Traditional Chinese medicine composition for rheumatoid arthritis pulmonary interstitial lesion as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention belongs to the technical field of medicines for treating rheumatoid arthritis complications, and particularly relates to a traditional Chinese medicine composition for rheumatoid arthritis interstitial pulmonary lesion as well as a preparation method and application of the traditional Chinese medicine composition. The traditional Chinese medicine composition comprises ginseng, astragalus membranaceus, prepared rehmannia root, schisandra chinensis, radix asteris, white mulberry root-bark, angelica sinensis, eclipta, radix glehniae, salvia miltiorrhiza, turmeric, exocarpium citri rubrum and liquorice. The traditional Chinese medicine composition has the effects of regulating qi and blood and treating both symptoms and root causes, is suitable for the symptoms of lung arthralgia, deficiency of both qi and yin and stasis of veins and collaterals, can obviously relieve the lung function of patients with rheumatoid arthritis interstitial pulmonary disease, reduces the symptom scores of shortness of breath, dry cough and progressive dyspnea, and improves the curative effect. And the progress of RA-ILD can be effectively inhibited by reducing macrophage apoptosis, activating and proliferating myofibroblasts and inhibiting MMT.

Description

Technical Field

[0001] The present invention belongs to the technical field of drugs for treating complications of rheumatoid arthritis, and in particular relates to a traditional Chinese medicine composition for treating interstitial lung lesions of rheumatoid arthritis, and a preparation method and application thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that primarily affects peripheral joints. However, its lesions are not limited to joints; they can also cause visceral damage. Interstitial lung disease (ILD) is the most common manifestation of visceral involvement in RA. Rheumatoid arthritis-interstitial lung disease (RA-ILD) is often overlooked in its early stages due to its subtle symptoms. However, in its later stages, it can progress to pulmonary fibrosis, resulting in a poor prognosis and being a leading cause of mortality in RA patients. Studies have shown that 11% to 26% of RA patients develop ILD. The median survival for RA-ILD patients is 2.6 years, with a 9-year survival rate of only 39%. In recent years, the incidence and mortality of this disease have been increasing year by year, garnering significant attention from the medical community.

[0003] Drug treatments for RA-ILD mainly include immunosuppressants, glucocorticoids, biological agents, and anti-fibrotic drugs. These drugs all have varying degrees of adverse reactions and have limited effects on improving symptoms, failing to achieve ideal therapeutic effects. Summary of the Invention

[0004] To address the above technical issues, the present invention provides a traditional Chinese medicine composition for treating interstitial lung disease in rheumatoid arthritis, as well as its preparation method and application. This traditional Chinese medicine composition can significantly improve the lung function of patients with RA-ILD, alleviate RA symptoms, and significantly improve shortness of breath, dry cough, and progressive dyspnea, with proven efficacy.

[0005] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions: A first aspect of the present invention provides a traditional Chinese medicine composition for rheumatoid arthritis interstitial lung lesions, the raw materials of which include 8-12 parts of ginseng, 25-35 parts of astragalus, 25-35 parts of prepared rehmannia, 5-7 parts of schisandra, 8-12 parts of aster, 10-14 parts of morus white bark, 8-12 parts of angelica, 16-24 parts of eclipta, 25-35 parts of northern adenophora, 12-18 parts of tangerine peel and 5-7 parts of liquorice; the raw materials of the traditional Chinese medicine composition also include salvia miltiorrhiza and turmeric, when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis interstitial lung lesions with blood stasis constitution, the mass proportion of salvia miltiorrhiza is 16-24 parts, and the mass proportion of turmeric is 10-14 parts; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis interstitial lung lesions with non-blood stasis constitution, the mass proportion of salvia miltiorrhiza is 8-12 parts, and the mass proportion of turmeric is 7-9 parts.

