JP4500989B2 - Photo-curable bioabsorbable material - Google Patents

Description

  The present invention relates to a photocurable bioabsorbable material and a photocurable biological tissue fixing material. Specifically, the present invention relates to a photocurable biological tissue immobilization material that is obtained by curing a biodegradable polymer having a double bond with light to be immobilized on the biological tissue.

  During the surgical operation, soft tissues such as skin and organs are joined in the living body for a period of 1 to 2 weeks until the damaged tissue is restored to its original form and the wound is healed by its own tissue regeneration and repair function. It is necessary to withstand the pulsating pressure, contraction force, or external force to maintain the bonding force.

Conventionally, anastomosis using a suture needle and a suture is generally performed for joining tissues. As an alternative tissue bonding method, a method using an adhesive has been developed for a long time. (1) Cyano, which utilizes the fact that a liquid cyanoacrylate monomer is polymerized and cured by moisture in a short time. Acrylate-based adhesive (Non-patent Document 1), (2) Fibrin glue using a mechanism of blood coagulation in vivo in which fibrinogen forms an insoluble fibrin clot by the action of thrombin (Non-patent Document 2), (3) A gelatin-based adhesive in which gelatin and resorcinol are crosslinked with formalin has been put into practical use. (Non Patent Literature 3)
Tseng YC; Tabata Y .; Hyon SH; Ikada Y. In vitro toxicity test of 2-cyanoacrylate polymers by cell culture method.J. Biomed. Mater. Res. 24: 1355-1367; 1990. Matras H. Fibrin seal: the state of the art.J. Oral Maxillofac Surg. 43: 605-611; 1985. Bachet, J .; Goudot, B .; Dreyfus, G .; Banfi, C .; Ayle, NA; Aota, M .; Brodaty, D .; Dubois, C .; Deleutdecker, P .; Guilmet, D. The proper use of glue: a 20-year experience with the GRF glue in acute aortic dissection.J. Card. Surg. 12: 243-253; 1997.

  Cyanoacrylate adhesives have excellent fast-curing properties and high adhesion to tissues. On the other hand, cured products lack flexibility and are extremely hard compared to soft biological tissues. And may interfere with wound healing. In addition, since decomposition in a living body is slow from half a year to one year, it is easily encapsulated and becomes a foreign substance. Furthermore, there are problems such as the generation of highly toxic formaldehyde during decomposition. Fibrin glue has insufficient adhesion to living tissue, and cannot easily follow the movement of the tissue and easily peels from the tissue. Moreover, since it is a human blood product, there is a concern about viral infections such as hepatitis and AIDS. Furthermore, there is a problem that it is more expensive than other tissue adhesives and is difficult to use in large quantities. Gelatin-based adhesives exhibit high tissue adhesion, but it has been pointed out that formalin, which is a cross-linking agent for gelatin, causes a cross-linking reaction with in vivo proteins and exhibits toxicity.

  In order to solve the above-mentioned problems, the present invention provides a photocurable polymer material having a strong affinity for a living tissue having flexibility.

  The present invention is also capable of firmly adhering to a living tissue by quickly curing on the surface of a moist living tissue by a simple light irradiation operation without using a toxic chemical, and the cured product is flexible and biodegradable. An object of the present invention is to provide a medical tissue adhesive in which the degradation product does not exhibit toxicity.

The present invention relates to the following photocurable biological tissue fixing material and photocurable biological tissue fixing material.
1. A photocurable bioabsorbable material having the following repeating units (I) and (III) and further containing the repeating unit (II) as required:
(I) Repeating unit derived from aliphatic dicarboxylic acid and / or aliphatic hydroxycarboxylic acid (II) Repeating unit derived from glycidol represented by the following formula
_{- {OCH 2 CH (CH 2} OH)} -
Or
_{- {OCH 2 CH (OH)} CH 2} -
(III) A repeating unit represented by the following formula having a photocurable group
_{- {OCH 2 CH (CH 2} OR)} -
Or
_{- {OCH 2 CH (OR)} CH 2} -
{Wherein R represents a photocurable group having a double bond}.
2. Further having a photoreactive compound The photocurable bioabsorbable material described in 1.
3. 1 above. A photocurable biological tissue immobilization material comprising the material described in 1.

