CN114272446A - Degradable drug-loaded bile pancreatic duct stent and preparation method thereof - Google Patents
Degradable drug-loaded bile pancreatic duct stent and preparation method thereof Download PDFInfo
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Images
Abstract
The invention provides a degradable drug-loaded bile pancreatic duct stent and a preparation method thereof, and the preparation method comprises the steps of dissolving an anionic polymer in water, adding an organic reducing agent and an antiproliferative drug, and uniformly dispersing to obtain an anionic polymer solution; dissolving a cationic polymer in an organic acid solution to obtain a cationic polymer organic acid solution; polishing the degradable metal stent by using organic acid chemical polishing solution to remove surface impurities; soaking the polished degradable metal stent in a polyethyleneimine aqueous solution to obtain an amino-modified degradable metal stent; and (3) alternately dipping the degradable metal stent modified by the amino in an anionic polymer solution and a cationic polymer solution for multiple times to obtain the degradable drug-loaded bile-pancreatic duct stent. The stent coating prepared by the invention has compact structure and strong binding force between the stent and the coating, the stent is not easy to fall off in vivo for a long time, and is completely degraded within 2 to 3 years after being implanted in vivo, so that the stent can be applied to the medical field of clinic and the like.
Description
Technical Field
The invention relates to the medical field of treatment of pancreaticobiliary stricture clinical diseases, in particular to a degradable drug-loaded bile duct pancreatic duct stent and a preparation method thereof.
Background
Pancreaticobiliary stricture is a common clinical disease, patients suffer from great pain after the disease is developed, complications are many, and the recurrence rate of the disease of the patients is high. Pancreaticobiliary stenosis and obstruction are important causes of gallstone and acute pancreatitis, hemodynamics disorder, pyemia and systemic multiple organ insufficiency are induced in a short time after acute pancreatitis is caused, and the death rate of patients is up to 30%. The treatment mode of pancreatitis mainly comprises operation treatment and interventional endoscope treatment. Although the surgical treatment is the fundamental treatment mode for treating the disease, the surgical treatment has long period, large wound, great pain for patients and slow recovery, because the surgical treatment needs the resection of high-position bile duct cancer or the resection of pancreas and duodenum. The used bile duct and pancreatic duct supports are mainly two types, namely a plastic support with fixed diameter and a self-expansion metal support, the interventional endoscope treatment has better treatment effect on chronic pancreaticobiliary stenosis, especially, the average drainage unobstructed time of the metal support is 7 months, and the average drainage unobstructed time of the plastic support is 5 months.
The plastic support is relatively cheap, and can be taken out of the body after being blocked or no longer needed, but the plastic support is easy to collapse, so that the pipeline is narrowed again; the main materials of the metal stent are non-absorbable metal materials such as stainless steel, nickel-titanium alloy, platinum-iridium alloy, cobalt-chromium alloy, tantalum, titanium and the like, the metal stent can not be removed after being placed in the body, certain toxic and side effects are generated on the whole body and local parts for a long time according to clinical records, namely the metal stent can not be degraded in the existing pancreaticobiliary stricture endoscopic interventional therapy, the hyperplasia of the inner wall of the bile duct can be caused for a long time and other problems exist
Therefore, it is necessary to provide a degradable bile-pancreatic duct stent with good mechanical properties and a preparation method thereof.
Disclosure of Invention
The invention provides a degradable biliary-pancreatic duct stent and a preparation method thereof, and aims to solve the problems that a metal stent is not degradable in the existing cholangiopancreatography narrow interventional therapy, the inner wall of a bile duct is proliferated for a long time, and the application of the stent in the medical fields of biliary-pancreatic duct narrow clinical disease treatment and the like is limited.
In order to achieve the above object, the present invention provides a method for preparing a degradable bile-pancreatic duct stent, comprising the steps of:
dissolving an anionic polymer in water, adding an organic reducing agent and an antiproliferative drug, and uniformly dispersing to obtain an anionic polymer solution;
dissolving a cationic polymer in an organic acid solution to obtain a cationic polymer organic acid solution;
polishing the degradable metal stent by using organic acid chemical polishing solution to remove surface impurities;
soaking the polished degradable metal stent in a polyethyleneimine aqueous solution to obtain an amino-modified degradable metal stent;
and alternately dipping the degradable metal stent modified by the amino group in the anionic polymer solution and the cationic polymer solution for multiple times to obtain the degradable drug-loaded bile-pancreatic duct stent.
Further, the chemical polishing solution comprises 4-15% of glycolic acid, 1-10% of citric acid, 1-5% of thiourea, 3-5% of triethanolamine, 2-5% of sodium dodecyl benzene sulfonate, 1-6% of fatty alcohol-polyoxyethylene ether, 3-5% of glycerol, 4-12% of silica sol, 15-250 nm of silica sol and the balance of water.
