CA2005659A1 - Hydrogels based on fluorine-containing and saccharide monomers - Google Patents
Hydrogels based on fluorine-containing and saccharide monomersInfo
- Publication number
- CA2005659A1 CA2005659A1 CA002005659A CA2005659A CA2005659A1 CA 2005659 A1 CA2005659 A1 CA 2005659A1 CA 002005659 A CA002005659 A CA 002005659A CA 2005659 A CA2005659 A CA 2005659A CA 2005659 A1 CA2005659 A1 CA 2005659A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- isopropylidene
- vinyl monomer
- vinyl
- hydrogel according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/22—Esters containing halogen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
- G02B1/041—Lenses
- G02B1/043—Contact lenses
Abstract
V-17364/+/T1T7 Hydrogels based on fluorine-containing saccharide monomers Abstract The invention relates to a hydrogel which is a copolymer of a polymerizable monomer mixture which contains a) 2-85 mol-% of a hydrophobic vinyl monomer with at least three fluorine atoms,b) 2-80 mol-% of a hydrophobic polyhydroxy vinyl monomer whose hydroxyl groups are in protected form, c) 2-70 mol-% of a hydrophilic vinyl monomer and, d) based on the total amount of monomers a)-c), 0-5 mol-% of a crosslinker, in which hydrogel the hydroxyl groups of the segments formed by the monomers b) are in protected or in free form.
These hydrogels can be used, for example, as contact lenses, intraocular lenses or in other areas of application where biologically tolerated materials are required.
These hydrogels can be used, for example, as contact lenses, intraocular lenses or in other areas of application where biologically tolerated materials are required.
Description
5~3 V-17364/~rlT 7 Hydrogels based on fluorine-containing and saccharide monomers The present invention relates to novel hydrogels, processes for the preparation thereof, uses of the hydrogels, for example as contact lenses, intraocular lenses or in other areas of application where biologically tolerated materials are required, as well as abovementioned articles consisting essentially of the novel hydrogels. The novel hydrogels are distinguished by particular advantages relating to, for example, oxygen permeability, water content and mechanical stabili~,r.
It is known that hydrogels ~crosslinked polymers with a limited swellability in water) have an oxygen permeability which depends on the water content. It increases with increasing water content. It is furthermore known that polymers which contain fluorine-containing structural units and those having a structure based on polysiloxanes are distinguished by particularly high oxygen permeabilities. However, the water content of polymers which consist entirely or predominantly of the two last-mentioned groups of substances is low.
The basically desired high oxygen perrneability is normaUy achieved in the knownpolymers at the expense of other serious disadvantages. Thus, hydrogels with a high water content normally have a low mechanical stability such as, for example, tear strength.
Polymers composed of silicones or fluorine-containing materials are highly hydrophobic and, correspondingly, poorly suited for use as, for exarnple, contact lenses.
The present invention provides a remedy for this by disclosing hydrogels which, owing to an appropriate choice of materials, have an extremely beneficial combination of properties. In particular, the oxygen permeability can be influenced both by controlling the fluorine content and by controlling the water content, independently of one another.
The invention relates to a hydrogel which is a copolymer of a polymerizable monomer mixture which contains a) 2-85 moI-% of a hydrophobic vinyl monomer with at least three fluorine atoms,b) 2-80 mol-% of a hydrophobic polyhydroxy vinyl monomer whose hydroxyl groups are in protected form, c) 2-70 mol-%~of a hydrophilic vinyl monomer and, 0~;59 d) based on the total amount of the monomers a)-c), 0-5 mol-% of a crosslinker, in which hydrogel the hydroxyl groups of the segments formed by the monomers b) a-re in protected or in free form.
The hydrophobic vinyl monomer with at least 3 fluorine atoms a) is, in particular, selected from the compounds of the formula I
Rl I
H2c=c-coo(cH2)n(cF2)mcF2x (I) in which Rl is hydrogen or methyl, n is a number from 1 ~o 4, m is a number from 0 to 19, X is hydrogen or fluorine; with the proviso that X is fluorine when m is 0; as well as from hexafluoroisopropyl acrylate, hexafluoroisopropyl methacrylate and 2,3,4,5,6-pentafluoro-styrene. It is possible to use as monomer a) one of the monomers defined above or a mixture of several of these monomers.
The proportion of vinyl monomer a) in the monomer mixture is preferably 10-80 mol-%, particularly preferably 20-60 mol-%, and in a special embodiment 30 mol-%.
Preferred monomers of the formula I are those in which Rl is methyl, n is 1 or 2, m is 1 to 4 and X is fluorine.
Examples of fluorine-containing monomers of the formula I are 2,2,3,3,4,4,4-hepta-fluorobutyl acrylate and methacrylate (also called heptafluoropropyl-methyl acrylate and methacrylate respectively), nonafluorobutyl-methyl and -ethyl acrylate and methacrylate, C6Fl3-methyl and -ethyl acrylate and methacrylate, C8Fl7- and ClOF21-methyl and -ethyl acrylate and methacrylate. 2,2,3,3,4,4,4-Heptafluorobutyl methacrylate (F7BuMA) is particularly preferred.
The polyhydroxy vinyl monomer b) whose hydroxyl groups are in protected form is a vinyl monomer which is derived from a saccharide or a sugar alcohol. It has, in particular, dther forrnula II
Rl H2C=C-COO-R (II) , : -: ` : . ' ' `
:
Z~l)S~;5~
in which Rl is hydrogen or methyl, and R2 is a saccharide residue whose hydro;~yl growps are in protected form, or folmula III
Rl I
H~C=C-COO-C}~2(C~lOH)p-CH20H (III) in which Rl is hydrogen or methyl, p is a number from 1 to 8, and in which the hydroxyl groups are in protected form. It is possible to use as monomer b) one of the monomers defined above or a mixture of several of these monomers.
The proportion of the vinyl monomers b) in the monomer mixture is preferably 10-70 mol-%, particularly preferably 20-60 mol-%, and in a special embodiment 30 mol-%.
The saccharide residues R2 in the vinyl monomers of the formula II are preferably residues of monosaccharides which have 4 to 6 carbon atoms and whose hydroxyl groups are in protected form. Examples of monosaccharides of this type are erythrose, threose,arabinose, ribose, xylose, glucose, mannose, galactose, fructose and sorbose. The configuration of these saccharide residues, for example as furanoside or as pyranoside, is immaterial in this connection.
In the case of the vinyl monomer of the forrnula III which is derived from a sugar alcohol and in which the hydroxyl groups are in protected form, p is preferably a number from 2 to 4. This formula also embraces all conceivable positional isomers. Examples of sugar alcohols from which compounds of the formula III are derived are xylitol, adonitol, arabitol, sorbitol, mannitol or dulcitol.
The hydroxyl groups of the compounds of the formula II and III, which are in protected form, are preferably protected in pairs as acid-labile ketals, for example and preferably as addition products with a ketone. Two hydroxyl groups which are together protected as a ketal are, for example, protected together by means of a preferably substituted methylene group, such as by lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene.
Partlcularly preferred representatives of the vinyl monomers of the formula II are :
,; . , .
51~5~3 3-0-acryloyl-1,2;5,6-di-0-isopropylidene-a-D-(-)-glucofuranose (3-ADPGlu) of theformula IIa (Rl = H), O R
Il I
\C/
H3C \o- H ,0 H (IIa) < ~1 I ~ ~ I ~CH3 H O--C
.~ CH3 l-O-methacryloyl-2,3;4,5-di-0-isopropylidene-,B-D-(-)-fructopyranose (l-MDPFru) of the fonnula IIb (Rl = methyl) and l-O-acryloyl-2,3;4,5-di-0-isopropylidene-,B-D-(-)-fructopyranose (l-ADPFru) of the forrnula IIb (Rl = H), H3C~ ~CH3 H /¦ `.
o~ 11 (llb) CH2--O--C C = CH2 / \ 11 3-0-methacryloyl-di-0-isopropylidene-,~-D-f;uctopyranose (3-MDPFru) (isomer of IIb with Rl = methyl), 3-0-acryloyl-di-0-isopropylidene-,1~-D-fructopyranose (3-ADPFru) (isomer of IIb with Rl = H) as well as l-O-methacryloyl-2,3;4,6-di-0-isopropylidene-a-L-(-)-sorbofuranose (l-MlDPSorb) of the fonnula IIc (Kl = methyl) and , .
.
20~ 5~3 l-O-acryloyl-2,3;4,6-di-0-isopropylidene-oc-L-(-)-sorl~ofuranose (l-ADPSorb) of the formula IIc (Rl = H) C
o /1 H / \¦ O
H2C~ (rlc C
Particularly preferred representatives of the vinyl monomers of the formula III are 5-0-methacryloyl-1,2;3,4-di-0-isopropylidene-DL-xylitol (5-MDPXy) (Rl = methyl) and 5-0-acryloyl-1,2;3,4-di-0-isopropylidene-DL-xylitol (5-ADPXy) (Rl = H) of the formula lIIa O Rl Rl O
Il l l 11 H27-0-C-C=CH2 U2C=C--C-O fH2 H-C-O~ ~CH3 ~C
O-C-H \CH3 N3C --~O (IIIa) H-C O~ ~CH3 H3C~ jO-C-H
H2C- \CH3 H3C/ \O-CH2 The hydrophilic vinyl monomers c) which can be used according to the invention are preferably acrylates and methacrylates of the formula:
: Rl HzC=C-CooR3 :
.
', .
' ~ .
i5 in which Rl is hydrogen or methyl, and R3 iS a hydrocarbon radical which has 1 to 10 carbon atoms and is substituted one or more times by a group which confers solubility in water, such as carboxyl, hydroxyl or tert-amino, for example tert-lower-alkylamino with 1 tO 7 carbon atoms per lower alkyl group, a polyethylene oxide group with 2-100 repeating units, preferably with 2-40 repeating units, or by a sulfate, phosphate, sulfonate or phosphonate group, such as, for example, an appropriately substituted alkyl, cycloalkyl or phenyl radical or a combination of such radicals, such as phenylalkyl or alkylcycloalkyl, as well as from acrylamides and methacrylarnides of the formula H2C=C-CON ~
. Rl R4 in which R4 is hydrogen or C1-C4aL~cyl; acrylamides and methacrylamides of the formula CH2=7-CONHRS
Rl in which Rs has the meaning of R3 or R4; maleates and fumarates of the formula R300C-CH=CH-CooR3;
crotonates of the formula CH3-CH=CH-CooR3;
vinyl ethers of the formula H2C=CH-OR;
vinyl-substituted five- or six-membered heterocycles with one or two nitrogen atoms as well as N-vinyllactams, such as N-vinyl-2-pyrrolidone, and carboxylic acids with vinyl unsaturation and a total of 3 to 10 carbon atoms, such as methacrylic acid, crotonic acid, fumarie acid or cinnamlc aeid.
21~)5~35~
Preferred examples are hydroxyl-substituted C2-C4alkyl (meth)acrylates, five- toseven-membered N-vinyllactams, N,N-di-CI-C~,a~kyl(meth)acrylami~les and carboxylic acids with vinyl unsaturation and a total of 3 to 5 carbon atoms.
The proportion of the vinyl monomer c) in the monomer mixture is preferably 10-60 mol-% and particularly preferably 20-~0 mol-%. It is also possible to use from the monomers c) one of the monomers de~lned above, or a mixture of several of these monomers.
