JPS62183768A - Living body affinity material and its production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION 1. Background of the Invention (Technical Field) The present invention relates to a biocompatible material and a method for producing the same. Details) The present invention relates to a biocompatible material comprising a polyion complex with improved mechanical strength and a method for producing the same.

(Prior Art) Currently, various biocompatible materials are being developed in response to the strong demand for d3 in the medical field, and Bolyion Complex is one of them.

Polyelectrolytes dissociate in aqueous solutions to form giant ions. Therefore, strong electrostatic interactions occur within and between molecules. Coulomb force is a strong secondary bonding force and is well known as a non-directional long-distance force. When aqueous solutions of a polycation and a polyanion are mixed, an aggregation of oppositely charged polymer electrolytes, that is, a polyion complex, is formed and precipitated due to interaction triggered by Coulomb force.

The interface of the polyion complex thus formed has a micro-inconstrained 7 structure in which hydrophobic domains are dispersed in hydrophilic domains mainly containing ionic bonding parts. Since this composition is similar to the surface condition of living tissues, the biocompatibility of polyion complexes was noticed early on (Michaelis et al., 1965).
s et al,, Ind, Eng, Chem
,.

57, 32 (1965)), and numerous studies have been conducted to date. For example, anionic complex gel is non-toxic and non-irritating to living organisms, and has almost no thrombosis, albumin adsorption, or platelet adhesion, making it an excellent material for implantation in the body (Katama et al., 1980 [K
, ni ataoka et at,, )Iakromo
l, Chem.

, 181.1363 (1980)); polyion complexes containing polysaccharide derivatives were also investigated;
The same weakly anionic complexes as body tissue surfaces do not form thrombi and are good compatible covering materials (Kikuchi et al., 1980).
MaCrOIIIOl, Chem, Rapid C
ommun, 1, 253 (1980)] and others have been reported.

Furthermore, studies have recently been conducted on the antithrombotic properties of polyion complexes between cellulose derivatives, such as polyanions such as carboxymethyl cellulose and polycations such as quaternary ammonium salts of hydroxyethyl cellulose. It has been reported that it has antithrombotic properties, bioabsorbability, etc., and that polyion complexes between these cellulose derivatives are soluble in formic acid monosolvents in addition to ternary polyion complex solvents such as acetone/KBr/water. (Ito et al.

April 1984, Proceedings of the Society of Polymer Science, No. 28
-29 pages).

However, such a polyion complex between cellulose derivatives significantly reduces its strength in water. Therefore, its use is extremely limited.

In order to increase the mechanical strength of the polyion complex between cellulose derivatives, it is conceivable to use a crosslinking agent to crosslink the cellulose derivatives forming the complex, but such a method naturally damages the strength of the complex itself. The structure of the polyion complex changes, and the inherent biocompatibility of the polyion complex cannot be expected.

On the other hand, for polyvinyl alcohol or polyvinyl alcohol mixtures, there are known manufacturing methods that use repeated freezing or frozen partial dehydration methods to have high water content, rubber-like elasticity, and excellent mechanical strength, but in general, materials that do not contain polyvinyl alcohol It was considered impossible if you were in d3.

II. OBJECTS OF THE INVENTION Accordingly, the present invention aims to provide improved biocompatible materials and methods for their production.

The present invention also aims to provide a biocompatible material with improved mechanical strength and a method for producing the same. A further object of the present invention is to provide a biocompatible material that can be widely used by improving the strength of a polyion complex between cellulose derivatives in an aqueous solution, and a method for producing the same.

The above advantages can be achieved by using a biocompatible material consisting of a gel obtained by repeatedly freezing or partially dehydrating a cellulose derivative-cellulose derivative polyion complex formed between a polyanionic cellulose derivative and a polyanionic cellulose derivative.

The present invention also provides a biocompatible material in which the polycationic cellulose derivative is a strongly basic cellulose derivative.

The above may also include mixing a solution of a polyanionic cellulose derivative and a solution of a polycationic cellulose derivative to form a polyion complex between cellulose derivatives, and repeatedly freezing or partially freezing the resulting polyion complex between cellulose derivatives. This is achieved by a method for producing a biocompatible material.

The present invention also involves separating and drying the formed polyion complex between cellulose derivatives, dissolving it in a solvent, molding it into a predetermined shape, removing the solvent, and then immersing it in water for a certain period of time to form a high moisture content polyion complex. 1 shows a method for producing a biocompatible material that is repeatedly frozen or frozen partially dehydrated. Furthermore, the present invention provides a method for producing a biocompatible material using formic acid as a solvent.

Detailed description of the IV0 invention The present invention will be described in detail below based on embodiments.

