WO2022237842A1 - 一种治疗类风湿关节炎的药物组合物及其制备方法 - Google Patents
一种治疗类风湿关节炎的药物组合物及其制备方法 Download PDFInfo
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Definitions
- the invention relates to a traditional Chinese medicine composition for treating rheumatoid arthritis and a preparation method thereof, which belongs to the field of application of Chinese herbal medicines and is mainly used clinically for rheumatoid arthritis.
- the symptoms include limb joint swelling, pain, tenderness, morning stiffness, joint Unfavorable flexion and extension, limited movement, numbness and heaviness of limbs, subcutaneous nodules, chills and aversion to wind, mental fatigue, etc.
- Rheumatoid arthritis is a systemic autoimmune disease characterized by erosive arthritis.
- the prevalence rate of this disease is 0.8% (range is 0.3% ⁇ 2.1%) of the population, and it is more common in women, and the number of women patients is about 3 times that of men.
- RA can occur at any age, with the peak incidence at the age of 30 to 50.
- the prevalence rate of RA is 0.34% in the north and 0.32% in the south.
- the main clinical manifestations of RA are symmetrical and persistent joint swelling and pain, often accompanied by morning stiffness.
- the affected joints are the proximal interphalangeal joints, metacarpophalangeal joints, wrist, elbow and toe joints;
- the jaw, sternoclavicular, and acromioclavicular joints may also be affected.
- the "swan neck” and “button flower” deformities of the fingers, joint ankylosis and subluxation of the metacarpophalangeal joints may appear, and the metacarpophalangeal joints deviate to the ulnar side.
- subcutaneous nodules may also appear, known as rheumatoid nodules; some patients may also have extra-articular manifestations such as lungs, eyes, cardiovascular system, and nervous system.
- RA autoimmune disease mainly chronic inflammation of the synovial membrane, pannus formation, and cartilage and bone destruction of the joint, which eventually lead to joint deformity and loss of function.
- RA is very harmful, the patient population is large, and the disability rate is high.
- the disability rate is 60% in 5 to 10 years, 90% in 30 years, and 50% in 5 years with extra-articular manifestations. , has become one of the main causes of labor force loss and disability in our country. In addition, most patients cannot receive effective and timely treatment. Therefore, it is urgent to actively carry out research on the prevention and treatment of RA.
- the treatment of RA has been a long-term research difficulty and hotspot in the field of rheumatology.
- the purpose of western medicine treatment of this disease is mainly to reduce or eliminate joint swelling, pain, morning stiffness or extra-articular symptoms caused by arthritis; to control the disease To prevent and reduce the destruction of joint bone, to achieve long-term clinical remission, to maintain the function of the affected joint as much as possible; to promote the repair of the damaged joint bone and improve its function; at the same time, the control system is involved, but the current application
- the drugs used to treat RA are all considered palliative treatments aimed at relieving clinical symptoms.
- Drug therapy for RA generally includes five types: nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, glucocorticoids, anticytokine agents, and immunomodulators.
- nonsteroidal anti-inflammatory drugs disease-modifying antirheumatic drugs
- glucocorticoids glucocorticoids
- anticytokine agents glucocorticoids
- immunomodulators include ibuprofen, naproxen, indomethacin, and diclofenac.
- these drugs cannot prevent the development of the disease and the occurrence of complications, and there are some side effects such as: gastrointestinal irritation, nitrogen quality Hyperemia, platelet dysfunction, allergic rhinitis and exacerbation of asthma, etc. Renal interstitial damage may occur after long-term use of these drugs.
- Methotrexate sulfasalazine, leflunomide, penicillamine, azathioprine, cyclophosphamide, cyclosporine, etc.
- Most of the antirheumatic drugs that improve the condition have liver and kidney dysfunction, gastrointestinal reactions, Adverse reactions such as bone marrow suppression; long-term application of glucocorticoids can not prevent the destruction of joint structure, can not improve the development of lesions, and the tolerance of long-term application increases, making it difficult to withdraw the drug. After regular medical treatment, the patient's condition is still uncontrollable. In order to correct the deformity and improve the quality of life, surgical treatment can be considered.
- the commonly used operations mainly include synovectomy, artificial joint replacement, arthrodesis and soft tissue repair, but surgical treatment is not necessary. The disease cannot be cured, and drug treatment is still required after surgery.
- autologous stem cell transplantation, T cell vaccine, and mesenchymal stem cell therapy may be effective in remission of RA, but they are only applicable to a small number of patients, and further clinical research is still needed. Therefore, seeking new treatment methods and measures, developing high-efficiency and low-toxic drugs and effective and reasonable treatment plans are important measures to significantly improve the symptoms of patients and reduce the incidence of RA disability, and are also the frontiers that are generally valued by the medical community at home and abroad. sex issues.
- the western medicines currently used for the treatment of RA mainly include antirheumatic drugs for improving symptoms and antirheumatic drugs for disease control.
- the latter category of drugs is still in the stage of exploration and experimentation, and the former category mainly includes non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biological agents, and glucocorticoids.
- Non-steroidal anti-inflammatory drugs mainly inhibit the activity of cyclooxygenase (COX) and reduce the synthesis of prostaglandins to have anti-inflammatory, analgesic, antipyretic and joint swelling effects.
- COX cyclooxygenase
- They are the most commonly used clinical drugs for the treatment of RA.
- such drugs have gastrointestinal symptoms, liver and kidney function damage, and possible increased cardiovascular adverse events, so the use of these drugs is limited for patients with the above diseases, and even ordinary patients need the lowest effective dose and short course of treatment.
- DMARDs Disease-modifying antirheumatic drugs
- These drugs do not have obvious analgesic and anti-inflammatory effects, so they are also called slow-acting anti-rheumatic drugs, but they can delay or control the progress of the disease. Gastrointestinal discomfort, hair loss, skin rash, liver and kidney damage, leukopenia, bone marrow suppression and other adverse reactions are common with these drugs. Clinically, early use is emphasized. For patients with complicated conditions, multi-joint involvement or extra-articular symptoms, multi-drug combination is required.
- TNF tumor necrosis factor
- IL interleukin
- rituximab rituximab
- T cell co-stimulatory signal inhibitors etc., because they are mostly injected subcutaneously or intravenously, there are infections, infusion reactions and high blood pressure, rash, itching, fever, nausea, joint pain and drugs Induced lupus-like syndrome, demyelinating lesions and other adverse reactions.
- Glucocorticoids It can quickly improve joint swelling and pain and systemic symptoms.
- short-acting hormones can be given, and the dose depends on the severity of the disease.
- the use of hormones has disadvantages such as difficulty in withdrawing the drug, and easy recurrence of the disease after stopping the drug.
- the pharmaceutical composition of the present invention is made by Professor Wu Yiling, honorary president of Hebei Yiling Hospital, academician of the Chinese Academy of Engineering, vice president of the Chinese Association of Traditional Chinese Medicine, and vice president of the Chinese Association of Integrative Medicine, based on the theory of collateral diseases in traditional Chinese medicine. , Dampness, heat, phlegm, blood stasis, and deficiency "cause collateral blockage to comprehensively analyze the pathogenesis and treatment of rheumatoid arthritis in traditional Chinese medicine, and combine years of clinical experience in the treatment of rheumatoid arthritis with empirical prescriptions for rheumatoid arthritis. It has been used clinically for nearly 20 years and has definite clinical curative effect.
- the pharmaceutical composition of the present invention is innovative in the principle of cubes and the composition of prescriptions.
- the etiology and incidence of the disease are comprehensively considered from various pathogenic factors such as wind, cold, dampness, heat, phlegm, stasis, and deficiency;
- the deficiency of righteousness and evil attacking the collaterals are the pathological basis of the disease, and the phlegm and blood stasis cementation and blockage of the collaterals are the main pathological links of the disease;
- the main treatment principles are the main treatment methods of expelling wind and cold, removing dampness, replenishing qi, removing blood stasis and dredging collaterals.
- the medicine is composed of Astragalus, Gentiana, Fangji, Heishun Tablets, Polygonum cuspidatum, Miltonia Spatholobus, Clematis, mustard seed, white peony root, rehmannia glutinosa, angelica, vinegar myrrh, Cyperus cyperi, Guizhi, and Achyranthes bidentata.
- Astragalus and Gentiana chinensis are used as kings to play the functions of expelling wind, dispelling cold and dehumidification, nourishing qi, dredging collaterals and relieving pain; at the same time, choosing Fangji to strengthen dispelling damp, dredging collaterals and relieving pain, Heishun tablets warming meridians, dispelling cold and dredging collaterals, Polygonum cuspidatum clearing heat, promoting dampness and relieving pain, chicken Blood vine and blood dissipating blood stasis and dredging collaterals are the merits of ministerial medicines helping monarch medicine to disperse evil spirits; together with Clematis clematis dispelling rheumatism, dredging collaterals and arthralgia, mustard seed dispelling phlegm and dredging collaterals, benefiting qi and dispelling stagnation, white peony root, Rehmannia glutinosa nourishes blood and nourishes yin
- This guideline comprehensively treats the internal and external causes of rheumatoid arthritis, which not only helps to improve symptoms such as local joint swelling and pain, morning stiffness, poor flexion and extension, and limited mobility, but also significantly improves limb numbness, severe chills, and nausea.
