WO1990011306A1

WO1990011306A1 - Hydrogels based on sugar alcohol monomers

Info

Publication number: WO1990011306A1
Application number: PCT/EP1990/000448
Authority: WO
Inventors: Norbert Klaus; Gerhard Kossmehl; Horst SCHÄFER; Jürgen VOLKHEIMER
Original assignee: Ciba-Geigy Ag
Priority date: 1989-03-28
Filing date: 1990-03-19
Publication date: 1990-10-04
Also published as: CA2028112A1; EP0417235A1; GR900100213A; AU5286390A; PT93577A; JPH03505688A

Abstract

The invention relates to a hydrogel which is a copolymer of a polymerizable monomer mixture which contains a) 5-95 mole % of a hydrophobic polyhydroxyvinyl monomer whose hydroxyl groups are in protected form, b) 5-95 mole % of a hydrophilic vinyl monomer, c) 0-40 mole % of a hydrophobic vinyl monomer containing a maximum of two fluorine atoms, and d) 0-5 mole %, relative to the total amount of monomers a)-c), of a crosslinking agent, in which hydrogel the hydroxyl groups of the segments formed by the monomers a) are in protected or free form, and the proportion of the hydrophobic vinyl monomer c), if it is not zero, is at least 25 mole %. These hydrogels can be used, for example, as contact lenses, intraocular lenses or in other areas of application in which biocompatible materials are necessary.

Description

Hvdrogels based on sugar alcohol monomers

The present invention relates to novel hydrogels, a process for their preparation, uses of the hydrogels, for example as contact lenses, intraocular lenses or in other areas of application in which biocompatible materials are necessary, and to the abovementioned articles essentially comprising the novel hydrogels. The novel hydrogels are distinguished by particular advantages with respect, for example, to oxygen permeability, water content and mechanical stability.

It is known that hydrogels (crosslinked polymers which are swellable in water to a limited extent) have an oxygen permeability which depends on the water content. It increases with increasing water content. The high oxygen permeability which is fundamentally desired is normally achieved in the known polymers by accepting other severe disadvantages. Thus, hydrogels having a high water content normally have low mechanical stability, such as tear strength.

DE-A-3,215,918 has already disclosed hydrogels, and contact lenses made therefrom, which contain a copolymer of a methacrylate of a xylitol whose hydroxyl groups are in ketal form, and at least one hydrophobic and/or hydrophilic comonomer. However, these copolymers either contain no hydrophilic copolymer component or, if they do, contain a hydrophobic comonomer component in a relatively small amount, ie. at least in an amount lower than 25 mole per cent.

By contrast, the copolymers according to the invention always contain a hydrophilic comonomer component besides the ester of an unsaturated carboxylic acid having 3 or 4 carbon atoms with a sugar alcohol whose hydroxyl groups are in protected form. A hydrophobic comonomer component may be entirely absent or present in amounts of at least 25 mole per cent. Insofar, the present invention enriches the state of the art, since novel hydrogels are disclosed which, due to an appropriate choice of material, have an extremely favourable combination of properties, such as high water content, good oxygen permeability and high mechanical strength. The last-mentioned property may be still further improved by adding at least 25 mole per cent of a hydrophobic component. In particular, the oxygen permeability can be controlled even after the polymerization, independently of the material composition, by modifying the water content.

The invention therefore relates to a hydrogel which is a copolymer of a polymerizable monomer mixture which contains

a) 5-95 mole % of a hydrophobic polyhydroxyvinyl monomer whose hydroxyl groups are in protected form, b) 5-95 mole % of a hydrophilic vinyl monomer, c) 0-40 mole % of a hydrophobic vinyl monomer containing a maximum of two fluorine atoms, and d) 0-5 mole % , relative to the total amount of monomers a)-c), of a crosslinking agent,

in which hydrogel the hydroxyl groups of the segments formed by the monomers a) are in protected or free form, and the proportion of the hydrophobic vinyl monomer c), if it is not zero, is at least 25 mole %.

In the context of this application, vinyl monomers are not taken to mean exclusively monomers which contain the vinyl group (-CH=CH₂), but generally those which contain a carbon-carbon double bond. Specific preferred meanings of the word component "vinyl" in vinyl monomers will become clear from the preferred embodiments below.

The polyhydroxyvinyl monomer a) whose hydroxyl groups are in protected form is a vinyl monomer derived from a sugar alcohol. It has, in particular, the formula I

R¹-COO-CH₂(CHOH)_p-CH2θH (J)

in which R¹ is -C^alkenyl, p is a number from 1 to 8 and the hydroxyl groups are in protected form, and furthermore positional isomers thereof in which the R--CO- group is bonded to a different oxygen atom, and the oxygen atom to which this group is bonded in the depicted formula I is one of the hydroxyl groups which are in protected form. Monomer a) may be one of the above-defined monomers or a mixture of several different monomers of those defined above.

The proportion of vinyl monomers a) in the monomer mixture is preferably 5-80 mole % or 10-65 mole % and particularly preferably 20-60 mole % or 30-70 mole %, depending on whether component c) is present.

In the vinyl monomer, derived from a sugar alcohol, of the formula I in which the hydroxyl groups are in protected form, p is preferably a number from 2 to 4. Examples of sugar alcohols from which compounds of the formula I are derived are xylitol, adonitol, arabitol, sorbitol, mannitol or dulcitol. Xylitol is preferred. C₂-C₃Alkenyl is vinyl, 1 -methyl vinyl or 2-methylvinyl.

The protected hydroxyl groups of the compounds of the formula I are preferably protected in pairs as acid-labile ketals, for example and preferably as addition products with a ketone. Two hydroxyl groups which are jointly protected as a ketal are protected, for example, together by means of a preferably substituted methylene group, such as by lower alkylidene, for example isopropylidene, isobutylidene or 2-methyl-4-pentylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene.

Particularly preferred representatives of the vinyl monomers of the formula I are 5-0-methacryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol (5-MDPXy) of the formula JH (R^a = methyl, R^b = H), 5-0-acryloyl-l,2_.3_.4-di-0-isopropylidene-DL-xylitol (5-ADPXy) of the formula II (R^a and R^b = H) and

5-0-crotonyl-l,2;3,4-di-O-isopropylidene-DL-xylitol (5-CDPXy) of the formula II (R^a = H, R^b = methyl)

and the positional-isomeric compounds 3-O-methacryloyl- l,2;4,5-di-0-isopropylidenexylitol and 3-O-acryloyl- 1 ,2;4,5-di-0-isopropylidenexylitol.

The hydrophilic vinyl monomers b) which can be used according to the invention are preferably acrylates and methacrylates of the formula

R²

H C=C-COOR³ ,

in which R² is hydrogen or methyl, and R³ is a hydrocarbon radical having 1 to 10 carbon atoms which is monosubstituted or polysubstituted by a water-solubilizing group, such as carboxyl, hydroxyl or tert-amino, for example tertQower alkyl)amino having 1 to 7 carbon atoms per lower alkyl group, by a polyethylene oxide group having 2-100 recurring units, preferably having 2-40 recurring units, or by a sulfate, phosphate, sulfonate or phosphonate group, for example a correspondingly substituted alkyl, cycloalkyl or phenyl radical or a combination of such radicals, such as phenylalkyl or alkylcycloalkyl, furthermore, aery lamides and methacrylamides of the formula

in which R⁴ is hydrogen or C C₄alkyl; acrylamides and methacrylamides of the formula

CH₂=C-CONHR 5

R²

in which R⁵ is as defined for R³ or R⁴; maleates and fumarates of the formula

R³OOC-CH=CH-COOR³ ;

crotonates of the formula CH₃-CH=CH-COOR³ :

vinyl ethers of the formula

H₂C=CH-OR^J

vinyl-substituted five- or six-membered heterocyclic compounds having one or two nitrogen atoms, and N-vinyllactams, such as N-vinyl-2-pyrrolidone, and vinylically unsaturated carboxylic acids having a total of 3 to 10 carbon atoms, such as methacrylic acid, crotonic acid, fumaric acid or cinnamic acid.

