AU1740792A

AU1740792A - Polymer coatings

Info

Publication number: AU1740792A
Application number: AU17407/92A
Authority: AU
Inventors: Ajay Kumar Luthra; Shivpal Singh Sandhu
Original assignee: BioInteractions Ltd
Current assignee: BioInteractions Ltd
Priority date: 1991-06-27
Filing date: 1992-05-18
Publication date: 1993-01-25
Also published as: GB9113875D0; GB9325786D0; WO1993000391A1; EP0591233A1; GB2273102A; JPH06508645A

Description

POLYMER COATINGS

This invention relates to the field of polymer coatings. More specifically, it is concerned with coating polymers on to substrates, and embraces methods of coating substrates with polymers, substrates which have been coated by means of the invention, and such coated substrates in the form of contact lenses for the human (or indeed mammalian) eye. Furthermore, to the extent that classes of coating polymer disclosed herein are novel, they and the methods of making them are also within the.scope of the invention.

In principle, contact lenses can be made from a wide variety of materials, provided that they meet the necessary requirements for optical clarity, formability and shape stability, non-irritation to the eye, and so on. In practice, contact lenses tend to be made from certain presently preferred materials, including polymers of hydroxyethylmethacrylate (HEMA) and N-vinylpyrrolidone. While these polymerised monomers may make up the bulk of the lens material, say 98%, small amounts of cross-linking agents, such as 2% of ethyl dimethacrylate and 2% of methacrylic acid, may be copolymerised. The lens structure includes voids which are occupied with water, which may make up from typically 38%, up to 60 or 70%, of the total lens weight.

Hydrophilic contact lenses display an affinity for tear calcium and proteins, especially lysozyme, amino acids and glycoproteins, and these readily adhere to the lens surface. It is generally known and accepted that such deposits on contact lenses may cause a decrease in wearing comfort leading to a corresponding decrease in wearing time. Deposits may cause patient's eyes to become infected and it is not uncommon for a subsequent decrease in visual acuity to occur. Several contact lens care systems have been devised and used for cleaning and disinfecting lenses. Contact lenses with deposits resulting from tear ingredients are usually cleaned with a surfactant cleaner on a daily basis. Soft contact lenses are cleaned additionally with an enzymatic cleaner to remove protein deposits thoroughly. However, even when contact lenses are repeatedly put on and taken off over a period of several months, tear components are sometimes absorbed/adsorbed on the contact lens surface despite use of cleaners.

Soft and hard contact lenses carrying an anionic charge can be co plexed with polymers bearing a cationic charge to form a polyelectrolyte complex which reduces the tendency for tear proteins to adhere to a lens surface. However, the interaction between the cationic polymer and the anionic surface of the lens is generally weak, and dissipation of the cationic polymer occurs rapidly in most prior art constructions. As a result, tear proteins are deposited on the lens, and the wearer begins to feel discomfort and must clean the contact lens before rewetting the lens surface with the cationic polymer to form another protective polyelectrolyte complex.

It is an object of this invention to provide the lens surfaces of soft and hard contact lenses, and other substrates, with polymer coatings which are chemically bonded thereto.

In one aspect the invention provides a method of coating a polymeric substrate having functional groups in the substrate polymer chain at surface portions thereof which comprises reacting said functional groups with complementary functional groups on a hydrophilic coating polymer in a predominantly aqueous medium to form covalent linkages between the coating polymer and the substrate polymer. The conditions should be such as to avoid degradation of either polymer.

The coating polymer may be in solution or dispersion in the aqueous reaction medium. The substrate polymer may advantageously be a hydrogel, that is to say a gel in which the liquid is water. The coating formed on the substrate polymer is also preferably a hydrogel. The coating is desirably continuous. 5

In a specific embodiment, the invention provides a method of rendering a contact lens that has functional groups (most suitably hydroxyl, carboxyl, amide, amino and sulphonate groups) more compatible with the eye by covalently bonding a polymer to the 0 surface of the lens, which enhances the hydrophilic character of the lens for a longer time relative to an untreated surface, and which reduces the tendency for tear proteins to adhere to the lens surface. The preferred coating polymers are those that form a covalently bound hydrogel at the lens surface, which absorbs water, ^{i 5} his good water retention and is compatible with the physiological structure of the eye. Desirably, a durable protective coating is formed which provides long lasting comfort to the eye. The most suitable coatings are hydrophilic and are more resistant to protein deposition than the substrate polymer. Desirable coatings also 20 reduce the deposition of lipids and of ions, such as calcium ions.

The invention also extends, in another aspect, to a substrate polymer coated by the foregoing method, and in particular to a contact lens so coated.

^5

The invention accordingly provides a contact lens, which may comprise a soft or hard contact lens polymer, synthetic or natural, forming the corrective optical element of the lens, having a coating suitable for use in the human eye, wherein the coating 0 comprises a polymer that is covalently bonded to the surface of the lens polymer, thus forming a thin protective layer or coating covalently linked to the lens surface.

In a preferred embodiment a soft or hard contact lens comprises a 5 polymer containing functional groups such as hydroxyl, carboxyl, amide, amino or sulphonic acid, on to which the polymer coating can be chemically bonded. The functional groups may carry an ionic charge or may have the potential of carrying an ionic charge, for example ions formally derivable by the gain or loss of a proton or electron, or equivalent. Accordingly, references to carboxyl ^•groups and to sulphonic acid groups include carboxylate and sulphonate anions, for example.

Examples of suitable substrate materials include the following polymers with surface functional groups.

Soft hydrophilic contact lens polymer substrates may be crosslinked hydroxyethylmethacrylate (HEMA), crosslinked HEMA and methacrylic acid, and crosslinked HEMA and N-vinylpyrrolidone.

Contact lenses made from natural polymers include cellulose acetate butyrate polymers (retaining free hydroxyl groups).

Contact lenses made from synthetic polymers include polyvinyl alcohol (retaining free hydroxyl groups).

Examples of oxygen permeable hard contact lens polymer substrates include polyfluoroacrylate, polysiloxanyl acrylate and methacrylate polymers, which carry an ionic charge, or retain free hydroxyl groups.

