阅读说明：本技术 一种新型溶石剂 (Novel stone dissolving agent ) 是由 宋红红 陈梓衡 张�杰 倪磊 凌晓峰 徐怡庄 冯娟 于 2020-04-17 设计创作，主要内容包括：本发明提供了一种聚乙二醇丁醚溶石剂,毒性低,副作用小,可用于治疗肝内胆管结石。该溶石剂为水溶性溶石剂,便于减少聚乙二醇丁醚的浓度,并且可以在胆汁残留情况下进行溶石,溶石后方便清洗,减少残留。本发明提供的溶石剂可以实现胆囊结石、肝外胆管结石和肝内胆管结石的溶解,副作用小,因此本发明的溶石剂有望用于临床胆结石病人的非手术疗。(The invention provides a polyethylene glycol monobutyl ether litholytic agent which has low toxicity and small side effect and can be used for treating intrahepatic bile duct calculi. The litholytic agent is water-soluble litholytic agent, is convenient for reducing the concentration of the polyethylene glycol butyl ether, can dissolve the stone under the condition of bile residue, is convenient to clean after dissolving the stone, and reduces residue. The litholytic agent provided by the invention can realize the dissolution of gall-bladder stones, extrahepatic bile duct stones and intrahepatic bile duct stones, and has small side effect, so that the litholytic agent is expected to be used for non-operative treatment of clinical cholelithiasis patients.)

1. A novel litholytic agent, comprising butyl ether polyethylene glycol.

2. The litholytic agent of claim 1, further comprising water.

3. A litholytic agent according to claim 1 or 2, wherein the butyl ether of polyethylene glycol has a number average molecular weight of 5 to 500.

4. A litholytic agent according to any one of claims 1 to 3, further comprising a surfactant, a proteolytic agent, a complexing agent, or an anti-inflammatory agent.

5. A litholytic agent according to any one of claims 1-4, wherein the concentration of said surfactant in the litholytic agent is 0.01-3.0 g/mL, and the concentration of said complexing agent is 0.005-0.1 g/mL.

6. A litholytic agent according to any of claims 1 to 4, wherein said litholytic agent is useful for dissolving cholesterol gallstones, bile pigment gallstones or mixed gallstones.

7. Use of a litholytic agent according to any one of claims 1 to 6 in the manufacture of a medicament for treating gallstones.

8. The use according to claim 7, wherein the volume ratio of the polyethylene glycol butyl ether to water is (1-50): 1 for cholesterol-type gallstones.

9. The use according to claim 7, wherein the volume ratio of the polyethylene glycol butyl ether to the water is (2-50): 1 for mixed gallstones.

10. The use according to claim 7, wherein the volume ratio of the polyethylene glycol butyl ether to water is (5-50): 1 for cholechrome gallstones.

Technical Field

The invention relates to a novel litholytic agent for dissolving gallstones, in particular to a polymer litholytic agent.

Background

The bile is the secretion of liver cells, wherein 97% of the bile is water, and contains bile acid, bile salt, cholesterol, fatty acid, lecithin, inorganic salt and the like, and the daily bile secretion of an adult is about 800-1000 ml. Bile is secreted by liver cells, flows into duodenum through hepatic duct and common bile duct, or flows into gallbladder for storage through hepatic duct and cystic duct, and is discharged from gallbladder and flows into duodenum when necessary for digestion. When the concentration of cholesterol in bile is too high, it will precipitate out and form gallstone. Therefore, gallstones may be classified into intrahepatic bile duct stones, gall bladder stones, and common bile duct stones according to the location of the disease. Can be classified into cholesterol gallstones with a cholesterol content of 70% or more, cholesterol gallstone with a cholesterol content of 30% or less, and mixed gallstones with a cholesterol content of 30% to 70%. The cholesterol gallstones are white or light yellow, generally round or oval, and are further divided into cholecalciferol stones and melanin gallstones, wherein the cholecalciferol gallstones are generally tan or brownish black, are soft and unshaped, are shaped like silt, mainly comprise free bile pigments, calcium salts, bacteria, worm eggs or cells and the like, and the melanin gallstones are generally black or brownish black, spherical, insoluble black bile pigment polymers, various calcium salts and mucus glycoprotein. The mixed gallstone is dark green or brown yellow, mostly polyhedral and round, and mainly comprises cholesterol, cholesterol and calcium salt.

