Traditional Chinese medicine composition for treating RA-ILD, extract and preparation method thereof

Abstract

The invention provides a composition for treating rheumatoid arthritis complicated with interstitial lung disease (RA-ILD). Specifically, the invention provides a traditional Chinese medicine composition which is composed of the following raw medicinal materials or extracts thereof: raw astragalus membranaceus, hairyvein agrimony, thunberg fritillary bulb, ginger processed pinellia, curcuma zedoary, caulis sinomenii and gentiana macrophylla. The composition disclosed by the invention can be used for improving the symptoms of arthritis combined with interstitial lung diseases, remarkably relieving lung interstitial inflammation and fibrosis and improving the treatment effect.

Description

Technical Field

[0001] The present invention relates to the field of traditional Chinese medicine treatment, and in particular to a traditional Chinese medicine composition and extract for treating RA-ILD and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by progressive joint destruction. RA-associated interstitial lung disease (RA-ILD) is a severe extra-articular manifestation of RA. 10% of RA patients experience symptoms of ILD, and survival is low.

[0003] The pathogenesis of RA-ILD is complex. Numerous studies have consistently confirmed that age, smoking, and dust are causative factors. Clinically, dry cough, chest tightness, and shortness of breath are the primary symptoms. As the disease progresses, diffuse inflammation develops in the lungs, accompanied by impaired gas exchange and progressive alveolar septal fibrosis. Currently, there is no clear clinical treatment plan. Treatment of RA-ILD primarily involves treating arthritis while simultaneously alleviating lung inflammation to prevent acute exacerbations. Glucocorticoids, immunosuppressants, and antirheumatic drugs are used to treat RA, and nintedanib is used to treat pulmonary fibrosis.

[0004] Therefore, there is an urgent need to develop safer and more effective drugs to treat RA-ILD. Summary of the Invention

[0005] The present invention aims to provide a safe and effective drug for treating RA-ILD, and specifically designs a traditional Chinese medicine composition, an extract and a preparation method thereof for treating RA-ILD.

[0006] In a first aspect of the present invention, a traditional Chinese medicine composition is provided, which is composed of the following raw medicinal materials or their extracts: raw astragalus, herb agrimony, fritillaria thunbergii, pinellia ternata, zedoaria, sinomenine, and gentiana macrophylla.

[0007] In another preferred embodiment, the raw medicinal materials include fresh medicinal materials, partially dried medicinal materials, dried medicinal materials or a combination thereof.

[0008] In another preferred embodiment, when the composition comprises raw medicinal materials, the weight portion thereof is calculated based on the dry weight of the corresponding raw medicinal materials.

[0009] In another preferred embodiment, when the composition comprises extracts of raw medicinal materials, the amount of the extracts is calculated based on the dry weight of the corresponding raw medicinal materials.

[0010] In another preferred embodiment, the extract includes: a water extract, an alcohol extract, an aqueous solvent extract, a carbon dioxide supercritical extract or an effective ingredient, or a combination thereof. Preferably, the extract is a water extract or an alcohol extract.

[0011] In another preferred embodiment, the alcohol includes: C1-C6 alcohol, such as methanol, ethanol, propanol, or a combination thereof.

[0012] In another preferred embodiment, the active ingredient includes a single ingredient or a mixed ingredient.

[0013] In another preferred embodiment, the Chinese medicine composition is composed of the following raw medicinal materials or their extracts:

[0014] 2-70 parts by weight of raw astragalus (preferably 4-50 parts by weight, more preferably 10-50 parts by weight, for example 10, 15, 20, 25, 30, 40, 50);

[0015] 2-50 parts by weight of Curcuma zedoaria (preferably 4-30 parts by weight, more preferably 10-30 parts by weight, for example 10, 15, 20, 25, 30);

[0016] 2-50 parts by weight of Fritillaria thunbergii (preferably 4-30 parts by weight, more preferably 5-20 parts by weight, for example 10, 15, 20);

[0017] 2-50 parts by weight of Zingiber officinale (preferably 4-30 parts by weight, more preferably 5-20 parts by weight, for example 10, 15, 20);

[0018] Gentiana macrophylla 2-50 parts by weight (preferably 4-30 parts by weight, more preferably 5-20 parts by weight, for example 10, 15, 20, 25);

[0019] 2-50 parts by weight of Sinomenium sinensis (preferably 4-30 parts by weight, more preferably 10-30 parts by weight, for example 10, 15, 20, 25, 30);

[0020] Agrimony 2-50 parts by weight (preferably 4-30 parts by weight, more preferably 10-30 parts by weight, for example 10, 15, 20, 25, 30).

[0021] In another preferred embodiment, the Chinese medicine composition is composed of the following raw medicinal materials or their extracts:

[0022] 4-50 parts by weight of raw astragalus;

[0023] 4-30 parts by weight of Curcuma zedoaria;

[0024] 4-30 parts by weight of Fritillaria thunbergii;

[0025] 4-30 parts by weight of Zingiber officinale;

[0026] Gentiana macrophylla 4-30 parts by weight;

[0027] 4-30 parts by weight of Sinomenium sinomenium;

[0028] 4-30 parts by weight of Agrimony Root.