Hereinafter, the present invention will be described in more detail.
(I) Repeating unit derived from aliphatic dicarboxylic acid and / or aliphatic hydroxycarboxylic acid As aliphatic dicarboxylic acid, succinic acid, oxalic acid, malonic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid , Sebacic acid, malic acid, tartaric acid, and aliphatic hydroxycarboxylic acids include glycolic acid, lactic acid, glyceric acid, tartronic acid, and the like.
(II) Repeating unit derived from glycidol The repeating unit represented by the following formula (II) can be exemplified:
_{- {OCH 2 CH (CH 2} OH)} - or _{- {OCH 2 CH (OH)} CH 2} - (II)
The repeating unit of the formula (II) is formed when the epoxy group of glycidol is ring-opened, and forms an ester bond with the dicarboxylic acid or hydroxycarboxylic acid corresponding to the repeating unit (I), or the glycidol is polymerized. An ether bond is formed. If the glycidol proton moves when the base attacks the epoxy ring and cleaves, a repeating unit represented by “— {OCH ₂ CH (OH) CH ₂ } —” is generated.
(III) Repeating unit having a photocurable group The repeating unit represented by the following formula (III) can be exemplified:
_{- {OCH 2 CH (CH 2} OR)} - or _{- {OCH 2 CH (OR)} CH 2} - (III)
{Wherein R represents a photocurable group having a double bond}.

  The repeating unit of the formula (III) is a carboxylic acid compound represented by R—OH (for example, may have a substituent (o-, m-, p-) styrene carboxylic acid, acrylic acid, methacrylic acid and the like) and dehydrating condensation, and introducing a photopolymerizable group represented by R through an ester bond. Examples of the substituent of (o-, m-, p-) styrene carboxylic acid include halogen atom (F, Cl, Br, I), OH, methoxy, ethoxy, methyl, hydroxymethyl, cyano, amino and the like. .

The photocurable group represented by R introduced into the raw material polymer widely includes those having a double bond capable of radical polymerization by light. Preferred photocurable _{group, CH 2 = CH-C 6} H 4 -CO-, CH 2 = CH-CO-, CH 2 = CH (CH 3) into -CO- such a molecule having a double bond As long as it is any one, preferably CH ₂ ═CH—C ₆ H ₄ —CO—. Introduction of a photocurable group having a double bond is 1-ethyl-3-(-dimethylaminopropyl) carbodiimide hydrochloride or 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide meso-p-toluenesulfone. It is preferable to carry out by ester linkage using a water-soluble carbodiimide-based coupling reagent such as acid, but chemical coupling by a bivalent crosslinking reagent such as ethyl chloroformate, carbonyldiimidazole, dimethyladipine imidate, disuccinimidyl suberate, etc. It may be introduced via. Further, a polyethylene glycol chain or a long alkyl chain may be introduced as a spacer in the bond between the raw polymer and the photocurable group.

  The starting polymer having the repeating unit of the formula (I) and the repeating unit of the formula (II) is known or can be easily synthesized according to a known method using a known monomer.

In the reaction of the raw polymer with the carboxylic acid compound, when all CH ₂ OH of the repeating unit of the formula (II) is converted to CH ₂ OR (R is as defined above), There will be no repeat unit of formula (II) in the curable polymer. However, normally, the OH groups of the repeating unit of the formula (II) are not all converted to OR groups. Usually, in the photocurable bioabsorbable material of the present invention, the repeating unit of the formula (II) Exists.

In the photocurable polymer of the present invention, the molar ratio of the repeating units (I) to (III) is:
Repeating unit (I): Repeating unit (II): Repeating unit (III) =
0 to 80 mol%: 0 to 80 mol%: 5 to 50 mol%; preferably
30-75 mol%: 0-40 mol%: 10-30 mol%; more preferably
45-70 mol%: 20-30 mol%: 15-25 mol%.

  The molecular weight of the photocurable polymer of the present invention is about 300 to 30000, preferably about 2500 to 10,000, and more preferably about 3000 to 4000. The molecular weight can be measured by GPC method.

  In one of the preferred embodiments, the features of the photocurable living tissue immobilization material of the present invention are specifically listed: (1) it can be quickly gelled by a light irradiation operation, and (2) in the presence of water such as body fluid and blood. (3) Hardened gel has physical flexibility that can follow the movement of living tissue, and flexibility can be easily changed by changing the type and content of each repeating unit. It is adjustable, and (4) it is excellent in biocompatibility due to the use of an aliphatic ester, and (5) it has biodegradability, and the degradation product has low toxicity or non-toxicity.

