CN100500139C - External use medicine for treating rheumatic arthritis, and its preparation method - Google Patents

Abstract

An exterior-applied medicine for treating rheumatic arthritides is prepared through extracting the active components from wild aconite root, long pepper and myrobalan fruit, mixing them with matrix, nitrone and propanediol, and stirring.

Description

A kind of external used medicine for the treatment of rheumatic arthritis and preparation method thereof

Invention field

The present invention relates to a kind of external used medicine and preparation method thereof, particularly a kind of external used medicine that is used for the treatment of rheumatic arthritis and preparation method thereof.

Background technology

Mongolian medicine's mongolian medicine and Chinese medicine have very dark origin relation, aspect the treatment rheumatic arthritis, the Mongolian medicine has rich experience, people from Meng ethnic group is nomadic on northern grassland, the world of ice and snow, wind and cold invasion and attack, the sickness rate of rheumatic arthritis is higher, and the Mongolian medicine has summed up many effective side's medicines in secular medical practice, and the Mongolia patent drug NARU SANWEI WAN promptly is one of them.This medicine is a peroral dosage form, and the treatment rheumatic arthritis has curative effect preferably, but because the oral administration mode has stimulation to gastrointestinal, and blood concentration fluctuation is bigger, excessive easy generation toxicity and influence the performance of drug effect.

Transdermal formulation is the focus of studying in the field of medicaments in recent ten years, is an emerging field in the pharmaceutics, be considered to the 4th generation preparation research emphasis.Transdermal delivery system (TransdermDelivery System, TDS), claim Transcutaneous Therapeutic System (Transdermal TherapeuticSystem again, TTS), mean that with the skin mode medication of applying ointment or plaster medicine absorbs through blood capillary by skin with certain speed and enters a kind of administering mode that the body circulation produces drug effect.Habit is called external used medicine (patch) in American-European countries, and at home naming is paster more.In a broad sense, it comprises the various dosage forms that are applied to produce on the skin Absorption, and as ointment, plaster, liniment, microemulsion, cream, liniment, cataplasma also is one of them.

Chinese medicine patcher is a focus of domestic Recent study, and Chinese medicine patcher is with behind Chinese medicine extract and the suitable hydrophilic matrix mixing, coats a kind of external transdermal drug-delivery preparation on the backing.Chinese medicine patcher belongs to the typing cataplasma, and drug loading is greatly the big advantage of one.Have again and contain a certain amount of moisture in the Chinese medicine patcher, easily make keratodermatitis softening and help the Transdermal absorption of medicine, and also fine to the biocompatibility and the affinity of skin, breathability and absorption of perspiration are also better, and also have reusability good, be difficult for plurality of advantages such as allergy.

Summary of the invention

One object of the present invention is to disclose a kind of external used medicine; Another object of the present invention is to disclose a kind of external used medicine that is used for the treatment of rheumatic arthritis; The 3rd purpose of the present invention is to disclose a kind of preparation method of external used medicine.

The raw material of external used medicine of the present invention is formed and proportioning following (by weight):

Radix Aconiti Kusnezoffii extract 4-6 weight portion Fructus Piperis Longi extractum 2-4 weight portion

Fructus Chebulae's extractum 2-4 weight portion;

Above-mentioned extractum is mixed the back to add azone, adds propylene glycol according to the 2-6% of its volume according to the 2-6% of its volume;

Wherein, Radix Aconiti Kusnezoffii extract is prepared as follows: Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; Fructus Piperis Longi extractum is prepared as follows: with the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Fructus Chebulae's extractum is prepared as follows: get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum.

It is (by weight) that the raw material of external used medicine of the present invention is formed optimum ratio:

Radix Aconiti Kusnezoffii extract 5 weight portion Fructus Piperis Longi extractum 3 weight portions

Fructus Chebulae's extractum 3 weight portions;

Above-mentioned extractum is mixed the back to add azone, adds propylene glycol according to 4% of its volume according to 4% of its volume;

It is (by weight) that the raw material of external used medicine of the present invention is formed optimum ratio:

Radix Aconiti Kusnezoffii extract 4 weight portion Fructus Piperis Longi extractum 4 weight portions

Fructus Chebulae's extractum 2 weight portions;

Above-mentioned extractum is mixed the back to add azone, adds propylene glycol according to 4% of its volume according to 4% of its volume;

External used medicine of the present invention can add following substrate (by weight):

Gelatin, sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol, part by weight are 1-3:1-3:0.5-1.5:0.5-1:0.4-0.6, and substrate and medicine material weight ratio are 1-3:1-3.

