copolymer and vinyl monomer containing azetidinium, silicone hydrogel contact lens and methods of pr

专利摘要:
COPOLYMERS CONTAINING AZETIDINUM AND USES OF THE SAME. The present invention relates to copolymers containing azetidinium and vinyl monomers and their use in forming non-silicone hydrogel coatings on silicone hydrogel contact lenses.
公开号:BR112014028700B1
申请号:R112014028700-7
申请日:2013-06-10
公开日:2021-01-05
发明作者:Troy Vernon Holland；Frank Chang；Yongxing Qiu；John Dallas Pruitt；Chung-Yuan Chang；Manivakkam J. Shankernarayanan；Robert Scott；Yash Kapoor
申请人:Alcon Inc.；
IPC主号:

专利说明:

[001] The present invention generally relates to vinyl monomers and copolymers containing azetidinium suitable for applying a hydrogel coating to a silicone hydrogel contact lens in an economical, fast and efficient manner. In addition, the present invention provides an ophthalmic lens product. Background
[002] Soft silicone hydrogel contact lenses are increasingly becoming popular because of their high oxygen permeability and comfort. But, a silicone hydrogel material typically has a surface, or at least some areas of its surface, that is hydrophobic (non-wettable) and susceptible to the absorption of lipids or proteins from the eye environment and can adhere to the eye. Thus, a silicone hydrogel contact lens will usually require a surface modification.
[003] A known approach for modifying the hydrophilicity of a relatively hydrophobic contact lens material is through the use of a plasma treatment, for example, commercial lenses such as Focus NIGHT & DAY® and O2OPTIX® (CIBA VISION), and PUREVISION® (Bausch & Lomb) use this approach in their production processes. The advantages of a plasma coating, such as, for example, those found with Focus NIGHT & DAY®, are its durability, relatively high hydrophilicity / humectability and low susceptibility to deposition and adsorption of lipid and protein. But, plasma treatment of silicone hydrogel contact lenses may not be economical, because preformed contact lenses must typically be dried before plasma treatment and because of the high relative capital investment associated with treatment equipment. with plasma.
[004] Several other approaches are proposed and / or used to modify the hydrophilicity of the surface of a silicone hydrogel contact lens. Examples of such other approaches include incorporation of wetting agents (hydrophilic polymers) into a lens formulation to make the hydrogel silicone contact lens (see, for example, U.S. Patent Nos. 6367929, 6822016, 7052131, and 7249848) ; a layer-by-layer (LbL) polyionic material deposition technique (see, for example, US Patent Nos. 6451871; 6719929; 6793973; 6884457; 6896926; 6926965; 6940580; and 7297725, and Ordering Publications United States Patent No. 2007 / 0229758A1; 2008 / 0174035A1 and 2008 / 0152800A1); crosslinking of LbL coatings on contact lenses has been proposed in the jointly owned copending US Patent Application Publications No. 2008/0226922 A1 and 2009/0186229 A1; and attachment of hydrophilic polymers to contact lenses according to various mechanisms (see, for example, U.S. Patent No. 6099122, 6436481, 6440571, 6447920, 6465056, 6521352, 6586038, 6623747, 6730366, 6734321, 6835410, 6878399, 6923978, 6440571, and 6500481, US Patent Application Publications No. 2009 / 0145086A1, 2009 / 0145091A1, 2008 / 0142038A1, and 2007 / 0122540A1). Although those techniques can be used in rendering a wetted silicone hydrogel material, there are some shortcomings in those techniques. For example, wetting agents can impart blurriness to the resulting lenses because of their incompatibility with other silicone components in the lens formulation and may not provide a durable hydrophilic surface for long-term use. LbL coatings may not be as durable as plasma coatings and may have relatively high densities of surface changes; that can interfere with cleaning the contact lens and disinfecting solutions. The crosslinked LbL coatings may have lower hydrophilicity and / or wettability than the original LbL coatings (before crosslinking) and still have high relative densities of surface loads. In addition, they may not be economical and / or quick and effective to implement in a mass production environment, because they typically require relatively long time and / or involve multiple laborious steps to obtain a hydrophilic coating.
[005] Recently, a new economic approach has been described in US Patent Application Publication No. 2012/0026457 A1 (hereby incorporated by reference in its entirety) to apply a non-silicone hydrogel coating to a silicone contact lens hydrogel. It is reported in the publication that a partially cross-linked hydrophilic polymeric material derived from a polyamidoamine epichlorohydrin (PAE) and a wetting agent are used to form a non-silicone hydrogel coating on a contact lens. Although this new approach can provide silicone hydrogel contact lenses with durable hydrophilic coatings on them, its applicability and advantages may be limited by the lack of versatility and controllability in the hydrophilicity levels and / or reactive functional group contents of the partially cross-linked hydrophilic polymeric material.
[006] Therefore, there is still a need for reactive copolymers that have a desired level of hydrophilicity and / or functional group content to apply a non-silicone hydrogel coating to a silicone hydrogel contact lens. Summary of the Invention
[007] The invention, in the first aspect, provides a vinyl monomer containing azetidinium.
[008] The invention, in the second aspect, provides a copolymer containing azetidinium comprising monomeric units containing azetidinium derived from at least one vinyl monomer containing azetidinium of the invention and monomeric units derived from at least one vinyl monomer selected from the group consisting of a vinyl monomer containing carboxyl, a vinyl monomer containing amino, a hydrophobic vinyl monomer, and a combination thereof.
[009] The invention, in the third aspect, provides a method for producing coated silicone hydrogel contact lenses, each having a crosslinked hydrophilic coating on it, the method of the invention comprising the steps of: (a) obtaining a contact lens from hydrogel silicone; (b) applying a main coating of a fixing polymer to the silicone hydrogel contact lens, wherein the fixing polymer is a homopolymer or copolymer of a vinyl monomer containing carboxyl and / or a copolymer containing azetidinium of the invention; and (c) heating the silicone hydrogel contact lens in an aqueous solution in the presence of a thermally water-soluble hydrophilic polymeric material comprising azetidinium, carboxyl, amino, and / or thiol groups, to and at a temperature of about 40 ° C. ° C to 140 ° C for a period of time sufficient to induce intermolecular and intramolecular crosslinking reactions between an azetidinium group and an amino or carboxyl group, thus forming a durable non-silicone hydrogel coating on the silicone hydrogel contact lens, provided that at least one of the fixing polymers and the thermally water-soluble hydrophilic polymeric material comprise azetidinium groups.
[0010] The invention, in the fourth aspect, provides a method for producing silicone hydrogel contact lenses, each having a crosslinked hydrophilic coating on it, the method of the invention comprising the steps of: (a) obtaining a silicone contact lens hydrogel of a lens-forming composition comprising an azetidinium-containing copolymer of the invention; (b) heating the silicone hydrogel contact lens in an aqueous solution in the presence of a thermally water-soluble hydrophilic polymeric material comprising azetidinium, carboxyl, amino, and / or thiol groups, to and at a temperature of about 40 ° At about 140 ° C for a period of time sufficient to induce intermolecular and intramolecular crosslinking reactions between an azetidinium group and an amino or carboxyl group, thus forming a durable non-silicone hydrogel coating on the silicone hydrogel contact lens.
[0011] In the fifth aspect, the invention provides a silicone hydrogel contact lens comprising a non-silicone hydrogel coating thereon, wherein the non-silicone hydrogel coating is obtained by thermally inducing intermolecular and intramolecular crosslinking of a thermally crosslinkable hydrophilic polymeric material comprising monomeric units containing azetidinium derived from at least one vinyl monomer containing azetidinium, reactive monomeric units derived from a vinyl monomer having an amino or carboxyl group, and hydrophilic monomeric units derived from a hydrophilic vinyl monomer, wherein the contact lens of hydrogel silicone has an oxygen permeability of at least about 40 barriers, a surface wetting characterized by a water contact angle of about 100 degrees or less, and a good coating durability characterized by the survival of a digital friction test .
[0012] In the sixth aspect, the invention provides an ophthalmic product, which comprises a sterile and sealed lens package, in which the lens package comprises: a post-autoclave lens packaging solution and a silicone hydrogel contact lens readily usable immersed in it, wherein the readily usable hydrogel silicone contact lens comprises a crosslinked hydrophilic coating obtained by autoclaving an original hydrogel silicone contact lens that has amino groups and / or carboxyl groups on and / or close to the lens surface of original hydrogel silicone contact in a pre-autoclave packaging solution containing a water soluble and thermally crosslinkable hydrophilic polymeric material comprising from 0.001% to about 25 mol% of monomer units containing azetidinium derived from at least one vinyl monomer containing azetidinium, in which the hydrophilic polymeric material is covalently attached to the silicone hydrogel contact lens at through the second covalent bonds, each formed between an amino or carboxyl group on and / or near the surface of the silicone hydrogel contact lens and an azetidinium group of the hydrophilic polymeric material, wherein the post-autoclave packaging solution comprises at least one buffering agent in an amount sufficient to maintain a pH of about 6.0 to about 8.5 and a hydrolyzed product of the hydrophilic polymeric material and has a tonicity of about 200 to about 450 milliosmol (mOsm) and a viscosity of about 1 centipoise to about 10 centipoises.
[0013] These and other aspects of the invention will become evident from the description below of the presently preferred modalities. The detailed description is merely illustrative of the invention and does not limit the scope of the invention, which is defined by the appended and equivalent claims thereof. As would be obvious to a person skilled in the art, many variations and modifications of the invention can be made without departing from the spirit and scope of the new concepts of disclosure. Brief Description of the Drawing
[0014] Figure 1 shows absorptions and releases of polyhexamethylene biguanide (PHMB) through various contact lenses. Detailed Description of the Modalities of the Invention
[0015] Unless defined, on the contrary, all the technical and scientific terms used here have the same meaning as commonly understood by a technician in the subject to which this invention belongs. Generally, the nomenclature used here and laboratory procedures are well known and commonly used in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. Where a term is provided in the singular, the inventors also contemplate the plural of that term. The nomenclature used here and the laboratory procedures described below are those well known and commonly used in the art. Also, as used in the specification including the appended claims, reference to singular forms such as "one", "one" and "o / a" includes the plural, and reference to a particular numeric value includes at least that particular value, a unless the context clearly indicates otherwise. "About" as used here means that a number referred to as "about" comprises the quoted number plus or minus 1 to 10% of that quoted number.
[0016] A "silicone hydrogel contact lens" refers to a contact lens comprising a silicone hydrogel material. A "silicone hydrogel" refers to a cross-linked polymeric material containing silicone that can absorb at least 10 weight percent water when it is fully hydrated and is obtained by copolymerizing a polymerizable composition comprising at least one vinyl monomer containing silicone or at least at least one vinyl macromer containing silicone or at least one prepolymer containing silicone having ethylenically unsaturated groups.
[0017] As used in this patent application, the term "hydrogel" or "hydrogel material" refers to a cross-linked polymeric material that is not soluble in water and can contain at least 10% by weight of water within its polymeric matrix when fully hydrated.
[0018] As used in this patent application, the term "non-silicone hydrogel" refers to a hydrogel that is theoretically silicon-free.
[0019] A "vinyl monomer", as used here, refers to a compound that has a single ethylenically unsaturated group and can be polymerized actinically or thermally.
[0020] The term "olefinically unsaturated group" or "ethylenically unsaturated group" is used here in a broad sense and is intended to encompass any groups containing at least one group> C = C <. Exemplary ethylenically unsaturated groups include, without limitation, (meth) acryloyl methacryloyl
alila, vinyl
styrene, or other groups containing C = C.
[0021] The term "(meth) acrylamide" refers to methacrylamide and / or acrylamide.
[0022] The term "(meth) acrylate" refers to methacrylate and / or acrylate.
[0023] A "hydrophilic vinyl monomer", as used here, refers to a vinyl monomer that as a homopolymer typically produces a polymer that is soluble in water or can absorb at least 10 weight percent water.
[0024] A "hydrophobic vinyl monomer", as used here, refers to a vinyl monomer that as a homopolymer typically produces a polymer that is insoluble in water and can absorb less than 10 weight percent water.
[0025] as used in that patent application, the term "macromer" or "prepolymer" refers to a medium or high molecular weight compound or polymer that contains two or more ethylenically unsaturated groups. Medium and high molecular weight typically means average molecular weights greater than 700 Daltons.
[0026] As used in that patent application, the term "crosslinker" refers to a compound that has at least two ethylenically unsaturated groups. A "crosslinking agent" refers to a crosslinker that has a molecular weight of about 700 Daltons or less.
[0027] As used in this patent application, the term "polymer" means a material formed by the polymerization / crosslinking of one or more monomers or macromers or prepolymers.
[0028] As used in this patent application, the term "molecular weight" of a polymeric material (including monomeric or macromeric materials) refers to the weight average molecular weight unless specifically stated otherwise or unless test conditions indicate otherwise.
[0029] As used in this patent application, the term "amino group" refers to a primary or secondary amino group of the formula - NHR ', where R' is hydrogen or a substituted or unsubstituted, linear C1-C20 alkyl group or branched, unless specifically stated otherwise.
[0030] The term "vinyl monomer containing carboxyl" refers to a vinyl monomer that has a carboxyl group (-COOH).
[0031] The term "vinyl monomer containing amino" refers to a vinyl monomer that has an amino group.
[0032] The term "azetidinium" refers to a radical (or group)
positively charged, trivalent where Ti, T2 and T3 are a direct link.
[0033] The term "phosphorylcholine" refers to a Zwitterionic group of
R where n is an integer from 1 to 5 and R1, R2 and R3 independently of one another are C1-C8 alkyl or C1-C8 hydroxyalkyl.
[0034] The term "azlactone" refers to a monovalent radical of
, where p is 0 or 1; T4 and T5 independently of each other is an alkyl group having 1 to 14 carbon atoms, a cycloalkyl group having 3 to 14 carbon atoms, an aryl group having 5 to 12 ring atoms, a arenyl group having 6 to 26 carbon atoms and 0 to 3 sulfur, nitrogen and / or oxygen, or T4 and T5 taken together with the carbon to which they are attached can form a carbocyclic ring containing 5 to 8 ring atoms.
[0035] As used in this patent application, the term "non-reactive hydrophilic vinyl monomer" refers to a hydrophilic vinyl monomer free of the carboxyl or amino group.
[0036] The term "polysiloxane segment" refers to a divalent radical that has the formula
wherein R4, R5, R6, R7, R8, R9, R10, R11, independently of one another, are C1- C10 alkyl, C1-C4 alkyl- or C1-C4-phenyl substituted by alkoxy, C1-C10 fluoroalkyl, C1 -C10 fluoroether, C6-C18 aryl radical, -alk- (OC2H4) n1-OR9 where alkyl is divalent C1-C6-alkylene radical, R9 is H or C1-C4 alkyl and n1 is an integer from 1 to 10, m1 and m2 independently of each other are an integer from 0 to 50 and (m1 + m2) is from 1 to 100.
[0037] The term "water soluble" in reference to a polymer means that the polymer can be dissolved in water to an extent sufficient to form an aqueous solution of the polymer having a concentration of about 0.05% to about 30% by weight at room temperature (for example, from about 22 oC to about 28 oC).
[0038] A "water contact angle" refers to an average water contact angle (that is, contact angles measured by the Sessile Drop method), which is obtained by averaging contact angle measurements with at least 3 individual contact lenses.
[0039] The term "integrality" in reference to a coating on a silicone hydrogel contact lens is intended to describe the extent to which the contact lens can be colored by Sudan Black in a Sudan Black staining test described in Example 1. Good Integrality of the coating on a silicone hydrogel contact lens means that there is virtually no Sudan Black staining of the contact lens.
[0040] The term "durability" in reference to a coating on a silicone hydrogel contact lens is intended to describe that the coating on the silicone hydrogel contact lens can survive a digital friction test.
[0041] As used here, "surviving a digital friction test" or "surviving a durability test" in reference to a coating on a contact lens means that after digitally rubbing the lens according to a procedure described in the Example 1, the angle of contact of water in the digitally rubbed lens is still about 100 degrees or less, preferably about 90 degrees or less, more preferably about 80 degrees or less, more preferably about 70 degrees or less.
[0042] The intrinsic "oxygen permeability", Dk, of a material is the rate at which oxygen will pass through a material. As used in this patent application, the term "oxygen permeability (Dk)" in reference to a hydrogel (silicone or non-silicone) or a contact lens means a measured oxygen permeability (Dk) that is corrected for surface strength for oxygen flow caused by the boundary layer effect according to the procedures described in Example 1 of 2012/0026457 A1 (here incorporated by reference in its entirety). Oxygen permeability is conventionally expressed in units of barriers ("barrers"), where "barrier" is defined as [(cm3 of oxygen) (mm) / (cm2) (s) (mm Hg)] x 10-10.
[0043] The "oxygen transmissibility", Dk / t, of a lens or material is the rate at which oxygen will pass through a specific lens or material with an average thickness of t [in units of mm] over the area that is measured. Oxygen transmissibility is conventionally expressed in units of barrers / mm, where "barrers / mm" is defined as [(cm3 of oxygen) / (cm2) (sec) (mm Hg)] x 10-9.
[0044] The "ionic permeability" through a lens correlates with the Ionoflux Diffusion Coefficient. The Ionoflux Diffusion Coefficient, D (in units of [mm2 / min]), is determined by applying Fick's law as follows: D = - n '/ (A x dc / dx) where n' = transport rate ion [mol / min]; A = exposed lens area [mm2]; dc = concentration difference [mol / L]; dx = lens thickness [mm].
[0045] "Ophthalmologically compatible", as used here, refers to a material or surface of a material that may be in close contact with the eye environment for an extended period of time without significantly impairing the eye environment and without significant discomfort for the user.