[0006] Ginseng tastes sweet and slightly bitter, is slightly warm in nature, and enters the spleen and lung meridians. It has the effects of greatly replenishing vital energy, tonifying the spleen and lungs, calming the mind and improving intelligence, promoting fluid production and quenching thirst, strengthening the kidneys and promoting yang, and strengthening the body's resistance and dispelling evil. Astragalus is sweet in taste and slightly warm in nature. It enters the spleen and lung meridians and has the effects of strengthening the spleen and replenishing the middle, raising yang and lifting sunken, strengthening the body's defense and strengthening the exterior, promoting diuresis and reducing swelling, and expelling toxins and promoting tissue regeneration. Rehmannia root is sweet in taste and slightly warm in nature. It enters the liver and kidney meridians and has the effects of nourishing blood, tonifying yin, replenishing essence and filling marrow. Schisandra chinensis tastes sour and sweet, is warm in nature, and enters the lung, heart, and kidney meridians. It has the effects of astringing, strengthening qi, promoting fluid production, and nourishing the kidneys and calming the mind. Aster tastes bitter, sweet, and pungent, is warm in nature, and enters the lung meridian. It has the effects of moistening the lungs, relieving coughs, and reducing phlegm. Morus alba bark is sweet in taste and cold in nature. It enters the lung and spleen meridians and has the effects of clearing lung heat, resolving phlegm and relieving asthma. Angelica sinensis is sweet and spicy in taste, warm in nature, and enters the liver, heart, and spleen meridians. It has the effects of nourishing blood, regulating menstruation and relieving pain, promoting blood circulation, and moistening the intestines and promoting bowel movements. Eclipta prostrata is sweet and sour in nature, cold in nature, and enters the liver and kidney meridians. It has the effects of nourishing yin and kidney, cooling blood and stopping bleeding. Adenophora adenophora has a sweet and slightly bitter taste and a slightly cold nature. It enters the lung and stomach meridians and has the effects of nourishing yin, clearing the lungs, and benefiting the stomach and promoting fluid production. Danshen tastes bitter and is slightly cold in nature. It enters the heart and liver meridians and has the effects of promoting blood circulation and removing blood stasis, relieving menstruation and pain, clearing the heart and relieving restlessness, cooling blood and eliminating carbuncle. Turmeric tastes pungent and bitter, is warm in nature, and enters the liver and spleen meridians. It has the effects of promoting blood circulation and qi, relieving menstruation and pain, and promoting bile secretion and relieving jaundice. Tangerine peel tastes pungent and bitter, is warm in nature, and enters the lung and spleen meridians. It has the effects of dispelling cold and dampness, regulating qi and resolving phlegm. Licorice is sweet in taste and neutral in nature. It enters the heart, lung, spleen, and stomach meridians. It has the effects of tonifying the spleen and replenishing qi, clearing away heat and detoxifying, removing phlegm and relieving cough, relieving acute pain, and harmonizing the properties of other medicines.

[0007] This prescription primarily aims to replenish qi and nourish yin, while also promoting blood circulation and relieving numbness. Ginseng and astragalus membranaceus serve as the main ingredients, tonifying lung qi and strengthening the body's exterior. Rehmannia root, Aster tataricus, Polygonum multiflorum, and Adenophora australis serve as the auxiliary ingredients, replenishing blood and nourishing yin, moistening the lungs and resolving phlegm. Schisandra chinensis, Morus alba bark, Angelica sinensis, Salvia miltiorrhiza, Curcuma longa, and Tangerine peel are used as adjuvants to astringe the lungs, relieve asthma, resolve phlegm, and unclog the meridians. Raw licorice is used to balance the various herbs. The entire prescription harmonizes qi and blood, addressing both the symptoms and the root cause. It is suitable for lung bi syndromes characterized by both qi and yin deficiency and blood stasis in the meridians.

[0008] The Danshen and Turmeric in this prescription act as "regulatory drugs" for blood stasis. The dosage should be adjusted based on whether the patient has a blood stasis constitution. If the patient has a dark purple tongue and a deep, wiry pulse, this indicates a blood stasis constitution and requires increased dosages of Danshen and Turmeric, i.e., 6-24 parts Danshen and 10-14 parts Turmeric. If the patient does not have a blood stasis constitution, use 8-12 parts Danshen and 7-9 parts Turmeric.

[0009] There are many types of Chinese medicine, many of which have similar effects. However, only when they are properly combined can the efficacy of the Chinese medicine be maximized and the desired therapeutic effect achieved. For this prescription, each medicine is irreplaceable and cannot be replaced by other Chinese medicines with similar functions. The specific reasons are as follows: ① The main and auxiliary drugs determine the fundamental efficacy of the prescription and cannot be changed. Main Herbs (Ginseng and Astragalus): Ginseng greatly replenishes vital energy, while Astragalus replenishes qi and strengthens the exterior, forming a dual-tonifying structure of "vital qi and defensive qi." Substituting Codonopsis with similar efficacy would result in insufficient qi replenishment, while replacing it with American ginseng would be too cold, undermining the warming and tonic tone of the formula. Assistant herbs (Aster tataricus, Rehmannia glutinosa, Adenophora australis, and Eclipta prostrata): Rehmannia glutinosa nourishes kidney yin, Adenophora australis nourishes lung and stomach yin, and Eclipta prostrata tonifies liver and kidney yin and cools the blood. These three herbs address yin deficiency in the upper, middle, and lower burners. Substituting any one of them will result in less effective yin nourishment. For example, replacing Rehmannia glutinosa with Rehmannia glutinosa (from the same herbal source) will reduce its nourishing properties but weaken its ability to replenish true yin. Substituting it with Ophiopogon japonicus will negate its kidney-essence tonification.