Wherein, the gallstone is mainly cholesterol gallstone, mixed gallstone mainly comprising cholesterol or melanin gallstone, and the gallstone is cut off when the gallstone is serious. Extrahepatic bile duct stones are classified as secondary and primary stones. Secondary calculus is mainly cholelithiasis which is mainly characterized in that cholecystolithiasis is excreted into bile duct and stays in the bile duct, and is cholesterol type cholelithiasis or melanin cholelithiasis. The primary calculus is brown cholelithiasis or mixed cholelithiasis, and is induced by biliary tract infection, biliary tract obstruction and biliary tract foreign matter. In severe cases, cholecystectomy, choledocholithiasis, T-tube drainage, etc. are required. Intrahepatic bile duct calculi, also called hepatobiliary calculi, are calculi in bile ducts above the junction of the left and right hepatic ducts, are generally bilirubin gallstones, and are common and intractable biliary diseases in China. Calculus of intrahepatic duct has complicated etiology, and is mainly related to infection of biliary tract, parasite in biliary tract, bile stagnation, anatomical variation of bile duct, and malnutrition. At present, the operation treatment is mainly adopted, and the principle is to take out calculus as far as possible, relieve biliary stricture and obstruction, remove calculus parts and infection focus, and partially resect liver when serious.

Among the methods for treating gallstones, conservative treatment is accepted by most people. The direct gallstone dissolving therapy is to inject the gallstone dissolving agent directly into the position of the gallstone to dissolve the gallstone, aiming at not damaging bile ducts, keeping gall bladder and liver tissues of patients and avoiding pain and burden of operation. The litholytic method is simple and convenient in percutaneous transhepatic puncture catheterization under the guidance of ultrasound, has little pain, and can avoid the damage caused by X-ray monitoring in the retrograde gallbladder intubation under the endoscope. The interventional ultrasound technology should be continuously improved to solve the problem of complications. If the lithotripsy is combined with external shock wave lithotripsy, the infiltration of lithotripsy medicine and the dissolution of gallstone are facilitated, and the lithotripsy effect is improved. The technology is yet to be developed and perfected. Firstly, a diagnosis standard for judging components of the gallstone is formulated, and the position of the gallstone is comprehensively judged by combining methods such as ultrasound, CT, cholangiography and the like. Meanwhile, the litholytic medicament needs to be further developed, in particular to a litholytic agent for mixed gallstones with high calcium content and bile pigment type gallstones. The direct contact litholytic method has the advantages of small damage, little pain and definite curative effect. Especially for intrahepatic bile duct calculi, if a litholytic agent with small side effect can be developed, the treatment difficulty of intrahepatic bile duct calculi can be greatly reduced.

Therefore, various litholytic agents are explored and researched, but the existing litholytic agents have large side effects on human bodies, have poor litholytic effect on bile pigment type gallstones and mixed gallstones, need to be further researched, and can be used for dissolving and treating intrahepatic bile duct stones, gall-bladder stones and common bile duct stones.

Based on the above problems, there is a need for developing a new gallstone-dissolving agent which can dissolve not only cholesterol-type gallstones but also bile pigment-type gallstones and mixed gallstones, has low side effects, reduces the injury to the human body from surgical treatment, and reduces the additional injury of the gallstone-dissolving agent to the human body.

Disclosure of Invention

In order to solve the above problems, the present inventors have conducted extensive studies and found that when polyethylene glycol monobutyl ether is used as a gallstone-dissolving agent, the polymer has low toxicity and few side effects, and can dissolve cholesterol-type gallstones, mixed-type gallstones and bile pigment-type gallstones, thereby achieving a very good stone-dissolving effect, and is expected to be directly used for dissolving and treating intrahepatic bile duct stones, thereby completing the present invention.

