WO2022227331A1 - 一种预防类风湿关节炎的组合物及其制备方法与应用 - Google Patents

一种预防类风湿关节炎的组合物及其制备方法与应用 Download PDF

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WO2022227331A1
WO2022227331A1 PCT/CN2021/111561 CN2021111561W WO2022227331A1 WO 2022227331 A1 WO2022227331 A1 WO 2022227331A1 CN 2021111561 W CN2021111561 W CN 2021111561W WO 2022227331 A1 WO2022227331 A1 WO 2022227331A1
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parts
rheumatoid arthritis
composition
preventing rheumatoid
present
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PCT/CN2021/111561
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English (en)
French (fr)
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黄闰月
温泽淮
黄清春
赵越
吴晓东
陈秀敏
夏璇
郭晓慧
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广东省中医院
广州中医药大学第二附属医院
广州中医药大学第二临床医学院
广东省中医药科学院
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Priority to SE2351358A priority Critical patent/SE2351358A1/en
Publication of WO2022227331A1 publication Critical patent/WO2022227331A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8994—Coix (Job's tears)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/17—Gnetophyta, e.g. Ephedraceae (Mormon-tea family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/284—Atractylodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of traditional Chinese medicine, and particularly relates to a composition for preventing rheumatoid arthritis and a preparation method and application thereof.
  • RA Rheumatoid arthritis
  • cartilage damage and bone destruction The clinical manifestations are symmetrical and persistent joint swelling and pain, often accompanied by morning stiffness. , severe cases can lead to progressive disability, systemic complications, early death and other consequences.
  • the European League against Rheumatism proposed that the occurrence and development of RA can be divided into six stages, including the stage of RA-related genetic risk factors, the stage of RA-related environmental factors, and the stage of RA-related systemic autoimmunity. Stage, stage without clinical symptoms of arthritis, stage of undifferentiated arthritis and classification diagnosis of RA stage.
  • the stage with RA-related genetic risk factors, the stage of RA-related environmental risk factors, the stage of RA-related systemic immune disorders, and the stage without clinical arthritis are collectively referred to as pre-clinical RA, namely pre-RA (Preclinical rheumatoid arthritis, Pre-RA). not RA.
  • Pre-RA preclinical stage
  • a composition for preventing rheumatoid arthritis which is made 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 30 parts, 1-15 parts of ephedra, 5-30 parts of Guizhi, 5-30 parts of Zhigancao, 5-30 parts of Atractylodes, and 10-60 parts of Astragalus.
  • Coix seed, Atractylodes, Ephedra Coix seed and Atractylodes Rhizoma invigorate the spleen and infiltrate dampness, and ephedra warms the meridians and disperses cold, and can help astragalus and cinnamon twigs to remove dampness and relieve pain.
  • Adjuvant white peony root, angelica. Baishao combined with Astragalus, nourishes blood and softens the liver, controls the dryness of Astragalus; Angelica sinensis powder is mild and clear, nourishes blood and activates blood and promotes Qi.
  • the medicine Zhigancao. Licorice reconciles various medicines.
  • Coix seed the dried mature seed kernel of the Poaceae Coix lacryma-jobi L.var.ma-yuen (Roman.) Stapf. Sweet, light, cool. Returns to the spleen, stomach and lung meridians. Invigorating the spleen, invigorating the spleen, invigorating the spleen and eliminating dampness, eliminating paralysis and stopping diarrhea, clearing heat and expelling thickening.
  • Angelica The dried root of Angelica sinensis (Oliv.) Diels of the Umbelliferae plant. Sweet, spicy, warm. Returns liver, heart and spleen meridians. Nourishes blood and activates blood, regulates menstruation and relieves pain, and relaxes bowels.
  • Paeonia lactiflora The dried root of the Ranunculaceae plant Paeonia lactiflora Pall. Bitter, sour, slightly cold. Return to the liver and spleen meridians. Calming the liver and relieving pain, nourishing blood and regulating menstruation, astringing yin and stopping sweating.
