CN100382815C - Compound composition for treating arthralgia caused by wind-dampness and preparation thereof - Google Patents

Abstract

The present invention relates to a compound composition with traditional Chinese drugs for treating rheumatism. The compound composition comprises the following crude drugs: Radix Zanthoxyli, stauntonvine, Chinese tinospora, climbing entada, Radix Clematidis, thickleaf croton root, etc., and oral preparations or injections are prepared by matching the extracts of the crude drugs with proper kinds of auxiliary materials or matrixes in pharmacy. The present invention is used for treating rheumatalgia, arthralgia and limb pain due to rheumatism.

Description

A kind of pharmaceutical composition and preparation thereof for the treatment of rheumatic arthralgia

Technical field

The present invention relates to a kind of pharmaceutical composition and preparation thereof for the treatment of rheumatic arthralgia.

Background technology

The compound recipe anti-rheumatism is to have expelling wind and removing dampness, promoting blood circulation to remove blood stasis, and the compound Chinese medicinal preparation of muscles and tendons relaxing to alleviate pain function is applicable to that rheumatic arthritis, rheumatoid arthritis, gout, soft tissue injury cause pain etc.This medicine standard is now recorded in " national standard for traditional Chinese medicines compilation " meridians limbs fascicle, and standard is numbered WS-11515 (ZD-1515) 2002.Commercially available compound recipe anti-rheumatism is a conventional tablet: coated tablet, Film coated tablets.Be that Luofu Mountain, Guangdong pharmaceutical Co. Ltd produces for many years, be used for the treatment of rheumatoid arthritis.The tool expelling wind and removing dampness, promoting blood circulation to remove blood stasis, muscles and tendons relaxing to alleviate pain.Be used for effects such as rheumatic arthralgia anti-inflammatory and antalgic.

For a long time, the homonym situation was very general during Chinese crude drug used.The compound recipe anti-rheumatism by: Six-element Chinese medicines such as Radix Zanthoxyli, Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae), Herba Lycopodii, Caulis Bauhihiae Championii, Radix Clematidis, Radix Crotonis Crassifolii are formed.All the time, former mixing of Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) medical material base reaches tens of kinds more than, the national drug standards are not given clearly record, and only include Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) at the 5th appendix of Chinese traditional patent formulation preparation: its base was root or the stem and leaf of Araliaceae schefflera arboricola Scheffleraarboricola Hagata originally.The medicinal plants of including medicine name or different name in the Chinese medicine voluminous dictionary and be Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) reaches tens of kinds.The medical material base that Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) adopted in Luofu Mountain, Guangdong pharmaceutical Co. Ltd compound recipe anti-rheumatism prescription was the inside business secret of manufacturing enterprise originally, had no precedent open.

Summary of the invention

The objective of the invention is to based on compound recipe anti-rheumatism prescription, select suitable treatment rheumatic arthralgia, arthritis, arthralgic Lardizabalaceae plant Caulis et folium stauntoniae to originate as the best of Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) medical material, confirm that through pharmacological evaluation extract safety, the pharmacological research of this prescription combination all are better than the Araliaceae schefflera arboricola as Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae).The invention discloses the purposes that compound recipe anti-rheumatism preparation is used for the treatment of rheumatic arthralgia, rheumatalgia, arthralgia and treatment gout.

The weight proportion of the used medical material of the present invention is:

1 ~ 3 part of 1.5 ~ 4.5 parts of Herba Lycopodii of 1.5 ~ 4.5 parts of Caulis et folium stauntoniaes of Radix Zanthoxyli

0.5 ~ 1.5 part of 0.5 ~ 1.5 part of Radix Crotonis Crassifolii of 1 ~ 3 part of Radix Clematidis of Caulis Bauhihiae Championii

Caulis et folium stauntoniae: this product is the dry stem of Lardizabalaceae plant Caulis et folium stauntoniae Stauntonia chinensis DC.

Herba Lycopodii: this product is the dry rattan of menispermaceae plant China limacia sagittata Tinospoora sinensis (Lour) Merr..

Caulis Bauhihiae Championii: this product is the dry rattan of leguminous plant Ke Caulis Endadae phaseoloidis Entada phaseoloides (1.) Merr. or Caulis Bauhiniae Championii Bauhinia championi (Benth.) Benth..

Radix Crotonis Crassifolii: this product is the dry root of euphorbia plant Radix Crotonis Crassifolii Croton crassifdius Geisel..

Other medical materials all use by the record of document specifies such as Chinese Pharmacopoeia.

The following weight proportion of preferred use:

2 parts of 3 parts of Herba Lycopodii of 3 parts of Caulis et folium stauntoniaes of Radix Zanthoxyli

1 part of 1 part of Radix Crotonis Crassifolii of 2 parts of Radix Clematidis of Caulis Bauhihiae Championii

The medicinal substances extract of above-mentioned weight proportion cooperates the pharmaceutically alleged adjuvant or the substrate of the suitable kind of employing to make oral formulations or injection preparation.

When making oral formulations such as tablet, be preferably as follows prescription:

Radix Zanthoxyli 750g Caulis et folium stauntoniae 750g Herba Lycopodii 500g

Caulis Bauhihiae Championii 500g Radix Clematidis 250g Radix Crotonis Crassifolii 250g

Make 1000.

When making injection, be preferably as follows prescription:

Radix Zanthoxyli 2500g Caulis et folium stauntoniae 2500g Herba Lycopodii 1667g

Caulis Bauhihiae Championii 1667g Radix Clematidis 833g Radix Crotonis Crassifolii 833g

Make 1000ml.