The invention aims to provide a litholytic agent for dissolving gallstones, which comprises polyethylene glycol butyl ether.

The litholytic agent further comprises a surfactant, a proteolytic agent, a complexing agent, or an anti-inflammatory agent.

The litholytic agent can be used to dissolve cholesterol-type gallstones, bile pigment-type gallstones or mixed gallstones. The cholesterol content of the cholesterol gallstone is more than 70%, the cholesterol content of the cholesterol pigment gallstone is less than 30%, and the content of the mixed gallstone is between 30% and 70%.

The invention also aims to provide application of the litholytic agent in preparing a medicament for treating gallstones.

The administration mode of the litholytic agent comprises the way of percutaneous transhepatic puncture sinus intubation or retrograde insertion of a nasal-biliary catheter through a duodenoscope, and the like, and the litholytic agent is injected to directly contact with gallstones.

The stone dissolving agent has the following beneficial effects:

(1) the litholytic agent provided by the invention is used for dissolving gallstones in clinic, the toxicity of the polyethylene glycol butyl ether is low, the side effect is small, and the litholytic agent can enter gallbladders and extrahepatic bile duct stones, especially intrahepatic bile duct stones, to be contacted with litholytic agents.

(2) The litholytic agent is matched with water for use, so that the toxicity is further reduced, the residual litholytic agent can be cleaned and extracted through an aqueous solvent after litholytic is finished, the residue is less, and a small amount of residual polyethylene glycol butyl ether has small side effect on liver and kidney of a human body, and can be used for preparing litholytic agents. And litholysis can be performed under the condition of bile residue.

(3) The litholytic agent is added with the surfactant, the protein lytic agent, the complexing agent or the anti-inflammatory agent, so that the litholytic effect of the litholytic agent can be improved, the litholytic time can be shortened, and the treatment period can be further shortened.

Drawings

FIG. 1 is a graph showing the dissolution effect of butyl cellosolve in the present invention on cholesterol gallstones;

FIG. 2 is a graph showing the dissolution effect of butyl cellosolve in the present invention on mixed gallstones;

FIG. 3 is a graph showing the effect of PEG-butyl ether in dissolving bile pigment type gallstones in the present invention.

Detailed Description

The present invention will now be described in detail by way of specific embodiments, and features and advantages of the present invention will become more apparent and apparent from the following description.

The existing litholytic agent mainly dissolves cholesterol gallstones, has low dissolution rate in dissolving bile pigment gallstones and mixed gallstones, and has large side effect on human bodies, even damages liver and kidney. The need exists for developing a litholytic agent which can dissolve mixed gallstones, particularly bile pigment gallstones, and which can reduce the side effects of the litholytic process and the residual litholytic agent after entering the human body, reduce the residual litholytic agent and be difficult.

In the present invention, the litholytic agent comprises polyethylene glycol butyl ether. The main chain of the polyethylene glycol butyl ether is a polyethylene glycol chain, and the end group of the polyethylene glycol butyl ether is provided with a butyl ether group and a hydroxyl group. The metabolic points of the ethylene glycol chain are mainly hydroxyl, alcohol dehydrogenase oxidizes alcohol groups into carboxylic acid, the damage is small, the alcohol groups can be methylated, the metabolic points are occupied, toxic metabolites cannot be generated, and meanwhile, the toxicity of the metabolites of the butyl ether group in a human body is low. The polyethylene glycol butyl ether is used as the main stone dissolving component of the stone dissolving agent, so that the toxic and side effects of the stone dissolving agent on human bodies can be effectively reduced.

In the invention, a large number of experiments prove that the polyethylene glycol butyl ether can effectively dissolve cholesterol gallstones, mixed gallstones and bile pigment gallstones. The polyethylene glycol monobutyl ether can be matched with water for use, still has a good stone dissolving effect, can reduce the using amount of the polyethylene glycol monobutyl ether and the concentration of the polyethylene glycol monobutyl ether, and can also wash out the stone dissolving agent through water or an aqueous solvent such as physiological saline after stone dissolving, thereby reducing the residue of the stone dissolving agent in a body.

