CN1084344C

CN1084344C - The multipolymer that three components are new reaches the eye wafer of being made by it

Info

Publication number: CN1084344C
Application number: CN96199271A
Authority: CN
Inventors: 李福绵
Original assignee: Santen Pharmaceutical Co Ltd
Current assignee: Santen Pharmaceutical Co Ltd
Priority date: 1995-12-22
Filing date: 1996-12-23
Publication date: 2002-05-08
Anticipated expiration: 2016-12-23

Abstract

The present invention relates to a kind of folding intraocular wafer material, it is characterized in that structural unit by following [I], [II], [III] expression constitutes, [I] accounts for that 60-80% (W/W), [II] account for 10-30% (W/W), [III] accounts for 5-20% (W/W), and all weight is 100%, in the formula, R ¹Expression hydrogen atom or alkyl, R ²The expression alkylidene group, this alkylidene group can replace with hydroxyl, also Sauerstoffatom can be arranged in this alkylidene chain in addition.R ³Expression [IIa], [IIb], [IIc] .R ⁵, R ⁶, R ⁷And R ⁸Represent hydrogen atom or alkyl respectively, m, n, p and q represent integer or the singly-bound of 1-4, R ⁴Expression hydrogen atom or alkyl.R ⁹Expression hydrogen atom or alkyl, R ¹⁰The expression alkyl.

Description

The multipolymer that three components are new reaches the eye wafer of being made by it

Technical field that the present invention belongs to

The present invention relates to eye and use wafer, particularly be applicable to the multipolymer (copolymer) of folding intraocular wafer (foldableIOL).

Prior art

Intraocular wafer (IOL) is the crystalline of plucking when substituting cataract operation, and the wafer of implanting since beginning to be used for to transplant in 1949, has carried out various researchs for its material.But operation method also has big change, and with the operation method progressive while, the characteristic that requires for IOL is also changing.Recently, along with popularizing of ultrasonic emulsification attraction technology etc., make the otch of plucking the turbid water crystal and opening very little, just can finish operation, thereupon, the characteristic that requires for the IOL that implants is also in variation constantly.For example in order to implant from little otch, can to implant with folding form, and open in the eye capsule, be exactly the characteristic of so-called collapsible IOL.At this,, various researchs have been carried out for the material of IOL.Material as IOL, in the past, be extensive use of poly methyl methacrylate (PMMA), silicone, acrylic resin, but material as collapsible IOL, can use polysiloxane and acrylic resin, recently, also can use the multipolymer etc. of hydroxyethyl meth acrylate and methyl methacrylate etc.In addition, these materials are studied, in order to prevent that ultraviolet ray is for amphiblestroid influence, make it contain UV light absorber such as dihydroxy benaophenonel and hydroxy phenyl benzotriazole, and then, for improving biological fitness, preventing that cell etc. is precipitated as purpose, in fact also use surface with IOL, carry out coating with polyoses such as heparin.

But, for the Acrylic Acid Monomer with pyrrolidone group with feature of the present invention is the unitary polymkeric substance of its part-structure, be that the report example of the polymkeric substance of purpose has with wafer particularly to be used for eye, for example, the multipolymer of methacryloxyethyl-2-Pyrrolidone and vinylformic acid etc. (Japanese Patent discloses communique No. 28705/1992), carry out the polymkeric substance (Japanese Patent discloses communique No. 43208/1990) that acid amides bonded monomer is formed by vinylformic acid and pyrrolidone, on the polyoxy alkylidene skeleton, has the polymkeric substance (Japanese Patent discloses communique No. 8218/1990) of pyrrolidone group etc., but when particularly disclosing three component based copolymers, the multipolymer (Japanese Patent discloses communique No. 105250/1978) of vinyl pyrrolidone and hydroxyethyl meth acrylate and methyl methacrylate is disclosed only, the multipolymer of methacryloxyethyl-2-Pyrrolidone and alkyl methacrylate and fluoroalkyl methacrylic ester (Japanese Patent discloses communique No. 150197/1993) etc.And then it is main purpose that these researchs are used on soft contact crystal, rather than is purpose to be applied to wafer, particularly for the application possibility aspect of the collapsible IOL of main purpose of the present invention, does not point out fully.

The problem that invention will solve

The present invention is with the eye wafer, in more detail, is the purpose that is applied as with collapsible IOL, but when the material of the collapsible IOL of research, needs to consider specific refractory power, tensile strength, recovery speed etc.For example,

1) if specific refractory power is low excessively, the thickness of IOL too increases, and specific refractory power is when too high, and then the contraction difference of periphery becomes big, so need suitable specific refractory power.Specifically, 1.4～1.6 scopes preferably.