External used medicine of the present invention can add following matrix optimization proportioning (by weight):

Gelatin, sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol, part by weight are 2:2:1:0.8:0.5 or 2.5:1.5:1.2:0.6:0.6, and substrate and medicine material weight ratio are 1.5:2.5.

The preparation method of the invention described above external used medicine:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin (AB-8), flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min (the back timing of boiling), constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; Add penetrating agent azone and propylene glycol, mix, make ointment, plaster, liniment, microemulsion, cream, the liniment of clinical acceptance, cataplasma etc.

The preparation method of external used medicine cataplasma of the present invention:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin (AB-8), flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min (the back timing of boiling), constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; After earlier adjuvants such as sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol being mixed, again gelatin is added, heat and stir 20～40min; That that is mixed in proportion mixed with substrate as-3 cataplasma principal agents, add penetrating agent azone and propylene glycol, mix, make cataplasma.

External used medicine anti-inflammatory and antalgic of the present invention.Be used for rheumatic arthralgia, rheumatoid arthritis, rheumatic Bi syndrome, scapulohumeral periarthritis, shoulder back of the body lumbago.Cataplasma of the present invention (that is as-3 cataplasmas) ointment color is a dark-brown, and the about 25-35% of mastic water content has aromatic odor, and modest viscosity is peeled off basic noresidue, good permeability.

Advantage of the present invention shows four aspects: the one, and can avoid contingent liver of oral administration " first pass effect " and medicine to degrade at gastrointestinal, substantially eliminated medicine to the gastrointestinal stimulation, the absorption of medicine is not subjected to the influence of gastrointestinal factors, reduce the individual variation of medication, can effectively improve drug effect; The 2nd, medicine is entered in the body with constant speed percutaneous, reduced administration number of times, prolong dosing interval; The 3rd, can keep constant blood drug level, produce stable drug effect, the blood drug level peak valley phenomenon of having avoided oral administration to cause has reduced toxicity; Four are to use conveniently, and interruption of the administration at any time, especially are fit to the patient of old man and unsuitable oral administration.

Following experimental example is used to further specify the present invention:

Experimental example 1That measures and optimizes the ratio of penetrating agent as the percutaneous rate of-3 cataplasma principal agents

One, experimentation

1 experimental technique

1.1 that is as the preparation of-3 cataplasma principal agents

According to that ratio as-3 prescription 5:3:3, take by weighing Radix Aconiti Kusnezoffii extract thick paste 7.64g (being equivalent to the 100g crude drug), Fructus Piperis Longi extractum 4.32g (being equivalent to the 60g crude drug), Fructus Chebulae's extractum 15.48g (being equivalent to the 60g crude drug), place the 50ml volumetric flask, add dehydrated alcohol to scale, shake up, that obtains concentration and be 548.8mg/ml is as-3 cataplasma principal agent transdermal medicinal liquids.According to the preliminary experiment result, add transdermal enhancer azone and propylene glycol, be mixed with and respectively contain 2%, 4% and three kinds of transdermal medicinal liquids of 6% azone+propylene glycol.All getting 0.2ml during experiment evenly coats and carries out the transdermal diffusion test on the Corium Mus.

1.2 transdermal diffusion test method

Earlier magnetic stick is placed on and accepts in the pond, the rat skin in vitro of preparation is lain in accept the upper end, pond again, stratum corneum side upwards will discharge the pond then and be fixed in clip and accept on the pond.Get that and evenly be applied on the keratodermatitis as-3 cataplasma principal agent transdermal medicinal liquids, acceptable solution is injected by probe tube with syringe and accept the pond, the emptying air makes the skin another side closely contact with acceptable solution.Constant speed stirs (120r/min), respectively at 1,3,6,12,18,24h extracts acceptable solution 1.0ml, adds the fresh acceptable solution of 1.0ml again.