The water-soluble monomers which can be used include: 2-hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, polyethoxyethyl and polyethoxypropyl acrylates and methacrylates as well as the corresponding acrylamides and methacrylamides, acrylamide and methacrylamide, N-methylacrylamide and -methacrylamide, bisacetone-acrylamide, 2-hydroxyethylacrylamide, dimethylacrylamide and -methacrylamide as well as methylolacrylamide and -methacrylamide, N,N-dimethyl- and N,N-diethylaminoethyl acrylate and methacrylate as well as the corresponding acrylamides and methacrylamides, N-tert-butylaminoethyl methacrylate and -methacrylamide, 2- and 4-vinylpyridine, ~- and 2-methyl-5-vinylpyridine, N-methyl-4-vinylpiperidine, l-vinyl- and 2-methyl-1-vinyl-imidazole, dimethylallylamine and methyldiallylamine as well as para- and ortho-aminostyrene, dimethylaminoethyl vinyl ether, N-vinylpyrrolidone and 2-pyrrolidinoethyl methacrylate, acrylic and methacrylic acid, itaconic acid, cinnamic acid, crotonic acid, fumaric acid, maleic acid and their hydroxy-lower-alkyl mono- and diesters such as 2-hydroxyethyl and di-(2-hydroxy)-ethyl fumarate, maleate and itaconate, as well as 3-hydroxypropyl butyl fumarate and di-polyaLIcoxyalkyl fumarates, maleates and itaconates, maleic anhydride, sodium acrylate and methacrylate, 2-methacryloyloxy-ethylsulfonic 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-vinylcaprolactam, as well as the quaternized derivatives of cationic monomers which are obtained by quaternization with selected alkylating agents, for example halogenated hydrocarbons such as methyl iodide, benzyI chloride or hexadecyl chloride, epoxides such as glycidol, epichlorohydlin or ethylene oxide, acrylic acid, dimethyl sulfate, methyl sulfate and propane sultone.
A more complete list o~ water-soluble monomers which can be used in connection with the invenh is to be found In: R.H. Yocum and E.B. Nyquist, Functional Monomers, :
volume 1, pages 424-440 (M. Dekker, N.Y. 1973).
Preferred monomers are 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, N,N-dimethylacrylamide as well as acrylic and methacrylic acid.
Crosslinkers d) are, in particular, diolefinic monomers, ~or example allyl acrylate and methacrylate, diacrylates and dimethacrylates of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and, in general, polyethylene oxide glycol, diacrylates and dimethacrylates of 1,4-butanediol and poly-n-butylene oxide glycol, diacrylates and dimethacrylates of propylene glycol and polypropylene oxide glycol, thiodiethylene glycol diacrylate and dimethacrylate, di-(2-hydroxyethyl) sulfonediacrylate and dimethacrylate, neopentyl glycol diacrylate and dimethacrylate, tri-methylolpropane tri- and tetraacrylate, pentaerythritol tri- and tetraacrylate, divinylbenzene, divinyl ether, divinyl sulfone, disiloxanyl-bis-3-hydroxypropyl diacrylate or methacrylate and related compounds. Ethylene glycol dimethacrylate is preferred.
The crosslinker is, when present, preferably added in amounts of 0.01-1 mol-%, particularly preferably in the amount of 0.2 mol-%, in each case based on the total amount of monomers a) to c).
The hydrogels according to the invention are generated by radical copolymerization either in bulk or in the presence of small amounts of solvent. The polymerization is expediently carried out at elevated temperature, preferably in the presence of an initiator forming free radicals, for example at a temperature in the range from about 30C to about 105C. These initiators are preferably peroxides or azo catalysts with a half-life of at least 20 minutes at the polymerization temperature. Typical examples of peroxy compounds which can be used are isopropyl percarbonate, tert-butyl peroctoate, benzoyl peroxide, lauroyl peroxide, decanoyl peroxide, acetyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert-butyl~peroxyacetate, propionyl peroxide, 2,4-dichlorobenzoyl peroxide1 tert-butyl peroxypivaIate, pelargonyl peroxide, 2,5-dimethyl-2,5-bis-(2-ethylhexanoylperoxy)-hexane, p-chlorobenzoyl peroxide, tert-butyl peroxybutyrate, tert-butylperoxymaleic acid, tert-butylperoxyisopropyl carbonate and bis-(1-hydroxycyclohexyl)-peroxide.
Azo compounds include 2,2-azo-bis-isobutyronitrile, 2,2'-azo-bis-(2,4-dimethylvalero-nitrile)j 1,1'-azo-bis-(cyclohexanecarbonitrile) and 2,2'-azo-bis-(2,4-dimethyl-4-methoxyvaleromtrile). ~
.
~5~
It is also possible in this connection to use other mechanisms forming free rac~icals, suchas radiation with, for example, X-rays, electron beams and UV radiation.
The amount of initiator can vary between 0.002 and 1 mol-% based on components a) to d), but is preferably 0.03 to 0.3 mol-%.
The monomers to be polymerized are expediently puri~led before the polymerization, in particular to remove inhibi,ors with which they are stabilized. Thus, for example, they are washed with suitable dilute aqueous bases such as alkali metal hydroxides, for exarnple sodium hydroxide solution, and purified by distillation under mild temperature conditions.
The polymerization mixtures are polymerized on the laboratory scale in a manner known per se, for example in a cylinder mould, by subjecting them in plastic syringes to a temperature programme in which the temperature is raised stepwise from 30C to about 100C. The steps in temperature can, for example, be between 5 and 10(:, remaining at each temperature for 1 to 5 hours. Two-hour intervals are customary, but it is also possible to maintain individual temperatures for up to 20 hours. Normally, conditioning is carried out at temperatures around 100C for 5 to 20 hours at the end.
.; .
- In order to obtain hydrogels according to the invention, the copolymers obtainable as described above must be hydrated. This is expediently carried out by storage in aqueous buffered sodium chloride solution, which is preferably isotonic. The polymers are normally cut into thin discs before the hydradon.
The hydroxyl groups present in the segments formed by the vinyl monomers b) in the hydrogels described above are still in protected form, for example as isopropylidene ketals. The hydrogels are therefore still relatively strongly hydrophobic. They can be converted~into hydrogels according to the invention, which contain the hydroxyl groups present in the segments formed by the vinyl monomers b) in free form, by eliminating the protective groups. Thl~ can be carried out by introduction into an acid medium, as is generally known for acetal cleavages, for example according to GB 2091750 (Tanaka et al.).
The elimination~ of protective groups makes the segments formed by the vinyl monomers b) hydrophilic or highly hydrophilic. It is possible in this way to increase distinctly the .
--- - ~ , .
, ..
, 0~6S~3 ability of the hydrogels to absorb water. Even after the polymerization the oxygen permeability can be influenced in this way, with the content of fluorine-containirlg monomers and other constituents remaining the same. The hydrogels according to the invention therefore have the advantage that the oxygen permeability can be controlled by two measures which are independent of one another: the content of vinyl monomers a) on the one hand, and the hydrolysis of the hydroxyl protective groups on the vinyl monomer b) on the other hand.
Another surprising aspect of the invention is that hydrophilic monomers c) yield, with the hydrophobic monomers a) and ~he saccharide or sugar alcohol monomers, polymers which in fact have no phase separation either in the unswollen or in the swollen state (hydrogel) and thus are optically clear. This is possible because the monomers a) forrn, with the saccharide monomers which have been rendered hydrophobic by, for example, iso-propylidene protective groups and which are highly hydrophilic without corresponding protective groups, a clear solution which is able to take up the hydrophilic monomers c).
The hydrogels according to the invention have very good oxygen permeabilities and, at the same time, are hydrophilic and, in addition, mechanically stable, i.e. they have, for example, a high tear strength. They are therefore excellendy suited as materials for contact lenses or intraocular lenses as well as other biologically tolerated materials, for example implants, eye bandages, transdermal systems or other forms of medicament carriers.
Contact lenses can be produced from the said hydrogels in a manner known per se. For this purpose, the mixtures to be polymerized are polymerized, for example, in a cylindrical mould and, after removal from the mould, the resulting rods are divided into discs or buttons which can be further processed mechanically. Alternatively, the polymerization can also be carried out in lens moulds so that the polymers are obtained directly as lens blanks.
The reaction is preferably carried out under an inert atmosphere when it takes place in open moulds. It is known that oxygen inhibits the polymerization and results in increased polymerizatian :times. If closed moulds are used to forrn the polymer, the moulds are composed of inert materials with low oxygen permeability and non-stick praperties.
Examples of suitable mould materials are polytetrafluoroethylene, such as Teflon(~, silicone rubber, polyethylene, polypropylene and polyesters such as Mylar(~. When a sultable release~ agent is employed, it is also possible to use moulds made of glass and .
' , . .
0~S~,591 metal.
The mc,nomers which are used are known, some of them can be bought, or they can be prepared by processes known per se.
The examples which follow explain the subject-matter of the invention but without restricting it to the scope of the examples, for instance. When amounts are stated, percentages are molar percentages unless expressly stated otherwise. Temperatures are stated in degrees Celsius.
The abbreviations which are used have the following meanings:
AIBN azoisobutyronitrile EGDM ethylene glycol dimethacrylate F7BuM~A heptafluoropropyl-methyl methacrylate HEMA 2-hydroxyethyl methacrylate VP vinylpyrrolidone With regard tO the abbreviations for the monomers b) which are used, reference may be made to the explanations in connection with formulae II and III.
General information:
F7BuMA (Ventron C~mbH) - stabilized with hydroquinone - VP (Fluka) - stabilized with N,N'-di-sec-butyl-p-phenylenediamine - and HEMA (Rohm GmbH) - stabilized with hydroquinone and hydroquinone monomethyl ether - are freed of inhibitors by the relevant monomer (100 ml amounts) being washed with 3xlO0 ml of 5% sodium hydroxide solution and lxlO0 ml of water, dried over Na2SO~ and then distilled free of inhibitor while avoiding overheating due to the heating bath. The cloudy fore-run (about 10 ml) is discarded. In the case of ~3MA the EGDM content in the initial monomer determined by gas chromatography (a mean of 0.14 mol-%) is taken into account. 1-MDPFru, 1-ADPFru and 1-MDPSorb are available only as syrup, not in crystalline form. Because of their high viscosity at room temperature, it is impossible to carry out weighings as accurately as necessary; for this reason these monomers are weighed at 50C, in which case themeasurement error can be reduced to below 1 mg. Because there is a risk of polymenzation at 50C, the syrupy inhibitor-free monomers are heated in amounts of about 4 g in 10 ml flasks on a hot plate at 50C and directly weighed into a 25 ml .
- . . ~ ~ , -;~00~6~3 Erlenmeyer flask.
Example 1: 4.555 g of HEMA, 4.683 g of F7BuMA, 1.74g g of 5-MDPXy, 13.4 mg of EGDM and, ~Inally, 5.5 mg of AIBN are weighed into a 25 ml Erlenmeyer flask. Thepolymerization mixture is then stirred at 20C for 1 hour until all the crystals in the mixture have completely dissolved. Once a homogeneous liquid mixture has been produced, it is introduced into 10 ml plastic syringes (from Henke-Sass Wolf, Tuttlingen, material: polyethylene and polypropylene, melting point about 140C, internal diameter:
16 mm). The air is forced out, the syringe nozzles are sealed by melting, and the pistons are secured by a wire. The syringes sealed in this way are placed in a waterbath taking care that the surface of the water is always at a higher level than the surface of the monomer mixture in the syringe. Polymerization is now carried out for 2 hours each at 30C, 40C, 50C, 60C and 70C. The post-polymerization of the syringes with their solid contents is then carried out in a drying oven at 80C for 2 hours and then at 90C for 5 hours. The resulting polymers are removed from the syringes and conditioned at 90C
for 8 hours. A cylindrical hard polymer is obtained. The polymer sample is crystal clear and colourless.
Example 2-13: Clear colourless polymers with the compositions indicated in Table la are obtained in an analogous manner.
:
Table la: Composition of polymer samples 1-13 S~nplcF7BuMa 5-MDPXy ~IEMA eGDM AIBN
No.mol% g mol% g mol~ g mol% g mg .