The invention does however extend to the coating of many other polymer substrates with suitable surface functional groups, including those used as contact lens materials, as are well known in the art.

Surprisingly a range of water soluble hydrophilic polymers when covalently bonded to the surface of soft or hard contact lenses provide a hydrophilic surface which reduces the tendency for tear proteins to adhere to a lens surface. These water soluble hydrophilic polymers can be non-ionic and cationic synthetic or natural polymers. Preferred types of covalent bonding between the respective functional groups on the substrate polymer and the coating polymer include, but are not limited to, carbonate bonding with hydroxyl functional groups on the substrate, ester bonding with carboxyl groups, urethane bonding with amino groups, sulphonic ester bonding with sulphonic acid groups, ether or ester linkages with epoxide groups, urea with hydroxyl groups to form carbamate ester and urea with lens surface carboxyl groups to form acyl carbamate, and amide bonding between an amine and lens carboxyl groups. The reactions between the respective functional groups have as a comnon feature that they all take place in aqueous media under relatively mild conditions to bind the coating polymer to the substrate surface without degrading either polymer.

Other examples of covalent bonding between functional groups on the respective polymers, in accordance with the invention, include amide, urea, allophanate, biuret, acyl urea and carbodiimide linkages.

Hydrophilic synthetic non-ionic polymers useful as the covalently bound coating polymer include homopolymers, copolymers and graft copolymers of polyvinylalcohol (PVA), homopolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO), copolymers of poly¬ ethylene oxide and polypropylene oxide, and graft copolymers of siloxanes and polyethylene oxide or polypropylene oxide. Hydro¬ philic natural polymers useful as the covalently bound coating polymer include homopolymers, copolymers and graft copolymers of cellulose and its derivatives, chitin and chitosan. The following examples of different kinds of polymer are suitable as the coating agent to be covalently bound to the substrate.

Polyvinyl alcohol (PVA) can be covalently bonded to the surface of soft and oxygen permeable hard contact lens to provide a permanent hydrophilic coating which reduces the tendency for tear proteins to adhere to the lens surface. PVA can be covalently bonded to the surface of a contact lens using conventional water soluble coupling agents or by linking epoxide functionalities on PVA by which it can then be linked to the lens surface.

PVA can be grafted with polyethylene oxide (PEO) or polypropylene oxide (PPO) or a mixture of the two. The graft copolymers can then be covalently bonded to the lens surface using conventional chemistry. In the practice of the invention, PEO and PPO may have the structures shown in Formulae (1) and (2) below :

(1) X-(CH2-CH₂-0)_nCH₂-CH2-Y (PEO)

(2) X-(CH₂-CH-0)_nCH₂-CH-Y (PPO)

CH, CH-

where both X and Y can be -OH, -0-CH₂-CH(NH₂)-CH₃, -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6, ie including -O-CO-NH2), -C00H, epoxide, H₂C=CH-C0-0- (acrylate), H₂C=C(CH₃)-C0-0- (methacrylate), -0CH₃, -OC2H5, propoxy, butoxy and allyloxy. Compounds in which at least o e of X and Y is -0-C0-(CH2)_n-NH2 are novel. r

It is to to be understood that having regard to the inherent asymmetry of PPO (2), the respective terminal X and Y groups can be interchanged in Formula (2).

Molecular weights of (1) and (2) can vary from less than 100 up to 20,000.

Suitable graft copolymers of PVA and PEO, and of PVA and PPO, can also be achieved by reacting PVA with ethylene oxide and propylene oxide respectively, or with a mixture of ethylene oxide and propylene oxide to obtain PVA graft copolymer containing both PEO and PPO. Alternatively instead of ethylene oxide and propylene oxide, ethylene carbonate and propylene carbonate can be used to achieve the same result. The above graft copolymers can then be covalently bonded to the lens surface using conventional chemistry. Polydimethylsiloxanes can be grafted with (1) or (2) or both through a hydrosilation reaction to form a coating polymer. In (1) and (2), X may be acrylate or methacrylate and Y can be OH, epoxide, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂ (where n is from 0 5 to 6).

In addition to (1) and (2) being grafted on to polydimethyl- siloxanes, glycidyl acrylates (GA), glycidyl methacylates (GM), epoxypropyl acrylate (EPA) and epoxypropyl methacrylate (EPM) may 10 also be grafted, to form a range of novel coating polymers.

The novel polydimethylsiloxane graft copolymers have the following general formula:

(CH₃)₃SiO-f((CH₃)₂SiO)_χ-(CH₃SiO)_y ^■S1(CH₃)₃ LPEO/PPO/GA/GM/EPA/EPM_ n

The coefficients x, y and n can vary to give molecular weights in a broad range of 3000 to 100,000.

The above water soluble hydrophilic polymers may be covalently bonded to the lens surface using conventional chemistry.

Ethylene oxide and propylene oxide can react with cellulose to ²⁵ produce graft copolymers of PEO-cellulose and PPO-cellulose, or a mixture of ethylene oxide and propylene oxide may be used to give PEO/PPO-cellulose graft copolymer. The same result can also be achieved by using ethylene carbonate and propylene carbonate. Analoαous results are achieved with hydroxyethyl cellulose in place ³⁰ of c€ lose

Alternatively, (1) and (2) can be grafted on to hydroxyethyl- cellulose and then covalently bonded to the surface of the contact lens.

35 Hydroxyethyl cellulose can also have epoxide functionalities through which it can be covalently bonded using conventional water soluble coupling agents.

5 Chitin and chitosan can also be grafted with PEO and PPO using ethylene oxide and propylene oxide or a mixture of both to form a further range of novel coating polymers. The graft copolymers may then be covalently bonded to the lens surface.

10 Soft and oxygen permeable hard contact lenses can also be made more resistant to tear protein deposition by directly polymerising ethylene oxide or propylene oxide or a mixture of the two on to the contact lens. Alternatively, PEO and/or PPO may be grafted directly on to the lens surface. The same results can be achieved 5 by using ethylene carbonate and/or propylene carbonate instead of ethylene and propylene oxides.