  • Ephedra The dried herbaceous stems of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C.A.Mey. or Ephedra equisetina Bge. Pungent, slightly bitter, warm. Returns to the lung and bladder meridians. Sweating and dispelling cold, dispelling lung and relieving asthma, diuresis and swelling.
  • Cinnamon twigs dried shoots of the Lauraceae plant Cinnamomum cassia Presl. Spicy, sweet, warm. Return to the heart, lung and bladder meridians. Sweating and releasing muscles, warming and dredging meridians, helping yang to transform qi, and calming chong and lowering qi.
  • Zhigancao Leguminosae, licorice is a perennial herb. The medicinal parts are roots and rhizomes. It is made by concocting licorice with honey and boiled water. Gan, flat. The medicinal properties are mild, can sink and descend, can float and sink, and return to the heart, lung, spleen and stomach meridians. It is good at reconciling the properties of various medicines.
  • Atractylodes dried rhizomes of Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz. Pungent, bitter, warm. Return to the spleen, stomach and liver meridians. Dry dampness and strengthen the spleen, dispel wind and dispel cold, improve eyesight.
  • Astragalus The dried root of the legume Astragalus membranaceus (Fisch.) Bge.var. mongolicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. Gan, Wen. Return to the lung and spleen meridians. Invigorating Qi and solidifying the surface, diuretic support toxins, expelling pus, astringing sores and producing muscles.
  • the composition for preventing rheumatoid arthritis is made from the following raw material components in parts by mass: 30 parts of raw 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 Zhigancao, 15 parts of Atractylodes, and 30 parts of Astragalus.
  • the traditional Chinese medicine composition provided by the invention has the functions of improving symptoms and reducing the risk of rheumatoid arthritis in the preclinical stage, and has no obvious liver and kidney toxicity.
  • the components are respectively crushed, sieved and mixed to obtain the composition for preventing rheumatoid arthritis.
  • compositions for preventing rheumatoid arthritis in preparing a medicament for preventing and/or treating rheumatoid arthritis.
  • a traditional Chinese medicine preparation which uses the above-mentioned composition for preventing rheumatoid arthritis as an active ingredient.
  • the traditional Chinese medicine preparation further includes medically acceptable excipients.
  • the adjuvant is at least one of a sustained release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.
  • the selected adjuvants in the present invention are conventional adjuvants in the field of traditional Chinese medicine pharmacy, for example, the slow-release agent and excipient can be water, the filler can be starch, sucrose, and the binder can be cellulose derivatives, alginate, gelatin and Polyvinylpyrrolidone, wetting agent can be glycerin, disintegrating agent can be agar, calcium carbonate and sodium bicarbonate, absorption accelerator can be quaternary ammonium compound, adsorption carrier can be kaolin and bentonite, surfactant can be hexadecane Alcohol, lubricants can be talc, calcium/magnesium stearate, polyethylene glycol.
  • other adjuvants such as flavors, sweeteners, etc. can be added.
  • the dosage form of the traditional Chinese medicine preparation of the present invention can be conventional traditional Chinese medicinal forms such as decoction, tablet, capsule, pill, powder, granule, syrup and the like.
  • 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 section shows that it can effectively inhibit the proliferation of synovial tissue, reduce the Inflammatory cell infiltration and delaying the destruction of bone and cartilage; can significantly reduce the expression levels of inflammatory cytokines TNF- ⁇ and IL-1 ⁇ in serum of CIA rats; improve symptoms, bone protection and anti-inflammatory effects in CIA rats.
  • composition for preventing rheumatoid arthritis of the present invention has the potential effect of reducing CCP antibody, RF, hsCRP and ESR, and has potential joint protection effect.