- Systemic clinical symptoms such as wind, mental fatigue and fatigue can improve the quality of life of patients, showing the unique advantages of this prescription.
- the pharmaceutical composition of the present invention is innovative in etiology and pathogenesis, prescription principles and prescription composition .
- Rheumatoid arthritis is a disease caused by external factors such as wind-cold-damp pathogenic numbness obstructing the collaterals, coupled with deficiency of righteousness, phlegm and blood stasis obstructing the collaterals, and agglomeration and formation.
- Insufficiency of righteousness "Nei Jing” pointed out that "when evil gathers together, its Qi must be deficient", “wind, wind, cold and heat must not be deficient, evil is not the only one to hurt people”, and the deficiency of righteousness plays a decisive role in the pathogenesis of arthralgia.
- Insufficient righteousness mainly includes insufficiency of congenital endowment, old age, kidney deficiency, loss of work and rest, postpartum and post-illness, which can damage righteousness.
- kidney deficiency is its root. Kidney governs bones, old people with kidney deficiency, insufficient marrow, bone loss of nourishment, then you can see arthralgia manifestations such as lumbar spine, joint, and heel pain. At the same time, when the kidney is deficient in old age, the righteous energy will be insufficient, the defenses will not be solidified, and the intersectoral muscles will be empty, so that evils such as wind, cold, and dampness will easily invade the body and cause this disease.
- Phlegm coagulation and blood stasis are not only the pathological products produced by pathogenic factors acting on the body, but also act on the body alone as a cause of disease, just as Yu Chang's "Medical Law” said: "The evil of wind, cold and dampness three numbness Every time I borrow the phlegm in someone's chest, I will help each other.”
- the long-term illness will affect the circulation of Qi and blood, so that blood stagnates into stasis, body fluid coagulates into phlegm, phlegm and blood stasis intertwine, block and close collaterals, and penetrate deep into bones; Where the collaterals are, the disease is lingering and difficult to heal.
- rheumatoid arthritis is mainly characterized by joint swelling and pain. Cold, dampness, heat, phlegm, blood stasis, deficiency and other pathological factors are related, and are closely related to collaterals. Although the syndromes are different from cold, heat, deficiency and excess, the common lesion feature is blockage of qi and blood in the collaterals of intersectary, fascia and joints, so "unblocking collaterals" is the general treatment principle.
- Dispelling pathogenic factors and dispersing numbness, replenishing qi and dredging collaterals are the main therapeutic principles for this disease, and establishing expelling wind and cold for dehumidification, replenishing qi, removing blood stasis and dredging collaterals are the main therapeutic methods for this disease.
- the inventor believes that according to the pathogenesis characteristics of traditional Chinese medicine in rheumatoid arthritis that "wind, cold, dampness, heat, phlegm, blood stasis, and deficiency" lead to obstruction of collaterals, the method of "dispelling wind and cold and removing dampness, replenishing qi and removing blood stasis” Collateral" is the treatment method, and complex syndromes are treated with complex prescriptions. Therefore, the prescriptions of this medicine have more medicinal flavors, and the principle of compatibility of two monarchs and four ministers is adopted.
- composition for treating rheumatoid arthritis of the present invention includes the following components in parts by weight: 120-190 parts of Radix Astragali, 120-190 parts of Gentiana, 45-80 parts of Fangji, 45-80 parts of Aconite, and 110-180 parts of Polygonum cuspidatum , Caulis Spatholobus 110-180, Clematis 110-180, Mustard Seed 20-40, Paeoniae Alba 45-80, Rehmannia 120-190, Angelica 45-80, Myrrh 40-65, Fragrance Attach 40-65 parts, Guizhi 45-80 parts, Achyranthes bidentata 45-80 parts.
- composition for treating rheumatoid arthritis preferably includes the following components in parts by weight: 120 parts of Astragalus, 190 parts of Gentiana, 45 parts of Fangji, 80 parts of Aconite, 110 parts of Polygonum cuspidatum, 180 parts of Caulis Spatholobus, Weiling 110 parts of fairy, 40 parts of mustard seed, 45 parts of white peony root, 190 parts of rehmannia glutinosa, 45 parts of angelica, 65 parts of myrrh, 40 parts of Cyperus cyperi, 80 parts of cassia twig, and 45 parts of achyranthes bidentata.
- composition for treating rheumatoid arthritis preferably includes the following components in parts by weight: 150 parts of Astragalus, 160 parts of Gentiana, 60 parts of Fangji, 65 parts of Aconite, 120 parts of Polygonum cuspidatum, 130 parts of Caulis Spatholobus, Weiling 135 parts of fairy, 35 parts of mustard seed, 50 parts of white peony root, 160 parts of rehmannia glutinosa, 60 parts of angelica, 55 parts of myrrh, 45 parts of Cyperus Cyperus, 60 parts of Guizhi, and 60 parts of Achyranthes bidentata.
- composition for treating rheumatoid arthritis preferably includes the following components in parts by weight: 146 parts of Astragalus, 139 parts of Gentiana, 58 parts of Fangji, 75 parts of Aconite, 120 parts of Polygonum cuspidatum, 125 parts of Spatholobus, Weling 135 parts of fairy, 28 parts of mustard seed, 60 parts of white peony root, 150 parts of rehmannia glutinosa, 70 parts of angelica, 60 parts of myrrh, 60 parts of Cyperus cyperi, 70 parts of cassia twig, and 70 parts of achyranthes bidentata.
- the composition for treating rheumatoid arthritis preferably includes the following components in parts by weight: 156 parts of Astragalus, 156 parts of Gentiana, 63 parts of Fangji, 63 parts of Aconite, 146 parts of Polygonum cuspidatum, 146 parts of Spatholobus, Weiling 146 parts of fairy, 31 parts of mustard seed, 63 parts of white peony root, 156 parts of rehmannia glutinosa, 63 parts of angelica, 52 parts of myrrh, 52 parts of Cyperus cyperi, 63 parts of cassia twig, and 63 parts of achyranthes bidentata.
- the aconite is preferably Heishun tablets
- the myrrh is preferably myrrha aceticum
- the achyranthes bidentata is preferably Chuan Achyranthes bidentata.
- the dosage form of the composition of the present invention can be capsule, tablet, pill, oral liquid, granule or powder.
- the active component of the pharmaceutical composition of the present invention is made by the following steps:
- step C Combine step C and D clear cream, mix evenly, dry, and pulverize to obtain mixed clear cream powder;
- the fine powder obtained in step A, the volatile oil obtained in step B, and the cream powder obtained in step E jointly constitute the active components of the pharmaceutical composition of the present invention.
- the preparation technology of the capsule in the pharmaceutical composition preparation of the present invention is:
- step E Combine the clear paste obtained in step C and step D, mix evenly, dry, and pulverize to obtain mixed clear paste powder, spray into the volatile oil obtained in step B, add the sterilized powder in step A, spray granulate, granulate, and pack into capsules to obtain .
- the preparation technology of the tablet in the pharmaceutical composition preparation of the present invention is:
- step C Combine step C and the clear cream obtained in step D, mix well, dry, and pulverize to obtain mixed clear cream powder;
- step F after taking the volatile oil obtained in step B for clathrate, clathrate for subsequent use;
- step A Parts, granulate the sterilized powder obtained in step A and the clear paste powder obtained in step E, granulate, add the clathrate obtained in step F, and press the conventional method to obtain final product.
- the process of inclusion inclusion of volatile oil in the pharmaceutical composition of the present invention is as follows: take cyclodextrin with 6-10 times the amount of volatile oil, add water with 6-10 times the amount of cyclodextrin, after grinding, add volatile oil and 90-95% ethanol, etc. volume of the mixture, continue to grind evenly, and then dry.
- the present invention also protects the application of the pharmaceutical composition of the present invention in the preparation of anti-inflammatory drugs.
- the present invention also protects the application of the pharmaceutical composition of the present invention in the preparation of drugs for inhibiting the increase of capillary permeability.
- the present invention also protects the application of the pharmaceutical composition of the present invention in the preparation of analgesic drugs.
- the present invention also protects the preparation of the pharmaceutical composition of the present invention to inhibit the proliferation of spleen lymphocytes and the production of serum type II collagen antibodies, reduce the content of inflammatory cytokines IL-1 and TNF- ⁇ , and inhibit the production of rheumatoid factors IgG and IgM. application in medicines.