Preference is given to for example hydro xyl-substituted C₂-C₄alkyl (meth)acrylates, five- to seven-membered N-vinyllactams, N,N-di-C C₄alkyl(meth)acrylamides and vinylically unsaturated carboxylic acids having a total of 3 to 5 carbon atoms.

The proportion of the vinyl monomer b) in the monomer mixture is preferably 20-95 or 10-65 mole % and particularly preferably 10-50 or 30-70 mole %, depending on the proportion of the vinyl monomer c). The monomer b) may be one of the above-defined monomers or a mixture of several different monomers of those defined above.

The water-soluble monomers b) which can be used include: 2-hydroxyethyl acrylate and methacrylate, 2- and 3-hydroxypropyl acrylate and methacrylate, 2,3-dihydroxypropyl acrylate and methacrylate, polyethoxyethyl acrylate and methacrylate, and polyethoxypropyl acrylate and methacrylate, and the corresponding acrylamides and methacrylamides, acrylamide and methacrylamide, N-methylacrylamide and N-methylmethacrylamide, bisacetoneacrylamide, 2-hydroxylethylacrylamide, dimethylacrylamide, dimethylmethacrylamide, methylolacrylamide and methylolmethacrylamide, N,N-dimethyl- and N,N-diethylaminoethyl acrylate and methacrylate, and the corresponding acrylamides and methacrylamides, N-tert-butylaminoethyl methacrylate, N-tert-butylaminoethyl methacrylamide, 2- and 4-vinylpyridine, 4- and 2-methyl-5-vinylpyridine, N-methyl-4-vinylpiperidine, 1 -vinyl and 2-methyl-l-vinylimidazole, dimethylallylamine and methyldiallylamine, para-, meta- and ortho-aminostyrene, dimethylaminoethyl vinyl ether, N-vinylpyrrolidone and 2-pyιτolidinoethyl methacrylate, acrylic acid and methacrylic acid, itaconic acid, cinnamic acid, crotonic acid, fumaric acid, maleic acid and the hydroxy(lower alkyl) monoesters and diesters thereof, such as 2-hydroxyethyl fumarate, maleate and itaconate and di-(2-hydroxy)ethyl fumarate, maleate and itaconate, 3-hydroxypropylbutyl fumarate and di-poly(alkoxyalkyl) fumarates, maleates and itaconates, maleic anhydride, sodium acrylate and sodium methacrylate, 2-methacryloyloxyethylsulfonic acid, 2-acrylamido-2-methylpropanesulfonic acid, 2-phosphatoethyl methacrylate, vinylsulfonic acid, sodium vinylsulfonate, p-styrenesulfonic acid, sodium p-styrenesulfonate and allylsulfonic acid, N-vinylpyrrolidone, N-vinylpyridone, N-vinylcaprolactam, and furthermore the quaternized derivatives of canonic monomers obtained by quatemization using selected alkylating agents, for example halogenated hydrocarbons, such as methyl iodide, benzyl chloride or hexadecyl chloride, epoxides, such as glycidol, epichlorohydrin or ethylene oxide, acrylic acid, dimethyl sulfate, methyl sulfate and propane sultone.

A more complete list of water-soluble monomers which can be used in connection with this invention can be found in: R.H. Yocum and E.B. Nyquist, Functional Monomers, Volume 1, pp.424-440 (M. Dekker, N.Y. 1973).

Preferred monomers b) are 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, N,N-dimethylacrylamide, acrylic acid and methacrylic acid.

Examples of suitable hydrophobic vinyl monomers c) which are in some cases used according to the invention are: acrylates and methacrylates of the formula

H₂C=C-COOR⁶ ,

acrylamides and methacrylamides of the formula

R^*-

H₂C=C-CONH-R⁶

maleates and fumarates of the formula

R⁶OOC-CH=CH-COOR⁶ itaconates of the formula

CH₂

R°OOC-C-CH₂-COOR^b

crotonates of the formula

H₃C-CH=CH-COOR⁶

vinyl esters of the formula

R^b-COO-CH=CH₂

and vinyl ethers of the formula

H₂C=CH-0-R^b

in which R² is hydrogen or methyl, and R⁶ is a linear or branched aliphatic, cycloaliphatic or aromatic group having 1 to 21 carbon atoms, for example an appropriately substituted alkyl, cycloalkyl or phenyl radical or a combination of such radicals, such as phenylalk yl or alkylcycloalkyl, which may contain ether or thioether bonds, sulfoxide or sulfone groups or a carbonyl group; or R⁶ is a heterocyclic group which contains oxygen, sulfur or nitrogen atoms and 5 or 6 or, if it is bicyclic, up to 10 ring atoms, or a polypropylene oxide or poly-n-butylene oxide group having 2 to 50 recurring alkoxy units, or R⁶ is an alkyl group having 1 to 12 carbon atoms which contains halogen atoms, of which, however, at most two are fluorine atoms, or R⁶ is a siloxane group having 1 to 6 Si atoms.

Preference is given, in particular, to

esters or Cs-Cycycloalkyl esters of vinylically unsaturated carboxylic acids having 3 to 5 carbon atoms.

The proportion of the vinyl monomers c) in the monomer mixture is either 0 mole % or in a preferred embodiment 25-35 mole % and in a specific embodiment 30 mole % . The monomers c) can also be one of the above-defined monomers or a mixture of several different monomers of those defined above. Examples of suitable hydrophobic monomers are: methyl acrylate and methacrylate, ethyl acrylate and methacrylate, propyl acrylate and methacrylate, isopropyl acrylate and methacrylate, butyl acrylate and methacrylate, isobutyl acrylate and methacrylate, tert-butyl acrylate and methacrylate, ethoxyethyl acrylate and methacrylate, methoxyethyl acrylate and methacrylate, benzyl acrylate and methacrylate, phenyl acrylate and methacrylate, cyclohexyl acrylate and methacrylate, trimethylcyclohexyl acrylate and methacrylate, isobornyl acrylate and methacrylate, dicyclopentadienyl acrylate and methacrylate, norbornylmethyl acrylate and methacrylate, cyclododecyl acrylate and methacrylate, 1,1,3,3-tetramethylbutyl acrylate and methacrylate, n-butyl acrylate and methacrylate, n-octyl acrylate and methacrylate, 2-ethylhexyl acrylate and methacrylate, decyl acrylate and methacrylate, dodecyl acrylate and methacrylate, tridecyl acrylate and methacrylate, octadecyl acrylate and methacrylate, glycidyl acrylate and methacrylate, ethylthioethyl acrylate and methacrylate, furfuryl acrylate and methacrylate, tri-, tetra- and pentasiloxanylpropyl acrylate and methacrylate, and the corresponding amides; N-(l,l-dimethyl-3-oxobutyI)acrylamide; mono- and dimethyl fumarate, maleate and itaconate; diethyl fumarate; isopropyl fumarate and itaconate and diisopropyl fumarate and itaconate; mono- and diphenyl fumarate and itaconate, and methylphenyl fumarate and itaconate; methyl crotonate and ethyl crotonate; methyl vinyl ether and methoxyethyl vinyl ether, vinyl acetate, vinyl propionate, vinyl benzoate, acrylonitrile, styrene, α-methylstyrene and tert-butylstyrene.

Preferred monomers c) are methyl methacrylate, n-butyl methacrylate, isopropyl methacrylate, isobutyl methacrylate, cyclohexyl methacrylate or a mixture thereof.

The cros slinking agents d) are, in particular, diolefinic monomers, for example allyl acrylate, allyl methacrylate, ethylene glycol diacrylate and dimethacrylate, diethylene glycol diacrylate and dimethacrylate, triethylene glycol diacrylate and dimethacrylate, tetraethylene glycol diacrylate and dimethacrylate and generally polyethylene oxide glycol diacrylate and dimethacrylate, 1,4-butanediol diacrylate and dimethacrylate, poly-n-butylene oxide glycol diacrylate and dimethacrylate, propylene glycol diacrylate and dimethacrylate, polypropylene oxide glycol diacrylate and dimethacrylate, thiodiethylene glycol diacrylate and dimethacrylate, di-(2-hydroxyethyl)sulfonyl diacrylate and dimethacrylate, neopentyl glycol diacrylate and dimethacrylate, trimethylolpropane triacrylate and tetraacrylate, pentaerythritol triacrylate and tetraacrylate, divinylbenzene, divinyl ether, divinyl sulfone, disiloxanylbis-3-hydroxypropyl diacrylate and methacrylate, and related compounds. Ethylene glycol dimethacrylate is preferred.

If present, the crosslinking agent is preferably added in amounts of from 0.01-1 mole %, particularly preferably in an amount of from 0.2-1 mole %, in each case relative to the total amount of monomers a) to c).

A preferred hydrogel comprises a monomer mixture containing

5-80 mole % of vinyl monomer a), 20-95 mole % of vinyl monomer b) and 0 mole % of vinyl monomer c).

A further preferred hydrogel comprises a monomer mixture containing

10-65 mole % of vinyl monomer a),

10-65 mole % of vinyl monomer b) and

25-35 mole % of vinyl monomer c), in particular 30 mole % of c).

A particularly preferred hydrogel comprises a monomer mixture containing 30-70 mole % of vinyl monomer a), 30-70 mole % of vinyl monomer b) and 0 mole % of vinyl monomer c).

A likewise particularly preferred hydrogel comprises a monomer mixture containing 20-60 mole % of vinyl monomer a), 10-50 mole % of vinyl monomer b) and 30 mole % of vinyl monomer c).

The hydrogels according to the invention are produced, for example, by thermal polymerization or by free-radical copolymerization, either in bulk or in the presence of small amounts of solvent. Polymerization is expediently carried out at elevated temperature, preferably in the presence of an initiator which forms free radicals, for example at a temperature in the range of about 30°C to about 105°C. These initiators are preferably peroxides or azo catalysts having a half-life time period of at least 20 minutes at the polymerization temperature. Typical examples of peroxy compounds which can be used are isopropyl percarbonate, tert-butyl peroctanoate, benzoyl peroxide, lauroyl peroxide, decanoyl peroxide, acetyl peroxide, succinyl peroxide, methyl ethyl ketone peroxide, tert-butyl peroxyacetate, propionyl peroxide, 2,4-dichlorobenzoyl peroxide, tert-butyl peroxypivalate, pelargonyl peroxide, 2,5-dimethyl-2,5-bis(2-ethylhexanoyl- peroxy)hexane, p-chlorobenzoyl peroxide, tert-butyl peroxybutyrate, tert-butylperoxy- maleic acid, tert-butyl peroxyisopropylcarbonate and bis(l-hydroxycyclohexyl) peroxide.

The azo compounds include 2,2-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethyl- valeronitrile), l, -azobis(cyclohexanecarbonitrile) and 2,2'-azobis(2,4-dimethyl- 4-methoxyvaleronitrile).

It is also possible here to use other mechanisms which form free radicals, such as irradiation with, for example, X-rays, electron beams and UV radiation.

The amount of initiator can vary between 0.001 and 1 mole %, relative to components a) to d), but is preferably 0.01 to 0.3 mole %.

The monomers to be polymerized are expediently purified before the polymerization, in particular to remove inhibitors with which they are stabilized. Thus, for example, they are washed with suitable dilute aqueous bases, such as alkali metal hydroxides, for example sodium hydroxide solution, and purified by distillation under gentle temperature conditions.

The polymerization mixtures are polymerized on a laboratory scale in a manner known per se, for example in a cylindrical mould, by subjecting them, in plastic syringes, to a temperature programme in which the temperature is increased from 30°C in steps to about 100°C. The temperature steps can be, for example, between 5 and 10°C, with a residence time of 1 to 12 hours per temperature. Two- or five-hour intervals are customary, but individual temperatures can also be maintained for up to 20 hours. Conditioning at the end for 5 to 20 hours at temperatures between 70 and 100°C is usual.

In order to obtain hydrogels according to the invention, the copolymers obtainable as described above must be hydrated. This is expediently carried out by storing them in aqueous buffered saline solution, which is preferably isotonic. Before the hydration, the polymers are normally cut into thin discs.

The above-described hydrogels contain, in the segments formed by the vinyl monomers a), the hydroxyl groups which are present there still in protected form, for example as isopropylidene ketals. They are therefore still relatively highly hydrophobic. They can be converted into hydrogels according to the invention which contain, in the segments formed by the vinyl monomers a), the hydroxyl groups present there in free form by removing the protecting groups. This can be accomplished by introducing them into an acidic medium, as is generally known for acetal cleavages, for example in accordance with GB 2,091,750 (Tanaka et al).

The protecting-group removal causes the segments formed by the vinyl monomers a) to become hydrophilic to highly hydrophilic. The ability of the hydrogels to absorb water can thereby be significantly increased. In this way, the oxygen permeability can still be affected after the polymerization while the material composition remains fundamentally the same. The hydrogels according to the invention therefore have the advantage that the oxygen permeability can be controlled by two mutually independent measures: the content of vinyl monomers a), b) and c) on the one hand, and the hydrolysis of the hydroxyl-protecting groups of the vinyl monomer a) on the other hand.

A further surprising aspect of the invention is that the hydrophilic monomers b) with the^' hydrophobic monomers c) and the sugar alcohol monomers give polymers at all which, both in the unswollen and in the swollen state (hydrogel), do not have phase separation and are thus optically clear.

The hydrogels according to the invention have very good oxygen permeabilities and are at the same time hydrophilic and, in addition, mechanically stable, ie. they have, for example, a high tear strength. They are therefore highly suitable as materials for contact lenses or intraocular lenses and as other biocompatible materials, for example implants, eye bandages, transdermal systems or other forms of medicament carriers.

The production of contact lenses from the hydrogels mentioned can be effected in a manner known per se. To this end, the mixtures to be polymerized are polymerized, for example, in a cylindrical mould, and the rods obtainable are cut, after being released from the mould, into discs or buttons, which can be further processed mechanically. Alternatively, the polymerization can be carried out in lens moulds, so that lens blanks are obtained directly as polymers.

The reaction is preferably carried out under an inert atmosphere if it is carried out in open moulds. As is known, oxygen inhibits the polymerization and results in longer polymerization times. If closed moulds are used to form the polymer, the moulds comprise inert materials having low oxygen permeability and non-stick properties. Examples of suitable mould materials are polytetrafluoroethylene, such as Teflon®, silicone rubber, polyethylene, polypropylene and polyesters, such as Mylar®. If a suitable release agent is used, glass and metal moulds can also be used.

The monomers b) and c) used are known, are in some cases commercially available, or can be prepared by processes known per se.