  • Figure 1 is a flow chart of the experimental design of the type II collagen (Col II)-induced arthritis (CIA) rat model
  • Fig. 2 is the body weight change trend of each group of rats in the CIA rat experimental part of the present invention
  • Fig. 3 is the spleen index comparison of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 4 is the thymus index contrast of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 5 is the ankle joint swelling degree measurement result of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 6 is the change of ankle joint swelling degree before and after administration of each group of rats in the CIA rat experimental part of the present invention
  • Fig. 7 is the serum TNF- ⁇ result after the treatment of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 8 is the serum IL-1 ⁇ result of each group of rats in the CIA rat experimental part of the present invention after treatment;
  • Fig. 9 is a typical photograph of joint swelling after the treatment of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 10 is the X-ray photograph of the ankle joint after the treatment of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 11 is the pathological picture of ankle joint HE after the treatment of each group of rats in the CIA rat experimental part of the present invention
  • Figures 12 to 13 are diagrams of anti-CCP antibodies and their changes before and after treatment in clinical trial patients of the present invention.
  • Figures 14 to 15 are diagrams of RF titers and their changes before and after treatment in clinical trial patients of the present invention.
  • Figures 16 to 17 are graphs of the hsCRP titer and its changes before and after treatment in clinical trial patients of the present invention.
  • Figures 18-19 are diagrams of ESR titers and their changes before and after treatment in clinical trial patients of the present invention.
  • the traditional Chinese medicine decoction for preventing rheumatoid arthritis in this example 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 cinnamon stick, 15 g of licorice root, 15 g of Chinese herbal medicine, and 30 g of astragalus root.
  • the raw materials are weighed according to the weight ratio, crushed, sieved and mixed respectively to obtain a composition for preventing rheumatoid arthritis. , and the aqueous extract was subjected to rotary evaporation to obtain 150 mL of solution, that is.
  • bovine type 2 collagen (Lot: 20021, Chondrex, USA) and incomplete Freund's adjuvant. (Lot: 7002, Chondrex, USA) was mixed and emulsified according to the volume ratio of 1:1, using a homogenizer (IKA Germany) was homogenized for 30 min, and the rats were anesthetized with 10% chloral hydrate on the first day, and 200ug/rat was injected subcutaneously in the tail and paw of the rats at multiple points; on the eighth day, a booster immunization (100ug per rat), the model was established for a total of 14 days, and a rat model of collagen-induced arthritis (CIA) was obtained.
  • the experimental design process is shown in Figure 1.
  • composition group was given the traditional Chinese medicine decoction of Example 1, and the daily dose was converted into a clinically equivalent dose of 12.3 g/kg, which was administered by gavage every day; the methotrexate group was given methotrexate (MTX) intervention, and the administration
  • the dose converted into a clinical equivalent dose was 1.02 mg/kg, which was administered by intragastric administration twice a week; the rats in the normal group and the CIA model group were intragastrically administered with normal saline every day.
  • the dosing cycle is 35 days.
  • the drug interventions in each group are shown in Table 1:
  • composition group was compared with the normal group, the CIA model group and the methotrexate group, and the swelling degree of the hind foot and ankle joints of the rats, the X-ray imaging changes of the hind limbs of the rats, the joint pathological sections, and serum inflammatory cells were observed.
  • TNF- ⁇ tumor necrosis factor ⁇
  • IL-1 ⁇ interleukin 1 ⁇
  • the body weight change trend of the rats in each group is shown in Figure 2, the comparison of the spleen index is shown in Figure 3, and the comparison of the thymus index is shown in Figure 4. It can be seen from Figures 2 to 4 that there was no statistical difference in the body weight, thymus coefficient and spleen coefficient of the rats in each group (p>0.05). This shows that the traditional Chinese medicine composition of the present invention has no obvious effect on the body weight, thymus gland coefficient and spleen coefficient of CIA rats.
  • Figure 9 shows typical photos of joint swelling of rats in each group after treatment. It can be seen from Figure 9 that after 1 month of treatment and administration, the degree of foot swelling of CIA rats in the composition group is less than that in the model group. This shows that the traditional Chinese medicine composition of the present invention can reduce the swelling of the foot of CIA rats.
  • Figure 10 shows the X-ray pictures of the ankle joints of the rats in each group after treatment.
  • the part circled by the small red circle in the figure shows the destruction of the joint bone
  • the part circled by the large yellow circle shows the swelling of the foot pad.