Notably, the litholytic agent also comprises water. When the addition of the polyethylene glycol butyl ether is changed from 1mL to 10mL relative to 1mL of water, the dissolution rate of the cholesterol gallstone can reach 100 percent. In an in vitro litholytic experiment, when the volume ratio of the polyethylene glycol butyl ether to water is 1:1, the litholytic rate can still reach 100% within 100min, only a small amount of floccules remain after litholytic, and the floccules can be washed out along with the litholytic agent in clinical use, and when the concentration of the litholytic agent is increased, the remaining fine particles disappear. When the volume ratio of the polyethylene glycol butyl ether to the water is 1:1, the dissolution rate of 100% can be achieved within 100min, and when the volume ratio of the polyethylene glycol butyl ether to the water is 10:1, the dissolution rate of 100% can be achieved within 10 min.

Compared with 1mL of water, when the addition amount of the polyethylene glycol butyl ether is 10mL, the mixed gallstone is dissolved, and the dissolution rate can reach 100% within 80 min; compared with 1mL of water, when the addition amount of the polyethylene glycol butyl ether is 2mL, the mixed gallstone can be dissolved, the dissolution rate can reach 100% within 90min, and the effect of reducing the concentration of the polyethylene glycol butyl ether on the dissolution time in the process of dissolving the mixed gallstone is seen to be small, so that the concentration can be reduced in the actual use process, and the effect of a high-concentration litholytic agent on human organs is reduced.

When the polyethylene glycol butyl ether is used for dissolving the bile pigment type gallstone, compared with 1mL of water, the dissolving rate of the 10mL of the stone dissolving agent can reach 25-30% within 100min, and the bile pigment type gallstone can be completely dissolved after the stone dissolving time is prolonged without any residue. However, the addition of 2mL of the litholytic agent to 1mL of water failed to dissolve the black bile pigment type gallstones.

Therefore, in the clinical use process, the polyethylene glycol monobutyl ether litholytic agent with proper concentration can be prepared according to the type of gallstone for application.

When the polyethylene glycol monobutyl ether litholytic agent is used for dissolving cholesterol type gallstones, the volume ratio of the polyethylene glycol monobutyl ether to water is (1-50): 1, preferably (1-15): 1, and more preferably (1-10): 1.

When the polyethylene glycol monobutyl ether litholytic agent is used for dissolving mixed gallstones, the volume ratio of the polyethylene glycol monobutyl ether to water is (2-50): 1, preferably (2-25): 1, and more preferably (2-15): 1.

When the polyethylene glycol monobutyl ether litholytic agent is used for dissolving bile pigment type gallstones, the volume ratio of the polyethylene glycol monobutyl ether to water is (5-50): 1, preferably (5-25): 1, and more preferably (5-15): 1.

In the invention, the polyethylene glycol monobutyl ether litholytic agent has good litholytic effect on cholesterol-type gallstones and mixed gallstones, can completely dissolve gallstones in a short time, has longer litholytic time than the cholesterol-type gallstones and the mixed gallstones when dissolving bile pigment-type gallstones, can be pertinently adjusted when being clinically used, is used for dissolving gallstones into fine particles, adjusts the litholytic time according to clinical conditions, and is beneficial to discharge the bile pigment-type gallstones.

It is worth noting that compared with the existing litholytic agent, the polyethylene glycol monobutyl ether litholytic agent of the invention can greatly reduce toxic and side effects, and the metabolite in vivo is expected to have little harm. Is expected to be used for dissolving the calculus of the intrahepatic bile duct, greatly relieves the pain of treatment and retains the hepatic tissue of a patient. Can also be used for dissolving cholecystolithiasis and extrahepatic bile duct lithiasis in vivo, and can avoid cutting gallbladder of a patient and damaging bile duct.