1.3 the preprocess method of sample liquid

1.3.1 the preprocess method in the mensuration acceptable solution during mesaconitine

With the acceptable solution that extracts when 1h, 3h, 6h, 12h, 18h, the 24h respectively, place the centrifuge tube of 1.5ml, on thermostat water bath, volatilize, add the 1.0ml dichloromethane, the sonic oscillation dissolution residual substance, centrifugal 10min (4000r/min) draws supernatant 0.5ml and moves in the high performance liquid chromatogram sample bottle to be measured.

1.3.2 the preprocess method in the mensuration acceptable solution during piperine

With the acceptable solution that extracts when 1h, 3h, 6h, 12h, 18h, the 24h respectively, place the centrifuge tube of 1.5ml, on thermostat water bath, volatilize, add the 1.0ml dehydrated alcohol, the sonic oscillation dissolution residual substance, centrifugal 10min (4000r/min) draws supernatant and moves in the high performance liquid chromatogram sample bottle to be measured.

1.4 chromatographic condition

1.4.1 measure the chromatographic condition of mesaconitine

Chromatographic column: Hypersil ODS C ₁₈Post (4.6mm * 150mm, 5 μ m); Mobile phase: methanol-water-chloroform-diethylamine (70:30:30:0.2); Flow velocity: 1.0ml/min; 25 ℃ of column temperatures; Detect wavelength: 240nm.

1.4.2 measure the chromatographic condition of piperine

Chromatographic column: Hypersil ODS C ₁₈Post (4.6mm * 150mm, 5 μ m); Mobile phase: methanol-water (77:23); Flow velocity: 1.0ml/min; 25 ℃ of column temperatures; Detect wavelength: 343nm.

2 statistical processing methods

Experimental data is handled with the SPSS11.5 statistical software, adopts one factor analysis of variance (one-wayANOVA) method to carry out statistical analysis.(x ± s) expression with the statistical significance boundary of P＜0.05 as significant difference, draws cartogram with Mi crosoft Excel XP to data with mean ± standard deviation.

Two, experimental result

The penetration enhancer of 1 different proportion is to that transdermal enhancing effect as mesaconitine in-3 cataplasma principal agents

1.1 that is as the content of mesaconitine in-3 cataplasma principal agent transdermal acceptable solutions

The pretreated sample liquid 0.5ml of different time points is added in the high performance liquid chromatogram sample bottle, and auto injection 10 μ l get chromatogram, optimize integration, and external standard method is calculated mesaconitine content, the results are shown in Table 1.

That content as mesaconitine in-3 cataplasma principal agent transdermal acceptable solutions of table 1 (μ g/10 μ l, x ± s)

Annotate: azone+propylene glycol compares * P＜0.05 for each 4% group and each 2% group and each 6% group

The result learns by statistics and handles the back and show, the content of the mesaconitine in each 4% group of transdermal acceptable solution of azone+propylene glycol at 1h, 12h, 18h and 24h apparently higher than 2% group and 6% group, significant difference (P＜0.05).

1.2 that is as the accumulative total infiltration capacity (Q) of mesaconitine in-3 cataplasma principal agents

The volume of diffusion cell is 7.0ml in the experiment, and sampling amount is 1.0ml, and infiltrating area is 2.92cm ²,, calculate accumulative total infiltration capacity (Q) according to following formula according to the concentration of mesaconitine in the transdermal acceptable solution that records

$Q=\frac{\mathrm{Cn}\×7.0+\underset{i=1}{\overset{n-1}{\mathrm{\Σ}}}\mathrm{Ci}\×1.0}{S}\mathrm{\μg}$

In the formula, Cn: n the drug level that sample point records; Ci: i the drug level that sample point records; S: infiltrating area.The accumulative total infiltration capacity (Q) of the mesaconitine that calculates according to formula sees Table 2.

