CA1330674C - Polyvinyl alcohol derivatives containing pendant vinylic monomer reaction product units bound through ether groups and hydrogel contact lenses made therefrom - Google Patents

Abstract

Polyvinyl alcohol derivatives containing pendant vinylic monomer reaction product units bound through ether groups and hydrogel contact lenses made therefrom Abstract A contact lens of a crosslinked, organic aprotic solvent insoluble, substantially transparent polymer of a derivative of a polyvinyl alcohol having a weight average molecular weight of at least about 2,000, containing an effective amount between about 0.1 and 90 percent, based on the number of hydroxyl groups on said polyvinyl alcohol, of a crosslinked addition reaction product of units of the formula

Description

'' 1 330674 6V-16816/~/CGC 1320 Polyvinyl alcohol derivatives containing pendant vinylic monomer reaction product units bound through ether groups and hydrogel contact lenses made therefrom The instant invention relstes to polyvinyl alcohol (PVA) ether deriva-tives containing pendant reactive vinylic units bound to the polyvinyl alcohol backbone, through ether groups, which are optionally further rescted with a conventional vinylic monomer, and which are crosslinked to form soft hydrogel contact lenses possessing high oxygen permeability and mechsnical strength and capable of being sterilized in either boiling water or dilute hydrogen peroxide solutions.

In genersl, most existing hydrogel soft contact lens materials sre bssed on HEMA, also known aæ hydroxyethyl methacrylate or as ethyleneglycol monomethacrylate, with one or more optional comonomers as described in U.S. Patent Nos. 2,976,576, 3,841,935 and 3,985,697. Other hydrogels based on N-vinylpyrrolidone copolymers and acrylamide copolymers are disclosed in U.S. Patent Nos. 3,639,524 and 3,929,741. These prior hydrogel polymers generally suffer from several inherent problems:
a) relstively weak mechanical strength, low dissolved oxygen permeability or a combinatlon of both and b) most lenses are made by either of two procedures, one requiring costly lsthing and polishing steps and the other using delicate spin casting techniques where polymerization, crosslinking, and shaping are done simultaneously.

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~` - I 330674 Polyvinyl alcohol has also been proposed as a contact lens material.
Several reagents have been suggested to crosslink PVA for this purpose:
formalin and acid catalysis, Japanese Patent 72/06910; dialdehyde of PVA
with PVA and acid catalysis, Japanese Patent application 50/115258; and glyoxal, V.S. Patent No. 3,408,429. These PVA crosslinked materials suffer from hydrolyzable acetal or hemiacetal linkages.

Silberman and Kohn, ACS Polymer Preprints 24, 262 - 3, 465 - 6 (1983) and J. Polym. Sci. Chem. 23, 327 - 336 (1985) prepared 2-benzyloxyethylmetha-crylate (BzOEMA) and graft polymerized it onto PVA by anionic and free radical catalysis. Membranes for contact lens applications were prepared by dissolving the PVA-graft-BzOEMA in dimethyl sulfoxide, casting it on a Teflon~surface and immersing it in acetone to precipitate a film which is later swollen in water. However such graft polymerization is generally accompanied by oxidation and degradation of the PVA and by the orienta-tion effects ln the casting procedure thereby promoting anisotropy in the mechanical properties.

Grafted PVAs have also been made by procedures that do not involve the formation of a radical on a polymer backbone. For example:

In U.S. Patent 4,085,168 (1978) a PVA-graft copolymer useful as a hydrogel contact lens is made by first forming a hydrophobic macromer, such as polystyrene or polymethylmethacrylate, by an anionic mechanism and capping with a polymerizable (meth)acrylate group. This macromer is then copolymerized free radically with vinyl acetate. After hydrolysis of the acetate group a comb-like structure with a PVA backbone and pendant hydrophobic chains of similar molecular weight is produced. Though clear, transparent films can be produced by this method, the actual chemistry involves several complicated steps, some of which require moisture sensitive precautions.

Also in U.S. Patent 4,426,492 (1984) certain carboxylated PVA deri-vatives, useful as disposable, hydrogel soft contact lenses, are di-sclosed. It is broadly disclosed that certain carboxylated PVA deri-vatives may be internally plasticized by esterification with a poly-glycolether such as poly(ethyleneglycol). However, esterification ~ l~rac~e ~rn4rl<

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reactions are normally difficult to be precisely reproduced, and, in addition, mixing problems may be experienced due to phase separation of two high molecular weight polymers.

PVA has been reacted with isocyanstes forming urethane linkages, for `~ example:

In U.S. Patent 3,776,889 (1973) PVA has been fully reacted with allyl-isocyanate for use in a photoresist printing plate composition. In U.S. 3,928,299 (1975), isocyanatoethyl methacrylate (IEM) was reacted with certain hydroxyalkyl methscrylate containing polymers forming a urethane linkage and the polymer used in relief printing plates or circuits to form hard, insoluble coatings.

In U.S. Pat. Nos. 4,665,123 (1987) and 4,670,506 (1987) are described polyvinyl alcohol derivatives containing pendant (meth)acryloyl units bound to the polyvinyl alcohol backbone, through urethane groups, which ~ in the case of the former patent are further reacted with a conventional p vinylic monomer, and which can be crosslinked to form soft hydrogel lenses.

PVA with ether linkagas have been made, for example:

In U.S. Patent 4,433,179 (1984) is described a process for the prepara-tion of poly-allyl ethers of high degree of allylation by derivatizing polyhydroxy compounds with allyl halides under phase transfer catalysis ~ conditions. PVA of molecular weights 2,000 and 14,000 are exemplified as q being derivstized with 78 % and 62 % of the maximum theoretical number of double bonds.
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~ In the European patent application EP-17796-A (198~) is described a j process for the production of water-soluble unsaturated polymerizable methylol acrylamide derivatives of polyols. It is exemplified to form a poly ~vinyl alcohol) with 49 % of the hydroxy groups of the polymer substituted with acrylamidomethyl groups. However, no suggestion of contact lenses is taught or suggested.

