[go: up one dir, main page]

WO2007024015A1 - Materiau pour prevenir l'adherence tissulaire et l'arthrogrypose - Google Patents

Materiau pour prevenir l'adherence tissulaire et l'arthrogrypose Download PDF

Info

Publication number
WO2007024015A1
WO2007024015A1 PCT/JP2006/317152 JP2006317152W WO2007024015A1 WO 2007024015 A1 WO2007024015 A1 WO 2007024015A1 JP 2006317152 W JP2006317152 W JP 2006317152W WO 2007024015 A1 WO2007024015 A1 WO 2007024015A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
polymer
containing polymer
phosphorylcholine
represented
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2006/317152
Other languages
English (en)
Japanese (ja)
Inventor
Kozo Nakamura
Kazuhiko Ishihara
Mizuna Kimura
Hiroshi Kawaguchi
Toru Moro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Tokyo NUC
Original Assignee
University of Tokyo NUC
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 University of Tokyo NUC filed Critical University of Tokyo NUC
Publication of WO2007024015A1 publication Critical patent/WO2007024015A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L101/00—Compositions of unspecified macromolecular compounds
    • C08L101/02—Compositions of unspecified macromolecular compounds characterised by the presence of specified groups, e.g. terminal or pendant functional groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L43/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing boron, silicon, phosphorus, selenium, tellurium or a metal; Compositions of derivatives of such polymers
    • C08L43/02—Homopolymers or copolymers of monomers containing phosphorus
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group