[0010] ②Drug pairs with fixed compatibility experience cannot be separated Morus alba bark and Tangerine peel are a combination for expectorant: Morus alba bark moistens the lungs and clears heat, while Tangerine peel regulates qi and resolves phlegm. The two together form a closed loop of "clearing and resolving." Using Fritillaria thunbergii in place of Morus alba bark would negate its diuretic function. Schisandra chinensis and Angelica sinensis are a key combination for harmony: Schisandra chinensis's acidic properties astringe Qi, while Angelica sinensis's pungent properties disperse and activate blood circulation. The combination of the two, one astringent and one dispersing, prevents both stagnation caused by tonics and excessive blood circulation. Substituting Cornus officinalis for Schisandra chinensis loses its ability to promote fluid production; substituting Chuanxiong for Angelica sinensis results in an overly potent blood-clearing effect. The combination of turmeric and salvia miltiorrhiza: salvia miltiorrhiza cools blood, activates blood circulation and removes blood stasis, while turmeric warms yang, activates blood circulation and removes blood stasis. The combination of the two can activate blood circulation and remove blood stasis while being warm but not dry or hot, cool but not stagnant or congested. It can activate blood circulation without damaging it, and has the effect of activating blood circulation without consuming Qi.

[0011] ③Key drugs that play multiple regulatory roles and cannot be replaced The overall network structure of the medicinal properties and flavors in a prescription maintains a four-dimensional balance of Qi, Yin, Phlegm, and Stasis. The overall cold-warm ratio of the prescription is 5 cold: 4 warm: 3 neutral. Substituting a single medicinal flavor can alter the overall bias of the prescription. For example, replacing the neutral Aster with the warm Coltsfoot Flower would shift the prescription toward a warming and drying effect.

[0012] ④The irreplaceable special status of drug formulations Licorice: It not only harmonizes the various herbs, but modern pharmacological studies have shown that its glycyrrhizic acid component can reduce the potential hepatotoxicity of Aster and Morus alba in the formula. Schisandra chinensis: Modern pharmacological research shows that its lignan components can regulate both the central nervous system (calming the nerves) and the respiratory system (antitussive), and there is no equivalent substitute.

[0013] Therefore, the Chinese medicine in this prescription cannot be easily replaced with other Chinese medicines with similar effects, otherwise it will have a very significant impact on the efficacy of the original prescription, and may even greatly reduce the efficacy of the entire prescription or cause a drastic change.

[0014] Macrophage-myofibroblast transition (MMT)-induced myofibroblast activation is the primary cause of RA-ILD disease progression, and the immune-inflammatory cascade is the primary driver of MMT. Animal experiments have demonstrated that this traditional Chinese medicine composition can significantly downregulate the levels of inflammatory and fibrotic factors in RA-ILD rats, improve the tissue structure and cell morphology of their feet and lungs, effectively prevent macrophage apoptosis, reduce myofibroblast activation and proliferation, and reduce the number of MMT cells co-expressing CD86+α-SMA. Clinical trials have also demonstrated that the traditional Chinese medicine composition provided by the present invention can significantly improve lung collagen deposition in RA-ILD patients, reduce the swelling index and tenderness index of rheumatoid arthritis, lower the DAS28 score, and significantly improve symptoms of shortness of breath, dry cough, and progressive dyspnea, with a proven efficacy. Therefore, this traditional Chinese medicine composition is useful for treating RA-ILD.

[0015] Preferably, the raw materials of the traditional Chinese medicine composition include 9-11 parts of ginseng, 27-33 parts of astragalus, 27-33 parts of rehmannia root, 5.5-6.5 parts of schisandra, 9-11 parts of aster, 11-13 parts of mulberry bark, 9-11 parts of angelica, 18-22 parts of eclipta, 27-33 parts of northern adenophora, 13.5-16.5 parts of tangerine peel and 5.5-6.5 parts of liquorice in proportion by mass; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions with blood stasis constitution, the mass proportion of salvia miltiorrhiza is 18-22 parts, and the mass proportion of turmeric is 11-13 parts; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions with non-blood stasis constitution, the mass proportion of salvia miltiorrhiza is 9-11 parts, and the mass proportion of turmeric is 7.5-8.5 parts.

[0016] Preferably, the raw materials of the traditional Chinese medicine composition include 10 parts of ginseng, 30 parts of astragalus, 30 parts of prepared rehmannia, 6 parts of schisandra, 10 parts of aster, 12 parts of morus bark, 10 parts of angelica, 20 parts of eclipta, 30 parts of northern adenophora, 15 parts of tangerine peel and 6 parts of liquorice in proportion by mass; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions with blood stasis constitution, the mass proportion of salvia miltiorrhiza is 20 parts and the mass proportion of turmeric is 12 parts; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions with non-blood stasis constitution, the mass proportion of salvia miltiorrhiza is 10 parts and the mass proportion of turmeric is 8 parts.

[0017] In clinical application, the weight of each portion of the composition is 0.8-1.2 g.

[0018] A second aspect of the present invention provides a method for preparing the aforementioned traditional Chinese medicine composition, comprising extracting the raw materials with water. The resulting extract can be taken directly, concentrated, dried, and stored for immediate use. The extract, its concentrate, or dried product can also be combined with pharmaceutically acceptable excipients to form a conventional formulation for use.

[0019] Preferably, the extraction method is decoction extraction.