That accumulative total infiltration capacity Q (μ g/cm of table 2 as mesaconitine in-3 cataplasma principal agents ²X ± s)

The result shows that the 24h accumulative total infiltration capacity (Q) of mesaconitine is 26.1781 μ g/cm in each 4% group of transdermal acceptable solution of azone+propylene glycol ², apparently higher than 2% group and 6% group.

1.3 that is as the percutaneous rate constant (J) of mesaconitine in-3 cataplasma principal agents

With the accumulative total infiltration capacity (Q) of mesaconitine to time T _1/2Carry out linear regression, the gained equation is the Higuchi equation, and the gained slope is percutaneous rate constant J (the μ g/cm of mesaconitine ²H), see Table 3.

Table 3 that Higuchi equation and percutaneous rate constant (J) as mesaconitine in-3 cataplasma principal agents

Calculate, the percutaneous rate constant of mesaconitine is 5.60567 μ g/cm in each 4% group of transdermal acceptable solution of azone+propylene glycol ²H is apparently higher than 2% group and 6% group.

The penetration enhancer of 2 different proportions is to that transdermal enhancing effect as piperine in-3 cataplasma principal agents

2.1 that is as the content of piperine in-3 cataplasma principal agent transdermal acceptable solutions

The pretreated sample liquid 0.5ml of different time points is added in the high performance liquid chromatogram sample bottle, and auto injection 20 μ l get chromatogram, optimize integration, and external standard method is calculated content of piperine, the results are shown in Table 4.

That content as piperine in-3 cataplasma principal agent transdermal acceptable solutions of table 4 (μ g/20 μ l, x ± s)

The result shows that azone+propylene glycol respectively is that 6% group of content of piperine in the transdermal acceptable solution is higher than 2% group and 4% group, but difference not significantly (P〉0.05) between three groups of the statistical procedures.

2.2 that is as the accumulative total infiltration capacity (Q) of piperine in-3 cataplasma principal agents

The volume of diffusion cell is 7.0ml in the experiment, and sampling amount is 1.0ml, and infiltrating area is 2.92cm ²,, calculate accumulative total infiltration capacity (Q) according to following formula according to the concentration of piperine in the transdermal acceptable solution that records

$Q=\frac{\mathrm{Cn}\×7.0+\underset{i=1}{\overset{n-1}{\mathrm{\Σ}}}\mathrm{Ci}\×1.0}{S}\mathrm{\μg}$

In the formula, Cn: n the drug level that sample point records; Ci: i the drug level that sample point records; S: infiltrating area.The accumulative total infiltration capacity (Q) of the piperine that calculates according to formula sees Table 5.

That accumulative total infiltration capacity Q (μ g/cm of table 5 as piperine in-3 cataplasma principal agents ², x ± s)

The result shows that the 24h accumulative total infiltration capacity (Q) of piperine is 199.2911 μ g/cm in each 6% group of transdermal acceptable solution of azone+propylene glycol ², be higher than 2% group and 4% group.

2.3 that is as the percutaneous rate constant (J) of piperine in-3 cataplasma principal agents

With the accumulative total infiltration capacity (Q) of piperine to time T _1/2Carry out linear regression, the gained equation is the Higuchi equation, and the gained slope is percutaneous rate constant J (the μ g/cm of piperine ²H), see Table 6.

Table 6 that Higuchi equation and percutaneous rate constant (J) as piperine in-3 cataplasma principal agents

Calculate, the percutaneous rate constant J of piperine is 49.10839 μ g/cm in each 6% group of transdermal acceptable solution of azone+propylene glycol ²H is apparently higher than 2% group and 4% group.

Originally experimental results show that azone, propylene glycol respectively be 4% o'clock to Radix Aconiti Kusnezoffii extract in the transdermal facilitation of mesaconitine best, the percutaneous rate constant is 5.60567 μ g/cm ²H ^-1Azone, propylene glycol respectively be 6% o'clock to Fructus Piperis Longi extractum in the transdermal facilitation of piperine best, the percutaneous rate constant is 49.10839 μ g/cm ²H ^-1, think that respectively is 4% the most suitable as the ratio of-3 cataplasma penetration enhancer with azone, propylene glycol.