[0029] In another preferred embodiment, the Chinese medicine composition is composed of the following raw medicinal materials or their extracts:

[0030] 10-50 parts by weight of raw astragalus;

[0031] 10-30 parts by weight of Curcuma zedoaria;

[0032] 5-20 parts by weight of Fritillaria thunbergii;

[0033] 5-20 parts by weight of Zingiber officinale;

[0034] Gentiana macrophylla 5-20 parts by weight;

[0035] 10-30 parts by weight of Sinomenium sinomenium;

[0036] 10-30 parts by weight of Agrimony Root.

[0037] In another preferred example, in the traditional Chinese medicine composition, the weight ratio of Curcuma zedoaria, Fritillaria thunbergii, Pinellia ternata, Gentiana macrophylla, Caulis Sinomenii and Herba Agrimoniae is (0.5-1.2):(0.5-1.2):(0.5-1.2):(0.5-1.2):(0.5-1.2):(0.5-1.2), preferably 1:1:(0.7-1):(0.7-1):1:1.

[0038] In another preferred example, in the traditional Chinese medicine composition, the weight ratio of raw astragalus, zedoaria, fritillaria thunbergii, pinellia ternata, gentiana macrophylla, sinomenine hydropiper, and agrimony is (1.5-2.5): (0.5-1.2): (0.5-1.2): (0.5-1.2): (0.5-1.2): (0.5-1.2), preferably 2:1:1: (0.7-1): (0.7-1): 1:1.

[0039] In another preferred example, the Chinese medicine composition is composed of the following raw medicinal materials or their extracts: 18 grams of raw astragalus, 15 grams of zedoaria, 12 grams of thunbergia, 9 grams of ginger pinellia, 9 grams of gentiana, 12 grams of Sinomenium sinomenium, and 15 grams of agrimony.

[0040] In another preferred example, the Chinese medicine composition is composed of the following raw medicinal materials or their extracts: 30 grams of raw astragalus, 15 grams of zedoary zedoary, 15 grams of thunbergia thunbergii, 9 grams of pinellia ternata, 9 grams of gentiana macrophylla, 12 grams of sinomenine, and 12 grams of agrimony.

[0041] In the second aspect of the present invention, a Chinese medicine composition extractant is provided, wherein the extractant is prepared by extracting the Chinese medicine composition described in the first aspect of the present invention, wherein the extraction solvent of the extractant is selected from the following group: water and ethanol.

[0042] In another preferred embodiment, the solid-liquid ratio of the traditional Chinese medicine composition and the extraction solvent is 1:6-20, calculated by mass ratio, for example, 8, 10, or 14.

[0043] In another preferred embodiment, the extractant includes an extractant with unadjusted (or unchanged) concentration, a concentrated extractant, and a diluted extractant.

[0044] In another preferred embodiment, the extractant is a decoction or extract of the traditional Chinese medicine composition.

[0045] In another preferred embodiment, the extractant is a concentrated decoction or extract.

[0046] In another preferred embodiment, the relative density of the extract is 1-1.5, preferably 1-1.25 or 1.4-1.5.

[0047] In the third aspect of the present invention, a method for preparing the Chinese medicine composition according to the first aspect of the present invention or the extractant of the Chinese medicine composition according to the second aspect of the present invention is provided.

[0048] i) comprising the steps of:

[0049] a1) providing raw medicinal materials, wherein the raw medicinal materials are as described in the first aspect;

[0050] b1) mixing the raw medicinal materials with water, decocting the mixture, and filtering the mixture to obtain a first decoction;

[0051] c1) concentrating the first decoction obtained in step b1) to obtain a first extract;

[0052] d1) mixing the first extract obtained in step c1) with the alcohol solution, allowing the mixture to stand, and concentrating the mixture a second time to obtain a second extract;

[0053] In another preferred embodiment, in the step b1), the amount of water added is 18-30 times the weight of the raw material.

[0054] In another preferred embodiment, in the step b1), water 12-16 times the mass of the raw medicinal material is first added, decocted, and then water 6-15 times the mass of the raw medicinal material is added, and filtered to obtain the first decoction.

[0055] In another preferred embodiment, in the step d1), after mixing with the alcohol solution, the alcohol concentration of the obtained solution is 50-80% (v / v).

[0056] Alternatively, ii) comprises the steps of:

[0057] a2) providing raw medicinal materials, wherein the raw medicinal materials are as described in the first aspect;

[0058] b2) mixing the raw medicinal material with the alcohol solution, decocting the mixture, and filtering to obtain a second decoction;

[0059] c2) concentrating the second decoction obtained in step b2) to obtain a third extract;

[0060] In another preferred embodiment, in the step b2), the alcohol solution is 50-90% (v / v).

[0061] In another preferred embodiment, in the step b2), the amount of the alcohol solution added is 8-10 times the mass ratio of the raw medicinal material.

[0062] In another preferred embodiment, in the step b2), the decocting times are 2-3 times.

[0063] In another preferred embodiment, in the step b2), the decocting time is 1-3 hours each time.

[0064] Alternatively, iii) comprises the steps of:

[0065] a3) providing raw medicinal materials, wherein the raw medicinal materials are as described in the first aspect;

[0066] b3) mixing the raw medicinal material with the alcohol solution and decocting the mixture, then adding water and continuing to decoct the mixture, and finally filtering the mixture to obtain a third decoction;

[0067] c3) concentrating the third decoction obtained in step b3) to obtain a fourth extract.