Further, the anionic polymer is one or more of sodium alginate, hyaluronic acid, transparent lipopolysaccharide, heparin, silk fibroin and polypeptide chain, and the cationic polymer is chitosan.
Furthermore, the concentration of the anionic polymer solution is 1-3 wt%, the concentration of the cationic polymer solution is 1-3 wt%, the concentration of the antiproliferative drug is 0.002-0.006 g/ml, the concentration of the organic reducing agent is 0.016-0.03 g/ml, and the concentration of the polyethyleneimine aqueous solution is 0.5 wt%.
Furthermore, the degradable metal stent is prepared by smelting, pouring, heat treatment, forging, drilling and drawing the degradable metal capillary tube and then is prepared by laser engraving.
Further, the organic reducing agent is one or two of dithiothreitol or tris (2-carbonylethyl) phosphate.
Furthermore, the antiproliferative drug is one or two of mitomycin or paclitaxel.
Furthermore, the time of each impregnation in the impregnation process is 5-10min, the times of alternate impregnation are 8-12, the molecular self-assembly efficiency is related to the concentration of the strong electrolyte, and the assembly efficiency can be controlled by adding a NaCl aqueous solution with the concentration of 1 m.
The invention also provides a degradable gallbladder-pancreatic duct stent which comprises a degradable metal stent main body and a medicine-carrying slow-release coating, wherein the medicine-carrying slow-release coating comprises an organic reducing agent and an anti-proliferative drug.
Further, the length of the stent is 3-5cm, the inner diameter of the stent is 3-6mm, and the degradable metal is zinc alloy or magnesium alloy.
The scheme of the invention has the following beneficial effects:
1. the drug-loaded slow-release coating prepared by the LBL molecular deposition method has a compact structure and strong binding force, the degradable biliary pancreatic duct stent is not easy to fall off in vivo for a long time, has better mechanical support performance for treating chronic pancreatitis, pancreaticobiliary duct stenosis, can keep pancreatic juice and biliary juice drainage on a narrow part for a long time, is completely degraded within 2-3 years after being implanted in a body, and does not influence subsequent operation or endoscope interventional therapy.
2. The degradable bile-pancreatic duct stent is implanted into a patient body by adopting an endoscopic interventional operation, so that the pain of the patient is less, the recovery is fast, the probability of the occurrence of the pancreatic-biliary duct infarction of the degradable bile-pancreatic duct stent is reduced compared with a titanium alloy stent and a cobalt-chromium alloy stent without coatings, and the biocompatibility is improved.
3. The degradable bile-pancreatic duct stent has a compact drug-loaded slow-release coating, anti-proliferation drugs are slowly released, the later-stage proliferation of the pancreatic-biliary duct can be avoided, the organic reducing agent can reduce disulfide bonds in proteins to avoid the proteins from adhering to the stent, and the aggregation and infarction of albumin and pancreatic stone protein at the initial end and the tail end of the stent in the later stage are greatly reduced.
Drawings
In order to more clearly illustrate the technical solution of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings described below are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without inventive labor.
Fig. 1 is a picture of a degradable metal stent provided in an embodiment of the present invention;
fig. 2 is a schematic diagram of the formation of a drug-loaded slow-release coating of the degradable biliary pancreatic duct stent provided by the embodiment of the invention.
Reference numerals: 1 zinc alloy stent surface; 2 amino adhered on the surface of the bracket; 3 a alginic acid group; 4 mitomycin; 5. tris (2-carbonylethyl) phosphonium hydrochloride; 6. a chitosan macromolecule.
Detailed Description
In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to the accompanying drawings and the detailed description.
In the embodiment of the invention, the adopted degradable metal stent is a degradable zinc alloy stent specially manufactured by Hunan Hua Yan Baiao medical science and technology Limited company, the degradable zinc alloy capillary tube is prepared by smelting, pouring, heat treating, forging, drilling and drawing, and the degradable zinc alloy stent with the length of 3-5cm and the inner diameter of 3-6mm is carved by laser, as shown in figure 1.
As shown in figure 2, the degradable zinc alloy stent can react with sodium alginate after being modified by amino, both tris (2-carbonyl ethyl) phosphate and mitomycin are anions which are crosslinked into a film with anions on the surface layer of the stent, chitosan is polycation, a chitosan film is formed on the outer layer, wherein chitosan and sodium alginate are crosslinked into gel, tris (2-carbonyl ethyl) phosphate and mitomycin are wrapped on the surface of the stent, and a dense coating with a drug slow release effect is formed by layer-by-layer wrapping.
Example 1
A preparation method of a degradable bile pancreatic duct stent comprises the following steps:
dissolving sodium alginate in 500ml of water, and then adding 12.4g of tris (2-carbonylethyl) phosphate and 2g of mitomycin to disperse uniformly to obtain a wt 1% sodium alginate aqueous solution;
dissolving chitosan in acetic acid solution to obtain wt 2% chitosan acetic acid solution;
polishing the degradable metal bracket by using organic acid chemical polishing solution to remove surface impurities, wherein the chemical polishing solution comprises 10% of glycolic acid, 5% of citric acid, 3% of thiourea, 4% of triethanolamine, 3% of sodium dodecyl benzene sulfonate, 4% of fatty alcohol-polyoxyethylene ether, 4% of glycerol, 8% of silica sol, 15nm-150nm of silica sol and the balance of water;
soaking the polished degradable metal stent in wt 0.5% polyethyleneimine water solution for 5min to obtain an amino-modified degradable metal stent;
and alternately dipping the degradable metal stent modified by the amino group in the sodium alginate aqueous solution and the chitosan acetic acid solution for 10 times to obtain the degradable drug-loaded bile-pancreatic duct stent.
Example 2
A preparation method of a degradable bile pancreatic duct stent comprises the following steps:
dissolving sodium alginate in 500ml of water, and then adding 10g of tris (2-carbonyl ethyl) phosphate and 1g of mitomycin to disperse uniformly to obtain a wt 1% sodium alginate aqueous solution;
dissolving chitosan in acetic acid solution to obtain 1.5 wt% chitosan acetic acid solution;
polishing the degradable metal bracket by using organic acid chemical polishing solution to remove surface impurities, wherein the chemical polishing solution comprises 5% of oxalic acid, 3% of citric acid, 2% of benzotriazole, 4% of urea, 3% of sodium dodecyl benzene sulfonate, 4% of alkylphenol polyoxyethylene, 1% of silicone oil, 6% of alumina sol, 20-250 nm of silica sol particle size and the balance of water;
soaking the polished degradable metal stent in wt 0.5% polyethyleneimine water solution for 8min to obtain an amino-modified degradable metal stent;
and alternately dipping the degradable metal stent modified by the amino group in the sodium alginate aqueous solution and the chitosan acetic acid solution for 8 times to obtain the degradable drug-loaded bile-pancreatic duct stent.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. The preparation method of the degradable drug-loaded bile pancreatic duct stent is characterized by comprising the following steps:
dissolving an anionic polymer in water, adding an organic reducing agent and an antiproliferative drug, and uniformly dispersing to obtain an anionic polymer solution;
dissolving a cationic polymer in an organic acid solution to obtain a cationic polymer organic acid solution;
polishing the degradable metal stent by using organic acid chemical polishing solution to remove surface impurities;
soaking the polished degradable metal stent in a polyethyleneimine aqueous solution to obtain an amino-modified degradable metal stent;
and alternately dipping the degradable metal stent modified by the amino group in the anionic polymer solution and the cationic polymer solution for multiple times to obtain the degradable drug-loaded bile-pancreatic duct stent.
2. The preparation method of claim 1, wherein the chemical polishing solution comprises 4-15% of glycolic acid, 1-10% of citric acid, 1-5% of thiourea, 3-5% of triethanolamine, 2-5% of sodium dodecyl benzene sulfonate, 1-6% of fatty alcohol-polyoxyethylene ether, 3-5% of glycerol, 4-12% of silica sol, 15-250 nm of silica sol and the balance of water.
3. The method of claim 1, wherein the anionic polymer is one or more of sodium alginate, hyaluronic acid, hyaluronic lipopolysaccharide, heparin, silk fibroin, or polypeptide chain, and the cationic polymer is chitosan.
4. The method of claim 1, wherein the concentration of the anionic polymer solution is wt 1% -3%, the concentration of the cationic polymer solution is wt 1% -3%, the concentration of the antiproliferative drug is 0.002g/ml-0.006g/ml, the concentration of the organic reducing agent is 0.016g/ml-0.03g/ml, and the concentration of the polyethyleneimine aqueous solution is wt 0.5%.
5. The preparation method of claim 1, wherein the degradable metal stent is prepared by melting, pouring, heat treating, forging, drilling and drawing a degradable metal capillary tube and then laser engraving.
6. The method of claim 1, wherein the organic reducing agent is one or both of dithiothreitol and tris (2-carbonylethyl) phosphate.
7. The method of claim 1, wherein the antiproliferative drug is one or both of mitomycin and paclitaxel.
8. The preparation method according to claim 1, wherein the time of each impregnation in the impregnation process is 5-10min, and the number of alternate impregnations is 8-12.
9. A degradable drug-loaded bile pancreatic duct stent obtained by the preparation method according to any of claims 1 to 8, which comprises a degradable metal stent main body and a drug-loaded slow-release coating, wherein the drug-loaded slow-release coating comprises an organic reducing agent and an antiproliferative drug.
10. The degradable drug-loaded bile pancreatic duct stent obtained by the preparation method of claim 9, wherein the length of the stent is 3-5cm, the inner diameter of the stent is 3-6mm, and the degradable metal is zinc alloy or magnesium alloy.
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