  The polymer of the present invention is synthesized from a polyester having a reactive side chain, and the polyester having a reactive side chain is prepared by utilizing a monomer having an epoxy ring such as a glycidyl compound, polyaddition with a dicarboxylic acid, a lactone, an acid. It is synthesized by ring-opening copolymerization with an anhydride or the like. It is also possible to change the type of reactive side chain by appropriately selecting the monomer.

  The compound for introducing the photocurable group R having a double bond may be any radically polymerizable monomer, oligomer, or polymer, and a polyfunctional vinyl such as bifunctional or trifunctional. Compounds are preferred. One preferred embodiment is polyethylene glycol diacrylate having a molecular weight of about 1000.

  The material of the present invention preferably promotes photocuring by using a polymer having repeating units (I) to (III) and a photoreactive compound in combination.

  Photoreactive compounds are organic compounds that generate radicals upon irradiation with light. For example, carbonyl compounds such as camphorquinone, acetophenone, benzophenone, dimethoxyphenylacetophenone and their derivatives, sulfur compounds such as dithiocarbamate, xanthate, thiophenol, and the like Derivatives thereof, peroxides such as benzoyl peroxide, butyl peroxide and derivatives thereof, azobis compounds such as azobisisobutyronitrile, azobisisobutyric acid ester and derivatives thereof, halogen compounds such as bromopropane, chloromethylnaphthalene and the like Derivatives thereof, azide compounds such as phenyl azide and derivatives thereof, xanthene dyes such as rhodamine, erythrone, fluorescene, eosin and the like Derivatives, riboflavin and at least one selected from the group consisting of derivatives thereof, or a mixture to which a proton donor such as amines is added, preferably camphorquinone alone or further mixed with dimethylaminoethyl methacrylate . In the case where the photoreactive compound is a photoreactive raw material polymer in which the photoreactive compound is introduced into the side chain of the raw material polymer, the paste made of the photoreactive raw material polymer not using the raw material polymer is also immobilized. It can be used as an agent.

  The photoreactive compound is used in an amount of about 0.01 to 10 parts by weight, preferably about 0.1 to 5 parts by weight, more preferably about 0.5 to 3 parts by weight per 100 parts by weight of the photocurable polymer of the present invention. it can.

  The light source in the light irradiation is, for example, a halogen lamp, a xenon lamp, an incandescent lamp, a mercury lamp, an excimer laser, an argon ion laser, or the like, preferably a halogen lamp, and preferably a light having a wavelength of 300 to 500 nm. The irradiation time is preferably about 1 minute.

  Curing of the photocurable tissue adhesive of the present invention proceeds by the following mechanism. First, when a photoreactive compound is irradiated with light, radicals are generated. The polymerization reaction of the photocurable group contained in the raw material polymer is initiated by the generated radical. Further, when a vinyl compound is present, a copolymerization reaction with a raw material polymer occurs. By these polymerization reactions, cross-linking occurs between the raw material polymers or even between the vinyl compounds to give a gel-like cured product.

  According to the present invention, a medical tissue comprising a mixed aqueous solution obtained by mixing a polyester-based raw material polymer having a photocurable group at least in part with a photoreactive compound in a gel form by light and adhering to a living tissue. Adhesive can be provided. With this tissue adhesive, it is possible to quickly adhere to a living tissue or to join tissues without damaging the living tissue simply by irradiating light. In addition, the tissue adhesive component, the cured product, and the decomposition product are all non-toxic. Use of this tissue adhesive not only simplifies the operation and shortens the operation time, but also provides hemostasis for bleeding from the site of adhesion detachment, liver, spleen, and other organs, or filling from the dead space It is possible to provide a new procedure that cannot be performed by the suturing method. Moreover, it is also possible to use the polyether which is a glycidol polymer instead of polyester. The reactive side chain can also be used as a bioabsorbable material having a drug sustained-release function by introducing a drug in addition to the introduction of a photocurable group.

Next, the present invention will be specifically described with reference to examples.
Synthesis example 1
Synthesis of biodegradable polymer having reactive side chain Glycidol and ε-caprolactone were mixed in 0.1 mol each, 0.5 mol% of crushed sodium hydroxide was added, and the mixture was stirred at 60 ° C. for 72 hours. Other basic reagents such as magnesium ethoxide can be substituted for the initiator. Purification was performed by dissolving in a methanol / chloroform mixed solution and then reprecipitating from petroleum ether. The mixed solvent at the time of purification is changed depending on the composition ratio of the copolymer, and the mixing ratio is between 10/0 and 1/10, centering on 75/25. After drying under reduced pressure, a pasty copolyester ether was obtained in a yield of 80%.

