CN1436801A - Synthesis and application of post-operative adhesion-preventing material - Google Patents
Synthesis and application of post-operative adhesion-preventing material Download PDFInfo
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- CN1436801A CN1436801A CN 02113330 CN02113330A CN1436801A CN 1436801 A CN1436801 A CN 1436801A CN 02113330 CN02113330 CN 02113330 CN 02113330 A CN02113330 A CN 02113330A CN 1436801 A CN1436801 A CN 1436801A
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Abstract
The present invention in the synthesis and application of post-operative adhesion-preventing membrane material. Polylactate-polyvinyl alcohol copolymer, which has viscosity-average molecular weight of 100 KD and polyvinyl alcohol structure unit content of 0.5-50 %, is first synthesized through solution polymerization process by using alkyl metal compound as catalyst. The copolymer is then processed into sterilized membrane for preventing post-operative adhesion. The present invention one ideal material for preventing post-operative adhesion makes it possible to reduce effectively post-operative complication, reduce patient's pain and save medical expense.
Description
The present invention's " a kind of post-operative adhesion-preventing material synthetic and use " relates to the synthetic of the poly-DL lactic acid-co-glycolic acid of novel material that a kind of post-operation adhesion preventing film uses and as the application of post-operation adhesion preventing film.
Tissue adhesion is that one of unsolved important topic has still been arranged since the history of operation both at home and abroad.There are nearly various types of operation cases of ten million in the whole nation every year, and nearly all operation all relates to anti and local anti-inflammatory problem between the tissue.It not only can cause severe complication, as: can cause adhesive ileus after belly, the operation on pelvis, can cause postoperative epilepsy after the operation of opening cranium, the Tiroidina postoperative can cause Secondary cases only stimulate the menstrual flow the damage etc., and be the main reason that complication obviously increases when performing the operation once more, as the damage of enteron aisle glandular tube, only logical nerve and parathyroid injury etc.Problems such as transparent resin acid sodium and the chitin glue that uses clinically exists purity not high enough at present, and is poor to a lot of preventing adhesiving effects, and no local anti-inflammatory disease acts on, and application surface is narrow.
Past only limits to abdominal operation Film with Preventing Adhesion intestinal obstruction in the research of prevention of postoperative adhesion.Once put silicone oil with the abdominal cavity inner face, methods such as medium molecular dextran and streptokinase, but all do not have positive effect.Silicone oil can not be absorbed by the body, although little to the body pungency, is stranded in intraperitoneal for a long time, will produce to stimulate can to cause and ooze out, and cause adhesion.Medium molecular dextran has pungency to tissue owing to be that height oozes body fluid, makes and organizes congestion and edema, and oozing out increases and cause adhesion.Streptokinase is to inject in Intraabdominal micropore tubule from being detained, in the hope of solution fibrin, but owing to can only inject in a small amount, pore can get clogged and tubule transposition etc. all multifactor, curative effect is not remarkable yet.Therefore, wait in expectation for a long time clinically novel material of a kind of convenience, safe and effective anti and novel method come out.
The widespread use in modern medicine of macromolecular material and mixture thereof is one of present comparatively ideal biological medical polymer material and biodegradable absorbs, has obtained drugs approved by FDA and has been used for biomedical every field.At present, in order to improve the over-all properties of poly-DL lactic acid, in poly-DL acid segment, introduce the polyglycolic acid structural unit, gather DL lactic acid-co-glycolic acid and synthesize, this material has good biocompatibility, the blood consistency, snappiness and biodegradable absorptivity have demonstrated superiority, on document aspect clinical application, be catalyzer mostly with the tin salt, under high vacuum, adopt the method for melt polymerization, prepare poly-DL lactic acid-co-glycolic acid, up to now, Shang Weijian prepares high-molecular-weight poly DL lactic acid-co-glycolic acid with the method for solution polymerization.And that we have broken through is efficient, the gordian technique of non-toxic catalyst and normal pressure, solution polymerization, has synthesized poly-DL lactic acid-co-glycolic acid, and this law is created by us, is characterized in: technology is easy, react controlled and good reproducibility.
The objective of the invention is to adopt poly-DL lactic acid-co-glycolic acid as the post-operation adhesion preventing film, overcoming the defective of existing poly-lactic acid material, and reach convenient, the safety and the effective purpose of anti.
