A composition for preventing rheumatoid arthritis, its preparation method and application

Abstract

The present invention belongs to the field of traditional Chinese medicine, and particularly relates to a composition for preventing rheumatoid arthritis, a preparation method thereof, and an application. The composition for preventing rheumatoid arthritis according to the present invention is prepared from the following raw material components in parts by mass: 15-60 parts of raw coix seed, 5-30 parts of angelica, 5-30 parts of white peony root, 1-15 parts of ephedra, 5-30 parts of cassia twig, 5-30 parts of roasted licorice root, 5-30 parts of atractylodes rhizome, and 10-60 parts of astragalus membranaceus. Experimental results on CIA rat models show that the composition for preventing rheumatoid arthritis according to the present invention can significantly reduce the joint swelling degree of CIA rats. X-ray results show that it can improve bone destruction, and pathological sections show that it has good effects in inhibiting synovial tissue proliferation, reducing inflammatory cell infiltration, and delaying bone and cartilage destruction; it has the effects of improving symptoms, protecting bones, and anti-inflammation on CIA rats.

Description

Technical Field

[0001] The present invention belongs to the field of traditional Chinese medicine, and particularly relates to a composition for preventing rheumatoid arthritis, a preparation method thereof, and an application thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease characterized by cartilage damage and bone destruction. The clinical manifestations are symmetrical and persistent joint swelling and pain, often accompanied by morning stiffness. In severe cases, it can lead to progressive disability, systemic complications, early death and other consequences.

[0003] In 2012, the European League Against Rheumatism (EULAR) proposed that the occurrence and development of RA are specifically divided into 6 stages, including the stage of RA-related genetic risk factors, the stage of RA-related environmental factors, the stage of RA-related systemic autoimmunity, the stage without clinical arthritis symptoms, the stage of undifferentiated arthritis, and the stage of classified diagnosis of RA. The stages of RA-related genetic risk factors, RA-related environmental risk factors, RA-related systemic immune disorder stage, and the stage without clinical arthritis are collectively referred to as the preclinical stage of RA, that is, pre-RA (Preclinical rheumatoid arthritis, Pre-RA), rather than RA.

[0004] Research shows that the disease has already started to be active before detectable clinical symptoms appear. There is a nearly 30% probability that patients with arthritis and positive related antibodies will develop into RA within one year. Therefore, compared with patients with clearly diagnosed RA, appropriate intervention in patients in the preclinical stage (i.e., Pre-RA) will more effectively prevent the progression of the disease.

[0005] At present, there is no unified consensus on the treatment of Pre-RA internationally, and there is a lack of drugs that are recognized as safe and effective in blocking the progression of Pre-RA to RA. Actively exploring preventive treatment programs for Pre-RA is a current research hotspot. Compared with Western medicine, traditional Chinese medicine has the advantages of being more stable, safer, and having fewer side effects. Therefore, finding an effective traditional Chinese medicine program for intervening in Pre-RA is a difficulty and confusion in the field of traditional Chinese medicine. Summary of the Invention

[0006] According to one aspect of the present invention, there is provided a composition for preventing rheumatoid arthritis, which is prepared from the following raw material components in parts by mass: 15-60 parts of raw coix seed, 5-30 parts of angelica, 5-30 parts of white peony root, 1-15 parts of ephedra, 5-30 parts of cassia twig, 5-30 parts of roasted licorice root, 5-30 parts of atractylodes rhizome, and 10-60 parts of astragalus membranaceus.

[0007] Principle of the formula composition of the traditional Chinese medicine composition of the present invention:

[0008] King drugs: Astragalus membranaceus and Ramulus Cinnamomi. Ramulus Cinnamomi disperses wind-cold and warms the channels to relieve arthralgia. When combined with Astragalus membranaceus, it benefits qi and warms yang, and promotes blood circulation and dredges the channels.

[0009] Minister drugs: Coix seed, Rhizoma Atractylodis, and Herba Ephedrae. Coix seed and Rhizoma Atractylodis strengthen the spleen and promote diuresis to eliminate dampness. Herba Ephedrae warms the channels to dispel cold, and can assist Astragalus membranaceus and Ramulus Cinnamomi to eliminate dampness, dredge the channels and relieve pain.