FIG. 1 shows the ¹ H-NMR data of the obtained copolymer of ε-caprolactone and glycidol.
Synthesis example 2
A copolymer of succinic anhydride and glycidol was obtained in the same manner as above except that succinic anhydride was used instead of ε-caprolactone.

FIG. 2 shows the ¹ H-NMR data of the obtained copolymer of succinic anhydride and glycidol.

  Table 1 shows the measurement results of the yield, the molecular weight measured by the GPC method, the copolymerization ratio, and the viscosity when the catalyst and the charging ratio are changed as described in Table 1.

Synthesis example 3
Synthesis of vinylated polyesters of copolymers of succinic anhydride and glycidol
To a 100 mL two-necked flask, 20 mL of DMF and 4-vinylbenzoic acid (18 mmol, 2.66 g) were sequentially added and dissolved by stirring while cooling with ice in a nitrogen atmosphere. DMF (15 mL) was placed in another flask, and DCC (19 mmol, 4.0 g) was dissolved while cooling in an ice bath. This was added dropwise to the previous solution over 30 minutes under ice cooling. The mixed solution was returned to room temperature and stirring was continued for 1 hour. 2.5 g of the ring-opening copolymer obtained in Synthesis Example 2 was placed in another flask and dissolved in 15 mL of DMF. This was added dropwise to the above mixed solvent over 30 minutes under ice cooling. The reaction solution was returned to room temperature and stirring was continued overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Extraction with methanol from the obtained residue and concentration with an evaporator gave the desired vinylated polyester. The yield was 40%, and the rate of introduction of vinyl side chains was about 1 per 1000 molecular weight.

The results of introduction of the vinylated polyester obtained under various conditions are shown in Table 2, and ¹ H-NMR data of the vinylated polyester obtained with run ¹ are shown in FIG. In Table 2, WSC means water-soluble carbodiimide, SA means succinic anhydride, and GL means glycidol.

Synthesis example 4
Synthesis of acrylic esters
Except for using equimolar acrylic acid in place of 4-vinylbenzoic acid and using the ring-opening copolymer obtained in Synthesis Example 1 instead of the ring-opening copolymer obtained in Synthesis Example 2. In the same manner as in Synthesis Example 3, a polyester in which an acrylic acid group was introduced into poly (ε-caprolactone / glycidol) was obtained. It was confirmed by ¹ H-NMR data that the polyester was obtained. ^{The 1} H-NMR data is shown in FIG.
Example 1
Photocurability of photocurable bioabsorbable immobilizing material 30 mg (Wa) of the photocurable material of the present invention obtained in Synthesis Examples 3 and 4 was added to camphorquinone (CQ) and 2-dimethylaminoethyl methacrylate (DMAEMA). Are mixed at 0.5 wt% and 1.5 wt%, respectively, and visible light from a halogen lamp (Tokuso, power light, irradiation wavelength: 400-600 nm, irradiation intensity: 200 mW / cm ² ) on a glass petri dish for a predetermined time Irradiated. Chloroform was added to the irradiated product and left for 30 minutes. The non-gelling part dissolved in chloroform was removed as a chloroform solution, vacuum-dried and then weighed (Wb) to determine the gelation rate. Further, water was added to the gelled sample, and after standing for 30 minutes, the water was removed, the weight was measured (Wc), and the degree of swelling was measured.

  The results of using the photocurable material of Synthesis Example 4 are shown in Table 3.

  In Table 3, run1 is obtained by introducing 50% of an acrylic acid group (relative to the glycidol residue) into a copolymer of ε-caprolactone / glycidol = 50/50 (molar ratio). ) :( II) :( III) = 50: 25: 25 (molar ratio)).

  run2 is a copolymer of ε-caprolactone / glycidol = 50/50, in which 25% of an acrylic acid group is introduced (relative to the glycidol residue) (in the repeating unit, (I) :( II) :( III) = 50: 37.5: 12.5 (molar ratio)).

  run 3 is a homopolymer of glycidol with 50% acrylic acid group introduced.

  The gelation rate of the vinylated polyester was determined from (Wb-Wa) / Wa × 100 (%), and the swelling degree of the resulting gel was determined from (Wc-Wb) / Wb. About 70% of gelation was converted by irradiation for 1 minute, and the gelation rate did not change much after longer irradiation (run 2). In addition, the amount of gel formation tended to increase as the amount of photocurable group introduced into the vinylated polyester increased. Furthermore, even a vinylized glycidol homopolymer (polyether) could be photocured.