2) owing to using tweezers that collapsible IOL is implanted, so need have the tensile strength of anti-its operation.

3) collapsible IOL must be recovered to original shape in capsule after implantation.Recovery speed according to operator's custom, ability and difference, but generally speaking, along with recovery speeds up, strengthens the possibility of the physical abuse of perienchyma.On the other hand, along with recovery speed is slack-off, when operating time is elongated, produces dysgenic possibility for perienchyma and become big.Therefore, for collapsible IOL, require suitable recovery speed.

And then, need to consider to be shaped easily.

Consider these viewpoints, but the various collapsible IOL of practical application, but wish the preferred material of exploitation.

The solution of problem

The present inventor, consider above-mentioned problem, research is for the result of the material of collapsible IOL application preferably, find, by vinylformic acid hydroxyalkyl ester derivative, acrylic acid alkyl ester derivative and contain the multipolymer that three components of the acrylic acid derivative of pyrrolidone group are formed, can become good material especially.

Content of the present invention

The present invention relates to by following a), b) and c) after the monomer of expression carries out copolymerization, the multipolymer that obtains and the multipolymer and the method for making that constitute with the structural unit of following [I], [II] and [III] expression and the wafer of using that uses this multipolymer

[in the formula, R ¹Expression hydrogen atom or low alkyl group, R ²The expression low-grade alkylidene, this alkylidene group can replace with hydroxyl, and also Sauerstoffatom can be arranged in this alkylidene chain, below identical.]

[in the formula, R ³Expression

(R ⁵, R ⁶, R ⁷And R ⁸Represent hydrogen atom or low alkyl group respectively, m, n, p and q represent 1～4 integer) or singly-bound, R ₄Expression hydrogen atom or low alkyl group.Below identical.]

[in the formula, R ⁹Expression hydrogen atom or low alkyl group, R ¹⁰The expression low alkyl group.Below identical.]

When representing with structural unit, be that the structural unit by following [I], [II] and [III] expression constitutes, [I] accounts for that 60～80% (W/W), [II] account for 10～30% (W/W), [III] accounts for 5～20% (W/W), and all total amounts are 100%.

Above-mentioned various in, the alkyl of the straight or branched with 1～6 carbon atom of low alkyl group nail base, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, hexyl etc., low-grade alkylidene is meant-CH ₂-,-(CH ₂) ₂-,-(CH ₂) ₃-,-C (CH ₃) ₂-,-(CH ₂) ₄-,-(CH ₂) ₆The alkylidene group of-the straight or branched that waits with 1～6 carbon atom.In above-mentioned, more preferred example can be enumerated R ¹Be hydrogen atom or methyl, R ²Be-(CH ₂) ₂-or-(CH ₂) ₃-, R ³Be-OCH ₂-,-OCH ₂CH ₂-,-NHCH ₂-or singly-bound, R ⁴Be hydrogen atom or methyl, R ⁹Be hydrogen atom or methyl, R ¹⁰Be methyl or isobutyl-.

As being used in combination, preferably with above-mentioned each use that combines, R in the particularly preferred combination ¹Be methyl, R ²Be-(CH ₂) ₂-, R ³Be-OCH ₂CH ₂-, R ⁴Be methyl, R ⁹Be methyl, R ¹⁰It is methyl.

The unitary ratio of copolymer structure according to the present invention, preferably [I] is 65～75% (W/W), [II] is 15～25% (W/W), [III] is 5～15% (W/W) (all being 100%), particularly preferably being [I] is 70% (W/W), [II] is 21% (W/W), and [III] is 9% (W/W).

According to the R that is preferably of the present invention ¹Be hydrogen atom or methyl, R ²For-(CH ₂) ₂-or (CH ₂) ₃-, R ³For-OCH ₂-,-OCH ₂CH ₂-,-NHCH ₂-or singly-bound, R ⁴Be hydrogen atom or methyl, R ⁹Be hydrogen atom or methyl, R ¹⁰Be methyl or isobutyl-, [I] is 60～80% (W/W), and [II] is 10～30% (W/W), and [III] is 5～20% (W/W), and all is 100% multipolymer, particularly R ¹Be methyl, R ²Be ethylidene, R ³For-OCH ₂CH ₂-, R ⁴Be methyl, R ⁹Be methyl, R ¹⁰Be methyl, [I] is 70% (W/W), and [II] is 21% (W/W), and [III] is the multipolymer of 9% (W/W).

Multipolymer of the present invention be by with a), b) and c) each monomer composition, by using under Potassium Persulphate, ammonium persulphate, benzophenone or the condition of methacryloxy dihydroxy benaophenonel as initiator, copolymerization and can making well.