[0010] Assistant drugs: Radix Paeoniae Alba and Radix Angelicae Sinensis. Radix Paeoniae Alba is used as an assistant to Astragalus membranaceus, nourishing blood and softening the liver, and restraining the dryness of Astragalus membranaceus; Radix Angelicae Sinensis is pungent, dispersing, mild in nature and warming, nourishing blood and promoting blood circulation, and promoting qi movement while nourishing blood.

[0011] Guiding drug: Prepared Licorice Root. Licorice Root harmonizes all the drugs.

[0012] Coix seed: The dry and mature semen of Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf, a plant of the Gramineae family. Sweet, light, and cool. It belongs to the spleen, stomach, and lung meridians. It strengthens the spleen and promotes diuresis to eliminate dampness, relieves arthralgia and stops diarrhea, and clears heat and expels pus.

[0013] Radix Angelicae Sinensis: The dry root of Angelica sinensis (Oliv.) Diels, a plant of the Umbelliferae family. Sweet, pungent, and warm. It belongs to the liver, heart, and spleen meridians. It nourishes blood and promotes blood circulation, regulates menstruation and relieves pain, and moistens the intestines and promotes defecation.

[0014] Radix Paeoniae Alba: The dry root of Paeonia lactiflora Pall., a plant of the Ranunculaceae family. Bitter, sour, and slightly cold. It belongs to the liver and spleen meridians. It soothes the liver and relieves pain, nourishes blood and regulates menstruation, and astringes yin and stops sweating.

[0015] Herba Ephedrae: The dry herbaceous stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C. A. Mey., or Ephedra equisetina Bge., plants of the Ephedraceae family. Pungent, slightly bitter, and warm. It belongs to the lung and bladder meridians. It induces sweating and dispels cold, disperses the lung qi and relieves asthma, and promotes diuresis and reduces swelling.

[0016] Ramulus Cinnamomi: The dry young twig of Cinnamomum cassia Presl, a plant of the Lauraceae family. Pungent, sweet, and warm. It belongs to the heart, lung, and bladder meridians. It induces sweating and relieves the exterior syndrome, warms and dredges the channels, promotes yang qi transformation, and calms the adverse qi and reduces qi counterflow.

[0017] Prepared Licorice Root: A perennial herb of the Leguminosae family and the Glycyrrhiza genus. The medicinal part is the root and rhizome, which is prepared by frying licorice root with honey and boiling water. Sweet, flat. Its medicinal properties are mild, it can sink and descend, and it can float and sink. It belongs to the heart, lung, spleen, and stomach meridians. It can both invigorate the middle energizer and replenish qi, and is also good at harmonizing the properties of all drugs.

[0018] Atractylodes Rhizome: The dried rhizome of the Compositae plant Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz. It is pungent, bitter, and warm in nature. It acts on the spleen, stomach, and liver meridians. It can dry dampness and strengthen the spleen, dispel wind and cold, and improve eyesight.

[0019] Astragalus Root: The dried root of the Leguminosae plant Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. It is sweet and warm in nature. It acts on the lung and spleen meridians. It can tonify qi and consolidate the exterior, induce diuresis and expel toxins, drain pus, and promote granulation for sore healing.

[0020] In some embodiments, the composition for preventing rheumatoid arthritis is prepared from the following raw material components by mass: 30 parts of Coix Seed, 10 parts of Angelica Sinensis, 10 parts of White Peony Root, 3 parts of Ephedra, 10 parts of Cinnamon Twig, 15 parts of Prepared Licorice Root, 15 parts of Atractylodes Rhizome, and 30 parts of Astragalus Root.

[0021] The traditional Chinese medicine composition provided by the present invention has the effects of improving symptoms and reducing the risk of onset of pre - clinical rheumatoid arthritis, and has no obvious liver and kidney toxicity.