[0046] The term "ophthalmologically safe" with respect to a packaging solution for sterilizing and storing contact lenses means that a contact lens stored in the solution is safe for direct placement in the eye without rinsing after autoclaving and that the solution is safe and comfortable enough for daily contact with the eye through a contact lens. An ophthalmologically safe packaging solution after autoclaving has a tonicity and pH that are compatible with the eye and is substantially free of ocularly irritating or ocularly cytotoxic materials in accordance with international ISO standards and US FDA regulations.
[0047] An "organic-based solution" refers to a solution that is a homogeneous mixture consisting of an organic-based solvent and one or more solutes dissolved in the organic-based solvent. An organic-based coating solution refers to an organic-based solution containing at least one polymeric coating material as a solute in the solution.
[0048] An "organic-based solvent" is intended to describe a solvent system consisting of one or more organic solvents and optionally about 40% or less, preferably about 30% or less, more preferably about 20% or less, even more preferably about 10% or less, in particular about 5% or less by weight of water relative to the weight of the solvent system.
[0049] The invention is generally related to copolymers containing azetidinium and their use in forming a non-silicone hydrogel coating on a silicone hydrogel (SiHy) contact lens. An azetidinium-containing copolymer of the invention can be adapted to have desired degrees of hydrophilicity / hydrophobicity and / or azetidinium contents. Such copolymers containing azetidinium can be used as a fixing polymer and / or a reactive hydrophilic polymer to form a hydrogel coating, according to a thermally induced reaction mechanism involving an azetidinium group as illustrated in Scheme I
Scheme I in which T1, T2 and T3 are independent of each other; X1 is -S-, -OC (= O) -, -O-, or -NR'- where R 'is hydrogen, a substituted or unsubstituted, linear or branched C1-C20 alkyl group; T6 is a polymer chain or a C1 to C20 unsubstituted or substituted, linear or branched alkyl group. Such a reaction can be carried out conveniently and directly in a lens pack during autoclave (ie, heat the lens pack with the lens in a pack solution from about 118 ° C to about 125 ° C for approximately 20 to 40 minutes under pressure) which is a sterilization process commonly used in the contact lens industry.
[0050] The invention, in one aspect, provides a class of vinyl monomers containing azetidinium of the formula (1)
where: R "is hydrogen or methyl; T7 and T8 independent of each other are C1 to C14 alkyl group; Y1, Y2, and Y3 independent of each other are a bond selected from the group consisting of a direct bond, -O-, -NR'-, -C (O) -NR'-, -NR'-C (O) -, -OC (O) -NH-, -NH-C (O) -O-, - NR'-C (O) -NH-, -NH-C (O) -NR'-, -C (O) -O-, -OC (O) -, -NH-C (O) -NH-Z0- NH-C (O) -NH-, -OC (O) -NH-Z0-NH-C (O) -O-, -OC (O) -NH-Z0-NH-C (O) - NH-, and -NH -C (O) -NH-Z0-NH-C (O) -O-; R 'is hydrogen, a substituted or unsubstituted, linear or branched C1-C20 alkyl group; Z0 is a C2-C12 linear or branched radical alkylene or a divalent C5-C45 cycloaliphatic or aliphatic-cycloaliphatic radical optionally containing one or more bonds of -O-, -NR'- and -C (O) -, R 'is as defined above; Z1, Z2, and Z3 independent of each other are a direct bond, a divalent radical C1-C20 alkylene substituted or unsubstituted, linear or branched optionally containing there one or more bonds of an -O-, -NR'-, and -C (O) - a radical divale n C1-C7 alkyleneoxy C1-C7 alkylene, a divalent radical of - (CH (R '') CH2O) r1-CH (R '') CH2- where R '' is as defined above and r1 is an integer of 1 to 20, an unsubstituted phenylene divalent radical, C1-C4 alkyl or C1-C4 alkoxy substituted phenylene radical or C7-C12 aralkylene divalent radical, a divalent C5-C45 cycloaliphatic or aliphatic-cycloaliphatic radical optionally containing one or more bonds of -O-, -NR '-, and -C (O) -, a divalent C6-C24 aromatic or araliphatic radical, or combinations thereof.
[0051] A vinyl monomer containing azetidinium of the invention can be prepared according to a two-step process. In the first step, a dialkylamine (HNT7T8) can react with epichlorohydrin

to form an azetidinium compound of, wherein T7 and T8, independent of each other, are C1 to C14 alkyl group. In the second step, the resulting azetidinium compound reacts, in the absence of a coupling agent, with an ethylenically functionalized vinyl monomer selected from the group consisting of (meth) acrylic acid halide (chloride, bromide or iodide), (meth) acrylic anhydride, maleic anhydride, a vinyl monomer containing epoxy, a C2-C6 isocyanatoalkyl (meth) acrylate, a vinyl monomer containing aziridine, and a vinyl monomer containing azlactone, under well-known conditions of coupling reactions between a hydroxyl group and another functional group (acid halide group, acid anhydride group, epoxy group, isocyanate group, azeridine group, or azlactone group). Alternatively, the resulting azetidinium compound reacts in the presence of a coupling agent (for example, a diisocyanate compound, a diacid halide compound, a di-azlactone compound, or a diepoxy compound), with an ethylenically functional vinyl monomer selected from the group consisting of (meth) C2 to C6 hydroxylalkyl acrylate, (meth) C2 to C6 hydroxyalkyl acrylate, allyl alcohol, allylamine, (meth) amino-C2-C6 alkyl acrylate, vinylamine, (meth) amino-C2- acrylamide C6 alkyl, acrylic acid, and C1-C4 alkylacrylic acid (e.g., ethylacrylic methacrylic acid, propylacrylic acid, butylacrylic acid), under well-known coupling reaction conditions.
[0052] A "coupling reaction" is intended to describe any reaction between a pair of corresponding functional groups in the presence or absence of a coupling agent to form covalent bonds or bonds under various reaction conditions well known to a person skilled in the art, such as , for example, oxidation reduction conditions, dehydration condensation conditions, addition conditions, substitution (or displacement) conditions, Diels-Alder reaction conditions, cationic crosslinking conditions, ring opening conditions, hardening conditions epoxy and combinations thereof. Non-limiting examples of coupling reactions under various reaction conditions between a pair of co-reactive functional groups are given below for illustrative purposes. For example, a hydroxyl group reacts with an acid chloride or bromide group or with an acid anhydride group to form an ester bond (-C (O) -O-); a hydroxyl (or hydroxy) reacts with an isocyanate to form a urethane bond; a hydroxyl reacts with an epoxy or aziridine to form an ether bond containing OH or NH2 (-CH (OH) -CH2-O- or - CH (NH2) -CH2-O-); a hydroxyl group reacts with an azlactone group in the presence of a catalyst to form an amidoalkylenecarboxy (-OC (O) - (CH2) p-CT4T5-C (O) -NH-) bond; an amino group reacts with an aldehyde group to form a Schiff base that can be further reduced; an amino-NHR 'group reacts with an acid chloride or bromide group or with an acid anhydride group to form an amide bond (-CO-NR'-); an amino-NHR 'group reacts with an isocyanate group to form a urea bond (-NR "-C (O) -NH-); an amino-NHR' group reacts with an epoxy or aziridine group to form an amine bond containing OH or NH2 ((-CH (OH) -CH2-NR'- or - CH (NH2) -CH2-NR'-); an amino-NHR 'group reacts (opening the ring) with an azlactone group to form a alkylene-diamido (-C (O) NR '- (CH2) p-CT4T5-C (O) -NH-) bond; an amino-NHR' group reacts with a carboxylic acid group in the presence of a coupling agent - carbodiimide (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), N, N'-dicyclohexylcarbodiimide (DCC), 1-cyclohexyl- 3- (2-morpholinoethyl) carbodiimide, di -isodiisopropyl carbodiimide, or mixtures thereof) to form an amide bond, a carboxyl group reacts with an epoxy group to form an ester bond.
[0053] Any suitable C4-C24 diisocyanates can be used in the invention. Examples of preferred diisocyanates include without limitation isophorone diisocyanate, hexamethyl-1,6-diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, toluene diisocyanate, 4.4 'diisocyanate -diphenyl, 4,4'-diphenylmethane diisocyanate, p-phenylene diisocyanate, 1,4-phenylene 4,4'-diphenyl diisocyanate, 1,3-bis- ( 4,4'-methyl isocyanate), cyclohexane diisocyanate, and combinations thereof.
[0054] Any suitable diacid halides can be used in the invention. Examples of preferred diacid halide include, without limitation, fumaryl chloride, suberoyl chloride, succinyl chloride, phthaloyl chloride, isophthaloyl chloride, terephthaloyl chloride, sebacoyl chloride, adipoyl chloride, trimethyladipoyl chloride, azela chloride , dodecanedioic acid chloride, succinic chloride, glutaric chloride, oxalyl chloride, dimer acid chloride, and combinations thereof.
[0055] Any suitable diepoxy compounds can be used in the invention. Examples of preferred diepoxy compounds are diglycidyl ether of neopentyl glycol, diglycidyl ether of 1,4-butanediol, diglycidyl ether of 1,6-hexanediol, diglycidyl ether of glycerol, diglycidyl ether of glycol, diglycidyl of ether of glycol, diglycidyl of ether polyethylene glycol, diglycidyl ether of propylene glycol, diglycidyl ether of dipropylene glycol, and combinations thereof. Such diepoxy compounds are commercially available (for example, those DENACOL series diepoxy compounds from Nagase ChemteX Corporation).
[0056] Any suitable C10-C24 diazlactone compounds can be used in the invention. Examples of such diazlactone compounds are those described in United States Patent No. 4,485,236 (incorporated herein by reference in its entirety).
[0057] Preferred examples of vinyl monomers containing aziridine include, without limitation, 3- (1-aziridinyl) propyl (meth) acrylate, 4- (1-aziridinyl) butyl (meth) acrylate, 6 (meth) acrylate - (1-aziridinyl) hexyl, and 8- (1-aziridinyl) octyl (meth) acrylate).
[0058] Preferred examples of epoxy-containing vinyl monomers include, without limitation, glycidyl (meth) acrylate, glycidyl vinyl ether, and glycidyl allyl ether.
[0059] Preferred examples of vinyl monomers containing azlactone include, without limitation, 2-vinyl-4,4-dimethyl-1,3-oxazolin-5-one, 2-isopropenyl-4,4-dimethyl-1,3- oxazolin-5-one, 2-vinyl-4-methyl-4-ethyl-1,3-oxazolin-5-one, 2-isopropenyl-4-methyl-4-butyl-1,3-oxazolin-5-one, 2-vinyl- 4,4-dibutyl-1,3-oxazolin-5-one, 2-isopropenyl-4-methyl-4-dodecyl-1,3-oxazolin-5-one, 2-isopropenyl-4,4- diphenyl-1,3-oxazolin-5-one, 2-isopropenyl-4,4-pentamethylene-1,3-oxazolin-5-one, 2-isopropenyl-4,4-tetramethylene-1,3-oxazolin-5- one, 2-vinyl-4,4-diethyl-1,3-oxazolin-5-one, 2-vinyl-4-methyl-4-nonyl-1,3-oxazolin-5-one, 2-isopropenyl-4- methyl-4-phenyl-1,3-oxazolin-5-one, 2-isopropenyl-4-methyl-4-benzyl-1,3-oxazolin-5-one, 2-vinyl-4,4-pentamethylene-1, 3-oxazolin-5-one, and 2-vinyl-4,4-dimethyl-1,3-oxazolin-6-one (with 2-vinyl-4,4-dimethyl-1,3-oxazolin-5-one ( VDMO) and 2-isopropenyl-4,4-dimethyl-1,3-oxazolin-5-one (IPDMO) as the most preferred vinyl monomers containing azlactone).
[0060] The reaction conditions for the coupling reactions described above are taught in textbooks and are well known to a person skilled in the art.
[0061] This aspect of the invention is also related to another class of vinyl monomers containing azetidinium of the invention represented by formula (2)
where: p1, p2, and p3 independent of each other are zero or 1; R "is hydrogen or methyl; Y4 is a bond selected from the group consisting of a direct bond, -O-, -NR'-, -C (O) -NR'-, -NR'-C (O) -, - OC (O) -NH-, -NH-C (O) -O-, -NR'-C (O) -NH-, -NH-C (O) -NR'-, -C (O) -O -, - OC (O) -, R 'is hydrogen, a substituted or unsubstituted, linear or branched C1-C20 alkyl group; Z4, is a direct bond, a substituted or unsubstituted, linear C1-C20 alkylene radical or optionally branched containing there one or more bonds of -O-, - NR'-, and -C (O) -, a divalent radical of C1-C7 alkyleneoxy C1-C7 alkylene, or a divalent radical of - (CH (R '') CH2O) r1-CH (R '') CH2- where R '' is as defined above and r1 is an integer from 1 to 20; and Z5 is an unsubstituted or substituted, linear C1-C20 alkyl group or branched, - (CH2) r2-O- (CH2CH2O) r1-Z6 where r1 is as defined above, r2 is zero or an integer from 1 to 7, and Z6 is a C1-C5 alkyl.
[0062] This class of vinyl monomers containing azetidinium can be prepared by the reaction of epichlorohydrin directly with a vinyl monomer having a secondary amine group (-NH-) under reaction conditions known to a person skilled in the art. Examples of vinyl monomers include, but are not limited to: N-allyl C1-C12 alkanamine (eg, N-ethyl-2-methylalylamine, N-ethylalylamine, N-allylmethylamine, N-allyl-1-pentanamine, N-allyl-2 -methyl-1-pentanamine, N-Allyl-2,3-dimethyl-1-pentanamine, N-allyl-1-hexanamine, N-allyl-2-methyl-1-hexanamine, N-allyl-1-heptanamine, N -allyl-1-octanamine, N-allyl-1-ecanamine, N-allyl-1-dodecanamine); a vinyl monomer containing a secondary amine that is obtained by reacting an epoxy compound having a single epoxy group (eg, 1,2-epoxy C3-C12 alkanes, or monoeppoxy-terminated polyethylene glycol) with allylamine, vinylamine, (meth) acrylate amino-C2-C6 alkyl, or (meth) acrylamide of amino-C2-C6 alkyl or by reaction of a C1-C12 alkanamine or amino-C2-C12 alkanol or with a vinyl monomer containing epoxy (for example, (meth) acrylate of glycidyl, glycidyl vinyl ether, or glycidyl allyl ether) under coupling reaction conditions well known to a person skilled in the art.
[0063] A vinyl monomer containing azetidinium of the invention can find particular use in the preparation of suitable copolymers to form non-silicone hydrogel coatings on SiHy contact lenses and / or to form a main anchor coating on SiHy contact lenses.
[0064] The invention, in another aspect, provides a copolymer containing azetidinium comprising monomer units containing azetidinium derived from at least one vinyl monomer having an azetidinium group (preferably from a vinyl monomer containing azetidinium of the formula (1) or (2) as described above) and monomer units derived from at least one vinyl monomer selected from the group consisting of a carboxyl-containing vinyl monomer, an amino-containing vinyl monomer, a hydrophobic vinyl monomer, and a combination thereof.
[0065] Preferred examples of vinyl monomers containing carboxyl include, without limitation, acrylic acid, a C1-C4-alkyl acrylic acid (e.g., methacrylic acid, ethylacrylic acid, propylacrylic acid, butylacrylic acid), N, N-2- acid acrylamidoglycolic acid, beta-methyl-acrylic acid (crotonic acid), alpha-phenyl acrylic acid, beta-acryloxy propionic acid, sorbic acid, angelic acid, cinnamic acid, 1-carboxy-4-phenyl butadiene-1,3, itaconic acid citraconic, mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric acid, and combination thereof.
[0066] Examples of preferred amino-containing vinyl monomers include amino (C) -C2-C4 alkyl acrylate, allylamine, vinylamine, amino-C1-C4 alkyl (meth) acrylamide, N-allyl C1-C12 alkanamine (e.g. N-ethyl-2-methylalylamine, N-ethylalylamine, N-allylmethylamine, N-allyl-1-pentanamine, N-allyl-2-methyl-1-pentanamine, N-allyl-2,3-dimethyl-1-pentanamine, N-allyl-1-hexanamine, N-allyl-2-methyl-1-hexanamine, N-allyl-1-heptanamine, N-allyl-1-octanamine, N-allyl-1-echanamine, N-allyl-1- dodecanamine), a coupling reaction product of an epoxy compound having a single epoxy group (for example, 1,2-epoxy C3-C12 alkanes, or monoeppoxy-terminated polyethylene glycol) with allylamine, vinylamine, (methyl) amino-acrylate C2-C6 alkyl, or (meth) acrylamide of amino-C2-C6 alkyl, a coupling reaction product of a C1-C12 alkanamine or C2-C12 aminoalkanol or with a vinyl monomer containing epoxy (for example, (meth) acrylate glycidyl, vinyl glycidyl ether, or allyl glycidyl ether), and combinations thereof.
[0067] Preferred examples of hydrophobic vinyl monomers include (meth) methyl acrylate, (meth) ethyl acrylate, (meth) propyl acrylate, (meth) isopropyl acrylate, (meth) butyl acrylate, (meth) acrylate sec-butyl, isobutyl (meth) acrylate, t-butyl (meth) acrylate, cyclohexylacrylate, 2-ethylhexylacrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl valerate, styrene, chloroprene, vinyl chloride, vinylidene chloride, acrylonitrile, 1-butene, butadiene, methacrylonitrile, vinyl toluene, ethyl vinyl ether, perfluorohexylethyl-thiocarbonyl-aminoethyl-methacrylate, isobornyl methacrylate, trifluoroethyl methacrylate -isopropyl, hexafluorobutyl methacrylate, vinyl monomer containing siloxane, a vinyl monomer containing polysiloxane (having about 3 to about 40 silicone atoms), and combinations thereof.
