract is 1:1.

[0011] This invention also provides a traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancies, which is prepared from the following raw materials in the indicated weight ratios:

[0012] Ginseng extract 0.8-1.2 parts, Astragalus extract 0.8-1.2 parts;

[0013] The ginseng extract mentioned is a water extract of ginseng; the astragalus extract mentioned is a water extract of astragalus.

[0014] Preferably, it is prepared from raw materials in the following weight ratio:

[0015] One part ginseng extract and one part astragalus extract.

[0016] It is a pharmaceutically commonly used preparation made by adding pharmaceutically acceptable excipients or auxiliary ingredients, with ginseng extract and astragalus extract as active ingredients.

[0017] The preparations mentioned above are granules, tablets, capsules, and pills.

[0018] This invention also provides a method for preparing the aforementioned traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancies, which includes the following steps:

[0019] a. Preparation of ginseng extract:

[0020] Take ginseng slices, soak them, add water and decoct, filter, concentrate and dry to obtain ginseng extract;

[0021] b. Preparation of Astragalus extract:

[0022] Take Astragalus membranaceus slices, soak them, decoct them in water, filter, concentrate, and dry them to obtain Astragalus membranaceus extract;

[0023] c. Mix ginseng extract and astragalus extract in the specified weight ratio, and add pharmaceutically acceptable excipients or auxiliary ingredients to prepare a commonly used pharmaceutical preparation.

[0024] This invention provides the use of the aforementioned traditional Chinese medicine composition in the preparation of a drug that promotes cervical ripening in full-term pregnancies.

[0025] The medication described is one that improves the Bishop score of the cervix, increases the vaginal delivery rate, or promotes the softening and loosening of cervical tissue.

[0026] Addressing the shortcomings of existing technologies, such as complex formulations, poor quality control, and treatment methods that are too aggressive and unsuitable for the constitution of postpartum women with weak Qi and blood, this invention provides a composition prepared from ginseng extract and astragalus extract for promoting cervical ripening in full-term pregnancies. This invention uses only two herbs in its formulation, ensuring high quality control; its treatment method focuses on tonifying Qi, aligning with the traditional Chinese medicine principle of "tonifying to promote flow" in postpartum care, providing a safe and effective new oral option for promoting cervical ripening in full-term pregnancies with poor cervical conditions.

[0027] The purpose of this invention is to address the shortcomings of existing cervical ripening drugs and traditional Chinese medicine compound formulas, such as complex formulations, poor quality control, overly aggressive treatment methods, and potential depletion of qi and blood. This invention provides a traditional Chinese medicine granule for promoting cervical ripening in full-term pregnancies, along with its preparation method and application. This invention features a simplified formulation, controllable quality, high safety, and a clear mechanism of action. It can significantly improve cervical Bishop scores and vaginal delivery rates, and is non-addictive with low side effects.

[0028] This invention relates to traditional Chinese medicine granules, guided by TCM theory. Cervical ripening, in TCM, is part of the physiological process of "opening and closing of the uterine cavity" before labor. The *Jingyue Quanshu* (Complete Works of Jingyue) states, "The ease or difficulty of childbirth depends entirely on the deficiency or excess of Qi and blood." Poor cervical ripening manifests as a stubborn, unyielding cervix and failure of the uterine cavity to open, falling under the category of insufficient Qi and blood and malnourishment of the uterus in TCM. Based on the above research, this invention combines ginseng and astragalus, following the principle of synergistic compatibility. Ginseng is the primary herb for replenishing Qi, effectively tonifying the original Qi, restoring the pulse and consolidating the body, tonifying the spleen and lungs, and generating fluids and nourishing blood. Its nature is stabilizing and does not disperse, directly tonifying the root of the five internal organs. Astragalus effectively tonifies Qi and raises Yang, consolidates the exterior and stops sweating, promotes diuresis and reduces swelling, generates fluids and nourishes blood, promotes circulation and relieves stagnation, promotes pus drainage and detoxification, and promotes tissue regeneration. Its nature is mobile and does not stagnate, effectively reaching the surface of the body and replenishing defensive Qi. These two ingredients work synergistically, one acting as a regulator and the other as a protector, one internal and the other external, to jointly replenish qi, consolidate the body's defenses, and support the fetus. This invention uses ginseng and astragalus as the principal herbs, which are sweet and warm in nature, nourishing the spleen and stomach, and supporting the generation of qi and blood. When qi and blood are abundant, the uterus is nourished, the uterine opening is facilitated, and thus the physiological maturation of the cervix is ​​promoted. This formula is rationally formulated, has a good function in promoting cervical maturation, and is non-addictive with low side effects.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The Chinese medicine granules of the present invention promote cervical ripening in full-term pregnancy combine ginseng and astragalus. Ginseng greatly replenishes vital energy, and astragalus replenishes qi and raises yang. The two complement each other and work together to replenish qi, consolidate the body, support the body and stabilize the fetus. The formula is concise (only two herbs), which is significantly simpler than the existing compound Chinese medicine formulas for promoting cervical ripening (most of which are composed of five or more herbs). The effective ingredients are clear, which is convenient for standardized production and quality control. It is non-addictive and has low side effects.

[0031] (2) Ginseng extract and Astragalus extract are combined in a specific ratio of 1:1 and processed into Chinese medicine granules by water extraction, concentration and granulation. The granules have excellent effects on promoting cervical ripening. Clinical trials have shown that the present invention can significantly improve the Bishop score of the cervix (from <6 points to ≥6 points) and increase the vaginal delivery rate.

