CN1473572A - Hyaluronic acid gel with iron ion and medicine used for preventing adhesion after operation - Google Patents
Hyaluronic acid gel with iron ion and medicine used for preventing adhesion after operation Download PDFInfo
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- CN1473572A CN1473572A CNA031338437A CN03133843A CN1473572A CN 1473572 A CN1473572 A CN 1473572A CN A031338437 A CNA031338437 A CN A031338437A CN 03133843 A CN03133843 A CN 03133843A CN 1473572 A CN1473572 A CN 1473572A
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- hyaluronic acid
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Abstract
The present invention relates to a novel adhesion preventing agent with wide application in preventing post-operation adhesion. The present invention features that under acid condition, hyaluronic acid and ferric chloride are mixed for full crosslinking to form iron crosslinked hyaluronic acid derivative with increased molecular weight and prolonged degradation period, and organic high molecular matter capable of suppressing collagen synthesis is then added to further strengthen the adhesion preventing effect. The adhesion preventing biological material of the present invention has good biocompatibility and long retention period inside body, and can prevent post-operation adhesion effectively before degrading automatically into harmless matter.
Description
Affiliated field
The invention belongs to a kind of novel anti-blocking agent, add the hyaluronic acid derivatives of iron ion especially for the band medicine of operation back anti, the tissue adhesion field has very widely and uses after preventing surgical operation.
Background technology
1. the cause of anti-blocking agent
The exploitation of anti-blocking agent results from the concern of medical profession to the surgery postoperative intestinal adhesion.Difficulty that the adhesion increase is performed the operation once more and the potential danger that further complication takes place.Therefore, the reason of further investigation adhesion formation is with the primary study direction of prevention and the current surgical field of minimizing surgical postoperative adhesion having become.At present, the method of minimizing adhesion commonly used has two kinds: 1) directly pour into various materials, reduce or suppress formation (Wiseman D.Polymers for the prevention ofsurgical adhesions.In:Domb AJ, the ed.Polymeric site-specific pharmacotherapy.NewYork:John Wiley ﹠amp of fibrous connective tissue; Sons, 1994.370～421), but the whole body administration lacks the half-life that fast Absorption that effective pharmaceutical carrier can not reach adhesion position, peritoneum has limited medicine; 2) use interleaving agent, mechanical barrier (Pijfman BM is provided between wound tissue, Dorr PJ, Brommer EJP, et al.Prevention of adhesions:review.EurJ Obstet Gynecol Reprod Biol, 1994,53:155～163), but the reason that interleaving agent in vivo can't biodegradation, retention time is short and lack aspects such as safety does not obtain clinical generally approval as yet.Therefore, the anti preparation of further research, exploitation different dosage form, molecular weight, concentration will be started huge social and economic benefit at field of medicaments.
2. hyaluronic anti effect
Hyaluronic acid and crosslinked hyaluronic acid are in the pre-effect that has aspect antiseized clearly, and its ultimate principle is based on hyaluronic acid and and crosslinked hyaluronan molecule excellent biological compatibility, physics (rheology) characteristic and unique biological effect.But natural hyaluronic acid is because shorter in the implant site retention time, and its Film with Preventing Adhesion effect can not reach ideal effect.20th century the mid-80, Balazs etc. have developed crosslinked hyaluronic acid, and its biological nature and clinical practice carried out exploring (Balazs EA, Leshchiner EA.Hyluronan, its cross-linked derivative---hylan andtheir medical applications.In:Inagaki H, Phillips GO, eds.In cellulosicsutilization:research and rewards in cellulossics.New York:Elsevier Appl Science, 1989.233～241), find that crosslinked hyaluronic acid has excellent biological compatibility, and longer in the retention time of organizing that.Since then, crosslinked hyaluronic acid is as effective preparation of prevention and minimizing tissue adhesion, and its application causes widely to be paid attention to.