Report such as Lee CK (Spine 1,984 9 305) polylactic acid membrane has the effect that promotes that scar is grown and alleviated epidural adhesion, (Spine 1,986 11 843) such as Yoshihiro M have also carried out the experiment of pre-epidural adhesion preventing with polylactic acid membrane, the result shows that polylactic acid membrane shows, reduces epidural scarring and forms and adhesion; Gan Zhihua etc. (applied chemistry 1,997 14 84) report has carried out the experimentation on animals of tendon anti with pla-pcl-poly-DL lactic acid copolymer film, show that this co-polymer membrane has certain anti effect, be not difficult to find out from The above results, although polylactic acid membrane and pla-pcl-poly-DL lactic acid copolymer film all has certain anti effect, but the fragility of the former film and the degradation cycle of latter's film are long, absorb slow disadvantage, but limited their range of application to a certain extent.As everyone knows, the degradation speed of polyglycolic acid is the fastest in several Biodegradable materials, so our the poly-DL lactic acid-co-glycolic acid of development will have the processibility of film preferably, the snappiness of film and short degradation cycle.
The objective of the invention is to realize by following scheme.
The present invention adopts poly-DL lactic acid-co-glycolic acid as the Antiadhesive film material, and its viscosity-average molecular weight is greater than 100,000, and the content of its polyglycolic acid structural unit is 0.5-50%, and optimum content is 4-30%.
The molecular weight regulator that the present invention adopts is a Fatty Alcohol(C12-C14 and C12-C18), generally uses the Fatty Alcohol(C12-C14 and C12-C18) of 12-24 carbon atom, and wherein the Fatty Alcohol(C12-C14 and C12-C18) with 12-18 carbon atom is good, as dodecanol, and Stearyl alcohol etc., the consumption of conditioning agent is decided on the molecular weight size of multipolymer.
The alkyl metal cpd catalyzer that the present invention is suitable for mainly is zinc ethyl (ZnEt
2), triisobutyl aluminium [Al (iBu)
3], dibutyl magnesium [Mg (Bu)
2] etc., the solution that general and solvent is made into 0.1-1M concentration uses, and catalyst consumption is good with the 0.01-1.0% of total monomer weight.
The solvent that the present invention is suitable for mainly contains toluene, dimethylbenzene, trichloromethane, methylene dichloride etc., and solvent needs drying to handle before use, carries out Zheng Evaporated purifying again in the presence of sodium Metal 99.5.
Before the polyreaction, reactor needs through inert gas replacement, needs carry out polymerization under protection of inert gas after reinforced, is reflected under the normal pressure and carries out, and temperature of reaction generally is 60-220 ℃, and is good with 110-160 ℃.
The processing of resulting polymers, the mensuration of purifying and molecular weight is undertaken by Chang Fangfa.
Through being processed into Antiadhesive film, its thickness is the 0.01-1 millimeter with poly-DL lactic acid-co-glycolic acid in the present invention, and by sterilization, after the sterilising treatment, the back anti is used to perform the operation.To gather the Antiadhesive film that DL lactic acid-co-glycolic acid is made, safety evaluation and experimentation on animals through material prove, the film made from this material has good snappiness, biodegradable absorptivity favorable tissue consistency and blood consistency, and this film is fixed in the anti position surface of a wound, to prevent itself and peripheral organization's adhesion, not only can prevent intraperitoneal intestinal adhesion, and can prevent the liver visceral surface, the adhesion of hepatic portal hepatoduodenal ligament, the esophagus adhesion of Tiroidina art, because of girdle sensation, the subarachnoid space adhesion of operation of opening cranium, the adhesion (uterine tube of pelvic cavity viscera, the uterus ovary), the pleural adhesion in thoracic cavity etc. can reduce postoperative complication effectively, have avoided operation once more, improved operative effect, reduced patient's misery, saved medical expense, this a kind of really convenience, safety, the effectively method of post-operation adhesion preventing.
The molecular weight of the poly-DL-lactic acid-co-glycolic acid of the inventive method system can reach 10～500,000.
Embodiment 1
Thermometer is being housed, is adding 24 gram DL-rac-Lactides in the reaction flask of agitator and condenser, 6 gram glycollide and an amount of toluene, the air of logical nitrogen replacement(metathesis)reaction system is warmed up to 120 ℃ under nitrogen atmosphere, treat that two kinds of lactides dissolve fully after, be cooled to 110 ℃, drip Al (i-Bu)
30.15 milliliter of toluene solution (concentration is 0.5M), react to viscosity increase can't stir till, about 1.5-2 hour, the cooling stopped reaction adds acetone solution, with methanol extraction, row 26 gram poly-DL-lactic acid-co-glycolic acids after the vacuum-drying, viscosity-average molecular weight is 350,000.