[0032] (3) The present invention has confirmed through animal experiments that ginseng and astragalus granules can significantly promote the loose remodeling of uterine tissue, reduce the collagen area ratio of cervical tissue, and upregulate the expression levels of PGE2, IL-1β, IL-6 and MMP-9. Its mechanism of action in promoting cervical maturation is clear and has a significant synergistic effect.

[0033] (4) This invention focuses on replenishing qi, which is in line with the traditional Chinese medicine concept of "replenishing to promote circulation" in women's pregnancy and childbirth. It avoids the risk of qi and blood depletion and damage to blood in women with weak qi and blood due to existing blood-activating and stasis-removing compound prescriptions, and is highly safe.

[0034] (5) This invention is an oral granule, which is non-invasive and has good patient compliance. It is inexpensive and suitable for promotion and application in primary medical institutions. It is in line with the national policy goal of reducing the cesarean section rate and has important clinical significance and social value. Attached Figure Description

[0035] Figure 1 Changes in Bishop scores before and after treatment in both groups (*** indicates comparison with the same group before treatment, P<0.001; ### indicates comparison with the control group at the same time point after treatment, P<0.001. Statistical methods used included repeated measures two-way ANOVA and Bonferroni post-hoc test. The overall interaction effect was significant (F=24.26, P<0.001). There was no significant difference in baseline levels between the two groups before treatment (P>0.05)).

[0036] Figure 2 Comparison of pregnancy outcomes between the two groups of pregnant women (A. Comparison of the percentage of vaginal delivery to cesarean section between the two groups; B. Comparison of postpartum hemorrhage between the two groups. Data are expressed as mean ± standard deviation (Mean ± SD); Fisher's exact test was used for comparisons between groups in Figure A, *P<0.05 (compared with the control group); Independent samples t-test was used for comparisons between groups in Figure B, t(198)=0.63, P>0.05. Control group n=100, Shenqi Granules group n=100).

[0037] Figure 3 Effects of Shenqi Granules on the levels of PGE2, IL-1β, IL-6, and MMP-9 in uterine tissue of mice in late pregnancy. Uterine tissue homogenates were collected from each group of mice, and the levels of each indicator in the supernatant were detected by ELISA (A: PGE2; B: IL-1β; C: IL-6; D: MMP-9. The units for PGE2, IL-1β, and IL-6 were pg / mL, and the unit for MMP-9 was ng / mL. The sample size for each group was n=10. Data are expressed as mean ± standard error (Mean ± SEM). One-way ANOVA was used for comparisons among multiple groups, and LSD was used for post-hoc pairwise comparisons; * P < 0.05, *** P < 0.001).

[0038] Figure 4Effects of Shenqi Granules on the Morphology of Uterine Tissue in Late Pregnancy Mice (Uterine tissues from mice in each group were paraffin-embedded, sectioned, and stained with H&E. Morphological changes were observed under a light microscope. A: Representative images of H&E-stained uterine tissues from each group, scale bar = 20 μm. B: Quantitative statistics on the percentage of loose uterine tissue area in each group relative to the total field of view. Sample size n=6 per group. Data are expressed as mean ± standard error (Mean ± SEM). One-way ANOVA was used for comparisons among multiple groups, and LSD method was used for post-hoc pairwise comparisons; *P<0.05, **P<0.01, ***P<0.001).

[0039] Figure 5 Uterine tissues from mice in each group were collected, paraffin-embedded, sectioned, and stained with Masson's stain. The distribution and deposition of collagen fibers were observed under a light microscope (representative images of Masson's staining of uterine tissues from each group of mice; collagen fibers appear blue, and muscle fibers appear red; scale bar = 20 μm). B: Quantitative statistics on the percentage of collagen area in the uterine tissue of each group of mice relative to the total field of view. The sample size for each group was n = 6. Data are expressed as mean ± standard error (Mean ± SEM). One-way ANOVA was used for comparisons among multiple groups, and LSD method was used for post-hoc pairwise comparisons; *** P < 0.001). Detailed Implementation

[0040] The following non-limiting embodiments are intended to enable those skilled in the art to more fully understand the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection of the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection of the present invention.

[0041] The present invention will be further described below with reference to specific embodiments. All Chinese medicinal materials used in the embodiments of the present invention comply with the relevant provisions of Part I of the 2020 edition of the Pharmacopoeia of the People's Republic of China, and other chemical reagents, unless otherwise specified, are obtained through conventional commercial channels.

[0042] Example 1: Preparation process of the traditional Chinese medicine composition granules of the present invention (hereinafter referred to as "Ginseng and Astragalus Granules")

[0043] Specifications: 5 g / bag

[0044] Quantity: 1000 bags

[0045] Total finished product: 5.0 kg

[0046] Raw material ratio: Ginseng: Astragalus = 6.7:8 (calculated based on a ginseng extract yield of 30% and an astragalus extract yield of 25%)

[0047] I. Prescription Composition (1000 sachets)

[0048]

[0049] II. Preparation of Ginseng Extract

[0050] (a) Raw materials

[0051] Take 6.70 kg of ginseng slices that meet the requirements of the Chinese Pharmacopoeia, remove impurities, clean and cut them into slices 2-3 mm thick, and use them for later use after passing the inspection.

[0052] (ii) Soaking

[0053] Place the ginseng slices into a multi-functional extraction tank, add purified water, and soak at room temperature for 60 minutes to allow the medicinal material to fully absorb water.