Effect of the present invention:

Test one:

Compound recipe anti-rheumatism acute toxicity comparative test that different basic sources medical material is made and analgesia comparative test:

The compound Chinese medicinal preparation that the compound recipe anti-rheumatism is made up of Six-element Chinese medicines such as Radix Zanthoxyli, Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae), Herba Lycopodii, Caulis Bauhihiae Championii, Radix Clematidis, Radix Crotonis Crassifoliis, all the time, the Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) medical material exists the homonym kind to reach tens of kinds.Chinese traditional patent formulation preparation Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) that appendix is put down in writing is: be root or the stem and leaf of Araliaceae schefflera arboricola Schefflera arboricolaHagata.For confirming the science of the present invention in the former selection of medical material base, the spy carry out this test.

1. material

1.1 be subjected to reagent

FUFANG FENGSHINING PIAN dry extract (Caulis et folium stauntoniae), lot number: 031023, every gram is equivalent to raw medicinal herbs 15g.This batch extractum Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) that feeds intake uses Caulis et folium stauntoniae, the i.e. dry stem of Lardizabalaceae plant Caulis et folium stauntoniae Stauntonia chinensis DC.

FUFANG FENGSHINING PIAN dry extract (schefflera arboricola), lot number: sieve medicine examination 031001, every gram is equivalent to raw medicinal herbs 15g.This batch extractum Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) that feeds intake is root or the stem and leaf of Araliaceae schefflera arboricola Schefflera arboricola Hagata.

Preparation: get above-mentioned two kinds of dry extracts respectively and put in the mortar and grind, add a small amount of distilled water and grind evenly, adding distil water promptly get the 8g/ml concentration liquid to 50ml again, and this concentration is that irrigation stomach device can pour into the intravital Cmax of animal, shakes up to be positioned over 4 ℃ of refrigerators preservations.

Each organizes medicinal liquid all to irritate the administration of stomach mode, 1 day 1 time, irritates the long-pending 0.4ml/10g of being of body of stomach.

Matched group is given the isometric(al) distilled water.

1.2 animal

Kunming kind white mice, 18～22g, 100, male and female half and half.

2. method and result

2.1 method: get qualified mice, at least 20 every group, male and female half and half are administered once with variable concentrations every day, and dead maximal dose not occurring with the animal capable tolerance is tolerance dose.

Experimental result: get 100 of 18-22g Kunming mouses, male and female half and half are divided into 5 groups, and fasting be can't help water 12 hours, give two batches of dry extract medicinal liquids of FUFANG FENGSHINING PIAN medicinal liquid 4.0g/ml, 4.8g/ml with 0.4ml/10g administration volume; 1.0g/ml, 1.2g/ml concentration, (this concentration through give examination obtain), gastric infusion 1 time is observed after the administration reaction of animals situation in the 48hr, morning and afternoon every day, each was observed once.Observe animal appearance, behavior, secretions, Excreta etc.Write down the zero-time, the order of severity, persistent period of death condition, poisoning symptom and the toxic reaction of all animals, whether reversible etc.Dying and dead animal are in time carried out gross anatomy, observe main organs, after the observation period finishes, carry out gross anatomy.Record observed result (see Table 1 and table 2).

The result judges: recover normal, other no abnormality seen after part lassitude, 30min are arranged behind the animals administer.Determine that by above result formal test mouse stomach FUFANG FENGSHINING PIAN dry extract (Caulis et folium stauntoniae) maximal dose gets 160g/kg, irritate stomach FUFANG FENGSHINING PIAN dry extract (schefflera arboricola) maximal dose and get 40g/kg.

Table 1 FUFANG FENGSHINING PIAN gastric infusion maximum tolerance determination result

Group	Number of animals (only)	Maximum concentration (c) g/ml that is subjected to	Irritate the long-pending ml (V) of body of stomach	Death toll (only)	Survival rate (%)
						The blank group	20	-	0.4ml/10g	0	100
031023 (Caulis et folium stauntoniae group)	20	4g/ml	0.4ml/10g	0	100
						031001 (schefflera arboricola group)	20	1g/ml	0.4ml/10g	0	100

Continuous table 1:

Group	Dead concentration (g/kg) appears	The long-pending ml (V) of filling body of stomach when death occurring	Number of animals (only)	Death toll (only)	The mice maximum tolerated dose (c * V)
						The blank group	-	0.4ml/10g	20	0	-
031023 (Caulis et folium stauntoniae group)	4.8g/ml	0.4ml/10g	20	1	≤160g/kg
						031001 (schefflera arboricola group)	1.2g/ml	0.4ml/10g	20	1	≤40g/kg

3 acute toxicity comparative test conclusions:

Foundation: maximum tolerance multiple=mice maximum tolerated dose * on average become body weight for humans/adult's consumption every day;

Full side takes 5 every day by patient's compound recipe anti-rheumatism of 60kg body weight, 4 times on the one, takes the crude drug amount and is: 60g.

The compound recipe anti-rheumatism dry extract that Caulis et folium stauntoniae uses as Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae), mice lavage administration maximum tolerated dose is 160g/kg, is equivalent to more than 160 times of clinical 60kg people's consumption per day.

With the compound recipe anti-rheumatism dry extract that the duck's foot rattan is used as Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae), mice lavage administration maximum tolerated dose is 40g/kg, is equivalent to more than 40 times of clinical 60kg people's consumption per day.

Conclusion: Caulis et folium stauntoniae is higher as Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) safety in utilization in the compound recipe anti-rheumatism.