  • FIG 11 The histopathological analysis of the ankle joints of the rats in each group after treatment is shown in Figure 11. It can be seen from Figure 11 that, compared with the normal group, the articular surface of the CIA model group disappeared and the joint cavity was multi-inflammatory cell infiltration, synovial hyperplasia, and connective tissue. The tissue inflammatory cell infiltration was serious; the joint cavity of the composition group was relatively clean, the inflammatory infiltration and other conditions were obviously improved, and the synovial hyperplasia was improved to some extent.
  • the traditional Chinese medicine composition of the present invention has the effects of improving the proliferation of CIA rat ankle synovial tissue, reducing the infiltration of inflammatory cells, and delaying the destruction of bone and cartilage.
  • 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 section shows that it can effectively inhibit the proliferation of synovial tissue, reduce the infiltration of inflammatory cells, and delay the bone destruction. It can significantly reduce the expression levels of inflammatory cytokines TNF- ⁇ and IL-1 ⁇ in serum of CIA rats; it can improve symptoms, bone protection and anti-inflammatory effects in CIA rats.
  • Example 1 of the present invention The traditional Chinese medicine decoction of Example 1 of the present invention, one dose per day, 150 mL per dose, divided into two warm doses, twice a day, for a treatment period of 6 months.
  • Figures 12-13 are graphs of anti-CCP antibodies and their changes before and after treatment. On the whole, after 24 weeks of treatment, the proportion of high titers of patients' CCP antibody titers decreased, and the overall antibody decline rate was 56% (P>0.05).
  • Figures 14-15 are diagrams of RF titers and their changes before and after treatment. As can be seen from the figure, the overall RF titer ratio of the patients did not change much, and the RF decline rate was 66.67% after 24 weeks of treatment (P>0.05).