Homopolymers of (1) and (2) can also be used to covalently bond to the contact lens surface to provide a hydrophilic coating which 0 reduces the tendency of tear proteins to deposit on to the lens surface.

For such homopolymers of (1) and (2), X can be either acrylate or methacrylate and Y can be OH, COOH, epoxide, 0CH , OC2H5, propoxy, 5 butoxy, allyloxy, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6).

In (1) and (2), the presence of the vinyl double bond when X is acrylate or methacrylate enables the molecule to be homopolymerised ® to produce polymers with pendant OH, COOH, epoxide, 0CH₃, OC2H5, propoxy, butoxy, allyloxy, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂, or a mixture of pendant groups. For example, if (1) in which X is acrylate and Y is OH is polymerised then all pendant groups will be OH. However, if it is polymerised with another molecule, where X is the same but Y is an epoxide or any of the other pendant groups, then a mixture of two pendant groups is achieved. The mixture need not be limited to a mixture of two pendant groups, but can be more than two.

Similarly (1) and (2) can be copolymerised when X is either methacrylate or acrylate and Y for both (1) and (2) can be the same or different groups.

Both (1) and (2) can also be copolymerised with a variety of unsaturated monomers when X for (1) and (2) is either methacrylate or acrylate and Y can be any of OH, COOH, epoxide, 0CH₃, OC2H5, propoxy, butoxy, allyloxy, -0-CH2-CH(NH )-CH₃, and -0-C0-(CH )_n-NH2. Suitable unsaturated monomers for co- polymerisation include vinylene carbonate, hydroxyethylmethacry¬ late, hydroxypropylmethacrylate, hydroxyethyl acrylate, hydroxypropylacryl te, n-vinylpyrrolidone, acrylamide, hydroxybutylacrylate, hydroxybutylmethacrylate, butylacrylamide, dihydroxypropylacrylate, dihydroxypropylmethacrylate, epoxypropyl- acrylate, epoxypropylmethacrylate, glycidyl acrylate, glycidyl methacrylate, and hydroxypropylmethacrylamide.

Synthetic cationic polymers which can be covalently bonded to the lens surface include cationic PVA, and copolymers of polyethylene oxide and polypropylene oxide. In such copolymers, with reference to Formulae (1) and (2), X may be acrylate or methacrylate and Y can be OH, epoxide, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6). (1) and (2) can then be copolymerised with :

(a) (1) or (2) where X is acrylate or methacrylate Y can be

(b) other cationic polymerisable monomers which include : dimethylaminoethyl acrylate and methacrylate, 2-methacryloyl- oxyethyltrimethylammonium chloride, 3-methacτylamidopropyl di ethylamine, 3-methacrylamidopropyl trimethylammonium chloride, 1-vinyl and 2-methyl 1-vinylimidazole, 3-acrylamido-3-methylbutyl- dimethylamine, 3-acrylamido-3-methylbutyl trimethylammonium chloride, N-(3-methacryloyloxy-2-hydroxypropyl) trimethylammonium chloride, diallyldimethylammonium chloride and methylsulphate, vinylbenzyltrimethylammonium chloride.

In addition to the grafting species for polydi ethylsiloxanes given earlier for the covalent linkage of non-ionic graft copolymers of polydimethylsiloxanes to the substrate polymer, all grafting monomers given in (a) and (b) above may also be used to provide cationic graft copolymers of polydimethylsiloxanes.

Cationic natural polymers which may be covalently bonded to a substrate such as a lens surface include cationic cellulose and chitosan.

The invention 1s further illustrated in the following examples.

Example 1

Coating a substrate with PVA-PEO graft copoly er - Formula (1 ), X and Y both OH. Molecular weight ca. 600.

14g PEO was dissolved in anhydrous acetone. 3.3g carbonyl diimidazole (CDI) was also dissolved in anhydrous acetone and placed in a dry dropping funnel. The CDI was added dropwise to the PEO over a period of one hour. The solution was left to stir for a further one hour after which the acetone was evaporated off under reduced pressure.

3g PVA (25,000 M.Wt) was dissolved in 40mM potassium bicarbonate buffer (pH 8.5) with boiling. When the solution had cooled, CDI-activated PEO was added and the mixture was magnetically stirred for twenty-four hours. The solution was next dialysed for twenty-four hours, then the resultant PVA-PEO graft copolymer was freeze dried.

The copolymer was dissolved in anhydrous dimethylsulphoxide (DMSO). 5 CDI (3.3g) was dissolved in DMSO and added dropwise over a period of one hour. The solution was further stirred for one hour before the DMSO was distilled off under reduced pressure.

Three high water content contact lenses of polyhydroxyethyl- 0 methacrylate (polyHEMA) containing methacrylic acid were washed in water and each of them placed in 5ml of potassium bicarbonate buffer (40mM, pH 8.5). To each of the lenses 150mg of CDI- actlvated PVA-PEO graft copolymer was added and left for twenty- four hours. PVA-PEO graft copolymer was linked to the surface via 5 carbonate bonds to surface OH groups and via ester bonds to surface COOH groups. The contact lenses were removed, washed in water and placed in phosphate buffered saline (PBS) (lOmM, pH 7.4).

Protein absorption studies _Λ

Analysis of protein film deposits on the lenses after human wear indicate that the film consists primarily of denatured lysozyme. Since lysozyme comprises only 18 per cent of the total tear proteins, it appears to be selectively absorbed and denatured on 5 the surfaces of soft hydrophilic lenses.

Lysozyme absorption studies were carried out by incubating the lens in 5ml of lysozyme solution for approximately twenty-four hours. 0.05% w/v lysozyme was dissolved in PBS. After twenty-four hours ⁰ the lysozyme solution was measured spectrophotometrically at 281.6nm. Control solutions contained untreated contact lenses.

The results showed that there was a 90% reduction in lysozyme absorption when compared against the untreated lenses. 5 Exa ple 2

Coating a substrate with PVA-PEO graft copolymer - Formula (1), X is OH and Y -0CH₃. PEO molecular weight ranged from 300 to 5000.

As in Example 1, the PEO was activated with CDI (mole ratio 1:1) in acetone and reacted with PVA in 40mM potassium bicarbonate buffer (pH 8.5) for twenty-four hours. The solution was next dialysed for twenty-four hours, then the resultant PVA-PEO graft copolymer was freeze dried.

The copolymer was dissolved in anhydrous acetone. CDI (3.3g) was dissolved in acetone and added dropwise over a period of one hour. The solution was further stirred for one hour before the acetone was distilled off under reduced pressure.

As in Example 1, three high water content polyHEMA contact lenses were treated with 150mg of the CDI-activated PVA-PEO graft copolymer. The graft copolymer was linked to surface OH groups via a carbonate linkage and to surface COOH groups via an ester linkage.

Lysozyme absorption studies showed that after treatment there was a 90% reduction in lysozyme absorption relative to the control untreated lens.

Example 3

PV0-PE0 graft copolymers were synthesised as in Example 2. The graft copolymer was linked to the lens surface using a water soluble carbodiimide (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (EDC).

Three high water content polyHEMA contact lenses were each placed in 5ml distilled water (pH 6) containing 20mg EDC and incubated at room temperature for six hours. To this solution 150mg of PVA-PEO graft copolymer was added and the temperature of the solution was gradually raised to 80°C over a period of one hour and maintained at 80°C for two hours. The graft copolymer was linked to the lens surface COOH groups via an ester linkage.

Lysozyme absorption studies showed that after treatment there was a 90% reduction in lysozyme absorption relative to the control.

Example 4

Coating a substrate with PVA-PEO graft copolymer - Formula (1 ), X being OH and Y epoxide. Molecular weight 1000.

3g PVA (25000 M.Wt) was dissolved in distilled water (100ml) with boiling. When the solution had cooled, 20g PEO and 2ml NaOH (1M) were added. The solution was left stirring for twenty-four hours at room temperature. The solution was neutralised with 1M HC1 and then dialysed for twenty-four hours and freeze dried.

The resultant graft copolymer of PVA-PEO was either dissolved in 100ml anhydrous acetone or anhydrous DMSO to which was added 3.3g CDI dissolved in either acetone or DMSO over a period of one hour. The solution was left stirring for another hour and then the solvent was removed under reduced pressure.

As in Example 1, three high water content polyHEMA contact lenses were treated with 150mg of the CDI-activated PVA-PEO graft copolymer. The graft copolymer was linked to surface OH groups via a carbonate bond and to surface COOH groups via an ester linkage.

Lysozyme absorption studies showed that after treatment there was a 90% reduction in lysozyme absorption relative to the control untreated lens. Example 5

3g PVA (25000 M.Wt) was dissolved in 100ml distilled water after boiling. 2ml of NaOH (1M) was added to the cooled solution. 5 Ethylene oxide was cooled to below 0° C and poured into the vessel, and the vessel temperature was maintained at approximately 2° C. The reaction was stopped when PVA could be dissolved in acetone.

The solution was neutralised, dialysed for twenty-four hours and 10 freeze dried. PVA-PEO graft copolymer was dissolved in acetone and activated with CDI (3.3g).

Soft high water content polyHEMA lenses (as in Example 1) were incubated with 150mg of the polymer. The graft copolymer was 5 covalently bonded to the lens surface. The graft copolymer formed a carbonate bond with surface OH groups and an ester linkage with surface COOH.

Protein absorption studies showed a 95% reduction in lysozyme ²⁰ absorption relative to untreated contact lenses.

Example 6

²⁵ Polydimethylsiloxanes grafted with PEO (Formula (1), Y being OH) also showed greater than 90% reduction in lysozyme absorption when the polymers were covalently bonded to the lens surface of high water content polyHEMA contact lenses using CDI. on

PEO molecular weights ranged from 350-2500 and the overall graft copolymer molecular weight of polydimethylsiloxanes and PEO ranged from 4000-30,000. All or half PEO hydroxyl groups were activated on the polymers with CDI in acetone, before linking to the lens surface took place in potassium bicarbonate buffer. The PEO n hydroxyl groups which were activated with CDI reacted with the lens surface hydroxyl groups to form a carbonate bond and also formed ester l inkages with surface COOH groups.

Example 7 ^*

Polydimethylsiloxanes grafted with PEO (Formula (1), Y being OH) and glycidylacrylate, the molecular weight of the graft copolymers being in the range 5000-10000, were incubated with soft high water content polyHEMA lenses (as in Example 1) in the presence of a Lewis acid. The cocktail contained one contact lens in 5ml distilled water with 250mg graft copolymer and 0.5ml Lewis acid. The solution was left at room temperature for twenty-four hours. The graft copolymer was covalently bound to the lens surface via the epoxide group on the glycidylacrylate. The epoxide formed an ether linkage with surface OH groups and an ester linkage with surface COOH groups.

The lenses were washed and assayed for protein absorption. There was an 85% reduction in protein absorption relative to the untreated lens.

Example 8

Hydroxyethylcellulose was reacted with ethylene oxide (as in Example 3). The reactior of ethylene oxide with hydroxyethyl- cellulose was stopped wht.i the polymer completely dissolved in acetone. The polymer was activated with CDI in acetone and the acetone was removed under reduced pressure. 200mg of the CDI activated PEO-cellulose was incubated with high water content polyHEMA contact lenses (as in Example 1) and oxygen permeable hard contact lenses (polysiloxanyl methacrylate copolymerised with methacrylic add) for twenty-four hours. The coating polymer formed a hydrophilic coating chemically bonded to the lens surface. In the polyHEMA lens, the chemical bond was a carbonate bond with lens surface OH groups and an ester linkage with surface COOH for both polyHEMA and the oxygen permeable hard lenses.

The lenses were tested for lysozyme absorption. Greater than 90% reduction in lysozyme absorption was observed for both types of lenses.

Example 9

High water content polyHEMA and oxygen permeable hard contact lenses (polysiloxanyl methacrylate copolymerised with methacrylic acid) were placed in vials. To each of these vials 5ml distilled water was added and 250mg ethylene carbonate. Potassium carbonate (50mg) was added and the solution warmed to ca. 60°C for two hours. Ethylene carbonate reacted with the lens surface to form polyethylene oxide polymer on both lens types. However, the initial bond with the lens surface is dependent on the functional group present. If OH is present, the initial bond is an ether linkage, and if COOH is present, then an initial ester bond is formed.

The lenses were washed and tested for lysozyme absorption. Greater than 90% reduction in protein absorption was observed for the treated lenses when compared to control untreated lenses,

Example 10

Coating a substrate with PEO polymer - Formula (1), X is OH and Y -0CH₃. PEO polymers of molecular weights between 200 and 5000 were used, including molecular weights of 200, 350, 550, 750, 1000, 2000 and 5000.

CDI was dissolved in anhydrous acetone. PEO was also dissolved in anhydrous acetone and placed in a dry dropping funnel. The PEO was added dropwise to the CDI over a period of one hour. The solution was left to stir for a further one hour, after which the acetone was evaporated off under reduced pressure. Mole ratio 1:1 was used to obtain CDI-activated PEO polymer.

As in Example 1, three high water content polyHEMA contact lenses were treated with 200mg of the CDI-activated PEO polymer. The polymer was linked to surface OH groups via a carbonate linkage and to surface COOH groups via an ester linkage.

Lysozyme and albumin absorption studies showed that after treatment there was 90% reduction in lysozyme and albumin absorption relative to the control untreated lens.

Example 11

Coating a substrate with PEO polymers - Formula (1), X is OH and Y is (a) OH and (b) -0CH₃. PEO polymers with molecular weights of between 200 and 20000 were used, including 200, 550, 750, 1000, 2000, 5000, 10000 and 20000.

As in Example 3, three high water content contact lenses were each placed in 5ml distilled water (pH 6) containing 20mg EDC and incubated at room temperature for six hours. To this solution 400mg PEO polymer was added and the temperature of the solution was gradually raised to 80°C over a period of one hour and maintained at 80°C for two hours.

The polymer was linked to the lens surface COOH groups via an e er linkage.

Lysozyme and albumin studies showed that after treatment there was a 90% reduction in lysozyme and albumin absorption relative to the control. Example 12

Coating a substrate with PEO polymer - Formula (1 ), X is -OCH2-CNH2

CH-

and Y -0CH₃. Molecular weights of the PEO polymer varied from 200 to 10000.

As in Example 10, the PEO polymer was activated with CDI and reacted with three high water content polyHEMA contact lenses and three oxygen permeable hard contact lenses (as in Example 8). In the polyHEMA lens, the chemical bond was a urethane linkage with lens surface OH groups and an amide linkage with surface COOH for both polyHEMA and the oxygen permeable hard lens.

The lenses were tested for both lysozyme and albumin absorption. Greater than 90% reduction in lysozyme and albumin was observed for both types of lenses.

Example 13

Coating a substrate with PEO polymer - Formula (1), X is -OCH2-CNH2

CH₃ and Y -0CH₃. Molecular weights of the PEO polymer varied from 200 to 10000.

As in Example 3, EDC was used to couple the PEO polymer to the lens COOH groups, but instead of forming an ester linkage (as in Example 3) an amide bond was formed.

Lysozyme and albumin studies showed that after treatment there was a 90% reduction in lysozyme and albumin relative to the control. Exa ple 14

Coating a substrate with PEO polymer - Formula (1), X is -O-C- H2

0 and Y is (a) OH, (b) -0CH₃ and (c) -0-C-NH₂

0

Molecular weights of the PEO polymer varied from 200 to 20000.

The above polymer is formed by reacting a PEO polymer (Formula 1) where X is OH and Y is OH or -0CH₃ with urea. PEO polymer and urea are refluxed for six hours in an organic solvent (dioxane or toluene).

The organic solvent is removed under reduced pressure. The resultant PEO polymer is then linked to the surface of the contact lens either by using CDI (as in Example 10) or by using EDC (as in Example 3). With CDI the chemical bond formed with lens surface OH groups was a carbamate ester and an acyl carbamate with lens COOH groups. Similarly, with EDC the bond formed is also a carbamate ester with lens COOH groups.

Lysozyme studies showed that after treatment there was a 90% reduction in lysozyme absorption relative to the control untreated lens.

Example 15

Coating a substrate with PEO polymers.

(i) Formula (1), X is methacrylate and Y is OH. Molecular weight of PEO polymer can vary between 200 and 2000.

The above PEO polymer was homo-polymerised in water. 90 wt% distilled water was de-gassed and purged with nitrogen for half an hour and then heated to 80°C. PEO polymer (10 wt%) containing 230mg potassium persulphate (dissolved in 2ml distilled water) was added slowly to the heated water (under nitrogen) over a period of fifteen minutes. The reaction was allowed to continue for one hour. The polymer was then dialysed for twenty-four hours and freeze dried.

(ii) Formula (1), X is methacrylate and Y is -0CH₃. Molecular weight of PEO polymer can vary between 200 and 5000.

Co-polymerisation of PEO polymers in (i) and (ii) was carried out with different mole ratios and different molecular weights. Examples of copolymers of (i) and (ii) are given in Table 1.

Table 1

The polymers in Table 1 were then linked to the surface of polyHEMA high water content contact lenses either by using CDI (as in Example 10) or by using EDC (as in Example 3). With CDI the chemical bond was a carbonate with lens surface OH groups and an ester with surface COOH groups. With EDC the chemical bond was an ester with surface COOH groups. Example 16

Coating a substrate with PEO polymers - Formula (1) where X is methacrylate and Y is -O-C-NH 0

The above PEO polymer was synthesised as described below. A mole ratio of 1:1 of urea and PEO polymer - Formula (1), X is methacrylate and Y is OH (molecular weight 350) was refluxed for six hours in anhydrous dioxane or toluene. The solvent was then removed under reduced pressure. Similarly, other molecular weights of Formula (1), where X is methacrylate and Y is OH were reacted with urea (eg molecular weights 550, 750 and 1000).