[0020] More preferably, the extraction is performed 2 to 3 times, the mass of the water in each extraction is 3 to 5 times the mass of the raw material, the extraction time is 25 to 35 minutes, and the extracts obtained from each extraction are combined.

[0021] More preferably, the extraction is performed twice, with each extraction lasting 30 minutes.

[0022] The third aspect of the present invention provides the use of the above-mentioned traditional Chinese medicine composition or the traditional Chinese medicine composition prepared according to the above-mentioned preparation method in the preparation of a drug for treating interstitial lung lesions caused by rheumatoid arthritis.

[0023] Preferably, the drug is an oral preparation, including but not limited to oral liquid, powder, granules, capsules, tablets, etc.

[0024] Preferably, the medicine further comprises a pharmaceutically acceptable excipient. The above-mentioned Chinese herbal extract is extracted and then mixed with the excipient to prepare a corresponding conventional oral preparation.

[0025] The beneficial effects of the present invention are as follows: the Chinese medicine composition provided by the present invention harmonizes qi and blood, takes into account both the symptoms and the root cause, and is suitable for lung bi, qi and yin deficiency, and blood stasis syndrome. For patients with RA-ILD, the Chinese medicine composition can significantly alleviate the symptoms of rheumatoid arthritis, improve collagen deposition in lung tissue, and reduce the symptom scores of shortness of breath, dry cough, and progressive dyspnea in RA-ILD. For RA-ILD rats, the Chinese medicine composition can downregulate the level of pro-fibrotic factors, regulate immune inflammation, reduce macrophage apoptosis and myofibroblast activation and proliferation, inhibit MMT, and thus effectively inhibit the progression of RA-ILD. The Chinese medicine composition provides a new option for the drug treatment of RA-ILD and can be promoted and used in clinical applications to benefit more patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The deposition of type I collagen (COL-1) and type III collagen (COL-3) in the lung tissues of each group of patients in Example 16; Figure 2 DAS28 scores of rheumatoid arthritis symptoms in each group of patients in Example 16; * indicates P < 0.05; Figure 3 is the RA-ILD symptom score for each group of patients in Example 16; Figure 4 A timeline for preparing the RA-ILD rat model in Example 17; Figure 5 The serum immune inflammatory factor levels of RA-ILD rats in Example 17; * indicates P < 0.05; Figure 6 Fibrosis factor levels in RA-ILD rats in Example 17; * indicates P < 0.05; Figure 7 The structure and cell morphology of the foot and lung of RA-ILD rats in Example 17; Figure 8 This is the macrophage apoptosis in RA-ILD rats in Example 17; Figure 9 Activation of lung myofibroblasts in RA-ILD rats in Example 17; Figure 10 This is the situation of CD86+α-SMA co-expressing MMT cells in RA-ILD rats in Example 17. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0028] The ginseng, astragalus, rehmannia root, schisandra chinensis, aster, mulberry bark, angelica, eclipta prostrata, adenophora, salvia miltiorrhiza, turmeric, tangerine peel and licorice used in the following examples all comply with the relevant provisions under the various medicinal materials in the main text of the Chinese Pharmacopoeia (2020 edition).

[0029] Unless otherwise specified, the raw materials and reagents used in the following examples were obtained from commercial sources.

[0030] Example 1 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with blood stasis constitution. The raw materials of each dose are 10g of ginseng, 30g of astragalus, 30g of prepared rehmannia, 6g of schisandra, 10g of aster, 12g of mulberry bark, 10g of angelica, 20g of Ecliptae, 30g of northern adenophora, 20g of salvia miltiorrhiza, 12g of turmeric, 15g of tangerine peel, and 6g of liquorice.

[0031] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 4 times the amount of water, boil over high heat, then simmer over low heat for 30 minutes, filter, add 4 times the amount of water to the residue, boil over high heat, then simmer over low heat for 30 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0032] Example 2 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with blood stasis constitution. The raw materials of each dose are 9g of ginseng, 27g of astragalus, 27g of prepared rehmannia, 5.5g of schisandra, 9g of aster, 11g of mulberry bark, 9g of angelica, 18g of Eclipta prostrata, 27g of northern adenophora, 18g of salvia miltiorrhiza, 11g of turmeric, 13.5g of tangerine peel, and 5.5g of liquorice.

[0033] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 4 times the amount of water, boil over high heat, then simmer over low heat for 30 minutes, filter, add 4 times the amount of water to the residue, boil over high heat, then simmer over low heat for 30 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0034] Example 3 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with blood stasis constitution. The raw materials of each dose are 11g of ginseng, 33g of astragalus, 33g of prepared rehmannia, 6.5g of schisandra, 11g of aster, 13g of mulberry bark, 11g of angelica, 22g of Ecliptae, 33g of northern adenophora, 22g of salvia miltiorrhiza, 13g of turmeric, 16.5g of tangerine peel, and 6.5g of licorice.