General the most widely used is Diisopropyl azodicarboxylate as the polymerization starter of making multipolymer, but in its method, and the material as the collapsible IOL of the application's purpose can not get the physical strength that should be satisfied with.The present inventor is for polymerization starter, study intensively, found that by using Potassium Persulphate, ammonium persulphate, benzophenone or methacryloxy dihydroxy benaophenonel as polymerization starter, can obtain material, have the multipolymer of the physical strength that should satisfy as collapsible IOL.

In addition, as the molecular weight (viscosity-average molecular weight) of multipolymer of the present invention, so long as just can more than 10,000.Generally, in polymkeric substance, molecular weight not too influences the characteristic of multipolymer, and is not important factor, but influential for the intensity of copolymerization.Molecular weight and intensity about 10,000 when following, roughly be the collinear proportionlity, but if surpass 10,000, it is maximum that intensity reaches, and near stable.Therefore,, can not obtain stable intensity, in addition, be prone to problem on the intensity as collapsible IOL, but reach more than 10,000 below 10,000, just almost no problem.But molecular weight is too high, and is bad as the intensity of collapsible IOL, so be 10,000～100,000 as the preferred molecular weight ranges of multipolymer, the molecular weight of the multipolymer that obtains as following embodiment is also in this scope.

According to formation of the present invention,, as required, can set specific refractory power, tensile strength, recovery speed etc. by the suitable ratio of selecting each composition.For example, increase structural unit I) ratio, for specific refractory power and recovery speed, almost not influence, but tensile strength has the trend that reduces a little.Increase structural unit II) ratio, the effect of the specific refractory power that can be improved, to the almost not influence of recovery speed, but tensile strength has the trend that reduces a little.Increase structural unit III) ratio can improve recovery speed and strengthen tensile strength, but specific refractory power has the trend that diminishes a little.By utilizing these characteristics well, can obtain desirable collapsible IOL.The preferred ratio of each structural unit as mentioned above, if when using preferred composition ratio, be 1.4～1.6 in specific refractory power, recovery speed is not too fast, slow only speed, promptly 3～6 seconds, tensile strength is the tensile strength of firmly operating with tweezers fully anti-, when promptly in fact implanting intraocular (during swelling), just can obtain the above collapsible IOL of 10psi.In addition, recovery speed is according to above-mentioned operator's custom and difference also can be set in about 3～6 seconds ± 2 seconds.

For collapsible IOL, have hydrophobicly and hydrophilic, use according to purpose respectively, but multipolymer of the present invention is hydrophilic.When hydrophilic collapsible IOL, under drying regime, circulate, keeping, before use, use the distilled water swelling, the implantation intraocular.Hydrophilic degree according to water ratio, can be inferred, but influential for the biocompatible of collapsible IOL, flexibility etc.Under situation of the present invention,, can select water ratio by selecting the ratio of each structural unit.For example, increase structural unit I) and ratio II), water ratio is improved, increase structural unit III) ratio, water ratio is reduced.As water ratio, preferably 25～50%.

For preventing that retina is had bad influence, and be widely used in the technology that contains UV light absorber among the IOL, but also can contain suitable UV light absorber among the present invention.About its method that contains, method (method that in fact is widely used) that physically contains UV light absorber and the method that UV light absorber is chemically combined (UV light absorber itself also becomes the monomer composition that forms multipolymer) with multipolymer are arranged, in the present invention, also can utilize two kinds of methods.Particularly when the latter, when using IOL, the big advantage that has UV light absorber can from IOL, not spill.

Here said Chemical bond is meant that UV light absorber originally as the compound with the two keys of polymerizability, can enter in the multipolymer with above-mentioned monomer copolymerizable.The amount of UV light absorber is from all looking like minute quantity, the characteristic of multipolymer itself is influenced hardly, but multipolymer becomes fragile too much the time.Its content is 0.5～2.0 weight % of multipolymer preferably, more preferably 0.8～1.5 weight %.

Kind as UV light absorber, just there is no particular limitation so long as can be used for IOL, being exemplified as can be with benzophenone series or benzotriazole system or their acrylic acid derivative, particularly, dihydroxy benaophenonel or hydroxybenzotriazole or their acrylic acid derivative, for example 4-methacryloxy-2-dihydroxy benaophenonel is suitable.

Multipolymer of the present invention also can carry out crosslinkedly intermolecular, by crosslinked, can regulate physical strength and water-intake rate.Can enumerate acrylic ester or acrylamide linking agent as linking agent, can exemplify particularly and be Ethylene glycol dimethacrylate, diethyleneglycol dimethacrylate(DEGDMA) or N, N '-methylene radical two (acrylamide).The polymkeric substance hardening for a long time of the amount of linking agent, recovery speed accelerates, but becomes fragile on the contrary.Its amount is 0.01～2.0 weight % of multipolymer preferably, and more preferably 0.1～1.5 weight % particularly preferably is 0.5～1.0 weight %.

For improving the organism suitability, preventing that cell etc. is precipitated as purpose, technology with polyose coating IOL surface just is being used recently, but owing to have the free hydroxyl at the end of multipolymer of the present invention, so can carry out covalent attachment with polyose, the problem of coating stripping does not take place.In addition, also can be easy to make it to form covalent linkage, for example, just can as long as use divinylsulfone to handle.As the object lesson of polyose, preferably heparin or hyaluronic acid or its salt (sodium salt, sylvite etc.).

And then as the feature of multipolymer of the present invention, can enumerate the acrylic acid derivative that contains as the pyrrolidone group of feature composition is composition b) and monomer reaction rate (monomer reactivity ratio, MRR) the r of composition between a) ₁* r ₂Near 1.0.r ₁* r ₂Near 1.0 are expression polymerizations ideally.If be 2-hydroxyethyl methacrylate, composition b a) with composition) be vinylformic acid N-pyrrolidone ethyl ester as object lesson, r then ₁* r ₂Be 1.03.The mensuration of this MRR is carried out according to the method (J.Am.Chem.Soc., 1994,66,1594) of Mayo-Lewis.

The present invention relates to have flexual softish IOL matrix,, when clamping operation, stay residual set to restoring behind the tweezers folder, often need certain hour with tweezers at such IOL.But multipolymer of the present invention has good Restoration, can solve such problem.

And then, after turn white in the treatment of cataract or glaucoma etc., also can use laser, but after implanting IOL, in the time of need carrying out such treatment, when silicone-based IOL in the past, often lenticular opacity damages the transparency, in addition, also may produce sex change a little, and how much damage the visual field at periphery.But, when multipolymer of the present invention, do not find such muddiness, also can keep its transparency, and the sex change of periphery takes place hardly.Multipolymer of the present invention can easily be shaped as the collapsible IOL of actual use.Its available known method that is shaped is carried out.Multipolymer of the present invention is suitable especially for collapsible IOL, but its character also can be applied on the soft contact crystal aptly.

Specify to implementing the solution of the present invention below by embodiment.

Reference example (monomeric synthetic)

Synthesizing of reference example 1 vinylformic acid 2-(2-Pyrrolidone-1-yl) ethyl ester (PyEA)

In chloroform (150ml) solution of 1-(2-hydroxyethyl)-2-Pyrrolidone (50ml) and triethylamine (85ml), stir on one side, on one side with following 2 hours of chloroform (100ml) drips of solution of acrylate chloride (50ml).With reaction solution under 4 ℃, stir 20 hours, stirred 2 hours down at 50 ℃, filter after the cooling.Concentrating under reduced pressure is cleaned, carried out to filtrate with 15% aqueous sodium carbonate.The oily matter that obtains is carried out underpressure distillation, and the yield with 70% obtains title compound.Bp:112-113 ℃/0.5 holder (Torr) NMR (ppm, TMS, CDCl ₃): 6.14 (m, 3H), 5.80 (s, 1H), 4.30 (t, 2H), 3.60 (m, 4H), 2.20 (m, 4H) IR (KBr, cm ^-1): 1735,1676,1639,1361

With reference example 1 in the same manner, obtain following compound.

Methacrylic acid 2-(2-Pyrrolidone-1 base) ethyl ester (PyEMA) bp:120-122 ℃/0.5 holder (Torr) NMR (ppm, TMS, CDCl ₃): 6.10 (s, 3H), 5.59 (s, 1H), 4.29 (t, 2H), 3.59 (m, 4H), 2.30 (m, 4H), 1.94 (m, 3H) IR (KBr, cm ^-1): 1735,1676,1639,1361

Vinylformic acid 2-Pyrrolidone-1-base methyl esters (PyMA) bp:92-93 ℃/0.5 holder (Torr) NMR (ppm, TMS, CDCl ₃): 6.34-6.83 (m, 2H), 6.06-6.12 (m, 1H), 5.37 (m, 2H), 3.57-3.69 (m, 2H), 1.91-2.50 (m, 4H) IR (KBr, cm ^-1): 1708,1639,1415

Methacrylic acid 2-Pyrrolidone-1-base methyl esters (PyMMA) bp:95-96 ℃/0.5 holder (Torr) NMR (ppm, TMS, CDCl ₃): 6.13-6.16 (s, 1H), 5.59-5.61 (m, 1H), 5.41 (s, 2H), 3.55 (t, 2H), 1.9-2.43 (m, 4H), 1.96 (m, 3H) IR (KBr, cm ^-1): 1716,1636,1420

Synthesizing of reference example 2N-(2-Pyrrolidone-1-ylmethyl) acrylamide (PyMAm)

With 1 methoxymethyl-2-Pyrrolidone (65.6g), acrylamide (75.5g), toluenesulphonic acids (0.20g) and thiodiphenylamine (0.20g) one side the methyl alcohol that distillates generation of mixture, Yi Bian under nitrogen atmosphere, stirred 1 hour down at 150 ℃.Trub, from acetone recrystallization, the yield with 40% obtains title compound.mp：73～74℃NMR(ppm，TMS，CDCl ₃)：7.31(m，1H)，6.19-6.31(m，2H)，5.56-5.72(m，1H)，4.75-4.81(d，2H)，3.50-3.66(t，2H)，1.91-2.44(m，4H)IR(KBr，cm ^-1)：3440，1680，1200-1600

With reference example 2 in the same manner, obtain following compound.

N-(2-Pyrrolidone-1-ylmethyl) Methacrylamide (PyMMAm) mp:101～102 ℃ of NMR (ppm, TMS, CDCl ₃): 6.70 (s, 1H), 5.69 (s, 1H), 5.35 (s, 1H), 4.70-4.80 (d, 2H), 3.45-3.62 (t, 2H), 1.95-2.45 (m, 7H)

Reference example 3,1-acryl-2-Pyrrolidone (NAPy) synthetic.

Use 2-Pyrrolidone and acrylate chloride, carry out reference example 1 and operate in the same manner, the yield with 70% obtains title compound.Bp:85-86 ℃/0.5 holder (Torr) NMR (ppm, TMS, CDCl ₃): 7.31-7.65 (m, 1H), 6.56-6.59 (m, 1H), 5.74-5.96 (m, 1H), 3.77-3.96 (m, 2H), 2.52-2.73 (m, 2H), 1.85-2.24 (2m, 2H) IR (KBr, cm ^-1): 1737,1679,1408

With reference example 3 in the same manner, obtain following compound.

1-methacryloyl-2-Pyrrolidone (NMAPy) bp:88-89 ℃/0.5 holder (Torr) NMR (ppm, TMS, CDCl ₃): 5.28-5.34 (s, 2H), 3.72-3.90 (m, 2H), 2.57-2.67 (m, 2H), 2.00-2.16 (m, 2H), 1.97-1.99 (s, 3H) IR (KBr, cm ^-1): 1745,1676,1403

Embodiment (the synthetic making that reaches the sheet of making by its multipolymer of multipolymer)

The making of the multipolymer (HEMA-PyEMA-MMA) that embodiment 1. is made up of 2-hydroxyethyl methacrylate (HEMA), methacrylic acid 2-(2-Pyrrolidone-1-yl) ethyl ester (PyEMA) and methyl methacrylate (MMA) synthetic and the sheet made by its multipolymer.

With HEMA, PyEMA and MMA, with 70/20/10 (v/v; If be converted into w/w, be 70/21/9) ratio, mix, and then the Potassium Persulphate of 0.2 weight % and 10 weight % water are carried out the blended mixture join the interval that keeps 0.5mm or 0.1mm with dividing plate, between 2 sheet glass having fixed with clip (6cm * 5cm, the sheet glass that uses siloxane-based sealing agent to handle), under 60 ℃, carry out radical polymerization in 22 hours, under 90 ℃, carry out aftertreatment in 2 hours and finish polymerization.This sheet is taken off from sheet glass, be dipped into distilled water, remove unreacted monomer, obtain sheet as the multipolymer of purpose.In addition, the interval of 2 sheet glass is selected as required.

With embodiment 1 in the same manner, obtain following multipolymer and by its sheet of forming.HEMA-PyEA-MMA, HEMA-PyMA-MMA, HEMA-PyMMA-MMA, HEMA-NAPy-MMA, HEMA-PyMAm-MMA, HEMA-PyMMAm-MMA, HEA-PyEA-MA, HEA-PyMAm-MA, HPMA-PyEA-MMA, the above-mentioned abbreviation of HEMA-PyEA-i-BuMA is represented following compound (following identical)

HEMA: 2-hydroxyethyl methacrylate

HEA: vinylformic acid 2-hydroxy methacrylate

HPMA: methacrylic acid 2-hydroxy propyl ester

NAPy:1-acryl-2-Pyrrolidone

PyEA: vinylformic acid 2-(2-Pyrrolidone-1-yl) ethyl ester

PyEMA: methacrylic acid 2-(2-Pyrrolidone-1-yl) ethyl ester

PyMA: vinylformic acid 2-Pyrrolidone-1-base methyl esters

PyMMA: methacrylic acid 2-Pyrrolidone-1-base methyl esters

PyMAm:N-(2-Pyrrolidone-1-ylmethyl) acrylamide

PyMMAm:N-(2-Pyrrolidone-1-ylmethyl) Methacrylamide

MMA: methyl methacrylate

MA: methyl acrylate

I-BuMA: Propenoic acid, 2-methyl, isobutyl ester

NMAPy:1-methacryloyl-2-Pyrrolidone

These multipolymers and sheet thereof use the method for following embodiment 2, also can be made into.

Embodiment 2. synthesizes and makes the making of the sheet of being made up of its multipolymer by the photopolymerization of multipolymer (HEMA-PyEMA-MMA).

With HEMA, PyEMA and MMA, with 70/20/10 (v/v; If be converted into w/w, be 70/21/9) ratio mix, and then, add the benzophenone (or 4-methacryloxy-2-dihydroxy benaophenonel) of 2 weight % and the methacrylic acid N of 0.4 weight %, the N-dimethylamino ethyl ester, to carry out mixed mixture, join the interval that keeps 0.5mm or 0.1mm with dividing plate, between 2 sheet glass having fixed with clip (6cm * 5cm, the sheet glass that uses siloxane-based sealing agent to handle), use the 80w mercuryvapour lamp, carry out 48 hours uviolizing, make it carry out photopolymerization.This sheet is taken off from sheet glass, be immersed in the distilled water, remove unreacted monomer, obtain sheet as the multipolymer of purpose.In addition, the interval of 2 sheet glass is selected as required.

The multipolymer that embodiment 3. is crosslinked synthetic and by the making of its sheet of making.

In the operation of embodiment 1, in the mixture before radical polymerization, add the methacrylate glycol ester (EGMA) of 1.0 weight %, below operate in the same manner with embodiment 1, obtain intermolecular cross-linking multipolymer and by its sheet of forming.

As linking agent, can use other double methyl methacrylate, N of methacrylate glycol ether ester (DEGMA) class, the bisacrylamide of N '-methylene-bisacrylamide class, in addition, and as required, the also optional content of selecting linking agent.

The numerical example of the sheet of the multipolymer that makes for the method with embodiment 1 or 3, its physicochemical property are as shown in table 1.In the table, what make the * mark is that expression makes with the method for embodiment 3, and other are that method by embodiment 1 and 2 makes.In addition, embodiment 2 is to use photopolymerisable another kind of synthesis method, but the physicochemical property of the multipolymer that obtains with obtain with embodiment 1, do not have difference in fact.

Table 1

The moisture refraction tensile strength of multipolymer return rate % leads the wet speed of doing
	Qualified HEMA-PyEA-i-BuMA* 31 1.45 51.3-of HEMA-PyEA-MMA 34 1.45 29.2 1000 qualified HEMA-PyEMA-MMA 31 1.45 32.1 1050 qualified HEMA-PyMA-MMA 33 1.45 82.3 2313 qualified HEMA-PyMMA-MMA 28 1.44 193.6 806 qualified HEMA-NAPy-MMA qualified HPMA-PyEA-MMA* 40 1.43 19.2-of qualified HEMA-PyMMAm-MMA* 36 1.45 65.9-of 33 1.46 58.1 2389 qualified HEMA-PyMAm-MMA* 40 1.44 41.4-are qualified

*: according to embodiment 3 synthetic, crosslinked multipolymer

The mensuration of the physicochemical property shown in the table 1 is carried out as follows.

Water ratio: will be cut into discoid multipolymer sheet, be added to the water (0 ℃, more than 2 days), make water content reach equilibrium state after, remove moisture attached to the surface, be weighed as W ₁With under reduced pressure 60 ℃ on sample, carry out 48 hours processed, claim the weight of drying regime to be taken as W ₂

Calculate (W ₁-W ₂)/W ₁Calculate water ratio.

Specific refractory power: use the Abbe refractometer, measure.

Tensile strength: use the YQ-Z-7 determinator, measure with the draw speed of 12cm/min.Unit represents with psi.So-called " wet ", expression are the equilibrium states that water reaches when making its swelling." do " is meant the state of doing when in blocks.

Recovery speed: the water swelling is reached the equilibrated sheet, be cut into 3.0 * 3.0cm size, behind the tweezers lamination, measure the time that resets into original state.Time applicatory is about 3～6 seconds ± 2 seconds, but the preferred time promptly as long as in 3～6 seconds scope, just is decided to be " qualified ".

The synthetic of multipolymer that embodiment 4. contains UV light absorber reaches by its sheet of making.

In the operation of embodiment 1, in the mixture before radical polymerization, 4-methacryloxy-2-the dihydroxy benaophenonel (MAHBP) that adds 0.8-1.5 weight %, below operate in the same manner with embodiment 1, the chemical bond form that obtains contain UV light absorber multipolymer and by its sheet of forming.

When measuring the ultra-violet absorption spectrum (Shimazu UV-250) of this sheet, absorb the following wavelength of 400nm well.By the suitable UV light absorber of selecting, can change the scope of absorbing wavelength.

Embodiment 5. processes for the sheet surface by polyose

With the multipolymer sheet that embodiment 1 makes, join in the heparin solution (5%) after 24 hours, be exposed to air 1 hour.Its sheet under 40 ℃, is immersed in the sodium carbonate buffer (pH11) that contains diethyl sulfone (0.1%), then, cleans with phosphoric acid buffer, water is fully clean again, makes the sheet of the covalency state of heparin and oh group.

As polyose,, also can obtain identical sheet even use hyaluronate sodium to replace heparin.

Reference example 4. monomer reaction rates (monomer reactvity ratio, mensuration MRR)

Measure acrylic acid derivative as the pyrrolidone group of the monomer composition of the feature that contains polymkeric substance of the present invention (as typical example, use PyEA) corresponding monomer with its polymeric is (as typical example, monomer reaction rate use HEMA) (monomer reactivity ratio, MRR).

For 1 part of HEMA, with PyEA, in 1～10 part of scope the change and mix, adding is as the Diisopropyl azodicarboxylate of polymerization starter, puts in the sealed glass container of discharging gas, by at 60 ℃, carry out 10-45 minute processing, with polymer controls below 10%.After the reaction, in sherwood oil, the multipolymer that obtains is precipitated.By the nitrogen quantitative analysis, obtain the PyEA amount in the multipolymer.According to Mayo-Lewis method (J.Am.Chem.Soc., 1994,66,1594), obtain the reactive ratio r of PyEA/HEMA ₁And r ₂r ₁Be 0.43, r ₂Be 2.40, the r of monomer reaction rate ₁* r ₂Be 1.03.

Effect of the present invention

The invention provides the eye wafer, particularly the suitable new copolymer that is used in collapsible IOL.

Its advantage is as follows.

1) shown from folded state restoration fast.

2) shown good refractive index.

3) good physical strength (tensile strength).

4) by changing the component ratio of each monomer, can obtain desirable character.

5) namely use the tweezers operation, also leave no trace.

6) do not cause muddiness with Ear Mucosa Treated by He Ne Laser Irradiation yet, can keep the transparency.

7) owing in molecule, having hydroxyl, so after copolymer generates, can carry out hydration.

8) surperficial available polysaccharide is processed easily, and becomes the covalency state, so do not break away from.

9) intermolecular can be easily crosslinked.

10) acrylic acid derivative that contains as the pyrrolidone group of the monomer composition of polymer features of the present invention is composition b) and the r of composition monomer reaction rate (monomer reactivity ratio, MRR) a)₁×r ₂Near 1.0. r₁×r ₂Near 1.0, expression can be carried out desirable polymerization.

Claims

1. multipolymer is characterized in that being made of the structural unit of following [I], [II], [III] expression, and wherein [I] accounts for that 60-80% (W/W), [II] account for 10-30% (W/W), [III] accounts for 5-20% (W/W), and all total amounts are 100%,

In the formula, R ¹Expression hydrogen atom or low alkyl group, R ²The expression low-grade alkylidene, this low-grade alkylidene can replace with hydroxyl, and also Sauerstoffatom can be arranged in this low-grade alkylidene chain, In the formula, R ³Expression Perhaps singly-bound, wherein, R ⁵, R ⁶, R ⁷And R ⁸Represent hydrogen atom or low alkyl group respectively, m, n, p and q represent the integer of 1-4, R ⁴Expression hydrogen atom or low alkyl group,

In the formula, R ⁹Expression hydrogen atom or low alkyl group, R ¹⁰The expression low alkyl group.

2. multipolymer according to claim 1, wherein molecular weight is 10,000-100,000.

3. multipolymer according to claim 1, wherein R ¹Be hydrogen atom or methyl, R ²Be-(CH ₂) ₂-or-(CH ₂) ₃-.

4. multipolymer according to claim 1, wherein R ³Be-OCH ₂-,-OCH ₂CH ₂-,-NHCH ₂-or singly-bound, R ⁴Expression hydrogen atom or methyl.

5. multipolymer according to claim 1, wherein R ⁹Expression hydrogen atom or methyl, R ¹⁰Expression methyl or isobutyl-.

