JP4718766B2 - Blood filter - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a medical device that can reduce damage to biological components when used in contact with in vivo tissues and blood, and a method for manufacturing the same.
[0002]
[Prior art]
When a biological component such as blood comes into contact with the surface of the medical material, nonspecific adsorption, denaturation, and multilayer adsorption of the protein in the biological tissue occur, and activation of the coagulation system, complement system, platelet system, and the like occurs. Therefore, in developing a medical device, it is indispensable to impart blood compatibility to the surface of a medical material that is a contact interface with a living body. Specifically, excellent blood compatibility is required for medical devices such as artificial lung devices, dialysis devices, blood storage bags, platelet storage bags, blood circuits, indwelling needles, catheters, guide wires, and stents. In blood filters used in the field of blood transfusion, side effects that are considered to be based on activation of the coagulation system and the complement system have become a problem during blood filtration. Therefore, it is necessary to suppress blood activation (coagulation system, complement system, platelet system) that causes the above-mentioned side effects. For example, the production of bradykinin, which is a representative example of activation of the coagulation system and complement system, is known to be triggered by contact activities such as adsorption of coagulation factor XII, which is a plasma protein, and denaturation on the blood filter surface. ing. Therefore, if it is possible to suppress damage to blood components during filtration, it is considered that side effects during blood transfusion can be reduced.
[0003]
As a known medical material that is considered to have little adhesion of blood components at the time of contact with blood, a medical material mainly composed of 2-hydroxyethyl methacrylate (HEMA) or polyvinyl alcohol is known (non-patented). Reference 1 or Non-Patent Document 2), in addition to soft contact lenses, it is used as a carrier for artificial vitreous and drug delivery systems. However, since it has a hydroxyl group, activation of the complement system occurs and is a problem.
In addition, medical devices having a polymer material containing acrylamide as a main component on the surface are known, and since they do not contain hydroxyl groups, they are used without activating the complement system. When activated and the blood is returned to the body, there is a problem of inducing thrombus formation.
[0004]
Examples of other medical materials include polyethylene glycol (poly (ethylene glycol), PEG) (see Non-Patent Document 3 or Non-Patent Document 4). PEG has very good blood compatibility, and many applied studies in the medical field have been conducted. However, since PEG is water-soluble, when it is used as a medical material, it needs to be used as a block copolymer or graft copolymer with another polymer. Moreover, although the method of modifying the material surface with a PEG chain | strength using plasma activation is also known, an advanced technique and equipment are required.
As described above, in a medical device used in contact with a conventional in vivo tissue or blood, it is possible to easily obtain a synthetic polymer material that satisfies the function of suppressing the activation of the coagulation system, the complement system, or the platelet system. could not.
[0005]
[Non-Patent Document 1]
Nobuo Nakabayashi, Kazuhiko Ishihara, Yasuhiko Iwasaki, “Biomaterial”, Corona, 1999 [Non-Patent Document 2]
Tsuruta, T .; , Contemporary topics in polymeric materials for biomedical applications, “ADVANCED POLYMER SCIENCE”, 1996, 126, p. 1-51
[Non-Patent Document 3]
Mori, Y .; Nagaoka, S .; Takiguchi, T .; Kikuchi, T .; Noguchi, N .; Tanzawa, H .; Noishiki, Y .; , A new antimicrobial material with long polyoxyethylene oxide chains, “Journal of American Society of Artificial Organs”, 1982, 28, p. 459-463
[Non-Patent Document 4]
Harris JM, ed, Poly (ethylene glycol) chemistry, Biotechnical and Biomedical Application, (USA), Plenum Press, 1992.
[0006]
[Problems to be solved by the invention]
The present invention provides a medical device excellent in blood compatibility that can suppress the activation of a coagulation system, a complement system, or a platelet system when it comes into contact with tissue or blood in a living body.
[0007]
[Means for Solving the Problems]
Such an object is achieved by the present invention of the following (1) to (2).
[0008]
(1) Medical used in contact with tissue or blood in vivo, comprising a polymer having a repeating unit represented by the general formula A as a main component on at least a part of a surface in contact with blood Tools.
