JP2006335658A - Patency-enhancing sheet and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a patency-enhancing sheet that is kept indwelled as it is in a subcutaneous tissue of a portion having been subjected to a surgery treatment of a living organism so that it covers the treated portion and is sutured. <P>SOLUTION: The manufacturing method of the patency-enhancing sheet comprises planarly spreading an aqueous solution comprising a visible light-crosslinkable substance such as eosinated gelatin, a hydrogen donor and at least one selected from among argatroban, statin and tacrolimus, and radiating it with visible light to photocrosslink and insolubilize the substance. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for manufacturing a patency improving sheet used after surgery such as cardiac bypass surgery and aneurysm clip occlusion, and a patency improving sheet manufactured by this method.

  After surgery such as cardiac bypass or aneurysm clip occlusion, heparinization treatment is performed in the short term in order to prevent occlusion of blood vessels connected by baopath, that is, to improve patency. In the long term, thrombus inhibitors such as warfarin potassium are administered medically.

  Medical systemic therapy is performed mainly for heparinization to improve patency, but it is difficult to apply to patients with a tendency to bleed and sometimes severe, such as multiple organ bleeding Side effects are also a problem.

  Thrombolytic agents that are followed up in the medium to long term continue even after the patient is discharged, and treatment such as tooth extraction is contraindicated and is harmful.

  An object of this invention is to provide the patency improvement sheet | seat used as it is left as it is so that it may cover the biological tissue which carried out the surgical treatment, and it sews.

The method for producing a patency improving sheet of the present invention (Claim 1) comprises the following compound (A), a hydrogen donor, mycophenolate mofetil, azathioprine, mizolymbin, methotrexate, prednisolone, methylprednisolone, cyclosporine, cyclophosphine From famide, lopenzalit, actarit, salazosulfapridin, tacrolimus, alteplase, nasarplase, warfarin potassium, cilostazol, pretal, ticlopidine hydrochloride, urokinase, ethyl icosapentate, sarpogrelate hydrochloride, thixonase, beraprost sodium, aspirin, heparin, and argatroban An aqueous solution containing at least one selected from the above is spread into a surface and irradiated with visible light to be photocrosslinked / insolubilized. The one in which the features.
(A) collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin, entactin, gazein, polyethylene glycol, modified with xanthene dye Polypropylene glycol, polyglycidol, side chain esterified product of polyglycidol, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide And at least one selected from the group consisting of polyvinylpyrrolidone.

  The method for producing a patency improving sheet according to claim 2 is characterized in that, in claim 1, the thickness of the aqueous solution extending in a planar shape is 100 μm to 5 mm.

  The method for producing a patency improving sheet of claim 3 is characterized in that in claim 1 or 2, the aqueous solution is dried after spreading, and then the visible light is irradiated.

  The method for producing a patency improving sheet according to claim 4 is the method according to any one of claims 1 to 3, wherein the hydrogen donor is thiol, alcohol, reducing sugar, polyphenol, or at least one N-alkyl in one molecule and It is a compound having an N, N-dialkylamino group.

  The method for producing a patency improving sheet according to claim 5 is characterized in that, in any one of claims 1 to 4, the xanthene dye is eosin.

  The method for producing a patency improving sheet of claim 6 is characterized in that, in any one of claims 1 to 5, (A) is gelatin.

  The method for producing a patency improving sheet according to claim 7 is characterized in that, in claim 6, gelatin is one in which 1 to 10 xanthene dye molecules are introduced in one molecule.

  The method for producing a patency improving sheet of claim 8 is characterized in that, in claim 7, gelatin is one in which 2 to 6 xanthene dye molecules are introduced in one molecule.

  A patency improving sheet according to a ninth aspect is manufactured by the manufacturing method according to any one of the first to eighth aspects.

  Immunosuppressants such as mycophenolate mofetil, azathioprine, mizolimbin, methotrexate, prednisolone, methylprednisolone, cyclosporine, cyclophosphamide, lopenzalit, actarit, salazosulfapridin, and tacrolimus reduce the proliferation of smooth muscle cells in the vascular wall. It suppresses and has an effect of suppressing thickening of the intima.

  Anticoagulants such as alteplase, nasarplase, warfarin potassium, cilostazol, pretal, ticlopidine hydrochloride, urokinase, ethyl icosapentate, sarpogrelate hydrochloride, thixonase, beraprost sodium, aspirin, heparin, argatroban have thrombus generation suppression or thrombolytic effects .