  • Figures 16-17 are graphs of hsCRP titers and their changes before and after treatment. As can be seen from the figure, after 24 weeks of treatment, the hsCRP decreased rate was 45% (P>0.05), and the overall titer ratio did not change much.
  • FIGs 18-19 are diagrams of ESR titers and their changes before and after treatment. It can be seen from the figure that after 24 weeks of treatment, the ESR decline rate was 44% (P>0.05), and the overall titer ratio did not change much.
  • composition for preventing rheumatoid arthritis of the present invention has the potential effect of reducing CCP antibody, RF, hsCRP and ESR, and has potential joint protection effect.

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Abstract

本发明属于中药领域，具体涉及一种预防类风湿关节炎的组合物及其制备方法与应用。本发明的预防类风湿关节炎的组合物以质量份计由如下原料组分制成：生薏苡仁15-60份、当归5-30份、白芍5-30份、麻黄1-15份、桂枝5-30份、炙甘草5-30份、苍术5-30份、黄芪10-60份。经CIA大鼠模型实验证明，本发明的预防类风湿关节炎的组合物可明显减轻CIA大鼠关节肿胀度，X线显示能改善骨破坏，病理切片显示有良好的抑制滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏的效果；对CIA大鼠具有改善症状、骨保护及抗炎的作用。

Description

一种预防类风湿关节炎的组合物及其制备方法与应用 技术领域
本发明属于中药领域，具体涉及一种预防类风湿关节炎的组合物及其制备方法与应用。
背景技术
类风湿关节炎(rheumatoid arthritis,RA)是一种常见的慢性炎症性自身免疫性疾病，以软骨损伤、骨破坏为特点，临床表现为对称性、持续性关节肿胀和疼痛，常伴有晨僵，严重者可导致进行性残疾、全身并发症、早期死亡等后果。
2012年欧洲抗风湿病联盟(European League Against Rheumatism,EULAR)提出，将RA的发生、发展具体分为6个阶段，包括RA相关遗传风险因素阶段、RA相关环境因素阶段、RA相关系统性自身免疫阶段、无临床关节炎症状阶段、未分化关节炎阶段及分类诊断RA阶段。而具有RA相关遗传风险因素阶段、RA相关环境风险因素阶段、RA相关系统免疫紊乱阶段及无临床关节炎阶段总称为RA的临床前期，即pre-RA(Preclinical rheumatoid arthritis,Pre-RA)，而不是RA。
研究表明疾病在可检测到临床症状之前就已经开始活跃，出现关节炎与相关抗体阳性的患者有将近30％的概率在一年内发展成RA。因此，相对于明确诊断的RA患者，适当干预处于临床前期阶段(即Pre-RA)的患者会更有效地阻止疾病的进展。
目前国际对于Pre-RA的治疗尚未形成统一的共识，缺乏公认安全有效阻断Pre-RA往RA进展的药物，积极探索Pre-RA的预防性治疗方案是当下的研究热点。与西药相比，中药具有更稳定、更安全、副作用更少的优点，因此，寻找一种有效的干预Pre-RA的中药方案是中医界的一个难点和困惑。
发明内容
根据本发明的一个方面，提供了一种预防类风湿关节炎的组合物，以质量份计由如下原料组分制成：生薏苡仁15-60份、当归5-30份、白芍5-30份、麻黄1-15份、桂枝5-30份、炙甘草5-30份、苍术5-30份、黄芪10-60份。
本发明的中药组合物遣方原理：
君药：黄芪、桂枝。桂枝散风寒而温经通痹，与黄芪配伍，益气温阳，和血通经。