- the rheumatoid arthritis treated by the pharmaceutical composition of the present invention is preferably adjuvant arthritis or type II collagen-induced arthritis.
- the specific drug compatibility is: Monarch drug: Radix Astragali, Gentiana quinquefolium. Astragalus: sweet and slightly warm, it is specially used to invigorate qi. It is a holy medicine for invigorating qi. It can greatly nourish the qi of the lungs and spleen inside, and strengthen the appearance and health outside. Spleen, defends the spleen, suppresses sweat, and is also a medicine for dispelling wind and transporting poison"; "Materia Medica Zhengyi” says: "(Astragalus) has a strong skin flavor and thick texture, and its power is all in the skin, so it can directly reach the skin surface of the human body.
- the medicinal gas is thin and the taste is strong, it can nourish the triple burner and strengthen the body, fill the interstices, and take it as the Qi of the monarch to nourish the lungs and spleen, and it is most suitable for nourishing the Qi and strengthening the surface to prevent the invasion of external evils.
- Gentiana pungent in taste, sweet in nature, flat in nature, expelling wind and dampness, dispelling cold and relaxing tendons, activating collaterals and relieving pain.
- “Materia Medica” says: “Gentati chinensis, bitterness can be vented, pungent can be dispersed, and slight temperature can benefit.
- Gentiana quinquefolium dispels wind and dampness, combined with Astragalus membranaceus to replenish qi and eliminate evil, expelling evil without harming the righteousness, while Astragalus obtains Gentiana quinquefolium to replenish qi without retaining evil spirits, relying on the inside, and exogenous evils go away without returning.
- the two medicines are used together, and they are played together Invigorating qi, expelling wind, removing dampness and dispelling cold, dredging collaterals and relieving pain, used as monarch drug.
- Herbs Fangji, Heishun tablets, Polygonum cuspidatum, Millipede spatholobus.
- Fangji Bitter in taste and cold in nature, better than dispelling dampness, dredging collaterals and relieving pain.
- "On the Nature of Medicine” said it: “Treat damp air outlet surface deviation, pain in hands and feet, scattered phlegm”, help Gentiana chinensis to strengthen the effect of removing dampness; Aconite is warm and hot in nature, walks but does not keep it, can warm the meridians, dispel coldness, remove dampness, relieve pain, and has the effects of expelling wind and dampness, dispelling cold and relieving pain.
- Adjuvant Clematis, mustard seed, white peony root, rehmannia glutinosa, angelica, vinegar myrrh, Cyperus cyperi.
- Clematis Spicy and salty in taste and warm in nature, it has the effect of expelling wind and dampness, dredging collaterals and relieving pain. Clematis can dispel wind-dampness, clear the meridians, and relieve numbness and pain. It is an important medicine for treating arthralgia syndrome. Also", Zuoqin Gentiana and Fangji are used to enhance the effect of expelling wind and dampness, whichever is good at walking, dredging collaterals and opening numbness.
- Radix Paeoniae Alba bitter in taste, cool in acidity, nourishing blood and dredging pulse, relieving spasm and relieving pain.
- "Shen Nong's Materia Medica” says it “removes blood numbness”
- "Bie Lu” says it: “smooth blood vessels”.
- Rehmannia glutinosa sweet in taste and cold in nature, nourishes blood and nourishes yin, unblocks blood vessels, expels blood numbness, its effect of nourishing yin can also be used to make warm properties such as Heishun slices and Caulis Spatholobus, and plays the role of nourishing and activating blood together with white peony root , Qubi syndrome blood stasis disease.
- Angelica sweet in taste, pungent and warm in nature, to treat wind, first treat blood, blood promotes wind to extinguish itself, and has the function of nourishing blood, promoting blood circulation and dredging collaterals.
- "Materia Medica Justice” “Angelica, with its sweet and heavy taste, can only nourish blood, and its qi is light and pungent, so it can also promote blood circulation. There is movement in the tonic, and tonic in the action. It is the qi medicine in the blood, and it also nourishes the blood.
- the holy medicine in the Chinese herb is also ...
- Rhizoma Rhizoma Rhizoma Rhizoma Cyperi Acrid in taste, slightly sweet in nature, calm in nature, function to promote qi and relieve depression, regulate qi and relieve pain.
- Qi is the commander of blood, and when Qi moves, blood moves.
- Rhizoma Rhizoma Rhizoma Cyperi promotes Qi to activate blood, and it plays the effect of regulating Qi, promoting blood circulation and dredging collaterals together with myrrh.
- Guizhi Sichuan Achyranthes bidentata.
- Guizhi sweet and pungent in taste and warm in nature, pungent and warm to dredge the collaterals, strengthen the function of warming the meridians and dredging the collaterals, just as the "Benjing Shuzheng” says: “Cinnamon twigs can benefit the joints, warm the meridians and unblock the meridian, this is the body", and at the same time, it can dispel wind and cold, one by one.
- Evil "Changsha Yaojie” says that it is "good at relieving wind and evil, most regulating wood qi, relaxing tendons and convulsions, sharpening joints and obstructions...
- All medicines are used at the same time, containing cold and temperature in one body, curing and tonifying in one furnace, and combining all kinds of products such as expelling wind, dispelling cold, dehumidification, clearing heat, replenishing qi, promoting blood circulation, eliminating phlegm, dredging collaterals, etc. Dispelling numbness, replenishing qi and dredging collaterals.” If the evils of wind, cold, dampness, phlegm, blood stasis and heat are dissipated, righteous energy is restored, phlegm and blood stasis are eliminated, numbness is relieved, collaterals are unblocked, and Qi and blood flow smoothly, the disease will naturally heal.
- the pharmaceutical composition of the invention has the effects of expelling wind, dispelling cold and dehumidification, replenishing qi, removing blood stasis and dredging collaterals. Indications for rheumatoid arthritis due to wind-cold-damp arthralgia, qi deficiency and collateral stasis, and stagnation of phlegm and blood stasis.
- the tablet is a dry solid with stable and controllable quality.
- Some drugs that are prone to oxidative deterioration and deliquescence can be protected by coating. Light, air, moisture, etc. have little effect on them, and can also cover up the bad smell of traditional Chinese medicine.
- tablet production is mechanized and has a high degree of automation, which is suitable for industrialization promotion.
- Astragalus mainly contains triterpenoid saponins, flavonoids and polysaccharides. Modern studies have shown that Astragalus decoction has obvious tonic effects, and saponins, flavonoids, and polysaccharides are all active ingredients and are easily soluble in hot water, so it is appropriate to use water decoction.
- Gentiana It mainly contains iridoid glycosides such as gentiopicroside and glucoside.
- the iridoid glycosides are easily soluble in water or ethanol and other solutions, and the genital alcohol extract has obvious anti-inflammatory effect. Combined with the solvent investigation results, 70% ethanol is used for extraction.
- Fangji It mainly contains tetrahydroisoquinoline alkaloids such as tetrandrine, fangchinoline, and cynophylline. Fangji alkaloids have analgesic and anti-inflammatory effects, are not easily soluble in water, and are easily soluble in organic solvents such as ethanol. Combined with the results of solvent investigation, they can be easily extracted with alcohol.
- Aconite It mainly contains diterpene diester alkaloids. Aconite decoction has inhibitory effect on various animal models of acute and chronic inflammation, so it is advisable to use water decoction.
- Spatholobus Spatholobus: It mainly contains isoflavones, flavonoids, triterpenoids and sterols. Mainly alcohol-soluble components, extracted with 70% ethanol.
- Angelica mainly contains volatile oils, organic acids, and polysaccharides. Modern research shows that the volatile oil of Angelica sinensis can inhibit the contraction of uterine smooth muscle, etc. At present, the volatile oil of Angelica sinensis is mainly used for the treatment of dysmenorrhea and irregular menstruation.
- the main function of angelica in this prescription is to promote blood circulation, and the ferulic acid contained in it has the effect of inhibiting platelet aggregation and antithrombotic effect, and is the main component of promoting blood circulation. Combined with the solvent investigation results, it is extracted with 70% ethanol.
- Clematis It mainly contains oleanane-type triterpene saponins. Saponins are easily soluble in water, so it is advisable to use water decoction.
- Mustard It mainly contains various isothiocyanates such as sinapine and its glycosides, fatty acids, nitrogenous compounds and amino acids. Modern studies have shown that sinapine thiocyanate has anti-inflammatory effects, and its extraction rate in ethanol is relatively high.
- Rehmannia glutinosa It mainly contains iridoid glycosides, polysaccharides and other components, and is easily soluble in water, so it is advisable to use water decoction.