[0068] Preferred examples of vinyl monomers containing siloxane include N- [tris (trimethylsiloxy) silylpropyl] - (meth) acrylamide, N- [tris (dimethylpropyl-siloxy) silyl propyl] (meth) acrylamide, N- [tris (dimethylphenylsiloxy) - silylpropyl] (meth) acrylamide, N- [tris (dimethylethylsiloxy) silylpropyl] (meth) acrylamide, N- (2-hydroxy-3- (3- (bis (trimethylsilyloxy) methylsilyl) propyloxy) propyl) -2-methyl acrylamide, N- (2-hydroxy-3- (3- (bis (trimethyl-silyloxy) methylsilyl) propyloxy) propyl) acrylamide, N, N-bis [2-hydroxy-3- (3- (bis (trimethylsilyloxy) methyl) ) propyloxy) propyl] -2-methyl acrylamide, N, N-bis [2-hydroxy-3- (3- (bis (trimethylsilyloxy) methylsilyl) propyloxy) propyl] acrylamide, N- (2-hydroxy-3- (3- (tris (trimethylsilyloxy) silyl) -propyloxy) propyl) -2-methyl acrylamide, N- (2-hydroxy- 3- (3- (tris (trimethylsilyloxy) silyl) propyloxy) -propyl) acrylamide, N, N -bis [2- hydroxy-3- (3- (tris (trimethylsilyloxy) silyl) propyloxy) propyl] -2-methyl acrylamide, N, N-bis [2-hydroxy-3- (3- (tris (trimethylsilyloxy) silyl ) propyloxy) propyl] acrylamide a, N- [2-hydroxy-3- (3- (t-butyldimethylsilyl) propyloxy) propyl] -2-methyl acrylamide, N- [2-hydroxy-3- (3- (t-butyldimethylsilyl) propyloxy) propyl] acrylamide, N, N-bis [2-hydroxy-3- (3- (t-butyldimethylsilyl) -propyloxy) propyl] -2-methyl acrylamide, N, N-bis [2-hydroxy-3- (3- (t -butyldimethylsilyl) propyloxy) -propyl] acrylamide, 3-methacryloxy propylpentamethyldisiloxane, tris (trimethylsilyloxy) silylpropyl methacrylate (TRIS), (3-methacryloxy-2-hydroxypropyloxy) -propyl-methyl-2-methyl-3-methylsily hydroxypropyloxy) propyltris (trimethylsiloxy) silane, 3-methacryloxy-2- (2-hydroxyethoxy) -propyloxy) propylbis (trimethylsiloxy) methylsilane, N-2-methacryloxyethyl-O- (methyl-bis-trimethylsilyl) -3-propyl , 3- (trimethylsilyl) -propylvinyl carbonate, 3- (vinyloxycarbonylthio) propyl-tris (trimethylsiloxy) silane, 3- [tris (trimethylsiloxy) silyl] propylvinyl carbamate, 3- [tris (trimethylsiloxy) silyl] carbamate] propyl allyl, 3- [tris (trimethylsiloxy) silyl] carbonyl propyl vinyl, carbonate of t-butyldimethyl-siloxyethyl vinyl, trimethylsilylethyl vinyl carbonate, trimethylsilylmethyl vinyl carbonate, and combinations thereof.
[0069] A "vinyl monomer containing polysiloxane" refers to a vinyl monomer comprising a single ethylenically unsaturated group and at least one poly (C1-C6 alkyl-substituted siloxane) segment. Preferred examples of a vinyl monomer containing polysiloxane having about 3 to about 40 mono- (meth) acrylate-terminated polydimethylsiloxanes of various molecular weights (e.g., mono-C1- terminated mono-3-methacryloxypropyl, poly-terminated polydimethylsiloxane C4 alkyl, or finished mono- (3-methacryloxy-2-hydroxypropyloxy) propyl, mono-C1-C4 alkyl polydimethylsiloxane), mono-vinyl-terminated polydimethylsiloxanes, mono- (meth) acrylamide-terminated polycarbonate, polydimethylsilaminates; -finished, monovinylcarbonate-finished polydimethylsiloxanes, and combinations thereof. Alternatively, monoethylene functionalized polysiloxanes can be obtained by ethylene functionalization of monofunctionalized polysiloxanes (i.e., with a single terminal functional group, such as, for example, -NH2, -OH, -COOH, epoxy group, halide, etc.) as described above. Suitable monofunctionalized polysiloxanes are commercially available, for example, from Aldrich, ABCR GmbH & Co., Fluorochem, or Gelest, Inc, Morrisville, PA.
[0070] It is reported that the hydrogen dissociation constants (pKa) are about 4.0 for polyacrylic acid, about 5.3 for polymethacrylic acid, about 6.3 for polyethylacrylic acid, about 6.7 for acid polypropylacrylic, and about 7.4 for polybutylacrylic acid (see, H. Dong, J. Phys. Chem. A 112 (49): 12687-12694 (2008); F. Mitsuko, R. Grubbs, and JD Baldeschwieler, J Colloid Interface Sci. 185: 210-216 (1997); SJ Grainger and EH El-Sayed, in Biologically-Responsive Hybrid Biomaterials: A Reference for Material Scientists and Bioengineers, E. Jabbari et A. Khademhosseini, Eds., Boston, MA: Artech Publishing (2010), Chapter 7, pp171-190). Because of the differences in pKa, the degrees of ionization of the carboxyl groups of those polymers at neutral pH can be significantly different and may have different levels of absorption of positively charged antimicrobial agents (for example, PHMB, aldox, POLIQUAD, etc.) present in the lens care solutions. It is believed that where the azetidinium-containing polymer for a coating on a SiHy contact lens is composed primarily of methacrylic acid or ethylacrylic acid, the absorption of those positively charged antimicrobial agents present in the lens care solutions can be minimized.
[0071] In a preferred embodiment, an azetidinium-containing copolymer of the invention preferably comprises: monomeric units containing azetidinium derived from at least one vinyl monomer containing azetidinium of the formula (1) or (2) (as described above); and carboxyl-containing monomer units derived from carboxyl-containing vinyl monomer (preferably selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, maleic acid, and combinations thereof, most preferably selected from the group consisting of methacrylic acid, ethylacrylic acid , and combination thereof, even more preferably derived from methacrylic acid); and optionally amino-containing monomer units derived from at least one vinyl monomer containing amino [referably selected from the group consisting of (meth) acrylate-C2-C4 alkyl, allylamine, vinylamine, (meth) acrylamide of amino-C1-C4 alkyl, C1-C12 N-allyl alkanamine (for example, N-ethyl-2-methylalylamine, N-ethylalylamine, N-allylmethylamine, N-allyl-1-pentanamine, N-allyl-2-methyl-1-pentanamine, N- allyl-2,3-dimethyl-1-pentanamine, N-allyl-1-hexanamine, N-allyl-2-methyl-1-hexanamine, N-allyl-1-heptanamine, N-allyl-1-octanamine, N- allyl-1-ecanamine, N-allyl-1-dodecanamine), a coupling reaction product of an epoxy compound having a single epoxy group (eg, 1,2-epoxy C3-C12 alkanes, or finished monoeppoxy polyethylene glycol) with allylamine, vinylamine, (meth) acrylate of C2-C6 alkyl, or (meth) acrylamide of amino-C2-C6 alkyl, a coupling reaction product of a C1-C12 alkanamine or C2-C12 aminoalkan or with a monomer vinyl containing epoxy (p for example, glycidyl (meth) acrylate, glycidyl vinyl ether, or allyl glycidyl ether), and combinations thereof].
[0072] In another preferred embodiment, an azetidinium-containing copolymer of the invention preferably comprises: azetidinium-containing monomer units derived from at least one azetidinium-containing vinyl monomer of formula (1) or (2) (as described above); carboxyl-containing monomer units derived from a carboxyl-containing vinyl monomer, preferably selected from the group, consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, maleic acid, and combinations thereof (most preferably selected from the group consisting of methacrylic acid, acid ethylacrylic, and combination thereof, even more preferably derived from acid methacrylic); and hydrophobic monomer units derived from at least one hydrophobic vinyl monomer (preferably selected from the group consisting of (meth) methyl acrylate, (meth) ethyl acrylate, (meth) propyl acrylate, (meth) isopropyl acrylate, (meth) butyl acrylate, sec-butyl (meth) acrylate, isobutyl (meth) acrylate, t-butyl acrylate, cyclohexylacrylate, 2-ethylhexylacrylate, vinyl acetate, vinyl propionate, vinyl butyrate , vinyl valerate, styrene, chloroprene, vinyl chloride, vinylidene chloride, acrylonitrile, 1-butene, butadiene, methacrylonitrile, vinyl toluene, ethyl vinyl ether, perfluoro-hexylethyl-thio-carbonyl-aminoethyl-methacrylate, methacrylate isobornyl, trifluoroethyl methacrylate, hexafluoro-isopropyl methacrylate, hexafluorobutyl methacrylate, vinyl monomer containing siloxane, a vinyl monomer containing polysiloxane having about 3 to about 40 silicone atoms, and combinations thereof, more preferred initially selected from the group consisting of at least one vinyl monomer containing siloxane, at least one vinyl monomer containing polysiloxane and combinations thereof); and optionally amino-containing monomer units derived from at least one vinyl monomer containing amino [referably selected from the group consisting of (meth) acrylate-C2-C4 alkyl, allylamine, vinylamine, (meth) acrylamide of amino-C1-C4 alkyl, C1-C12 N-allyl alkanamine (for example, N-ethyl-2-methylalylamine, N-ethylalylamine, N-allylmethylamine, N-allyl-1-pentanamine, N-allyl-2-methyl-1-pentanamine, N- allyl-2,3-dimethyl-1-pentanamine, N-allyl-1-hexanamine, N-allyl-2-methyl-1-hexanamine, N-allyl-1-heptanamine, N-allyl-1-octanamine, N- allyl-1-ecanamine, N-allyl-1-dodecanamine), a coupling reaction product of an epoxy compound having a single epoxy group (eg, 1,2-epoxy C3-C12 alkanes, or finished monoeppoxy polyethylene glycol) with allylamine, vinylamine, amino-C2-C6 alkyl (meth) acrylate, or amino-C2-C6 alkyl (meth) acrylamide, a coupling reaction product of a C1-C12 alkanamine or C2-C12 aminoalkan or with a monomer vinyl containing epoxy ( for example, glycidyl (meth) acrylate, glycidyl vinyl ether, or glycidyl allyl ether), and combinations thereof].
[0073] In another preferred embodiment, an azetidinium-containing copolymer of the invention preferably comprises: azetidinium-containing monomer units derived from at least one azetidinium-containing vinyl monomer of formula (1) or (2) (as described above); hydrophobic monomer units derived from at least one hydrophobic vinyl monomer (preferably selected from the group consisting of (meth) methyl acrylate, (meth) ethyl acrylate, (meth) propyl acrylate, (meth) isopropyl acrylate, (meth) acrylate butyl, sec-butyl (meth) acrylate, isobutyl (meth) acrylate, t-butyl (meth) acrylate, cyclohexylacrylate, 2-ethylhexylacrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl valerate, styrene, chloroprene, vinyl chloride, vinylidene chloride, acrylonitrile, 1-butene, butadiene, methacrylonitrile, vinyl toluene, ethyl vinyl ether, perfluoro-hexylethyl-thio-carbonyl-aminoethyl-methacrylate, isobornate methacrylate , trifluoroethyl methacrylate, hexafluoro isopropyl methacrylate, hexafluorobutyl methacrylate, vinyl monomer containing siloxane, a vinyl monomer containing polysiloxane having about 3 to about 40 silicone atoms, and combinations thereof, more preferred ially selected from the group consisting of at least one vinyl monomer containing siloxane, at least one vinyl monomer containing polysiloxane, and combinations thereof); and optionally amino-containing monomer units derived from at least one vinyl monomer containing amino [referably selected from the group consisting of (meth) acrylate-C2-C4 alkyl, allylamine, vinylamine, (meth) acrylamide of amino-C1-C4 alkyl, C1-C12 N-allyl alkanamine (for example, N-ethyl-2-methylalylamine, N-ethylalylamine, N-allylmethylamine, N-allyl-1-pentanamine, N-allyl-2-methyl-1-pentanamine, N- allyl-2,3-dimethyl-1-pentanamine, N-allyl-1-hexanamine, N-allyl-2-methyl-1-hexanamine, N-allyl-1-heptanamine, N-allyl-1-octanamine, N- allyl-1-ecanamine, N-allyl-1-dodecanamine), a coupling reaction product of an epoxy compound having a single epoxy group (for example, 1,2-epoxy C3-C12 alkanes, or finished mono-epoxy polyethylene glycol) with allylamine, vinylamine, (meth) acrylate of C2-C6 alkyl, or (meth) acrylamide of amino-C2-C6 alkyl, a coupling reaction product of a C1- C12 alkanamine or C2-C12 aminoalkanol or with a monomer vinyl containing epoxy (for example, (meth) glycidyl acrylate, glycidyl vinyl ether, or glycidyl allyl ether), and combinations thereof].
[0074] In another preferred embodiment, an azetidinium-containing copolymer of the invention preferably comprises: (1) azetidinium-containing monomer units derived from at least one azetidinium-containing vinyl monomer of formula (1) or (2) (as described above); (2) reactive monomer units which are carboxyl-containing monomer units and / or amino-containing monomer units, wherein the carboxyl-containing monomer units are derived from at least one carboxyl-containing vinyl monomer (any of those described above) and in which the monomer units amino-containing vinyls are derived from at least one amino-containing vinyl monomer (any of those described above); and (3) at least about 50%, preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 75 mol% of unreacted hydrophilic monomer units derived from at least one hydrophilic vinyl monomer selected from the group consisting of (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-vinylpyrrolidone, (meth) N, N, -dimethylaminoethyl, N, N-dimethylaminopropyl (meth) acrylate - mide, glycerol methacrylate, 3-acryloylamino-1-propanol, N-hydroxyethyl acrylamide, N- [tris (hydroxymethyl) methyl] -acrylamide, N-methyl-3-methylene-2-pyrrolidone, 1-ethyl-3- methylene-2-pyrrolidone, pyrrolidone, 1-ethyl-5-methylene-2-pyrrolidone, pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone, 2-hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, (meth) C1-C4-alkoxy polyethylene glycol acrylate having a weight average molecular weight of up to 1500 Daltons, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl lN-methyl acetamide, allyl alcohol, vinyl alcohol (hydrolyzed form of vinyl acetate in the copolymer), a vinyl monomer containing phosphorylcholine (including (meth) acryloyloxyethyl phosphorylcholine and those described in U.S. Patent No. 5,461,433, incorporated herein by reference in its entirety), a vinyl monomer containing sugar (for example, (meth) erythritol acrylate, (meth) arabitol acrylate, (meth) mannitol acrylate, (meth) ducitol acrylate, (meth) fucitol acrylate, (meth) iditol acrylate, (meth) inositol acrylate, (meth) xylitol acrylate, (meth) sorbitol acrylate, (meth) glucose acrylate, (meth) fructose acrylate, (meth) galactose acrylate, and combinations thereof (preferably selected from the group consisting of (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-vinylpyrrolidone, (meth) N, N, -dimethylaminoethyl acrylate, glycerol methacrylate, 3-acryloylamino-1 -propanol, N-hydroxyethyl acrylamide, N- [tris (hydroxymethyl) methyl] -acrylamide, N-methyl-3 -methylene-2-pyrrolidone, 1-ethyl-3-methylene-2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 1-ethyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene -2-pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone, 2-hydroxyethyl (meth) acrylate, C1-C4-alkoxy polyethylene glycol acrylate having a weight average molecular weight of up to 1500 Daltons, N -vinyl formamide, N-vinyl acetamide, N-vinyl-N-methyl acetamide, allyl alcohol, a vinyl monomer containing phosphorylcholine (including (meth) acryloyloxyethyl phosphorylcholine and those described in U.S. Patent No. 5,461,433, incorporated herein by reference in its entirety), (meth) erythritol acrylate, (meth) arabitol acrylate, (meth) mannitol acrylate, (meth) ducitol acrylate, (meth) fucitol acrylate, (meth) iditol acrylate, (meth) ) inositol acrylate, (meth) xylitol acrylate, (meth) sorbitol acrylate, (meth) glucose acrylate, (meth) fructose acrylate, (meth) galactose acrylate, and combinations thereof). More preferably, the copolymer comprises up to about 50%, preferably from about 2.5% to about 40%, more preferably from about 5% to about 30%, even more preferably from about 7.5% to about 25 mol% of monomer units containing azetidinium and reactive monomer units.
[0075] The weight average molecular weight Mw where an azetidinium-containing copolymer of the invention is at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about 100,000 Daltons, even more preferably from about 200,000 to about 1,000,000 Daltons.
[0076] A person skilled in the art knows very well how to prepare a copolymer containing azetidinium of the invention according to any known polymerization technique.
[0077] An azetidinium-containing copolymer of the invention may find particular use in the formation of cross-linked hydrophilic coatings on SiHy contact lenses.
[0078] The invention, in an additional aspect, provides a method for producing coated silicone hydrogel contact lenses each having a hydrophilic coating reticulated therein, the method of the invention comprising the steps of: (a) obtaining a contact lens from hydrogel silicone; (b) applying a main coating of a fixing polymer to the silicone hydrogel contact lens, wherein the fixing polymer is a homopolymer or copolymer of a vinyl monomer containing carboxyl and / or a copolymer containing azetidinium comprising the first units azetidinium-containing monomers derived from at least one azetidinium-containing vinyl monomer (preferably of formula (1) or (2) as described above) and monomeric units selected from the group consisting of carboxyl-containing monomer units derived from at least one carboxyl-containing vinyl monomer (any one of those described above), monomeric units containing amino derived from at least one vinyl monomer containing amino (any of those described above), hydrophobic monomeric units derived from at least one hydrophobic vinyl monomer (any of those described above), and combinations thereof ; and (c) heating the silicone hydrogel contact lens in an aqueous solution in the presence of a water-soluble hydrophilic polymeric material, thermally crosslinkable comprising reactive functional groups selected from the group consisting of azetidinium groups, carboxyl groups, amino groups, thiol groups and combinations thereof, at and at a temperature of about 40 ° C to about 140 ° C for a period of time sufficient to induce intermolecular and intramolecular crosslinking reaction between an azetidinium group and an amino or carboxyl group, thus forming a coating of durable non-silicone hydrogel on the silicone hydrogel contact lens, provided that at least one of the fixing polymer and the thermally crosslinkable hydrophilic polymeric material comprises azetidinium groups.