The above PEO polymers were then either homo-polymerised or copolymerised with :

(a) Formula (1), where X is methacrylate and Y is OH, molecular weights 350, 550 and 750.

(b) Formula (1), where X is methacrylate and Y is -0CH₃, molecular weights 350, 550, 750, 1000 and 2000.

(c) A mixture of PEO polymers in (a) and (b).

The polymers were then linked to the surface of polyHEMA high water content contact lenses either by using CDI (as in Example 10) or by using EDC (as in Example 3). With CDI the chemical bond was a carbamate ester with lens surface OH groups and an acyl carbamate with surface COOH groups. With EDC the chemical bond was also an acyl carbamate with surface COOH groups.

Lysozyme and albumin studies showed that after treatment there was a 90% reduction in lysozyme and albumin absorption relative to the control untreated lens. Exa ple 17

Acrylamide and methacrylamide were (separately) copolymerised (as in Example 15) with:

(c) A mixture of (a) and (b).

The mole % of acrylamide varied between 10 and 90 mol% in the above polymerisation mixtures.

The polymers were linked to the surface of polyHEMA high water content contact lenses either by using CDI (as in Example 10) or by using EDC (as in Example 3). With CDI the chemical bond was a carbonate bond between polymer OH groups and lens surface OH groups or a carbamate ester with acrylamide or methacrylamide. An ester bond was formed between polymer OH groups and lens surface COOH groups or an acyl carbamate with acrylamide or methacrylamide. With EDC the chemical bond was either an ester between polymer OH groups and lens surface COOH groups or an acyl carbamate with acrylamide or methacrylamide with lens surface COOH groups.

Lysozyme and albumin studies showed that after treatment there was a 95% reduction in lysozyme and albumin absorption relative to the control untreated lens.

Example 18

Vinylene carbonate (mol% 20, 40 and 60) was copolymerised (as in Example 15) with PEO polymer Formula (1), where X is methacrylate and Y is -0CH₃, molecular weight 350. Similarly vinylene carbonate (mol% 20, 40 and 60) was copolymerised with other molecular weight PEO polymers of the above structure (eg 550, 750, 1000 and 2000).

Vinylene carbonate (mol% 20, 40 and 60) was also copolymerised with PEO polymer Formula (1), where X is methacrylate and Y is OH, molecular weight 350.

The above polymers were dialysed for twenty-four hours and freeze dried.

Polymerisation reactions of the above copolymers were also carried out in organic solvents such as toluene and isopropanol under nitrogen using VAZ067 (du Pont) (2,2-azobis(2-methylbutane- nitrile)) as catalyst. The mixtures were allowed to reflux for twenty-four hours, after which the solvent was removed under reduced pressure.

Three high water content polyHEMA contact lenses were placed in potassium carbonate (pH 9.0) and 300mg of one of the above polymers was added.

The polymers were linked to the lens surface OH groups via an ether linkage and to the lens COOH groups via an ester linkage,

Lysozyme and albumin studies showed that after treatment there was an 85% reduction in lysozyme and albumin absorption relative to the control untreated lens,

Example 19

Glycidyl methacrylate (mol% 20, 40 and 60) was copolymerised (as 1n Example 15) with PEO polymer Formula (1), where X is methacrylate and Y is -0CH₃, molecular weight 350. Similarly glycidyl methacrylate (mol% 20, 40 and 60) was copolymerised with other molecular weight PEO polymers of the above structure (eg molecular weights 550, 750, 1000 and 2000).

Glycidyl methacrylate (mol% 20, 40 and 60) was also copolymerised with PEO polymer Formula (1), where X is methacrylate and Y is OH molecular weights 350 and 550.

In addition, 40 mo1% glycidyl methacrylate was copolymerised with 30 mol% PEO polymer - Formula (1), where X is methacrylate and Y is -0CH₃ (molecular weight 2000) and 30 mol% PEO polymer - Formula (1), where X is methacrylate and Y is OH (molecular weight 350).

The above polymers were dialysed for twenty-four hours and freeze dried. Polymerisation reactions of the above copolymers were also carried out in organic solvents such as toluene under nitrogen using VAZ0 67 (du Pont) as catalyst. The mixtures were allowed to reflux for twenty-four hours, after which the solvent was removed under reduced pressure.

Three high water content polyHEMA contact lenses were placed in distilled water (pH 10) and 300mg of one of the above polymers was added. The polymers were linked to the lens surface OH groups via an ether linkage and to the lens COOH groups via an ester linkage,

Lysozyme studies showed that after treatment there was an 85% reduction in lysozyme absorption relative to the control untreated lens.

Example 20

N-vinyl pyrrolidone (mol% 20, 40 and 60) was copolymerised (as in Example 15) with PEO polymer - Formula (1), where X is methacrylate and Y is -0CH₃, molecular weight 350. Similarly N-vinyl pyrrolidone (mol% 20, 40 and 60) was copolymerised with other molecular weight PEO polymers of the above structure (eg molecular weights 550 and 750).

The above polymers were dialysed for twenty-four hours and freeze dried.

The polymers were then linked to the surface of polyHEMA high water content contact lenses either by using CDI (as in Example 10) or by using EDC (as in Example 3). With CDI the chemical bond was a carbonate with lens surface OH groups and an ester with surface COOH groups. With EDC the chemical bond was an ester with surface COOH groups.

Lysozyme studies showed that after treatment there was an 80% reduction in lysozyme absorption relative to the control untreated lens.

Example 21

Hydroxyethylmethacrylate (HEMA) (mol% 20, 40 and 60) was copolymerised (as in Example 15) with PEO polymer - Formula (1), where X is methacrylate and Y is -0CH₃, molecular weight 350. Similarly, HEMA (mol% 20, 40, and 60) was copolymerised with other molecular weight PEO polymers of the above structure (eg molecular weights 550, 750, 1000 and 2000).

The above polymers ere dialysed for twenty-four hours and freeze dried.