The biocompatible material of the present invention has its mechanical strength increased by repeated freezing or frozen partial dehydration without impairing the excellent biocompatibility of the polyion complex between cellulose derivatives.

The polyion complex between cellulose derivatives related to the biocompatible material of the present invention is an aggregate formed by interaction triggered by Coulomb force between a polyanionic cellulose derivative and a polycationic cellulose derivative, as is known. be. The interface has a micro-heterogeneous structure in which hydrophobic domains are dispersed in hydrophilic domains mainly containing ionic binding parts. Furthermore, the water included in the complex is fixed by interactions between dipoles and between dipoles and ions, so its movement is restricted.

In the biocompatible material of the present invention, examples of polyanionic cellulose derivatives constituting such a polyion complex between cellulose derivatives include celluloses such as carboxymethylcellulose, carboxyethylcellulose, sulfoethylcellulose, and sulfopropylcellulose. There are cellulose ethers such as ethers, cellulose phosphate, cellulose 5A acid, cellulose acetate, cellulose propionate, cellulose acetate, etc., while polycationic cellulose derivatives include, for example, aminoethyl cellulose,
Examples include cellulose ethers such as N-dimethylaminoethylcellulose and N-diethylaminoethylcellulose, and quaternary ammonia salt derivatives such as cellulose tetraammonium salt and hydroxyethylcellulose tetraammonium salt. Further, the degree of substitution of these cellulose derivatives is 0.

05-3, O, preferably 0.3-3.0.

The polyion complex between cellulose derivatives used in the present invention may be any complex formed between an anionic cellulose MP and a cationic cellulose derivative as described above, but especially one polycationic cellulose. When it is a strongly basic cellulose derivative such as a quaternary ammonia salt derivative, it exhibits particularly excellent biocompatibility (Ito et al., April 1984, The Society of Polymer Science, Proceedings, No. 28) (See pages 29 to 29).

The biocompatible material of the present invention is a gel obtained by repeatedly freezing or freezing partially dehydrating a polyion complex between cellulose derivatives, and although its detailed structure is not clear, its mechanical strength is significantly improved and it can be dissolved in an aqueous solution. It has become clear that even when immersed in water for a long time, it maintains high strength with almost no expansion. Furthermore, the inherent antithrombotic effect and biocompatibility such as bioabsorbability of the polyion complex between cellulose derivatives are maintained without any loss.

The biocompatible material of the present invention is prepared as follows.

That is, first, as is well known, a solution of an anionic cellulose derivative and a solution of a cationic cellulose derivative are mixed to form a polyion complex between cellulose derivatives. The solvent for each solution of cellulose can be any solvent as long as it dissolves both cellulose derivatives, but cellulose can be used as long as it is insoluble in the polyion complex between cellulose derivatives that is formed. This is particularly preferred because the formation of an interderivative polyion complex can be visually recognized as a precipitate and separation is easy. For example, in the case of a combination of carboxymethylcellulose and hydroxyethylcellulose tetraammonium salt, the intercellulose derivative polyion complex formed when these aqueous solutions are mixed is obtained as a precipitate.

The biocompatible material 1 of the present invention can be prepared by isolating the polyion complex between cellulose derivatives formed in this manner and then repeatedly freezing or dehydrating the frozen portion, but desirably, the formed cellulose XS interbody polyion complex is After isolating the polyion complex, it is preferable to mold it into a predetermined shape and then repeatedly freeze it or dehydrate the frozen part. For example, the formed polyion complex between cellulose derivatives is partially dried, then dissolved in a solvent, molded into a predetermined shape, and after removing the solvent, immersed in water for a certain period of time,
After forming a high moisture content polyion complex, it is repeatedly frozen or frozen partially dehydrated.

In this case, as the solvent for the cellulose XS interbody polyion complex, a ternary polyion complex solvent goat acid such as acetone/KE' or r/water may be used, but formic acid is particularly preferred.

Repeated freezing of the polyion complex between cellulose derivatives involves first (a) bringing the polyion complex between cellulose derivatives into contact with water, preferably distilled water, to form a highly water-containing gel state, and then (b) at a temperature of 0°C or lower, preferably Steps (a) to (C) of freezing at a temperature of -30 to -5°C, and further (C) thawing at a temperature of 4°C or higher, preferably 4 to 25°C, are performed at least once; Preferably 5~
This is done by repeating 25 times.

In addition, the frozen partial dehydration of the polyion complex between cellulose derivatives is carried out by first (a) bringing the polyion complex between cellulose derivatives into contact with water, preferably distilled water, to form a highly water-containing gel state, and then (b) at a temperature of 0°C or lower, preferably is frozen at a temperature of -30 to -5℃, and finally (C)
This is done by partially sublimating the water in the gel by reducing the pressure to below water vapor pressure, preferably below 1 mmt+g.