[0054] (III) Extraction

[0055] The process involves a three-stage water extraction: 1. First stage: Add purified water, heat to a gentle boil, extract for 90 minutes, and filter; 2. Second stage: Add purified water to the residue, extract for another 60 minutes, and filter; 3. Third stage: Add purified water again, extract for 30 minutes, and filter.

[0056] The three extracts were combined, filtered through a 100-mesh sieve, and then filtered through a plate and frame filter to obtain a clear extract.

[0057] (iv) Reduced pressure concentration

[0058] The extract was concentrated under reduced pressure in a vacuum concentrator and then concentrated at a lower temperature to the specified solids content to obtain ginseng concentrated extract.

[0059] (v) Spray drying

[0060] The concentrated extract was fed into a spray dryer, and the ginseng extract powder was collected after drying. After passing the content and moisture tests, 2.00 kg of ginseng extract was obtained.

[0061] III. Preparation of Astragalus Extract

[0062] (a) Raw materials

[0063] Take 8.00 kg of Astragalus membranaceus slices that meet the requirements of the Chinese Pharmacopoeia, clean and cut them for later use.

[0064] (ii) Soaking

[0065] Add purified water and soak for 60 minutes.

[0066] (III) Extraction

[0067] The process employed a three-stage water extraction process: 1. First extraction: 90 min; 2. Second extraction: 60 min; 3. Third extraction: 30 min.

[0068] The three extracts were combined after filtration.

[0069] (iv) Reduced pressure concentration

[0070] The extract was concentrated under reduced pressure to obtain concentrated Astragalus extract.

[0071] (v) Spray drying

[0072] After spray drying, the extract powder was collected. After passing inspection, 2.00 kg of Astragalus extract was obtained.

[0073] IV. Mixing

[0074] Weigh out the following separately: 2.00 kg of ginseng extract, 2.00 kg of astragalus extract, and 0.90 kg of dextrin.

[0075] Mix in a V-type mixer for 20 minutes to ensure thorough mixing of the extract and dextrin. Prepare an aqueous solution of povidone K30 at a suitable concentration for use as a binder in wet granulation.

[0076] V. Wet Granulation

[0077] The mixed powder is fed into a high-speed wet granulator, and povidone K30 binder is sprayed on to form a uniform soft mass. The granulator then produces wet granules, which pass through a granulation sieve, exhibiting uniform particle size and no obvious agglomeration.

[0078] VI. Drying

[0079] The wet granules are placed in a fluidized bed dryer for drying. After drying, the moisture content of the granules is tested, and the granules are discharged after meeting the quality requirements.

[0080] VII. Granulation

[0081] The dried granules are granulated by a granulator to remove excessively coarse and fine particles, resulting in uniform particle size. The granules are then mixed again.

[0082] 8. Packaging

[0083] The granules are quantitatively packaged by an automatic granule packaging machine, with each bag containing 5.0 g. Pharmaceutical composite film is used for heat sealing during packaging. After packaging, the granules undergo inspection for appearance, weight variation, moisture content, content, and microbial limits. Only those that pass the inspection are stored in the warehouse.

[0084] Example 2: Preparation of Astragalus and Ginseng Granules of the Present Invention (Direct Addition of Extract)

[0085] Specifications: 5 g / bag

[0086] Quantity: 200 bags

[0087] Total finished product: 1.0 kg

[0088] Prescription composition (200 sachets):

[0089]

[0090] (Each bag contains 2.0g of ginseng extract, equivalent to 6.7g of raw ginseng; and 2.0g of astragalus extract, equivalent to 8.0g of raw astragalus.)

[0091] Preparation method:

[0092] Weigh out the prescribed amounts of ginseng extract, astragalus extract, and dextrin, and mix them in a V-type mixer for 20 minutes to ensure thorough mixing. Prepare an aqueous solution of povidone K30 at a suitable concentration for use as a wet granulation binder. Feed the mixed powder into a high-speed wet granulator, spray in the povidone K30 binder to form a soft mass, granulate through a 14-mesh sieve, dry the wet granules in a fluidized bed dryer at 55°C, sizing and mixing them thoroughly. Then, use an automatic packaging machine to quantitatively package them into 200 bags, each containing 5.0 g. After passing inspection, store them in the warehouse.

[0093] Comparative Example 1: Preparation of Ginseng Single-Drug Granules (Extract Directly Added)

[0094] Specifications: 5 g / bag

[0095] Quantity: 100 bags

[0096] Total finished product: 0.5 kg

[0097] Prescription composition (100 sachets):

[0098]

[0099] (Each bag contains 4.0 g of ginseng extract, equivalent to 13.4 g of raw ginseng.)

[0100] Preparation method:

[0101] Weigh the ginseng extract and dextrin according to the above prescription, and mix them in a V-type mixer for 20 minutes to ensure thorough mixing. Prepare an aqueous solution of povidone K30 of appropriate concentration as a wet granulation binder. Feed the mixed powder into a high-speed wet granulator, spray in the povidone K30 binder to form a soft mass, granulate through a 14-mesh sieve, dry the wet granules in a fluidized bed dryer at 55℃, mix them thoroughly, and quantitatively package them into 100 bags of 5.0 g each using an automatic packaging machine. After passing inspection, store the packaged product in the warehouse.

