A Chinese medicine composition for treating primary Sjögren's syndrome and its application

Abstract

The invention discloses a Chinese medicine composition for treating primary Sjögren's syndrome and its application. The Chinese medicine composition has a reasonable ratio design and is obtained through a large number of experimental screenings and long-term clinical experience accumulation, so that it has the functions of nourishing yin and moistening dryness, strengthening the spleen and removing dampness, and can enhance the salivary gland secretion function of Sjögren's syndrome model mice, improve salivary gland lymphocyte infiltration, and reduce abnormally elevated MDSC cells in the spleen, reduce the disease activity of Sjögren's syndrome patients, and improve the quality of life. In particular, it has the advantages of good efficacy and more significant effect for yin deficiency and dampness type Sjögren's syndrome. The Chinese medicine composition of the present invention can be administered alone or in combination. The pharmaceutical composition of the present invention is a safe and effective pure Chinese medicine preparation, has no toxic side effects, and the quality of the composition of the medicine is easy to control, low cost, and has good application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and in particular to a traditional Chinese medicine composition for treating primary Sjögren's syndrome and application thereof. Background Art

[0002] Primary Sjögren's syndrome (PSS) is a chronic systemic autoimmune disease that mainly affects exocrine glands, and its main clinical manifestations are dry mouth and dry eyes. According to statistics, the international prevalence of primary Sjögren's syndrome is 0.5% to 1.56%, which is a common autoimmune disease. In PSS, symptoms such as dry mouth and eyes seriously affect the quality of life of patients. In addition, about 1 / 3 of patients may have multi-system involvement outside the glands. Such as thrombocytopenia, interstitial lung disease, renal tubular acidosis, etc.; these extra-glandular damages seriously endanger the life and health of patients. In addition to physical symptoms, PSS patients are more likely to have psychological symptoms such as anxiety and depression, which also poses a great threat to the mental health of patients.

[0003] At present, the pathogenesis of primary Sjögren's syndrome is not very clear. It is generally believed that the onset of this disease is often closely related to factors such as the body's genetics, immune system dysfunction, and viral infection. There is currently no cure for this disease, and the goal of treatment is to relieve local symptoms and prevent complications. In Western medicine, there is currently a lack of effective treatment methods for this disease. The treatment mainly includes symptomatic relief of symptoms, or the use of immunosuppressive drugs to relieve extra-glandular damage. The representative drug for treatment is hydroxychloroquine sulfate, but symptomatic treatment is difficult to delay extra-glandular damage, and immunosuppressive treatment cannot improve the symptoms of dryness, and complications such as infection are prone to occur, which has limitations. Traditional Chinese medicine has unique advantages in the treatment of Sjögren's syndrome due to its good overall efficacy, and has a broad clinical basis in the treatment of PSS. In the traditional Chinese medicine treatment of PSS, yin-nourishing drugs are most commonly used. For example, invention patent CN107669889A discloses a traditional Chinese medicine composition for treating Sjögren's syndrome, which comprises 22-35 parts by weight of Scrophularia ningpoensis, 20-30 parts by weight of Rehmannia glutinosa, 18-26 parts by weight of Pueraria lobata, 15-25 parts by weight of Atractylodes macrocephala and 12-18 parts by weight of Cortex Moutan. It can improve immunity by nourishing yin, promoting body fluid, strengthening spleen and activating blood circulation, and achieve the purpose of nourishing various orifices and relieving dryness by regulating the ascending and descending and dispersing movement of Qi, body fluid and blood. Invention patent CN116920052A discloses a Chinese medicine composition for treating primary Sjögren's syndrome with depression. The Chinese medicine composition is made of the following raw materials in parts by weight: 28-32 parts of Rehmannia root, 8-12 parts of Cornus officinalis, 8-12 parts of Dioscorea opposita, 8-15 parts of Bupleurum root, 8-12 parts of stir-fried white peony root, 8-12 parts of Adenophora adenophora, 8-15 parts of Ophiopogon japonicus, 14-18 parts of Poria, 8-12 parts of Dendrobium officinale, 14-18 parts of Salvia miltiorrhiza, 4-8 parts of pomegranate peel, and 4-8 parts of Licorice. The purpose of treating primary Sjögren's syndrome with depression is achieved by invigorating the kidney and soothing the liver, harmonizing yin and yang, nourishing blood and replenishing qi, and promoting blood circulation and removing blood stasis. Most of the above prescriptions take Yin deficiency and fluid deficiency as the main etiology and pathogenesis, and take nourishing Yin and producing fluid as the main treatment principle. However, the syndrome of Sjögren's syndrome in traditional Chinese medicine is divided into Yin deficiency and fluid deficiency syndrome, Qi and Yin deficiency syndrome, Yin deficiency and internal heat syndrome, dryness and dampness syndrome, and dryness and dampness syndrome (Yin deficiency and dampness). Among them, patients with Yin deficiency and dampness syndrome not only have an absolute deficiency of body fluid, but also have pathological characteristics of relative deficiency of body fluid such as uneven distribution of body fluid due to dampness blocking the Qi mechanism. In addition, the spleen is the hub of the middle jiao, responsible for transporting and transforming water and dampness, and likes dryness and hates dampness. If only promoting the production of body fluid is the main treatment principle of Sjögren's syndrome, it will further affect the spleen's transportation and transformation of water and grain. Therefore, the treatment method with nourishing Yin and producing fluid as the main treatment principle is ineffective for patients with Yin deficiency and dampness syndrome and is prone to side effects such as diarrhea. Therefore, it is urgent to find new and effective treatment methods for Yin deficiency and dampness syndrome. Summary of the invention

[0004] In view of the above-mentioned deficiencies in the prior art, the technical problem to be solved by the present invention is: how to provide a Chinese medicine composition and its application that can significantly improve the clinical symptoms of patients with primary Sjögren's syndrome, improve life treatment, and slow down the progression of the disease. A new treatment scheme for Sjögren's syndrome is explored, which has a good therapeutic effect on patients with yin deficiency and dampness, and provides a new idea for the treatment of Sjögren's syndrome.

[0005] In order to solve the above technical problems, the present invention adopts the following technical scheme: a traditional Chinese medicine composition for treating primary Sjögren's syndrome, comprising the following components in parts by weight: 15-45 parts of Astragalus, 10-15 parts of Ophiopogon japonicus, 15-30 parts of Adenophora australis, 10-15 parts of Rehmannia root, 10-15 parts of Schisandra chinensis, 10-15 parts of Cimicifuga heracleifolia, 10-15 parts of Salt Alisma Orientalis, 10-20 parts of Atractylodes lancea, 10-15 parts of Phellodendron chinense, 10-15 parts of Tangerine peel, 10-15 parts of Citrus reticulatae, 5-10 parts of Angelica sinensis, 20-30 parts of Pueraria root, 15-20 parts of Atractylodes macrocephala and 15-20 parts of Jiaoliu Shenqu. The present invention combines the clinical practice and working basis of traditional Chinese medicine in treating Sjögren's syndrome, improves the peripheral gland secretion function of Sjögren's syndrome patients and Sjögren's syndrome model mice, and takes the Sjögren's syndrome activity score as the efficacy index, and through dialectical analysis of the pathogenesis of Sjögren's syndrome and sorting out the efficacy of Chinese herbal medicines, it is found that astragalus, ophiopogon, adenophora australis, raw rehmannia, schisandra, cimicifuga, salt arisaema, atractylodes, phellodendron, tangerine peel, green peel, angelica, kudzu root, atractylodes and scorched six Shenqu have the synergistic effects of nourishing yin and moistening dryness, strengthening the spleen and removing dampness, and have a good therapeutic effect on Sjögren's syndrome of yin deficiency and dampness, thereby forming the present invention.

[0006] Among them, the medicinal properties of each component are as follows:

[0007] Astragalus: It belongs to the lung meridian and spleen meridian. It has the effects of replenishing qi and strengthening the exterior, promoting diuresis and expelling toxins, draining pus, and healing sores and promoting tissue regeneration.

[0008] Ophiopogon japonicus: It belongs to the heart meridian, lung meridian and stomach meridian. It has the effects of nourishing yin and moistening the lungs, clearing the heart and relieving troubles, and benefiting the stomach and producing body fluids.

[0009] Adenophora australis: It belongs to the lung meridian and stomach meridian. It has the effects of nourishing yin, clearing the lungs, removing phlegm and relieving cough.

[0010] Raw Rehmannia root: It enters the heart meridian, liver meridian and kidney meridian. It has the effects of nourishing yin, clearing away heat, cooling blood and replenishing blood.

[0011] Schisandra chinensis: It belongs to the lung meridian, heart meridian and kidney meridian. It has the effects of astringing, strengthening qi and promoting body fluid, nourishing the kidney and calming the mind.

[0012] Cimicifuga: It belongs to the lung meridian, spleen meridian and stomach meridian. It has the effects of raising yang, dispelling wind, clearing rashes and detoxifying.

[0013] Salt-leaved amaranth: It belongs to the kidney meridian and bladder meridian. It has the effects of promoting diuresis and eliminating dampness, relieving heat and relieving stranguria.

[0014] Atractylodes: It belongs to the spleen meridian, stomach meridian, and liver meridian. It has the effects of strengthening the spleen, drying dampness, relieving depression, and eliminating filth.

[0015] Huangbai: It belongs to the kidney meridian and bladder meridian. It has the effects of clearing away heat, drying dampness, purging fire and detoxifying.

[0016] Tangerine peel: It belongs to the lung meridian and spleen meridian. It has the effects of regulating qi, regulating the middle, drying dampness and resolving phlegm.

[0017] Qingpi: It belongs to the liver meridian and gallbladder meridian. It has the effects of soothing the liver and breaking up qi, dispersing stagnation and eliminating phlegm.

[0018] Angelica sinensis: It belongs to the liver meridian, heart meridian and spleen meridian. It has the effects of nourishing blood and activating blood circulation, regulating menstruation and relieving pain, and moistening the intestines and relieving constipation.

[0019] Pueraria root: It belongs to the spleen meridian, stomach meridian, lung meridian and bladder meridian. It has the effects of raising yang and relieving muscles, clearing rashes and stopping diarrhea, and relieving restlessness and fever.

[0020] Atractylodes macrocephala: belongs to the spleen meridian and stomach meridian. It has the effects of tonifying the spleen, benefiting the stomach, drying dampness, harmonizing the middle and calming the fetus.

[0021] Jiao Liu Shen Qu: It belongs to the spleen meridian and stomach meridian. It has the effects of strengthening the spleen and stomach, and promoting digestion and regulating the middle.

[0022] The Chinese medicine compound medicine theory basis of the present invention is: at the beginning of the onset of Sjogren's syndrome, deficiency of body fluid can be seen. Body fluid is one of the important substances for maintaining normal life activities of the human body. Body fluid is produced from water and grain, and is distributed throughout the body through the spleen and stomach decomposition and transformation, the small intestine separating the clear and secreting the turbid, the large intestine conducting, the lung qi distribution, and the three burners unblocking, playing the role of moisturizing and nourishing. The so-called "drinking in the stomach, overflowing essence and qi, transported to the spleen, the spleen qi disperses essence, transported to the lungs, regulating the water channels, transported to the bladder, water and body fluid are distributed in four directions, and the five meridians run in parallel". On the contrary, if the ability of the middle burner to transport and transform water and grain is insufficient, it will cause dampness. As the Jingyue Complete Book says: "Drinking is a kind of water... These are all the residues of water and grain." The ancients said that "body fluid and qi go hand in hand". Body fluid can carry qi. If body fluid is deficient, qi will be weak. Qi can move body fluid. If qi is weak, it cannot promote the distribution of body fluid throughout the body. Stagnation of body fluid will cause dampness. The generation of dampness further aggravates the deficiency of body fluids. For example, in Treatise on Warm Diseases, Lower Jiao, Cold and Dampness, it is said that "when the evil water is prosperous, the normal water will be deficient". The generation of dampness aggravates the deficiency of body fluids. Dampness is a yin evil that consumes yang qi. Ye Tianshi said, "Taiyin spleen and earth are transported by yang". Dampness traps spleen yang, which further aggravates the obstruction of water and grain transportation. When body fluids cannot be carried up to the mouth, patients will experience dry mouth, dry lips, cracked tongue, reduced saliva, abnormal taste and other discomforts. Therefore, in the pathological mechanism of Sjögren's syndrome, there is a unified dialectical relationship between the deficiency of body fluids and the generation of dampness. The two are closely related in pathogenesis, can exist in the pathogenesis at the same time, and can synergistically promote the development of the pathogenesis, causing other evils and harming the body. The deficiency of body fluids is an important pathological basis for the generation of dampness, and the generation of dampness is the driving force for the progression of the pathogenesis of the deficiency of body fluids.

[0023] In the composition of the present invention, astragalus root nourishes the middle yang, so that the middle jiao can be transported, and the combination of white atractylodes and atractylodes further strengthens the spleen yang, removes dampness and turbidity, nourishes the spleen and stomach to slowly produce body fluid, ophiopogon japonicus, adenophora australis, and raw rehmannia root urgently replenish the yin fluid of deficiency, and cimicifuga ascends the upper jiao to raise the clear yang, so that the body fluid is presented to the skin pores, and oriental water and phellodendron go to the lower jiao to reduce turbid qi, giving dampness a way out, tangerine peel and green peel regulate the qi mechanism, so that the qi mechanism of the triple jiao can be transported, kudzu root produces body fluid and raises clearness, dredges tendons and collaterals, and body fluid and blood have the same origin, and angelica is added to replenish blood and promote blood circulation, and schisandra chinensis invigorates qi and produces body fluid, nourishes the kidney and calms the mind, and relieves the anxiety often seen in patients with Sjogren's syndrome, and Liushenqu helps the middle jiao to decompose water and grain, and the source of the prosperous body fluid, and all the medicines are used together, one is to nourish the middle jiao, so that the water and grain can be transported, and the source of dampness is generated, and the other is to raise the clearness and reduce turbidity, so that the body fluid is normally distributed. The whole recipe plays the role of nourishing yin and moistening dryness, and strengthening the spleen and removing dampness.

[0024] Preferably, the Chinese medicine composition includes the following components in parts by weight: 15 parts of Astragalus, 15 parts of Ophiopogon japonicus, 30 parts of Adenophora australis, 15 parts of Rehmannia root, 10 parts of Schisandra chinensis, 10 parts of Cimicifuga heracleifolia, 10 parts of Salt Alisma orientalis, 15 parts of Atractylodes lancea, 15 parts of Phellodendron chinense, 10 parts of Citrus reticulata, 10 parts of Citrus aurantium, 5 parts of Angelica sinensis, 30 parts of Pueraria root, 15 parts of Atractylodes macrocephala and 15 parts of Jiaoliu Shenqu.

[0025] Preferably, the primary Sjögren's syndrome is of the yin deficiency and dampness type.

[0026] Another object of the present invention is to provide the use of the above-mentioned Chinese medicine composition in the preparation of a drug for treating primary Sjögren's syndrome.

[0027] Preferably, the drug further comprises pharmaceutically acceptable carriers and excipients.

[0028] Preferably, the dosage form of the drug includes decoction, granules, tablets, capsules or oral liquid.

[0029] Another object of the present invention is to provide a pharmaceutical preparation for treating primary Sjögren's syndrome, wherein the pharmaceutical preparation uses the above-mentioned traditional Chinese medicine composition or the extract of the traditional Chinese medicine composition as an effective ingredient.

[0030] Another object of the present invention is to provide a composite pharmaceutical preparation for treating primary Sjögren's syndrome, wherein the composite pharmaceutical preparation comprises the above-mentioned traditional Chinese medicine composition or an extract of the traditional Chinese medicine composition and hydroxychloroquine sulfate.

[0031] Preferably, the pharmaceutical preparation further comprises a pharmaceutically acceptable carrier and excipients.

[0032] Preferably, the dosage form of the pharmaceutical preparation includes decoction, granules, tablets, capsules or oral liquid.

[0033] Preferably, the primary Sjögren's syndrome is of the yin deficiency and dampness type.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] 1. The proportion design of the Chinese medicine composition of the present invention is reasonable, and it is obtained through a large number of experimental screenings and long-term clinical experience accumulation, so that it has the functions of nourishing yin and moistening dryness, strengthening the spleen and removing dampness, and can enhance the salivary gland secretion function of Sjögren's syndrome model mice, improve salivary gland lymphocyte infiltration, and reduce abnormally elevated MDSC cells in the spleen, reduce the disease activity of Sjögren's syndrome patients, and improve the quality of life. Especially for the Yin deficiency and dampness type Sjögren's syndrome, it has the advantages of good efficacy and more significant effect. The pharmaceutical composition of the present invention is a safe and effective pure Chinese medicine preparation, has no toxic and side effects, and the quality of the composition is easy to control, low cost, and has good application prospects. The present invention provides a new idea and theoretical basis for the research on the treatment of Sjögren's syndrome, which is of great significance.

[0036] 2. Animal experiments show that the Chinese medicine composition of the present invention can improve the salivary gland secretion function of Sjögren's syndrome model mice, reduce salivary gland lymphocyte infiltration, and reduce the proportion of MDSC cells in the spleen of mice, indicating that the Chinese medicine composition of the present invention can be used for the treatment of Sjögren's syndrome. In clinical applications, it was found that the Chinese medicine composition of the present invention combined with hydroxychloroquine sulfate, the synergistic effect of the two can improve the peripheral gland secretion function of patients with primary Sjögren's syndrome, reduce the disease activity of patients with Sjögren's syndrome, and improve the quality of life of patients. The synergistic effect of the two is significantly better than that of the single medication. The Chinese medicine composition of the present invention can be administered alone or in combination, and the therapeutic effect is significant. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Figure 2 shows the salivary flow rate of mice in different treatment groups before and after 16 weeks of treatment.

[0038] Figure 2 Statistical graph of the percentage of salivary gland lymphocyte infiltration area in mice under different treatment groups.

[0039] Figure 3 The percentage of MDSC cells in the spleen of mice in different treatment groups. DETAILED DESCRIPTION

[0040] The present invention is further described in detail below in conjunction with the examples. The mice used in the following examples were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., weighing 20±2 grams, SPF grade, and the animal license number was SCXK (Su) 2018-0008. The experimental animals were raised in the SPF animal laboratory of Chongqing Traditional Chinese Medicine Hospital, with a room temperature of (25±2)°C and free access to food and water. All the Chinese medicine raw materials used were purchased from Chongqing Traditional Chinese Medicine Hospital.

[0041] 1. A Chinese medicine composition for treating primary Sjögren's syndrome

[0042] Example 1

[0043] A Chinese medicine composition for treating primary Sjögren's syndrome comprises the following components by weight: 15 parts of Astragalus, 15 parts of Radix Ophiopogonis, 30 parts of Radix Adenophorae, 15 parts of Radix Rehmanniae, 10 parts of Fructus Schisandrae Chinensis, 10 parts of Rhizoma Cimicifugae, 10 parts of Rhizoma Cimicifugae, 10 parts of Rhizoma Alismatis, 15 parts of Rhizoma Atractylodis Macrocephalae, 15 parts of Rhizoma Atractylodis Macrocephalae, 10 parts of Pericarpium Citri Reticulatae, 10 parts of Pericarpium Citri Reticulatae, 5 parts of Radix Angelicae Sinensis, 30 parts of Radix Puerariae, 15 parts of Rhizoma Atractylodis Macrocephalae and 15 parts of Rhizoma Scorched Ligustici Radix. The composition is prepared by the following steps: weighing each raw material and soaking the medicine in water for 30 minutes, boiling over high heat and then decocting over low heat for 30 minutes, filtering out the medicine juice, repeating twice, mixing the medicine juice, concentrating it into a medicine liquid containing 0.5 g / mL of the raw medicine, and placing it in a refrigerator at 4°C for standby use.

[0044] Example 2

[0045] A Chinese medicine composition for treating primary Sjögren's syndrome comprises the following components by weight: 45 parts of Astragalus, 10 parts of Radix Ophiopogonis, 20 parts of Radix Adenophorae, 15 parts of Radix Rehmanniae, 10 parts of Fructus Schisandrae Chinensis, 10 parts of Rhizoma Cimicifugae, 10 parts of Rhizoma Cimicifugae, 10 parts of Rhizoma Alismatis, 10 parts of Atractylodes, 10 parts of Cortex Phellodendri, 10 parts of Pericarpium Citri Reticulatae, 10 parts of Pericarpium Citri Reticulatae, 5 parts of Radix Angelicae Sinensis, 25 parts of Radix Puerariae, 15 parts of Rhizoma Atractylodis Macrocephalae and 20 parts of Rhizoma Scorched Ligustici Radix. The composition is prepared by the following steps: weighing each raw material and soaking the medicine in water for 30 minutes, boiling over high heat and then decocting over low heat for 30 minutes, filtering out the medicine juice, repeating twice, mixing the medicine juice, concentrating it into a medicine liquid containing 0.5 g / mL of the raw medicine, and placing it in a refrigerator at 4°C for standby use.

[0046] 2. Application of Chinese medicine composition

[0047] 1. In order to verify whether the Chinese medicine composition of the present invention has a therapeutic effect on PSS, 4-week-old NOD / Ltj female mice and ICR female mice were selected. Female NOD mice were used as model mice. NOD mice are a type of spontaneous mouse model commonly used for Sjögren's syndrome. When the mice are 9 weeks old, the submandibular glands will gradually be infiltrated and destroyed by lymphocytes. After 1 week of adaptive feeding, 10 NOD mice were randomly divided into 2 groups, namely the test group (HSCY) and the model group (Model), and 5 ICR mice were adaptively fed for 1 week as the control group (Control). The test group was gavaged with 10g / kg of the medicinal solution prepared in Example 1 every day, and the model group and the control group were gavaged with the same dose of normal saline every day. After 4 weeks, it was changed to gavage every other day for 12 weeks.

[0048] 1) The salivary flow rate of mice was measured before the first administration and 16 weeks after administration (21 weeks of age). Specific method: After anesthesia, the mice were intraperitoneally injected with pilocarpine (2 mg / kg). Subsequently, the researchers immediately collected the saliva of the mice, and the mice were kept in an inverted position. A centrifuge tube was placed at the bottom of the mouth to allow saliva to flow into the centrifuge tube. Saliva was collected continuously for 15 minutes. After centrifugation, the volume of saliva was measured, and finally the salivary flow rate of the mice (μL / 15min) was calculated. The results are as follows Figure 1 shown.

[0049] As can be seen from the figure, before treatment, the salivary flow rate of the mice in the control group was significantly higher than that of the mice in the model group and the experimental group (P < 0.001), and there was no significant difference in the salivary flow rate between the mice in the model group and the experimental group (P > 0.05). After 16 weeks of treatment, compared with the model group, the salivary flow rate of the mice in the experimental group was significantly improved (P = 0.0017), approaching the salivary flow rate level of the mice in the control group.

[0050] 2) After 16 weeks of treatment, mice were killed by cervical dislocation at 21 weeks of age, and one submandibular gland was removed from one side, immediately fixed with 4% paraformaldehyde, and embedded in paraffin. All sections were cut into 2 μm thick sections and stained with hematoxylin and eosin for 3 minutes. The sections were observed and images were collected under a microscope, and the area of ​​lymphocyte infiltration lesions in each field of view was calculated using Image J software. Finally, the ratio of the submandibular gland lymphocyte infiltration area to the total area was calculated. The results are shown in Figure 2. Figure 2 shown.

[0051] As can be seen from the figure, after 16 weeks of treatment, the area of ​​infiltrating lymphocytes calculated in the salivary gland HE sections of the mice in the control group was significantly lower than that of the mice in the model group and the experimental group (P<0.0001). Compared with the mice in the model group, the area of ​​infiltrating lymphocytes calculated in the salivary gland HE sections of the mice in the experimental group of the present invention was significantly reduced (P=0.415). This shows that the Chinese medicine composition of the present invention can effectively control the infiltration area of ​​salivary gland lymphocytes in NOD mice and reduce salivary gland inflammation in SS model mice.

[0052] 3) After 16 weeks of drug treatment, mice were killed by cervical dislocation at 21 weeks of age, and the spleens of mice were removed and ground in RPMI1640 medium. Two times of red blood cell lysis solution was added to the spleen grinding solution, and lysed at room temperature for 20 minutes. After removing the red blood cell lysis solution, the spleen cell suspension was washed with PBS. The resuspended cells were filtered through a 40μm cell filter. To identify cell surface markers, the cell suspension was incubated with Fc receptor blockers at 4°C for 15 minutes. The suspension was incubated with mouse antibodies (CD11b, Gr-1) at 4°C for 30 minutes, and the fixable active dye eFluor was added to the suspension to distinguish dead cells from live cells. To detect intracellular cytokine levels, the cells were pre-incubated with PMA, ionomycin, and protein transport inhibitor A in RPMI 1640 medium at 37°C for 6 hours. Subsequently, the cells were fixed and permeabilized for 30 min, and then incubated at room temperature for 30 min before flow cytometry analysis using a flow cytometer. The data were analyzed using FlowJo_v10.6.2 software. The results are shown in Figure 3 shown.

[0053] As can be seen from the figure, compared with the model group mice, the MDSC level in the spleen of the test group mice was significantly decreased (P=0.079), indicating that the Chinese medicine composition of the present invention can improve the proportion of MDSC cells in the spleen of NOD mice.

[0054] In summary, the Chinese medicine composition of the present invention can enhance the salivary gland secretion function of Sjögren's syndrome model mice, improve salivary gland lymphocyte infiltration, and reduce the abnormally elevated MDSC cells in the spleen.

[0055] 2. The Chinese medicine composition of the present invention is used in combination with hydroxychloroquine sulfate

[0056] 1) Case inclusion criteria

[0057] TCM diagnostic criteria

[0058] Refer to the relevant standards in the "Guidelines for the Diagnosis and Treatment of Sjögren's Syndrome" and "Syndrome Differentiation" issued by the Chinese Association of Traditional Chinese Medicine. Main symptoms: ① dry mouth and tongue; ② dry eyes without tears. Secondary symptoms: ① limb pain; ② poor appetite; ③ fatigue; ④ dry skin; ⑤ dry stool. Tongue and pulse: pale tongue, greasy coating, little fluid, slippery pulse. Diagnostic criteria: 2 main symptoms plus any 2 secondary symptoms, refer to the tongue and pulse for diagnosis.

[0059] Western medicine diagnostic criteria

[0060] Refer to the diagnostic criteria for primary Sjögren's syndrome developed by the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) in 2016.

[0061] Inclusion criteria: patients with at least one symptom of dry eyes or dry mouth, that is, at least one of the following is positive:

[0062] (1) Unbearable dry eyes every day for more than 3 months;

[0063] (2) recurrent gritty sensation in the eyes;

[0064] (3) artificial tears need to be used 3 or more times a day;

[0065] (4) Daily dry mouth for more than 3 months;

[0066] (5) Those who need to drink water frequently to help swallow dry food or those suspected of SS who have at least one positive system in the EULAR SS Disease Activity Index (ESSDAI) questionnaire.

[0067] Exclusion criteria: Patients with the following diseases should be excluded because they may have overlapping clinical manifestations or interfere with diagnostic test results:

[0068] (1) History of head and neck radiotherapy;

[0069] (2) active hepatitis C virus infection;

[0070] (3) AIDS;

[0071] (4) Sarcoidosis;

[0072] (5) Amyloidosis;

[0073] (6) Graft-versus-host disease;

[0074] (7) IgG4-related diseases.

[0075] Applicable to anyone who meets the above inclusion criteria and excludes the exclusion criteria, and the sum of the following five scores ≥ 4 is diagnosed as pSS:

[0076] (1) Focal lymphocytic infiltration of the labial gland with a focal index ≥ 1 focus / 4 mm2, 3 points;

[0077] (2) serum anti-SSA antibody was positive, 3 points;

[0078] (3) at least one eye with corneal staining score (OSS) ≥5 or Van Bijsterveld score ≥4, which was 1 point;

[0079] (4) at least one tear secretion test (Schirmer test) ≤ 5 mm / 5 min, 1 point;

[0080] (5) Unstimulated whole saliva flow rate ≤ 0.1 ml / min (Navazesh and Kumar method), scored 1 point.

[0081] Patients who routinely use cholinergic drugs should fully stop taking the drugs before undergoing the above-mentioned examinations (3), (4), and (5) to assess dry mouth and eyes.

[0082] Case inclusion criteria

[0083] ①Conform to the Western medical diagnosis of primary Sjögren's syndrome;

[0084] ②Meet the TCM diagnostic criteria for Yin deficiency and dampness syndrome and its combined syndromes.

[0085] Case exclusion criteria

[0086] ①Exclude secondary Sjögren's syndrome;

[0087] ② Exclude patients with other TCM syndromes;

[0088] ③ Patients with severe primary diseases, liver, kidney, or heart dysfunction;

[0089] ④ Patients who are unable to cooperate due to mental illness or other reasons.

[0090] Criteria for rejection, dropout and termination of the experiment

[0091] ① Exclusion: Subjects who should not be included in the group but have been included should be excluded, including: those who were mistakenly included, misdiagnosed, did not take the medicine once, and have no test records.

[0092] The reasons for the exclusion of cases should be stated, and their data should be kept for future reference. No statistical analysis of efficacy will be conducted, but those who have received at least one treatment and have at least one safety record can participate in the adverse reaction analysis.

[0093] ② Dropout: Patients who have been enrolled but have not completed the clinical plan should be considered as dropout in the following circumstances: patients withdraw on their own, are lost to follow-up, have poor compliance, or are ordered to withdraw by the physician due to complications.

[0094] The reasons for dropouts should be explained. If there is baseline efficacy data, the last result of the primary efficacy indicator can be transferred to the final result for statistical analysis, and the data should be retained for future reference.

[0095] ③Complete termination of the trial: when safety issues are discovered, the efficacy is too poor, or there are major errors in the plan.

[0096] 2) A total of 88 patients were included in this study, all from the outpatient department of rheumatology of Chongqing Traditional Chinese Medicine Hospital. According to their existing treatment plans, they were divided into the combination of Chinese and Western medicine group and the Western medicine group (44 cases in each group). During the clinical observation process, 2 patients in the combination of Chinese and Western medicine group dropped out due to loss of contact; 3 patients in the Western medicine group dropped out due to changes in treatment plans. A total of 42 cases were actually included in the combination of Chinese and Western medicine group and 41 cases in the Western medicine group, for a total of 83 cases. There were 42 cases in the combination of Chinese and Western medicine group, including 1 male and 41 females; there were 41 cases in the Western medicine group, including 0 males and 41 females. The gender distribution of the two groups was comparable (P=0.320). Before treatment, there was no statistically significant difference in the average age, ESSPRI, each single ESSPRI score, binocular Schimer I test and salivary flow rate between the combination of Chinese and Western medicine group and the Western medicine group, and they were comparable (P=>0.05), as shown in Tables 1 to 5.

[0097] Table 1 Age distribution of cases

[0098]

[0099]

[0100] Table 2 ESSPRI score table before treatment

[0101]

[0102] Table 3 Single ESSPRI score table before treatment

[0103]

[0104] Table 4 Comparison of Schimer I test before treatment

[0105]

[0106] Table 5 Comparison of salivary flow rate of cases before treatment

[0107]

[0108] Patients in the western medicine group were made to take hydroxychloroquine sulfate tablets (Fenle) (0.1g / tablet, manufacturer: Shanghai Shangyao Chinese and Western Pharmaceutical Co., Ltd., national medicine standard: H19990263), 2 times a day, 2 tablets each time, taken after meals. Patients in the combination of Chinese and Western medicine group were made to take the medicament prepared in Example 1 of the present invention on the basis of the western medicine group, 1 dose per day (liquid prepared in Example 1), divided into 3 times after meals, 30 minutes apart from the western medicine. The observation course of treatment for both the combination of Chinese and Western medicine group and the western medicine group was 12 weeks. Then the total effective rate, ESSPRI, each single ESSPRI score, binocular Schimer I test and salivary flow rate of the combination of Chinese and Western medicine group and the western medicine group were compared, and the specific data are shown in Tables 6 to 10.

[0109] The ESSPRI score is a disease activity index recognized by EULAR (European League Against Rheumatism) in 2010. Previous studies have determined that a decrease in the ESSPRI value of ≥1 point is the minimum meaningful improvement. Therefore, the treatment response in this study defines symptom improvement as a decrease in the ESSPRI of ≥1 point. A decrease in the ESSPRI of ≥1 point is considered effective, otherwise it is considered ineffective.

[0110] Total effective rate = [number of effective cases / total number of cases] × 100%

[0111] Table 6 Total effective rate of cases after treatment

[0112]

[0113] Table 7 ESSPRI scores of cases after treatment

[0114]

[0115]

[0116] Table 8 ESSPRI scores of each item after treatment

[0117]

[0118] Table 9 Schimer I test after treatment

[0119]

[0120] Table 10 Saliva flow rate of cases after treatment

[0121]

[0122] As can be seen from Table 6, the total effective rate of the combined Chinese and Western medicine group was 92.86%, and the total effective rate of the Western medicine group was 68.29%. The total effective rate of the combined Chinese and Western medicine group was 24.57% higher than that of the Western medicine group, and the difference was statistically significant (P = 0.005 < 0.05). The intra-group comparison of the ESSPRI scores of the two groups of drugs showed that both groups of drugs had a significant effect on patients with Sjögren's syndrome.

[0123] (P<0.001), while the inter-group comparison showed that the ESSPRI score of the combined Chinese and Western medicine group decreased significantly more than that of the Western medicine group (Table 7), and the difference between the two groups was statistically significant (P<0.001). In terms of overall efficacy, the combined Chinese and Western medicine group had better efficacy. In terms of single ESSPRI scores, both groups could effectively improve the patients' symptoms of dry mouth, dry eyes, fatigue and limb pain (P<0.001), but the inter-group comparison showed that the combined Chinese and Western medicine group had better improvement in dry mouth, dry eyes and limb pain than the Western medicine group (P<0.05), while there was no statistically significant difference in fatigue scores (P>0.05) (Table 8). In the tear secretion function test of the two groups, the tear secretion function and salivary flow rate of both eyes of patients in the combined Chinese and Western medicine group and the Western medicine group were significantly enhanced after treatment (P < 0.05). Compared with the two groups, the Schimer I test and salivary flow rate test of both eyes in the combined Chinese and Western medicine group were better than those in the Western medicine group, and the difference was statistically significant (P < 0.05) (Table 9, Table 10).

[0124] In summary, clinical studies have shown that the Chinese medicine composition of the present invention is used in combination with hydroxychloroquine sulfate, and the two have a synergistic effect, which is significantly better than using either drug alone, and can enhance the peripheral gland secretion function of patients with Sjögren's syndrome and improve the symptoms of patients with Sjögren's syndrome.

[0125] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A Chinese medicine composition for treating primary Sjögren's syndrome, characterized in that: The invention is composed of the following components in parts by weight: 15-45 parts of astragalus, 10-15 parts of ophiopogon, 15-30 parts of adenophora australis, 10-15 parts of raw rehmannia, 10-15 parts of schisandra, 10-15 parts of cimicifuga, 10-15 parts of salt alisma, 10-20 parts of atractylodes, 10-15 parts of phellodendron, 10-15 parts of tangerine peel, 10-15 parts of green peel, 5-10 parts of angelica, 20-30 parts of kudzu root, 15-20 parts of atractylodes and 15-20 parts of jiaoliu shenqu; the primary Sjögren's syndrome is of yin deficiency and dampness type.

2. The Chinese medicine composition for treating primary Sjögren's syndrome according to claim 1, characterized in that: The invention is composed of the following components in parts by weight: 15 parts of astragalus, 15 parts of ophiopogon, 30 parts of adenophora australis, 15 parts of raw rehmannia, 10 parts of schisandra, 10 parts of cimicifuga, 10 parts of salt alisma, 15 parts of atractylodes, 15 parts of phellodendron, 10 parts of tangerine peel, 10 parts of green peel, 5 parts of angelica, 30 parts of kudzu root, 15 parts of atractylodes and 15 parts of scorched six shenqu.

3. Use of the Chinese medicine composition as claimed in claim 1 or 2 in the preparation of a drug for treating primary Sjögren's syndrome, wherein the primary Sjögren's syndrome is of the yin deficiency and dampness type.

4. The use according to claim 3, characterized in that: The medicine also includes pharmaceutically acceptable carriers and excipients.

5. The application according to claim 3, characterized in that: The dosage form of the medicine includes decoction, granules, tablets, capsules or oral liquid.

6. A pharmaceutical preparation for treating primary Sjögren's syndrome, characterized in that: The pharmaceutical preparation uses the Chinese medicine composition or the extract of the Chinese medicine composition as claimed in claim 1 or 2 as an effective ingredient, and the primary Sjögren's syndrome is of the yin deficiency and dampness type.

7. A composite pharmaceutical preparation for treating primary Sjögren's syndrome, characterized in that: The composite pharmaceutical preparation comprises the Chinese medicine composition or the extract of the Chinese medicine composition according to claim 1 or 2 and hydroxychloroquine sulfate, and the primary Sjögren's syndrome is of the yin deficiency and dampness type.

8. The pharmaceutical preparation according to claim 6 or 7, characterized in that The pharmaceutical preparation also includes pharmaceutically acceptable carriers and excipients.

9. The pharmaceutical preparation according to claim 6 or 7, characterized in that The dosage form of the pharmaceutical preparation includes decoction, granules, tablets, capsules or oral liquid.

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