JP2002241426A - Medical polymer and method for purifying the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polymer which is suitable as a medical material such as a biomaterial, and a method for producing the polymer. SOLUTION: The medical polymer comprises a low molecular weight polymer at a content of 20% or less, wherein the low molecular weight polymer has a molecular weight of 1/4 or less of the molecular weight to a peak top in a molecular weight distribution curve. The method for producing the polymer comprises a process for purifying the polymer, wherein the process comprises adding a non-solvent to a polymer solution containing of the polymer and at least one solvent to cause the liquid-liquid phase separation of a polymer-rich phase solution and a polymer-poor phase solution, followed by separating the polymer-rich phase solution to recover.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a synthetic polymer suitable as a medical material such as an artificial organ, a medical device material, a culture bed material or a biological material, and a method for producing the same. In particular, the present invention relates to a polymer having a reduced content of a monomer and a low polymer which have a serious adverse effect when used for a medical material, and a method for producing the polymer.

[0002]

2. Description of the Related Art In recent years, the importance of medical polymer materials such as biomaterials has been increasing as a pioneering new field of medicine, that is, treatment of diseases by substituting functions of living organs with reduced or malfunctioning functions. I have. The use of medical polymer materials can be broadly classified into three categories ("medical polymer materials", a new polymer material One Po
int No. 20 Yoshito Raft, edited by The Society of Polymer Science, Kyoritsu Shuppan, 1989). One is used as a supplementary use up to clinical examination, surgery, treatment, and can be exemplified by syringes, catheters, infusion sets, wound dressings, etc.
Its use is temporary. The second one is used as a substitute for a function that is reduced or lost, and is used for a long time in contact with the human body such as artificial blood vessels, various artificial organs represented by artificial kidneys, dentures, contact lenses, Third, drug applications include formulation applications for the purpose of sustained release, targeting and stabilization of drugs.

Many polymer materials have been tried for these medical polymers to date, such as polystyrene, polyethylene, polysulfone, silicone resin, polypropylene, polyvinylpyrrolidone, polymethyl (meth) acrylate, polymethylpentene, and the like. Poly
Examples thereof include 2-hydroxyethyl (meth) acrylate, polyvinylidene fluoride, polyethylene glycol, epoxy resin, nylon, polyvinyl chloride, ionomer, polyurethane, and polyester.

[0004] Since these polymer materials come into direct or indirect contact with the human body, their biocompatibility is a very important factor, although the degree varies depending on the application. However, some of these polymer materials may not be suitable for use in medical applications due to problems such as acute toxicity and heat generation due to elution of low molecular substances such as monomers and oligomers contained in the materials. there were.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a polymer having a small amount of eluted substances such as monomers and low polymers which have a serious adverse effect on medical applications such as biomaterials in molecular weight distribution, and a method for producing the same. It is in.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and found that polymers used for medical purposes such as biomaterials have a peak top molecular weight in a molecular weight distribution curve. It has been found that when the content of the low polymer having a molecular weight of 1/4 or less exceeds 20%, the above problem occurs.

[0007] Further, a reprecipitation purification method, which is an ordinary technique for purifying a polymer, that is, a polymer solution as it is or a polymer solution is prepared by dissolving a polymer in a solvent, and then the polymer solution is dissolved in a large amount of non-solvent with respect to the polymer solution amount In the method of purifying the polymer by adding the polymer solution, it was found that the problematic low polymer could hardly be removed, or that purification unevenness was large between purification lots.

Therefore, the present inventors have conducted a liquid-liquid phase separation of a homogeneous polymer solution into a polymer concentrated phase solution and a polymer dilute phase solution, whereby a relatively low-soluble high polymer is incorporated in the polymer concentrated phase solution. We attempted to transfer (partition) the remaining low polymer into the polymer dilute phase solution and thought that it was easy to transfer (partition). As a result, compared with the reprecipitation purification method, the amount of waste liquid generated during purification was smaller, and reproducibility was improved. The present invention has been found that excellent and efficient removal of low polymers and residual monomers can be achieved.

That is, the present invention provides (1) a medical polymer in which the content of a low polymer having a molecular weight of 1/4 or less of the peak top molecular weight in the molecular weight distribution curve is 20% or less, (2) The polymer according to the above (1), wherein the polymer is a copolymer having a nonionic hydrophilic group,
(3) The polymer according to the above (1) or (2), wherein the polymer is a copolymer having a nonionic hydrophilic group and a basic nitrogen-containing functional group, and (4) a polymer and one or more solvents. After the liquid-liquid phase separation into a polymer rich phase solution and a polymer dilute phase solution by adding a non-solvent to the polymer solution, the above-mentioned method characterized by comprising a polymer purification step of separating and recovering only the polymer rich phase solution. (1) A method for producing a polymer according to (3).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. In the production method of the present invention, the purification method by the non-solvent induced phase separation method is a very effective method for efficiently removing eluates such as low polymers which have a serious adverse effect on medical applications. For this purpose, first, a polymer solution comprising a polymer and one or more solvents is subjected to liquid-liquid phase separation into a polymer concentrated phase solution and a polymer dilute phase solution by a non-solvent induced phase separation method, and then only the polymer concentrated phase solution is separated. It is necessary to collect them separately. The liquid-liquid phase separation into a polymer rich phase solution and a polymer dilute phase solution allows for a polymer solution (polymer rich phase solution) with a high molecular weight distribution and a low polymer low molecular weight distribution, and a large amount of monomers and low polymers. Thus, it can be divided into a polymer solution (polymer dilute phase solution) having a high molecular weight and a small molecular weight distribution.

In the present invention, the term "low polymer" refers to a polymer having a peak top molecular weight in a molecular weight curve (refer to FIG. 1) measured by gel permeation chromatography (GPC) of the polymer, ie, 1/4 or less of a molecular weight having a maximum intensity. Dimers, trimers, oligomers and polymers having a molecular weight of In the molecular weight curve, the content of the low polymer having a molecular weight of 1/4 or less of the peak top molecular weight is defined as 1/1 of the peak top molecular weight when the peak area in the molecular weight curve shown in FIG.
It means the ratio of the peak area portion of 4 or less. The method of obtaining the molecular weight curve (method of measuring the molecular weight distribution) will be described later.

In FIG. 1, the horizontal axis represents the molecular weight, and the vertical axis represents the RI (intensity by a differential refractometer).

When the polymer solution is separated in a liquid-liquid phase in a certain container and left for a certain period of time, the polymer solution is phase-separated into a complete two-phase solution (see FIG. 2). Since the polymer concentrated phase solution having a higher specific gravity becomes the lower solution, it is possible to separate and collect the polymer concentrated phase solution by removing the polymer diluted phase solution on the upper side or extracting only the polymer concentrated phase solution. .

Further, by separating and recovering the polymer concentrated phase solution and removing the solvent, impurities such as monomers dissolved in the solvent can be reduced, so that the purification degree can be further improved. The method for removing the solvent is not particularly limited. For example, a heating drying method, a vacuum drying method, a heating vacuum drying method, a freeze drying method, a spray drying method and the like can be exemplified, but a spray drying method is preferred from the viewpoint of productivity and simplicity.

The liquid-liquid phase separation referred to in the present invention is to separate a polymer solution, which is uniformly dissolved at a certain temperature, into two-phase solutions (polymer-rich phase solution and polymer-dilute phase solution) having different polymer concentrations and molecular weight distributions. And does not include a phase change in which a solid or solid polymer precipitates.

The non-solvent induced phase separation method (Non-solvent-induced phase separation) according to the present invention
solvent InducedPhase Sepa
A ratio method is a method in which a non-solvent of a polymer is added to a polymer solution that is uniformly dissolved at a certain temperature to form the polymer solution into a plurality of phases (for example, a liquid phase and a liquid phase, or a liquid phase and a solid phase, Or a liquid phase, a liquid phase and a solid phase). Among them, in the present invention, only a phase change that is divided into a liquid phase and a liquid phase is used.

The polymer solution used in the present invention comprises at least a polymer and one or more solvents. The polymer to be purified according to the present invention is insoluble in water, but may be dissolved in other solvents, and is not particularly limited.For example, polysulfone-based polymers, polyvinyl chloride-based polymers, polyvinylidene chloride-based polymers,
A polyvinylidene fluoride polymer, a (meth) acrylate polymer and a hydrophilic polymer are used. The hydrophilic polymer used in the present invention, which swells in water but does not dissolve in water, is not particularly limited and is not particularly limited, and includes a sulfonic acid group, a carboxyl group, a carbonyl group, an amino group, an amide group, and a cyano group , A hydroxyl group, a methoxy group, a phosphoric acid group, an oxyethylene group, an imino group, an imide group, an imino ether group, a pyridine group, a pyrrolidone group, an imidazole group, a quaternary ammonium group and the like. Can be.

In particular, when the purified polymer is used as a filter material for leukocyte removal, a copolymer having a nonionic hydrophilic group is preferable in terms of platelet non-adsorbing property, and a nonionic hydrophilic group and a basic nitrogen-containing functional group are preferred. The copolymer having a group is particularly preferred because it has a selective adsorption property of platelet non-adsorption and leukocyte adsorption.

In the present invention, examples of the nonionic hydrophilic group include a hydroxyl group, an ether group, an ester group and an amide group. As the monomer containing a nonionic hydrophilic group, a monomer containing the above-mentioned hydroxyl group and amide group, for example, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, vinyl alcohol (after polymerization as vinyl acetate, Hydrolysis), (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-vinylpyrrolidone and the like. Examples of the monomer containing an ether group as a nonionic hydrophilic group include alkoxypolyethylene glycol (meth) acrylates such as methoxytriethylene glycol (meth) acrylate and methoxytetraethylene glycol (meth) acrylate.

The basic nitrogen-containing functional groups include nitrogen-containing aromatic groups such as primary amino group, secondary amino group, tertiary amino group, quaternary ammonium group, pyridine group and imidazole group. Is mentioned. Examples of the monomer having a basic nitrogen-containing functional group include allylamine; dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, dimethylaminopropyl (meth) acrylate, 3-dimethylamino-2-hydroxyl (meth) acrylate, and the like. (Meth) acrylic acid derivative; p (para) -dimethylaminomethylstyrene, p-
Styrene derivatives such as dimethylaminoethylstyrene; 2
Vinyl derivatives of nitrogen-containing aromatic compounds such as -vinylpyridine, 4-vinylpyridine and 4-vinylimidazole; and derivatives in which the above-mentioned vinyl compounds have been converted into quaternary ammonium salts by alkyl halide or the like.

The solvent used for dissolving the polymer includes, for example, glycols such as ethylene glycol and diethylene glycol if the polymer is a copolymer of 2-hydroxyethyl (meth) acrylate and dimethylaminoethyl (meth) acrylate; Alcohols such as methanol, ethanol, n (normal) -propyl alcohol, iso-propyl alcohol, and t (tert-butyl) alcohol; N, N-dimethylformamide, methylcellosolve and the like.

The non-solvent for the polymer is, for example, water if the polymer is a copolymer of 2-hydroxyethyl (meth) acrylate and dimethylaminoethyl (meth) acrylate; n-hexane, n-heptane; Toluene, xylene; aliphatic hydrocarbons such as ketones such as acetone and methyl ethyl ketone; salts; alkalis; liquids or solids which do not dissolve polymers such as acids but are compatible with solvents are used.

The combination of a solvent and a non-solvent that induces liquid-liquid phase separation may be, for example, ethanol if the polymer is a copolymer of 2-hydroxyethyl (meth) acrylate and dimethylaminoethyl (meth) acrylate. (Solvent) and water (non-solvent), ethanol (solvent) and n-
Hexane (non-solvent) and the like can be mentioned.

In the non-solvent induced phase separation method of the present invention, the amount of the non-solvent added to the polymer solution is 2
-If a non-solvent composed of a copolymer of hydroxyethyl (meth) acrylate and dimethylaminoethyl (meth) acrylate and ethanol (solvent) is water or hexane, the polymer solution is 2.5 to 4.0 ( volume)
Twice the amount of non-solvent is used.

The concentration of the polymer in the polymer solution is not particularly limited since it varies depending on the kind and molecular weight of the polymer used, but it is 0.1% by weight to 70% by weight, preferably 1% by weight.
% To 60% by weight, more preferably 5% to 50% by weight. If the polymer concentration is less than 0.1% by weight, the recovery of the polymer at the time of purification is poor, so that it is not efficient. is there. In addition, by controlling the solution viscosity and the dissolved state, the molecular weight distribution in the polymer rich phase solution and the polymer dilute phase solution can be controlled, so for the purpose of controlling the solution viscosity and the dissolved state,
Compatible with solvents such as water, salts, alkalis and acids,
It is also possible to add a plurality of non-solvents that do not dissolve the polymer, and the type and amount of the non-solvent may be optionally determined depending on the combination.

Examples of the present invention will be described below, but the present invention is not limited to these examples. The column was connected to a solution obtained by dissolving the polymer in a solution obtained by adding LiBr (lithium bromide) to N, N-dimethylformamide so that the molecular weight distribution and average molecular weight of the polymer became 1 mmol (hereinafter referred to as "solution A"). Gel permeation chromatography (GPC) (main unit: manufactured by Tosoh Corporation)
HLC-8020 + analysis program: GPC: LALL
2.03) at a temperature of 40 ° C.
(Differential refractometer). The column is a guard column (TSK guardcolum H manufactured by Tosoh Corporation).
_XL- H) and this column (previous column: T, manufactured by Tosoh Corporation)
A column composed of SKgel GMH _XL B0032 and a subsequent column: TSKgel α-M B0011 manufactured by Tosoh Corporation was used. The usage conditions (measurement conditions)
Mobile phase (developing solution): Solution A, FLOW Rate: 1 m
L / min, column temperature: 40 ° C. The molecular weight distribution and average molecular weight of the polymer were calculated by calculating the known molecular weight of polymethyl methacrylate (MM-10 set) manufactured by GL Sciences Co., Ltd. (manufactured by Polymer Laboratories) and GPC measurement of the polymethyl methacrylate Value (R
For example, the relationship with the E.T.

The amount of the residual monomer was measured by gas chromatography (GC) connected to a column (UltraAlloy-1 manufactured by Frontier Laboratories) (HP6890A manufactured by Hewlett-Packard Company + detector: FI).
D). Column temperature was 5 minutes 5 minutes after injection.
After maintaining the temperature at 0 ° C., the temperature was raised at a rate of 10 ° C./min, and the final temperature was set at 250 ° C. Other conditions for use (measurement) were as follows: inlet temperature: 150 ° C., sample injection amount:
3 μL, carrier gas: helium, and a split injection method was used.

The acute toxicity test of the polymer was performed as follows. (Preparation of Test Solution) A polymer formed into a film having a thickness of 0.22 mm to 0.26 mm in a glass container having an internal volume of about 500 mL and conforming to the alkali dissolution test of the glass container test for injection of the Japanese Pharmacopoeia. 2 g (all of which had been cut into a size of about 2 cm ² ) and 300 mL of physiological saline (physiological saline solution of Japanese Pharmacopoeia manufactured by Otsuka Pharmaceutical Co., Ltd.) were added. Furthermore, a shaking type thermostat (WATER BATH INC manufactured by YAMATO Co., Ltd.)
After shaking at a shaking speed (120 times / min) at a temperature of 70 ° C. ± 5 ° C. for 1 hour using a UBATOR BT-47), the solution was left to reach room temperature, and the liquid excluding the polymer was removed from the test solution. And

(Acute Toxicity Test) According to the dialysis type artificial kidney apparatus approval standard V-7, test liquids of 50 mL / ml were used for each of 10 homogeneous or pure male mice weighing 17 g to 23 g.
It was injected intravenously at a rate of kg, and observed for 5 days after the injection to check for abnormalities or death.

[0029]

Example 1 (Preparation of polymer solution) Ethanol (1,
000 mL) into a reaction vessel equipped with a reflux device.
After bubbling and stirring the solution with nitrogen at 5 ° C. for 1 hour, 252.2 g (1.94 mol) of 2-hydroxyethyl (meth) acrylate and dimethylaminoethyl (meth) acrylate 9. 42g
(0.06 mol) was added, and then 496.74 mg (0.002 mol) of azobisisovaleronitrile was added as an initiator and reacted for 2 hours to obtain a polymer solution.
As a result of analyzing this polymer solution, a copolymer composed of 97 mol% of 2-hydroxyethyl (meth) acrylate and 3 mol% of dimethylaminoethyl (meth) acrylate (weight average molecular weight 570,000, peak top molecular weight 3.75 × 10 ⁵ , a low polymer content of 26.0% and a monomer content of 1559 ppm). The copolymer concentration in the polymer solution is 3
It was 9% by weight.

(Purification of Polymer) A three-fold volume of pure water was gradually added dropwise to the polymer solution obtained by the above method at 25 ° C. with uniform stirring, followed by liquid-liquid phase separation. Only the phase solution was separated and collected. Further, the polymer concentrated phase solution was vacuum-dried at 40 ° C. to obtain a dried polymer. When the polymer concentration is 1 mg /
After dissolving with the solution A to a concentration of mL, the molecular weight distribution was measured. In addition, the amount of the monomer was measured using a solution in which the dried polymer was dissolved in N, N-dimethylformamide so as to have a concentration of 20% by weight. Table 1 shows changes in the contents of the monomer and the low polymer before and after the purification of the polymer. Table 2 shows the results of the acute toxicity test of the purified polymer. It became clear that the content of the monomer and the low polymer was reduced by the purification. In addition, it became clear that this purified polymer had no problem in an acute toxicity test.

[0031]

Example 2 To the polymer solution used in Example 1 was added twice the volume of ethanol and uniformly dissolved at 40 ° C. After the liquid-liquid phase separation was performed by dropping 0.033 times the volume of n-hexane with respect to the polymer solution little by little with respect to the polymer solution while uniformly stirring the solution at 40 ° C., only the polymer concentrated phase solution was separated and recovered. Except for the above, the same operation as in Example 1 was performed. Table 1 shows changes in the contents of the monomer and the low polymer before and after the purification of the polymer. Table 2 shows the results of the acute toxicity test of the purified polymer. It became clear that the content of the monomer and the low polymer was reduced by the purification. In addition, it became clear that this purified polymer had no problem in an acute toxicity test.

[0032]

Example 3 (Preparation of polymer solution) Ethanol (1,
000 mL) into a reaction vessel equipped with a reflux device.
After stirring the solution with nitrogen bubbling at 5 ° C. for 1 hour, 247.0 g (1.90 mol) of 2-hydroxyethyl (meth) acrylate and 18.1 g of diethylaminoethyl (meth) acrylate while maintaining the nitrogen atmosphere.
(0.10 mol) was added, and then 496.74 mg (0.002 mol) of azobisisovaleronitrile was added as an initiator and reacted for 2 hours to obtain a polymer solution.
As a result of analyzing this polymer solution, a copolymer composed of 95 mol% of 2-hydroxyethyl (meth) acrylate and 5 mol% of diethylaminoethyl (meth) acrylate (weight average molecular weight 650,000, peak top molecular weight 3.62 × 10 6 ⁵ , a low polymer content of 21.2% and a monomer content of 2038 ppm) were found to be produced. The copolymer concentration in the polymer solution is 4
It was 1% by weight.

(Purification of polymer) The same operation as in Example 1 was performed except that the above-mentioned polymer solution was used instead of the polymer solution used in Example 1. Table 1 shows changes in the contents of the monomer and the low polymer before and after the purification of the polymer. Table 2 shows the results of the acute toxicity test of the purified polymer. It became clear that the content of the monomer and the low polymer was reduced by the purification. In addition, it became clear that this purified polymer had no problem in an acute toxicity test.

[0034]

COMPARATIVE EXAMPLE 1 The polymer solution used in Example 1 was dropped and added dropwise to a 20-fold volume of xylene while stirring uniformly, and then reprecipitated and purified by solid-liquid phase separation.
Example 1 was repeated except that the precipitate was vacuum dried at 40 ° C.
The same operation as described above was performed. Table 1 shows the change in the weight average molecular weight and the change in the content of the monomer and the low polymer before and after the purification of the polymer. Table 2 shows the results of the acute toxicity test of the purified polymer.

[0035]

[Table 1]

[0036]

[Table 2]

[0037]

EFFECTS OF THE INVENTION The polymer of the present invention has a low molecular weight distribution with a small amount of eluted substances such as monomers and low polymers, so that it can be used for medical applications such as artificial organs, medical equipment materials, culture bed materials or biomaterials, and general industrial applications. Can be used.

[Brief description of the drawings]

FIG. 1 is a diagram illustrating the molecular weight distribution of a polymer of the present invention.

FIG. 2 is a diagram illustrating the concept of liquid-liquid phase separation of the present invention.

[Explanation of symbols]

 A Uniform polymer solution B Non-solvent induced phase separation (non-solvent added to polymer solution) C Polymer dilute phase solution (homogeneous polymer solution) D Polymer rich phase solution (homogeneous polymer solution)

Continued on the front page F term (reference) 4C081 AA02 AB19 AC08 CA081 CC02 DA02 DA03 4J100 AB07Q AC03P AC04P AC24P AD02P AL01P AL08P AL08Q AL09P AM15P AM19P AN03Q AQ08P AQ12Q AQ19Q BA03Q BA05P BA08P BA31QCA01 GC01

Claims (4)

[Claims] 1. A medical polymer wherein the content of a low polymer having a molecular weight of 1/4 or less of a peak top molecular weight in a molecular weight distribution curve is 20% or less. 2. The polymer according to claim 1, wherein the polymer is a copolymer having a nonionic hydrophilic group. 3. The polymer according to claim 1, wherein the polymer is a copolymer having a nonionic hydrophilic group and a basic nitrogen-containing functional group. 4. A liquid-liquid phase separation into a polymer concentrated phase solution and a polymer dilute phase solution by adding a non-solvent to a polymer solution comprising a polymer and one or more solvents, and then only the polymer concentrated phase solution is separated. The method for producing a polymer according to any one of claims 1 to 3, further comprising a purification step of the polymer to be recovered.