[0022] According to another aspect of the present invention, a preparation method of the above - mentioned composition for preventing rheumatoid arthritis is provided: each component is separately pulverized, sieved, and mixed to obtain the composition for preventing rheumatoid arthritis.

[0023] According to another aspect of the present invention, an application of the above - mentioned composition for preventing rheumatoid arthritis in the preparation of drugs for preventing and / or treating rheumatoid arthritis is provided.

[0024] According to another aspect of the present invention, a traditional Chinese medicine preparation is provided, which uses the above - mentioned composition for preventing rheumatoid arthritis as an active ingredient.

[0025] In some embodiments, the traditional Chinese medicine preparation further includes pharmaceutically acceptable excipients. Preferably, the excipients are at least one of sustained - release agents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, adsorption carriers, surfactants, and lubricants. The excipients selected in the present invention are conventional excipients in the field of traditional Chinese medicine pharmacy. For example, the sustained - release agent and excipient can be water, the filler can be starch or sucrose, the binder can be cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone, the wetting agent can be glycerol, the disintegrant can be agar, calcium carbonate, and sodium bicarbonate, the absorption promoter can be quaternary ammonium compounds, the adsorption carrier can be kaolin and bentonite, the surfactant can be cetyl alcohol, and the lubricant can be talc powder, calcium / magnesium stearate, and polyethylene glycol. In addition, other adjuvants such as flavoring agents and sweetening agents can also be added.

[0026] The dosage form of the traditional Chinese medicine preparation of the present invention can be conventional traditional Chinese medicine dosage forms such as decoction, tablets, capsules, pills, powders, granules, syrup, etc.

[0027] According to another aspect of the present invention, there is provided an application of the above-mentioned traditional Chinese medicine preparation in the preparation of a drug for preventing and / or treating rheumatoid arthritis.

[0028] Proved by experiments on CIA rat models, the composition for preventing rheumatoid arthritis of the present invention can significantly reduce the joint swelling degree of CIA rats. X-ray shows that it can improve bone destruction. Pathological sections show that it has good effects of inhibiting synovial tissue proliferation, reducing inflammatory cell infiltration, and delaying bone and cartilage destruction; it can significantly reduce the expression levels of inflammatory cytokines TNF-α and IL-1β in the serum of CIA rats; it has the effects of improving symptoms, bone protection and anti-inflammation on CIA rats.

[0029] Clinical experiments prove that the composition for preventing rheumatoid arthritis of the present invention has the potential effects of reducing CCP antibody, RF, hsCRP, and ESR, and has potential joint protection effects. Description of the Drawings

[0030] Figure 1 It is a flow chart of the experimental design of a type II collagen (ColⅡ)-induced arthritis (CIA) rat model;

[0031] Figure 2 It is the weight change trend of rats in each group in the experimental part of CIA rats of the present invention;

[0032] Figure 3 It is the comparison of spleen indices of rats in each group in the experimental part of CIA rats of the present invention;

[0033] Figure 4 It is the comparison of thymus indices of rats in each group in the experimental part of CIA rats of the present invention;

[0034] Figure 5 It is the measurement result of ankle joint swelling degree of rats in each group in the experimental part of CIA rats of the present invention;

[0035] Figure 6 It is the change of ankle joint swelling degree of rats in each group before and after administration in the experimental part of CIA rats of the present invention;

[0036] Figure 7 It is the serum TNF-α result of rats in each group after treatment in the experimental part of CIA rats of the present invention;

[0037] Figure 8 It is the serum IL-1β result of rats in each group after treatment in the experimental part of CIA rats of the present invention;

[0038] Figure 9 These are typical photos of joint swelling in rats of each group after treatment in the CIA rat experiment part of the present invention;

[0039] Figure 10 These are X-ray pictures of the ankle joints of rats in each group after treatment in the CIA rat experiment part of the present invention;

[0040] Figure 11 These are HE pathological pictures of the ankle joints of rats in each group after treatment in the CIA rat experiment part of the present invention;

[0041] Figures 12 - 13 These are pictures of anti-CCP antibodies and their changes in patients before and after treatment in the clinical experiment of the present invention;

[0042] Figures 14 - 15 These are pictures of RF titers and their changes in patients before and after treatment in the clinical experiment of the present invention;

[0043] Figures 16 - 17 These are pictures of hsCRP titers and their changes in patients before and after treatment in the clinical experiment of the present invention;

[0044] Figures 18 - 19 These are pictures of ESR titers and their changes in patients before and after treatment in the clinical experiment of the present invention. Detailed implementation manners

[0045] The present invention will be further described in detail below in conjunction with specific embodiments.

