CN100571727C - Direct lytic agent of a kind of Chinese medicine compound cholelithiasis and preparation method thereof - Google Patents

Abstract

The present invention discloses and a kind ofly is used for directly being poured into the human body biliary system with direct lytic agent of the dissolved Chinese medicine compound cholelithiasis of cholelithiasis and preparation method thereof, it is made up of Herba Artemisiae Scopariae 10-30%, Fructus Aurantii 10-20%, Endothelium Corneum Gigeriae Galli 10-20%, behind ethanol extraction, add tween 80 and water is formulated.The present invention utilizes the natural resources of Chinese medicinal materials of China's abundant, extracts the lithodialysis active component of several Chinese medicines, forms the compound preparation based on Chinese medicine, carries out cholelithiasis dissolution experiment in the external body, prepares the direct lytic agent of cholelithiasis of high-efficiency low-toxicity.This medicine pharmacodynamics experiment confirm litholytic effect in animal body is good, animals administer can dissolve the human gallstones of implanting after 7 days fully, do not see significant change before the hemogram of animal and each internal organs and the administration, acute toxicity testing and irritation test show this product safety non-toxic, basic nonirritant.Can be used for the treatment of clinical cholelithiasis patient's non-operative treatment.The present invention provides a kind of new medicine of being made up of Chinese medicine compound for direct perfusion litholytic therapy.

Description

Direct lytic agent of a kind of Chinese medicine compound cholelithiasis and preparation method thereof

Technical field

The present invention relates to be used for directly be poured into the human body biliary system with the direct lytic agent of the dissolved Chinese medicine compound cholelithiasis of cholelithiasis.It particularly is the direct lytic agent of cholelithiasis of raw material with Chinese medicine Herba Artemisiae Scopariae, Fructus Aurantii, Endothelium Corneum Gigeriae Galli.

Background technology

Cholelithiasis is a kind of commonly encountered diseases that endangers health of people, in recent years owing to China's living standards of the people improve, and the change of dietary habit, environmental factors changes, and the sickness rate of cholelithiasis is the trend that rises year by year.Domestic and international natural crowd's generaI investigation sickness rate is about 10%.It is 2.5-12% that 300,000 people of China part provinces and cities generally investigate its sickness rate.Along with age increase sickness rate also increases, the old man's sickness rate more than 80 years old can be up to 23%.Calculate about 5,320 ten thousand people of national cholelithiasis patient.

Operation is the main means of treatment cholelithiasis, but still has some problems: (1) has certain operative mortality and complication; (2) postoperative remnant gallstone rate height; (3) old or have other serious disease corrective surgeries dangerous big; (4) the part patient fears operation or refusal hands art; (5) doctor wishes that also some case do not treat by operation repeatedly again; (6) medical expense is bigger.Therefore, it is significant that active research is used non-surgical treatment.

Non-surgical treatment has at present: through scope biliary tract stone extraction, extracorporeal shock-wave lithotomy and medicine lithodialysis, calculus.To carry out vater's papilla through the scope biliary tract stone extraction and cut, belong to the invasive treatment; Extracorporeal shock-wave lithotomy only can have certain damage to hepatic tissue, and need combine with lithodialysis, lithagogue method at big cholelithiasis more than the 2.0cm, otherwise rubble is divided a word with a hyphen at the end of a line at biliary tract and easily caused and block and infect.The medicine litholytic therapy is divided into oral drugs lithodialysis and direct dabbling drug lithodialysis.

Oral drug therapy be the easiest, to the Therapeutic Method of the basic no pain of patient, yearned for by people always.As far back as nineteen thirty-seven Neubridge at first with the method for oral bile acid treatment cholelithiasis, but up to the end of the sixties because the origin cause of formation of bile metabolism and cholelithiasis has had deep understanding, oral drugs litholytic method is just developed.Up to the present the oral drugs lithodialysis also only limits to the dissolving cholesterol calculus, and clinical effectiveness is poor.The main medicine of using has: (1) chenodeoxycholic acid (Chenodeoxycholicacid CDCA), can enlarge the cholic acid pond, and reduce the saturation of bile cholesterol.But dosage is big, and the course of treatment is long, external 2 years complete molten rates of calculus only 13.5%, and the calculus regeneration rate is 25-50% after the drug withdrawal.Prolonged application is toxic to liver, part patient's diarrhoea, and low density lipoprotein, LDL increases in the blood, causes arteriosclerosis.(2) ursodesoxycholic acid (Ursodeoxycholic acid UDCA): litholytic effect is good than CDCA, and does not have the above-mentioned side effect of CDCA.But the expense costliness, the course of treatment is also very long, and the lithodialysis rate about 40% in external 2 years, recurrence of hepatolithiasis rate 16-33% after the drug withdrawal.(3) treatment by Chinese herbs: traditional Chinese medical herbal treatment cholelithiasis all was based on the anti-discharging calculus of function of gallbladder promoting in the past, thereby tens kinds of cholagogic and lithagogue soup are arranged.Its effect mainly is depressed liver-energy dispersing and function of gallbladder promoting, clearing away heat-damp and promoting diuresis, activating blood circulation to dissipate blood stasis.The mechanism of action may be: the expansion choledochal sphincter, promote row's gallbladder function, and increase choleresis, shrink gallbladder, lax Qddis sphincter increases biliary tract wriggling and anti-inflammation.Treatment by Chinese herbs is higher to the clinical symptom remission rate of cholelithiasis, but lithagogue rate and to arrange quiet rate many below 30%.In a word, the oral drugs lithodialysis will have new progress, waits further effort.

Directly the dabbling drug lithodialysis be with the lithodialysis agent through T pipe (postoperative) or keep somewhere nose bile duct or percutaneous through scope and inject biliary system through liver etc., make the lithodialysis agent directly contact cholelithiasis and make its dissolving.The characteristics of this method are: medicine can directly contact with cholelithiasis, can be without liver metabolism, and it is fast to produce effects, and artificial control is easy to do.But need directly lithodialysis agent safely and effectively.The representational medicine that forefathers once studied has: (1) sad monoesters (Monooctanion MO) U.S. FDA exemplary application in 1980.Its commodity are called Capmul, and every 100ml MO can dissolve the 11.7g cholesterol.Contain the 40-94% cholesterol calculus in external MO dissolving and need more than 50 hours.1985, inject MO lithodialysis result in U.S.'s data 343 routine bile ducts: 26% is molten entirely, and 29% is partly dissolved, and 36% is invalid, and 9% because its side effect and stopped treatment.The side effect incidence rate is 67%.Wherein 41% multiple side effect occurs, as pancreatitis, obstructive jaundice, septicemia etc.Clinical practice at present is less.(2) methyl tert-butyl ether (Methyltertbutylether, MTBE).Be a kind of aliphatic GENERAL ANESTHETICS, penetrating odor is arranged, boiling point is 55.2 ℃, proportion 0.74.1985 annual reports are 20g/100ml to the dissolubility of cholesterol, fast 50 times than MO of the speed of dissolving cholesterol.External can be in 60-100 minute abundant people's cholelithiasis of dissolving cholesterol content 40-94%.Zoopery is implanted the dog gallbladder with people's cholelithiasis, and diameter 1.8cm, cholesterol level pour into MTBE more than 90%, and the time of dissolving cholelithiasis fully is 4-16 hour.It is clinical that Allen reported first in 1985 is used for MTBE, major side effects for feel sick, vomiting, drowsiness, serum transaminase increase, hemolytic reaction has deadly case individually.Domestic Zhang Min found by the animal toxicity experiment in 1986, the MTBE of denier injects vein, peritoneal cavity or gastric can cause the rapid death of animal, and medicine enters liver can cause hepatic necrosis, can cause the acute inflammation of mucous epithelium and erosion to come off when dissolving gallbladder and calculus of bile duct.Bile pigment calculus there is not dissolution.Because MTBE also has dissolution to rubber, Gu general T pipe use is restricted at present clinical seldom application.(3) dextrorotation hesperidene (D-Limonene) and Fructus Citri tangerinae oil: the dextrorotation hesperidene is the monoene terpene of taking from the Fericarpium Citri Limoniae.Igimi first Application in 1970, the solubilized cholesterol.Side effect is to produce stomachache and diarrhoea the treatment initial stage, and body is had certain zest.Domestic similar formulations is a compound recipe Fructus Citri tangerinae oil emulsion.Its main component is a Fructus Citri tangerinae oil, contains the dextrorotation hesperidene more than 90%.The eighties is domestic once 27 hospital application said preparation 226 examples of 13 provinces and cities, intrahepatic calculi 192 examples wherein, choledocholithiasis 33 examples, cholelithiasis 1 example.Behind the perfusion therapy, confirm calculus complete obiteration 101 examples (44.7%) through X line radiography, calculus reduces or the person's of dwindling 88 examples (38%), the no obvious change example in treatment back, total effective rate 83.6%.Middle nineteen nineties is retrograde gallbladder intubate perfusion Chinese medicine No. 1 (compound recipe oleum Citri sinensis preparation) clinical treatment cholelithiasis of lithodialysis (cholesterol type calculus) 44 examples under the useful scope in addition, and 75% reaches complete molten effect, does not find tangible toxic action.Compound recipe Fructus Citri tangerinae oil emulsion is domestic more representational compound preparation, but it is on probation to only limit to laboratory research and clinical principium, from target safely and efficiently one segment distance is arranged still, at present in clinical less application.About with the herbal mixture be main component the direct lytic agent of cholelithiasis preparation and use and not appear in the newspapers as yet.

The present invention utilizes the natural resources of Chinese medicinal materials of China's abundant, extracts the lithodialysis active component of several Chinese medicines, through a large amount of prescription screening experiments, forms the compound preparation based on Chinese medicine, prepares the direct lytic agent of cholelithiasis of high-efficiency low-toxicity.

Summary of the invention

The object of the present invention is to provide and a kind ofly be used for directly being poured into the human body biliary system the direct lytic agent of the dissolved Chinese medicine compound cholelithiasis of cholelithiasis.

Another object of the present invention is to provide the preparation method of the direct lytic agent of a kind of Chinese medicine compound cholelithiasis.

The present invention seeks to be achieved through the following technical solutions:

The direct lytic agent crude drug of Chinese medicine compound cholelithiasis is made by Herba Artemisiae Scopariae 10-30%, Fructus Aurantii 10-20%, Endothelium Corneum Gigeriae Galli 10-20%; Solubilizing agent tween 80 1-5%.

Preparation method of the present invention:

More than three flavors, get Herba Artemisiae Scopariae respectively and add 50-70% ethanol 8-12 doubly, reflux, extract, 1-3 time, each 1-3 hour, merge extractive liquid,, recovery ethanol is with standby behind the activated carbon decolorizing; Fructus Aurantii adds 70-95% ethanol 4-6 doubly, reflux, extract, 1-3 time, and each 1-3 hour, merge extractive liquid, reclaims ethanol, and was standby; Endothelium Corneum Gigeriae Galli adds 50-70% ethanol 5-6 doubly, reflux, extract, 1-2 time, and each 1-2 hour, merge extractive liquid, reclaims ethanol, and was standby; Get above-mentioned three kinds of extracting solution mix homogeneously, add the tween 80 mixing of 1-5%, the sodium carbonate with 10% is regulated pH to 6-8, and adding distil water is to full dose.

Medicine of the present invention pharmacodynamics experiment confirm litholytic effect in animal body is good, animals administer can dissolve the human gallstones of implanting after 7 days fully, do not see significant change before the hemogram of animal and each internal organs and the administration, acute toxicity testing and irritation test show this product safety non-toxic, basic nonirritant.Can be used for the treatment of clinical cholelithiasis patient's non-operative treatment.The present invention provides a kind of new medicine of being made up of Chinese medicine compound for directly perfusion litholytic therapy and combination of Chinese and Western medicine clinical treatment calculus.

Below be method and the result who uses pharmacodynamic experiment, acute toxicity testing and irritant experiment that the sample of prescription of the present invention and method preparation carries out.

1. the pharmacodynamic experiment of lithodialysis agent reaches the influence to biochemical indicator and internal organs

Experimental technique: 10 of New Zealand white rabbit, male and female half and half, body weight 2.0kg～2.5kg, fasting is 12 hours before the art, is divided into 2 groups at random.Every example is got 2 pieces in people's cholelithiasis sample, is divided into 2 groups after the pairing at random.Anesthesia back aseptic condition is inserted each one piece in rabbit gallbladder, fistulation, indwelling drug infusion catheter.Pour into lithodialysis agent and normal saline contrast respectively by fistula catheter after one week.Each 0.5ml/kg body weight, 1 time/day.Put to death respectively after one week, get in the gallbladder and weigh after residual stone drying, the constant weight.Get the following biochemical indicator of hematometry: glucose (GLU), glutamate pyruvate transaminase (ALT), blood urea nitrogen (BUN).Take off the row internal organs and do pathologic finding: gallbladder, liver, pancreas, stomach, small intestinal, heart, brain, kidney, spleen, lungs.

Experimental result:

After (1) one week, the calculosis that lithodialysis agent administration group is inserted all dissolves.Matched group calculus weight does not have significant change.

(2) the basic no change of every biochemical indicator before and after the laboratory animal administration.

(3) the laboratory animal brain after the agent of perfusion lithodialysis, heart, lungs, gastrointestinal tract, kidney, liver, spleen, pancreas, gallbladder all do not have obvious pathological change.

The lithodialysis experimental result shows in the animal body, and the direct lithodialysis agent of Chinese medicine compound provided by the present invention can make the human gallstones of implanting in the rabbit gallbladder dissolve fully, and the every biochemical indicator and the internal organs of laboratory animal be there is no influence.

2. the acute toxicity test of lithodialysis agent.

Experimental technique: 60 of kunming mices, body weight 18-22g is divided into 6 groups at random, 10 every group.Behind the 4h, give the lithodialysis agent respectively and irritate stomach on an empty stomach, dosage is every 10g body weight 0.32,0.36,0.40,0.44,0.49,0.54ml.

Experimental result: only 0.44 group of dead mouse is 1.All the other each groups all do not have dead.Show this lithodialysis agent high safety.

3. the mucomembranous pungency test of lithodialysis agent.

Experimental technique: get the lithodialysis agent and do the rabbit conjunctival stimulation test.Respectively lithodialysis agent and normal saline are splashed in rabbit left eye and the right eye.Observe rabbit and have or not scratch reaction and conjunctiva variation.

Experimental result: rabbit does not have the reaction of obviously scratching.Observe 24 hours rabbit conjunctivals and do not have untoward reaction such as obvious hyperemia.

Above pharmacodynamic experiment and toxicological experiment result illustrate that the direct lithodialysis agent of Chinese medicine compound cholelithiasis is a kind of safe, direct lytic agent of cholelithiasis efficiently.

Embodiment

Herba Artemisiae Scopariae 200g Fructus Aurantii 100g Endothelium Corneum Gigeriae Galli 100g

More than three flavors, get Herba Artemisiae Scopariae respectively and add 10 times of 60% ethanol, reflux, extract, 2 times, each 1 hour, merge extractive liquid, reclaimed ethanol, with standby behind the activated carbon decolorizing; Fructus Aurantii adds 4 times of 95% ethanol, reflux, extract, 1 time, and each 2 hours, merge extractive liquid, reclaims ethanol, and was standby; Endothelium Corneum Gigeriae Galli adds 5 times of 50% ethanol, reflux, extract, 2 times, and each 1 hour, merge extractive liquid, reclaims ethanol, and was standby; Get above-mentioned three kinds of extracting solution mix homogeneously, add 3% tween 80 mixing, the sodium carbonate with 10% is regulated pH to 7, and adding distil water is to 1000ml.Promptly.

Claims (2)

1, a kind ofly is used for directly being poured into the human body biliary system, it is characterized in that adopting following method preparation: choose crude drug by weight: Herba Artemisiae Scopariae 10-30%, Fructus Aurantii 10-20%, Endothelium Corneum Gigeriae Galli 10-20% the direct lithodialysis agent of the dissolved Chinese medicine compound cholelithiasis of cholelithiasis; More than three flavors, get Herba Artemisiae Scopariae respectively and add 50-70% ethanol 8-12 doubly, reflux, extract, 1-3 time, each 1-3 hour, merge extractive liquid,, recovery ethanol is with standby behind the activated carbon decolorizing; Fructus Aurantii adds 70-95% ethanol 4-6 doubly, reflux, extract, 1-3 time, and each 1-3 hour, merge extractive liquid, reclaims ethanol, and was standby; Endothelium Corneum Gigeriae Galli adds 50-70% ethanol 5-6 doubly, reflux, extract, 1-2 time, and each 1-2 hour, merge extractive liquid, reclaims ethanol, and was standby; Get above-mentioned three kinds of extracting solution mix homogeneously, add the tween 80 mixing of 1-5%, the sodium carbonate with 10% is regulated pH to 6-8, and adding distil water is to full dose.

2, the preparation method of the direct lithodialysis agent of Chinese medicine compound cholelithiasis as claimed in claim 1 is characterized in that this method is: choose crude drug by weight: Herba Artemisiae Scopariae 10-30%, Fructus Aurantii 10-20%, Endothelium Corneum Gigeriae Galli 10-20%;

More than three flavors, get Herba Artemisiae Scopariae respectively and add 50-70% ethanol 8-12 doubly, reflux, extract, 1-3 time, each 1-3 hour, merge extractive liquid,, recovery ethanol is with standby behind the activated carbon decolorizing; Fructus Aurantii adds 70-95% ethanol 4-6 doubly, reflux, extract, 1-3 time, and each 1-3 hour, merge extractive liquid, reclaims ethanol, and was standby; Endothelium Corneum Gigeriae Galli adds 50-70% ethanol 5-6 doubly, reflux, extract, 1-2 time, and each 1-2 hour, merge extractive liquid, reclaims ethanol, and was standby; Get above-mentioned three kinds of extracting solution mix homogeneously, add the tween 80 mixing of 1-5%, the sodium carbonate with 10% is regulated pH to 6-8, and adding distil water is to full dose.