CN113491682A - Gallstone dissolving agent - Google Patents
Gallstone dissolving agent Download PDFInfo
- Publication number
- CN113491682A CN113491682A CN202010252269.4A CN202010252269A CN113491682A CN 113491682 A CN113491682 A CN 113491682A CN 202010252269 A CN202010252269 A CN 202010252269A CN 113491682 A CN113491682 A CN 113491682A
- Authority
- CN
- China
- Prior art keywords
- agent
- litholytic
- gallstones
- dissolving
- diethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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Abstract
The invention provides a gallstone dissolving agent, which is prepared by mixing low-toxicity polyglycol ether with water, can be directly introduced into gallbladders and the like, and can be dissolved by contacting with gallstones. The litholytic agent provided by the invention can realize the dissolution of gallstone and reduce the side effect of a human body, so that the litholytic agent is expected to be used for the non-operative therapy treatment of clinical gallstone patients.
Description
Technical Field
The invention relates to a novel stone dissolving agent for dissolving gallstones, in particular to a low-toxicity polyethylene glycol ether stone dissolving agent.
Background
Gallstones, also known as cholelithiasis, are diseases in which stones occur in the biliary tract, including the gallbladder or bile ducts. After the calculus is formed in the gallbladder, the mucous membrane of the gallbladder can be stimulated, so that not only can chronic inflammation of the gallbladder be caused, but also secondary infection can be caused after the calculus is stuck at the neck part or the cystic duct of the gallbladder, acute inflammation of the gallbladder can be caused, and gallbladder cancer can be caused due to the chronic stimulation of the calculus to the mucous membrane of the gallbladder.
Among the methods for treating gallstones, conservative treatment is accepted by most people. Because the oral litholytic therapy has long course of treatment and high cost, patients have various toxic reactions in the treatment process, the recurrence rate is high, and the oral litholytic therapy is not ideal. The direct contact litholytic method has small damage, can relieve the pain of patients, has definite curative effect and simple and convenient operation, is particularly suitable for patients who cannot tolerate anesthesia, operation and refusal operation, but has certain difference in curative effect and side effect of different litholytic medicaments.
At present, people explore and research various litholytic agents. Methyl tert-butyl ether (MTBE) is the most commonly used litholytic agent for dissolving cholesterol stones at present, and is excellent in litholytic effect and operation, but methyl tert-butyl ether has numerous side effects in clinical application, MTBE can cause fatal hemolysis after entering blood, local stimulation is large, erosion and bleeding on the surface of gallbladder mucosa can be seen after 1 hour of gallbladder perfusion, and the gallbladder mucosa is necrotized and stripped, so that the clinical application prospect is not optimistic. Ethyl propionate as litholytic agent can be decomposed into ethanol and propionyl coenzyme A, litholysis is rapid in vitro, and side effects of the litholytic agent are transient hypotension, pain of perfusion parts, and great damage to liver when being administered in large dose. Caprylic acid monoglyceride can only dissolve cholesterol type gallstone, and adverse reaction is mainly manifested by local stimulation, and can cause acute inflammation and mucosal ulceration of gallbladder, bile duct base gastrointestinal mucosa of different degrees. In 343 clinical reports, the prepared medicinal preparation is completely dissolved at 26 percent, partially dissolved at 29 percent and ineffective at 36 percent, 9 percent of cases stop treatment due to adverse reactions, and 67 percent of cases have adverse reactions with different degrees, wherein 12 cases have various fatal adverse reactions such as acute cholangitis, acute pancreatitis, septicemia and the like.
Based on the above problems, there is a need for developing a new gallstone-dissolving agent capable of dissolving gallstones rapidly and reducing side effects to alleviate the pain of patients during treatment and recovery in clinical practice.
Disclosure of Invention
The present inventors have conducted intensive studies in order to solve the above problems and found that a low-toxicity polyethylene glycol ether or polyethylene glycol ether ester as a gallstone-dissolving agent achieves a very good stone-dissolving effect with little side effects, thereby completing the present invention.