Definitions

  • the present invention relates to a tissue adhesion and joint contracture prevention material using a biocompatible polymer gel.
  • the living body has a physiological action to try to heal the damaged part. 'After the surgery, this physiology works and the damaged part is healed.
  • tissue adhesion occurs where organs that should be separated from each other are connected and fused by fibrous tissue. Tissue adhesion after surgery is almost inevitable, and this tissue adhesion is known to cause a new dysfunction with a high probability.
  • joint contracture occurs in trauma and surgery near the joint, where joint movement is limited by adhesion of tissues around the joint.
  • Synthetic polymer materials have a low permeability to humoral factors that play an important role in the healing process and may impair the healing of damaged tissue.
  • synthetic polymer materials are generally incompatible with living organisms and may cause a foreign body reaction.
  • bioabsorbability is low, extraction is necessary, and there is a possibility that new adhesion may be caused by extraction of the synthetic polymer.
  • bioabsorbable materials are associated with cell infiltration in the process of absorption, and there is a concern that some degree of adhesion is difficult to avoid. Also controls the absorption rate in vivo Is difficult.
  • tissue adhesion prevention materials are difficult to handle due to their lack of flexibility, and the surgical field is in a moist environment due to blood and exudates. It is difficult to fix these materials to the target site. 'Under such circumstances, development of simpler and more effective tissue adhesion and joint contracture prevention materials is desired in the clinical field.
  • An object of the present invention is to provide a gel composition excellent in biocompatibility, and an adhesion prevention material and a joint contracture prevention material containing the gel composition.
  • the present inventor has conducted intensive research.
  • the present inventor has proposed a monomer having a polar group having a structure similar to the polar group of the phospholipid that is the main component of the biological membrane (for example, 2-methacryloyloxychetylphosphoryl p-phosphorus; MPC)
  • MPC 2-methacryloyloxychetylphosphoryl p-phosphorus
  • Polymer A obtained from a monomer having an acidic group and polymer B obtained from MPC and a hydrophobic monomer were mixed in the presence of a polyvalent metal ion to obtain a gel composition.
  • the decomposition rate of the gel composition can be controlled by the concentration of polyvalent metal ions or the composition of the polymer.
  • the obtained gel composition was found to be very useful as an agent for preventing tissue adhesion and joint contracture, particularly from the viewpoint of biocompatibility and controllable degradation rate, completed. That is, the present invention is as follows.
  • a phosphorylcholine structure-containing polymer A obtained by polymerizing a monomer having a phosphorylcholine structure and a monomer having an acidic group, a phosphorylcholine structure A monomer having a ⁇ to become phospho Rirukorin structure-containing polymer B and a monomer having a hydrophobic group, and gel-like sets Narubutsu 0 comprising a polyvalent metal ion....
  • a joint contracture-preventing material comprising the composition according to (1) or (2).
  • a method for producing a gel composition comprising mixing an aqueous solution of phosphorylcholine structure-containing polymer ⁇ and an aqueous solution of phosphorylcholine structure-containing polymer B in the presence of a polyvalent metal ion. Further, the present invention relates to the following.
  • a method for preventing adhesion or joint contracture characterized in that an aqueous solution of a phosphorylcholine structure-containing polymer A and an aqueous solution of a polymer B containing a phosphorylcholine structure are mixed in the presence of a polyvalent metal ion.
  • the phosphorylcholine structure-containing polymer A has the following general formula' ():.
  • Rla and Rib are independently the same or different and each represents a hydrogen atom, a methyl group or an ethyl group; R 2a represents a group represented by 1 X la — R 3a ,
  • Xia is an optionally substituted phenyl group or one C (O) one, one C (O) O—, one O—, — C (D) NH—, or Represents an S---
  • R 3a has the following formula (2):
  • n represents an integer of 2 to 12
  • m represents an integer of 2 to 4
  • R 1, R 5a and RGa are each independently the same or different, linear or branched Represents an alkyl group having 1 to 4 carbon atoms, and represents a group represented by
  • a 1 represents 0.10 to 0.95 and b i represents 0.05 to 0.90 (provided that .a i + bi is 1 or less). ] Can be mentioned.
  • R lc and R ld are independently the same or different and each represents a hydrogen atom, a methyl group or an ethyl group,
  • R 2c represents a group represented by 1 X lc —R 3c ,
  • R2d represents a group represented by one XW and one R3d
  • X ld are each independently the same or different, a phenyl group which may have a substituent or _ C (O) 1, 1 C (O) O—, 1 0_, 1 C (O) NH—, or a group represented by S— R 3c is the following formula (4)
  • R, R5c and RSc are each independently the same or different, linear or branched Represents an alkyl group having 1 to 4 carbon atoms in the form of
  • R 3d is one (CH 2 ) ⁇ R 7d
  • R 7d represents a hydrogen atom or a phenyl group which may have a substituent. However, when R 7d is a hydrogen atom, ⁇ represents an integer from 2 to 18, and is a phenyl group. I represents an integer of 0 to 6),
  • c ⁇ represents .30 ⁇ 0.95, di represents 0.70 ⁇ 0.05 (However, 1+ (11 is 1 or less)
  • the phosphorylcholine structure-containing polymer A may be represented by the following formula (5).
  • a 2 is 0 ⁇ 10 to 0.95
  • b 2 represents from 0.05 to 0.90 (however, & 2 +) 2 is 1 or less. ) ]
  • the phosphorylcholine structure-containing polymer B is It may be represented by the following formula (6) ' c
  • C2 is from .30 to 0.95
  • d 2 is 0: 70 to 0.05 represents a (however, c 2 + d 2 is 1 or less.).
  • the phosphorylcholine structure-containing polymer B may be represented by the following formula (7). '
