Traditional Chinese medicine composition for preventing and treating pregnancy complications as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention discloses a traditional Chinese medicine composition for preventing and treating pregnancy complications as well as a preparation method and application thereof. The composition is composed of medicinal and edible traditional Chinese medicines including radix rehmanniae recen, fructus gardeniae, gastrodia elata, fructus lycii and exocarpium citri rubrum, and mulberry leaves, ramulus uncariae cum uncis and the like can be selectively added. The preparation method comprises the steps of extracting volatile oil by steam distillation, leaching by a solvent, concentrating, mixing and the like, and can be combined with ultrasonic crushing to strengthen extraction. The composition is based on the treatment method of nourishing kidney, containing wood, clearing heat, calming liver, dissolving turbidity and preventing miscarriage in traditional Chinese medicine, has the effects of multi-target synergistic pressure reduction, proteinuria improvement and fetal development promotion aiming at the pathogenesis of yin deficiency and yang hyperactivity in the gestation period, is high in safety and free of fetal toxic and side effects, and is suitable for prevention and treatment of hypertensive diseases in the gestation period such as preeclampsia and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine compositions, in particular to a traditional Chinese medicine composition for preventing and treating pregnancy complications and a preparation method thereof, which is especially suitable for preventing and treating gestational hypertension and related symptoms. BACKGROUND

[0002] Preeclampsia (PE) is a multisystem disorder occurring after 20 weeks of gestation, characterized by new-onset hypertension and proteinuria, often accompanied by multiple organ dysfunction. The global incidence is about 5%–10%, and the incidence in China is 3%–5%. It is one of the important causes of maternal and perinatal mortality. The specific etiology and pathogenesis of the disease have not been fully elucidated, and the clinical treatment is mainly symptomatic treatment, including antihypertensive and antispasmodic measures.

[0003] In antihypertensive therapy, oral drugs such as labetalol and nifedipine are recommended by guidelines, but they can pass through the placental barrier and potentially cause intrauterine fetal growth retardation, neonatal hypotension, bradycardia, hypoglycemia, and respiratory depression in the fetus. There are certain limitations in clinical application. Magnesium sulfate, an antispasmodic drug, is used as a first-line drug, which can relieve symptoms, but long-term use may cause maternal magnesium poisoning and is associated with decreased Apgar scores in newborns, and its safety is also questionable. At present, termination of pregnancy is the only way to cure preeclampsia, but it often leads to iatrogenic preterm birth, increases perinatal mortality, and brings significant social and economic burden. In terms of prevention, low-dose aspirin is recommended for high-risk groups, but there is still a potential risk of placental abruption and postpartum hemorrhage.

[0004] Traditional Chinese medicine has the characteristics of overall regulation and multi-target intervention in the prevention and treatment of gestational diseases, especially "food-medicine homologous" traditional Chinese medicine compounds, which are more suitable for use during pregnancy due to their high safety and small side effects. Preeclampsia belongs to the categories of "zihun", "zizhong", and "zixian" in traditional Chinese medicine, and the core pathogenesis is "yin deficiency and yang hyperactivity, internal movement of liver wind", often accompanied by spleen and kidney deficiency and internal resistance of phlegm-dampness. Therefore, traditional Chinese medicine compounds with the principles of nourishing the kidney, soothing the liver, clearing heat and resolving turbidity have potential advantages.

[0005] At present, there is still a lack of a compound composition based on "food-medicine homologous" traditional Chinese medicine with safety and specificity for the prevention and treatment of the disease. Therefore, it is of great significance to develop a traditional Chinese medicine composition that meets the "food-medicine homologous" concept, has a rigorous composition, and is suitable for use during pregnancy, to improve the maternal and infant outcomes and make up for the shortcomings of existing treatment methods. SUMMARY

[0006] The present application aims to provide a traditional Chinese medicine composition for preventing and treating pregnancy complications, and a preparation method and application thereof.

[0007] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0008] The first aspect of the present application provides a traditional Chinese medicine composition for preventing and treating pregnancy complications, which is prepared from the following raw materials by weight: Rehmanniae Radix 20-30 parts, Gardeniae Fructus 9-15 parts, Gastrodiae Rhizoma 9-15 parts, Fructus Lycii 10-30 parts, and Citri Reticulatae Pericarpium 3-9 parts.