The monomers of the formula I can be prepared, for example, by reacting a compound of the formula El

HOCH₂(CHOH)p-CH₂OH (HI)

in which p is a number from 1 to 8, and in which (p+1) hydroxyl groups are in protected form, or, if appropriate, a mixture of two or more different compounds of the formula HI as defined above, but which differ in that a different hydroxyl group is in each case not in protected form, or a reactive derivative of a compound of the formula in or of a mixture of compounds of the formula III, with a reactive derivative of a compound of the formula IV

R--COOH (IV)

in which R¹ is C₂-C₃alkenyl, and, if necessary, an isomer mixture obtained is resolved.

A reactive derivative of a compound of the formula IV is, in particular, a carboxylic anhydride, such as an internal anhydride or an anhydride with a hydrohalic acid, such as with hydrochloric acid. Compounds of this type are, for example, acrylyl chloride, methacrylyl chloride or crotonyl chloride or methacrylic anhydride.

A reactive derivative of a compound of the formula in is, for example, a metal salt of a compound of the formula III, for example an alkali metal salt, such as a sodium salt.

The reaction is carried out, starting from a compound of the formula HI having one free hydroxyl group, preferably in an inert solvent, such as an organic base, for example a tertiary amine, such as pyridine, at temperatures between -40 and 100°C, in particular with exclusion of moisture, such as by working under a protective-gas atmosphere, for example with nitrogen gas. Starting from a reactive derivative of a compound of the formula HI, the inert solvent used is preferably a hydrocarbon or a hydrocarbon mixture whose boiling range is advantageously above 50°C. Otherwise, the process conditions are essentially identical. Specific advantageous process parameters are given in the examples.

For the resolution of isomer mixtures obtained, chromatographic methods are suitable, in particular those using water/lower alkanol mixtures as the eluent, for example water/methanol mixtures. High-pressure liquid chromatography (HPLC) is particularly suitable. Specific advantageous process parameters are given in the examples.

The starting compounds of the formula III, as defined above, can be prepared in a manner known per se, for example from compounds of the formula HI in which (p+2) hydroxyl groups are in free form, by reaction with a ketone, for example acetone.

The examples below illustrate the subject-matter of the invention, but without representing a limitation, for example to the scope of the examples. Percentages in amount data are mole per cent, unless expressly stated otherwise. Temperatures are given in degrees Celsius.

The abbreviations used have the following meanings:

AIBN azoisobutyronitrile

BuMA n-butyl methacrylate

EGDMA ethylene glycol dimethacrylate

HEMA 2-hydroxyethyl methacrylate

MMA methyl methacrylate

Regarding the abbreviations of the monomers a) used, reference is made to the explanations in connection with formula I.

General information on Examples 1-7:

GC: Perkin-Elmer Sigma 1, glass column (length: 1250 mm, internal diameter 3 mm)

Packing material Chromosorb G containing 5 % of polyethylene succinate

35, column temperature 170°C, carrier gas He, 25 ml/min. Analytical HPLC:

Steel column (length 250 mm, 04.6 mm) Packing material 5 C18 Nucleosil, Macherey and Nagel, Integrator Chromatopac C-R 3A Shimadzu, 20°C.

Preparative HPLC:

Steel column (length 250 mm, 0 32 mm)

Packing material 7 C18 Nucleosil, Macherey and Nagel, 20°C.

Example 1: l,2;3,4-Di-0-isopropylidene -DL-xylitol

300 g of xylitol (1.97 mol) are reacted at 25 °C with acetone by a method of R.S. Tipson and L.H. Cretcher. J. Org. Chem. 8, 95 (1943) and P.A. Levenne and R.S. Tipson. J. Biol. Chem.115, 731 (1936) and ibid.106, 113 (1935). The product is distilled in an oil-pump vacuum (75°C, 0.03 hPa). The syrup obtained contains about 90 % of the title compound as the major product and l,2;4,5-di-0-isopropylidenexylitol as a by-product.

In order to isolate the title compound, the syrup is distilled over a 70 cm packed column filled with Brunswick coils (diameter: 4 mm) in an oil-pump vacuum (0.03 hPa) (head temperature: 75°C; bottom temperature 135°C; withdrawal dripping rate: 1 drop/3 s). The syrup is withdrawn in 10 fractions of about 30 g each. As the GC of the first fraction shows, the by-product (retention time: 6.3 min) is highly concentrated in the first fraction (peak area proportion 30 %). The proportion of the by-product considerably decreases continuously from the 1st to the 4th fraction. It is no longer detectable in the GC in the 6th fraction. Fractions 6 to 10 comprise GC-pure l,2;3,4-di-0-isopropylidene-DL-xylitol (retention time: 10.5 min; Rf: 0.69 in absolute ethanol; Rf: 0.65 in absolute methanol).

m.p.: 36-37°C; m.p. (lit): 36°C (N. Baggett et al., J. Chem. Soc. 1965, 3382) or m.p. (lit): 32-34°C . Okuda et al., Carbohydr. Res. 67, 117 (1978).

Example 2: 1,2;4,5 -Di-O-isopropylidenexylitol

This compound is separated from 3.00 g (12.9 mmol) of the first fraction from the

Brunswick coil distillation described in Example 1 by means of preparative HPLC (eluent: mixture of 30 % by volume of methanol and 70 % by volume of water, flow rate 42 ml/min; amount injected: 300 μl of substance; pressure 140 bar, detection: Knauer refractometer).

The methanol and the water are stripped off from a total of 1 1 of the resultant solution on a Rotavapor. The syrup which remains is distilled using a bulb tube column in an oil-pump vacuum (75 °C, 0.03 hPa). The l,2;4,5-di-O-isopropylidenexylitol obtained has the following chromatographic characteristic data:

Rf: 0.60 (in absolute ethanol); 0.58 (in absolute methanol); GC: retention time: 6.3 min.

Example 3: 5-0-Methacryloyl- 2;3,4-di-0-isopropylidene-DL-xylitol a) Synthetic route I: 10 ml of methacrylic anhydride (0.071 mol) are added at 20°C to 8.94 g (39 mmol) of l,2;3,4-di-0-isopropylidene-DL-xylitol, dissolved in 50 ml of pyridine. The reaction mixture is stirred at 80°C for 4 hours with exclusion of moisture and, after cooling to 20°C, mixed with 50 ml of water. This solution is extracted three times with 100 ml of petroleum ether (boiling range 90-100°C) in each case. The combined petroleum ether phases are washed by shaking once with 300 ml of 5 % sodium hydroxide solution and once with 300 ml of water and are subsequently dried over sodium sulfate. 0.03 g of tert-butylpyrocatechol is added, the petroleum ether is removed, and the residue is distilled on a Rotavapor in a water-pump vacuum without a condenser, the receiving flask being cooled with ice water (b.p. 93°C/0.05 hPa, bath temperature 130°C). 5-O-Methacryloyl-l,2;3,4-di-O-isopropylidene-DL-xylitol is obtained as a colourless syrup which begins to crystallize after storage at 0°C for two months. The crystals are dissolved in 6.5 ml of petroleum ether (boiling range 80-100°C) at 20°C and recrystallized as described under b).

b) Synthetic route II: 13.2 g of 60 % sodium hydride/mineral oil dispersion (___. 7.9 g, 0.33 mol of sodium hydride) from Janssen Chimica are washed twice with petroleum ether under a nitrogen atmosphere in order to remove the mineral oil. To do this, the sodium hydride dispersion is stirred for 15 minutes at 60°C with 200 ml of petroleum ether (boiling range: 90-100°C). When, after a further 15 minutes, the sodium hydride has settled on the flask bottom, the petroleum ether is decanted off and the sodium hydride is again washed in the same way with 200 ml of petroleum ether. The petroleum ether is again decanted off. 225 ml of petroleum ether (boiling range 90-100°C) are added to the washed sodium hydride, and 75 g (0.325 mol) of syrupy l,2;3,4-di-0-isopropylidene-DL-xylitol are subsequently added slowly at 20°C in a stream of nitrogen (evolution of hydrogen!).

This reaction mixture is stirred for 2 hours at 60°C under nitrogen and subsequently cooled to -10°C. 31.5 ml (0.33 mol) of methacrylyl chloride (from Fluka), dissolved in 150 ml of petroleum ether (boiling range 90-100°C), are then slowly added dropwise (exothermic reaction!) with stirring and with exclusion of moisture at a rate such that the temperature remains between -5°C and -10°C. The flask is kept at -10°C overnight. The mixture is subsequently stirred at 60°C for 1 hour and cooled to 20°C, and the precipitate is filtered off. The precipitate is washed with 150 ml of petroleum ether. The combined filtrates are washed once with 750 ml of 5 % sodium hydroxide solution and once with 750 ml of water and are dried over sodium sulfate.0.25 g of tert-butylpyrocatechol is subsequently added (as inhibitor). The petroleum ether is removed on a Rotavapor in a water-pump vacuum at 30°C, and the syrup which remains is distilled in an oil-pump vacuum without condenser. The receiving flask is cooled with ice water (b.p. 98°C/0.07 hPa, bath temperature 130°C). 5-0-Methacryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol is obtained as a colourless syrup.

Seed crystals can be obtained, as described in Example 4, using a sublimation apparatus. 60 ml of petroleum ether (boiling range 80-100°C) are dissolved in 78 g of the syrup obtained. The solution is cooled to -20°C and then, after a seed crystal has been added, left to crystallize for 24 hours. The petroleum ether, cooled to -20°C, is subsequently poured quickly off the crystals. The crystals are dried at 20°C in an oil-pump vacuum and comminuted. The crystals obtained in this way are subsequently crystallized again as described.

M.p.: 35-35.5°C; m.p. (lit.): 33°C (A.N. Anikeeva and S.N. Danilov, Zh. Obshch. Khim.

34 (4), 1063-4 (1964); Chem. Abstr. 61, 1929 f (1964)).

GC: Retention time: 8.0 min; analytical HPLC: retention time: 24.5 min.

Example 4: 5-0-Acryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol 8.75 g of 60 % sodium hydride/mineral oil dispersion ( ≤. 5.25 g of sodium hydride, 0.219 mol) are washed twice analogously to Example 3 with 65 ml of petroleum ether (boiling range: 90-100°C) in each case under nitrogen. 400 ml of petroleum ether (boiling range 90-100°C) are added to the washed sodium hydride, and 50.0 g (215 mmol) of syrup-form l,2;3,4-di-0-isopropylidene -DL-xylitol are subsequently added slowly at 20°C in a stream of nitrogen (evolution of hydrogen!). This reaction mixture is stirred at 80°C for 4 hours under nitrogen and subsequently cooled to -35°C (with stirring). 17.5 ml (215 mmol) of distilled acrylyl chloride from Fluka are then dissolved in 250 ml of dry petroleum ether and slowly added dropwise (exothermic reaction!) with stirring (about 2 hours) and with exclusion of moisture at a rate such that the temperature remains between -30 and -35°C. The flask is kept at -10°C overnight. The mixture is then stirred at 20°C for 1 hour, and the precipitate is filtered off with suction using a D4 frit. The solution is concentrated to 150 ml on a Rotavapor (water bath 27°C) in a water-pump vacuum, washed by shaking twice with 150 ml of 5 % sodium hydroxide solution in each case and dried over sodium sulfate. 0.25 g of tert-butylpyrocatechol is added to this solution; the petroleum ether is stripped off on a Rotavapor (water bath 27°C). The syrup which remains is distilled in an oil-pump vaccum without condenser. The receiving flask is cooled with ice water, b.p. 81°C/0.08 hPa, bath temperature 110°C. 5-0-Acryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol is obtained as a colourless syrup.

In order to produce crystals, the following procedure is adopted: 0.5 g of the syrup obtained is transferred into a sublimation apparatus. The cold finger is cooled to -50°C, and the syrup is warmed to 70°C in an oil-pump vacuum (0.04 hPa). After about 1 hour, the syrup has distilled onto the cold finger. The syrup crystallizes slowly on the cold finger while the cold finger is warmed to 20°C.

22 g of the syrup obtained are dissolved in 100 ml of petroleum ether (boiling range 80-100°C) at 20°C, and this solution is washed by shaking twice with 100 ml of 5 % sodium hydroxide solution in each case and once with 100 ml of water. The solution is dried over sodium sulfate, subsequently concentrated to 65 ml on a Rotavapor (water-bath temperature 27 °C) in a water-pump vacuum, and recrystallized as under Example 3b.

C₁₄H₂₂0₆ (286.3) calc. C58.73 H 7.75 found C59.18 H 7.72

M.p.: 32-33°C, white crystals, ⁿ²° = 1.4561 (syrup)

Rf: 0.90 (in absolute ethanol), 0.90 (in absolute methanol), GC: retention time 7.8 min.

Example 5: 5-0-Crotonoyl-l,2;3,4-di-0-isopropylidene-DL-xylitol 1.6 g of 60 % sodium hydride/mineral oil dispersion (__= 0.96 g of sodium hydride, 40 mmol) are washed as described in Example 3. 30 ml of petroleum ether (boiling range 90-100°C) are added to the washed sodium hydride, and 10.0 g (43 mmol) of syrupy l,2;3,4-di-0-isopropylidene-DL-xylitol are subsequently added slowly at 20°C in a stream of nitrogen (evolution of hydrogen!). The mixture is then stirred at 70°C for 3 hours under a nitrogen atmosphere. The mixture is cooled to 20°C and 4 ml (40 mmol) of crotonyl chloride, dissolved in 20 ml of petroleum ether (boiling range 80-100°C), are added dropwise at 20°C with exclusion of moisture. This reaction mixture is stirred at 20°C for 1 week with exclusion of moisture, and the precipitate is subsequently filtered off. The filtrate is washed by shaking twice with 30 ml of 5 % sodium hydroxide solution in each case and once with 30 ml of water, and is dried over sodium sulfate. The petroleum ether is subsequently stripped off on a Rotavapor in a water-pump vacuum. The syrup which remains is distilled in an oil-pump vacuum without condenser (b.p. 95°C/0.09 hPa, bath temperature 135°C). 5-0-Crotonoyl-l,2;3,4-di-0-isopropylidene-DL-xylitol is obtained as a colourless syrup which crystallizes slowly at 20°C.

The syrup obtained is dissolved in 7 ml of petroleum ether (boiling range 80-100°C), cooled to -20°C and, after a seed crystal has been added, left to crystallize for 24 hours. The crystals, cooled to -20°C, are subsequently filtered off quickly under suction using a frit and dried at 20°C in an oil-pump vacuum.

Cι₅H₂₄0₆ (300.4) calc. C 59.99 H 8.05 found C 59.84 H 8.08

M.p.: 41.5-42.5°C, white crystals n²⁰ = 1.4610 (syrup), Rf: 0.89 (in absolute ethanol), 0.87 (in absolute methanol).

Example 6: 3-0-Methacryloyl-l,2;4,5-di-0-isopropylidenexylitol 7.5 g (32 mmol) of the isomer mixture from the first fraction of the Brunswick coil distillation from Example 1 are reacted analogously by synthetic route I (see Example 3) and a further 7.5 g by synthetic route II (see Example 3). The syrup obtained by synthetic route I (6.00 g, 67 %) and the syrup obtained by synthetic route π (6.50 g, 73 %) each contain 5-0-methacryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol as the major product and contain the title compound as a by-product. The methanol is stripped off from the total of 21 of resultant solution on a Rotavapor in a water-pump vacuum (bath temperature 30°C). The aqueous solution which remains is extracted twice with 1 1 of petroleum ether (boiling range 80-100°C) in each case. The combined petroleum ether phases are dried over sodium sulfate. Petroleum ether is stripped off on a Rotavapor in a water-pump vacuum (water-bath temperature 27°C). The syrup which remains crystallizes slowly at 20°C. The crystals of 3-0-methacryloyl-l,2;4,5-di-0-isopropylidenexylitol are dried at 20°C in an oil-pump vacuum. M.p.: 69-70°C; GC: retention time: 5.7 min.

The title compound can also be separated off from

5-0-methacryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol by preparative HPLC (eluent: solution of 60 % by volume of methanol and 40 % by volume of water, flow rate: 50 ml/min, amount injected 1 ml, pressure 140 bar, detection UV 254).

Rf: 0.86 (in absolute ethanol, 20°C), 0.78 (in absolute methanol, 20°C), analytical HPLC: retention time 20.8 min, same conditions as in Example 3.

Example 7: 3-0-AcrvIoyl-L2;4,5-di-0-isopropylidenexylitol 7.5 g (32 mmol) of the isomer mixture from the first fraction of the Brunswick coil distillation from Example 1 are reacted analogously to Example 4. The syrup obtained contains 5-0-acryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol as the major product and contains the title compound as the by-product. The title compound is separated off from 5-0-acryloyl-l,2;3,4-di-0-isopropylidene-DL-xylitol by preparative HPLC. The solution obtained (1 1), comprising 3-O-acryloyl-l,2;4,5-di-O-isopropylidenexylitol, methanol and water, is worked up as described in Example 6.

M.p.: 65-66°C; GC: retention time 6.0 min.

General data regarding the examples below:

HEMA (Rohm GmbH) - stabilized with hydroquinone and hydroquinone monomethyl ether - is freed from the inhibitors by washing the pertinent monomer (100 ml amounts) with 3x100 ml of 5 % sodium hydroxide solution and 1x100 ml of water, drying the solution over Na₂S0₄ and distilling the product without inhibitor, avoiding overheating due to the heating bath. The cloudy initial fraction (about 10 ml) is discarded. When weighing out HEMA, the EGDMA content (on average 0.14 mole %) determined by gas chromatography in the starting monomer is taken into account. The initial weight of monomers is a total of 11.00 g per batch. 5.5 mg of AIBN are added to all the batches. The AIBN is only added last to samples 8, 9, 17, 18, 26, 33, 34, 41, 42, 49 and 50 after the 5-MDP-Xy or 5-ADP-Xy crystals have been rapidly melted at 50°C and after the melts have cooled to 20°C.

Example 8: (described for sample 21 as an example): 4.611 g of HEMA, 2.124 g of MMA, 4.247 g of 5-MDPXy, 18.2 mg of EGDMA and 5.5 mg of AIBN are weighed out into a 25 ml conical flask. The polymerization batch is then stirred at 20°C for 1 hour until all the crystals have dissolved completely in the mixture. When a homogeneous liquid mixture has been produced, it is transferred into 10-ml plastic syringes (Henke-Sass Wolf, Tuttlingen, material: polyethylene and polypropylene, melting point about 140°C, internal diameter: 16 mm). The air is forced out, the syringe batches are melted, and the stamp is fastened by a wire. The syringes sealed in this way are placed in a water bath, it being ensured that the water surface always has a higher level than the surface of the monomer mixture in the syringe. The polymerization is then carried out for 12 hours at 30°C, 5 hours at 40°C, and 2 hours at each of 50°C, 60°C and 70°C. The syringes with their solid contents are then post-polymerized in a drying oven for 2 hours at 80°C and then for 5 hours at 90°C. The polymers obtained are removed from the syringes and conditioned for 8 hours at 90°C. A cylindrical, hard polymer is obtained. The polymer sample is hard and glass-clear.

Tables la and lb below indicate the material composition of the monomer mixtures, which are reacted analogously to the procedure described above for sample 21. Polymer samples 35-40, 43-48, 51-55 and 59-62 are hard and cloudy. All the other samples are hard and glass-clear. The initial weight of AIBN is always 5.5 mg.

Table la: Composition of samples 1-34

Sample EGDMA HEMA 5-MDP-Xy MMA (a) or BuMA (b)

No. [mole %] [mg] [mole %] [g] [mole %] [gl [mole %] [g]

1 0.2 10.0 100 10.990 0

2 0.2 10.5 95 9.802 5 1.188

3 0.2 10.9 90 8.750 10 2.239

4 0.2 11.7 80 6.974 20 4.015 .

5 0.2 12.3 70 5.530 30 5.458

6 0.2 12.5 65 4.905 35 6.083

7 0.2 13.2 50 3326 50 7.661

8 0.2 13.9 25 1389 75 9.597

9 0.2 14.5 0 100 10.986

10 1.0 141.9 100 10.858 0

11 1.0 134.4 95 9.691 5 1.175

12 1.0 127.8 90 8.657 10 2.215

13 1.0 116.5 80 6.907 20 3.977

14 1.0 107.4 70 5.482 30 5.411

15 1.0 103.4 65 4.865 35 6.032

16 1.0 93.4 50 3302 50 7.605

17 1.0 81.0 - 25 1381 75 9.538

18 1.0 72.1 0 100 10.928

19 0.2 18.3 70 8.263 0 30 2.719 (a)

20 0.2 18.3 60 6.213 10 2.385 30 2.385 (a)

21 0.2 18.2 50 4.611 20 4.247 30 2.124 (a)

22 0.2 18.2 40 3325 30 5.743 30 1.914 (a)

23 0.2 18.2 30 2.270 40 6.970 30 1.742 (a)

24 0.2 18.2 20 1389 50 7.994 30 1.599 (a)

25 0.2 18.1 10 0.641 60 8.863 30 1.477 (a)

26 0.2 18.1 0 70 9.609 30 1.373 (a)

27 0.2 16.6 70 7.486 0 30 3.173 (b)

28 0.2 16.7 60 5.694 10 2.185 30 3.104 (b)

29 0.2 16.9 50 4.265 20 3.929 30 2.790 (b)

30 0.2 17.0 ^■ 40 3.098 30 5351 30 2.534 (b)

31 0.2 17.0 30 2.128 40 6.535 30 2320 (b)

32 0.2 17.1 20 1309 50 7.534 30 2.140 (b)

33 0.2 17.2 10 0.607 60 8390 30 1.986 (b)

34 0.2 17.2 0 70 9.130 30 1.853 (b)

Table lb: Composition of samples 35-66

Example 9: Hydration of the polymer discs

The polymers from Example 8 are cut into discs (diameter: 11.9 to 12.1 mm, thickness: 0.137 to 0.256 mm) and polished. The diameter D_p, the thickness d_p and the weight W_p of the discs are determined. D_p is determined using a magnifying glass with measurement scale and d_p is determined using a micrometer screw. The polymer discs obtained in this way are stored for 10 days at 35°C in aqueous "buffered isotonic saline solution" (300 mosmol; pH 7.2; 3.04 g of Na₂HP0₄ x 2H₂0, 0.84 g of NaH₂P0₄ x H₂0 and 8.00 g of NaCl per 1 1 of solution), which is replaced twice. Exampel 10: Hydrolysis of the polymer discs

In accordance with the method of Tanaka et al. (German Offenlegungsschri ft 3,200,479), the polymer discs from Example 9 are stored at 20°C for 30 minutes in a 50 % aqueous formic acid solution and then for 2 hours in 6N hydrochloric acid at 20°C in order to remove isopropylidene protecting groups. After hydrolysis, the discs are placed in 2 % aqueous soda solution at 20°C for 15 minutes and then stored for 10 days at 35°C in "buffered isotonic saline solution" (as in Example 8), the solution being replaced twice. With the exception of polymers 37-40, 45-48,52-54 and 60-62, which are slightly to very cloudy, the other polymer discs are glass-clear and colourless.

Hydrolysis proceeds very easily in all the polymers - in some cases even in only 50 % formic acid. This can be detected from the increasing swelling.

The removal of the isopropylidene protecting groups, and thus liberation of the OH groups on the saccharide molecules, by 6N HC1 at 20°C has been studied in detail. The question of whether cleavage of the ester bond via which the saccharide unit is bonded to the polymer structure also occurs under the given conditions has also been clarified here.

It is known [T. Tanaka, Spektrum der Wissenschaft 78 (March 1981)] that hydrogels containing carboxyl groups have a higher water content and a greater linear expansion on transfer from aqueous saline solution into distilled water. Accordingly, the values for water content and linear expansion should increase when the polymer discs are transferred from "buffered isotonic saline solution" into distilled water. In addition, the IR spectra of these samples (washed until salt-free and then dried) should contain absorptions for carboxyl and maybe also carboxylate groups if ester cleavage has taken place to a considerable extent (sensitivity of IR spectroscopy) during removal of the protecting groups.

Most of the samples from the sample series Nos. 35-66 exhibit this type of increase in the linear expansions and the IR absorptions in the range from 2500 to 2700 cm^"1 and at 1570 cm^"1 which are typical for carboxyl groups, while the band at 3000 cm^"1 is covered by the strong CH₂ band at 2490 cm^"1 and the very strong, broad OH band at 3400 cm^"1 and cannot therefore be evaluated with certainty. For polymer sample Nos. 1-34, neither an increase in the linear expansion nor the appearance of IR bands characteristic of carboxyl or carboxylate groups were found. This allows the conclusion that ester cleavage of this type occurs significantly more quickly in acrylic esters containing saccharide units, while it is not observed under the hydrolysis conditions used here in the case of methacrylates.

Example 11: Water content and linear swelling of the hydrated polymer discs

(unhydrolysed)

Unhydrolysed polymer discs from the examples above are investigated for water content

(H) at 35°C after swelling in "buffered isotonic saline solution" and for linear expansion

(LE). The values determined are summarised in Table 2. The water content drops with increasing proportion of hydrophobic di-O-isopropylidene-DL-xylitol units in the polymer. This also applies to the linear expansion.

Table 2

Polymer H [%] Polymer LE [%] sample from at 35°C sample from at 35°C

Example 8 Example 8

1 38.4 35 17.5

2 31.5 36 15.0

3 26.9 37 13.4

4 18.7 38 8.8

5 14.0 39 5.8

6 11.5 40 3.5

7 6.6 41 1.0

9 1 43 16.7

10 35.5 44 13.4

11 28.5 45 12.1

12 25.5 46 8.4

13 18.0 47 5.8

14 13.8 48 2.1

15 11.5 49 1.0

16 6.6 50 0

18 1 51 7.5

19 19.9 52 5.8

20 14.5 53 2.5

21 9.8 54 2.5

22 6.5 55 2.1

23 4.2 56 1.6

24 2.9 57 1.0

25 2.0 58 0.8

26 1.2 59 5.0

27 12.0 60 3.6

28 8.9 61 2.5

29 6.0 62 2.5

30 4.0 63 0.8

64 0.6

Example 12: Water content and linear expansion of the hydrolysed and swollen polymer samples

Table 3 below shows the values for the water content and the linear expansion for the hydrolysed polymer samples in which the isopropylidene protecting groups on the 5-MDPXy units (or analogous units) have been removed. The water content and the linear swelling increase considerably with increasing proportion of xylitol units in the hydrogel. The values for the water content are also given for the commercially available lenses W 38 and WCE. Table 3

Polymersample H [%] LE [%] fromExample8 at35°C at35^CC

1 37 19

2 45 23

3 52 28

4 65 41

5 74 50

6 76 54

7 83 72

9 88 97

10 35 17

11 42 20

12 48 26

13 58 34

14 66 43

15 69 47

16 74 53

17 82 64

18 83 68

19 20 7

20 33 14

21 47 22

22 59 32

23 69 42

24 75 53

25 80 64

26 84 72

27 12 4

28 21 6

29 31 12

30 44 18

31 56 25

32 64 32

33 71 37

34 74 44

35 37 17 Polymer sample H [%] LE [%] from Example 8 at 35°C at 35°C

36 43 20

37 50 27

38 64 40

39 78 62

40 87 88

41 94 106

43 33 16

44 39 18

45 47 23

46 60 34

47 73 49

48 81 61

49 74

50 90 87

51 20 5

52 34 13

53 49 21

54 61 33

55 72 48

56 80 62

57 84 75

58 88 88

59 12 4

60 23 8

61 35 15

62 47 20

63 57 27

64 65 33

W38 38

WCE 57

Example 13: Transmission of visible light

The hydrogel discs from samples 1-34 of Example 8 are placed between quartz plates, and the transmission of visible rays is measured between wavelengths 400 and 800 nm. The transmission for visible light increases continuously between 400 and 800 nm and is greater than 90 % for all the samples. Thus, for example, a transmission of 92 % at 400 nm, 94 % at 600 nm and 95 % at 800 nm is measured on the hydrolysed polymer disc No. 22 (thickness 0.209 mm).

Example 14: Content of extractable components

For samples 1-34 of Example 8, the content of extractable components (R) is low, ie. a maximum of 4.5 %, and in most samples is 2 % or less. R increases only relatively little with increasing xylitol content and thus increasing water content. Comparable polymers in which the xylitol units have been replaced by N-vinylpyrrolidin-2-one units have, by contrast, up to 30 % by weight of extractable components at significantly lower water contents. In view of the hydrolysis carried out in accordance with Example 10 and in view of the high water contents, these are astonishingly low R values. This speaks both in favour of very good copolymerization and against ester cleavage during the hydrolysis.

The situation is different in the case of samples 35-64 of Example 8, for which the R values are up to 17 % by weight. Even in the case of these samples, however, they are usually 10 % or significantly less. Here, R increases relatively fast with increasing xylitol content, and thus increasing water content. It may be assumed that this high percentage of extractable components is also attributable to partial cleavage of the ester bonds during the hydrolysis (see comments in Example 10).

Example 15: Determination of the oxygen permeability

The measurement is carried out using a Createch permeometer, model 201 [1032 Neilson St., California 94706) with an Ag anode and a Pt cathode by the method of J. Fatt (Am. J. Optom. and Physiol. Optics, 48, 545 (1971)] at 35°C. The electrodes are positioned in a plexiglass holder. The atmospheric humidity is greater than 90 % for the measurements.

The values for oxygen permeability of some hydrated and/or hydrolysed polymer discs from Example 8 are shown in Table 4 - expressed as the permeation coefficient ^p ₀ ,

2 transmissibility , and as the oxygen flow ^J _n . For the purposes of comparison, the 2 ^υ2 values for two commercially available hydrogel materials (W38 = polyHEMA crosslinked with EGDMA, WCE = copolymer of VP and methyl methacrylate, both Ciba Vision) are added.

The thicknesses d_f of the discs with water contents greater than 40% are determined via the linear swelling LE. The thicknesses of the other discs are measured using a thickness-measuring instrument. Table 4 contains the values for the oxygen permeability of the polymer samples 20, 37, 39 and 41 after hydration and for the polymer samples 20-22, 25, 35, 54-56 and 58 after hydrolysis. Table 4

Example 16: Ball indentation hardness

Sample cylinders (0 130 mm, D = 4.0 mm) are machined from the polymer discs from some of the above examples and polished. The ball indentation hardness K is determined at 23 °C using an apparatus from Zwick. The K values of the polymer discs investigated, measured 60 seconds after commencing loading, are summarised in Table 5.

Table 5

Polymer sample K[N/mm²] from Example No. 8

59 127 60 120 61 107 62 92 63 75 64 52

Claims

What is claimed is:

1. A hydrogel which is a copolymer of a polymerizable monomer mixture which contains

a) 5-95 mole % of a hydrophobic polyhydroxyvinyl monomer whose hydroxyl groups are in protected form, b) 5-95 mole % of a hydrophilic vinyl monomer, c) 0-40 mole % of a hydrophobic vinyl monomer containing a maximum of two fluorine atoms, and d) 0-5 mole %, relative to the total amount of monomers a)-c), of a crosslinking agent,

2. A hydrogel according to claim 1, wherein the vinyl monomer a) is selected from the compounds of the formula I

R^*-COO-CH₂(CHOH)_p-CH₂OH (I)

in which R¹ is C₂-C₃alkenyl, p is a number from 1 to 8 and the hydroxyl groups are in protected form, and furthermore positional isomers thereof in which the R--CO- group is bonded to a different oxygen atom, and the oxygen atom to which this group is bonded in the depicted formula I is one of the hydroxyl groups which are in protected form.

3. A hydrogel according to claim 1, wherein the vinyl monomer b) is selected from acrylates and methacrylates of the formula

R²

H₂C=C-COOR³

in which R² is hydrogen or methyl, and R³ is a hydrocarbon radical having 1 to 10 carbon atoms which is monosubstituted or polysubstituted by a water-solubilizing group, such as carboxyl, hydroxyl or tert-amino, by a polyethylene oxide group having 2-100 recurring units, or by a sulfate, phosphate, sulfonate or phosphate group, furthermore acrylamides and methacrylamides of the formula

in which R⁴ is hydrogen or C_rC₄alkyl; acrylamides and methacrylamides of the formula

R³OOC-CH=CH-COOR³ ;

crotonates of the formula

CH₃-CH=CH-COOR^*- ;

vinyl ethers of the formula

H₂C=CH-OR^J

and N-vinyllactams.

4. A hydrogel according to claim 1, wherein the vinyl monomer c) is selected from acrylates and methacrylates of the formula

H₂C=C-COOR⁶ , acrylamides and methacrylamides of the formula

H₂C=C-CONH-R⁶

maleates and fumarates of the formula

R⁶OOC-CH=CH-COOR⁶

itaconates of the formula

CH

R⁶OOC-C-CH₂-COOR⁶

crotonates of the formula

H₃C-CH=CH-COOR⁶

vinyl esters of the formula

R^t -COO-CH=CH₂

and vinyl ethers of the formula

H₂C=CH-0-R°

in which R² is hydrogen or methyl, and R⁶ is a linear or branched aliphatic, cycloaliphatic or aromatic group having 1 to 21 carbon atoms, which may contain ether or thioether bonds, sulfoxide or sulfone groups or a carbonyl group; or R⁶ is a heterocyclic group which contains oxygen, sulfur or nitrogen atoms and 5 or 6 or, if it is bicyclic, up to 10 ring atoms, or a polypropylene oxide or poly-n-butylene oxide group having 2 to 50 recurring alkoxy units, or R⁶ is an alkyl group having 1 to 12 carbon atoms which contains halogen atoms, of which, however, at most two are fluorine atoms, or R⁶ is a siloxane group having 1 to 6 Si atoms.

5. A hydrogel according to claim 1, in which the hydroxyl groups of the segments formed by the monomers a) are in protected form or in some cases protected form.

6. A hydrogel according to claim 1, in which the hydroxyl groups of the segments formed by the monomers a) are in free form.

7. A hydrogel according to claim 1, wherein the monomer mixture contains 5-80 mole % of vinyl monomer a),

20-95 mole % of vinyl monomer b) and 0 mole % of vinyl monomer c).

8. A hydrogel according to claim 7, wherein the monomer mixture contains 30-70 mole % of vinyl monomer a),

30-70 mole % of vinyl monomer b) and 0 mole % of vinyl monomer c).

9. A hydrogel according to claim 1, wherein the monomer mixture contains 10-65 mole % of vinyl monomer a),

10-65 mole % of vinyl monomer b) and

25-35 mole % of vinyl monomer c), in particular 30 mole % of c).

10. A hydrogel according to claim 9, wherein the monomer mixture contains 20-60 mole % of vinyl monomer a),

10-50 mole % of vinyl monomer b) and 30 mole % of vinyl monomer c).

11. A hydrogel according to claim 2, wherein the vinyl monomer a) is a compound of the formula I in which p is 2 to 4.

12. A hydrogel according to claim 11, wherein the vinyl monomer a) is a compound of the formula I which is derived from a sugar alcohol selected from xylitol, adonitol, arabitol, sorbitol, mannitol and dulcitol.

13. A hydrogel according to claim 12, wherein the vinyl monomer a) is selected from the compounds of the formula π

in which R^a and R^b, independently of one another, are hydrogen or methyl, and positional isomers thereof.

14. A hydrogel according to claim 13, wherein the vinyl monomer a) is selected from the compounds of the formula II.

15. A hydrogel according to claim 1, wherein the vinyl monomer b) is selected from hydroxy-substituted C -C alkyl (meth)acrylates, five- to seven-membered N-vinyllactams, N,N-di-Cj-C₄alkyl(meth)acrylamides and vinylically unsaturated carboxylic acids having a total of 3 to 5 carbon atoms.

16. A hydrogel according to claim 15, wherein the vinyl monomer b) is selected from 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, N,N-dimethylacrylamide, acrylic acid and methacrylic acid.

17. A hydrogel according to claim 1, wherein the vinyl monomer c) is selected from C₁-C alkyl esters or C^-Cvcycloalkyl esters of vinylically unsaturated carboxylic acids having 3 to 5 carbon atoms.

18. A hydrogel according to claim 17, wherein the vinyl monomer c) is selected from methyl methacrylate, n-butyl methacrylate, isopropyl methacrylate, isobutyl methacrylate and cyclohexyl methacrylate.

19. A hydrogel according to claim 1, wherein the vinyl monomer a) is selected from the compounds of the formula II according to claim 13 and positional isomers thereof, the vinyl monomer b) is selected from 2-hydroxyethyl methacrylate and

N-vinyl -2 -pyrrolidone, and the vinyl monomer c) is selected from methyl methacrylate and butyl methacrylate.

20. A hydrogel according to claim 19, wherein the vinyl monomer a) is selected from the compounds of the formula II.

21. A contact lens essentially comprising a hydrogel according to claim 1.

22. An intraocular lens essentially comprising a hydrogel according to claim 1.

23. The use of a hydrogel according to claim 1 for the production of a contact lens.

24. The use of a hydrogel according to claim 1 for the production of an intraocular lens.

25. A process for the preparation of a hydrogel according to claim 1 by free-radical copolymerization.

26. A process for the preparation of a hydrogel according to claim 6 by free-radical copolymerization and acidic hydrolysis of the hydroxyl-protecting groups.

27. A process for the production of a contact lens essentially comprising a hydrogel according to claim 1 by free-radical copolymerization and subsequent machining in a manner known per se.