[0035] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 4 times the amount of water, boil over high heat, then simmer over low heat for 30 minutes, filter, add 4 times the amount of water to the residue, boil over high heat, then simmer over low heat for 30 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0036] Example 4 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with blood stasis constitution. The raw materials of each dose are 8g of ginseng, 25g of astragalus, 25g of prepared rehmannia, 5g of schisandra, 8g of aster, 10g of mulberry bark, 8g of angelica, 16g of Eclipta prostrata, 25g of northern adenophora, 16g of salvia miltiorrhiza, 10g of turmeric, 12g of tangerine peel, and 5g of liquorice.

[0037] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 5 times the amount of water, boil over high heat, then simmer over low heat for 35 minutes, filter, add 3 times the amount of water to the residue, boil over high heat, then simmer over low heat for 25 minutes, filter, add 3 times the amount of water to the residue again, boil over high heat, then simmer over low heat for 25 minutes, filter, and combine the filtrates obtained from the three decoctions to obtain the product.

[0038] Example 5 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with blood stasis constitution. The raw materials of each dose are 12g of ginseng, 35g of astragalus, 35g of prepared rehmannia, 7g of schisandra, 12g of aster, 14g of mulberry bark, 12g of angelica, 24g of Ecliptae, 35g of northern adenophora, 24g of salvia miltiorrhiza, 14g of turmeric, 18g of tangerine peel, and 7g of liquorice.

[0039] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 5 times the amount of water, boil over high heat, then simmer over low heat for 35 minutes, filter, add 3 times the amount of water to the residue, boil over high heat, then simmer over low heat for 25 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0040] Example 6 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with non-blood stasis constitution. The raw materials of each dose are 10g of ginseng, 30g of astragalus, 30g of prepared rehmannia, 6g of schisandra, 10g of aster, 12g of mulberry bark, 10g of angelica, 20g of Ecliptae, 30g of northern adenophora, 10g of salvia miltiorrhiza, 8g of turmeric, 15g of tangerine peel, and 6g of liquorice.

[0041] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 4 times the amount of water, boil over high heat, then simmer over low heat for 30 minutes, filter, add 4 times the amount of water to the residue, boil over high heat, then simmer over low heat for 30 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0042] Example 7 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with non-blood stasis constitution. The raw materials of each dose are 9g of ginseng, 27g of astragalus, 27g of prepared rehmannia, 5.5g of schisandra, 9g of aster, 11g of mulberry bark, 9g of angelica, 18g of Eclipta prostrata, 27g of northern adenophora, 9g of salvia miltiorrhiza, 7.5g of turmeric, 13.5g of tangerine peel, and 5.5g of liquorice.

[0043] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 4 times the amount of water, boil over high heat, then simmer over low heat for 30 minutes, filter, add 4 times the amount of water to the residue, boil over high heat, then simmer over low heat for 30 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0044] Example 8 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with non-blood stasis constitution. The raw materials of each dose are 11g of ginseng, 33g of astragalus, 33g of prepared rehmannia, 6.5g of schisandra, 11g of aster, 13g of mulberry bark, 11g of angelica, 22g of Ecliptae, 33g of northern adenophora, 11g of salvia miltiorrhiza, 8.5g of turmeric, 16.5g of tangerine peel, and 6.5g of licorice.

[0045] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 4 times the amount of water, boil over high heat, then simmer over low heat for 30 minutes, filter, add 4 times the amount of water to the residue, boil over high heat, then simmer over low heat for 30 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0046] Example 9 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with non-blood stasis constitution. The raw materials of each dose are 8g of ginseng, 25g of astragalus, 25g of prepared rehmannia, 5g of schisandra, 8g of aster, 10g of mulberry bark, 8g of angelica, 16g of Eclipta prostrata, 25g of northern adenophora, 8g of salvia miltiorrhiza, 7g of turmeric, 12g of tangerine peel, and 5g of licorice.

[0047] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 5 times the amount of water, boil over high heat, then simmer over low heat for 35 minutes, filter, add 3 times the amount of water to the residue, boil over high heat, then simmer over low heat for 25 minutes, filter, add 3 times the amount of water to the residue again, boil over high heat, then simmer over low heat for 25 minutes, filter, and combine the filtrates obtained from the three decoctions to obtain the product.

[0048] Example 10 The embodiment of the present invention provides a traditional Chinese medicine composition for patients with RA-ILD with non-blood stasis constitution. The raw materials of each dose are 12g of ginseng, 35g of astragalus, 35g of prepared rehmannia, 7g of schisandra, 12g of aster, 14g of mulberry bark, 12g of angelica, 24g of Eclipta prostrata, 35g of northern adenophora, 12g of salvia miltiorrhiza, 9g of turmeric, 18g of tangerine peel, and 7g of liquorice.

[0049] The preparation method is as follows: take the above-mentioned Chinese herbal medicine slices, first add 5 times the amount of water, boil over high heat, then simmer over low heat for 35 minutes, filter, add 3 times the amount of water to the residue, boil over high heat, then simmer over low heat for 25 minutes, filter, and combine the filtrates obtained from the two decoctions to obtain the product.