1 30 4.683 10 1.749 60 4.555 0.2 0.0134 5.5 2 30 4.296 20 3.208 50 3.483 0.2 0.0138 5.5 3 30 3.g68 30 4.445 40 2.573 0.2 0.0141 S.5 4 30 3.687 40 5.506 30 1.793 0.2 0.0144 5.5 3.442 50 6A27 20 1.116 0.2 0.0146 5.5 6 30 3.æg 60 7.233 10 0.524 0.2 0.0148 5.5 7 30 3.040 70 7.945 0 0.2 0.0150 5.5 5-ADPXy mol% g 8 30 2.941 30 3.141 40 1.908 0.2 0.0104 4.0 3-ADPGlu mol9'o g 9 30 2.833 30 3.321 40 1.837 0.2 0.0101 4.0 l-MDPFru mol~ g 2.781 30 3.406 40 1.804 0.2 0.0099 4.0 . l-ADPFru mol~b g ;
11 30 2.833 30 3.321 40 1.837 0.2 0.0101 4.0 l-MDPSorb ~ mol~o g 12 30 2.781 30 3.406 40 1.804 0.2 0.0099 4.0 l-ADPSorb mol~o g 13 30 2.833 30 3.321 40 1.837 02 ~ 0~ 4.0 :
Examples 14-36: Bubble-free, clear, colourless polymers with the compositions indicated in Table lb are obtain~d in a manner analogous to Exarnple 1, although the following temperature programme is USPd, unlike Example 1: ;
Polymerization for 15 hours at 30Cj for 2 hours each at 40C, 50C, 60C, for 12 hours at 65C, for 2 hours at 70C, for 2 hours at 80C, for 12 hours at 85C, for 8 hours at 90C
.. ;
:
.
~ . . , : , , ;5~
and for 12 hours at 98~C. After the resulting polymers have been removed from the syringes, conditioning at 98C is carried out for 12 hours.
Table lb: Composition of polymer samples 14-36 Samplc F7BuMa Monosaccharid e HEMA/VP F,GDM
No. mol% g molc~o g mol~o g ~n~ o g 5-MDPXy HEMA
14 10 1.1193 70 8.777 201.0894 0.2 001374 2.266 6C 7.614 201.103 0.2 0.01391 16 40 4.648 40 5.207 201.136 0.2 0.01426 17 50 5.885 30 3.955 201.145 0.2 0.01444 18 60 7.154 20 2.671 201.1~0 0.2 0.01463 19 70 8AS9 10 1.353 201.175 0.2 0.01483 .. 20 80 9.793 0 0.00 201.191 0.2 0.01502 l-MDPFru 21 10 1.042 70 8.931 201.0140 0.2 0.012AS
22 20 2.128 60 7.818 201.039 0.2 0.01306 23 40 4.452 40 5.452 201.084 0.2 0.01365 24 50 5.695 30 4.184 201.108 0.2 0.01397 6.995 20 2.855 201.135 0.2 0.01431 26 70 8.3604 10 1.463 201.162 0.2 0.01466 27 80 9.793 0 0.00 201.191 0.2 0.01502 .
3-MDPFru VP
28 20 2.1621 60 7.9309 200.896 0.2 0.013140 29 30 3.3134 50 6.758~ 20~ 0.916 0.2 0.01632 40 4.5164 40 5.5311 200.9360 0.2 0.01669 31 50 5.7784 30 4.2461 200.9671 0.2 0.01709 32 60 7.1029 20 2.8991 200.9813 0.2 0.017501 33 70 8.4911 10 1.4~57 201.0056 0.2 0.017934 ~ 3-ADPF}u 34 40 4.6155 ~40 SAll 200.9583 0.2 0.017060 ; 5.878530 4.132g 200.9742 0.2 0.017374 36: 60 7.182920 2.807 200.9935 0.2 0.017700 Initiator per sample: 5.5 mg of AIBN
Example 37: HYdration of the polYmer discs The polymers from Examples 1-36 are cut into discs (diameter: 11.5 to 12 mm, thickness:
0.152 to~0.271 mm)~and polished. The diameter Dp, the thickness dp and the weight Gp of the~discs~are determined. Dp is determined wlth a lens with measuring divisions, and dp is determined with a micrometer screw. The polymer discs obtained in this way are stored in : : , aqueous "buffered isotonic sodium chloride solution" (300 mosmol; pH 7.2; 3.04 g of Na2TlPO4 x 2H20, 0.84 g of NaH2PO4 x H20 cmd 8.00 g of NaCI per 11 of s()lution), which is renewed 2x. All the polymer discs appear crystal clear and are harcl after the hydration.
Example 38: Hydrolysis of the polymer discs Based on the method of Tanaka et al. (GB 2091750) the polymer discs from Example 37 are stored in a ~0% aqueous ~ormic acid solution at 20C for 30 minwtes and then in 6N
hydrochloric acid at 50C for 2 hours to eliminate the isopropylidene protective groups.
After the hydrolysis, the discs are placed in 2% aqueous sodium carbonate solution at 20C for 15 minutes and then stored in "buffered isotonic sodium chloride solution" (as in Example 37) at room temperature for 10 days, the solution being renewed 2x. ~part from polymer disc No. 8, all the discs are colourless and crystal clear. With the exception of polymers 1, 2, 9, lO and 12, which are hard, the other polymer discs are soft materials.
The elimination of the isopropylidene protective groups and thus the liberation of the OH
groups on the saccharide molecules by 6N HCl at 20C was studied in detail. The question of whether, under the stated conditions, cleavage of the ester linkage, via which the saccharide unit is bonded to the polymer framework, takes place was also examined thereby.
It is known [T. Tanaka, Spektrum der Wissenschaft 78 (March 1981)], that hydrogels which contain carboxyl groups have a higher water content and a greater linear expansion when transferred from aqueous salt solution into distilled water. Accordingly, the values for the water content and linear expansion ought to increase when the polymer discs are transferred from "buffered isotonic sodium chloride solution" into distilled water. In addition, the IR spectra of these samples (washed salt-free and then dried) ought to contain absorptions for carboxyl and, possibly also, carboxylate groups if ester cleavage has taken place to a considerable extent (sensitivity of IR spectroscopy) during the elimination of protective groups.
Samples nos. 8, 9, 11 and 13 show such an increase in the linear expansion and the I~
absorptions typical of carboxyl groups in the region from 2500 to 2700 cm-l and at 1570 cm~l, whereas the band at 3000 cm-1 cannot be evaluated with certainty owing to the strong CH2 band at 2490 cm-l and the very strong and broad OH band at 3400 cm-l.Nelther an increase in the linear expansion nor the occurrence of IR bands characteristic of "
'. ~, .: ' .
~ , 2~ 59 carboxyl or carboxylate groups was found for polymer samples nos. 1-7, 1() and 12.
The conclusion to be drawn from this is that an ester cleavage of this type occurs with acrylic esters with saccharide units, whereas it is not observed in the case of methacrylates under the hydrolysis conditions employed here.
Example 39: Water content and linear swellin~ of the hydrated polymer discs (unhydro,lysedl Unhydrolysed polymer discs from the previous examples are examined for their water content (H) at 35C after swelling in "buffered isotonic sodium chloride solution" and for their linear expansion (LE~. The values determined are compiled in Table 2. Both the water content and the lillear expansion are overall very low for polymer samples 1-7, and they decrease as the proportion of F7BuMA and of the protected 5-MDPXy increases, which is attributable to the hydrophobic nature of both these monomers. The same applies to polymer samples 8-13, in which the water content is below 2% throughout and the linear expanslon is virtually zero.
.
:
i , . .
.
, , : .
:
Table _ Polymer H [%] L-E [%~
of Example at 35C at 35C
8-13 <2 ~0 14 17.33 1~ 2.19 .~ 16 1.835 19 0.1~3 22 1.92 23 1.49 24 1.04 0.98 26 0.92 27 0.61 28 2.39 29 1.50 1.42 31 1.40 32 1.20 36 1.54 . . _ Example 40: Water content and linear expansion of the hvdrolvsed and swollen polYmer samples Table 3 which follows shows the values for the water content and the linear expansion of the hydrolysed polymer samples, in which the isopropylidene protective groups on the S-MDPXy units (or analogous units) are eliminated. Polymer samples with comparable contents of VP in place of 5-MDPXy have lower values for the water content and the linear expansion. The values for the water content are also given -for commercially available lenses W 38 and WCF,.
:
~ ; " ,,. . ,.' . , . ., 5~t Table 3 Polymer H [%~ LE [%I
of Exampleat 35C at 35C
3 42 17.5 4 50 23.0 54 27.0 6 57 29.5 7 59 30.0 8 45 20.0 11 42 17.0 . 12 35 13 45 19.0 14 79.2 62.6 66.4 40.7 16 40.4 16.9 17 24.3 5.1 18 14.3 2.7 19 4.4 1.7 1.6 0.0 21 89.0 48.7 22 66.9 28.7 23 27.6 0.9 24 15.0 0.9 12.4 0.0 26 6.5 0.0 27 1.6 0.0 28 67.5 21.4 29 52.5 12 2 30.9 4 2 31 10.0 1.3 32 5.1 0.8 33 6.2 0.8 34 48.0 12.2 27.8 5.5 36 10.4 5.0 . _ _ Example 41: Determination of the oxygen pe meabilitY
The measurement is carried out with a Createch Permeometer, model 201 [1032 Neilson St., Californ:ia 94 706) with an Ag anode and Pt cathode by the method of J. Fatt (Am. J.
Optom. and Physiol. Optics, 48,54$ (1971)] at 35C. The electrodes are positioned in a : .
.
.
~Z0~Si65~3 Plexiglass holder. The humidity during the measurements is above 90%.
The va]ues for the oxygen perrneability of the hydrated and hydrolysed polymer discs nos, 1-13 are indicated in Table 4a - expressed as permeation coefficient Po , transmissibility To and oxygen flux J0 . For the purposes of comparison, the values for two commercially available hydrogel materials (W 38 = PolyHEMA crosslinked with EGDM, WCE = copolymer of VP and methyl methacrylate, both Titmus Eurocon GmbH) are included.
able 4b contains the 2' T 2 and J2 values for the hydrated polymer samples nos.
14-20, 22, 23 and 29-36, The saccharide units in these hydrated polymer samples (with water contents which are generally below 2%, see Tab, 2) are in the hydrophobic form with isopropylidene protective groups and contribute only slightly to the oxygenpermeability.
Table 4c contains the values for the oxygen permeability for the hydrolysed polymer samples nos, 14-36 (hydrogels).
' .
, - , . . :
, Table 4a . .. . . ... .. .
Polymer of Po 10-11 To 10-9 Jo Example No. 2 2 2 (hydrated)(hydro- r ml (2) cm l r m1 (2) 1 r 1ll (2) Iysed)L ml s mm(Hg)~L cm2 s mm(Hg)~ L cm2, . _ 1 4.2 1.1 0.6 4 3.8 1.3 0.7 3.4 1.2 0.7 1 6.8 2.6 1.5 2 1 1.9 5.5 3.1 3 17.9 7.3 4.1 4 22.8 8.~ 4.7 . 5 26.4 9.3 5.2 6 28.5 1 1.9 6.6 7 32.0 13.9 7.8 8 20.9 8.1 4.5 9 18.1 7.9 4.4 9.3 4.4 2.5 11 17.3 g.7 5.4 ~2 16.1 6.7 3.7 13 20.1 9.1 5.1 W38 8.3 4.4 2.5 WCE 22.9 _ 6.1 :
~ . . .
:. .
,. ~ , , .
, ,. , ~ .
65~
Table 4b Po 10-1 1 2 2 Sample No.r ml (2) cm2 1 r ml (2) 1 r ~"o2~1 L ml s mm (Hg)~L cm2 s mm (Hg)~ Lcm2, h J
14 5.11 3.01 1.68 8.34 3.9 2.18 16 12.68 5.03 2.80 17 11.86 6.27 3.48 18 14.93 8.03 4.48 19 30.10 13.44 7.50 43.13 26.30 1~.67 22 4.95 2.66 1.48 23 7.79 4.28 2.39 29 6.12 3.5 1~95 8.17 5.79 3.23 31 12.31 6.35 3.54 32 18.51 9.85 4.49 33 24.67 13.78 7.69 34 8il2 4.08 2.27 11.80 6.02 3.36 36 15.96 9.73 5.43 :
:
:~: :
, :
:
:
... , , :
- -.. . . ". . . . .
. i .- .
, ~. ~ , .
Table 4c .. ~ _ .
