Grafted polymer and use thereof

Abstract

To provide a polymer for use as a coating of biomedical devices such as contact lenses.SOLUTION: A grafted glycosaminoglycan polymer which is a reaction product of (a) a glycosaminoglycan having a polymer backbone containing reactive functional groups, wherein any of the reactive functional groups is an epoxide-reactive functional group, (b) a polyol, and (c) an epoxy alcohol, the grafted glycosaminoglycan polymer comprising one or more side chains including a polyalkylene glycol-containing residue grafted to the epoxide-reactive functional group of the polymer backbone of the glycosaminoglycan, the polyalkylene glycol-containing residue being derived from a polymeric compound or a salt thereof having the following structure: Z-(((CH2)a-O)b)c-Y (wherein Z is a terminal capping group, Y is a reactive functional group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2).SELECTED DRAWING: None

Description

[Background technology]

[0001] Priority claims This application claims priority to U.S. Provisional Patent Application No. 62 / 903,206, entitled "Grafted Polymer and Use Thereof," filed September 20, 2019, and incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates generally to grafted polymers and uses thereof.

[0003] It is highly desirable for contact lenses to be as comfortable as possible for the wearer. Contact lens manufacturers are continually working to improve lens comfort. Despite this, many people who wear contact lenses experience dryness or eye irritation throughout the day, especially at the end of the day. Inadequately wetted lenses will, at some point, cause significant discomfort to the lens wearer. While wetting drops can be used as needed to alleviate such discomfort, it is preferable to prevent such discomfort from occurring in the first place.

[0004] Glycosaminoglycans (GAGs) are a group of polysaccharides constructed from repeating disaccharide units. Due to their high polarity and water affinity, GAGs can be found in many systems of the human and animal body. For example, GAGs occur on the surface of cells and in the extracellular matrix of animal organisms such as skin, cartilage, and lungs.

[0005] GAGs each have a chemical structure containing a repeating basic disaccharide structure consisting of uronic acid and hexosamine, and are optionally sulfated to various degrees. GAGs are primarily classified into three groups based on the disaccharides they comprise: the first group consisting of compounds composed of chondroitin sulfate or dermatan sulfate, the second group consisting of compounds composed of heparan sulfate or heparin, and the third group consisting of hyaluronic acid compounds. For example, compounds composed of chondroitin sulfate or dermatan sulfate consist of a disaccharide: uronic acid (glucuronic acid or iduronic acid) (β1→3) N-acetylgalactosamine, compounds composed of heparan sulfate or heparin consist of a disaccharide: uronic acid (glucuronic acid or iduronic acid) (β1→4) N-acetylglucosamine, and hyaluronic acid consists of a disaccharide: glucuronic acid (β1→3) N-acetylglucosamine. In addition, due to the combination of sulfation modifications, their structures are highly diverse.

[0006] These GAGs are known as important biological materials that possess both physicochemical properties derived from their characteristic viscoelasticity and biological properties mediated by interactions with various functional proteins, depending on their molecular size and sulfation pattern.

[0007] It is desirable to provide improved GAGs that can make biomedical devices such as contact lenses as comfortable as possible for the wearer and exhibit suitable physical and chemical properties, such as lubricity and wettability. Summary of the Invention

[0008] According to one exemplary embodiment, a grafted glycosaminoglycan polymer is provided, the grafted glycosaminoglycan polymer comprising a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone.

[0009] According to a second exemplary embodiment, a crosslinked polymer network is provided, comprising the reaction product of one or more grafted glycosaminoglycan polymers comprising a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone, and one or more crosslinking agents.

[0010] According to a third exemplary embodiment, there is provided a crosslinked polymer network comprising the reaction product of one or more glycosaminoglycans having a polymer backbone comprising one or more reactive functional groups, one or more polymers comprising polyalkylene glycol chains and at least one reactive end group or salt thereof, and one or more crosslinking agents.

[0011] According to a fourth exemplary embodiment, there is provided a biomedical device having a coating on a surface thereof, the coating comprising one or more grafted glycosaminoglycan polymers comprising a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone.

[0012] According to a fifth exemplary embodiment, there is provided a packaging system for storing ophthalmic devices, the packaging system comprising: a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising one or more grafted glycosaminoglycan polymers, the glycosaminoglycan having a polymer backbone and one or more side chains comprising polyalkylene glycol-containing residues grafted to the polymer backbone; wherein the aqueous packaging solution has an osmolality of at least about 200 mOsm / kg, a pH of about 6 to about 9, and is sterilized.

[0013] According to a sixth exemplary embodiment, there is provided a method for preparing a package containing a storable, sterile ophthalmic device, the method comprising: (a) immersing the ophthalmic device in an aqueous packaging solution containing one or more grafted glycosaminoglycan polymers, the glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone, the aqueous packaging solution having an osmolality of at least about 200 mOsm / kg and a pH in the range of about 6 to about 9; (b) packaging the aqueous packaging solution and the ophthalmic device in a manner that prevents contamination of the ophthalmic device with microorganisms; and (c) steam sterilizing the packaged solution and ophthalmic device.

[0014] According to a seventh exemplary embodiment, there is provided an aqueous ophthalmic composition comprising one or more grafted glycosaminoglycan polymers comprising a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone, wherein the aqueous ophthalmic composition has an osmolality in the range of about 200 mOsmol / kg to about 500 mOsmol / kg.

[0015] According to an eighth exemplary embodiment, there is provided a gel composition for promoting wound healing, the gel composition comprising one or more grafted glycosaminoglycan polymers comprising a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone.

[0016] According to a ninth exemplary embodiment, there is provided a wound dressing comprising a gel composition comprising one or more grafted glycosaminoglycan polymers, the glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone.

[0017] The grafted glycosaminoglycan polymers and / or crosslinked polymer networks described in exemplary embodiments herein advantageously exhibit suitable physical and chemical properties, such as oxygen permeability, lubricity, adhesion, and wettability, for prolonged contact with the body due to the grafting of polyalkylene glycol-containing residues onto reactive functional groups in the glycosaminoglycan polymer backbone. The grafted glycosaminoglycan polymers and / or crosslinked polymer networks are believed to advantageously exhibit less enzymatic, oxidative, and thermal degradation, thereby exhibiting greater stability, longer shelf life, and desirable conformational rigidity. In addition, the grafted glycosaminoglycan polymers and / or crosslinked polymer networks are believed to further advantageously exhibit anti-biofouling, anti-protein deposition, and antibacterial activity for prolonged contact with the body.

[0018] The grafted glycosaminoglycan polymers and / or crosslinked polymer networks described in the exemplary embodiments herein can advantageously provide improved lubricity to the surface of biomedical devices, such as contact lenses. For example, the benefits of improved lubricity using grafted glycosaminoglycan polymers and / or crosslinked polymer networks include minimized interactions between the contact lens and its respective packaging blister, a lens surface that is more robust to processing and handling conditions and improved comfort upon insertion into a subject's eye, and reduced deposition (e.g., proteins, lipids), thus potentially reducing biofilm formation on the lens surface by contact lens wearers.

[0019] Additionally, the grafted glycosaminoglycan polymers and / or crosslinked polymer networks described in the exemplary embodiments herein advantageously provide improved wettability to the surface of biomedical devices, such as contact lenses. Benefits of improving wettability using the grafted glycosaminoglycan polymers of the present invention may include, for example, retarding evaporation of the device's aqueous layer for moisturizing properties similar to a coating on the ocular surface, thus potentially alleviating dry eye symptoms.

[0020] Additionally, the grafted glycosaminoglycan polymers and / or crosslinked polymer networks described in exemplary embodiments herein advantageously provide improved stability and increased shelf life of packaging solutions when combined with one or more comfort agents. DETAILED DESCRIPTION OF THE INVENTION

[0021] Exemplary embodiments described herein are directed to grafted glycosaminoglycan polymers and / or crosslinked polymer networks useful, for example, for treating the surfaces of biomedical devices intended for direct contact with bodily tissues or fluids, packaging solutions in packaging systems for storing ophthalmic devices, aqueous ophthalmic compositions, gel compositions, and wound dressings. Generally, grafted glycosaminoglycan polymers include glycosaminoglycans (GAGs) having a polymer backbone and one or more side chains containing polyalkylene glycol-containing residues grafted to the polymer backbone. GAGs are single molecules with many alternating subunits. Generally, GAGs are represented by the formula ABABAB, where A is a uronic acid and B is an amino sugar that may or may not be O-sulfated or N-sulfated, and the A and B units may be heterogeneous in terms of epimer content or sulfation. Any natural or synthetic polymer containing uronic acid can be used. Other GAGs are sulfated with different sugars. There are many different types of GAGs with commonly understood structures, such as chondroitin sulfate (e.g., chondroitin 4- and 6-sulfate), heparan, heparin sulfate, heparosan, dermatan, dermatan sulfate, hyaluronic acid or its salts, such as sodium or potassium hyaluronate, keratan sulfate, and other disaccharides, such as sucrose, lactulose, lactose, maltose, trehalose, cellobiose, mannobiose, and chitobiose. Glycosaminoglycans can be purchased from Sigma and many other biochemical suppliers, such as HTL Biotechnology (France). In an exemplary embodiment, the GAG ​​is hyaluronic acid. In one embodiment, the GAG ​​is chondroitin sulfate.

[0022] GAG has reactive functional groups in the polymer backbone for grafting polyalkylene glycol-containing residues, including polyalkylene glycol derivatives.Suitable reactive functional groups in the polymer backbone include carboxylate-containing groups, hydroxyl-containing groups, silicon hydride groups, sulfur-containing groups such as thiol, and other groups including polymerizable functional groups such as allyl groups, vinyl groups, acrylates, methacrylates, methacrylamides, etc.In addition, the sugar ring of GAG can be opened to form aldehydes for further functionalization. GAGs for use herein can have a weight average molecular weight ranging from about 10,000 to about 3,000,000 Daltons (Da), with lower limits of about 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000, and upper limits of about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, or up to about 2,800,000 Da, any of the lower limits can be combined with any of the upper limits.

[0023] Hyaluronic acid is a well-known, naturally occurring, water-soluble, biodegradable polymer composed of two alternatively linked sugars, D-glucuronic acid and N-acetylglucosamine, linked via alternating β-(1,4) and β-(1,3) glycosidic bonds. Hyaluronic acid is a non-sulfated GAG. The polymer is hydrophilic and has high viscosity in aqueous solution at relatively low solute concentrations. It often occurs naturally as its sodium salt, sodium hyaluronate. Methods for preparing commercially available hyaluronan and its salts are well known. Hyaluronan can be purchased from Seikagaku Company, Clear Solutions Biotech, Inc., Pharmacia Inc., Sigma Inc., as well as many other suppliers, including HTL Biotechnology, Contipro, and Bloomage Biotechnology Corporation. Hyaluronic acid has a repeating unit structure represented by the following formula: [ka] Thus, the repeating units in hyaluronic acid can be: [ka]

[0024] Generally, hyaluronic acid or its salts can have from about 2 to about 1,500,000 disaccharide units. In one embodiment, the hyaluronic acid or salt thereof can have a weight average molecular weight in the range of about 10,000 to about 3,000,000 Da, with lower limits of about 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000, and upper limits of about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, or up to about 2,800,000 Da, and any of the lower limits can be combined with any of the upper limits.

[0025] Chondroitin sulfate is a linear sulfated polysaccharide composed of repeating β-D-glucuronic acid (GlcA) and N-acetyl-β-D-galactosamine (GalNAc) units arranged in a sequence by GlcA-β(1,3)-GalNAc-β(1,4) glycosidic linkages. In one embodiment, chondroitin sulfate has one or more repeating units of the structure represented by the following formula: [ka]

[0026] In one exemplary embodiment, chondroitin sulfate has a repeating unit of the structure represented by the following formula: [ka]

[0027] Generally, chondroitin sulfate can have about 2 to about 1,500,000 repeating units. In one embodiment, chondroitin sulfate can have a weight-average molecular weight in the range of about 10,000 to about 3,000,000 Da, with the lower limit being about 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000. The limits are about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, or about 3,000,000 Da, and any of the lower limits can be combined with any of the upper limits, and any of the upper limits can be combined with any of the upper limits.

[0028] In one exemplary embodiment, dermatan sulfate has a repeating unit of a structure represented by the following formula: [ka]

[0029] Generally, dermatan sulfate can have from about 2 to about 1,500,000 repeating units. In one embodiment, chondroitin sulfate can have a weight average molecular weight in the range of from about 10,000 to about 3,000,000 Da, with the lower limit being about 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000. The limits are about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, or about 3,000,000 Da, and any of the lower limits can be combined with any of the upper limits, and any of the upper limits can be combined with any of the upper limits.

[0030] In an exemplary embodiment, heparin and heparin sulfate have repeating units of a structure represented by the following formula: [ka]

[0031] Generally, heparin and heparin sulfate can have from about 2 to about 1,500,000 repeating units. In one embodiment, chondroitin sulfate can have a weight average molecular weight ranging from about 10,000 to about 3,000,000 Da, with a lower limit of about 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000. The limits are about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, or about 3,000,000 Da, and any of the lower limits can be combined with any of the upper limits, and any of the upper limits can be combined with any of the upper limits.

[0032] In one exemplary embodiment, the keratan sulfate has a repeating unit of a structure represented by the following formula: [ka]

[0033] Generally, keratan sulfate can have about 2 to about 1,500,000 repeating units. In one embodiment, chondroitin sulfate can have a weight-average molecular weight in the range of about 10,000 to about 3,000,000 Da, with lower limits of about 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, and 100,000. The limits are about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, or about 3,000,000, and any of the lower limits can be combined with any of the upper limits, and any of the upper limits can be combined with any of the upper limits.

[0034] The polyalkylene glycol-containing residue grafted to the reactive functional group in the polymer backbone of the GAG ​​is derived from a polymer comprising a polyalkylene glycol chain and at least one reactive end group or its salt (e.g., HCl). The polyalkylene glycol chain can range from 2 to 10,000 subunits or 2 to 5,000 subunits. In one embodiment, the polyalkylene glycol chain has the structure: -((CH2) a -O) b -, where "a" is 2 to 6, or 2 to 4, and "b" is 2 to 10,000, or 2 to 5000. In an exemplary embodiment, the polyalkylene glycol is (e.g., -(CH2CH2O) b -) (i.e., PEG), polypropylene glycol chains (e.g., -(CH2CH2CH2O) b -), polybutylene glycol chains (e.g., -(CH2CH2CH2CH2O) b -), ethylene oxide-propylene oxide chains, and ethylene oxide-butylene oxide chains.

[0035] At least one reactive end group comprises a reactive functional group that can be grafted onto a reactive functional group in the polymer backbone of the GAG. Suitable reactive functional groups include, for example, halogens, amino groups, aldehyde groups, carboxylic acid groups, alcohol groups, thiol groups, hydrazide groups, glycidyl groups, and the like. These groups are connected to the polymer compound by a linker group "X." Examples of reactive functional groups include -X-PDMS-NH2 (where PDMS is polydimethylsiloxane having a molecular weight ranging from about 100 to about 150,000 Da), -X-OH, -X-NH2, -X-SH, and -XC(O)-R' (where R' is hydrogen or an organic hydrocarbyl moiety consisting of 1 to 20 carbon atoms, such as a lower alkyl group (e.g., methyl, ethyl, propyl, etc.) or benzyl).

[0036] Suitable linker groups "X" for connecting the reactive functional end group to the polymer include, for example, any of the following: -C(O)-, -NC(O)-NH-CH-, -NC(O)-NH-CH-CH-, -CH-, -CH-CH-, -CH-CH-, -CH-CH-CH-, -CH-CH-CH-CH-, -CH-O-CH-, -CH-CH-CH-O-CH-, -C(O)-NH-CH-, -C(O)-NH-CH-, -CH2-C(O)-NH-CH2-, -CH2-CH2-C(O)-NH-, -C(O)-NH-CH2-CH2-CH2-, -CH2-C(O)-NH-CH2-CH2-, -CH2-CH2-C(O)-NH-CH2-, -C(O)-NH-CH2 -CH2-CH2-CH2-, -CH2-C(O)-NH-CH2-CH2-CH2-, -CH2-CH2-C(O)-NH-CH2-CH2-, -CH2-CH2-CH2-C(O)-NH-CH2-, -CH2-CH2-CH2-(Si-O-Si) n -O-Si-CH2-CH2-CH2- (wherein n=3 to 100), and combinations of two or more of any of the foregoing.

[0037] The other end group may be either an inert end-capping group or a reactive end-capping group. An inert end-capping group is one that does not readily undergo chemical transformation under typical synthetic reaction conditions. A reactive end-capping group can be used for further crosslinking. Suitable end-capping groups include, for example, alkoxy groups, hydroxyl groups, thiol groups, amine groups, and ethylenically polymerizable groups such as acrylate or methacrylate groups. An alkoxy group is represented by the general formula -OR, where R is an organic moiety composed of 1 to 20 carbon atoms, such as a lower alkyl group (e.g., methyl or ethyl) or benzyl. However, R may be saturated or unsaturated, including aryl, heteroaryl, cyclo, heterocyclo, and substituted forms of any of the foregoing. For example, an end-capped PEG may have the structure RO-(CHCHO). n -, where R is as defined above. In an exemplary embodiment, suitable terminal groups include, by way of example, -OCH, -OCHCH, -OCH(CH), -NH, -OH, and -SH.

[0038] Polymers comprising a polyalkylene glycol chain and at least one reactive end group or salt thereof for use in the present invention include polymers having a variety of molecular weights, structures, or geometries (e.g., branched, linear, etc.). In an exemplary embodiment, the weight-average molecular weight of a polymer comprising a polyalkylene glycol chain and at least one reactive end group or salt thereof can range from about 100 Da to about 10,000 Da. For example, in one exemplary embodiment, the weight-average molecular weight of a polymer comprising a polyalkylene glycol chain and at least one reactive end group or salt thereof can be greater than about 100 Daltons, or greater than about 250 Da, or greater than about 500 Da, or greater than about 750 Da, or greater than about 1,000 Da, or greater than about 2,000 Da, or greater than about 5,000 Da, or greater than about 7,500 Da. In another exemplary embodiment, the weight average molecular weight of the polymer comprising a polyalkylene glycol chain and at least one reactive end group or salt thereof can be less than about 10,000 Da, or less than about 7,500 Da, or less than about 5,000 Da, or less than about 2,000 Da, or less than about 1,000 Da, or less than about 750 Da, or less than about 600 Da. As one of ordinary skill in the art will appreciate, any molecular weight between those listed above can be used.

[0039] The foregoing polymers are commercially available from a variety of sources, such as BroadPharm, Sigma, JenKem, and Advanced Polymer Materials Inc., or can be prepared according to methods well known in the art.

[0040] In an exemplary embodiment, the polymer comprising a polyalkylene glycol chain and at least one reactive end group or salt thereof has the following structure: Z-(((CH2) a -O) b ) c -Y (wherein Z is an end cap group, Y is a reactive functional group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2), or a salt thereof.

[0041] Z is an end-cap (or end-capping) group, which may be an inert or reactive group present at the end of a polymeric compound, such as a polyethylene glycol (PEG) polymer. Suitable end-capping groups include any of those discussed above.

[0042] Y is a reactive functional group that can be grafted onto a reactive functional group in the polymer backbone of the GAG. Suitable reactive functional groups include any of those discussed above. Suitable linker groups "X" for connecting the reactive functional group to any of those discussed above.

[0043] The polymeric compound may be derived from a polyalkylene glycol. Generally, a polyalkylene glycol has the following structure: -((CH) a -O) b -, where "a" is 2 to 6, or 2 to 4, and "b" is 2 to 10,000, or 2 to 5000. In an exemplary embodiment, the polyalkylene glycol is polyethylene glycol (e.g., -(CH2CH2O) b -), polypropylene glycol (e.g., -(CH2CH2CH2O) b -), polybutylene glycol (e.g., -(CH2CH2CH2CH2O) b -), ethylene oxide-propylene oxide, and ethylene oxide-butylene oxide. Polyalkylene glycols for use in the present invention include polyalkylene glycols having various molecular weights, structures or geometries (e.g., branched, linear, etc.) as discussed above.

[0044] In one embodiment, representative examples of polymers for use herein include any of the following: [ka] In the formula, n is 2 to 10,000.

[0045] The grafted glycosaminoglycan polymers disclosed herein can be obtained by grafting reactive functional groups of one or more polymers containing polyalkylene glycol chains onto reactive functional groups in the glycosaminoglycan polymer backbone. For example, in one exemplary embodiment, the amine-reactive end groups of a polymer containing polyalkylene glycol chains can be grafted onto carboxylic acid groups in the glycosaminoglycan polymer backbone. The graft polymerization reaction can achieve a degree of grafting, i.e., the number of side chains in the polymer backbone containing polyalkylene glycol-containing residues, ranging from about 5 to about 100%. In one exemplary embodiment, the degree of grafting can range from about 10 to about 90%. In one exemplary embodiment, the degree of grafting can range from about 20 to about 80%.

[0046] In one exemplary embodiment, the grafting reaction can be carried out by reacting the glycosaminoglycan with the polymer under suitable grafting conditions to form a random or block copolymer using a catalyst system such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) / N-hydroxysuccinimide (NHS) or EDC / hydroxybenzotriazole (HOBt) coupling in water at a pH of about 6.8 and about 1 to about 5 weight percent dissolved solids.

[0047] In one exemplary embodiment, glycosaminoglycans can be added to the reaction in an amount ranging from about 0.05% to about 10% by weight. In one exemplary embodiment, glycosaminoglycans can be added to the reaction in an amount ranging from about 0.5% to about 5% by weight.

[0048] In one embodiment, the polymer containing polyalkylene glycol chains can be added to the reaction in an amount ranging from about 0.01% to about 20% by weight. In an exemplary embodiment, the polymer containing polyalkylene glycol chains can be added to the reaction in an amount ranging from about 0.10% to about 0.5% by weight.

[0049] The grafting reaction is typically carried out in the presence of a catalyst system. In some embodiments, the catalyst system is a carbodiimide catalyst system, such as EDC. In some embodiments, a cocatalyst is used in conjunction with the carbodiimide catalyst system. Suitable cocatalysts include, for example, HOBt, NHS, and sulfo-N-hydroxysuccinimide (sulfo-NHS). In some embodiments, the catalyst system comprises EDC / NHS. In one embodiment, EDC is added to the reaction in an amount ranging from about 0.01% to about 20% by weight. In one embodiment, NHS is added to the reaction in an amount ranging from about 0.01% to about 20% by weight.

[0050] In another embodiment, the grafting reaction is carried out by reacting the glycosaminoglycan with a monomer capable of forming a polymer containing a polyalkylene glycol chain and at least one reactive end group or salt thereof in situ. For example, this reaction can be carried out by first forming a solution containing at least the glycosaminoglycan and a cocatalyst system. The glycosaminoglycan is then activated by adding an activator to the solution. Suitable activators include, for example, one or more epoxyamines. Epoxyamines are generally molecules containing both at least one amine moiety (e.g., primary amine, secondary amine, tertiary amine, or quaternary amine) and at least one epoxide moiety. The epoxyamine compound can be a monoepoxyamine compound and / or a polyepoxyamine compound, i.e., an epoxyamine containing one or more amine groups and one or more epoxide groups. In one embodiment, suitable epoxyamine compounds have an amine moiety of C1-C. 30The epoxy amine is a compound linked to an epoxide moiety by an alkylene group. Suitable epoxy amine compounds include, for example, epoxyethylamine, epoxypropylamine, epoxybutylamine, and epoxyamylamine. The activation reaction can be carried out at a suitable temperature for a period of time to react the activator with the glycosaminoglycan, for example, at room temperature, for a period ranging from about 10 hours to about 48 hours. In one embodiment, the epoxy amine can be added to the reaction mixture in an amount ranging from about 0.01 to about 50% by weight.

[0051] After the activator is reacted with the glycosaminoglycan, a monomer capable of forming a polymer containing a polyalkylene glycol chain and at least one reactive end group or a salt thereof in situ is added to the reaction mixture. In one embodiment, the monomer includes a polyol and an epoxy alcohol. Suitable polyols include, for example, one or more diols. Representative diols include, for example, C2-C6 alkyl esters such as ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 2-methyl-1,3-propanediol, and poloxamer 407. 12 The epoxy alcohol compound may be a monoepoxy alcohol compound and / or a polyepoxy alcohol compound, i.e., an epoxy alcohol containing one or more alcohol groups and one or more epoxide groups. In one embodiment, a suitable epoxy alcohol compound has an alcohol moiety of C1 to C6. 30 The epoxy alcohol compounds are compounds linked to an epoxide moiety by alkylene and / or alkyne groups. Suitable epoxy alcohol compounds include, for example, glycidyl alcohol, 3-oxiranyl-2-propen-1-ol, 3-(2-oxiranyl)2-propen-1-ol, 1-(2,3-dihydroxypropyl)4-(2-oxiranylmethyl)ester of 2-butenedioic acid, and 1-(2-hydroxyethyl)2-(2-oxiranylmethyl)ester of 1,2-benzenedicarboxylic acid.

[0052] Generally, the polyol and epoxy alcohol can be added to the reaction mixture sequentially or simultaneously. In one embodiment, the polyol is added to the reaction mixture and reacted with the activated glycosaminoglycan, which is then reacted with the polyol to form the polyalkylene glycol-containing residue. This reaction can be carried out at a suitable temperature and for a period of time ranging from about 10 hours to about 48 hours, for example, at room temperature, to maximize the yield of the product polyalkylene glycol residue on the glycosaminoglycan polymer backbone. In one embodiment, the polyol can be added to the reaction mixture in an amount ranging from about 0.01 to about 50% by weight, and the epoxy alcohol can be added to the reaction mixture in an amount ranging from about 0.01 to about 50% by weight.

[0053] The resulting grafted glycosaminoglycan polymers can be random or block copolymers. In an exemplary embodiment, the grafted glycosaminoglycan polymers disclosed herein can have a weight average molecular weight ranging from about 20,000 to about 6,000,000 Da, with lower limits of about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100 Da. ,000 Da, with an upper limit of about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, about 2,000,000, about 3,000,000, about 4,000,000, about 5,000,000, or up to about 6,000,000 Da.

[0054] In another embodiment, the crosslinked polymer network can be formed by either reacting the grafted glycosaminoglycan polymer described above with one or more crosslinking agents or by adding one or more crosslinking agents to the grafting reaction mixture. The crosslinking agent for use herein can be any suitable crosslinking agent known in the art. In general, suitable crosslinking agents are, for example, crosslinking agents having functional groups complementary to those of the grafted glycosaminoglycan polymer. In one embodiment, suitable crosslinking agents include, for example, bifunctional or multifunctional crosslinking agents. Bifunctional or multifunctional crosslinking agents contain two or more functional groups capable of reacting with the functional groups of the grafted glycosaminoglycan polymer, resulting in the formation of covalent bonds.

[0055] Suitable bifunctional or polyfunctional crosslinkers include, for example, divinyl sulfone, diepoxides, multiepoxides, dihydrazides, dihydric alcohols, polyhydric alcohols, polyhydric thiols, anhydrides, carbodiimides, polycarboxylic acids, carboxymethyl thiols, cysteine, and cysteine-like amino acids. In one embodiment, the bifunctional or polyfunctional crosslinker is a bis-epoxide or polyepoxide, such as a diglycidyl ether derivative. According to one embodiment, the bifunctional or polyfunctional epoxide crosslinker contains two or more glycidyl ether functional groups. The glycidyl ether functional groups react with the primary hydroxyl groups of hyaluronic acid and chondroitin sulfate to form ether bonds. In one embodiment, suitable difunctional or polyfunctional crosslinkers include, for example, 1,4-butanediol diglycidyl ether (BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), diepoxyoctane, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ester, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether, pentaerythritol polyglycidyl ether, sorbitol polyglycidyl ether, 1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, pentaerythritol tetraglycidyl ether, polyepoxides, and the like.

[0056] Suitable dihydrazide crosslinkers include, for example, succinic acid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, pimelic acid dihydrazide, suberic acid dihydrazide, azalaic acid dihydrazide, sebacic acid dihydrazide, undecanedioic acid dihydrazide, dodecanedioic acid dihydrazide, brassylic acid dihydrazide, tetradecanedioic acid dihydrazide, pentadecanedioic acid dihydrazide, thapsic acid dihydrazide, octadecanedioic acid dihydrazide, and the like.

[0057] Suitable dihydric alcohol crosslinkers include, for example, ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, neopentyl glycol, 1,3-propanediol, hexylene glycol, pentylene glycol, heptylene glycol, octylene glycol, etc. Suitable polyhydric alcohol crosslinkers include, for example, glycerin, pentaerythrite, xylitol, galactitol, etc. Suitable carbodiimide coupling agents include, for example, compounds of the formula XN=C=NX, where each X is independently a C1-C6 alkyl group optionally substituted with 1-2 dialkylamino groups, or a C5-C6 cycloalkyl group, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and cyclohexylcarbodiimide. Suitable anhydride crosslinkers include, for example, methacrylic anhydride, succinic anhydride, etc. In one embodiment, suitable crosslinkers are aldehyde crosslinkers such as, for example, formaldehyde, gluteraldehyde, gluraraldehyde, etc. In one embodiment, suitable crosslinkers include, for example, polyethylene glycol diacrylate, polyethylene glycol diamine, urea, diisocyanates, etc.

[0058] In one embodiment, the crosslinked polymer network described in the exemplary embodiments herein can be obtained by forming a solution of one or more grafted glycosaminoglycan polymers and adding one or more of the aforementioned crosslinking agents. In one embodiment, the crosslinked polymer network described in the exemplary embodiments herein can be obtained by adding one or more of the aforementioned crosslinking agents to a solution of one or more glycosaminoglycan polymers and one or more grafted polymers. The solution is stirred for a suitable time sufficient to crosslink the reaction mixture. In one embodiment, crosslinking can be carried out at 1°C to about 99°C for a period of about 2 hours to about 48 hours.

[0059] The solution can contain a suitable solvent, such as water, crown ether, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and other aprotic solvents. The pH of the solution can be adjusted, if necessary, by adding a hydroxide, such as sodium hydroxide. Generally, the crosslinker can be added to the solution in an amount ranging from about 0.01% to about 10% by weight, based on the total weight of the solution. When crosslinking the grafted glycosaminoglycan polymer, the amount of the grafted glycosaminoglycan polymer can range from about 0.010% to about 50% by weight, based on the total weight of the solution. In one embodiment, the amount of the grafted glycosaminoglycan polymer can range from about 0.01% to about 5% by weight, based on the total weight of the solution.

[0060] In one embodiment, one or more glycosaminoglycans can be added to the reaction of the grafted glycosaminoglycan polymer and one or more crosslinkers to form a crosslinked polymer network, i.e., the grafted glycosaminoglycan polymer can be crosslinked with one or more glycosaminoglycans. Generally, the one or more glycosaminoglycans can be any of the glycosaminoglycans discussed above. In one embodiment, the one or more glycosaminoglycans are hyaluronic acid. In one embodiment, the one or more glycosaminoglycans are chondroitin sulfate. In one embodiment, the one or more glycosaminoglycans comprise hyaluronic acid and chondroitin sulfate. In an exemplary embodiment, the amount of the one or more glycosaminoglycans can range from about 0.010% to about 50% by weight based on the total weight of the solution. In one embodiment, the amount of the one or more glycosaminoglycans can range from about 0.01% to about 5% by weight based on the total weight of the solution.

[0061] The one or more crosslinkers have functional groups complementary to the grafted glycosaminoglycan polymer and the glycosaminoglycan. Suitable crosslinkers, such as bifunctional or polyfunctional crosslinkers, connect the grafted glycosaminoglycan polymer to the glycosaminoglycan and also act as a spacer between the grafted glycosaminoglycan polymer and the glycosaminoglycan.

[0062] It will be readily apparent to those skilled in the art that the reaction product will comprise a complex mixture of compounds including, for example, grafted glycosaminoglycan polymers cross-linked with glycosaminoglycans, grafted glycosaminoglycan polymers cross-linked with grafted glycosaminoglycan polymers, glycosaminoglycans cross-linked with glycosaminoglycans, unreacted grafted glycosaminoglycan polymers, and unreacted glycosaminoglycans. For example, in one exemplary embodiment, the grafted glycosaminoglycan polymer crosslinked with the glycosaminoglycan can have a weight average molecular weight in the range of about 20,000 to about 6,000,000 Da, with a lower limit of about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da; The upper limits are about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, about 2,000,000, about 3,000,000, about 4,000,000, about 5,000,000, or up to about 6,000,000 Da, and any of the lower limits can be combined with any of the upper limits. It is not necessary to isolate one or more specific components of the reaction product mixture. In fact, the reaction product mixture can be used as is. If necessary, any excess crosslinker can be removed by dialysis or precipitation in ethanol.

[0063] In one exemplary embodiment, a biomedical device is provided that includes one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks described herein on its surface. The grafted glycosaminoglycan polymers and / or crosslinked polymer networks may be provided over the entire surface of the biomedical device or over only a portion of the surface of the biomedical device. The grafted glycosaminoglycan polymers and / or crosslinked polymer networks may also be provided within the structure of the biomedical device. As used herein, the term "biomedical device" should be understood to mean any article designed for use in or on mammalian tissue or body fluid, preferably human tissue or body fluid. Representative examples of biomedical devices include, but are not limited to, artificial ureters, diaphragms, intrauterine contraceptive devices, heart valves, catheters, denture liners, prosthetic devices, and ophthalmic lens applications, where the lenses are intended for direct placement in or on the eye, such as intraocular devices and contact lenses. In one exemplary embodiment, the biomedical device is an ophthalmic device, particularly a contact lens, and most particularly a contact lens made from a silicone hydrogel.

[0064] As used herein, the term "ophthalmic device" refers to a device that resides in and on the eye. These devices can provide optical correction, wound care, tissue repair, drug delivery, diagnostic functions, or cosmetic enhancement or effect, or a combination of these properties. Useful ophthalmic devices include, but are not limited to, ophthalmic lenses, such as soft contact lenses (e.g., hydrogel soft lenses and non-hydrogel soft lenses), hard contact lenses (e.g., gas-permeable hard lens materials), intraocular lenses, overlay lenses, intraocular inserts, optical inserts, and viscoelastics. As will be understood by those skilled in the art, a lens is considered "soft" if it can fold back on itself without breaking.

[0065] The biomedical device whose surface is modified according to the present invention can be any material known in the art that can form the above-mentioned biomedical device.In one embodiment, the biomedical device includes a device formed from a material that is not itself hydrophilic.Such a device is formed from a material known in the art, for example, polysiloxane, perfluoropolyether, for example, fluorinated poly(meth)acrylate or equivalent fluorinated polymer derived from other polymerizable carboxylic acids, polyalkyl(meth)acrylate or equivalent alkylester polymer derived from other polymerizable carboxylic acids, or fluorinated polyolefins such as fluorinated ethylene propylene polymers, or tetrafluoroethylene, preferably tetrafluoroethylene combined with dioxole, for example, perfluoro-2,2-dimethyl-1,3-dioxole. Representative examples of suitable bulk materials include Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon, Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon, or Teflon AF. AF) materials, such as, but not limited to, Teflon AF1600 or Teflon AF2400, which are copolymers of about 63 to about 73 mol % perfluoro-2,2-dimethyl-1,3-dioxole and about 37 to about 27 mol % tetrafluoroethylene, or copolymers of about 80 to about 90 mol % perfluoro-2,2-dimethyl-1,3-dioxole and about 20 to about 10 mol % tetrafluoroethylene.

[0066] In another embodiment, the biomedical device includes an ophthalmic device formed from a material that is itself hydrophilic because reactive groups, such as carboxyl, carbamoyl, sulfate, sulfonate, phosphate, amine, ammonium, or hydroxyl groups, are inherently present in the material and are also present on the surface of the biomedical device produced therefrom. Such ophthalmic devices are formed from materials known in the art, including, for example, polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinylpyrrolidone (PVP), polyacrylic acid, polymethacrylic acid, polyacrylamide, polydimethylacrylamide (DMA), polyvinyl alcohol, etc., as well as copolymers thereof, for example, formed from two or more monomers selected from hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinylpyrrolidone, acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, vinyl alcohol, etc. Representative examples of suitable bulk materials include, but are not limited to, Polymacon, Tefilcon, Methafilcon, Deltafilcon, Bufilcon, Phemfilcon, Ocufilcon, Focofilcon, Etafilcon, Hefilcon, Vifilcon, Tetrafilcon, Perfilcon, Droxifilcon, Dimefilcon, Isofilcon, Mafilcon, Nelfilcon, Atlafilcon, and the like. Examples of other suitable bulk materials include Balafilcon A, Hilafilcon A, Alphafilcon A, Bilafilcon B, Samfilcon A, and the like.

[0067] In another embodiment, the surface-modified biomedical device includes a device formed from a material that is an amphiphilic segmented copolymer containing at least one hydrophobic segment and at least one hydrophilic segment, which are linked via bonds or bridging members.

[0068] The biocompatible materials herein are particularly useful for both soft and hard materials commonly used in ophthalmic lenses, including contact lenses.Generally, non-hydrogel materials are hydrophobic polymeric materials that do not contain water in their equilibrium state.Typical non-hydrogel materials include silicone acrylics, such as those made from bulky silicone monomers (e.g., tris(trimethylsiloxy)silylpropyl methacrylate, commonly known as "TRIS" monomer), methacrylate end-capped poly(dimethylsiloxane) prepolymers, or silicones with fluoroalkyl side groups (polysiloxanes are also commonly known as silicone polymers).

[0069] Hydrogel materials, on the other hand, comprise hydrated crosslinked polymer systems containing water in an equilibrium state. Hydrogel materials contain about 5% or more by weight of water (e.g., up to about 80% by weight). Preferred hydrogel materials include silicone hydrogel materials. In one preferred embodiment, the materials include vinyl-functionalized polydimethylsiloxane copolymerized with hydrophilic monomers, and fluorinated methacrylate and methacrylate-functionalized fluorinated polyethylene oxide copolymerized with hydrophilic monomers. Representative examples of suitable materials for use herein include those disclosed in U.S. Pat. Nos. 5,310,779, 5,387,662, 5,449,729, 5,512,205, 5,610,252, 5,616,757, 5,708,094, 5,710,302, 5,714,557, and 5,908,906, the contents of which are incorporated herein by reference.

[0070] In one embodiment, hydrogel materials for biomedical devices such as contact lenses can contain hydrophilic monomers, such as one or more unsaturated carboxylic acids, vinyl lactams, amides, polymerizable amines, vinyl carbonates, vinyl carbamates, oxazolone monomers, copolymers thereof, and mixtures thereof. Useful amides include acrylamides, such as N,N-dimethylacrylamide and N,N-dimethylmethacrylamide. Useful vinyl lactams include cyclic lactams such as N-vinyl-2-pyrrolidone. Other examples of hydrophilic monomers include hydrophilic prepolymers, such as poly(alkene glycols) functionalized with polymerizable groups. Examples of useful functionalized poly(alkene glycols) include poly(diethylene glycols) of various chain lengths containing monomethacrylate or dimethacrylate end caps. In a preferred embodiment, the poly(alkene glycol) polymer contains at least two alkene glycol monomer units. Still further examples are the hydrophilic vinyl carbonate or hydrophilic vinyl carbamate monomers disclosed in U.S. Patent No. 5,070,215 and the hydrophilic oxazolone monomers disclosed in U.S. Patent No. 4,910,277. Other suitable hydrophilic monomers will be apparent to those skilled in the art. In another embodiment, the hydrogel material can contain a siloxane-containing monomer and at least one of the aforementioned hydrophilic monomers and / or prepolymers.

[0071] Non-limiting examples of hydrophobic monomers include C1-C 20 Alkyl and C3-C 20 Cycloalkyl (meth)acrylates, substituted and unsubstituted aryl (meth)acrylates (wherein the aryl group contains 6 to 36 carbon atoms), (meth)acrylonitrile, styrene, lower alkyl styrene, lower alkyl vinyl ether, and C2 to C6 10 There are perfluoroalkyl(meth)acrylates and the corresponding partially fluorinated (meth)acrylates.

[0072] A wide variety of materials can be used herein, with silicone hydrogel contact lens materials being particularly preferred. Silicone hydrogels generally have a water content greater than about 5% by weight, more typically about 10 to about 80% by weight. Such materials are typically prepared by polymerizing a mixture containing at least one silicone-containing monomer and at least one hydrophilic monomer. Typically, the silicone-containing monomer or the hydrophilic monomer functions as the crosslinker (a crosslinker is defined as a monomer having multiple polymerizable functional groups), or a separate crosslinker may be used. Applicable silicone-containing monomers for use in forming silicone hydrogels are well known in the art, with many examples provided in U.S. Pat. Nos. 4,136,250, 4,153,641, 4,740,533, 5,034,461, 5,070,215, 5,260,000, 5,310,779, and 5,358,995.

[0073] Representative examples of applicable silicon-containing monomers include bulky polysiloxanyl alkyl (meth)acrylic monomers. Examples of bulky polysiloxanyl alkyl (meth)acrylic monomers are represented by the structure of Formula I: [ka] In the formula, X represents -O- or -NR-, R represents hydrogen or C1-C4 alkyl, and each R 1 independently represent hydrogen or methyl, and each R 2 independently represent a lower alkyl radical, a phenyl radical, or a group represented by the formula: [ka] In the formula, each R 2’ independently represent a lower alkyl or phenyl radical, and h is 1 to 10.

[0074] Representative examples of other applicable silicon-containing monomers generally include, but are not limited to, bulky polysiloxanyl alkylcarbamate monomers as shown in Formula Ia: [ka] In the formula, X represents -NR-, R represents hydrogen or C1-C4 alkyl, and R 1 represents hydrogen or methyl, and each R 2 independently represent a lower alkyl radical, a phenyl radical, or a group represented by the formula: [ka] In the formula, each R 2’ independently represent a lower alkyl or phenyl radical, h is 1-10, etc.

[0075] Examples of bulky monomers include 3-methacryloyloxypropyltris(trimethyl-siloxy)silane or tris(trimethylsiloxy)silylpropyl methacrylate (sometimes referred to as TRIS), and tris(trimethylsiloxy)silylpropyl vinylcarbamate (sometimes referred to as TRIS-VC), and mixtures thereof.

[0076] Such bulky monomers may be copolymerized with silicone macromonomers, which are poly(organosiloxanes) capped with unsaturated groups at two or more ends of the molecule. U.S. Patent No. 4,153,641 discloses various unsaturated groups, such as acryloxy or methacryloxy groups.

[0077] Another class of representative silicone-containing monomers includes, but is not limited to, silicone-containing vinyl carbonate or vinyl carbamate monomers such as 1,3-bis[4-vinyloxycarbonyloxy]but-1-yl]tetramethyldisiloxane, 3-(trimethylsilyl)propyl vinyl carbonate, 3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane], 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate, 3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate, 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbonate, t-butyldimethylsiloxyethyl vinyl carbonate, trimethylsilylethyl vinyl carbonate, trimethylsilylmethyl vinyl carbonate, and the like, and mixtures thereof.

[0078] Another type of silicon-containing monomer includes polyurethane-polysiloxane macromonomers (sometimes referred to as prepolymers), which can have a hard-soft-hard block structure like conventional urethane elastomers. These may be end-capped with hydrophilic monomers such as HEMA. Examples of such silicone urethanes are disclosed in various publications, including Lai, Yu-Chin, "The Role of Bulky Polysiloxanylalkyl Methacryates in Polyurethane-Polysiloxane Hydrogels," Journal of Applied Polymer Science, Vol. 60, 1193-1199 (1996). PCT Published Application No. WO 96 / 31792 discloses examples of such monomers, the entire disclosure of which is incorporated herein by reference. Further examples of silicone urethane monomers are represented by Formulae II and III: E(*D*A*D*G) a *D*A*D*E', or (II) E(*D*G*D*A) a *D*A*D*E', or (III) During the ceremony, D independently represents an alkyl diradical, alkylcycloalkyl diradical, cycloalkyl diradical, aryl diradical, or alkylaryl diradical having from 6 to about 30 carbon atoms; G independently represents an alkyl diradical, cycloalkyl diradical, alkylcycloalkyl diradical, aryl diradical, or alkylaryl diradical having from 1 to about 40 carbon atoms, which may contain ether, thio, or amine linkages in the backbone; * represents a urethane or ureido bond, a is at least 1, A independently represents a divalent polymerizable radical of formula IV: [ka] In the formula, each R S independently represent an alkyl or fluoro-substituted alkyl group having 1 to about 10 carbon atoms which may contain ether linkages between the carbon atoms; m' is at least 1; and p is a number providing a moiety weight of from about 400 to about 10,000; Each of E and E′ independently represents a polymerizable unsaturated organic radical represented by formula V: [ka] In the formula, R 3 is hydrogen or methyl, R 4 is hydrogen, an alkyl radical having 1 to 6 carbon atoms, or -CO-YR 6 is a radical, and Y is —O—, —S—, or —NH—; R 5 is a divalent alkylene radical having 1 to about 10 carbon atoms; R 6 is an alkyl radical having 1 to about 12 carbon atoms; X represents -CO- or -OCO-; Z represents -O- or -NH-; Ar represents an aromatic radical having from about 6 to about 30 carbon atoms; w is 0 to 6, x is 0 or 1, y is 0 or 1, and z is 0 or 1.

[0079] A preferred silicone-containing urethane monomer is represented by Formula VI: [ka] In the formula, m is at least 1, preferably 3 or 4, a is at least 1, preferably 1, p is a number providing a site weight of about 400 to about 10,000, preferably at least about 30, and R 7 is the diradical of a diisocyanate after removal of an isocyanate group, such as the diradical of isophorone diisocyanate, and each E" is a group represented by: [ka]

[0080] In another embodiment of the present invention, the silicone hydrogel material comprises (in bulk, i.e., in the copolymerized monomer mixture) about 5 to about 50 weight percent, preferably about 10 to about 25 weight percent, of one or more silicone macromonomers; about 5 to about 75 weight percent, preferably about 30 to about 60 weight percent, of one or more polysiloxanylalkyl(meth)acrylic monomers; and about 10 to about 50 weight percent, preferably about 20 to about 40 weight percent, of a hydrophilic monomer. Generally, silicone macromonomers are poly(organosiloxanes) capped with unsaturated groups at two or more ends of the molecule. In addition to the end groups in the above structural formula, U.S. Pat. No. 4,153,641 discloses additional unsaturated groups, including acryloxy or methacryloxy. Fumarate-containing materials, such as those disclosed in U.S. Pat. Nos. 5,310,779, 5,449,729, and 5,512,205, are also useful substrates according to the present invention. The silane macromonomer may be a silicon-containing vinyl carbonate or vinyl carbamate, or a polyurethane-polysiloxane having one or more hard-soft blocks and end-capped with a hydrophilic monomer.

[0081] Another class of representative silicone-containing monomers includes fluorinated monomers. Such monomers have been used in the formation of fluorosilicone hydrogels to reduce the buildup of deposits on contact lenses made therefrom, as disclosed, for example, in U.S. Patent Nos. 4,954,587, 5,010,141, 5,079,319, and 7,994,356. Also, certain fluorinated side groups, i.e., The use of silicone-containing monomers having -(CF2)-H has been found to improve compatibility between the hydrophilic and silicone-containing monomer units. See, for example, U.S. Patent Nos. 5,321,108 and 5,387,662.

[0082] The silicone materials listed above are merely exemplary, and other materials for use as substrates that can benefit from coating with a hydrophilic coating composition according to the present invention and that are disclosed in various publications and are continually being developed for use in contact lenses and other medical devices can also be used. For example, the biomedical device can be formed from at least a cationic monomer, such as a cationic silicone-containing monomer or a cationic fluorinated silicone-containing monomer.

[0083] Contact lenses for application in the present invention can be manufactured using various conventional techniques to obtain molded articles with the desired posterior and anterior lens surfaces. Spin-casting methods are disclosed in U.S. Patent Nos. 3,408,429 and 3,660,545, and static-casting methods are disclosed in U.S. Patent Nos. 4,113,224, 4,197,266, and 5,271,876. Following curing of the monomer mixture, machining operations can be performed to provide a contact lens with the desired final configuration. For example, U.S. Patent No. 4,555,732 discloses a process in which an excess monomer mixture is spin-cast into a mold and cured to form a molded article with an anterior lens surface and a relatively large thickness. The posterior surface of the cured spin-cast article is then lathe-cut to provide a contact lens with the desired thickness and posterior lens surface. Lathe-cutting the lens surface may be followed by further machining operations, such as edge-finishing.

[0084] Typically, an organic diluent is included in the initial monomer mixture to minimize phase separation in the polymerization product produced by polymerization of the monomer mixture and to lower the glass transition temperature of the reacting polymer mixture, allowing for a more efficient curing process and ultimately resulting in a more uniform polymerization product. Sufficient uniformity of the initial monomer mixture and polymerization product is particularly important for silicone hydrogels, as they contain primarily silicone-containing monomers that may tend to separate from the hydrophilic comonomers.

[0085] Suitable organic diluents include, for example, C6 to C 10 Included are linear aliphatic monohydric alcohols such as n-hexanol and n-nonanol, diols such as ethylene glycol, polyols such as glycerin, ethers such as diethylene glycol monoethyl ether, ketones such as methyl ethyl ketone, esters such as methyl enanthate, and hydrocarbons such as toluene. Preferably, the organic diluent is sufficiently volatile to facilitate removal from the cured article by evaporation at or near ambient pressure.

[0086] Generally, the diluent may comprise from about 5 to about 60 weight percent of the monomer mixture, with from about 10 to about 50 weight percent being particularly preferred. If desired, the cured lens can be subjected to solvent removal, which can be accomplished by evaporation at or near ambient pressure or under vacuum. High temperatures can be used to reduce the time required to evaporate the diluent.

[0087] After the organic diluent is removed, the lens may then be released from the mold and subjected to an optional machining operation. Machining steps include, for example, buffing or polishing the lens edge and / or surface. Generally, such machining processes may be performed before or after the article is released from the mold parts. As an example, the lens may be dry-released from the mold by using vacuum tweezers to lift the lens from the mold.

[0088] As those skilled in the art will readily understand, the biomedical device surface functional groups of the biomedical devices disclosed herein may be inherently present on the device surface. However, if the biomedical device contains too few or no functional groups, the device surface can be modified, for example, by plasma chemical methods (see, for example, WO94 / 06485) or by conventional functionalization with groups such as -OH or -COH. Suitable biomedical device surface functional groups of biomedical devices include a wide variety of groups well known to those skilled in the art. Representative examples of such functional groups include, but are not limited to, hydroxy groups, cis-1,2-diols, cis-1,3-diols, alpha-hydroxy acid groups (e.g., sialic acid, salicylic acid), carboxylic acids, dicarboxylic acids, catechols, silanols, silicates, and the like.

[0089] In one embodiment, the biomedical device is subjected to an oxidative surface treatment, such as corona discharge or plasma oxidation, followed by treatment with one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks as disclosed herein. For example, a biomedical device, such as a silicone hydrogel formulation containing a hydrophilic polymer (e.g., poly(N,N-dimethylacrylamide) or poly(N-vinylpyrrolidone)), is subjected to an oxidative surface treatment to form silicates on at least the lens surface, and then the lens is treated with an aqueous solution containing one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks as disclosed herein to provide a lubricating, stable, and highly wettable surface coating. The complex formation treatment is advantageously carried out under autoclave conditions (sterile conditions).

[0090] Standard processes, such as plasma processes (also referred to as "electrical glow discharge processes"), provide a thin, durable surface on a biomedical device prior to bonding one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks to at least a portion of the surface. Examples of such plasma processes are provided in U.S. Patent Nos. 4,143,949, 4,312,575, and 5,464,667.

[0091] Plasma processes are generally well known in the art, but a brief overview is provided below. Plasma surface treatment involves passing a gas through an electric discharge at low pressure. The discharge may be radio-frequency (typically 13.56 MHz), although microwave and other frequencies may be used. The discharge generates ultraviolet (UV) radiation, which, in addition to being absorbed by the gaseous atoms and molecules, generates energetic electrons and ions, atoms (ground and excited), molecules, and radicals. Thus, plasma is a complex mixture of atoms and molecules in both ground and excited states that reaches a steady state after the discharge is initiated. The circulating electric field causes these excited atoms and molecules to collide not only with each other but also with the walls of the chamber and the surface of the material being treated.

[0092] It has been shown that deposition of coatings onto material surfaces from plasmas is possible from high-energy plasmas without the assistance of sputtering (sputter-assisted deposition). Monomers can be deposited from the gas phase and polymerized onto substrates using continuous or pulsed plasmas, preferably up to about 1000 watts, in low-pressure atmospheres (about 0.005 to about 5 Torr, preferably about 0.001 to about 1 Torr). For example, modulated plasmas can be applied on for about 100 milliseconds and then off. In addition, liquid nitrogen cooling can be used to condense vapors from the gas phase onto the substrate, and then plasma is used to chemically react these materials with the substrate. However, plasmas do not require the use of external cooling or heating to induce deposition. Low- or high-wattage plasmas (e.g., about 5 to about 1000 watts, preferably about 20 to about 500 watts) can coat even the most chemically resistant substrates, including silicones.

[0093] After initiation by a low-energy discharge, collisions between energetic free electrons present in the plasma result in the formation of ions, excited molecules, and free radicals. Once formed, such species can react not only with themselves in the gas phase but also with additional ground-state molecules. Plasma processing can be understood as an energy-dependent process involving energetic gas molecules. For chemical reactions to occur at the lens surface, the required species (elements or molecules) are required in terms of charge state and particle energy. Radio frequency plasmas generally generate a distribution of energetic species. Typically, "particle energy" refers to the average of the so-called Boltzmann energy distribution for the energetic species. In low-density plasmas, the electron energy distribution can be related by the ratio (E / p) of the electric field strength sustaining the plasma to the emission pressure. As understood by those skilled in the art, the plasma power density P is a function of wattage, pressure, gas flow rate, etc.Background information regarding plasma technology is incorporated herein by reference and includes the following: A.T. Bell, Proc. Intl. Conf. Phenom. Ioniz. Gases, "Chemical Reaction in Nonequilibrium Plasmas", 19-33 (1977); J.M. Tibbitt, R. Jensen, A.T. Bell, M. Shen, Macromolecules, "A Model for the Kinetics of Plasma Polymerization", 3, 648-653 (1977); J.M. Tibbitt, M. Shen, A.T. Bell, J. Macromol. Sci.-Chem., "Structural Characterization of Plasma-Polymerized Hydrocarbons", A10, 1623-1648 (1976); C.P. Ho, H. Yasuda, J. Biomed. Mater. Res., "Ultrathin coating of plasma polymer of methane applied on the surface of silicone contact lenses”, 22, 919-937 (1988); H. Kobayashi, A.T. Bell, M. Shen, Macromolecules, “Plasma Polymerization of Saturated and Unsaturated Hydrocarbons”, 3, 277-283 (1974); R.Y. Chen, U.S. Patent No. 4,143,949, March 13, 1979, “Process for Putting a Hydrophilic Coating on a Hydrophobic Contact Lens”, and H. Yasuda, H.C. Marsh, M.O. Bumgarner, N. Morosoff, J. of Appl. Poly. Sci., “Polymerization of Organic Compounds in an Electroless Glow Discharge. VI. Acetylene with Unusual Co-monomers”, 19, 2845-2858 (1975).

[0094] Based on this previous work in the field of plasma technology, we can understand the effect of changes in pressure and discharge power on the rate of plasma modification. As pressure increases, the rate generally decreases. Thus, as pressure increases, the ratio of the field strength that sustains the plasma to the gas pressure decreases, causing a decrease in the average electron energy. The decrease in electron energy causes a decrease in the rate coefficients of all electron-molecule collision processes. A further consequence of increasing pressure is a decrease in electron density. If pressure is held constant, there should be a linear relationship between electron density and power.

[0095] In practice, contact lenses are surface treated by placing the contact lenses in an unhydrated state in a glow discharge reactor (e.g., a vacuum chamber). Such reactors are commercially available. The lenses can be supported in the reactor on an aluminum tray (which acts as an electrode) or other support devices designed to adjust the position of the lenses. The use of special support devices that allow surface treatment on both sides of the lenses is known in the art and can be used herein.

[0096] As described above, the surface of a lens, e.g., a silicone hydrogel continuous wear lens, is first treated, e.g., oxidized, by the use of plasma to facilitate the subsequent deposition of grafted glycosaminoglycan polymer and / or crosslinked polymer network layers on the lens. Such plasma treatment of the lens can be accomplished in an atmosphere of a suitable medium, e.g., an oxidizing medium such as oxygen, air, water, peroxide, O2 (oxygen gas), or a suitable combination thereof, typically at a discharge frequency of about 13.56 MHz, preferably at about 20 to about 500 watts, at a pressure of about 0.1 to about 1.0 Torr, for a period of about 10 seconds to about 10 minutes or more, more preferably about 1 to about 10 minutes. A relatively "intense" plasma is preferably utilized in this step, e.g., ambient air drawn through a five percent (5%) hydrogen peroxide solution. Those skilled in the art will recognize other methods for improving or promoting the adhesion of the subsequent grafted glycosaminoglycan polymer and / or crosslinked polymer network layers.

[0097] The biomedical device then undergoes a surface treatment. Generally, a biomedical device, such as a wettable silicone-based hydrogel lens, is contacted with a solution containing at least one or more of the grafted glycosaminoglycan polymers and / or one or more of the cross-linked polymer networks disclosed herein, whereby the grafted glycosaminoglycan polymers and / or cross-linked polymer networks form complexes with multiple biomedical device surface functional groups on the surface of the biomedical device. The biomedical device can be contacted with the solution containing at least one or more of the grafted glycosaminoglycan polymers and / or one or more of the cross-linked polymer networks directly within the mold assembly, or the biomedical device can be released from the mold assembly and then contacted with the solution. This solution may be an aqueous solution containing one or more of the grafted glycosaminoglycan polymers and / or one or more of the cross-linked polymer networks, which can provide a lubricating, stable, and highly wettable surface. The complex formation treatment is advantageously carried out under autoclave conditions.

[0098] Solutions generally include eye drop solutions and contact lens treatment solutions that are instilled directly into the eye, such as for rewetting contact lenses during wear, as well as compositions for instillation directly into the eye, including those that qualify as multi-purpose solutions. Ophthalmic compositions also include compositions that are instilled indirectly into the eye, such as contact lens treatment solutions for treating contact lenses before they are inserted on the eye, or packaging solutions for storing lenses.

[0099] In exemplary embodiments, the aqueous ophthalmic composition has an osmolality in the range of about 200 mOsmol / kg to about 500 mOsmol / kg and is in the form of an eye care or contact lens care product selected from the group consisting of eye drops, contact lens preservative solution, contact lens cleaning solution, and contact lens multi-purpose solution.

[0100] The ophthalmically acceptable solution disclosed herein is physiologically compatible. Specifically, the composition must be "ophthalmically safe" for use with contact lenses, meaning that the contact lenses treated with the solution are generally suitable and safe for direct placement on the eye without rinsing, i.e., the solution is safe and comfortable for daily contact with the eye through a contact lens wetted with the solution. An ophthalmically safe composition has a tonicity and pH that is compatible with the eye and contains materials and amounts thereof that are non-cytotoxic in accordance with ISO (International Organization for Standardization) standards and US FDA regulations. The composition must be sterile, in that the absence of microbial contaminants in the product prior to release must be statistically demonstrated to the extent required for such products.

[0101] Generally, one or more of the grafted glycosaminoglycan polymers and / or one or more of the crosslinked polymer networks disclosed herein may be present in the ophthalmic solution in an amount ranging from about 0.001 to about 10% w / w. In another embodiment, one or more of the grafted glycosaminoglycan polymers and / or one or more of the crosslinked polymer networks disclosed herein may be present in the ophthalmic solution in an amount ranging from about 0.1 to about 2% w / w.

[0102] Ophthalmic solutions may be in the form of drops and are useful as components of contact lens cleaning, disinfecting, or conditioning compositions containing such materials. In one embodiment, the compositions and / or solutions disclosed herein may be formulated as "multi-purpose solutions." Multi-purpose solutions are useful for cleaning, disinfecting, storing, and rinsing lenses, particularly soft contact lenses. Multi-purpose solutions do not preclude the possibility that some wearers, such as those particularly sensitive to chemical disinfectants or other chemical agents, may prefer to clean or wet their contact lenses with a separate solution, such as sterile saline, before inserting the lenses. The term "multi-purpose solution" also does not preclude the possibility of routine cleaning agents not used daily, or supplemental cleaning agents for further protein removal, such as enzymatic cleaners typically used weekly. The term "cleaning" means that the solution contains one or more agents in a concentration sufficient to loosen and remove loosely held lens deposits and other contaminants on the surface of the contact lens, which may be used in combination with a finger action (e.g., manual rubbing of the lens with the solution) or an accessory device that agitates the solution in contact with the lens, e.g., a mechanical cleaning aid.

[0103] Conventionally, commercially available multi-purpose solutions have required a regimen involving mechanical rubbing of lenses with the multi-purpose solution to provide the necessary disinfection and cleaning. Such regimens are required under government regulatory authorities (e.g., the FDA or the U.S. Food and Drug Administration (FDA)) for chemical disinfection systems that do not qualify as chemical disinfecting solutions. In one embodiment of the present invention, a cleaning and disinfecting product can be formulated that can provide improved cleaning and disinfection without a rubbing regimen, while being gentle enough to be used as a wetting agent, such as an eye drop. For example, a product that qualifies as a chemical disinfecting solution must meet the germicidal performance standards established by the U.S. FDA (May 1, 1997) for contact lens care products, which do not involve rubbing of the lenses. In one embodiment of the present invention, the composition is formulated to meet the requirements of the FDA or ISO stand-alone procedures for contact lens disinfection products. Similarly, the compositions disclosed herein can be formulated to provide enhanced cleaning without the use of a rubbing regimen. Such a formulation may ensure higher patient compliance and greater universal appeal than conventional multi-purpose disinfecting and cleaning products. The multi-purpose solution can have a viscosity of less than about 75 cps, or from about 1 to about 50 cps, or from about 1 to about 25 cps, or at least about 95 weight / volume percent water in the total composition.

[0104] In addition to one or more of the grafted glycosaminoglycan polymers and / or one or more of the crosslinked polymer networks disclosed herein, the aqueous ophthalmic solution may contain one or more antimicrobial agents, preservatives, etc. The composition generally includes a primary antimicrobial agent. Suitable antimicrobial agents for use in the present invention include chemicals that derive their antimicrobial activity through chemical or physical interactions with microorganisms. These agents may be used alone or in combination.

[0105] Suitable known ophthalmically acceptable antimicrobial agents include, but are not limited to, biguanides or salts or free bases thereof, quaternary ammonium compounds or salts or free bases thereof, terpenes or derivatives thereof, branched glycerol monoalkyl ethers, branched glycerol monoalkyl amines, branched glycerol monoalkyl sulfides, fatty acid monoesters (fatty acid monoesters comprising an aliphatic fatty acid moiety having 6 to 14 carbon atoms and an aliphatic hydroxyl moiety), amidoamine compounds, and the like, and combinations thereof.

[0106] The biguanide antibacterial agent suitable for use in the ophthalmic composition can be any biguanide or its salt known in the art.Representative biguanides include non-polymeric biguanides, polymeric biguanides, and their salts, as well as their free bases, and mixtures thereof.Representative non-polymeric biguanides are bis(biguanides), such as alexidine, chlorhexidine, alexidine salts, such as alexidine HCl, chlorhexidine salts, alexidine free base, and mixtures thereof.Alexidine and chlorhexidine salts can be either organic or inorganic, and are typically bactericidal nitrates, acetates, phosphates, sulfates, halides, and the like.

[0107] Representative polymeric biguanides include polymeric hexamethylene biguanide (PHMB) (commercially available from Zeneca, Wilmington, Del.), their polymers, and water-soluble salts. In one embodiment, the water-soluble polymeric biguanides for use herein can have a number-average molecular weight of at least about 1,000, or from about 1,000 to about 50,000. Suitable water-soluble salts of the free base include, but are not limited to, hydrochloride, borate, acetate, gluconate, sulfonate, tartrate, and citrate. Hexamethylene biguanide polymers, also commonly referred to as polyaminopropyl biguanide (PAPB), have number-average molecular weights of up to about 100,000. Such compounds are known and are disclosed in U.S. Pat. No. 4,758,595, incorporated herein by reference.

[0108] PHMB, or polyhexamethylene biguanide, is best described as a polymeric biguanide composition containing at least three, and preferably at least six, biguanide polymers, designated PHMB-A, PHMB-CG, and PHMB-CGA, whose general chemical structures are shown below. [ka]

[0109] For each of these polymers, "n" represents the average number of repeating groups. In fact, a distribution of polymer lengths will exist for each of the polymers shown. Traditional synthetic routes to PHMB provided polymeric biguanide compositions with approximately 50% by weight of the polymeric composition as PHMB-CGA, i.e., with a cyanoguanidino end cap at one end and an amine at the other, approximately 25% by weight of PHMB-A, and approximately 25% by weight of PHMB-CG. Given this approximate weight ratio of the three major PHMB polymers, the proportion of cyanoguadino end caps is also approximately 50% of the total number of end groups. In this application, this traditional polymeric biguanide composition is referred to as poly(hexamethylene biguanide) or PHMB.

[0110] 13 Polymeric biguanide compositions containing less than 18 mol% of terminal amine groups as measured by C NMR can also be used. The polymeric biguanide compositions can also be characterized by a relative increase in the molar concentration of terminal guanidine groups or terminal cyanoguarugino groups. For example, in one embodiment, the biguanide composition contains less than about 18 mol% of terminal amine groups and greater than or equal to about 40 mol% of terminal guanidine groups. In another embodiment, the biguanide composition contains less than about 18 mol% of terminal amine groups and greater than or equal to about 55 mol% of terminal guanidine groups.

[0111] In this application, this biguanide composition is referred to as PHMB-CG*, and the polymeric biguanide composition in the general sense is referred to as "hexamethylene biguanide," which those skilled in the art will recognize as including both PHMB and PHMB-CG*.

[0112] Representative examples of suitable quaternary ammonium compounds for use in the ophthalmic compositions of the present invention include, but are not limited to, poly[(dimethyliminio)-2-butene-1,4-diyl chloride] and [4-tris(2-hydroxyethyl)ammonio]-2-butenyl-w-[tris(2-hydroxyethyl)ammonio]-dichloride (Chemical Registry Number 75345-27-6), commonly known as Polyquaternium 1, available under the trade name ONAMER® M (Stepan Company, Northfield, Illinois), and mixtures thereof.

[0113] Terpene antimicrobial agents suitable for use in the ophthalmic compositions of the present invention include any monoterpene, sesquiterpene, and / or diterpene or derivative thereof. Acyclic, monocyclic, and / or bicyclic mono-, sesqui-, and / or diterpenes, as well as those with a higher number of rings, may be used. As used herein, a "derivative" of a terpene should be understood to mean a terpene hydrocarbon having one or more functional groups, such as a terpene alcohol, terpene ether, terpene ester, terpene aldehyde, terpene ketone, etc., and combinations thereof. Both trans and cis isomers are suitable herein. The terpene moiety in the terpenes and derivatives can contain from 6 to about 100 carbon atoms, preferably from about 10 to about 25 carbon atoms.

[0114] Representative examples of suitable terpene alcohol antimicrobial agents include verbenol, trans-pinocarveol, cis-2-pinanol, nopol, isoborneol, carveol, piperitol, thymol, α-terpineol, terpinen-4-ol, menthol, 1,8-terpine, dihydro-terpineol, nerol, geraniol, linalool, citronellol, hydroxycitronellol, 3,7-dimethyloctanol, dihydro-myrcenol, tetrahydro-alloocimenol, perillic alcohol, falcarindiol, and the like, and mixtures thereof.

[0115] Representative examples of suitable terpene ether and terpene ester antimicrobial agents include 1,8-cineole, 1,4-cineole, isobornyl methyl ether, rosopyran, α-terpinyl methyl ether, menthofuran, trans-anethole, methyl chavicol, allocimene diepoxide, limonene monoepoxide, isobornyl acetate, nonyl acetate, α-terpinyl acetate, linalyl acetate, geranyl acetate, citronellyl acetate, dihydro-terpinyl acetate, meryl acetate, and the like, and mixtures thereof.

[0116] Representative examples of terpene aldehyde and terpene ketone antimicrobial agents include myrtenal, campholenic aldehyde, perillaldehyde, citronellal, citral, hydroxycitronellal, camphor, verbenone, carbenone, dihydrocarvone, carvone, piperitone, menthone, geranylacetone, pseudoionone, α-ionine, isopseudo-methylionone, n-pseudo-methylionone, iso-methylionone, n-methylionone, and the like, and mixtures thereof. Any other terpene hydrocarbons having functional groups known in the art may be used in the compositions of the present invention herein.

[0117] In one embodiment, terpenes or derivatives thereof suitable as antimicrobial agents include tricyclene, α-pinene, terpinolene, carveol, amyl alcohol, nerol, β-santalol, citral, pinene, nerol, β-ionone, caryophyllene (from clove), guaiol, anisaldehyde, cedrol, linalool, d-limonene (orange oil, lemon oil), longifolene, anisyl alcohol, patchouli alcohol, α-cadinene, 1,8-cineole, ρ-cymene, 3-carene, ρ-8-menthane, trans-menthone, borneol, α-fenchol, isoamyl acetate, terpine, ketone ... These include, but are not limited to, hyalaldehyde, ionones, geraniol (derived from roses and other flowers), myberry wax (derived from bayberry wax, bay laurel, and verbena oil), nerol, citronellol, carbachol, eugenol, carvone, α-terpineol, anethole, camphor, menthol, limonene, nerolidol, farnesol, phytol, carotene (vitamin A1), squalene, thymol, tocotrienols, perillyl alcohol, borneol, cymene, carene, terpenes, linalool, 1-terpene-4-ol, zingiberene (derived from ginger), and mixtures thereof.

[0118] In one embodiment, the compound of component (ii) of the ophthalmic composition comprises a branched glycerol monoalkyl ether. In another embodiment, the compound of component (ii) of the ophthalmic composition comprises a branched glycerol monoalkyl amine. In another embodiment, the compound of component (ii) of the ophthalmic composition comprises a branched glycerol monoalkyl sulfide. In yet another embodiment, the compound of component (ii) of the ophthalmic composition comprises a mixture of any one of a branched glycerol monoalkyl ether, a branched glycerol monoalkyl amine, or a branched glycerol monoalkyl sulfide.

[0119] In one embodiment, the branched glycerol monoalkyl ether for use in the ophthalmic composition of the present invention is 3-[(2-ethylhexyl)oxy]-1,2-propanediol (EHOPD). In another embodiment, the branched glycerol monoalkylamine is 3-[(2-ethylhexyl)amino]-1,2-propanediol (EHAPD). In another embodiment, the branched glycerol monoalkyl sulfide is 3-[(2-ethylhexyl)thio]-1,2-propanediol (EHSPD). In yet another embodiment, the ophthalmic composition comprises a mixture of any one of EHOPD, EHAPD, and EHSPD. The chemical structures of EHOPD, EHAPD, and EHSPD are set forth below. [ka]

[0120] EHOPD, also known as octoxyglycerin, is sold under the trade name Sensiva® SC50 (Schulke & Mayr). EHOPD is a branched glycerol monoalkyl ether that is mild to the skin and known to exhibit antibacterial activity against various Gram-positive bacteria, including Micrococcus luteus, Corynebacterium aquaticum, Corynebacterium flavescens, Corynebacterium callunae, and Corynebacterium nephredi. Therefore, EHOPD is used in various skin deodorant formulations at concentrations of approximately 0.2 to 3 percent by weight. EHAPD can be prepared from 2-ethylhexylamine and 2,3-epoxy-1-propanediol using chemistry well known to those skilled in the art. EHSPD can be prepared from 2-ethylhexylthiol and 2,3-epoxy-1-propanediol using chemistry well known to those skilled in the art.

[0121] Fatty acid monoesters suitable for use in the ophthalmic compositions disclosed herein include fatty acid monoesters comprising an aliphatic fatty acid moiety having 6 to 14 carbon atoms and an aliphatic hydroxyl moiety.

[0122] The term "aliphatic" refers to a straight-chain or branched-chain, saturated or unsaturated hydrocarbon having 6 to 14 carbon atoms. In one embodiment, the aliphatic fatty acid moiety is a straight-chain, saturated or unsaturated hydrocarbon having 8 to 10 carbon atoms. In another embodiment, the aliphatic fatty acid moiety is a branched-chain, saturated or unsaturated hydrocarbon having 8 to 10 carbon atoms.

[0123] The aliphatic hydroxyl moiety of the fatty acid monoester can be any aliphatic compound having at least one hydroxyl group. In many embodiments, the aliphatic hydroxyl moiety has 3 to 9 carbon atoms. The aliphatic hydroxyl moiety can include, but is not limited to, propylene glycol, glycerol, polyalkylene glycols such as polyethylene glycol or polypropylene glycol, cyclic polyols such as sorbitan, glucose, mannose, sucrose, fructose, fucose, and inisitol, and derivatives thereof, and linear polyols such as mannitol and sorbitol, and derivatives thereof, and mixtures thereof.

[0124] Representative examples of amidoamines suitable for use in the ophthalmic compositions disclosed herein include those amidoamines of the following general formula: R 15 -(OCH2CH2) m -X-(CH2) n -Y(wherein, R 15 C6~C 30 is a saturated or unsaturated hydrocarbon, examples of which include straight or branched chain, substituted or unsubstituted alkyl, alkylaryl, or alkoxyaryl groups; m is 0 to 16; n is 2 to 16; and X is -C(O)-NR 16 -or-R 16 NC(O)- and Y is -N(R17 )2 and R 16 and R 17 wherein each is independently hydrogen, C1-C8 saturated or unsaturated alkyl, or hydroxyalkyl), or a pharmaceutically acceptable salt thereof.

[0125] Some of the amidoamines utilized in the present invention are available from commercial sources. For example, myristamidopropyl dimethylamine is available from Alcon Inc. (Fort Worth, Texas) under the trade name Aldox®, lauramidopropyl dimethylamine is available from Inolex Chemical Company (Philadelphia, Pennsylvania) under the trade name LEXAMINE® L-13, and stearamidopropyl dimethylamine is also available from Inolex Chemical Company as LEXAMINE® S-13. The above-mentioned amidoamines can be synthesized according to known techniques, including those described in U.S. Pat. No. 5,573,726.

[0126] The amount of primary antimicrobial agent may vary depending on the specific agent used. For the aforementioned organic nitrogen-containing agents, such agents are typically present in concentrations ranging from about 0.00001 to about 0.5% by weight, or from about 0.00003 to about 0.05% by weight. For sorbic acid, higher amounts, typically from about 0.01 to about 1% by weight, or from about 0.1 to about 0.5% by weight, may be required. Preferably, the antimicrobial agent is used in an amount that at least partially reduces the microbial population in the formulation being used. If desired, the antimicrobial agent can be used in a disinfecting amount that reduces the microbial bioburden by at least 2 log orders in 4 hours, and more preferably by 1 log order in 1 hour. Most preferably, the disinfecting amount is an amount that eliminates the microbial bioburden on contact lenses when used in the recommended soaking time regimen (FDA Chemical Disinfection Effectiveness Testing - Contact Lens Solution Draft Guidelines, July 1985).

[0127] The aqueous solutions may further contain one or more other ingredients commonly present in ophthalmic solutions, such as surfactants, tonicity adjusting agents, buffers, chelating agents, pH adjusters, viscosity adjusters, and demulcents, as discussed above, and which help make the ophthalmic compositions more comfortable for the user and / or more effective for their intended use.

[0128] The pH of the solutions and / or compositions disclosed herein may be maintained within the range of about 4.0 to about 9.0, or about 5.0 to about 8.0, or about 6.0 to about 8.0, or about 6.5 to about 7.8. In one embodiment, the pH value is at most about 7 or greater.

[0129] In one embodiment, the biomedical device is transferred to an individual lens package containing a buffered saline solution containing at least one of the grafted glycosaminoglycan polymers and / or one or more of the crosslinked polymer networks disclosed herein. Generally, the storage packaging system for an ophthalmic device disclosed herein includes at least a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution. In one embodiment, the sealed container is a hermetically sealed blister pack, in which a recessed well containing an ophthalmic device such as a contact lens is covered by a metal or plastic sheet adapted to be peeled to open the blister pack. The sealed container may be made of any suitable, generally inert packaging material that provides a reasonable degree of protection for the lens, preferably a plastic material such as polyalkylene, PVC, or polyamide.

[0130] The amount of one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks used in the packaging solution for storing ophthalmic devices in the packaging systems disclosed herein is an amount effective to improve the surface properties of the ophthalmic device. The grafted glycosaminoglycan polymers and crosslinked polymer networks are believed to enhance initial and long-term comfort when a contact lens packaged in the solution and then removed from the packaging system is placed on the eye for wear. In one embodiment, the concentration of the one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks in the packaging solution ranges from about 0.01 to about 20% w / w. In one embodiment, the concentration of the one or more crosslinked polymer networks present in the packaging solution ranges from about 0.02 to about 0.1% w / w.

[0131] The packaging solution disclosed herein is physiologically compatible. Specifically, the solution must be "ophthalmically safe" for use with lenses such as contact lenses, which means that the contact lenses treated with the solution are generally suitable and safe for direct placement on the eyes without rinsing, that is, the solution is safe and comfortable for daily contact with the eyes by contact lenses wetted with the solution. An ophthalmically safe solution has a tonicity and pH that is compatible with the eye and contains materials and amounts that are non-cytotoxic according to ISO standards and U.S. Food and Drug Administration (FDA) regulations.

[0132] The packaging solution must also be sterile, in that the absence of microbial contamination in the product prior to demolding must be statistically demonstrated to the extent necessary for such a product. Liquid media useful in the present invention are selected to enable and even facilitate the lens treatment or treatments of the present invention without having a substantial detrimental effect on the lens being treated or cared for. In one embodiment, the liquid medium is aqueous-based. Particularly useful aqueous liquid media are those derived from saline, such as conventional saline or conventional buffered saline solutions.

[0133] The pH of the packaging solution should be maintained within the range of about 6 to about 9, or about 6.5 to about 7.8. Suitable buffers, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of NaHPO, NaHPO, and KHPO), as well as mixtures thereof, may be added. Generally, the buffer will be used in an amount ranging from about 0.05 to about 2.5 weight percent of the solution. In one embodiment, the buffer is used in an amount ranging from about 0.1 to about 1.5 weight percent of the solution. In one embodiment, the packaging solution of the present invention contains a borate buffer, such as a borate buffer containing one or more of boric acid, sodium borate, potassium tetraborate, potassium metaborate, or mixtures thereof.

[0134] In one embodiment, the packaging solution can further contain one or more comfort agents to increase the stability of the grafted glycosaminoglycan polymer and / or crosslinked polymer network and to increase the shelf life of the packaging solution. Suitable comfort agents include, for example, polyols, antioxidants, and complex carbohydrates. Suitable polyols include, but are not limited to, glucose, mannitol, erythritol, sorbitol, polyvinyl alcohol, maltose, glycerol, and trehelose. Suitable antioxidants include, but are not limited to, α-tocopherol and other water-soluble vitamin E moieties, ascorbic acid, ascorbyl glucoside, cysteine, carnosol, carnitine, epicatechin, gallic acid, resveratrol, ellagic acid, pychogenol, lycopene, astaxanthin, coenzyme Q10, caffeic acid, hydroquinone monomethyl ether, and butylated hydroxytoluene. Suitable complex carbohydrates include, but are not limited to, tremella polysaccharides and carboxymethylcellulose. In one embodiment, the packaging solution contains one or more comfort agents in an amount ranging from about 0 to about 5 weight percent of the solution. In another embodiment, the packaging solution contains one or more comfort agents in an amount ranging from about 0.01 to about 2 weight percent of the solution.

[0135] Typically, the packaging solution is also adjusted with a tonicity agent to approximate the osmolality of normal tears, equivalent to 0.9 percent sodium chloride or 2.5 percent glycerol. The packaging solution is made substantially isotonic using saline alone or in combination; if it is not, simply mixed with sterile water to make it hypotonic or hypertonic, the lens will lose its desirable optical parameters. Similarly, excess saline can result in the formation of a hypertonic solution that causes stinging and eye irritation.

[0136] Suitable tonicity adjusting agents include, for example, sodium and potassium chloride, dextrose, glycerin, calcium and magnesium chloride, and the like, and mixtures thereof. These tonicity adjusting agents are typically used individually in amounts ranging from about 0.01 to about 2.5% weight / volume. In one embodiment, the tonicity adjusting agent is used in an amount ranging from about 0.2 to about 1.5% weight / volume. The tonicity adjusting agent will be used in an amount that provides a final osmolality of at least about 200 mOsm / kg. In one embodiment, the tonicity adjusting agent is used in an amount that provides a final osmolality of about 200 to about 400 mOsm / kg. In one embodiment, the tonicity adjusting agent is used in an amount that provides a final osmolality of about 250 to about 350 mOsm / kg. In one embodiment, the tonicity adjusting agent is used in an amount that provides a final osmolality of about 280 to about 320 mOsm / kg.

[0137] If desired, one or more additional components can be included in the packaging solution. Such additional component or components are selected to impart or provide at least one beneficial or desired property to the packaging solution. Generally, the additional component can be selected from one or more components conventionally used in ophthalmic device care compositions. Suitable additional components include, for example, cleaning agents, wetting agents, nutrients, sequestering agents, viscosity-increasing agents, contact lens conditioning agents, antioxidants, etc., and mixtures thereof. Each of these additional components can be included in the packaging solution in an amount effective to impart or provide beneficial or desired properties to the packaging solution. For example, such additional components can be included in the packaging solution in an amount similar to the amount of such components used in other, for example, conventional contact lens care products.

[0138] Suitable sequestering agents include, for example, disodium ethylenediaminetetraacetic acid, alkali metal hexametaphosphate, citric acid, sodium citrate, and the like, and mixtures thereof.

[0139] Suitable viscosity-enhancing agents include, for example, hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like, and mixtures thereof.

[0140] Suitable antioxidants include, for example, sodium metabisulfite, sodium thiosulfate, N-acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, and the like, and mixtures thereof.

[0141] A method for packaging and storing a biomedical device, such as a contact lens, includes at least packaging the biomedical device immersed in the aqueous packaging solution described above. The method may include immersing the biomedical device in the aqueous packaging solution immediately after the manufacture of the contact lens and before delivery to the customer / wearer. Alternatively, packaging and storage in the packaging solution may occur at an intermediate point before delivery to the final customer (wearer), but after the manufacture and transportation of the lens in a dry state, and the dry lens is hydrated by immersing the lens in the packaging solution. Thus, a package for delivery to a customer may include a sealed container containing one or more unused contact lenses immersed in the aqueous packaging solution according to the present invention.

[0142] In one embodiment, the steps leading to the packaging system of the present invention include (1) molding a biomedical device in a mold comprising at least first and second mold parts, (2) hydrating and washing the biomedical device in a container comprising at least one of the mold parts, (3) introducing a packaging solution having grafted glycosaminoglycan polymers and / or crosslinked polymer networks into the container with the biomedical device supported therein, and (4) sealing the container. In one embodiment, the method also includes the step of sterilizing the contents of the container. Sterilization may be carried out before or, most conveniently, after sealing the container, by any suitable method known in the art, for example, by steam sterilization or autoclaving the sealed container at a temperature of about 12°C or above.

[0143] In another embodiment, one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks disclosed herein can be used in a gel formulation. As will be readily understood by those skilled in the art of formulation, a gel is a semi-solid, suspension-type system. Thus, in one embodiment, a gel formulation can include one or more grafted glycosaminoglycan polymers and / or one or more crosslinked polymer networks and one or more gel-forming agents. A gel-forming agent for use herein can be any gelling agent typically used in the art for semi-solid gel formulations. As used herein, the term "gelling agent" is intended to mean a compound used to turn a liquid vehicle into a jelly-like vehicle. Exemplary gelling agents include, by way of example and not limitation, synthetic macromolecules, cellulose derivatives (e.g., carboxymethylcellulose and hydroxypropylmethylcellulose), and natural gums (e.g., tragacanth). Synthetic macromolecules include carbomers (e.g., Carbomer 910, 934, 934P, 940, 941, and 1342), which are high molecular weight, water-soluble polymers of acrylic acid crosslinked with allyl ethers of sucrose and / or pentaerythritol. Carbomers have different viscosities depending on their polymeric composition. Gelling agents can be selected from synthetic or semi-synthetic polymeric materials, polyacrylate copolymers, cellulose derivatives, and polymethyl vinyl ether / maleic anhydride copolymers. For example, various grades of Carbopol can be used in the present invention, such as Carbopol 934, 940, 941, 974, 980, 981, 1342, 5984, ETD 2020, ETD 2050, and Ultrez 10 (available from Noveon, Cleveland, Ohio). The gel composition can include Carbopol 980 as a gelling agent. Carbopol is a carbomer. Generally, carbomers are synthetic high molecular weight polymers of acrylic acid crosslinked with either allyl sucrose or allyl ethers of pentaerythritol.

[0144] The gelation mechanism relies on neutralization of the carboxylic acid moieties, which form soluble salts. The polymer is hydrophilic and produces a sparkling, transparent gel upon neutralization. Carbomer gel has good thermal stability, in that gel viscosity and yield value are essentially unaffected by temperature. As a topical product, carbomer gel has optimal rheological properties. Its inherent pseudoplastic flow allows for immediate recovery of viscosity upon cessation of shear, and its high yield value and rapid break make it ideal for dispensing. In this pharmaceutical formulation, carbomer gel is used as a suspending or viscosity-enhancing agent. Aqueous solutions of carbopol are inherently acidic due to the presence of free carboxylic acid residues. Neutralization of this solution crosslinks and gelatinizes the polymer, forming a viscous, monolithic structure of the desired viscosity. The amount of gelling agent varies widely, typically ranging from about 0.1% w / w to about 10% w / w.

[0145] The gel composition can be incorporated into wound dressings (e.g., bandages, adhesive plasters, transdermal patches). Generally, in these embodiments, the gel composition is embedded within a puff, gauze, fleece, gel, powder, sponge, or other material associated with a second layer to form the wound dressing. Absorption enhancers can also be used to increase the flux of the composition, particularly the therapeutic protein within the composition, across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the therapeutic protein in a polymer matrix or gel.

[0146] In certain embodiments, the second layer of the wound dressing can be an elastomeric layer, a vapor-permeable film, a waterproof film, a woven or nonwoven fabric, a mesh, etc. The composition-containing layer and the second layer can be joined using any suitable method (e.g., application of an adhesive such as a pressure-sensitive adhesive, a hot melt adhesive, a curable adhesive, etc.; application of heat or pressure such as lamination; physical bonding by the use of sutures, studs, other fasteners, etc.).

[0147] The wound dressing may include an adhesive for attachment to skin or other tissue. While any adhesive suitable for forming a bond with skin or other tissue can be used, in certain embodiments, a pressure-sensitive adhesive is used. A pressure-sensitive adhesive is generally defined as an adhesive that adheres to a substrate when light pressure is applied, but leaves little to no residue when removed. Pressure-sensitive adhesives include solvent-in-solution adhesives, hot-melt adhesives, water-based emulsion adhesives, calenderable adhesives, and radiation-curable adhesives.

[0148] The most commonly used elastomers in pressure sensitive adhesives can include natural rubber, styrene-butadiene latex, polyisobutylene, butyl rubber, acrylic, and silicone.

[0149] In exemplary embodiments, acrylic polymer or silicone-based pressure-sensitive adhesives can be used. Acrylic polymers often have low levels of allergenicity, can be cleanly removed from the skin, have a low odor, and may have a low rate of mechanical and chemical irritation. Medical-grade silicone pressure-sensitive adhesives can be selected for biocompatibility.

[0150] Among the factors influencing the suitability of a pressure-sensitive adhesive for use in wound dressings of certain embodiments are the absence of skin-irritating components, sufficient adhesive strength so that the adhesive can be cleanly removed from the skin, the ability to accommodate skin movement without undue mechanical skin irritation, and good resistance to body fluids.

[0151] The following examples are provided to enable one skilled in the art to practice the invention and are illustrative only and should not be construed as limiting the scope of the invention, which is defined by the claims.

[0152] Example 1 Preparation of PEGylated hyaluronic acid (HA) (48 kDa HA) using 2-(2-aminoethoxy)ethanol according to the general reaction scheme: [ka] In the formula, n is 50 to 1,000.

[0153] To a 1 L, 3-neck flask equipped with a 3.5-inch propeller blade and overhead stirrer was added 5.00 g of HA (12.4 mmol, based on a molecular weight (Mw) of 403.31 for the disaccharide unit) (48 kDa) and 495 mL of deionized (DI) water. The mixture was stirred for 4 hours to ensure complete dissolution, resulting in a clear solution with a pH of approximately 6.5. After 4 hours, the pH was adjusted to 5.02 using 1 N hydrochloric acid. To this solution was added 1.484 g (12.9 mmol, 104 mol % based on Mw of the disaccharide unit) of N-hydroxysuccinimide (NHS) in 5 mL of DI water. Next, 2.377 g (12.4 mmol, 100 mol % based on Mw of the disaccharide unit) of dimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) was added to 5 mL of DI water. After 30 minutes of activation, 1.356 g of 2-(2-aminoethoxy)ethanol (PEG-2) (12.9 mmol, 104 mol % based on the disaccharide unit) was added, pre-dissolved in 5 mL of DI water. The reaction was allowed to proceed for 24 hours at room temperature. After 24 hours, the solution was resuspended in Amberlite IR 120 Na at 0.35 g of resin per gram of 1 wt % functionalized hyaluronate. + The solution was stirred for 1 hour in the presence of a resin in the form of dimethylformamide. After vacuum filtration to remove the resin, the solution was placed in a 12,000-14,000 molecular weight cutoff (MWCO) dialysis bag. The bags were stirred for 4 hours in 5 mM phosphate buffer, pH 7.4, containing 100 mM NaCl, followed by 18 hours in 5 mM phosphate buffer, pH 7.4, containing 50 mM NaCl, and then stirred for 2 days in a continuous stream of DI water. After dialysis, the solution was lyophilized to yield 5 g of the product of Example 1.

[0154] Analysis of the dialyzed material (i.e., the final product) by size-exclusion chromatography (SEC-MALS) indicated a weight-average molecular weight of 44,095 Da. Characterization of the material was performed by size-exclusion chromatography, NMR, and high-resolution LC-MS of the enzymatically digested by-products.

[0155] Example 2 Preparation of PEGylated hyaluronic acid (1.2 MDa HA) using 2-(2-aminoethoxy)ethanol according to the general reaction scheme: [ka] In the formula, n is 100 to 10,000.

[0156] To a 1 L round-bottom flask equipped with a 3.5-inch propeller blade and overhead stirrer, 495 mL of DI water and 5.00 g of HA (1.2 MDa, 12.4 mmol based on a Mw of 403.31 for the disaccharide unit) were added. The solution was then stirred for 22 hours to ensure complete dissolution of the material, resulting in a clear solution with a pH of approximately 6.5. The pH of the solution was adjusted to 5.00 with 1 N hydrochloric acid solution. To this solution was added 0.314 g (2.73 mmol, 22 mol % based on the Mw of the disaccharide unit) of N-hydroxysuccinimide (NHS) in 5 mL of DI water. Next, 0.475 g (2.48 mmol, 20 mol % based on the Mw of the disaccharide unit) of dimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) was added to the solution in 5 mL of DI water. After 2 hours, the pH was 5.05 when 0.29 g of 2-(2-aminoethoxy)ethanol (PEG-2) (2.73 mmol, 22 mol % based on the Mw of the disaccharide unit) in 5 mL of DI water was added. The addition caused the pH to rise to 7.78. The reaction mixture was then stirred for an additional 16 hours, at which point the pH decreased to 7.07.

[0157] The solution was then dialyzed for 3 hours using a 12000-14000 MWCO RC (Regenerated Cellulose) membrane in 5 mM PBS buffer pH 7.4 containing 100 mM NaCl for the first bath. This bath was then replaced with 5 mM PBS buffer pH 7.4 containing 50 mM NaCl for an additional 3 hours. The bath was then replaced with DI water overnight. The following day, dialysis continued for 8 hours using a continuous flow of DI water for the fourth bath, and then the fifth bath was left in DI water overnight. The following day, dialysis continued for 8 hours using a continuous flow of DI water for the sixth bath. The solution was then dialyzed using Amberlite IR 120 Na at 0.35 g of resin per gram of 1 wt% PEG-functionalized hyaluronate solution. + The mixture was stirred for 1.5 hours in the presence of the resin in the form of a fibrous material, which was then freeze-dried for 3 days to give 3.8 g (74% yield).

[0158] Analysis of the final product by size exclusion chromatography indicated a weight-average molecular weight of 1,225,139 Da. Characterization of the material was carried out by size exclusion chromatography, NMR, and high-resolution LC-MS of the enzymatically digested by-products.

[0159] Example 3 Preparation of covalently crosslinked networks of PEG-functionalized hyaluronic acid and 1,4-butanediol diglycidyl ether (BDDE) according to the general reaction scheme: [ka] In the formula, n is 50 to 10,000, and n1 is 1 to 10,000.

[0160] 0.5 g of PEG-functionalized HA (2.056 mmol based on the Mw of 486.40 for the disaccharide units) from Example 1 above was dissolved in DI water at 0.5 wt % and stirred at 300 RPM for 22 hours to ensure complete dissolution of the material. The pH was adjusted to 12 using 1N sodium hydroxide, and then 0.212 g of BDDE (1.049 mmol, 102 mol % based on the disaccharide units) was added and stirred at 500 RPM for 24 hours. The reaction mixture was then poured into an excess of ethanol. The precipitate that formed was filtered and washed three times with ethanol, followed by drying under vacuum for an additional 24 hours. Characterization of the material was performed by size exclusion chromatography. This reaction produced the following products 1-4. [ka] where n is as defined above.

[0161] Example 4 Preparation of covalently crosslinked networks of PEG-functionalized hyaluronic acid and BDDE according to the general reaction scheme: [ka] In the formula, n is 50 to 10,000, and n1 is 1 to 10,000.

[0162] 0.5 g of PEG-functionalized HA (2.056 mmol, based on a Mw of 486.40 for the disaccharide units) from Example 2 was dissolved in DI water at 0.5 wt % and stirred at 300 RPM for 22 hours to ensure complete dissolution of the material. The pH was adjusted to 12 using 1N sodium hydroxide, and then 0.212 g of BDDE (1.049 mmol, 102 mol % based on the disaccharide units) was added and stirred at 500 RPM for 24 hours. The reaction mixture was then poured into an excess of ethanol. The precipitate that formed was filtered, washed three times with ethanol, and then dried under vacuum for an additional 24 hours. This reaction yielded products 1-4, as shown in Example 3. Characterization of the materials was performed by size exclusion chromatography.

[0163] Example 5 Preparation of PEGylated hyaluronic acid (1.2 MDa HA) using mPEG-NH2500 (methoxypolyethylene glycol amine 550) according to the general reaction scheme: [ka] In the formula, n is 25 to 10,000.

[0164] To a 1 L round-bottom flask equipped with a 3.5-inch propeller blade and overhead stirrer, 400 mL of DI water and 5.00 g of HA (1.2 MDa, 12.4 mmol based on a Mw of 403.31 for the disaccharide unit) were added. The solution was then stirred for 16 hours to ensure complete dissolution of the material, resulting in a clear solution with a pH of approximately 6.5. To this solution was added 0.22 g (1.92 mmol, 15.5 mol % based on the Mw of the disaccharide unit) of N-hydroxysuccinimide (NHS) in 5 mL of dimethyl sulfoxide (DMSO). Next, 0.36 g (1.88 mmol, 15.2 mol % based on the Mw of the disaccharide unit) of dimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) in 5 mL of DI water was added. After 10 minutes, 0.68 g of m-PEG-NH2 (1.24 mmol, 10 mol% based on the Mw of the disaccharide unit) in 5 mL of DI water was added. The remaining 70 mL of DI water was added to make a 1 wt% HA solution, resulting in a solution with a pH of 6.3. The pH was increased to 6.4 by adding 0.25 N NaOH, and the reaction was continued for 24 hours.

[0165] The reaction product was filtered using a cloth filter to remove impurities and insoluble materials. The reaction product was then precipitated in 4000 mL of acetone with constant stirring by slowly adding the reaction product using a liquid addition funnel. The precipitate was further dissolved in DI water (400 mL) with constant stirring. Once completely dissolved, the above precipitation was repeated twice (for a total of three precipitations). The residue was dried under high vacuum at 35°C for 8 hours.

[0166] Example 6 The reaction scheme of Example 5 was repeated, except that HA (35 kDa) was used with mPEG-NH2 (550), to give the structure shown in Example 5.

[0167] Example 7 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 1. [Table 1]

[0168] Example 8 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 2. [Table 2]

[0169] Example 9 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 3. [Table 3]

[0170] Example 10 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 4. [Table 4]

[0171] Example 11 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 5. [Table 5]

[0172] Example 12 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 6. [Table 6]

[0173] Example 13 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 7. [Table 7]

[0174] Example 14 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 8. [Table 8]

[0175] Example 15 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 9. [Table 9]

[0176] Example 16 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 10. [Table 10]

[0177] Example 17 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 11. [Table 11]

[0178] Example 18 A packaging solution is made by mixing the following ingredients in the respective amounts listed in Table 12. [Table 12]

[0179] Example 19 A packaging solution was made by mixing the following ingredients in the respective amounts listed in Table 13. [Table 13]

[0180] Example 20 A packaging solution was made by mixing the following ingredients in the respective amounts listed in Table 14. [Table 14]

[0181] Example 21 A packaging solution was made by mixing the following ingredients in the respective amounts listed in Table 15. [Table 15]

[0182] Example 22 Autoclave degradation was tested on HA-2PEG and showed no statistically significant changes in pH, viscosity, and osmolality even after two autoclave cycles, as shown in Table 16 below. [Table 16]

[0183] Example 23 Contact lenses made from balafilcon A were cast and processed according to standard manufacturing procedures. Balafilcon A is a copolymer of 3-[tris(trimethylsiloxy)silyl]propyl vinylcarbamate, N-vinyl-2-pyrrolidone (NVP), 1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane, and N-vinyloxycarbonylalanine. All balafilcon A lenses were treated with air plasma before exposure to the crosslinked polymer network.

[0184] To coat with the grafted polymer of Example 1, each lens is placed in a polypropylene blister package containing 3.8 mL of a 100 or 250 ppm (wt / vol) solution of the grafted polymer dissolved in an appropriate buffer system, such as phosphate buffered saline system (PBS), borate buffered saline (BBS), with or without 300 ppm EDTA. The blister package is sealed with a foil lid stock and autoclaved at 121° C. for 30 minutes.

[0185] Example 24 Contact lenses made from balafilcon A are cast and processed according to standard manufacturing procedures. Balafilcon A is a copolymer of 3-[tris(trimethylsiloxy)silyl]propyl vinylcarbamate, N-vinyl-2-pyrrolidone (NVP), 1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane, and N-vinyloxycarbonylalanine. All balafilcon A lenses are air-plasma treated before exposure to the crosslinked polymer network.

[0186] To coat with the grafted polymer of Example 2, each lens is placed in a polypropylene blister package containing 3.8 mL of a 100 or 250 ppm (wt / vol) solution of the grafted polymer dissolved in an appropriate buffer system, e.g., PBS, BBS, with or without 300 ppm EDTA. The blister package is sealed with a foil lid stock and autoclaved at 121°C for 30 minutes.

[0187] Example 25 Preparation of in situ PEG functionalization of hyaluronic acid (48 kDa HA) according to the following general reaction scheme: [ka]

[0188] To a 1 L, 3-neck flask equipped with a 3.5-inch propeller blade and overhead stirrer, add 5.00 g of HA (12.4 mmol, based on a molecular weight (Mw) of 403.31 for the disaccharide unit) (48 kDa) and 495 mL of deionized (DI) water. Stir the mixture for 4 hours to ensure complete dissolution and obtain a clear solution with a pH of approximately 6.5. After 4 hours, adjust the pH to 5.02 using 1 N hydrochloric acid. To this solution, add 1.484 g (12.9 mmol, 104 mol % based on Mw of the disaccharide unit) of N-hydroxysuccinimide (NHS) in 5 mL of DI water. Next, add 2.377 g (12.4 mmol, 100 mol % based on Mw of the disaccharide unit) of dimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) to 5 mL of DI water. After 30 minutes of activation, 0.906 g of epoxypropylamine (12.4 mmol, 100 mol % based on the disaccharide unit) was added, pre-dissolved in 5 mL of DI water. The reaction was allowed to proceed at room temperature for 24 hours.

[0189] After 24 hours, adjust the pH to 8 using 1N NaOH. Add 0.77 g of ethylene glycol (12.4 mmol, 100 mol% based on the disaccharide unit) pre-dissolved in 5 mL of DI water. Allow the reaction to proceed at room temperature for 4 hours. Add 0.919 g of glycidol (12.4 mmol, 100 mol% based on the disaccharide unit) pre-dissolved in 5 mL of DI water. Allow the reaction to proceed at room temperature for 24 hours. After 24 hours, place the solution in a 12,000-14,000 molecular weight cutoff (MWCO) dialysis bag. Stir the bags in 5 mM phosphate buffer pH 7.4 containing 100 mM NaCl for 4 hours, then in 5 mM phosphate buffer pH 7.4 containing 50 mM NaCl for 18 hours, then stir in a continuous flow of DI water for 2 days. After dialysis, the solution was reconstituted with Amberlite IR 120 Na at 0.35 g of resin per gram of 1 wt % functionalized hyaluronate solution. + The mixture is stirred for 1.5 hours in the presence of the resin in the form of a HCl solution. After removing the resin by vacuum filtration, the solution is lyophilized to give 5 g of product.

[0190] Characterization of the products is performed by size exclusion chromatography, NMR, and high-resolution LC-MS of enzymatically digested by-products.

[0191] Example 26 Preparation of in situ PEG functionalization of hyaluronic acid (1.2 MDa HA) according to the following general reaction scheme: [ka]

[0192] To a 1 L, 3-neck flask equipped with a 3.5-inch propeller blade and overhead stirrer, add 5.00 g of HA (12.4 mmol, based on a molecular weight (Mw) of 403.31 for the disaccharide unit) (1.2 MDa) and 495 mL of deionized (DI) water. The mixture is stirred for 4 hours to ensure complete dissolution and to obtain a clear solution with a pH of approximately 6.5. After 4 hours, the pH is adjusted to 5.02 using 1 N hydrochloric acid. To this solution, add 1.484 g (12.9 mmol, 104 mol % based on Mw of the disaccharide unit) of N-hydroxysuccinimide (NHS) in 5 mL of DI water. Next, add 2.377 g (12.4 mmol, 100 mol % based on Mw of the disaccharide unit) of dimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) to 5 mL of DI water. After 30 minutes of activation, 0.906 g of epoxypropylamine (12.4 mmol, 100 mol % based on the disaccharide unit) is added, pre-dissolved in 5 mL of DI water. The reaction is allowed to proceed at room temperature for 24 hours.

[0193] After 24 hours, the pH is adjusted to 8 using 1N NaOH. Next, 0.77 g of ethylene glycol (12.4 mmol, 100 mol% based on the disaccharide unit) is added, pre-dissolved in 5 mL of DI water. The reaction is allowed to proceed at room temperature for 4 hours. After 4 hours, 0.919 g of glycidol (12.4 mmol, 100 mol% based on the disaccharide unit) is added, pre-dissolved in 5 mL of DI water. The reaction is allowed to proceed at room temperature for 24 hours. After 24 hours, the solution is placed in a 12,000-14,000 molecular weight cutoff (MWCO) dialysis bag. The bags are stirred for 4 hours in 5 mM phosphate buffer pH 7.4 containing 100 mM NaCl, followed by 18 hours in 5 mM phosphate buffer pH 7.4 containing 50 mM NaCl, followed by 2 days of stirring in a continuous flow of DI water. After dialysis, the solution was reconstituted with Amberlite IR 120 Na at 0.35 g of resin per gram of 1 wt % functionalized hyaluronate solution. + The mixture is stirred for 1.5 hours in the presence of the resin in the form of a HCl solution. After removing the resin by vacuum filtration, the solution is lyophilized to give 5 g of product.

[0194] Characterization is performed by size exclusion chromatography, NMR, and high-resolution LC-MS of enzymatically digested by-products.

[0195] It will be understood that various modifications can be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions implemented as the best mode for operating the invention described above are for illustrative purposes only. Those skilled in the art may implement other configurations and methods without departing from the scope and spirit of the invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the features and advantages added herein.

Claims

1. A grafted glycosaminoglycan polymer comprising a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted to the polymer backbone.

2. 2. The grafted glycosaminoglycan polymer of claim 1, wherein the glycosaminoglycan is selected from the group consisting of chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, heparosan, hyaluronan, hyaluronic acid, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, mannobiose, chitobiose, chitosan, and cellulose.

3. The polyalkylene glycol-containing residue has the following structure: Z-(((CH ２ ) ａ -O) ｂ ) ｃ -Y 3. The grafted glycosaminoglycan polymer according to claim 1 or 2, which is derived from a polymer compound having the formula: (wherein Z is a reactive or non-reactive end cap group, Y is a reactive functional group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2), or a salt thereof.

4. 4. The grafted glycosaminoglycan polymer of claim 3, wherein Z is selected from the group consisting of an alkoxy group, a hydroxyl group, a glycidyl group, a thiol group, and an amine group.

5. Z is -OCH ３ , -NH ２ 4. The grafted glycosaminoglycan polymer of claim 3, wherein the hydroxyl group is selected from the group consisting of -OH, and -SH.

6. Y is -X-NH ２ , —X-polydimethylsiloxane-NH ２ 4. The grafted glycosaminoglycan polymer of claim 3, wherein X is a linker group and R' is selected from the group consisting of -X-SH, -X-C(O)-R', -X-SH, and -X-C(O)-R', where X is a linker group and R' is hydrogen or an organic moiety composed of 1 to 20 carbon atoms.

7. The polyalkylene glycol-containing residue has the following structure: 【Chemical 1】 2. The grafted glycosaminoglycan polymer of claim 1, which is derived from a polymer having the formula: wherein n is 2 to 10,000, or a salt thereof.

8. The grafted glycosaminoglycan polymer of claim 1 or 2, which is a reaction product comprising one or more glycosaminoglycans having a polymer backbone containing one or more reactive functional groups, and one or more polymers containing a polyalkylene glycol chain and at least one reactive end group or a salt thereof.

9. 8. A crosslinked polymer network comprising a reaction product comprising one or more grafted glycosaminoglycan polymers according to any one of claims 1 to 7 and one or more first crosslinkers.

10. The polyalkylene glycol-containing residue has the following structure: Z-(((CH ２ ) ａ -O) ｂ ) ｃ -Y 10. The crosslinked polymer network of claim 9, derived from a polymer having the formula: wherein Z is a reactive or non-reactive end cap group, Y is a reactive functional end group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2, or a salt thereof.

11. Y is -X-NH ２ 11. The crosslinked polymer network of claim 10, wherein X is a linker group and R' is selected from the group of -X-SH, -X-C(O)-R', -X-SH, and -X-C(O)-R', where X is a linker group and R' is hydrogen or an organic moiety comprised of 1 to 20 carbon atoms.

12. 11. The crosslinked polymer network of claim 10, wherein Z is selected from the group consisting of an alkoxy group, a hydroxyl group, a glycidyl group, a thiol group, and an amine group.

13. 13. The crosslinked polymer network of any one of claims 9 to 12, wherein the one or more first crosslinkers are bifunctional or multifunctional crosslinkers comprising two or more reactive functional groups.

14. The one or more first crosslinkers are selected from the group consisting of bis-aminopropyl-polydimethylsiloxane, 1,4-butanediol diglycidyl ether (BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), diepoxyoctane, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, 13. The crosslinked polymer network of any one of claims 9 to 12, comprising a difunctional or polyfunctional crosslinker selected from the group consisting of ethers, polyglycerol polyglycidyl esters, diglycerol polyglycidyl ethers, glycerol polyglycidyl ethers, trimethylolpropane polyglycidyl ethers, pentaerythritol polyglycidyl ethers, sorbitol polyglycidyl ethers, 1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, pentaerythritol tetraglycidyl ether, and polyepoxides.

15. 13. The crosslinked polymer network of any one of claims 9 to 12, wherein the one or more first crosslinkers comprise a dihydrazide crosslinker selected from the group consisting of succinic acid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, pimelic acid dihydrazide, suberic acid dihydrazide, azalacic acid dihydrazide, sebacic acid dihydrazide, undecanedioic acid dihydrazide, dodecanedioic acid dihydrazide, brassylic acid dihydrazide, tetradecanedioic acid dihydrazide, pentadecanedioic acid dihydrazide, thapsic acid dihydrazide, and octadecanedioic acid dihydrazide.

16. 13. The crosslinked polymer network of any one of claims 9 to 12, wherein the one or more first crosslinkers comprise a dihydric alcohol crosslinker selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol diethylene glycol, dipropylene glycol, neopentyl glycol, 1,3-propanediol, hexylene glycol, pentylene glycol, heptylene glycol, and octylene glycol.

17. 13. The crosslinked polymer network of any one of claims 9 to 12, wherein the one or more first crosslinkers comprise a polyhydric alcohol crosslinker selected from the group consisting of glycerin, pentaerythrite, xylitol, and galactitol.

18. The one or more first crosslinkers comprise a carbodiimide crosslinker of formula XN=C=N-X, where each X is independently a C=C optionally substituted with 1 to 2 dialkylamino groups. １ ~C ６ alkyl or C ５ ~C ６ The crosslinked polymer network of any one of claims 9 to 12, wherein the group is a cycloalkyl group.

19. 13. The crosslinked polymer network of any one of claims 9 to 12, wherein the one or more first crosslinkers are selected from the group consisting of methacrylic anhydride, octeyl succinic anhydride, formaldehyde, gluteraldehyde, gluralaldehyde, acid chlorides, n-hydroxysuccinimide, polyethylene glycol diacrylate, polyethylene glycol diamine, divinyl sulfone, urea, and diisocyanates.

20. The reaction product is about 0.01 to about 50 wt. % of the one or more grafted glycosaminoglycan polymers, based on the total weight of the reaction product; and from about 0.01 to about 10 wt. % of the one or more first crosslinkers, based on the total weight of the reaction product.

21. 21. The crosslinked polymer network of any one of claims 9 to 20, having a weight average molecular weight in the range of about 20,000 to about 6,000,000 Daltons (Da).

22. 22. The crosslinked polymer network of any one of claims 9 to 21, wherein one or more additional glycosaminoglycans are crosslinked to the reaction product with a second crosslinker.

23. 23. The crosslinked polymer network of claim 22, wherein the second crosslinker is the same as the first crosslinker.

24. The grafted glycosaminoglycan polymer of claim 8, wherein the reaction product of the one or more glycosaminoglycans having a polymer backbone comprising one or more reactive functional groups and the one or more polymers comprising a polyalkylene glycol chain and at least one reactive end group or a salt thereof further comprises one or more first crosslinkers.

25. The polyalkylene glycol chain has the structure: -((CH ２ ) ａ -O) ｂ 25. The crosslinked polymer network of claim 24, comprising: wherein "a" is 2 to 6, or 2 to 4, and "b" is 2 to 10,000, or 2 to 5000.

26. The at least one reactive end group is —X—NH ２ 25. The crosslinked polymer network of claim 24, wherein X is a linker group and R' is selected from the group consisting of -X-SH, and -X-C(O)-R', where X is a linker group and R' is hydrogen or an organic moiety comprised of 1 to 20 carbon atoms.

27. 27. The crosslinked polymer network of any one of claims 24 to 26, wherein the other end group of the one or more polymers is selected from the group consisting of an alkoxy group, a hydroxyl group, a glycidyl group, a thiol group, and an amine group.

28. 28. The crosslinked polymer network of any one of claims 24 to 27, wherein the one or more first crosslinkers are bifunctional or multifunctional crosslinkers comprising two or more reactive functional groups.

29. The one or more first crosslinkers are selected from the group consisting of bis-aminopropyl-polydimethylsiloxane, 1,4-butanediol diglycidyl ether (BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), diepoxyoctane, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether 28. The crosslinked polymer network of any one of claims 24 to 27, comprising a difunctional or polyfunctional crosslinker selected from the group consisting of 1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, pentaerythritol tetraglycidyl ether, 1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, 1,2,7,8-diep ...

30. 28. The crosslinked polymer network of any one of claims 24-27, wherein the one or more first crosslinkers comprise a dihydrazide crosslinker selected from the group consisting of succinic acid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, pimelic acid dihydrazide, suberic acid dihydrazide, azalic acid dihydrazide, sebacic acid dihydrazide, undecanedioic acid dihydrazide, dodecanedioic acid dihydrazide, brassylic acid dihydrazide, tetradecanedioic acid dihydrazide, pentadecanedioic acid dihydrazide, thapsic acid dihydrazide, and octadecanedioic acid dihydrazide.

31. 28. The crosslinked polymer network of any one of claims 24-27, wherein the one or more first crosslinkers comprise a dihydric alcohol crosslinker selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol diethylene glycol, dipropylene glycol, neopentyl glycol, 1,3-propanediol, hexylene glycol, pentylene glycol, heptylene glycol, and octylene glycol.

32. 28. The crosslinked polymer network of any one of claims 24-27, wherein the one or more first crosslinkers comprise a polyhydric alcohol crosslinker selected from the group consisting of glycerin, pentaerythrite, xylitol, and galactitol.

33. The one or more first crosslinkers comprise a carbodiimide crosslinker of formula XN=C=N-X, where each X is independently a C=C optionally substituted with 1 to 2 dialkylamino groups. １ ~C ６ alkyl or C ５ ~C ６ The crosslinked polymer network of any one of claims 24 to 27, wherein the group is a cycloalkyl group.

34. 28. The crosslinked polymer network of any one of claims 24 to 27, wherein the one or more first crosslinkers are selected from the group consisting of methacrylic anhydride, octeyl succinic anhydride, formaldehyde, gluteraldehyde, gluralaldehyde, acid chlorides, n-hydroxysuccinimide, polyethylene glycol diacrylate, polyethylene glycol diamine, divinyl sulfone, urea, and diisocyanates.

35. 35. The crosslinked polymer network of any one of claims 24 to 34, having a weight average molecular weight in the range of about 20,000 to about 6,000,000 Daltons (Da).

36. A biomedical device having a coating on its surface, said coating comprising one or more of the grafted glycosaminoglycan polymers of any one of claims 1 to 8.

37. 37. The biomedical device of claim 36, wherein the biomedical device is an ophthalmic lens.

38. 38. The biomedical device of claim 37, wherein the ophthalmic lens is a contact lens or an intraocular lens.

39. A biomedical device having a coating on a surface thereof, said coating comprising one or more of the crosslinked polymer networks of any one of claims 9 to 23.

40. 40. The biomedical device of claim 39, wherein the biomedical device is an ophthalmic lens.

41. 41. The biomedical device of claim 40, wherein the ophthalmic lens is a contact lens or an intraocular lens.

42. 36. A biomedical device having a coating on a surface thereof, said coating comprising one or more of the crosslinked polymer networks of any one of claims 24 to 35.

43. 43. The biomedical device of claim 42, wherein the biomedical device is an ophthalmic lens.

44. 44. The biomedical device of claim 43, wherein the ophthalmic lens is a contact lens or an intraocular lens.

45. 10. A packaging system for storing ophthalmic devices, comprising: a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising one or more of the grafted glycosaminoglycan polymers of any one of claims 1 to 8, wherein the aqueous packaging solution has an osmolality of at least about 200 mOsm / kg, a pH of about 6 to about 9, and is sterilized.

46. 46. ​​The packaging system of claim 45, wherein the one or more unused ophthalmic devices are contact lenses.

47. 47. The packaging system of claim 45 or 46, wherein the aqueous packaging solution further comprises one or more comfort agents.

48. 48. The packaging system of claim 47, wherein the one or more comfort agents are selected from the group consisting of polyols, antioxidants, and complex carbohydrates.

49. 48. The packaging system of claim 47, wherein the one or more comfort agents are selected from the group consisting of glucose, mannitol, erythritol, sorbitol, polyvinyl alcohol, maltose, glycerol, and trehelose, alpha-tocopherol acetate, ascorbic acid, ascorbyl glucoside, cysteine, carnosol, carnitine, epicatechin, gallic acid, resveratrol, ellagic acid, pychogenol, lycopene, astaxanthin, coenzyme Q10, caffeic acid, butylated hydroxytoluene, hydroquinone monomethyl ether, tremella polysaccharide, and carboxymethylcellulose.

50. 24. A packaging system for storing an ophthalmic device, comprising: a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising one or more of the crosslinked polymer networks of any one of claims 9 to 23, wherein the aqueous packaging solution has an osmolality of at least about 200 mOsm / kg, a pH of about 6 to about 9, and is sterilized.

51. 51. The packaging system of claim 50, wherein the one or more unused ophthalmic devices are contact lenses.

52. 52. The packaging system of claim 50 or 51, wherein the aqueous packaging solution further comprises one or more comfort agents.

53. 53. The packaging system of claim 52, wherein the one or more comfort agents are selected from the group consisting of polyols, antioxidants, and complex carbohydrates.

54. 53. The packaging system of claim 52, wherein the one or more comfort agents are selected from the group consisting of glucose, mannitol, erythritol, sorbitol, polyvinyl alcohol, maltose, glycerol, and trehalose, α-tocopherol acetate, ascorbic acid, ascorbyl glucoside, cysteine, carnosol, carnitine, epicatechin, gallic acid, resveratrol, ellagic acid, pycogenol, lycopene, astaxanthin, coenzyme Q10, caffeic acid, butylated hydroxytoluene, hydroquinone monomethyl ether, tremella fuciformis polysaccharide, and carboxymethylcellulose.

55. 36. A packaging system for storing ophthalmic devices, comprising: a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising one or more of the crosslinked polymer networks of any one of claims 24 to 35, wherein the aqueous packaging solution has an osmolality of at least about 200 mOsm / kg, a pH of about 6 to about 9, and is sterilized.

56. 56. The packaging system of claim 55, wherein the one or more unused ophthalmic devices are contact lenses.

57. 57. The packaging system of claim 55 or 56, wherein the aqueous packaging solution further comprises one or more comfort agents.

58. 58. The packaging system of claim 57, wherein the one or more comfort agents are selected from the group consisting of polyols, antioxidants, and complex carbohydrates.

59. 58. The packaging system of claim 57, wherein the one or more comfort agents are selected from the group consisting of glucose, mannitol, erythritol, sorbitol, polyvinyl alcohol, maltose, glycerol, and trehalose, α-tocopherol acetate, ascorbic acid, ascorbyl glucoside, cysteine, carnosol, carnitine, epicatechin, gallic acid, resveratrol, ellagic acid, pycogenol, lycopene, astaxanthin, coenzyme Q10, caffeic acid, butylated hydroxytoluene, hydroquinone monomethyl ether, tremella fuciformis polysaccharide, and carboxymethylcellulose.

60. 1. A method for preparing a package containing a storable, sterile ophthalmic device, the method comprising: (a) immersing an ophthalmic device in an aqueous packaging solution comprising one or more of the grafted glycosaminoglycan polymers of any one of claims 1 to 8, said solution having an osmolality of at least about 200 mOsm / kg and a pH in the range of about 6 to about 9; (b) packaging the aqueous packaging solution and the ophthalmic device in a manner that prevents contamination of the ophthalmic device with microorganisms; (c) sterilizing the packaged solution and said ophthalmic device.

61. 1. A method for preparing a package containing a storable, sterile ophthalmic device, the method comprising: (a) immersing an ophthalmic device in an aqueous packaging solution comprising one or more of the crosslinked polymer networks of any one of claims 9 to 23, said solution having an osmolality of at least about 200 mOsm / kg and a pH in the range of about 6 to about 9; (b) packaging the aqueous packaging solution and the ophthalmic device in a manner that prevents contamination of the ophthalmic device with microorganisms; (c) sterilizing the packaged solution and said ophthalmic device.

62. 1. A method for preparing a package containing a storable, sterile ophthalmic device, the method comprising: (a) immersing an ophthalmic device in an aqueous packaging solution comprising one or more of the crosslinked polymer networks of any one of claims 24 to 35, said solution having an osmolality of at least about 200 mOsm / kg and a pH in the range of about 6 to about 9; (b) packaging the aqueous packaging solution and the ophthalmic device in a manner that prevents contamination of the ophthalmic device with microorganisms; (c) sterilizing the packaged solution and said ophthalmic device.

63. 10. An aqueous ophthalmic composition comprising one or more of the grafted glycosaminoglycan polymers of any one of claims 1 to 8, wherein the aqueous ophthalmic composition has an osmolality in the range of about 200 mOsmol / kg to about 500 mOsmol / kg.

64. 64. The aqueous ophthalmic composition of claim 63 in the form of an eye care or contact lens care product selected from the group consisting of eye drops, contact lens preservative solution, contact lens cleaning solution, and multi-purpose contact lens solution.

65. 64. The aqueous ophthalmic composition of claim 63 in the form of a multipurpose solution or rewetting drops.

66. 24. An aqueous ophthalmic composition comprising one or more of the crosslinked polymer networks of any one of claims 9 to 23, wherein the aqueous ophthalmic composition has an osmolality in the range of about 200 mOsmol / kg to about 500 mOsmol / kg.

67. 67. The aqueous ophthalmic composition of claim 66 in the form of an eye care or contact lens care product selected from the group consisting of eye drops, contact lens preservative solution, contact lens cleaning solution, and multi-purpose contact lens solution.

68. 67. The aqueous ophthalmic composition of claim 66 in the form of a multipurpose solution or rewetting drops.

69. 36. An aqueous ophthalmic composition comprising one or more of the crosslinked polymer networks of any one of claims 24 to 35, wherein the aqueous ophthalmic composition has an osmolality in the range of about 200 mOsmol / kg to about 500 mOsmol / kg.

70. 70. The aqueous ophthalmic composition of claim 69 in the form of an eye care or contact lens care product selected from the group consisting of eye drops, contact lens preservative solution, contact lens cleaning solution, and multi-purpose contact lens solution.

71. 70. The aqueous ophthalmic composition of claim 69 in the form of a multipurpose solution or rewetting drops.

72. A gel composition for promoting wound healing, said gel composition comprising one or more of the grafted glycosaminoglycan polymers of any one of claims 1 to 8.

73. 73. A wound dressing comprising the gel composition of claim 72.

74. A gel composition for promoting wound healing, said gel composition comprising one or more of the crosslinked polymer networks of any one of claims 9 to 23.

75. 75. A wound dressing comprising the gel composition of claim 74.

76. 36. A gel composition for promoting wound healing, said gel composition comprising one or more of the crosslinked polymer networks of any one of claims 24 to 35.

77. 77. A wound dressing comprising the gel composition of claim 76.

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