The invention aims to provide a gallstone dissolving agent, which comprises one or more of low-toxicity polyethylene glycol ether or polyethylene glycol ether ester.
The litholytic agent further comprises a surfactant, a proteolytic agent, or an anti-inflammatory agent.
The litholytic agent is used for dissolving cholesterol-type gallstones, bile pigment-type gallstones or mixed gallstones.
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 duct catheterization or retrograde gallbladder intubation under an endoscope and the like, and the litholytic agent is infused into the gallbladder to be directly contacted with gallstones.
The stone dissolving agent has the following beneficial effects:
(1) the litholytic agent can be prepared according to the type and the position of gallstones in clinic, so that the toxicity of the litholytic agent is reduced, and the side effect on a human body is reduced.
(2) The litholytic agent can be used by being matched with water, the toxicity is further reduced, and positions of gall bladder and the like can be cleaned by water or aqueous solution after litholysis is finished, so that the residue of the litholytic agent in a body is reduced, and the litholytic agent can be used for preparing litholytic agents.
(3) The litholytic agent can be added with a surfactant, a protein lytic agent or an anti-inflammatory agent, so that the litholytic effect of the litholytic agent can be ensured, the toxic and side effects are reduced, and the burden of a human body is further reduced.
Drawings
FIG. 1 shows a schematic representation of the litholytic agent administration mode of the present invention;
FIG. 2 is a graph showing the effect of the litholytic agent 1-3 of the present invention in dissolving gallstones;
FIG. 3 is a graph showing the effect of the litholytic agent 2-1 of the present invention in dissolving gallstones;
FIG. 4 is a graph showing the effect of the litholytic agent 3-1 of the present invention in dissolving gallstones.
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 stone dissolving agent comprises one or more of low-toxicity polyethylene glycol ether or polyethylene glycol ether ester.
The low-toxicity polyethylene glycol ether or polyethylene glycol ether ester is selected from one or more of diethylene glycol diethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether or diethylene glycol monoethyl ether acetate, preferably from one or more of diethylene glycol diethyl ether, diethylene glycol monoethyl ether or diethylene glycol monoethyl ether acetate, and more preferably from one or two of diethylene glycol diethyl ether or diethylene glycol monoethyl ether acetate.
In the invention, a large number of experiments show that the polyethylene glycol ether or the polyethylene glycol ether ester can quickly dissolve gallstones and can be prepared with water for use, and the dissolution speed is reduced with the reduction of the content of the polyethylene glycol ether in the stone dissolving agent, but the in vitro stone dissolving can still be completed in a short time.
In the invention, the mass concentration of cholesterol in the cholesterol gallstone is more than 70 percent; the mass concentration of cholesterol in the cholelithiasis is less than 30 percent, and the mass concentration of cholesterol in the mixed cholelithiasis is 30 to 70 percent.
In the invention, by taking diethylene glycol diethyl ether as an example of a single-dosage litholytic agent, when the addition amount of the diethylene glycol diethyl ether is changed from 1mL to 10mL relative to 1mL of water, the time for dissolving a certain amount of cholesterol-type gallstones is gradually shortened, and when the volume ratio of the diethylene glycol diethyl ether to the water is 1:1, the cholesterol-type gallstones can be quickly dissolved, only powdery fine particles are remained, and the powdery fine particles can be discharged together with the litholytic agent in clinical use, and the remained fine particles disappear immediately after the concentration of the litholytic agent is increased. In an in vitro cholesterol gallstone dissolving experiment, when the volume concentration of the diethylene glycol diethyl ether litholytic agent is more than or equal to 50%, the litholytic rate can reach 100% within 10-100 min.
When the diethylene glycol diethyl ether litholytic agent is used for dissolving cholesterol gallstone, the volume ratio of the diethylene glycol diethyl ether to water is (1-20): 1, preferably (1-15): 1, and more preferably (1-10): 1.