P~ lo-11To 10-9 Jo 2 Samplo No. 2 r ml (2) ~m ~ ml (2) ~1 (~1 L ml s -mm (Hg) om2 - 5. mm (Hg) cm~ h 4 41.15 19.23 10.73 32.01 14.04 7.83 6 22.67 7.29 4.07 17 16.4 6.84 3.82 18 16.85 7.02 3.92 19 20.2 8.92 9.98 29.8 16.3 9.09 21 40 29.85 16.66 22 32.08 13.77 7.68 23 14.99 7.31 4.08 24C (12.37)(4.78) (2.7~) 25C (15.6)(7.04) (3.93) 26C (21.7)(12.6) (7.03) 27 29.8 16.3 9.09 28 26.09 11.7 6.53 29 21.32 11.34 6.32 11.11 7.17 4.00 31 12.57 6.7 3.73 32 18.05 9.35 5.21 33 27.53 14.27 7.96 34 13.5 11.34 6.32 19.9 9.9 5.52 36 ~2 13.67 7.62 C samples: hydrolysed for only 2 hours Example 42: Ball indentation hardness The polymer discs from some of the preceding examples are converted into sample cylinders (diameter 130 mm, thickness 4.0 mm) by turning and polishing. The ballindentation hardness K is determined using a Zwick apparatus at 23C The sample cylinders of polymer discs nos. 2-7 shattered during the measurement. The K values of the tested polymer discs are compiled in Table 5.
. ~
:~ , , ~: :
: . . . , ::, - .
, ;, ' ' ~' '' ' ' .'ZOO~it~
Table 5 Polymer of K[N/mm2]
Example No. after 30 s after 6û s 15* 127.6 122.0 16* 112.6 106.3 17 112.6 106.3 lB 101.5 97.0 19 84.6 79.8 81.5 77.3 21 182.0 174.0 22 173.5 166.4 23 153.1 147.2 24 143.0 136.7 124.0 112.6 26 96.0 92.3 27 ~1.5 77.3 28* 159.5 29* 153.1 30* 147.2 31** 132.0 127.6 32 127.6 112.6 33 106.3 100.7 34 127.6 123.5 116.0 109.4 36 103.5 98.2 * Samples broken up: 14 before the measurement 15 ~nd 16 after the measurement 28 to 30 affer 60 s * r A crack in the ~iddle after the measurement ::
~: :
, ,, : .
.
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:
'
It is known that hydrogels ~crosslinked polymers with a limited swellability in water) have an oxygen permeability which depends on the water content. It increases with increasing water content. It is furthermore known that polymers which contain fluorine-containing structural units and those having a structure based on polysiloxanes are distinguished by particularly high oxygen permeabilities. However, the water content of polymers which consist entirely or predominantly of the two last-mentioned groups of substances is low.
The basically desired high oxygen perrneability is normaUy achieved in the knownpolymers at the expense of other serious disadvantages. Thus, hydrogels with a high water content normally have a low mechanical stability such as, for example, tear strength.
Polymers composed of silicones or fluorine-containing materials are highly hydrophobic and, correspondingly, poorly suited for use as, for exarnple, contact lenses.
The present invention provides a remedy for this by disclosing hydrogels which, owing to an appropriate choice of materials, have an extremely beneficial combination of properties. In particular, the oxygen permeability can be influenced both by controlling the fluorine content and by controlling the water content, independently of one another.
The invention relates to a hydrogel which is a copolymer of a polymerizable monomer mixture which contains a) 2-85 moI-% of a hydrophobic vinyl monomer with at least three fluorine atoms,b) 2-80 mol-% of a hydrophobic polyhydroxy vinyl monomer whose hydroxyl groups are in protected form, c) 2-70 mol-%~of a hydrophilic vinyl monomer and, 0~;59 d) based on the total amount of the monomers a)-c), 0-5 mol-% of a crosslinker, in which hydrogel the hydroxyl groups of the segments formed by the monomers b) a-re in protected or in free form.
The hydrophobic vinyl monomer with at least 3 fluorine atoms a) is, in particular, selected from the compounds of the formula I
Rl I
H2c=c-coo(cH2)n(cF2)mcF2x (I) in which Rl is hydrogen or methyl, n is a number from 1 ~o 4, m is a number from 0 to 19, X is hydrogen or fluorine; with the proviso that X is fluorine when m is 0; as well as from hexafluoroisopropyl acrylate, hexafluoroisopropyl methacrylate and 2,3,4,5,6-pentafluoro-styrene. It is possible to use as monomer a) one of the monomers defined above or a mixture of several of these monomers.
The proportion of vinyl monomer a) in the monomer mixture is preferably 10-80 mol-%, particularly preferably 20-60 mol-%, and in a special embodiment 30 mol-%.
Preferred monomers of the formula I are those in which Rl is methyl, n is 1 or 2, m is 1 to 4 and X is fluorine.
Examples of fluorine-containing monomers of the formula I are 2,2,3,3,4,4,4-hepta-fluorobutyl acrylate and methacrylate (also called heptafluoropropyl-methyl acrylate and methacrylate respectively), nonafluorobutyl-methyl and -ethyl acrylate and methacrylate, C6Fl3-methyl and -ethyl acrylate and methacrylate, C8Fl7- and ClOF21-methyl and -ethyl acrylate and methacrylate. 2,2,3,3,4,4,4-Heptafluorobutyl methacrylate (F7BuMA) is particularly preferred.
The polyhydroxy vinyl monomer b) whose hydroxyl groups are in protected form is a vinyl monomer which is derived from a saccharide or a sugar alcohol. It has, in particular, dther forrnula II
Rl H2C=C-COO-R (II) , : -: ` : . ' ' `
:
Z~l)S~;5~
in which Rl is hydrogen or methyl, and R2 is a saccharide residue whose hydro;~yl growps are in protected form, or folmula III
Rl I
H~C=C-COO-C}~2(C~lOH)p-CH20H (III) in which Rl is hydrogen or methyl, p is a number from 1 to 8, and in which the hydroxyl groups are in protected form. It is possible to use as monomer b) one of the monomers defined above or a mixture of several of these monomers.
The proportion of the vinyl monomers b) in the monomer mixture is preferably 10-70 mol-%, particularly preferably 20-60 mol-%, and in a special embodiment 30 mol-%.
The saccharide residues R2 in the vinyl monomers of the formula II are preferably residues of monosaccharides which have 4 to 6 carbon atoms and whose hydroxyl groups are in protected form. Examples of monosaccharides of this type are erythrose, threose,arabinose, ribose, xylose, glucose, mannose, galactose, fructose and sorbose. The configuration of these saccharide residues, for example as furanoside or as pyranoside, is immaterial in this connection.
In the case of the vinyl monomer of the forrnula III which is derived from a sugar alcohol and in which the hydroxyl groups are in protected form, p is preferably a number from 2 to 4. This formula also embraces all conceivable positional isomers. Examples of sugar alcohols from which compounds of the formula III are derived are xylitol, adonitol, arabitol, sorbitol, mannitol or dulcitol.
The hydroxyl groups of the compounds of the formula II and III, which are in protected form, are preferably protected in pairs as acid-labile ketals, for example and preferably as addition products with a ketone. Two hydroxyl groups which are together protected as a ketal are, for example, protected together by means of a preferably substituted methylene group, such as by lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene.
Partlcularly preferred representatives of the vinyl monomers of the formula II are :
,; . , .
51~5~3 3-0-acryloyl-1,2;5,6-di-0-isopropylidene-a-D-(-)-glucofuranose (3-ADPGlu) of theformula IIa (Rl = H), O R
Il I
\C/
H3C \o- H ,0 H (IIa) < ~1 I ~ ~ I ~CH3 H O--C
.~ CH3 l-O-methacryloyl-2,3;4,5-di-0-isopropylidene-,B-D-(-)-fructopyranose (l-MDPFru) of the fonnula IIb (Rl = methyl) and l-O-acryloyl-2,3;4,5-di-0-isopropylidene-,B-D-(-)-fructopyranose (l-ADPFru) of the forrnula IIb (Rl = H), H3C~ ~CH3 H /¦ `.
o~ 11 (llb) CH2--O--C C = CH2 / \ 11 3-0-methacryloyl-di-0-isopropylidene-,~-D-f;uctopyranose (3-MDPFru) (isomer of IIb with Rl = methyl), 3-0-acryloyl-di-0-isopropylidene-,1~-D-fructopyranose (3-ADPFru) (isomer of IIb with Rl = H) as well as l-O-methacryloyl-2,3;4,6-di-0-isopropylidene-a-L-(-)-sorbofuranose (l-MlDPSorb) of the fonnula IIc (Kl = methyl) and , .
.
20~ 5~3 l-O-acryloyl-2,3;4,6-di-0-isopropylidene-oc-L-(-)-sorl~ofuranose (l-ADPSorb) of the formula IIc (Rl = H) C
o /1 H / \¦ O
H2C~ (rlc C
Particularly preferred representatives of the vinyl monomers of the formula III are 5-0-methacryloyl-1,2;3,4-di-0-isopropylidene-DL-xylitol (5-MDPXy) (Rl = methyl) and 5-0-acryloyl-1,2;3,4-di-0-isopropylidene-DL-xylitol (5-ADPXy) (Rl = H) of the formula lIIa O Rl Rl O
Il l l 11 H27-0-C-C=CH2 U2C=C--C-O fH2 H-C-O~ ~CH3 ~C
O-C-H \CH3 N3C --~O (IIIa) H-C O~ ~CH3 H3C~ jO-C-H
H2C- \CH3 H3C/ \O-CH2 The hydrophilic vinyl monomers c) which can be used according to the invention are preferably acrylates and methacrylates of the formula:
: Rl HzC=C-CooR3 :
.
', .
' ~ .
i5 in which Rl is hydrogen or methyl, and R3 iS a hydrocarbon radical which has 1 to 10 carbon atoms and is substituted one or more times by a group which confers solubility in water, such as carboxyl, hydroxyl or tert-amino, for example tert-lower-alkylamino with 1 tO 7 carbon atoms per lower alkyl group, a polyethylene oxide group with 2-100 repeating units, preferably with 2-40 repeating units, or by a sulfate, phosphate, sulfonate or phosphonate group, such as, for example, an appropriately substituted alkyl, cycloalkyl or phenyl radical or a combination of such radicals, such as phenylalkyl or alkylcycloalkyl, as well as from acrylamides and methacrylarnides of the formula H2C=C-CON ~
. Rl R4 in which R4 is hydrogen or C1-C4aL~cyl; acrylamides and methacrylamides of the formula CH2=7-CONHRS
Rl in which Rs has the meaning of R3 or R4; maleates and fumarates of the formula R300C-CH=CH-CooR3;
crotonates of the formula CH3-CH=CH-CooR3;
vinyl ethers of the formula H2C=CH-OR;
vinyl-substituted five- or six-membered heterocycles with one or two nitrogen atoms as well as N-vinyllactams, such as N-vinyl-2-pyrrolidone, and carboxylic acids with vinyl unsaturation and a total of 3 to 10 carbon atoms, such as methacrylic acid, crotonic acid, fumarie acid or cinnamlc aeid.
21~)5~35~
Preferred examples are hydroxyl-substituted C2-C4alkyl (meth)acrylates, five- toseven-membered N-vinyllactams, N,N-di-CI-C~,a~kyl(meth)acrylami~les and carboxylic acids with vinyl unsaturation and a total of 3 to 5 carbon atoms.
The proportion of the vinyl monomer c) in the monomer mixture is preferably 10-60 mol-% and particularly preferably 20-~0 mol-%. It is also possible to use from the monomers c) one of the monomers de~lned above, or a mixture of several of these monomers.