Experimental example 2That percutaneous rate as piperine in-3 cataplasmas is measured

One, experimental technique and date processing

1 experimental technique

1.1 the preparation of rat Corium Mus and transdermal diffusion test method

(injection position is near groin with 10% urethanes intraperitoneal injection of anesthesia with rat, to guarantee the complete of abdominal part Corium Mus), the Mus platform is fixed in back of the body position, the depilatory that will contain 10% sodium sulfide with toothbrush is applied on the belly wool of rat uniformly, about 3～5min, when its colour changed into yellow of Mus hair is the mucus shape, fall the Mus hair with flushing with clean water, gauze is dried skin.Put to death two days later, will take off plucked Corium Mus with shears and take off, subcutaneous tissue and fat that cleaning is remaining are immersed in the normal saline 1～2 ℃ of preservation of refrigerator.

Get that during mensuration and be cut into circle as-3 cataplasmas by the diffusion cell internal diameter, area is 2.92cm ², be attached to horny layer one side of Corium Mus.

1.2 the pretreatment of sample liquid

With the acceptable solution that extracts at 1h, 3h, 6h, 12h, 18h, 24h respectively, place the centrifuge tube of 1.5ml, on thermostat water bath, volatilize, add the 1.0ml dehydrated alcohol, the sonic oscillation dissolution residual substance, place 2h, centrifugal 10min (4000r/min), the absorption supernatant moves in the high performance liquid chromatogram sample bottle to be measured.

1.3 chromatographic condition

Chromatographic column: Hypersil ODS C ₁₈Post (4.6mm * 150mm, 5 μ m); Mobile phase: methanol-water (77: 23); Flow velocity: 0.8ml/min; 26 ℃ of column temperatures; Detect wavelength: 343nm.

1.4 the preparation of accurate product solution and the foundation of standard curve

Precision takes by weighing piperine standard substance 5mg, places the 10ml volumetric flask, adds dehydrated alcohol to scale, shakes up.Get 0.2ml, 0.4ml, 0.8ml, 1.2ml, 1.6ml,, place the 2ml volumetric flask respectively, add dehydrated alcohol to scale, shake up, obtain the serial solution that concentration is respectively 50 μ g/ml, 100 μ g/ml, 200 μ g/ml, 300 μ g/ml, 400 μ g/ml, get each 20 μ l sample introduction of this serial solution and measure, the retention time of piperine is at 3.814min.

Carry out linear regression with piperine concentration (X) and respective peaks area (Y), the standard curve equation that obtains piperine is Y=53.8818345X-2.0127857, r=0.99991, and piperine concentration linear relationship between 50 μ g/ml～400 μ g/ml is good.

2 statistical processing methods

Experimental data is handled with the SPSS11.5 statistical software, adopts one factor analysis of variance (one-wayANOVA) method to carry out statistical analysis.(x ± s) expression with the statistical significance boundary of P＜0.05 as significant difference, draws cartogram with Microsoft Excel XP to data with mean ± standard deviation.

Two, experimental result

1 that content as piperine in-3 cataplasma transdermal acceptable solutions

The pretreated sample liquid 0.5ml of different time points is added in the high performance liquid chromatogram sample bottle, and auto injection 20 μ l get chromatogram, optimize integration, and external standard method is calculated content of piperine, the results are shown in Table 7.

That content as piperine in-3 cataplasma transdermal acceptable solutions of table 7 (μ g/20 μ l, x ± s)

Annotate: high dose group and low dose group be * P＜0.05 relatively

As can be seen from Table 7, the content of piperine prolongs in time and increases gradually in the transdermal acceptable solution, and the content of piperine and the initial concentration of high, medium and low dosage group transdermal acceptable solution are proportional.Statistical procedures shows that high dose group 6h～24h and low dose group comparing difference be (P＜0.05) significantly.