[Chemical 2]
(Wherein R ¹ is CH ₂ , C ₂ H ₄ , C ₃ H ₆ , or C ₄ H ₈ , R ² is CH ₃ , C ₂ H ₅ , C ₃ H ₇ , or C ₄ H ₉ ; R ³ represents hydrogen or a methyl group, respectively.)
[0009]
(2) The medical device according to (1), wherein R ¹ is an ethylene group, R ² is a methyl group, and R ³ is hydrogen or a methyl group.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the medical device of the present invention will be described in detail.
The medical device of the present invention has a polymer having a repeating unit represented by the following general formula A as a main constituent component, that is, a polymer having a so-called alkoxyalkyl (meth) acrylamide as a main constituent component on the surface. .
The surface of the medical device as used in the present invention refers to the surface of the material that constitutes the medical device that comes into contact with blood or the like when the medical device is used, and the surface portion of the hole in the material.
In the present specification, “used in contact with tissue or blood in a living body” means skin (including the epidermis and dermis here) and eyes (cornea) which are outer surface tissues of the living body. Except for forms used in contact with each other, it is meant to include all other cases, for example, a form used in contact with the tissue or blood in a state where it is placed in the living body, or in a state where the tissue in the living body is exposed. As a matter of course, a form used in contact with blood which is an in-vivo component taken out of the body in the extracorporeal circulation medical material is used.
[0011]
[Chemical 3]
(Wherein R ¹ is CH ₂ , C ₂ H ₄ , C ₃ H ₆ , or C ₄ H ₈ , R ² is CH ₃ , C ₂ H ₅ , C ₃ H ₇ , or C ₄ H ₉ ; R ³ represents hydrogen or a methyl group, respectively.)
[0012]
The polymer mainly composed of alkoxyalkyl (meth) acrylamide in the present invention is a polymer composed of one or more of the following alkoxyalkyl (meth) acrylamides, or other monomer copolymerizable therewith It is a copolymer. The alkoxyalkyl (meth) acrylamide represents one in the case where R ³ is hydrogen and one in the case of a methyl group, and each may be a single or a mixture of both.
[0013]
Examples of the alkoxyalkyl (meth) acrylamide include methoxymethyl (meth) acrylamide, methoxyethyl (meth) acrylamide, methoxypropyl (meth) acrylamide, methoxybutyl (meth) acrylamide, ethoxymethyl (meth) acrylamide, and ethoxyethyl (meth). Examples include acrylamide, ethoxypropyl (meth) acrylamide, ethoxybutyl (meth) acrylamide, propoxymethyl (meth) acrylamide, propoxyethyl (meth) acrylamide, propoxypropyl (meth) acrylamide, and propoxybutyl (meth) acrylamide. Methoxyalkyl (meth) acrylamide is preferred from the viewpoint of economy and operability. Furthermore, methoxyethyl (meth) acrylamide is more preferable.
[0014]
Other monomers copolymerizable with alkoxyalkyl (meth) acrylamide include alkyl acrylamides such as acrylamide, t-butyl acrylamide, n-butyl acrylamide, i-butyl acrylamide, hexyl acrylamide and heptyl acrylamide; N, N-dimethyl acrylamide N, N-diethylacrylamide and other dialkylacrylamides; aminomethyl acrylate, aminoethyl acrylate and aminoisopropyl acrylate and other aminoalkyl acrylates; diaminomethyl acrylate, diaminoethyl acrylate and diaminobutyl acrylate and other diaminoalkyl acrylates; methacrylamide; N N, such as N, N-dimethylmethacrylamide, N, N-diethylmethacrylamide N-dialkylmethacrylamide; aminoalkyl methacrylate such as aminomethyl methacrylate and aminoethyl methacrylate; diaminoalkyl methacrylate such as diaminomethyl methacrylate and diaminoethyl methacrylate; methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, hexyl acrylate, 2-ethylhexyl Examples include alkyl acrylates such as acrylates; alkyl methacrylates such as methyl methacrylate, ethyl methacrylate, butyl methacrylate, and hexyl methacrylate.
[0015]
These other monomers are used in a composition ratio that does not impair the blood compatibility of the resulting polymer. The alkoxyalkyl (meth) acrylamide is preferably about 30% to 99% by weight, and more preferably 50% to 99% by weight, based on the weight of all monomers in the copolymer.
The copolymer of the present invention may be any of a random copolymer, a block copolymer, and a graft copolymer.
Various polymers produced in this way can be used alone as a surface treatment agent for medical devices, or any of the polymers of the present invention can be used alone, or a plurality of polymers can be used in combination. You can also
[0016]
The number average molecular weight of the alkoxyalkyl (meth) acrylamide polymer thus obtained is preferably 10,000 to 500,000, more preferably 30,000 to 100,000.
[0017]
In addition, the medical device used in contact with the in vivo tissue or blood of the present invention only needs to have a polymer having alkoxyalkyl (meth) acrylamide as a constituent component on the surface, and is composed only of the polymer. It need not be an article. This is because the surface structure of the material is closely related to biocompatibility. Therefore, the substrate may be coated with the polymer. Further, the medical device itself may be composed of the polymer.
[0018]
In the present invention, the material and shape of the substrate are not particularly limited, and may be, for example, a porous body, fiber, non-woven fabric, particle, film, sheet, tube, hollow fiber or powder. The materials include natural polymers such as Kinishiki and hemp, nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polysulfone, polyethersulfone, poly (meth) acrylate, and ethylene-vinyl alcohol copolymer. And synthetic polymers such as butadiene-acrylonitrile copolymer or a mixture thereof. Moreover, a metal, ceramics, those composite materials, etc. can be illustrated and you may comprise from several base material.
[0019]
The medical substrate of the present invention can be used for medical devices used in contact with in vivo tissues and blood, and can be used in implantable artificial organs and therapeutic instruments, extracorporeal circulation type artificial organs, and catheters ( Medical services such as angiographic catheters, guide wires, circulatory catheters such as PTCA catheters, gastrointestinal catheters, gastrointestinal catheters, gastrointestinal catheters such as esophageal tubes, tubes, urinary catheters, urinary catheters such as urinary catheters, etc. Polyalkoxyalkyl (meth) acrylamide is present on at least a part of the surface of the device that contacts the blood, preferably almost the entire surface that contacts the blood.
The polymer mainly composed of polyalkoxyalkyl (meth) acrylamide of the present invention is a hemostatic agent, an adhesive for living tissue, a repair material for tissue regeneration, a carrier for a sustained drug release system, a hybrid such as an artificial pancreas or an artificial liver. It may be used as a matrix material for artificial organs, artificial blood vessels, embolic materials, scaffolds for cell engineering, and the like.
[0020]
In these medical devices, surface lubricity may be further imparted to facilitate insertion into a blood vessel or tissue and prevent damage to the tissue.
As a method for imparting surface lubricity, a method in which a water-soluble polymer is insolubilized to form a water-absorbing gel layer on the material surface is excellent. According to this method, a material surface having both biocompatibility and surface lubricity can be provided.
Although the polymer of the present invention is a material excellent in blood compatibility itself, it can further carry various physiologically active substances, so that not only blood filters but also blood storage containers, blood circuits, indwelling needles, catheters It can be used for various medical devices such as guide wires, stents, artificial lung devices, and dialysis devices.
[0021]
Specifically, there is an example of a blood filter in which the polymer of the present invention is coated on at least a part of the substrate surface constituting the blood filter.
In addition, there is an example of a blood bag in which the polymer is coated on at least a part of a blood bag and a surface of a tube communicating with the blood bag in contact with blood.
In addition, blood in an extracorporeal circulation blood circuit composed of an instrument side blood circuit unit composed of a tube, an arterial filter, a centrifugal pump, a hemoconcentrator, a cardio pregear, etc., and an operative field side blood circuit unit composed of a tube, catheter, soccer, etc There is an example of an extracorporeal circulation blood circuit in which at least a part of a surface in contact with the body is coated with the polymer.
Further, an inner needle having a sharp needle tip at a distal end, an inner needle hub installed on the proximal end side of the inner needle, a hollow outer needle into which the inner needle can be inserted, and a proximal end side of the outer needle An indwelling needle assembly comprising: an outer needle hub installed on the inner needle; a protector mounted on the inner needle and movable in the axial direction of the inner needle; and a connecting means for connecting the outer needle hub and the protector. There is an example of an indwelling needle assembly in which at least a part of a three-dimensional surface in contact with blood is coated with the polymer.
In addition, there is an example of a catheter in which at least a part of a surface of a long tube and an adapter connected to the proximal end (hand side) of the catheter that comes into contact with blood is coated with the polymer.
[0022]
In addition, there is an example of a guide wire in which at least a part of the surface of the guide wire that contacts blood is coated with the polymer.
In addition, blood of stents of various shapes, such as hollow tubular bodies made of metal materials or polymer materials, with pores formed on the side surfaces, metal material wires or polymer material fibers knitted into a cylindrical shape, etc. There is an example of a stent in which at least a part of a surface in contact with the polymer is coated with the polymer.
[0023]
Further, as shown in FIG. 1, a large number of gas exchange porous hollow fiber membranes 3 are accommodated in the housing 2, blood flows on the outer surface side of the hollow fiber membranes 3, and oxygen-containing gas is contained in the hollow fiber membranes 3. The outer surface or outer surface layer 3a of the hollow fiber membrane 3 shown in FIG. 2 of the hollow blood membrane external blood perfusion type artificial lung 1 of the type in which the fluid flows is coated with the polymer 18 and the inner 3c of the hollow fiber membrane 3 Includes an example of an artificial lung in which the polymer is substantially absent.
Further, a dialysate circuit including at least one dialysate container filled with dialysate and at least one drainage container for collecting dialysate, and starting from the dialysate container, or As an end point, there is an example of a dialysis machine in which at least a part of a surface in contact with blood of a dialysis machine having a liquid feeding means for feeding dialysate is coated with the polymer.
[0024]
The polymerization reaction itself for producing the polymer of the present invention is not particularly limited, and polymerization is carried out by a known method such as radical polymerization, ionic polymerization, photopolymerization, or polymerization using a macromer. In addition, a macromer refers to the oligomer which has a polymerizable functional group, especially a double bond at the terminal.
[0025]
The polymerization reaction is preferably performed in a temperature range of 40 ° C to 100 ° C, more preferably in a temperature range of 60 ° C to 90 ° C, and further preferably in a temperature range of 70 ° C to 80 ° C. The pressure is preferably Changsho.
In the above polymerization reaction, the solvent is preferably a solvent capable of dissolving alkoxyalkyl (meth) acrylamide. As the solvent, an aliphatic or aromatic organic solvent is used. For example, ether solvents such as dioxane, tetrahydrofuran and diethyl ether; halogenated aromatic hydrocarbons such as o-dichlorobenzene; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; benzene, toluene and the like Aromatic hydrocarbons; aliphatic hydrocarbons such as hexane or pentane are used, and ether solvents such as dioxane are preferably used.
[0026]
Examples of the method for holding the polymer on the surface of the medical device include known methods such as a coating method, a graft polymerization using radiation, electron beam and ultraviolet rays, and a method of introducing a chemical reaction with a functional group of a substrate. It is done. Among these, the coating method is particularly preferable in practical use because the manufacturing operation is easy. Furthermore, there are coating methods, spraying methods, dipping methods and the like as coating methods, and any of them can be applied without any particular limitation.
The film thickness is preferably 0.1 μm to 1 mm. For example, the coating treatment by the polymer coating method is performed by a simple operation such as immersing the filter medium in a coating solution in which the copolymer is dissolved in an appropriate solvent, removing the excess solution, and then air-drying. it can. In addition, in order to more firmly fix the copolymer to the filter medium, heat can be applied to the filter medium after coating to further improve the adhesion between the filter medium and the copolymer.
Moreover, you may fix | immobilize by bridge | crosslinking the surface. As a method for crosslinking, a crosslinkable monomer may be introduced as a comonomer component. Moreover, you may bridge | crosslink by an electron beam, a gamma ray, and light irradiation.
[0027]
In addition to compounds having a plurality of vinyl groups or allyl groups in one molecule such as methylenebisacrylamide, trimethylolpropane diacrylate, triallyl isocyanate, trimethylolpropane triacrylate, tetramethylolmethane tetraacrylate, etc. And polyethylene glycol diacrylate. Among them, when various functional groups are introduced using polyethylene glycol diacrylate, the introduction rate of the compound having a functional group is high, and further, a polyethylene glycol chain can also be introduced and rendered hydrophilic as described above. This is preferable because nonspecific adsorption of cells and proteins other than the intended purpose is suppressed. In this case, the molecular weight of the polyethylene glycol chain is preferably 100 to 10,000, and more preferably 500 to 6,000.
[0028]
As described above, when a polymer containing alkoxyalkyl (meth) acrylamide as a main component is introduced into at least a part of the surface of a medical device that comes into contact with blood, it has moderate hydrophilicity without the presence of hydroxyl groups. Therefore, the activation of the coagulation system, complement system, and platelet system can be suppressed, and excellent blood compatibility can be expressed.
[0029]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further, this invention is not limited by these.
[Example 1 and Comparative Examples 1 to 4]
(Monomer synthesis)
To 33 g of methoxyethylamine (Nacalai Tesque) and 100 g of triethylamine (Tokyo Kasei) dissolved in 100 ml of toluene (Kanto Kagaku), 36.2 g of acrylic acid chloride (Tokyo Kasei) was added dropwise with stirring under ice cooling for 3 hours. For 3 hours. The resulting yellow solid material was dissolved in toluene and filtered. The filtrate was evaporated to give a yellow liquid. The obtained liquid was distilled (83 ° C., 0.25 mmHg) to obtain 40 g of methoxyethyl acrylamide monomer.
[0030]
(Polymer synthesis)
Add 0.2 wt% of azobisisobutyronitrile (radical polymerization initiator) (Tokyo Kasei) to 10 g of methoxyethyl acrylamide monomer and bubbling nitrogen in 60 g of 1,4-dioxane (Kanto Chemical). The polymerization was carried out at 75 ° C. for 8 hours. After the completion of the polymerization reaction, the white solid substance is dissolved in methanol (Kanto Chemical) and added dropwise to n-hexane (Kanto Chemical) / diethyl ether (Kanto Chemical) = 3/2 (v / v) to precipitate the product. Got. The obtained product was dissolved in methanol, further purified twice by the same method, and dried under reduced pressure overnight. The structure of the obtained polymer was confirmed by ¹ H-NMR. From the results of GPC molecular weight analysis, the number average molecular weight (Mn) was 38,000 and the molecular weight distribution (Mw / Mn) was 2.5. The obtained polymer solution was surface-coated on a polyethylene terephthalate plate, and the solvent was evaporated to dryness to obtain a film containing polymethoxyethylacrylamide as a constituent. This thin film was crosslinked by irradiating with 80 kGy (10 kGy / h for 8 hours) of γ rays using ⁶⁰ Co as a radiation source (Example 1).
[0031]
Similarly, 2-hydroxyethyl methacrylate was polymerized in ethanol using azobisisobutyronitrile (0.1% by weight) as an initiator. The obtained polymer solution was surface-coated on a polyethylene terephthalate plate, the solvent was evaporated to dryness, and the film containing poly (2-hydroxyethyl methacrylate) as a constituent component was irradiated with γ rays to perform crosslinking (comparison). Example 1).
Similarly, a polyacrylamide crosslinked film was prepared (Comparative Example 2).
In order to investigate the compatibility with blood, Example 1, Comparative Example 1, Comparative Example 2, polypropylene sheet not subjected to surface treatment (Comparative Example 3), polyethylene terephthalate sheet not subjected to surface treatment (Comparative Example 4), Platelet adhesion test was performed. That is, human platelet-rich plasma anticoagulated with sodium citrate was brought into contact with the material surface at 37 ° C. for 120 minutes, rinsed with a phosphate buffer solution, fixed with glutaraldehyde, and sample surface 1 × 10 ⁴ μm. ^The number of platelets adhering to ² was observed with an electron microscope. According to the degree of progress of the change in the adhesion form of platelets, it was classified into I (normal), II (pseudopod formation), and III (extension) types, and the compatibility with blood was evaluated.
Table 1 shows the relative number of adherent platelets when the total platelet count adhered to the polyethylene terephthalate sheet (Comparative Example 4) is 1000. As a result, it was shown that the surface containing polymethoxyethyl acrylamide as a constituent component has a small number of platelet adhesion, small morphological change (fake foot formation and extension) of the adhered platelet, and small platelet activation.
[0032]
[Table 1]
[0033]
[Example 2 and Comparative Examples 5 to 7]
The polyurethane porous body was immersed in the polymer solution prepared in Example 1 to coat the polymer, and then shower washed with warm water at 60 ° C. for 4 hours. After the porous body was dried, it was punched out to a thickness of 0.6 mm and a diameter of 55 mm to prepare a blood filter, incorporated into a blood circuit, and blood was sampled during human blood filtration to determine the amount of bradykinin produced (Example 2). The amount of bradykinin produced was determined by adding 5 mM 1,10-phenanthroline (Tokyo Kasei), a bradykinin degradation inhibitor, to the sampled blood, separating the plasma by centrifugation, cryopreserving it, and using the RIA-PEG method. It was measured by. Table 2 shows the amount of bradykinin production.
Moreover, the untreated urethane porous body to which no coating was applied was mounted on the same blood circuit as in Example 2 (Comparative Example 5), human blood was filtered, and bradykinin production was determined. The results are shown in Table 2.
[0034]
Then, as a coating polymer, poly (2-hydroxyethyl methacrylate) (Comparative Example 6) and polyacrylamide (Comparative Example 7) are coated on a porous urethane material in the same manner as in Example 2 to obtain a blood filter. The blood was filtered to determine the amount of bradykinin production. The results are shown in Table 2.
[0035]
[Table 2]
[0036]
As is clear from Table 2, on the surface of Example 2, the amount of bradykinin produced during filtration was suppressed to about ¼ compared to the untreated filter of Comparative Example 5. In Comparative Examples 6 and 7, the production of bradykinin was not significantly reduced compared to Comparative Example 5.
[0037]
【The invention's effect】
As described above, the present invention is characterized by having a polymer mainly composed of alkoxyalkyl (meth) acrylamide on at least a part of the surface in contact with blood. In this case, it is possible to suppress the activation of the coagulation system, complement system, and platelet system. Therefore, it has excellent blood compatibility. Therefore, materials that are extremely useful as artificial organs or medical devices such as artificial kidney membranes, plasma separation membranes, catheters, artificial lung membranes, and artificial blood vessels are provided.
[Brief description of the drawings]
FIG. 1 is a cross-sectional view showing an embodiment of a hollow fiber membrane external blood perfusion oxygenator that is an embodiment of the present invention.
FIG. 2 is a cross-sectional view of a hollow fiber membrane used in a hollow fiber membrane external blood perfusion oxygenator that is an embodiment of the present invention.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 Hollow fiber membrane external blood perfusion type artificial lung 2 Housing 3 Hollow fiber membrane 3a Outer surface layer 3b Inner surface layer 3c Inner surface layer 3d Gas passages 4 and 5 Partition 6 Blood inlet 7 Blood outlet 8 Gas inlet 9 Gas outlet 12 Blood Chamber 18 Polymer

Claims (2)

A blood filter comprising a polymer having a repeating unit represented by the general formula A as a main component on at least a part of a surface in contact with blood .
(Wherein R ¹ is CH ₂ , C ₂ H ₄ , C ₃ H ₆ , or C ₄ H ₈ , R ² is CH ₃ , C ₂ H ₅ , C ₃ H ₇ , or C ₄ H ₉ ; R ³ represents hydrogen or a methyl group, respectively.) The blood filter according to claim 1, wherein the R ¹ is an ethylene group, the R ² is a methyl group, and the R ³ is hydrogen or a methyl group.