臣药：薏苡仁、苍术、麻黄。薏苡仁、苍术健脾渗湿，麻黄温经散寒性，可助黄芪、桂枝以除湿通痹止痛。
佐药：白芍、当归。白芍佐黄芪，养血柔肝、制黄芪之燥；当归辛散性温和通，养血活血兼以行气。
使药：炙甘草。甘草调和诸药。
薏苡仁：禾本科植物薏苡Coix lacryma-jobi L.var.ma-yuen(Roman.)Stapf的干燥成熟种仁。甘、淡，凉。归脾、胃、肺经。健脾渗湿，除痹止泻，清热排浓。
当归：伞形科植物当归Angelica sinensis(Oliv.)Diels的干燥根。甘、辛，温。归肝、心、脾经。补血活血，调经止痛，润肠通便。
白芍：毛茛科植物芍药Paeonia lactiflora Pall.的干燥根。苦、酸，微寒。归肝、脾经。平肝止痛，养血调经，敛阴止汗。
麻黄：麻黄科植物草麻黄Ephedra sinica Stapf、中麻黄Ephedra intermedia Schrenk et C.A.Mey.或木贼麻黄Ephedra equisetina Bge.的干燥草质茎。辛、微苦，温。归肺、膀胱经。发汗散寒，宣肺平喘，利水消肿。
桂枝：樟科植物肉桂Cinnamomum cassia Presl的干燥嫩枝。辛、甘，温。归心、肺、膀胱经。发汗解肌，温通经脉，助阳化气，平冲降气。
炙甘草：豆科、甘草属多年生草本，药用部位是根及根茎，为将甘草用蜂蜜、开水炮制而成。甘，平。药性缓和，能沉能降，能浮能沉，归心、肺、脾、胃经。既能补中益气，又善于调和诸药性能。
苍术：菊科植物茅苍术Atractylodes lancea(Thunb.)DC.或北苍术Atractylodes chinensis(DC.)Koidz.的干燥根茎。辛、苦，温。归脾、胃、肝经。燥湿健脾，祛风散寒，明目。
黄芪：豆科植物蒙古黄芪Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao或膜荚黄芪Astragalus membranaceus(Fisch.)Bge.的干燥根。甘，温。归肺、脾经。补气固表，利尿托毒，排脓，敛疮生肌。
在一些实施方式中，预防类风湿关节炎的组合物以质量份计由如下原料组分制成：生薏苡仁30份、当归10份、白芍10份、麻黄3份、桂枝10份、炙甘草15份、苍术15份、黄芪30份。
本发明提供的中药组合物对临床前期类风湿关节炎具有改善症状、降低发病风险的作用，且无明显肝肾毒性。
根据本发明的另一个方面，提供了上述的预防类风湿关节炎的组合物的制备方法：将各组分分别粉碎、过筛、混合，得到预防类风湿关节炎的组合物。
根据本发明的另一个方面，提供了上述的预防类风湿关节炎的组合物在制备预防和/或治疗类风湿关节炎药物中的应用。
根据本发明的另一个方面，提供了一种中药制剂，其以上述的预防类风湿关节炎的组合物为有效成分。
在一些实施方式中，中药制剂还包括医学上可接受的辅料。优选的，辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂、润滑剂中的至少一种。本发明所选辅料为中药制药领域的常规辅料，例如，缓释剂、赋形剂可为水，填充剂可为淀粉、蔗糖，粘合剂可为纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮，湿润剂可为甘油，崩解剂可为琼脂、碳酸钙和碳酸氢钠，吸收促进剂可为季铵化合物，吸附载体可为高岭土和皂粘土，表面活性剂可为十六烷醇，润滑剂可为滑石粉、硬脂酸钙/镁、聚乙二醇。此外还可加入其它辅剂如香味剂、甜味剂等。
本发明的中药制剂的剂型可为汤剂、片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂等常规中药剂型。
根据本发明的另一个方面，提供了一种上述的中药制剂在制备预防和/或治疗类风湿关节炎药物中的应用。
经CIA大鼠模型实验证明，本发明的预防类风湿关节炎的组合物可明显减轻CIA大鼠关节肿胀度，X线显示能改善骨破坏，病理切片显示有良好的抑制滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏的效果；可显著降低CIA大鼠血清中炎症细胞因子TNF-α和IL-1β表达水平；对CIA大鼠具有改善症状、骨保护及抗炎的作用。
临床实验证明，本发明的预防类风湿关节炎的组合物有降低CCP抗体、RF、hsCRP、ESR的潜在效果，且具有潜在的关节保护作用。
附图说明
图1是二型胶原(ColⅡ)诱导关节炎(CIA)大鼠模型实验设计流程图；
图2是本发明CIA大鼠实验部分各组大鼠的体重变化趋势；
图3是本发明CIA大鼠实验部分各组大鼠的脾脏指数对比；