The water-soluble monomers which can be used include: 2-hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, polyethoxyethyl and polyethoxypropyl acrylates and methacrylates as well as the corresponding acrylamides and methacrylamides, acrylamide and methacrylamide, N-methylacrylamide and -methacrylamide, bisacetone-acrylamide, 2-hydroxyethylacrylamide, dimethylacrylamide and -methacrylamide as well as methylolacrylamide and -methacrylamide, N,N-dimethyl- and N,N-diethylaminoethyl acrylate and methacrylate as well as the corresponding acrylamides and methacrylamides, N-tert-butylaminoethyl methacrylate and -methacrylamide, 2- and 4-vinylpyridine, ~- and 2-methyl-5-vinylpyridine, N-methyl-4-vinylpiperidine, l-vinyl- and 2-methyl-1-vinyl-imidazole, dimethylallylamine and methyldiallylamine as well as para- and ortho-aminostyrene, dimethylaminoethyl vinyl ether, N-vinylpyrrolidone and 2-pyrrolidinoethyl methacrylate, acrylic and methacrylic acid, itaconic acid, cinnamic acid, crotonic acid, fumaric acid, maleic acid and their hydroxy-lower-alkyl mono- and diesters such as 2-hydroxyethyl and di-(2-hydroxy)-ethyl fumarate, maleate and itaconate, as well as 3-hydroxypropyl butyl fumarate and di-polyaLIcoxyalkyl fumarates, maleates and itaconates, maleic anhydride, sodium acrylate and methacrylate, 2-methacryloyloxy-ethylsulfonic 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-vinylcaprolactam, as well as the quaternized derivatives of cationic monomers which are obtained by quaternization with selected alkylating agents, for example halogenated hydrocarbons such as methyl iodide, benzyI chloride or hexadecyl chloride, epoxides such as glycidol, epichlorohydlin or ethylene oxide, acrylic acid, dimethyl sulfate, methyl sulfate and propane sultone.
A more complete list o~ water-soluble monomers which can be used in connection with the invenh is to be found In: R.H. Yocum and E.B. Nyquist, Functional Monomers, :
volume 1, pages 424-440 (M. Dekker, N.Y. 1973).
Preferred monomers are 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, N,N-dimethylacrylamide as well as acrylic and methacrylic acid.
Crosslinkers d) are, in particular, diolefinic monomers, ~or example allyl acrylate and methacrylate, diacrylates and dimethacrylates of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and, in general, polyethylene oxide glycol, diacrylates and dimethacrylates of 1,4-butanediol and poly-n-butylene oxide glycol, diacrylates and dimethacrylates of propylene glycol and polypropylene oxide glycol, thiodiethylene glycol diacrylate and dimethacrylate, di-(2-hydroxyethyl) sulfonediacrylate and dimethacrylate, neopentyl glycol diacrylate and dimethacrylate, tri-methylolpropane tri- and tetraacrylate, pentaerythritol tri- and tetraacrylate, divinylbenzene, divinyl ether, divinyl sulfone, disiloxanyl-bis-3-hydroxypropyl diacrylate or methacrylate and related compounds. Ethylene glycol dimethacrylate is preferred.
The crosslinker is, when present, preferably added in amounts of 0.01-1 mol-%, particularly preferably in the amount of 0.2 mol-%, in each case based on the total amount of monomers a) to c).
The hydrogels according to the invention are generated by radical copolymerization either in bulk or in the presence of small amounts of solvent. The polymerization is expediently carried out at elevated temperature, preferably in the presence of an initiator forming free radicals, for example at a temperature in the range from about 30C to about 105C. These initiators are preferably peroxides or azo catalysts with a half-life of at least 20 minutes at the polymerization temperature. Typical examples of peroxy compounds which can be used are isopropyl percarbonate, tert-butyl peroctoate, benzoyl peroxide, lauroyl peroxide, decanoyl peroxide, acetyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert-butyl~peroxyacetate, propionyl peroxide, 2,4-dichlorobenzoyl peroxide1 tert-butyl peroxypivaIate, pelargonyl peroxide, 2,5-dimethyl-2,5-bis-(2-ethylhexanoylperoxy)-hexane, p-chlorobenzoyl peroxide, tert-butyl peroxybutyrate, tert-butylperoxymaleic acid, tert-butylperoxyisopropyl carbonate and bis-(1-hydroxycyclohexyl)-peroxide.
Azo compounds include 2,2-azo-bis-isobutyronitrile, 2,2'-azo-bis-(2,4-dimethylvalero-nitrile)j 1,1'-azo-bis-(cyclohexanecarbonitrile) and 2,2'-azo-bis-(2,4-dimethyl-4-methoxyvaleromtrile). ~
.
~5~
It is also possible in this connection to use other mechanisms forming free rac~icals, suchas radiation with, for example, X-rays, electron beams and UV radiation.
The amount of initiator can vary between 0.002 and 1 mol-% based on components a) to d), but is preferably 0.03 to 0.3 mol-%.
The monomers to be polymerized are expediently puri~led before the polymerization, in particular to remove inhibi,ors with which they are stabilized. Thus, for example, they are washed with suitable dilute aqueous bases such as alkali metal hydroxides, for exarnple sodium hydroxide solution, and purified by distillation under mild temperature conditions.
The polymerization mixtures are polymerized on the laboratory scale in a manner known per se, for example in a cylinder mould, by subjecting them in plastic syringes to a temperature programme in which the temperature is raised stepwise from 30C to about 100C. The steps in temperature can, for example, be between 5 and 10(:, remaining at each temperature for 1 to 5 hours. Two-hour intervals are customary, but it is also possible to maintain individual temperatures for up to 20 hours. Normally, conditioning is carried out at temperatures around 100C for 5 to 20 hours at the end.
.; .
- In order to obtain hydrogels according to the invention, the copolymers obtainable as described above must be hydrated. This is expediently carried out by storage in aqueous buffered sodium chloride solution, which is preferably isotonic. The polymers are normally cut into thin discs before the hydradon.
The hydroxyl groups present in the segments formed by the vinyl monomers b) in the hydrogels described above are still in protected form, for example as isopropylidene ketals. The hydrogels are therefore still relatively strongly hydrophobic. They can be converted~into hydrogels according to the invention, which contain the hydroxyl groups present in the segments formed by the vinyl monomers b) in free form, by eliminating the protective groups. Thl~ can be carried out by introduction into an acid medium, as is generally known for acetal cleavages, for example according to GB 2091750 (Tanaka et al.).
The elimination~ of protective groups makes the segments formed by the vinyl monomers b) hydrophilic or highly hydrophilic. It is possible in this way to increase distinctly the .
--- - ~ , .
, ..
, 0~6S~3 ability of the hydrogels to absorb water. Even after the polymerization the oxygen permeability can be influenced in this way, with the content of fluorine-containirlg monomers and other constituents remaining the same. The hydrogels according to the invention therefore have the advantage that the oxygen permeability can be controlled by two measures which are independent of one another: the content of vinyl monomers a) on the one hand, and the hydrolysis of the hydroxyl protective groups on the vinyl monomer b) on the other hand.
Another surprising aspect of the invention is that hydrophilic monomers c) yield, with the hydrophobic monomers a) and ~he saccharide or sugar alcohol monomers, polymers which in fact have no phase separation either in the unswollen or in the swollen state (hydrogel) and thus are optically clear. This is possible because the monomers a) forrn, with the saccharide monomers which have been rendered hydrophobic by, for example, iso-propylidene protective groups and which are highly hydrophilic without corresponding protective groups, a clear solution which is able to take up the hydrophilic monomers c).
The hydrogels according to the invention have very good oxygen permeabilities and, at the same time, are hydrophilic and, in addition, mechanically stable, i.e. they have, for example, a high tear strength. They are therefore excellendy suited as materials for contact lenses or intraocular lenses as well as other biologically tolerated materials, for example implants, eye bandages, transdermal systems or other forms of medicament carriers.
Contact lenses can be produced from the said hydrogels in a manner known per se. For this purpose, the mixtures to be polymerized are polymerized, for example, in a cylindrical mould and, after removal from the mould, the resulting rods are divided into discs or buttons which can be further processed mechanically. Alternatively, the polymerization can also be carried out in lens moulds so that the polymers are obtained directly as lens blanks.
The reaction is preferably carried out under an inert atmosphere when it takes place in open moulds. It is known that oxygen inhibits the polymerization and results in increased polymerizatian :times. If closed moulds are used to forrn the polymer, the moulds are composed of inert materials with low oxygen permeability and non-stick praperties.
Examples of suitable mould materials are polytetrafluoroethylene, such as Teflon(~, silicone rubber, polyethylene, polypropylene and polyesters such as Mylar(~. When a sultable release~ agent is employed, it is also possible to use moulds made of glass and .
' , . .
0~S~,591 metal.
The mc,nomers which are used are known, some of them can be bought, or they can be prepared by processes known per se.
The examples which follow explain the subject-matter of the invention but without restricting it to the scope of the examples, for instance. When amounts are stated, percentages are molar percentages unless expressly stated otherwise. Temperatures are stated in degrees Celsius.
The abbreviations which are used have the following meanings:
AIBN azoisobutyronitrile EGDM ethylene glycol dimethacrylate F7BuM~A heptafluoropropyl-methyl methacrylate HEMA 2-hydroxyethyl methacrylate VP vinylpyrrolidone With regard tO the abbreviations for the monomers b) which are used, reference may be made to the explanations in connection with formulae II and III.
General information:
F7BuMA (Ventron C~mbH) - stabilized with hydroquinone - VP (Fluka) - stabilized with N,N'-di-sec-butyl-p-phenylenediamine - and HEMA (Rohm GmbH) - stabilized with hydroquinone and hydroquinone monomethyl ether - are freed of inhibitors by the relevant monomer (100 ml amounts) being washed with 3xlO0 ml of 5% sodium hydroxide solution and lxlO0 ml of water, dried over Na2SO~ and then distilled free of inhibitor while avoiding overheating due to the heating bath. The cloudy fore-run (about 10 ml) is discarded. In the case of ~3MA the EGDM content in the initial monomer determined by gas chromatography (a mean of 0.14 mol-%) is taken into account. 1-MDPFru, 1-ADPFru and 1-MDPSorb are available only as syrup, not in crystalline form. Because of their high viscosity at room temperature, it is impossible to carry out weighings as accurately as necessary; for this reason these monomers are weighed at 50C, in which case themeasurement error can be reduced to below 1 mg. Because there is a risk of polymenzation at 50C, the syrupy inhibitor-free monomers are heated in amounts of about 4 g in 10 ml flasks on a hot plate at 50C and directly weighed into a 25 ml .
- . . ~ ~ , -;~00~6~3 Erlenmeyer flask.
Example 1: 4.555 g of HEMA, 4.683 g of F7BuMA, 1.74g g of 5-MDPXy, 13.4 mg of EGDM and, ~Inally, 5.5 mg of AIBN are weighed into a 25 ml Erlenmeyer flask. Thepolymerization mixture is then stirred at 20C for 1 hour until all the crystals in the mixture have completely dissolved. Once a homogeneous liquid mixture has been produced, it is introduced into 10 ml plastic syringes (from Henke-Sass Wolf, Tuttlingen, material: polyethylene and polypropylene, melting point about 140C, internal diameter:
16 mm). The air is forced out, the syringe nozzles are sealed by melting, and the pistons are secured by a wire. The syringes sealed in this way are placed in a waterbath taking care that the surface of the water is always at a higher level than the surface of the monomer mixture in the syringe. Polymerization is now carried out for 2 hours each at 30C, 40C, 50C, 60C and 70C. The post-polymerization of the syringes with their solid contents is then carried out in a drying oven at 80C for 2 hours and then at 90C for 5 hours. The resulting polymers are removed from the syringes and conditioned at 90C
for 8 hours. A cylindrical hard polymer is obtained. The polymer sample is crystal clear and colourless.
Example 2-13: Clear colourless polymers with the compositions indicated in Table la are obtained in an analogous manner.
:
Table la: Composition of polymer samples 1-13 S~nplcF7BuMa 5-MDPXy ~IEMA eGDM AIBN
No.mol% g mol% g mol~ g mol% g mg .