[0068] In another preferred embodiment, the alcohol is selected from the group consisting of water, methanol, ethanol, propanol, or a combination thereof, and preferably the alcohol is ethanol.

[0069] In another preferred embodiment, the alcohol is ethanol with a volume fraction of 50-90%.

[0070] In another preferred embodiment, the decoction temperature is 60-100°C.

[0071] In another preferred embodiment, in step b1), the mass ratio of the raw medicinal material to water is 8-14.

[0072] In another preferred embodiment, in step b1), the decoction is performed 2-3 times, and the decoction time for each decoction is independently 0.5-5 hours, preferably 1-3 hours.

[0073] In another preferred embodiment, in step c1), the relative density of the extract A is 1-1.5, preferably 1.2-1.35.

[0074] In another preferred embodiment, the step d1) comprises: mixing the extract A obtained in step c1) with ethanol to a concentration of 50-80% alcohol, allowing the mixture to stand, and concentrating the supernatant twice to obtain extract B.

[0075] In another preferred embodiment, the relative density of the extract B is 1-1.5, preferably 1.4-1.5.

[0076] In another preferred embodiment, in step b2), the mass ratio of the raw medicinal material to the alcohol is 8-14, preferably 8-10.

[0077] In another preferred embodiment, in step b2), the decoction is performed 2-3 times, and the decoction time for each decoction is independently 0.5-5 hours, preferably 1-3 hours.

[0078] In another preferred embodiment, in step c2), the relative density of the extract C is 1-1.5, preferably 1.05-1.4.

[0079] In another preferred embodiment, in step b3), the alcohol is ethanol with a volume fraction of 50-90%.

[0080] In another preferred embodiment, in step b3), the mass ratio of the raw medicinal material to alcohol is 8-14, preferably 8-10; the mass ratio of the raw medicinal material to water is 6-14, preferably 6-10.

[0081] In another preferred embodiment, in step b3), the decocting time is independently 0.5-5 h, preferably 1-3 h.

[0082] In another preferred embodiment, in step c3), the relative density of the extract D is 1-1.5, preferably 1.4-1.5.

[0083] In another preferred embodiment, the method further comprises a post-processing step of drying under reduced pressure and pulverizing to obtain extract powder.

[0084] In a fourth aspect of the present invention, a pharmaceutical preparation is provided, comprising:

[0085] i) the Chinese medicine composition according to the first aspect of the present invention or the extractant of the Chinese medicine composition according to the second aspect of the present invention;

[0086] ii) other pharmaceutically acceptable excipients, carriers or vehicles.

[0087] In another preferred embodiment, the pharmaceutical preparation is a traditional Chinese medicine preparation.

[0088] In another preferred embodiment, the preparation is an oral preparation or a non-oral preparation.

[0089] In another preferred embodiment, the preparation includes a liquid preparation, a semisolid preparation, or a solid preparation.

[0090] In another preferred embodiment, the preparation includes: powder, granule, capsule, mixture, powder, injection, tincture, oral solution, tablet, lozenge, or pill.

[0091] In another preferred embodiment, the preparation method of the preparation comprises:

[0092] The extract described in the second aspect of the present invention is post-treated to obtain extract powder, which is added with pharmaceutical excipients, mixed evenly, granulated, and tableted to prepare tablets of 0.1-1 g each.

[0093] In the fifth aspect of the present invention, there is provided the use of the traditional Chinese medicine composition as described in the first aspect of the present invention, the traditional Chinese medicine composition extract as described in the second aspect of the present invention, or the pharmaceutical preparation as described in the third aspect of the present invention, for preparing medicines and / or health products for preventing and / or treating rheumatoid arthritis and / or pulmonary complications caused by it.

[0094] In another preferred embodiment, the rheumatoid arthritis is an autoimmune disease caused by antigen stimulation, wherein the antigen includes lipopolysaccharide, virus, and bacterial toxin.

[0095] In another preferred embodiment, the pulmonary complication is: interstitial pneumonia

[0096] In another preferred embodiment, the prevention and / or treatment of rheumatoid arthritis and / or its complications include improvement of the following indicators: reduction of lung inflammatory cell infiltration and / or lung fibrosis

[0097] In the sixth aspect of the present invention, a method for treating RA and its pulmonary complications is provided, comprising the steps of administering a medically effective amount of the composition of the first aspect or the pharmaceutical preparation of the third aspect to a subject in need thereof.

[0098] In another preferred embodiment, the subject is a patient with rheumatoid arthritis or a patient with rheumatoid arthritis and its pulmonary complications.

[0099] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figure 1 The figure shows the results of HE staining of the lungs in animal experiments.

[0101] Figure 2The figure shows the results of Masson staining of the lungs in animal experiments. DETAILED DESCRIPTION

[0102] After extensive and in-depth research, the inventors have developed a traditional Chinese medicine composition for the treatment of rheumatoid arthritis combined with interstitial lung disease. Specifically, the composition of the present invention is a "Rheumatism and Lung Bi Recipe," which includes raw astragalus, herb agrimony, fritillary bulb of thunbergii, pinellia tuber, zedoaria, sinomenine, and gentiana macrophylla, and is designed to regulate liver qi, dispel rheumatism, and relieve pain. The composition of the present invention can prevent, treat, and / or alleviate the symptoms of arthritis combined with interstitial lung disease, and reduce damage from pulmonary fibrosis, making it ideally suited for the preparation of pharmaceutical and / or health product compositions for the prevention, treatment, and / or alleviation of this disease. This is the basis for the completion of the present invention.

[0103] Terminology

[0104] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0105] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0106] As used herein, the term "relative density" refers to the ratio of the density of a substance to the density of a reference substance under respective specified conditions. In the present invention, the reference substance is the density of water at 4°C (used as 1), and the relative density is the ratio of the density of another substance (such as an extract) to the density of water at 4°C.

[0107] As used herein, the term "pharmaceutically acceptable excipient, carrier or vehicle" refers to a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation and allergic reactions), that is, has a reasonable benefit / risk ratio.

[0108] As used herein, the term "effective amount" refers to an amount that produces a function or activity in humans and / or animals and is acceptable to humans and / or animals. Those skilled in the art will appreciate that the "effective amount" may vary depending on the form of the pharmaceutical composition, the severity of the disease, and the combination with other drugs.

[0109] The "prevention," "treatment," or "improvement" of the present invention includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, elimination, or reversal. In some embodiments, the Chinese medicine composition or pharmaceutical preparation of the present invention can prevent the development of RA and / or RA-induced multi-organ complications, or reduce, inhibit, and / or reverse existing RA and / or RA-induced multi-organ complications by, for example, at least about 10%, at least about 30%, at least about 50%, or at least about 80%, compared to the levels observed in the absence of the Chinese medicine composition or pharmaceutical preparation of the present invention.

[0110] As used herein, the terms "parts by weight" and "parts by weight" are used interchangeably, and the parts by weight may be any fixed weight expressed in milligrams, grams, or kilograms (e.g., 1 mg, 1 g, 2 g, or 1 kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b may be composed of 1 gram of component a + 9 grams of component b, or 10 grams of component a + 90 grams of component b, etc. In the composition described in 25, the percentage content of a component = (parts by weight of the component / sum of the parts by weight of all components) × 100%. Therefore, in a composition consisting of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and the content of component b is 90%.

[0111] As used herein, the term "raw medicinal material" refers to the Chinese medicinal material used as the active medicinal material in the compositions of the present invention. Such medicinal materials may be in various forms, including (but not limited to) dried medicinal materials, fresh medicinal materials, raw medicinal materials, cooked medicinal materials, processed medicinal materials, or combinations thereof. Furthermore, when the compositions of the present invention contain an extract of a raw medicinal material, the term also includes the raw medicinal material corresponding to the raw medicinal material extract or the corresponding raw medicinal material used to prepare the extract.

[0112] As used herein, the term "material-to-liquid ratio" refers to the ratio (w / v) of the mass of the solid "material" to the volume of the "liquid" as the leachate.

[0113] Rheumatoid arthritis with interstitial lung disease (RA-ILD)

[0114] Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease characterized by widespread, persistent synovitis and symmetrical, destructive joint changes. Rheumatoid-arthritis-related interstitial lung disease (RA-ILD) is one of the most serious extra-articular manifestations of RA. RA is highly prevalent, affecting 0.5%-1% of the world's population. Its unclear pathogenesis and severe symptoms have made it a global problem. As RA progresses, the lungs, heart, liver, kidneys, and nervous system are gradually affected. The gradual loss of function in these organs leads to various complications beyond the joints. Approximately 60%-80% of patients experience lung involvement, and approximately 2%-10% of these patients experience significant pulmonary symptoms. Clinically, RA-ILD patients experience pulmonary symptoms such as shortness of breath, cyanosis, and edema, in addition to joint pain, swelling, stiffness, and deformity. RA combined with interstitial lung disease increases the risk of death in RA patients. A Danish study showed that the 10-year mortality rate in RA-ILD patients was 60.1%, while the 10-year mortality rate in RA patients without ILD was 34.5%.

[0115] The Chinese medicine composition of the present invention

[0116] The present invention provides a Chinese medicine composition that can be used to prevent, treat and / or improve RA-ILD

[0117] Theoretical Support: RA is classified as a "bi syndrome" in Traditional Chinese Medicine (TCM). RA and its visceral complications fall under the category of "five-body bi" that transforms into "five-organ bi" within the bi syndrome. The Yellow Emperor's Classic of Internal Medicine states, "The mixed arrival of wind, cold, and dampness results in bi." Wind, cold, and dampness block the meridians, stagnating qi and blood in the joints and hindering flexion and extension. If the disease persists, it can spread internally, leading to bi in the five internal organs. The Yellow Emperor's Classic of Internal Medicine states, "Lung bi presents with irritability, fullness, wheezing, and vomiting." The Su Wen Bi Lun states, "If skin bi persists, it is further affected by pathogenic factors and internalizes to the lungs." Furthermore, the Su Wen Yu Ji Zhen Zang Lun states, "When the disease enters the lungs, it is called lung bi." Symptoms of "lung bi" include irritability, fullness, wheezing, and vomiting, all caused by persistent bi that internalizes the lungs, a true reflection of the clinical symptoms of RA-ILD.

[0118] Explanation of the formula: Professor Shi Qi of Shanghai University of Traditional Chinese Medicine, inheriting Shi's traumatology philosophy of "focusing on Qi and prioritizing blood," developed the Fengshi Feibi formula to treat lung bi syndrome. The formula consists of seven herbs: raw astragalus (Astragalus membranaceus (Fisch.) Bunge), herb agrimonia (Agrimonia pilosa Ledeb), fritillaria thunbergia (Fritillaria thunbergia), ginger pinellia (Pinelliae Rhizoma Praepapatum Cum Zingibere et Alumine), zedoary turmeric (Curcumaphaeocaulis Vai), vine of green wind (Sinomenium acutum), and qinjiao (Gentiana macrophylla Pall). In this formula, raw Astragalus and Herba Agrimoniae are both monarch herbs. Raw Astragalus is sweet and slightly warm in nature, entering the spleen and lung meridians, and has the effects of strengthening the spleen, replenishing qi, and consolidating the exterior. Herba Agrimoniae is bitter and astringent, with a cold nature, entering the heart, liver, and lung meridians, nourishing blood and having astringent and hemostatic effects. The combination of these two herbs has the effect of replenishing qi and tonifying the lungs. Fritillaria thunbergii and Pinellia ternata are both assistant herbs. Fritillaria thunbergii is bitter and cold in nature, clearing heat, resolving phlegm, relieving cough, detoxifying, and dispersing nodules. Pinellia ternata is pungent and warm in nature, resolving phlegm and dispersing nodules. Gentiana macrophylla dispels wind and relieves pain, while Sinomenium chinense dispels rheumatism and dredges the meridians. Curcuma zedoaria is an adjuvant herb that promotes qi and resolves blood circulation. This formula for rheumatic lung bi effectively invigorates qi and blood circulation, dispels wind and dampness, clears heat, relieves numbness, and relieves pain. Clinically, it is primarily used to treat lung bi symptoms of cough, asthma, and fullness.

[0119] The present inventors have confirmed the effects of Fengshi Feibi prescription on alleviating lung inflammation and alleviating lung fibrosis in interstitial pneumonia by using an interstitial pneumonia model.

[0120] In the present invention, a compound prescription for treating rheumatic and lung-suppressing pain developed by Professor Shi Qi of Shanghai University of Traditional Chinese Medicine is used to treat RA-ILD. The compound prescription for treating rheumatic and lung-suppressing pain is supported by extracts of astragalus, herb agrimony, fritillaria thunbergii, pinellia ternata, zedoaria, sinomenine, and gentiana macrophylla.

[0121] In the present invention, a preferred "Rheumatic Lung Bi Prescription" is composed of 2-70 grams of raw astragalus, 2-50 grams of zedoaria, 2-50 grams of thunbergia, 2-50 grams of ginger pinellia, 2-50 grams of gentiana, 2-50 grams of Sinomenium, and 2-50 grams of agrimony.

[0122] In the present invention, a preferred "Rheumatic Lung Bi Prescription" is composed of 18 grams of raw astragalus, 15 grams of zedoaria, 12 grams of thunbergia, 9 grams of ginger pinellia, 9 grams of gentiana, 12 grams of Sinomenium, and 15 grams of agrimony.

[0123] In the present invention, a preferred "Rheumatic Lung Bi Prescription" is composed of 30 grams of raw astragalus, 15 grams of zedoaria, 15 grams of thunbergia, 9 grams of ginger pinellia, 9 grams of gentiana, 12 grams of Sinomenium, and 12 grams of agrimony.

[0124] Extractant of the present invention and preparation method thereof

[0125] The present invention provides an extractant of a traditional Chinese medicine composition, wherein the extractant is prepared by extracting the traditional Chinese medicine composition of the present invention with water and / or ethanol.

[0126] As used herein, the "extractant of the present invention" refers to an extract in the form of a decoction or an extract obtained by extracting the traditional Chinese medicine composition of the present invention with ethanol or water solvent, precipitating with alcohol, and filtration.

[0127] In the present invention, a preferred extractant is a concentrated decoction or extract, with a relative density of 1-1.5, preferably 1-1.25 or 1.4-1.5.

[0128] The present invention also provides a method for preparing the extractant.

[0129] 1) The process includes the following steps:

[0130] Weigh each raw material according to the weight ratio, soak, add 8-14 times of water, decoct 2-3 times, decoct for 1-3 hours each time, combine the decoctions, filter, and concentrate the filtrate to an extract with a relative density of 1.2-1.35, and set aside;

[0131] Add ethanol to the extract to make the alcohol concentration 50-80%, let it stand overnight, and concentrate the supernatant to an extract with a relative density of 1.4-1.5;

[0132] 2) The process includes the following steps:

[0133] Weigh each raw material according to the weight ratio, soak it, add 8-10 times of 50-90% ethanol, decoct it 2-3 times, decoct it for 1-3 hours each time, combine the decoctions, filter, and concentrate the filtrate to a concentrated extract with a relative density of 1.05-1.4, and set aside;

[0134] The concentrated extract is dried under reduced pressure and crushed to obtain extract powder;

[0135] 3) The process includes the following steps:

[0136] Weigh each raw material according to the weight ratio, soak, and decoct twice, each decoction for 1-3 hours, add 8-10 times of 50-90% ethanol for the first decoction, and add 6-10 times of water for the second decoction. Filter the decoction and concentrate it to a concentrated extract with a relative density of 1.3-1.4, and set aside;

[0137] The concentrated extract is dried under reduced pressure and crushed to obtain extract powder;

[0138] The effective components of the Chinese medicine composition of the present invention are purified by extraction with ethanol or water solvent and alcohol precipitation and filtration. The extraction method is selected based on the physical and chemical properties of the effective components in the medicine, and the extraction solvent and extraction conditions of alcohol precipitation and filtration are selected. The purification method is selected by ethanol precipitation for purification under the premise of ensuring the therapeutic effect.

[0139] Preparation and administration

[0140] The present invention provides a preparation, including but not limited to pharmaceutical preparations or health product preparations, comprising one or more medicinal materials or extracts thereof selected from the group consisting of raw astragalus, zedoary turmeric, fritillaria thunbergii, pinellia ternata, gentiana macrophylla, sinomenine, and agrimony. The raw medicinal materials or extracts thereof may be present in an amount of 0.1-99.9 wt%, based on the weight of the preparation. The composition may further comprise a pharmaceutically or health product-acceptable carrier.

[0141] In the present invention, it should be understood that the extract includes not only the concentrated solution (such as an extract) or active ingredient (such as a powder) obtained by extracting the raw medicinal materials, but also the concentrated solution (such as an extract) or active ingredient mixture obtained by extracting a single medicinal material from the raw medicinal materials (including the mixture of concentrated solutions, active ingredients, or concentrated solutions). The active ingredient of the raw medicinal materials includes a single ingredient or a mixture of ingredients.

[0142] There are no particular limitations on the dosage form of the preparation of the present invention, and any dosage form suitable for mammals may be used. Preferably, the dosage form may include tablets, capsules, granules, pills, mixtures, powders, oral liquids, buccal tablets, or aerosols. From the perspective of ease of preparation, administration, or administration, the preferred composition is a solid-state preparation. Oral administration is preferred.

[0143] The preparations of the present invention may be added with various conventional carriers and / or excipients required for preparing different dosage forms. The excipients described herein are pharmaceutically acceptable excipients and include dextrin, lactose, sodium bicarbonate, citric acid, sodium hydroxymethyl starch, micropowdered silica gel, starch, soluble starch, polyethylene glycol, or magnesium stearate. Conventional methods for preparing traditional Chinese medicines may be used to prepare the preparations into any commonly used dosage form, such as tablets, capsules, granules, capsules, pills, and powders.

[0144] Some examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffers, chelating agents, thickeners, pH regulators, transdermal enhancers, colorants, flavorings, stabilizers, antioxidants, preservatives, antibacterial agents, pyrogen-free water, etc.

[0145] The preparation of the present invention can avoid the temporary boiling of Chinese herbal decoctions before taking, which is easy to mold and deteriorate for a long time and brings a lot of inconvenience to patients. According to the characteristics of clinical medication, the physical and chemical properties of the main medicinal flavors in the prescription are preserved, and modern preparation technology is combined to prepare solid preparations such as granules, tablets, capsules, powders, etc., which can conveniently and effectively meet the needs of patients.

[0146] In a preferred embodiment, based on the total dry weight of the raw medicinal materials, each gram or each milliliter of the preparation corresponds to 5-50 grams, preferably 10-20 grams of medicinal materials.

[0147] In a preferred embodiment, the preparation method of the preparation of the present invention comprises the following steps:

[0148] The concentrated extract is dried under reduced pressure and crushed to obtain extract powder; the extract powder is added with pharmaceutical excipients, mixed evenly, granulated, and pressed into 10 tablets, each tablet being 0.45 g; or prepared into granules, capsules, mixtures or powders.

[0149] The preparation of the present invention can be directly used to prepare drugs for preventing and / or treating RA and / or pulmonary complications caused by RA. The preparation of the present invention may also contain other optional medicinal materials or extracts thereof or other drugs effective for treating and / or preventing RA and / or pulmonary complications caused by RA. Preferably, the preparation of the present invention can alleviate RA and / or multi-organ complications caused by RA caused by antigen stimulation, wherein the antigen includes lipopolysaccharide, virus, bacterial toxin. More preferably, the preparation of the present invention can alleviate RA and / or pulmonary complications caused by RA caused by lipopolysaccharide stimulation.

[0150] Typically, the formulations of the present invention are administered daily at a dose of 0.001-20 g / kg (preferably 1-1.5 g / kg) of animal body weight, preferably in 1-4 divided doses per day, or in a sustained-release form. For most mammals, the total daily dose is 0.05-600 g. Of course, the specific dosage will vary depending on the mode of administration, dosage form, and severity of the disease being treated, and the route of administration is within the skill of the skilled physician. Administration can be carried out by conventional routes, including, but not limited to, oral, intramuscular, transdermal, or topical administration. Oral administration is preferred.

[0151] The present invention also provides a method for preventing and / or treating RA and / or pulmonary complications caused by RA, comprising the step of administering the composition or formulation of the present invention to a subject in need thereof. The subject may be a human or a non-human mammal (e.g., a dog, pig, cat, monkey, sheep, horse, cow, etc.).

[0152] Compared with the prior art, the present invention has the following beneficial effects:

[0153] 1) The Chinese medicine composition of the present invention has a definite therapeutic effect and high safety

[0154] 2) The preparation method of the Chinese medicine composition of the present invention is simple, low-cost, and the raw materials are readily available.

[0155] 3) The Chinese medicine composition of the present invention can reduce lung inflammatory cell infiltration and lung fibrosis.

[0156] 4) The Chinese medicine composition of the present invention can improve rheumatoid arthritis combined with interstitial lung disease.

[0157] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0158] Example 1

[0159] 30 grams of raw Astragalus, 15 grams of Curcuma, 15 grams of Fritillaria thunbergii, 12 grams of Pinellia ternata, 12 grams of Gentiana macrophylla, 15 grams of Caulis Sinomenii, and 30 grams of Agrimoniae.

[0160] Take each raw material drug, soak for 1 hour, decoct twice, each decoction for 1 hour, add 14 times the amount of water (by mass ratio) for the first decoction, and 10 times the amount of water for the second decoction, combine the decoctions, filter, and concentrate the filtrate to an extract with a relative density of 1.05-1.07, and set aside;

[0161] Add ethanol to the extract to make the alcohol concentration 50-80%, let it stand overnight, and concentrate the supernatant to a relative density of 1.3-1.4 to obtain a concentrated extract;

[0162] The concentrated extract is dried under reduced pressure and pulverized to obtain extract powder. The extract powder is added to pharmaceutical excipients, mixed thoroughly, granulated, and pressed into 1000 tablets, each weighing 0.5 g. Take 10 tablets daily. Alternatively, the extract can be prepared into granules, capsules, mixtures, or powders according to conventional pharmaceutical methods.

[0163] Example 2

[0164] 18 grams of raw Astragalus, 15 grams of Curcuma, 12 grams of Fritillaria thunbergii, 9 grams of Pinellia ternata, 9 grams of Gentiana macrophylla, 12 grams of Sinomenium wilfordii, and 15 grams of Agrimoniae.

[0165] Prepare each drug substance according to the method described in Example 1 to obtain an extract powder. Add the extract powder to the pharmaceutical excipients, mix thoroughly, granulate, and compress into 1000 tablets, each weighing 0.5 g. Take 10 tablets daily. Alternatively, the extract powder can be prepared into granules, capsules, mixtures, or powders according to conventional pharmaceutical methods.

[0166] Example 3

[0167] 30 grams of raw Astragalus, 15 grams of Curcuma, 15 grams of Fritillaria thunbergii, 9 grams of Pinellia ternata, 9 grams of Gentiana macrophylla, 12 grams of Caulis Sinomenii, and 12 grams of Agrimoniae.

[0168] Prepare each drug substance according to the method described in Example 1 to obtain an extract powder. Add the extract powder to the pharmaceutical excipients, mix thoroughly, granulate, and compress into 1000 tablets, each weighing 0.5 g. Take 10 tablets daily. Alternatively, the extract powder can be prepared into granules, capsules, mixtures, or powders according to conventional pharmaceutical methods.

[0169] Example 4

[0170] Weigh each raw material according to the weight ratio described in Example 1, soak it in 8-10 times (by mass ratio) of 50-90% ethanol, decoct it 2-3 times, decoct it for 1-3 hours each time, combine the decoctions, filter, and concentrate the filtrate to a concentrated extract with a relative density of 1.05-1.4 for later use;

[0171] The concentrated extract is dried under reduced pressure and crushed to obtain extract powder.

[0172] Example 5

[0173] Weigh each raw material drug according to the weight ratio described in Example 1, add 8-10 times (by mass ratio) of 50-90% ethanol to soak and decoct, then add 6-10 times of water to decoct again, each decoction is 1-3 hours, the decoction is filtered, and concentrated to a concentrated extract with a relative density of 1.3-1.4, and set aside;

[0174] The concentrated extract is dried under reduced pressure and crushed to obtain extract powder.

[0175] Example 6

[0176] Twenty-four 3-month-old clean-grade female C57 mice were randomly divided into a normal control group, a model+normal saline group, and a model+Fengshi Feibi prescription group.

[0177] The mice in the normal control group were not treated; the mice in the model+normal saline group and the model+Fengshi Feibi prescription group were intraperitoneally injected with lipopolysaccharide (LPS) at 10 mg / kg every day for 5 days.

[0178] Starting on the first day of LPS injection, mice in the model + Fengshi Feibi Fang group were gavaged with 139.5 mg / kg of Fengshi Feibi Fang. Mice in the model + saline group were gavaged with an equal volume of saline daily for 14 days. Lung tissue was removed on day 15, fixed with formalin, dehydrated, and then stained with HE and Masson's staining.

[0179] 6.1 In vivo lung HE staining results from animal experiments

[0180] like Figure 1 As shown in the figure, compared with the normal control group, the lung interstitial, vascular, and airway tissues of the mice in the model + saline group were diffusely infiltrated with mild to moderate inflammatory infiltration. The walls of medium and small arteries were thickened, and the lumen was lined with feather-like epithelial cells.

[0181] Compared with the model + saline group, the model + Fengshi Feibi prescription group had a significantly reduced area of ​​inflammation. The results suggest that the Fengshi Feibi prescription can reduce the degree of inflammation in the lung tissue of patients with interstitial lung disease.

[0182] 6.2 In vivo lung Masson staining results in animal experiments

[0183] like Figure 2 As shown in the figure, compared with the normal control group mice, large areas of collagen fiber tissue proliferation were observed around the bronchi, pulmonary interstitium, and blood vessels in the lungs of the mice in the model + normal saline group.

[0184] Compared with the model + saline group, the model + Fengshi Feibi prescription group showed a significant reduction in the area of ​​pulmonary fibrosis. The results suggest that the Fengshi Feibi prescription can reduce the degree of fibrosis in the lung tissue of patients with interstitial lung disease.

[0185] discuss

[0186] HE staining results showed that the Chinese herbal composition of the present invention alleviated lipopolysaccharide (LPS)-induced lung inflammation in mice and reduced lung inflammatory cell infiltration. Masson staining also showed that the Chinese herbal composition of the present invention alleviated LPS-induced lung fibrosis in mice. In summary, the Chinese herbal composition of the present invention exhibited excellent effects in inhibiting inflammatory cell infiltration, reducing the area of ​​inflammation, and alleviating fibrosis in the lung tissue of rheumatoid arthritis model mice, making it highly suitable for treating rheumatoid arthritis and its pulmonary complications.

[0187] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A Chinese medicine composition, characterized in that The Chinese medicine composition is composed of the following raw medicinal materials or their extracts: Raw Astragalus, Herba Agrimoniae, Fritillariae Thunbergii, Pinellia ternata, Curcuma zedoaria, Caulis Sinomenii, and Gentiana macrophylla.

2. The Chinese medicine composition according to claim 1, wherein The Chinese medicine composition is composed of the following raw medicinal materials or their extracts: 2-70 parts by weight of raw astragalus; 2-50 parts by weight of Curcuma zedoaria; 2-50 parts by weight of Fritillaria thunbergii; 2-50 parts by weight of Zingiber officinale; Gentiana macrophylla 2-50 parts by weight; 2-50 parts by weight of Sinomenium sinomenium; 2-50 parts by weight of Agrimony Root.

3. The Chinese medicine composition according to claim 1, wherein The Chinese medicine composition is composed of the following raw medicinal materials or their extracts: 4-50 parts by weight of raw astragalus; 4-30 parts by weight of Curcuma zedoaria; 4-30 parts by weight of Fritillaria thunbergii; 4-30 parts by weight of Zingiber officinale; Gentiana macrophylla 4-30 parts by weight; 4-30 parts by weight of Sinomenium sinomenium; 4-30 parts by weight of Agrimony Root.

4. The Chinese medicine composition according to claim 1, wherein The Chinese medicine composition is composed of the following raw medicinal materials or their extracts: 10-50 parts by weight of raw astragalus; 10-30 parts by weight of Curcuma zedoaria; 5-20 parts by weight of Fritillaria thunbergii; 5-20 parts by weight of Zingiber officinale; Gentiana macrophylla 5-20 parts by weight; 10-30 parts by weight of Sinomenium sinomenium; 10-30 parts by weight of Agrimony Root.

5. The Chinese medicine composition according to claim 1, wherein In the traditional Chinese medicine composition, the weight ratio of Curcuma zedoaria, Fritillaria thunbergii, Pinellia ternata, Gentiana macrophylla, Caulis Sinomenii and Herba Agrimoniae is (0.5-1.2):(0.5-1.2):(0.5-1.2):(0.5-1.2):(0.5-1.2), preferably 1:1:(0.7-1):(0.7-1):1:

1.

6. A Chinese medicine composition extractant, characterized in that: The extractant is prepared by extracting the traditional Chinese medicine composition according to claim 1, wherein the extraction solvent of the extractant is selected from the following group: water and ethanol.

7. The extractant of the Chinese medicine composition according to claim 6, characterized in that The material-liquid ratio of the traditional Chinese medicine composition to the extraction solvent is 1:6-20, calculated by mass ratio.

8. A method for preparing the Chinese medicine composition according to claim 1 or the extractant of the Chinese medicine composition according to claim 6, characterized in that: i) comprising the steps of: a1) providing raw medicinal materials, wherein the raw medicinal materials are as described in claim 1; b1) mixing the raw medicinal materials with water, decocting the mixture, and filtering the mixture to obtain a first decoction; c1) concentrating the first decoction obtained in step b1) to obtain a first extract; d1) mixing the first extract obtained in step c1) with the alcohol solution, allowing the mixture to stand, and concentrating the mixture a second time to obtain a second extract; Alternatively, ii) comprises the steps of: a2) providing raw medicinal materials, wherein the raw medicinal materials are as described in claim 1; b2) mixing the raw medicinal material with the alcohol solution, decocting the mixture, and filtering to obtain a second decoction; c2) concentrating the second decoction obtained in step b2) to obtain a third extract; Alternatively, iii) comprises the steps of: a3) providing raw medicinal materials, wherein the raw medicinal materials are as described in claim 1; b3) mixing the raw medicinal material with the alcohol solution and decocting the mixture, then adding water and continuing to decoct the mixture, and finally filtering the mixture to obtain a third decoction; c3) concentrating the third decoction obtained in step b3) to obtain a fourth extract.

9. A pharmaceutical preparation, characterized in that The formulation comprises: i) the Chinese medicine composition according to claim 1 or the extract of the Chinese medicine composition according to claim 6; ii) other pharmaceutically acceptable excipients, carriers or vehicles.

10. Use of the Chinese medicine composition according to claim 1, the Chinese medicine composition extract according to claim 6, or the pharmaceutical preparation according to claim 9, characterized in that: Used for preparing medicines or health products for preventing and / or treating rheumatoid arthritis or interstitial lung complications caused by rheumatoid arthritis.

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