2 those accumulative total infiltration capacities (Q) as piperine in-3 cataplasmas

The volume of diffusion cell is 7.0ml in the experiment, and sampling amount is 1.0ml, and infiltrating area is 2.92cm ²,, calculate accumulative total infiltration capacity (Q) according to following formula according to the concentration of piperine in the transdermal acceptable solution that records

$Q=\frac{\mathrm{Cn}\×7.0+\underset{i=1}{\overset{n-1}{\mathrm{\Σ}}}\mathrm{Ci}\×1.0}{S}\mathrm{\μg}$

In the formula, Cn: n the drug level that sample point records; Ci: i the drug level that sample point records; S: infiltrating area.The accumulative total infiltration capacity (Q) of the piperine that calculates according to formula sees Table 8.

That accumulative total infiltration capacity Q (μ g/cm of table 8 as piperine in-3 cataplasmas ², x ± s)

3 those percutaneous rate constants (J) as piperine in-3 cataplasmas

With the accumulative total infiltration capacity (Q) of piperine to time T _1/2Carry out linear regression, the gained equation is the Higuchi equation, and the gained slope is percutaneous rate constant J (the μ g/cm of piperine ²H), see Table 9.

Table 9 that Higuchi equation and percutaneous rate constant (J) as piperine in-3 cataplasmas

Experimental result shows that the piperine in the cataplasma can see through rat skin preferably under this experiment condition, and burst size is directly proportional with initial concentration, and the Transdermal absorption Higuchi equation is promptly accumulated infiltration capacity Q and t _1/2Linear.That percutaneous rate as piperine in-3 cataplasmas of high, medium and low dosage is respectively 93.71958 μ g/cm ²H, 84.889841 μ g/cm ²H and 76.68393 μ g/cm ²H.

Concrete data relatively during high dose (600mg/ml) Fructus Piperis Longi extractum transdermal experiment, contain 120mg Fructus Piperis Longi extractum among the 0.2ml, seeing through area is 2.92cm ², promptly content is 41.096mg/cm ²That is 6.296mg/cm as Fructus Piperis Longi extractum content in-3 cataplasmas for high dose ², 2.92cm ²Total content be 18.384mg.Both compare, and concentration differs 6.53 times (41.096/6.296), and the percutaneous rate constant differs 2.83 times (265.5747/93.71958).The concentration of middle dosage differs 7.25 times, and the percutaneous rate constant differs 2.45 times.The concentration of low dosage differs 8.7 times, and the percutaneous rate constant differs 2.3 times.Comparing data sees Table 10.

Table 10 Fructus Piperis Longi extractum and that comparison as the piperine percutaneous rate constant in-3 cataplasmas

By more as can be seen, though that content as Fructus Piperis Longi extractum in-3 cataplasmas obviously reduces, wherein the percutaneous rate constant of contained piperine is still higher relatively, illustrates that piperine has transdermal characteristic preferably in the Fructus Piperis Longi.

Embodiment 1:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin (AB-8), flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min (the back timing of boiling), constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Press 5:3:3 mixed Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; Mix with conventional substrate, add penetrating agent azone and propylene glycol (respectively being 4%), mix into even ointment; Cut into 10cm * 10cm (100cm ²) square sheet, plastic bag sealing packing, 4 ℃ of preservations of refrigerator.Be used for the treatment of rheumatic arthritis.

Embodiment 2:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin (AB-8), flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min (the back timing of boiling), constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Press 5:3:3 mixed Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; After earlier adjuvants such as sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol being mixed, gelatin is added, heat (50 ℃ of temperature) stirs 20～40min, generally about 25min again; Gelatin, sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol etc., ratio is 2:2:1:0.8:0.5; That that is mixed in proportion mixed with substrate as-3 cataplasma principal agents, add penetrating agent azone and propylene glycol (respectively being 4%), mix into even ointment; Heat and soften that, ointment is coated on the backing with the cataplasma coating machine as-3 cataplasma ointment; Cut into 10cm * 10cm (100cm ²) square sheet, plastic bag sealing packing, 4 ℃ of preservations of refrigerator.Cataplasma ointment color is a dark-brown, and the mastic water content is about 28%, and aromatic odor is arranged.Be used for rheumatic arthralgia, rheumatoid arthritis, rheumatic Bi syndrome, scapulohumeral periarthritis, shoulder back of the body lumbago; Using method: external is affixed on the affected part.