- Radix Paeoniae Alba It mainly contains paeoniflorin, hydroxypaeoniflorin, benzoylpaeoniflorin and other glycosides and tannins. Paeoniflorin has the functions of inhibiting platelet aggregation, analgesia and anti-inflammation, and its extraction rate in ethanol is relatively high. Combined with the results of solvent investigation, 70% ethanol was used for extraction.
- Myrrh It mainly contains components such as volatile oil, resin and gum. In the prescription, myrrh is used for promoting blood circulation and relieving pain. Modern research shows that both myrrh volatile oil and water decoction have the effect of prolonging blood clotting time, and myrrh volatile oil has anti-inflammatory effect, so it is extracted by steam distillation, and the volatile oil is collected and distilled. An extraction method in which an aqueous solution is combined with a water decoction. Cyperus Cyperus: It mainly contains volatile oil, and the oil mainly contains sesquiterpenes such as ⁇ -cyperone and its oxides.
- the volatile oil and water decoction have analgesic effect, so steam distillation is used for extraction, the volatile oil is collected, and the water solution and water decoction are combined after distillation.
- Polygonum cuspidatum mainly contains polydatin, anthraquinone, tannin and other ingredients. The extraction rates of polydatin and anthraquinones in ethanol are relatively high, and combined with the results of solvent investigation, 70% ethanol was used for extraction.
- Cinnamon twig It mainly contains volatile oil and water-soluble components such as trans-cinnamic acid and protocatechuic aldehyde.
- the main component in the oil is cinnamic aldehyde, which has anti-inflammatory effects, and the combination of cinnamon twig and Astragalus decoction can significantly enhance the anti-inflammatory and analgesic effects of Astragalus Therefore, steam distillation is used to extract, the volatile oil is collected, and the aqueous solution and decoction are combined after distillation.
- Sichuan Achyranthes bidentata should contain sterols. The decoction has obvious effects of improving microcirculation and anti-inflammation. Therefore, it is advisable to use water decoction.
- Oil production Pale yellow light oil, stratification is slow, accompanied by white emulsion steaming out.
- the average oil yield is 0.79%.
- the volatile oil did not increase after 6 hours of extraction, indicating that the extraction was basically complete.
- Oil condition brownish yellow light oil, easy to stratify.
- the direct oil extraction rate of decoction pieces is low, the average oil yield rate is 0.34%; the oil yield rate of 3-5mm particles and particles below 3mm is not much different, the average oil yield rate is 0.54%, so Cyperus cyperus is coarsely crushed into about 5mm or less Granules are suitable for oil extraction.
- the volatile oils of Cyperus cyperi with different particle sizes did not increase after 7 hours of extraction, indicating that the extraction was basically complete.
- Oil condition light green light oil, easy to layer.
- the average oil yield is 1.35%.
- the volatile oil did not increase after 7 hours of extraction, indicating that the extraction was basically complete.
- the granules before tablet compression in Example 1 and the capsules in Example 2 were used as test samples, as well as the pre-tablet preparations prepared by a comparative example in which the same medical material exceeded the scope of the claims.
- the granules are used as samples, and the Health Analysis and Testing Center of Beijing University of Traditional Chinese Medicine is entrusted to conduct efficacy evaluation experiments.
- the pharmaceutical composition tablet of the present invention is clinically used to treat rheumatoid arthritis.
- This experiment was carried out by establishing an adjuvant-induced rat joint model (adjuvant arthritis, AA) and a type II collagen-induced rat joint model (collagen induced arthritis, CIA).
- AA adjuvant-induced rat joint model
- CIA collagen induced arthritis
- AA is an ideal arthritis model close to human rheumatoid arthritis. It is mainly mediated by cellular immunity. Its symptoms and pathological manifestations are similar to those of human rheumatoid arthritis, but its pathogenesis is not consistent.
- the pathogenesis of type II collagen-induced arthritis animal models is closer to that of human RA.
- this test selects the above two models for research, and the AA model mainly studies the drug effect evaluation of the prophylactic administration of the pharmaceutical composition of the present invention.
- the drug efficacy evaluation of prevention and treatment administration was carried out at the same time, and the curative effect mechanism of the pharmaceutical composition of the present invention was preliminarily studied in the treatment administration, so as to provide experimental basis for the clinical treatment of rheumatoid arthritis by this product.
- the results of the study were summarized according to the "Approval Measures for New Drugs", "Guidelines for Research on New Drugs of Traditional Chinese Medicine” and “Measures for the Administration of Drug Registration".
- Animals SD rats, male and female, weighing 180-200 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. License number SCXK (Beijing) 2006-0009.
- Test drug The pharmaceutical composition of the present invention is provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd., and the adult dosage is 17g crude drug/day.
- the pharmaceutical compositions 1 and 2 of the present invention and the comparison drug group are yellow-brown granules, each gram is equivalent to 3.5g crude drug.
- the pharmaceutical composition of the present invention is formulated with 0.5% sodium carboxymethyl cellulose for use at required concentration.
- Positive control drug dexamethasone tablets, Tianjin Lisheng Pharmaceutical Co., Ltd., batch number 20090105. Specification 0.75mg/tablet. Oral administration, the initial dose for adults is 0.75-3.00 mg (1-4 tablets), 2-4 times a day. The maintenance dose is about 0.75mg (1 tablet) a day, depending on the condition.
- IFA Incomplete Freund's adjuvant
- BCG was purchased from China Institute for the Control of Pharmaceutical and Biological Products, batch number 20110130.
- PRMI1640 medium GIBCO product, batch number 1024455. Add penicillin 100u/ml, streptomycin 100u/ml, glutamine 2mM before use of 1640 culture medium, add 10% inactivated fetal bovine serum to complete 1640 culture medium.
- YLS-7B toe volume measuring instrument is a product of Huaibei Zhenghua Biological Instrument Co., Ltd.
- Grouping and administration of experimental animals SD rats were randomly divided into 6 groups. That is, the normal control group was given an equal volume of vehicle; the adjuvant arthritis model group was given an equal volume of vehicle; the pharmaceutical composition 1 of the present invention, the pharmaceutical composition 2 of the present invention, and the comparative drug group were administered by intragastric administration the next day after the model was prepared.
- the dose was 2.26g/kg, which was equivalent to 8 times the daily dosage for adults; the positive control drug group was given 0.1 mg/kg of dexamethasone, which was equivalent to 8 times the daily dosage for adults.
- the administration volume of each group was 1ml/100g body weight.
- the pharmaceutical composition group 1 of the present invention can significantly reduce the toe volume of rats compared with the model group at 15d after immunization, and continue to 30d (p ⁇ 0.05), and the pharmaceutical composition group 2 of the present invention can significantly reduce the toe volume of rats at 15d, 19d, and 27d after immunization. and 30d were significantly reduced compared with the model control group (p ⁇ 0.05). There was a tendency to suppress toe swelling in the control group, but it was not statistically significant. The results are shown in Tables 1-1 and 1-2.
- Table 1-1 Effect of the pharmaceutical composition of the present invention on the swelling of the opposite lateral foot in rats with adjuvant arthritis
- Table 1-2 Effect of the pharmaceutical composition of the present invention on the swelling of the opposite lateral foot in rats with adjuvant arthritis
- Groups 1 and 2 of the pharmaceutical composition of the present invention can also significantly inhibit the proliferation of splenic T lymphocytes in adjuvant arthritis model rats (p ⁇ 0.01 and p ⁇ 0.05). See Table 2.
- the rat AA model was executed by decapitation on the 30th day after modeling, and the right ankle joint was taken, fixed in formalin, and wrapped in paraffin. Buried sections, HE staining method. The results showed that the matrix of the connective tissue in the joint capsule of rats in the normal group was in a colloidal state, mainly collagen fibers, with few small blood vessels and a small amount of macrophages, plasma cells, mast cells and lymphocytes.
- synovial cells 1-2 layers of synovial cells can be seen in the synovial tissue of the joint, mature synovial tissue can be seen under the synovial membrane, and a few small blood vessels can be seen, the synovial cells are arranged neatly and flat, the articular surface is smooth, and there is no exudation in the joint cavity things.
- the joint skeletal muscle cells of rats in the normal group were in the form of strips or blocks, and there was less connective tissue between the muscle cells, and fibroblasts and macrophages were occasionally seen in the connective tissue.
- macrophages, plasma cells, and mast cells in the connective tissue of the joint capsule of rats, and inflammatory cells existed in groups, occupying a large part of the tissue space.
- the synovial tissue in the model group was significantly thickened, the synoviocytes proliferated significantly, the cell layer increased significantly, the cells swelled, and a large number of lymphocytes, plasma cells, macrophages and a small amount of polymorphonuclear leukocytes infiltrated, fibrous tissue hyperplasia, and small blood vessels were seen.