4, the mice hot plate is caused the influence of pain

Press hot plate method,, use 10 of two batches, every dosage group respectively 60 mices, with same dose (the g/kg per minute is gastric infusion 7 days continuously, the mice pain reaction when observing after the last administration 15 minutes, 60 minutes, 120 minutes, result such as following table:

The different medical materials of table 2 make compound recipe anti-rheumatism extractum causes pain to hot plate influence

5, influence conclusion (of pressure testing) to what the mice hot plate caused pain: between two groups when Isodose concentration to the significant difference that influences of the mice threshold of pain, P＜0.01.Test shows, the relevant composition of Caulis et folium stauntoniae plays an important role aspect the mice threshold of pain influencing, and dose dependent is good, and simultaneously, the A group is better than the compound recipe anti-rheumatism analgesic activity that B group Araliaceae schefflera arboricola is made.Explanation is used as Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) in the compound recipe anti-rheumatism with Caulis et folium stauntoniae has better analgesia effect.

Test two:

The compound recipe anti-rheumatism is treated rheumatoid arthritis, is improved the clinical trial summary of gout symptom

Be objective evaluation compound recipe anti-rheumatism treatment rheumatoid joint clinical efficacy and safety, take random packet, the test method of contrast, curative effect is checked through Ridit, and compound recipe anti-rheumatism preparation and matched group phenylpropionic acid NSAID (non-steroidal anti-inflammatory drug) one meloxicam do not have significant difference on therapeutic effect.

1. case is selected

1.1 Western medicine diagnose standard

Related content with reference to " new Chinese medicine clinical research guideline " (trying), Americanism damp disease association rheumatoid arthritis diagnostic criteria (1987) is formulated.

1.1.1 morning, deadlock was at least 1 hour, continued at least 6 weeks.

1.1.2 wrist, metacarpophalangeal joints or proximal interphalangeal joint are swollen, continue at least 6 weeks.

1.1.3 the symmetry swollen joint continued at least 6 weeks.

1.1.4 the change of hands X line.

1.1.5 the rheumatoid factor positive, titer＞1: 32.

1.2 function of joint grade scale

The I level: daily routines are not limited.

II level: have the joint motion of moderate strength limited, but can satisfy the daily routines needs.

The III level: there is tangible limitation of activity in the joint, and the patient can not be engaged in most of occupations or can not take care of oneself well.

The IV level: LOM or be forced to the bed maybe can only be sitting on the wheelchair.

1.3X line by stages

The I phase: normal or joint end osteoporosis.

The II phase: joint end osteoporosis, idol have joint subchondral cyst sample to destroy or bone erosion changes.

The III phase: significantly capsule destroys under the articular cartilage, and the joint space is narrow, the subluxation of joint deformity.

The IV phase: except that II, III phase change, and fibroid or bony ankylosis are arranged.

1.4 tcm syndrome diagnostic criteria

Formulate with reference to " new Chinese medicine clinical research guideline " (trying), " Chinese Internal Medicine " (high medical college teaching material the 4th edition) related content.

1.4.1 cold-dampness numbness card

A, primary symptom: joint cold type of pain and swelling, pain increase in intensity under coldness, pain alleviated while getting warmth, the joint joint stuffiness, morning deadlock, joint deformity.

B, inferior disease: thirsty, sweating, yellow urine, big dry stool.

C, tongue arteries and veins: red tongue, yellow fur is thick, and is greasy, slippery and rapid pulse or stringy and rolling pulse.

1.4.2 symptom scalar quantization standard:

A, primary symptom

A.1 arthralgia

Do not have	No pain.	0 minute
			Gently	Pain is light, still can stand, or pain when fatigue or Changes in weather only, do not influence work substantially	2 minutes
In	Pain is heavier, working and having a rest all is affected	4 minutes
			Heavy	Pain is serious, is difficult to stand, and has a strong impact on to have a rest and work, need be used analgesic	6 minutes

A.2 arthroncus

Do not have

The joint does not have swelling.

0 minute

Gently	The joint is slightly swollen, skin texture shoals, and the joint has the bone sign still obvious	2 minutes
			In	The joint moderate is swollen, arthroncus is obvious, and skin texture disappears substantially, and the bone sign is not obvious	4 minutes
Heavy	Joint severe is swollen, arthroncus very, skin is tight, the bone marks obliterated	6 minutes

A.3 joint stuffiness

Do not have	No activity is not limited.	0 minute
			Gently	Joint motion is slightly limited, and range of motion reduces＜1/3	2 minutes
In	Joint motion is slightly limited, and range of motion reduces 〉=1/3	4 minutes
			Heavy	Joint motion is slightly limited, and range of motion reduces 〉=2/3	6 minutes

A.4 morning deadlock

Do not have	No morning deadlock	0 minute
			Gently	Refuse to budge morning continuous time＜1 hour	2 minutes
In	Refuse to budge morning continuous time 〉=1 hour,＜2 hours	4 minutes
			Heavy	Refuse to budge morning continuous time 〉=2 hour	6 minutes

B, inferior disease

B.1 aversion to wind and cold

Do not have	No morning deadlock	0 minute
			Gently	Refuse to budge morning continuous time＜1 hour	1 minute
In	Refuse to budge morning continuous time 〉=1 hour,＜2 hours	2 minutes
			Heavy	Refuse to budge morning continuous time 〉=2 hour	3 minutes

B.2 limbs are heavy

Do not have	No limbs are heavy	0 minute
			Gently	Idol has limbs heavy	1 minute
In	Often limbs are heavy	2 minutes
			Heavy	Often limbs are heavy, do not desire activity	3 minutes

C, tongue arteries and veins

Describe and do not keep the score.

1.5 case is included standard in

1.5.1 meet rheumatoid joint Western medicine diagnose standard.

1.5.2 meet the tcm syndrome diagnostic criteria.

1.5.3 the age was at 18～50 years old.

Enter stable at least 30 days of test predose 1.5.4 accept the patient of nonsteroidal antiinflammatory drug and hormone therapy, and remain unchanged in the later treatment.The patient who accepts other state of an illness improvement must discontinue medication more than 30 days.

