JPH0364485B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to an antiblood coagulant for imparting excellent antithrombotic properties to medical materials that come into contact with blood. [Prior Art] Generally, medical equipment used in direct contact with blood, such as artificial organs, artificial blood vessels, and blood transfusion devices, must have anti-blood coagulation properties (anti-thrombotic properties), as well as durability. It is desired to have sufficient properties in terms of moldability, moldability, and mechanical strength. Conventionally, such materials have been known to be able to bind antihematogenic agents such as heparin and fibrinolytic active factors such as urokinase to polymeric materials (for example, Japanese Patent Application Laid-open No. 128162-1982). (Japanese Patent Application Laid-Open No. 58-92363). However, when trying to introduce functional groups that can bind with these drugs into polymeric materials, there are drawbacks such as deterioration of properties such as mechanical properties and complicated operations that require a large amount of man-hours. . On the other hand, attempts to make heparin lipophilic
This has already been done by Halbert et al., but since this is based on complex formation with a cationic substance,
When heparin, an anticoagulant, elutes, cationic substances also elute at the same time, leading to hemolysis.
It had drawbacks such as having an adverse effect on living organisms (J.
Biomed.Mater.Res., Vol.4, 549~ (1970). [Objective of the Invention] In view of the current situation of improving the antithrombotic properties of medical materials, the present invention provides a material that can be easily applied or mixed to general-purpose materials to impart antithrombotic properties, and that also prevents the elution of harmful substances. As a result of research in an attempt to obtain an anticoagulant that does not involve blood coagulation, we discovered that anticoagulant substances such as heparin can be made lipophilic by introducing a long-chain alkyl group through a covalent bond. Based on this, various studies have been conducted and the present invention has been completed. [Structure of the Invention] In other words, the present invention is an anticoagulant characterized in that a long chain alkyl group is bonded to a natural mucopolysaccharide having an anticoagulant effect using a carbodiimide coupling agent. . Examples of natural mucopolysaccharides having anticoagulant effects used in the present invention include heparin, heparitin sulfate, chondroitin sulfate, and the like. In addition, the long-chain alkyl group in the present invention is not particularly limited, but from the viewpoint of fat solubility and anticoagulant activity of the target product of the present invention,
Alkyl groups having 4 to 20 carbon atoms are suitable. Raw material compounds having such long-chain alkyl groups include n-butylamine, n-hexylamine, 1
- 1-Amino alkanes such as aminododecane and aliphatic carboxylic acids such as butanoic acid, pentanoic acid, and caproic acid can be used, and for the purpose of imparting lipophilicity while maintaining the inherent anticoagulant activity of mucopolysaccharides. Any of these may be used and is not particularly limited. The reaction method of natural mucopolysaccharide and long-chain alkyl compound is not particularly limited, but for example,
When using 1-aminododecane as the 1-aminoalkane, it is suspended in an acidic aqueous solution using a water-soluble carbodiimide coupling agent.
The reaction is carried out by stirring for an hour. After the reaction, the mixture is poured into ethanol to precipitate and remove soluble materials. Furthermore, after washing thoroughly with ethanol, it is vacuum dried at room temperature. In this way, fat-solubilized alkylheparin is obtained as a white solid. An example of this reaction process is shown in FIG. Furthermore, when using an aliphatic carboxylic acid, the reaction can be carried out in substantially the same manner using a carbodiimide coupling agent. The method of applying the lipophilized heparin thus obtained to medical devices that require high antithrombotic properties, such as intravascular indwelling catheters and arterial bypass tubes, is not particularly limited. Antithrombotic properties can be easily imparted to general-purpose materials. The lipophilized heparin obtained as described above was dissolved in a polar solvent such as dimethylformamide or dimethyl sulfoxide, and polyurethane,
If it is applied directly to the surface of a catheter made of polyvinyl chloride, polyester, etc. and dried, it can very easily impart high antithrombotic properties. In addition, if you want to maintain antithrombotic properties for an even longer period of time, for example, apply a solution of polyurethane and the lipophilized heparin dissolved in a solvent such as dimethylformamide to a glass rod or glass plate and dry it. Alternatively, by applying it to a tube of other base material and drying it, fat-solubilized heparin can be easily supported not only on the surface but also inside, and it is released slowly over a long period of time. It is possible to maintain long-term antithrombotic properties. [Effects of the Invention] The anticoagulant according to the present invention can be synthesized by a relatively simple method, and can be very easily applied to or mixed with various general-purpose materials to impart antithrombotic properties. It is suitable as an anti-blood coagulant because it does not elute cationic substances, which is a defect of conventional methods, and does not have an adverse effect on blood. Example ★Synthesis of fat-solubilized heparin Heparin sodium salt (manufactured by Hanui Chemical Co., Ltd.) 0.3g
was dissolved in 50 ml of water, adjusted to pH4.75 with 0.1N-HCl, and then dissolved in water-soluble carbodiimide (1-ethyl-3-
0.4 g of (3-dimethylaminopropyl)carbodiimide hydrochloride) dissolved in 5 ml of water was added dropwise. 4 while keeping the pH constant
The mixture was gently stirred at ℃ for 12 hours. After the reaction, impurities were removed by dialysis, and the reactant was collected and dried under vacuum. Dissolve this in 20ml of water and use 1-aminododecane.
0.2 g was dissolved in 2 ml of N,N'-dimethylformamide and added, and the mixture was reacted at room temperature for 24 hours with vigorous stirring. Add the reaction product to 200ml of ethanol,
The final product was collected by centrifugation. This reaction process is shown in FIG. As a result of elemental analysis, the product (C12-Heparin) was found to contain 40% by weight of 1-aminododecane and to be soluble in polar organic solvents such as dimethylformamide and dimethysulfoxide.
In addition, as shown in Figure 2, the infrared spectrum (A) of C12-Heparin has a large absorption of methylene and methyl groups around 2900 cm ^-1 compared to the spectrum (B) of Heparin before the reaction. has appeared,
It was confirmed that 1-aminododecane was introduced into heparin. Furthermore, as a result of measuring the activated partial thromboplastin time using a conventional method, it was confirmed that the anticoagulant property was approximately 80% that of heparin. ★In vitro antithrombotic test Glass, Teflon (trade name), polyethylene terephthalate (PET), polyether urethane urea (PEUU), polyacrylonitrile (PAN),
A method reported by Imai et al. (J .Biomed.Mater.Res., Vol.6, 165~
172 (1972)) using adult dog ACD blood. The results are shown in Table 1, with the amount of thrombus generated on polyether urethane urea not coated with lipophilized heparin being taken as 100%. As is clear from Table 1, most of the materials did not generate thrombus, and the surfaces of various materials could be easily improved to have highly antithrombotic properties.

【table】

[Table] In addition, when a sample obtained by mixing PEUU with lipophilized heparin was immersed in Tris buffer (PH7.4) to examine the sustained release of lipophilized heparin, the outflow rate immediately after the start of sustained release was Although it was large, the release apparently stopped after 8 days with a residual rate of about 20%. Early excellent in vitro
The anticoagulant activity is believed to be due to lipophilized heparin released from the material surface.

[Brief explanation of drawings]

FIG. 1 is a diagram showing an example of a reaction process between heparin and 1-aminoalkane, and FIG. 2 is a diagram showing an infrared absorption spectrum of alkylated heparin.

Claims (1)

[Claims] 1. A natural mucopolysaccharide having an anticoagulant effect,
An anticoagulant characterized in that a long chain alkyl group is engaged with a carbodiimide coupling agent. 2. The anti-blood coagulant according to claim 1, wherein the natural mucopolysaccharide is heparin, heparitin sulfate, or chondroitin sulfate.