  • the polyvalent metal ion is, for example, an iron (III) ion.
  • the final concentration of the polyvalent metal ion is, for example, 0.05 to 0.25M.
  • the present invention provides a gel composition of the present invention, a tissue adhesion-containing material containing the gel composition of the present invention, a joint contracture prevention material, and methods for producing them. .
  • the gel composition of the present invention and the adhesion / contracture prevention t ' have high biocompatibility, and are preferably less likely to cause a foreign body reaction in the living body, and are safe in the living body even after decomposition. It is.
  • the gel composition of the present invention and the adhesion / contraction restraint material can control the biodegradation rate depending on the concentration of the polyvalent metal ion to be added. Therefore, depending on the purpose of use and the use site, the adhesion / contraction It is possible to control the decomposition rate of the prevention material.
  • the gel composition and the adhesion / contracture prevention material of the present invention preferably suppress adhesion of cells to the surface and entry of cells to the damaged site, thereby significantly preventing adhesion / contracture. be able to. '
  • the gel composition of the present invention preferably has the following characteristics, that is, it quickly gels in a surgical field that is a moist environment, fits to a damaged site, and is easily molded according to the surgical site. It is very useful as an anti-adhesion / contracture material because of its elasticity and easy handling.
  • Figure 1 shows the results of an experiment using a mouse eating model with MPC polymer-treated microparticles. ' ⁇
  • FIG. 2 is a graph showing the degradation rate of the gel composition of the present invention in PBS.
  • Fig. 3 is a diagram showing the diffusion chamber and the implantation under the rat used for the degradation rate of the gel composition according to the in vivo model.
  • FIG. 4 is a diagram showing the results of macroscopic findings of the experiment shown in Example 8.
  • FIG. 5 is a diagram showing the results of SEM findings of the experiment shown in Example 8.
  • FIG. 6 is a diagram showing the viscoelasticity of the gel composition of the present invention.
  • FIG. 7 is a diagram showing the adhesiveness of cells to the surface of the gel-like yarn of the present invention. The results after 3 hours from the start of culture are shown.
  • Figure 8 shows the deep flexor muscle (FDP) tendon in the Rabbit flexor tendon injury model. ⁇ '
  • FIG. 9 shows the FDP tendon after tendon suture.
  • FIG. 10 is a view showing a tendon after 3 weeks of suture (control).
  • Fig. 11 shows a tendon 3 weeks after suturing (iron ion: 0.071M).
  • Fig. 1 2 shows a tendon 3 weeks after suturing (iron ion: 0.071M).
  • the gel composition of the present invention includes a phosphorylcholine structure-containing polymer A obtained by polymerizing a monomer having a phosphorylcholine structure, a monomer having an acidic group, a monomer having a phosphorylcholine structure, and a monomer having a hydrophobic group.
  • each of the phosphorylcholine structure-containing polymers A and B is a monomer containing a phosphorylcholine structure having a structure similar to that of the polar group of the phospholipid (phosphatidylcholine), which is a main component of the biological membrane (for example, 2-methacryloyloxy).
  • Shetyl phosphorylcholine (MPC) is contained as a component.
  • the gel composition of the present invention has a very good biocompatibility, particularly a biomaterial, on the surface of the biological membrane. It gives the non-adsorbing and non-activating properties of body molecules. Therefore, the gel composition of the present invention can effectively suppress nonspecific adsorption to various biological components. ''
  • the gel composition of the present invention can control the degradation rate depending on the concentration of the polyvalent metal ion added, the composition of the hydrophilic unit in the polymer, or the composition of the hydrophobic unit. . It is considered that the acidic group of polymer A and the hydrophobic group of polymer B are bonded through this polyvalent metal ion. '
  • phosphorylcholine structure-containing polymer A phosphorylcholine.
  • examples of the acidic group contained in the phosphorylcholine structure-containing polymer A include a carboxyl group, a phosphoric acid group, and a boronic acid group, and a carboxyl group is preferred.
  • Polymer A containing a phosphorylcholine structure is, for example, represented by the following general formula (8):
  • the phosphorylcholine structure-containing polymer A includes a phosphorylcholine structure-containing polymer represented by the following general formula '(1). .
  • Rla and Rib are independently the same or different and each represents a hydrogen atom, a methyl group or an ethyl group,
  • R 2a represents a group represented by one X la — R 3a,.
  • X is a phenyl group which may have a substituent, or one c (o) —, one C (O) O—, one O—, one C (O) NH—, or one S.
  • R 3a has the following formula (2): '
  • R 4a , .R5a and R 6a are each independently the same or different, linear Or a branched alkyl group-: represents an alkyl group having from 4 to 4).
  • a 1 represents 0.10 to 0.95
  • b i represents 0.05 to 0.90.
  • the substituent of “optionally substituted phenyl group” is, for example, a linear or branched alkyl group having 1 to 4 carbon atoms such as a methyl group or an ethyl group, a methoxy group, Examples thereof include linear or branched alkoxy groups having 1 to 4 carbon atoms such as ethoxy groups, and halogen atoms (for example, fluorine, chlorine, bromine, iodine).
  • the phenyl group in the above formula is substituted with the same or different 1 to 4 above substituents. May be.
  • linear or branched alkyl group having 1 to 4 carbon atoms means, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n.-butyl group, isobutyl group, , Sec-butyl group, tert-butyl group are included.
  • a i and bi indicate the ratio of the number of units represented by the general formula (8) or general formula (9) ′ to the total number of monomer units contained in the polymer A.