[0050] Example 11 The embodiment of the present invention provides a Chinese medicine oral liquid for RA-ILD, and the preparation method thereof is as follows: dissolving the Chinese medicine composition of any one of Examples 1 to 10 in water, adding stevioside, tragacanth gum and potassium sorbate according to the conventional amount of excipients and actual needs, mixing and filling.

[0051] Stevioside can be replaced by other pharmaceutically acceptable flavoring agents, tragacanth gum can be replaced by other pharmaceutically acceptable thickeners, and potassium sorbate can be replaced by other pharmaceutically acceptable preservatives.

[0052] Example 12 The present invention provides a traditional Chinese medicine powder for RA-ILD. The preparation method of the traditional Chinese medicine powder is as follows: the traditional Chinese medicine composition of any one of Examples 1 to 10 is concentrated at 50-60° C., dried, and then crushed; aspartame or sucralose is added according to the conventional amount of excipients and actual needs; the mixture is mixed evenly and then packaged to obtain the powder.

[0053] Aspartame or sucralose may be replaced with other pharmaceutically acceptable flavoring agents.

[0054] Example 13 An embodiment of the present invention provides a traditional Chinese medicine granule for RA-ILD, and the preparation method thereof is as follows: the traditional Chinese medicine composition of any one of Examples 1 to 10 is concentrated and dried at 50-60° C., crushed, and pregelatinized starch and dextrin are added according to the conventional amount of excipients and actual needs, mixed evenly, and purified water is added to prepare a soft material, granulated into 16-18 mesh, dried at 50-60° C., and then granulated into 18-20 mesh, and packaged to obtain the product.

[0055] Pregelatinized starch and dextrin can be replaced by other pharmaceutically acceptable granule excipients. Flavoring agents and other excipients can also be added to the granules according to clinical needs.

[0056] Example 14 An embodiment of the present invention provides a traditional Chinese medicine hard capsule for RA-ILD. The preparation method thereof is as follows: the traditional Chinese medicine composition of any one of Examples 1 to 10 is concentrated and dried at 50-60° C., crushed, and then pregelatinized starch, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose are added according to the conventional amount of excipients and actual needs, mixed, and granulated in one step using a 3% HPMC aqueous solution to 22-24 mesh granules, 1% magnesium stearate is added, and the mixture is evenly mixed and filled into a hard capsule shell to obtain the product.

[0057] Pregelatinized starch and microcrystalline cellulose can be replaced by other pharmaceutically acceptable fillers, low-substituted hydroxypropyl cellulose can be replaced by other pharmaceutically acceptable disintegrants, 3% HPMC aqueous solution can be replaced by other pharmaceutically acceptable binders, and magnesium stearate can be replaced by other pharmaceutically acceptable glidants.

[0058] Example 15 An embodiment of the present invention provides a traditional Chinese medicine tablet for RA-ILD, and the preparation method thereof is as follows: the traditional Chinese medicine composition of any one of Examples 1 to 10 is concentrated and dried at 50-60° C., and after crushing, pregelatinized starch, microcrystalline cellulose, and cross-linked polyvinylpyrrolidone are added according to the conventional amount of excipients and actual needs, mixed, and a soft material is prepared using 3% sodium carboxymethyl cellulose as a binder, granulated into 20-22 mesh, dried at 50-60° C., and granulated into 22-24 mesh, and 2% cross-linked polyvinylpyrrolidone, 1% magnesium stearate, and 0.5% talc are added, mixed, and tableted to obtain the product.

[0059] Pregelatinized starch and microcrystalline cellulose can be replaced with other pharmaceutically acceptable fillers, crospovidone can be replaced with other pharmaceutically acceptable disintegrants, and magnesium stearate and talc can be replaced with other pharmaceutically acceptable lubricants and glidants. The tablets can also be film-coated or sugar-coated according to clinical needs.

[0060] Example 16 The examples of the present invention provide retrospective application data of the traditional Chinese medicine composition obtained in Example 1 in improving the clinical symptoms of RA-ILD.

[0061] 1. Grouping and administration method The clinical medication status and clinical efficacy data of RA-ILD patients admitted to the First Affiliated Hospital of Henan University of Traditional Chinese Medicine from January 2024 to March 2025 were collected. According to the actual clinical medication method of the patients, RA-ILD patients with blood stasis constitution who took the Chinese medicine composition of Example 1 (recorded as the Chinese medicine group) and RA-ILD patients with blood stasis constitution who took prednisone acetate tablets (recorded as the control group) were selected for data comparison. There were 33 people in each group, and the medication cycle was 14 days. There was no significant difference in the baseline levels of age, gender, etc. of the patients. Dosage of each group: ① Traditional Chinese medicine group: took the traditional Chinese medicine composition of Example 1, 1 dose per day, twice a day, once in the morning and once in the evening; ②Control group: 1 tablet of prednisone acetate (10 mg), taken orally once a day.