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In U.S. Re. 27,401 (1972) Wichterle and Lim prepared a PVA-methacrylste i.e. a PVA that was esterified 1 % with methacrylic acid anhydride, dissolved the same to make a 25 % aqueous solution, and polymerized the mixture in a flat mold using potassium persulfate and sodium thiosulfate as initiator to form a hydrogel membrane. This type of hydrogel was disclosed for contact lens use. However, such lenses tend to be fragile.

Also in V.S. Patent 4,347,198 (1982) it is disclosed to mix a hydrophilic component, e.g. N-vinyl pyrrolidone, a hydrophobic component, e.g. methyl methacrylate, crosslinking agent and initiator in a solvent, e.g. di-metbyl sulfoxide and crosslink the whole mixture in a mold. After equilibration in water a soft hydrogel contact lens is produced. Similar-ly a lens is disclosed as produced by mixing a polymethylmethacrylate with pendant vinyl groups with N-vinylpyrrolidone and polymerizing the mixture. It is also broadly disclosed to use a PVA esterified with methacrylic acid as the hydrophilic component of a contact lens mixture.

It is an object of the present invention to provide polyvinyl alcohol ether derivatives containing (meth)acryloyl units, which are optionally further reacted with a conventional vinylic monomer, and which then can be crosslinked to form a soft water-swellable hydrogel contact lens having high mechanical strength, medium to high water content, superior optical clarity and high oxygen permeability.

It i8 a further object of the present invention to provide aqueous swollen contact lenses obviating, or substantially reducing, the draw-backs of the prior art.

It is a further object of the present invention to provide a method of preparing such conta~t lenses by crosslinking such polyvinyl alcohol ether derivatives containing (meth)acryloyl units, and optionally sdditional vinylic monomer reaction products, in an organic aprotic solvent in a mold, such as a spin cast mold or a static cast mold, and equilibrating the resulting aprotic solvent swollen crosslinked contact lens in an aqueous medium.

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~. s ` The instant invention provides an organic aprotic solvent insoluble - polymer in the form of a substantially transparent contact lens which is i a derivative of a polyvinyl alcohol having a weight average molecular weight of at least about 2,000, containing an effective amount between about 0.1 and 90 percent, based on the number of hydroxyl groups on said polyvinyl alcohol, of a crogslinked addition reaction product of units of the formula H-CHz-Q ~I) ~ 1-A-~-A'- ~ ~H
h in the presence or absence of a polymerizable vinylic monomer wherein R1 is a divalent aliphatic, cycloaliphatic, aryl, aralkyl or alkaryl group; A is -O-, -NH- or -NHCON(R")- where R" is hydrogen or lower alkyl and A' is a direct bond; or A is a direct bond and A' is -O-or -O-CH2-; R2 is hydrogen or methyl; and R3 is hydrogen, methyl or -COOR~ where R~ is hydrogen or lower alkyl; with the proviso that if R2 is methyl, R3 is hydrogen; and wherein the polymerizable vinylic monomer, if present, is hydrophobic or is a mixture of hydrophobic and hydro-philic vinylic monomers in which mixture at least 50 % of vinyl monomers are hydrophobic.
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Where Rl is a divalent aliphatic group it is preferably straight or branched chain alkylene of l to 20 carbon atoms, or straight or branched chain alkylene of 2 to about 100 carbon atoms interrupted by one or more hetero atoms or hetero atom containing groups, such as carbonyloxy, oxycarbonylamido, sulfonamido, carbonamido, sulfonyl, sulfoxy, or preferably oxy, and is further unsubstituted or substitutsd by hydroxy.
Advantageously, where slkylene has more than about 10 carbon atoms, the number of hetero atoms present is at least one per each lO carbon atoms.
One preferred subembodiment includes for example alkoxylated divalent groups such as -Ra-o-~Rb-o3--RC wherein Ra and Rc are independently alkylene of up to 8 carbon atoms, unsubstituted or substituted by ,"

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c i - 6 - 1 330674 g hydroxy, Rb is alkylene of 2 to 4 carbon atoms and n is 1 to about 20.
Alkylene Rl more preferably has 2 to 10 carbon atoms and i5 unsubstituted or substituted by hydroxy. Suitable examples include ethylene, propylene or hydroxy substituted propylene.

Where R~ i9 a divalent aryl group, it is preferably phenylene which is unsubstituted or substituted by lower alkyl or lower alkoxy, and more preferably 1,3- or 1,4-phenylene.

A saturated cycloaliphatic divalent group R1 is preferably cyclohexylene or cyclohexylene lower alkylene, e.g. cyclohexylenemethylene, which i9 unsubstituted or substituted by one or more methyl groups in the cyclo-hexylene moiety, such as trimethylcyclohexylenemethylene, e.g. the isophorone divalent radical.

Where R1 is a divalent aralkyl or alkaryl group, the aryl moiety thereof is preferably phenylene which is unsubstituted or substituted by lower alkyl or lower alkoxy and the alkylene moiety thereof is preferably lower alkylene, such as methylene or ethylene. Accordingly, such R1 is e.g.
phenylenemethylene or methylenephenylene.

Preferred are contact lenses of polymers of formula I wherein R1 is lower alkylene or lower alkylene interrupted by one group selected from carbonyloxy, carbonamido and oxycarbonylamido, A is -O- and A' i9 a direct bond.

Lower alkyl has up to 7 carbon atoms, preferably up to 4 and is e.g.
methyl, ethyl, propyl, butyl and t-butyl.

Lower alkoxy has up to 7 carbon atoms, preferably up to 4 and is e.g.
methoxy, ethoxy, propoxy, butoxy and t-butoxy.

Lower alkylene has up to 7 carbon atoms, preferably up to 4 and is e.g.
methylene, ethylene, propylene and butylene.

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_ 7 _ ~330674 The polyvinyl alcohol polymer derivatives containiDg units of formula I
may easily be prepared by reacting a polyvinyl alcohol, having a weight average molecular weight of at least about 2,000, containing for example units of the formula -~H-CH2- (II) ~H
with about 0.1 to about 90 percent, based upon the number of hydroxyl groups in said poylvinyl alcohol, of a hydroxyl reactive monomer of the formula Rs_A_8_A ~~= RH (III) wherein A, A', R2 and R3 are as above defined and Rs is a hydroxyl reactive moiety such that the reaction of the Rs moiety with a hydroxy group of a unit of formula II results in the subunit -O-Rl- of formula I, at a temperature between about -10C to abut 150C optionally in the presence of a conventional solvent, preferably an aprotic solvent, in the further presence or absence of a catalytic amount of acid or bas$c catalyst. Suitable terminating groups of the moieties Rs sre e.g. epoxy, halo, vinyl sulfone, ~-halo carbonyl or hydroxyl, each of those being part of the subunit Rl to be introduced into the reaction product of formula I.

To obtain those polyvinyl alcohol polymer derivatives containing units of formula I wherein R4 is hydrogen, the corresponding polymers wherein R4 is lower alkyl can subsequently be treated with aqueous base, such as an alkali metal hydroxide aqueous solution, at an elevated temperature, e.g. between about 40 to about 80C, followed by neutralization of the resulting carboxylate salt with an acid, such as aqueous hydrochloric acid under ambient conditions.

Suitable aprotic solvents for conducting the reactlon between the unlts of formula II and the hydroxyl reactive moiety of formula III include formamide, dimethylformamide, phosphoric acid tri-dimethylamide, N-methyl-2-pyrrolidone, dimethylacetamide, acetamide, acetonitrile and preferably dimethyl sulfoxide.

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For certain reactants aqueous or aqueous/organic solvents may be used.

Suitable catalysts can be either Lewis bases or Lewis acids. Preferably the catalyst is an organic base such as tertiary amines for example trimethylamine, triethylamine, N,N-dimethylbenzylamine and in aqueous solvent systems inorganic bases such as sodium or potassium hydroxide can be used as well as other bases such as tetrabutylammonium fluoride or sodium acetate. Suitable acid catalysts can include fluoroboric acid, zinc fluoroborate, zinc chloride, aluminum chloride, hydrochloric, nitric and sulfuric acids - or Lewis acid adducts such as boron trifluoride etherate or organo-metallic compounds such as dibutyltin dilaurate. Where Rs contains a hydroxyl groups as the reactive functionality an acid catalyst is preferred.

Polyvinyl alcohols containing units of the formula II are widely available.

Preferably, the polyvinyl alcohol has a weight average molecular weight of at least 10,000. As an upper limit, the polyvinyl alcohol may have a weight average molecular weight of up to 1,000,000. Preferably, the polyvinyl alcohol has a weight average molecular weight of up to 300,000, ~~
more preferably up to 100,000, most preferably up to 50,000.

Ordinarily, polyvinyl alcohol predominantly possesses a poly(2-hydroxy)-ethylene structure. However, the polyvinyl alcohol starting material may also contain hydroxyl groups in the form of 1,2-glycols, such as copoly-mer units of 1,2-dihydroxyethylene in the chain, obtained for example, by alkaline hydrolysis of vinyl acetate-vinylene carbonate copolymers.

Moreover, the polyvinyl alcohol may contain minor amounts of copolymer units of ethylene, propylene, acrylamide, methacrylamide, dimethylacryl-amide, hydroxyethyl methacrylate, methyl methacrylate, methyl acrylate, ethyl acrylate, vinyl pyrrolidone, hydroxyethyl acrylate, allyl alcohol, styrene and the like.

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g Commercial polyvinyl alcohol resin may be used such as Vinol~ 107 manufactured by Air Products (MW = 22 - 31,000, 98 - 98.8 % hydrolyzed), Polysciences 4397 (M~ = 25,000, 98.5 YO hydrolyzed), BF 14 by Chan Chun, Elvanol~ 90 - 50 by DuPont, UF-120 by Unitika, Mowiol~ 10-98 and 20-98 by Hoechst. Some other manufacturers are Nippon Gohsei (Gohsenol~), Monsanto (Gelvatol~), Wacker (Polyviol~) as well as the Japanese manufacturers Kuraray, Denki and Shin-Etsu.

As noted above, copolymers of hydrolyzed vinyl acetate can be used and are commercially available such as hydrolyzed ethylene vinyl acetate (EVA), vinyl chloride-vinylacetate, N-vinyl pyrrolidone-vinyl acetate and maleic anhydride-vinyl acetate.

Polyvinyl alcohol is ordinarily prepared by hydrolysis of the corre-sponding homopolymeric polyvinyl acetate. In a preferred embodiment the polyvinyl alcohol contains less than 50 % polyvinyl acetate units, more preferably less than 20 % polyvinyl acetate units.

One method of roughly estimating the weight average molecular weight ofpolyvinyl alcohol is by the viscosity of a 4 % aqueous solution at 20C~
for example a viscosity of l - 2 cP corresponds to a molecular weight of ~ 3,000, a viscosity of 7 cP corresponds to a molecular weight of ~ 25,000 (98 - 100 % hydrolyæed), while a viscosity of 60 cP corre-sponds to a molecular weight of ~ 130,000 (99 - 100 % hydrolyzed).
Preferably the polyvinyl alcohol should have a minimum viscosity of 2 cP
and the upper limit of molecular weight is dictated by the ability to stir and pour solutions without introduction of air bubbles - this value is approximately 60 - 70 cP. It is important to note that the manu-facturers' claim of molecular weight (based on viscosity data) does not necessarily correspond to that obtained by gel permeation chromato-graphy (GPC) which is dependent on the standards used. In Table l are presented a range of polyviDyl alcohols and the GPC results determined using polyacrylamide standards ln aqueous solution.