- the synovial layer adheres to the cartilage, cartilage degeneration, fibrous exudation can be seen in the joint cavity, and the synovial membrane invades the cartilage, causing destruction of cartilage and bone, mostly manifested as hyperplastic inflammation.
- connective tissue between muscle cells in skeletal muscle cells there is less connective tissue between muscle cells in skeletal muscle cells, but more between muscle fascicles, fibroblasts and macrophages are occasionally seen in the connective tissues between fascicles, but there are mostly inflammatory cells in groups, which is exudative inflammation .
- the connective tissue between the skeletal muscle cells was less, and no obvious fibroblasts and macrophages were seen, which was normal tissue morphology; Normal synoviocytes are about 1-3 layers, neatly arranged, regular cell shape, no inflammatory cell infiltration and pannus formation.
- the connective tissue of the joint capsule of the pharmaceutical composition group 1 of the present invention is basically normal, inflammatory cells are rarely seen, the connective tissue between muscle cells is less, the surface of the cartilage tissue on both sides of the joint is smooth, and the synoviocytes are about 1-3 layers, which is similar to the normal group. There is a small amount of inflammatory cell infiltration. There are inflammatory cells scattered in the connective tissue of the joint capsule of the pharmaceutical composition group 2 of the present invention, small blood vessels are arranged, and macrophages, plasma cells, mast cells, etc.
- Histology showed that there were a large number of inflammatory cells in the connective tissue of the joint capsule of rats with adjuvant arthritis, and the joint synoviocytes proliferated significantly, and a large number of lymphocytes, plasma cells, macrophages and a small amount of polymorphonuclear leukocytes were infiltrated, and fibrous tissue hyperplasia , a significant increase in small blood vessels.
- the toe volume of the positive control drug dexamethasone group was significantly smaller than that of the model control group from 15 days after immunization until the end of the experiment (p ⁇ 0.01); Proliferation (p ⁇ 0.01). Histology showed that there were a few scattered inflammatory cells in the connective tissue of the joint capsule, and the synoviocytes were in about 1-3 layers, arranged neatly, with regular cell shape, and no obvious inflammatory cell infiltration was seen.
- the pharmaceutical composition group 1 of the present invention can significantly reduce the toe volume of rats compared with the model group at 15 days after immunization, and continue to 30 days (p ⁇ 0.05). Compared with the model control group, the 19d, 27d and 30d decreased significantly (p ⁇ 0.05). Groups 1 and 2 of the pharmaceutical composition of the present invention can also significantly inhibit the proliferation of splenic T lymphocytes in adjuvant arthritis model rats (p ⁇ 0.01 and p ⁇ 0.05). Histology shows: the connective tissue of the joint capsule of the pharmaceutical composition 1 and 2 of the present invention is basically normal, with a small amount of inflammatory cells, the surface of the articular cartilage tissue is basically normal or slightly damaged, with a small amount of inflammatory cell infiltration and fibrous tissue.
- Test two the effect of prophylactic administration of the pharmaceutical composition of the present invention on type II collagen-induced arthritis in rats
- Test 2 SD rats were used to prepare a type II collagen-induced arthritis model in rats, and the effect of the pharmaceutical composition of the present invention on the prevention and treatment of the model was evaluated mainly by observing the immune arthritis index, the volume change of the right toe, and the histological changes of the joints. effect.
- Animals SD rats, male and female, weighing 180-200 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. License number SCXK (Beijing) 2006-0009.
- Test drug The pharmaceutical composition of the present invention is provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd., and the adult dosage is 17g/crude drug/day.
- the pharmaceutical compositions 1 and 2 of the present invention and the comparison drug group are yellow-brown granules, each gram is equivalent to 3.5g crude drug. Batch number: 110301.
- the pharmaceutical composition of the present invention is formulated with 0.5% sodium carboxymethyl cellulose for use at required concentration.
- IFA Incomplete Freund's adjuvant
- acid-soluble type II collagen collagen II, 3806)
- BCG was purchased from China Institute for the Control of Pharmaceutical and Biological Products, batch number 20110130.
- YLS-7B toe volume measuring instrument is a product of Huaibei Zhenghua Biological Instrument Co., Ltd.
- rat collagen arthritis model Dissolve bovine type II collagen in 0.1M glacial acetic acid, overnight at 4°C. Then it is ground evenly with CFA to make an emulsion containing type II collagen of 2 mg/ml, and the above-mentioned emulsion is subcutaneously injected into the model group and each administration group with 150 ⁇ l/ left foot and root of tail at multiple points to immunize rats (each rat is equivalent to 1 mg/ml). After injecting 150 ⁇ g of type II collagen), on the 10th day, each rat was injected with 150 ⁇ l of the same emulsion at the base of the tail to boost immunization. The normal control group did not receive any treatment.
- Grouping and administration of experimental animals SD rats were randomly divided into 6 groups. That is, the normal control group was given an equal volume of vehicle; the collagen arthritis model group was given an equal volume of vehicle; the pharmaceutical composition 1 of the present invention, the pharmaceutical composition 2 of the present invention, and the comparative drug group were administered by intragastric administration the next day after the model was prepared, and the dosage It was 2.26g/kg, which was equivalent to 8 times of the daily dose of adults; the positive control drug group was given 0.1 mg/kg of dexamethasone, which was equivalent to 8 times of the daily dose of adults.
- the administration volume of each group was 1ml/100g body weight.
- the arthritis index showed that the type II collagen model group was significantly different from the normal control group from the 14th day to the end of the 50th day of the experiment, indicating that the model was successfully prepared.
- the immunization of each administration group of the pharmaceutical composition of the present invention begins to have no significant difference compared with the model group to 31d, and from 31d to 43d, the arthritis index of the pharmaceutical composition group 1 of the present invention is significantly alleviated compared with the model group (p ⁇ 0.05 and p ⁇ 0.01); the pharmaceutical composition group 2 of the present invention was significantly relieved from 35d to 43d compared with the model group (p ⁇ 0.05).
- composition 1 and 2 of the present invention can suppress the inflammatory peak that occurs in the later period of rats caused by type II collagen immunization, but along with the model group inflammation subsides gradually, there is no difference between the pharmaceutical composition administration group of the present invention and the model group. Significant difference.
- the arthritis index of the dexamethasone group was significantly lower than that of the model group from 18 days after immunization until the end of the experiment (p ⁇ 0.01). The results are shown in Table 3-1 and 3-2.
- Table 3-1 Effect of prophylactic administration of the pharmaceutical composition of the present invention on the arthritis index of collagen-induced arthritis in rats
- Table 3-2 Effect of prophylactic administration of the pharmaceutical composition of the present invention on the arthritis index of collagen-induced arthritis in rats
- the pharmaceutical composition group 1 of the present invention began to significantly reduce the toe volume of the rats compared with the model group at 22d after immunization, and continued to 43d (p ⁇ 0.05). Significantly reduce the toe volume of rats, and continue to 39d (p ⁇ 0.05), but along with model group inflammation subsides, the effect of inhibiting toe swelling of pharmaceutical composition 1 and 2 of the present invention is then not significant compared with model group sexual difference. Compared with the drug group, the effect of inhibiting toe swelling was not obvious. The results are shown in Table 4-1 and 4-2.
- Table 4-1 The effect of prophylactic administration of the pharmaceutical composition of the present invention on the volume of right paw toes of rats with arthritis induced by collagen
- Table 4-2 The effect of prophylactic administration of the pharmaceutical composition of the present invention on the volume of right paw toes of rats with arthritis induced by collagen
- inflammatory cell infiltration can be seen in the joint connective tissue and muscle tissue
- neutrophils, monocytes, especially lymphocytes in the synovial tissue can be seen in the articular cartilage, the infiltration of blood vessels, the deformation and hyperplasia of the intima of the blood vessels, and the narrowing of the lumen Or obstruction, accompanied by pannus formation, a large amount of cellulose exudation under the synoviocytes, and collagen fiber deposition.
- the connective tissue and muscle tissue of the joints were basically normal, the synovial cells of the articular cartilage proliferated slightly, and the infiltration of inflammatory cells was not obvious.
- a small amount of inflammatory cell infiltration is found in the joint connective tissue of groups 1 and 2, the muscle tissue is basically normal, the synovial cells in the joint cavity proliferate slightly, inflammatory cell infiltration, a small amount of fibrous hyperplasia, and blood vessels are slightly hyperplastic.
- the pharmaceutical composition 1 and 2 groups of the present invention have a better effect on improving tissue damage caused by collagen arthritis.
- the arthritis index of the collagen-induced arthritis model rats was significantly higher than that of the normal control group at about 14 days after the first immunization, and the toe volume was significantly higher than that of the normal control group at about the 18th day after the first immunization, The significant difference was maintained until the end of the experiment (p ⁇ 0.01).
- the arthritis index and toe volume of the model group peaked around the 35th to 39th day after the first immunization, and then decreased as the inflammation subsided.