[0102] Comparative Example 2: Preparation of Astragalus membranaceus single-herb granules (extract directly added)

[0103] Specifications: 5 g / bag

[0104] Quantity: 100 bags

[0105] Total finished product: 0.5 kg

[0106] Prescription composition (100 sachets):

[0107]

[0108] (Each sachet contains 4.0 g of Astragalus extract, equivalent to 16.0 g of raw Astragalus root.)

[0109] Preparation method:

[0110] Weigh out the above-prescribed amounts of Astragalus extract and dextrin, and mix them in a V-type mixer for 20 minutes to ensure thorough mixing. Prepare an aqueous solution of povidone K30 at a suitable concentration for use as a wet granulation binder. Feed the mixed powder into a high-speed wet granulator, spray in the povidone K30 binder to form a soft mass, granulate through a 14-mesh sieve, dry the wet granules in a fluidized bed dryer at 55°C, sizing and mixing them thoroughly. Then, use an automatic packaging machine to quantitatively package them into 100 bags, each containing 5.0 g. After passing inspection, store them in the warehouse.

[0111] The following pharmacodynamic tests demonstrate the beneficial effects of this invention.

[0112] Case Study 1: Clinical Trial of Ginseng and Astragalus Granules Promoting Cervical Rising in Full-Term Pregnancy

[0113] 1. Research Methods

[0114] 1.1 Experimental Design

[0115] A randomized, parallel, controlled clinical trial design was adopted.

[0116] 1.2 Grouping Method

[0117] The enrolled mothers were randomly divided into the following two groups using a random number table method:

[0118] (1) Control group of 100 cases: did not take ginseng and astragalus granules, and were treated according to routine obstetric procedures before and during delivery;

[0119] (2) 100 cases in the Ginseng and Astragalus Granules group: In addition to routine treatment, patients were given Ginseng and Astragalus Granules prepared according to Example 1. Administration method: 10g (2 packets) every 6 hours, taken with warm water, until delivery.

[0120] 1.3 Research Subjects

[0121] Two hundred full-term pregnant women who delivered in the obstetrics department of our hospital between January 2023 and May 2024 were selected.

[0122] Inclusion criteria: (1) Singleton cephalic presentation, full-term pregnancy (gestational age ≥37 weeks and ≤41 weeks); (2) Bishop score of cervix <6 points; (3) Entering the latent labor period (regular uterine contractions, cervical dilation <3cm); (4) No contraindications to vaginal delivery; (5) Age 20 to 40 years; (6) Informed consent from the patient and signing of the informed consent form.

[0123] Exclusion criteria: (1) Pregnancy complications such as gestational hypertension and gestational diabetes; (2) Premature rupture of membranes; (3) Fetal distress; (4) Allergy to the components of the test drug; (5) Comorbid serious diseases of the heart, liver, kidneys, etc.; (6) History of mental illness.

[0124] Exclusion and withdrawal criteria: (1) those who do not take the medication according to the prescribed plan; (2) those who need to terminate the pregnancy or undergo cesarean section due to changes in their condition; (3) those who voluntarily request to withdraw; (4) those who need to stop taking the medication due to serious adverse reactions.

[0125] 1.3 Ethical Requirements

[0126] This study was reviewed and approved by the hospital's ethics committee. The use of Shenqi granules as an additional intervention to routine care is not a replacement for any routine obstetric care, and patients may withdraw from the study at any time.

[0127] 1.4 Observation Indicators

[0128] (1) Main therapeutic indicators

[0129] Cervical Bishop score before medication and during labor.

[0130] (2) Secondary efficacy indicators

[0131] Delivery method (vaginal delivery / cesarean section) and reasons for cesarean section.

[0132] (3) Safety indicators

[0133] Record adverse reactions in the mother during and after medication use.

[0134] 1.6 Statistical Methods

[0135] GraphPad Prism statistical software was used for analysis. Quantitative data are expressed as mean ± standard deviation (mean ± standard deviation). The data are expressed as follows: baseline data and postpartum hemorrhage volume between the two groups were compared using independent samples t-tests. Overall comparisons of cervical Bishop scores before and after treatment between the two groups were performed using repeated measures two-way ANOVA (Revised Measures Two-Way RM-ANOVA), with Bonferroni correction used for multiple comparisons between groups; paired t-tests were used for comparisons within the same group before and after treatment. Categorical data (transportation method) are expressed as percentages, and Fisher's exact test was used for comparisons between groups. All tests were two-tailed, and p < 0.05 was considered statistically significant.

[0136] 2. Experimental Results

[0137] 2.1 Comparison of general information between the two groups of mothers

[0138] This study included 200 parturients, with 100 in the control group and 100 in the Shenqi granule group. As shown in Table 1, there were no statistically significant differences in age, gestational age, and other general characteristics between the two groups (P>0.05), indicating comparability.

[0139] Table 1 Comparison of general information of the two groups of mothers ( )

[0140]

[0141] Note: There were no statistically significant differences in general data between the two groups (P > 0.05), indicating they are comparable.

[0142] 2. Comparison of Bishop scores of the cervix before and after medication in the two groups.

