CN1331913C - Synthesis and application of post-operative adhesion-preventing material - Google Patents

Abstract

The present invention "Synthesis and application of a new material for postoperative anti-adhesion film" uses an alkyl metal compound as a catalyst, and synthesizes a polylactic acid-polyglycolic acid copolymer by solution polymerization for the first time, and its viscosity-average molecular weight is greater than 100,000 , the content of polyglycolic acid structural unit is 0.5-50%, and it is processed into a film with this material. After disinfection and sterilization, it is used for postoperative anti-adhesion. It can effectively reduce surgical complications and relieve patients’ pain. It is an ideal new material and a postoperative anti-adhesion method to save medical expenses.

Description

Synthesis and application of a new material for postoperative anti-adhesion film

technical field

The invention relates to the synthesis of a new material polyDL lactic acid-polyglycolic acid copolymer for postoperative anti-adhesion film and its application as postoperative anti-adhesion film.

Background technique

Postoperative adhesion is one of the important issues that have not been solved at home and abroad since the history of surgery. There are nearly ten million cases of various types of surgery in the country every year, and almost all of them involve anti-adhesion between tissues and local anti-inflammation. It can not only cause serious complications, such as: adhesive intestinal obstruction after abdominal and pelvic surgery, postoperative epilepsy after craniotomy, secondary meridian damage after thyroid surgery, etc. The most important reason for the significant increase in complications at the time, such as intestinal duct damage, Weitong nerve and parathyroid damage. Sodium hyaluronate and chitin gum currently used clinically have problems such as insufficient purity, poor anti-adhesion effect, no local anti-inflammatory effect, and narrow application range.

Past studies on the prevention of postoperative adhesions were limited to the prevention of adhesive ileus during abdominal surgery. Silicone oil, middle molecule dextran and streptokinase have been used in the abdominal cavity, but all have no obvious effect. Silicone oil cannot be absorbed by the human body. Although it is less irritating to the body, if it stays in the abdominal cavity for a long time, it will cause irritation and exudation, which will lead to adhesion. Because middle molecular dextran is a hyperosmotic body fluid, it is irritating to the tissue, causing tissue congestion and edema, increasing exudation and causing adhesion. Streptokinase is injected from the microporous tubules retained in the abdominal cavity in order to dissolve fibrin, but because only a small amount can be injected, the tubule holes can be blocked, tubule translocation and many other factors, the curative effect is not significant. Therefore, a kind of convenient, safe and effective anti-adhesion new material and new method have long been expected clinically.

Polymer materials and their composites have been widely used in modern medicine, and biodegradable and absorbable polymer materials are the most active frontier field in biomedical materials. Among them, polylactic acid and its copolymers are currently one of the ideal biomedical polymer materials, and have been approved by the US FDA for use in various fields of biomedicine. At present, in order to improve the comprehensive performance of DL lactic acid, polyglycolic acid structural units are introduced into the polyDL acid chain segment to synthesize poly DL lactic acid-polyglycolic acid copolymer, which has excellent biocompatibility and blood compatibility. properties, flexibility and biodegradable absorbability have shown superiority in clinical application. In the literature, mostly stannous salts are used as catalysts to prepare poly DL lactic acid- Polyglycolic acid copolymers, so far, have not been seen to prepare high molecular weight polyDL lactic acid-polyglycolic acid copolymers by melt polymerization. And we have broken through the key technology of high-efficiency, non-toxic catalyst and atmospheric pressure, solution polymerization, and synthesized poly-DL lactic acid-polyglycolic acid copolymer. This method is our original creation. Its characteristics are: simple process, controllable and repeatable reaction Good sex.

Lee CK et al. (Spine 1984 9 305) reported that polylactic acid film can promote scar growth and reduce epidural adhesions. Yoshihiro M et al. (Spine 1986 11 843) also used polylactic acid film to prevent epidural adhesions. The results show that polylactic acid film shows that it can reduce epidural scar formation and adhesion; Gan Zhihua et al. (Applied Chemistry 1997 1484) reported that polycaprolactone-polyDL lactic acid copolymer film has carried out tendon anti-adhesion animal experiments, showing that this copolymerization The material film has a certain anti-adhesion effect. It is not difficult to see from the above results that although the polylactic acid film and the polycaprolactone-polyDL lactic acid copolymer film both have a certain anti-adhesion effect, the brittleness of the former film and the brittleness of the latter film The disadvantages of long degradation cycle and slow absorption limit their application scope to a certain extent. As we all know, the degradation rate of polyglycolic acid is the fastest among several biodegradable materials, so the polyDL lactic acid-polyglycolic acid copolymer we developed will have better film processability, film flexibility and relatively high Short degradation cycle.

Contents of the invention

One of the purposes of the present invention is to use an alkyl metal compound as a catalyst, and -DL-lactide and glycolide carry out a solution copolymerization reaction to obtain a poly-DL lactic acid-polyglycolic acid copolymer; the second purpose of the present invention is to Poly-DL lactic acid-polyglycolic acid copolymer is used as postoperative anti-adhesion film to overcome the defects of existing poly-lactic acid materials and achieve the purpose of convenient, safe and effective anti-adhesion.

The object of the present invention is achieved by the following scheme:

A method for synthesizing new materials for postoperative anti-adhesion film, characterized in that: carry out solution copolymerization reaction with -DL-lactide and glycolide; the catalyst used in the copolymerization reaction is selected from metal alkyl compounds Triisobutylaluminum or diethylzinc in the mixture is carried out under the protection of an inert gas, and the reaction temperature is between 60-220°C; the solvent used in the copolymerization reaction is an aromatic hydrocarbon or a halogenated alkane;

A further feature is that a molecular weight regulator is added in the reaction.

The amount of glycolide used in the present invention is 0.5-50% (percentage by weight) of the total weight of the monomers.

The solvent consumption of the present invention is monomer: solvent=1 (weight): 0-9 (volume); A solute of unit weight should adopt the solvent of more than zero and less than 9 parts of unit volume.

The invention adopts poly DL lactic acid-poly glycolic acid copolymer as the anti-adhesion film material, its viscosity average molecular weight is greater than 100,000, the content of polyglycolic acid structural unit is 0.5-80%, and the optimal content is 4-30%.

The molecular weight regulator that the present invention adopts is aliphatic alcohol, generally with the aliphatic alcohol of 12-24 carbon atoms, wherein with the aliphatic alcohol of 12-18 carbon atom is good, as dodecyl alcohol, stearyl alcohol etc., regulates The dosage of the agent depends on the molecular weight of the copolymer.

The alkyl metal compound catalysts applicable to the present invention are mainly diethylzinc (ZnEt ₂ ), triisobutylaluminum [Al(iBu) ₃ ], butylmagnesium [Mg(Bu) ₂ ], etc., generally formulated with a solvent The solution with a concentration of 0.1-1M is used, and the dosage of the catalyst is preferably 0.01-1.0% of the total weight of the monomer.

The solvents applicable to the present invention mainly include aromatic hydrocarbons or halogenated alkanes such as toluene, xylene, chloroform, methylene chloride, etc., and the solvents need to be dried before use, and then distilled and purified in the presence of metallic sodium.

Before the polymerization reaction, the reactor needs to be replaced by an inert gas. After feeding, the polymerization needs to be carried out under the protection of an inert gas. The reaction is carried out under normal pressure. The reaction temperature is generally 60-220°C, preferably 110-160°C.

The treatment, purification and determination of the molecular weight of the obtained polymer were carried out in the usual manner.

In the present invention, poly-DL lactic acid-polyglycolic acid copolymer is processed into an anti-adhesion film with a thickness of 0.01-1 mm, which is used for post-operation anti-adhesion after being sterilized and sterilized. The anti-adhesion film made of poly DL lactic acid-polyglycolic acid copolymer has been proved by the safety evaluation of the material and animal experiments that the film made of this material has excellent flexibility and can be biodegradable and absorbable. Compatibility and hemocompatibility, the film is fixed on the wound surface of the anti-adhesion site to prevent it from adhering to peripheral tissues, not only preventing intestinal adhesions in the abdominal cavity, but also preventing adhesions on the surface of the liver and the hepatic porta-hepatoduodenal ligament , Esophageal adhesions in thyroid surgery, due to the sense of tightness, subarachnoid adhesions in craniotomy, adhesions in pelvic organs (fallopian tubes, uterus and ovaries), adhesions in thoracic pleura, etc., can effectively reduce surgical complications and avoid recurrence. Surgery improves the curative effect of the operation, reduces the pain of the patient, and saves medical expenses. This is indeed a convenient, safe and effective postoperative anti-adhesion method.

The molecular weight of the polyDL-lactic acid-polyglycolic acid copolymer prepared by the method of the invention can reach 100,000-500,000.

Detailed ways

Example 1

Add 24 grams of DL-lactide, 6 grams of glycolide and an appropriate amount of toluene to a reaction flask equipped with a thermometer, a stirrer and a condenser, replace the air in the reaction system with nitrogen, and heat up to 120 ° C under a nitrogen atmosphere. After the two lactides are completely dissolved, lower the temperature to 110°C, add 0.15 ml of Al(i-Bu) ₃ toluene solution (concentration: 0.5M) dropwise, react until the viscosity increases and cannot be stirred, about 1.5-2 hours, cool Stop the reaction, add acetone to dissolve, precipitate with methanol, and dry in vacuum to dry 26 grams of poly-DL-lactic acid-polyglycolic acid copolymer with a viscosity average molecular weight of 350,000.

Example 2

The experimental device and operation are the same as in Example 1. Add 24 grams of DL lactide, 6 grams of lactide, 0.04 grams of stearyl alcohol and an appropriate amount of toluene into the reaction bottle, pass nitrogen, heat up to 120 ° C, and wait until the two lactides are completely After dissolving, cool down to 110°C, add 0.15 ml of Al(i-Bu) ₃ toluene solution (concentration: 0.5M), react until the viscosity increases and cannot be stirred, about 1.5-2 hours, cool to stop the reaction, add acetone to dissolve , Precipitate with methanol, dry in 25 grams of poly-DL-lactic acid-polyglycolic acid copolymer after vacuum drying, viscosity average molecular weight is 270,000.

Example 3

The experimental device and operation are the same as in Example 1. Add 25.5 grams of DL-lactide, 4.5 grams of lactide and an appropriate amount of toluene into the reaction bottle, pass nitrogen and raise the temperature to 120°C. After the two lactides are completely dissolved, cool down to 110°C. , add 0.13 milliliters of ZnEt ₂ toluene solution (concentration is 0.4M), react until the viscosity increases and cannot be stirred, about 1.5-2 hours, cool to stop the reaction, add acetone to dissolve, precipitate with methanol, and dry 24 grams of poly- DL-lactic acid-polyglycolic acid copolymer with a viscosity average molecular weight of 280,000.

Example 4

The experimental device and operation are the same as in Example 1. Add 25.5 grams of DL lactide, 4.5 grams of lactide, 0.04 grams of stearyl alcohol and an appropriate amount of toluene into the reaction bottle, pass nitrogen, and raise the temperature to 120 ° C. After the two lactides are completely After dissolving, lower the temperature to 110°C, add 0.13 ml of ZnEt ₂ toluene solution (concentration: 0.4M), react until the viscosity increases and cannot be stirred, about 1.5-2 hours, cool to stop the reaction, add acetone to dissolve, precipitate with methanol, vacuum After drying, 23 grams of poly-DL-lactic acid-polyglycolic acid copolymers were processed, and the viscosity-average molecular weight was 210,000.