1 30 4.683 10 1.749 60 4.555 0.2 0.0134 5.5 2 30 4.296 20 3.208 50 3.483 0.2 0.0138 5.5 3 30 3.g68 30 4.445 40 2.573 0.2 0.0141 S.5 4 30 3.687 40 5.506 30 1.793 0.2 0.0144 5.5 3.442 50 6A27 20 1.116 0.2 0.0146 5.5 6 30 3.æg 60 7.233 10 0.524 0.2 0.0148 5.5 7 30 3.040 70 7.945 0 0.2 0.0150 5.5 5-ADPXy mol% g 8 30 2.941 30 3.141 40 1.908 0.2 0.0104 4.0 3-ADPGlu mol9'o g 9 30 2.833 30 3.321 40 1.837 0.2 0.0101 4.0 l-MDPFru mol~ g 2.781 30 3.406 40 1.804 0.2 0.0099 4.0 . l-ADPFru mol~b g ;
11 30 2.833 30 3.321 40 1.837 0.2 0.0101 4.0 l-MDPSorb ~ mol~o g 12 30 2.781 30 3.406 40 1.804 0.2 0.0099 4.0 l-ADPSorb mol~o g 13 30 2.833 30 3.321 40 1.837 02 ~ 0~ 4.0 :
Examples 14-36: Bubble-free, clear, colourless polymers with the compositions indicated in Table lb are obtain~d in a manner analogous to Exarnple 1, although the following temperature programme is USPd, unlike Example 1: ;
Polymerization for 15 hours at 30Cj for 2 hours each at 40C, 50C, 60C, for 12 hours at 65C, for 2 hours at 70C, for 2 hours at 80C, for 12 hours at 85C, for 8 hours at 90C
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and for 12 hours at 98~C. After the resulting polymers have been removed from the syringes, conditioning at 98C is carried out for 12 hours.
Table lb: Composition of polymer samples 14-36 Samplc F7BuMa Monosaccharid e HEMA/VP F,GDM
No. mol% g molc~o g mol~o g ~n~ o g 5-MDPXy HEMA
14 10 1.1193 70 8.777 201.0894 0.2 001374 2.266 6C 7.614 201.103 0.2 0.01391 16 40 4.648 40 5.207 201.136 0.2 0.01426 17 50 5.885 30 3.955 201.145 0.2 0.01444 18 60 7.154 20 2.671 201.1~0 0.2 0.01463 19 70 8AS9 10 1.353 201.175 0.2 0.01483 .. 20 80 9.793 0 0.00 201.191 0.2 0.01502 l-MDPFru 21 10 1.042 70 8.931 201.0140 0.2 0.012AS
22 20 2.128 60 7.818 201.039 0.2 0.01306 23 40 4.452 40 5.452 201.084 0.2 0.01365 24 50 5.695 30 4.184 201.108 0.2 0.01397 6.995 20 2.855 201.135 0.2 0.01431 26 70 8.3604 10 1.463 201.162 0.2 0.01466 27 80 9.793 0 0.00 201.191 0.2 0.01502 .
3-MDPFru VP
28 20 2.1621 60 7.9309 200.896 0.2 0.013140 29 30 3.3134 50 6.758~ 20~ 0.916 0.2 0.01632 40 4.5164 40 5.5311 200.9360 0.2 0.01669 31 50 5.7784 30 4.2461 200.9671 0.2 0.01709 32 60 7.1029 20 2.8991 200.9813 0.2 0.017501 33 70 8.4911 10 1.4~57 201.0056 0.2 0.017934 ~ 3-ADPF}u 34 40 4.6155 ~40 SAll 200.9583 0.2 0.017060 ; 5.878530 4.132g 200.9742 0.2 0.017374 36: 60 7.182920 2.807 200.9935 0.2 0.017700 Initiator per sample: 5.5 mg of AIBN
Example 37: HYdration of the polYmer discs The polymers from Examples 1-36 are cut into discs (diameter: 11.5 to 12 mm, thickness:
0.152 to~0.271 mm)~and polished. The diameter Dp, the thickness dp and the weight Gp of the~discs~are determined. Dp is determined wlth a lens with measuring divisions, and dp is determined with a micrometer screw. The polymer discs obtained in this way are stored in : : , aqueous "buffered isotonic sodium chloride solution" (300 mosmol; pH 7.2; 3.04 g of Na2TlPO4 x 2H20, 0.84 g of NaH2PO4 x H20 cmd 8.00 g of NaCI per 11 of s()lution), which is renewed 2x. All the polymer discs appear crystal clear and are harcl after the hydration.
Example 38: Hydrolysis of the polymer discs Based on the method of Tanaka et al. (GB 2091750) the polymer discs from Example 37 are stored in a ~0% aqueous ~ormic acid solution at 20C for 30 minwtes and then in 6N
hydrochloric acid at 50C for 2 hours to eliminate the isopropylidene protective groups.
After the hydrolysis, the discs are placed in 2% aqueous sodium carbonate solution at 20C for 15 minutes and then stored in "buffered isotonic sodium chloride solution" (as in Example 37) at room temperature for 10 days, the solution being renewed 2x. ~part from polymer disc No. 8, all the discs are colourless and crystal clear. With the exception of polymers 1, 2, 9, lO and 12, which are hard, the other polymer discs are soft materials.
The elimination of the isopropylidene protective groups and thus the liberation of the OH
groups on the saccharide molecules by 6N HCl at 20C was studied in detail. The question of whether, under the stated conditions, cleavage of the ester linkage, via which the saccharide unit is bonded to the polymer framework, takes place was also examined thereby.
It is known [T. Tanaka, Spektrum der Wissenschaft 78 (March 1981)], that hydrogels which contain carboxyl groups have a higher water content and a greater linear expansion when transferred from aqueous salt solution into distilled water. Accordingly, the values for the water content and linear expansion ought to increase when the polymer discs are transferred from "buffered isotonic sodium chloride solution" into distilled water. In addition, the IR spectra of these samples (washed salt-free and then dried) ought to contain absorptions for carboxyl and, possibly also, carboxylate groups if ester cleavage has taken place to a considerable extent (sensitivity of IR spectroscopy) during the elimination of protective groups.
Samples nos. 8, 9, 11 and 13 show such an increase in the linear expansion and the I~
absorptions typical of carboxyl groups in the region from 2500 to 2700 cm-l and at 1570 cm~l, whereas the band at 3000 cm-1 cannot be evaluated with certainty owing to the strong CH2 band at 2490 cm-l and the very strong and broad OH band at 3400 cm-l.Nelther an increase in the linear expansion nor the occurrence of IR bands characteristic of "
'. ~, .: ' .
~ , 2~ 59 carboxyl or carboxylate groups was found for polymer samples nos. 1-7, 1() and 12.
The conclusion to be drawn from this is that an ester cleavage of this type occurs with acrylic esters with saccharide units, whereas it is not observed in the case of methacrylates under the hydrolysis conditions employed here.
Example 39: Water content and linear swellin~ of the hydrated polymer discs (unhydro,lysedl Unhydrolysed polymer discs from the previous examples are examined for their water content (H) at 35C after swelling in "buffered isotonic sodium chloride solution" and for their linear expansion (LE~. The values determined are compiled in Table 2. Both the water content and the lillear expansion are overall very low for polymer samples 1-7, and they decrease as the proportion of F7BuMA and of the protected 5-MDPXy increases, which is attributable to the hydrophobic nature of both these monomers. The same applies to polymer samples 8-13, in which the water content is below 2% throughout and the linear expanslon is virtually zero.
.
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Table _ Polymer H [%] L-E [%~
of Example at 35C at 35C
8-13 <2 ~0 14 17.33 1~ 2.19 .~ 16 1.835 19 0.1~3 22 1.92 23 1.49 24 1.04 0.98 26 0.92 27 0.61 28 2.39 29 1.50 1.42 31 1.40 32 1.20 36 1.54 . . _ Example 40: Water content and linear expansion of the hvdrolvsed and swollen polYmer samples Table 3 which follows shows the values for the water content and the linear expansion of the hydrolysed polymer samples, in which the isopropylidene protective groups on the S-MDPXy units (or analogous units) are eliminated. Polymer samples with comparable contents of VP in place of 5-MDPXy have lower values for the water content and the linear expansion. The values for the water content are also given -for commercially available lenses W 38 and WCF,.
:
~ ; " ,,. . ,.' . , . ., 5~t Table 3 Polymer H [%~ LE [%I
of Exampleat 35C at 35C
3 42 17.5 4 50 23.0 54 27.0 6 57 29.5 7 59 30.0 8 45 20.0 11 42 17.0 . 12 35 13 45 19.0 14 79.2 62.6 66.4 40.7 16 40.4 16.9 17 24.3 5.1 18 14.3 2.7 19 4.4 1.7 1.6 0.0 21 89.0 48.7 22 66.9 28.7 23 27.6 0.9 24 15.0 0.9 12.4 0.0 26 6.5 0.0 27 1.6 0.0 28 67.5 21.4 29 52.5 12 2 30.9 4 2 31 10.0 1.3 32 5.1 0.8 33 6.2 0.8 34 48.0 12.2 27.8 5.5 36 10.4 5.0 . _ _ Example 41: Determination of the oxygen pe meabilitY
The measurement is carried out with a Createch Permeometer, model 201 [1032 Neilson St., Californ:ia 94 706) with an Ag anode and Pt cathode by the method of J. Fatt (Am. J.
Optom. and Physiol. Optics, 48,54$ (1971)] at 35C. The electrodes are positioned in a : .
.
.
~Z0~Si65~3 Plexiglass holder. The humidity during the measurements is above 90%.
The va]ues for the oxygen perrneability of the hydrated and hydrolysed polymer discs nos, 1-13 are indicated in Table 4a - expressed as permeation coefficient Po , transmissibility To and oxygen flux J0 . For the purposes of comparison, the values for two commercially available hydrogel materials (W 38 = PolyHEMA crosslinked with EGDM, WCE = copolymer of VP and methyl methacrylate, both Titmus Eurocon GmbH) are included.
able 4b contains the 2' T 2 and J2 values for the hydrated polymer samples nos.
14-20, 22, 23 and 29-36, The saccharide units in these hydrated polymer samples (with water contents which are generally below 2%, see Tab, 2) are in the hydrophobic form with isopropylidene protective groups and contribute only slightly to the oxygenpermeability.
Table 4c contains the values for the oxygen permeability for the hydrolysed polymer samples nos, 14-36 (hydrogels).
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, Table 4a . .. . . ... .. .
Polymer of Po 10-11 To 10-9 Jo Example No. 2 2 2 (hydrated)(hydro- r ml (2) cm l r m1 (2) 1 r 1ll (2) Iysed)L ml s mm(Hg)~L cm2 s mm(Hg)~ L cm2, . _ 1 4.2 1.1 0.6 4 3.8 1.3 0.7 3.4 1.2 0.7 1 6.8 2.6 1.5 2 1 1.9 5.5 3.1 3 17.9 7.3 4.1 4 22.8 8.~ 4.7 . 5 26.4 9.3 5.2 6 28.5 1 1.9 6.6 7 32.0 13.9 7.8 8 20.9 8.1 4.5 9 18.1 7.9 4.4 9.3 4.4 2.5 11 17.3 g.7 5.4 ~2 16.1 6.7 3.7 13 20.1 9.1 5.1 W38 8.3 4.4 2.5 WCE 22.9 _ 6.1 :
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Table 4b Po 10-1 1 2 2 Sample No.r ml (2) cm2 1 r ml (2) 1 r ~"o2~1 L ml s mm (Hg)~L cm2 s mm (Hg)~ Lcm2, h J
14 5.11 3.01 1.68 8.34 3.9 2.18 16 12.68 5.03 2.80 17 11.86 6.27 3.48 18 14.93 8.03 4.48 19 30.10 13.44 7.50 43.13 26.30 1~.67 22 4.95 2.66 1.48 23 7.79 4.28 2.39 29 6.12 3.5 1~95 8.17 5.79 3.23 31 12.31 6.35 3.54 32 18.51 9.85 4.49 33 24.67 13.78 7.69 34 8il2 4.08 2.27 11.80 6.02 3.36 36 15.96 9.73 5.43 :
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Table 4c .. ~ _ .
P~ lo-11To 10-9 Jo 2 Samplo No. 2 r ml (2) ~m ~ ml (2) ~1 (~1 L ml s -mm (Hg) om2 - 5. mm (Hg) cm~ h 4 41.15 19.23 10.73 32.01 14.04 7.83 6 22.67 7.29 4.07 17 16.4 6.84 3.82 18 16.85 7.02 3.92 19 20.2 8.92 9.98 29.8 16.3 9.09 21 40 29.85 16.66 22 32.08 13.77 7.68 23 14.99 7.31 4.08 24C (12.37)(4.78) (2.7~) 25C (15.6)(7.04) (3.93) 26C (21.7)(12.6) (7.03) 27 29.8 16.3 9.09 28 26.09 11.7 6.53 29 21.32 11.34 6.32 11.11 7.17 4.00 31 12.57 6.7 3.73 32 18.05 9.35 5.21 33 27.53 14.27 7.96 34 13.5 11.34 6.32 19.9 9.9 5.52 36 ~2 13.67 7.62 C samples: hydrolysed for only 2 hours Example 42: Ball indentation hardness The polymer discs from some of the preceding examples are converted into sample cylinders (diameter 130 mm, thickness 4.0 mm) by turning and polishing. The ballindentation hardness K is determined using a Zwick apparatus at 23C The sample cylinders of polymer discs nos. 2-7 shattered during the measurement. The K values of the tested polymer discs are compiled in Table 5.
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Table 5 Polymer of K[N/mm2]
Example No. after 30 s after 6û s 15* 127.6 122.0 16* 112.6 106.3 17 112.6 106.3 lB 101.5 97.0 19 84.6 79.8 81.5 77.3 21 182.0 174.0 22 173.5 166.4 23 153.1 147.2 24 143.0 136.7 124.0 112.6 26 96.0 92.3 27 ~1.5 77.3 28* 159.5 29* 153.1 30* 147.2 31** 132.0 127.6 32 127.6 112.6 33 106.3 100.7 34 127.6 123.5 116.0 109.4 36 103.5 98.2 * Samples broken up: 14 before the measurement 15 ~nd 16 after the measurement 28 to 30 affer 60 s * r A crack in the ~iddle after the measurement ::
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Claims (25)
1. A hydrogel which is a copolymer of a polymerizable monomer mixture which contains a) 2-85 mol-% of a hydrophobic vinyl monomer with at least three fluorine atoms,b) 2-80 mol-% of a hydrophobic polyhydroxy vinyl monomer whose hydroxyl groups are in protected form, c) 2-70 mol-% of a hydrophilic vinyl monomer and, d) based on the total amount of monomers a)-c), 0-5 mol-% of a crosslinker, in which hydrogel the hydroxyl groups of the segments formed by the monomers b) are in protected or in free form.
2. A hydrogel according to claim 1, wherein the vinyl monomer a) is selected from the compounds of the formula I
(I) in which R1 is hydrogen or methyl, n is a number from 1 to 4, m is a number from 0 to 19, X is hydrogen or fluorine; with the proviso that X is fluorine when m is 0; as well as from hexafluoroisopropyl acrylate, hexafluoroisopropyl methacrylate and 2,3,4,5,6-penta-fluorostyrene.
(I) in which R1 is hydrogen or methyl, n is a number from 1 to 4, m is a number from 0 to 19, X is hydrogen or fluorine; with the proviso that X is fluorine when m is 0; as well as from hexafluoroisopropyl acrylate, hexafluoroisopropyl methacrylate and 2,3,4,5,6-penta-fluorostyrene.
3. A hydrogel according to claim 1, wherein the polyhydloxy vinyl monomer b) whose hydroxyl groups are in protected form is a vinyl monomer which is derived from asaccharide or a sugar alcohol, and has either formula II
(II) in which R1 is hydrogen or methyl, and R2 is a saccharide residue whose hydroxyl groups are in protected form, or formula III
(III) in which R1 is hydrogen or methyl, p is a number from 1 to 8, and in which the hydroxyl groups are in protected form.
(II) in which R1 is hydrogen or methyl, and R2 is a saccharide residue whose hydroxyl groups are in protected form, or formula III
(III) in which R1 is hydrogen or methyl, p is a number from 1 to 8, and in which the hydroxyl groups are in protected form.
4. A hydrogel according to claim 1, wherein the vinyl monomer c) is selected from among acrylates and methacrylates of the formula:
in which R1 is hydrogen or methyl, and R3 is a hydrocarbon radical which has 1 to 10 carbon atoms and is substituted one or more times by a group which confers solubility in water, such as carboxyl, hydroxyl or tert-amino, a polyethylene oxide group with 2-100 repeating units, or by a sulfate, phosphate, sulfonate or phosphonate group, as well as from acrylamides and methacrylamides of the formula in which R4 is hydrogen or C1-C4alkyl; acrylamides and methacrylamides of the formula in which R5 has the meaning of 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-OR3;
vinyl-substituted five- or six-membered heterocycles with one or two nitrogen atoms, especially N-vinyllactams with 4-6 carbon atoms, and carboxylic acids with vinylunsaturation and a total of 3-10 carbon atoms.
in which R1 is hydrogen or methyl, and R3 is a hydrocarbon radical which has 1 to 10 carbon atoms and is substituted one or more times by a group which confers solubility in water, such as carboxyl, hydroxyl or tert-amino, a polyethylene oxide group with 2-100 repeating units, or by a sulfate, phosphate, sulfonate or phosphonate group, as well as from acrylamides and methacrylamides of the formula in which R4 is hydrogen or C1-C4alkyl; acrylamides and methacrylamides of the formula in which R5 has the meaning of 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-OR3;
vinyl-substituted five- or six-membered heterocycles with one or two nitrogen atoms, especially N-vinyllactams with 4-6 carbon atoms, and carboxylic acids with vinylunsaturation and a total of 3-10 carbon atoms.
5. A hydrogel according to claim 1, wherein the vinyl monomer a) is selected from the compounds of the formula I
(I) in which R1 is hydrogen or methyl, n is a number from 1 to 4, m is a number from O to 19, X is hydrogen or fluorine; with the proviso that X is fluorine when m is O; as well as from hexafluoroisopropyl acrylate, hexafluoroisopropyl methacrylate and 2,3,4,5,6-penta-fluorostyrene, the polyhydroxy vinyl monomer b) whose hydroxyl groups are in protected form is a vinyl monomer which is derived from a saccharide or a sugar alcohol, and has either formula II
(II) in which R1 is hydrogen or methyl, and R2 is a saccharide residue whose hydroxyl groups are in protected form, or formula III
(III) in which R1 is hydrogen or methyl, p is a number from 1 to 8, and in which the hydroxyl groups are in protected form and the vinyl monomer c) is selected from acrylates and methacrylates of the formula:
in which R1 is hydrogen or methyl, and R3 is a hydrocarbon radical which has 1 to 10 carbon atoms and is substituted one or more times by a group which confers solubility in water, such as carboxyl, hydroxyl or tert-amino, a polyethylene oxide group with 2-100 repeating units, or by a sulfate, phosphate. sulfonate or phosphonate group, as well as from acrylamides and methacrylamides of the formula in which R4 is hydrogen or C1-C4alkyl; acrylamides and methacrylamides of the formula in which R5 has the meaning of 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-OR3 and N-vinyllactams.
(I) in which R1 is hydrogen or methyl, n is a number from 1 to 4, m is a number from O to 19, X is hydrogen or fluorine; with the proviso that X is fluorine when m is O; as well as from hexafluoroisopropyl acrylate, hexafluoroisopropyl methacrylate and 2,3,4,5,6-penta-fluorostyrene, the polyhydroxy vinyl monomer b) whose hydroxyl groups are in protected form is a vinyl monomer which is derived from a saccharide or a sugar alcohol, and has either formula II
(II) in which R1 is hydrogen or methyl, and R2 is a saccharide residue whose hydroxyl groups are in protected form, or formula III
(III) in which R1 is hydrogen or methyl, p is a number from 1 to 8, and in which the hydroxyl groups are in protected form and the vinyl monomer c) is selected from acrylates and methacrylates of the formula:
in which R1 is hydrogen or methyl, and R3 is a hydrocarbon radical which has 1 to 10 carbon atoms and is substituted one or more times by a group which confers solubility in water, such as carboxyl, hydroxyl or tert-amino, a polyethylene oxide group with 2-100 repeating units, or by a sulfate, phosphate. sulfonate or phosphonate group, as well as from acrylamides and methacrylamides of the formula in which R4 is hydrogen or C1-C4alkyl; acrylamides and methacrylamides of the formula in which R5 has the meaning of 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-OR3 and N-vinyllactams.
6. A hydrogel according to claim 1, in which the hydroxyl groups of the segments formed by the monomers b) are in protected form or partially in protected form.
7. A hydrogel according to claim 1, in which the hydroxyl groups of the segments formed by the monomers b) are in free form.
8. A hydrogel according to claim 1, wherein the monomer mixture contains 10-80 mol-% vinyl monomers a), 10-70 mol-% vinyl monomers b) and 10-60 mol-% vinyl monomers c).
9. A hydrogel according to claim 8, wherein the monomer mixture contains 20-60 mol-% vinyl monomers a), 20-60 mol-% vinyl monomers b) and 20-40 mol-% vinyl monomers c).
10. A hydrogel according to claim 9, wherein the monomer mixture contains 30 mol-%
vinyl monomers a) and/or 30 mol-% vinyl monomers b).
vinyl monomers a) and/or 30 mol-% vinyl monomers b).
11. A hydrogel according to either of claims 2 or 5, wherein the vinyl monomer a) has the formula I in which R1 is methyl, n is 1 or 2, m is 1 to 4, and X is fluorine.
12. A hydrogel according to claim 11, wherein the vinyl monomer a) is 2,2,3,3,4,4,4-heptafluorobutyl methacrylate.
13. A hydrogel according to either of claims 3 or 5, wherein the vinyl monomer b) is a compound of the formula II in which R2 is selected from the residues of the mono-saccharides erythrose, threose, arabinose, ribose, xylose, glucose, mannose, galactose, fructose and sorbose.
14. A hydrogel according to either of claims 3 or 5, wherein the vinyl monomer b) is a compound of the formula III which is derived from a sugar alcohol selected from xylitol, adonitol, arabitol, sorbitol, mannitol and dulcitol.
15. A hydrogel according to either of claims 13 or 14, wherein the vinyl monomer b) is selected from:
3-O-acryloyl-1,2;5,6-di-O-isopropylidene-.alpha.-D-(-)-glucofuranose (3-ADPGlu),1-O-methacryloyl-2,3;4,5-di-O-isopropylidene-,.beta.-D-(-)-fructopyranose (1-MDPFru), 1-O-acryloyl-2,3;4,5-di-O-isopropylidene-.beta.-D (-)-fructopyranose (1-ADPFru),3-O-methacryloyl-di-O-isopropylidene-.beta.-1)-fructopyranose (3-MDPFru), 3-O-acryloyl-di-O-isopropylidene-,.beta.-D-fructopyranose (3-ADPFru), 1-O-methacryloyl-2,3;4,6-di-O-isopropylidene-.alpha.-L-(-)-sorbofuranose (1-MDPSorb), 1-O-acryloyl-2,3;4,6-di-O-isopropylidene-.alpha.-L-(-)- sorbofuranose (1-ADPSorb), 5-O-methacryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-MDPXy) and 5-O-acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-ADPXy).
3-O-acryloyl-1,2;5,6-di-O-isopropylidene-.alpha.-D-(-)-glucofuranose (3-ADPGlu),1-O-methacryloyl-2,3;4,5-di-O-isopropylidene-,.beta.-D-(-)-fructopyranose (1-MDPFru), 1-O-acryloyl-2,3;4,5-di-O-isopropylidene-.beta.-D (-)-fructopyranose (1-ADPFru),3-O-methacryloyl-di-O-isopropylidene-.beta.-1)-fructopyranose (3-MDPFru), 3-O-acryloyl-di-O-isopropylidene-,.beta.-D-fructopyranose (3-ADPFru), 1-O-methacryloyl-2,3;4,6-di-O-isopropylidene-.alpha.-L-(-)-sorbofuranose (1-MDPSorb), 1-O-acryloyl-2,3;4,6-di-O-isopropylidene-.alpha.-L-(-)- sorbofuranose (1-ADPSorb), 5-O-methacryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-MDPXy) and 5-O-acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-ADPXy).
16. A hydrogel according to either of claims 1 or 4, wherein the vinyl monomer c) is selected from hydroxyl-substituted C2-C4alkyl(meth)acrylates, five- to seven-membered N-vinyllactams, N,N-di-C1-C4alkyl (meth)acrylamides and carboxylic acids with vinyl unsaturation and a total of 3 to 5 carbon atoms.