  Statins are not meant to inhibit LDL biosynthetic enzymes in the liver, but suppress intimal thickening by local anti-inflammatory action.

  In the patency improving sheet and the method for producing the same according to the present invention, a biodegradable water-soluble polymer compound modified with a xanthene dye is crosslinked by irradiating visible light in the presence of a hydrogen donor. Can be insolubilized. This aqueous solution contains mycophenolate mofetil, azathioprine, mizoline, methotrexate, prednisolone, methylprednisolone, cyclosporine, cyclophosphamide, lopenzalit, actarit, salazosulfapridin, tacrolimus, alteplase, nasalplase, warfarin potassium, cilostazol hydrochloride, cilostazol hydrochloride, Since ticlopidine, urokinase, ethyl icosapentate, sarpogrelate hydrochloride, thixonase, beraprost sodium, aspirin, heparin, argatroban and statin are contained, the argatroban and the like are contained in the gel sheet. This argatroban or the like is directly diffused and released from the gel sheet. The polymer compound that is the gel substrate is biodegraded and gradually absorbed into the living body.

  In the present invention, the aqueous solution of the polymer compound is spread and photocrosslinked in this way, and no organic solvent is used for preparation. Therefore, no organic solvent remains in the gel.

  The gel constituting the prepared patency improving sheet is flexible, and can be placed and sutured as it is so as to cover a living tissue such as a surgically treated heart wall. Since the indwelling gel-like sheet is flexible, the living tissue is not extremely compressed.

  Since this gel-like sheet is prepared by crosslinking with visible light, there is little risk of generating harmful decomposition products, and the activity of drugs that are sensitive to light is not impaired.

  Hereinafter, the present invention will be described in more detail.

  In the present invention, the substance (A) is used as a substance that gels by generating radicals by irradiation with visible light.

  As the xanthene dye in the compound (A), eosin is preferable, and as the substance (A), eosinized gelatin is preferable. This eosinized gelatin will be described later.

  When gelatin is modified with a xanthene dye, the number of xanthene dye molecules introduced per molecule of gelatin is preferably 10 or less, and particularly preferably 2 to 6. When this introduction number is more than 10, gelatin becomes hardly soluble in water, and eventually the patency improving sheet becomes hard.

  In the present invention, a hydrogen donor is used as a proton donor which is a radical counter. As the hydrogen donor, thiol, alcohol, reducing sugar, polyphenol, a compound having at least one N-alkyl and / or N, N-dialkylamino group in one molecule, and the like are preferable, and particularly in one molecule. Compounds having at least one N-alkyl and / or N, N-dialkylamino group are preferred.

  In the present invention, the aqueous solution further contains at least one of argatroban, statin and tacrolimus (hereinafter sometimes referred to as argatroban).

  The concentration of the substance (A) in the aqueous solution is preferably about 0.1 to 50% by weight.

  The ratio of the above (A), hydrogen donor, argatroban, etc. in the aqueous solution is 0.01-150 parts by weight of hydrogen donor and 0.01-150 parts by weight of argatroban, etc. with respect to 1 part by weight of (A). Preferably there is.

  This aqueous solution is preferably spread in a planar shape so as to have a thickness of about 100 μm to 5 mm, and is photocrosslinked and insolubilized by irradiation with visible light to obtain a patency improving sheet.

  The spreading may be performed by pouring or pouring the aqueous solution into or out of the mold, or may be performed by applying to the mold with a brush or a spatula. The molding surface of the mold may be a flat surface or a curved surface. The sheet may be spread like a curtain from a nozzle having a slit-like opening.

  After this spreading, drying may be performed. When the molding surface is a curved surface, it is preferable to perform drying. When a molding die in which at least a part of the molding surface is a curved surface is used, a curved sheet can be molded so as to roughly match the curved surface of the organ.

  Next, eosinized gelatin suitable for use in the present invention will be described.

  Here, the gelatin may be a normal gelatin having a molecular weight of 5,000 to 100,000 and an amino group of about 10 to 100 per molecule.

  Eosinized gelatin is prepared by introducing eosin into the side chain of gelatin according to the following reaction.

  The number of eosin introduced into the gelatin molecule can be calculated based on, for example, the absorbance of an aqueous solution of eosinized gelatin measured at the maximum absorption wavelength of eosin at 522 nm and the molar extinction coefficient of eosin (ε = 94755). The number is preferably 1 to 10, more preferably about 2 to 5, with respect to the molecule. If the number of compounds having a photosensitive group such as eosin is small, the gelation rate is lowered, and if it is larger than necessary, the inherent flexibility of gelatin may be impaired, and it may be hardly soluble in water. , Biodegradability may be impaired.

  This eosinized gelatin is a viscous liquid. For example, when an aqueous solution having a concentration of 1 to 10% by weight is used, visible light having a relatively low illuminance of about 300 to 30,000 lx, particularly about 300 to 15,000 lx, and having a low influence on the living body is reduced to about 0.1%. It can be cured in a gel form by irradiation for about 1 to 30 minutes.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples.

Example 1
[Synthesis of eosinized gelatin]
In the presence of gelatin (molecular weight 95,000, amino group content approximately 37 / molecule) and water-soluble carbodiimide N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide (WSC), By attaching eosin to the amino group of the side chain, about 5 eosin was introduced per gelatin molecule to synthesize eosinized gelatin.

[Preparation of solution containing polymer modified with xanthene dye, hydrogen donor and argatroban]
The synthesized eosinized gelatin was dissolved and mixed to a final concentration of 10% by weight, 1,1,4,7,10,10-hexamethyltriethylenetetramine to a final concentration of 1.2% by weight, and argatroban to a final concentration of 5% by weight. And a solution containing a polymer compound modified with a xanthene dye, a hydrogen donor, and argatroban.

[Create patency improvement sheet]
As a thickness of 200μm to radiation sterilized Petri dish, was spread by pouring the solution, Tokuso power lights (Tokuyama, halogen lamp, wavelength 400 nm to 520 nm) so as to be irradiation intensity 200 mW / cm ² at Was insolubilized by irradiation with visible light for 20 minutes. After the cross-linking, a red elastic flexible sheet derived from eosin was obtained.

  It was confirmed that argatroban was released for about 5 days after immersion when this sheet was immersed in raw food and argatroban was detected over time.

[Evaluation of patency improvement]
The abdominal aorta of two mice was excised from a 20 mm long exfoliated incision, exchanged with each other and sutured with a host blood vessel, and the prepared sheet was covered and covered so as to cover the transplant site. When angiography was performed 3 days later, it was confirmed that there was no stenosis and the patient was patent.

Claims (9)

A compound of the following (A);
With hydrogen donors,
Mycophenolate mofetil, azathioprine, mizolimbin, methotrexate, prednisolone, methylprednisolone, cyclosporine, cyclophosphamide, lopenzalit, actarit, salazosulfapridin, tacrolimus, alteplase, nasalplase, warfarin potassium, cilostazol, pitaline hydrochloride At least one selected from ethyl icosapentate, sarpogrelate hydrochloride, thixonase, beraprost sodium, aspirin, heparin, argatroban and statin,
A method for producing a patency-improving sheet, which comprises spreading an aqueous solution containing a surface to form a photocrosslink and insolubilizing it by irradiation with visible light.
(A) collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin, entactin, gazein, polyethylene glycol, modified with xanthene dye Polypropylene glycol, polyglycidol, side chain esterified product of polyglycidol, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide And at least one selected from the group consisting of polyvinylpyrrolidone.   The method for producing a patency improving sheet according to claim 1, wherein the thickness of the aqueous solution spreading in a planar shape is 100 μm to 5 mm.   3. The method for producing a patency improving sheet according to claim 1, wherein the aqueous solution is dried after spreading and then irradiated with the visible light.   4. The hydrogen donor according to claim 1, wherein the hydrogen donor is a thiol, an alcohol, a reducing sugar, a polyphenol, or a compound having at least one N-alkyl and / or N, N-dialkylamino group in one molecule. The manufacturing method of the patency improvement sheet | seat characterized by the above-mentioned.   5. The method for producing a patency improving sheet according to claim 1, wherein the xanthene dye is eosin.   The method for producing a patency improving sheet according to any one of claims 1 to 5, wherein (A) is gelatin.   7. The method for producing a patency improving sheet according to claim 6, wherein gelatin contains 1 to 10 xanthene dye molecules introduced in one molecule.   8. The method for producing a patency improving sheet according to claim 7, wherein the gelatin is obtained by introducing 2 to 6 xanthene dye molecules into one molecule.   A patency improving sheet produced by the production method according to any one of claims 1 to 8.