[0046] Embodiment 1

[0047] The traditional Chinese medicine decoction for preventing rheumatoid arthritis in this embodiment is prepared from the following components: 30 g of coix seed, 10 g of angelica, 10 g of white peony root, 3 g of ephedra, 10 g of cassia twig, 15 g of roasted licorice root, 15 g of atractylodes rhizome, and 30 g of astragalus membranaceus.

[0048] The traditional Chinese medicine decoction in this embodiment is prepared by the following method:

[0049] Weigh the raw materials according to the weight ratio, crush, sieve, and mix the raw materials to obtain a composition for preventing rheumatoid arthritis. Boil the obtained composition for preventing rheumatoid arthritis with 3000 mL of ionized water for 60 min, remove the residue by centrifugation, and evaporate the aqueous extract by rotary evaporation to obtain 150 mL of solution, thus obtaining it.

[0050] It should be noted that the above preparation method of the traditional Chinese medicine decoction is only exemplary and does not limit the scope protected by the present invention. Of course, it can also be prepared by using the techniques commonly used in the art, and they are not listed one by one here.

[0051] Next, in order to explore the prevention and treatment effects of the composition for preventing rheumatoid arthritis of the present invention on rheumatoid arthritis, a type II collagen (ColⅡ)-induced arthritis (CIA) rat model experiment and a clinical experiment were conducted.

[0052] I. Type II collagen (ColⅡ)-induced arthritis (CIA) rat model experiment

[0053] 1. Experimental subjects

[0054] Forty 8-week-old female SPF-grade healthy Wistar rats, weighing 180 - 220 g, were randomly divided into 4 groups: normal group, CIA model group, methotrexate (MTX) group, and composition group, with 10 rats in each group.

[0055] 2. Modeling method and drug administration

[0056] Except for the normal group, arthritis rat models were constructed by inducing with bovine type II collagen in the remaining groups. The specific modeling method was as follows: Bovine type II collagen (Lot: 20021, Chondrex, USA) and incomplete Freund's adjuvant (Lot: 7002, Chondrex, USA) were mixed and emulsified at a volume ratio of 1:1, and homogenized with a homogenizer ( Germany) for 30 min. On the first day, the rats were anesthetized with 10% chloral hydrate by volume, and 200 μg / rat was injected subcutaneously at multiple points on the rat tail and subcutaneously on the paws; on the eighth day, a booster immunization was performed once (100 μg / rat). The modeling lasted for 14 days to obtain a type II collagen-induced arthritis (CIA) rat model. On this basis of the CIA model, continuous drug administration was started on the 15th day for 35 days. The experimental design process is as Figure 1 shown.

[0057] The composition group was given the traditional Chinese medicine decoction of Example 1, and the daily drug administration dose was converted into the clinical equivalent dose of 12.3 g / kg and administered by gavage every day; the methotrexate group was given methotrexate (MTX) intervention, and the drug administration dose was converted into the clinical equivalent dose of 1.02 mg / kg and administered by gavage 2 times a week; the normal group and the CIA model group were given normal saline by gavage every day. The drug administration cycle was 35 days for all groups. The drug intervention conditions of each group (all converted into clinical drug administration doses) are shown in Table 1:

[0058] Table 1 Drug intervention conditions of each group

[0059] Group Number of animals / only Model establishment Drug administration Normal group 10 None Normal saline CIA model group 10 CIA model Normal saline Methotrexate group 10 CIA model MTX (1.02 mg / kg / twice a week) Composition group 10 CIA model Traditional Chinese medicine decoction of Example 1 (12.3 g / kg / d)

[0060] On the 50th day of the experiment, the composition group was compared with the normal group, the CIA model group, and the methotrexate group to observe the swelling degree of the hind foot ankle joints of the rats, the X-ray imaging changes of the hind limbs of the rats, joint pathological sections, the expression levels of serum inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), and the expression of spleen-thymus coefficients.