[0079] A technician on the subject knows very well how to make contact lenses. For example, contact lenses can be produced in a conventional "rotating casting mold", as described, for example, in U.S. Patent No. 3,408,429, or by the complete molten molding process in a static form, as described in US Patent Nos. 4,347,198; 5,508,317; 5,583,463; 5,789,464; and 5,849,810, or by cutting around silicone hydrogel buttons as used in the manufacture of custom contact lenses. In molten molding, a lens formulation is typically dispensed in molds and cured (i.e., polymerized and / or cross-linked) in molds to make contact lenses. For the production of silicone hydrogel (SiHy) contact lenses, a SiHy lens forming composition (or SiHy lens formulation) for cast casting or rotary casting molding or for making SiHy rods used in cutting around Contact lenses generally comprise at least one component selected from the group consisting of a vinyl monomer containing silicone, a vinyl macromer containing silicone, a prepolymer containing silicone, a hydrophilic vinyl monomer, a hydrophobic vinyl monomer, a crosslinking agent (a compound having a molecular weight of about 700 Daltons or less and containing at least two ethylenically unsaturated groups), a free radical initiator (photoinitiator or thermal initiator), a hydrophilic macromer / vinyl prepolymer, and combination thereof, as well known to a person skilled in the art. A SiHy contact lens formulation may also comprise other necessary components known to a person skilled in the art, such as, for example, a UV-absorbing agent, a visibility dyeing agent (for example, dyes, pigments, or mixtures antimicrobial agents (for example, preferably silver nanoparticles), a bioactive agent, leachable lubricants, leachable tear stabilizing agents and mixtures thereof, as known to a person skilled in the art. The resulting SiHy contact lenses can then be subjected to extraction with an extraction solvent to remove unpolymerized components from the resulting lenses and for hydration process, as known to a person skilled in the art. In addition, a preformed SiHy contact lens may be a colored contact lens (i.e., a SiHy contact lens having at least one colored pattern printed on it as well known to a person skilled in the art).
[0080] Numerous SiHy lens formulations including various combinations of components described above have been described in numerous patents and patent applications published at the end of that patent application. All of them can be used to obtain a SiHy lens to be coated. A SiHy lens formulation for making commercial SiHy lenses, such as lotrafilcon A, lotrafilcon B, delefilcon A, balafilcon A, galyfilcon A, senofilcon A, narafilcon A, narafilcon B, comfilcon A, enfilcon A, asmofilcon A, or similarly, it can also be used in the manufacture of SiHy contact lenses to be coated in this invention.
[0081] According to the invention, a main coating is formed by contacting a SiHy contact lens (to be coated) with a fixing polymer solution. Contact of the contact lens with a fixing polymer solution can occur by immersing it in the coating solution or spraying it with the coating solution. A contact process involves only immersing the contact lens in a bath of a fixation polymer solution for a period of time or alternatively dipping the contact lens dryly in a series of baths of fixing polymer solutions for a period of time. shorter time set for each bath. Another contact process involves spraying only a solution of the fixation polymer. However, several alternatives that involve various combinations of spraying and diving steps can be designed by a person skilled in the art.
[0082] The contact time of a contact lens with a fixing polymer solution can last up to about 10 minutes, preferably from about 5 to about 360 seconds, more preferably from about 5 to about 250 seconds, even more preferably from about 5 to 200 seconds.
[0083] According to the invention, the fixation polymer is a linear or branched or cross-linked polymer, as long as it is soluble in water, an organic solvent, a mixture of two or more organic solvents, a mixture of water with one or more organic solvents.
[0084] All preferred modalities and modalities of vinyl monomers containing carboxyl, vinyl monomers containing azetidinium, vinyl monomers containing amino, hydrophobic vinyl monomers, non-reactive hydrophilic vinyl monomers, and copolymers containing azetidinium were described above and can be used in this aspect of the above and can be used in this aspect of the invention. .
[0085] In a preferred embodiment, a fixation polymer of the invention preferably comprises monomeric units containing carboxyl derived from a vinyl monomer containing carboxyl preferably selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, maleic acid, and combinations of them, most preferably selected from the group consisting of methacrylic acid, ethylacrylic acid, and combination thereof, even more preferably derived from methacrylic acid.
[0086] In another preferred embodiment, the fixation polymer is: polyacrylic acid (PAA); polymethacrylic acid (PMAA); polyethylacrylic acid, polypropylacrylic acid; a copolymer of at least two vinyl monomers selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, and propylacrylic acid; polymalleic acid (i.e., partially or fully hydrolyzed polymalleic anhydride); a maleic acid copolymer and one or more vinyl monomers (for example, ethylene, methyl vinyl ether, vinyl acetate, and / or isobutylene); a copolymer composed of from about 0.05% to about 20% (preferably from about 0.1% to about 15%, more preferably from about 0.5% to about 10%) in mol of a monomer azetidinium-containing vinyl (preferably an azetidinium-containing vinyl monomer of formula (1) as described above) and from about 80% to about 99.95 mol% of one or more carboxyl-containing vinyl monomers selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, and a combination thereof; a reaction product of a
azetidinium compound of which T7 and T8 as defined above with polymalonic anhydride or with a maleic anhydride copolymer and one or more vinyl monomers (for example, ethylene, methyl vinyl ether, vinyl acetate, and / or isobutylene), where the molar equivalent ratio of the azetidinium compound to maleic anhydride is about 0.25 or less (preferably about 0.2 or less, more preferably about 0.15 or less, even more preferably about 0.1 or less) ; and combinations thereof.
[0087] In another preferred embodiment, a fixing polymer of the invention preferably comprises: carboxyl-containing monomer units derived from a carboxyl-containing vinyl monomer preferably selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, maleic acid, and combinations thereof (most preferably selected from the group consisting of methacrylic acid, ethylacrylic acid, and combination thereof, even more preferably derived from methacrylic acid); and azetidinium-containing monomer units derived from at least one azetidinium-containing vinyl monomer of formula (1) or (2) (as described above).
[0088] In another preferred embodiment, a fixing polymer of the invention preferably comprises: monomeric units containing carboxyl derived from a vinyl monomer containing carboxyl preferably selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, maleic acid, and combinations thereof (most preferably selected from the group consisting of methacrylic acid, ethylacrylic acid, and combination thereof, even more preferably methacrylic acid derivatives); monomer units containing azetidinium derived from at least one vinyl monomer containing azetidinium of formula (1) or (2) (as described above); and hydrophobic monomer units derived from at least one hydrophobic vinyl monomer (preferably at least one vinyl monomer containing siloxane and / or at least one vinyl monomer containing polysiloxane).
[0089] In another preferred embodiment, a fixing polymer of the invention preferably comprises: monomer units containing azetidinium derived from at least one vinyl monomer containing azetidinium of formula (1) or (2) (as described above); and hydrophobic monomer units derived from at least one hydrophobic vinyl monomer (preferably at least one vinyl monomer containing siloxane and / or at least one vinyl monomer containing polysiloxane).
[0090] In another preferred embodiment, a fixing polymer of the invention preferably comprises: monomeric units containing carboxyl derived from a vinyl monomer containing carboxyl preferably selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, propylacrylic acid, maleic acid, and combinations thereof (most preferably selected from the group consisting of methacrylic acid, ethylacrylic acid, and combination thereof, even more preferably derived from methacrylic acid); and hydrophobic monomer units derived from at least one hydrophobic vinyl monomer (preferably at least one vinyl monomer containing siloxane and / or at least one vinyl monomer containing polysiloxane).
[0091] The average molecular weight Mw of a fixing polymer to form a main anchor coating is at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about 100,000 Daltons, even more preferably from about 200,000 to about 1,000,000 Daltons.
[0092] A fixing polymer solution to form a main coating on contact lenses can be prepared by dissolving one or more fixing polymers in water, a mixture of water and a water-miscible organic solvent, an organic solvent, or a mixture of one or more organic solvents. Preferably, the fixing polymer is dissolved in a mixture of water and one or more organic solvents, an organic solvent, or a mixture of one or more organic solvents. It is believed that a solvent system containing at least one organic solvent can swell a silicone hydrogel contact lens so that a portion of the fixing polymer can penetrate the silicone hydrogel contact lens and increase the durability of the main coating.
[0093] Any organic solvents can be used in the preparation of a fixing polymer solution. Examples of organic solvents include, without limitation, tetrahydrofuran, tripropylene glycol methyl ether, dipropylene glycol methyl ether, n-butyl ethylene glycol ether, ketones (e.g., acetone, methyl ethyl ketone, etc.), n- diethylene glycol butyl ether, diethylene glycol methyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, propylene glycol methyl acetate, dipropylene glycol methyl acetate, n-propylene glycol ether, n- dipropylene glycol propyl ether, tripropylene glycol n-butyl ether, propylene glycol n-butyl ether, dipropylene glycol n-butyl ether, tripropylene glycol n-butyl ether, propylene glycol phenyl ether, dipropylene glycol dimethyl ether, polyethylene glycols, polypropylene glycols, ethyl acetate, butyl acetate, amyl acetate, methyl lactate, ethyl lactate, i-propyl lactate, methylene chloride, methanol, ethanol, 1- or 2-propanol, 1- or 2-butanol, tert-butanol, tert-amyl alcohol, menthol, cyclohexanol, cyclopentanol and exonorborneol, 2-pentanol, 3-pentanol, 2-hexanol, 3-hexanol, 3-methyl-2-butanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 3-octanol, norborneol, 2-methyl-2-pentanol, 2,3-dimethyl-2-butanol, 3-methyl-3-pentanol, 1-methylcyclohexanol, 2-methyl-2-hexanol, 3,7- dimethyl-3-octanol, 1-chloro-2-methyl-2-propanol, 2-methyl-2-heptanol, 2-methyl-2-octanol, 2-2-methyl-2-nonanol, 2-methyl-2- decanol, 3-methyl-3-hexanol, 3-methyl-3-heptanol, 4-methyl-4-heptanol, 3-methyl-3-octanol, 4-methyl-4-octanol, 3-methyl-3-nonanol, 4-methyl-4-nonanol, 3-methyl-3-octanol, 3-ethyl-3-hexanol, 3-methyl-3-heptanol, 4-ethyl-4-heptanol, 4-propyl-4-heptanol, 4- isopropyl-4-heptanol, 2,4-dimethyl-2-pentanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-ethylcyclopentanol, 3-hydroxy-3-methyl-1-butene, 4-hydroxy-4-methyl-1- cyclopentanol, 2-phenyl-2-propanol, 2-methoxy-2-methyl-2-propanol 2,3,4-trimethyl-3-pentanol, 3,7-dimethyl-3-octanol, 2-phenyl-2-butanol , 2-methyl-1-phenyl-2-propanol and 3-ethyl-3-pen tanol, 1-ethoxy-2-propanol, 1-methyl-2-pyrrolidone, N, N-dimethylpropionamide, dimethyl formamide, dimethyl acetamide, dimethyl propionamide, N-methyl pyrrolidinone, and mixtures thereof.
[0094] According to that aspect of the invention, wherein the water soluble, thermally crosslinkable hydrophilic polymeric material can be any water soluble polymer as long as it contains reactive groups selected from the group consisting of azetidinium groups, carboxyl groups, amino groups, groups thiol, and combinations thereof. Preferably, a thermally crosslinkable, water-soluble hydrophilic polymeric material is: (i) an azetidinium-containing copolymer of the invention (as described above and can be used here) comprising at least about 50%, preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 75 mol% of non-reactive hydrophilic monomer units derived from at least one hydrophilic vinyl monomer (any of those described above); (ii) a reaction product of a copolymer containing azetidinium (as described above and can be used here) being free of any silicone with at least one hydrophilicity enhancing agent having at least one reactive functional group selected from the group consisting of a group amino, carboxyl group, thiol group, and combinations thereof; (iii) a polyaminoamide-epichlorohydrin reaction product with at least one hydrophilicity-enhancing agent having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group, and combinations thereof; and (iv) a water-soluble hydrophilic polymer having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group, and combinations thereof.
[0095] The term "hydrophilicity enhancing agent" refers to a hydrophilic organic compound or polymer that can react with an azetidinium-containing copolymer of the invention to form a product with the hydrophilicity enhancing agent covalently incorporated therein as hydrophilic moieties and / or hydrophilic chains. Any suitable hydrophilicity enhancing agents can be used in the invention as long as they contain at least one amino group, at least one carboxyl group, and / or at least one thiol group.
[0096] A preferred class of hydrophilicity enhancing agents includes, without limitation: monosaccharides containing amino, carboxyl or thiol (eg, 3-amino-1,2-propanediol, 1-thiolglycerol, 5-keto-D-gluconic acid , galactosamine, glucosamine, galacturonic acid, gluconic acid, glucosaminic acid, mannosamine, saccharic acid 1,4-lactone, saccharide, ketodeoxynonulosonic acid, N-methyl-D-glucamine, 1-amino-1-de0xi-β-D- galactose, 1-amino-1-deoxysorbitol, 1-methylamino-1-deoxysorbitol, N-aminoethyl gluconamide); disaccharides containing amino, carboxyl or thiol (for example, chondroitinam disaccharide sodium salt, di (β-D-xylopyranosyl) amine, digalacturonic acid, heparin disaccharide, hyaluronic acid disaccharide, Lactobionic acid); oligosaccharides containing amino, carboxyl or thiol (for example, sodium salt of carboxymethyl-β-cyclodextrin, trigalacturonic acid); and combinations thereof.
[0097] Another preferred class of hydrophilicity-enhancing agents are hydrophilic polymers having one or more amino, carboxyl and / or thiol groups. More preferably, the content of the monomeric units having an amino group (-NHR 'with R' as defined above), carboxyl (-COOH) and / or thiol (-SH) in a hydrophilic polymer as a hydrophilicity enhancing agent is less than about 40%, preferably less than about 30%, more preferably less than about 20%, even more preferably less than about 10%, by weight based on the total weight of the hydrophilic polymer.
[0098] A preferred class of hydrophilic polymers as hydrophilicity enhancing agents are polysaccharides containing amino or carboxyl, for example, such as carboxymethylcellulose (having a carboxyl content of about 40% or less, which is estimated based on the composition of repeat units, - [C6H10- mO5 (CH2CO2H) m] - where m is 1 to 3), carboxyethylcellulose (having a carboxyl content of about 36% or less, which is estimated based on the composition of units repetition, - [C6H10- mO5 (C2H4CO2H) m] - where m is 1 to 3) carboxypropylcellulose (having a carboxyl content of about 32% or less, which is estimated based on the composition of repetition units, - [C6H10- mO5 (C3H6CO2H) m] -, where m is 1 to 3), hyaluronic acid (having a carboxyl content of about 11%, which is estimated based on the composition of repeat units, - ( C13H20O9NCO2H) -), chondroitin sulfate (having a carboxyl content of about 9.8%, which is estimated based on the co mposition of repetition units, - (C12H18O13NS CO2H) -), or combinations thereof.
[0099] Another preferred class of hydrophilic polymers as hydrophilicity enhancing agents include, without limitation: poly (ethylene glycol) (PEG) with monoamino, carboxyl or thiol group (eg, PEG-NH2, PEG-SH, PEG-COOH ); H2N-PEG-NH2; HOOC-PEG-COOH; HS-PEG-SH; H2N-PEG-COOH; HOOC-PEG-SH; H2N-PEG-SH; Multibrake PEG with one or more amino, carboxyl or thiol groups; PEG dendrimers with one or more amino, carboxyl or thiol groups; a homo or copolymer terminated with diamino or dicarboxyl of a non-reactive hydrophilic vinyl monomer; a monoamino or monocarboxyl terminated homo or copolymer of a non-reactive hydrophilic vinyl monomer; a copolymer which is a polymerization product of a composition comprising (1) about 60% by weight or less, preferably from about 0.1% to about 30%, more preferably from about 0.5% to about 20% , even more preferably from about 1% to about 15%, by weight of one or more reactive vinyl monomers and (2) at least one non-reactive hydrophilic vinyl monomer and / or at least one phosphorylcholine-containing vinyl monomer; and combinations thereof. Reactive vinyl monomer (s) and non-reactive hydrophilic vinyl monomer (s) are those described above.
More preferably, a hydrophilic polymer as a hydrophilicity enhancing agent is PEG-NH2; PEG-SH; PEG-COOH; H2N-PEG-NH2; HOOC-PEG-COOH; HS-PEG-SH; H2N-PEG-COOH; HOOC-PEG-SH; H2N-PEG-SH; Multibrake PEG with one or more amino, carboxyl or thiol groups; PEG dendrimer with one or more amino, carboxyl or thiol groups; a monoamino, monocarboxyl, diamino or dicarboyl homo or copolymer of a non-reactive hydrophilic vinyl monomer selected from the group consisting of acrylamide (AAm), N, N-dimethylacrylamide (DMA), N-vinylpyrrolidone (NVP), N-vinyl- N-methyl acetamide, (meth) glycerol acrylate, (meth) hydroxyethyl acrylate, N-hydroxyethyl (meth) acrylamide, (meth) C1-C4-alkoxy polyethylene glycol having a weight average molecular weight of up to 400 Daltons, vinyl alcohol, N-methyl-3-methylene-2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene-2-pyrrolidone, N, N-dimethylaminoethyl (meth) acrylate, N, N-dimethylaminopropyl (meth) acrylamide, (meth) acryloyloxyethyl phosphorylcholine, and combinations thereof; a copolymer which is a polymerization product of a composition comprising (1) from about 0.1% to about 30%, preferably from about 0.5% to about 20%, more preferably from about 1% to about 15% by weight of (meth) acrylic acid, C2-C12 alkylacrylic acid, vinylamine, allylamine, and / or (meth) acrylate of C2-C4 alkyl, and (2) (meth) acryloyloxyethyl phosphorylcholine and / or at least one non-reactive hydrophilic vinyl monomer selected from the group consisting of acrylamide, N, N-dimethylacrylamide, N-vinylpyrrolidone, N-vinyl-N-methyl acetamide, (meth) glycerol acrylate, (meth) hydroxyethyl acrylate, N -hydroxyethyl (meth) acrylamide, (meth) acrylate of C1-C4-alkoxy polyethylene glycol having a weight average molecular weight of up to 400 Daltons, vinyl alcohol, and a combination thereof.
[00101] More preferably, the hydrophilicity-enhancing agent as a hydrophilicity-enhancing agent is PEG-NH2; PEG-SH; PEG-COOH; monoamino, monocarboxyl, diamino or dicarboxyl terminated polyvinylpyrrolidone; monoamino, monocarboxyl, diamino or dicarboxyl terminated polyacrylamide; monoamino, monocarboxyl, diamino or dicarboxyl terminated poly (DMA); poly (DMA-co-NVP) terminated with monoamino or monocarboxyl, diamino or dicarboxyl; monoamino, monocarboxyl, diamino or dicarboxyl-terminated poly (NVP-co-N, N-dimethylaminoethyl (meth) acrylate)); poly (vinyl alcohol) terminated with monoamino, monocarboxyl, diamino or dicarboxyl; monopoly terminated poly [(meth) acryloyloxyethyl phosphorylcholine] monopoly, diamino or dicarboxyl homopolymer or copolymer; poly (NVP-co-vinyl alcohol) terminated with monoamino, monocarboxyl, diamino or dicarboxyl; poly (DMA-co-vinyl alcohol) terminated with monoamino, monocarboxyl, diamino or dicarboxyl; poly [(meth) acrylic acid-co-acrylamide] with about 0.1% to about 30%, preferably from about 0.5% to about 20%, more preferably from about 1% to about 15 % by weight of (meth) acrylic acid; poly [(meth) acrylic acid-co-NVP] with about 0.1% to about 30%, preferably from about 0.5% to about 20%, more preferably from about 1% to about 15 % by weight of (meth) acrylic acid; a copolymer which is a polymerization product of a composition comprising (1) (meth) acryloyloxyethyl phosphorylcholine and (2) from about 0.1% to about 30%, preferably from about 0.5% to about 20% , more preferably from about 1% to about 15%, by weight of a vinyl monomer containing carboxylic acid and / or an vinyl monomer containing amino, and a combination thereof.
[00102] PEGs with functional groups and multi-arm PEGs with functional groups can be obtained from several commercial suppliers, for example, Poliscience and Shearwater Polimers, inc., Etc.
[00103] Homo or finished monoamino, monocarboxyl, diamino or dicarboxyl copolymers of one or more non-reactive hydrophilic vinyl monomers or of a vinyl monomer containing phosphorylcholine can be prepared according to procedures described in United States Patent No. 6,218,508, incorporated herein by reference in its entirety. For example, to prepare a diamino or dicarboxyl-terminated homo or copolymer of a non-reactive hydrophilic vinyl monomer, the non-reactive vinyl monomer, a chain transfer agent with an amino or carboxyl group (for example, 2-aminoethanethiol, 2-acid -mercaptopropinic, thioglycolic acid, thiolactic acid, or other hydroxy mercaptans, aminomercaptanes, or mercaptans containing carboxyl) and optionally other vinyl monomers are copolymerized (thermally or actinically) with a reactive vinyl monomer (having an amino or carboxyl group), in the presence of an amino group free radical initiator. Generally, the molar ratio between a chain transfer agent and all those of the vinyl monomers other than the reactive vinyl monomer is about 1: 5 to about 1: 100, while the molar ratio between the transfer agent and the vinyl monomer reactive is 1: 1. In such a preparation, the chain transfer agent with an amino or carboxyl group is used to control the molecular weight of the resulting hydrophilic polymer and forms a terminal end of the resulting hydrophilic polymer so as to provide the resulting hydrophilic polymer with an amino or carboxyl group. , while the reactive vinyl monomer provides the other carboxyl or amino terminal group for the resulting hydrophilic polymer. Similarly, to prepare a finished monoamino or monocarboxyl homo or copolymer of a non-reactive hydrophilic vinyl monomer, the non-reactive vinyl monomer, a chain transfer agent with an amino or carboxyl group (for example, 2-aminoethanethiol, 2- mercaptopropinic, thioglycolic acid, thiolactic acid, or other hydroxy mercaptans, aminomercaptanes, or mercaptans containing carboxyl) and optionally other vinyl monomers are copolymerized (thermally or actinically) in the absence of any reactive vinyl monomer.
[00104] As used in this patent application, a copolymer of a non-reactive hydrophilic vinyl monomer refers to a polymerization product of a non-reactive hydrophilic vinyl monomer with one or more additional vinyl monomers. Copolymers comprising a non-reactive hydrophilic vinyl monomer and a reactive vinyl monomer (e.g., a carboxyl-containing vinyl monomer) can be prepared according to any well-known radical polymerization methods or obtained from commercial suppliers. Copolymers containing methacryloyloxyethyl phosphorylcholine and vinyl monomer containing carboxyl can be obtained from NOP Corporation (for example, LIPIDURE® -A and -AF).
[00105] The weight average molecular weight Mw of the hydrophilic polymer having at least one amino, carboxyl or thiol group (as a hydrophilicity enhancing agent) is preferably from about 500 to about 1,000,000, more preferably from about 1,000 to about 500,000.
[00106] Polyaminoamide-epichlorohydrin (PAE) (or polyamide-polyamine-epichlorohydrin or polyamide-epichlorohydrin) are commercially available, such as, for example, Kymene® or Policup® resins (functionalized epichlorohydrin adipic acid of diethylenetriamine copolymers) Hercules or Policup® or Servamina®de Servo / Delden. Alternatively, PAE can be obtained by governing the epichlorohydrin with a poly (amidoamine) which is a polycondensate derived from a polyamine and a dicarboxylic acid (for example, adipic acid-diethylene triamine copolymers). The reaction conditions for epichlorohydrin functionalization of a polyamidoamine polymer are taught in EP1465931 (incorporated herein by reference in its entirety).
[00107] According to the invention, the reaction between a hydrophilicity enhancing agent and a copolymer containing azetidinium of the invention (or polyamidoamine-epichlorohydrin) is carried out at a temperature of about 40 ° C to about 100 ° C for a sufficient time (from about 0.3 hour to about 24 hours, preferably from about 1 hour to about 12 hours, even more preferably from about 2 hours to about 8 hours) to form a hydrophilic polymeric material soluble in water and thermally crosslinkable containing reactive functional groups (azetidinium, carboxyl, amino, and / or thiol groups).
[00108] In a preferred embodiment, the thermally crosslinkable hydrophilic polymeric material is an azetidinium copolymer of the invention comprising: (1) up to about 50% (preferably from about 2.5% to about 40%, more preferably from about 5% to about 30%, even more preferably from about 7.5% to about 25%) by mol of the azetidinium-containing monomer units (derived from at least one vinyl monomer containing azetidinium of the formula (1) or ( 2) as defined above) and reactive monomer units; and (2) at least about 50%, preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 75 mol% of non-reactive hydrophilic monomer units derived from at least one hydrophilic vinyl monomer selected from the group consisting of (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-vinylpyrrolidone, (meth) N, N, -dimethylaminoethyl acrylate, N, N-dimethylaminopropyl (meth) acrylamide, methacrylate glycerol, 3-acryloylamino-1-propanol, N-hydroxyethyl acrylamide, N- [tris (hydroxymethyl) methyl] -acrylamide, N-methyl-3-methylene-2-pyrrolidone, 1-ethyl-3-methylene-2- pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 1-ethyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene-2-pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone, (meth) 2-hydroxyethyl acrylate, (meth) hydroxypropyl acrylate, (meth) C1-C4-alkoxy polyethylene glycol having a weight average molecular weight of up to 1500 Daltons, N-vinyl formamide, N-vinyl a cetamide, N-vinyl isopropylamide, N-vinyl-N-methyl acetamide, allyl alcohol, vinyl alcohol (hydrolyzed form of vinyl acetate in the copolymer), a vinyl monomer containing phosphorylcholine (including (meth) acryloyloxyethyl phosphorylcholine and those described in the Northern Patent -American No. 5,461,433, incorporated herein by reference in its entirety), a vinyl monomer containing sugar (for example, (meth) erythritol acrylate, (meth) arabitol acrylate, (meth) mannitol acrylate, (met) ducitol acrylate, (meth) fucitol acrylate, (meth) iditol acrylate, (meth) inositol acrylate, (meth) xylitol acrylate, (meth) sorbitol acrylate, (meth) glucose acrylate, (meth) acrylate fructose, (meth) galactose acrylate), and combinations thereof.
[00109] According to this aspect of the invention, the heating step is preferably carried out by autoclaving the hydrogel silicone contact lens immersed in a packaging solution (ie, a buffered aqueous solution) in a sealed lens package in a temperature from about 118 ° C to about 125 ° C for approximately 20 to 90 minutes. According to this embodiment of the invention, the packaging solution is an aqueous buffered solution that is ophthalmologically safe after autoclaving.
[00110] Lens packs (or containers) are well known to a person skilled in the art for autoclaving and storing a contact lens. Any lens packs can be used in the invention. Preferably, a lens pack is a blister pack comprising a base and a cover, where the cover is detachably sealed to the base, where the base includes a cavity for receiving a sterile packaging solution and the contact lens.
[00111] The lenses are packaged in individual packages, sealed and sterilized (for example, by autoclaving at about 120 ° C or more for at least 30 minutes under pressure) before distribution to users. A person skilled in the art will understand how to seal and sterilize lens packaging.
[00112] According to the invention, a packaging solution contains at least one buffering agent and one or more other ingredients known to the person skilled in the art. Examples of other ingredients include, without limitation, tonicity agents, surfactants, antibacterial agents, preservatives, and lubricants (for example, cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone).
[00113] The packaging solution contains a buffering agent in an amount sufficient to maintain a pH of the packaging solution in the desired range, for example, preferably in a physiologically acceptable range of about 6 to about 8.5. Any known, physiologically compatible buffering agents can be used. Buffering agents suitable as a constituent of the contact lens care composition according to the invention are known to the person skilled in the art. Examples are boric acid, borates, for example, sodium borate, citric acid, citrates, for example, potassium citrate, bicarbonates, for example, sodium bicarbonate, TRIS (2-amino-2-hydroxymethyl-1,3-propanediol ), Bis-Tris (Bis- (2-hydroxyethyl) -imino-tris- (hydroxymethyl) -methane), bis-aminopolyols, triethanolamine, ACES (N- (2-hydroxyethyl) -2-aminoethanesulfonic acid), BES (acid N, N-Bis (2-hydroxyethyl) -2-aminoethanesulfonic acid), HEPES (4- (2-hydroxyethyl) -1- piperazine ethanesulfonic acid), MES (2- (N-morpholino) ethanesulfonic acid), MOPS (3- [N-morpholino] - propanesulfonic), PIPES (piperazine-N, N'-bis (2-ethanesulfonic acid), TES (N- [Tris (hydroxymethyl) methyl] -2-aminoethanesulfonic acid), salts thereof, phosphate, for example Na2HPO4, NaH2PO4, and KH2PO4 or mixtures thereof A preferred bis-aminopoliol is 1,3-bis (tris [hydroxymethyl] methylamino) propane (bis-TRIS-propane) .The amount of each buffering agent in a packaging solution is preferably 0, 001% to 2%, preferably from 0.01% to 1%; more preferably from about 0.05% to about 0.30% by weight.
[00114] The packaging solution has a tonicity of about 200 to about 450 milliosmol (mOsm), preferably from about 250 to about 350 mOsm. The tonicity of a packaging solution can be adjusted by adding organic or inorganic substances that affect tonicity. Suitable ocularly acceptable tonicity agents include, but are not limited to, sodium chloride, potassium chloride, glycerol, propylene glycol, polyols, mannitols, sorbitol, xylitol and mixtures thereof.
[00115] A packaging solution of the invention has a viscosity of about 1 centipoise to about 8 centipoise, more preferably about 1.5 centipoise to about 5 centipoise, at 25 ° C.
[00116] In a preferred embodiment, the packaging solution preferably comprises from about 0.01% to about 2%, more preferably from about 0.05% to about 1.5%, even more preferably from about 0.1% to about 1%, more preferably from about 0.2% to about 0.5%, by weight of a thermally crosslinkable hydrophilic polymeric material of the invention.
[00117] In another preferred embodiment, a method of the invention may further comprise, prior to the heating step, the steps of: contacting the silicone hydrogel contact lens at room temperature with an aqueous solution of the thermally crosslinkable hydrophilic polymeric material to form a top layer (ie, an LbL coating) of the thermally crosslinkable hydrophilic polymeric material on the surface of the silicone hydrogel contact lens, immersing the silicone hydrogel contact lens with the top layer of the thermally crosslinkable hydrophilic polymeric material in a packaging solution in a lens packaging; sealing the lens packaging; and autoclaving the package with the silicone hydrogel contact lens there to form a crosslinked hydrophilic coating on the silicone hydrogel contact lens. As it is positively charged, it is believed that the thermally crosslinkable hydrophilic polymeric material is capable of forming, in the main coating of a silicone hydrogel contact lens, a non-covalently bonded layer through physical interactions.
[00118] A silicone hydrogel contact lens obtained according to a method of the invention has a surface hydrophilicity / humectability characterized by having an average contact angle with water preferably about 90 degrees or less, more preferably about 80 degrees or less, even more preferably about 70 degrees or less, more preferably about 60 degrees or less.
[00119] All of the various embodiments including the preferred embodiments of a vinyl monomer containing azetidinium are described above and can be used in that aspect of the invention.
[00120] It should be understood that, while various embodiments including the preferred embodiments of the invention can be separately described above, they can be combined and / or used together in any desirable manner in that aspect of the invention.
[00121] The invention, in another additional aspect, provides a method for producing silicone hydrogel contact lenses, each having a hydrophilic coating reticulated therein, the method of the invention comprising the steps of: (a) obtaining a contact lens from hydrogel silicone of a lens-forming composition comprising an azetidinium-containing copolymer (as described above) and / or an azetidinium-containing vinyl monomer of formula (1) or (2) as defined above; (b) heating the silicone hydrogel contact lens in an aqueous solution in the presence of a water soluble hydrophilic polymeric material, thermally crosslinkable comprising reactive groups selected from the group consisting of azetidinium groups, carboxyl groups, amino groups, thiol groups and combinations of themselves, at and at a temperature of about 40 ° C to about 140 ° C for a period of time sufficient to induce intermolecular and intramolecular cross-linking reactions between an azetidinium group and an amino or carboxyl group, thus forming a durable coating of non-silicone hydrogel on the silicone hydrogel contact lens, where the non-silicone hydrogel coating is anchored on the silicone hydrogel contact lens through the azetidinium groups of the azetidinium-containing copolymer on and / or near the surface of the silicone hydrogel contact lens .
[00122] It is believed that a portion of the copolymer containing azetidinium and / or monomeric units containing azetidinium can be located on and / or near the surface of the silicone hydrogel contact lens obtained from the lens forming composition comprising the copolymer containing azetidinium. Those azetidinium groups on and / or close to the lens surface can serve as anchorage points for attaching the non-silicone hydrogel coating.
[00123] In a preferred embodiment, the copolymer containing azetidinium is compatible with polyesterizable components in the lens-forming composition and comprises monomeric units containing azetidinium derived from a vinyl monomer containing azetidinium of the formula (1) or (2) as defined above and units hydrophobic monomers derived from a hydrophobic vinyl monomer. More preferably, the azetidinium-containing copolymer is substantially free (preferably free of) any unsaturated ethylene group.
[00124] The term "compatible with polymerizable components in the lens forming composition" in reference to a copolymer containing azetidinium means that the lens forming composition comprising the copolymer containing azetidinium and the polymerizable components has an optical transmissibility (between 400 nm at 700 nm) of at least about 85%, more preferably at least about 90%, even more preferably at least about 95%, more preferably at least about 98%.
[00125] In a preferred embodiment, the method further comprises a step of applying a main coating of a fixing polymer on the silicone hydrogel contact lens. All embodiments (including preferred embodiments) of the attachment polymers described above can be used in that preferred embodiment of the method of the invention in this regard.
[00126] Preferably, the heating step is performed by autoclaving the silicone hydrogel contact lens immersed in a packaging solution (ie, a buffered aqueous solution) in a sealed lens package at a temperature of about 118 ° C at about 125 ° C for approximately 20 to 90 minutes.
[00127] Preferably, the packaging solution comprises from about 0.01% to about 2%, preferably from about 0.05% to about 1.5%, more preferably from about 0.1% to about from 1%, even more preferably from about 0.2% to about 0.5%, by weight of the thermally crosslinkable hydrophilic polymeric material.
[00128] All the various modalities including preferred modalities of a silicone hydrogel contact lens, a SiHy lens formulation, a vinyl monomer containing azetidinium, a fixing polymer and its uses to form a main coating, a soluble hydrophilic polymeric material in water, thermally crosslinkable, the stage of heating the silicone hydrogel contact lens in an aqueous solution in the presence of a water soluble hydrophilic polymeric material, thermally crosslinkable, a lens packaging solution and components thereof, lens packaging, are described above and can be combined and / or used together in this aspect of the invention.
[00129] Still in an additional aspect, the invention provides a silicone hydrogel contact lens comprising a lens body made of a silicone hydrogel material and a non-silicone hydrogel coating thereon, in which the non-silicone hydrogel coating is obtained by thermal induction of intermolecular and intramolecular crosslinking of a thermally crosslinkable hydrophilic polymeric material comprising monomer units containing azetidinium derived from at least one vinyl monomer containing azetidinium (preferably a monomer of formula (1) or (2) described above) and reactive monomer units derived from a vinyl monomer having an amino or carboxyl group, in which the hydrogel silicone contact lens has an oxygen permeability of at least about 40 barrers, a surface humectability characterized by a water contact angle of about 100 degrees or less, and a good coating durability characterized by the survival of and a digital friction test.
[00130] According to the invention, a lens body refers to a preformed silicone hydrogel contact lens to be coated and is obtained from a silicone hydrogel lens formulation (composition) as described above.
[00131] In a preferred embodiment, the silicone hydrogel contact lens has at least one property selected from the group consisting of: an oxygen permeability of at least about 375 x 10-10 [(cm3 of oxygen) (mm) / (cm2) (s) (kPa)] (50 barriers), preferably at least about 450 x 10-10 [(cm3 of oxygen) (mm) / (cm2) (s) (kPa)] (60 barriers), more preferably at least about 525 x 10-10 [(cm3 of oxygen) (mm) / (cm2) (s) (kPa)] (70 barriers); an elastic modulus of about 1.5 MPa or less, preferably about 1.2 MPa or less, more preferably about 1.0 or less, even more preferably from about 0.3 MPa to about 1.0 MPa ; a water content preferably from about 18% to about 70%, more preferably from about 20% to about 60% by weight when fully hydrated; and combination thereof.
[00132] Various embodiments including preferred embodiments of a silicone hydrogel contact lens to be coated, vinyl monomer containing azetidinium, and a thermally crosslinkable hydrophilic polymeric material are described above and can be combined and / or used together in this aspect of the invention.
[00133] The water content of a silicone hydrogel contact lens can be measured according to the Mass Technique as disclosed in US 5,849,811.
[00134] In yet another additional aspect, the invention provides an ophthalmic product comprising a sterile and sealed lens package, wherein the lens package comprises: a post-autoclave lens packaging solution and a silicone hydrogel contact lens readily usable immersed therein, where the readily usable silicone hydrogel contact lens comprises a crosslinked hydrophilic coating obtained by autoclaving an original hydrogel silicone contact lens having amino groups and / or carboxyl groups on and / or close to the lens surface of original hydrogel silicone contact in a pre-autoclave packaging solution containing a water soluble and thermally crosslinkable hydrophilic polymeric material comprising from 0.001% to about 25 mol% of monomer units containing azetidinium derived from at least one vinyl monomer containing azetidinium, in which the hydrophilic polymeric material is covalently attached to the contact lens of silicone hydrogel through second covalent bonds, each formed between an amino or carboxyl group on and / or near the surface of the silicone hydrogel contact lens and an azetidinium group of the hydrophilic polymeric material, in which the post-autoclave packaging solution comprises at least at least one buffering agent in an amount sufficient to maintain a pH of about 6.0 to about 8.5 and a hydrolyzed product of the hydrophilic polymeric material and has a tonicity of about 200 to about 450 milliosmol (mOsm) and a viscosity of about 1 centipoise to about 10 centipoises.
[00135] All the various modalities including preferred modalities of a silicone hydrogel contact lens, a SiHy lens formulation, a vinyl monomer containing azetidinium, a fixation polymer and its uses to form a main coating, a soluble hydrophilic polymeric material in water, thermally crosslinkable, the stage of heating the silicone hydrogel contact lens in an aqueous solution in the presence of a water soluble hydrophilic polymeric material, thermally crosslinkable, a lens packaging solution and components thereof, lens packaging, are described above and can be combined and / or used together in this aspect of the invention.
[00136] The previous disclosure will allow a technician in the subject to practice the invention. Various modifications, variations and combinations can be made for the various modalities described here. In order to better allow the reader to understand the specific modalities and their benefits, reference is made to the following examples. It is intended that the specification and examples are considered as exemplary.
[00137] Although various embodiments of the invention have been described using specific terms, devices and methods, such description is for illustrative purposes only. The words used are description words other than limitation. It should be understood that changes and variations can be made by those skilled in the art without departing from the spirit and scope of the present invention, which is set out in the following claims. In addition, it should be understood that aspects of the various modalities can be exchanged in whole or in part or can be combined in any and / or used together. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained herein. Example 1 Oxygen Permeability Measurements
[00138] The apparent oxygen permeability (Dkapp), the apparent transmissibility of oxygen (Dk / t), the intrinsic (or tip-corrected) oxygen permeability (Dkc) of a lens and a material lens are determined according to procedures described in Example 1 of U.S. Patent Application Publication No. 2012/0026457 A1 (incorporated herein by reference in its entirety). Lubricity Assessment
[00139] The lubricity rating is a qualitative rating scheme where 0 is designated to control lenses coated with polyacrylic acid (PAA), 1 is designated for commercial Oasys® / TruEye® lenses and 5 is designated for commercial Air Optix® lenses . The samples are rinsed with excess DI water for at least three times and then transferred to PBS before evaluation. Before the assessment, hands are rinsed with a soap solution, rinsed thoroughly with DI water and then dried with KimWipe® towels. The samples are handled between the fingers and a numerical number is assigned to each sample in relation to the standard lenses described above. For example, if the lenses are determined to be only slightly better than Air Optix® lenses, then they are assigned a number 4. To maintain consistency, all ratings are independently collected by the same two operators to avoid errors and the data so far reveal very good qualitative agreement and consistency in the assessment.
[00140] Surface hydrophilicity / wetting tests. The contact angle of water in a contact lens is a general measure of the hydrophilicity of the surface (or wettability) of the contact lens. In particular, a low water contact angle corresponds to the most hydrophilic surface. Contact lens mean contact angles (Sessile Drop) are measured using a VCA 2500 XE contact angle measuring device from AST, Inc., located in Boston, Massachusetts. This equipment is capable of measuring forward or reverse contact angles or sessile (static) contact angles. The measurements are carried out in fully hydrated contact lenses and immediately after drying blot as follows. A contact lens is removed from the bottle and washed three times in ~ 200 ml of fresh DI water in order to remove lightly clustered packaging additives from the lens surface. The lens is then placed on top of a clean lint-free cloth (Alpha Wipe TX1009), very clean to remove water from the surface, mounted on the contact angle measurement stand, dried with a blow of dry air and finally the contact angle of sessile drop is automatically measured using the software provided by the manufacturer. The DI water used to measure the contact angle has a resistance> 18MQcm and the droplet volume used is 2μl. Typically, uncoated silicone hydrogel lenses (after autoclaving) have a sessile drop contact angle of around 120 degrees. The tweezers and the pedestal are well washed with isopropanol and rinsed with DI water before coming into contact with the contact lenses.
[00141] Water Break Time Tests (WBUT). The wettability of the lenses (after autoclaving) is also assessed by determining the time required for the water film to break on the lens surface. Briefly, the lenses are removed from the bottle and washed 3 times in ~ 200 ml and fresh DI water in order to remove lightly clustered packaging additives from the lens surface. The lens is removed from the solution and held against a bright light source. The time it takes for the water film to break (to get wet) exposing the underlying lens material is visually noted. Uncoated lenses typically break instantly by removing DI water and are assigned a 0 second WBUT. Lenses that exhibit WBUT> 5 seconds are considered humectable and are expected to exhibit adequate humectability (ability to support tear film) in the eye.
[00142] Integrality Tests of the Coating. The completeness of a coating on the surface of a contact lens can be tested according to the Sudan Black staining test as follows. Contact lenses with a coating (an LbL coating, a plasma coating, or any other coatings) are dipped in a Sudan Black dye solution (Sudan Black in vitamin E oil). Sudan Black dye is hydrophobic and has a great tendency to be adsorbed by a hydrophobic material or on a hydrophobic lens surface or hydrophobic spots on a partially coated surface of a hydrophobic lens (for example, silicone hydrogel contact lens). If the coating on a hydrophobic lens is intact, no colored spots should be observed on the lens. All lenses under test are fully hydrated.
[00143] Coating durability tests. The lenses are digitally rubbed (using disposable, powder-free latex gloves) with Solo-care® multipurpose lens care solution for 30 times and then rinsed with saline. The above procedure is repeated a few times, for example, 1 to 30 times, (ie, number of digital friction tests that mimic cleaning and immersion cycles). The lenses are then subjected to the Sudan Black test (that is, the coating completeness test described above) to examine whether the coating is still intact. To survive the digital friction test, there are no significantly increased staining points (for example, staining points covering no more than about 5% of the total lens surface). The contact angles of the water are measured to determine the durability of the coating.
[00144] Lens Tests with Contact Lens Analyzer at low pH (CLAN low pH). Tests with CLAN at low pH for covering the coating on the lens surfaces using hydrophobic dye (Nile red, also known as Nile Blue Oxazone). Any hydrophobic areas exposed on the lens will attach to the hydrophobic dye. If a homogeneous coating on the lens is intact, no colored spots should be observed on the lens. The test is done by immersing a contact lens in the HCl (aq) at 1N for about 30 seconds, followed by a 2 second dip in a red Nile solution (1-propanol / n-Heptane), and finally a dip 30 seconds in DI water to rinse off the excess dye. The lens is then placed in the CLAN (digital camera in a fixed focus through a magnifying optics and filter) where the lens is then illuminated with the fluorescence-emitting light. The image is captured and analyzed by the image processing software for the fluorescence hydrophobic dye adsorbed by the hydrophobic surfaces. The lens is considered a failure if the sum of half the number of light pixels and half the number of dark pixels is greater than 5000.
[00145] Granule Test. The granule test is used to determine the negative charge on the surface of the contact lens. A granule test value of 50 or less is acceptable for the load on the lens surface. The higher values also reflect if the packaged coating is unable to cover a lens coated with PAA / PMAA which usually has granule numbers> 200. In this method, 0.2 g of Dovex 1x4 50 to 100 mesh chloride form (CAS 69011-19-4) is measured in a centrifuge cup followed by the addition of 4 ml of PBS (phosphate buffered saline). A lens is placed on the back of the tube and the tube is shaken for 1 min at 300 rpm. After that, the tube is rinsed and replaced with 5 ml of PBS followed by stirring for 1 min at 300 rpm to get rid of any surface granules. The lens is then analyzed under a microscope and the granules are counted.
[00146] TBO test. A dibasic sodium phosphate stock solution (0.2% w / w, pH 2) is prepared. A sodium bicarbonate stock solution (0.2% w / w, pH 10) is prepared. A stock solution of Toluidine Blue O (abbreviated TBO, 2000 ppm) is prepared in water. Set two digital block heaters to 35 and 50oC. Freshly diluted 0.1% (w / w) solutions of both pH 2 and pH 10 buffers are prepared. TBO solution is prepared at c50 ppm of the TBO stock solution (2000 ppm). Rinse each lens to be tested in 100 mL of DI water for about 5 minutes. Dry each lens to remove excess water using synthetic Alpha wipe cleaners. The lenses are placed on a 24-well TCPS plate (one lens per well). Pour 1.5 ml of the dye solution at 50 ppm in each well and place the plate in the heating block at 50 ° C for 30 minutes. After the staining step above is complete, the lenses are removed and placed in new wells on a 24-well TCPS plate. Pour into a fresh 1.5 ml of 0.1% pH 10 buffer solution and then leave the lenses at room temperature for 5 min. After the rinsing step above is complete, remove the lenses and place them in new wells on a 24-well TCPS plate. Pour into fresh 1.5 ml of 0.1% pH 10 buffer solution. Leave the plate in the block heater set at 35 ° C for 30 min. Remove the lenses from the wells and gently dry the excess dye using Alpha wipe synthetic cleaners. The lenses are placed in the wells of a new 24-well TCPS plate and poured into 1.5 ml of solution with 0.1% pH 2. Leave the plate in the block heater set at 50 ° C for 30 min. The bound dye is released from the lens during this step. The lens is removed from the well. The solutions will be used for UV-VIS analysis and quantification. The calibration standards are prepared from 0 to 100 ppm TBO in pH 2 0.1% solution. Measure the spectrum of standard TBO solutions, unknown solutions for coated lenses, and solutions for an uncoated lens at wavelengths 625, 630, and 635. Subtracting the absorbance values of uncoated lens solutions from solutions coated lens, then the calibration cure is used to determine the amount of TBO.
[00147] PHMB method. 1 liter of phosphate buffered saline (PBS) is prepared by dissolving 7.85 g of NaCl, 0.773 g of monobasic sodium phosphate, and 4.759 g of dibasic sodium phosphate in purified water. The pH is adjusted to 7.1 to 7.3 as needed. ATS solution is prepared by combining 4,500 grams of NaCl, 0.074 g of calcium chloride dihydrate, 0.550 g of citric acid monohydrate, 1,400 g of sodium citrate, and 493.475 g of purified water. Adjust the pH to 7.0. PHMB solution at 10 ppm in PBS is prepared. Each lens is placed in 3 ml of PHMB solution at 10 ppm overnight (> 16 hours). The lenses are removed, then dried to remove excess PBS solution. 2 dry lenses are placed in 2 mL of ATS solution. Shake using an orbital shaker at 250 rpm for 2 hours. After 2 hours, the lenses are carefully removed from the solution to minimize loss of solution. Standard PHMB solutions in PBS (0.5, 1, 2, 4, 8, and 10 ppm) are prepared. Using a 1 cm quartz cell, absorbance at 240 nm is measured for the standard, absorption and release samples to determine the PHMB concentration. Example 2 Synthesis of diethyl azetidinium methacrylate ester chloride salt (AZM)
[00148] 2a. Synthesis of diethyl hydroxyl azetidinium chloride. Diethyl amine (50 g, 0.686 mol) is dissolved in 25 ml of dry acetonitrile under argon. The solution is cooled in an ice bath at 0oC. To this solution, epichlorohydrin (63.248 g, 0.684 mol) in 20 mL of dry acetonitrile is added. After the mixture is stirred at 0oC for about 5 hours, the reaction is then carried out at room temperature for another 27 hours. The solid product is collected by filtration and washed with cold acetonitrile a few times. Typical production is in the range of 30 to 50%.

[00149] 2b: Synthesis of diethyl azetidinium methacrylate ester (AZM) salt. In a Schlenk flask equipped with a nitrogen flow, the obtained hydroxy azetidinium chloride salt (60 g, 0.362 mole) is dissolved in 336 ml of dry acetonitrile. To this solution, methacrylic acid anhydride (45.73 g, 0.297 mol) and di-tert-butyl-4-methylphenol (7 mg) are added over about 5 minutes at room temperature. The reaction mixture is then stirred at room temperature for about 18 hours. The acetonitrile is evaporated and the residue is suspended in 1 L of acetonitrile / diethyl ether (1: 1) solvent mixture. The solid product is collected by filtration and dried. Typical production is around 55%.
Example 3 Synthesis of Coating Polymers in the Package (IPC)
[00150] 3a. Preparation of copolymer containing AZM / APMA / PEG / DMA for IPC. In a 500 mL glass reaction jar, 5.0 grams of a solution of methoxy polyethylene glycol 2000 methacrylate (PEG2000-MA) (50% in water), 1.0 gram of aminopropylmethacrylamide (APMA), 1.0 gram of AZM prepared in Example 2, 5.47 grams of N, N'-dimethylacrylamide (DMA), and 3.00 ml of Irgacure 2959 solution (1% in water) are dissolved in 184.53 grams of citrate buffer 33.75 mM (pH 4). A lid is placed on the reaction jar that contains at least 4 ground joints. One used for a glass stirring shaft, one for a thermocouple, one for a nitrogen inlet, and one for sampling access. The solution is sparged with nitrogen for 20 minutes at about 200 mL / min. The nitrogen flow rate is reduced to about 150 mL / min. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with RPR-3500 UV lamps. Four UV lamps are switched on for about 1 hour at an intensity of about 2.0 mW / cm2. After about an hour, the solution is vacuum filtered through a qualitative paper filter. The copolymer solution is then purified using 50kDa of dialysis membranes against water for 24 hours using a water flow rate of about 40 mL / min. The solids content is determined and diluted to 2% if necessary.
[00151] 3b. Preparation of copolymer containing AZM / APMA / Acrylamide for IPC. In a 500 mL glass reaction jar, 1.5 grams of aminopropylmethacrylamide (APMA), 1.5 grams of AZM prepared in Example 2, 6.97 grams of acrylamide, and 3.00 mL of Irgacure 2959 solution ( 1% in water) are dissolved in 187.03 grams of 33.75 mM citrate buffer (pH 4). A lid is placed on the reaction jar that contains at least 4 ground joints, one used for a glass stirring shaft, one for a thermocouple, one for a nitrogen inlet, and one for sampling access. The solution is sparged with nitrogen for 20 minutes at about 200 mL / min. The nitrogen flow rate is reduced to about 150 mL / min. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Four UV lamps are switched on for 1 hour at an intensity of about 2.0 mW / cm2. After 1 hour, the solution is vacuum filtered through a qualitative paper filter. The copolymer solution is then purified using 50kDa of dialysis membranes against water for 24 hours using a flow rate of about 40 mL / min. The solids content is determined and diluted to 2% if necessary.
[00152] 3c. Preparation of copolymer containing AZM / APMA / PEG / AGA for IPC. In a 500 mL glass reaction jar, 5.0 grams of a 50% solution of PEG2000-MA in water, 1.0 grams of aminopropylmethacrylamide (APMA), 1.0 grams of AZM prepared in Example 2, 5.47 grams of acryloyl glucosamine (AGA), and 3.00 mL of a 1% solution of Irgacure 2959 in water are dissolved in 184.53 grams of 33.75 mM citrate buffer (pH 4). A lid is placed on the reaction jar that contains at least 4 ground joints, one used for a glass stirring shaft, one for a thermocouple, one for a nitrogen inlet, and one for sampling access. The solution is sparged with nitrogen for 20 minutes at about 200 mL / min. The nitrogen flow rate is reduced to about 150 mL / min. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Four UV lamps are switched on for 1 hour at an intensity of about 2.0 mW / cm2. After about an hour, the solution is vacuum filtered through the qualitative paper filter. The copolymer solution is then purified using 50kDa of dialysis membranes against water for 24 hours. The solids content is determined and diluted to 2% if necessary.
[00153] 3d. Preparation of copolymers containing AZM / APMA / AA / Acrylamide for IPC. In a 500 mL glass reaction jar, 1.5 grams of aminopropylmethacrylamide (APMA), 1.5 grams of AZM prepared in Example 2, 0.2 grams of acid acrylic, 6.77 grams of acrylamide, and 3, 00 mL of a 1% solution of Irgacure 2959 in water is dissolved in 187.03 grams of 33.75 mM citrate buffer (pH 4). A lid is placed on the reaction jar that contains at least 4 ground joints, one used for a glass stirring shaft, one for a thermocouple, one for a nitrogen inlet, and one for sampling access. The solution is sparged with nitrogen for 20 minutes at about 200 mL / min. The nitrogen flow rate is reduced to about 150 mL / min. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Four UV lamps are switched on for about an hour at an intensity of about 2.0 mW / cm2. After about an hour, the solution is vacuum filtered through the qualitative paper filter. The copolymer solution is then purified using 50kDa of dialysis membranes against water for 24 hours using a flow rate of about 40 mL / min. The solids content is determined and diluted to 2% if necessary. Example 4 Synthesis of amphiphilic copolymers (ACP)
[00154] 4a. Preparation of copolymers containing AZM / AA / PDMS / DMA. In a 1 L glass reaction jar, 6.0 grams of finished monomethacryloxypropyl polydimethylsiloxane (Gelest catalog # MCR-M11) (PDMS 1000-MA) are added. A lid is placed on the reaction jar that contains 4 ground-up joints, one used for a glass stirring shaft, one for a thermocouple, one for vacuum and nitrogen inlet, one for a pressure equalizing addition funnel of 200 mL, and one for sampling access. A 0.2 kPa (2 mbar) vacuum is drawn to degas the PDMS1000-MA for 10 minutes. After about 10 minutes, the reaction jar is filled with nitrogen. This degassing and nitrogen filling procedure is repeated 6 times. In the 200 mL pressure equalization funnel, 3.0 grams of AZM prepared in Example 2, 6.0 grams of acrylic acid (AA), 14.91 grams of DMA, and 3.00 mL of a solution of Irgacure 2959 at 1% in t-amyl alcohol are dissolved in 100.3 grams of t-amyl alcohol and 33.3 grams of methanol. A vacuum of 10 kPa (100 mbar) is drawn into the solution in the addition funnel for about 10 minutes. After about 10 minutes, the funnel is filled with nitrogen. This degassing and nitrogen filling procedure is repeated 3 times. After PDMS1000-MA and solution have been degassed, add the solution to the jar with PDMS1000-MA. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Two UV lamps are switched on for about an hour at an intensity of about 2.0 mW / cm2. The copolymer solution is then purified using 25kDa of dialysis membranes against 1-PrOH for about 35 hours including two changes of 1-PrOH (1-propanol) during that time. The solids content is determined and diluted to 10% if necessary.
[00155] 4b. Preparation of copolymer containing AZM / AA / Bulky TRIS / DMA. The procedure is the same as 4a except 6.0 grams of bulky TRIS (Gelest catalog # MCT-M11) are used instead of PDMS1000-MA.
[00156] 4c. Preparation of copolymer containing AZM / AA / POSS-MA / DMA. In a 1 L glass reaction jar, 6.0 grams of POSS® methacrylIsobutil (Hybrid Plastics catalog # MA0702, CAS # 307531-94-8) (hereinafter "POSS-MA), 3.0 grams of AZM prepared in Example 2, 6.0 grams of acrylic acid (AA), 14.91 grams of DMA, 3.00 mL of a 1% solution of Irgacure 2959 in t-amyl alcohol, 100.3 grams of t-amyl alcohol, and 33.5 g of methanol are added. The solution is sparged with nitrogen for 20 minutes at about 200 ml / min. The nitrogen flow rate is reduced to about 150 ml / min. The stirring speed is adjusted to 150 rpm The reaction jar is placed in a UV Rayonet reactor with RPR-3500 UV lamps. Two UV lamps are switched on for 45 minutes. The copolymer solution is then purified using 25kD dialysis membranes against 1-PrOH for about 35 minutes. The solids content is determined and diluted to 10% if necessary.
[00157] 4d. Preparation of AZM / AA / TRIS / DMA or copolymer containing. The procedure is the same as 4c except 6.0 grams of TRIS are used instead of or 6.0 grams of POSS-MA.
[00158] 4e. Preparation of copolymers containing AZM / AA / PDMS / DMA. In a 1 L glass reaction jar, 3.0 grams of finished monomethacryloxypropyl polydimethylsiloxane (Gelest catalog # MCR-M11) (PDMS 1000-MA) are added. A lid is placed on the reaction jar that contains 4 ground-up joints, one used for a glass stirring shaft, one for a thermocouple, one for vacuum and nitrogen inlet, one for a pressure equalizing addition funnel of 200 mL, and one for sampling access. A vacuum of 0.2 kPa (2 mbar) is drawn to degas the PDMS1000-MA for 10 minutes. After about 10 minutes, the reaction jar is filled with nitrogen. This degassing and nitrogen filling procedure is repeated 6 times. In the 200 mL pressure equalization funnel, 3.0 grams of AZM prepared in Example 2, 12.0 grams of acrylic acid (AA), 11.91 grams of DMA, and 3.00 mL of a solution of Irgacure 2959 at 1% in t-amyl alcohol are dissolved in 67 grams of t-amyl alcohol and 67 grams of methanol. A vacuum of 17.5 kPa (175 mbar) is drawn into the solution in the addition funnel for about 10 minutes. After about 10 minutes, the funnel is filled with nitrogen. This degassing and nitrogen filling procedure is repeated 3 times. After PDMS1000-MA and solution have been degassed, add the solution to the jar with PDMS1000-MA. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Two UV lamps are switched on for about an hour at an intensity of about 2.0 mW / cm2. The copolymer solution is then purified using 25kDa of dialysis membranes against 1-PrOH for about 35 hours including two changes of 1-PrOH (1-propanol) during that time. The solids content is determined and diluted by 10% if necessary. Example 5
[00159] Preparation of phosphate concentrate / citrate buffer. The buffer concentrate is prepared by dissolving 0.484 wt% sodium citrate dihydrate, 0.708 wt% dibasic sodium phosphate, 0.088 wt% monobasic sodium phosphate, monohydrate, and 1.486 wt% chloride sodium in DI water. The pH is adjusted to about 7.2, if necessary.
[00160] Preparation of IPC saline solutions with copolymers containing AZM. Coating solutions in the packaging (IPC-5A to IPC-5D) are prepared from copolymer solutions containing 2% AZM (3a to 3d of Example 3) and the buffer concentrate prepared above and have the compositions shown in the table below. The pH from IPC-5A to IPC-5D is adjusted, if necessary, to pH 7.2 to 7.4.

[00161] Preparation of IPC-5E. Partial sodium salt Poly (AAm-co-AA) (90/10) (~ 90% solid content, poly (AAm-co-AA) 90/10, Mw 200,000) is purchased from Polisciences, Inc. and used as required Received. Polyamidonamine epichlorohydrin (PAE) (Kymene, an azetidinium content of 0.46 tested with NMR) is purchased from Ashland as an aqueous solution and used as received. IPC-5E is prepared by dissolving about 0.07% w / w of poly (AAm-co-AA) (90/10) and about 0.15% PAE (millimolar equivalents of an initial azetidinium of about 8.8 millimol) in phosphate buffered saline (PBS) (about 0.044% w / w NaH2PO ^ H2O, about 0.388% w / w Na2HPO4 ^ 2H2O, about 0.79% w / w p of NaCl) and adjusting the pH to 7.2 ~ 7.4. Then, the IPC-5E is pretreated with heat for about 6 hours at about 60oC (pretreated with heat). During this heat pretreatment, poly (AAm-co-AA) and PAE are partially cross-linked (that is, they do not consume all PAE azetidinium groups) to form a hydrophilic, water-soluble and thermally crosslinkable polymeric material containing groups azetidinium within the IPC-5E branched polymer network. After pre-treatment with heat, the IPC-5E is cooled to room temperature then filtered using a 0.22 micron PES membrane filter. Example 6
[00162] Silicone hydrogel contact lenses with a PAA coating on them are prepared according to the procedures (lens formulation, molds, molten molding conditions, lens extraction, PAA coating solution, PAA coating procedures , etc.) described in Example 19 of U.S. Patent Application Publication No. 2012/0026458 A1 (incorporated herein by reference in its entirety).
[00163] PAA coating solution. A polyacrylic acid (PAA) coating solution is prepared by dissolving an amount of PAA (MW: 450kDa, from Lubrizol) in a given volume of 1-propanol (1-PrOH) to have a concentration of about 0.44% by weight and the pH is adjusted with formic acid to about 2.0.
[00164] Contact lenses with a PAA coating on them are packed in polypropylene lens packaging shells (one lens per shell) each containing 0.55 mL of one of the following packaging solutions: phosphate buffered saline (PBS) and IPC-5A to IPC-5D (prepared in Example 5). The blisters are then sealed with foil and sterilized for about 30 minutes at 121oC. Crosslinked coatings are formed during autoclaving on those lenses immersed in a saline packaging solution containing a copolymer containing azetidinium or polymeric material. The resulting lenses after autoclave are characterized and the results are reported in the table below.
Example 7
[00165] Preparation of the Lenses. Silicone hydrogel contact lenses are prepared by molten molding according to the procedures (the lens formulation, molds, molten molding conditions, etc.) described in Example 19 of the publication of U.S. Patent Application No. 2012 / 0026458 A1 (incorporated herein by reference in its entirety).
[00166] PMAA coating solutions. A polymethacrylic acid (PMAA) solution is prepared by dissolving PMAA (Mn ~ 418K) and formic acid in a given volume of a water / 1-propanol mixture, and then diluted with water and 1-propanol to form coating solutions. PMAA having the following compositions:
[00167] 40xPMAA: PMAA (0.011% w / w); 1-propanol (86.19% w / w); water (9.63% w / w); and formic acid (3.74% w / w).
[00168] FS PMAA: PMAA (0.44% w / w); 1-propanol (86.63% w / w); water (9.63% w / w); and formic acid (3.74% w / w).
[00169] PMAA coated lenses. The cast-molded contact lenses obtained as above are extracted and coated when immersed in the following series of baths: DI water bath for about 56 seconds; 3 baths of methyl ethyl ketone (MEK) for about 22, 78, 226 seconds respectively; a DI water bath for about 56 seconds; a bath of PMAA coating solution (prepared above) for about 100 seconds; a bath of a 50% water / 1-propanol / 50% mixture for about 56 seconds; a water bath for about 56 seconds; a phosphate buffered saline bath for about 56 seconds; and a DI water bath for about 56 seconds.
[00170] Application of reticulated coating. Contact lenses with a PMAA coating on them are packaged in polypropylene lens packaging shells / blisters (one lens per shell) each containing 0.55 mL of one of the following packaging saline solutions: PBS (as control), IPC-5A (prepared in Example 5), and IPC-5B (prepared in Example 5). The blisters are then sealed with foil and sterilized for about 30 minutes at about 121oC. Cross-linked coatings are formed during autoclaving on those lenses immersed in a saline packaging solution containing a copolymer containing azetidinium or polymeric material.
[00171] Characterization of SiHy lenses. The resulting lenses after autoclave are characterized and the results are reported in the table below.
Example 8
[00172] This example illustrates the preparation of an amphiphilic copolymer (ACP) using AZM (as prepared in Example 2) and acrylic acid to provide a crosslinkable primary coating designed to react with the IPC copolymer.
[00173] The structure of such a copolymer is shown below.

[00174] AZM is the electrophile and acrylic acid is the nucleophile in the copolymer. Both can react with a crosslinkable copolymer added to a saline solution to apply a crosslinked coating to the packaging on a silicone hydrogel contact lens. The copolymer also incorporates the polydimethylsiloxane (PDMS) segment to provide a hydrophobic interaction to attach the copolymer to the surface of a hydrophobic lens (for example, a silicone hydrogel contact lens). DMA is used to provide hydrophilicity and high molecular weight copolymers. The copolymer has much less acrylic acid content (concentration) compared to polyacrylic acid (PAA) or polymethacrylic acid homopolymers (PMAA).
[00175] The preferred range of percentages by weight of monomers used in a reaction mixture to prepare a copolymer of the invention is listed in Table 1 below. The copolymer is prepared according to the procedure similar to that described in Example 4 to prepare Copolymer 4a.

[00176] Preparation of the Lenses. Silicone hydrogel contact lenses are prepared by melted mold according to the procedures (the lens formulation, molds, molten molding conditions, etc.) described in Example 19 of the publication of U.S. Patent Application No. 2012 / 0026458 A1 (incorporated herein by reference in its entirety).
[00177] Preparation of ACP coating solutions. Amphiphilic copolymer solutions (hereinafter ACP I to IV coating solutions) are each prepared by dissolving one of the ACP copolymers 4a to 4e (about 10% of the solution) prepared in Example 4 in a mixture of 1-propanol (85% ) and water (15%). The concentration of ACP is about 1% by weight.
[00178] ACP coated lenses. Cast-molded contact lenses as above are extracted and coated with ACP when immersed in the following series of baths: a DI water bath for about 56 seconds; 3 MEK baths for about 22, 78, and 224 seconds, respectively; a DI water bath for about 56 seconds; a bath of ACP coating solution (about 1% by weight) in a mixture of 1-propanol / water (85% / 15%) for about 180 seconds; a bath of a water / 1-propanol mixture (58% / 42%) for about 180 seconds; a bath of a water / 1-propanol mixture (72% / 28%) for about 180 seconds; and a DI water bath for about 180 seconds. ACP-I coated lenses are obtained using ACP I coating solution (containing ACP 4a copolymer); ACP-II coated lenses are obtained using ACP II coating solution (containing ACP 4b copolymer); ACP-III coated lenses are obtained using ACP II coating solution (containing ACP 4c copolymer); ACP-IV coated lenses are obtained using ACP IV coating solution (containing ACP 4d copolymer). Control lenses A are obtained according to the above procedures, except that bath 6 is ACP-free and contains only the solvent mixture.
[00179] Application of reticulated coating. The ACP coated contact lenses prepared above are packaged in polypropylene lens packaging shells (one lens per shell) each containing 0.55 mL of one of the following packaging saline solutions: PBS (as control) and IPC- 5E (prepared in Example 5). Control lenses A are packed in polypropylene lens packaging shells / blisters (one lens per shell) each containing 0.55 mL of PBS. Control lenses B are ACP coated lenses that are packed in polypropylene lens packaging shells / blisters (one lens per shell) each containing 0.55 mL of PBS. The blisters are then sealed with foil and sterilized for 30 minutes at about 121oC. Cross-linked coatings are formed during autoclaving on those lenses immersed in a saline packaging solution containing a copolymer containing azetidinium or polymeric material.
[00180] Characterization of SiHy lenses. The resultant lenses after autoclave are characterized and the results are reported in the table below.
Example 9
[00181] Preparation of the lenses. Silicone hydrogel contact lenses with a PAA coating on them are prepared according to the procedures (lens formulation, molds, molten molding conditions, lens extraction, PAA coating solution, PAA coating procedures, etc. .) described in Example 19 of U.S. Patent Application Publication No. 2012/0026458 A1 (incorporated herein by reference in its entirety).
[00182] Preparation of copolymer containing AZM / APMA / DMA. In a 500 mL glass reaction jar, 1.0 grams of aminopropylmethacrylamide (APMA), 2.5 grams of AZM prepared in Example 2, 6.47 grams of N, N'-dimethylacrylamide (DMA), and 3, 00 ml of Irgacure 2959 solution (1% in water) are dissolved in 187.0 grams of citrate buffer at 33.75 mM (pH 4). A lid is placed on the reaction jar that contains at least 4 ground joints. One used for a glass stirring shaft, one for a thermocouple, one for a nitrogen inlet, and one for sampling access. The solution is sparged with nitrogen for 20 minutes at about 200 mL / min. The nitrogen flow rate is reduced to about 150 mL / min. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Four UV lamps are switched on for about 1 hour at an intensity of about 2.0 mW / cm2. After about an hour, the solution is vacuum filtered through the qualitative paper filter. The copolymer solution is then purified using 50kDa of dialysis membranes against water for 24 hours using a water flow rate of about 40 mL / min. The solids content is determined and diluted to 2% if necessary.