Embodiment 3:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin (AB-8), flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min (the back timing of boiling), constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Press 4:4:2 mixed Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; Mix with conventional substrate, add penetrating agent azone and propylene glycol (respectively being 4%), mix into even ointment; Cut into 10cm * 10cm (100cm ²) square sheet, plastic bag sealing packing, 4 ℃ of preservations of refrigerator.Be used for the treatment of rheumatic arthritis.

Embodiment 4:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin (AB-8), flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min (the back timing of boiling), constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Press 4:4:2 mixed Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; After earlier adjuvants such as sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol being mixed, gelatin is added, heat (50 ℃ of temperature) stirs 20～40min, generally about 25min again; Gelatin, sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol etc., ratio is or 2.5:1.5:1.2:0.6:0.6; That that is mixed in proportion mixed with substrate as-3 cataplasma principal agents, add penetrating agent azone and propylene glycol (respectively being 4%), mix into even ointment; Heat and soften that, ointment is coated on the backing with the cataplasma coating machine as-3 cataplasma ointment; Cut into 10cm * 10cm (100cm ²) square sheet, plastic bag sealing packing, 4 ℃ of preservations of refrigerator.Cataplasma ointment color is a dark-brown, and the mastic water content is about 28%, and aromatic odor is arranged.Be used for rheumatic arthralgia, rheumatoid arthritis, rheumatic Bi syndrome, scapulohumeral periarthritis, shoulder back of the body lumbago; Using method: external is affixed on the affected part.

Claims (12)

1, a kind of external used medicine that is used for the treatment of rheumatic arthritis is characterized in that this external used medicine is to be made by following method:

Radix Aconiti Kusnezoffii extract thick paste 3-7 weight portion Fructus Piperis Longi extractum 1-5 weight portion

Fructus Chebulae's extractum 1-5 weight portion;

After above-mentioned extractum mixing, according to the 2-6% adding azone of its volume, according to the 2-6% adding propylene glycol of its volume, that is, this medicine is made ointment, plaster, liniment, microemulsion, cream, liniment or the cataplasma of clinical acceptance;

Wherein, Radix Aconiti Kusnezoffii extract is prepared as follows: Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste;

Fructus Piperis Longi extractum is prepared as follows: with the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract;

Fructus Chebulae's extractum is prepared as follows: get dry Fructus Chebulae's decoction pieces, be crushed to 2～3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum.

2, external used medicine as claimed in claim 1 is characterized in that this external used medicine is to be made by following method:

Radix Aconiti Kusnezoffii extract thick paste 5 weight portion Fructus Piperis Longi extractum 3 weight portions

Fructus Chebulae's extractum 3 weight portions

Above-mentioned extractum is mixed the back to add azone, adds propylene glycol according to 4% of its volume according to 4% of its volume; That is, this medicine is made ointment, plaster, liniment, microemulsion, cream, liniment or the cataplasma of clinical acceptance;

Wherein, Radix Aconiti Kusnezoffii extract is prepared as follows: Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste;

Fructus Piperis Longi extractum is prepared as follows: with the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract;

Fructus Chebulae's extractum is prepared as follows: get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum.

3, external used medicine as claimed in claim 1 is characterized in that this external used medicine is to be made by following method:

Radix Aconiti Kusnezoffii extract thick paste 4 weight portion Fructus Piperis Longi extractum 4 weight portions

Fructus Chebulae's extractum 2 weight portions

Above-mentioned extractum is mixed the back to add azone, adds propylene glycol according to 4% of its volume according to 4% of its volume; That is, this medicine is made ointment, plaster, liniment, microemulsion, cream, liniment or the cataplasma of clinical acceptance;

Wherein, Radix Aconiti Kusnezoffii extract is prepared as follows: Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste;

Fructus Piperis Longi extractum is prepared as follows: with the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract;

Fructus Chebulae's extractum is prepared as follows: get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum.

4,, it is characterized in that this external used medicine adds following substrate as claim 1,2 or 3 described external used medicines:

Gelatin, sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol, part by weight are 1-3:1-3:0.5-1.5:0.5-1:0.4-0.6, and substrate and medicine material weight ratio are 1-3:1-3.

5, external used medicine as claimed in claim 4 is characterized in that this external used medicine adds following substrate:

Gelatin, sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol, part by weight are 2:2:1:0.8:0.5 or 2.5:1.5:1.2:0.6:0.6, and substrate and medicine material weight ratio are 1.5:2.5.

6, the preparation method of claim 1,2 or 3 described external used medicines is characterized in that this method is:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; Add penetrating agent azone and propylene glycol and mix, that is, this medicine is made ointment, plaster, liniment, microemulsion, cream, liniment or the cataplasma of clinical acceptance.

7, the preparation method of the described external used medicine of claim 6 is characterized in that this method is:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; Add penetrating agent azone and propylene glycol and mix, that is, this medicine is made ointment, plaster, liniment, microemulsion, cream, liniment or the cataplasma of clinical acceptance.

8, the preparation method of the described external used medicine of claim 4 is characterized in that this method is:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; After earlier sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol adjuvant being mixed, again gelatin is added, heat and stir 20 ~ 40min; The principal agent that is mixed in proportion is mixed with substrate, add penetrating agent azone and propylene glycol, mix, make cataplasma.

9, the preparation method of external used medicine as claimed in claim 5 is characterized in that this method is:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 20-40min, and heating decocts 1-2 time, decocting time 90-120min; Decocting liquid negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use the 70-90% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 20-40min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2-3 time, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; After earlier sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol adjuvant being mixed, again gelatin is added, heat and stir 20 ~ 40min; The principal agent that is mixed in proportion is mixed with substrate, add penetrating agent azone and propylene glycol, mix, make cataplasma.

10, the preparation method of external used medicine as claimed in claim 8 or 9 is characterized in that this method is:

Radix Aconiti Kusnezoffii crude drug water oozes bubble 30min, and heating decocts 2 times, and the 1st fries in shallow oil: the 1000g crude drug adds water 12L, fries in shallow oil 120min; The 2nd fries in shallow oil: add water 10L, fry in shallow oil 90min; After twice decocting liquid merges, negative pressure leaching, filtrate adds the deionized water adjusted volume, gets the drug solns that contains of 8ml/g, and regulates pH to 5.0; The filtrate upper prop is crossed macroporous resin, flow velocity 3ml/min; With deionized water flush away impurity, flow velocity 6ml/min; Use 80% ethanol elution, flow velocity 3ml/min, eluent reclaims ethanol with rotary evaporator, concentrates; Concentrated solution continues to be evaporated to the thick paste shape with water-bath, is the Radix Aconiti Kusnezoffii extract thick paste; With the Fructus Piperis Longi levigation, 95% ethanol that adds 3 times of amounts oozes bubble 3 times continuously, merges sepage, and negative pressure-pumping filters; Remove ethanol with the rotary evaporator backflow, get the Fructus Piperis Longi ethanol extract; Get dry Fructus Chebulae's decoction pieces, be crushed to 2 ~ 3mm bulk, with distilled water immersion 6～12h; Heating decocts 30min, constantly replenishes distilled water during the decoction, to guarantee constancy of volume; With 4 layers of filtered through gauze decocting liquid, medicinal residues are with an amount of distilled water wash 2 times, and after washing liquid and filtrate merged, reuse filter paper negative pressure leaching once; Filtrate water bath evaporate to dryness gets Fructus Chebulae's extractum; Be mixed in proportion Radix Aconiti Kusnezoffii extract, Fructus Piperis Longi extractum and Fructus Chebulae's extractum; After earlier sodium polyacrylate, glycerol, sodium carboxymethyl cellulose, polyvinyl alcohol adjuvant being mixed, again gelatin is added, heat and stir 25min; The principal agent that is mixed in proportion is mixed with substrate, add penetrating agent azone and propylene glycol, mix into even ointment; Mix, make cataplasma.

11, as claim 1,2, the application of 3 or 5 described medicines in the medicine of preparation treatment rheumatic arthritis.

12, the application of medicine as claimed in claim 4 in the medicine of preparation treatment rheumatic arthritis.