1.5.5 signature enters the clinical research Informed Consent Form.

1.6 case exclusion standard

1.6.1 do not meet the above-mentioned standard person of including in.

1.6.2 patients with terminal, joint severe deformities, function of joint IV level person.

1.6.3 overlapping other rheumatisms such as systemic lupus erythematosus (sle), dry syndrome, serious knee osteoarthritis etc.

1.6.4 merge to have the inclination, serious disease patients such as brain, liver, kidney and hemopoietic system.

1.6.5 woman, psychotic in gestation or age of sucking.

1.7 reject the case standard

1.3.1 after including in, find not meet to include standard person in.

1.3.2 do not use the medicine person after including in.

The case standard 1.6 come off

1.6.1 can't judge curative effect person's (, merge and use the other treatment medicine) not by the scheme medication.

1.6.2 untoward reaction occurs, should count the untoward reaction statistics.

2. physical data

2.1 sex distributes

2.2 age distribution: see Table 2.

The age distribution of table 2 case

Treatment group minimal ages 18 years old, maximum 48 years old age, average 33.66 ± 7.52 years old.Matched group minimal ages 2l year, maximum 49 years old, average 35.29 ± 6.81 years old.Check through t; P＞0.05, relatively there was no significant difference has comparability.

2.2 the course of disease distributes: see Table 3

The table 3 case course of disease (year) distributes

The treatment group course of disease is the shortest 3 months, and is the longest 9 years, average 2.00 ± 1.23 years.The matched group course of disease is the shortest 4 months, and is the longest 10.5, average 1.894 ± 1.25 years.Check through t: P＞0.05, there was no significant difference.Has comparability.

3. observation index

3.1 general physical examination: body temperature, heart rate, blood pressure, pulse etc.

3.2 safety detects

3.2.1 blood, urine, stool routine inspection.(treatment before and after look)

3.2.2 the heart, liver, kidney function test.(treatment before and after look)

3.2.3 untoward reaction that may occur and coherent detection index.The time of origin of itemized record untoward reaction, clinical symptoms, persistent period, treatment measures and extinction time.

3.3 health giving quality detects

3.3.1 related symptoms primary symptom, hold concurrently disease and the variation of tongue arteries and veins

Arthralgia, arthroncus, joint joint stuffiness, deadlock in morning (min) and relevant performance; Aversion to wind and cold, limbs are heavy and tongue arteries and veins etc.

3.3.2 relevant sign

Articular pain, arthroncus, function of joint, the average grip of both hands (mmHg), joint X line by stages, deadlock, the horizontal vision synopsis of pain l0cm method (VAS) test in morning.

3.3.3 physico-chemical examination

Joint X ray examination, RF, ESR (Wei Shi method), CRP, uric acid concentration in the blood.

4. observational technique

4.1 adopt the random packet contrast method, compound recipe anti-rheumatism Capsules group 63 examples, compound recipe anti-rheumatism injection group 62 examples, matched group 62 examples.

4.2 dosage, number of times and the course of treatment

4.2.1 dosage, number of times

The treatment group:

A. compound recipe anti-rheumatism capsule is each 2, every day 3 times, oral.Product batch number: 0306231, provide by Guangdong LuoFoshan Medicine Co., Ltd.

B. compound recipe anti-rheumatism injection, each 2～4ml, every day 1～2, intramuscular injection.Product batch number: 0307112, provide by Guangdong LuoFoshan Medicine Co., Ltd.

Matched group: meloxicam tablet, each 1,7.5m/ sheet.Every day 2 times, oral.0306110, provide by Guangdong LuoFoshan Medicine Co., Ltd.During gouty attack,acute, add and take colchicine 0.5mg, 1～2 hour 1 time, till the severe pain alleviation.

4.2.2 the course of treatment: 30 days is a course of treatment, judges curative effect after all treating two courses of treatment.

4.3 drug combination situation: except that the medicine that scheme is determined, other associated treatment medicine of stopping using.

4.4 the compliance measure of clinical trial: provide the information material of this test to experimenter or family members, the details of relevant clinical trial is described; With and right and possible being benefited.Clinical research person answers the patient and painstaking patient that treats, to obtain patient's trust.

4.5 untoward reaction is observed

4.5.1 main observe the malaise symptoms that occurs together with medication and allergy etc., and blood, urine, just conventional, cardiorenal function check unusual.Untoward reaction to duration of test occurs should be recorded in its kind, degree, time of occurrence, persistent period, treatment measures, pass through etc. on the observation table.

4.5.2 when untoward reaction occurring, observe the doctor and can whether stop clinical trial, the case because of the untoward reaction drug withdrawal is carried out tracing observation, its result of itemized record according to state of an illness decision.

4.5.3 in test as severely adverse event occurs, researcher should adopt suitable protective measure to the experimenter immediately, and report test director immediately, and the latter should report local medicine management department in 24 hours.

4.6 clinical trial record

4.6.1 all case should be observed in strict accordance with clinical protocol, conscientiously fills in the medical history record form.Record faithfully experimenter's medicining condition.

4.6.2 case history and medical history record form must not be changed as protocol, must not change protocol when doing any corrigendum, can only take additional description to give reasons, by the physician's signature who participates in clinical trial and date.

4.6.3 answer the various lab testing data of itemized record in the clinical trial, clinic case should stick on the initial report list on the medical history record.

4.6.4 the experimental data in normal range also should record, must be examined data significantly higher or beyond clinical tolerance interval, does necessary explanation by the doctor who participates in clinical trial.

5. observation of curative effect

5.1 efficacy determination

5.1.1 disease comprehensive therapeutic effect criterion

A. the whole improvement rate of produce effects cardinal symptom, sign 〉=75%.Erythrocyte sedimentation rate and c reactive protein normally or obviously improve or are approaching normal.

B. progressive cardinal symptom, the whole improvement rate of sign 〉=50%.Erythrocyte sedimentation rate and c reactive protein have improvement.

C. effective cardinal symptom, the whole improvement rate of sign 〉=30%.Erythrocyte sedimentation rate and c reactive protein have improvement or do not have improvement.

D. invalid cardinal symptom, the whole improvement rate of sign＜30%.Erythrocyte sedimentation rate and c reactive protein do not have improvement.

Attached: cardinal symptom, sign be meant the stiff time of articular pain, arthroncus number, morning (minute), 5 of the average grips of both hands (mmHg), pain level vision synopsis numerical value etc.Whole improvement rate is meant that the percentage rate that improves of above 5 indexs promptly asks its meansigma methods after (a value treatment back value before the treatment)/treat preceding value * 100% addition.

5.1.2 therapeutic effect of syndrome criterion

A. the various transference cures in back are treated in recovery from illness, and the syndrome integrated value reduces 〉=95%.

B. each symptom of produce effects treatment back obviously alleviates, and the syndrome integrated value reduces 〉=70%,＜95%.

C. effectively each symptom of treatment back alleviates to some extent, and the syndrome integrated value reduces 〉=30%,＜70%.

D. each symptom does not have to alleviate or have and increases the weight of after the futile treatment, and the syndrome integrated value subtracts＜and 30%.

5.2 safety classification

There is not any untoward reaction, I. safely; Safety indexes is no abnormal.

II. compare safety, mild adverse effects is arranged, do not need to do any processing and can continue medication; Safety indexes is checked no abnormal.

III., safety issue is arranged, moderate untoward reaction is arranged, or the safety indexes inspection there is mile abnormality, can continue medication after dealing with.

IV. end to observe because of serious adverse reaction, or the safety indexes inspection is obviously unusual.

5.3 curative effect of disease is relatively:

Table 3 case curative effect of disease relatively

Learn check by statistics, Ridit analyzes: Capsules group and matched group do not have significant difference, P＞0.05, and the injection group is better than Capsules group and matched group, significant difference, P＜0.01.

Exponential integrals comparisons such as hypozygal pain, arthroncus before and after the treatment of table 4 case (X ± S)

Before and after the treatment in the group relatively, t check P＜0.05, and significant difference is arranged, and treat forward and backward and matched group compares P＞0.05 there was no significant difference.

5.4 the tcm syndrome curative effect relatively

Syndrome integration comparison before and after the table 5 case treatment treatment (X ± S)

Group is relatively interior before and after the treatment, and t checks P＜0.05, and significant difference is arranged, and compares P＞0.05 there was no significant difference with matched group before and after the treatment.

5.5 the laboratory is checked

Attacking 6 laboratories checks relatively

Group is relatively interior before and after the treatment, and t checks P＜0.05, and significant difference is arranged, and compares P＞0.05 there was no significant difference with matched group before and after the treatment.

5.6 administration time relatively

Table 7 administration time is fewer

The course of treatment, relatively t checked P＜0.05, and significant difference is arranged.The treatment group obvious top grade course of treatment and matched group.

5.6 treatment group uric acid concentration laboratory indexes check result:

Treatment group hyperuricemia has clear improvement, the little mM of the average range of decrease 50.5+12.8 of treatment group uric acid concentration/liter, the average little mM of 330+17.5 in treatment back/liter, the matched group hyperuricemia does not have significant change, 410.6 ± 23.5 little mMs/liter.

5.7 treatment group safety laboratory indexes check result

Platelet, routine urinalysis before and after the treatment, just indexs monitorings such as routine, liver function, renal function, electrocardiogram there is no unusually.The clinical observation treatment group is not seen obvious adverse reaction.Meloxicam is stupid propionic non-steroid antiphlogistic, and analgesia, antiinflammation during the treatment rheumatoid arthritis have obtained common approval.Colchicine is treatment gout medicine commonly used.Arthromyodynia that the traditional Chinese medical science is referred to as is by plain body weakness, insufficiency of vital energy and blood, and interspaces of skin and muscles being loose, the place, residence is moist more, or suffers wind and rain, and heresy that wind and cold is damp and hot taken advantage of a weak point in opponent's defence and invaded, due to the meridians of being detained, the muscle joint.QI and blood impatency not general rule causes symptoms such as joint joint stuffiness.Similar with the rheumatoid arthritis symptom.Control and to dispel wind and remove dampness, promoting blood circulation to remove blood stasis, muscles and tendons relaxing to alleviate pain.

Radix Zanthoxyli nature and flavor in the compound recipe anti-rheumatism prescription are arduous, warm, function dispelling wind and removing obstruction in the collateral, reducing swelling and alleviating pain.The dispelling the wind and dampness pathogens osteodynia, traumatic injury." herbal classic " cloud: " the main air cold-damp, severe and migratory arthralgia is painful, removes the extremity gas of fainting, gonalgia." Herba Lycopodii nature and flavor toil, temperature.The effect expelling wind and cold, dehumidifying detumescence, relaxing muscles and tendons to promote blood circulation.Control anemofrigid-damp arthralgia, joint aches, skin numbness, tetraparesis, edema, traumatic injury.Radix Clematidis nature and flavor suffering is salty, warm, the function wind-damp dispelling, and the meridian dredging, expectorant saliva, all medicines cooperate in the sides such as the hypochondriac lump of loosing, the merit of playing expelling wind and cold, blood circulation promoting and blood stasis dispelling, muscles and tendons relaxing to alleviate pain altogether.