3. collagen inhibitors effect
Tranilast (tranilast), its chemistry N-(3,4-dimethoxy cinnamoyl) ortho-aminobenzoic acid by name, chemical structural formula is as follows:
Tranilast can suppress the release of collagen synthase histamine and prostaglandin, suppress collagen regeneration (M.Furukawa, S.Taniguchi, T.Kono and M.Ishii.inhibition of collagen biosynthesis of fibroblastsfrom hypertrophic scar tissue and normal tissue by tranilast of pemirolastpotassium.Journal of Dermatological Science.1995 (10)).And collagen is one of main component of adhesion, also is the main component of forming scar tissue, by suppressing collagen regeneration, can suppress the generation of adhesion.(HaruyoshiYamada，Shingo?Tajima，Takeji?Nishikawa.Tranilast?inhibits?collagen?synthesis?innormal，scleroderma?and?keloid?fibroblasts?at?a?late?passage?culture?but?not?at?anearly?passae?culture.Journal?of?Dermatological?Science.1995，9：45-47)
CLINICAL PHARMACOKINETIS STUDY ON shows that oral tranilast capsule can be absorbed rapidly after the administration, reaches the highest blood drug level after about 2～3 hours, and it is about 8 hours that blood plasma is eliminated the half-life.Drug main will be got rid of from urine, and its metabolite mainly is 4 demethylations of tranilast and the conjugate of sulphuric acid and glucuronic acid.
4. the development situation of hyaluronic acid anti reagent
The report that the hyaluronic acid Film with Preventing Adhesion forms early than before 30 years, studies show that hyaluronic acid keeps the long time in vivo, is that to obtain enough and persistent adhesion preventive effect necessary.According to document announcement, hyaluronic acid can effectively reduce adhesion and form, and particularly reduces the formation of adhesion of tendon.1986, a large amount of zooperies found that crosslinked insoluble hyaluronic acid derivatives can reduce adhesion of tendon significantly and form.In this experiment, crosslinked hyaluronic acid derivatives has retention time more longways in the injury, reaction can not cause inflammation, can not suppress wound healing (Weiss C yet, Levy H, Denlinger IL, et al.Therole of Na-hylan in reducing postsurgical tendon adhesion.Part 1.Bull Hosp Jt DisOrthop Inst.1987,46:9～15 ﹠amp; Weiss C, Suros J, Michalow A, et al.The role of Na-hylanin reducing postsurgical tendon adhesion.Part 2.Bull Hosp Jt Dis OrthopInst.1987,47:31～39).
Recently, Biomatrix company has developed and has utilized orthopedics's ground hyaluronic acid anti preparation.In prevention abdominal cavity, cardiovascular and operation on pelvis posterior synechiae, the barrier type material is the most effective, can the mechanical isolation injury, prevent to form between the tissue surface the netted structure of fibrin.The interleaving agent that with the hyaluronic acid is the main component listing the earliest is the Seprafilm of Genzyme company, said preparation is a kind of hyaluronic acid-CMC film that combines with the hyaluronic acid of bacterial fermentation method preparation and sodium carboxymethyl cellulose (CMC), and easy hydration also is dissolved in the water-soluble medium.
A lot of research institutions have realized that hyaluronic acid solution and film are a kind of prevention or the effective ways that reduce adhesion, and the anti preparation of active opening hyalomitome acidic group.The product Lubricoat of Lifecore biomedical company is exactly the crosslinked hyaluronic acid preparation of a kind of ferrum, and the prevention postoperative intestinal adhesion is had certain effect.
Summary of the invention
The objective of the invention is to propose a kind of good biocompatibility, the crosslinked hyalomitome acidic group gel of iron ion that can effectively prevent postoperative intestinal adhesion be used to the to perform the operation preparation method of tranilast medicament slow release system of back anti, the band medicine of the back anti that both had been used to perform the operation added the hyaluronic acid derivatives of iron ion.
For achieving the above object, the present invention proposes the hyaluronic acid derivatives that a kind of band medicine that is used to perform the operation the back anti adds iron ion, and preparation method is:
(1) hyaluronic acid is added deionized water, be configured to mass percent and be 1% hyaluronic acid solution, be stirred well to dissolving;
(2) with FeCl
3Add 1M HCl, be configured to FeCl
3Solution;
(3) 1M HCl is dropwise added hyaluronic acid solution, stir simultaneously, make the two fully mixed, reach 4.75 until its pH value;
(4) with FeCl
3Solution dropwise adds above-mentioned solution, fully stirs;
(5) dropwise add 1M NaOH in above-mentioned solution, become gel until solution, pH value is 7;
(6) with above-mentioned gel lyophilizing, be pressed into powder;
(7) above-mentioned powder is put into disinfection cabinet ozonization 2 times;
(8) above-mentioned powder and tranilast drug powder are mixed (1%: 99%)-(30%: 70%) in certain proportion, dissolve in the aseptic PBS of 0.1M, be stirred well to and form the even gel system.
Tranilast drug powder described in the step (8) also can add between arbitrary step of step (1)～(7).
Sterilization method described in the step (7) also can adopt and comprise ultra-vioket radiation, Co
50Irradiation waits other sterilization methods.
This system can be used for comprising the prevention of the caused adhesions of damage that all surgical operations caused such as orthopaedics, gynecological, abdominal cavity.
The crosslinked hyaluronic acid of the used ferrum of the present invention is in the pre-effect that has aspect antiseized clearly, and its ultimate principle is based on its molecule excellent biological compatibility, physics (rheology) characteristic and unique biological effect.
Many studies show that, because the hyaluronan molecule amount is less, local in vivo retention time is short, has only after surgery and in early days Film with Preventing Adhesion is had certain effect, late period, effect was not obvious.We select to introduce iron ion according to existing patented technology, make itself and cross-linking hyaluronic acid, increase hyaluronic molecular weight, prolong material retention time in vivo.Derivatives of hyaluronic acids after crosslinked is owing to have more intensive network structure and long retention time, form physical barriers at tissue surface and will organize isolation, the activation of inflammation-inhibiting cell and gathering, the aspects such as gathering that are reduced to fibrocyte, fibrinogen are all stronger than hyaluronic acid, estimate to have better preventing adhesiving effect.And iron ion is the element necessary to human body, does not worry can damaging human body at the degraded afterproduct.
In crosslinked hyaluronic acid, add collagen inhibitors, strengthen the ability that crosslinked hyaluronic acid Film with Preventing Adhesion forms.Research points out that tranilast can suppress the release of collagen synthase, histamine and prostaglandin, suppresses collagen regeneration.And collagen is one of main component of adhesion, also is the main component of forming scar tissue, by suppressing collagen regeneration, can suppress the generation of adhesion.
Owing to existing the whole body administration to lack the reasons such as half-life that fast Absorption that effective pharmaceutical carrier can not reach adhesion position, peritoneum limited medicine, direct drug injection thing Film with Preventing Adhesion makes that its preventive effect is undesirable.And crosslinked hyaluronic acid is good drug delivery system, and the effect of controlled-release function and targeted delivery of drugs is arranged.Directly with this system coating damage location, reach the adhesion position thereby medicine is accurate to after operation, and the speed that peritoneum absorbs is controlled, the chemoprophylaxis effect is promoted, thus better prevention of postoperative adhesion.
Because good biocompatibility of the present invention, retention time is longer in vivo.And the crosslinked hyaluronic acid of ferrum is the good isolation layer, is again good drug delivery system, cooperates the collagen inhibitor, can fundamentally solve the problem of operation back anti.
Key content of the present invention is: utilize hyaluronic acid to do drug delivery system, add the formation that collagen inhibitors further suppresses adhesion in hyaluronic acid preparation.Utilize the preventing adhesiving effect of the drug effect enhancing hyaluronic acid preparation of collagen inhibitors.
The specific embodiment
Embodiment one:
The band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation, and preparation method is:
(1) hyaluronic acid is added deionized water, be configured to mass percent and be 1% hyaluronic acid solution, be stirred well to dissolving;
(2) with FeCl
3Add 1M HCl, be configured to the quality volumetric concentration and be 1.5% FeCl
3Solution;
(3) 1M HCl is dropwise added hyaluronic acid solution, stir simultaneously, make the two fully mixed, reach 4.75 until its pH value;
(4) will be 3: 10 FeCl with above-mentioned liquor capacity ratio
3Solution dropwise adds above-mentioned solution, fully stirs 10-20min;
(5) dropwise add 1M NaOH in above-mentioned solution, become gel until solution, pH value is 7;
(6) with above-mentioned gel lyophilizing, be pressed into powder;
(7) above-mentioned powder is put into disinfection cabinet ozonization 2 times;
(8) above-mentioned powder and tranilast drug powder is mixed with the ratio of 1: 20 (weight ratio), dissolve in the aseptic PBS of 0.1M,
Be stirred well to and form the even gel system.
Embodiment two:
The band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation, and preparation method is:
(1) hyaluronic acid is added deionized water, be configured to mass percent and be 1% hyaluronic acid solution, be stirred well to dissolving;
(2) with FeCl
3Add 1M HCl, be configured to the quality volumetric concentration and be 1.5% FeCl
3Solution;
(3) 1M HCl is dropwise added hyaluronic acid solution, stir simultaneously, make the two fully mixed, reach 4.75 until its pH value;
(4) will be 3: 10 FeCl with above-mentioned liquor capacity ratio
3Solution dropwise adds above-mentioned solution, fully stirs 10 ~ 20min;
(5) dropwise add 1M NaOH in above-mentioned solution, become gel until solution, pH value is 7;
(6) with above-mentioned gel lyophilizing, be pressed into powder;
(7) with above-mentioned powder ultra-vioket radiation;
(8) above-mentioned powder and tranilast drug powder is mixed with 1: 2 ratio, dissolve in the aseptic PBS of 0.1M, be stirred well to and form the even gel system.
Embodiment three:
The band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation, and preparation method is:
(1) hyaluronic acid is added deionized water, be configured to mass percent and be 1% hyaluronic acid solution, be stirred well to dissolving;
(2) with FeCl
3Add 1M HCl, be configured to the quality volumetric concentration and be 1.5% FeCl
3Solution;
(3) 1M HCl is dropwise added hyaluronic acid solution, stir simultaneously, make the two fully mixed, reach 4.75 until its pH value;
(4) will be 3: 10 FeCl with above-mentioned liquor capacity ratio
3Solution dropwise adds above-mentioned solution, fully stirs 10 ~ 20min;
(5) dropwise add 1M NaOH in above-mentioned solution, become gel until solution, pH value is 7;
(6) with above-mentioned gel lyophilizing, be pressed into powder;
(7) above-mentioned powder is put into Co
60Illumination-based disinfection;
(8) above-mentioned powder and tranilast drug powder is mixed with the ratio of 5: 1 (weight ratio), dissolve in the aseptic PBS of 0.1M, be stirred well to and form the even gel system.
Claims (4)
1. the band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation, and preparation method is:
(1) hyaluronic acid is added deionized water, be configured to mass percent and be 1% hyaluronic acid solution, be stirred well to dissolving;
(2) with FeCl
3Add 1M HCl, be configured to FeCl
3Solution;
(3) 1M HCl is dropwise added hyaluronic acid solution, stir simultaneously, make the two fully mixed, reach 4.75 until its pH value;
(4) with FeCl
3Solution dropwise adds above-mentioned solution, fully stirs;
(5) dropwise add 1M NaOH in above-mentioned solution, become gel until solution, pH value is 7;
(6) with above-mentioned gel lyophilizing, be pressed into powder;
(7) above-mentioned powder is put into disinfection cabinet ozonization 2 times;
(8) above-mentioned powder and tranilast drug powder are mixed (1%: 99%)-(30%: 70%) in certain proportion, dissolve in the aseptic PBS of 0.1M, be stirred well to and form the even gel system.
2. the band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation according to claim 1 is described, and preparation method is:
(8) the tranilast drug powder described in also can add between arbitrary step of step (1)～(7).
3. the band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation according to claim 1 is described, and preparation method is:
(7) sterilization method described in also can adopt and comprise ultra-vioket radiation, Co
60Irradiation waits other sterilization methods.
4. the band medicine of anti adds the hyaluronic acid derivatives of iron ion after being used to perform the operation, and purposes is that this system can be used for comprising the prevention of the caused adhesions of damage that all surgical operations caused such as orthopaedics, gynecological, abdominal cavity.
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| CN 03133843 CN1245165C (en) | 2003-07-01 | 2003-07-01 | Hyaluronic acid gel with iron ion and medicine used for preventing adhesion after operation |
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| CN1473572A true CN1473572A (en) | 2004-02-11 |
| CN1245165C CN1245165C (en) | 2006-03-15 |
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| JP2007528391A (en) * | 2004-03-10 | 2007-10-11 | エシコン・インコーポレイテッド | Drug-enhanced adhesion prevention |
| CN101879334A (en) * | 2010-06-21 | 2010-11-10 | 甘少磊 | Surgery adhesion prevention compound gel material containing calcium ions and hyaluronic acid and preparation method thereof |
| CN101156969B (en) * | 2007-10-26 | 2011-06-08 | 北京奥精医药科技有限公司 | Anti-conglutination material containing calcium ion and carboxymethyl cellulose after operation as well as its preparing method |
| CN102580134A (en) * | 2011-12-20 | 2012-07-18 | 山东省医疗器械研究所 | Biological and haemostatic wound dressing and preparation method thereof |
| CN102793952A (en) * | 2012-08-20 | 2012-11-28 | 山东省立医院 | Gel material for preventing intestinal adhesion |
| CN102921033A (en) * | 2009-10-26 | 2013-02-13 | 日产化学工业株式会社 | Cosmetic and external skin preparation, and medical instrument |
| CN109106975A (en) * | 2018-07-23 | 2019-01-01 | 西安交通大学 | A kind of preparation method and application of the quick selfreparing gel with intelligent antibacterial and long-acting biological molecule release function |
| CN109890847A (en) * | 2016-10-31 | 2019-06-14 | 丘比株式会社 | Gel combination and its manufacturing method |
| CN110123741A (en) * | 2019-06-24 | 2019-08-16 | 中国医学科学院基础医学研究所 | A kind of iron cross-linked-hyaluronic acid nanogel, preparation method and purposes |
| 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 |
| CN112552534A (en) * | 2021-01-14 | 2021-03-26 | 安阳师范学院 | Stretchable self-healing stimulation response biopolymer hydrogel |
| CN112940302A (en) * | 2021-03-04 | 2021-06-11 | 兰州大学 | Metal ion mediated collagen gel, preparation method and application |
| CN114984329A (en) * | 2022-06-06 | 2022-09-02 | 上海交通大学医学院附属第九人民医院 | Injectable drug-loaded hydrogel for preventing and treating postoperative abdominal adhesion |
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- 2003-07-01 CN CN 03133843 patent/CN1245165C/en not_active Expired - Fee Related
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2007528391A (en) * | 2004-03-10 | 2007-10-11 | エシコン・インコーポレイテッド | Drug-enhanced adhesion prevention |
| CN101156969B (en) * | 2007-10-26 | 2011-06-08 | 北京奥精医药科技有限公司 | Anti-conglutination material containing calcium ion and carboxymethyl cellulose after operation as well as its preparing method |
| CN105664223A (en) * | 2009-10-26 | 2016-06-15 | 日产化学工业株式会社 | Cosmetic and external skin preparation, and medical instrument |
| CN102921033A (en) * | 2009-10-26 | 2013-02-13 | 日产化学工业株式会社 | Cosmetic and external skin preparation, and medical instrument |
| CN105664223B (en) * | 2009-10-26 | 2018-12-04 | 日产化学工业株式会社 | Cosmetic preparation, skin preparations for extenal use and medical instrument |
| CN101879334A (en) * | 2010-06-21 | 2010-11-10 | 甘少磊 | Surgery adhesion prevention compound gel material containing calcium ions and hyaluronic acid and preparation method thereof |
| CN102580134A (en) * | 2011-12-20 | 2012-07-18 | 山东省医疗器械研究所 | Biological and haemostatic wound dressing and preparation method thereof |
| CN102793952A (en) * | 2012-08-20 | 2012-11-28 | 山东省立医院 | Gel material for preventing intestinal adhesion |
| CN102793952B (en) * | 2012-08-20 | 2013-11-13 | 山东省立医院 | Gel material for preventing intestinal adhesion |
| CN109890847A (en) * | 2016-10-31 | 2019-06-14 | 丘比株式会社 | Gel combination and its manufacturing method |
| CN109106975A (en) * | 2018-07-23 | 2019-01-01 | 西安交通大学 | A kind of preparation method and application of the quick selfreparing gel with intelligent antibacterial and long-acting biological molecule release function |
| 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 |
| CN110123741A (en) * | 2019-06-24 | 2019-08-16 | 中国医学科学院基础医学研究所 | A kind of iron cross-linked-hyaluronic acid nanogel, preparation method and purposes |
| CN112940302B (en) * | 2020-08-26 | 2022-12-06 | 胶原蛋白(武汉)生物科技有限公司 | Metal ion mediated collagen gel, preparation method and application |
| CN112552534A (en) * | 2021-01-14 | 2021-03-26 | 安阳师范学院 | Stretchable self-healing stimulation response biopolymer hydrogel |
| CN112552534B (en) * | 2021-01-14 | 2021-07-02 | 安阳师范学院 | Stretchable self-healing stimulation response biopolymer hydrogel |
| CN112940302A (en) * | 2021-03-04 | 2021-06-11 | 兰州大学 | Metal ion mediated collagen gel, preparation method and application |
| CN114984329A (en) * | 2022-06-06 | 2022-09-02 | 上海交通大学医学院附属第九人民医院 | Injectable drug-loaded hydrogel for preventing and treating postoperative abdominal adhesion |
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Assignee: Liaoning Biomedical Materials R&D Center Co., Ltd. Assignor: Yinyi Biological Materical Research and Development Co., Ltd., Dalian Contract fulfillment period: 2008.12.1 to 2016.11.30 Contract record no.: 2008210000084 Denomination of invention: Hyaluronic acid gel with iron ion and medicine used for preventing adhesion after operation Granted publication date: 20060315 License type: Exclusive license Record date: 20081209 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.12.1 TO 2016.11.30; CHANGE OF CONTRACT Name of requester: LIAONING BIOLOGY MEDICINE MATERIALS RESEARCH CENTE Effective date: 20081209 |
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