Moreover, the result of a time-dependent change of what introduce | transduced 4-vinylbenzoic acid group into (succinic anhydride / glycidol) of the synthesis example 3 is shown in FIG.
Example 2
Hydrolyzability of photocured tissue fixing agent Gel (10 mg) of vinylated polyester of (succinic anhydride / glycidol) prepared based on Example 1 was added to a buffered aqueous solution adjusted to a predetermined pH, and 37 ° C. It was made to shake in the constant temperature bath. The solution was collected after a predetermined time. This was filtered through a filter (DISMIC-25HP, 20 μm) to remove insolubles. One drop of 6N HCl aqueous solution was added to the filtrate, and the carbon concentration derived from organic substances dissolved in the aqueous solution was measured using a total organic carbon meter (Shimadzu Corporation, TOC-5000A). The results are shown in FIG. The gel was shaken in a pH 7 1% PBS solution. There was almost no change in shape even after 24 hours. On the other hand, when it was shaken in sodium hydroxide at pH 13, the concentration of organic carbon in the solution increased with time. It can be said that the gel obtained from vinylated polyester is hydrolysable.
Example 3
Application to electrode coating The kidney sympathetic nerve or decompression nerve of the vagina was exposed, and the stainless steel wire electrode in which each nerve bundle was wound at an interval of about 1 mm was pulled up and separated from the living tissue. Vinylated polyester was applied to the electrode part. Since the polyester has an appropriate viscosity, it can be limited to a local area. When the coated portion was irradiated with a halogen lamp, the polyester hardened in a gel state, and the cured product did not dissolve even when washed with physiological saline. Moreover, it was possible to acquire an active electrical signal from the nerve bundle in a state of being in contact with the tissue after being cured.

  FIG. 7 shows the result of immobilization of the electrode on the decompression nerve. As shown in FIG. 6, the potential signal did not change before and after the light treatment, indicating that it is effective as a fixing agent.

  The results of immobilizing the electrodes on the kidney sympathetic nerve are shown in FIG. As shown in FIG. 7, the potential signal did not change before and after the light treatment, indicating that it is effective as a fixing agent.

The ¹ H-NMR data of the copolymer of ε-caprolactone and glycidol obtained in Synthesis Example 1 are shown. The ¹ H-NMR data of the copolymer of succinic anhydride and glycidol obtained in Synthesis Example 2 are shown. ¹ H-NMR data of the vinylated polyester obtained in Synthesis Example 3 are shown. Synthesis Example Poly obtained in 4 (.epsilon.-caprolactone / glycidol) shows a ¹ H-NMR data of the polyester obtained by introducing an acrylic acid group. The photocurability of what introduce | transduced 4-vinylbenzoic acid group into (succinic anhydride / glycidol) is shown. The hydrolyzable result of the photocured tissue fixing agent of Example 2 is shown. In FIG. 6, the total organic carbon concentration represents the concentration of an organic component solubilized as a result of hydrolysis in an aqueous solution. The result of fixation to the decompression nerve of an electrode is shown. The result of the fixation | immobilization to the kidney sympathetic nerve of an electrode is shown.

Claims (3)

Comprising a photocurable bioabsorbable material have the following repeating units (I) and (III), photocurable biological tissue immobilizing material:
(I) an aliphatic dicarboxylic acid and / or repeating units of derived from an aliphatic hydroxycarboxylic acid
( III) Repeating unit represented by the following formula having a photocurable group-{OCH ₂ CH (CH ₂ OR)}-
Or _{- {OCH 2 CH (OR)} CH 2} -
{Wherein R represents a photocurable group having a double bond}. A photocurable biological tissue immobilization material having the following repeating units (I) and (III) and further including a photocurable bioabsorbable material containing the repeating unit (II):
(I) Repeating units derived from aliphatic dicarboxylic acids and / or aliphatic hydroxycarboxylic acids
(II) A repeating unit derived from glycidol represented by the following formula
-{OCH ₂ CH (CH ₂ OH)}-
Or
-{OCH ₂ CH (OH) CH ₂ }-
(III) A repeating unit represented by the following formula having a photocurable group
-{OCH ₂ CH (CH ₂ OR)}-
Or
-{OCH ₂ CH (OR) CH ₂ }-
{Wherein R represents a photocurable group having a double bond}. The photocurable biological tissue immobilization material according to claim 1 or 2, wherein the photocurable bioabsorbable material further comprises a photoreactive compound.

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