[0143] Table 2 shows the comparison of cervical Bishop scores before and after medication in the two groups. Figure 1 Before treatment, the Bishop score of the control group was (1.91±0.77) points, and that of the Shenqi granule group was (1.89±0.75) points. There was no statistically significant difference between the baseline levels of the two groups (P>0.05), indicating comparability. After the intervention, the Bishop scores of both groups significantly increased compared to before treatment (within-group comparisons, P<0.001). Specifically, the score at the time of labor in the control group was (5.83±0.79) points, while that in the Shenqi granule group was (6.64±1.03) points. Repeated measures two-way ANOVA showed a statistically significant interaction effect between group and time (F-interaction = 24.26, P<0.001), suggesting a significant difference in the time-dependent effect of Shenqi granules on promoting cervical ripening compared to the control group. After treatment, the Bishop score of the Shenqi granule group was significantly higher than that of the control group, with a highly statistically significant difference (Bonferroni corrected P<0.001).

[0144] Table 2. Comparison of Bishop scores of the cervix between the two groups before medication and at the onset of labor (points). )

[0145]

[0146] Note: Values ​​in the table are expressed as mean ± standard deviation (Mean ± SD). Superscript *** indicates a comparison with pre-treatment levels in the same group, with P < 0.001; superscript ### indicates a comparison with the control group at the same time point after treatment, with P < 0.001 in the Shenqi granules group after treatment. Overall statistical analysis was performed using repeated measures two-way ANOVA, and the interaction effect was significant (F = 24.26, P < 0.001). Multiple comparisons between groups were corrected using the Bonferroni method. The baseline levels of the two groups before treatment were comparable (P > 0.05).

[0147] 3. Comparison of pregnancy outcomes between the two groups of pregnant women

[0148] The comparison of the two delivery methods is shown in Table 3 and... Figure 2 The vaginal delivery rate in the Shenqi granule group was higher than that in the control group, while the cesarean section rate was lower, and the differences between the groups were statistically significant (Fisher's exact test, P<0.05). Comparison of postpartum hemorrhage between the two groups is shown below. Figure 3 The postpartum hemorrhage volume in the Shenqi granule group was (218.1±50.59) mL, while that in the control group was (224.5±88.90) mL. There was no statistically significant difference between the groups (t(198)=0.63, P>0.05), suggesting that Shenqi granules do not increase the risk of postpartum hemorrhage.

[0149] Table 3 Comparison of pregnancy outcomes between the two groups of pregnant women

[0150]

[0151] Note: Delivery method is expressed as a percentage (n (%)), and Fisher's exact test was used for comparisons between groups; postpartum hemorrhage is expressed as mean ± standard deviation (Mean ± SD), and independent samples t-test was used for comparisons between groups. * indicates comparison with the control group, P < 0.05. The vaginal delivery rate in the Shenqi granule group was higher than that in the control group, and the cesarean section rate was lower than that in the control group (Fisher's exact test, P < 0.05); there was no statistically significant difference in postpartum hemorrhage between the two groups (t(198) = 0.63, P > 0.05).

[0152] 4. Safety Evaluation

[0153] No clinically significant abnormalities were observed in blood routine tests, liver and kidney function tests, coagulation function tests, and electrocardiograms before and after treatment in either group of mothers, and there were no statistically significant differences between the groups (P>0.05). No adverse reactions related to the test drug occurred in either group, and no patients dropped out due to adverse reactions. Apgar scores at 1 minute and 5 minutes after birth were normal (≥8 points) in both groups, and there were no statistically significant differences between the groups (P>0.05). This suggests that Shenqi granules have good safety for both mother and child during cervical ripening.

[0154] Experiment Example 2: Animal Experiment of Cervical Rising Promoted by Ginseng and Astragalus Granules

[0155] 1. Research Methods

[0156] 1.1 Laboratory Animals and Grouping

[0157] Eight-week-old SPF-grade C57BL / 6C mice were purchased from Shaanxi Shanyao Medical Biotechnology Co., Ltd. After one week of acclimatization, they were mated together at a female-to-male ratio of 2:1. Vaginal smears of the female mice were examined at 9:00 AM daily, and the day on which sperm was found was counted as day 1 of pregnancy (D1). Pregnant mice were randomly divided into 5 groups: model group, misoprostol group, ginseng and astragalus granule group, ginseng group, and astragalus group, with 10 mice in each group; non-pregnant female mice of the same age were used as a blank control group, for a total of 6 groups.

[0158] 1.2 Dosing regimen

[0159] The gavage volume for each group was calculated as 1 mL / 100g body weight. The specific administration regimen is as follows:

[0160] ① Blank control group (non-pregnant group): No medication was given, and the animals were fed according to routine conditions;

[0161] ②Pregnancy control group (model group): No medication was given, and the animals were fed according to routine conditions;

[0162] ③ Ginseng and Astragalus Granules Group: Ginseng and Astragalus granules were prepared according to the method in Example 1 (each 5 g granules contained 2.0 g each of ginseng and astragalus extracts, equivalent to 6.7 g of crude ginseng and 8.0 g of crude astragalus, respectively). Before use, a 1.6 g / mL suspension was prepared with distilled water and administered by gavage at a dose of 16 g granules / kg (equivalent to 21.44 g / kg of crude ginseng and 25.6 g / kg of crude astragalus), once daily for 2 consecutive days (D16–D17). Dosage basis: The daily clinical dose for humans is 40 g granules / 60 kg, which is equivalent to 0.67 g granules / kg; the equivalent dose for mice based on body surface area is 8.2 g granules / kg. Based on preliminary experiments and the feasibility of gavage administration, the final dosage was determined to be 16 g granules / kg, with a dosage volume calculated at 10 mL / kg.

[0163] Specifically, the dosage used in the ginseng and astragalus granule group was 21.44 g / kg of raw ginseng and 25.6 g / kg of raw astragalus.

[0164] ④ Misoprostol group (positive control group): Misoprostol tablets (M6807, Merck) were ground before use, prepared with normal saline, and administered via intraperitoneal injection. The dosage was 5 μg / kg, administered as a single injection on D17. The dosage was calculated based on the clinical adult daily dose of 25 μg / 60 kg and converted by body surface area.

[0165] ⑤ Ginseng single-drug group: Ginseng single-drug granules were prepared according to the method of Comparative Example 1 (each 5 g granules contained 4.0 g of ginseng extract, equivalent to 13.4 g of crude ginseng). Before use, a suspension of 0.8 g granules / mL was prepared with distilled water and administered by gavage. The dosage was 8 g granules / kg (equivalent to 21.44 g / kg of crude ginseng), once a day for 2 consecutive days (D16~D17).

[0166] That is, the amount of raw ginseng used in the ginseng single-herb group was 21.44 g / kg.

[0167] ⑥ Astragalus monotherapy group: Astragalus monotherapy granules were prepared according to the method of Comparative Example 2 (each 5 g granules contained 4.0 g of Astragalus extract, equivalent to 16.0 g of raw Astragalus). Before use, the granules were prepared into a suspension of 0.8 g granules / mL with distilled water and administered by gavage at a dose of 8 g granules / kg (equivalent to 25.6 g / kg of raw Astragalus), once a day for 2 consecutive days (D16~D17).

[0168] That is: the amount of raw Astragalus membranaceus used in the Astragalus membranaceus single-herb group was 25.6 g / kg.

[0169] The dosage of the ginseng single-herb group and the astragalus single-herb group was set according to the principle of equal dosage (the dosage of the single herb is consistent with the content of the component in the compound), which is an equal multiple of the content of the corresponding single herb in the ginseng and astragalus granules compound.

[0170] 1.3 Observation Indicators

[0171] (1) HE staining and morphological observation of cervical tissue

[0172] Cervical tissue was collected, fixed in 4% paraformaldehyde for 24 h, dehydrated with graded ethanol, cleared in xylene, embedded in paraffin, sectioned (4-5 μm thick), dewaxed in xylene, hydrated with graded ethanol, stained with hematoxylin for 5-10 min, rinsed with running water, differentiated with 1% hydrochloric acid ethanol, rinsed with running water, stained with eosin for 1-3 min, dehydrated with graded ethanol, cleared in xylene, mounted with neutral resin, observed and photographed under a light microscope.

[0173] Observation content: morphology and degree of looseness of uterine tissue.

[0174] Quantitative analysis: Image analysis was performed using ImageJ software to calculate the loose area ratio.

[0175]

[0176] (2) Masson staining and collagen quantification of cervical tissue

[0177] Paraffin sections of cervical tissue (4–5 μm thick) were dewaxed with xylene, hydrated with graded ethanol, rinsed with distilled water, stained with Masson's compound stain for 5–10 min, rinsed with 0.2% glacial acetic acid aqueous solution, differentiated with phosphomolybdic acid for 5–10 min, stained with aniline blue for 5–10 min, dehydrated with graded ethanol, cleared with xylene, mounted with neutral resin, and observed and photographed under a light microscope. In Masson staining, collagen fibers appeared blue, and muscle fibers appeared red.

[0178] Quantitative analysis: The color deconvolution function in ImageJ software was used for quantitative analysis to calculate the collagen area ratio.

[0179]

[0180] (3) Detection of cytokine and enzyme content in cervical tissue homogenate

[0181] Mouse cervical tissue was weighed and added to homogenate buffer at a ratio of 1:9 (w / v) of tissue mass to pre-cooled PBS (pH 7.4, containing protease inhibitors) (10 μmol / L indomethacin was added for PGE2 detection to inhibit further prostaglandin synthesis after in vitro). The homogenate was thoroughly homogenized under ice bath conditions. The homogenate was centrifuged at 4 ℃ and 12,000 rpm for 15 min, and the supernatant was collected for later use. Mouse PGE2 (Abcam, ab316263), IL-1β (Abcam, ab197742), IL-6 (Abcam, ab222503), and MMP-9 (Abcam, ab253227) ELISA kits were used, strictly following the instructions. Each sample was tested in duplicate. The concentrations of each indicator in the samples were calculated based on the standard curve. PGE2, IL-1β, and IL-6 results are expressed as pg / mL, and MMP-9 results are expressed as ng / mL.

[0182] (4) Calculation of the combined index of the two drugs and determination of their synergy using Jin Zhengjun's Q-value method

[0183] The combined effect of the two drugs was evaluated using the Jin Zhengjun Q-value method, with the formula: Q = Eab / (Ea + Eb - Ea × Eb). Where Eab is the measured effect value of the combined drug group, Ea is the measured effect value of drug A used alone, and Eb is the measured effect value of drug B used alone. Judgment criteria: a Q value of 0.85–1.15 indicates a simple additive effect between the two drugs; Q > 1.15 indicates synergistic effect; and Q < 0.85 indicates antagonism.

[0184] (5) Safety observation

[0185] The general behavior, mental state, diet and water intake, activity and mortality of mice in each group were observed to evaluate the safety and tolerability of Shenqi Granules in mice in late pregnancy.

[0186] 1.4 Statistical Methods

[0187] GraphPad Prism statistical software was used for analysis. Quantitative data are expressed as mean ± standard deviation (mean ± standard deviation). The numbers indicate that comparisons among multiple groups were performed using one-way ANOVA, and pairwise comparisons were performed using the LSD-t test. P < 0.05 was considered statistically significant.

[0188] 2. Experimental Results

[0189] 2.1 Effects of Shenqi Granules on the levels of PGE2, IL-1β, IL-6 and MMP-9 in uterine tissue of mice in late pregnancy

[0190] To observe the effect of Shenqi granules on the expression of cervical maturation-related factors in uterine tissue of mice in late pregnancy, the levels of PGE2, IL-1β, IL-6, and MMP-9 in uterine tissue homogenates of each group of mice were detected by ELISA. ELISA results showed ( Figure 3Compared with the non-pregnant group, the levels of PGE2, IL-1β, IL-6, and MMP-9 in the uterine tissue of mice in the pregnancy blank group were significantly increased, indicating that the uterine tissue microenvironment of mice in late pregnancy showed a high expression state of cervical ripening and labor initiation-related factors, and the pregnancy model was successfully established. Compared with the pregnancy blank group, the levels of the above indicators in each treatment group were further increased, with the most significant increase in the Shenqi granule group. Compared with the pregnancy-misoprostol group, the levels of all indicators in the pregnancy-Shenqi granule group were further upregulated, indicating that Shenqi granules are superior to the positive control drug misoprostol in promoting the expression of cervical ripening-related factors. In terms of component-specific comparison, although the pregnancy-ginseng control group and the pregnancy-astragalus control group could upregulate the levels of the above factors to varying degrees, the increase was not as great as that in the pregnancy-Shenqi granule group, indicating that the effect of Shenqi compound in promoting cervical ripening is better than that of single ginseng or astragalus, reflecting the synergistic effect of compound administration. The above results indicate that Shenqi granules can effectively promote cervical maturation in late pregnancy by upregulating the expression of cervical maturation-related factors such as PGE2, IL-1β, IL-6 and MMP-9, and the compound formula is more effective than single Chinese medicine ingredients.

[0191] 2.2 Effects of Shenqi Granules on Uterine Histomorphology in Late Pregnancy Mice

[0192] To observe the effects of Shenqi granules on the morphology of uterine tissue in late-pregnancy mice, uterine tissue from each group of mice was subjected to H&E staining. Histological changes were observed under a light microscope, and the percentage of loose area in the total field of view was quantitatively analyzed. The H&E staining results showed ( Figure 4 A) In the non-pregnant group, the uterine tissue of mice showed intact morphology and structure, with tightly arranged cells, dense stroma, and no obvious loose areas. Compared with the non-pregnant group, the area of ​​loose areas in the uterine tissue of pregnant control group mice was significantly increased. Figure 4(B) This indicates that the cervical tissue in late pregnancy has undergone physiological tissue remodeling and softening, preparing for delivery. Compared with the control group, the area of ​​the loose uterine tissue in mice in the pregnancy-misoprostol group, pregnancy-ginseng and astragalus granule group, pregnancy-ginseng control group, and pregnancy-astragalus control group was significantly increased, the interstitial spaces were significantly widened, the fibrous structure was loose, and the extracellular matrix showed obvious remodeling characteristics, indicating that the above interventions can effectively promote cervical maturation in late pregnancy. Among them, the increase in the area of ​​the loose uterine tissue in the ginseng and astragalus granule group was the most significant. Further comparison of the differences between the different treatment groups showed that compared with the pregnancy-misoprostol group, the area of ​​the loose uterine tissue in mice in the pregnancy-ginseng and astragalus granule group was further increased, suggesting that the effect of ginseng and astragalus granules in promoting cervical softening is better than that of the positive control drug misoprostol. In terms of comparing the individual prescriptions, although the pregnancy-ginseng control group and the pregnancy-astragalus control group could increase the area of ​​loose uterine tissue to varying degrees, the increase was not as great as that of the pregnancy-ginseng-astragalus granules group. This suggests that the ginseng-astragalus compound is superior to single ginseng or astragalus in promoting the softening of loose cervical tissue, demonstrating the synergistic effect of the compound prescription.

[0193] H&E staining and histological observation (Table 4) showed that, compared with the pregnant control group, the degree of uterine tissue loosening in mice in each treatment group increased, suggesting that each drug had a certain loosening effect. Among them, the percentage of loose uterine tissue in the Shenqi granule group was 26.38%, significantly higher than that in the ginseng single-drug group (9.74%) and the astragalus single-drug group (13.65%). Calculated using Jin Zhengjun's Q-value method, the combined index Q value of Shenqi granules was 1.20 (>1.15), indicating that the two single herbs in the Shenqi granule formula exhibited a synergistic effect, and its effect in promoting uterine tissue loosening was superior to that of the individual herbs used alone.

[0194] Table 4 Comparison of percentage of uterine loose tissue, effectiveness rate, and combined index (Q value) among groups

[0195]

[0196] 2.3 Effects of Shenqi Granules on Collagen Fiber Deposition in Uterine Tissue of Mice in Late Pregnancy

[0197] To observe the effects of Shenqi granules on collagen fiber deposition and distribution in the uterine tissue of mice in late pregnancy, uterine tissue from each group of mice was subjected to Masson staining. Changes in collagen fibers were observed under a light microscope, and the percentage of collagen area in the total field of view was quantitatively analyzed. Masson staining results showed ( Figure 5 A) The uterine tissue of non-pregnant mice was rich in collagen fibers, which were continuously and densely distributed, appearing deep blue, and the tissue structure was intact. Compared with the non-pregnant group, the percentage of collagen area in the uterine tissue of pregnant mice was significantly reduced. Figure 5(B) The blue collagen fibers were significantly reduced and sparsely distributed, indicating that physiological degradation of cervical collagen fibers occurred in late pregnancy, preparing for cervical softening. Compared with the blank control group, there was no significant difference in the percentage of collagen area in the uterine tissue of mice in the pregnancy-misoprostol group, the pregnancy-ginseng control group, and the pregnancy-astragalus control group. Compared with the blank control group, the percentage of collagen area in the uterine tissue of mice in the pregnancy-ginseng-astragalus granule group was significantly reduced, and the blue collagen fibers were significantly reduced, broken, and sparsely distributed, indicating that ginseng-astragalus granules can effectively promote collagen degradation and remodeling in cervical tissue in late pregnancy. In terms of component-specific comparison, compared with the pregnancy-ginseng control group and the pregnancy-astragalus control group, the percentage of collagen area in the pregnancy-ginseng-astragalus granule group was significantly reduced, indicating that the ginseng-astragalus compound is superior to single ginseng or astragalus in promoting collagen degradation, demonstrating the synergistic effect of the compound formulation.

[0198] Masson staining results showed that, compared with the pregnant control group, the proportion of collagen area in the uterine tissue of mice in each treatment group increased, indicating that each drug had a certain collagen deposition-promoting effect. Among them, the proportion of collagen area in the uterine tissue of the Shenqi granule group was 23.19%, significantly higher than that of the ginseng single-drug group (1.66%) and the astragalus single-drug group (0.36%). Calculated using Jin Zhengjun's Q-value method, the combined index Q of the Shenqi granule group was 13.69, much greater than 1.15, indicating that the combined use of the two drugs in the Shenqi granule group had a significant synergistic effect, and its effect on promoting collagen deposition in uterine tissue was significantly better than that of the individual drugs used alone.

[0199] Table 5 Comparison of uterine collagen area percentage, effectiveness rate, and combined index (Q value) among different groups

[0200]

[0201] 2.4 Safety and Tolerance Observation of Ginseng and Astragalus Granules in Late Pregnancy Mice

[0202] During the experiment, the general behavior, mental state, diet and water intake, activity level, and mortality of mice in each group were observed to evaluate the safety and tolerability of Shenqi granules in late-pregnancy mice. No mice in any group died throughout the experiment; they maintained good mental state, were responsive, had normal coat luster, and showed no significant abnormalities in diet, water intake, or spontaneous activity. No acute toxicity reactions such as rapid breathing, tremors, convulsions, salivation, diarrhea, or vomiting were observed after administration, nor were any local irritants such as hair loss, rash, or skin ulcers observed. Gross examination of the major organs (heart, liver, spleen, lungs, kidneys, etc.) of the mice in each group revealed no obvious pathological changes such as congestion, edema, hemorrhage, necrosis, or abnormal coloration. These results indicate that Shenqi granules (administered according to the dosage and regimen of this experiment) did not cause significant acute toxicity reactions or adverse events in late-pregnancy mice, demonstrating good tolerability and safety.

Claims

1. The use of ginseng extract and astragalus extract in combination in the preparation of drugs that promote cervical ripening in full-term pregnancies.

2. The use according to claim 1, characterized in that: The weight ratio of the ginseng extract to the astragalus extract is (0.8-1.2):(0.8-1.2); the ginseng extract is a water extract of ginseng; the astragalus extract is a water extract of astragalus.

3. The use according to claim 2, characterized in that: The weight ratio of the ginseng extract to the astragalus extract is 1:

1.

4. A traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancies, characterized in that: It is prepared from the following raw materials in the following weight ratio: Ginseng extract 0.8-1.2 parts, Astragalus extract 0.8-1.2 parts; The ginseng extract mentioned is a water extract of ginseng; the astragalus extract mentioned is a water extract of astragalus.

5. The traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancy according to claim 4, characterized in that: It is prepared from the following raw materials in the following weight ratio: One part ginseng extract and one part astragalus extract.

6. The traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancy as described in claim 4 or 5, characterized in that: It is a pharmaceutically commonly used preparation made by adding pharmaceutically acceptable excipients or auxiliary ingredients, with ginseng extract and astragalus extract as active ingredients.

7. The traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancy according to claim 6, characterized in that: The preparations mentioned are granules, tablets, capsules, and pills.

8. The method for preparing the traditional Chinese medicine composition for promoting cervical ripening in full-term pregnancy according to any one of claims 4-7, characterized in that: It includes the following steps: a. Preparation of ginseng extract: Take ginseng slices, soak them, add water and decoct, filter, concentrate and dry to obtain ginseng extract; b. Preparation of Astragalus extract: Take Astragalus membranaceus slices, soak them, decoct them in water, filter, concentrate, and dry them to obtain Astragalus membranaceus extract; c. Mix ginseng extract and astragalus extract in the specified weight ratio, and add pharmaceutically acceptable excipients or auxiliary ingredients to prepare a commonly used pharmaceutical preparation.

9. The use of the traditional Chinese medicine composition according to any one of claims 4-7 in the preparation of a medicament for promoting cervical ripening in full-term pregnancy.

10. The use according to claim 9, characterized in that: The medication described is one that improves the Bishop score of the cervix, increases the vaginal delivery rate, or promotes the softening and loosening of cervical tissue.

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