The traditional litholytic agent Methyl Tertiary Butyl Ether (MTBE) has high toxicity (LD50 rats orally take 4g/kg, data source: NIOSH of national institute of occupational safety and health, USA), the boiling point is as low as 55 ℃, MTBE shows similar integral metabolism in rats and human bodies in relevant animal experiments and human body metabolism observation, and MTBE is acted by enzymeOxidative demethylation to formaldehyde and tert-butanol (TBA), formaldehyde rapidly metabolizes to formate and CO₂And further metabolism of TBA mainly generates alpha-hydroxyisobutyric acid, wherein formaldehyde has great damage to human bodies. The data show that the enzymes catalyzing MTBE biotransformation to form formaldehyde and TBA in human bodies exist in the liver in a large amount, so that the metabolism of the MTBE in the human bodies is supposed to occur mainly in the liver, and the metabolic products have great damage to the liver and kidney. And methyl tert-butyl ether has poor effect of dissolving bile pigment type gallstones, and is difficult to dissolve bile pigment type gallstones.

The number average molecular weight of the polyethylene glycol butyl ether is 5-500, preferably 150-280, and more preferably 200-210.

In a preferred mode of the present invention, the litholytic agent further comprises a surfactant, a proteolytic agent, a complexing agent, or an anti-inflammatory agent.

The surfactant is added into the litholytic agent, so that the litholytic agent not only can solubilize, but also has the effects of emulsification, wetting, decontamination, sterilization and the like. The surfactant is selected from benzalkonium bromide, lecithin, amino acid type, betaine type, polyethylene glycol, polysorbate and poloxamer, preferably selected from lecithin, polyethylene glycol, polysorbate and poloxamer, and more preferably selected from lecithin or poloxamer.

Lecithin can regulate serum lipid level, reduce cholesterol level, protect liver, and enhance immunity and anti-fatty liver activity. The lecithin is added into the litholytic agent, so that a certain liver protection capability can be provided, and the damage of the litholytic agent to the liver can be reduced.

Poloxamers are polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymers in which the polyoxyethylene chains are relatively hydrophilic and the polyoxypropylene chains are relatively lipophilic. According to the invention, poloxamer is added, so that on one hand, the uniform and stable litholytic agent can be formed with water, and on the other hand, due to the addition of poloxamer, the use amount of the polyalkylol butyl ether can be reduced, and the side effect of the litholytic agent on a human body can be reduced.

The concentration of the surfactant in the litholytic agent is 0.01-3.0 g/mL, preferably 0.05-1.5 g/mL, and more preferably 0.08-1 g/mL.

At present, more than 70 percent of cholesterol in cholesterol gallstones also contains a small amount of bilirubin, cholic acid, phospholipid, protein, free fatty acid, calcium salt, magnesium salt and the like; in the mixed gallstone, 30-70% of cholesterol is cholesterol, and also contains cholesterin, calcium salt and the like; the main components of bile pigment type gallstone include free bile pigment, bile pigment polymer, various calcium salts and mucus glycoprotein, calcium salt, bacteria, worm egg, etc. Therefore, in the present invention, it is preferable to add a protein dissolving agent in order to promote the litholytic effect of gallstones. In order to improve the resistance of the liver, biliary tract and gallbladder to litholytic agents, it is preferable to add an anti-inflammatory agent

The protein dissolving agent is selected from guanidine hydrochloride, urea, thiourea, 3- [3- (cholamidopropyl) dimethylamino ] propane sulfonate (CHAPS), Dithiothreitol (DTT), preferably guanidine hydrochloride, urea, thiourea or CHAPS, more preferably one or more of guanidine hydrochloride, urea or thiourea.

Thiourea can destroy hydrogen bonds formed between protein molecules, and prevent protein aggregation caused by the hydrogen bonds and formation of secondary structures in the process of protein migration. During the use process, the urea is required to be matched for use.

CHAPS is an amphoteric surfactant, has cholic acid and thiobetaine in a molecular structure, can protect the natural state of protein, and can dissolve membrane protein, thereby releasing the interaction between protein and protein.

DTT can reduce disulfide bonds in proteins, preventing intra-or intermolecular disulfide bonds of proteins formed between cysteines in proteins. Wherein the intermediate formed in the first step is unstable because the second thiol group on DTT tends to link to the oxidized sulfur atom, which quickly converts the intermediate into a cyclic oxidized structure of DTT, thereby completing the reduction of the disulfide bond. The reducing power of DTT is influenced by pH, and the effect of DTT can be exerted only when the pH is more than 7. This is because only deprotonated thiolate anions are reactive, thiols are not, and the material is long-term imported and expensive.

The solubilization of the guanidine hydrochloride and urea on hydrophobic amino acid residues is realized by the fact that the guanidine hydrochloride and urea have the capacity of forming hydrogen bonds, the guanidine hydrochloride and urea can break the hydrogen bonds when being used in a high-concentration (4-8 mol/L) aqueous solution, and therefore the guanidine hydrochloride and urea become better solvents of nonpolar residues, hydrophobic residues in protein molecules are stretched and solubility is increased, and the protein is denatured to different degrees.

At room temperature, 3-4 mol/L guanidine hydrochloride can transform globular protein from natural state to the middle point of the denaturation state, usually increasing the concentration of the denaturant can increase the denaturation degree, and about 6mol/L guanidine hydrochloride can transform protein into the denaturation state completely. Guanidine hydrochloride, due to its ionic nature, is generally present in a fully denatured state in a random coil conformation in 8mol/L guanidine hydrochloride solution.

The urea has slower and weaker dissolving capacity than guanidine hydrochloride, the protein solubility is 70-90%, and the urea can be cracked to form cyanate when the acting time is longer or the temperature is higher, so that the amino group of the recombinant protein is subjected to covalent modification, but the urea has the advantages of no ionization, neutrality, low cost and the like.

Guanidine hydrochloride has stronger dissolving capacity and denaturation capacity compared with urea, does not cause covalent modification of recombinant protein, but has high cost and is easy to generate precipitate under the acidic condition; the urea has relatively weak dissolving capacity, but has the advantages of no ionization, neutrality, low cost, no protein precipitation after protein renaturation, etc. In practical application, the stone dissolving agent is selected for use according to the use environment of the stone dissolving agent.

The concentration of guanidine hydrochloride in the litholytic agent is 0.1-8 mol/L, preferably 1-7 mol/L, and more preferably 2-6 mol/L.

The concentration of urea in the litholytic agent is 0.1-8 mol/L, preferably 1-7 mol/L, and more preferably 2-6 mol/L.

The complexing agent is selected from ethylene glycol diethyl diamine tetraacetic acid (EGTA), Ethylene Diamine Tetraacetic Acid (EDTA), disodium ethylene diamine tetraacetic acid (EDTA-2Na) or nitrilotriacetic acid (NTA), preferably ethylene glycol diethyl diamine tetraacetic acid (EGTA), disodium ethylene diamine tetraacetic acid (EDTA-2Na) or Ethylene Diamine Tetraacetic Acid (EDTA), and more preferably disodium ethylene diamine tetraacetic acid (EDTA-2 Na).

EDTA, EDTA-2Na and EGTA are good solvents for bile pigment type gallstones, and because the bile pigment and calcium content in bile pigment type gallstones is very high, calcium in the bile pigment type gallstones can be effectively dissolved, and the bile pigment type gallstones can be complexed with calcium ions in the presence of magnesium ions. The calcium ion complexing agent is added into the stone dissolving agent, so that gallstones, particularly bile pigment type gallstones, can be cracked, calcium ions in the gallstones are dissolved out of the gallstones, the surfaces of the gallstones are damaged layer by layer, and gradual dissolution is realized.

In addition, under the action of the solubilizer, the litholytic agent with weak polarity and EDTA-2Na molecules with strong polarity have mutual solubilization function, and the synergistic effect of the components is exerted. The concentration of the complexing agent is 0.005-0.1 g/mL, preferably 0.008-0.08 g/mL, and more preferably 0.01-0.05 g/mL.

The anti-inflammatory agent is selected from taurocholic acid, taurodeoxycholic acid, chenodeoxycholic acid and ursodeoxycholic acid, preferably selected from taurocholic acid and taurocholic acid, and more preferably selected from taurocholic acid. Taurocholic acid can reduce permeability of capillary vessel of inflammatory tissue, inhibit inflammatory swelling, and inhibit generation of inflammatory mediators such as nitric oxide, prostaglandin E2, histamine, etc.

The administration mode of the litholytic agent comprises the way of percutaneous transhepatic puncture sinus intubation or retrograde insertion of a nasal-biliary catheter through a duodenoscope, and the like, and the litholytic agent is injected to directly contact with gallstones.

In clinical treatment, the latex tube is required to be frequently used in a treatment appliance, the traditional litholytic agent has a certain swelling effect on the latex tube, so that harmful ingredients in the latex tube are easily dissolved and enter a human body along with the litholytic agent, and the toxic effect of the litholytic agent on the human body is increased.

The polyethylene glycol monobutyl ether litholytic agent has very small swelling effect on the latex tube, and serious swelling can bring great negative effect on gallstone dissolving operation, thereby further ensuring the reliability and safety of the litholytic agent.

The polyethylene glycol monobutyl ether litholytic agent can dissolve bile pigment type gallstones and mixed gallstones formed in the intrahepatic bile ducts, and is expected to solve the problem of high treatment difficulty of intrahepatic bile duct stones. The polyethylene glycol butyl ether is a polymer, and has low toxicity and small metabolic side effect. The addition of the surfactant, the protein dissolving agent, the complexing agent or the anti-inflammatory agent can promote the litholytic effect, protect human tissues and is expected to achieve good clinical use effect.

Examples

Example 1

Mixing polyethylene glycol monobutyl ether with water according to the volume ratio of 10mL:1mL, 8mL:4mL and 5mL:5mL, and magnetically stirring for 2min to obtain uniform and stable litholytic agent 1-1, litholytic agent 1-2 and litholytic agent 1-3.

Weighing three complete cholesterol gallstones (gallstone is from patient, woman, 44 years old) about 0.12g respectively, putting into the gallstone dissolving agent, crushing and dissolving the gallstones by using an ultrasonic cleaner (ultrasonic power 240W), and recording an experimental phenomenon every 10 min. When 10min, the gallstone in the litholytic agent 1-1 is completely dissolved, and after the cholesterol gallstone is completely dissolved, the color of the litholytic agent is changed from colorless transparency to deep yellow transparency; when 30min, the gallstone in the stone dissolving agent 1-2 is completely dissolved, and the color of the stone dissolving agent is changed from colorless and transparent to yellow and transparent; when the time is 90min, the gallstone in the litholytic agent 1-3 is completely dissolved, the color of the litholytic agent is changed from colorless transparency to light yellow non-transparent solution, and the dissolving effect is shown in figure 1. And (3) sucking out the stone dissolving agent by using an injector with a needle head diameter of 0.7 mm, wherein only a small amount of flocculent impurities exist at the bottom of the cup corresponding to 1-3 of the stone dissolving agent.

Weighing three complete mixed gallstones (gallstone is from patient, woman, 33 years old) about 0.15g respectively, putting into 1-1 and 1-2 litholytic agents respectively, crushing and dissolving the gallstones by using an ultrasonic cleaner (ultrasonic power 240W), and recording an experimental phenomenon every 10 min. The stone dissolving agent 1-1 and the stone dissolving agent 1-2 completely dissolve the mixed gallstone within 80min and 90min respectively, the color of the stone dissolving agent 1-1 is changed from colorless transparent solution to deep yellow transparent solution in the stone dissolving process, the color of the stone dissolving agent 1-2 is changed from colorless transparent solution to yellow green transparent solution and then to brown yellow transparent solution, and the stone dissolving effect is shown in figure 2. Respectively using syringes with 0.7 mm needle diameter to suck 1-1 and 1-2 of the litholytic agent out, wherein no residue is left at the bottom of the beaker.

Weighing about 0.1g of three complete bile pigment gallstones (gallstones are from patients, men and 67 years old) respectively, putting the gallstones into 1-1 parts of a litholytic agent and 1-2 parts of the litholytic agent respectively, crushing and dissolving the gallstones by using an ultrasonic cleaner (with the ultrasonic power of 240W), and recording the experimental phenomenon once every 10 min. The litholytic agent 1-1 can completely dissolve bile pigment type gallstones within 500min, the original litholytic process is adopted, the litholytic agent 1-1 is changed into brown from colorless transparent solution firstly and then gradually changed into black brown, the gallstones are gradually broken and dissolved from complete blocks, an injector with a needle diameter of 0.7 mm is used for sucking the litholytic agent, no residual substances exist at the bottom of the cup, and the litholytic agent effect is shown in figure 3. The gallstones in the litholytic agent 1-2 are not completely dissolved in 500min, the original colorless transparent solution of the litholytic agent 1-2 is changed into yellow-green, then into brown-yellow and finally into black-brown, which shows that the bile pigment gallstones are partially dissolved in the litholytic agent 1-2, as shown in figure 3, a syringe with a needle head of 0.7 mm in diameter is used for sucking out the litholytic agent 1-2, and the residual part of the bottom of the cup is the undissolved black bile pigment type gallstones.

The polyethylene glycol butyl ether can well dissolve cholesterol gallstones, mixed gallstones and cholechrome gallstones, and can completely dissolve the cholesterol gallstones and the mixed gallstones even if the concentration is reduced to a medium concentration.

Example 2

The stone dissolving agent has swelling effect on the latex tube used in the gall-stone dissolving operation. Different solvents cause different swelling degrees of the latex tube, and serious swelling appears to bring great negative effects to the gall-stone dissolving operation.

The effect of the following litholytic agents on the degree of swelling of latex tubes was studied:

1-1 of litholytic agent: 10mL of polyethylene glycol butyl ether and 1mL of water.

And (3) taking the latex tube, completely soaking the latex tube in the stone dissolving agent for 24 hours, and comparing the changes of the mass, the volume and the length of the latex tube before and after soaking. Deionized water was used as a negative control group, and conventional litholytic agents isoamyl acetate and methyl tertiary butyl ether were used as positive control groups.

Before soaking, the mass of the latex tube is weighed, and the length of the latex tube is measured by a steel plate ruler. And adding a fixed amount of deionized water into the measuring cylinder, immersing the latex tube into the measuring cylinder, and reading the difference to obtain the volume of the latex tube.

The latex tube was allowed to dry naturally for 1 hour at room temperature, then placed in the four litholytic agents described above, and the comparative latex tube was soaked in sufficient amounts of deionized water, isoamyl acetate, and methyl t-butyl ether for 24 hours. After completion of the soaking and after natural drying at room temperature for 1 hour, the mass, length and volume of the latex tube were measured in the same manner as described above, and the results are shown in Table 1.

TABLE 1 emulsion tube Change ratio before and after immersion

The data change before and after the latex tube is soaked shows that the existing stone dissolving agent isoamyl acetate and methyl tert-butyl ether can obviously cause the swelling of the latex tube, and the stone dissolving agent provided by the invention has smaller swelling effect on the latex tube. The latex tube soaked in the litholytic agent 1-1 is slightly reduced in length, but slightly increased in mass, indicating that the length change is caused by deformation. But the deformation swelling of the latex tube in the litholytic agent 1-1 is greatly reduced compared with the swelling change of the latex tube in isoamyl acetate and methyl tert-butyl ether.

The invention has been described in detail with reference to specific embodiments and/or illustrative examples and the accompanying drawings, which, however, should not be construed as limiting the invention. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.