[0062] 2. Testing indicators: (1) IHC staining to detect lung structure and cell morphology Lung tissue samples (1-3 mm) obtained under bronchoscopy were subjected to IHC staining to observe the deposition of type I collagen (COL-1) and type III collagen (COL-3) in lung tissue.

[0063] (2) Rheumatoid arthritis symptom score, RA-ILD symptom score The rheumatoid arthritis symptom score (DAS28) and the RA-ILD TCM clinical symptom score (Table 1, the scoring criteria were formulated in accordance with the Guiding Principles for Clinical Research of New Chinese Medicines) were used to score the symptoms of RA-ILD patients with blood stasis constitution in the TCM group before and after treatment to evaluate the clinical efficacy.

[0064] Table 1 Traditional Chinese Medicine clinical symptom scoring table for RA-ILD

[0065] 3. Research results: like Figures 1-3 As shown, the Chinese medicine composition of Example 1 can significantly improve lung tissue collagen deposition ( Figure 1 ), reduce the swelling index and tenderness index of rheumatoid arthritis, and reduce the DAS28 score ( Figure 2 ), significantly improving the symptoms of shortness of breath, dry cough, and progressive dyspnea in RA-ILD, with a definite therapeutic effect ( Figure 3 ).

[0066] Example 17 The present invention provides the efficacy and mechanism of the Chinese medicine composition obtained in Example 1 in improving RA-ILD.

[0067] 1. Modeling method and grouping: (1) Construction of RA-ILD rat model Eight-week-old female SD rats were housed in a pathogen-free graded barrier system at a temperature of 22 ± 1°C, a relative humidity of 50 ± 5%, and a 12 h / 12 ​​h light / dark cycle (light on from 7:00 to 19:00). They were given free access to irradiated sterilized standard rodent chow (purchased from SPF (Beijing) Biotechnology Co., Ltd., SPF-F02-002, with a main component of crude protein ≥ 20%, crude fat ≥ 4%, and an irradiation dose ≥ 25 kGy).

[0068] Under sterile conditions, RA was induced using a collagen-induced arthritis (CIA) model: 10 mg of type II collagen was fully dissolved in 0.1 mol / L glacial acetic acid to a concentration of 4 mg / mL, and mixed with an equal volume of complete Freund's adjuvant to prepare a type II collagen emulsion. 0.5 mL of type II collagen emulsion was injected intradermally at the base of the tail of each rat, and on the 7th day, 0.5 mL of type II collagen emulsion was injected in the same manner to induce RA. On the 8th day, interstitial lung disease was induced by intratracheal instillation of bleomycin (BLM) 1.5 U / kg / time. On the 28th day after administration, the RA-ILD model was successfully established, and the normal control group was given a one-time nasal instillation of 300 μL of normal saline. The timeline of the preparation of the RA-ILD rat model is shown in Figure 4 .

[0069] (2) Grouping and dosing of experimental animals The experimental animals were divided into groups, with 10 animals in each group. Drugs or pure water intervention were given according to different groups. The specific groups, drug administration time and dosage are shown in Table 2.

[0070] Table 2 Summary of administration time and dosage in RA-ILD rats

[0071] Note: The Chinese medicine composition is the Chinese medicine composition prepared in Example 1; 1-30 days after modeling is the rat drug gavage cycle, and the rat dosage is converted according to the dosage for a 60 kg adult.

[0072] 2. Testing indicators: (1) The levels of immune inflammatory factors (TNF-α, IL-6, IL-7) and pro-fibrotic factors (CTGF, TGF-β, MMP-1, MMP-7) in rat serum were detected by ELISA.

[0073] (2) Detection of the structure and cell morphology of rat feet and lungs by HE staining Foot and lung tissues from all groups of RA-ILD rats were fixed with 4% paraformaldehyde, embedded in paraffin, and cut into 5-µm-thick sections. After dewaxing and permeabilization, HE staining was performed to examine the structure and cellular morphology of the foot and lung.

[0074] (3) Masson staining was used to examine the structure and cell morphology of rat lungs.

[0075] Lung tissues from RA-ILD rats in each group were fixed with 4% paraformaldehyde, embedded in paraffin, and cut into 5-µm-thick sections. After dewaxing and permeabilization, the sections were stained with Masson's staining to examine lung structure and cellular morphology.

[0076] (4) Detection of pulmonary myofibroblast activation by BrdU staining.

[0077] Lung tissues from RA-ILD rats in each group were fixed with 4% paraformaldehyde, embedded in paraffin, and cut into 5-µm-thick sections. After dewaxing and permeabilization, BrdE staining was performed to detect the activation of pulmonary myofibroblasts.

[0078] (5) Fluorescence tunnel detection of apoptosis of lung macrophages.

[0079] Lung tissues from RA-ILD rats in each group were fixed with 4% paraformaldehyde, embedded in paraffin, and cut into 5-µm-thick sections. After dewaxing and permeabilization, fluorescent tunnel staining was performed to detect apoptosis of pulmonary macrophages.

