CN101450117B - Rheumatism treatment medicine composition, formulation and preparation method - Google Patents
Rheumatism treatment medicine composition, formulation and preparation method Download PDFInfo
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Abstract
The invention discloses a technology for treating rheumatism belonging to the traditional medicine field. A pharmaceutical composition for treating rheumatism is extracted from the equal weight parts of the following raw materials: radix aconite praeparata, radix aconite kusnezoffii praeparata, sappan wood, cassia twig and muscardine silkworm. The advantages of the invention is that: the rheumatism capsule prescription stemmed from Song dynasty is a traditional Chinese medical secret recipe for treating rheumatisms verified by textual research; it has functions of cold dispelling, dampness removing, clots absorbing and channels activating; and has evident effect in treatment of cold, dampness, impotency of rheumatic and rheumatoid arthritis and blood sludging channel blocking diseases.
Description
Technical field
The present invention relates to a kind of MT rheumatism treatment technique, the rheumatismal pharmaceutical composition of a kind of treatment and preparation method thereof of more specifically saying so belongs to the traditional medicine field.
Background technology
Rheumatism is a kind of common clinical, frequently-occurring disease, and the motherland tradition traditional Chinese medical science is referred to as " arthromyodynia ", is because exopathogen invasion and attack human body impatency meridians such as wind, cold, wet, heat, due to QI-blood circulation is smooth.With muscles and bones, muscle, joint ache, the disease of main performances such as numb, joint stuffiness or arthroncus." element is asked: the numbness opinion " points out: " its migratory BI-syndrome caused mainly by pathogenic wind, BI-syndrome caused mainly by pathogenic cold being called painful BI, dampness victor for numbness also." " Required Readings for Medical Professionals, numbness " done good summary to arthromyodynia treatment, proposed employing Eradicates wind, dehumidifying, cold expelling, QI invigorating, enriched blood and the Therapeutic Method of " control wind and control blood earlier, the blood sector-style is from going out ".The disease that rheumatism comprises is a lot of, it be meant the present cause and onset of disease mechanism of a big class do not study as yet clear, based on infringement synovial membrane, cartilage, BJM, ligament etc., and the systemic disease that can invade a plurality of systems.Be referred to as to past attempts narrow sense " the former disease of axil ", " connective tissue disease ".
The classification to rheumatism at present mainly comprises: autoimmunity rheumatism (just belonging to this type of as rheumatoid arthritis), endocrine-metabolic rheumatism (as gout), infectious rheumatism (as tuberculous arthritis), degeneration rheumatism (as the moxibustion of osteoproliferation joint), heritability rheumatism (as ochronosis) and other be the systemic disease that mainly shows with arthritis.
Rheumatoid arthritis be a kind of chronic repeatedly the outbreak change into main painful diseases with panarthritis disease, be a kind of commonly encountered diseases, frequently-occurring disease.Disease time can a few days, a few weeks or months, and have activeness in various degree, often involve throughout one's life, form long-term ailingly, only also have because of the swelling and the expansion of joint tissue, and local pain just takes place when having only joint motions.Rheumatoid arthritis morbidity often has General Symptoms in early days, as heating, tired, diet is depressed, whole body discomfort etc., severe patient can be simultaneously with anemia.Main clinical manifestation is an arthropathy, and arthrosis is a symmetry often, involves little joint, and is the most common with the multitudinous toe joint of the proximal interphalangeal joint of hands, carpal joint, foot, seriously involves big joint and ridge joints such as elbow, shoulder ankle, knee joint.End-stage patients are mainly that joint dislocation, subluxation, deformity change, movable serious hindrance, and patient can't take care of oneself etc.
According to the health ministry investigation statistics, annual because of rheumatism, rheumatoid, osteopathia, directly or indirectly death toll reaches 1,500,000 people approximately.Therefore, treatment rheumatism, rheumatoid, osteopathia are in an emergency in the whole nation, and be very urgent.
Summary of the invention
First technical problem that the present invention will solve is: provide a kind of treatment rheumatismal pharmaceutical composition.
Second technical problem that the present invention will solve is: providing with the aforementioned pharmaceutical compositions is the MT rheumatism capsule of active component.
The 3rd technical problem that the present invention will solve is: provide a kind of industrialization to prepare the method for MT rheumatism capsule.
To achieve these goals, the present invention adopts following technical scheme:
The rheumatismal pharmaceutical composition of a kind of treatment is made by the following medicine material extraction that waits parts by weight: Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata, Lignum Sappan, Ramulus Cinnamomi and Bombyx Batryticatus.
The present invention is a secret recipe, comes from the Song dynasty, and drug effect is peculiar, and is evident in efficacy: Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata: all have effects such as expelling wind and removing dampness, antalgic.Modern study shows that the main effective ingredient of Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata is alkaloid component, and experimentation shows that the water of Radix Aconiti Preparata and Radix Aconiti Kusnezoffii Preparata, alcohol extract all have effects such as analgesia, antiinflammatory, warming YANG.Lignum Sappan, Ramulus Cinnamomi: Lignum Sappan promoting the circulation of blood blood stasis dispelling, reducing swelling and alleviating pain, Ramulus Cinnamomi promoting the flow of QI-blood by warming the meridian, supporing yang activating QI.Modern study shows that the two all contains volatile oil component, and the two contained volatile oil all has antiinflammatory, effect such as antibacterial.Bombyx Batryticatus: have effects such as dispelling wind-evil and transforming calculus.Modern study shows, mainly contains fat, aminoacid, ammonium oxalate and trace element etc. in the Bombyx Batryticatus, has experiment to show that its alcohol, aqueous extract all have effects such as calmness, analgesia and convulsion.
Medicinal material processing should meet following standard: Radix Aconiti Preparata: through identifying this product is the dry parent root of cohosh Aconitum carmichjaelii Debx. Aconitum carmichaeli Debx., be soaked in water to the interior no dried heart, take out, (or steaming 6-8 hour) cuts the interior no white heart to getting big to add water boil 4-6 hour, mouth is tasted little when numb feeling in the tongue is arranged, and takes out, and dries in the air to sixty percent to do, section, drying.Should meet " regulation under Chinese pharmacopoeia Radix Aconiti of version in 2000 and the Radix Aconiti Preparata item.Radix Aconiti Kusnezoffii Preparata: through identifying this product is the dried root of cohosh Aconitum kusnezoffii Reichb Aconitum kusnezoffii Reichb., is soaked in water to the interior no dried heart, takes out, add decocting in water to get big cut in the no white heart, mouth is tasted little when numb feeling in the tongue is arranged, taking-up, dry in the air to sixty percent dried back shave, drying.Should meet " regulation under Chinese pharmacopoeia Radix Aconiti Kusnezoffii of version in 2000 and the Radix Aconiti Kusnezoffii Preparata item.Lignum Sappan: through identifying this product is the dry duramen of leguminous plant Lignum Sappan Caesalpinia sappan L., meets " the pertinent regulations under Chinese pharmacopoeia Lignum Sappan item in 2000.Be sawn into the section that is about 3cm, be split into sheet again and use.Ramulus Cinnamomi: through identifying this product is the dry twig of canella Cortex Cinnamomi Cinnamomum cassia Presl.Meet " regulation under Ramulus Cinnamomi item of Chinese pharmacopoeia version in 2000.Need remove impurity before feeding intake, steep slightly, clean, run through, shave dries.Bombyx Batryticatus: through identifying this product is that the larva in the insecticide silkworm Bombyx mori Linnaeus.4-5 of pretty young woman section age infects (or artificial vaccination) muscardine Beauveria bassiana (Bals.) Vuillant and lethal dry body.Meet " the pertinent regulations under Bombyx Batryticatus item of Chinese pharmacopoeia version in 2000.Dry before using.
The rheumatismal pharmaceutical preparation of a kind of treatment is made up of aforementioned pharmaceutical compositions and pharmacy acceptable auxiliary as active component.
Described pharmaceutical preparation can be for decoction, oral liquid, medicated wine, powder, pill, conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/dosage forms such as position releasing piece, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, granule, oral liquid, membrane, patch.
Described pharmaceutics acceptable auxiliary is selected from the compositions of one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, magnesium stearate, citric acid and sodium sulfite etc., belongs to this area routine techniques.
The invention provides the rheumatismal capsule of a kind of treatment (MT rheumatism capsule), extract by each 100-600g of Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata, Lignum Sappan, Ramulus Cinnamomi and Bombyx Batryticatus (preferred 100-300g) and make active component; Add an amount of dextrin, make 1000 of capsules.
Existing hydrophilic component in the main effective site of each flavour of a drug also has lipophilic ingredients in the prescription, so the suitable solid preparation of making; Secret recipe amount every day is 16g, gets extract powder by the inventive method extraction concentrate drying and is about 0.7g/ day, adds β-about 0.2g of CD inclusion complex, and total amount is about 1g, and after the adding appropriate amount of auxiliary materials, tablet, capsule all can be made.Consider capsule the outward appearance the same with tablet is bright and clean, dose is little except that having, swallow easily, good stability, be not subject to the characteristics such as influence of dampness, airborne oxygen and light, it is fast also to have disintegrate, drug release and stripping are fast, absorb better the also more high advantage of bioavailability.So plan to make capsule after we extract.
A kind of method of the MT of preparation rheumatism capsule: Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ; Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex is ground into fine powder 40 ± 1 ℃ of cold drying, and is standby; Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, the extractum that to be concentrated into 50 ℃ of following relative densities be 1.30-1.35, drying under reduced pressure is ground into fine powder, and is standby; Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 60～80% (preferred 70%) 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into 50 ℃ of relative densities be 1.30～1.35 extractum, drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and adds an amount of dextrin, mixing, the alcohol granulation of the 75-95% that with concentration is, drying, the Capsules of packing into, promptly.
We's medicine is after extracting, and gained semi-finished product viscosity is bigger, and the easy moisture absorption, and the semi-finished product yield is per diem obeyed crude drug 16g and calculated about 7% in addition, and day clothes semi-finished product are 1.0g, and dose is less, intends the adding proper amount of diluting.The diluent that Chinese medicine preparation is commonly used is starch, dextrin, lactose etc.Because dextrin is than starch good water solubility, thereby be more conducive to the release and the stripping of medicine, and hygroscopicity is little, more cheap than lactose again, be diluent so select dextrin.Get above-mentioned extract powder, add 0.25,0.5,1.0 times in dextrin then respectively, add β-CD inclusion complex, mixing is with the alcohol granulation of debita spissitudo, drying.The result shows: it is good that semi-finished product add 0.5 and 1.0 times of person's performance, and add 0.25 times of person of dextrin, sticking sieve during granulation, and granule moisture absorption deliquescing is so determine to add the dextrin of 0.5 times of about semi-finished product amount (water extract, ethanol extract and β-CD inclusion complex sum).
Phenomenons such as because characteristics such as the semi-finished product viscosity Da Yi moisture absorptions, some methods are granulated, and the grain color that then be prone to the sticking roller bearing of medicated powder, lumps, makes is inhomogeneous, thus intend adopting wet granulation, and add an amount of wetting agent.Wetting agent commonly used in the preparation has water, ethanol, starch slurry, syrup etc., because our gained semi-finished product have certain viscosity, behind chance water or the starch slurry, caking makes the granulation operating difficulties rapidly, therefore selects ethanol as wetting agent.Get an amount of semi-finished product, add certain density ethanol, can moistening, and bring out itself viscosity, and make to be agglomerated into soft material, be easy to granulate.Concentration commonly used during alcohol granulation is 30%-70%, because our gained semi-finished product water solublity is big, viscosity is big, so should select the higher alcohol granulation of concentration.Get above-mentioned semi-finished product (water extract, ethanol extract and β-CD inclusion complex) mixing, add 75%, 85%, 95% ethanol then respectively, mixing is granulated.The result shows: during with 75% alcohol granulation, and the sticking sieve of gained soft material, the difficulty of granulating; During with 95% alcohol granulation, the gained granule is few, fine powder is many; During with 85% alcohol granulation, gained soft material humidity and viscosity are all granulated than suitable, so determine that concentration of alcohol is 85%.
Moisture absorption is recurrent unstable variation of solid preparation, and usually is the precondition that causes other variation.So by investigating contrast powder and particulate CRH value, from the necessity of an aspect proof granulating process.Get 8 in exsiccator, bottom adds the sulphuric acid of variable concentrations or the supersaturated solution of salt respectively, to keep certain relative humidity.Accurate respectively 8 parts in fixed granule that has prepared and the medicated powder that claims in the weighing botle of the constant weight of packing into, is opened the weighing bottle cap, puts into above-mentioned exsiccator, and is airtight, places 25 ℃ of isoperibols to keep 7 days, opens exsiccator, and the weighing bottle cap is covered completely, and precision is weighed.Calculate dry weight and weight in wet base, and the hydroscopicity of count particles and medicated powder thus, draw the moisture equilibrium at dry side curve and also obtain critical relative humidity (CRH), the results are shown in Table 1.
Table 1: medicated powder and the contrast of particulate hydroscopicity
Critical relative humidity is a water soluble drug moisture absorption whether marginal value, and various water soluble drugs respectively have its inherent CRH value, and available CRH value is made the index of hygroscopicity size, and promptly the CRH value is big more, is difficult for moisture absorption more.From above-mentioned experimental result as can be seen, medicated powder is after granulating, and its CRH value increases, and hygroscopicity reduces, and shows that medicated powder is more stable after granulating.
Pharmacodynamic test of active extract of the present invention causes acute and chronic inflammatory animal models such as rat paw edema from adjuvant-induced arthritis, granulation tissue hyperplasia, yeast, and aspect such as immunoloregulation function totally 8 indexs, the MT rheumatism capsule has been carried out pharmacodynamic experiment research, simultaneously, the rat long term toxicity test that has carried out acute toxicity test and 6 months is observed.Its pharmacological toxicology result of the test is summarized as follows: the result shows: (1) MT rheumatism capsule can significantly suppress constitutional arthritis and the Secondary cases arthritis that Freund ' s Freund's complete adjuvant brings out, pathological observation thinks that this medicine can obviously improve the lesion degree of ankle joint due to the Freund ' s Freund's complete adjuvant, and prompting MT rheumatism capsule has tangible preventive effect and therapeutical effect to the adjuvanticity chronic arthritis.(2) the MT rheumatism capsule has remarkable inhibitory action to cott on pellet-induced granuloma formation, shows that this medicine has the antiinflammatory action of highly significant to subacute inflammation.(3) the MT rheumatism capsule can obviously resist yeast and cause rat paw edema, shows that this medicine has the antiinflammatory action of highly significant to acute inflammation.(4) MT rheumatism capsule Dichlorodiphenyl Acetate (H+) induced mice abdominal cavity capillary permeability is hyperfunction has a tangible antagonism.(5) MT rheumatism capsule Dichlorodiphenyl Acetate causes that mice pain has obvious analgesic activity.(6) the MT rheumatism capsule has obvious inhibitory action to DNCB induced mice delayed hypersensitivity.(7) the MT rheumatism capsule can obviously suppress the bone-marrow-derived lymphocyte conversion, points out this medical instrument that the effect that suppresses humoral immunization is arranged.(8) the MT rheumatism capsule can obviously suppress the T lymphocyte transformation, points out this medical instrument that the effect that suppresses cellular immunization is arranged.(9) in adjuvant-induced arthritis, mice delayed hypersensitivity and T lymphocyte transformation experiment, the MT rheumatism capsule all demonstrates certain inhibitory action to the immune organ index.Prompting MT rheumatism capsule has significant prevention and therapeutical effect to autoimmune chronic arthritis, the propagation of acute, subacute inflammation, inflammation is reached exudative inflammation mutually have the obvious suppression effect, certain analgesic activity is arranged, and can significantly regulate body's immunological function.
Recommendation use amount of the present invention is that three times on the oral one, each 0.5 restrains.
Advantage of the present invention is: MT rheumatism capsule prescription comes from the Song dynasty, and the Chinese medicine secret recipe of Song dynasty treatment rheumatism is thought in textual criticism.Have dispelling cold and removing dampness, the effect of disperse blood stasis and dredge collateral is used for rheumatism, rheumatoid arthritis cold-damp impatency, and syndrome of static blood blocking collaterals is evident in efficacy.
The invention will be further described below in conjunction with the specific embodiment, and embodiments of the present invention are not limited to this, every according to principle perhaps in disclosed by the invention, any this area of enforcement be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
Embodiment 1: the preparation capsule
One. prescription:
Radix Aconiti Preparata 600g Radix Aconiti Kusnezoffii Preparata 600g Lignum Sappan 600g Ramulus Cinnamomi 600g Bombyx Batryticatus 600g
Two. method for making:
The above five tastes, Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ.Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, and make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex cold drying (40 ℃) is ground into fine powder, and is standby.Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, be concentrated into relative density 1.30-1.35 (50 ℃) extractum, drying under reduced pressure is ground into fine powder, and is standby.Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 70% 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into relative density be 1.30～1.35 (50 ℃), drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and it is an amount of to add dextrin, mixing, alcohol granulation with 85% concentration, drying, the Capsules of packing into, promptly.
Per 1000 capsules contain: extract powder 159g, β-CD inclusion complex 11g, dextrin 80g; The content of capsule Chinese medicine and adjuvant is the 0.25g/ grain.
Embodiment 2: the preparation capsule
One. prescription:
Radix Aconiti Preparata 300g Radix Aconiti Kusnezoffii Preparata 300g Lignum Sappan 300g Ramulus Cinnamomi 300g Bombyx Batryticatus 300g
Two. method for making:
The above five tastes, Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ.Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, and make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex cold drying (40C) is ground into fine powder, and is standby.Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, be concentrated into relative density 1.30-1.35 (50 ℃) extractum, drying under reduced pressure is ground into fine powder, and is standby.Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 70% 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into relative density be 1.30～1.35 (50 ℃), drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and it is an amount of to add dextrin, mixing, alcohol granulation with 85% concentration, drying, the Capsules of packing into, promptly.
Per 1000 capsules contain: extract powder 80g, β-CD inclusion complex 6g, dextrin 164g; The content of capsule Chinese medicine and adjuvant is the 0.25g/ grain.
Embodiment 3: the preparation capsule
One. prescription:
Radix Aconiti Preparata 150g Radix Aconiti Kusnezoffii Preparata 150g Lignum Sappan 150g Ramulus Cinnamomi 150g Bombyx Batryticatus 150g
Two. method for making:
The above five tastes, Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ.Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, and make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex cold drying (40 ℃) is ground into fine powder, and is standby.Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, be concentrated into relative density 1.30-1.35 (50 ℃) extractum, drying under reduced pressure is ground into fine powder, and is standby.Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 70% 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into relative density be 1.30～1.35 (50 ℃), drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and it is an amount of to add dextrin, mixing, alcohol granulation with 85% concentration, drying, the Capsules of packing into, promptly.
Per 1000 capsules contain: extract powder 45g, β-CD inclusion complex 5g, dextrin 200; The content of capsule Chinese medicine and adjuvant is the 0.25g/ grain.
Embodiment 4: toxicity test
One. acute toxicity test in mice
The MT rheumatism capsule in 1: 0.85 ratio establish 191.8,163.0,138.5,117.8,5 dosage groups of 100.0g crude drug/kg, give mouse stomach once, observed 14 days.
Experimental result: except that 100.0g crude drug/kg group, death all appears in other each dosage groups, and is dead in big 24h of dead mice, and accelerated breathing is twitched, and respiratory failure causes death.Survival mice about 2h that reposes recovers normal activity gradually, hair color light, behavior normally, do not see abnormal responses such as diarrhoea, convulsions, mice feed, drinking-water, neural reflex etc. and matched group no significant difference.Use the Bliss statistical method, record median lethal dose(LD 50) LD50=140.8187g crude drug/kg, standard error Sx50=0.0173 g crude drug/kg, 95% fiducial limit C.L=152.2374---the 130.2565g crude drug/kg of MT rheumatism capsule.MT rheumatism capsule clinical application amount is 16g crude drug/day/60Kg people, and 0.27g crude drug/day/Kg people, (140.8187g crude drug/kg) is 828 times of per kilogram people dosage every day to its LD50.
Two. the rat long term toxicity test
It is the 10g crude drug that the clinical people of MT rheumatism capsule intends day dosing, calculates with 60kg body weight people, is 0.17g crude drug/kg. people.The rat long term toxicity test of MT rheumatism capsule establish height (16g crude drug/kg), in (8g crude drug/kg), low (three dosage groups of 4g crude drug/kg) are equivalent to 60,30,15 times of clinical per kilogram people respectively.
The Wistar rat, SPF, body weight 80～120g, male and female half and half after one week of the GLP of the court laboratory rearing, are divided into totally 4 groups of matched group, high, medium and low dosage groups at random by body weight.The rat oral gavage administration, once a day, the 0.5ml/100g body weight, continuous irrigation stomach 6 months, matched group is irritated capacity distilled water such as stomach.Experimental session is observed the general situation of animal, and administration is measured every indexs such as rat blood, blood biochemical, urine, electrocardiogram respectively after 3 months and 6 months.Put to death part animal (female, hero about half and half) in 3 months and 6 months respectively, detect animal important organ coefficient and histopathologic change.Each is organized and surpluss 10 animals (male and female each 5) drug withdrawal, and carry out convalescent period and observed 1 month, and above-mentioned every index of repetition measurement and histopathology check.The result is as follows for MT rheumatism capsule rat long term toxicity test:
Administration 3 months: the general situation of animal is observed, and does not see abnormal responses such as outward appearance change, nervous system, digestive system occur; Hematological indices measurement result: the equal no significant difference of the more every index of male rat and matched group.Female rats, high dose group Gr, Mo obviously raise than matched group, and Ly obviously reduces, and low dose group Mo obviously raises, all the other each index no significant differences; Blood biochemical is learned every index determining result: male rat and matched group compare, and middle dosage group blood glucose (GLU) obviously raises, and low dose group serum glutamic oxalacetic transaminase (AST) obviously reduces, all the other every index no significant differences.Female rats administration 3 months and matched group compare, and high, medium and low dosage group Cre all obviously reduces, and low dose group TP, ALB, CHO obviously raise; Electrocardioscopy: male and each index of female rats electrocardiogram of three dosage groups and matched group be no significant difference relatively all; Internal organs index statistics: in the male rat, low dose group and matched group comparison lung index obviously reduce; The equal no significant difference of each dosage group of female rats.
Administration 6 months: the general situation of animal is observed, and does not see abnormal responses such as outward appearance change, nervous system, digestive system occur; The hematological indices measurement result: the male rat low dose group obviously raises than matched group Mo, female rats high and low dose group RBC, HCT obviously reduce, and high dose group Ly obviously reduces, and Gr obviously raises, in, low dose group Mo obviously raises all the other each index no significant differences; Blood biochemical is learned every index determining result: male rat and matched group compare, and high dose group AST obviously reduces, and low dose group GLU obviously raises, all the other every index no significant differences; In the female rats, low dose group GLU obviously raises; Electrocardioscopy: male and each index of female rats electrocardiogram of three dosage groups and matched group be no significant difference relatively all.But ventricular premature contraction appears in high dose group male rat (No. 92) electrocardiogram.Artrial premature beat appears in high dose group female rats (No. 50) electrocardiogram, and middle dosage group female rats (No. 91) electrocardiogram presents the artrial premature beat premature ventricular beat; Internal organs index statistics: male rat high dose group stomach index obviously increases, all the other every index no significant differences.Female rats high dose group liver index obviously reduces, and the ovary index obviously increases, and middle dosage group renal index, adrenal gland's index obviously reduce, and all the other each indexs and matched group be no significant difference relatively all.
Convalescent period: the general situation of animal is observed, the reaction of no abnormality seens such as outward appearance, nervous system, digestive system; Hematological indices measurement result: male, female rats convalescent period and the equal no significant difference of each index of matched group; Blood biochemical is learned measurement result: male rat high dose group AST obviously reduces, all the other every index no significant differences; Each each index of dosage group of female rats is than the equal no significant difference of matched group: Electrocardioscopy: male and each index of female rats electrocardiogram and the relatively more equal no significant difference of matched group; Internal organs index statistics: male, each each index of dosage group of female rats and the relatively more equal no significant difference of matched group.
Rats Organs and Tissues tissue pathology checking conclusion: MT rheumatism capsule rat long term toxicity test, administration three months, administration six months and convalescent period matched group and the pathologic finding of organs and tissues such as each administration group (high dose group, middle dosage group and low dose group) animal heart of being inspected by ready samples, liver, spleen, lung, kidney, adrenal gland, brain, thyroid, optic nerve, hypophysis, lymph node, thymus, pancreas, digestive system stomach, duodenum, reproductive system uterus, ovary, testis, epididymis, prostate in, 1 animal liver nuclear of administration experiment in three months high dose group concentrates; The heart, liver, the kidney of 1 of six months experiment high dose group ♂, 1 of ♀ has pathological changes in various degree, and liver, the kidney that middle dosage group ♀ is 1 has pathological changes in various degree; 1 animal liver far-end of convalescent period high dose group ♀ mild cerebral ischemic.The pathological changes of these internal organs and the toxicity of medicine have certain relation, and convalescent period send the animal viscera pathological changes than six months alleviate to some extent, and reversibility is arranged.
Above blood, biochemistry etc. have part index number and matched group that notable difference is relatively arranged, but its measured value is substantially in normal range.
Embodiment 5: pharmacodynamic experiment
Following experimental drug thing is semi-finished product (be the mixture that extract powder and β-CD inclusion complex is formed, do not contain the adjuvant dextrin) that according to the method preparation of embodiment 1 name is called MT rheumatism capsule, code name MT.
One. adopt Freund ' s Freund's complete adjuvant to bring out rat arthritis model, observe the MT rheumatism capsule arthritic preventive effect of autoimmune chronic and therapeutical effect.
1. method: the Wistar rat, male, at the GLP of China Academy of TCM laboratory rearing after three days, select 130 of the healthy rats of body weight 150～180g, at first be divided into two parts at random: 70 of prevention administration parts, 60 of treatment administration parts by rat body weight.70 rats of prevention administration are divided into normal control group, prophylaxis model group, prevention prednisolone acetate group, prevention MT rheumatism capsule 0.6,1.2,2.4g crude drug/kg group at random by body weight again, and totally 6 groups, 10 of normal control groups, all the other respectively organize 12.60 rats of treatment administration wouldn't divide into groups sub-cage rearing.
All rats are adopted the volumetric values of the preceding left and right sufficient sole of the foot of volumetric method determination experiment, as causing scorching preceding volumetric values.Experimental rat except that normal control group (10) (promptly 120), right back sufficient plantar subcutaneous injection Freund ' the s Freund's complete adjuvant 0.1ml of every rat causes inflammation.
Prevention is respectively organized rat 1h before causing inflammation and is begun gastric infusion, the 1ml/100g body weight, and once a day, continuous 21 days, normal control group and model group were irritated capacity distilled water such as stomach.When measuring each group of prevention and causing scorching back 3h, 2 days, 3 days, 5 days, 7 days, 9 days, 11 days, 13 days, 15 days, 17 days, 19 days and 21 days, the volumetric values of the left and right sufficient sole of the foot of rat.Calculate the volume difference (homonymy causes scorching sufficient sole of the foot volumetric values-homonymy and causes scorching front foot sole of the foot volumetric values) of the left and right sufficient sole of the foot of every Mus respectively.
The rat of treatment part is measured and causes scorching back 3 days, 7 days, the volumetric values of the left and right sufficient sole of the foot, 60 rats to treat part by the left sufficient sole of the foot volumetric values of measuring in the 7th day are divided into treatment model group, treatment prednisolone acetate group, treatment MT rheumatism capsule 0.6,1.2,2.4g crude drug/kg at random and organize totally 5 groups, 12 every group.Respectively group is from causing beginning in the 7th day administration of scorching back in treatment, and the 1ml/100g body weight once a day, continuous 17 days, is treated model group and irritated capacity distilled water such as stomach.Each group of treatment is measured the volumetric values of the left and right sufficient sole of the foot of rat that causes scorching back 9 days, 11 days, 13 days, 15 days, 17 days, 19 days, 21 days, 23 days.And calculate the volume difference (homonymy causes scorching sufficient sole of the foot volumetric values one homonymy and causes scorching front foot sole of the foot volumetric values) of the left and right sufficient sole of the foot of every Mus respectively.
Experimental session, record animal food-intake is weighed every other day.Every day the close observation animal situations such as activity, behavior feed drinking-water, observe and note down the appearance situation of secondary inflammations such as rat ears, tail, left pedal swelling, mark every other day by the arthritis index standards of grading of new Chinese medicine guide; Tested the 22nd, 23 day, about 1/2 laboratory animal of normal control group and prevention are respectively organized laboratory animal and are weighed after (fasting 16h before), the anesthesia of lumbar injection 20% urethane, abdominal aortic blood: get 1.9 sodium citrate anticoagulation 5ml, be used to measure whole blood viscosity, plasma viscosity, packed cell volume, fiber protein content; Get the non-anticoagulation of 2ml and be used to measure serum il-1 β (IL-1 β), interleukin-6 (IL-6), tumor necrosis factor (TNF); Test the 24th, 25 day about 1/2 laboratory animal of normal control group and the same operation of laboratory animal is respectively organized in treatment, get blood and carry out above-mentioned every mensuration; All animals are put to death after getting blood.Dissect, get thymus, spleen, adrenal gland and weigh, calculate the organ index; Get the left and right side ankle joint, be fixed in 10% formalin, carry out the histopathology check.
2. result: see Table 2 to table 8.
Table 2: right sufficient sole of the foot statistical result showed: cause scorching the 7th day, model group, prednisone group, MT rheumatism capsule 0.6,1.2,2.4g/kg group compare with matched group, the right sufficient sole of the foot volume determination value of rat obviously increases (p＜0.001), shows the right pedal swelling model establishment of the preceding rat of treatment.After the treatment administration, model group and matched group relatively cause all obviously swelling (p＜0.001) of the right sufficient sole of the foot of each time point of scorching back; Each treats administration group and model group relatively, and the 11st, 13,17,19,21,23 days right pedal swellings of positive drug prednisone obviously reduce (p＜0.05), and three dosage groups treatments of MT rheumatism capsule administration has and reduces right pedal swelling trend, but all by statistics; The sufficient sole of the foot statistical result showed in a left side: cause scorching the 7th day, model group, prednisone group, MT rheumatism capsule 0.6,1.2,2.4g/kg group compare with matched group, and the sufficient sole of the foot solid measure value in a rat left side has the trend of increasing, not statistically significant.Treatment administration model group rat sufficient sole of the foot volumetric values in a left side and matched group relatively all obviously increase (p＜0.05 or p＜0.01 or p＜0.001) from the 9th day to 23 days left pedal swellings, show the success of secondary inflammation model; Each treats the administration group and model group compares, the 11st, 13,15,17,19,21,23 days left pedal swellings of positive drug prednisone group obviously reduce (p＜0.05 or p＜0.01 or p＜0.001), MT rheumatism capsule 0.6g/kg organizes the 23rd day left pedal swelling and obviously reduces (p＜0.05), obviously reduce (p＜0.05) 1.2g/kg organize the 17th day left pedal swelling, obviously reduce (p＜0.05) 2.4g/kg organize the 11st, 13,15 day left pedal swelling, all the other each points have the trend of reducing.
Table 3 is respectively organized the statistical result of rat paw difference for the treatment administration.Right sufficient sole of the foot statistical result showed: cause scorching the 7th day, model group, prednisone group, MT rheumatism capsule 0.6,1.2,2.4g/kg organize with matched group and compare, and the right sufficient sole of the foot difference of rat obviously increases, and show the right pedal swelling model establishment of the preceding rat of treatment.After the treatment administration, model group and matched group compare, and the right pedal swelling difference of each time point all obviously increases (p＜0.001); Each treats administration group and model group relatively, positive drug prednisone the 11st, 13,, 15,17,19,21,23 days right sufficient sole of the foot differences obviously reduce (p＜0.05 or p＜0.01), three dosage groups treatments of MT rheumatism capsule administrations and model group comparison no significant difference; The sufficient sole of the foot statistical result showed in a left side: cause scorching the 7th day, model group, prednisone group, MT rheumatism capsule 0.6,1.2,2.4g/kg group compare no significant difference with matched group.Treatment administration model group rat sufficient sole of the foot volumetric values in a left side and matched group relatively all obviously increase (p＜0.05 or p＜0.01 or p＜0.001) from the 9th day to 23 days left pedal swelling differences, show the success of secondary inflammation model; Each treats the administration group and model group compares, the 9th, 11,13,15,17,19,21,23 days left pedal swelling differences of positive drug prednisone group obviously reduce (p＜0.05 or p＜0.001), MT rheumatism capsule 0.6g/kg organizes the 23rd day left pedal swelling difference and obviously reduces (p＜0.01), obviously reduce (p＜0.05 or p＜0.01) 1.2g/kg organize the 13rd, 15,17,19,23 day left pedal swelling difference, 2.4g/kg organizes the 11st, 13,15 day left pedal swelling difference and obviously reduces (p＜0.05 or p＜0.01).
Table 4 is the influence of MT rheumatism capsule to the adjuvant arthritis rats arthritis index: the arthritis index of prophylaxis model group rat obviously increases (p＜0.001) than matched group; The 3rd, 9,17,19,21 days arthritis index of prevention prednisone group obviously reduces (p＜0.05 or p＜0.001) than model group, prevention MT rheumatism capsule 0.6g/kg organizes the 9th day arthritis index and is starkly lower than model group (p＜0.05), be starkly lower than model group (p＜0.05 or p＜0.01) 1.2g/kg organize the 3rd, 17,19,21 day arthritis index, 2.4g/kg organizes the 17th, 19,21 day arthritis index and is starkly lower than model group (p＜0.05 or p＜0.01); The arthritis index of treatment model group rat obviously increases (p＜0.001) than matched group; The 9th, 19,21,23 days arthritis index of treatment prednisone group obviously reduces (p＜0.05) than model group, treatment MT rheumatism capsule 0.6,1.2g/kg organize the 21st day arthritis index and are starkly lower than model group (p＜0.05), and the 2.4g/kg group is organized the 17th day arthritis index and is starkly lower than model group (p＜0.05).
Table 5:MT rheumatism capsule is to the pathological examination of the right ankle joint of adjuvant arthritis rats
The P value is to compare with model group
Table 5 shows, prevention and treatment model group right side ankle joint lesion degree and matched group relatively have notable difference (p＜0.01), and prednisone and MT rheumatism capsule prevent and treat each dosage group and all can obviously improve right side ankle joint lesion degree (p＜0.05) due to the Freund ' s Freund's complete adjuvant.
Table 6:MT rheumatism capsule is to the influence of adjuvant arthritis rats serum pro-inflammatory cytokine
Annotate: in () is number of animals; Compare with matched group: ##p＜0.01 ###p＜0.001
Compare with model group: * * * p＜0.001
Table 6 shows that IL-1 β, IL-6, the equal no significant difference of TNF are respectively organized in prevention; Treatment model group serum il-1 β, IL-6 are than matched group obviously raise (p＜0.01 or p＜0.001), to serum TNF no significant difference (being to cause scorching 23 days at this moment), prednisone, MT rheumatism capsule 1.2,2.4g/kg group all do not have obvious influence to IL-1 β, IL-6, TNF, and only MT rheumatism capsule 0.6g/kg group is than model group obviously raise (p＜0.001).
Table 7:MT rheumatism capsule is to the influence of adjuvant arthritis rats immune organ
Compare with matched group:
#P＜0.05
##P＜0.01; Compare with model group: * p＜0.05 * * p＜0.01
Table 7 shows, thymus, spleen and adrenal gland's index of prevention and treatment model group are in the apparent in view increase of matched group (p＜0.05 or p＜0.01), prevention prednisone group thymus index obviously reduces (p＜0.01) than model group, prevention MT rheumatism capsule 2.4g/kg group obviously reduces adrenal gland's index (p＜0.05), and all the other each groups all do not have obvious influence to the immune organ index.
Table 8:MT rheumatism capsule is to the influence of adjuvant arthritis rats hemorheology
Compare with matched group: #p＜0.05 ##p＜0.001
In the table 8, prevention and treatment model group and matched group are relatively, fiber protein content and plasma viscosity no significant difference, packed cell volume and whole blood viscosity are than matched group obviously raise (p＜0.05 or p＜0.01), show that erythrocyte number increases in the blood, blood thickens, and blood viscosity raises, and each dosage group of prednisone and MT rheumatism capsule does not all have obvious influence to fiber protein content, plasma viscosity, packed cell volume and whole blood viscosity.
3. brief summary: (1) prevention administration, three dosage groups of MT rheumatism capsule all can obviously suppress constitutional arthroncus and the Secondary cases arthroncus that Freund ' s Freund's complete adjuvant brings out.The treatment administration, the MT rheumatism capsule is not obvious to the constitutional arthroncus curative effect that Freund ' s Freund's complete adjuvant brings out, and arthroncus has certain therapeutical effect to Secondary cases.(2) the MT rheumatism capsule can obviously reduce arthritis index, show the secondary inflammation at positions such as the ear due to Freund ' the s Freund's complete adjuvant, tail, fore paw, left back pawl and to have tangible prevention and therapeutical effect as: tuberosity, rubescent, toe joint, ankle joint, pedal swelling etc.(3) serum il-1, IL-6, TNF there is not obvious influence.(4) MT rheumatism capsule prevention administration 2.4g/kg group can obviously reduce adrenal gland's index, and thymus index and spleen index are not had obvious influence.(5) the MT rheumatism capsule does not improve significantly to the blood viscosity increase that Freund ' s Freund's complete adjuvant causes.(6) pathological examination result: model group right side ankle joint presents pathological change in various degree, MT rheumatism capsule prevention and treat the lesion degree that each dosage group all can obviously be improved right side ankle joint due to Freund ' the s Freund's complete adjuvant.Left side ankle joint model group is not seen obvious pathological change, and this medicine does not have obvious influence to the left side ankle joint.
Two. adopt rat cotton balls implantation to observe of the influence of MT rheumatism capsule to granulation hyperplasia.
1. method: the Wistar rat, SPF, male, body weight 150～180g is divided into totally 5 groups of model group, aspirin, MT rheumatism capsule 0.6,1.2,2.4g crude drug/kg group at random by body weight.The equal gastric infusion of each administration group, the 1ml/100g body weight, once a day, continuous 9 days, model group was irritated capacity distilled water such as stomach.
Rat is fed two days later at laboratory, and every rat is used the ether light anaesthesia, cuts off belly wool, under the sterile working, undergo surgery iodine tincture and alcohol disinfecting skin of abdomen, otch, under the groin of rat both sides, implant a dry cotton ball (through autoclaved heavy 20mg) respectively, skin suture.After operation is finished, be divided into above-mentioned 5 experimental grouies by body weight.Began to irritate stomach the same day, the 1ml/100g body weight, once a day, continuous 9 days, model group was irritated capacity distilled water such as stomach.Tested the 10th day, the rat back sacrificed by decapitation (before, water 12h is can't help in fasting) of weighing separates bilateral granulation tissue, thymus, adrenal gland, spleen and weighs.Granulation tissue is weighed after placing 60 ℃ of baking oven inner drying 12h.Calculate each organ coefficient and granuloma coefficient net weight.
Organ coefficient=[heavy (the g)/body weight (g) of internal organs] * 100
Organ coefficient suppression ratio (%)=(model group organ coefficient average-medication group organ coefficient average)/model group organ coefficient average * 100
The former dry cotton ball of granuloma net weight=bilateral granuloma dry weight/2-heavy (20mg)
Granuloma coefficient=[granuloma net weight (g)/body weight (g)] * 100
The t inspection statistics the results are shown in Table 12 between group.
2. the result adds up: represent t inspection statistics between group with x ± SD.
Table 9:MT rheumatism capsule is to the influence of rat granuloma hamartoplasia
Compare with model group: * p＜0.05 * * p＜0.01 * * * p＜0.001
The result shows: MT rheumatism capsule 1.2,2.4g crude drug/kg group have remarkable inhibitory action to cott on pellet-induced granuloma formation, point out this medicine that the inflammation propagation phase is had significant inhibitory effect.
Three. adopt yeast to cause rat foot claw swelling method, cause the acute inflammation model.Observe the antiinflammatory action of MT rheumatism capsule.
1. method: the Wistar rat is divided into totally 5 groups of model group, aspirin, MT rheumatism capsule 0.6,1.2,2.4g crude drug/kg group, 10 every group at random by body weight.The equal gastric infusion of each administration group, the 1ml/100g body weight, once a day, continuous three days, model group was irritated capacity distilled water such as stomach.
1h after the last administration causes inflammation in the sufficient plantar subcutaneous injection 10% yeast physiological salt liquid 0.1ml in a rat left side, with volumetric method (capillary tube measurement by magnification device) measure respectively each Mus cause scorching before and cause scorching after the sufficient sole of the foot volume of 1,2,4,6 h.Calculate every rat cause scorching before, sufficient sole of the foot volume difference (sufficient sole of the foot volume difference=cause the consistent scorching front foot sole of the foot volume difference of scorching sufficient sole of the foot volume difference).With each group rat paw volume difference, the model group with corresponding time point compares respectively, organizes a t inspection statistics.
2. the result adds up: with each group rat paw volume difference, the model group with corresponding time point compares respectively.Represent t inspection statistics between group with x ± SD.The results are shown in Table 10.
Table 10:MT rheumatism capsule brings out the influence (n=10) of rat paw edema to yeast
Model group compares: * p＜0.05 * * p＜0.01 * * * p＜0.001
Table 10 is the result show: three dosage groups of MT rheumatism capsule all can obviously be resisted yeast and cause rat paw edema, point out this medicine acute inflammation to be had the antiinflammatory action of highly significant.
Four .MT rheumatism capsules are to the hyperfunction influence of lumbar injection acetic acid (HAc) induced mice abdominal cavity capillary permeability
1. material and instrument:
Positive control drug: aspirin enteric coatel tablets, Bailu Pharmaceutical Co., Ltd., Shaanxi, lot number 020521.
Modeling medication: glacial acetic acid, A.R, Beijing Chemical Plant, lot number 20021024; Azovan blue: West Germany Serva import packing, China Drug Co.'s Beijing purchasing and supply station, lot number 972285.
Experimental animal: the ICR mice, secondary, male, body weight 18～22g, the quality certification number: SCXK (capital) 2002-0001, available from the department of the Chinese Academy of Sciences of Department Of Medicine, Peking University's laboratory animal section.
Test apparatus: Suo Fu ST 21 desk type high speed refrigerated centrifugers (U.S.); ZS-3 type semi-automatic biochemical analyzer, Beijing Zhongsheng Biological Engineering High Technology Company of Institute of Biophysics, Academia Sinica.
2. method: ICR kind mice, male, be divided into totally 5 groups on model, aspirin, MT rheumatism capsule 0.8,1.6,3.2g crude drug/kg group at random by body weight.The equal gastric infusion of each administration group, the 0.2ml/10g body weight, once a day, continuous three days, model group was irritated capacity distilled water such as stomach.
1h after the last administration, each organizes mouse tail vein injection 0.5% azovan blue normal saline solution 0.2ml/10g body weight, lumbar injection 0.7%HAC solution 0.1ml/10g body weight immediately, behind the 20min mice being taken off cervical vertebra puts to death, intraperitoneal injection of saline 2ml soft 30 times, cuts open the belly, the sucking-off cleaning mixture, reuse normal saline 4ml divides and washs abdominal cavity, sucking-off cleaning mixture for several times, merge the back and replenish normal saline to 10ml, the centrifugal 15min of 3000rpm gets supernatant in the 578nm colorimetric, measures optical density, make azovan blue solution standard curve, calculate the amount of dye that its mouse peritoneal infiltrates.
3. the result adds up: with
Expression, t inspection statistics between group.The results are shown in Table 11.
Table 11:MT rheumatism capsule is to the influence of mice capillary permeability
Compare with model group: * p＜0.05 * * p＜0.01 * * p＜0.001
It is hyperfunction that table 11 shows aspirin, MT rheumatism capsule 1.6, the 3.2g crude drug/the kg group can obviously suppress acetic acid (H+) induced mice abdominal cavity capillary permeability.
4. brief summary: MT rheumatism capsule 1.6,3.2g crude drug/kg group Dichlorodiphenyl Acetate (H+) induced mice abdominal cavity capillary permeability is hyperfunction to have tangible antagonism.MT rheumatism capsule Dichlorodiphenyl Acetate (H+) induced mice abdominal cavity capillary permeability is hyperfunction to have tangible antagonism.
Five .MT rheumatism capsule Dichlorodiphenyl Acetates cause the influence of mouse writhing experiment
1. method: the ICR mice, SPF, male, body weight 18～20g, the quality certification number: SCXK (capital) 2002-0003, available from Beijing Vital River Experimental Animals Technology Co., Ltd..ICR kind mice, male, be divided into totally 5 groups on model, aspirin, MT rheumatism capsule 0.8,1.6,3.2g crude drug/kg group at random by body weight.The equal gastric infusion of each administration group, the 0.2ml/10g body weight, once a day, continuous three days, model group was irritated capacity distilled water such as stomach.
1h after the last administration, each organizes mouse peritoneal injection 0.7%HAC solution 0.1ml/10g body weight, and each Mus is turned round the body number of times in the record 20min.T inspection statistics between group.
2. the result adds up: with
Expression, t inspection statistics between group.The results are shown in Table 12.
3. result
Table 12:MT rheumatism capsule is to the influence of mouse writhing number of times
Compare with model group: * p＜0.05
4. brief summary: as can be seen from Table 12, aspirin, MT rheumatism capsule 1.6,3.2g crude drug/kg group Dichlorodiphenyl Acetate cause that mice pain has obvious analgesic activity.
Six .MT rheumatism capsules are to the influence of 2,4 dinitrochlorobenzene induced mice delayed hypersensitivitys
1. method: male BALB/c mouse, SPF, body weight 18～22g is divided into totally 6 groups of normal control groups, model group, prednisone 25mg/kg, MT rheumatism capsule 0.8,1.6,3.2g crude drug/kg group at random by body weight.The equal gastric infusion of each administration group, the 0.2ml/10g body weight, every day 1 time, continuous 10 days, normal control group, model group were irritated capacity distilled water such as stomach.
Experiment mice all loses hair or feathers with barium sulfate batter abdominal part.Except that the normal control group, all the other respectively organize mice in irritating stomach the 2nd day, with 5%DNCB ethanol liquid sensitization, promptly draw 5%DNCB ethanol liquid with micro sample adding appliance, 40ul/ only, evenly spread upon on the skin of abdomen that has lost hair or feathers, area is about 2cm * 2cm, and the normal control group such as smears at the dehydrated alcohol of capacity homalographic.Administration the 9th day is attacked the mouse right ear of sensitization once more with 1%DNCB Fructus Canarii albi fluid, 40ul/ only, smearing method is the same, normal control group mouse right ear such as smears at the capacity olive oil.Putting to death mice (fasting 16h before) behind the 24h, with card punch is laid diameter 0.7cm on left and right two ears of each Mus ear, weigh respectively, is the delayed hypersensitivity value with the difference of left and right sides ear weight, calculates suppression ratio.Get thymus simultaneously, spleen is weighed, and calculates organ index.
2. the result adds up: with
Expression, t inspection statistics between group.The results are shown in Table 13.
Table 13:MT rheumatism capsule is to the exempt from service influence of organ of DNCB induced mice
Compare with matched group:
###P＜0.001
Compare with model group: * * p＜0.01 * * * p＜0.001
Table 13 shows: model group and matched group compare, and index and spleen index obviously increases (p＜0.001), thymus index no significant difference; Prednisone, MT rheumatism capsule 3.2g/kg group can obviously reduce index and spleen index and thymus index (p＜0.001, p＜0.01).MT rheumatism capsule 1.6,3.2g/kg dosage group all can obviously suppress DNCB induced mice delayed hypersensitivity, and the 3.2g/kg group can obviously reduce index and spleen index and thymus index.
Seven. adopt mouse boosting cell 3H-TdR to mix method, carried out the conversion test of spleen bone-marrow-derived lymphocyte
1. method: BALB/C mice; male 50; be divided into 5 groups at random by body weight, be respectively matched group, positive drug cyclophosphamide (Hualian Pharmaceutical Co., Ltd., Shanghai's production, cy) 0.2g/kg group, MT rheumatism capsule 0.8g crude drug/kg, 1.6g crude drug/kg, 3.2g crude drug/kg group.Each dosage group gastric infusion of MT rheumatism capsule, once a day, continuous 14 days, the 0.2ml/10g body weight, the normal control group is irritated capacity distilled water such as stomach.
In experiment the 11st day, cyclophosphamide (cy) group ip in mice cy 200mg/kg once tested the 15th day, plucked the eyeball sacrificed by exsanguination, won spleen under the aseptic condition, and with containing 10% calf serum RPMI-1640, weight/ml makes splenocyte suspension (5 * 10 by the 15mg spleen
6/ ml)
[6]Cross 200 order steel wires, put in the ice bath stand-by.Precision takes by weighing LPS, is made into 1000 μ g/ml with 1640 liquid.Get the flat culture plate in 96 holes, every hole adds splenocyte suspension 100 μ l, and every spleen is made diplopore, and a hole does not add LPS, and a hole adds LPS 10 μ l, adds 10% calf serum RPMI-1640 again, and making every hole final volume is 200 μ l, shakes up, and puts 37 ℃, 5%CO
2Incubator is cultivated 72h, 24h before stopping cultivating, and every hole adds
3H-TdR 3.7 * 104Bq/20 μ l, cultivation finishes, and uses bull cell harvestor collecting cell on 49 flint glass F fibrous filter membranes, and uses distilled water, 5% trichloroacetic acid, dehydrated alcohol sucking filtration successively, filter membrane is put in the scintillation vial, the activity cpm value of mixing with liquid flashing counting determining.
2. the result adds up: with
Expression, the t-inspection statistics is analyzed between group.The results are shown in Table 14.
The influence that table 14:MT rheumatism capsule transforms the mice spleen bone-marrow-derived lymphocyte
Compare * p＜0.05 * * p＜0.01 * * * p＜0.001 with matched group
Table 14 is the result show, positive control drug cy and MT rheumatism capsule 3.2g crude drug/kg can obviously suppress not add the spleen bone-marrow-derived lymphocyte conversion of LPS, can obviously suppress to add the spleen bone-marrow-derived lymphocyte conversion of LPS again; MT rheumatism capsule 1.6g, 0.8g crude drug/kg can suppress not add the bone-marrow-derived lymphocyte conversion of LPS.
3. brief summary: result of the test, MT rheumatism capsule can obviously suppress bone-marrow-derived lymphocyte and transform, and show that this medical instrument has the effect of obvious inhibition humoral immunization.
Eight. adopt mouse boosting cell 3H-TdR to mix method, carried out spleen T lymphocyte transformation test
1. method: experiment grouping and route of administration, capacity, time, splenocyte suspension preparation are with experiment seven.
Precision takes by weighing ConA, and it is standby to be made into 100 μ g/ml with 1640 liquid.Get the flat culture plate in 96 holes, every hole adds splenocyte suspension (cell concentration is the same) 100 μ l, and every spleen is made diplopore, one hole does not add ConA, and a hole adds ConA 20 μ l, adds 10% calf serum RPMI-1640 again, making every hole final volume is 200 μ l, shakes up cell culture, adding
3H-TdR, collecting cell, mensuration cpm value method are the same.
Dissection is won mouse thymus simultaneously, spleen is weighed, and the ratio that calculates thymus, spleen and body weight is index.
2. the result adds up: with
Expression, the t-inspection statistics is analyzed between group.The results are shown in Table 15-16.
Table 15:MT rheumatism capsule is to the LT influence of mice spleen T
Compare * p＜0.05 * * p＜0.01 * * * p＜0.001 with matched group
Table 15 is the result show, the T lymphocyte transformation that MT rheumatism capsule 3.2g, 1.6g crude drug/kg two dosage can obviously suppress not add ConA and add ConA.Positive control drug cy also suppresses the T lymphocyte transformation significantly.
Table 16:MT rheumatism capsule is to the exponential influence of mouse immune organ
Compare * p＜0.05 * * p＜0.01 * * * p＜0.001 with matched group
Table 16 is the result show, MT rheumatism capsule 3.2g, 1.6g crude drug/kg two dosage can obviously suppress spleen and thymus index, and 0.8g crude drug/kg can suppress index and spleen index.Positive control cy is to the exponential inhibitory action highly significant of immune organ.
3. brief summary: the MT rheumatism capsule can obviously suppress the T lymphocyte transformation, and can suppress spleen, thymus index, shows that this medical instrument has obvious inhibition cellular immunization and the exponential effect of immune organ.
Claims (6)
1. the rheumatismal pharmaceutical composition of treatment is made by the following medicine material extraction that waits parts by weight: Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata, Lignum Sappan, Ramulus Cinnamomi and Bombyx Batryticatus;
Concrete preparation method is: Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ; Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex is ground into fine powder 40 ± 1 ℃ of cold drying, and is standby; Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, the extractum that to be concentrated into 50 ℃ of following relative densities be 1.30-1.35, drying under reduced pressure is ground into fine powder, and is standby; Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 60～80% 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into 50 ℃ of relative densities be 1.30～1.35 extractum, drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and adds an amount of dextrin, mixing, with concentration is the alcohol granulation of 75-95%, drying, the Capsules of packing into, promptly.
2. the rheumatismal capsule of treatment is characterized in that: extracted by each 100-600g of Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata, Lignum Sappan, Ramulus Cinnamomi and Bombyx Batryticatus and make active component; Add an amount of dextrin, make 1000 of capsules;
Concrete preparation method is: Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ; Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex is ground into fine powder 40 ± 1 ℃ of cold drying, and is standby; Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, the extractum that to be concentrated into 50 ℃ of following relative densities be 1.30-1.35, drying under reduced pressure is ground into fine powder, and is standby; Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 60～80% 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into 50 ℃ of relative densities be 1.30～1.35 extractum, drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and adds an amount of dextrin, mixing, with concentration is the alcohol granulation of 75-95%, drying, the Capsules of packing into, promptly.
3. the rheumatismal capsule of a kind of treatment according to claim 2 is characterized in that: extracted by each 100-300g of Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata, Lignum Sappan, Ramulus Cinnamomi and Bombyx Batryticatus and make active component; Add an amount of dextrin, make 1000 of capsules.
4. one kind prepares the rheumatismal capsular method of treatment, and it is characterized in that: Lignum Sappan, Ramulus Cinnamomi add 6 times of amounts of water, and steam distillation 10 hours is collected volatile oil, filters, and aqueous solution and medicinal residues are continued to employ; Get the beta-schardinger dextrin-of 10 times of amounts of volatile oil, soluble in water, and be heated to 50 ℃, make saturated beta-schardinger dextrin-aqueous solution, under constantly stirring, add volatile oil, continue stirring again and stop after 0.5 hour, inclusion complex is ground into fine powder 40 ± 1 ℃ of cold drying, and is standby; Get Bombyx Batryticatus and the above-mentioned medicinal residues of carrying behind the oil and add 4 times of water gagings and close and fry in shallow oil three times, each 0.5 hour, filter, merge three decocting liquids and the above-mentioned aqueous solution of carrying behind the oil, the extractum that to be concentrated into 50 ℃ of following relative densities be 1.30-1.35, drying under reduced pressure is ground into fine powder, and is standby; Get Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata with 3 times of amounts of ethanol reflux, extract, of 60～80% 3 times, each 1 hour, merge alcohol extract, reclaim ethanol, and to be concentrated into 50 ℃ of relative densities be 1.30～1.35 extractum, drying under reduced pressure, be ground into fine powder, and β-CD inclusion complex fine powder, water extract fine powder mix, and adds an amount of dextrin, mixing, with concentration is the alcohol granulation of 75-95%, drying, the Capsules of packing into, promptly.
5. rheumatismal capsular method is treated in a kind of preparation according to claim 4, it is characterized in that: the described Radix Aconiti Preparata, Radix Aconiti Kusnezoffii Preparata got is with 3 times of amounts of ethanol reflux, extract, of 70% 3 times.
6. rheumatismal capsular method is treated in a kind of preparation according to claim 4, it is characterized in that: described is 85% alcohol granulation with concentration.
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| CN2007101786609A CN101450117B (en) | 2007-12-03 | 2007-12-03 | Rheumatism treatment medicine composition, formulation and preparation method |
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| CN103990029A (en) * | 2014-06-11 | 2014-08-20 | 孟宪玲 | Traditional Chinese medicine composition for treating rheumatoid arthritis |
| CN104107292A (en) * | 2014-07-03 | 2014-10-22 | 赵兰 | Traditional Chinese medicine preparation used for treating hyperosteogeny, and preparation method and application thereof |
| CN105395907B (en) * | 2015-12-08 | 2019-11-12 | 北京协和制药二厂 | A kind of tablet of the active component containing Rhizoma Gastrodiae and preparation method thereof |
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| CN1333028A (en) * | 2000-07-12 | 2002-01-30 | 赵树人 | External liniment for treating rheumatic arthritis |
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| CN1333028A (en) * | 2000-07-12 | 2002-01-30 | 赵树人 | External liniment for treating rheumatic arthritis |
Non-Patent Citations (3)
| Title |
|---|
| 彭跃钢.类风湿性关节炎中医药治疗进展.《广西中医药》.2006,第29卷(第4期),1-3页. * |
| 赵承来.痹症用药浅析.《中医药研究》.2002,第18卷(第5期),30-31页. * |
| 金渊光等.中医药治疗类风湿性关节炎特点的回顾性分析.《中国临床康复》.2005,第9卷(第15期),152-155页. * |
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