Contain multiple flavonoid glycoside in the Caulis et folium stauntoniae, be apt to control all kinds of neuropathic pains.

The present invention adopts the mutual compatibility of above each medicine, by improving the antihyperuricemic symptom, the gout outbreak is had clear improvement.

The specific embodiment:

Embodiment 1: a kind of preparation for the treatment of the pharmaceutical composition and the tablet thereof of rheumatic arthralgia:

The weight proportion of used medical material:

Radix Zanthoxyli 750 Caulis et folium stauntoniaes 750 Herba Lycopodii 500

Caulis Bauhihiae Championii 500 Radix Clematidis 250 Radix Crotonis Crassifoliis 250

Starch 30g magnesium stearate 1g

Above Six-element medical material, Caulis et folium stauntoniae, Radix Zanthoxyli, Radix Crotonis Crassifolii are ground into coarse powder, make solvent with 65% ethanol, soaked 24 hours, according to the percolation under fluid extract and the extractum item (appendix I0 of Chinese Pharmacopoeia version in 2000), with 6 times of amount 65% ethanol percolations, percolation speed is 3mlkg ^-1Min ^-1, collect percolate, reclaim ethanol and be concentrated into the thick paste that relative density is 1.24～1.26 (40 ℃).Herba Lycopodii, Radix Clematidis, Caulis Bauhihiae Championii add 8 times of water gagings and decoct secondary, each 2 hours, collecting decoction, filter, filtrate is concentrated into the thick paste that relative density is 1.24～1.26 (40 ℃), merges with above-mentioned thick paste, drying under reduced pressure is ground into fine powder, adds starch, the system, add magnesium stearate, drying, tabletting, coating, promptly.

Embodiment 2: a kind of preparation for the treatment of the pharmaceutical composition and the drop pill thereof of rheumatic arthralgia:

The weight proportion of used medical material:

Radix Zanthoxyli 750 Caulis et folium stauntoniaes 750 Herba Lycopodii 500

Caulis Bauhihiae Championii 500 Radix Clematidis 250 Radix Crotonis Crassifoliis 250

Polyethylene glycol 6000: Polyethylene Glycol 9000 (9: 1) 120g

Make 5000

A) above six medical materials, Caulis et folium stauntoniae, Radix Zanthoxyli, Radix Crotonis Crassifolii are ground into coarse powder, make solvent with 65% ethanol, according to " percolation under Chinese pharmacopoeia fluid extract and the extractum item carries out percolation, collect percolate, reclaim the thick paste of the relative density 1.24～1.26 of ethanol.

B) Herba Lycopodii, Radix Clematidis, Caulis Bauhihiae Championii decoct with water 2 times, and each 2 hours, merging filtrate filtered, and filtrate and above-mentioned thick paste merge.Be concentrated into the clear paste of relative density 1.24～1.26 (40 ℃)

Preparation drop pill: above-mentioned steps a, b clear paste merge, drying be ground into 80 orders～120 order fine powders, or above-mentioned clear paste spray drying obtains fine powder, taking polyethylene glycol 6000: 60～75 ℃ of heating and melting of Polyethylene Glycol 9000 (7.5: 2.5) water-bath, add the fine powder of medicinal substances extract, mix homogeneously splashes in the two first class silicone oil liquid coolants while hot, drip and make drop pill, ball heavily is controlled to be 0.045～0.055, removes liquid coolant, promptly gets the commodity drop pill.

3 one kinds of preparations for the treatment of the pharmaceutical composition and the dispersible tablet thereof of rheumatic arthralgia of embodiment

The weight proportion of used medical material:

Radix Zanthoxyli 750 Caulis et folium stauntoniaes 750 Herba Lycopodii 500

Caulis Bauhihiae Championii 500 Radix Clematidis 250 Radix Crotonis Crassifoliis 250

Filler: 60 parts of pregelatinized Starch and 20 parts of compositions of lactose;

8 parts of disintegrating agents;

Lubricant is 1 part of a magnesium stearate;

Correctives is 0.5 part of an xylitol;

Step 1:

A) above six medical materials, Caulis et folium stauntoniae, Radix Zanthoxyli, Radix Crotonis Crassifolii are ground into coarse powder, make solvent with 65% ethanol, according to " percolation under Chinese pharmacopoeia fluid extract and the extractum item carries out percolation, collect percolate, reclaim the thick paste of the relative density 1.24～1.26 of ethanol.

B) Herba Lycopodii, Radix Clematidis, Caulis Bauhihiae Championii decoct with water 2 times, and each 2 hours, merging filtrate filtered, and filtrate and above-mentioned thick paste merge.Be concentrated into the clear paste of relative density 1.24～1.26 (40 ℃)

Above-mentioned steps a, b clear paste merge, and drying is ground into 80 orders～120 order fine powders, or above-mentioned clear paste spray drying obtains fine powder, and be standby.

Step 2: the clear paste spray drying of above-mentioned steps 1, the powder that gets dry extract is standby.Get dried cream powder, 60 parts of pregelatinized Starch, 60 parts of lactose, reach 4 parts of mix homogeneously of disintegrating agent, granulate drying with content 95% alcoholic acid alcoholic solution moistening, granulate, add stearic 1 part in magnesium and the 0.5 part of tabletting of xylitol calculated of 6 parts of disintegrating agents and lubricant, that is, make 1000.

Crospolyvinylpyrrolidone is a The disintegrating agents of dispersible tablets, removes crospolyvinylpyrrolidone can also be: carboxymethyl starch sodium or low-substituted hydroxypropyl cellulose or cross-linked carboxymethyl cellulose sodium.

The dilute alcohol solution of polyvinylpyrrolidone is the wetting agent in the dispersible tablet.Wetting agent in its dispersible tablet can also be the alcoholic solution of 40% ethanol～95% alcoholic solution or starch slurry or polyvinylpyrrolidone.