[0080] (6) Number of MMT cells co-expressing CD86+α-SMA by immunofluorescence staining Double fluorescent immunostaining was used to specifically label lung tissue sections with CD86 and α-SMA. Cells co-expressing CD86+α-SMA+ were observed and counted under a fluorescence microscope. Cell counting was then performed under multiple fields of view to calculate the number of co-expressing cells.

[0081] 3. Research results: like Figures 5 to 7 As shown, the Chinese medicine composition prepared in Example 1 can significantly downregulate the levels of inflammatory factors in RA-ILD rats ( Figure 5 ) and profibrotic factor levels ( Figure 6 ), improving the tissue structure and cell morphology of the feet and lungs of RA-ILD rats ( Figure 7 ).

[0082] like Figures 8 to 10 As shown, the Chinese medicine composition prepared in Example 1 can prevent macrophage apoptosis ( Figure 8 ), reducing myofibroblast activation and proliferation ( Figure 9 ), reducing the number of MMT cells co-expressing CD86+α-SMA ( Figure 10 ).

[0083] The above results show that the Chinese medicine composition prepared in Example 1 has a definite therapeutic effect in treating RA-ILD.

[0084] 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 or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A Chinese medicine composition for treating interstitial lung lesions in rheumatoid arthritis, characterized in that: The raw materials of the traditional Chinese medicine composition include 8-12 parts of ginseng, 25-35 parts of astragalus, 25-35 parts of prepared rehmannia, 5-7 parts of schisandra, 8-12 parts of aster, 10-14 parts of morus bark, 8-12 parts of angelica, 16-24 parts of eclipta, 25-35 parts of northern adenophora, 12-18 parts of tangerine peel and 5-7 parts of liquorice in proportions by mass; the raw materials of the traditional Chinese medicine composition also include salvia miltiorrhiza and turmeric. When the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions with blood stasis constitution, the mass proportion of the salvia miltiorrhiza is 16-24 parts, and the mass proportion of the turmeric is 10-14 parts; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions with non-blood stasis constitution, the mass proportion of the salvia miltiorrhiza is 8-12 parts, and the mass proportion of the turmeric is 7-9 parts.

2. The Chinese medicine composition according to claim 1, characterized in that The raw materials of the traditional Chinese medicine composition include 9-11 parts of ginseng, 27-33 parts of astragalus, 27-33 parts of rehmannia root, 5.5-6.5 parts of schisandra chinensis, 9-11 parts of aster, 11-13 parts of morus bark, 9-11 parts of angelica, 18-22 parts of eclipta, 27-33 parts of northern adenophora, 13.5-16.5 parts of tangerine peel and 5.5-6.5 parts of liquorice in proportions by mass; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions of blood stasis constitution, the mass proportions of salvia miltiorrhiza are 18-22 parts, and the mass proportions of turmeric are 11-13 parts; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions of non-blood stasis constitution, the mass proportions of salvia miltiorrhiza are 9-11 parts, and the mass proportions of turmeric are 7.5-8.5 parts.

3. The Chinese medicine composition according to claim 2, characterized in that The raw materials of the traditional Chinese medicine composition include 10 parts of ginseng, 30 parts of astragalus, 30 parts of prepared rehmannia, 6 parts of schisandra, 10 parts of aster, 12 parts of mulberry bark, 10 parts of angelica, 20 parts of eclipta, 30 parts of northern adenophora, 15 parts of tangerine peel and 6 parts of liquorice in proportion by mass; when the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions of blood stasis constitution, the mass proportion of salvia miltiorrhiza is 20 parts and the mass proportion of turmeric is 12 parts; When the traditional Chinese medicine composition is used for patients with rheumatoid arthritis and interstitial lung lesions of non-blood stasis constitution, the mass parts of the salvia miltiorrhiza is 10 parts, and the mass parts of the turmeric is 8 parts.

4. The method for preparing the Chinese medicine composition according to any one of claims 1 to 3, characterized in that: The raw material was extracted with water.

5. The preparation method according to claim 4, characterized in that The extraction method is decoction extraction.

6. The preparation method according to claim 5, characterized in that The extraction was performed 2 to 3 times, with the mass of the water in each extraction being 3 to 5 times the mass of the raw material, and the extraction time for each extraction being 25 to 35 minutes. The extracts obtained from each extraction were combined.

7. The preparation method according to claim 6, characterized in that Extract twice, each time for 30 minutes.

8. Use of the Chinese medicine composition according to any one of claims 1 to 3 or the Chinese medicine composition prepared by the preparation method according to any one of claims 4 to 7 in the preparation of a medicament for treating interstitial lung lesions caused by rheumatoid arthritis.

9. The use according to claim 8, characterized in that The medicine is an oral preparation.

10. The use according to claim 8, characterized in that The medicament further includes a pharmaceutically acceptable excipient.

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