  • abi and the total value ( ⁇ +) are 1 or less.
  • the phosphorylcholine structure-containing polymer ⁇ may be a binary copolymer consisting of the general formula (8) and the general formula (9), or a copolymer of three or more that further contains other monomer units as constituent units. It may be a polymer. Examples of other monomer units include attalyldo, N-butylpyrrolidone, acrylonitrile, and the like. In the case of a ternary or higher copolymer, the ratio of the total number of monomer units represented by the general formula (8) and the number of monomer units represented by the general formula (9) to the total number of monomer units is 0.80. The above is preferable.
  • each monomer unit can have an arbitrary position or arrangement order in the polymer individually. That is, the phosphorylcholine structure-containing polymer A may be a random copolymer or a 'block copolymer. '
  • the monomer unit represented by the above formula (8) has a phorylcholine structure.
  • the phosphorylcholine structure is represented by the following formula:
  • the side chain group having a phosphorylcholine structure is not limited, but includes, but is not limited to, an oxhetylphosphorylcholine group, an oxybutylphosphorylcholine group, an oxyhexylphosphorylcholine group, an oxydecylphosphorylcholine group, a A xetoxyphosphorylcholine group is exemplified, and among them, an oxetylphosphorylcholine group is preferable.
  • the monomer unit represented by the formula (8 ') includes the following formula (1 0):
  • MPC 2-methacryloyloxychetyl phosphorylcholine
  • the monomer unit represented by the above formula (9) contains an acidic group.
  • Examples of such a monomer unit include the following formula (1 1):
  • the preferred phosphorylcholine structure-containing polymer A is represented by the following formula: (Five)
  • a 2 and b 2 represent the ratio of the number of each unit to the total number of mono units contained in the polymer A.
  • a 2 , b 2 , and (a 2 + b 2 ) should be 1 or less.
  • the phosphorylcholine structure-containing polymer B is a polymer obtained by polymerizing a monomer having a phosphorylcholine structure and a monomer having a hydrophobic group.
  • examples of the hydrophobic group contained in the phosphorylcholine structure-containing polymer B include an alkyl group and a phenyl group.
  • the polymer B containing a phosphorylcholine structure is represented, for example, by the following general formula (1 2):
  • each of the above monomer units may be contained in the phosphorylcholine structure-containing polymer B as long as it is contained in the general formula (1 2) or (' 1 3).
  • the phosphorylcholine structure-containing polymer B includes a phosphorylcholine structure-containing polymer represented by the following general formula (3).
  • R lc and Rid are each independently the same or different and represent a hydrogen atom, a methyl group or an ethyl group;
  • R 2c represents a group represented by 1 X lc —R 3c ,
  • R 2d represents a group represented by 1 X ld _R. 3d ,
  • R 3c is the following formula (4): O 4c
  • R 6c (wherein g represents an integer of 2 to 12, h represents an integer of 2 to 4, R 4c, R 5c and R 6c are each independently the same or different, Represents a chain or branched alkyl group having 1 to 4 carbon atoms.
  • R3d is one (CH 2 ) j—R 7d
  • R 7d represents a hydrogen atom or an optionally substituted Fuweniru group, provided that j when R 7 d is a hydrogen atom is an integer of 2 to 1 8, j in the case of canvas sulfonyl group Represents an integer of 0 to 6).
  • c 1 represents 0.30 to 0.95, and represents 0.70 to 0.05.
  • the substituent of “optionally substituted phenyl group” has the same meaning as described above.
  • the full groups in the above formulas may be substituted with 1 to 4 of the same or different substituents. .
  • linear or branched alkyl group having 1 to 4 carbon atoms has the same meaning as described above.
  • ci and di indicate the ratio of each unit number represented by the general formula (1 2) or general formula (1 3) to the total number of mono units contained in the polymer B.
  • C l, d and the total value (C i + d iL) is 1 or less.
  • the phosphorylcholine structure-containing polymer B may be a binary copolymer composed of the general formula (1 2) and the general formula (1 3), or a copolymer of three or more terpolymers further containing other monomer units as constituent units. It may be a coalescence. Examples of other monomers include acrylamide, N-vinylpyrrolidone, acrylonitrile, and the like. In the case of a ternary or higher copolymer, the ratio of the total number of monomer units represented by the general formula (1 2) and the number of monomolecular units represented by the general formula (1 3) to the total number of monomer units is 0.80. The above is preferable.
  • each monomer unit can individually take an arbitrary position or arrangement order in the polymer. That is, the phosphorylcholine structure-containing polymer B may be a random copolymer or a block copolymer.
  • the monomer unit represented by the above formula (1 2) has a phosphorylcholine structure.
  • the monomer unit represented by the formula (1 2 ') includes the following formula (1 0):.
  • a monomer unit represented by the formula (2_metataloyloxetyl phosphorylcholine; MPC) is preferred.
  • MPC for example, can be prepared by the method described in “Kazuhiko Ishihara, Tomoko Ueda, and Nobuo Nakabayashi, Polymer Journal, 22, 355-360 (1990)”.
  • the monomer unit represented by the above formula (1 3) contains a hydrophobic group, and is preferably a methacrylic acid ester.
  • Examples of the monomer unit represented by the formula (I. 3 ) include the following formula (1 4):
  • the monomer unit shown by can be mentioned.
  • a preferable phosphorylcholine structure-containing polymer B is represented by the following formula (6):
  • C2 represents 0.30 to 0.95
  • d2 represents 0.70 to 0.05
  • c 3 is .30-0.95
  • d 3 represents the 0.70 to 0.05
  • c 2 , d 2 , c 3 , and d 3 represent the ratio of each unit to the total number of monomer units contained in polymer B.
  • C 2, d 2 , c 3 ds, (c 2 + d 2 ) and (c 3 + d 3) are 1 or less.
  • any polyvalent metal ion can be used as long as it is a divalent or higher valent metal ion, but preferably a trivalent or higher valent metal ion. is there.