The concentration of the diethylene glycol diethyl ether single-dosage litholytic agent required for dissolving mixed type and cholechrome type gallstones is larger than that of cholesterol type gallstones. When the addition amount of the diethylene glycol diethyl ether is changed from 2mL to 10mL relative to 1mL of water, when a certain amount of mixed gallstone is dissolved, the gallstone can be completely dissolved within 30min, and the stone dissolving rate is 100%; when a certain amount of bile pigment type gallstone is dissolved, the stone dissolving rate is rapidly reduced, and the stone dissolving rate can reach 20-25% in 100 min. The diethylene glycol diethyl ether single-dosage type litholytic agent with the volume ratio of the diethylene glycol diethyl ether to the water of 2:1 shows better litholytic effect than the high-concentration diethylene glycol diethyl ether single-dosage type litholytic agent in the process of continuously dissolving the calculus. When the volume ratio of the diethylene glycol diethyl ether to the water is 2:1, the litholytic agent can completely dissolve bile pigment type gallstones within 400 min.
When the diethylene glycol diethyl ether litholytic agent is used for dissolving bile pigment type and mixed type gallstones, the volume ratio of the diethylene glycol diethyl ether to water is (2-30): 1, preferably (2-25): 1, and more preferably (2-20): 1.
Increasing the concentration of diethylene glycol diethyl ether shortens the litholytic time, but increases the irritation and damage to the human body (LD50 rat orally 4970mg/kg, LD50 rabbit skin 6700 μ L/kg, data source: NIOSH, national institute of occupational safety and health, USA), and decreasing the concentration increases the litholytic time, so that the concentration of diethylene glycol diethyl ether is adjusted to meet the requirement of use.
In the invention, triethylene glycol monoethyl ether is taken as an example of a single-dosage type litholytic agent, and the triethylene glycol monoethyl ether is matched with water for use, in an in vitro litholytic experiment, the cholesterol-type and mixed-type gallstones can be ultrasonically dissolved by the triethylene glycol monoethyl ether litholytic agent with the volume fraction of more than 85% within 100min, no residue is left, the litholytic rate reaches 100%, and when the triethylene glycol monoethyl ether is reduced to a medium concentration, the litholytic rate is rapidly reduced, so that the cholesterol-type gallstones are difficult to dissolve.
When dissolving bile pigment type gallstone, the dissolving rate of the triethylene glycol monoethyl ether stone dissolving agent with the volume fraction of more than 85% is relatively slow, and when the dissolving time is 100min, the dissolving rate can reach 17%.
When the triethylene glycol monoethyl ether litholytic agent is used for dissolving gallstones, the volume ratio of triethylene glycol monoethyl ether to water is (4-20): 1, preferably (4-15): 1, and more preferably (4-10): 1. Triethylene glycol monoethyl ether has low toxicity (LD50 rat takes 10.6g/kg orally, LD50 rabbit skin 8.2g/kg, data source: Pattern's Toxicology V (fifth edition) (1-9):221), and can be used together with other solvents to reduce toxicity and improve litholytic effect.
In the invention, when dissolving the stones by using diethylene glycol monoethyl ether acetate as a single-dosage type stone dissolving agent, the high-concentration diethylene glycol monoethyl ether acetate stone dissolving agent has good stone dissolving effect on cholesterol-type and mixed-type gallstones, can dissolve the cholesterol-type gallstones ultrasonically within 20min and dissolve the mixed gallstones ultrasonically within 40min, has no residue, and has the stone dissolving rate reaching 100%. When the high-concentration diethylene glycol monoethyl ether acetate litholytic agent is used for dissolving bile pigment type gallstones, the litholytic rate can reach 21.3% in 100 min.
In the diethylene glycol monoethyl ether acetate litholytic agent, the volume ratio of diethylene glycol monoethyl ether acetate to water is (8-30): 1, preferably (8-25): 1, and more preferably (8-20): 1.
Diethylene glycol monoethyl ether acetate belongs to a slightly toxic substance (LD50 rat takes 11g/kg orally, LD50 rabbit skin 15.1mg/kg, data source: Union carbide company data), and can reduce human body damage, gall bladder and bile duct stimulation and the like when used for dissolving stone in vivo.
In the invention, the single-dosage polyethylene glycol ether and polyethylene glycol ether ester litholytic agent has good litholytic effect on cholesterol-type and mixed-type gallstones, can completely dissolve stones in a short time, has longer litholytic time than cholesterol-type and mixed-type gallstones when dissolving bile pigment-type gallstones, can be pertinently adjusted when being clinically used, is used for dissolving stones into dischargeable smooth massive stones, and is beneficial to discharge of the bile pigment-type gallstones.
The traditional litholytic agent Methyl Tertiary Butyl Ether (MTBE) is high in toxicity (LD50 rats take 4g/kg orally, data source: NIOSH of national institute of occupational safety and health), the boiling point is 55 ℃, but the volatility of the methyl tertiary butyl ether is relatively strong, the methyl tertiary butyl ether still volatilizes to generate high pressure when the litholytic agent is applied to a human body, and meanwhile, the methyl tertiary butyl ether can generate an irritating smell which is very uncomfortable to people. The methyl tertiary butyl ether can completely dissolve gallstones with the cholesterol content of 40-94% in 60-100 minutes in vitro. In vivo animal experiments show that the methyl tert-butyl ether can be completely dissolved and implanted into the gall bladder of the dog within 4-16 hours, and the diameter of the methyl tert-butyl ether is l.8cm-1Human cholesterol gallstones with cholesterol content of 90-94%. (Chinese Community physicians, 2004,101, (6): 2-4). However, methyl tert-butyl ether hardly dissolves bile pigment gallstones having a cholesterol content of 30% or less. In relevant animal experiments and human metabolic observation, MTBE shows similar integral metabolism in rats and human bodies, MTBE is oxidized and demethylated to generate formaldehyde and Tertiary Butanol (TBA) under the action of enzyme, and formaldehyde is rapidly metabolized to form 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 the biotransformation of MTBE into formaldehyde and TBA in human bodies are only abundantly present in the liver, and the metabolism of MTBE in human bodies is presumed to mainly occur in the liver, and the metabolic products have great damage to the liver and kidney.
In the invention, the litholytic agent is monoethyl ether or diethyl ether with a diethylene glycol chain or a triethylene glycol chain. The metabolic point of the diol chain is mainly-OH, alcohol dehydrogenase oxidizes alcohol groups into carboxylic acid, the damage is small, the alcohol dehydrogenase can be methylated, the metabolic point is occupied, and the metabolite toxicity of the ether group in a human body is low. The stone dissolving agent is dissolved in water or is matched with water for use, so that most of the stone dissolving agent is conveniently extracted from the body and washed after stone dissolving, and the residual quantity is very small, therefore, the stone dissolving agent is expected to greatly reduce the harm of the stone dissolving agent to the human body.
In a preferred mode of the invention, the litholytic agent further comprises a surfactant, a proteolytic 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.
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 against 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 ] propanesulfonate inner salt (CHAPS), Dithiothreitol (DTT), preferably guanidine hydrochloride, urea 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 used as a protein dissolving agent, is an amphoteric surfactant, has a cholic acid and a thiobetaine in a molecular structure, can protect the natural state of protein, and dissolves membrane protein, thereby releasing the interaction between the protein and the 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.
Guanidine hydrochloride and urea have solubilization to hydrophobic amino acid residue, because guanidine hydrochloride and urea have the ability to form hydrogen bonds, guanidine hydrochloride and urea can break the hydrogen bonds when in high concentration (4-8 mol/L) aqueous solution, make guanidine hydrochloride and urea can dissolve nonpolar residue well, make the hydrophobic residue extension and the solubility increase in the protein molecule, thus make the protein denaturize to different extent.
At room temperature, 3-4 mol/L of guanidine hydrochloride can enable globular protein to be converted from a natural state to the midpoint of a denatured state, the denaturation degree can be improved by increasing the concentration of a denaturing agent, and the protein can be completely converted into the denatured state by the guanidine hydrochloride with the concentration of 6 mol/L. Guanidine hydrochloride, because of its ionic nature, generally exists in a fully denatured state in a random coil conformation in an 8mol/L solution of guanidine hydrochloride.
The urea has weaker dissolving capacity than guanidine hydrochloride, the dissolving speed is slow, the solubility of protein in the urea is 70% -90%, the urea can be cracked to form cyanate when the acting time is longer or the temperature is higher, the amino group of the recombinant protein is subjected to covalent modification, and the urea has the advantages of no ionization, neutrality, low cost and the like.
Guanidine hydrochloride has stronger dissolving capacity and denaturation capacity than 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 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 biliary tract catheterization (PTCD) or endoscopic retrograde gallbladder intubation (ERCG) and the like, and the litholytic agent is infused into the gallbladder to be directly contacted with gallstones, as shown in figure 1.
The litholytic agent has small total usage amount, can dissolve cholesterol type, cholesterin type and mixed type gallstones by adding water for dilution, and can reduce the usage amount of ether solvents and reduce the generation of side effects of human bodies. The addition of the surfactant, the protein dissolving agent or the anti-inflammatory agent can promote the litholytic effect, reduce tissue damage and further reduce the usage amount of ether solvents, thereby being expected to achieve good clinical use effect.
Examples
Example 1
Mixing diethylene glycol diethyl ether and 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, female, and 44 years old) about 0.12g respectively, placing into the litholytic agent, crushing and dissolving the gallstones with an ultrasonic cleaner (ultrasonic power 240W), and recording the experimental phenomenon every 10 min. When 10min, gallstone in the litholytic agent 1-1 is completely dissolved; when 30min, gallstone in the litholytic agent 1-2 is completely dissolved; the gallstone in the litholytic agent 1-3 is completely dissolved in 100 min. And (3) sucking out the residual liquid by using a syringe with a needle head diameter of 0.7 mm, wherein no residue exists in beakers corresponding to the litholytic agents 1-1 and 1-2, and only a small amount of powdery substances exist in beakers corresponding to the litholytic agents 1-3.
Weighing three complete mixed gallstones (gallstones are from patients and women, 33 years old) of about 0.15g respectively, putting the gallstones into 1-1 parts of a litholytic agent, 1-2 parts of the litholytic agent and 1-3 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. 1-1 part of the litholytic agent, 1-2 parts of the litholytic agent and 1-3 parts of the litholytic agent are respectively used for completely dissolving the mixed gallstones within 10min, 30min and 110 min. 1-1 part of the litholytic agent, 1-2 parts of the litholytic agent and 1-3 parts of the litholytic agent in the beaker can be sucked out by using an injector with the needle head diameter of 0.7 mm, and the bottom of the beaker has no impurities.
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, 1-2 parts of the litholytic agent and 1-3 parts of the litholytic agent, crushing and dissolving the gallstones by using an ultrasonic cleaner (with the ultrasonic power of 240W), and recording the experimental phenomenon every 10 min. 1-1 part of litholytic agent, 1-2 parts of litholytic agent and 1-3 parts of litholytic agent can completely dissolve bile pigment type gallstone within 510min, 400min and 620min respectively. And (3) sucking 1-1 parts of the stone dissolving agent and 1-2 parts of the stone dissolving agent in the beaker by using an injector with a needle head diameter of 0.7 mm, wherein the bottom of the beaker is free from impurities. After the litholytic agent 1-3 is sucked out by a syringe with the needle diameter of 0.7 mm, a small amount of powdery substance is remained at the bottom of the cup. During the actual treatment process, the powdery substances can be discharged out of the body along with the litholytic agent and the cleaning agent.
The litholytic agent 1-3 has litholytic effect in dissolving cholesterol type gallstone, mixed gallstone and cholechrome type gallstone as shown in figure 2. The litholytic agent 1-3 is colorless transparent liquid, after the light yellow cholesterol type gallstone is added, the litholytic agent gradually becomes light yellow along with the progress of litholysis, the color of the solvent changes into yellow along with the increase of time, and the cholesterol type gallstone is firstly reduced and then gradually dissolved and disappears in the litholysis process. After the brown mixed gallstone is dissolved, the stone dissolving agent turns yellow and then gradually turns into a reddish brown liquid, and the mixed gallstone is dissolved and disappears. 1-3, the litholytic agent is changed into reddish brown firstly and then into black brown when dissolving the bile pigment type gallstone, the bile pigment type gallstone is partially dissolved and dispersed into small particles firstly and then is gradually dissolved, and the small particles are remained at the bottom of the cup and can be discharged out of the body along with the litholytic agent and the cleaning agent in clinical use.
It is demonstrated that diethylene glycol diethyl ether can dissolve cholesterol-type and mixed-type gallstones well, and can completely dissolve cholesterol-type gallstones even if the concentration is reduced to a medium concentration.
Example 2
Mixing triethylene glycol monoethyl 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 2-1, litholytic agent 2-2 and litholytic agent 2-3.
Three complete cholesterol gallstones (gallstones from patients, women, age 44) of about 0.12g are weighed and respectively put into the litholytic agent, an ultrasonic cleaner (ultrasonic power 240W) is used for breaking and dissolving the gallstones, and the experimental phenomenon is recorded every 10 min. When the time is 90min, the gallstones in the stone dissolving agent 2-1 are completely dissolved, and the gallstones in the stone dissolving agent 2-2 and the stone dissolving agent 2-3 are not changed greatly. The liquid dissolved by the litholytic agent 2-1 is sucked out by using a syringe with the needle diameter of 0.7 mm, and no residue is left at the bottom of the cup.
Weighing about three 0.15g of complete mixed gallstones (gallstones are from patients and women, 33 years old) respectively, putting the gallstones into a litholytic agent 2-1, crushing and dissolving the gallstones by using an ultrasonic cleaner (with ultrasonic power of 240W), and recording the experimental phenomenon every 10 min. The litholytic agent 2-1 can completely dissolve mixed gallstone within 90 min. Using an injector with a needle head diameter of 0.7 mm to suck out the litholytic agent 2-1 in the beaker, wherein the bottom of the beaker is free from impurities.
Weighing about 0.1g of three complete bile pigment gallstones (gallstones are from patients, male, and 67 years old) respectively, putting into 2-1 parts of a litholytic agent, crushing and dissolving the gallstones by using an ultrasonic cleaner (ultrasonic power 240W), and recording the experimental phenomenon every 10 min. Can completely dissolve bile pigment type gallstone within 510 min. Using an injector with a needle head diameter of 0.7 mm to suck out the litholytic agent 2-1 in the beaker, wherein the bottom of the beaker is free from impurities.
The litholytic agent 2-1 has litholytic effect in dissolving cholesterol type gallstone, mixed gallstone and cholechrome type gallstone as shown in figure 3.
The litholytic agent 2-1 is a colorless transparent liquid. After the light yellow cholesterol gallstone is added, the litholytic agent gradually becomes light yellow along with the progress of litholysis, the color of the solvent is deepened to be yellow along with the increase of time, and the cholesterol gallstone is firstly reduced and then gradually dissolved and disappeared in the litholysis process.
When the brown mixed gallstone is dissolved, the stone dissolving agent is firstly changed into yellow, and then gradually changed into a reddish brown liquid, so that the mixed gallstone is dissolved and disappears.
The litholytic agent 2-1 is in the cholecystochromic gallstone, the litholytic agent is changed into yellow brown firstly and then into black brown, the cholecystochromic gallstone is partially dissolved and dispersed into small particles firstly and then is gradually dissolved, and the small particles are remained at the bottom of the cup, and can be discharged out of the body along with the litholytic agent and a cleaning agent in clinical use.
The results show that triethylene glycol monoethyl ether has good litholytic effect at high concentration, and triethylene glycol monoethyl ether has low toxicity, and can be used in combination with other solvents, so that the toxicity of the litholytic agent is reduced, and the litholytic effect is improved.
Example 3
Mixing diethylene glycol monoethyl ether acetate and 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 3-1, litholytic agent 3-2 and litholytic agent 3-3.
Three complete cholesterol gallstones (gallstones from patients, women, age 44) of about 0.12g are weighed and respectively put into the litholytic agent, an ultrasonic cleaner (ultrasonic power 240W) is used for breaking and dissolving the gallstones, and the experimental phenomenon is recorded every 10 min. When 10min, gallstone in the stone dissolving agent 3-1 is completely dissolved; at 100min, 3-2 parts of the litholytic agent and 3-3 parts of the litholytic agent are not completely dissolved, and the litholytic rate is 83% and 67% respectively calculated by the mass reduction of gallstones. Using an injector with a needle head diameter of 0.7 mm to suck out the 3-1 of the litholytic agent in the beaker, wherein the bottom of the beaker is free from impurities.
Weighing about three 0.15g of complete mixed gallstones (gallstones are from patients and women, 33 years old) respectively, putting the gallstones into a litholytic agent 3-1, crushing and dissolving the gallstones by using an ultrasonic cleaner (with ultrasonic power of 240W), and recording the experimental phenomenon every 10 min. The litholytic agent 3-1 can completely dissolve mixed gallstone within 40 min. Using an injector with a needle head diameter of 0.7 mm to suck out the 3-1 of the litholytic agent in the beaker, wherein the bottom of the beaker is free from impurities.
Weighing about 0.1g of three complete bile pigment gallstones (gallstones are from patients, male, and 67 years old) respectively, putting into a litholytic agent 3-1, crushing and dissolving the gallstones by using an ultrasonic cleaner (ultrasonic power 240W), and recording the experimental phenomenon every 10 min. Can completely dissolve bile pigment type gallstone within 470 min. Using an injector with a needle head diameter of 0.7 mm to suck out the 3-1 of the litholytic agent in the beaker, wherein the bottom of the beaker is free from impurities.
The litholytic agent 3-1 has litholytic effect in dissolving cholesterol type gallstone, mixed gallstone and cholechrome type gallstone as shown in figure 4.
The litholytic agent 3-1 is a colorless transparent liquid. After the light yellow cholesterol gallstone is added, the litholytic agent gradually becomes light yellow along with the progress of litholysis, the color of the solvent becomes yellow along with the increase of time, and the cholesterol gallstone is firstly reduced and then gradually dissolved and disappears in the litholysis process.
When the brown mixed gallstone is dissolved, the stone dissolving agent is firstly changed into yellow, and then gradually changed into a tawny liquid, so that the mixed gallstone is dissolved and disappears.
The litholytic agent 3-1 is used for treating cholelithiasis, wherein the litholytic agent is changed into yellow brown firstly and then into black brown, and the cholelithiasis is partially dissolved and dispersed into small granules firstly and then gradually dissolved and disappeared.
The diethylene glycol monoethyl ether acetate has good litholytic effect under high concentration, and the diethylene glycol monoethyl ether acetate has low toxicity, can be used by matching with other solvents, reduces the toxicity of the litholytic agent, and improves the litholytic effect.
Example 4
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 can bring great negative effects to the gallstone dissolving operation.
The effect of the following four litholytic agents on the degree of swelling of the latex tube was studied:
1-1 of litholytic agent: 1mL of diethylene glycol diethyl ether and 10mL of water;
1-2 parts of litholytic agent: 4mL of diethylene glycol diethyl ether and 8mL of water;
2-1 of litholytic agent: 1mL of triethylene glycol monoethyl ether and 10mL of water;
3-1 of litholytic agent: diethylene glycol monoethyl ether acetate (10 mL:1 mL).
And taking four sections of long latex tubes, completely soaking the four sections of long latex tubes in the four stone dissolving agents for 24 hours, and comparing the changes of the mass, the volume and the length of the latex tubes 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
It can be seen from the data change before and after latex tube soaking that the existing stone-dissolving agent isoamyl acetate and methyl tert-butyl ether can obviously cause the swelling of the latex tube, and the swelling of the latex tube by the stone-dissolving agent provided by the invention is obviously reduced.
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.
Claims (10)
1. A stone dissolving agent, characterized in that the stone dissolving agent comprises one or more of low toxicity polyethylene glycol ether or polyethylene glycol ether ester.
2. A stone dissolving agent as claimed in claim 1, characterized in that the low toxicity polyethylene glycol ether or polyethylene glycol ether ester is selected from one or more of diethylene glycol diethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, diethylene glycol monoethyl ether acetate.
3. A stone dissolving agent as claimed in claim 1 or 2, characterized in that the low toxicity polyethylene glycol ether or polyethylene glycol ether ester is selected from one or more of diethylene glycol diethyl ether, diethylene glycol monoethyl ether or diethylene glycol monoethyl ether acetate.
4. A litholytic agent according to any one of claims 1 to 3, further comprising water.
5. A litholytic agent according to any one of claims 1 to 4, further comprising a surfactant, a proteolytic agent, or an anti-inflammatory agent.
6. The litholytic agent of claim 5, wherein said litholytic agent is used to dissolve cholesterol-type gallstones, bile pigment-type gallstones, and/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. Use according to claim 7,
the volume ratio of the diethylene glycol diethyl ether to water is (1-20) to 1 for cholesterol gallstones,
the volume ratio of the diethylene glycol diethyl ether to water is (2-30): 1 for mixed gallstones and bile pigment gallstones.
9. The use according to claim 7, wherein the volume ratio of triethylene glycol monoethyl ether to water is (4-20): 1.
10. The use according to claim 7, wherein the volume ratio of diethylene glycol monoethyl ether acetate to water is (8-30): 1.
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| CN202010252269.4A CN113491682A (en) | 2020-04-01 | 2020-04-01 | Gallstone dissolving agent |
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| CN202010252269.4A CN113491682A (en) | 2020-04-01 | 2020-04-01 | Gallstone dissolving agent |
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Citations (5)
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|---|---|---|---|---|
| WO1993012774A1 (en) * | 1991-12-20 | 1993-07-08 | Baxter International Inc. | Microemulsions for gallstone dissolution |
| CN101062406A (en) * | 2007-05-17 | 2007-10-31 | 青岛大学 | Reeombinnt human granulocyte colony stimulating factor microemulsion |
| WO2013077383A1 (en) * | 2011-11-25 | 2013-05-30 | 東ソー株式会社 | Washing agent composition and washing method using same |
| CN105672005A (en) * | 2016-04-01 | 2016-06-15 | 吴江市林旺纺织厂 | Environment-friendly acidic fabric color fixing agent and preparation method thereof |
| CN106366899A (en) * | 2016-08-27 | 2017-02-01 | 安徽省金盾涂料有限责任公司 | High-wear-resistant antibacterial acrylate paint |
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2020
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993012774A1 (en) * | 1991-12-20 | 1993-07-08 | Baxter International Inc. | Microemulsions for gallstone dissolution |
| CN101062406A (en) * | 2007-05-17 | 2007-10-31 | 青岛大学 | Reeombinnt human granulocyte colony stimulating factor microemulsion |
| WO2013077383A1 (en) * | 2011-11-25 | 2013-05-30 | 東ソー株式会社 | Washing agent composition and washing method using same |
| CN105672005A (en) * | 2016-04-01 | 2016-06-15 | 吴江市林旺纺织厂 | Environment-friendly acidic fabric color fixing agent and preparation method thereof |
| CN106366899A (en) * | 2016-08-27 | 2017-02-01 | 安徽省金盾涂料有限责任公司 | High-wear-resistant antibacterial acrylate paint |
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