17. A hydrogel according to claim 16, wherein the vinyl monomer c) is selected from 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, N,N-dimethylacrylamide as well as acrylic and methacrylic acid.
18. A hydrogel according to claim 1, wher.alpha.ein the vinyl monomer a) is 2,2,3,3,4,4,4-heptafluorobutyl methacrylate, the vinyl monomer b) is selected from 3-O-acryloyl- 1 ,2;5,6-di-O-isopropylidene-.alpha.-D-(-)-glucofuranose (3-ADPGlu), 1-O-methacryloyl-2,3;4,5-di-O-isopropylidene-.beta.-D-(-)-fructopyranose (1-MDPFru), 1-O-acryloyl-2,3;4,5-di-O-isopropylidene-.beta.-D-(-)-fructopyranose (1-ADPFru),3-O-methacryloyl-di-O-isopropylidene-,.beta.-D-fructopyranose (3-MDPFru), 3-O-acryloyl-di-O-isopropylidene-,.beta.-D-fructopyranose (3-AC)PFru), 1-O-methacryloyl-2,3;4,6-di-O-isopropylidene-.alpha.-L-(-)-sorbofuranose (1-MDPSorb), 1-O-acryloyl-2,3;4,6-di-O-isopropylidene-.alpha.-L-(-)-sorbofuranose (1-ADPSorb), 5-O-methacryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-MDPXy) and 5-O-acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-ADPXy) and the vinyl monomer c) is selected from 2-hydroxyethyl methacrylate and N-vinyl-2-pyrrolidone.
19. A contact lens essentially consisting of a hydrogel according to claim 1.
20. An intraocular lens essentially consisting of a hydrogel according to claim 1.
21. The use of a hydrogel according to claim 1 for the production of a contact lens.
22. The use of a hydrogel according to claim 1 for the production of an intraocular lens.
23. A process for the preparation of a hydrogel according to claim 1 by radical copolymerization.
24. A process according to claim 23 for the preparation of a hydrogel as defined in claim 7 by radical copolymerization and acid hydrolysis of the hydroxyl protective groups.
25. A process for the production of a contact lens essentially consisting of a hydrogel according to claim 1 by radical copolymerization and subsequent mechanical processing in a manner known per se.
FO 7.4/JD/sm*
FO 7.4/JD/sm*
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3842752.4 | 1988-12-19 | ||
| DE3842752 | 1988-12-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2005659A1 true CA2005659A1 (en) | 1990-06-19 |
Family
ID=6369551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002005659A Abandoned CA2005659A1 (en) | 1988-12-19 | 1989-12-15 | Hydrogels based on fluorine-containing and saccharide monomers |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5155194A (en) |
| EP (1) | EP0374752B1 (en) |
| JP (1) | JPH02229814A (en) |
| AT (1) | ATE117699T1 (en) |
| AU (1) | AU631162B2 (en) |
| CA (1) | CA2005659A1 (en) |
| DE (1) | DE58908944D1 (en) |
| DK (1) | DK642189A (en) |
| ES (1) | ES2066834T3 (en) |
| IE (1) | IE64998B1 (en) |
| PT (1) | PT92608B (en) |
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| US5470931A (en) * | 1990-12-07 | 1995-11-28 | Hawaiian Sugar Planters' Association | Thermostable polymers from 1',2',3,3',4,4',6,6'-octa-O-allylsucrose |
| IL109221A (en) * | 1993-04-12 | 1998-04-05 | Johnson & Johnson Vision Prod | Polymeric ophthalmic lens with crosslinker containing saccharide residue |
| US5665840A (en) * | 1994-11-18 | 1997-09-09 | Novartis Corporation | Polymeric networks from water-soluble prepolymers |
| JP2967093B2 (en) * | 1995-02-23 | 1999-10-25 | ホーヤ株式会社 | Flexible intraocular lens |
| US6018001A (en) * | 1997-01-23 | 2000-01-25 | Menicon Co., Ltd. | Process for producing contact lens with hydrophilic surface and contact lens obtained thereby |
| US6018033A (en) * | 1997-05-13 | 2000-01-25 | Purdue Research Foundation | Hydrophilic, hydrophobic, and thermoreversible saccharide gels and forms, and methods for producing same |
| WO1998058686A1 (en) * | 1997-06-24 | 1998-12-30 | SCA Mölnlycke AB | Absorbent polymer material based on renewable starting materials |
| TW494125B (en) | 1997-07-11 | 2002-07-11 | Rohm And Haas Compary | Preparation of fluorinated polymers |
| AU9326598A (en) * | 1997-11-24 | 1999-06-10 | Johnson & Johnson Vision Products, Inc. | Polymeric ophthalmic lens with crosslinker containing saccharide residue |
| US6500481B1 (en) | 1998-06-11 | 2002-12-31 | Johnson & Johnson Vision Care, Inc. | Biomedical devices with amid-containing coatings |
| US6478423B1 (en) | 1999-10-12 | 2002-11-12 | Johnson & Johnson Vison Care, Inc. | Contact lens coating selection and manufacturing process |
| JP2005531648A (en) | 2002-04-11 | 2005-10-20 | カルボマー インク | Biocompatible materials and probes |
| ES2319042B1 (en) * | 2007-05-25 | 2010-02-12 | Universidad Del Pais Vasco | BIOCOMPATIBLE MICROGELS AND ITS APPLICATIONS. |
| DE102008002375A1 (en) | 2008-06-12 | 2009-12-17 | Evonik Röhm Gmbh | Hydrogel based on silicone-containing copolymers |
| WO2011079380A1 (en) | 2009-12-30 | 2011-07-07 | Axcelon Biopolymers Corporation | Transparent bacterial cellulose nanocomposite hydrogels |
| TWI707926B (en) | 2010-07-30 | 2020-10-21 | 瑞士商愛爾康公司 | Readily-usable silicone hydrogel contact lenses |
| JP6017572B2 (en) | 2011-10-12 | 2016-11-02 | ノバルティス アーゲー | Method for producing UV-absorbing ophthalmic lens by coating |
| ES2798109T3 (en) * | 2012-01-25 | 2020-12-09 | Univ Akron | Polymerizable fluorinated hydrogels for wound dressings and procedures for making them |
| WO2014095690A1 (en) | 2012-12-17 | 2014-06-26 | Novartis Ag | Method for making improved uv-absorbing ophthalmic lenses |
| US9708087B2 (en) | 2013-12-17 | 2017-07-18 | Novartis Ag | Silicone hydrogel lens with a crosslinked hydrophilic coating |
| EP3186070B1 (en) | 2014-08-26 | 2019-09-25 | Novartis AG | Method for applying stable coating on silicone hydrogel contact lenses |
| EP3391101B1 (en) | 2015-12-15 | 2020-07-08 | Alcon Inc. | Method for applying stable coating on silicone hydrogel contact lenses |
| WO2017188373A1 (en) * | 2016-04-28 | 2017-11-02 | 日油株式会社 | Polyoxyethylene compound having multiple hydroxyl groups at end, and contact lens |
| US11029446B2 (en) | 2017-12-13 | 2021-06-08 | Alcon Inc. | Method for producing MPS-compatible water gradient contact lenses |
| CN114989344B (en) * | 2022-06-14 | 2023-09-19 | 万华化学集团股份有限公司 | Vinylidene fluoride copolymer, preparation method thereof and application thereof in lithium ion battery |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3654244A (en) * | 1970-03-16 | 1972-04-04 | Us Agriculture | Polymers for soil-release textile finishes |
| US3808179A (en) * | 1972-06-16 | 1974-04-30 | Polycon Laboratories | Oxygen-permeable contact lens composition,methods and article of manufacture |
| US3989656A (en) * | 1972-07-06 | 1976-11-02 | Karme Company Ltd. | Dextran-alkyl methacrylate graft composition for contact lens and corneas |
| JPS543738B2 (en) * | 1974-05-27 | 1979-02-26 | ||
| US4130706A (en) * | 1977-08-08 | 1978-12-19 | E. I. Du Pont De Nemours And Company | Hydrophilic, oxygen permeable contact lens |
| CA1187645A (en) * | 1981-01-12 | 1985-05-21 | Kyoichi Tanaka | Contact lens and process for preparing the same |
| CA1182614A (en) * | 1981-05-01 | 1985-02-19 | Kyoichi Tanaka | Contact lens and process for preparing the same |
| JPS5817412A (en) * | 1981-07-24 | 1983-02-01 | Toyo Contact Lens Co Ltd | Manufacture of hard contact lens having hydrophilic surface |
| EP0100381B1 (en) * | 1982-07-30 | 1986-09-17 | Hoya Corporation | Soft contact lens |
| US4638040A (en) * | 1983-06-03 | 1987-01-20 | Minnesota Mining And Manufacturing Company | Acrylate and methacrylate monomers and polymers |
| GB8422950D0 (en) * | 1984-09-11 | 1984-10-17 | Warne K J | Hydrogel |
| JPS61126052A (en) * | 1984-11-20 | 1986-06-13 | Green Cross Corp:The | Fluorine-containing methacrylic acid ester |
| ATE127592T1 (en) * | 1984-12-18 | 1995-09-15 | Tr Dev Ltd | HYDROGEL-FORMING POLYMERS. |
| JPS62123425A (en) * | 1985-08-02 | 1987-06-04 | Sharp Corp | Liquid crystal display element |
| US4686267A (en) * | 1985-10-11 | 1987-08-11 | Polymer Technology Corporation | Fluorine containing polymeric compositions useful in contact lenses |
| US4996275A (en) * | 1985-10-11 | 1991-02-26 | Polymer Technology Corporation | Fluorine containing polymeric compositions useful in contact lenses |
| JPH0629918B2 (en) * | 1986-03-03 | 1994-04-20 | 株式会社サンコンタクトレンズ | Oxygen permeable contact lens material |
| US4990582A (en) * | 1986-07-18 | 1991-02-05 | Salamone Joseph C | Fluorine containing soft contact lens hydrogels |
| WO1988005060A1 (en) * | 1987-01-07 | 1988-07-14 | Chang Sing Hsiung | Wettable, hydrophilic, soft and oxygen permeable copolymer compositions |
| AU618817B2 (en) * | 1988-07-05 | 1992-01-09 | Novartis Ag | Dimethylacrylamide-copolymer hydrogels with high oxygen permeability |
-
1989
- 1989-12-15 AT AT89123225T patent/ATE117699T1/en not_active IP Right Cessation
- 1989-12-15 DE DE58908944T patent/DE58908944D1/en not_active Expired - Fee Related
- 1989-12-15 ES ES89123225T patent/ES2066834T3/en not_active Expired - Lifetime
- 1989-12-15 AU AU46876/89A patent/AU631162B2/en not_active Ceased
- 1989-12-15 CA CA002005659A patent/CA2005659A1/en not_active Abandoned
- 1989-12-15 EP EP89123225A patent/EP0374752B1/en not_active Expired - Lifetime
- 1989-12-18 DK DK642189A patent/DK642189A/en not_active Application Discontinuation
- 1989-12-18 PT PT92608A patent/PT92608B/en not_active IP Right Cessation
- 1989-12-18 IE IE406689A patent/IE64998B1/en not_active IP Right Cessation
- 1989-12-19 JP JP1327482A patent/JPH02229814A/en active Pending
-
1991
- 1991-05-20 US US07/704,653 patent/US5155194A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0374752B1 (en) | 1995-01-25 |
| JPH02229814A (en) | 1990-09-12 |
| AU4687689A (en) | 1990-06-21 |
| DK642189D0 (en) | 1989-12-18 |
| DK642189A (en) | 1990-06-20 |
| ATE117699T1 (en) | 1995-02-15 |
| IE64998B1 (en) | 1995-10-04 |
| EP0374752A2 (en) | 1990-06-27 |
| PT92608A (en) | 1990-06-29 |
| DE58908944D1 (en) | 1995-03-09 |
| US5155194A (en) | 1992-10-13 |
| IE894066L (en) | 1990-06-19 |
| ES2066834T3 (en) | 1995-03-16 |
| PT92608B (en) | 1995-09-12 |
| EP0374752A3 (en) | 1991-08-28 |
| AU631162B2 (en) | 1992-11-19 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |