Amino Acid-Based Polymerizable Compounds and Ophthalmic Devices Prepared Therefrom

Abstract

The present invention is titled "Amino Acid-Based Polymerizable Compounds and Ophthalmic Devices Prepared Therefrom". The present invention provides amino acid-based polymerizable compounds and their use in ophthalmic devices. The amino acid-based polymerizable compound has Formula I: wherein R, R 1 and R 2 as described herein.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Patent Application Serial No. 17 / 317,287, filed May 11, 2021, and U.S. Provisional Patent Application Serial No. 63 / 039,493, filed Jun. 16, 2020, the entire disclosures of which are incorporated herein by reference. FIELD OF THE INVENTION

[0003] The present invention relates to amino acid-based polymerizable compounds, and polymers and ophthalmic devices made therefrom. BACKGROUND OF THE INVENTION

[0004] Since the 1950s, contact lenses have been used commercially to improve vision. The first contact lenses were made of hard materials. Although these lenses are still in use today, they are not suitable for all patients due to their poor initial comfort and their relatively low oxygen permeability. Subsequent developments in the field have led to hydrogel-based soft contact lenses, which are extremely popular today. Many users find soft lenses more comfortable, and the increased comfort level allows soft contact lens users to wear their lenses for longer periods of time than hard contact lens users.

[0005] Many users rely on contact lenses to meet their vision care needs, and thus there is a continuing drive in the industry to further improve the properties of contact lenses and other ophthalmic devices, such as increasing hydrophilicity or balanced water content, providing absorption of beneficial proteins such as lysozyme, and / or providing anti-fouling or antimicrobial activity. SUMMARY OF THE INVENTION

[0006] The present invention relates to novel amino acid-based polymerizable compounds suitable for use in ophthalmic devices such as contact lenses. For example, the compounds can be incorporated into the covalent structure of an ophthalmic device, or they can be polymerized and used as a coating or non-covalently linked additive to an ophthalmic device. The resulting ophthalmic devices exhibit advantageous properties, including increased water content, which is particularly desirable in hydrogel contact lenses.

[0007] Accordingly, in one aspect, the present invention provides an amino acid-based polymerizable compound of Formula I:

[0008]

[0009] wherein R is H, C(═O)R 3 , or R together with the nitrogen to which it is attached forms a polymerizable group, wherein R 3 is C1-C 25 alkyl or cycloalkyl; R 1is an amino acid residue or a derivative of an amino acid residue, wherein the derivative optionally contains a polymerizable group; and R 2 is OR 4 or N(H)-L-P g wherein R 4 is H, a metal cation or a C1-C6 alkyl group, L is a linking group, and P g is a polymerizable group, wherein the compound contains at least one polymerizable group.

[0010] In another aspect, the present invention provides an ophthalmic device comprising a polymer derived from an amino acid-based polymerizable compound as described herein. Detailed Description

[0011] It should be understood that the present invention is not limited to the details of the construction or process steps set forth in the following description. With the teachings herein, the present invention is capable of other embodiments and of being practiced or carried out in various ways.

[0012] The following definitions are provided with respect to the terms used in the present disclosure.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The definition of polymer conforms to those disclosed in Compendium of Polymer Terminology and Nomenclature, IUPAC Recommendations 2008, edited by Richard G. Jones, Jaroslav Kahovec, Robert Stepto, Edward S. Wilks, Michael Hess, Tatsuki Kitayama and W. Val Metanomski, IUPAC Recommendations 2008. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference.

[0014] As used herein, the term “(meth)” means an optional methyl substitution. Thus, terms such as “(meth)acrylate” mean both methacrylate and acrylate.

[0015] Wherever chemical structures are provided, it should be understood that the alternative options disclosed for substituents on the said structures can be combined in any combination. Thus, if the structure contains substituents R* and R**, each of which contains three lists of possible groups, 9 combinations are disclosed. The same applies to combinations of characteristics.

[0016] When subscripts such as in the general formula [***] nWhen "n" in [the formula] is used to describe the number of repeating units in the chemical formula of a polymer, the formula shall be interpreted as representing the number-average molecular weight of the macromolecule.

[0017] The term "individual" includes humans and vertebrates.

[0018] The term "ophthalmic device" refers to any device located in or on the eye or any part of the eye, including the ocular surface. These devices can provide optical correction, cosmetic enhancement, vision improvement, therapeutic benefits (such as acting as a bandage), or delivery of active components, such as pharmaceutical and nutritional formulation components or a combination of any of the foregoing functions. Examples of ophthalmic devices include, but are not limited to, lenses, optical and ocular inserts (including, but not limited to, punctal plugs, etc.). "Lenses" include soft contact lenses, rigid contact lenses, hybrid contact lenses, intraocular lenses, and overlay lenses. Ophthalmic devices can include contact lenses.

[0019] The term "contact lens" refers to an ophthalmic device that can be placed on the cornea of an individual's eye. Contact lenses can provide corrective, cosmetic, or therapeutic benefits, including wound healing, drug or nutritional formulation delivery, diagnostic evaluation or monitoring, ultraviolet light absorption, visible light or glare reduction, or any combination thereof. Contact lenses can be made of any suitable material known in the art and can be soft lenses, rigid lenses, or hybrid lenses that include at least two different parts having different physical, mechanical, or optical properties, such as modulus, water content, light transmission, or a combination thereof.

[0020] The ophthalmic device of the present invention can be composed of a silicone hydrogel or a conventional hydrogel. Silicone hydrogels generally contain at least one hydrophilic monomer and at least one silicone-containing component, which are covalently bonded to each other in the cured device.

[0021] "Target macromolecule" means a macromolecule synthesized from a reactive monomer mixture containing monomers, macromonomers, prepolymers, crosslinkers, initiators, additives, diluents, etc.

[0022] The term "polymerizable compound" means a compound containing one or more polymerizable groups. This term encompasses, for example, monomers, macromonomers, oligomers, prepolymers, crosslinkers, etc.

[0023] "Polymerizable group" refers to a group that can undergo chain-growth polymerization (such as free radical and / or cationic polymerization), for example, a carbon-carbon double bond that can polymerize when subjected to free radical polymerization initiation conditions. Non-limiting examples of free radical polymerizable groups include (meth)acrylate, styrene, vinyl ether, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, O-vinyl carbamate, O-vinyl carbonate, and other vinyl groups. Preferably, the free radical polymerizable groups include (meth)acrylate, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, and styryl functional groups, as well as mixtures of any of the foregoing substances. More preferably, the free radical polymerizable groups include (meth)acrylate, (meth)acrylamide, and mixtures thereof. The polymerizable group may be optionally substituted. For example, the nitrogen atom in (meth)acrylamide may be bonded to hydrogen, or the hydrogen may be replaced by an alkyl or cycloalkyl group (which may itself be further substituted).

[0024] Any type of free radical polymerization can be used, including but not limited to bulk, solution, suspension, and emulsion, as well as any of the controlled free radical polymerization methods, such as stable free radical polymerization, nitroxide-mediated living polymerization, atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, organotellurium-mediated living radical polymerization, etc.

[0025] "Monomer" is a monofunctional molecule that can undergo chain-growth polymerization (and specifically free radical polymerization) to form repeating units in the chemical structure of the target macromolecule. Some monomers have difunctional impurities that can act as crosslinking agents. "Hydrophilic monomer" further refers to a monomer that produces a clear single-phase solution when mixed with deionized water at a concentration of 5% by weight at 25°C. "Hydrophilic component" refers to a monomer, macromonomer, prepolymer, initiator, crosslinking agent, additive, or polymer that produces a clear single-phase solution when mixed with deionized water at a concentration of 5% by weight at 25°C. "Hydrophobic component" is a monomer, macromonomer, prepolymer, initiator, crosslinking agent, additive, or polymer that is slightly soluble or insoluble in deionized water at 25°C.

[0026] "Macromolecule" refers to an organic compound with a number average molecular weight greater than 1500, and it can be reactive or non-reactive.

[0027] "Macromonomer or macromer" is a macromolecule having a group of repeating units in a chemical structure that can undergo chain-growth polymerization (and specifically free-radical polymerization) to form a target macromolecule. Generally, the chemical structure of the macromonomer is different from that of the target macromolecule. In other words, the repeating units of the side groups of the macromonomer are different from those of the target macromolecule or its main chain. The difference between a monomer and a macromonomer is only one of chemical structure, molecular weight, and the molecular weight distribution of the side groups. Thus, and as used herein, the patent literature occasionally defines a monomer as a polymerizable compound having a relatively low molecular weight of about 1,500 daltons or less, which essentially includes some macromonomers. Specifically, monomethacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane (molecular weight = 500 - 1500 g / mol) (mPDMS) and mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether-terminated mono-n-butyl-terminated polydimethylsiloxane (molecular weight = 500 - 1500 g / mol) (OH-mPDMS) can be referred to as monomers or macromonomers. Additionally, the patent literature occasionally defines a macromonomer as having one or more polymerizable groups, thereby essentially expanding the general definition of a macromonomer to include prepolymers. Thus, and as used herein, difunctional and polyfunctional macromonomers, prepolymers, and crosslinkers can be used interchangeably.

[0028] "Silicone-containing component" is a monomer, macromonomer, prepolymer, crosslinker, initiator, additive, or polymer in a reactive mixture having at least one silicon-oxygen bond, which is typically in the form of a siloxane group, a siloxy group, a carbosiloxy group, and mixtures thereof.

[0029] Examples of silicone-containing components useful in the present invention can be found in U.S. Patent Nos. 3,808,178, 4,120,570, 4,136,250, 4,153,641, 4,740,533, 5,034,461, 5,070,215, 5,244,981, 5,314,960, 5,331,067, 5,371,147, 5,760,100, 5,849,811, 5,962,548, 5,965,631, 5,998,498, 6,367,929, 6,822,016, 6,943,203, 6,951,894, 7,052,131, 7,247,692, 7,396,890, 7,461,937, 7,468,398, 7,538,146, 7,553,880, 7,572,841, 7,666,921, 7,691,916, 7,786,185, 7,825,170, 7,915,323, 7,994,356, 8,022,158, 8,163,206, 8,273,802, 8,399,538, 8,415,404, 8,420,711, 8,450,387, 8,487,058, 8,568,626, 8,937,110, 8,937,111, 8,940,812, 8,980,972, 9,056,878, 9,125,808, 9,140,825, 9,156,934, 9,170,349, 9,217,813, 9,244,196, 9,244,197, 9,260,544, 9,297,928, 9,297,929 and European Patent No. 080539. These patents are hereby incorporated by reference in their entirety.

[0030] A "polymer" is a target macromolecule composed of repeating units of monomers used during polymerization.

[0031] A "homopolymer" is a polymer made from one monomer; a "copolymer" is a polymer made from two or more monomers; a "terpolymer" is a polymer made from three monomers. A "block copolymer" is composed of blocks or segments that are compositionally different. A diblock copolymer has two blocks. A triblock copolymer has three blocks. A "comb or graft copolymer" is made from at least one macromonomer.

[0032] A "repeating unit" is the smallest group of atoms in a polymer that corresponds to the polymerization of a specific monomer or macromonomer.

[0033] "Initiator" is a molecule that can decompose into free radicals, which can then react with monomers to initiate radical polymerization. Depending on temperature, thermal initiators decompose at a certain rate; typical examples are azo compounds such as 1,1'-azobisisobutyronitrile and 4,4'-azobis(4-cyanovaleric acid), peroxides such as benzoyl peroxide, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl perbenzoate, dicumyl peroxide and lauroyl peroxide, peracids such as peracetic acid and potassium persulfate, and various redox systems. Photoinitiators that decompose by photochemical methods; typical examples are benzil, benzoin, acetophenone, benzophenone, camphorquinone, and mixtures thereof, and derivatives of various monoacyl and diacyl phosphine oxides, and combinations thereof.

[0034] "Crosslinking agent" is a difunctional or polyfunctional monomer or macromonomer that can undergo radical polymerization at two or more positions on the molecule to form branch points and a polymer network. Common examples are ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, trimethylolpropane trimethacrylate, methylenebisacrylamide, triallyl cyanurate, etc.

[0035] "Prepolymer" is the reaction product of monomers that contains remaining polymerizable groups capable of undergoing further reaction to form a polymer.

[0036] "Polymer network" is a crosslinked macromolecule that can swell but not dissolve in a solvent. "Hydrogel" is a polymer network that swells in water or an aqueous solution and usually absorbs at least 10% by weight of water. "Silicone hydrogel" is a hydrogel made from at least one silicone-containing component and at least one hydrophilic component. The hydrophilic component may also include a non-reactive polymer.

[0037] "Conventional hydrogel" refers to a polymer network made from components that do not contain any silyloxy, siloxane, or carbosilane groups. Conventional hydrogels are prepared from a reactive mixture containing hydrophilic monomers. Examples include 2-hydroxyethyl methacrylate ("HEMA"), N-vinylpyrrolidone ("NVP"), N,N-dimethylacrylamide ("DMA"), or vinyl acetate. U.S. Patent Nos. 4,436,887, 4,495,313, 4,889,664, 5,006,622, 5,039459, 5,236,969, 5,270,418, 5,298,533, 5,824,719, 6,420,453, 6,423,761, 6,767,979, 7,934,830, 8,138,290, and 8,389,597 disclose the formation of conventional hydrogels. Conventional hydrogels can also be formed from polyvinyl alcohol. Conventional hydrogel lenses can include a coating, and the coating can be the same or a different material from the substrate. Conventional hydrogels can contain additives such as polyvinylpyrrolidone; and comonomers including polymerizable derivatives of phosphorylcholine, methacrylic acid, and the like. Commercially available conventional hydrogels include, but are not limited to, etafilcon, genfilcon, hilafilcon, lenifilcon, nesofilcon, omafilcon, polymacon, and verofilcon, including all their variants.

[0038] "Silicone hydrogel" refers to a polymer network made from at least one hydrophilic component and at least one silicone-containing component. Examples of suitable types of hydrophilic components that can be present in the reactive mixture include (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N-vinyl lactams, N-vinyl amides, N-vinyl imides, N-vinyl ureas, O-vinyl carbamates, O-vinyl carbonates, other hydrophilic vinyl compounds, and mixtures thereof. Silicone-containing components are well-known and have been widely described in the patent literature. For example, a silicone-containing component can contain at least one polymerizable group (e.g., (meth)acrylate, styryl, vinyl ether, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, O-vinyl carbamate, O-vinyl carbonate, vinyl group, or a mixture of the above), at least one siloxane group, and one or more linking groups (which can be bonds) that link one or more polymerizable groups to one or more siloxane groups. A silicone-containing component can, for example, contain 1 to 220 siloxane repeat units. A silicone-containing component can also contain at least one fluorine atom. Silicone hydrogel lenses can include a coating, and the coating can be the same or a different material from the substrate.

[0039] Examples of silicone hydrogels include acquafilcon, asmofilcon, balafilcon, comfilcon, delefilcon, enfilcon, fanfilcon, formofilcon, galyfilcon, lotrafilcon, narafilcon, riofilcon, samfilcon, senofilcon, somofilcon, and stenfilcon, including all their variants, and silicone hydrogels prepared as described in U.S. Patent Nos. 4,659,782, 4,659,783, 5,244,981, 5,314,960, 5,331,067, 5,371,147, 5,998,498, 6,087,415, 5,760,100, 5,776,999, 5,789,461, 5,849,811, 5,965,631, 6,367,929, 6,822,016, 6,867,245, 6,943,203, 7,247,692, 7,249,848, 7,553,880, 7,666,921, 7,786,185, 7,956,131, 8,022,158, 8,273,802, 8,399,538, 8,470,906, 8,450,387, 8,487,058, 8,507,577, 8,637,621, 8,703,891, 8,937,110, 8,937,111, 8,940,812, 9,056,878, 9,057,821, 9,125,808, 9,140,825, 9156,934, 9,170,349, 9,244,196, 9,244,197, 9,260,544, 9,297,928, 9,297,929, and WO 03 / 22321, WO 2008 / 061992, and US 2010 / 0048847. These patents are hereby incorporated by reference in their entirety.

[0040] An "interpenetrating polymer network" includes two or more networks that are at least partially intertwined at the molecular scale but are not covalently bonded to each other and cannot be separated without breaking chemical bonds. A "semi-interpenetrating polymer network" includes one or more networks and one or more polymers characterized by some mixing at the molecular level between at least one network and at least one polymer. A mixture of different polymers is a "polymer blend". Technically, a semi-interpenetrating network is a polymer blend, but in some cases, the polymers are entangled such that they cannot be easily removed.

[0041] The terms "reactive mixture" and "reactive monomer mixture" refer to a mixture of components (both reactive and non-reactive) that are mixed together and, when subjected to polymerization conditions, form the polymer network of the present invention, as well as ophthalmic devices and contact lenses made therefrom. The reactive monomer mixture can include reactive components such as monomers, macromonomers, prepolymers, crosslinkers, and initiators, additives (such as wetting agents), polymers, dyes, light-absorbing compounds (such as UV absorbers), pigments, dyes, and photochromic compounds (any of which can be reactive or non-reactive but capable of remaining in the resulting contact lens), as well as pharmaceutical and nutritional agent compounds and any diluents. It should be understood that a wide range of additives can be added based on the ophthalmic device to be made and its intended use. The concentration of the components of the reactive mixture is expressed as a weight percentage of all components in the reactive mixture (excluding diluents). When diluents are used, their concentration is expressed as a weight percentage based on the amount of all components in the reactive mixture and the diluents.

[0042] A "reactive component" is a component in the reactive mixture that becomes part of the chemical structure of the polymer network of the resulting hydrogel through covalent bonding, hydrogen bonding, electrostatic interactions, formation of interpenetrating polymer networks, or any other means.

[0043] The term "silicone hydrogel contact lens" refers to a hydrogel contact lens made from at least one silicone-containing compound. Compared to conventional hydrogels, silicone hydrogel contact lenses generally have improved oxygen permeability. Silicone hydrogel contact lenses utilize both their water and polymer contents to transport oxygen to the eye.

[0044] The term "polyfunctional" refers to a component having two or more polymerizable groups. The term "monofunctional" refers to a component having one polymerizable group.

[0045] The term "halogen" or "halo group" denotes fluorine, chlorine, bromine, and iodine.

[0046] "Alkyl" refers to an optionally substituted straight-chain or branched alkyl group containing a specified number of carbon atoms. If the number is not specified, the alkyl group (including any optional substituents on the alkyl) can contain 1 to 16 carbon atoms. Preferably, the alkyl group contains 1 to 10 carbon atoms, alternatively 1 to 8 carbon atoms, alternatively 1 to 6 carbon atoms, or alternatively 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, etc. Examples of substituents on the alkyl include one, two or three groups independently selected from the following: hydroxyl, amino, amide, alkoxyalkyl, oxo ((=O)), carboxyl, alkylcarboxyl, carbonyl, alkoxy, thioalkyl, carbamate, carbonate, halogen, phenyl, benzyl, and combinations thereof. Preferred substituents include hydroxyl, alkoxy, halo, alkoxyalkyl or oxo groups. "Alkylene" means a divalent alkyl group, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2- and -CH2CH2CH2CH2-.

[0047] "Haloalkyl" refers to an alkyl group as defined above substituted by one or more halogen atoms, where each halogen is independently F, Cl, Br or I. The preferred halogen is F. Preferred haloalkyl groups contain 1 to 6 carbons, more preferably 1 to 4 carbons, and even more preferably 1 to 2 carbons. "Haloalkyl" includes perhaloalkyl groups, such as -CF3- or -CF2CF3-. "Halomethylene" means a divalent haloalkyl group, such as -CH2CF2-.

[0048] "Cycloalkyl" refers to an optionally substituted cyclic hydrocarbon containing a specified number of ring carbon atoms. If the number is not indicated, the cycloalkyl can contain 3 to 12 ring carbon atoms. Preferably, it is a C3-C8 cycloalkyl group, C3-C7 cycloalkyl, more preferably C4-C7 cycloalkyl, and even more preferably C5-C6 cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of substituents on the cycloalkyl include one, two or three groups independently selected from the following: alkyl, hydroxyl, amino, amide, alkoxyalkyl, carbonyl, alkoxy, thioalkyl, amide, carbamate, carbonate, halo, phenyl, benzyl, and combinations thereof. Preferred substituents include hydroxyl, alkoxy, halo, alkoxyalkyl or oxo groups. "Cycloalkylene" means a divalent cycloalkyl group, such as 1,2-cyclohexylene, 1,3-cyclohexylene or 1,4-cyclohexylene.

[0049] "Heterocycloalkyl" means a cycloalkyl ring or ring system as defined above in which at least one ring carbon has been replaced by a heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring is optionally fused to or otherwise attached to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings and / or benzene rings. Preferred heterocycloalkyl groups have 5 to 7 members. More preferred heterocycloalkyl groups have 5 or 6 members. Heterocycloalkylene means a divalent heterocycloalkyl group.

[0050] "Aryl" means an optionally substituted aromatic hydrocarbon ring system containing at least one aromatic ring. An aryl group contains a specified number of ring carbon atoms. If no number is indicated, an aryl may contain 6 to 14 ring carbon atoms. The aromatic rings may be optionally fused to or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include phenyl, naphthyl, and biphenyl. Preferred examples of aryl groups include phenyl. Examples of substituents on the aryl include 1, 2, or 3 groups independently selected from: alkyl, hydroxy, amino, amido, alkoxyalkyl, carboxyl, alkylcarboxyl, carbonyl, alkoxy, thioalkyl, carbamate, carbonate, halo, phenyl, benzyl, and combinations thereof. "Arylene" means a divalent aryl group, such as 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene.

[0051] "Heteroaryl" means an aryl ring or ring system as defined above in which at least one ring carbon has been replaced by a heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused to or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings, or heterocycloalkyl rings. Examples of heteroaryl groups include pyridyl, furyl, and thienyl. "Heteroarylene" means a divalent heteroaryl group.

[0052] "Alkoxy" means an alkyl group attached to the parent molecular moiety by an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, and isopropoxy. "Thioalkyl" means an alkyl group attached to the parent molecule by a sulfur bridge. Examples of thioalkyl groups include, for example, methylthio, ethylthio, n-propylthio, and isopropylthio. "Aryloxy" means an aryl group attached to the parent molecular moiety by an oxygen bridge. Examples include phenoxy. "Cycloalkoxy" means a cycloalkyl group attached to the parent moiety by an oxygen bridge.

[0053] "Alkylamine" means an alkyl group attached to the parent molecular moiety by an -NH bridge. Alkyleneamine means a divalent alkylamine group, such as -CH2CH2NH-.

[0054] "Siloxanyl" refers to a structure having at least one Si-O-Si bond. Thus, for example, a siloxanyl group means a group having at least one Si-O-Si group (i.e., a siloxanyl group), and a siloxanyl compound means a compound having at least one Si-O-Si group. "Siloxanyl" encompasses monomers (e.g., Si-O-Si) as well as oligomeric / polymeric structures (e.g., -[Si-O] n -, where n is 2 or greater). Each silicon atom in the siloxanyl group is substituted with an independently selected R A group (where R A is defined as in options (b) to (i) of formula A) to complete its valence.

[0055] "Silyl" refers to a structure of the formula R3Si-, and "silyloxy" refers to a structure of the formula R3Si-O-, where each R in the silyl or silyloxy is independently selected from trimethylsilyloxy, C1-C8 alkyl (preferably C1-C3 alkyl, more preferably ethyl or methyl), and C3-C8 cycloalkyl.

[0056] "Alkyleneoxy" refers to a group having the general formula -(alkylene-O-) p - or -(O-alkylene) p -, where alkylene is as defined above, and p is from 1 to 200, or 1 to 100, or 1 to 50, or 1 to 25, or 1 to 20, or 1 to 10, where each alkylene is independently optionally substituted with one or more groups independently selected from hydroxyl, halo (e.g., fluorine), amino, amido, ether, carbonyl, carboxyl, and combinations thereof. If p is greater than 1, each alkylene may be the same or different, and the alkyleneoxy may be in a block or random configuration. When the alkyleneoxy forms a terminal group in the molecule, the terminal end of the alkyleneoxy may be, for example, a hydroxyl or an alkoxy (e.g., HO-[CH2CH2O] p - or CH3O-[CH2CH2O] p -). Examples of alkyleneoxy include poly(ethyleneoxy), poly(propyleneoxy), poly(butyleneoxy), and poly(ethyleneoxy-co-propyleneoxy).

[0057] "Oxaalkylene" refers to an alkylene group as defined above in which one or more non-adjacent CH2 groups have been replaced by oxygen atoms, such as -CH2CH2OCH(CH3)CH2-. "Thiaalkylene" refers to an alkylene group as defined above in which one or more non-adjacent CH2 groups have been replaced by sulfur atoms, such as -CH2CH2SCH(CH3)CH2-.

[0058] The term "linking group" refers to the moiety that connects the polymerizable group to the parent molecule. The linking group can be any moiety compatible with the compound, which is part of the compound and does not undesirably interfere with the polymerization of the compound and is stable under the polymerization conditions and the conditions for processing and storing the final product. For example, the linking group can be a chemical bond, or it can include one or more alkylene, haloalkylene, amide, amine, alkyleneamine, carbamate, ester (-CO2-), arylene, heteroarylene, cycloalkylene, heterocycloalkylene, alkoxy, oxaalkylene, thiaalkylene, haloalkoxy (alkoxy substituted with one or more halo groups, such as -OCF2-, -OCF2CF2-, -OCF2CH2-), siloxanyl, alkylsiloxanyl, or combinations thereof. The linking group can optionally be substituted with one or more substituent groups. Suitable substituent groups can include those independently selected from alkyl, halo (e.g., fluorine), hydroxy, HO-alkoxy, MeO-alkoxy, siloxanyl, silyloxy, silyloxy-alkoxy-, silyloxy-alkyl-alkoxy- (wherein there can be more than one alkoxy group and each methylene in the alkyl and alkoxy is independently optionally substituted with hydroxy), ether, amine, carbonyl, carbamate, and combinations thereof. The linking group can also be substituted with a polymerizable group such as (meth)acrylate (in addition to the polymerizable group to which the linking group is attached).

[0059] Preferred linking groups include alkylene, cycloalkylene, heterocycloalkylene, arylene (e.g., phenylene), heteroarylene, oxaalkylene, alkylene-amide-alkylene, alkylene-amine-alkylene, or combinations of any of the foregoing groups. Preferred linking groups also include C1-C8 alkylene (preferably C2-C6 alkylene such as ethylene or propylene), C1-C8 oxaalkylene (preferably C2-C6 oxaalkylene), C1-C8 alkylene-amide-C1-C8 alkylene, and C1-C8 alkylene-amine-C1-C8 alkylene, each of which is optionally substituted with 1 or 2 groups independently selected from hydroxy and silyloxy. Preferred linking groups also include carboxylate, amide, C1-C8 alkylene-carboxylate-C1-C8 alkylene, or C1-C8 alkylene-amide-C1-C8 alkylene.

[0060] When the linking group is composed of a combination of moieties (e.g., alkylene-cycloalkylene), the moieties can be present in any order. Nevertheless, the listed order represents the preferred order of the moieties as they appear in the compound starting from the terminal polymerizable group to which the linking group is attached.

[0061] "Optionally substituted" means that a moiety may contain one or more optional substituents. The term "optional substituent" means that a hydrogen atom in the following moieties is optionally replaced by a substituent. Any substituent that has steric utility and is synthetically feasible at the substitution site may be used. Identification of suitable optional substituents is well within the ability of one of ordinary skill in the art. Examples of "optional substituents" include, but are not limited to, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C3-C7 cycloalkyl, aryl, halo, hydroxy, amino, NR 4 R 5 、benzyl, SO3H, SO3Na or -Y-P g wherein R 4 and R 5 are independently H or C1-C6 alkyl, Y is a linking group; and P g is a polymerizable group. The foregoing substituents may be optionally substituted by optional substituents (unless otherwise specified, which is preferably not further substituted). For example, an alkyl may be substituted by a halo group (e.g., to produce CF3).

[0062] The term "amino acid residue" refers to a non-hydrogen group attached to the α-carbon of a natural α-amino acid, which may be represented by "R R " in the following structure:

[0063]

[0064] Preferred amino acid residues include residues of arginine (arg), asparagine (asn), histidine (his), alanine (ala), lysine (lys), glutamine (gln), glutamate (glu), tyrosine (tyr), tryptophan (trp), aspartic acid (asp), methionine (met), glycine (gly), valine (val), leucine (leu), isoleucine (ile), proline (pro), phenylalanine (phe), serine (ser) and threonine (thr). Additionally preferred amino acid residues include residues of arginine (arg), asparagine (asn), histidine (his), alanine (ala), lysine (lys), glutamine (gln), glutamate (glu), tyrosine (tyr), tryptophan (trp), aspartic acid (asp) and methionine (met). Additionally preferred amino acid residues include residues of arginine (arg), asparagine (asn) and histidine (his). "Derivatives of amino acid residues" means that the residue has been chemically modified, e.g., by replacing a hydrogen atom in the residue with another group.

[0065] Unless otherwise specified, ratios, percentages, parts, etc. are by weight.

[0066] Unless otherwise specified, a numerical range (e.g., "2 to 10") includes the numbers defining the range (e.g., 2 and 10).

[0067] As described above, the present invention provides amino acid-based polymerizable compounds. The compounds have the formula I:

[0068]

[0069] wherein R is H, C(=O)R 3 , or R together with the nitrogen to which it is attached forms a polymerizable group, wherein R 3 is C1-C 25 alkyl or cycloalkyl; R 1 is an amino acid residue or a derivative of an amino acid residue, wherein the derivative optionally contains a polymerizable group; and R 2 is OR 4 or N(H)-L-P g , wherein R 4 is H, a metal cation or C1-C6 alkyl, L is a linking group, and P g is a polymerizable group, wherein the compound contains at least one polymerizable group.

[0070] The compounds of formula I may include compounds of formula I-1, which are compounds of formula I wherein R 1 is an amino acid residue of arginine (arg), asparagine (asn) or histidine (his).

[0071] The compounds of formula I may include compounds of formula I-2, which are compounds of formula I wherein R 1 is a derivative of a cysteine (cys) amino acid residue.

[0072] The compounds of formula I-2 may include compounds of formula I-3, which are compounds of formula I-2 wherein R 1 is -CH2-SO3R 5 and R 5 is H, a metal cation (e.g., Na or K) or C1-C6 alkyl. Preferably, R 5 is Na.

[0073] The compounds of formula I-2 may include compounds of formula I-4, which are compounds of formula I-2 wherein R 1 is -CH2-S-L-P g wherein L is a linking group and P g is a polymerizable group.

[0074] The compound of formula I-4 may include the compound of formula I-5, which is the compound of formula I-4 wherein L is alkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, oxaalkylene, alkylene-amide-alkylene, alkylene-amine-alkylene or alkylene-ester-alkylene. Preferably, L in formula I-5 is alkylene-ester-alkylene. Preferably, at least one alkylene in alkylene-ester-alkylene is substituted by OH. More preferably, L in formula I-5 is -CH2CH2-C(=O)O-CH2CH(OH)CH2-.

[0075] The compounds of formula I-4 and I-5 may include the compound of formula I-6, which is wherein P g includes styryl, vinyl carbonate, vinyl ether, vinyl carbamate, N-vinyl lactam, N-vinyl amide, (meth)acrylate or (meth)acrylamide of the compound of formula I-4 or I-5. Preferably, P in formula I-6 g includes (meth)acrylate or (meth)acrylamide. More preferably, P in formula I-6 g includes methacrylate or methacrylamide. Further preferably, P in formula I-6 g includes methacrylate.

[0076] The compounds of formula I, I-1, I-2, I-3, I-4, I-5 and I-6 may include the compound of formula I-7, which is the compound of formula I, I-1, I-2, I-3, I-4, I-5 or I-6 wherein R is H.

[0077] The compounds of formula I, I-1, I-2, I-3, I-4, I-5 and I-6 may include the compound of formula I-8, which is the compound of formula I, I-1, I-2, I-3, I-4, I-5 or I-6 wherein R is C(=O)R 3 and R 3 is C5-C 20 alkyl of the compound of formula I, I-1, I-2, I-3, I-4, I-5 or I-6. Preferably, R 3 is C7 to C 15 alkyl, more preferably C8-C 12 alkyl.

[0078] The compounds of formula I, I-1, I-2, I-3, I-4, I-5 and I-6 may include the compound of formula I-9, which is the compound of formula I, I-1, I-2, I-3, I-4, I-5 or I-6 wherein R together with the nitrogen to which it is attached forms a polymerizable group. Preferably, in formula I-9, R together with the nitrogen to which it is attached forms a (meth)acrylamide group, more preferably a methacrylamide group.

[0079] Compounds of Formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 and I-9 may include compounds of Formula I-10, which are those wherein R 2 is OR 4 and R 4 is H or C1-C6 alkyl, of Formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 or I-9.

[0080] Compounds of Formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 and I-9 may include compounds of Formula I-11, which are those wherein R 2 is N(H)-L-P g of Formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 or I-9.

[0081] Compounds of Formula I-11 may include compounds of Formula I-12, which are those of Formula I-11 wherein L is alkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, oxaalkylene, alkylene-amide-alkylene, alkylene-amine-alkylene or alkylene-ester-alkylene. Preferably, L in Formula I-12 is alkylene, more preferably ethylene.

[0082] Compounds of Formula I-11 and I-12 may include compounds of Formula I-13, which are those of Formula I-11 or I-12 wherein P g includes styryl, vinyl carbonate, vinyl ether, vinyl carbamate, N-vinyl lactam, N-vinyl amide, (meth)acrylate or (meth)acrylamide. Preferably, P in Formula I-13 g includes (meth)acrylate or (meth)acrylamide. More preferably, P in Formula I-13 g includes methacrylate or methacrylamide. Further preferably, P in Formula I-13 g includes methacrylate.

[0083] Compounds of Formula I may include compounds of Formula II:

[0084]

[0085] wherein R 4 is H, a metal cation or C1-C6 alkyl; and R 6 is H or methyl. Preferably, R 4 is H. Preferably, R 6 is methyl.

[0086] Compounds of Formula I may include compounds of Formula III:

[0087]

[0088] wherein R 4 is H, a metal cation or a C1-C6 alkyl group, and R 6 is H or methyl. Preferably, R 4 is H. Preferably, R 6 is methyl.

[0089] The compound of formula I may include the compound of formula IV:

[0090]

[0091] wherein R 4 is H, a metal cation, a C1-C6 alkyl group; and R 6 is H or methyl. Preferably, R 4 is a C1-C6 alkyl group, more preferably a C1-C3 alkyl group, and even more preferably methyl. Preferably, R 6 is methyl.

[0092] The compound of formula I may include the compound of formula V:

[0093]

[0094] wherein R 3 is a C1-C 25 alkyl or cycloalkyl group; R 5 is H, a metal cation, a C1-C6 alkyl group; and R 6 is H or methyl. Preferably, R 3 is a C8-C 12 alkyl group. Preferably, R 5 is a metal cation, more preferably Na. Preferably, R 6 is methyl.

[0095] The compound of formula I may include the compound of formula VI:

[0096]

[0097] wherein R 4 is H, a metal cation or a C1-C6 alkyl group; and R 6 is H or methyl. Preferably, R 4 is H. Preferably, R 6 is methyl.

[0098] Exemplary compounds of formula I are shown in Table 1.

[0099] Table 1

[0100]

[0101]

[0102]

[0103] Preferred compounds include: methacryloyl arginine; methacryloyl asparagine; methyl methacryloyl histidine; sodium 2-decanamido-3-((2-methacryloyloxyethyl)amino)-3-oxopropane-1-sulfonate; and S-(3-(2-hydroxy-3-(methacryloyloxy)propoxy)-3-oxopropyl)-L-cysteine.

[0104] The amino acid-based polymerizable compounds of the present invention can be formed into polymers for introduction into ophthalmic devices by a variety of techniques. For example, the compounds can be homopolymerized or copolymerized into a polymer, which is then coated onto the ophthalmic device or added to a reactive monomer mixture for preparing the ophthalmic device (to form, for example, a semi-interpenetrating network with other components of the reactive monomer mixture).

[0105] The amino acid-based polymerizable compounds according to the present invention can also be introduced into ophthalmic devices via grafting, as further demonstrated in the examples. Exemplary grafting techniques are described in U.S. Pre-Grant Publication 20180037690, which is incorporated herein by reference in its entirety.

[0106] In addition, the amino acid-based polymerizable compounds according to the present invention can be included in a reactive monomer mixture containing other monomers suitable for preparing ophthalmic devices and reacted therewith under free radical polymerization conditions to form a polymer, whereby an ophthalmic device can be prepared. In addition to the amino acid-based polymerizable compounds described above, such reactive mixtures can also contain one or more monomers suitable for preparing the desired ophthalmic device and optional ingredients. Thus, the reactive mixture can, for example, contain: hydrophilic components, hydrophobic components, silicone-containing components, wetting agents (such as polyamides), crosslinking agents, and additional components (such as diluents and initiators).

[0107] Hydrophilic Component

[0108] Examples of suitable types of hydrophilic monomers include (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N-vinyl lactams, N-vinyl amides, N-vinyl imides, N-vinyl ureas, O-vinyl carbamates, O-vinyl carbonates, other hydrophilic vinyl compounds, and mixtures thereof.

[0109] Non-limiting examples of hydrophilic (meth)acrylate and (meth)acrylamide monomers include: acrylamide, N-isopropylacrylamide, N,N-dimethylaminopropyl (meth)acrylamide, N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2,3-dihydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 3-hydroxybutyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, N-(2-hydroxyethyl) (meth)acrylamide, N,N-bis(2-hydroxyethyl) (meth)acrylamide, N-(2-hydroxypropyl) (meth)acrylamide, N,N-bis(2-hydroxypropyl) (meth)acrylamide, N-(3-hydroxypropyl) (meth)acrylamide, N-(2-hydroxybutyl) (meth)acrylamide, N-(3-hydroxybutyl) (meth)acrylamide, N-(4-hydroxybutyl) (meth)acrylamide, 2-aminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, 2-aminopropyl (meth)acrylate, N-2-aminoethyl (meth)acrylamide, N-3-aminopropyl (meth)acrylamide, N-2-aminopropyl (meth)acrylamide, N,N-bis-2-aminoethyl (meth)acrylamide, N,N-bis-3-aminopropyl (meth)acrylamide, N,N-bis-2-aminopropyl (meth)acrylamide, glycerol methacrylate, polyethylene glycol monomethacrylate, (meth)acrylic acid, vinyl acetate, acrylonitrile, and mixtures thereof.

[0110] The hydrophilic monomer may also be ionic, including anionic, cationic, zwitterionic, betaine, and mixtures thereof. Non-limiting examples of such charged monomers include (meth)acrylic acid, N-[(vinyloxy)carbonyl]-β-alanine (VINAL), 3-acrylamidopropionic acid (ACA1), 5-acrylamidovaleric acid (ACA2), 3-acrylamido-3-methylbutyric acid (AMBA), 2-(methacryloyloxy)ethyltrimethylammonium chloride (Q salt or METAC), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), N-(2-carboxyethyl)-N,N-dimethyl-3-[(1-oxo-2-propen-1-yl)amino]-1-propanaminium inner salt (CBT), N,N-dimethyl-N-[3-[(1-oxo-2-propen-1-yl)amino]propyl]-3-sulfo-1-propanaminium inner salt (SBT), 4-hydroxy-N,N,N-trimethyl-9-oxo-4-oxide 3,5-dioxa-8-aza-4-phosphaundec-10-en-1-aminium inner salt (9CI) (PBT), 2-methacryloyloxyethylphosphorylcholine, 3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS), 3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS), 3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate (MAMPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS), and 3-((3-(methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS).

[0111] Non-limiting examples of hydrophilic N-vinyl lactam and N-vinyl amide monomers include: N-vinyl pyrrolidone (NVP), N-vinyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-caprolactam, N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinyl acetamide (NVA), N-vinyl-N-methyl acetamide (VMA), N-vinyl-N-ethyl acetamide, N-vinyl-N-ethyl formamide, N-vinyl formamide, N-vinyl-N-methyl propionamide, N-vinyl-N-methyl-2-methyl propionamide, N-vinyl-2-methyl propionamide, N-vinyl-N,N'-dimethyl urea, 1-methyl-3-methylene-2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene-2-pyrrolidone; 1-ethyl-5-methylene-2-pyrrolidone, N-methyl-3-methylene-2-pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone, 1-N-propyl-3-methylene-2-pyrrolidone, 1-N-propyl-5-methylene-2-pyrrolidone, 1-isopropyl-3-methylene-2-pyrrolidone, 1-isopropyl-5-methylene-2-pyrrolidone, N-vinyl-N-ethyl acetamide, N-vinyl-N-ethyl formamide, N-vinyl formamide, N-vinyl isopropyl amide, N-vinyl caprolactam, N-vinyl imidazole, and mixtures thereof.

[0112] Non-limiting examples of hydrophilic O-vinyl carbamate and O-vinyl carbonate monomers include N-2-hydroxyethyl vinyl carbamate and N-carboxy-β-alanine N-vinyl ester. Other examples of hydrophilic ethylene carbonate or vinyl carbamate monomers are disclosed in U.S. Patent 5,070,215. Hydrophilic oxazolone monomers are disclosed in U.S. Patent 4,910,277.

[0113] Other hydrophilic vinyl compounds include ethylene glycol vinyl ether (EGVE), di(ethylene glycol) vinyl ether (DEGVE), allyl alcohol, and 2-ethyl oxazoline.

[0114] The hydrophilic monomer can also be a linear or branched macromonomer or prepolymer of poly(ethylene glycol), poly(propylene glycol), or a statistical random or block copolymer of ethylene oxide and propylene oxide, having polymerizable moieties such as (meth)acrylate, styrene, vinyl ether, (meth)acrylamide, N-vinyl amide, etc. These macromonomers of polyethers have one polymerizable group; the prepolymers can have two or more polymerizable groups.

[0115] Preferred hydrophilic monomers of the present invention are DMA, NVP, HEMA, VMA, NVA, and mixtures thereof. Preferred hydrophilic monomers include a mixture of DMA and HEMA. Other suitable hydrophilic monomers will be apparent to those skilled in the art.

[0116] Generally, there is no particular limitation on the amount of hydrophilic monomer that may be present in the reactive monomer mixture. The amount of hydrophilic monomer can be selected based on the desired characteristics of the resulting hydrogel, including water content, light transmittance, wettability, protein absorption, etc. Wettability can be measured by contact angle, and the desired contact angle is less than about 100°, less than about 80°, and less than about 60°. Based on the total weight of the reactive components in the reactive monomer mixture, the hydrophilic monomer can be present, for example, in an amount in the range of about 0.1 wt% to about 100 wt%, alternatively in the range of about 1 wt% to about 80 wt%, alternatively in the range of about 5 wt% to about 65 wt%, alternatively in the range of about 40 to about 60 wt%, or alternatively in the range of about 55 wt% to about 60 wt%.

[0117] Silicone-Containing Component

[0118] The silicone-containing component suitable for the present invention comprises one or more polymerizable compounds, wherein each compound independently comprises at least one polymerizable group, at least one siloxane group, and one or more linking groups that link one or more polymerizable groups to one or more siloxane groups. The silicone-containing component may, for example, contain from 1 to 220 siloxane repeating units, such as the groups defined below. The silicone-containing component may also comprise at least one fluorine atom.

[0119] The silicone-containing component may comprise: one or more polymerizable groups as defined above; one or more optionally repeating siloxane units; and one or more linking groups that link the polymerizable groups to the siloxane units. The silicone-containing component may comprise: one or more polymerizable groups, which are independently (meth)acrylate, styryl, vinyl ether, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, O-vinyl carbamate, O-vinyl carbonate, vinyl group, or a mixture of the foregoing; one or more optionally repeating siloxane units; and one or more linking groups that link the polymerizable groups to the siloxane units.

[0120] The silicone-containing component may comprise: one or more polymerizable groups, which are independently (meth)acrylate, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, styryl or a mixture of the foregoing; one or more optionally repeating siloxane units; and one or more linking groups that link the polymerizable groups to the siloxane units.

[0121] The silicone-containing component may comprise: one or more polymerizable groups, which are independently (meth)acrylate, (meth)acrylamide or a mixture of the foregoing; one or more optionally repeating siloxane units; and one or more linking groups that link the polymerizable groups to the siloxane units.

[0122] The silicone-containing component of formula A may comprise one or more polymerizable compounds of formula A:

[0123]

[0124] wherein:

[0125] At least one R A is a group of formula R g -L-, wherein R g is a polymerizable group and L is a linking group, and the remaining Rs A are each independently:

[0126] (a) R g -L-,

[0127] (b) C1-C 16 alkyl optionally substituted with one or more hydroxyl, amino, amido, alkoxyalkyl, carboxyl, alkyl carboxyl, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, or combinations thereof,

[0128] (c) C3-C 12 cycloalkyl optionally substituted with one or more alkyl, hydroxyl, amino, amido, alkoxyalkyl, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, or combinations thereof,

[0129] (d) C6-C 14 aryl group optionally substituted with one or more alkyl, hydroxyl, amino, amido, alkoxyalkyl, carboxyl, alkyl carboxyl, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, or combinations thereof,

[0130] (e) halo,

[0131] (f) alkoxy, cyclic alkoxy or aryloxy,

[0132] (g) Silanyloxy,

[0133] (h) Alkoxyalkylene or alkoxyalkoxyalkylene, such as poly(ethyleneoxy)alkylene, poly(propyleneoxy)alkylene or poly(ethyleneoxy - co - propyleneoxy)alkylene, or

[0134] (i) A monovalent siloxane chain containing from 1 to 100 siloxane repeating units, the siloxane repeating units being optionally substituted with alkyl, alkoxy, hydroxy, amino, alkoxyalkyl, carboxyl, alkylcarboxyl, alkoxy, amido, carbamate, halo, or combinations thereof; and

[0135] n is from 0 to 500, or from 0 to 200, or from 0 to 100, or from 0 to 20, it being understood that when n is not 0, n is a distribution with a mode equal to the specified value. When n is 2 or greater, the SiO units may carry the same or different R A substituents, and if different R A substituents are present, the n groups may be in a random or block configuration.

[0136] In formula A, the three R A may each contain a polymerizable group, alternatively two R A may each contain a polymerizable group, or alternatively one R A may contain a polymerizable group.

[0137] Examples of the organosilicon - containing components suitable for the present invention include, but are not limited to, the compounds listed in Table A. If the compounds in Table A contain polysiloxane groups, unless otherwise specified, the number of SiO repeating units in such compounds is preferably from 3 to 100, more preferably from 3 to 40, or still more preferably from 3 to 20.

[0138] Table A

[0139]

[0140]

[0141] Additional non - limiting examples of suitable organosilicon - containing components are listed in Table B. Unless otherwise specified, in applicable cases, j2 is preferably from 1 to 100, more preferably from 3 to 40, or still more preferably from 3 to 15. In compounds containing j1 and j2, the sum of j1 and j2 is preferably from 2 to 100, more preferably from 3 to 40, or still more preferably from 3 to 15.

[0142] Table B

[0143]

[0144]

[0145] Mixtures of components containing silicone can be used. By way of example, suitable mixtures can include, but are not limited to: mixtures of mono-(2-hydroxy-3-methacryloyloxypropoxy)-propyl capped mono-n-butyl capped polydimethylsiloxanes (OH-mPDMS) with different molecular weights, such as mixtures of OH-mPDMS containing 4 and 15 SiO repeating units; mixtures of OH-mPDMS with different molecular weights (e.g., containing 4 and 15 repeating SiO repeating units) and a silicone-based crosslinker such as bis-3-acryloyloxy-2-hydroxypropoxypropyl polydimethylsiloxane (ac-PDMS); mixtures of 2-hydroxy-3-[3-methyl-3,3-bis(trimethylsilyloxy)silylpropoxy]-propyl methacrylate (SiMAA) and mono-methacryloyloxypropyl capped mono-n-butyl capped polydimethylsiloxane (mPDMS) such as mPDMS 1000.

[0146] The silicone-containing components for use in the present invention can have an average molecular weight of from about 400 Daltons to about 4000 Daltons.

[0147] Based on all the reactive components (excluding diluents) of the reactive mixture, one or more silicone-containing components can be present in an amount of up to about 95 wt%, or from about 10 wt% to about 80 wt%, or from about 20 wt% to about 70 wt%.

[0148] Polyamide

[0149] The reactive mixture can contain at least one polyamide. As used herein, the term "polyamide" refers to polymers and copolymers comprising repeating units containing amide groups. Polyamides can include cyclic amide groups, acyclic amide groups, and combinations thereof, and can be any polyamide known to those skilled in the art. Acyclic polyamides contain acyclic amide side groups and are capable of binding to hydroxyl groups. Cyclic polyamides contain cyclic amide groups and are capable of binding to hydroxyl groups.

[0150] Examples of suitable acyclic polyamides include polymers and copolymers comprising repeating units of formulae G and G1:

[0151]

[0152]

[0153] wherein X is a direct bond, -(CO)- or –(CONHR 44 )-, wherein R 44is a C1 to C3 alkyl group; R 40 is selected from H, a straight-chain or branched, substituted or unsubstituted C1 to C4 alkyl group; R 41 is selected from H, a straight-chain or branched, substituted or unsubstituted C1 to C4 alkyl group, an amino group having at most two carbon atoms, an amide group having at most four carbon atoms, and an alkoxy group having at most two carbon groups; R 42 is selected from H, a straight-chain or branched, substituted or unsubstituted C1 to C4 alkyl group; or methyl, ethoxy, hydroxyethyl, and hydroxymethyl; R 43 is selected from H, a straight-chain or branched, substituted or unsubstituted C1 to C4 alkyl group; or methyl, ethoxy, hydroxyethyl, and hydroxymethyl; wherein R 40 and R 41 together have 8 or fewer carbon atoms, including 7, 6, 5, 4, 3, or fewer; and wherein R 42 and R 43 together have 8 or fewer carbon atoms, including 7, 6, 5, 4, 3, or fewer. R 40 and R 41 together may have 6 or fewer or 4 or fewer carbon atoms. R 42 and R 43 together may have 6 or fewer carbon atoms. As used herein, a substituted alkyl group includes an alkyl group substituted with an amine, amide, ether, hydroxy, carbonyl, or carboxyl group or a combination thereof.

[0154] R 40 and R 41 may independently be selected from H, a substituted or unsubstituted C1 to C2 alkyl group. X may be a direct bond, and R 40 and R 41 may independently be selected from H, a substituted or unsubstituted C1 to C2 alkyl group. R 42 and R 43 may independently be selected from H, a substituted or unsubstituted C1 to C2 alkyl group, methyl, ethoxy, hydroxyethyl, and hydroxymethyl.

[0155] The acyclic polyamides of the present invention may comprise a majority of repeating units of formula G or formula G1, or the acyclic polyamides may comprise at least 50 mol% (including at least 70 mol% and at least 80 mol%) of repeating units of formula G or formula G1. Specific examples of repeating units of formula G and formula G1 include repeating units derived from: N-vinyl-N-methylacetamide, N-vinylacetamide, N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide, N-vinyl-2-methyl-propionamide, N-vinyl-N,N'-dimethylurea, N,N-dimethylacrylamide, methacrylamide, and acyclic amides of formula G2 and G3:

[0156]

[0157] Examples of suitable cyclic amides that can be used to form cyclic polyamides include α-lactams, β-lactams, γ-lactams, δ-lactams, and ε-lactams. Examples of suitable cyclic polyamides include polymers and copolymers containing repeating units of Formula G4:

[0158]

[0159] wherein R 45 is a hydrogen atom or a methyl group; wherein f is a number from 1 to 10; wherein X is a direct bond, -(CO)-, or –(CONHR 46 ), where R 46 is a C1 to C3 alkyl group. In Formula G4, f can be 8 or less, including 7, 6, 5, 4, 3, 2, or 1. In Formula G4, f can be 6 or less, including 5, 4, 3, 2, or 1. In Formula G4, f can be from 2 to 8, including 2, 3, 4, 5, 6, 7, or 8. In Formula G4, f can be 2 or 3. When X is a direct bond, f can be 2. In such cases, the cyclic polyamide can be polyvinylpyrrolidone (PVP).

[0160] The cyclic polyamides of the present invention can contain 50 mol% or more of the repeating units of Formula G4, or the cyclic polyamides can contain at least 50 mol% (including at least 70 mol% and at least 80 mol%) of the repeating units of Formula G4.

[0161] The polyamide may also be a copolymer comprising repeating units of both cyclic and acyclic amides. The additional repeating units may be formed from monomers selected from: hydroxyalkyl (meth)acrylates, alkyl (meth)acrylates, other hydrophilic monomers, and siloxane-substituted (meth)acrylates. Any of the monomers (listed as suitable hydrophilic monomers) may be used as a comonomer to form the additional repeating units. Specific examples of additional monomers that can be used to form the polyamide include 2-hydroxyethyl (meth)acrylate, vinyl acetate, acrylonitrile, hydroxypropyl (meth)acrylate, methyl (meth)acrylate, hydroxybutyl (meth)acrylate, dipropylene glycol mono(meth)acrylate, polyethylene glycol mono(meth)acrylate, etc., and mixtures thereof. It may also contain ionic monomers. Examples of ionic monomers include (meth)acrylic acid, N-[(vinyloxy)carbonyl]-β-alanine (VINAL, CAS#148969-96-4), 3-acrylamidopropionic acid (ACA1), 5-acrylamidovaleric acid (ACA2), 3-acrylamido-3-methylbutyric acid (AMBA), 2-(methacryloyloxy)ethyltrimethylammonium chloride (Q salt or METAC), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), N-(2-carboxyethyl)-N,N-dimethyl-3-[(1-oxo-2-propen-1-yl)amino]-1-propanaminium inner salt (CBT, carboxybetaine; CAS 79704-35-1), N,N-dimethyl-N-[3-[(1-oxo-2-propen-1-yl)amino]propyl]-3-sulfo-1-propanaminium inner salt (SBT, sulfobetaine, CAS 80293-60-3), 4-hydroxy-N,N,N-trimethyl-9-oxo-4-oxide 3,5-dioxa-8-aza-4-phosphaundec-10-en-1-aminium inner salt (9CI) (PBT, phosphobetaine, CAS 163674-35-9), 2-methacryloyloxyethylphosphorylcholine, 3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS), 3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS), 3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate (MAMPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS), (methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS).

[0162] The reactive monomer mixture may comprise both acyclic polyamides and cyclic polyamides or copolymers thereof. The acyclic polyamides may be any of those acyclic polyamides described herein or copolymers thereof, and the cyclic polyamides may be any of those cyclic polyamides described herein or copolymers thereof. The polyamides may be selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylmethylacetamide (PVMA), polydimethylacrylamide (PDMA), polyvinylacetamide (PNVA), poly(hydroxyethyl(meth)acrylamide), polyacrylamide, and copolymers and mixtures thereof. The polyamides may be a mixture of PVP (e.g., PVP K90) and PVMA (e.g., having an M w ) of about 570KDa).

[0163] In all cases, based on the total weight of the reactive components in the reactive monomer mixture, the total amount of all polyamides in the reactive mixture may range from 1 wt% to about 35 wt%, including in the range of about 1 wt% to about 15 wt% and in the range of about 5 wt% to about 15 wt%.

[0164] Without wishing to be bound by theory, when used with a silicone hydrogel, the polyamide acts as an internal wetting agent. The polyamides of the present invention may be non-polymerizable and, in this case, are incorporated into the silicone hydrogel as a semi-interpenetrating network. The polyamide is trapped or physically retained within the silicone hydrogel. Alternatively, the polyamides of the present invention are polymerizable, for example as polyamide macromonomers or prepolymers, and in this case are covalently incorporated into the silicone hydrogel. Mixtures of polymerizable and non-polymerizable polyamides may also be used.

[0165] When incorporating the polyamides into the reactive monomer mixture, their weight average molecular weight may be at least 100,000 daltons; greater than about 150,000 daltons; from about 150,000 daltons to about 2,000,000 daltons; from about 300,000 daltons to about 1,800,000 daltons. Higher molecular weight polyamides may be used if they are compatible with the reactive monomer mixture.

[0166] Crosslinking Agent

[0167] It is generally desirable to add one or more crosslinking agents (also known as crosslinking monomers, polyfunctional macromonomers, and prepolymers) to the reactive mixture. The crosslinking agents can be selected from difunctional crosslinking agents, trifunctional crosslinking agents, tetrafunctional crosslinking agents, and mixtures thereof, including silicone-containing and non-silicone-containing crosslinking agents. Non-silicone-containing crosslinking agents include ethylene glycol dimethacrylate (EGDMA), tetraethylene glycol dimethacrylate (TEGDMA), trimethylolpropane trimethacrylate (TMPTMA), triallyl cyanurate (TAC), glycerol trimethacrylate, hydroxyethyl vinyl carbonate methacrylate (HEMAVc), allyl methacrylate, methylene bisacrylamide (MBA), and polyethylene glycol dimethacrylate (wherein the polyethylene glycol has a molecular weight of at most about 5000 daltons). The crosslinking agents are used in the reactive mixture in conventional amounts (e.g., from about 0.000415 moles to about 0.0156 moles per 100 grams of the reactive formulation). Alternatively, if the hydrophilic monomers and / or silicone-containing components are polyfunctional due to molecular design or due to impurities, the addition of crosslinking agents to the reactive mixture is optional. Examples of hydrophilic monomers and macromonomers that can act as crosslinking agents and (when present) do not require the addition of additional crosslinking agents to the reactive mixture include (meth)acrylate- and (meth)acrylamide-terminated polyethers. Other crosslinking agents will be known to those skilled in the art and can be used to prepare the silicone hydrogels of the present invention.

[0168] It may be desirable to select crosslinking agents that have similar reactivity to one or more of the other reactive components in the formulation. In some cases, it may be desirable to select a mixture of crosslinking agents having different reactivities to control some of the physical, mechanical, or biological properties of the resulting silicone hydrogel. The structure and morphology of the silicone hydrogel can also be affected by one or more diluents and curing conditions used.

[0169] Polyfunctional silicone-containing components (including macromonomers, crosslinking agents, and prepolymers) can also be included to further increase the modulus and maintain the tensile strength. The silicone-containing crosslinking agents can be used alone or in combination with other crosslinking agents. Examples of silicone-containing components that can act as crosslinking agents and (when present) do not require the addition of crosslinking monomers to the reactive mixture include α,ω-bis(methacryloyloxypropyl)polydimethylsiloxane. Another example is bis-3-acryloyloxy-2-hydroxypropoxypropyl polydimethylsiloxane (ac-PDMS).

[0170] Crosslinkers having a rigid chemical structure and polymerizable groups capable of undergoing free radical polymerization can also be used. Non-limiting examples of suitable rigid structures include crosslinkers containing phenyl rings and benzyl rings, such as 1,4-phenylene diacrylate, 1,4-phenylene dimethacrylate, 2,2-bis(4-methacryloxyphenyl)-propane, 2,2-bis[4-(2-acryloxyethoxy)phenyl]propane, 2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane, and 4-vinylbenzyl methacrylate, and combinations thereof. Based on the total weight of all reactive components, the rigid crosslinker can be included in an amount between about 0.5 and about 15, or 2 to 10, 3 to 7. By adjusting the components in the reactive mixture, the physical and mechanical properties of the silicone hydrogel of the present invention can be optimized for specific uses.

[0171] Non-limiting examples of silicone crosslinkers also include the above-mentioned polyfunctional silicone-containing components, such as the polyfunctional compounds shown in Table B.

[0172] Additional Component

[0173] The reactive mixture can contain additional components, such as but not limited to diluents, initiators, UV absorbers, visible light absorbers, photochromic compounds, drugs, nutritional preparations, antibacterial substances, toners, pigments, copolymerizable dyes, non-polymerizable dyes, release agents, and combinations thereof.

[0174] The class of diluents suitable for the silicone hydrogel reactive mixture includes alcohols having 2 to 20 carbon atoms, amides derived from primary amines having 10 to 20 carbon atoms, and carboxylic acids having 8 to 20 carbon atoms. The diluent can be a primary alcohol, secondary alcohol, and tertiary alcohol.

[0175] Generally, the reactive components are mixed in a diluent to form a reactive mixture. Suitable diluents are known in the art. Diluents suitable for silicone hydrogels are disclosed in WO 03 / 022321 and US6020445, the disclosures of which are incorporated herein by reference.

[0176] The class of diluents suitable for the silicone hydrogel reactive mixture includes alcohols having 2 to 20 carbons, amides derived from primary amines having 10 to 20 carbon atoms, and carboxylic acids having 8 to 20 carbon atoms. Primary alcohols and tertiary alcohols can be used. Preferred classes include alcohols having 5 to 20 carbons and carboxylic acids having 10 to 20 carbon atoms.

[0177] Specific diluents that can be used include 1-ethoxy-2-propanol, diisopropylaminoethanol, isopropanol, 3,7-dimethyl-3-octanol, 1-decanol, 1-dodecanol, 1-octanol, 1-pentanol, 2-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, tert-amyl alcohol, tert-butyl alcohol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-propanol, 1-propanol, ethanol, 2-ethyl-1-butanol, (3-acetoxy-2-hydroxypropoxy)propylbis(trimethylsilyloxy)methylsilane, 1-tert-butoxy-2-propanol, 3,3-dimethyl-2-butanol, tert-butoxyethanol, 2-octyl-1-dodecanol, capric acid, octanoic acid, dodecanoic acid, 2-(diisopropylamino)ethanol, mixtures thereof, and the like. Examples of amide diluents include N,N-dimethylpropanamide and dimethylacetamide.

[0178] Preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, 2-pentanol, tert-amyl alcohol, tert-butyl alcohol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, ethanol, 3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, capric acid, octanoic acid, dodecanoic acid, mixtures thereof, and the like.

[0179] More preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 1-dodecanol, 3-methyl-3-pentanol, 1-pentanol, 2-pentanol, tert-amyl alcohol, tert-butyl alcohol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, 3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, mixtures thereof, and the like.

[0180] If a diluent is present, there is generally no particular limitation on the amount of the diluent present. When a diluent is used, based on the total weight of the reactive mixture (including reactive and non-reactive formulations), the diluent can be present in an amount in the range of about 2 wt% to about 70 wt% (including in the range of about 5 wt% to about 50 wt% and in the range of about 15 wt% to about 40 wt%). Mixtures of diluents can be used.

[0181] Polymerization initiators can be used in reactive mixtures. The polymerization initiators can include, for example, at least one of lauroyl peroxide, benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, etc. that generate free radicals at a moderate high temperature; and photoinitiator systems such as aromatic α-hydroxy ketones, alkoxyoxobenzoin, acetophenone, acylphosphine oxides, diacylphosphine oxides, and tertiary amine plus diketone, mixtures thereof, etc. Exemplary examples of photoinitiators are 1-hydroxycyclohexyl phenyl ketone, 2-hydroxy-2-methyl-1-phenylpropan-1-one, bis(2,6-dimethoxybenzoyl)-2,4,4-trimethylpentyl phosphine oxide (DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide (Irgacure 819), 2,4,6-trimethylbenzyl diphenyl phosphine oxide and 2,4,6-trimethylbenzoyl diphenyl phosphine oxide, benzoin methyl ester, and a composition of camphorquinone and ethyl 4-(N,N-dimethylamino)benzoate.

[0182] Visible light initiator systems that are commercially available (from IGM Resins B.V., The Netherlands) include 819, 1700, 1800, 819, 1850 and TPO initiator. UV photoinitiators that are commercially available (from IGM Resins B.V.) include 1173 and 2959. These and other photoinitiators that can be used are disclosed in Volume III, Photoinitiators for Free Radical Cationic & Anionic Photopolymerization, 2nd Edition, by J.V. Crivello & K. Dietliker; edited by G. Bradley; John Wiley and Sons; New York; 1998. The initiators are used in the reactive mixture in an effective amount to initiate the photopolymerization of the reactive mixture (for example, about 0.1 parts by weight to about 2 parts by weight per 100 parts of the reactive monomer mixture). Depending on the polymerization initiator used, appropriately selected heat or visible light or ultraviolet light or other means can be used to initiate the polymerization of the reactive mixture. Alternatively, initiation can be carried out using an electron beam in the absence of a photoinitiator. However, when using a photoinitiator, a preferred initiator is a diacylphosphine oxide such as bis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide ( a combination of (819) or 1-hydroxycyclohexyl phenyl ketone and bis(2,6-dimethoxybenzoyl)-2,4,4-trimethylpentyl phosphine oxide (DMBAPO).

[0183] In addition to the amino acid-based polymerizable compound of formula I, the reactive mixture for preparing the ophthalmic device of the present invention may further comprise any of the above other polymerizable compounds and optional components.

[0184] A preferred reactive mixture may comprise: an amino acid-based polymerizable compound of formula I, and a hydrophilic component.

[0185] A preferred reactive mixture may comprise: an amino acid-based polymerizable compound of formula I; and a hydrophilic component selected from DMA, NVP, HEMA, VMA, NVA, methacrylic acid, and mixtures thereof. Preferably, a mixture of HEMA and methacrylic acid.

[0186] A preferred reactive mixture may comprise: an amino acid-based polymerizable compound of formula I, a hydrophilic component, and a silicone-containing component.

[0187] A preferred reactive mixture may comprise: an amino acid-based polymerizable compound of formula I, a hydrophilic component, and a silicone-containing component comprising a compound of formula A.

[0188] A preferred reactive mixture may comprise: an amino acid-based polymerizable compound of formula I; a hydrophilic component selected from DMA, NVP, HEMA, VMA, NVA, and mixtures thereof; a silicone-containing component such as a compound of formula A; and an internal wetting agent.

[0189] A preferred reactive mixture may comprise: an amino acid-based polymerizable compound of formula I; a hydrophilic component selected from DMA, HEMA, and mixtures thereof; a silicone-containing component selected from 2-hydroxy-3-[3-methyl-3,3-bis(trimethylsilyloxy)silylpropoxy]-propyl methacrylate (SiMAA), mono-methacryloxypropyl-capped mono-n-butyl-capped polydimethylsiloxane (mPDMS), mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether-capped mono-n-butyl-capped polydimethylsiloxane (OH-mPDMS), and mixtures thereof; and a wetting agent (preferably PVP or PVMA). For the hydrophilic component, a mixture of DMA and HEMA is preferred. For the silicone-containing component, a mixture of SiMAA and mPDMS is preferred.

[0190] The preferred reactive mixture may comprise: an amino acid-based polymerizable compound of Formula I; a hydrophilic component comprising a mixture of DMA and HEMA; a silicone-containing component comprising a mixture of OH-mPDMS having 2 to 20 repeating units (preferably a mixture of 4 and 15 repeating units). Preferably, the reactive mixture further comprises a silicone-containing crosslinker such as ac-PDMS. Also preferably, the reactive mixture contains a wetting agent (preferably DMA, PVP, PVMA, or a mixture thereof).

[0191] The preferred reactive mixture may comprise: an amino acid-based polymerizable compound of Formula I; at least one polyamide between about 1 wt% and about 15 wt% (e.g., an acyclic polyamide, a cyclic polyamide, or a mixture thereof); at least one first monofunctional hydroxy-substituted poly(disubstituted siloxane) having 4 to 8 siloxane repeating units (e.g., OH-mPDMS, where n is 4 to 8, preferably n is 4); at least one second hydroxy-substituted poly(disubstituted siloxane) which is a monofunctional hydroxy-substituted poly(disubstituted siloxane) having 10 to 200, or 10 to 100, or 10 to 50, or 10 to 20 siloxane repeating units (e.g., OH-mPDMS, where n is 10 to 200, or 10 to 100, or 10 to 50, or 10 to 20, preferably n is 15); at least one hydrophilic monomer from about 5 wt% to about 35 wt%; and optionally a polyfunctional hydroxy-substituted poly(disubstituted siloxane) having 10 to 200 or 10 to 100 siloxane repeating units (e.g., ac-PDMS). Preferably, the first monofunctional hydroxy-substituted poly(disubstituted siloxane) and the second hydroxy-substituted poly(disubstituted siloxane) are present at a concentration such that the ratio of the weight percentage of the first monofunctional hydroxy-substituted poly(disubstituted siloxane) to the weight percentage of the second hydroxy-substituted poly(disubstituted siloxane) is from 0.4 to 1.3 or from 0.4 to 1.0.

[0192] The foregoing reactive mixture may contain optional ingredients such as, but not limited to, one or more initiators, internal wetting agents, crosslinkers, UV or high energy visible light absorbers, and diluents.

[0193] Curing of Hydrogel and Manufacture of Lenses

[0194] The reactive mixture can be formed by any of the methods known in the art, such as shaking or agitation, and is used by known methods to form polymeric articles or devices. The reactive components are mixed together with or without a diluent to form the reactive mixture.

[0195] For example, an ophthalmic device can be prepared by mixing reactive components and optionally one or more diluents with a polymerization initiator and curing under appropriate conditions to form a product, which can then be shaped into an appropriate shape by turning, cutting, etc. Alternatively, the reactive mixture can be placed in a mold and then cured into an appropriate article.

[0196] A method of manufacturing a molded ophthalmic device such as a silicone hydrogel contact lens can include: preparing a reactive monomer mixture; transferring the reactive monomer mixture onto a first mold; placing a second mold on top of the first mold filled with the reactive monomer mixture; and curing the reactive monomer mixture by free radical copolymerization to form a contact lens-shaped silicone hydrogel.

[0197] The reactive mixture can be cured via any known process for molding the reactive mixture during contact lens production, including rotational casting and static mold casting. Rotational casting is disclosed in U.S. Patent Nos. 3,408,429 and 3,660,545, and the static mold casting method is disclosed in U.S. Patent Nos. 4,113,224 and 4,197,266. The contact lenses of the present invention can be formed by directly molding a silicone hydrogel, which method is both economical and capable of precisely controlling the final shape of the hydrated lens. For this method, the reactive mixture is placed in a mold having the shape of the final desired silicone hydrogel, and the reactive mixture is subjected to conditions that polymerize the monomers, thereby producing a polymer having the approximate shape of the final desired product.

[0198] After curing, the lens can be extracted to remove unreacted components and release the lens from the lens mold. Extraction can be carried out using a conventional extraction liquid (such as an organic solvent like alcohol), or aqueous solution extraction can be used.

[0199] An aqueous solution is a solution containing water. The aqueous solutions of the present invention can contain at least about 20% by weight of water, or at least about 50% by weight of water, or at least about 70% by weight of water, or at least about 95% by weight of water. The aqueous solutions can also contain additional water-soluble formulations, such as inorganic salts or release agents, wetting agents, lubricants, drug and nutritional formulations, combinations thereof, etc. A release agent is a compound or mixture of compounds that, when combined with water, will shorten the time required to release the contact lens from the mold compared to using an aqueous solution without a release agent. The aqueous solutions may not require special treatment, such as purification, recycling, or special disposal procedures.

[0200] Extraction can be achieved, for example, by immersing the lens in an aqueous solution or exposing it to a flowing aqueous solution. Extraction can also include, for example, one or more of the following: heating the aqueous solution; stirring the aqueous solution; increasing the content of the mold release aid in the aqueous solution to a content sufficient to release the lens; mechanically or ultrasonically agitating the lens; and incorporating at least one filtering or extraction aid into the aqueous solution until a level sufficient to promote sufficient removal of unreacted components from the lens is reached. The above operations can be carried out in a batch or continuous process, with heating, stirring, or both, or without.

[0201] It may be desirable to apply physical agitation to facilitate leaching and demolding. For example, the lens mold part adhered with the lens can be vibrated or moved back and forth in the aqueous solution. Other methods can include ultrasonic waves through the aqueous solution.

[0202] The lens can be sterilized by known means, including but not limited to autoclaving.

[0203] The silicone hydrogel ophthalmic device (e.g., contact lens) according to the present invention preferably exhibits the following properties. There is a "about" before all values, and the device can have any combination of the listed properties. The properties can be determined by methods known to those skilled in the art, for example, as described in US Patent Publication US20180037690 before grant, which is incorporated herein by reference.

[0204] Equilibrium water content %: at least 20% or at least 25% and at most 80% or at most 70%

[0205] Haze: 30% or lower, or 10% or lower

[0206] Advancing dynamic contact angle (Wilhelmy plate method): 100° or smaller, or 80° or smaller, or 50° or smaller

[0207] Tensile modulus (psi): 150 or smaller, or 135 or smaller, 120 or smaller, or 80 to 135

[0208] Oxygen permeability (Dk, Barrers): at least 60 Barrers, or at least 80 Barrers, or at least 100 Barrers, or at least 150 Barrers, or at least 200 Barrers

[0209] Elongation at break: at least 100

[0210] For ionic silicone hydrogels, the following properties (in addition to the above) may also be preferred:

[0211] Lysozyme absorption rate (μg / lens): at least 100, or at least 150, or at least 500, or at least 700

[0212] Quaternary ammonium salt 1 (PQ1) uptake (%): 15 or less, or 10 or less, or 5 or less.

[0213] In addition to being introduced into the ophthalmic device by the above method, the amino acid-based polymerizable compound can alternatively (or additionally) be used in the blister pack packaging solution. Thus, according to this embodiment, a blister pack including an ophthalmic device and a packaging solution can be provided, wherein the packaging solution contains a polymer derived from the amino acid-based polymerizable compound as described above.

[0214] Blister packs generally include a bowl-shaped portion and a foil top. These packs contain soft contact lenses and their aqueous packaging solution. The bowl-shaped portion can be made of any suitable material. Generally, the bowl-shaped portion is made of a hydrophobic material such as polypropylene. Polypropylene is a commonly used material for contact lens packaging. Polypropylene has sufficient elasticity to withstand the sterilization steps of contact lens manufacturing and can be injection molded into many suitable shapes and sizes. For non-limiting examples of such packaging, see U.S. Pat. Nos. 4,691,820; 5,054,610; 5,337,888; 5,375,698; 5,409,104; 5,467,868; 5,515,964; 5,609,246; 5,695,049; 5,697,495; 5,704,468; 5,711,416; 5,722,536; 5,573,108; 5,823,327; 5,704,468; 5,983,608; 6,029,808; 6,044,966; and 6,401,915, all of which are hereby incorporated by reference in their entirety.

[0215] Packaging solutions used with ophthalmic devices such as contact lenses are well known. Suitable solutions include but are not limited to saline solutions, other buffers, and deionized water. For example, the packaging solution can be a saline solution containing salts, which include but are not limited to sodium chloride, sodium borate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, or their corresponding potassium salts. These components are usually combined to form a buffer solution containing an acid and its conjugate base, such that the addition of acid and base only causes a relatively small change in the pH value. The buffer can additionally contain 2-(N-morpholino)ethanesulfonic acid (MES), sodium hydroxide, 2,2-bis(hydroxymethyl)-2,2’,2”-nitrilotriethanol, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediaminetetraacetic acid, etc., and combinations thereof. Preferably, the solution is a borate buffered saline solution or a phosphate buffered saline solution.

[0216] Some embodiments of the present invention will now be described in detail in the following examples.

[0217] Examples

[0218] The test methods for characterizing contact lenses are described below. Some abbreviations are used as headings in the tables, and some standard deviations are reported in parentheses in the tables.

[0219] The contact lens diameter (DM) is measured on a calibrated Van Keuren micro-optical comparator equipped with a Mitutoyo digital micrometer head. The contact lens is placed concave side down in a crystal cell completely filled with a borate buffered packaging solution. The top lid is placed on the cell to ensure no air is trapped underneath. Subsequently, the cell is placed on the comparator stage, and the lens image is focused and aligned such that one edge of the lens touches the centerline on the screen. The first edge is marked, the lens is moved along its diameter until the second edge touches the centerline on the screen, and then the second edge is marked by pressing the data button again. Typically, two diameter measurements are made, and the average value is usually reported in millimeters and used to calculate the lens expansion coefficient.

[0220] The expansion coefficient (EP) of the lens is the ratio of the measured diameter of the lens after hydration and sterilization to the theoretical diameter of the front surface mold. A lens that expands upon hydration and sterilization has an expansion coefficient greater than 1; a lens that contracts upon hydration and sterilization has an expansion coefficient less than 1; a lens that does not change in diameter upon hydration and sterilization has an expansion coefficient of 1. The expansion coefficient is dimensionless.

[0221] In grafting experiments on silicone hydrogel contact lenses, the relative expansion coefficient (REF) is the ratio of the measured diameter of the grafted lens after hydration and sterilization to the measured diameter of the ungrafted base lens in deionized water.

[0222] The water content is determined by gravimetric analysis. Three test lenses are equilibrated in the packaging solution for 24 hours. Each test lens is removed from the packaging solution with a cotton swab and placed on a blotting paper moistened with the packaging solution. Both sides of the lens are made to contact the blotting paper. Each test lens is placed in the weighing pan of an analytical balance with forceps and weighed. All weight measurements are performed in triplicate, and the average of those values is used for calculation. The wet weight is defined as the total weight of the pan and the wet lens minus the weight of the pan weighed separately.

[0223] The dry weight is measured by placing the sample dish in a vacuum oven preheated to 60 °C for 30 minutes. Apply a vacuum until a pressure of at least 1 inch of mercury is obtained; allow a lower pressure. Close the vacuum valve and pump, and dry the lens for at least 12 hours, usually overnight. Open the bleed valve to allow dry air or dry nitrogen to enter. Once the oven reaches atmospheric pressure, remove the dish and weigh it. The dry weight is defined as the total weight of the dish and the dry lens minus the weight of the dish weighed separately. Calculate the water content of the test lens as follows: Water content % (WC%) = (wet weight - dry weight) / wet weight × 100. Calculate the average value and standard deviation of the water content, and report the average value as the water content % of the test lens.

[0224] Calculate the graft weight gain % (GWG%) as follows: (dry weight of the grafted lens - dry weight of the base lens) / dry weight of the base lens × 100. Equilibrate both the grafted lens and the base lens in deionized water for several hours to remove any residual salts before vacuum drying. Generally, weigh at least three lenses for each sample and take the average.

[0225] The refractive index (RI) of the contact lens is measured by a Leica ARIAS 500 Abbe refractometer in manual mode or by a Reichert ARIAS 500 Abbe refractometer in automatic mode with a prism gap distance of 100 microns. Calibrate the instrument with deionized water at 20 °C (+ / - 0.2 °C). Open the prism assembly and place the test lens on the lower prism between the magnetic points closest to the light source. If the prism is dry, apply a few drops of saline solution to the bottom prism. The front surface of the lens abuts against the bottom prism. Then close the prism assembly. Adjust the control so that the boundary between light and dark appears behind the crosshair area and measure the refractive index. Perform RI measurements on five test lenses. The average RI calculated from the five measurements is recorded as the refractive index along with its standard deviation.

[0226] Determine the oxygen permeability (D k ) by the polarographic method generally described in ISO 9913-1:1996 and ISO 18369-4:2006, with the following modifications. The measurement is carried out in an environment containing 2.1% oxygen, which is created by equipping the test chamber with nitrogen and air inputs set at an appropriate ratio, such as 1800 ml / min of nitrogen and 200 ml / min of air. Use the adjusted oxygen concentration to calculate t / D k . Use a boric acid buffered salt solution. Measure the dark current by using a humidified pure nitrogen environment without applying the MMA lens. Do not blot dry the lens before measurement. Stack four lenses instead of using lenses with different thicknesses (t) measured in centimeters. Use a curved sensor instead of a flat sensor; the radius is 7.8 mm. The calculation for the 7.8 mm radius sensor and 10% (v / v) air flow is as follows:

[0227] ·D k / t = (Measured current – dark current) × (2.97×10-8 mL O2 / (μA-sec-cm 2 -mm Hg)

[0228] · Edge correction is related to the D of the material k .

[0229] · For all D values less than 90 bar k :

[0230] · t / D k (Edge correction) = [1 + (5.88×t)] × (t / D k )

[0231] · For D values between 90 bar and 300 bar k :

[0232] · t / D k (Edge correction) = [1 + (3.56×t)] × (t / D k )

[0233] · For D values greater than 300 bar k :

[0234] · t / D k (Edge correction) = [1 + (3.16×t)] × (t / D k )

[0235] The un-edge-corrected D is calculated based on the reciprocal of the slope obtained from the linear regression analysis of the data k , where the x variable is the center thickness in centimeters and the y variable is the t / D k value. On the other hand, the edge-corrected D k (EC D k ) is calculated based on the reciprocal of the slope obtained from the linear regression analysis of the data k , where the x variable is the center thickness in centimeters and the y variable is the edge-corrected t / D k value. The resulting D

[0236] The wettability of the lens was determined using the following method. At room temperature, deionized water was used as the probe solution, and the dynamic contact angle (Cahn DCA) was measured by the Wilhelmy plate method using a Cahn DCA-315 instrument. The experiment was carried out by immersing a lens specimen with known parameters in a packaging solution with a known surface tension, while measuring the force exerted on the sample due to wetting by a sensitive balance. Based on the force data collected during the sample immersion, the advancing contact angle of the packaging solution on the lens was determined. The receding contact angle was also determined from the force data while withdrawing the sample from the liquid. The Wilhelmy plate method is based on the formula: Fg = γρcosθ - B, where F = the wetting force between the liquid and the lens (mg), g = the acceleration due to gravity (980.665 cm / sec 2 ), γ = the surface tension of the probe liquid (dynes / cm), ρ = the perimeter of the liquid / lens meniscus in contact with the lens (cm), θ = the dynamic contact angle (degrees), and B = the buoyancy force (mg). When the immersion depth is zero, B is zero. Four test strips were cut from the central region of the contact lens. The width of each strip was approximately 5 mm, and it was equilibrated in the packaging solution. Subsequently, each sample was cycled four times, and the results were averaged to obtain the advancing (adv) and receding (rec) contact angles of the lens. Contact angle hysteresis (CAH) is defined as the difference between the advancing and receding contact angles and can be used as a qualitative measure of surface roughness and heterogeneity, but other factors may also be involved. On a relative basis, surfaces with a larger CAH are expected to exhibit greater surface roughness and heterogeneity.

[0237] The mechanical properties of the contact lens were measured using a tensile testing machine, such as an Instron model 1122 or 5542 equipped with a load cell and pneumatic gripping control. A lens with a power of -1.00 diopters was preferred for its uniform thickness distribution at the center. A dogbone-shaped sample slice taken from a -1.00D lens with a length of 0.522 inches, an "ear" width of 0.276 inches, and a "neck" width of 0.213 inches was loaded into the fixture and stretched at a constant strain rate of 2 inches per minute until it broke. Before the test, the central thickness of the dogbone sample was measured using an electronic thickness gauge. Measure the initial gauge length (L o ) and the sample length at break (L f ). Measure at least five specimens of each composition, and calculate the percentage of elongation at break using the average value: % elongation = [(L f – L o ) / L o×100. The tensile modulus (TM) is calculated as the slope of the initial linear portion of the stress-strain curve; the modulus is in pounds per square inch or psi. The tensile strength (TS) is calculated from the peak load and the initial cross-sectional area: tensile strength = peak load divided by the initial cross-sectional area; the unit of tensile strength is psi. Toughness is calculated from the energy at break and the volume of the initial sample: toughness = energy at break divided by the volume of the initial sample; the unit of toughness is inch-pounds / inch 3 . The elongation at break (ETB) is also recorded as the percentage of strain at break.

[0238] The amount of lysozyme absorbed by the contact lens is measured by the HPLC-UV method. The lysozyme absorption rate is determined as the difference between the lysozyme content in the phosphate buffered saline solution (PBS) before the contact lens is immersed and the concentration in the test solution after the lens has been immersed at 37 °C for 72 hours.

[0239] The lysozyme immersion solution is prepared as follows: 0.215 ± 0.005 grams of lysozyme (purity = 93%) is placed into a 100 mL volumetric flask, then 50 mL of PBS is added to dissolve the lysozyme by vortexing, and then diluted to volume with PBS. The resulting lysozyme immersion solution is filtered / sterilized using a Millipore Stericup filtration device. The concentration of the lysozyme immersion solution is approximately 2000 μg / mL. The mass of lysozyme can be adjusted to account for purity fluctuations between batches such that a concentration of 2000 μg / mL can be achieved.

[0240] Three contact lenses are removed from their packages and blotted dry with a lint-free tissue to remove excess packaging solution. The lenses are placed into three separate 8 mL glass vials (one lens per vial). 1.5 mL of the cholesterol immersion solution is added to each vial. The vials are capped and checked to ensure that each lens is completely immersed in the immersion solution. As a control sample, 1.5 mL of the lysozyme immersion solution is added to three separate 8 mL glass vials. Subsequently, the samples are incubated on a New Brunswick Scientific incubator-shaker at 37 °C and 100 rpm for 72 hours.

[0241] The diluent is prepared by mixing 900 mL of water, 100 mL of acetonitrile, and 1 mL of trifluoroacetic acid in a 1 L glass bottle.

[0242] The lysozyme stock solution is prepared as follows: 0.240 ± 0.010 grams of lysozyme (purity = 93%) is placed into a 100 mL volumetric flask, and then diluted to volume with the diluent. The concentration of the lysozyme stock solution is approximately 2200 μg / mL.

[0243] As shown in Table C, a series of working standard solutions are prepared by mixing appropriate amounts of the lysozyme stock solution with the diluent using 5 mL volumetric flasks.

[0244] Table C. Working Standards

[0245]

[0246] A 10% (v / v) solution was prepared by adding 1 mL of trifluoroacetic acid to a 10 mL volumetric flask and then diluting with HPLC water. Samples for HPLC-UV analysis were prepared as follows: (1) by placing 1000 μL of the test sample and 10 μL of the 10% TFA solution into an autosampler vial, or (2) by placing 1000 μL of the reference standard and 10 μL of the reference standard diluent into an autosampler vial.

[0247] The analysis involved the following steps: “Standard 4” was injected 6 times to evaluate system suitability. The RSD% of the peak area and retention time must be < 0.5% to pass system suitability. The working standards 1 - 6 were injected to create a calibration curve. The square of the correlation coefficient (r 2 ) must be > 0.99. The test sample was injected, followed by the delimiter standard (Standard 4). The peak area of the delimiter standard must be ±1% of the average peak area of the system suitability injections.

[0248] A calibration curve was constructed by plotting the peak area values corresponding to the concentrations of the respective lysozyme working standard solutions. The concentration of lysozyme in the test sample was calculated by solving the linear equation. The updated unit of lysozyme is micrograms per milliliter or μg / mL. Typical equipment and its settings are listed below or shown in Table D.

[0249] · Instrument: Agilent 1200 HPLC, with UV detection (or equivalent HPLC-

[0250] UV)

[0251] · Detection: UV @ 280 nm (5 nm bandwidth)

[0252] · HPLC column: Phenomenex Luna C5 (50×4.6 mm) or Agilent PLRP-S

[0253] (50×4.6 mm)

[0254] · Mobile phase A: H2O (0.1% TFA)

[0255] · Mobile phase B: acetonitrile (0.1% TFA)

[0256] · Column temperature: 40 °C

[0257] · Injection volume: 10 μL

[0258] Table D. HPLC Running Conditions

[0259] Time (minutes) A％ B％ Flow Rate (mL / minute) 0.0 95 5 1.2 4.0 5 95 1.2 4.1 95 5 1.2 6.5 95 5 1.2

[0260] The present invention will now be described in connection with the following examples. Before describing the various exemplary embodiments of the present invention, it should be understood that the present invention is not limited to the construction details and processes mentioned in the following description. The present invention can have other embodiments and can be practiced or implemented in various ways.

[0261] The following abbreviations will be used in the examples and they have the following meanings:

[0262] DMA: N,N-dimethylacrylamide (Jarchem)

[0263] HEMA: 2-hydroxyethyl methacrylate (Bimax)

[0264] MAA: methacrylic acid (Acros)

[0265] Norbloc: 2-(2′-hydroxy-5-methacryloyloxyethylphenyl)-2H-benzotriazole (Janssen)

[0266] Blue HEMA: 1-amino-4-[3-(4-(2-methacryloyloxy-ethoxy)-6-chlorotriazin-2-ylamino)-4-sulfophenylamino]anthraquinone-2-sulfonic acid, as described in U.S. Patent No. 5,944,853

[0267] PVP K90: poly(N-vinylpyrrolidone) (ISP Ashland)

[0268] EGDMA: ethylene glycol dimethacrylate (Esstech)

[0269] TMPTMA: trimethylolpropane trimethacrylate (Esstech)

[0270] TEGDMA: tetraethylene glycol dimethacrylate (Esstech)

[0271] Omnirad 403: bis(2,6-dimethoxybenzoyl)-2,4,4-trimethylpentyl phosphine oxide

[0272] Omnirad 819: bis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide (IGM Resins)

[0273] Omnirad 1173: 2-hydroxy-2-methyl-1-phenylpropanone

[0274] Omnirad 1700: A mixture of 25 wt% Omnirad 403 and 75 wt% Omnirad 1173

[0275] HO-mPDMS: Poly(dimethylsiloxane) endblocked with mono(n-butyl) and mono(2-hydroxy-3-methacryloxypropyl)-propyl ether (M n = 400 - 1500 g / mol) (Ortec or DSM-Polymer Technology Group)

[0276] HO-mPDMS(n = 4):

[0277]

[0278] HO-mPDMS(n = 15):

[0279]

[0280] nBu: n-butyl

[0281] PP: Polypropylene, i.e., homopolymer of propylene

[0282] Z: Zeonor, i.e., polycycloolefin thermoplastic polymer (Nippon Zeon Co Ltd)

[0283] D3O: 3,7-dimethyl-3-octanol (Vigon)

[0284] Wt.%: Weight percent

[0285] BAGE: Borate glyceride (molar ratio of boric acid to glycerol is 1:2). Dissolve 299.3 g (mol) of glycerol and 99.8 g (mol) of boric acid in 1247.4 g of 5% (w / w) aqueous solution of ethylenediaminetetraacetic acid in a suitable reactor, and then heat it to 90°C - 94°C with stirring under mild vacuum (2 - 6 Torr) for 4 - 5 hours, and cool it to room temperature.

[0286] Borate buffer packing solution: Dissolve 18.52 g (300 mmol) of boric acid, 3.7 g (9.7 mmol) of sodium borate decahydrate, and 28 g (197 mmol) of sodium sulfate in sufficient deionized water to fill a 2-liter volumetric flask.

[0287] g: Gram

[0288] mg: Milligram

[0289] μg: Microgram

[0290] eq: Equivalent

[0291] mol: mole

[0292] mmol: millimole

[0293] mL: milliliter

[0294] M: molarity or mol / L

[0295] L: liter

[0296] mm: millimeter

[0297] cm: centimeter

[0298] nm: nanometer

[0299] HCl: hydrochloric acid

[0300] D: diopter

[0301] LED: light emitting diode

[0302] TL03 illumination: Phillips TLK 40W / 03 bulb

[0303] NMR: nuclear magnetic resonance spectroscopy

[0304] D2O: deuterium oxide

[0305] Example 1 - Synthesis of Methacryloyl Arginine (ARG-M)

[0306]

[0307] L-arginine hydrochloride (21.0 g, 0.1 mol) and sodium bicarbonate (16.8 g, 0.2 mol) were added to deionized water (100 mL). The solution was cooled to 5 °C and 17.0 g of methacrylic anhydride (12.5 mL, 0.11 mol) was added dropwise over a period of 10 minutes, and the mixture was stirred for 20 minutes. A few drops of ammonium hydroxide were added to adjust the pH to 8. The solution was filtered and washed three times with dichloromethane. The aqueous portion was lyophilized to give the product methacryloyl arginine (ARG-M) (98% yield). 1 1H NMR (500 MHz, D2O) δ (ppm): 1.32 - 1.81 (m, 4H, NHCH2CH2), 1.87 (s, 3H, CH3), 3.05 (m, 2H, CH2NH2CNH), 4.20 (m, 1H, NHCH), 5.37 (s, 1H, vinyl), 5.58 (s, 1H, vinyl).

[0308] Example 2 - Synthesis of Methacryloyl Asparagine (ASN-M)

[0309]

[0310] At room temperature, 17.2 g of methacrylic anhydride (about 0.11 mol) was added dropwise via a dropping funnel to an aqueous solution of L-asparagine (13.2 g, 0.1 mol) and sodium carbonate (25.0 g, 0.24 mol) stirred in a water bath, and the mixture was stirred for two hours. The mixture was acidified to a pH of about 2.0 with dilute hydrochloric acid. 0.200 g of butylated hydroxytoluene (BHT) was added to the solution, and the volatile components were evaporated under reduced pressure while maintaining the temperature below 20 °C. After drying, the solid was washed with acetonitrile (3 × 100 mL), and the solvent was decanted off after each wash. The residue was dissolved in methanol and filtered. 0.050 g of BHT was added to the filtrate, and the volatile components were evaporated under reduced pressure to obtain the desired product methacryloyl asparagine (ASN-M), as a colorless hygroscopic solid. 1 H NMR (500 MHz, D2O) δ (ppm): 1.97 (3H, s, CH3), 2.78 (1H, dd, J = 9.0, 5.0 Hz, CH2), 2.90 (1H, dd, J = 8.0, 5.0 Hz, CH2), 4.69 (dd, J = 9.0, 8.0 Hz), 5.51 (1H, s, vinyl), 5.76 (1H, s, vinyl).

[0311] Example 3 - Synthesis of Methacryloyl Histidine Methyl Ester (HIS-M)

[0312]

[0313] L-Histidine methyl ester dihydrochloride (10.0 g, about 0.041 mol) and triethylamine (16.6 g, about 4 eq.) were dissolved in 100 mL of methanol, and the solution was cooled in an ice bath while stirring continuously. Methacryloyl chloride (4.75 g, 1.1 eq.) was added dropwise to the solution while maintaining the temperature below 10 °C. Once the addition was complete, the volatile components were evaporated under reduced pressure. The residue was washed with dichloromethane and filtered. After evaporating the dichloromethane under reduced pressure, the residue was further washed with acetone to remove triethylammonium chloride. The filtrate was concentrated under reduced pressure, and the product was rinsed through a short silica gel plug with acetonitrile and methanol. The product methacryloyl histidine methyl ester (HIS-M) was obtained by evaporation. 1 H NMR (500 MHz, D2O) δ (ppm) 3.73 (3H, s, CH3), 2.9 - 3.15 (2H, m, CH2), 4.60 (1H, dd, J = 8.5, 5 Hz, CH), 5.31 (1H, bs, vinyl), 5.49 (1H, s, vinyl), 6.89–6.97 (1H, Ar-H), 6.79–8.08 (1H, Ar-H).

[0314] Example 4 - 2-Decanamido-3-((2-Methacryloyloxyethyl)Amino)-3-Oxopropane-1-Sulfonic Sodium (CYS-M)

[0315]

[0316] Cysteine monohydrate (40.0 g, 0.21 mol) was charged into a 1000 mL three-necked round-bottom flask equipped with a magnetic stir bar and a reflux condenser. The system was placed under a nitrogen blanket, and 600 mL of methanol was added thereto via syringe. Thionyl chloride (75 mL, 1.04 mol) was added dropwise to the stirred suspension, and the mixture was then heated to reflux for 5 h. As the reaction proceeded, the product crystallized out from the mixture. The reaction mixture was stored in the refrigerator overnight. The solid was filtered, washed with 5 × 50 mL of acetonitrile, and dried in a vacuum oven at 50 °C to obtain 34.7 g (88.7%) of the desired methyl 3-sulfolactate. 1 1H NMR (500 MHz, D2O) δ (ppm): 3.56 (d, 1H, J = 6.9 Hz, CH2SO3 - ), 3.65 (d, 1H, J = 4.5 Hz, CH2SO3 - ), 3.91 (s, 3H, OCH3), 4.63 (dd, 1H, J = 6.9, 4.5 Hz, CH).

[0317] Under a nitrogen blanket, 300 mL of anhydrous methanol and 30.3 g (3.0 eq.) of triethylamine were added to 18.3 g (0.1 mol) of methyl 3-sulfolactate in a three-necked round-bottom flask equipped with a magnetic stirrer and a reflux condenser. The mixture was stirred until homogeneous and cooled using an ice bath. Decanoyl chloride (23.75 g, 0.125 mol) was added dropwise to the solution while maintaining the reaction temperature below 25 °C. The solution was continuously stirred and allowed to warm to ambient temperature, after which anhydrous sodium carbonate (15.0 g, 0.15 mol) and 2-aminoethanol (12.2 g, 0.2 mol) were added, and the mixture was heated at 65 °C for 48 h. The reaction mixture was cooled to ambient temperature, and the volatile components were removed under reduced pressure. The residual solid was washed with acetonitrile (3 × 250 mL) on a sintered glass funnel to remove organic impurities, and the desired product sodium 2-decanamido-3-((2-hydroxyethyl)amino)-3-oxopropane-1-sulfonate was obtained by recrystallizing the residue from deionized water and then drying in a vacuum oven at 50 °C (yield 33.4 g, 86%). 1 1H NMR (500 MHz, D2O) δ (ppm): 0.87 (t, 3H, J = 6.8 Hz, CH3), 1.29 (bs, 12H, CH2s), 1.61 (t, 2H, J = 7.2 Hz, CH2), 2.33 (t, 2H, J = 7.2 Hz, CH2), 3.24 - 3.42 (m, 4H, CH2 amide, CH2SO3- ), 3.66 (t, 2H, J = 5.9 Hz, CH2OH), 4.72 (dd, 1H, J = 7.1, 8.1 Hz, CH). Sodium 2-decanamido-3-((2-hydroxyethyl)amino)-3-oxopropane-1-sulfonate (10.0 g, ca. 0.026 mol), butylated hydroxytoluene (0.150 g), and 10.0 mL of methacrylic anhydride (10.4 g, ca. 0.068 mol) were added to a 100 mL three-necked round-bottom flask equipped with a magnetic stirrer, heating mantle, and reflux condenser. The system was placed under a nitrogen atmosphere, and 50 mL of anhydrous N,N-dimethylformamide was added to the flask, at which point the material appeared to absorb the solvent and form a filter cake. As the temperature of the system increased, stirring improved and the mixture gradually became homogeneous. After heating at 90 °C for 20 h, the mixture was cooled to room temperature and added to 150 mL of acetonitrile and stirred at ambient temperature for 30 min. The white gel-like product, sodium 2-decanamido-3-((2-methacryloyloxyethyl)amino)-3-oxopropane-1-sulfonate (CYS-M), was filtered on a sintered glass funnel, washed with 3 × 50 mL of acetonitrile, and dried in vacuo at 50 °C. 1 1H NMR (500 MHz, D2O) δ (ppm): 0.86 (3H, t, CH3), 1.26 (12H, bs, CH2), 1.57 (2H, bs, CH2), 1.92 (3H, s, CH3), 2.29 (2H, t, CH2), 3.24 - 3.66 (4H, m, CH2NH and CH2S), 4.27 (2H, bs, CH2 ester), 4.79 (1H, m, CH), 5.62 (1H, s, vinyl), 6.15 (1H, s, vinyl).

[0318] Example 5 - S-(3-(2-Hydroxy-3-(Methacryloyloxy)Propoxy)-3-Oxopropyl)-L-Cysteine Acid (CYS-MA)

[0319]

[0320] In a 250 mL round-bottom flask, L-cysteine (15.13 g, 124.88 mmol) was dissolved in deionized water (100 mL). 3-(Acryloyloxy)-2-hydroxypropyl methacrylate (29.43 g, 137.36 mmol) was added to the stirred solution, and dimethylphenylphosphine (20 μL, 147 μmol) was added to the mixture. The aqueous mixture was stirred at ambient temperature for 2 h, after which the solution was washed with ethyl acetate (2 × 50 mL) and dichloromethane (2 × 50 mL). The desired product S-(3-(2-hydroxy-3-(methacryloyloxy)propoxy)-3-oxopropyl)-L-cysteine (CYS-MA) was isolated by freeze-drying as a pure white solid (39.6 g, 94% yield). 1 H NMR (500 MHz, D2O) δ (ppm): 1.89 (s, 3H, -CH3); 2.68 - 3.17 (m, 6H, -S-CH2-CH2-COO-, -S-CH2-CH(COO - )NH3 + ); 3.79 - 3.90 (m, 2H, CHOH, -CH(COO-)NH3 + ), 4.20 - 4.30 (m, 4H, -CH2-CHOH-CH2-); 5.70 (s, 1H, vinyl), 6.13 (s, 1H, vinyl).

[0321] Example 6 - Grafted Silicone Hydrogel Contact Lenses

[0322] A reactive monomer mixture was prepared, which consisted of 75 wt% of the formulation listed in Table 2 and 25 wt% of diluent D3O. The reactive monomer mixture was filtered through a 3 μm filter under pressure using a stainless-steel syringe and then degassed under reduced pressure for approximately thirty minutes. In a glove box with a nitrogen atmosphere and less than 0.2% oxygen (v / v), approximately 75 - 100 μL of the reactive mixture was dispensed at room temperature into a front-curved mold made of Zeonor using an Eppendorf pipette. Then a bottom-curved mold made of a 55:45 (w / w) blend of Zeonor and polypropylene was placed on the front-curved mold. The molds were equilibrated in the glove box for at least twelve hours before dispensing. A plate containing approximately four trays, each tray containing eight lens mold assemblies, was transferred to an adjacent glove box maintained at approximately 62 °C, and the lenses were cured from the top for 12 minutes using 435 nm LED light with an intensity of 4 mW / cm 2 intensity.

[0323] Work under yellow light and limit general exposure to additional light exposure (e.g., by wrapping the container with aluminum foil, etc.). Manually demold the lenses, where most of the lenses adhere to the front curve mold, and release them by suspending the lenses in 70% isopropyl alcohol for about one or two hours (about one lens per 15 mL), sometimes overnight, then washing twice with 70% isopropyl alcohol and twice with deionized water, and finally storing them in deionized water in an aluminum foil-covered container in the refrigerator. These lenses (7-Base) contain covalently bonded monoacylphosphine oxide groups from which chemical grafting reactions can be initiated. Each washing step lasts about 30 minutes. Those of ordinary skill in the art recognize that the exact lens detachment process can vary depending on the lens formulation and molding material in terms of the concentration of the isopropyl alcohol aqueous solution, the number of washes with each solvent, and the duration of each step. The purpose of the lens detachment process is to detach all lenses without defects and transform from a diluent-swollen network to a hydrogel swollen with deionized water or a packaging solution.

[0324] For each experiment, in a 250 mL glass wide-mouth bottle, suspend 50 lenses (7-Base) in 100 mL of a 5% (w / v) grafting solution consisting of a grafting monomer dissolved in 50:50 (v / v) aqueous 1,2-butanediol, and degas for 15 minutes under reduced pressure (about 40 mmHg), and purge with nitrogen. Cover the wide-mouth bottle and transfer it to a glove box with a nitrogen atmosphere, having less than 0.2% oxygen (v / v) and a temperature of 55 °C, and equilibrate on a shaker (180 rpm) for 90 minutes. Then the temperature of the suspension is 55 °C. Replace the top cover with a transparent plastic cover, and irradiate the suspension from the top using a 420 LED lamp while the wide-mouth bottle is still being shaken. The grafting conditions for each experiment are listed in Table 3 regarding the grafting monomer, its concentration in the grafting solution, the grafting irradiation intensity, and the grafting time. After irradiation, remove the lenses and wash twice with deionized water and twice with a borate buffer packaging solution. Store the lenses in vials. After equilibration for one day, examine the lenses and autoclave at 122 °C for 30 minutes. After sterilization, equilibrate the lenses for 3 - 4 days, and then measure the physical properties of the sterile lenses as listed in Table 4.

[0325] Table 2. Formulation Components

[0326]

[0327]

[0328] Table 3. Grafting Conditions

[0329]

[0330] Table 4. Grafted Contact Lens Characteristics

[0331]

[0332]

[0333] Result: By grafting amino acid-based monomers onto silicone hydrogel contact lenses, the physical and mechanical properties of the contact lenses were changed. The grafting increased the water content, which subsequently decreased the modulus and tensile strength. The grafting also altered the wettability of the lens. Lenses grafted with HIS-M and ARG-M showed little contact angle hysteresis.

[0334] Example 6 - Synthesis of Conventional Hydrogel Contact Lenses

[0335] A series of reactive monomer mixtures were prepared as follows: First, a "masterbatch" consisting of approximately 52 wt% of the formulation components listed in Table 5 and 48 wt% of the diluent BAGE was prepared, and then MAA, CYS-M, HIS-M, ARG-M, or ASN-M was added to 25 g aliquots of the masterbatch in an amount equivalent to the molar equivalent of 1.95 wt% MAA. Formulations containing MAA are commonly referred to as etafilcon. Thus, the resulting hydrogels contain the same number of repeating units of these monomers, such that changes in physical and mechanical properties can be attributed to their incorporation into the polymer network.

[0336] Each reactive monomer mixture was thoroughly mixed and filtered through a 3 μm filter under pressure using a stainless steel syringe, and then degassed under reduced pressure for approximately fifteen minutes. In a glove box with a nitrogen atmosphere and less than 0.2% oxygen (v / v), approximately 75 - 100 μL of the reactive mixture was dispensed into a front curve mold made of Zeonor at room temperature using an Eppendorf pipette. Then, a back curve mold made of polypropylene was placed on the front curve mold. The molds were equilibrated in the glove box for at least twelve hours before dispensing. A plate containing approximately four trays, each tray containing eight lens mold assemblies, was transferred to an adjacent glove box maintained at approximately 62 °C, and the lenses were cured from the top for 5 minutes using TL03 light with an intensity of 4.5 mW / cm 2 The strength of the TL03 light from the top cured the lenses for 5 minutes.

[0337] The lenses were manually demolded. Most of the lenses adhered to the front-curved mold and were released by suspending the lenses in 80% isopropanol for about one or two hours (about one lens per 15 mL), followed by washing twice with deionized water, and finally stored in a borate buffered packaging solution. Each washing step lasted about 30 minutes. One of ordinary skill in the art would recognize that the exact lens detachment process can vary depending on the lens formulation and molding material in terms of the concentration of the isopropanol aqueous solution, the number of washes with each solvent, and the duration of each step. The purpose of the lens detachment process is to detach all lenses without defects and transform from a diluent-swollen network to a hydrogel swollen with deionized water or packaging solution. The lenses were stored in vials. After equilibration for one day, the lenses were inspected and autoclaved at 122 °C for 30 minutes. Then, the physical and mechanical properties of the lenses were measured and summarized in Table 6.

[0338] Table 5. Formulation Components

[0339]

[0340] Table 6. Physical and Mechanical Properties of Conventional Hydrogel Contact Lenses

[0341]

[0342] Results: The examples demonstrate that the amino acid monomers of the present invention can be easily copolymerized with other monomers to form contact lenses.

[0343] Example 8 - Polymer

[0344] Preparation 1

[0345] 50.0 g (39.2 mmol) of tellurium powder was reacted with 14.4 mL of 3.0 M methyllithium solution (43.1 mmol) in anhydrous tetrahydrofuran to form a tellurolate intermediate, which was reacted with 8.82 g (45.1 mmol) of ethyl α-bromoisobutyrate to form the organotellurium living radical polymerization regulator ethyl 2-methyl-2-methyltellanyl-propionate (Te-Me). For the metal exchange step, the reaction was carried out using an ice bath. After the addition of ethyl α-bromoisobutyrate, the reaction mixture was warmed and maintained at room temperature until the reaction was complete (about 2 hours). Then, tetrahydrofuran was removed under reduced pressure in a rotary evaporator. The crude product was vacuum distilled at 50 - 55 °C (1 - 2 mbar) to obtain the organotellurium-mediated living radical polymerization regulator Te-Me, which was characterized by proton nuclear magnetic resonance spectroscopy.

[0346] The following Examples 8A to 8D are hypothetical examples and are used to further illustrate the present invention.

[0347] Example 8A

[0348] 20.0 g (100 mmol) of ASN-M and 578 mg (3.5 mmol) of AIBN were added to a 1 L reactor and dissolved in approximately 250 mL of a 50:50 (v / v) methanol / water solution. At room temperature, the solution was degassed by bubbling nitrogen through the system for approximately 15 minutes. The reaction mixture was heated at 60 °C - 62 °C for approximately 12 hours under a nitrogen atmosphere and then cooled to room temperature. The solvent was evaporated under reduced pressure. Acetone was added to the residue. The resulting mixture was heated to 62 °C with constant stirring and held for 12 hours; then, the mixture was cooled to room temperature. After standing at room temperature for two hours, the insoluble solid settled. The acetone was decanted and discarded. The crude product was rinsed in acetone at room temperature with stirring for an additional two hours. The acetone was decanted and discarded. The homopolymer was then dried in vacuo at 60 °C - 65 °C to constant weight.

[0349] Example 8B

[0350] 12.1 g (50 mmol) of ARG-M, 5.0 g (50 mmol) of DMA, and 578 mg (3.5 mmol) of AIBN were added to a 1 L reactor and dissolved in approximately 250 mL of a 50:50 (v / v) methanol / water solution. At room temperature, the solution was degassed by bubbling nitrogen through the system for approximately 15 minutes. The reaction mixture was heated at 60 °C - 62 °C for approximately 12 hours under a nitrogen atmosphere and then cooled to room temperature. The solvent was evaporated under reduced pressure. Acetone was added to the residue. The resulting mixture was heated to 62 °C with constant stirring and held for 12 hours; then, the mixture was cooled to room temperature. After standing at room temperature for two hours, the insoluble solid settled. The acetone was decanted and discarded. The crude product was rinsed in acetone at room temperature with stirring for an additional two hours. The acetone was decanted and discarded. The copolymer was then dried in vacuo at 60 °C - 65 °C to constant weight.

[0351] Example 8C

[0352] 11.9 g (50 mmol) of HIS-M, 5.0 g (50 mmol) of DMA, 907 mg (3.5 mmol) of Te-Me and 578 mg (3.5 mmol) of AIBN were added to a 1 L reactor and dissolved in approximately 250 mL of a 50:50 (v / v) methanol / water solution. At room temperature, the solution was degassed by bubbling nitrogen through the system for approximately 15 minutes. The reaction mixture was heated at 60 °C - 62 °C for approximately 12 hours under a nitrogen atmosphere and then cooled to room temperature. The solvent was evaporated under reduced pressure. Acetone was added to the residue. The resulting mixture was heated to 62 °C with constant stirring for 12 hours; then, the mixture was cooled to room temperature. After standing at room temperature for two hours, the insoluble solid settled. The acetone was decanted and discarded. With stirring, the crude product was rinsed in acetone at room temperature for two more hours. The acetone was decanted and discarded. Then the copolymer was dried in vacuo at 60 °C - 65 °C to constant weight.

[0353] Example 8D

[0354] 12.1 g (50 mmol) of ARG-M, 907 mg (3.5 mmol) of Te-Me and 578 mg (3.5 mmol) of AIBN were added to a 1 L reactor and dissolved in approximately 250 mL of 1-propanol. At room temperature, the solution was degassed by bubbling nitrogen through the system for approximately 15 minutes. The reaction mixture was heated at 60 °C - 62 °C for approximately 3 hours under a nitrogen atmosphere. 13.0 g (100 mmol) of HEMA was dissolved in 30 mL of 1-propanol, degassed by bubbling nitrogen through the system at room temperature for 15 minutes, charged into the reaction vessel, and heated at 70 °C - 72 °C for approximately 6 hours with constant stirring. Finally, 10.0 g (50 mmol) of ASN-M was dissolved in 30 mL of 1-propanol, degassed by bubbling nitrogen through the system at room temperature for 15 minutes, charged into the reaction vessel, and heated at 60 °C - 62 °C for approximately 4 hours with constant stirring.

[0355] The volatile components of the reaction mixture were removed under reduced pressure in a rotary evaporator. The crude product was redissolved in 400 mL of toluene at 60 °C and cooled to room temperature. The mixed solvent system was removed by rotary evaporation to obtain a crude product free of 1-propanol. This crude product contained methyl tellurium end groups. To remove this organometallic end group, the crude product was dissolved in 250 mL of toluene containing a certain amount of TEMPO, which was 3.5 times the theoretical molar amount of methyl tellurium. The solution was heated at 88 °C for 4 hours. The reaction mixture was cooled to room temperature, and then the volatile components were evaporated on a rotary evaporator at 60 °C - 65 °C. The residue was dissolved in 1000 mL of acetonitrile at 72 °C for 30 minutes to form a turbid solution. The turbid solution was cooled to room temperature. After standing for some time to allow the insoluble solids to settle, the solvent was decanted. The triblock copolymer was isolated by evaporating off the acetonitrile and drying to constant weight under vacuum at 60 °C - 65 °C. The triblock copolymer can be further purified by precipitation or extraction.

Claims

1. An ophthalmic device comprising an amino acid-based polymerizable compound of formula II, III, IV, V or VI: wherein R 3 is C1-C 25 alkyl or cycloalkyl; R 4 is H, a metal cation or C1-C6 alkyl; R 5 is H, a metal cation or C1-C6 alkyl; and R 6 is H or methyl, and wherein the amino acid-based polymerizable compound is introduced into the ophthalmic device by grafting.

2. The ophthalmic device according to claim 1, wherein the compound is: Methacryloyl arginine; Methacryloyl asparagine; Methacryloyl histidine methyl ester; Sodium 2-decanamido-3-((2-methacryloyloxyethyl)amino)-3-oxopropane-1-sulfonate; S-(3-(2-Hydroxy-3-(methacryloyloxy)propoxy)-3-oxopropyl)-L-cysteine; Methacryloyl phenylalanine; Methacryloyl lysine; Methacryloyl glutamine; Methacryloyl glutamic acid; Methacryloyl tyrosine; Acryloyl tryptophan; Acryloyl aspartic acid; or Acryloyl methionine.

3. An ophthalmic device comprising a free radical reaction product of an amino acid-based polymerizable compound as defined in claim 1 or 2 and one or more monomers suitable for preparing the ophthalmic device.

4. The ophthalmic device according to claim 3, wherein the monomers suitable for preparing the ophthalmic device are selected from hydrophilic components, hydrophobic components, organosilicon-containing components, and mixtures of two or more thereof.

5. The ophthalmic device according to any one of claims 3 to 4, wherein the ophthalmic device is an intraocular lens or a soft contact lens.

6. The ophthalmic device according to claim 5, wherein the ophthalmic device is a hydrogel contact lens.

7. The ophthalmic device according to claim 6, wherein the ophthalmic device is a non-silicone hydrogel or a silicone hydrogel.

Images