- Pathological observation showed: inflammatory cell infiltration in connective tissue and muscle tissue of model rats, hyperplasia of joint synovial tissue and infiltration of inflammatory cells, increased blood vessels accompanied by pannus formation, massive exudation of cellulose under synovial cells, and deposition of collagen fibers . Indicates that modeling is successful.
- the positive control drug dexamethasone can significantly inhibit the arthritis index and reduce the toe volume from the 18th day of the first immunization, and its inhibitory effect has been maintained until the end of the experiment. Compared with the model group, there were significant differences (p ⁇ 0.01). Pathological observation showed that the connective tissue and muscle tissue of the joints in the dexamethasone group were basically normal, the articular cartilage and synoviocytes proliferated slightly, and the infiltration of inflammatory cells was not obvious.
- composition group 1 of the present invention started to 43d from 31d after the first immunization, and pharmaceutical composition group 2 of the present invention all significantly reduced the arthritis index (p ⁇ 0.05 and p ⁇ 0.01), the pharmaceutical composition group 1 of the present invention can significantly reduce the toe volume of rats compared with the model group at 22d after the first immunization, and continue to 43d (p ⁇ 0.05), the pharmaceutical composition group of the present invention 2 Compared with the model group, the toe volume of the rats can be significantly reduced from 26 days after the first immunization, and lasted to 39 days (p ⁇ 0.05). Thereafter, as the inflammation of the model was gradually reduced, there was no significant difference between the control drug group and the model group.
- the pharmaceutical composition 1 and 2 groups of the present invention had a small amount of inflammatory cell infiltration in the joint connective tissue, and the muscle tissue was basically normal.
- synoviocytes proliferated slightly, inflammatory cell infiltration and a small amount of fibrous proliferation were seen, and blood vessels were mildly hyperplastic. Hyperplasia.
- Animals Lewis rats, male, weighing 170-190 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
- Animal certificate number license number SCXK (Beijing) 2006-0009.
- Test drug The pharmaceutical composition of the present invention is provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd., and the adult dosage is 17g/crude drug/day.
- the pharmaceutical compositions 1 and 2 of the present invention and the comparison drug group are yellow-brown granules, each gram is equivalent to 3.5g crude drug. Batch number: 110301.
- the pharmaceutical composition of the present invention is formulated with 0.5% sodium carboxymethyl cellulose for use at required concentration.
- IFA Incomplete Freund's adjuvant
- Acid-soluble type II collagen (collagen II, 3806) (batch number 130435) and MTT (66H5033) are Sigma products.
- BCG was purchased from China Institute for the Control of Pharmaceutical and Biological Products, batch number 20100130.
- PRMI1640 culture medium GIBCO product, batch number 1024455. Add penicillin 100u/ml, streptomycin 100u/ml, glutamine 2mM before use of 1640 culture medium, add 10% inactivated fetal bovine serum to complete 1640 culture medium.
- Rat IL-1 cytokine ELISA kit (batch number 1209145), TNF- ⁇ cytokine ELISA kit (batch number 1210132) and IL-10 cytokine ELISA kit (batch number 1210162) were purchased from Beijing Bangding Tech Biotech Co., Ltd. Technology Co., Ltd.
- HRP Horseradish enzyme
- YLS-7B toe volume measuring instrument is a product of Huaibei Zhenghua Biological Instrument Co., Ltd.
- Lewis rats were randomly divided into 6 groups, that is, the normal control group, which was given an equal volume of vehicle; the collagen-induced arthritis model group, which was given an equal volume of vehicle; intragastric administration began on the 14th day after the model was prepared
- pharmaceutical composition 1, 2 of the present invention and contrast drug group dosage is 2.26g/kg and is equivalent to 8 times of adult's daily dosage
- Positive control drug dexamethasone group gives dexamethasone 0.1mg/kg, is equivalent to adult's dosage 8 times.
- the administration volume of each group was 1ml/100g body weight.
- the arthritis index of dexamethasone was significantly lower than that of the model group (p ⁇ 0.05 or p ⁇ 0.01).
- the arthritis index of the pharmaceutical composition group 1 of the present invention was significantly reduced (p ⁇ 0.05 and p ⁇ 0.01) compared with the model group from 35 days (administration 21 days) until 47 days.
- the pharmaceutical composition group 2 of the present invention was significantly relieved from 39d (administration 25d) to 43d (p ⁇ 0.05). There was also a decreasing trend in the control drug group, but there was no significant difference.
- composition 1 and 2 of the present invention can suppress the inflammatory peak that occurs in the later stage of rats caused by type II collagen immunization, but along with the inflammation of the model subsides gradually, the difference between pharmaceutical composition 1 and 2 of the present invention and the model group There is no significant difference.
- the results are shown in Table 5-1 and 5-2.
- Table 5-1 Effect of therapeutic administration of the pharmaceutical composition of the present invention on the arthritis index of type II collagen-induced arthritis model rats
- Table 5-2 Effect of therapeutic administration of the pharmaceutical composition of the present invention on the arthritis index of type II collagen-induced arthritis model rats
- the influence of the pharmaceutical composition of the present invention on the toe volume of the collagen-induced rat arthritis model measure the volume of the right hind foot toe of each rat with a toe volume measuring instrument before causing inflammation, and start on the 14th day after the first immunization The volume of the paw was measured every 4 days until the end of 50 days. The changes in the paw volume of the rats in each group were observed. Data analysis using SPSS10.0 software, all data results are mean ⁇ standard deviation Indicates that the significance of the difference was analyzed using one-way ANOVA (One-Way ANOVA), and the LSD test was used for pairwise comparison between groups, and P ⁇ 0.05 was considered statistically significant.
- composition group 1 of the present invention began to significantly reduce the toe volume of rats compared with the model group at 35d after immunization (21d after administration), and continued to 47d (p ⁇ 0.05). After 39 days (25 days after administration), it can significantly reduce the toe volume of the rats compared with the model group, and last until 50 days (p ⁇ 0.05). The effect of the control drug group on inhibiting toe swelling was not obvious. The results are shown in Table 6-1 and 6-2.
- Table 6-1 The effect of therapeutic administration of the pharmaceutical composition of the present invention on the volume of the right foot toe of type II collagen-induced arthritis rats
- Table 6-2 The effect of therapeutic administration of the pharmaceutical composition of the present invention on the volume of the right foot toe of type II collagen-induced arthritis rats
- Table 7 Effect of the pharmaceutical composition of the present invention on the proliferation of spleen lymphocytes in rats with collagen arthritis
- Block with 1% BSA add serum diluted 1:100 in PBS, and incubate at 37°C for 2 hours; add horseradish enzyme (HRP)-labeled goat anti-rat IgG antibody diluted 1:8000, and incubate at 37°C for 1 hour
- HRP horseradish enzyme
- OPD reaction substrate stop the reaction with 2N sulfuric acid after 30 minutes
- OD optical density
- Table 8 Effect of the pharmaceutical composition of the present invention on type II collagen antibody in serum of collagen arthritis rats
- TNF- ⁇ Tumor necrosis factor- ⁇
- IL-1 interleukin-1
- TNF- ⁇ and IL-1 can participate in the pathogenesis and progression of rheumatoid through activating endothelial cells and promoting the synthesis and release of inflammatory factors.
- IL-10 is an important inhibitory cytokine, which can down-regulate the immune response and improve the inflammatory response of arthritis.
- the pharmaceutical composition 1 and 2 groups of the present invention can also significantly reduce the serum IL-1 and TNF- ⁇ levels (p ⁇ 0.05).
- the inhibitory cytokine IL-10 in the serum of the model group is significantly lower than that of the matched group (p ⁇ 0.01), but each group of the pharmaceutical composition of the present invention and dexamethasone have no obvious improvement on the reduction of IL-10 in the serum of the model rats. effect (p>0.05). See Table 9.
- Rheumatoid factor (RF) produced in patients with rheumatoid arthritis is the most common of its various autoantibodies, and it is an autoantibody against the Fc segment of IgG. RF can form immune complexes, activate complement and lead to vasculitis.
- IgG There are two main types of RF, IgG and IgM.
- IgM rheumatoid factor appears first, and IgG rheumatoid factor appears later.
- the contents of these two types of rheumatoid factors are closely related to the pathogenic process of rheumatoid arthritis.
- the rat serum to be tested was diluted 1:100 with PBS, added to the drop holes, and incubated at 37°C for 2 hours. Then add 1:8000 diluted horseradish enzyme (HRP)-labeled goat anti-rat IgG antibody or goat anti-rat IgM, and incubate at 37°C for 1 hour; add the OPD reaction substrate, stop the reaction with 2N sulfuric acid after 30 minutes; Read the optical density (OD) value at 492nm.