Embodiment 2
Experimental installation and operation add 24 gram DL rac-Lactides with embodiment 1 in reaction flask, 6 gram glycollide, 0.04 gram Stearyl alcohol and an amount of toluene, logical nitrogen is warming up to 120 ℃, treat that two kinds of lactides dissolve fully after, be cooled to 110 ℃, add Al (i-Bu)
30.15 milliliter of toluene solution (concentration is 0.5M), react to viscosity increase can't stir till, about 1.5-2 hour, the cooling stopped reaction adds acetone solution, with methanol extraction, get 25 grams after the vacuum-drying and gather-the DL-co-glycolic acid, viscosity-average molecular weight is 270,000.
Embodiment 3
Experimental installation and operation add 25.5 gram DL rac-Lactides with implementing 1 in reaction flask, 4.5 gram glycollide and an amount of toluene, logical nitrogen is warming up to 120 ℃, treat that two kinds of lactides dissolve fully after, be cooled to 110 ℃, add ZnEt
20.13 milliliter of toluene solution (concentration is 0.4M), react to viscosity increase can't stir till, about 1.5-2 hour, cooling stopped reaction, adding acetone solution.With methanol extraction, get 24 gram poly-DL-lactic acid-co-glycolic acids after the vacuum-drying, viscosity-average molecular weight is 280,000.
Embodiment 4
Experimental installation and operation add 25.5 gram DL rac-Lactides with embodiment 1 in reaction flask, 4.5 gram glycollide, 0.04 gram Stearyl alcohol and an amount of toluene, logical nitrogen is warmed up to 120 ℃, treat that two kinds of lactides dissolve fully after, be cooled to 110 ℃, add ZnEt
20.13 milliliter of toluene solution (concentration is 0.4M), react to viscosity increase can't stir till, about 1.5-2 hour, the cooling stopped reaction adds acetone solution, with methanol extraction, get 23 gram poly-DL-lactic acid-co-glycolic acids after the vacuum-drying, viscosity-average molecular weight is 210,000.
Embodiment 5
With molecular weight 300,000, polyglycolic acid structural unit content is 50%, thickness is 0.02 millimeter gathering--DL-lactic acid-co-glycolic acid film, the ethane via epoxyethane sterilization, sterilising treatment is used to prevent behind the vertebrae plate resection around the dura mater fibrosis and adhesion and operation on tendon, intestinal surgery, operation on biliary tract post-operation adhesion preventing.Experimentation on animals and clinical application test effect are good.
Embodiment 6
With molecular weight 120,000, polyglycolic acid structural unit content is 20%, thickness is poly-DL-lactic acid-co-glycolic acid film of 0.04 millimeter, the ethane via epoxyethane sterilization, sterilising treatment is used to prevent behind the vertebrae plate resection around the dura mater fibrosis and adhesion and operation on tendon, intestinal surgery, operation on biliary tract post-operation adhesion preventing.Experimentation on animals and clinical application test effect are good.
Embodiment 7
Molecular weight 500,000, polyglycolic acid structural unit content is 5%, thickness is poly--DL lactic acid-co-glycolic acid film of 03 millimeter, ethane via epoxyethane sterilization, sterilising treatment, be used to prevent behind the vertebrae plate resection around the dura mater fibrosis and adhesion and operation on tendon, intestinal surgery, operation on biliary tract post-operation adhesion preventing, experimentation on animals and clinical application test effect are good.
Embodiment 8
With molecular weight 350,000, polyglycolic acid structural unit content is 15%, thickness is poly-DL-lactic acid-co-glycolic acid film of 0.8 millimeter, ethane via epoxyethane sterilization, sterilising treatment, be used to prevent behind the vertebrae plate resection around the dura mater fibrosis and adhesion and operation on tendon, intestinal surgery, operation on biliary tract post-operation adhesion preventing, experimentation on animals and clinical application test effect are good.
Embodiment 9
With the polyglycolic acid structural unit content of molecular weight 250,000 is 10%, thickness is poly-DL-lactic acid-co-glycolic acid film of 0.06 millimeter, ethane via epoxyethane sterilization, sterilising treatment, be used to prevent behind the vertebrae plate resection around the dura mater fibrosis and adhesion and the operation of flesh key, intestinal surgery, operation on biliary tract post-operation adhesion preventing, experimentation on animals and clinical application test effect are good.
Claims (10)
1. one kind-DL-rac-Lactide and glycollide are carried out the method for solution copolymerization, it is characterized in that with the alkyl metal cpd being catalyzer, can add molecular weight regulator.
2. according to the described process for copolymerization of claim 1, the consumption that it is characterized in that glycollide is the 0.5-50% (weight) of total monomer weight.
3. according to the described process for copolymerization of claim 1, it is characterized in that catalyzer is triisobutyl aluminium and zinc ethyl
4. according to the described process for copolymerization of claim 1, it is characterized in that used molecular weight regulator is the Fatty Alcohol(C12-C14 and C12-C18) of 12-24 carbon atom.
5. according to the described process for copolymerization of claim 1, it is characterized in that solvent for use is aromatic hydrocarbons or halogenated alkane.
6. according to claim 1 and 5 described process for copolymerization, it is characterized in that solvent load is a monomer: solvent=1 (weight): 0-9 (volume)
7. the novel material of a post-operation adhesion preventing is characterized in that material consists of poly(lactic acid)-co-glycolic acid.
8. according to the viscosity-average molecular weight 100,000 of the described material of claim 7.
According to the content of polyglycolic acid structural unit in claim 7 and the 8 described materials at 0.5-80%, optimum content is 4-30%.
10. be processed into the film of 0.01-1 millimeter according to claim 7,8 and 9 described materials in use,, after the sterilising treatment, be used for post-operation adhesion preventing through sterilization.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021133301A CN1331913C (en) | 2002-02-05 | 2002-02-05 | Synthesis and application of post-operative adhesion-preventing material |
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|---|---|---|---|
| CNB021133301A CN1331913C (en) | 2002-02-05 | 2002-02-05 | Synthesis and application of post-operative adhesion-preventing material |
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| CN1436801A true CN1436801A (en) | 2003-08-20 |
| CN1331913C CN1331913C (en) | 2007-08-15 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068719A (en) * | 2011-01-18 | 2011-05-25 | 复旦大学 | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof |
| CN102558514A (en) * | 2011-12-29 | 2012-07-11 | 浙江宝诺生物科技有限公司 | Postoperative anti-adhesion membrane material capable of biodegradation and preparation method and application |
| CN102665780A (en) * | 2009-12-28 | 2012-09-12 | 川澄化学工业株式会社 | Anti-adhesion material |
| CN103251986A (en) * | 2013-05-17 | 2013-08-21 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN103254413A (en) * | 2013-05-21 | 2013-08-21 | 江苏金聚合金材料有限公司 | Method for preparing polyglycolic acid |
| CN107108871A (en) * | 2015-01-19 | 2017-08-29 | 日本曹达株式会社 | The manufacture method of polyester |
| CN110279902A (en) * | 2019-06-13 | 2019-09-27 | 四川大学华西医院 | A kind of neurosurgery post-operation anti-adhesion film and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0141431B1 (en) * | 1994-05-17 | 1998-07-01 | 김상웅 | Biodegradable hydrogel copolymer |
| IL118235A0 (en) * | 1996-05-13 | 1996-09-12 | Univ Ben Gurion | Composition and method for forming biodegradable implants in situ and uses of these implants |
| CN1146466A (en) * | 1996-06-24 | 1997-04-02 | 中国科学院成都有机化学研究所 | Synthetic method for biodegradability polyester material |
| CN1241442A (en) * | 1999-07-27 | 2000-01-19 | 林代平 | Post-operation adhesion preventing method |
-
2002
- 2002-02-05 CN CNB021133301A patent/CN1331913C/en not_active Expired - Fee Related
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102665780A (en) * | 2009-12-28 | 2012-09-12 | 川澄化学工业株式会社 | Anti-adhesion material |
| CN102665780B (en) * | 2009-12-28 | 2015-04-22 | 川澄化学工业株式会社 | Anti-adhesion material |
| CN102068719A (en) * | 2011-01-18 | 2011-05-25 | 复旦大学 | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof |
| CN102558514A (en) * | 2011-12-29 | 2012-07-11 | 浙江宝诺生物科技有限公司 | Postoperative anti-adhesion membrane material capable of biodegradation and preparation method and application |
| CN103251986A (en) * | 2013-05-17 | 2013-08-21 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN103251986B (en) * | 2013-05-17 | 2015-03-04 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN103254413A (en) * | 2013-05-21 | 2013-08-21 | 江苏金聚合金材料有限公司 | Method for preparing polyglycolic acid |
| CN103254413B (en) * | 2013-05-21 | 2015-06-17 | 江苏金聚合金材料有限公司 | Method for preparing polyglycolic acid |
| CN107108871A (en) * | 2015-01-19 | 2017-08-29 | 日本曹达株式会社 | The manufacture method of polyester |
| CN107108871B (en) * | 2015-01-19 | 2019-04-30 | 日本曹达株式会社 | The manufacturing method of polyester |
| CN110279902A (en) * | 2019-06-13 | 2019-09-27 | 四川大学华西医院 | A kind of neurosurgery post-operation anti-adhesion film and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN1331913C (en) | 2007-08-15 |
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