6. multipolymer according to claim 1, wherein R ¹Expression hydrogen atom or methyl, R ²Be-(CH ₂) ₂-or-(CH ₂) ₃-, R ³Be-OCH ₂-,-OCH ₂CH ₂-,-NHCH ₂-or singly-bound, R ⁴Expression hydrogen atom or methyl, R ⁹Expression hydrogen atom or methyl, R ¹⁰Expression methyl or isobutyl-.

7. multipolymer according to claim 1, wherein R ¹The expression methyl, R ²Be-(CH ₂) ₂-, R ³Be-OCH ₂CH ₂-, R ⁴The expression methyl, R ⁹The expression methyl, R ¹⁰The expression methyl.

8. multipolymer according to claim 1, wherein, [I] accounts for that 65～75% (W/W), [II] account for 15～25% (W/W), [III] accounts for 5～15% (W/W), all is 100%.

9. multipolymer according to claim 1, wherein, [I] accounts for that 70% (W/W), [II] account for 21% (W/W), [III] accounts for 9% (W/W).

10. multipolymer is characterized in that being made of the structural unit of following [I], [II], [III] expression, and wherein [I] accounts for that 60～80% (W/W), [II] account for 10～30% (W/W), [III] accounts for 5～20% (W/W), all is 100%, R ¹Be hydrogen atom or methyl, R ²Be-(CH ₂) ₂-or-(CH ₂) ₃-, R ³Be-OCH ₂-,-OCH ₂CH ₂-,-NHCH ₂-or singly-bound, R ⁴Be hydrogen atom or methyl, R ⁹Be hydrogen atom or methyl, R ¹⁰Be methyl or isobutyl-.

11. multipolymer according to claim 1, wherein [I] accounts for that 70% (W/W), [II] account for 21% (W/W), [III] accounts for 9% (W/W), R ¹Be methyl, R ²Be ethylidene, R ³Be-OCH ₂CH ₂-, R ⁴Be methyl, R ⁹Be methyl, R ¹⁰It is methyl.

12. multipolymer according to claim 1 wherein contains UV light absorber.

13. multipolymer according to claim 12 is characterized in that the form that contains of UV light absorber is for forming Chemical bond on the multipolymer.

14. multipolymer according to claim 13, wherein the content of UV light absorber is 0.5～2.0% (W/W) of multipolymer.

15. multipolymer according to claim 13, wherein the content of UV light absorber is 0.8～1.5% (W/W) of multipolymer.

16. multipolymer according to claim 12, wherein UV light absorber is a dihydroxy benaophenonel.

17. multipolymer according to claim 12, wherein UV light absorber is the acrylic acid series compound that contains dihydroxy benaophenonel residue or benzotriazole residue.

18. it is, crosslinked by acrylic ester or acrylamide linking agent according to claim 1 or 12 described multipolymers.

19. multipolymer according to claim 18, wherein linking agent is selected from Ethylene glycol dimethacrylate, dimethacrylate glycol ether ester or N, N '-methylene radical two (acrylamide), and the amount of its linking agent is 0.01～2.0 weight % of multipolymer.

20. multipolymer according to claim 18, wherein the amount of linking agent is 0.1～1.5 weight % of multipolymer.

21. multipolymer according to claim 18, wherein the amount of linking agent is 0.5～1.0 weight % of multipolymer.

22. according to the described multipolymer of claim 1,2 or 18, carry out surface working by polyose.

23. multipolymer according to claim 22, wherein surface working is that covalent linkage by multipolymer and polyose forms.

24. multipolymer according to claim 22, wherein the formation of covalent linkage forms by using divinylsulfone.

25. multipolymer according to claim 22, wherein polyose is heparin or hyaluronic acid or its salt.

26. an eye wafer is by claim 1,12,18 or 22 described multipolymer formed therebies.

27. a folding eye is used wafer, is by claim 1,12,18 or 22 described multipolymer formed therebies.

28. a folding eye is used wafer, is by claim 1,12,18 or 22 described multipolymer formed therebies, and have following characteristic:

A) specific refractory power is 1.4～1.6,

B) speed from folded state reinstatement attitude is 3～6 seconds,

C) tensile strength during swelling is more than the 10psi.

29. a folding eye is used wafer, is described copolymer molded by claim 1, contain UV light absorber in its multipolymer, and these is crosslinked by linking agent, and then with polyose surface working is carried out on the multipolymer surface.

30. folding eye wafer according to claim 29, wherein UV light absorber is the acrylic acid series compound that is selected from benzophenone series, benzotriazole system or contains dihydroxy benaophenonel residue or benzotriazole residue, linking agent is to be selected from acrylic ester or acrylamide, and polyose is to be selected from heparin or hyaluronic acid or its salt.