Note that the same biocompatible material of the present invention can be obtained regardless of whether it is obtained by a repeated freezing method or a frozen partial dehydration method.

(Example) The present invention will be explained in more detail below using Examples.

Example 1 A 2 W/V% aqueous solution of hydroxyethyl cellulose tetraammonium salt (substitution degree: 0.4>) was prepared, and O, I
Adjust to p118 using N Na0tl and convert this to A
It was made into a liquid.

On the other hand, carboxymethyl cellulose (degree of substitution: 0.8)
An aqueous solution of 'l w/v% was prepared and adjusted to 0118 using 0.1N NaOH, and this was used as Solution B.

The above liquids A and B were mixed, stirred once, and then left at room temperature.

The generated precipitate was centrifuged at 10°000G using 1i1.
The samples were collected by centrifugation for 30 minutes and dried using a vacuum oven. Next, this was dissolved in formic acid to prepare a 1 w/v% solution, and cast on a Teflon plate to form a polyion complex between cellulose derivatives with a thickness of 50 μm.
I made a sheet for Hiroshi. Next, this sheet was (a) immersed in distilled water to form a high water content gel, (b) frozen at 0°C or lower, and (C) thawed at 4°C or higher.
The operation (C) was repeated 15 times to obtain a polyion complex between repeatedly frozen cellulose derivatives. The obtained sheet of the polyion complex between cellulose derivatives subjected to repeated freezing treatment was immersed in distilled water for 2 hours and then taken out.
Table 1 shows the results of a tensile test carried out by cutting into 5 mnt x 10 mnt pieces.

Comparative Example 1 Example 1 except that repeated freezing treatment was not performed for comparison.
A sheet of polyion complex between cellulose derivatives obtained in the same manner as in Example 1 was immersed in distilled water for 2 hours and then taken out, cut into 5 mm x 1 Q mm pieces, and subjected to a tensile test.

The results are shown in Table 1.

Table 1 Sample number 1 4.62 1.18 2 3.24 1.00 or less 3
4.38 1.00 or less Example 2 and Comparative Example 2 Thickness 50
A 1 CmX I Cm piece of μm was prepared. When these sheets were immersed in front water for 2 hours, the area ratio of the expansion stage to the first sheet 1~ was investigated, and the area ratio of the expansion stage of Example 2 according to the present invention was 1.38 (although it was 8). On the other hand, in Comparative Example 1, it was 2.a1 times as large.

Example 3 A 2 W/V% aqueous solution of hydroxyethyl cellulose tetraammonium salt (degree of substitution: 0.4> was prepared,
The pH was adjusted to 8 using N NaOH, and this was used as a solution.

On the other hand, 'l w of cellulose sulfate (degree of substitution: 1.25)
/v% aqueous solution and send it to p using O, IN Mail.
119, and this was used as liquid C.

A sheet of polyion complex between repeatedly frozen cellulose derivatives was prepared in the same manner as in Example 1 except that this AFj and liquid C were used and the number of repetitions was 10 times. As in Example 1, the front part of this sheet was immersed in water for 2 hours and then taken out.
It was cut into 5 mm x 10 mm pieces and subjected to a tensile test. The results are not shown in Table 2.

Comparative Example 3 Example 3 except that repeated freezing treatment was not performed for comparison.
A sheet of cellulose aff 4-body polyion complex obtained in the same manner as in Example 1 was immersed in front water for 2 hours and then taken out, cut into 5 mm x 10 mm pieces, and subjected to a tensile test.

The results are shown in Table 2.

Table 2 Sample number 1 13.42 11.392 1
5.69 10.053 14.82
10.52 Example 4 and Comparative Example 4 A thickness of 50
A piece of 1 CmX i Cm of μ was prepared. When these sheets were immersed in front water for 2 hours, the area ratio of the expansion stage to the initial sheet was examined, and it was found that the area ratio of Example 4 related to the present invention was 2.51 times that of the first sheet. In Example 4, the increase was 1.19 times.

Example 5 Hydroxyethyl cellulose te 1-ra ammonium salt (
A 2W/V% aqueous solution with a substitution degree of 0.4> was prepared and 0.1N
The solution was adjusted to 0118 using NaOH and used as Solution A.

On the other hand, carboxymethyl cellulose (substitution α: 0.8)
An I W/V% aqueous solution was prepared and adjusted to p119 using 0.1N Na0+1, and this was used as liquid B.

The above solutions A and B were mixed and stirred, and then left at room temperature. The generated precipitate was centrifuged at 10°000G for 3
It was collected by centrifugation for 0 minutes and dried using a vacuum oven. Next, this was dissolved in formic acid to prepare an i w/v % solution. Refined polyester fibers (1 Kokusai 1.0@ manufactured by Yacho Kogyo Co., Ltd.) are immersed in the formic acid solution and deaerated, and then the polyester fibers are removed from the formic acid solution and dried at room temperature to form the polyester fibers with cellulose derivatives. Coated with polyion complex. Next, this polyester fiber is (a) immersed in front water to form a high water content gel, (
b) Freeze at 0°C or lower, and thaw at 4°C or higher (C). These operations (a) to (C) were repeated 20 times to perform repeated freezing ffi treatment.

The obtained polyester fibers coated with the repeatedly frozen cellulose-disorbent polyion complex were subjected to in-vivo testing by peripheral intravenous insertion in two adult animals.
o) An evaluation was conducted. That is, under general anesthesia, a hypodermic needle is inserted into both femoral veins and bilateral femoral veins (total of 4 locations) of a dog, the polyester fiber is inserted into the blood vessel through the needle hole in the direction of blood flow, and then only the needle is inserted. was removed and the fibers were fixed to nearby tissue to prevent them from entering the bloodstream. After 1 day, the dog was given 2-5 mg/ka of heparin under general anesthesia.
After intravenous injection, the acute blood layer was killed. Thereafter, the vein in the sample area was carefully opened and the presence or absence of thrombus adhering to the thread was visually observed. The results are shown in Table 3. The evaluation was shown using the following display method.

−・・・No thrombus +... Partial thrombosis.

++...Thrombosis all over.

＋＋＋・・・Blood vessel occlusion.

Comparative Example 5 Example 5 except that repeated freezing treatment was not performed for comparison.
The polyester fibers coated with a polyion complex between cellulose derivatives obtained in the same manner as in Example 5 were subjected to in-vivo protection by peripheral intravenous insertion using two adult animals. The results are shown in Table 3.

Table 3 Sample No. ■0 Effects of the Invention As described above, the present invention is obtained by repeatedly freezing or freezing partially dehydrating a cellulose derivative-cellulose derivative polyion complex formed between a polyanionic cellulose derivative and a polycationic cellulose derivative. Since it is a biocompatible material made of gel, its mechanical strength is improved and it can withstand 11% strength even when immersed in water for a long time. It has low moisture content and maintains the desired strength, and because it does not use crosslinking agents, it can be expected to have the inherent antithrombotic effect and biocompatibility such as bioabsorbability of the polyion complex between cellulose derivatives. Therefore, a wide range of applications are possible, such as wound dressings, membranes that prevent the growth of living tissue, artificial blood vessels, and artificial organs. It is also economically advantageous compared to other biocompatible materials.

Furthermore, the biocompatible material of the present invention can be expected to have particularly excellent biocompatibility when the cationic cellulose derivative forming the cellulose derivative-polyion complex is a strongly basic cellulose derivative.

The present invention also provides a method for forming a polyion complex between cellulose derivatives by mixing a solution of a polyanionic cellulose derivative and a solution of a polycationic cellulose derivative, and repeatedly freezing the obtained polyion complex between cellulose derivatives or Since this is a method for producing a biocompatible material characterized by 11;3 water retention, it is possible to easily and inexpensively provide a biocompatible material having the above-mentioned excellent performance.

Roughly, in the method for producing a biocompatible material of the present invention, the formed polyion complex between biocompatible materials is dried for a few minutes, then dissolved in a solvent, molded into a predetermined shape, and after removing the solvent. A biocompatible material can be more easily provided in a desired shape by immersing it in water for a certain period of time to form a high moisture content polyion complex, followed by repeated freezing or frozen partial dehydration. If used, products with excellent roughness can be obtained more easily.

Claims (5)

[Claims] (1) A biocompatible material consisting of a gel obtained by repeatedly freezing or partially dehydrating a cellulose derivative-cellulose derivative polyion complex formed between a polyanionic cellulose derivative and a polycationic cellulose derivative. (2) The biocompatible material according to claim 1, wherein the polycationic cellulose derivative is a strongly basic cellulose derivative. (3) A solution of a polyanionic cellulose derivative and a solution of a polycationic cellulose derivative are mixed to form a polyion complex between cellulose derivatives, and the obtained polyion complex between cellulose derivatives is repeatedly frozen or frozen partially dehydrated. A method for producing a biocompatible material. (4) The formed polyion complex between cellulose derivatives is separated and dried, then dissolved in a solvent, molded into a predetermined shape, the solvent removed, and immersed in water for a certain period of time to form a high moisture content polyion complex, and then repeated. The method for producing a biocompatible material according to claim 3, which comprises freezing or partially dehydrating the frozen material. (5) The method for producing a biocompatible material according to claim 4, which uses formic acid as a solvent.