Magnesium stearate lubricant in the above-mentioned dispersible tablet can also be: micropowder silica gel or Pulvis Talci.

Correctives xylitol in the above-mentioned dispersible tablet can also be sweet or mannitol or other medicinal correctives of A Basi.

Embodiment 4: a kind of preparation for the treatment of the pharmaceutical composition and the dispersible tablet thereof of rheumatic arthralgia

The weight proportion of used medical material:

Radix Zanthoxyli 750g Caulis et folium stauntoniae 750g Herba Lycopodii 500g

Caulis Bauhihiae Championii 500g Radix Clematidis 250g Radix Crotonis Crassifolii 250g

Filler: pregelatinized Starch 200g and lactose 320g;

Disintegrating agent 48g;

Lubricant: magnesium stearate 6g;

Correctives is xylitol 3g;

Get dried cream powder, pregelatinized Starch 400g, lactose 640g, reach disintegrating agent 18g mix homogeneously, dilute alcohol solution (5 parts of polyvinylpyrrolidones: moistening granulation 20% ethanol 100ml) with the content polyvinylpyrrolidone, dry, granulate, add stearic magnesium 6g of calculation of disintegrating agent 30g and lubricant and xylitol 3g tabletting, promptly get dispersible tablet.Make 1000.

Crospolyvinylpyrrolidone is a The disintegrating agents of dispersible tablets, removing crospolyvinylpyrrolidone can also be: carboxymethyl starch sodium or low-substituted hydroxypropyl cellulose or cross-linked carboxymethyl cellulose sodium, the best is a carboxymethyl starch sodium: the mixture of low-substituted hydroxypropyl cellulose (1: 3).

The dilute alcohol solution of polyvinylpyrrolidone is the wetting agent in the dispersible tablet.Wetting agent in its dispersible tablet can also be 40% ethanol～95% alcoholic solution or starch slurry or polyvinylpyrrolidone Alcoholic solution

Magnesium stearate lubricant in the above-mentioned dispersible tablet can also be: micropowder silica gel or Pulvis Talci.

Correctives xylitol in the above-mentioned dispersible tablet can also be sweet or mannitol or other medicinal correctives of A Basi.

Embodiment 5: a kind ofly treat the pharmaceutical composition of rheumatic arthralgia and the preparation of matrix type controlled release tablet thereof

The weight proportion of used medical material:

Radix Zanthoxyli 750 Caulis et folium stauntoniaes 750 Herba Lycopodii 500

Caulis Bauhihiae Championii 500 Radix Clematidis 250 Radix Crotonis Crassifoliis 250

Beta cyclodextrin 50g

Hydroxypropyl methylcellulose 65g

Coating solution 100ml

Filler precoking starch 50g, microcrystalline Cellulose 25g

Micropowder silica gel 3g

Method for making:

A) above six medical materials, Caulis et folium stauntoniae, Radix Zanthoxyli, Radix Crotonis Crassifolii are ground into coarse powder, make solvent with 65% ethanol, according to " percolation under Chinese pharmacopoeia fluid extract and the extractum item carries out percolation, collect percolate, reclaim the thick paste of the relative density 1.24～1.26 of ethanol.

B) Herba Lycopodii, Radix Clematidis, Caulis Bauhihiae Championii decoct with water 2 times, and each 2 hours, merging filtrate filtered, and filtrate and above-mentioned thick paste merge.Be concentrated into the clear paste of relative density 1.24～1.26 (40 ℃)

Two clear paste merge, and add beta cyclodextrin 50g, and the system granule after the granule coating, adds filler precoking starch 50g, microcrystalline Cellulose 25g, and lubricant micropowder silica gel tabletting promptly gets the matrix type controlled release tablet, and the gained tablet is coating once more, optimizes tablet appearance.

The capsular preparation of embodiment 6:PH dependent sustained release

Radix Zanthoxyli 750 Caulis et folium stauntoniaes 750 Herba Lycopodii 500

Caulis Bauhihiae Championii 500 Radix Clematidis 250 Radix Crotonis Crassifoliis 250

Hydroxypropyl methylcellulose 25g

Starch 80g

Coating solution i:7%HPMC aqueous solution

Coating solution ii:6%Eudragit L30-D-55 aqueous dispersion

Coating solution iii:8%Eudragit L100: S100 (1: 4) aqueous dispersion

(illustrate: Eudragit L30, Eudragit L100, Eudragit S100 are commercially available coating material)

A) above six medical materials, Caulis et folium stauntoniae, Radix Zanthoxyli, Radix Crotonis Crassifolii are ground into coarse powder, make solvent with 65% ethanol, according to " percolation under Chinese pharmacopoeia fluid extract and the extractum item carries out percolation, collect percolate, reclaim the thick paste of the relative density 1.24～1.26 of ethanol.

B) Herba Lycopodii, Radix Clematidis, Caulis Bauhihiae Championii decoct with water 2 times, and each 2 hours, merging filtrate filtered, and filtrate and above-mentioned thick paste merge.Be concentrated into the clear paste of relative density 1.24～1.26 (40 ℃)

Above-mentioned steps a, b clear paste merge, and drying is ground into 80 orders～120 order fine powders, or above-mentioned clear paste spray drying obtains fine powder,

Fine powder mixes with adjuvant hydroxypropyl methylcellulose, starch, uses 55% alcohol granulation, and oven dry is standby.

Uniform particles is divided into three parts, and respectively with PH gradient dependent form gradient coating solution coating, the granule behind the coating incapsulates and promptly gets compound recipe anti-rheumatism PH gradient dependent form gradient slow releasing capsule.