- HRP horseradish enzyme
- Table 10 Effects of the pharmaceutical composition of the present invention on serum IgG and IgM rheumatoid factor in rats with collagen arthritis
- the type II collagen-induced rat arthritis model was established using Lewis rats. It was found that the model rats began to develop arthritis symptoms about 14 days after the first immunization, and continued until the 50th day. Arthritis index and toe volume were significantly higher than those in the control group.
- the proliferation of type II collagen-specific splenic lymphocytes in model rats was significantly higher than that in the control group; serum type II collagen-specific antibodies, IgG and IgM rheumatoid factors, and inflammatory factors IL-1 and TNF- ⁇ were significantly higher than those in the control group (p ⁇ 0.01), the regulatory cytokine IL-10 in the serum was significantly lower than that in the control group.
- the above results show that: the type II collagen-induced rat joint model was successfully established, and the model rats had significant inflammatory responses and specific immune responses and inflammatory responses against type II collagen.
- the arthritis index of the positive control drug dexamethasone was significantly lower than that of the model group from 22 days after immunization to the end of the experiment (p ⁇ 0.05 or p ⁇ 0.01). From 22 days after immunization (8 days after administration) until the end of the experiment, the toe volume was significantly smaller than that of the arthritis model group (p ⁇ 0.05 or p ⁇ 0.01).
- Dexamethasone also significantly inhibited the proliferative response of spleen lymphocytes induced by type II collagen (p ⁇ 0.01), the production of type II collagen antibody in serum (p ⁇ 0.01), the inflammatory cytokines IL-1 and TNF- ⁇ in serum (p ⁇ 0.01) and the production of rheumatoid factors IgG and IgM (p ⁇ 0.01), but no significant effect on the regulatory cytokine IL-10.
- the arthritis index of the pharmaceutical composition group 1 of the present invention is from 35d (administration 21d) to 47d, and the arthritis index of the pharmaceutical composition group 2 of the present invention is significantly alleviated from 39d (administration 25d) to 43d compared with the model group (p ⁇ 0.05 and p ⁇ 0.01).
- the pharmaceutical composition group 1 of the present invention started from 35d after immunization (21d after administration) to 47d, and the pharmaceutical composition group 1 of the present invention significantly reduced the toes of rats compared with the model group from 39d (25d after administration) to 50d after immunization. Volume (p ⁇ 0.05).
- Groups 1 and 2 of the pharmaceutical composition of the present invention significantly inhibited the proliferation of collagen-specific lymphocytes in the spleen of collagen model rats (p ⁇ 0.05 or p ⁇ 0.01), and the production of type II collagen antibodies in serum (p ⁇ 0.05 or p ⁇ 0.01). p ⁇ 0.01), the content of inflammatory cytokines IL-1 and TNF- ⁇ in serum (p ⁇ 0.05) and the production of rheumatoid factors IgG and IgM (p ⁇ 0.05 or p ⁇ 0.01). However, it has no obvious improvement effect on the reduction of the regulatory cytokine IL-10 in the serum of model rats.
- Rheumatoid arthritis is a multisystem inflammatory autoimmune disease mainly involving peripheral joints.
- the main features of RA are joint inflammatory response and synovial angiogenesis, which lead to chronic synovial hyperplasia, further affecting cartilage and bone, leading to joint deformity and loss of function as the basic pathological changes.
- Rat adjuvant arthritis (AA) is an ideal arthritis model close to human rheumatoid arthritis, which can basically reflect the pathological changes of human rheumatoid arthritis.
- the main mechanism of arthritis is the activation of T cells by Mycobacterium tuberculosis, which participates in the pathogenesis of RA by releasing cytokines and activating macrophages.
- AA is mainly mediated by cellular immunity.
- the model is easy to operate and inexpensive.
- the onset of inflammation in the AA model was rapid, that is, the secondary inflammatory response of the contralateral paw appeared successively 10 days after the antigen challenge, and the peak of inflammation generally appeared at 20 to 25 days, and then the inflammatory response of the rat paw gradually subsided.
- the symptoms and pathological manifestations of the AA model are similar to those of human rheumatoid arthritis, their pathogenesis is not consistent.
- Type II collagen-induced arthritis (collagen induced arthritis, CIA) animal model is currently recognized as an ideal animal model for studying the pathogenesis of RA and developing new drugs for the treatment of RA, which is induced by type II collagen (Collagen II, CII), CII is the main component of cartilage and is an autoantigen for the pathogenesis of rheumatoid arthritis.
- Type II collagen antibodies can be detected in serum and synovial fluid of patients with clinical rheumatoid arthritis. Because the pathogenesis of the CIA model is closer to that of human RA, it is the preferred model for studying rheumatoid arthritis in recent years.
- CIA arthritis in rats is slower than the AA model, and swollen joints begin to appear about 2-3 weeks after the first immunization.
- the pathological manifestations are progressive synovitis and synovial hyperplasia, inflammatory cell infiltration, and cartilage destruction. Ultimately, joint damage and stiffness result.
- the joint inflammation of rats will last for a long time, and the clinical, histological and immunological changes are similar to those of human RA.
- the CIA model basically did not show obvious pathological changes, but after the booster immunization, the CIA paw swelling, arthritis score, and serum autoantibody levels all increased significantly, suggesting that there were pathological changes similar to clinical RA.
- the preventive administration was selected before the booster immunization (the next day after the first immunization), and the therapeutic administration was selected after the booster immunization (on the 4th day after the booster immunization).
- the results show that the pharmaceutical composition of the present invention can significantly reduce the toe volume after immunization of the adjuvant-induced arthritis model rats, can significantly inhibit the proliferation of spleen T lymphocytes in the model rats, and improve joint pathological changes.
- the research on type II collagen-induced arthritis shows that both prophylactic and therapeutic administration of the pharmaceutical composition of the present invention can significantly improve the joint index and toe swelling of model rats.
- the pharmaceutical composition of the present invention can also significantly improve the histological changes of the joints of model rats.
- the pharmaceutical composition of the present invention can reduce the content of type II collagen antibody and rheumatoid factor in the serum of model rats, inhibit the proliferation of spleen lymphocytes specific to type II collagen, and inhibit the inflammatory cytokine IL in serum. -1 and TNF- ⁇ production.
- the pharmaceutical composition of the present invention has a good prevention and treatment effect on adjuvant arthritis and type II collagen-induced arthritis, and its mechanism of action may be through inhibiting excessive lymphocyte response and inhibiting the specific activity of type II collagen. Sexual immune response and reduction of inflammatory cytokines are achieved.
- the formula of the raw material medicine is: Astragalus 156g, Gentiana 156g, Fangji 63g, Heishun tablets 63g, Polygonum cuspidatum 146g, Caulis Spatholobus 146g, Clematis 146g, Mustard Seed 31g, Radix Paeoniae Alba 63g, Rehmannia glutinosa 156g, Angelica 63g, Myrrha 52g, Rhizoma Cyperi 52g, Guizhi 63g, Sichuan Achyranthes bidentata 63g
- step C Combine step C and the clear cream obtained in step D, mix well, dry, and pulverize to obtain mixed clear cream powder;
- step F after taking the volatile oil obtained in step B for clathrate, clathrate for subsequent use;
- step G Granulate the sterilized powder obtained in step A and the clear paste powder obtained in step E, granulate, add the clathrate obtained in step F, and press into tablets according to the conventional method.
- the formula of the raw material medicine is: Astragalus 146g, Gentiana 139g, Fangji 58g, Heishun tablets 75g, Polygonum cuspidatum 120g, Caulis Spatholobus 125g, Clematis 135g, Mustard Seed 28g, Radix Paeoniae Alba 60g, Rehmannia glutinosa 150g, Angelica 70g, Myrrha 60g, Rhizoma Cyperi 60g, Guizhi 70g, Sichuan Achyranthes bidentata 70g.
- step E Combine the clear paste obtained in step C and step D, mix evenly, dry, and pulverize to obtain mixed clear paste powder, spray into the volatile oil obtained in step B, add the sterilized powder in step A, spray granulate, granulate, and pack into capsules to obtain .
- the formula of the raw material medicine is: Astragalus 150g, Gentiana 160g, Fangji 60g, Heishun tablets 65g, Polygonum cuspidatum 120g, Caulis Spatholobus 130g, Clematis 135g, mustard seed 35g, white peony root 50g, rehmannia glutinosa 160g, angelica 60g, myrrha 55g, Rhizoma Cyperi 45g, Guizhi 60g, Sichuan Achyranthes bidentata 60g.
- step E Combine the clear cream obtained in step C and step D, mix evenly, dry, and pulverize to obtain the mixed clear cream powder, spray into the volatile oil obtained in step B, add the sterilized powder in step A, spray and granulate, granulate, and obtain granules .
- the formula of the raw material medicine is: Astragalus 120g, Gentiana 190g, Heishun slice 45g, aconite 80g, Polygonum cuspidatum 110g, Caulis Spatholobus 180g, Clematis 110g, mustard seed 40g, white peony root 45g, rehmannia glutinosa 190g, angelica 45g, myrrha 65g, Rhizoma Cyperi 40g, Guizhi 80g, Sichuan Achyranthes bidentata 45g.
- step E Combine the clear cream obtained in step C and step D, mix evenly, dry, and pulverize to obtain mixed clear cream powder, add the fine powder obtained in step A, spray into the volatile oil obtained in step B, and make a pill according to a conventional method.
- Astragalus 190g Gentiana 120g, Fangji 80g, Heishun tablets 45g, Polygonum cuspidatum 180g, Caulis Spatholobus 110g, Clematis 180g, mustard seed 20g, white peony root 80g, rehmannia glutinosa 120g, angelica 80g, vinegar myrrh 40g, Cyperus cyperi 65g, cinnamon Branch 45g, Sichuan Achyranthes bidentata 80g.
- step E Combine the clear cream obtained in step C and step D, mix evenly, dry, and pulverize to obtain the mixed clear cream powder, spray into the volatile oil obtained in step B, add the sterilized powder in step A, spray and granulate, granulate, and obtain granules .
- the formula of raw materials is: Astragalus 220g, Gentiana 220g, Fangji 95g, Aconite 85g, Polygonum cuspidatum 192g, Caulis Spatholobus 80g, Clematis 90g, mustard seed 60g, white peony root 50g, rehmannia glutinosa 100g, angelica 100g, myrrh 35g, Cyperus cyperi 80g , Guizhi 35g, Achyranthes bidentata 90g
- step C Combine step C and the clear cream obtained in step D, mix well, dry, and pulverize to obtain mixed clear cream powder;
- step F after taking the volatile oil obtained in step B for clathrate, clathrate for subsequent use;
- step A Parts, granulate the sterilized powder obtained in step A and the clear paste powder obtained in step E, granulate, add the clathrate obtained in step F, and press the conventional method to obtain final product.
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Abstract
Description
Claims (16)
- 一种治疗风湿性关节炎的组合物,其特征在于该组合物包括如下重量份的组分:黄芪120-190份、秦艽120-190份、防己45-80份、附子45-80份、虎杖110-180份、鸡血藤110-180份、威灵仙110-180份、芥子20-40份、白芍45-80份、地黄120-190份、当归45-80份、没药40-65份、香附40-65份、桂枝45-80份、牛膝45-80份。
- 根据权利要求1所述的组合物,其特征在于该组合物包括如下重量份的组分:黄芪120份、秦艽190份、防己45份、附子80份、虎杖110份、鸡血藤180份、威灵仙110份、芥子40份、白芍45份、地黄190份、当归45份、没药65份、香附40份、桂枝80份、牛膝45份。
- 根据权利要求1所述的组合物,其特征在于该组合物包括如下重量份的组分:黄芪150份、秦艽160份、防己60份、附子65份、虎杖120份、鸡血藤130份、威灵仙135份、芥子35份、白芍50份、地黄160份、当归60份、没药55份、香附45份、桂枝60份、牛膝60份。
- 根据权利要求1所述的组合物,其特征在于该组合物包括如下重量份的组分:黄芪146份、秦艽139份、防己58份、附子75份、虎杖120份、鸡血藤125份、威灵仙135份、芥子28份、白芍60份、地黄150份、当归70份、没药60份、香附60份、桂枝70份、牛膝70份。
- 根据权利要求1所述的组合物,其特征在于该组合物包括如下重量份的组分:黄芪156份、秦艽156份、防己63份、附子63份、虎杖146份、鸡血藤146份、威灵仙146份、芥子31份、白芍63份、地黄156份、当归63份、没药52份、香附52份、桂枝63份、牛膝63份。
- 根据权利要求1-5任一所述的组合物,其特征在于该组合物的组分中,附子优选为黑顺片,没药优选为醋没药,牛膝优选为川牛膝。
- 根据权利要求1-5任一所述的组合物,其特征在于该组合物的制剂剂型为胶囊剂、片剂、丸剂、口服液、颗粒剂或散剂。
- 根据权利要求1-5任一所述的组合物,其特征在于该组合物的活性组分是由以下步骤制成:A、取防己粉碎成细粉,60份o-γ射线辐射灭菌,备用;B、取桂枝、没药、香附加5-8倍量水,水蒸气蒸馏法连续提取挥发油5-10小时,收集挥发油,蒸馏后的水溶液滤过,另器收集,备用;C、取秦艽、鸡血藤、当归、芥子、白芍、虎杖,加8-12倍量50-80%乙醇,回流提取1-3次,每次1小时,提取液滤过,减压回收乙醇,浓缩至相对密度为1.15±0.05的清膏,备用;D、取黄芪、附子、威灵仙、地黄、牛膝,加8-12倍量水,煎煮2-5次,每次1.5小时,煎煮液滤过,减压浓缩至相对密度为1.10±0.05的清膏,再与挥发油蒸馏后水溶液合并,减压浓 缩至相对密度为1.15±0.05的清膏,备用;E、将步骤C、D清膏合并,混匀,干燥,粉碎得混合清膏粉;步骤A所得的细粉,步骤B所得的挥发油,步骤E所得的清膏粉共同构成了本发明药物组合物的活性组分。
- 根据权利要求7所述的组合物,其特征在于胶囊剂的制备工艺为:A、取防己粉碎成细粉,60份o-γ射线辐射灭菌,备用;B、取桂枝、没药、香附加8倍量水,水蒸气蒸馏法连续提取挥发油10小时,收集挥发油,蒸馏后的水溶液滤过,另器收集,备用;C、取秦艽、鸡血藤、当归、芥子、白芍、虎杖,加10倍量70%乙醇,回流提取3次,每次1小时,提取液滤过,减压回收乙醇,浓缩至相对密度为1.15±0.05的清膏,备用;D、取黄芪、附子、威灵仙、地黄、牛膝,加8倍量水,煎煮4次,每次1.5小时,煎煮液滤过,减压浓缩至相对密度为1.10±0.05的清膏,再与挥发油蒸馏后水溶液合并,减压浓缩至相对密度为1.15±0.05的清膏,备用;E、将步骤C、步骤D所得清膏合并,混匀,干燥,粉碎得混合清膏粉,喷入步骤B所得挥发油,加入步骤A的灭菌粉喷雾制粒,整粒,装胶囊即得。
- 根据权利要求7所述的组合物,其特征在于片剂的制备工艺为:A、取防己粉碎成细粉,60份o-γ射线辐射灭菌,备用;B、取桂枝、没药、香附加6倍量水,水蒸气蒸馏法连续提取挥发油8小时,收集挥发油,蒸馏后的水溶液滤过,另器收集,备用;C、取秦艽、鸡血藤、当归、芥子、白芍、虎杖,加10倍量70%乙醇,回流提取3次,每次1小时,提取液滤过,减压回收乙醇,浓缩至相对密度为1.15±0.05的清膏,备用;D、取黄芪、附子、威灵仙、地黄、牛膝,加11倍量水,煎煮3次,每次1.5小时,煎煮液滤过,减压浓缩至相对密度为1.10±0.05的清膏,再与挥发油蒸馏后水溶液合并,减压浓缩至相对密度为1.15±0.05的清膏,备用;E、将步骤C、步骤D所得清膏合并,混匀,干燥,粉碎得混合清膏粉;F、取步骤B所得挥发油进行包合后,包合物备用;份、将步骤A所得灭菌粉与步骤E所得清膏粉制粒,整粒,加入步骤F所得的包合物,按常规方法压片即得。
- 根据权利要求9所述的组合物,其特征在于步骤F中包合的工艺为:取挥发油6-10倍量的环糊精,加入环糊精6-10倍量的水,进行研磨后,加入挥发油与90-95%乙醇等体积的混 合物,继续研磨均匀后,干燥即得。
- 根据权利要求1-5任一所述的组合物,其特征在于本药物组合物在制备抗炎药物中的应用。
- 根据权利要求1-5任一所述的组合物,其特征在于本药物组合物在制备抑制毛细血管通透性增高的药物中的应用。
- 根据权利要求1-5任一所述的组合物,其特征在于本药物组合物在制备镇痛药物中的应用。
- 根据权利要求1-5任一所述的组合物,其特征在于本药物组合物在制备抑制脾淋巴细胞增殖及血清II型胶原抗体的产生,降低炎症细胞因子IL-1、TNF-α含量,抑制类风湿因子IgG和IgM的产生的药物中的应用。
- 根据权利要求1-5任一所述的组合物,其特征在于所述类风湿性关节炎优选为佐剂关节炎或II型胶原诱导的关节炎。
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