A kind of Chinese medicine gel for the treatment of acute gouty arthritis
Technical field
The invention belongs to the field of Chinese medicines, relate to Chinese medicine for external application, be specifically related to a kind of Chinese medicine gel for the treatment of acute gouty arthritis and preparation method thereof.
Background technology
Gout is because long-term purine metabolic disturbance institute disease extremely, and clinical characters is a hyperuricemia, and acute arthritis is shown effect repeatedly, tophus deposition, chronic arthritis and joint deformity, parenchymal lesion of the kidney and uric-acid calculus formation.Have the statistics of closing, developed country's sickness rate is more than 0.3%, mainly concentrates on middle-aged and elderly people.Because increasing of animal proteinum and fat taken in the generally raising of living standards of the people, the prevalence cumulative year after year of China's gout is near developed country's sickness rate in recent years.
Gouty arthritis is because of purine metabolic disturbance, and the uric acid sodium salt is deposited on synovium of joint or cartilage, causes sliding the inflammatory reaction of cured and joint surrounding tissue.Acute gouty arthritis is the modal first symptom of gout, also is the fundamental type of gout.Psychentonia, overtired, take food high purine diet, joint injury, operation, infection etc. are common inducement.This disease onset irritability mostly is a side simple joint at first, and is the most common with the foot first big toe joint, a left side especially.Clinical manifestation be red, swollen, hot, the pain and the dyskinesia, arthralgia is split bone as tearing muscle.If the state of an illness is shown effect repeatedly, then can develop into polyarthritis.To the treatment of gout, still lack specific radical cure method at present.Though doctor trained in Western medicine has the colchicine of application anti-inflammatory analgetic, allopurinol suppresses the generation of uric acid, and propane sulfonic acid etc. promote the drainage of uric acid etc., and effect is not very good, adds serious toxic and side effects, has limited its clinical practice to some extent.Especially colchicine, though be the arthritic classical medicine of treatment acute gout, after it was oral, the part medicine combined with gastrointestinal tract mucous epithelial cell and causes gastrointestinal reaction, the dosage of therapeutic dose and gastrointestinal tract toxicity is approaching; Intravenously administrable then has inhibitory action to the mitosis of systemic cell.Therefore, the whole body administering mode has tangible toxicity, easily causes new iatrogenic disease, makes treatment more complicated, and the patient is difficult to adhere to treatment mostly, and is clinical rather thorny.Therefore, develop and a kind ofly can drain uric acid, it is synthetic to suppress uric acid, the dual intensity reducing swelling and alleviating pain, and treating both the principal and secondary aspects of a disease, taking convenience, dosage is little, safety, the Chinese patent medicine that has no side effect is very important.
Summary of the invention
The purpose of this invention is to provide a kind of Chinese medicine for external application for the treatment of acute gouty arthritis.Be specifically related to treat the Chinese medicine gel (trade name: the gout gel) of acute gouty arthritis.
Gel of the present invention is by raw material of Chinese medicine medicine Pseudobulbus Cremastrae Seu Pleiones, Radix Notoginseng and pharmaceutical carrier, prepare by following method: get described raw material of Chinese medicine and be ground into coarse powder, add organic solvent extraction, extracting solution reclaims solvent and is concentrated into 1.05-1.08 or drying under reduced pressure, add the polar solvent of 5-30% and the macromolecule viscous material of 0.5-20%, make gel.
Described polar solvent is selected from 1,2-propylene glycol or glycerol.
Described macromolecule viscous material comprises sodium carboxymethyl cellulose (CMC-Na), card pool nurse (Carbom) and hydroxypropyl cellulose (HPMC).
Described organic solvent is 50%-80% methanol or ethanol.
Preparation of the present invention adopts following raw material of Chinese medicine weight proportion: (every pair of Chinese medicine)
Pseudobulbus Cremastrae Seu Pleiones: Radix Notoginseng=1: 1~10, preferred Pseudobulbus Cremastrae Seu Pleiones: Radix Notoginseng=1: 4.
The raw material of Chinese medicine that gel of the present invention adopted, wherein Pseudobulbus Cremastrae Seu Pleiones is the dry bulb of liliaceous plant iphigenia indica Iphigenia indica Kunth et Benth.; Wherein Radix Notoginseng is the dry root of panax araliaceae plant Panax notoginseng (Burk.) F.H.Chen.
Its main component colchicine of described iphigenia indica be the classical medicine of treatment acute gouty arthritis, but the dosage of its oral medication dosage and gastrointestinal tract toxicity is approaching, and the whole body administering mode has tangible toxicity.The present invention adopts local occupation mode, makes the percutaneous dosing novel form, can avoid the toxic and side effects of whole body administering mode.
The present invention has carried out the quality standard detection, has wherein measured the content of colchicine in the preparation with the HPLC method; Differentiated Radix Notoginseng in the preparation with the TLC method; Check that item has carried out appearance character, pH value, content uniformity and the health examination of preparation.The preliminarily stabilised test shows that sample is basicly stable.
Differentiate: get preparation 1.0g of the present invention, add methanol 5ml and make dissolving, get supernatant, as need testing solution.Other gets Radix Notoginseng control medicinal material 1.0g, adds 70% ethanol 4ml and soaks 30min, and ultrasonic 15min places, and gets supernatant, volatilizes ethanol, and residue adds the 2ml dissolve with methanol, in contrast product medical material solution.Test according to thin layer chromatography (appendix VI B), draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, place below 10 ℃ with chloroform-methanol-water (13: 7: 2) that to take off layer solution in 12 hours be developing solvent, launch, take out, dry, spray is with 10% ethanol solution of sulfuric acid, and it is clear to be heated to the speckle colour developing in 100-105 ℃, takes out.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color, under the uviol lamp (365nm), show identical fluorescence speckle.
Differentiate a thin layer discriminating that is Radix Notoginseng down.The result shows that this law chromatographic isolation degree is good, and negative control is noiseless.
According to " regulation under an appendix I of Chinese pharmacopoeia version in 2000 the ointment item is checked the minimum fill of sample of the present invention, pH value, microbial limit etc., and the result meets the pharmacopeia regulation.
Adopt atomic absorption method to check heavy metal, arsenic salt, the result shows that heavy metal Pb is less than 1ppm, and the arsenic salt content is less than 3ppm.
Table 1 is Colchicine Content (mg/ props up) measurement result in the sample of the present invention.
Table 1
The present invention has carried out antiinflammatory, analgesia etc. and has cured mainly relevant pharmacodynamics test research with function, and the result confirms to have excellent curative.Investigate through safeties such as animal acute toxicity test, long term toxicity test, skin irritation test, skin anaphylactic tests, the result shows that the present invention is safe and reliable, has no side effect.The present invention is a Percutaneously administrable preparation, effect with heat clearing away collateral dredging, promoting blood circulation and stopping pain, the clinical treatment that is used for gouty arthritis, can avoid medicine at the various variable factors that gastrointestinal tract ran into and the first-pass effect of liver, the bioavailability height, effect is lasting, easy to use and interruption of the administration at any time.
The specific embodiment
Embodiment 1
Take off and state weight proportion Chinese crude drug Pseudobulbus Cremastrae Seu Pleiones: Radix Notoginseng=1: 1, two flavor pulverizing medicinal materials are become coarse powder, add 70% ethanol extraction, extracting solution reclaims solvent and is concentrated into 1.05-1.08 or drying under reduced pressure.Add 10% 1,2-propylene glycol and 5% card pool nurse, sodium hydroxide solution is transferred pH6.0, stirs, fill promptly gets and makes the skin gel.
Embodiment 2
Take off and state weight proportion Chinese crude drug Pseudobulbus Cremastrae Seu Pleiones: Radix Notoginseng=1: 4, two flavor pulverizing medicinal materials are become coarse powder, add 75% ethanol extraction, extracting solution reclaims solvent and is concentrated into 1.05-1.08 or drying under reduced pressure.Add 8% 1,2-propylene glycol and 6% card pool nurse, light sodium hydroxide solution is transferred pH6.0, stirs, fill promptly gets the skin gel.
Embodiment 3:
Get Pseudobulbus Cremastrae Seu Pleiones: Radix Notoginseng=1: 10, two flavor pulverizing medicinal materials are become coarse powder, add 70% ethanol extraction, extracting solution reclaims solvent and is concentrated into 1.05-1.08 or drying under reduced pressure.Add 15% 1,2-propylene glycol and 5% card pool nurse, light sodium hydroxide solution is transferred pH6.0, stirs, fill makes the skin gel.
The experiment of embodiment 4 pharmacological researches
Pharmacodynamic study, gel of the present invention by 1,2,4g crude drug/kg is to the administration of mice partial smearing, improves the threshold of pain of mice thermostimulation, mechanical stimulus, shortens the mice II phase reaction time of formalin-induced; Suppress the acute exudative inflammation reaction that dimethylbenzene stimulates mice ear to bring out; By 0.7,1.4,2.8g crude drug/kg is to the administration of rat partial smearing, suppresses the rat acute inflammatory reaction that micro-crystal type uric acid sodium brings out; By 0.4,0.8,1.6g crude drug/kg is to the administration of rabbit partial smearing, reduces leukocytic quantity in the gouty arthritis rabbit arthroedema, the ameliorate osteoarthritis degree; By 0.7,1.4,2.8g crude drug/kg is to the administration of rat partial smearing, and uric acid level in the metabolic arthritis rat model blood is not had obvious influence.Presentation of results, gel of the present invention has antiinflammatory, analgesic activity.
Studies on acute toxicity result shows that obvious acute toxic reaction is not seen in gel rabbit normal skin of the present invention and damaged skin administration.
The long term toxicity result of study shows, high and low two dosage of gel of the present invention are given normal and the continuous skin of damaged skin rat was smeared administration one month, general situation, hematology, blood biochemical, routine urinalysis, electrocardiogram, system's dissection, organ coefficient and histopathology to rat all do not have obvious influence, do not find toxic reaction, convalescent period does not also have the retardance toxic reaction, and it is 3g//day that rat non-toxic reaction consumption is provided.
The result of study of local application's safety shows, gel of the present invention repeatedly gives rabbit normal and damaged skin, the medication part is show speckle, edema and other abnormal response not, and skin irritation reaction mean scores is 0, and histopathology does not also see that normal and damaged skin has zest to rabbit; The administration of gel guinea pig skin, skin be show speckle, edema and other anaphylaxis not, and the skin allergy mean scores is 0, and the sensitization rate is 0%.Presentation of results, gel of the present invention does not have sensitization to rabbit skin nonirritant to guinea pig skin.
The experiment of embodiment 5 transdermal test in vitro
Prepare the isolated experiment Corium Mus according to a conventional method, store in after cleaning with physiological saline solution in-20 ℃ the cryogenic refrigerator, standby.Experimental provision: adopt Valia-Chien horizontal proliferation pond, improvement Franz diffusion cell.Get isolated skin and be fixed in the middle of the diffusion cell, make stratum corneum side to supply pool, acceptable solution is a distilled water.32 ± 0.5 ℃ of diffusion cell chuck internal recycle water temperatures, constant speed stirs.Pick up counting behind the application of sample balance 15min,, replenish the equivalent distilled water simultaneously in stipulated time point sampling.The concentration of each sample method testing index composition in accordance with regulations, the following formula correction of gained concentration: C
The n school=(C
N surveys+ V/V
r∑ C
p), C wherein
The n school: the drug level C after the correction
n Survey: the actual drug level ∑ C that records
p: the mensuration concentration sum V of each point before this sample point
r: the volume V of acceptable solution: sample volume.C with different time
The n schoolTo time t mapping, with the C after the diffusive equilibrium
The n schoolTo time t return equation: C
The n school=PAC
dT/V
r+ intercept, wherein P: infiltration coefficient A: diffusion cell cross-sectional area C
d: the concentration of supply pool Chinese medicine.
Set up analysis test method: chromatographic condition homogenous quantities standard.
The application of sample recovery test: (n=5) adds colchicine 200 μ g in the permeate of the blank skin of nude mice, after the centrifugal treating, gets the supernatant assay determination.Table 2 is application of sample recovery test result.The transdermal test in vitro result of the test of table 3 colchicine and Pseudobulbus Cremastrae seu Pleiones extract (μ g/ml).Table 4 is the transdermal test in vitro result of the test of colchicine and Pseudobulbus Cremastrae seu Pleiones extract.
Table 2
Table 3
Table 4
The result shows that colchicine and Pseudobulbus Cremastrae seu Pleiones extract can see through isolated skin, and the infiltration coefficient of Pseudobulbus Cremastrae Seu Pleiones is little than colchicine, but can shorten the transdermal time lag of colchicine.