The polymers were then linked to the surface of polyHEMA high water content contact lenses either by using CDI (as in Example 10) or by using EDC (as in Example 3). With CDI the chemical bond was a carbonate with lens surface OH groups and an ester with surface COOH groups. With EDC the chemical bond was an ester with surface COOH groups. Lysozy e studies showed that after treatment there was an 85% reduction in lysozyme absorption relative to the control untreated lens.

5

Example 22

2-methacryloyloxyethyltrimethylammonium chloride (mol% 10, 20 and 30) was copolymerised (as in Example 15) with PEO polymer - Formula ⁰ (1), where X is methacrylate and Y is OH (molecular weight 350). Similarly the above cationic monomer was copolymerised with other molecular weight PEO polymers of the above structure (eg molecular weights 550 and 750).

° The cationic monomer was also copolymerised with 40mol% PEO polymer - Formula (1), where X is methacrylate and Y is OH (molecular weight 350) and 30mol% PEO polymer - Formula (1), where X is methacrylate and Y is -0CH (molecular weight 2000).

The above copolymers were dialysed for twenty-four hours and freeze dried.

The polymers were then linked to the surface of polyHEMA high water content contact lenses by using EDC (as in Example 3). The chemical bond was an ester with surface COOH groups.

Lysozyme studies showed that after treatment there was an 85% reduction in lysozyme absorption relative to the control untreated lens. Ex ample 23

Cationic PVA (molecular weight 25000) (200mg) was linked to the surface of a polyHEMA high water content contact lens by using EDC (as in Example 3). The chemical bond was an ester with surface COOH groups.

Example 24

Cationic cellulose (molecular weight 50000) was linked to the surface of a polyHEMA contact lens in an identical fashion to that in Example 23, and similar reductions in lysozyme absorption were observed relative to the untreated control.

Claims

1. A method of coating a polymeric substrate having functional groups in the substrate polymer chain at surface portions thereof which comprises reacting said functional groups with complementary functional groups on a hydrophilic coating polymer in a predominantly aqueous medium to form covalent linkages between the coating polymer and the substrate polymer.

2. A method according to claim 1 wherein the substrate polymer is a hydrogel.

3. A method according to claim 1 or claim 2 wherein the coating formed on the substrate polymer is a hydrogel.

4. A method according to any one of the preceding claims wherein the coating is continuous.

5. A method according to any one of the preceding claims wherein the substrate material is selected from crosslinked hydroxyethylmethacryl te (HEMA), crosslinked HEMA and methacrylic acid, crosslinked HEMA and N-vinylpyrrolidone, cellulose acetate butyrate polymers (retaining free hydroxyl groups), polyvinyl alcohol (retaining free hydroxyl groups), polyfluoroacrylate, polysiloxanyl acrylate and methacrylate polymers carrying an ionic charge or retaining free hydroxyl groups.

6. A method according to any one of the preceding claims wherein the covalent bonding between the respective functional groups on the substrate polymer and the coating polymer is selected from carbonate bonding with hydroxyl functional groups on the substrate, ester bonding with carboxyl groups, urethane bonding with amino groups, sulphonic ester bonding with sulphonic acid groups, ether and ester linkages with epoxide groups, urea with hydroxyl groups to form carbamate ester and urea with substrate surface carboxyl groups to form acyl carbamate, and amide bonding between an amine and substrate carboxyl groups.

7. A method according to any one of the preceding claims wherein the covalent bonding between the respective functional groups on the substrate polymer and the coating polymer is selected from amide, urea, allophanate, biuret, acyl urea and carbodiimide linkages,

8. A method according to any one of the preceding claims wherein the covalently bound coating polymer is a hydrophilic polymer selected from homopolymers, copolymers and graft copolymers of polyvinylalcohol (PVA), homopolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO), copolymers of polyethylene oxide and polypropylene oxide, graft copolymers of siloxanes, and homopolymers, copolymers and graft copolymers of cellulose, chitin and chitosan.

9. A method according to claim 8 wherein the coating polymer comprises a graft copolymer of PVA with PEO or PPO or a mixture of the two covalently bonded to the substrate.

10. A method according to claim 9 wherein the graft copolymer of PVA and PEO, or of PVA and PPO, is achieved by reacting PVA with ethylene oxide or ethylene carbonate, or propylene oxide or propylene carbonate, respectively, or with a mixture thereof, to obtain PVA graft copolymer containing PEO and/or PPO.

11. A method according to any one of claims 8 to 10 wherein he PEO and PPO have tne structures shown in Formulae (1) and (2) below:

(1) X-(CH₂-CH2-0)_nCH₂-CH₂-Y (PEO)

(2) X-(CH₂-CH-0)_nCH₂-CH-Y (PPO)

3 3 where both X and Y are -OH, -0-CH₂-CH(NH₂)-CH₃, -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6), -COOH, epoxide, H₂C=CH-C0-0- (acrylate), H₂C=C(CH₃)-C0-0- (methacrylate), -0CH , -OC2H5, propoxy, butoxy or allyloxy, and the respective terminal X and Y groups can be interchanged in Formula (2).

12. A method according to claim 11 wherein the molecular weights of (1) and (2) are from less than 100 up to 20,000.

13. A method according to claim 8 wherein the coating polymer is a graft copolymer of a polydimethylsiloxane with (1) or (2) or both, wherein X is acrylate or methacrylate and Y is OH, epoxide, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6).

14. A method according to claim 8 wherein the coating polymer is a graft copolymer of a polydimethylsiloxane with a glycidyl acrylate (GA), a glycidyl methacylate (GM), an epoxypropyl acrylate (EPA), or an epoxypropyl methacrylate (EPM).

15. A method according to claim 8 wherein the coating polymer comprises a homopolymer of PEO or PPO of Formula (1) or (2) respectively.

16. A method according to claim 15 wherein the coating polymer comprises a homopolymer of PEO or PPO of Formula (1) or (2) respectively wherein X is either acrylate or methacrylate and Y is OH, COOH, epoxide, 0CH , OC2H5, propoxy, butoxy, allyloxy, -0-CH₂-CH(NH₂)-CH₃, -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6).

17. A method according to claim 8 wherein the coating polymer comprises a copolymer of PEO and PPO of Formula (1) and (2) respectively wherein X is either methacrylate or acrylate and Y for (1) and (2) can be the same or different groups.

18. A method according to claim 17 wherein X is either methacrylate or acrylate and Y is any of OH, COOH, epoxide, 0CH₃, OC2H5, propoxy, butoxy, allyloxy, -0-CH2-CH(NH₂)-CH₃, and -0-C0-(CH2)_n- H2 (where n is from 0 to 6), with an unsaturated monomer selected from vinylene carbonate, hydroxyethylmethacrylate, hydroxypropylmethacrylate, hydroxyethyl acrylate, hydroxypropylacrylate, N-vinylpyrrolidone, acrylamide, hydroxybutylacrylate, hydroxybutylmethacrylate, butylacrylamide, dihydroxypropylacrylate, dihydroxypropylmethacrylate, epoxypropylacrylate, epoxypropylmethacrylate, glycidyl acrylate, glycidyl methacrylate, and hydroxypropylmethacrylamide.

19. A method according to claim 8 wherein the coating polymer is selected from cationic PVA and synthetic cationic copolymers of polyethylene oxide and polypropylene oxide.

20. A method according to claim 19 wherein the coating polymer is a copolymer of a polydimethylsiloxane or of PEO or PPO of Formula (1) or (2), wherein X is acrylate or methacrylate and Y is OH, epoxide, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6), with PEO or PPO of Formula (1) or (2) where X is acrylate or methacrylate and Y is -OCH₂N(CH₂)₂, -0CH₂N⁺(CH₃)₃.C1^", -0CH₂ ⁺(C2H₅)₃.C1-, -0CH₂CH₂N(CH₂)₂. -0CH₂CH₂N⁺(CH₃)₃.Cr, -0CH₂CH2N⁺(C2H₅)₃.C1^", -0CH₂CH₂CH₂N(CH₂)₂, -0CH₂CH₂CH₂N⁺(CH₃)₃.C1~, -0CH2CH2CH₂ ⁺(C₂H₅)₃.Cr, -0CH(0H)CH₂CH₂N⁺(CH₃)₃.C1^" or -0CH₂CH(0H)CH₂N⁺(CH₃)₃,Cr

21. A method according to claim 19 wherein the coating polymer is a copolymer of a polydimethylsiloxane or of PEO or PPO of Formula (1) or (2), wherein X is acrylate or methacrylate and Y is OH, epoxide, -0-CH₂-CH(NH₂)-CH₃, or -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6), with another cationic polymerisable monomer selected from dimethylaminoethyl acrylate and methacrylate, 2-methacryloyl- oxyethyltrimethylammonium chloride, 3-methacrylamidopropyl dimethylamine, 3-methacrylamidopropyl trimethylammonium chloride, 1-vinyl and 2-methyl 1-vinylimidazole, 3-acrylamido-3-methylbutyl- dimethylamine, 3-acryl.amido-3-methylbutyl trimethylammonium chloride, N-(3-methacryloyloxy-2-hydroxypropyl) trimethylammonium chloride, diallyldimethylammonium chloride and methylsulphate, and vinylbenzyltrimethylammonium chloride.

22. A substrate polymer coated by a method according to any one of the preceding claims.

23. Polyethylene oxide (PEO) and polypropylene oxide (PPO) having a structure as shown in Formula (1) or (2) below:

(1) X-(CH₂-CH2-0)_nCH₂-CH2-Y (PEO)

(2) X-(CH₂-CH-0)_nCH₂-CH-Y (PPO)

CH CH

where one of X and Y is -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6), and the other is -OH, -0-CH₂-CH(NH₂)-CH₃, -0-C0-(CH₂)_n-NH₂ (where n is from 0 to 6), -COOH, epoxide, H₂C=CH-C0-0- (acrylate), H₂C=C(CH₃)-C0-0- (methacrylate), -0CH₃, -0C₂H₅, propoxy, butoxy or allyloxy.

24. Polydimethylsiloxane graft copolymers having the following general formula:

(CH₃)₃SiO-P((CH₃)₂SiO)_χ-(CH₃SiO)_y3-Si(CH₃)₃ L PEO/PPO/GA/GM/EPA/EPMj n

where PEO/PPO/GA/GM/EPA/EPM represents polyethylene oxide, polypropylene oxide, glycidyl acrylate, glycidyl methacylate, epoxypropyl acrylate, or epoxypropyl methacrylate copolymer moieties, and the coefficients x, y and n are such as to give a molecular weight in the broad range of 3000 to 100,000.

25. Graft copolymers of chitin and chitosan with PEO and PPO.

26. A method of increasing the resistance of soft and oxygen permeable hard contact lenses to tear protein deposition comprising directly polymerising ethylene oxide or ethylene carbonate, or propylene oxide or propylene carbonate, or a mixture thereof, on to the contact lens, or by grafting PEO and/or PPO directly on to the lens surface.

27. A method of rendering a contact lens that has functional groups more compatible with the eye, comprising covalently bonding a polymer coating to the surface of the lens as a substrate, whereby to enhance the hydrophilic character of the lens for a longer time relative to an untreated surface, and to reduce the tendency of tear proteins to adhere to the lens surface.

28. A method according to claim 27 wherein the functional groups are hydroxyl, carboxyl, amide, amino or sulphonate groups.

29. A method according to claim 27 or claim 28 wherein the coating polymer forms a covalently bound hydrogel at the lens surface.

30. A contact lens coated by a method according to any one of claims 26 to 29.

31. A contact lens having a coating suitable for use in the human eye, wherein the coating comprises a polymer that is covalently bonded to the surface of the lens polymer to form a thin protective layer or coating covalently linked to the lens surface.

32. A contact lens according to claim 31 which comprises a polymer containing hydroxyl, carboxyl, amide, amino or sulphonic acid functional groups on to which the polymer coating is chemically bonded.