图4是本发明CIA大鼠实验部分各组大鼠的胸腺指数对比；
图5是本发明CIA大鼠实验部分各组大鼠的踝关节肿胀度测量结果；
图6是本发明CIA大鼠实验部分各组大鼠给药前后踝关节肿胀度变化；
图7是本发明CIA大鼠实验部分各组大鼠治疗后的血清TNF-α结果；
图8是本发明CIA大鼠实验部分各组大鼠治疗后的血清IL-1β结果；
图9是本发明CIA大鼠实验部分各组大鼠治疗后的关节肿胀典型照片；
图10是本发明CIA大鼠实验部分各组大鼠治疗后的踝关节X光拍照图；
图11是本发明CIA大鼠实验部分各组大鼠治疗后的踝关节HE病理图；
图12～13是本发明临床实验患者治疗前后抗CCP抗体及其变化情况图；
图14～15是本发明临床实验患者治疗前后RF滴度及其变化情况图；
图16～17是本发明临床实验患者治疗前后hsCRP滴度及其变化情况图；
图18～19是本发明临床实验患者治疗前后ESR滴度及其变化情况图。
具体实施方式
下面结合具体实施例对本发明作进一步详细的说明。
实施例1
本实施例预防类风湿关节炎的中药汤剂，由以下组分制备得到：生薏苡仁30g、当归10g、白芍10g、麻黄3g、桂枝10g、炙甘草15g、苍术15g、黄芪30g。
本实施例的中药汤剂采取下述方法制备得到：
按重量配比称取原料，将原料分别粉碎、过筛、混合，得到预防类风湿关节炎的组合物，将得到的预防类风湿关节炎的组合物用3000mL离子水煎煮60min，去渣离心，水提液经过旋转蒸发，得到150mL溶液，即得。
应该说明的是，上述中药汤剂的制备方式只是示例性的，并不对本发明所保护的范围做限制，当然，还可以采用本领域通常使用技术进行制备，在此不一一举出。
下面，为探究本发明的预防类风湿关节炎的组合物对类风湿关节炎的防治效果，进行二型胶原(ColⅡ)诱导关节炎(CIA)大鼠模型实验和临床实验。
一、二型胶原(ColⅡ)诱导关节炎(CIA)大鼠模型实验
1、实验对象
40只8周龄雌性SPF级健康Wistar大鼠，体重180～220g，随机分为4组：正常组、CIA模型组、甲氨蝶呤(MTX)组、组合物组，每组10只。
2、造模方法及给药
除正常组外，其余各组均用牛二型胶原蛋白诱导构建关节炎大鼠模型，具体造模方法为：牛二型胶原蛋白(Lot:20021,Chondrex,USA)和不完全弗氏佐剂(Lot:7002,Chondrex,USA)按照体积比1:1混合乳化，用匀浆机(IKA
Figure PCTCN2021111561-appb-000001
Germany)匀浆30min，在第一天用体积分数为10％的水合氯醛将大鼠麻醉后，在大鼠尾部皮下、爪部皮下多点注射200ug/只；第八天加强免疫一次(100ug/只)，造模共计14天，得到II型胶原诱导型关节炎(CIA)大鼠模型，在此CIA模型基础上，第15天开始连续给药35天。实验设计流程如图1所示。
组合物组给予实施例1的中药汤剂，每天的给药剂量换算成临床等效剂量为12.3g/kg，每天灌胃；甲氨蝶呤组给予甲氨蝶呤(MTX)干预，给药剂量换算成临床等效剂量为1.02mg/kg，每周灌胃2次；正常组和CIA模型组大鼠每天给予生理盐水灌胃。给药周期均为35天。各组药物干预情况(均换算成临床给药剂量)如表1所示：
表1各组药物干预情况
组别 动物数目/只 造模 给药
正常组 10 无 生理盐水
CIA模型组 10 CIA模型 生理盐水
甲氨蝶呤组 10 CIA模型 MTX(1.02mg/kg/周2次)
组合物组 10 CIA模型 实施例1的中药汤剂(12.3g/kg/d)
实验第50天，将组合物组同正常组、CIA模型组、甲氨蝶呤组比较，观察大鼠后足踝关节肿胀度、大鼠后肢X线影像学改变、关节病理切片、血清炎症细胞因子肿瘤坏死因子α(TNF-α)和白介素1β(IL-1β)表达水平以及脾脏胸腺系数表达情况。
3、实验结果
(1)体重、胸腺系数、脾脏系数
各组大鼠的体重变化趋势如图2所示，脾脏指数对比如图3所示，胸腺指数对比如图4所示。从图2-图4可以看出，各组大鼠体重、胸腺系数、脾脏系数均无统计学差异(p＞0.05)。由此表明，本发明的中药组合物对CIA大鼠体重、胸腺系数、脾脏系数无明显影响。
(2)关节肿胀度
各组大鼠的踝关节肿胀度测量结果如图5所示，给药前后踝关节肿胀度变化如图6所示。从图5可以看出，治疗一周后模型组大鼠关节肿胀度相对其他三组的明显增大。从图6可以看出，治疗1个月后，组合物组和甲氨蝶呤组相对于模型组关节肿胀度明显下降(P<0.05)，由此表明，本发明的中药组合物可明显改善CIA大鼠关节肿胀度。
(3)血清炎症指标
各组大鼠治疗后的血清TNF-α结果分析如图7所示，从图7可以看出，相对于正常组，CIA模型组血清TNF-α水平显著升高(p＜0.05)。用药治疗后，组合物组与甲氨蝶呤组大鼠血清TNF-α表达均显著减少(p＜0.05)。由此可见本发明的组合物对CIA大鼠血清肿瘤坏死因子α水平有明显下调作用，表明本发明的组合物具有显著抗炎作用。
各组大鼠治疗后的血清IL-1β结果分析如图8所示，从图8可以看出，相对于正常组，CIA模型组血清IL-1β水平显著升高(p＜0.05)。用药治疗后，组合物组和甲氨蝶呤组大鼠血清IL-1β表达显著减少(p＜0.05)。由此可见本发明的组合物对CIA大鼠血清白介素1β水平有明显下调作用，表明本发明的组合物具有显著抗炎作用。
(4)大鼠足垫肿胀、炎性细胞浸润和关节破坏等情况
各组大鼠治疗后的关节肿胀典型照片如图9所示，从图9可以看出，经1个月治疗给药后，组合物组CIA大鼠足肿胀程度较模型组减轻。由此表明，本 发明的中药组合物可减轻CIA大鼠足肿胀。
各组大鼠治疗后的踝关节X光拍照图如图10所示，图中红色小圆圈圈起来的部分显示关节骨质破坏，黄色大圆圈圈起来的部分显示脚垫肿胀，从图10可以看出，经1个月治疗给药后，组合物组CIA大鼠足垫肿胀、关节破坏程度较模型组减轻。由此表明，本发明的中药组合物可减轻CIA大鼠足垫肿胀、关节破坏等情况。
各组大鼠治疗后的踝关节组织病理分析如图11所示，从图11可以看出，相对于正常组，CIA模型组关节面消失且关节腔多炎性细胞浸润、滑膜增生，结缔组织炎性细胞浸润严重；组合物组关节腔较干净，炎症浸润等情况明显改善，滑膜增生有所改善。由此表明本发明的中药组合物具有改善CIA大鼠踝关节滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏的效果。
结论：本发明的预防类风湿关节炎的组合物可明显减轻CIA大鼠关节肿胀度，X线显示能改善骨破坏，病理切片显示有良好的抑制滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏的效果；可显著降低CIA大鼠血清中炎症细胞因子TNF-α和IL-1β表达水平；对CIA大鼠具有改善症状、骨保护及抗炎的作用。
二、临床实验
本发明实施例1的中药汤剂，每日一剂，每剂150mL，分2次温服，一日两次，治疗周期6个月。
实验结果如下：
图12～13是治疗前后抗CCP抗体及其变化情况图。从整体上看，患者的CCP抗体滴度经过24周治疗后，高滴度所占比例均有所下降，总体抗体下降率为56％(P＞0.05)。
图14～15是治疗前后RF滴度及其变化情况图。从图中可以看出，患者整体RF滴度比例变化不大，经24周治疗后RF下降率为66.67％(P＞0.05)。
图16～17是治疗前后hsCRP滴度及其变化情况图。从图中可以看出，经过24周治疗后hsCRP下降率为45％(P＞0.05)，整体滴度比例变化不大。
图18～19是治疗前后ESR滴度及其变化情况图。从图中可以看出，经过24周治疗后ESR下降率为44％(P＞0.05)，整体滴度比例变化不大。
综上，本发明的预防类风湿关节炎的组合物有降低CCP抗体、RF、hsCRP、ESR的潜在效果，且具有潜在的关节保护作用。

Claims (8)

  1. 预防类风湿关节炎的组合物，其特征在于，以质量份计由如下原料组分制成：生薏苡仁15-60份、当归5-30份、白芍5-30份、麻黄1-15份、桂枝5-30份、炙甘草5-30份、苍术5-30份、黄芪10-60份。
  2. 根据权利要求1所述的预防类风湿关节炎的组合物，其特征在于，以质量份计由如下原料组分制成：生薏苡仁30份、当归10份、白芍10份、麻黄3份、桂枝10份、炙甘草15份、苍术15份、黄芪30份。
  3. 一种如权利要求1或2所述的预防类风湿关节炎的组合物的制备方法，其特征在于，将各组分分别粉碎、过筛、混合，得到预防类风湿关节炎的组合物。
  4. 一种如权利要求1或2所述的预防类风湿关节炎的组合物在制备预防和/或治疗类风湿关节炎药物中的应用。
  5. 一种中药制剂，其特征在于，其以权利要求1或2所述的预防类风湿关节炎的组合物为有效成分。
  6. 根据权利要求5所述的中药制剂，其特征在于，还包括医学上可接受的辅料。
  7. 根据权利要求6所述的中药制剂，其特征在于，所述辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂、润滑剂中的至少一种。
  8. 权利要求5-7任一项所述的中药制剂在制备预防和/或治疗类风湿关节炎药物中的应用。
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