Embodiment 7, a kind of pharmaceutical composition for the treatment of rheumatic arthralgia and injection thereof preparation;

The weight proportion of used medical material is:

Radix Zanthoxyli 2500g Caulis et folium stauntoniae 2500g Herba Lycopodii 1667g

Caulis Bauhihiae Championii 833g Radix Clematidis 833g Radix Crotonis Crassifolii 833g

Active carbon 1.5g

Above Six-element medical material adds 15 times of amounts of water at every turn, decocts twice, and 2 hours for the first time, 1.5 hours for the second time, collecting decoction filtered, and it is 1.30 clear paste that filtrate is concentrated into relative density under 40 ℃ of conditions; Add ethanol and make and contain alcohol amount, left standstill 24 hours, filter, filtrate recycling ethanol and to be concentrated into to 40 ℃ of conditions relative density be 1.30 clear paste to 75%; The same method of qinghuo reagent is precipitate with ethanol again, concentrates once.Clear paste after concentrating is put to room temperature, and adding water to and making relative density is under 25 ℃ of conditions 1.02, adds 1% neutral lead acetate of amount of liquid medicine, stirs, and leaves standstill 24 hours, filters.Get filtrate and add 10% sulfuric acid solution, left standstill 24 hours, filter to there not being the precipitation generation.Filtrate adds 10% sodium hydroxide solution to be made neutral, filters, and it is 1.30 clear paste that filtrate is concentrated into relative density under 40 ℃ of conditions.Qinghuo reagent adds ethanol and makes and contain alcohol amount to 80%, leaves standstill 24 hours, getting that supernatant reclaims ethanol and be concentrated into relative density under 40 ℃ of conditions is 1.31 clear paste, adds 10 times of amount waters for injection and dilutes cold preservation 12 hours, filter, filtrate adds the injection water dilution, regulates pH to neutral with 10% sodium hydroxide solution, add the injection water again to 1000ml, add active carbon 1.5g, boil, filter, fill, sterilization promptly gets compound recipe anti-rheumatism injection.

Embodiment 8: a kind of preparation for the treatment of the pharmaceutical composition and the drop pill thereof of rheumatic arthralgia:

The weight proportion of used medical material:

Radix Zanthoxyli 750 Caulis et folium stauntoniaes 750 Herba Lycopodii 500

Caulis Bauhihiae Championii 500 Radix Clematidis 250 Radix Crotonis Crassifoliis 250

Polyethylene glycol 6000: Polyethylene Glycol 9000 (9: 1) 120g

Make 5000

1 above six medical materials, Caulis et folium stauntoniae, Radix Crotonis Crassifolii are ground into coarse powder, make solvent with 10 times of amounts of 65% ethanol, according to " percolation under Chinese pharmacopoeia fluid extract and the extractum item carries out percolation, collect percolate, Radix Zanthoxyli is measured percolation for 8 times with hydrochloric 0.25% 65% ethanol, and two percolates pass through D101 respectively, reach the AB-8 resin, with 80～95% ethanol elutions, reclaim ethanol and get dry extract;

2 Herba Lycopodii, Radix Clematidis, Caulis Bauhihiae Championii, and Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae), Radix Crotonis Crassifolii, Radix Zanthoxyli diafiltration after medicinal residues decoct with water 2 times, each 2 hours, merging filtrate filtered, filtrate, is reclaimed ethanol and is got dry extract with 75% ethanol elution by the D101 resin;

3 preparation drop pill: above-mentioned steps 1,2 dry extract merge, be ground into 80 orders～120 order fine powders,, taking polyethylene glycol 6000: 60～75 ℃ of heating and melting of Polyethylene Glycol 9000 (7.5: 2.5) water-bath, the fine powder of adding medicinal substances extract, mix homogeneously, splash into while hot in the two first class silicone oil liquid coolants, drip and make drop pill, ball heavily is controlled to be 0.045～0.055, remove liquid coolant, promptly get the commodity drop pill.

Embodiment 9, a kind of preparation for the treatment of the pharmaceutical composition and the freeze-dried powder thereof of rheumatic arthralgia;

The weight proportion of used medical material is:

Radix Zanthoxyli 2500g Caulis et folium stauntoniae 2500g Herba Lycopodii 1667g

Caulis Bauhihiae Championii 833g Radix Clematidis 833g Radix Crotonis Crassifolii 833g

95% ethanol is an amount of

Above Six-element medical material is ground into coarse powder, places the supercritical extraction still, is solvent with 2.0 times of amount 95% ethanol, and temperature is controlled at 28～45 ℃, and pressure 5～15 MPas were extracted 0.5～2.5 hour.Reclaim ethanol and get clear paste, add an amount of water for injection, adjust PH to 4.0～6.5, boil, filter, packing, lyophilizing promptly gets compound recipe anti-rheumatism lyophilized powder type injection.

Claims (2)

1. pharmaceutical composition for the treatment of rheumatic arthralgia, it is characterized in that: the weight proportion of used medical material is:

1～3 part of 1.5～4.5 parts of Herba Lycopodii of 1.5～4.5 parts of Caulis et folium stauntoniaes of Radix Zanthoxyli

0.5～1.5 part of 0.5～1.5 part of Radix Crotonis Crassifolii of 1～3 part of Radix Clematidis of Caulis Bauhihiae Championii.

2. the pharmaceutical composition of treatment rheumatic arthralgia according to claim 1 is characterized in that: the weight proportion of used medical material is:

2 parts of 3 parts of Herba Lycopodii of 3 parts of Caulis et folium stauntoniaes of Radix Zanthoxyli

1 part of 1 part of Radix Crotonis Crassifolii of 2 parts of Radix Clematidis of Caulis Bauhihiae Championii.