Stock material or miscellaneous articles – Composite
Reexamination Certificate
2000-03-27
2003-04-29
Tarazano, D. Lawrence (Department: 1773)
Stock material or miscellaneous articles
Composite
C428S500000, C428S409000, C427S002100, C427S180000, C427S189000, C427S195000, C427S336000, C524S501000, C524S514000, C524S457000, C524S460000
Reexamination Certificate
active
06555225
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Filed of the Invention
The present invention relates to a (poly)ion complex which has an excellent characteristic in that it is insoluble in water but is soluble an aqueous (or water-containing) organic solvent. The ion complex according to the present invention is suitably usable for the coating of various kinds of base materials or substrates (such as biomedical material) with various kinds of ionic substances (e.g., a biologically or a physiologically active substance such as an anticoagulant or an antibacterial agent) by utilizing this characteristic, although it is difficult to effect such a coating while allowing the ionic substance to effectively exhibit its function.
2. Related Background Art
An ion complex or coating material, a coated product based on the ion complex, or a coating method according to the present invention are applicable without particular limitation to the field of coating of the surface of various kinds of base materials or substrates, especially to a field wherein the formation of a coating having an excellent coating property is required while causing such a complex to exhibit the function of the ionic component constituting the complex (e.g., fields such as medical use, electronic materials, and antistatic materials). However, at first, there will be described a background art relating to an embodiment of the ion complex according to the present invention to which not only a coating property but also an anticoagulant property has been imparted.
When blood comes into contact with an artificial material other than a living organism, the blood coagulation system is activated, by the surface of the material, to cause blood coagulation. The problem of such blood coagulation seriously hinders the development of therapeutic and diagnostic instruments or devices which are to come in contact with blood, and the development of an excellent anticoagulant material has been desired. With respect to the anticoagulant material, various kinds of surface structures and surface treating methods have been proposed but, at present, it is considered that heparinized materials show the best anticoagulant properties.
Heparin is an anticoagulant substance originated from a living organism and is a mucopolysaccharide having negative electric charges based on a large number of sulfuric acid groups thereof. The heparinizing methods which have conventionally been investigated are roughly classified into the following three types.
1) Simple blending method: A method wherein heparin is simply mixed into a resin. For example, it is said that a material which has been obtained by mixing heparin into an epoxy resin by using this method shows a good anticoagulant property. However, there is no bonding between such a polymer matrix and the heparin, and therefore the heparin is easily lost from the polymer matrix in blood, and there is a defect that the anticoagulant property thereof cannot be maintained for a long period of time.
2) Covalent bonding method: A method wherein heparin is chemically fixed, on the surface of a material to be coated, by covalent bonding by utilizing the functional group of the heparin. However, the quantity of the heparin which can be fixed by this method is about 0.1 &mgr;g/cm
2
at the maximum. In addition, the heparin is denatured by the chemical reaction, or the heparin is not released from the material to be coated, and therefore the resultant anticoagulant activity of the above material is insufficient, and at present, a satisfactory anticoagulant material has not been obtained yet.
3) Ionic bonding method: A method wherein heparin is electrostatically fixed on the surface of a material having positive charges by utilizing the negative charges of the heparin. It is said that this method imparts the best anticoagulant property to such a material.
As for the ionic bonding method, the following methods are known:
(a) A method wherein a quaternary ammonium salt-type surfactant such as benzalkonium chloride (BC) or tridodecylmethylammonium chloride (TDMAC) is adsorbed onto the surface of a material to be coated, and positive charges are introduced into the surface of the material; and
(b) A method wherein the surface of a material to be coated is coated with a water-insoluble polycation having a quaternary ammonium group in its main chain or side chain, and positive charges are introduced into the surface of the material.
In the above-mentioned method (a), the hydrophobic group of the TDMAC or BC is adsorbed onto the surface side of the material to be coated, and the hydrophilic quaternary nitrogen thereof is oriented toward the outside of the TDMAC or BC, whereby positive charges of high density can be introduced onto the material surface two-dimensionally. Accordingly, when such a surface is caused to contact an aqueous heparin solution, the heparin can be bonded to the surface of the material to be coated through ionic bonding.
Further, it is known that the ion complex of the TDMAC and heparin is soluble in some organic solvents, and the ion complex can be subjected to coating by using a solvent casting method (Atha, D., et al., Proc. Nat. Acad. of Sci., 81, 1030-1034 (1984)).
However, when the heparin-coated material obtained by the above-mentioned method (a) is actually used in blood, the BC and TDMAC which have been adsorbed onto the surface of the material to be coated are low-molecular substances and therefore there is produced a defect that these substances are dissolved into blood together with the heparin. When such a cationic surfactant is dissolved into blood, the cationic surfactant causes a problem such as hemolysis and agglomeration of plasma protein. Further, there is also a problem that when such a heparin-coated material is used, the heparin is bonded only to the surface portion thereof, and therefore the heparin flows out at an early stage.
It has also been proposed that in order to suppress the above-mentioned dissolution of the TDMAC, the ion complex of TDMAC and heparin is subjected to coating and thereafter the resultant product is irradiated with gamma rays to crosslink the TDMAC (U.S. Pat. No. 5,441,759). However, there is a fear that irradiation with gamma rays deteriorates the material to be coated.
On the other hand, as a product based on the above method (b), there is known “Anthron” (trademark, mfd. by Toray Industries, Inc.) as a material showing a good anticoagulant property. This material has been obtained by synthesizing a graft copolymer comprising a main chain of polyvinyl chloride, and a side chain bonded thereto comprising a random copolymer of a cationic monomer and a hydrophilic monomer; and then causing a coating layer which has been formed by using such a graft copolymer in advance, to occlude heparin thereinto. This material shows an anticoagulant property based on the slow release of heparin at a rate of 0.01 unit/cm
2
·min or more, when it is in contact with blood (Mori, Y., et al., Trans. Am. Soc. Artif. Intern. Organs, 24, 736 (1978)).
In the heparin-coated material obtained by this method, the dissolution of a substance other than heparin is suppressed. However, in this method, it is necessary that the surface of a material is coated with the water-insoluble polycation, in advance, by a solvent casting method, etc., and the solvent is evaporated, and thereafter the resultant product is immersed in a high-concentration aqueous heparin solution for a long period of time to form a complex thereof with the heparin. Such a process has a problem that it requires much labor and a long period of time, and further it must use an excess of expensive heparin.
Further, the inventor's research group has already disclosed a heparinized material characterized in that an ion pair of heparin and a polymer of a quaternary ammonium salt monomer having a polymerizable functional group and a hydrocarbon chain with a carbon number of not less than 10 and less than 30 is adsorbed onto a surface which is to be in contact with blood (Japanese Patent Application No. Hei. 6-162120, KOKAI (Japan
Kubota Sunao
Mori Yuichi
Yoshioka Hiroshi
M&M Laboratory Co., Ltd.
Tarazano D. Lawrence
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