[0009] Preferably, the traditional Chinese medicine composition is prepared from the following raw materials by weight: Rehmanniae Radix 24 parts, Gardeniae Fructus 12 parts, Gastrodiae Rhizoma 12 parts, Fructus Lycii 12 parts, and Citri Reticulatae Pericarpium 6 parts.

[0010] Further, the traditional Chinese medicine composition can further comprise the following raw materials by weight: Folium Mori 6-12 parts, Uncariae Ramulus 15-21 parts, Radix Stephaniae Tetrandrae 6-12 parts, and Chrysanthemi Flos 6-12 parts.

[0011] More preferably, the traditional Chinese medicine composition is prepared from the following raw materials by weight: Rehmanniae Radix 24 parts, Gardeniae Fructus 12 parts, Gastrodiae Rhizoma 12 parts, Fructus Lycii 12 parts, Citri Reticulatae Pericarpium 6 parts, Folium Mori 9 parts, Uncariae Ramulus 18 parts, Radix Stephaniae Tetrandrae 9 parts, and Chrysanthemi Flos 9 parts.

[0012] Rehmanniae Radix is the monarch drug in the prescription, which is sweet, bitter and cold, and is meridian-entering heart, liver and kidney, and has the effects of nourishing yin, cooling blood, filling essence and benefiting marrow. It can not only treat deficiency of essence and blood, but also can treat heat of liver yang. It is the core of "nourishing water and restraining wood". Gardeniae Fructus is the minister drug, which is bitter and cold, and is meridian-entering heart, lung and Sanjiao. It can clear away heat and remove irritability, clear heat and drain dampness, and help Rehmanniae Radix to clear and descend hyperactive yang. Its blood-cooling effect can treat restless movement of fetus due to blood heat. When combined with the monarch drug, it can not only clear away excessive heat, but also prevent Rehmanniae Radix from being greasy and stagnated. Gastrodiae Rhizoma and Fructus Lycii are the assistant drugs. Gastrodiae Rhizoma is sweet, pungent and flat, and is meridian-entering liver. It can calm wind and stop convulsion, and suppress liver yang. Fructus Lycii is sweet and flat, and is meridian-entering liver and kidney. It can nourish liver and kidney, benefit essence and eyesight, and help the monarch drug to treat deficiency of mother and fetus, and protect the root of fetus. Citri Reticulatae Pericarpium is the minister drug, which is pungent, bitter and warm, and is meridian-entering spleen and lung. It can promote qi and resolve phlegm, harmonize the center and descend adverse qi, and prevent Rehmanniae Radix from being greasy and stagnated, and treat deficiency of spleen and kidney. The whole prescription can nourish kidney and restrain wood, clear away heat and suppress liver, and treat restless movement of fetus due to turbid and treat hypertension during pregnancy, especially preeclampsia.

[0013] The second aspect of the present application provides a preparation method of the traditional Chinese medicine composition of the first aspect of the present application, which comprises the following steps:

[0014] (1) distill volatile oil from raw materials by water vapor distillation method to obtain volatile oil and dregs;

[0015] (2) soak the dregs in a solvent to obtain leaching liquor by filtration;

[0016] (3) distill and concentrate the leaching liquor;

[0017] (4) add volatile oil obtained in step (1), fresh orange juice and melted agar to the concentrated leaching liquor;

[0018] (5) seal and package the obtained product.

[0019] Preferably, steps (3) and (4) are carried out under negative pressure; the solvent can be selected from water, 75% ethanol or melted pork skin jelly; and ultrasonic waves with a frequency of 15-25 KHz can be used to assist in breaking cell walls during the leaching process of step (2) to improve extraction efficiency.

[0020] The third aspect of the present application provides use of the traditional Chinese medicine composition of the first aspect of the present application in the preparation of a drug for preventing and treating hypertensive disorder in pregnancy.

[0021] Preferably, the hypertensive disorder in pregnancy is preeclampsia.

[0022] The fourth aspect of the present application provides a pharmaceutical preparation comprising the traditional Chinese medicine composition of the first aspect of the present application and a pharmaceutically acceptable carrier.

[0023] Compared with the prior art, the present application has the following beneficial effects:

[0024] The traditional Chinese medicine composition of the present application is guided by the theory of traditional Chinese medicine, has strict compatibility and treats both symptoms and root causes. The selected medicinal materials are all homologous in medicinal and edible properties, have high safety and no risk of breaking blood and moving fetus, and are suitable for use during pregnancy. Modern pharmacological experiments prove that the composition has clear antihypertensive activity and a multi-target synergistic mechanism of action, can significantly improve TCM syndromes such as liver-yang hyperactivity and deficiency of both spleen and kidney, reduce pregnancy-induced hypertension, proteinuria and other pregnancy reactions, improve placental function and promote fetal development, and has no toxic effects on the main organs of the mother, thus having a good clinical application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 Figure 1 shows the effect of the traditional Chinese medicine composition of the present application on the systolic blood pressure (SBP) of preeclampsia model pregnant rats over time;

[0026] Figure 2 Figure 2 shows the effect of the traditional Chinese medicine composition of the present application on the diastolic blood pressure (DBP) of preeclampsia model pregnant rats over time;

[0027] Figure 3The schematic diagram of the comparison results of the 24-hour urine protein concentration of the pregnant mice in each group after the intervention of each traditional Chinese medicine composition of the present application is shown in the figure.

[0028] Figure 4 The schematic diagram of the comparison results of the average body weight of the fetal mice in each group after the intervention of each traditional Chinese medicine composition of the present application is shown in the figure.

[0029] Figure 5 The schematic diagram of the comparison results of the placental efficiency in each group after the intervention of each traditional Chinese medicine composition of the present application is shown in the figure.

[0030] Figure 6 The schematic diagram of the comparison results of the fetal mice absorption rate in each group after the intervention of each traditional Chinese medicine composition of the present application is shown in the figure.

[0031] Figure 7 The schematic diagram of the comparison results of the average number of live fetuses in each group of pregnant mice after the intervention of each traditional Chinese medicine composition of the present application is shown in the figure.

[0032] Figure 8 The H&E staining microscopic photos (×400) of the representative placental tissue sections in each group after the intervention of each traditional Chinese medicine composition of the present application are shown in the figure.

[0033] Figure 9 The H&E staining microscopic photos of the main organ (heart, liver, spleen, lung, kidney) tissue sections of the pregnant mice in each group after the intervention of each traditional Chinese medicine composition of the present application are shown in the figure.

[0034] The meaning of the labels in the figure: the Control group is a normal pregnancy control group, the PE group is an L-NAME-induced preeclampsia model group, the DHZZ1 group is a model group intervened by Dihuang Zhizi Decoction No. 1, the DHZZ2 group is a model group intervened by Dihuang Zhizi Decoction No. 2, and the DHZZ3 group is a model group intervened by Dihuang Zhizi Decoction No. 3. (Note: the data in the figure are represented by mean ± standard deviation, * represents P<0.05 compared with the Control group, and # represents P<0.05 compared with the PE group) DETAILED DESCRIPTION

[0035] The principles and features of the present application are described below, and the examples are only used to explain the present application and are not used to limit the scope of the present application.

[0036] Preparation of the traditional Chinese medicine composition (Dihuang Zhizi Decoction No. 1, DHZZ1) in Example 1

[0037] The present embodiment provides a traditional Chinese medicine composition for preventing and treating pregnancy complications, which is made from the following raw materials by weight: Dihuang 24g, Zhizi 12g, Tianma 12g, Gouqi 12g, and Juhong 6g.

[0038] The preparation method comprises the following steps:

[0039] (1) The above-mentioned raw materials after purification are mixed and put into an extraction device, and volatile oil is extracted by using water vapor distillation method. The distillation time is controlled to be 2-8 hours, and the volatile oil is collected and sealed for later use; and residue is separated.

[0040] (2) The obtained residue is placed in a container, and an appropriate amount of solvent water is added, and the mass / volume ratio of water to residue is 1:6-1:12 (W / V). The extraction is carried out at 80-100°C. Ultrasonic wave with a frequency of 20KHz is applied during the extraction. The extraction is carried out for 2 times, and each time is 1-2 hours.

[0041] (3) The extraction solutions are combined and filtered to obtain an extraction solution.

[0042] (4) The extraction solution is concentrated by vacuum distillation under negative pressure (-0.05 to -0.08 MPa) to obtain an extract with a relative density of 1.10-1.25 (60°C).

[0043] (5) Under stirring, the volatile oil obtained in step (1), fresh orange juice with a weight of 3%-10% of the extract, and agar with a weight of 1%-3% of the extract which is previously melted are sequentially added to the extract. This step can be carried out under negative pressure.

[0044] (6) After being fully mixed, the mixture is packaged and sealed to obtain the traditional Chinese medicine composition product.

[0045] Preparation of the traditional Chinese medicine composition (Dihuang Zhizi Decoction No. 2, DHZZ2) in Example 2

[0046] This example is basically the same as Example 1, except that the weight of the raw materials is adjusted as follows: raw rehmannia 20g, gardenia 15g, Gastrodia 9g, medlar 30g, tangerine red 3g. The preparation method is the same as that in Example 1.

[0047] Preparation of the traditional Chinese medicine composition (Dihuang Zhizi Decoction No. 3, DHZZ3) in Example 3

[0048] This example is basically the same as Example 1, except that the raw materials are increased by 9g of mulberry leaves, 18g of uncaria, 9g of peony root, and 9g of Chuzhou chrysanthemum on the basis of DHZZ1. That is, the total raw materials are: raw rehmannia 24g, gardenia 12g, Gastrodia 12g, medlar 12g, tangerine red 6g, mulberry leaves 9g, uncaria 18g, peony root 9g, and Chuzhou chrysanthemum 9g. The preparation method is the same as that in Example 1.

[0049] Pharmacodynamic evaluation experiment of the traditional Chinese medicine composition in Example 4

[0050] This example verifies the prevention and treatment effect of the traditional Chinese medicine composition prepared in Example 1 of the present application on the preeclampsia (PE) model through animal experiments.

[0051] 1. Model establishment and grouping

[0052] Healthy adult SPF C57BL / 6 mice (body weight needs to be supplemented, for example: 20±2g) are selected. Male and female mice are mated in a ratio of 3:1, and the day of vaginal plug loss is recorded as gestational day 1 (GD1). On GD10, the model group mice are induced by subcutaneous injection of L-NAME (50mg / kg / d), a nitric oxide synthase inhibitor, to induce a PE model. The systolic blood pressure (SBP) of the pregnant mice is monitored daily using a non-invasive tail artery blood pressure measurement system, and a SBP that is continuously higher than the mean value of the normal pregnant control group by more than 20mmHg is used as an indicator of model success.

[0053] The successfully modeled pregnant mice are randomly divided into a model group (PE), a DHZZ1 group, a DHZZ2 group, a DHZZ3 group, and a normal pregnant control group (Control), with the number of animals in each group being n=10.

[0054] 2. Drug intervention

[0055] From GD13, the Control group and the PE group are given the same volume of normal saline by gavage every day, and the DHZZ1, DHZZ2, and DHZZ3 groups are given the corresponding water solutions of the traditional Chinese medicine compositions prepared in the examples by gavage every day, at 4.03g / kg / d, 5.71g / kg / d, and 2.76g / kg / d (calculated based on crude drug dosage), respectively, with a gavage volume of 0.2mL / 20g body weight, and the intervention is continued until GD18.

[0056] 3. Observation indicators and methods

[0057] Blood pressure monitoring: The systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the pregnant mice in each group are dynamically measured on GD10, GD12, GD14, GD16, and GD18.

[0058] Urine protein detection: On GD18, the pregnant mice are placed in a metabolic cage to collect 24-hour urine, and the urine protein concentration (unit: mg / L) is determined using the Coomassie brilliant blue method or the sulfosalicylic acid method.

[0059] Pregnancy outcome evaluation: On GD18, a cesarean section is performed, and the number of live fetuses, resorbed fetuses, and dead fetuses is recorded; the body weight of each fetal mouse and the corresponding placental weight are accurately measured, and the placental efficiency (fetal mouse body weight / placental weight) and fetal mouse resorption rate (resorbed fetus number / total implantation number x 100%) are calculated.

[0060] Histopathological examination: The placenta and important organ tissues such as the heart, liver, spleen, lung, and kidney of the pregnant mice are surgically removed, fixed with 4% paraformaldehyde, routinely embedded in paraffin, sliced (thickness 4μm), stained with hematoxylin-eosin (H&E), and observed under an optical microscope to observe changes in tissue morphological structure and evaluate the possible therapeutic effects and toxicological effects of drug treatment.

[0061] Statistical analysis: all data were expressed as mean ± standard deviation It is indicated that single factor variance analysis method is used for comparison between groups by using SPSS software, and the difference is considered to have statistical significance when P<0.05.

[0062] 4、Experimental results

[0063] Blood pressure changes: as shown in Figure 1 and Figure 2 Compared with the Control group, the systolic pressure and diastolic pressure of the pregnant rats in the PE group were significantly increased (P<0.05). After intervention of the various traditional Chinese medicine compositions of the application (DHZZ1, DHZZ2, and DHZZ3 groups), the blood pressure of the pregnant rats was significantly lower than that of the PE group (P<0.05), and the numerical value was close to the level of the Control group.

[0064] Urine protein level: as shown in Figure 3 The 24-hour urine protein concentration of the pregnant rats in the PE group was significantly higher than that in the Control group (P<0.05). The urine protein concentration of each traditional Chinese medicine intervention group was significantly decreased compared with the PE group (P<0.05), indicating that the renal function was improved.

[0065] Pregnancy outcome: as shown in Figure 4 The average body weight of the fetal rats in each traditional Chinese medicine intervention group was significantly higher than that in the PE group (P<0.05); as shown in Figure 5 The placental efficiency of each traditional Chinese medicine intervention group had a trend of being higher than that of the PE group; as shown in Figure 6 and Figure 7 The fetal rat absorption rate of each traditional Chinese medicine intervention group was significantly lower than that of the PE group, and the average number of live fetuses was significantly higher than that of the PE group (P<0.05).

[0066] Histopathology: as shown in Figure 8 The placental H&E staining showed that the placental tissue of the PE group appeared typical pathological changes such as cell edema, widened interstitial space, and vascular structure disorder; the above pathological changes of each traditional Chinese medicine intervention group were obviously improved, and the tissue structure was closer to that of the Control group. As shown in Figure 9 The H&E staining of the main organs (heart, liver, spleen, lung, and kidney) showed that the organ tissue structure of the pregnant rats in each traditional Chinese medicine intervention group was complete, the cell morphology was normal, and no obvious pathological damage such as inflammatory cell infiltration, hemorrhage, and necrosis was observed, indicating that the traditional Chinese medicine compositions of the application had good safety.

[0067] In summary, the traditional Chinese medicine compositions provided by the application can effectively reduce the blood pressure and urine protein level of the PE model pregnant rats, improve the placental function, promote the normal development of the fetus, reduce the incidence of adverse pregnancy outcomes, and no obvious toxic effect is observed, which has a good prevention and treatment effect on preeclampsia.

[0068] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and that variations, modifications, substitutions and changes can be made by those skilled in the art without departing from the scope of the present application.

Claims

1. A traditional Chinese medicine composition for preventing and treating pregnancy complications, characterized in that, It is made from the following raw materials by weight: Rehmannia 20-30 parts, Cape jasmine 9-15 parts, Gastrodia 9-15 parts, Medlar 10-30 parts, Tangerine red 3-9 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, It is made from the following raw materials by weight: Rehmannia 24 parts, Cape jasmine 12 parts, Gastrodia 12 parts, Medlar 12 parts, Tangerine red 6 parts.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, It also contains the following raw materials by weight: Mulberry leaf 6-12 parts, Uncaria 15-21 parts, Red peony root 6-12 parts, Chuzhou chrysanthemum 6-12 parts.

4. The traditional Chinese medicine composition according to claim 3, characterized in that, It is made from the following raw materials by weight: Rehmannia 24 parts, Cape jasmine 12 parts, Gastrodia 12 parts, Medlar 12 parts, Tangerine red 6 parts, Mulberry leaf 9 parts, Uncaria 18 parts, Red peony root 9 parts, Chuzhou chrysanthemum 9 parts.

5. A method for preparing the traditional Chinese medicine composition according to any one of claims 1-4, characterized in that, It comprises the following steps: (1) Extracting volatile oil from raw materials by steam distillation method to obtain volatile oil and residue; (2) Putting the residue into solvent for leaching, and filtering to obtain leaching liquid; (3) Distilling and concentrating the leaching liquid; (4) Adding volatile oil obtained in step (1), fresh orange juice and melted agar to the concentrated leaching liquid; (5) Sealing and packaging the obtained product.

6. The method of claim 5, wherein, The steps (3) and (4) are carried out under negative pressure.

7. The method of claim 5, wherein, The solvent is water, 75% ethanol or melted pork skin jelly.

8. The method of claim 5, wherein, During the leaching process of step (2), ultrasonic wave with a frequency of 15-25 KHZ is used for cell wall breaking treatment.

9. Use of the traditional Chinese medicine composition according to any one of claims 1-4 in the preparation of a medicament for preventing and treating hypertensive disorder in pregnancy. Preferably, the hypertensive disorder in pregnancy is preeclampsia.

10. A pharmaceutical preparation, characterized in that, It comprises the traditional Chinese medicine composition according to any one of claims 1-4 and a pharmaceutically acceptable carrier.

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