Table 1 PVA MOLECULAR_IGIIT COMPARISON
Manufacturer Manufacturers' Claimed GPC, M
Mw CPS* w ~ . . _ __.
Polysciences 133,000 _ 66,000 Scientific Polymer Products 126,000 60 45,000 Scientific Polymer Products 115,000 - 69,000 ~- Shin-Etsu Pova~ C25 110,00065 + 538,000 ~L~ Air Products Vinol 350106 - 110,00055 - 6543,000 ~oechst, Moviol 66 - 100 100,00066 + ~ 26,000 -DuPont, Elvanol~HV100,000 55 - 6550,000 Polysciences 78,000 28 - 3237,000 Sigma 45,000 12 - 1430,000 Polysciences 25,000 6 - 8 20,000 ~ -Aldrich 14,000 - 33,000 Scientific Polymer Products 14,000 _ 22,000 4 % aqueous solutions at 20C.
The weight aversge ~olecular weight ranges specified in this disclosure are those obtained by GPC u~ing polyacrylamide standards in aqueous solution.

The hydroxyl reactive compounds of formula III are known, per se, or are easily prepared by conventional methods well known in the art.

Where, in the compounds of formula III, Rs contains a glycidyl group these may be prepared from an active hydrogen containing e.g. hydroxy precursor reacting with epichlorohydrin and optionally basic catalyst between about 0C and 100C in the presence or absence of an inert solvent. Suitable solvents include ethyl acetate, tetrahydrofuran, dimethylformamide and the like. A compound of formula III containing ~ within Rs an epoxy group may also be prepared from an olefin-containing3 precursor reacting with a peracid such as m-chloroperbenzoic acid in an~ inert solvent such as methylene chloride at about room temperature.
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``` 1 330674 .. -- 1 1 --Oxirane compounds may also be formed from the reaction of polyoxirane compounds with active hydrogen monomers leaving at least one oxirane moiety unreacted. A list of possible polyoxiranes may be found in U.S. Pat. No. 4,598,122, columns 4-7. For example, in the case of a di-oxirane, e.g. 1,4-butane diol diglycidyl ether, a substantially equimolar amount of hydroxyethyl methacrylate can be used under basic ~I conditions.

Also oxirane containing monomers can be formed from the reaction product of an active hydrogen containing oxirane e.g. glycidol with isocyanate containing monomers e.g. see U.S. Pat. No. 4,665,123, column 4, formula III.

~,t Other hydroxy reactive monomers of formula III as described above, e.g.
halo, can be formed by a similar synthetic route e.g. reacting a halo ~ -~
alcohol, such as chloroethanol with an isocyanate-containing monomer at a temperature between about 0C to about 100C in the presence or absence of an inert diluent, desirably in the presence of a conventional urethane catalyst such as stannous octoate or triethylamins and the like.

Preferred oxirane containing compounds include glycidyl methacrylate and glycidyl acrylate.
~, Where, in the compounds of formula III, Rs contains a vinyl sulfone these may be prepared from an active hydrogen (e.g. hydroxyl group) containing precursor reacted with divinyl sulfone.

The divinyl sulfone precursor reaction is run under similar conditions as ~` previously described for a polyoxirane precursor.
, , Where, in the compounds of formula III, Rs contains a reactive halo group, these can be formed from the corresponding alcohol by methods well known in the art. Another useful halo compound is the reaction product of an alcohol monomer with cyanuric chloride prepared preferably at low temperature i.e. 0-10C to obtain a monoadduct. Preferred halo compounds are vinyl chloroacetate, allyl chloroacetate and 2-chloroethyl meth-acrylate.

` 1 330674 As an alternate method to form an ether-linked PVA one can react the starting polyvinyl alcohol of formula (II) by known etherification reactions e.g. hydroxyethoxylation with, for example, an alkylene oxide preferably of 2 to 4 carbon atoms to form the corresponding hydroxy-alkoxylated polyvinyl alcohol ~even designated as "alkoxylated PVA"), or cyanoethylation to form the corresponding 2-cyanoethyl ether derivative of polyvinyl alcohol, or carbamoylethylation to form the corresponding 2-amidoethylether (as see C.A. ~inch, Polyvlnyl Alcohol, John Wiley Sons, New York, 1973, Chapter 9) followed by adduction with a coreactive group of a vinylic monomer. The etherification reactions can be done in aqueous, organic or aqueous/organic solvents, preferably aqueous, using basic catalysis (e.g. sodium hydroxide or triethylamine) at about 0C to 100C. Isocyanate, oxirane, alkyl halide, acid chloride, acid and ester groups for example are coreactive with hydroxyl or amino groups. Hydroxyl groups are also coreactive with each other under acid catalysis forming ether linkages. In the case of carbamoylethylation or cyanoethylation (after hydrolysis) an amino-polyvinyl alcohol can be formed under conventional reaction conditions. After carbamoylethylation or hydrolysis of the cyano group, the amide group can be converted to an amine by reaction with an al~ali metal hypohalite (e.g. sodium hypochlorite) in aqueous or aqueous/organic solvents at 0C to about 50. After cyano-ethylation, the cyano group can be hydrolyzed to the amide under aqueous acid (e.g. sulfuric) catalysis at 0C to about 100C.

The polymerizable vinylic monomer which may be used according to the invention may be hydrophobic or msy be a mixture of hydrophilic and hydrophobic vinylic monomer~ in which mixture at least 50 % of vinyl monomers are hydrophobic. Suitable vinylic monomers include those conventional vinylic monomers generally employed in the fabrication of soft ant hard contact lenses. By a hydrophilic vinylic monomer is meant a monomer which, when polymerized by conventional free radical polymeri-zation, characteristically yields a polymer which either dissolves in water or is capable of absorbing at least 10 % by weight water under ambient equilibrium conditions. Similarly, suitable hydrophobic vinylic monomers are those monomers which, when polymeriæed by conventional free ~'` ' - . , ~.;
radical polymerization, characteristically yleld a polymer which neither ; dissolves in water, nor is capable of absorbing at least 10 % by weight water under ambient ~i.e. 20C) equilibrium conditions.

In general, when the optional polymerizable monomer is present, between about 0.01 and about 80 units of conventional hydrophobic and/or hydro-philic monomer is reacted per unit of formula I.

If such a vinylic monomer is used, the polymers of the instant invention preferably contain at least about 0.1 to about 90 percent, more prefer-ably at least about 1.5 to 90 percent, based on the number of hydroxyl groups on the polyvinyl alcohol, of units of formula I, which are reacted with 0.01 to about 80 units of conventional monomer.
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In a preferred sub-embodiment of the instant invention, the polyvinyl alcohol derivative contains at least about 0.1 to about 20, preferably between about 1.5 and about 20 percent, based upon the number of hydroxyl groups of said polyvinyl alcohol, of units of formula I, which are reacted with 0.01 to 80 units of a vinylic monomer per unit of formula I, more preferably between about 0.5 to about 30 units of vinylic monomer per unit of formula I, and most preferably between about 2 and about 20 units of vinylic monomer per unit of formula I present iD the poly-vinyl alcohol polymer. In this preferred sub-embodiment a hydrophobic vinylic monomer is employed as the monomer reactant, or alternatively, a mixture of hydrophobic and hydrophilic monomers containing at least 50 weight percent of hydrophobic monomer, based upon total monomer reactant, is employed. The added hydrophobic monomer, or monomer mixture containing predominantly hydrophobic monomer, has been found to increase the mechanical strength of the ultimate final product soft contact lens material, to reduce in a generally predictable manner the amount of water contained in the contact lens material, and reduce the pore size of the contact lens material, thereby reducing the rate of accumulation of proteinaceous and non-proteinaceous debris associated with the normal day to day wearing and handling of contact lenses. Surprisingly, and most unexpectedly, the introduction of hydrophobic monomer, or monomer mixture containing at least 50 mole percent hydrophobic monomer, to the hydro-.' `-- ` 1 330674 philic polyvinyl alcohol containing units of formula I does not, uponreaction, result in phase separation of the reaction product. Rather, the product is optically clear, indicating substantially no phase separation.

The vinylic monomers are reacted with the polyvinyl alcohol derivative of formula I advantageously in the presence of an inert diluent or solvent, such as a suitable organic solvent, including a lower alkanol, e.g.
ethanol, methanol or the like, or an aprotic solvent such as dimethyl-formamide, acetamide, acetonitrile, dimethylacetamide, dimethylsulfoxide or mixtures thereof. Also, aqueous/organic solvent systems may be employed. Preferred is dimethylsulfoxide.

The vinylic monomer, or blend of vinylic monomers, are optionally combined with the polyvinyl alcohol derivative of formula I and poly-merized in the presence of a conventional free radical initiator, such as a peroxide, e.g. di-tert-butyl peroxide, benzoyl peroxide, lauryl peroxide, decanoyl peroxide, acetyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, 2,4-dichlorobenzoyl peroxide, isopropyl I peroctoate, tert-butyl hydroperoxide, tert-butyl perpivalate, tert-butyl ¦ peroctoate, diisopropyl peroxydicarbonate, cumene hydroperoxide, tert-! butyl perbenzoate, tert-butyl peroxymaleic acid, tert-butyl peroxy-¦ acetate, and potassium persulfate, an azo compound, e.g. 2,2'-azo-bls-isobutyronitrile, 2,2'-azo-bis-(2,4-dimethylvaleronitrile), 1,1'-azo-bis-(cyclohexane carbonitrile), 2,2'-azo-bis(2,4-dimethyl-4-methoxyvalero-nitrile) and phenyl azo isobutyronitrile, or in the presence of a photoinitiator, e.g. benzoin methyl ether and 1-hydroxycyclohexylphenyl ketone or actinic radiation such as W light, or ionizing rays e.g. gamma rays or X-rays, to form the resulting crosslinked polym~r.

The polyvinyl alcohol derivative of formula I and optionally added monomer is advantageously polymerized upon placement into a mold. The mold may be a conventional spin-casting mold for preparing contact lenses such as described in U.S. Patent No. 3,408,429, or in a static mold, e.g. as described in U.S. Patent No. 4,347,198. Alternately, one may prepare a swollen lens blank, dry the lens blank to form the corre-sponding xerogel, shape the xerogel into a contact lens precursor by ....
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: --lathing methods known to the art, and swell the shaped xerogel in aqueous medium to form the corresponding contact lens, as described in Reissue U.S. Patent No. 27,401.

The solution of polyvinyl alcohol derivative of formula I and optionally added vinylic monomer are advantageously placed into a mold in shape of a contact lens. Where the solvent employed is a strong swelling solvent, such that the resultant polymer shrinks in size upon equilibration with aqueous or aqueous saline solution, typically between about 10 to about 35 percent based on diameter, the mold is suitably enlarged to compensate for the post treatment shrinkage. Optimally the post treatment further includes a heat treatment of the molded lens shaped polymer. Such heat treatment is characteristically conducted at a temperature between about 60 and 100C, e.g. in the presence of an aqueous medium. This treatment may result in a further slight shrinkage, generally less than 15 % based on diameter. The treatment can vary greatly, but usually is accomplished in about 5 to 90 minutes. The purpose of this post treatment is to dimensionally stabilize the crosslinked contact lens material. Also, the treatment may further serve to sterilize such lens material.
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Suitable vinylic monomers for polymerization with the polyvinyl alcohol derivative of formula I include conventional hydrophobic and hydrophilic monomers. Suitable hydrophobic monomers include, without limitation, Cl 18-alkyl acrylates and methacrylstes, C3 l8-alkyl acrylamides and methacrylamides, acrylonitrile, methacrylonitrile, vinyl Cl 18-alkano-ates, C2 18-alkene~, C2 18-haloalkenes, styrene, Cl_6-alkyl styrenes, vinyl alkyl ethers wherein the alkyl portion has l to 6 carbon atoms, C3 12-perfluoroalkyl ethyl thiocarbonylaminoethyl acrylates and meth-acrylates, C3 12-fluoroalkyl acrylates and methacrylates, acryloxy and methacryloxy alkyl siloxanes, N-vinyl carbazole, Cl 12-alkyl esters of maleic, fumaric, itaconic, and mesaconic acids and the like. Examples of suitable hydrophobic monomers include methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, cyclohexyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, propyl methacrylate, vinyl acetate, yinyl propionate~ vinyl butyrate, vinyl valerate, styrene, chloroprene, vinyl chloride, vinylidene chloride, acrylonitrile, l-butene, butadiene, methacrylonitrile, vinyl toluene, vinyl ethyl ether, perfluorohexylethyl-' r ~
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thiocarbonylaminoethyl methacrylate, isobornyl methacrylate, hexafluoro-butyl methacrylate, 3-methacryloxypropylpentamethyldisiloxane, and bis~methacryloxypropyl)tetramethyldisiloxane.

Suitable hydrophilic monomers include, without limitation, hydroxy substituted lower alkyl acrylates and methacrylates, acrylamide, meth-acrylamide, Cl 2-lower alkyl acrylamide and methacrylamide, ethoxylated acrylates and methacrylates, hydroxy substituted lower alkyl acrylamide and methacrylamide, hydroxy substituted lower alkyl vinyl ethers, sodium ethylene sulfonate, sodium styrene sulfonate, 2-acrylamido-2-methyl-propanesulfonic acid, N-vinylpyrrole, N-vinylsuccinimide, N-vinyl pyrrolidone, 2- and 4-vinyl pyridine, acrylic acid, methacrylic acid, amino ~by amino including quaternary ammonium) -monolower-alkylamino- or diloweralkylamino-lower alkyl acrylates or methacrylates, allyl alcohol, and the like.

Specific hydrophilic monomers include hydroxyethyl methacrylate, hydroxy-ethyl acrylate, acrylamide, methacrylamide, dimethylacrylamide, allyl alcohol, vinyl pyridine, vinyl pyrrolidone, glycerol methacrylate, N-(1,1-dimethyl-3-oxobutyl)acrylamide, and the like.

Preferred hydrophobic monomers are mPthyl methacrylate and vinyl acetate.

Preferred hydrophilic monomers are 2-hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylamide, and dimethyl acrylamide.

Optionally, an additional conventional polyreactive crosslinking agent may be added, such as allyl compounds e.g. allyl methacrylate, diallyl itaconate, monoallyl itaconate, dially maleate, diallyl fumarate, diallyl succinate, diallyl phthalate, triallyl cyanurate, triallyl isocyanurate, diethylene glycol bis-allyl carbonate, triallyl phosphate, triallyl trimellitate, allyl ether, N,N-diallylmelamine; vinyl compounds, e.g.
divinyl benzene, N,N'-methylene bis acrylamide, ethylene glycol di-methacrylate, neopentylglycol dimethacrylate, tetraethylene glycol dimethacrylate, hexamethylene bis maleimide, divinyl urea, bisphenol A
l bis methacrylate, divinyl adipate, glycerin trimethacrylate, trimethylol-~ propane triacrylate, trivinyl trimellitate, 1,5-pentadiene, 1,3-bis~4-"I

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: ~ 33067 methacryloxybutyl) tetramethyl disiloxane, divinyl ether and divinyl sulfone; hydroxyl reactive compounds such as: polyvalent isocyanates e.g. hexamethylene diisocyanate, isophorone diisocyanate, toluene diisocyanate; polyaldehydes e.g. glutaraldehyde and glyoxal; polyacids e.g. glutaric acid and oxalic acid; polyepoxides e.g. butane diepoxide, vinylcyclohexane dioxide and butanediol diglycidyl ether; polyols (acid catalysis) e.g. dimethylol urea and diethylene glycol.

When employed, about 0.01 to 10 weight percent of crosslinking agent, based upon the weight of formula I derivative, may be present, preferably about 0.01 to about 5 percent, most preferably about 0.05 to 2 weight percent.

The resultant contact lenses are optically clear, strong, flexible, highly oxygen permeable and wettable. Further, the instant lenses are characterized by their ease of manufacture.

In the following examples, all parts are by weight unless otherwise described, temperatures are given in degrees Celsius.

The following example illustrates a range of water contents obtained using different levels of glycidyl methacrylate (GMA) with a polyvinyl alcohol (PVA).

Example 1: 3 g Air Products Vinol~ 107 (MW = 22-31,000, 98-98.$ 7O
;hydrolyzed) is di~solved in 27 g Aldrich Gold Label (99.9 %) dimethyl sulfoxide (DMSO) under house nitrogen at 60C (approximately 0.5 hour) in a three-neck round bottom flask with overhead stirring. The solution is then allowed to cool to room temperature. Then, in the case of sample 10, 0.195 g (9.98 mole % with respect to vinyl alcohol assuming 100 %
hydrolyzed PVA) distilled glycidyl methacrylate (GMA) (Pfaltz & Bauer) is added to 6.062 g of the PVA solution followed by adding 0.0162 g (0.26 wt % with respect to total reaction mixture) triethylamine (TEA).
This solution is allowed to react at 60C for 3 hours with magnetic stirring and then allowed to cool to room temperature. Then, 0.0067 g (0.11 wt % with respect to total reaction mixture) of the initiator 7~ Tracle-lna~k .- ~ - , . .

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i benzoin methyl ether (BME) is added, the solution mixed well, poured into flat "sandwich" molds and polymerlzed with W light (360 nm) at room temperature for four hours.

The polymerized films are removed from the molds and extracted succes~ively in 75 %, 50 ~O~ 25 %, 0 % DMSO/water solutions. The films are boiled in water for 10 minutes before % H20 content is determined. The other samples are prepared in a similar manner except for the amount of GMA added and, for samples 1 and 2, the irradiation time (9.5 hours).

Sample # Mole % % TEA % ~zO Observation After Irradiation, GMA Content Water Equilibration & Boiling 1 1.69 0.20 _ Film: elastic, weak, clear, colorless 2 1.96 0.23 _ Film: elastic, weak, clear, colorless 3 2.10 0.22 91.17 Film: clear, colorless 4 2.23 0.21 93.72 Film: clear, colorless, brittle 4.96 0.29 88.43 brittie 6 5.00 0.20 81.89 Film: clear, colorless, brittle 7 5.22 0.44 81.15 Film: clear, colorless (yellow when viewed through edge), weak 8 7.22 0.26 76.69 Film: clear, colorless, brittle 9 7.33 0.21 75.38 Film: clear, colorless (yellow when viewed through edge) 9.98 0.26 68.04 Film: clear, colorless (yellow when viewed through edge) As shown above, those sheets with a low mole ~O GMA ~< 2 %) are clear, colorless, weak and elastic. Shetts with approximately 2 mole % GMA are stronger than the low mole % GMA sheets and are clear and colorless.
Above 5 mole %, the sheets are clear and colorless but appear slightly yellow when viewed through the edge.

Water contents of these sheets range from 92 % for a 2 mole % GMA
solution to 68 % for a 9.98 mole % GMA solution.

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-~ 1 330674 Example 2: This example shows the effect of temperature on the PVA/GMA
reaction. The solutions are prepared in a similar manner to that in Example 1 with 10 mole % GMA and 0.2 ~O by weight triethylamine.

Sample 1~ Mole % Tempera- % TEA % H20 Observation After Irradiation, GMA ture (C) Content Water Equilibration & Boiling .. _ _ _ i 1 10.01 22 0.24 _ d d not polymerize, solution 2 10.28 30 0.26 _ did not polymerized, solution clear 3 10.26 40 0.29 _ Film: very brittle, yellowish 4 10.78 50 0.22 68.32 Film: yellow, slightly brittle 10.09 60 0.28 71.92 Film: yeliow, brittle 10.07 70 0.28 78.04 Film: very yellow, brittle ~, As shown above, it is necessary to attain a temperature of at least 40C
at this level GMA and TEA catalyst for sufficient adduction to the place tha, can lead to polymerization to a film. At temperatures below 40C the solution remains clear but does not polymerize. At temperatures between 40C and 70C the solutions polymerize but the films are increasingly yellow with increase in temperature.

ExamPle 3: This example shows the effect of temperature and catalyst level on the PVA/GMA reaction using low mole % GMA. The solutions are prepared in a similar manner to that in Example 1 with approximately 1 mole % GMA.

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; ' ~' '' . ' ,-'' - 20 _ 1330674 Sample # Mole % ~/~ TEA Tempera- Observation After Irradiation, GMA ture (C) Water Equilibration & Boiling 1 0.94 0.50 60 did not polymerize, clear solution 2 1.04 0.84 60 Film: clear, elastic, sticky, weak, 3 0.99 1.01 60 did not polymerize, clear solution 4 1.34 0.20 60 Film: not fully polymerized, clear, elastic, sticky 0.98 0.19 80 Film: more polymerized than ~t4, clear, elastic, sticky 6 1.15 0.22 100 Film: clear, yellow . . . 1.220.21 120 Film: clear, dark yellow, elastic As shown above, at 60C a polymerized sheet is obtained with 0.84 % TEA
~sample #2) but not with 0.5 and 1.01 % TEA ~samples 1 and 3). Varying the adduction reaction temperature from 60C to 120C results in partial-ly polymerized solutions at 80C to fully polymerized dark yellow sheets at 120C.

Exsmple 4: This example shows the effect of heating time and catalyst level on the PVA/GMA reaction. The solutions are prepared in a similar =anner to that in Kxa=ple I with approxi=ste1y 10 mo1e % Gh'A al 60C.

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Sample # Mole YO Time % TEA % H20 Observation After Irradiation, ~, GMA Heated Content Water Equilibration & Boiling 1 9.84 15 min 0.33 _ did not polymerize, yellow solution 2 10.50 30 min 0.27 _ Film: clear, yellow, very brittle 3 9.89 1 h 0.28 _ Film: clear, yellow, brittle 4 9.98 2 h 0.2569.45 Film: clear, colorless (yellow when viewed through edge) 10.40 3 h 0.2171.76 Film: clear, colorless (yellow ~ when viewed through edge) 6 9.86 30 min 0.51 _ Film: yellow, very brittle 7 9.98 1 h 0.4173.09 Film: clear, colorless (yellow when viewed through edge) 8 10.02 1 h 0.47 _ Film: clear, yellow, very brittle 9 9.64 2 h 0.4273.71 Film: clear, colorless (yellow when viewed through edge), 10.40 2 ~ h 0.4275.50 Film: clear, colorless (yellow when viewed through edge), brittle 11 10.40 3 h 0.4076.23 Film: clear, yellow As shown above, for the level of GMA and TEA chosen in sample 1, a filmforming polymerization does not occur after 15 minutes of heating but as seen in #2 at least about 30 minutes is needed. The color but not clarity appears to be a sensitive function of the level of GMA, TEA and the heating time.

Example 5: This example shows the effect of added comonomer on the physical properties, especially water content, of GMA modified PVA. The samples are prepared in a similar manner to Example 1 except that methyl ... .
methacrylate (MMA) is added to the reaction mixture just prior to the addition of BME.