Example 5

The poly-DL-lactic acid-polyglycolic acid copolymer film with a molecular weight of 300,000, a polyglycolic acid structural unit content of 50%, and a thickness of 0.02 mm is sterilized with ethylene oxide and sterilized for the prevention of laminectomy Fibrosis and adhesions around the posterior dura mater and anti-adhesion after tendon surgery, intestinal surgery, and biliary tract surgery. Animal experiments and clinical application tests have good results.

Example 6

The poly-DL-lactic acid-polyglycolic acid copolymer film with a molecular weight of 120,000, a polyglycolic acid structural unit content of 20%, and a thickness of 0.04 mm is sterilized and sterilized by ethylene oxide for the prevention of laminectomy Fibrosis and adhesion around the posterior dura mater and anti-adhesion in tendon surgery, intestinal surgery, and biliary tract surgery. Animal experiments and clinical application tests have good results.

Example 7

The poly-DL-lactic acid-polyglycolic acid copolymer film with a molecular weight of 500,000, a polyglycolic acid structural unit content of 5%, and a thickness of 0.3 mm is sterilized and sterilized by ethylene oxide for the prevention of laminectomy Fibrosis and adhesion around the posterior dura mater and anti-adhesion in tendon surgery, intestinal surgery, and biliary tract surgery. Animal experiments and clinical application tests have good results.

Example 8

The poly-DL-lactic acid-polyglycolic acid copolymer film with a molecular weight of 350,000, a polyglycolic acid structural unit content of 15%, and a thickness of 0.8 mm is sterilized and sterilized by ethylene oxide for the prevention of laminectomy Fibrosis and adhesion around the posterior dura mater and anti-adhesion in tendon surgery, intestinal surgery, and biliary tract surgery. Animal experiments and clinical application tests have good results.

Example 9

The poly-DL-lactic acid-polyglycolic acid copolymer film with a molecular weight of 250,000, a polyglycolic acid structural unit content of 10%, and a thickness of 0.06 mm is sterilized with ethylene oxide and sterilized for the prevention of laminectomy Fibrosis and adhesion around the posterior dura mater and anti-adhesion in tendon surgery, intestinal surgery, and biliary tract surgery. Animal experiments and clinical application tests have good results.

Claims (7)

1, a kind of synthetic method of postoperative anti-adhesion film with new material, it is characterized in that: carry out solution copolymerization reaction with -DL-lactide and glycolide; The catalyst used in described copolymerization reaction is selected from alkyl metal Triisobutylaluminum or diethylzinc in the compound is carried out under the protection of inert gas, and the reaction temperature is between 60-220° C.; the solvent used in the copolymerization reaction is aromatic hydrocarbon or halogenated alkane. 2. The method for synthesizing new materials for postoperative anti-adhesion film according to claim 1, characterized in that: a molecular weight regulator is added to the copolymerization reaction. 3. The method for synthesizing new materials for postoperative anti-adhesion film according to claim 1 or 2, characterized in that the reaction temperature is between 110-160°C. 4. The method for synthesizing new materials for postoperative anti-adhesion film according to claim 1 or 2, characterized in that: the used catalyst and solvent are formulated into a solution with a concentration of 0.1-1M, and the amount of the catalyst accounts for 2% of the total weight of the monomers. 0.01-1.0%. 5. The method for synthesizing new materials for postoperative anti-adhesion film according to claim 2, characterized in that: the molecular weight regulator is a fatty alcohol with 12-24 carbon atoms. 6. The method for synthesizing new materials for postoperative anti-adhesion film according to claim 5, characterized in that: the molecular weight regulator is dodecanol or stearyl alcohol. 7. The method for synthesizing new materials for postoperative anti-adhesion film according to claim 1 or 2, characterized in that the solvent used in the copolymerization reaction is xylene.