KR20010036249A - Polymethylmethacrylate with Hydrophilic Surfaces and Use Thereof for Opthalmic Materials - Google Patents

Abstract

PURPOSE: A poly-methyl methacrylate having hydrophilic surface and a use thereof as ophthalmic material are provided, which maintains an optical property of PMMA and which reduces adhesion growth of cell and protein. CONSTITUTION: A preparation method of poly-methyl methacrylate having hydrophilic surface is formed by bonding poly-ethylene oxide derivative of formula: NH2-R1-O-(CH2CH2O)n-X containing amino group at the end in the presence of catalyst at the surface of poly-methyl methacrylate chemically. In formula, R1 is (CH2CH2)2-3, n is 15-300, X is hydrogen, CH3, (CH2CH2)2-3-NH2 or (CH2CH2)2-3-NH-(CH2)3-SO3H. The molecular weight of poly-ethylene oxide is 200-10,000. The catalyst is tri-ethylamine.

Description

Polymethylmethacrylate with Hydrophilic Surfaces and Use Thereof for Opthalmic Materials}

The present invention relates to an ophthalmic material excellent in biocompatibility and a manufacturing method thereof. More specifically, a biological body prepared by chemically bonding a hydrophilic polyethylene oxide (PEO, also called polyethylene glycol (PEG))-based compound to the surface of polymethyl methacrylate (PMMA) or graft polymerization to hydrophilize The present invention relates to an ophthalmic material having excellent suitability and suppressing adhesion of proteins and cells, and a method for producing the same.

Conventionally, PMMA has been widely used in ophthalmic materials such as hard contact lenses, intraocular lenses, and artificial corneas because of its optical transparency, excellent weather resistance and stability in the body.

However, a hard contact lens made of PMMA material has a disadvantage of having a large foreign matter when worn and low oxygen permeability, and thus loses competitiveness to a polyhydroxyethyl methacrylate (PHEMA) -based flexible contact lens.

PMMA is also commonly used with silicone as an intraocular lens inserted into the eye. In addition, products with surface-hydrophilic properties have also been developed to improve the biocompatibility of PMMA. For example, heparin-coated intraocular lenses have been developed and used, which has been reported to reduce inflammatory response (M. Spangberg et al., ″ Improved biocompatibility of intraocular lenses by heparin surface modification: a 12-month implantation study in monkeys ″, J. Cataract Refract Surg 16, 170-7, 1990).

On the other hand, artificial corneas based on PMMA have been studied since the 1950s, and in the 1960s, Cardona developed bolt-nut products and used them until recently, but has not been satisfactory. There have been two major causes of failure of the developed corneals: first, the cornea implanted on the ocular surface is detached (ie, lack of biocompatibility) due to tight adhesion to surrounding tissues, and the second scar tissue is artificial. It can be divided into a case where the growth of the adhesion to the corneal surface and covering the optical part to pass the light is impossible. Therefore, in order to develop an ideal artificial cornea, it is essential to develop a material that has a suitable design and excellent biocompatibility with the transplanted surrounding tissue and suppresses the adhesion growth of scar tissue.

Currently, as described above, PMMA, which is used as an intraocular lens and an artificial cornea, is a polymer material having a very high hydrophobicity, and it can be seen that adhesion growth of cells and proteins is difficult on the surface of the hydrophilic material, but very easily on the hydrophobic material. As is known, efforts have been made to hydrophilize the surfaces of these PMMAs.

In this regard, it has been known that polyethylene oxide (PEO) -bound materials significantly reduce adhesion of blood components, proteins, cells, bacteria, etc. More effective (Ki Dong Park and Young Ha Kim et al. ″ Bacterial adhesion on PEG modified PU surfaces ″, Biomaterials, 19, 851, 1998; ″ Plasma protein adsorption to sulfonated PEO-grafted PU surface ″ , J. Biomed. Mater. Res., 30, 23, 1996).

In addition, protein adsorption of contact lenses may be carried out using copolymers containing PEO (e.g., U.S. Pat.Nos. 5,115,056 and 4,871,785) or coating compounds containing PEO (e.g., U.S. Patent No. 5,525,691). There has also been proposed a method of preventing cloudiness during wear by suppressing it.

However, in this method, these coating compounds are only physically bonded to the surface of the material, so that the coating layer is likely to be washed away by tears or the like during use, which is not permanent, and the copolymer coated with these compounds changes the properties of the entire material. There are disadvantages.

Therefore, there is a desire for development of a method capable of reducing the adhesion growth of cells and proteins while maintaining the optical properties of PMMA.

It is therefore an object of the present invention to provide a method of hydrophilizing the surface of PMMA, which further reduces the adhesion growth of cells and proteins, while maintaining the optical properties of the PMMA.

The object of the present invention can be achieved by a method of hydrophilizing the surface of a polymer material such as PMMA using chemical surface modification.

According to the present invention, the method of hydrophilizing the polymer surface of the PMMA hydrophilized PMMA is prepared by chemically bonding the hydrophilic compound of the PEO derivative to the polymer surface, or by graft polymerization of the hydrophilic monomer on the polymer surface. Such chemical bonding or graft polymerization of PEO derivatives has the advantage of obtaining a relatively uniform surface and is a stable method that is unlikely to be lost by physical washing since it is a chemical bond.

According to one embodiment of the present invention, surface hydrophilized PMMA is prepared by chemically bonding a PEO derivative, which is a hydrophilic compound, to the surface of the PMMA polymer.

In general, PMMA is a chemically stable polymer that has an ester bond. However, in the presence of a suitable catalyst, the ester group can be activated and reacted with the primary- or secondary amine compound to be substituted. Accordingly, the PEO derivative can be bonded to the surface of the PMMA by reacting the PMO with the PEO derivative containing an amino group at the terminal.

Catalysts that can be used in the above method include alkali metal hydroxides, trialkylamines and the like which are strong base compounds.

The PEO derivative to be used is a compound containing an amino group at both ends or one end, and has a structure represented by the following formula (1).

Wherein R ₁ is (CH ₂ CH ₂ ) _2-3 , n is 15 to 300, X is hydrogen, CH ₃ , (CH ₂ CH ₂ ) _2-3 -NH ₂ or (CH ₂ CH ₂ ) _2-3 -NH- (CH ₂ ) ₃ -SO ₃ H)

In the above formula, when X is a sulfonic acid end group, it can be easily introduced by reacting propane sulfone with a hydroxyl group or an amino group at the PEO terminal (see Dong Keun Han and Young Ha Kim et al. ″ Preparation and surface properties of PEO- sulfonate grafted PU for enhanced blood compatibility ″, J. Biomater.Sci., Polymer Ed., 4, 579, 1993; Ki Dong Park and Young Ha Kim et al. ″ Bacterial adhesion on PEG modified PU surfaces ″, Biomaterials, 19, 851, 1998).

In general, the molecular weight of the PEO derivative used in the present invention is not particularly limited, but considering the effect of hydrophilization and physiological function, the molecular weight of 200 to 10,000 is preferred, and the range of 500 to 5,000 is more preferred. Since the PEO derivative is well dissolved in water, the reaction may proceed in an aqueous solution, but in some cases, an organic solvent may be added. In this case, swelling and surface damage of PMMA due to the organic solvent may be caused, so that the unreacted PEO derivative is preferably washed with water sufficiently after the reaction and removed.

According to another embodiment of the present invention, a hydrophilized PMMA is prepared by graft polymerizing an acrylic or methacrylic acid based hydrophilic monomer containing PEO on the surface of the PMMA.

Since PMMA itself does not have a functional group capable of initiating polymerization, in order to graft polymerize the hydrophilic monomer on the surface of PMMA, a reaction point should be introduced by electron beam irradiation, plasma treatment, ozone treatment, or the like. However, since the electron beam or the plasma treatment method is difficult to uniformly treat according to the shape and the part of the specimen, it is preferable to uniformly react with ozone which is a gas.

That is, when the surface of the polymer is treated with ozone, peroxide groups are generated, and the generated peroxide groups are decomposed at about 50 ° C. or more to generate peroxide radicals, thereby enabling graft polymerization of monomers.

Acrylic or methacrylic acid-based hydrophilic monomers that can be used in the process of the present invention include acrylic acid and methacrylic acid containing carboxylic acid groups; Hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate containing a hydroxyl group; N-methylpyrrolidone; PEO (meth) acrylate etc. which contain PEO in pendant sulfonic acid etc. are mentioned. Of these, the structure of the derivative containing PEO can be represented by the formula (2), the range of the molecular weight of the effective PEO is as described above.

Wherein R ₂ is hydrogen or CH ₃ , n is 15 to 300 and Y is hydrogen, (CH ₂ ) ₃ -SO ₃ H or CH ₃ )

In order to evaluate the properties of the hydrophilized PMMA prepared according to the method of the present invention, the degree of hydrophilization and adhesion of scar tissue were measured according to the following method.

First, the degree of hydrophilization of the surface was evaluated quantitatively by measuring the contact angle. The contact angle has a static contact angle and a dynamic contact angle depending on the method. The dynamic contact angle has a higher hydrophilicity with a smaller receding angle. Five specimens were measured and averaged with a dynamic contact angle measuring device (Wilhelmy balance, Cahn Instrument Inc., DCA 315).

The degree of adhesion of scar tissue to the surface-modified PMMA was evaluated by measuring the number of cells attached to the specimen by an adhesion culture experiment using keratocytes. Specifically, surface-modified PMMA specimens were immobilized in a 24-well culture dish with instant adhesive and corneal cells at 4 x 10 ⁵ cells / ml in a minimum essential medium containing 10% fetal bovine serum (FBS). Suspended nutrient solution was dispensed 1 ml per well and incubated for 24 hours in a 5% CO ₂ incubator. The culture solution was removed, and the cells attached to the specimens were treated with trypsin, collected, stained with trypan blue, and the number of living cells was measured and compared. In the measurement, ten specimens were measured and averaged.

Although the present invention is described in more detail using the following examples, the invention is not limited by these examples.

<Example 1>

The experimental PMMA sheet (LG Chemical, 2 mm thick) was cut into 1 cm x 3 cm size, washed with ethanol and dried. 10 g of diamino PEO (NH ₂ -CH ₂ CH ₂ -PEO-CH ₂ CH ₂ -NH ₂ , molecular weight 1,000, Nippon Oil and Fats Co., Tokyo, Japan) containing an amino group at both ends thereof and a tree 10 g of ethylamine (Yakuri Pure Chemicals Co., Osaka, Japan) was added thereto, reacted at 60 ° C. for 6 hours, and then washed with secondary distilled water for 2 days.

As a result of measuring the dynamic contact angle, the advancing angle of the original PMMA was 97 degrees and the receding angle was 55 degrees, but after treatment, the advancing angle decreased by 75 degrees and the retreat angle by 42 degrees. It was.

Corneal Cell Attachment As a result of culture experiments, 72x10 ⁴ cells / ml of corneal cells were attached to the surface of PMMA before treatment, but only 15x10 ⁴ cells / ml of cells were attached to PMMA after surface modification. It was found.

<Example 2>

A surface modified PMMA specimen was prepared in the same manner as in Example 1 except that diaminoPEO having a molecular weight of 3,000 was used. The retraction angle in the obtained PMMA specimens was 40 degrees, and the attached corneal cells were 13x10 ⁴ cells / ml.

<Example 3>

15 g of PEO-diamino-propane sulfone and 1.5 g of purified by separating the precipitate was reacted in 50 ml of tetrahydrofuran, the amino acid groups are introduced at one end PEO acid _{(NH 2 -PEO-SO 3 H} ) having a molecular weight of 5,000 to Prepared. Surface treated PMMA was prepared in the same manner as in Example 1 using 15 g of aminoPEOsulfonic acid, 8 g of triethylamine, and 2 g of water. The retraction angle of the surface-treated PMMA was 32 degrees, and the attached corneal cells were 10 × 10 ⁴ cells / ml.

<Example 4>

The reaction was carried out in the same manner as in Example 3 except that the molecular weight of aminoPEOsulfonic acid was 1,000. The retraction angle of the treated PMMA was 35 degrees, and the attached corneal cells were 11 × 10 ⁴ cells / ml.

<Example 5>

PMMA specimens (size 1 cm x 3 cm, thickness 2 mm) were ozonated using an ozone generator (Model: OZ06, Peak Scientific Instruments Ltd., USA) for 2 hours at room temperature with an oxygen flow rate of 4.5 liters / minute and an oxygen pressure of 1 bar. , 20% by weight of PEO 1000 acrylate (PEGA, molecular weight of PEO 1,000, Nippon Oil and Fats Co., Tokyo, Japan) in an aqueous solution was reacted for 24 hours at 60 ℃ under a nitrogen atmosphere was graft polymerized. After the reaction, unreacted PEGA was removed by washing with distilled water for 2 days.

The receding contact angle of PMMA after graft polymerization was 44 degrees, which was significantly lower than 97 degrees of untreated PMMA, and attached corneal cells decreased from 72x10 ⁴ cells / ml to 13x10 ⁴ cells / ml.

<Example 6>

The same procedure as in Example 5 was carried out except that the PEO molecular weight of PEGA used was 3,000. The retraction angle of the treated PMMA was 41 degrees and the attached corneal cells were 11 × 10 ⁴ cells / ml.

<Example 7>

The same procedure as in Example 5 was used except that PEO methacrylate (PEGMA) having a molecular weight of PEO of 1,000 was used instead of PEGA. The retraction angle of the treated PMMA was 36 degrees and the attached corneal cells were 14 × 10 ⁴ cells / ml.

<Example 8>

The PEO hydroxyl group ends of PEGMA were substituted with sulfonic acid groups. 12 g of PEGMA was reacted with sodium in anhydrous tetrahydrofuran followed by 3 g of propanesulfone to separate and purify, and then the same was carried out as in Example 5 using the sulfonic acid PEGGMA obtained. The retraction angle of the treated PMMA was 23 degrees, and the attached corneal cells were 9 × 10 ⁴ cells / ml.

<Example 9>

Clinical trial

Cylindrical artificial corneas of 4 mm and 7 mm in diameter and 3.5 mm in length were respectively made of PMMA and implanted into the eye of the patient with the cornea and lens removed. A small diameter part was exposed to the outside of the eyeball to form an optical part, and a front flange was attached around the optical part. Conventional PMMA corneas were easily impaired by tears on the optical surface and cells attached to the cylinders and optical parts. However, the surface-hydrophilic PMMA products showed excellent function by removing these problems.

According to the present invention, an ophthalmic material of surface-hydrophilized PMMA can be obtained, which has a high hydrophilicity, is excellent in wettability of body fluids, and reduces adhesion of scar tissue at the time of procedure to the eye.

Claims (7)

A method for producing a surface-hydrophilized polymethyl methacrylate comprising chemically bonding a polyethylene oxide derivative represented by the formula (1) containing an amino group at an end thereof in the presence of a catalyst on the surface of the polymethyl methacrylate. <Formula 1> Wherein R ₁ is (CH ₂ CH ₂ ) _2-3 , n is 15 to 300, X is hydrogen, CH ₃ , (CH ₂ CH ₂ ) _2-3 -NH ₂ or (CH ₂ CH ₂ ) _2-3 -NH- (CH ₂ ) ₃ -SO ₃ H) The method of claim 1 wherein the polyethylene oxide has a molecular weight of 200 to 10,000, more preferably 500 to 5,000. The process of claim 1 wherein the catalyst is triethylamine. Preparation of the surface-hydrophilized polymethylmethacrylate including graft-polymerizing acrylic acid or methacrylic acid monomer containing polyethylene oxide in the branched chain represented by following General formula (2) on the surface of polymethylmethacrylate. Way. <Formula 2> Wherein R ₂ is hydrogen or CH ₃ , n is 15 to 300 and Y is hydrogen, (CH ₂ ) ₃ -SO ₃ H or CH ₃ ) The method of claim 4 wherein the polyethylene oxide has a molecular weight of 200 to 10,000, more preferably 500 to 5,000. The method of claim 4, wherein the graft polymerization is performed by a peroxide group generated by treating polymethylmethacrylate with ozone. Hydrophilized polymethylmethacrylate as an ophthalmic material prepared by the process according to claim 1.