  • iron (III) ions, aluminum (III) ions, cerium (IV) ions, and vanadium (V) ions can be mentioned. From the viewpoint of biocompatibility, iron (III) ions are preferable.
  • a salt of a polyvalent metal ion can also be used.
  • the salt of the polyvalent metal ion is not particularly limited, but is, for example, chloride.
  • the polyvalent metal ion causes an ionic bond between the hydroxide ion of polymer A and the side chain of polymer B.
  • the decomposition rate of the gel composition can be controlled by the polyvalent metal ion concentration.
  • the polyvalent metal ion is preferably used in a final concentration of 0.01 to 0.50M, preferably 0.03 to 0.30M, more preferably 0.05 to 0.25M when the gel composition is produced. As the concentration of the polyvalent metal ion is higher, the decomposition rate of the gel composition of the present invention becomes lower.
  • the production of the phosphorylcholine structure-containing polymer A or the phosphorylcholine structure-containing polymer 1B involves the polymerization reaction of monomers constituting each polymer, for example, MPC and methacrylic acid or MPC and methacrylic acid ester in the presence of an initiator in a solvent Can be obtained.
  • the solvent is not limited, and any solvent that dissolves the monomer may be used. Examples thereof include water, methanol, ethanol, propanol, tert.-butanol, dimethylolone amide, tetrahydrofuran, and mixtures thereof.
  • the initiator is not limited, and any ordinary radical initiator may be used.
  • ', 2,2'-azobisisoptyronitrile (AIBN), 2,2, -azobispentanoic acid, azobis maleeno- Examples include aliphatic azo compounds such as tolyl, and organic peroxides such as benzoyl peroxide, lauroyl peroxide, ammonium persulfate, and potassium persulfate.
  • the MPC that makes up the polymer consists of reacting triethylamine with a compound that is produced by reacting 2-chloro-2-ethyl-1,3-, 2-dioxaphoran with 2-hydroxyxetyl methacrylate in the presence of a base. Can be manufactured. Other monomers can be obtained by purchasing commercially available reagents. +
  • Polymer obtained by the polymerization reaction is suitable! Fractionation and purification.
  • Polymer fractionation and purification can be performed, for example, according to a known method using a difference in solubility in an organic solvent, a water-soluble solvent, or a permeable membrane.
  • the polymer may be lyophilized. ;
  • the unit number ratio of MPC unit a to methacrylic acid b in the phosphorylcholine structure-containing polymer A is in the range of 0.11 to: 19, and when a / b is 20, the effect of MPC unit is not expressed. I don't like it. On the other hand, if a Z b is less than 0.11, the gel will not form because the polymer will elongate due to strong repulsion of negative charges in water.
  • the unit number ratio of MPC unit c and methacrylate unit d in phosphorylcholine structure-containing polymer B is in the range of 0.43 to; 19 and c Z is 0.42, because the effect of MPC unit is not manifested. It is not preferable.
  • c / d exceeds 19, the polymer is highly hydrophilic and produces an aggregate structure in water. Does not cause gelation.
  • the polymers A and B can have various molecular weights depending on the purpose, but from the viewpoint of the strength of the copolymer material, the molecular weight is 5 Q 00 or more, preferably 10 0 0 0 or more.
  • the molecular weight of polymers A and B can be measured using gel permeation chromatography, light scattering.
  • the number average molecular weight is measured using gel permeation chromatography, it can be measured in a solvent such as water Z ethanol (for example, a ratio of 8 Z 2) using polyethylene darcol as a standard substance.
  • composition ratio of each monoya unit in the polymer can be determined by 1 H-NMR measurement.
  • iH-NMR may be measured by dissolving the polymer to be measured in heavy ethanol.
  • the method for producing the gel composition of the present invention is included in the present invention.
  • the gel composition of the present invention can be prepared by, for example, using an aqueous solution of a phosphorylcholine structure-containing polymer A and an aqueous solution of a phosphorylcholine structure-containing polymer B in the presence of a polyvalent metal ion (or a salt of a polyvalent metal ion). It can be synthesized by mixing. The gel composition is formed immediately after mixing. .,
  • the gel of the present invention can be obtained by filling a phosphorylcholine structure-containing polymer A and a phosphorylcholine structure-containing polymer B containing polyvalent metal ions into syringin ⁇ and discharging the polymer from the respective sills toward the same point.
  • a composition can be produced. .
  • the polyvalent metal ion may be added to the aqueous solution of the phosphorylcholine structure-containing polymer A or the aqueous solution of the phosphorylcholine structure-containing polymer B. Preferably, it is added in advance to the aqueous solution of the phosphorylcholine structure-containing polymer B. It is preferable to leave it.
  • Phosphorylcholine structure-containing polymer A aqueous solution and polymer B aqueous solution Each of the aqueous solutions is preferably 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 5 to 8% by weight.
  • the blending ratio of polymer A and 'polymer B contained in the gel composition of the present invention is 1:10.
  • each of the polymer A and the polymer B is 1 to
  • the polyvalent metal ion is 0.01-0.50M in the gel composition at the time of manufacture, preferably
  • the gel composition of the present invention contains 0 to 30%, preferably 0 to 10%, of components other than the polymer ⁇ , the polymer ⁇ ⁇ , and the polyvalent metal ion (hereinafter also referred to as “additive”). Preferably 0 to 3% may be contained.
  • the additive can be added to the gel composition of the present invention by adding it in advance to an aqueous solution of polymer soot or an aqueous solution of polymer B, for example.
  • the gel composition of the present invention is gel at 37 ° C, but generally exhibits a liquid state at a high temperature of 60 ° C or higher.
  • the “gel” composition means a composition having a dynamic elastic modulus larger than a dynamic loss rate (dynamic elastic modulus> dynamic loss rate).
  • the dynamic elastic modulus and dynamic loss rate are measured using a dynamic viscoelasticity measuring device (for example, Toyo Seiki Co., Ltd. (Japan), Leo Vibron (Japan), Rheometric Scientific (US), etc.). Can be measured. '
  • the present invention can provide a kit for producing the gel composition of the present invention. Since the kit of the present invention can produce a gel-like composition, it can also be used for prevention of tissue adhesion and joint contracture.
  • the kit of the present invention includes an aqueous solution of the phosphorylcholine structure-containing polymer A, an aqueous solution of the phosphorylcholine structure-containing polymer B, and a polyvalent metal ion.
  • the polyvalent metal ion may be added in advance to the aqueous solution of polymer A or the working solution of polymer B.
  • these polymers are included in the kit in a state filled in a syringe. You may have it.
  • kit of the present invention may further contain a container, a buffer solution, instructions, and the like.
  • the gel composition of the present invention can be used as a tissue adhesion preventing material and a joint contracture preventing material. Therefore, the present invention provides an adhesion prevention material and a joint contracture prevention material. '
  • adheresion means to connect and fuse between organs / tissues to be separated and fibrous tissue.
  • Joint contracture means that joint movement is limited by adhesion of tissues around the joint. ⁇ '
  • prevention means not to cause symptoms, to reduce the degree of occurrence of symptoms, to suppress the progression of symptoms, and the like.
  • the adhesion / contracture prevention material of the present invention preferably has the following characteristics.
  • Biocompatible phospholipid polymer having an acidic group for example, carboxyl group
  • a solution of A (liquid A) containing a phospholipid polymer (phosphorylcholine) containing a polyvalent metal ion.
  • liquid B aqueous solution of polymer structure-containing polymer (B)
  • the viscosity rapidly increases and gels, allowing it to adhere and fix to the damaged tissue surface. That is, the effect can be exerted continuously at the target site without any special fixing treatment.
  • the desired amount can be applied to the desired location without being affected by the size of the surgical field.
  • the gel composition of the present invention has viscoelasticity, it can be molded according to the surgical site. Therefore, it can be handled easily, and can be used for small surgical sites that were difficult with conventional techniques.
  • the gel composition can be produced by modifying the side chain of the liquid B with a polyvalent cation: ionic bond with the hydroxide ion of the liquid A. And, it is possible to control the decomposition rate using these ion concentrations, the composition of the hydrophilic unit, the composition of the hydrophobic unit, etc. as parameters. For example, after a surgical operation for tendon injury, the joint composition is required to be degraded in 3 weeks in order to start joint movement after external fixation for about 3 weeks, but the final concentration of iron chloride is 0.071. If it is ⁇ 0.142M, this decomposition rate can be obtained.
  • the gel composition of the present invention is decomposed into water and a small amount of biocompatible phospholipid polymer solutions A and B in vivo. Some medical materials using these biocompatible phospholipid solutions have already been put into practical use, and their in vivo safety has been confirmed.
  • the biocompatible phospholipid polymer gel has a three-dimensional three-dimensional network structure, and the grid width is nano-order. Therefore, it is possible to prevent the entry of cells that cause adhesion / contracture to the damaged site, but it does not prevent the penetration of humoral factors necessary for healing of the damaged site.
  • the anti-adhesion material of the present invention or the joint contracture-preventing material of the present invention may further contain components such as physiologically active substances and drugs as additives in addition to the gel composition of the present invention.
  • components include physiologically active substances or drugs that promote wound healing, physiologically active substances or drugs that have an anti-inflammatory action, and the like.
  • the present invention also provides an adhesion prevention method and a joint contracture prevention method. Adhesion of tissues by mixing phosphorylcholine structure-containing polymer A and phosphorylcholine structure-containing polymer B in the presence of a polyvalent metal ion near the target site, and covering the desired site with the desired amount of gel composition Or it can prevent contracture of Section W.
  • composition of each monomer unit contained in the polymer was determined according to the following method.
  • NMR-NMR was measured at 30 ° C by JEOL Co., Ltd., Hiichi 500 (500 MHz) using a sample solution in which 20 mg of polymer was dissolved in 1.5 mL of heavy ethanol (d-6). did.
  • the molecular weight was determined by gel permeation chromatography, using polyethylene glycol as the standard substance in a water / methanol (8 Z 2) mixed solvent.
  • Example 3 Synthesis of polymer: (Synthesis of polymer having phosphorylcholine group and carboxyl group)
  • the solution was freeze-dried to obtain a white solid polymer.
  • the yield was 80 g, and the yield was 53%.
  • Example 4 (MPC / BMA copolymer (Example 1) or MPCZSMA copolymer (Example 2), and MPCZMAA copolymer (Example 3))
  • a 5 wt% aqueous solution of the polymer synthesized in Example 1 or Example 2 and a 5 wt% aqueous solution of the polymer synthesized in Example 3 were prepared separately.
  • a predetermined amount of iron chloride was added to the polymer solution of Example 1 or Example 2, and 10 mL each of this solution and the polymer solution of Example 3 were placed in a glass bottle and mixed.
  • the viscosity of the solution increased rapidly and a gel formed immediately (hereinafter also referred to as “MPC polymer gel”).
  • the concentration of iron chloride added is as follows. Polymer Iron chloride final concentration (M)
  • the gel prepared in Example 4 is 37. It was immersed in a phosphate buffer solution of C (pH 7.4) and allowed to stand. 4 The residual rate (% ') was obtained from the change in the weight of the gel after 8 hours. . Polymer Iron chloride final concentration (M) 4 Gel remaining rate after 8 hours
  • Example 2 0.213 9 5%. From this example, it was shown that the decomposition rate of the gel composition of the present invention can be controlled by the iron ion concentration or the polymer composition to be added. ⁇ Reference example>
  • Example 1 As a reference example, for not adding iron chloride gel, the same experiment as in Example 5 rows ivy 0 Polymer Iron chloride final concentration (M) 4 Gel remaining rate after 8 hours. Example 1 0 0%
  • Example 2 0, 0%
  • Example 6 Experiment using mouse phagocytosis model
  • Polymeric microparticles with a diameter of 500 nm labeled with a fluorescent substance were treated with MPC polymer gel and exposed to a mouse macrophage cell line, J774.1 cells.
  • Liquid A aqueous solution of polymer prepared in Example 3
  • liquid polymer aqueous solution prepared in Example 1
  • 0.5 ml were mixed to prepare an MPC polymer gel.
  • 'Final concentrations of added iron ions are 0M, 0.00071M, 0.071M, 0.071M, and' 0.71M, respectively.
  • the silicon pack containing each gel was immersed in 30 ml of PBS. The weight of each silicon pack after 10 minutes, 1 day, 3 days, 7 days, and 14 days was measured.
  • the vertical axis in Figure 2 is the ratio of the weight of the pack after dialysis to the weight of the silicon pack before PBS penetration.
  • the loss of weight can be regarded as the disappearance of the gel in vivo. It was shown that the rate of gel degradation was reduced by the addition of iron ions. That is, by modifying the gel composition of the present invention with iron ions, It was shown that the degradation rate of the gel can be controlled.
  • Example 8 Examination of gel degradation rate by in vivo model
  • a diffusion chamber was fabricated in which cellulose membranes with a pore size of 0.3 zm were attached to both sides of the plastic ring.
  • Three types of MPC polymer gels with different iron ion concentrations were placed in the chamber, and the chamber was implanted subcutaneously in the rat.
  • the chamber was removed 3 weeks later (Fig. 3).
  • Figure 4 shows the results of macroscopic findings.
  • the control MPC polymer gel (iron: 0M) was already liquefied in the first week.
  • Two types of gels other than the control (iron ions: 0.071M, 0.142M) did not show significant changes in the first week.
  • the third week about half of the gel with an iron ion concentration of 0.071M appeared to be liquefied.
  • the gel with iron ion concentration of 0.142M remained almost gel-like.
  • Figure 6 shows a graph of the gel viscoelasticity evaluation results.
  • a gel is a composition having a dynamic modulus of elasticity larger than that of a dynamic loss, and an aqueous solution has a property that the dynamic loss rate exceeds the dynamic modulus of elasticity.
  • Two types of gels iron ions: 0 ⁇ 071 ⁇ , 0.142M) other than the control maintained the gel properties in both the 1M and 3rd weeks, with the dynamic elastic modulus exceeding the dynamic loss rate.
  • the gel-like composition of the present invention modified with iron ions can maintain gel properties for at least 3 weeks subcutaneously in rats.
  • Example 9 Examination of cell adhesion First, the culture surface of the cell culture dish was coated with MPC polymer gel (iron ion: 0.071M), and then the culture medium containing the osteoblast-like cell line MC3T3. The cell adhesion state over time was compared between the dish not coated with MPC polymer gel (control group) and the coated dish. The results after 36 hours of culture are shown in FIG. Cells were not attached to the dish coated with MPC polymer gel, and were floating.
  • the composition was shown to have a cell adhesion inhibitory effect.
  • the gel composition of the present invention since it is clear that the gel composition of the present invention has no cytotoxicity, the gel composition of the present invention is effective as an anti-adhesion material or a joint contracture prevention material.
  • Example 1 0 Usagi flexor tendon. Examination of tendon fusion and adhesion in the injury model The second, third, and fourth toe deep flexor muscle (FDP) tendon of the left forefoot of Usagi was cut with Zonell (Fig. 8) . After the cut tendon was sutured, MPC polymer gel was adhered around the sutured part and closed (Fig. 9). After closing, gypsum's steel wire was used to fix the foot outside. The wound was opened 3 weeks after the operation, the sutured part was observed, and the tendon was collected. Adhesion / union was evaluated by macroscopic findings of sutures and specimens of tendons.
  • the present invention provides a gel composition of the present invention, a tissue adhesion / joint contracture prevention material containing the gel composition of the present invention, and methods for producing them.
  • the gel-like composition of the present invention has a high biocompatibility, so it is difficult to cause a foreign body reaction in the living body, and is safe in the living body even after decomposition. Is
  • the gel-like composition and adhesion / contracture-preventing material of the present invention can control the biodegradation rate depending on the concentration of the polyvalent metal ion to be added. It is possible to control the degradation rate.
  • the gel-like composition and the adhesion / contracture prevention material of the present invention preferably suppress adhesion of cells to the surface and entry of cells to the damaged site, thereby significantly preventing adhesion / contracture. can do. ., ⁇
  • composition according to the present invention preferably has the following characteristics, that is, it quickly gels in a surgical operation in a moist environment, fits into a damaged site, is easy to mold according to the operated site, and is viscoelastic. It is extremely useful as an anti-adhesion material because it has the characteristics of being easy to handle.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Materials For Medical Uses (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Abstract

L’invention concerne une composition de gel contenant un polymère A ayant une structure de phosphorylcholine obtenu par polymérisation d’un monomère ayant une structure de phosphorylcholine et d’un monomère ayant un groupe acide, un polymère B ayant une structure de phosphorylcholine obtenu par polymérisation d'un monomère ayant une structure de phosphorylcholine et d’un monomère ayant un groupe hydrophobe, et un ion métallique polyvalent. L’invention concerne également un procédé de fabrication d’une telle composition.
PCT/JP2006/317152 2005-08-25 2006-08-24 Materiau pour prevenir l'adherence tissulaire et l'arthrogrypose Ceased WO2007024015A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005243984 2005-08-25
JP2005-243984 2005-08-25

Publications (1)

Publication Number Publication Date
WO2007024015A1 true WO2007024015A1 (fr) 2007-03-01

Family

ID=37771741

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/317152 Ceased WO2007024015A1 (fr) 2005-08-25 2006-08-24 Materiau pour prevenir l'adherence tissulaire et l'arthrogrypose

Country Status (1)

Country Link
WO (1) WO2007024015A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007314736A (ja) * 2006-05-23 2007-12-06 Kazuhiko Ishihara 生体成分固定化ポリマー組成物および三次元架橋体
WO2009066746A1 (fr) * 2007-11-22 2009-05-28 The University Of Tokyo Matériau destiné à la prévention de l'adhérence tissulaire et matériau destiné à la prévention des contractures articulaires

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03220120A (ja) * 1989-12-28 1991-09-27 Nitto Denko Corp アクリル系ゲル材およびアクリル系ゲル製剤
WO2000001424A1 (fr) * 1998-07-07 2000-01-13 Nof Corporation Preparation et materiau pour pansement, et methode de traitement des plaies
JP2000111847A (ja) * 1998-09-30 2000-04-21 Nof Corp ソフトコンタクトレンズ材料
JP2001261740A (ja) * 2000-03-14 2001-09-26 Nof Corp 末端官能性ホスホリルコリン類似基含有重合体、製造方法および用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03220120A (ja) * 1989-12-28 1991-09-27 Nitto Denko Corp アクリル系ゲル材およびアクリル系ゲル製剤
WO2000001424A1 (fr) * 1998-07-07 2000-01-13 Nof Corporation Preparation et materiau pour pansement, et methode de traitement des plaies
JP2000111847A (ja) * 1998-09-30 2000-04-21 Nof Corp ソフトコンタクトレンズ材料
JP2001261740A (ja) * 2000-03-14 2001-09-26 Nof Corp 末端官能性ホスホリルコリン類似基含有重合体、製造方法および用途

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007314736A (ja) * 2006-05-23 2007-12-06 Kazuhiko Ishihara 生体成分固定化ポリマー組成物および三次元架橋体
WO2009066746A1 (fr) * 2007-11-22 2009-05-28 The University Of Tokyo Matériau destiné à la prévention de l'adhérence tissulaire et matériau destiné à la prévention des contractures articulaires
JPWO2009066746A1 (ja) * 2007-11-22 2011-04-07 国立大学法人 東京大学 組織癒着防止材および関節拘縮防止材

Similar Documents

Publication Publication Date Title
CN106999270B (zh) 官能化的两性离子和混合电荷聚合物、相关的水凝胶及它们的使用方法
Li et al. Recruitment of multiple cell lines by collagen-synthetic copolymer matrices in corneal regeneration
JPWO2009066746A1 (ja) 組織癒着防止材および関節拘縮防止材
Lanzalaco et al. Polypropylene mesh for hernia repair with controllable cell adhesion/de-adhesion properties
EP2150282B1 (fr) Compositions et procédés pour la formation d'échafaudages
US20240123075A1 (en) N-Oxide and Ectoine Monomers, Polymers, Their Compositions, and Related Methods
US20210023259A1 (en) Poly (ionic liquid) compositions and their use as tissue adhesives
Li et al. Synthesis of thiol-terminated PEG-functionalized POSS cross-linkers and fabrication of high-strength and hydrolytic degradable hybrid hydrogels in aqueous phase
CN109705359B (zh) 一种改性聚乙二醇-聚癸二酸(pegs)可注射生物弹性体及其制备方法和应用
JP2022023994A (ja) タンパク質－ポリマー・コンジュゲートを含む有機溶媒不含組成物および該組成物の使用
Asanuma et al. Hybridization of poly (2-methacryloyloxyethyl phosphorylcholine-block-2-ethylhexyl methacrylate) with segmented polyurethane for reducing thrombogenicity
WO2007024015A1 (fr) Materiau pour prevenir l'adherence tissulaire et l'arthrogrypose
Chen et al. Amorphous zinc phosphate nanoclusters loaded polycarbonate thermosensitive hydrogel: An innovative strategy for promoting wound healing
JP3580022B2 (ja) ブロック共重合体および医療用材料
WO2019183637A1 (fr) Matériaux immunosuppresseurs et procédés associés
JP2008502388A (ja) 隔膜
JP6207520B2 (ja) Ｍｒｉ可視的な疎水性コポリマー
JP7251026B2 (ja) ポリマー化合物およびコーティング組成物
JPH0912904A (ja) 高分子材料、医学材料及び液状高分子組成物
Cano Salazar et al. Nanocomposites Comprise of Collagen and Acrylate-Derived Polymers for Biomedical Applications
Takami et al. Spontaneous formation of a hydrogel composed of water-soluble phospholipid polymers grafted with enantiomeric oligo (lactic acid) chains
WO2023249009A1 (fr) Composé polymère
JPH0691899B2 (ja) 抗血液凝固性高分子材料
JP2006249148A (ja) 静電結合型複合体組成物及び該組成物を用いた生体接着材
HK1260187A1 (en) Organic solvent free compositions comprising protein-polymer conjugates and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06783133

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP