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WO1993013137A1 - Procede d'insolubilisation de derives n-carboxyalkyle de chitosan - Google Patents

Procede d'insolubilisation de derives n-carboxyalkyle de chitosan Download PDF

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Publication number
WO1993013137A1
WO1993013137A1 PCT/US1992/010417 US9210417W WO9313137A1 WO 1993013137 A1 WO1993013137 A1 WO 1993013137A1 US 9210417 W US9210417 W US 9210417W WO 9313137 A1 WO9313137 A1 WO 9313137A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
set forth
film
derivative
carboxy
Prior art date
Application number
PCT/US1992/010417
Other languages
English (en)
Inventor
James J. Barry
Paul A. Higham
Noelle N. Mann
Original Assignee
Howmedica Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Howmedica Inc. filed Critical Howmedica Inc.
Priority to JP5511669A priority Critical patent/JPH0826081B2/ja
Priority to EP93900814A priority patent/EP0617707A1/fr
Publication of WO1993013137A1 publication Critical patent/WO1993013137A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides

Definitions

  • the present invention relates to a method of temporariiy insolubilizing films and gels of N-carboxyalkyl derivatives of chitosan to provide materials which can have varied degradation times for various biomedical applications such as adhesion prevention. More particularly, the method relates to an annealing process in which the material is insoiubilized by exposing film to temperatures between 50°C and 200°C for various lengths of time.
  • Chitin and chitosan are well known biocompatible materials whose preparation has been described in U.S. Patent 2,040,880, which issued on May 19, 1936.
  • the preparation of another chitosan derivative, N-carboxybutyl chitosan is described in U.S. Patent 4,835,265.
  • scar tissue results from the organization of fibrinous exudate on tissue surfaces due to the infliction of trauma or inflammation.
  • Vital tissues such as blood vessels, or organs including the kidney, liver, and intestines are coated with mucous or serous membranes so that they can function independently of each other.
  • mucous or serous membranes are the body wall pleura and the organ pleura in the thoracic cavity and the parietal peritoneum and mesentery in the abdominal cavity, each protecting the corresponding organs.
  • Surgical trauma or inflammation in those portions of the body coated with serous membranes could result in the build up of fibrinous exudate regardless of the size of the affected part.
  • Adhesions occur in the orthopedics field where conditions such as acute or chronic arthritis, suppurative, rheumatoid, gonorrheal, or tuberculous arthritis, or traumatic injuries at the joint, such as fracture or sprain, result in ankylotic diseases wherein the surface of the bones constituting the joint adhere to each other and thereby restrict the mobility of the joint.
  • congenital radioulnar syntosis wherein a spoke bone and an ulna adhere together, is difficult to remedy by a surgical operation, since the separated bones frequently re-adhere.
  • Adhesions are also prominent in tendon surgery. In this instance, there is a general tendency towards adhesion between the tendon and the surrounding sheath or other surroun ⁇ ding tissue during an immobilization period following the operation.
  • the laminectomy membrane is a well organized mass of fibrinous tissue which replaces the bone that was removed at the laminectomy. This fibrinous mass binds the dura to the overlying muscles. This causes narrowing of the spinal canal which places pressure on the cauda equina or nerve roots. This scar tissue formation may require reoperation which is tedious and dangerous leading to the possibility of dural tears and the damage to the emergent nerve roots resulting in motor weakness, sensory change, and painful paresthesia.
  • N-carboxyalkyl derivatives of chitosan is dissolved in a neutral pH aqueous solution or a slightly acidic solution.
  • the solution is then cast and dried to form a thin clear film.
  • the solution is poured into a mold (for example a petri dish) and lyophilized to form a sponge-type film with varying dimensions depending on the mold, the solution concentration, and the solution volume.
  • the resulting films are insolubilized by an annealing process in which they are exposed to temperatures between 50°C and 200°C for various periods of time depending on the desired length of insolubilization time, and ultimately bioresorption time.
  • the biodegradable polymer films to be used to inhibit fibrin formation and organization are materials which will eventually revert to the gel or solution state and ultimately be resorbed and metabolized by the body. As taught in co-pending application Serial Number 07/644,758, these materials include amino N-carboxyalkyl derivatives of chitosan. Chitosan is a partially deacetylated chitin defined for the purposes herein as being greater than 50% deacetylated.
  • N-carboxyalkyl derivatives used in the present invention are water soluble polymers which have not been crosslinked to form insoluble materials.
  • these materials are N-carboxymethyl chitosan, N-carboxybutyl chitosan, N,O carboxymethyl chitosan, and N,O-carboxybutyI chitosan, N-carboxy- ethyl chitosan, N.O-carboxyethyl chitosan, N,O-carboxypropyl chitosan, and N-carboxypropyl chitosan.
  • these materials can be temporarily insolubilized to form substances which will begin to degrade in a period of from 2-5 days to up to one year t ⁇ vitro.
  • these polymers would be in the form of a film, sponge, or woven sheet which will break down into visco-elastic materials.
  • these would be the use of N,O-carboxymethyl chitosan or N-carboxy- butyl chitosan films insolubilized by annealing with heat as described herein. While the exact mechanism which causes the insolubilization of the materials is unclear, it is postulated that either a dehydration mechanism, or a crystallization mechanism or a combination of the two is causing this phenomena.
  • Additives such as anti-thrombogenic materials may be added to the films before insolubilizing.
  • the materials may be formed into a viscous gel for injection into the affected location to prevent fibrinous buildup.
  • This gel could be used for applications where a shorter in_ vivo residence time is desired and/or the location would best be suited for prevention of adhesions with a material in this form.
  • the gels may be formed by placing the insolubilized films in a sterile aqueous media and heating the solution to increased temperatures until the film hydrates and swells to form a gelatinous mass.
  • the degree of insolubilization of the viscous gels can be varied by varying the temperature of the aqueous solution and the extent of time the film is allowed to remain in the solution.
  • the present invention has the added advantage that the insolubilization step can be done during the heat or steam sterilization of the device, if desired.
  • the resulting solution was then rendered free of all low molecular weight impurities by extensive dialysis with water via a 300K molecular weight cutoff membrane (Filtron - Norwood, MA) on the same ultra-filtration device. Films were then formed from this solution by both casting (allowing evaporation) on a non-stick surface such as a glass petri dish, or a piece of mylar film and by freeze drying by adding 300 ml of the solution to a 90 mm diameter disposable petri dish and lyophilized in a tray dryer for 72 hours at -50°C. The resulting films (either cast or freeze dried) were then insolubilized by placing the film into an oven at 121° c for 20 minutes (correlating to a standard autoclave cycle). Both films were placed in aqueous media and dissolved within 5 days. Based on the dissolution which did occur, the film would dissolve in approximately two months.
  • Example 2 Three films were prepared as described above in Example 1 by casting in a petri dish. Each was exposed to a different temperature for a period of 30 minutes. The first was heated at 76°C, the second at 121 °C and the third at 168°C. One f ⁇ m was cast and not treated. This served as a control.
  • the four films were placed in 5 cc of PBS and placed in an incubator at 37°C. At various times, the samples were removed and observed visually for solubility. Following this the incubation medium was removed from the dish and analyzed for soluble product via size exclusion chromatography. The control film was completely solubilized within one day. The film at 76°C indicated complete solubility between 1-2 days. The 121 °C treated film indicated complete solubility at 4-5 days, while the film treated at 168°C indicated no evidence of solubility up to 14 days.
  • Example 2 Three films were prepared as described above in Example 1 with the exception that the temperature of annealing was kept constant at 121 °C and the exposure time was varied between 15 minutes and 23 hours. Again, a non-treated film served as a control. AH films were evaluated as mentioned above. The film treated at 15 minutes indicated complete solubility in 2-3 days, the film treated for 60 minutes indicated solubility through 1 days (complete solubility had not yet been attained) while the film treated at 2 hours indicated no solubility in an excess of 14 days.
  • the degradation of the films / ⁇ vivo could be lengthened by increasing the annealing time and temperature.
  • a film which would degrade within 14 days is desirable and may be attained by annealing at 121 °C for about 60 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Surgery (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Treatments Of Macromolecular Shaped Articles (AREA)
  • Cosmetics (AREA)

Abstract

L'invention se rapporte à un procédé d'insolubilisation de films de dérivés N-carboxyalkyle de chitosan, dont le processus de recuit permet d'obtenir des matériaux qui peuvent avoir une perte de qualité à des moments variés. Ces matériaux peuvent être utilisés dans diverses applications biomédicales telles que la prévention de l'adhésion. Le procédé de recuit chauffe le film pendant des durées prédéterminées et à des températures prédéterminées afin de faire varier la solubilité du film.
PCT/US1992/010417 1991-12-20 1992-12-08 Procede d'insolubilisation de derives n-carboxyalkyle de chitosan WO1993013137A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5511669A JPH0826081B2 (ja) 1991-12-20 1992-12-08 キトサンのｎ−カルボキシアルキル誘導体を不溶化する方法
EP93900814A EP0617707A1 (fr) 1991-12-20 1992-12-08 Procede d'insolubilisation de derives n-carboxyalkyle de chitosan

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81218791A 1991-12-20 1991-12-20
US812,187 1991-12-20

Publications (1)

Publication Number Publication Date
WO1993013137A1 true WO1993013137A1 (fr) 1993-07-08

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/010417 WO1993013137A1 (fr) 1991-12-20 1992-12-08 Procede d'insolubilisation de derives n-carboxyalkyle de chitosan

Country Status (5)

Country Link
EP (1) EP0617707A1 (fr)
JP (1) JPH0826081B2 (fr)
AU (1) AU3235593A (fr)
CA (1) CA2125402A1 (fr)
WO (1) WO1993013137A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035433A1 (fr) * 1995-05-08 1996-11-14 Chitogenics, Inc. N,o-carboxymethylchitosan pour la prevention des adhesions chirurgicales
US5791352A (en) * 1996-06-19 1998-08-11 Fusion Medical Technologies, Inc. Methods and compositions for inhibiting tissue adhesion
US5888988A (en) * 1995-05-08 1999-03-30 Chitogenics, Inc. Covalently linked N,O-carboxymethylchitosan and uses thereof
US5931165A (en) * 1994-09-06 1999-08-03 Fusion Medical Technologies, Inc. Films having improved characteristics and methods for their preparation and use
WO2000071136A1 (fr) * 1999-05-20 2000-11-30 Chitogenics, Inc. Revetements n,o-carboxymethylchitosane adhesifs inhibant la fixation de cellules et de proteines a des substrats
FR2844717A1 (fr) * 2002-09-23 2004-03-26 Richard Cancel Plaque de renfort comprenant notamment du chitosane
US7265097B2 (en) 2002-08-20 2007-09-04 Chitogenics, Inc. Methods of drug delivery using sulphated chitinous polymers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4326523A (en) * 1980-08-25 1982-04-27 International Minerals & Chemical Corp. Method of supplying micronutrients to animals
US4619995A (en) * 1984-12-24 1986-10-28 Nova Chem Limited N,O-carboxymethyl chitosan and preparative method therefor
EP0426368A2 (fr) * 1989-10-31 1991-05-08 Howmedica Inc. Compositions contenant des dérivés de chitine pour empêcher l'adhésion

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4326523A (en) * 1980-08-25 1982-04-27 International Minerals & Chemical Corp. Method of supplying micronutrients to animals
US4619995A (en) * 1984-12-24 1986-10-28 Nova Chem Limited N,O-carboxymethyl chitosan and preparative method therefor
EP0426368A2 (fr) * 1989-10-31 1991-05-08 Howmedica Inc. Compositions contenant des dérivés de chitine pour empêcher l'adhésion

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, volume 100, no 22, 28 May 1984, (Columbus, Ohio, US), Ogawa, Kozo et al, "A new polymorph of chitosan", 667, THE ABSTRACT No 175178z, Macromolecules 1984, 17 22), 973-975, (e) *
Chemical Abstracts, volume 107, no 4, 27 July 1987, (Columbus, Ohio, US), Ban, Seiji et al, "Release of dimethacrylate monomers into water", 319, THE ABSTRACT No 28320f, Aichi Gakuin daigaku Shigakkaishi 1986, 24 4), 383-389, (e) *
Chemical Abstracts, volume 115, No. 20, 18 November 1991, (Columbus, Ohio, US), page 145, THE ABSTRACT No 210574j, JP, A, 3143901, (Nishiyama, Masashi et al) 19 June 1991 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5931165A (en) * 1994-09-06 1999-08-03 Fusion Medical Technologies, Inc. Films having improved characteristics and methods for their preparation and use
WO1996035433A1 (fr) * 1995-05-08 1996-11-14 Chitogenics, Inc. N,o-carboxymethylchitosan pour la prevention des adhesions chirurgicales
US5679658A (en) * 1995-05-08 1997-10-21 Chitogenics, Inc. N,O-carbonxymethylchitosan for prevention of surgical adhesions
US5888988A (en) * 1995-05-08 1999-03-30 Chitogenics, Inc. Covalently linked N,O-carboxymethylchitosan and uses thereof
US5791352A (en) * 1996-06-19 1998-08-11 Fusion Medical Technologies, Inc. Methods and compositions for inhibiting tissue adhesion
EP1003526A4 (fr) * 1997-05-06 2000-05-31 Chitogenics Inc N, o-carboxymethyl-chitosane a liaison covalente et ses applications
WO2000071136A1 (fr) * 1999-05-20 2000-11-30 Chitogenics, Inc. Revetements n,o-carboxymethylchitosane adhesifs inhibant la fixation de cellules et de proteines a des substrats
US6645947B1 (en) * 1999-05-20 2003-11-11 Chitogenics, Inc. Adhesive N, O-carboxymethylchitosan coatings which inhibit attachment of substrate-dependent cells and proteins
US6809085B1 (en) * 1999-05-20 2004-10-26 Chitogenics, Inc. Adherent N,O-Carboxymethylchitosan drug delivery devices for moist tissue and methods of their use
US6894035B2 (en) * 1999-05-20 2005-05-17 Chitogenics, Inc. Adhesive N,O-carboxymethylchitosan coatings which inhibit attachment of substrate-dependent cells and proteins
US7238678B2 (en) * 1999-05-20 2007-07-03 Chitogenics, Inc. Adhesive N,O-carboxymethylchitosan coatings which inhibit attachment of substrate-dependent cells and proteins
US7265097B2 (en) 2002-08-20 2007-09-04 Chitogenics, Inc. Methods of drug delivery using sulphated chitinous polymers
FR2844717A1 (fr) * 2002-09-23 2004-03-26 Richard Cancel Plaque de renfort comprenant notamment du chitosane
WO2004026358A1 (fr) * 2002-09-23 2004-04-01 Richard Cancel Plaque de renfort comprenant notamment du chitosane

Also Published As

Publication number Publication date
AU3235593A (en) 1993-07-28
CA2125402A1 (fr) 1993-07-08
EP0617707A1 (fr) 1994-10-05
JPH0826081B2 (ja) 1996-03-13
JPH06511279A (ja) 1994-12-15

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