[0061] 3. Experimental results

[0062] (1) Body weight, thymus coefficient, spleen coefficient

[0063] The changing trends of the body weights of the rats in each group were as Figure 2 shown, the comparison of spleen indices was as Figure 3 shown, and the comparison of thymus indices was as Figure 4 shown. It could be seen from Figures 2 - 4 that there were no statistically significant differences in the body weights, thymus coefficients, and spleen coefficients of the rats in each group (p > 0.05). This indicated that the traditional Chinese medicine composition of the present invention had no obvious effect on the body weight, thymus coefficient, and spleen coefficient of CIA rats.

[0064] (2) Joint swelling degree

[0065] The measurement results of the ankle joint swelling degrees of the rats in each group were as Figure 5 shown, and the changes in the ankle joint swelling degrees before and after drug administration were as Figure 6 shown. It could be seen from Figure 5 that after one week of treatment, the joint swelling degree of the rats in the model group was significantly increased compared with the other three groups. It could be seen from Figure 6 that after 1 month of treatment, the joint swelling degrees of the composition group and the methotrexate group were significantly decreased compared with the model group (P < 0.05). This indicated that the traditional Chinese medicine composition of the present invention could significantly improve the joint swelling degree of CIA rats.

[0066] (3) Serum inflammatory indicators

[0067] The analysis of the serum TNF-α results of the rats in each group after treatment was as Figure 7 shown. It could be seen from Figure 7 that compared with the normal group, the serum TNF-α level in the CIA model group was significantly increased (p < 0.05). After drug treatment, the expressions of serum TNF-α in the composition group and the methotrexate group of rats were both significantly decreased (p < 0.05). Thus, it could be seen that the composition of the present invention had an obvious down-regulating effect on the serum tumor necrosis factor α level of CIA rats, indicating that the composition of the present invention had a significant anti-inflammatory effect.

[0068] The analysis of the serum IL-1β results of the rats in each group after treatment was as Figure 8 shown. It could be seen from Figure 8It can be seen that, compared with the normal group, the serum IL-1β level in the CIA model group was significantly increased (p < 0.05). After treatment with the drug, the expression of serum IL-1β in the composition group and the methotrexate group of rats was significantly decreased (p < 0.05). Thus, it can be seen that the composition of the present invention has an obvious down-regulating effect on the serum interleukin 1β level of CIA rats, indicating that the composition of the present invention has a significant anti-inflammatory effect.

[0069] (4) Conditions such as rat paw swelling, inflammatory cell infiltration, and joint destruction

[0070] Typical photos of joint swelling in rats of each group after treatment are as Figure 9 shown. From Figure 9 it can be seen that after 1 month of treatment and administration, the degree of paw swelling in CIA rats in the composition group was reduced compared with the model group. Thus, it is shown that the traditional Chinese medicine composition of the present invention can reduce paw swelling in CIA rats.

[0071] X-ray photographs of the ankle joints of rats in each group after treatment are as Figure 10 shown. The part circled by the small red circle in the figure shows joint bone destruction, and the part circled by the large yellow circle shows paw swelling. From Figure 10 it can be seen that after 1 month of treatment and administration, the degree of paw swelling and joint destruction in CIA rats in the composition group was reduced compared with the model group. Thus, it is shown that the traditional Chinese medicine composition of the present invention can reduce paw swelling and joint destruction and other conditions in CIA rats.

[0072] Pathological analysis of the ankle joint tissues of rats in each group after treatment is as Figure 11 shown. From Figure 11 it can be seen that, compared with the normal group, the joint surface disappeared in the CIA model group, there was a lot of inflammatory cell infiltration in the joint cavity, synovial hyperplasia, and severe inflammatory cell infiltration in the connective tissue; the joint cavity in the composition group was cleaner, the inflammatory infiltration and other conditions were significantly improved, and the synovial hyperplasia was improved to some extent. Thus, it is shown that the traditional Chinese medicine composition of the present invention has the effects of improving the proliferation of synovial tissues in the ankle joints of CIA rats, reducing inflammatory cell infiltration, and delaying bone and cartilage destruction.

[0073] Conclusion: The composition for preventing rheumatoid arthritis of the present invention can significantly reduce the degree of joint swelling in CIA rats. X-ray shows that it can improve bone destruction, and pathological sections show that it has good effects of inhibiting synovial tissue proliferation, reducing inflammatory cell infiltration, and delaying bone and cartilage destruction; it can significantly reduce the expression levels of inflammatory cytokines TNF-α and IL-1β in the serum of CIA rats; it has the effects of improving symptoms, bone protection, and anti-inflammation on CIA rats.

[0074] II. Clinical experiment

[0075] The traditional Chinese medicine decoction of Example 1 of the present invention is taken once a day, 150 mL per dose, and taken warm twice a day, twice a day, and the treatment period is 6 months.

[0076] The experimental results are as follows:

[0077] Figures 12 - 13 It is a graph of anti-CCP antibody and its changes before and after treatment. Generally speaking, after 24 weeks of treatment, the proportion of high-titer CCP antibodies in patients decreased, and the overall antibody reduction rate was 56% (P>0.05).

[0078] Figures 14 - 15 It is a graph of RF titer and its changes before and after treatment. It can be seen from the graph that the change in the overall RF titer proportion in patients is not significant. After 24 weeks of treatment, the RF reduction rate is 66.67% (P>0.05).

[0079] Figures 16 - 17 It is a graph of hsCRP titer and its changes before and after treatment. It can be seen from the graph that after 24 weeks of treatment, the hsCRP reduction rate is 45% (P>0.05), and the change in the overall titer proportion is not significant.

[0080] Figures 18 - 19 It is a graph of ESR titer and its changes before and after treatment. It can be seen from the graph that after 24 weeks of treatment, the ESR reduction rate is 44% (P>0.05), and the change in the overall titer proportion is not significant.

[0081] In summary, the composition for preventing rheumatoid arthritis of the present invention has the potential effects of reducing anti-CCP antibody, RF, hsCRP, and ESR, and has a potential joint protection effect.

Claims

1. A composition for treating rheumatoid arthritis, characterized in that, It is made from the following raw material components by mass parts: 15 - 60 parts of raw coix seed, 5 - 30 parts of angelica, 5 - 30 parts of white peony root, 1 - 15 parts of ephedra, 5 - 30 parts of cassia twig, 5 - 30 parts of roasted licorice root, 5 - 30 parts of atractylodes rhizome, 10 - 60 parts of astragalus membranaceus.

2. The composition for treating rheumatoid arthritis according to claim 1, wherein It is made from the following raw material components by mass parts: 30 parts of raw coix seed, 10 parts of angelica, 10 parts of white peony root, 3 parts of ephedra, 10 parts of cassia twig, 15 parts of roasted licorice root, 15 parts of atractylodes rhizome, 30 parts of astragalus membranaceus.

3. A method for preparing a composition for treating rheumatoid arthritis as described in claim 1 or 2, characterized in that, Each component is separately pulverized, sieved, and mixed to obtain a composition for treating rheumatoid arthritis.

4. Use of a composition for treating rheumatoid arthritis as claimed in claim 1 or 2 in the preparation of a medicament for treating rheumatoid arthritis.

5. A traditional Chinese medicine preparation, characterized in that, It uses the composition for treating rheumatoid arthritis as claimed in claim 1 or 2 as an active ingredient.

6. The traditional Chinese medicine preparation according to claim 5, wherein It further includes a pharmaceutically acceptable excipient.

7. The traditional Chinese medicine preparation according to claim 6, characterized in that, The excipient is at least one of a shaping agent, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.

8. Use of the traditional Chinese medicine preparation as claimed in any one of claims 5 - 7 in the preparation of a medicament for treating rheumatoid arthritis.

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