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Sample # Mols ~0 % MMA % TEA % HzO Observation After Irradiation, GMA Content Water Equilibration ~ Boiling l 10.09O 0.28 71.92 Film: clear, yellow, brittle 2 9.659.85 0.23 60.79 Film: clear, yellow, brittle 3 10.0315.74 0.19 57.17 Film: clear, colorless (yellow when viewed through edge) 4 9.6820.74 0.20 54.88 Film: clear, colorless (yellow ~ h edge) As shown above, as the proportion of the added comonomer (MMA) is increased the corresponding water content decreases.

Example 6: This example shows an alternate method to form an ether-linked PVA using an hydroxyethoxylated PVA (EO-PVA) derivative. The solutions are prepared in a similar manner to that in Example l except that 1.5 g hydroxyethoxylated PVA (Polyscience, MW 175,000 made using 10 mole ethylene oxide to 1 mole vinyl alcohol of a 99 % hydrolyzed PVA) is dissolved in 13.5 g DMSO at 70C under N2 with stirring, cooled to room temperature (RT) and 20 (482 ~l), 3 (72.4 ~1), or 1 (24.1 ~l~ mole %
isocyanatoethyl methacrylate (IEN) (assuming 100 % hydroxyethylated) is added with rapid stirring. This solution is either reacted at RT over-night or with the addition of 0.0024 g sodium acetate trihydrate at RT
for 1 to 3 hours.

The IEM reacted hydroxyethoxylated PVA in DMSO is mixed with or withoutcomonomer snd 0.05 % initiator (i.e. benzoin methyl ether, BME), poured into molds and polymerized with UV light for 1 hour at RT. The poly-merized films are removed from the molds and extracted in distilled water. They sre boiled for 10 minute3 before water contents are done.
Note: samples 1-4 are reacted with sodium acetate for 3 hours and samples 5 and 6 are reacted for l hour.

Sample # Mole % % EO-PVA % % H2O Clarity IEM Comonomer BME (After Boiling) (After Boiling) ... _ .. _ , 1 1 100 _ 0.05 98.83 clear 2 1 49.7 50.3 MMA O.06 93.37 cloudy 3 1 33.4 66.6 MMA O.05 90.61 cloudy 4 1 24.7 75.3 MMA 0.05 88.84 opaque 3 100 _ 0.05 93.30 clear 6 3 75.1 24.9 MMA O.05 89.43 clear 100 0.05 76.84 clear ~MA = methyl methacrylate As shown above, clear (and wettable) films can be made using a deriva-tized PVA with or without added comonomer. Only at very high levels of MMA are the films not clear.

Example 7: This example illustrates a procedure for avoiding the yellow-ing that is sometimes observed in ether-linked PVA films. A 10 % solution of Vinol~107 in DMSO is modified with 10 mole % GMA (0.2 % by weight TEA
catalyst) by heating at 60C for 3 hours in a similar manner as shown in Example 1. This solution turns yellow while heating. Precipitation of the GMA modified PVA in isopropanol and redissolution in DMSO reRults in a disappearance of the yellow color.

Example 8: Several lenses are fabricated in contact lens molds made from polypropylene. The reaction solutions are made as in Example 1 both with and without MMA (13.5 % by weight with respect to PVA), 10 mole % GMA, O.2 % by weight TEA and BME ~O.13 % without MMA, 0.17 % with MMA~. These solutions are pipetted into the lens molds and are W cured for 4 hours.
After water extraction, boiling and equilibration in water the lenses come out optically clear with no obvious difference in strength or swelling relative to a sheet made of similar composition.

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Claims (8)

1. A soft waterswellable hydrogel contact lens which is the crosslinked, substantially transparent copolymerisation product of (a) a derivative of polyvinyl alcohol, having a weight average molecular weight of at least about 2000, wherein between 0.1 and 90 percent of the total number of hydroxyl groups on said polyvinyl alcohol are reacted to give a repeating structural unit of formula I
(I) wherein R1 is straight or branched chain alkylene of 1 to 20 carbon atoms, or straight or branched chain alkylene of 2 to about 100 carbon atoms interrrupted by one or more of carbonyloxy, oyxcarbonylamido, sulfonamido, carbonamido, sulfonyl, sulfoxy, or oxy, and R1 is further unsubstituted or substituted by hydroxy;
A is -O-, -NH- or -NHCON(R")- where R" is hydrogen or lower alkyl and A' is a direct bond; or A is a direct bond and A' is -O- or -O-CH2-;
R2 is hydrogen or methyl;
and R3 is hydrogen, methyl or -COOR4 where R4 is hydrogen or lower alkyl;
with the proviso that if R2 is methyl, R3 is hydrogen; and (b) a polymerizable vinyl monomer wherein for each repeating structural unit of formula I
there are from 0.01 to 80 units of said polymerizable vinyl monomer with the proviso that at least 50% by weight of the polymerizable vinyl monomer is a hydrophobic vinylmonomer.

2. A contact lens according to claim 1 wherein the polymerizable hydrophobic monomer is a lower alkyl methacrylate.

3. A contact lens according to claim 1 wherein R1 is lower alkylene or lower alkylene interrupted by one group selected from carbonyloxy, carbonamido and oxycarbonylamido, A is -O- and A' is a direct bond.

4. A contact lens according to claim 3 wherein the polymerizable hydrophobic monomer is a lower alkyl methacrylate.

5. A contact lens according to claim 1 wherein R1 is alkylene of 2 to 10 carbon atoms and is unsubstituted or substituted by hydroxy.

6. A contact lens according to claim 5 wherein the polymerizable hydrophobic monomer is a lower alkyl methacrylate.

7. A contact lens according to claim 1 wherein the polyvinyl alcohol has a weight average molecular weight of at least 10,000.

8. A contact lens according to claim 1 wherein between 0.1 and 20 percent of total number of hydroxyl groups of said polyvinyl alcohol are reacted to give a repeating structural unit of formula I.