[00183] Preparation of IPC saline solution using AZM / APMA / DMA copolymer. IPC 9A is prepared by making a 0.5% w / w solution of the AZM / APMA / DMA copolymer prepared above. A 2% copolymer solution is diluted by the PBS concentrate in Example 5 (50% w / w) and water (25% w / w) to achieve the final concentration of 0.5% w / w of salt partial sodium Poly (AAm-co-AA) (90/10) (~ 90% solid content, poly (AAm-co-AA) 90/10, Mw 200,000) is purchased from Polisciences, Inc. and used as received . IPC 9B is prepared by dissolving about 0.1% w / w of poly (AAm-co-AA) (90/10) and about 0.5% w / w of the AZM / APMA / DMA copolymer. IPC 9C is prepared by dissolving about 0.3% w / w of poly (AAm-co-AA) (90/10) and about 0.5% w / w of the AZM / APMA / DMA copolymer. Both IPC 9B and 9C are adjusted to pH 7.2 to 7.4 by adding about 0.044% w / w NaH2PO ^ H2O, about 0.388% w / w Na2HPO4 ^ 2H2O and about 0.79 % w / w NaCl. After that, IPC 9B and 9C are preheated for 10 hours at 70 ° C. During this heat pretreatment, poly (AAm-co-AA) and AZM copolymer are partially reacted with each other (ie, they do not consume all the azetidinium groups of the copolymer) to form a hydrophilic, water-soluble and thermally crosslinkable polymeric material containing azetidinium groups within the branched polymer network at IPC 9B and 9C. After pre-treatment with heat, the IPC is filtered using a 0.22 micron PES membrane filter.
[00184] Application of the reticulated coating. PAA coated lenses are packaged in polypropylene shells (one lens per shell) containing 0.65 ml of IPC 9A, 9B or 9C. Blisters are sealed and sterilized for 45 min at 121 ° C.
[00185] Characterization of the lenses. Tests are done on lenses to determine the effectiveness of saline solutions on the coating. As can be seen, the AZM / APMA / DMA copolymer itself is not able to provide good lubricity to the lenses, but adding poly (AAm-co-AA) improves lubricity tremendously.
Example 10
[00186] Preparation of the Lenses. Silicone hydrogel contact lenses with a PAA coating on them are prepared according to procedures (lens formulation, molds, cast mode conditions, lens extraction, PAA coating solution, PAA coating procedures, etc. .) described in Example 19 of U.S. Patent Application Publication No. 2012/0026458 A1 (incorporated herein by reference in its entirety).
[00187] Preparation of Copolymers of Methacrylic acid, Acrylic acid, and AZM. In a 500 mL glass reaction jar, methacrylic acid (MAA), acrylic acid (AA), 158 grams of 25% sodium citrate dihydrate solution in water, AZM prepared in Example 2, and 2, 65 mL of Irgacure 2959 solution (1% in water) is added. The pH is adjusted to 5.5 using 5N NaOH. Water is added up to 265 grams. A lid is placed on the reaction jar that contains at least 4 ground joints. One used for a glass stirring shaft, one for a thermocouple, one for a nitrogen inlet, and one for sampling access. The solution is sparged with nitrogen for 20 minutes at about 200 mL / min. The nitrogen flow rate is reduced to about 150 mL / min. The stirring speed is adjusted to 150 rpm. The reaction jar is placed in a UV Rayonet reactor with UV lamps RPR-3500. Two UV lamps are switched on for about 1 hour at an intensity of about 2.0 mW / cm2. After about an hour, the solution is vacuum filtered through the qualitative paper filter. The copolymer solution is then purified by ultrafiltration using 10kDa membranes until the solution conductively reaches less than 10uS / cm. The solids content is determined and diluted to 0.8% if necessary. Various copolymers are prepared for the reasons given in the table below.
Example 11
[00188] Preparation of the Lenses. Silicone hydrogel contact lenses are prepared by molten molding according to the procedures (the lens formulation, molds, molten molding conditions, etc.) described in Example 19 of the publication of U.S. Patent Application No. 2012 / 0026458 A1 (incorporated herein by reference in its entirety).
[00189] PMAA copolymer coating solution. Polymethacrylic acid (PMAA) copolymer coating solutions are prepared from the PMAA copolymers prepared in Example 10 to have the following composition: PMAA copolymer (0.011% w / w) which is one of the PMAA 10A to 10E prepared in the Example 10; 1-propanol (86.63% w / w); water (9.63% w / w); and formic acid (3.74% w / w).
[00190] PMAA copolymer coated lenses. The cast-molded contact lenses obtained as above are extracted and coated when immersed in the following series of baths: DI water bath for about 56 seconds; 3 baths of methyl ethyl ketone (MEK) for about 22, 78, 226 seconds, respectively; a DI water bath for about 56 seconds; a bath of PMAA copolymer coating solution (prepared above) for about 100 seconds; a bath of a 50% water / 1-propanol / 50% mixture for about 56 seconds; a water bath for about 56 seconds; a phosphate buffered saline bath for about 56 seconds; and a DI water bath for about 56 seconds. The lenses are immediately tested for acid group content by the TBO Assay as described in Example 1. Data are shown below.
Example 12
[00191] 13.0 g of methacrylic acid and 1.2 mg of mercaptoethanol are dissolved in 243.0 g of water and the pH adjusted to 3.0 by the addition of aqueous sodium hydroxide solution (33%). The solution is purged for 1 hour gently with nitrogen while stirring in a round flask. The solution is heated to 90 ° C after degassing. 3.6 mg of 2,2'- Azobis [2-methyl-N- (2-hydroxyethyl) propionamide] (VA-086, Wako) are separately dissolved in 5 ml of water, purged with nitrogen for 1 hour, filled in a syringe and added to the synthesis solution to initiate polymerization. The synthesis is carried out for 20 hours under agitation at 90 ° C. After polymerization, the pH of the synthesis solution is adjusted to pH = 3 by the addition of sulfuric acid and the PMAA is purified by aqueous ultrafiltration with 10 kDa of cellulose membranes (12x solvent exchange). PMAA is finally dried by lyophilization. Example 13
[00192] 15.0 g of methacrylic acid and 3.4 mg of mercaptoethanol are dissolved in 285.0 g of water and the pH adjusted to 3.5 by the addition of aqueous sodium hydroxide solution (33%). The solution is purged gently for 1 hour with nitrogen while stirring in a round flask. The solution is heated to 50 ° C after degassing. 9.1 mg of 2,2'-Azobis [2- (2-imidazolin-2-yl) propane] (VA-061, Wako) are separately dissolved in 5 ml of water, gently purged with nitrogen for 1 hour, filled in a syringe and added to the synthesis solution to initiate polymerization. The synthesis is carried out for 20 hours under agitation at 50 ° C. After polymerization, the pH of the synthesis solution is adjusted to pH = 3 by the addition of sulfuric acid and the PMAA is purified by aqueous ultrafiltration with 10 kDa of cellulose membranes (12x solvent exchange). PMAA is finally dried by lyophilization. Example 14
[00193] Various lenses (Purevision® by Bausch &Lamb; ACUVUE® 2® by Johnson &Johnson; SiHy lenses with FS PMAA / IPC-5A coating on them as prepared in Example 7; SiHy lenses with 40x PMAA coating / IPC-5A on them as prepared in Example 7; SiHy lenses with ACP-4e coating / IPC-5A on them as prepared according to the procedures described in Example 8 and when using ACP-4e prepared in Example 4 as the main coating and IPC saline solution IPC-5A prepared in Example 5 in the formation of the crosslinked coating) are tested for absorption of polyhexamethylene biguanide (PHMB) and release according to the procedures described in Example 1. The test results are shown in figure 1. PHMB absorption is minimal for lenses having a primary ACP coating.

权利要求:
Claims (20)
[0001]
1. Azetidinium copolymer, characterized by the fact that it comprises: (a) monomeric units derived from at least one vinyl monomer selected from the group consisting of a vinyl monomer containing carboxyl, a vinyl monomer containing amino, and a combination thereof ; wherein the carboxyl-containing vinyl monomer is selected from the group consisting of acrylic acid, a C1-C4-alkyl acrylic acid, N, N-2-acrylamidoglycolic acid, and a combination thereof, where the amino-containing vinyl monomer is selected from the group consisting of (meth) acrylate of C2-C4 alkyl, allylamine, vinylamine, (meth) acrylamide of amino-C1-C4 alkyl, N-allyl C1-C12 alkanamine, a coupling reaction product of an epoxy compound having a single epoxy group with allylamine, vinylamine, C2-C6 alkyl (meth) acrylate, or C2-C6 alkyl (meth) acrylamide, a coupling reaction product of a C1- C12 alkanamine or C2-C12 aminoalkanol or with an epoxy-containing vinyl monomer, and a combination thereof; and (b) monomer units containing azetidinium derived from at least one vinyl monomer containing azetidine which has the formula (2)
[0002]
2. Azetidinium copolymer according to claim 1, characterized by the fact that the azetidinium copolymer comprises the carboxyl-containing unit.
[0003]
3. Azetidinium copolymer, according to claim 1, characterized by the fact that the azetidinium copolymer comprises monomeric units containing carboxyl derived from a vinyl monomer containing carboxyl selected from the group consisting of methacrylic acid, ethylacrylic acid, and combination of the same.
[0004]
A copolymer containing azetidinium according to any of claims 1 to 3, characterized in that it comprises monomer units containing amino derived from at least one vinyl monomer containing amino selected from the group consisting of (meth) alkyl acrylate amino-C2-C4, allylamine, vinylamine, (meth) acrylamide alkyl amino-C1-C4, alkanamine N-ally C1-C12, a coupling reaction product of an epoxy compound featuring a single epoxy group with allylamine, vinylamine, ( met) amino C2-C6 alkyl acrylate, or (meth) acrylamide C2-C6 alkyl alkyl, a coupling reaction product of a C1- C12 alkanamine or C2-C12 aminoalkan or with an epoxy-containing vinyl monomer, and combinations of the same.
[0005]
5. Copolymer containing azetidinium, according to claim 1, characterized by the fact that it comprises: reactive monomeric units which are the monomeric units containing carboxyl and / or the monomeric units containing amino, and at least 50%, in mol of hydrophilic monomeric units non-reactive derivatives derived from at least one hydrophilic vinyl monomer selected from the group consisting of (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-vinylpyrrolidone, (N) N, N, -dimethylaminoethyl acrylate, N , N-dimethylaminopropyl (meth) acrylamide, glycerol methacrylate, 3-acryloylamino-1-propanol, N-hydroxyethyl acrylamide, N- [tris (hydroxymethyl) methyl] -acrylamide, N-methyl-3-methylene-2-pyrrolidone, 1-ethyl-3-methylene-2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 1-ethyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene-2-pyrrolidone, 5- ethyl-3-methylene-2-pyrrolidone, (meth) 2-hydroxyethyl acrylate, (meth) hydroxypropyl acrylate, (meth) C 1- C alkoxy acrylate - polyethylene glycol featuring an average molecular weight of up to 1500 Daltons, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl-N-methyl acetamide, allyl alcohol, vinyl alcohol, a vinyl monomer containing phosphorylcholine, (met) erythritol acrylate, (meth) arabitol acrylate, (meth) mannitol acrylate, (meth) ducitol acrylate, (meth) fucitol acrylate, (meth) iditol acrylate, (meth) inositol acrylate, (meth) acrylate xylitol, (meth) sorbitol acrylate, (meth) glucose acrylate, (meth) fructose acrylate, (meth) galactose acrylate, and combinations thereof.
[0006]
6. Copolymer containing azetidinium, according to claim 5, characterized by the fact that it comprises up to 50 mol% of monomeric units containing azetidinium and reactive monomeric units.
[0007]
7. Method for producing coated silicone hydrogel contact lenses featuring a crosslinked hydrophilic coating, characterized by the fact that it comprises the steps of: (a) obtaining a silicone hydrogel contact lens; (b) applying a main coating of a fixation polymer to the silicone hydrogel contact lens, the fixing polymer being a copolymer containing azetidinium, as defined in any one of claims 1 to 6; and (c) heating the silicone hydrogel contact lens in an aqueous solution in the presence of a water-soluble hydrophilic polymeric material, thermally crosslinkable comprising reactive functional groups selected from the group consisting of azetidinium groups, carboxyl groups, amino groups, thiol groups and combinations thereof, for and at a temperature of 40 ° C to 140 ° C for a period of time sufficient to induce intermolecular and intramolecular crosslinking reaction between an azetidinium group and an amino or carboxyl group, thus forming a durable coating not formed of silicone hydrogel on the silicone hydrogel contact lens.
[0008]
8. Method for producing silicone hydrogel contact lenses having a crosslinked hydrophilic coating, characterized by the fact that it comprises the steps of: (a) obtaining a silicone hydrogel contact lens by polymerizing in a mold of a lens-forming composition comprising a copolymer containing azetidinium, as defined in any of claims 1 to 6; (b) heat the silicone hydrogel contact lens obtained in an aqueous solution in the presence of a water soluble hydrophilic polymeric material, thermally crosslinkable comprising reactive functional groups selected from the group consisting of azetidinium groups, carboxyl groups, amino groups, thiol groups and combinations thereof, for and at a temperature of 40 ° C to 140 ° C for a period of time sufficient to induce intermolecular and intramolecular cross-linking reactions between an azetidinium group and an amino or carboxyl group, to form a durable coating non-formed silicone hydrogel on the silicone hydrogel contact lens, where this coating is anchored on the silicone hydrogel contact lens through the azetidinium groups of the azetidinium-containing copolymer on and / or near the surface of the silicone hydrogel contact lens.
[0009]
Method according to claim 8, characterized in that it comprises a step of applying a main coating of a fixing polymer on the silicone hydrogel contact lens, in which the fixing polymer is a homopolymer or copolymer of a vinyl monomer containing carboxyl.
[0010]
10. Method according to claim 9, characterized by the fact that the fixing polymer is: polyacrylic acid; polymethacrylic acid; polyethylacrylic acid, polypropylacrylic acid; a copolymer of at least two vinyl monomers selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, and propylacrylic acid; polymalleic acid; a maleic acid copolymer and one or more vinyl monomers; a copolymer composed of 0.05% to 20 mol% of a vinyl monomer containing azetidinium and 80% to 99.95 mol% of one or more vinyl monomers containing carboxyl selected from the group consisting of acrylic acid, acid methacrylic, ethylacrylic acid, propylacrylic acid, and a combination thereof; a reaction product of a
[0011]
11. Method according to claim 9, characterized by the fact that the fixation polymer is a copolymer composed of 0.05% to 20 mol% of a vinyl monomer containing azetidinium and 80% to 99.95% in mol of one or more vinyl monomers containing carboxyl selected from the group consisting of methacrylic acid, ethylacrylic acid, and a combination thereof; or a combination of them.
[0012]
Method according to any one of claims 7 to 11, characterized in that the thermally crosslinkable hydrophilic polymeric material is: (i) a copolymer containing azetidinium, as defined in claim 5 or 6; (ii) a reaction product of a copolymer containing azetidinium, as defined in claim 5 or 6, with at least one hydrophilicity enhancing agent having at least one reactive functional group selected from the group consisting of amino group, carboxyl group , thiol group, and combinations thereof; (iii) a polyaminoamide-epichlorohydrin reaction product with at least one hydrophilicity-enhancing agent having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group, and combinations thereof; (iv) a water-soluble hydrophilic polymer having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group, and combinations thereof; or (v) combinations thereof.
[0013]
13. Method according to any of claims 7 to 12, characterized in that the heating step is carried out by autoclaving the hydrogel silicone contact lens immersed in a packaging solution in a sealed lens packaging at a temperature from 118 ° C to 125 ° C for 20 to 90 minutes.
[0014]
14. Method according to claim 13, characterized in that the packaging solution comprises from 0.01% to 2% by weight of the thermally cross-linkable hydrophilic polymeric material.
[0015]
15. Silicone hydrogel contact lens, characterized by the fact that it is obtained according to a method, as defined in any of claims 7 to 14, and which has an oxygen permeability of at least 300 x 10-10 [( cm3 of oxygen) (mm) / (cm2) (s) (kPa)] (40 barriers), surface wetting determined by a water contact angle of 100 degrees or less, and good coating durability determined by survival of a digital friction test.
[0016]
16. Vinyl monomer containing azetidinium, characterized by the fact that it presents the formula (2)
[0017]
17. Method for producing silicone hydrogel contact lenses having a crosslinked hydrophilic coating, characterized by the fact that it comprises the steps of: (a) obtaining a silicone hydrogel contact lens by polymerization in a mold of a lens-forming composition comprising a first azetidinium-containing vinyl monomer and / or a first azetidinium-containing copolymer comprising first azetidinium-containing monomer units derived from at least a second azetidinium-containing vinyl monomer and hydrophobic monomeric units derived from at least one hydrophobic vinyl monomer, wherein the first and second vinyl monomers containing azetidinium independent of one another are a vinyl monomer containing azetidinium, as defined in claim 16; (b) heating the silicone hydrogel contact lens obtained in an aqueous solution in the presence of a water soluble hydrophilic polymeric material, thermally crosslinkable comprising reactive functional groups selected from the group consisting of azetidinium groups, carboxyl groups, amino groups, thiol groups and combinations thereof, for and at a temperature of 40 ° C to 140 ° C for a period of time sufficient to induce intermolecular and intramolecular cross-linking reactions between an azetidinium group and an amino or carboxyl group, to form a durable non-silicone coating hydrogel on the silicone hydrogel contact lens.
[0018]
18. Method, according to claim 17, characterized by the fact that the thermally crosslinkable hydrophilic polymeric material is: (i) a copolymer containing azetidinium, as defined in claim 5 or 6; (ii) a reaction product of a copolymer containing azetidinium, as defined in claim 5 or 6, with at least one hydrophilicity-enhancing agent having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group , and combinations thereof; (iii) a polyaminoamide-epichlorohydrin reaction product with at least one hydrophilicity-enhancing agent having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group, and combinations thereof; (iv) a water-soluble hydrophilic polymer having at least one reactive functional group selected from the group consisting of amino group, carboxyl group, thiol group, and combinations thereof; or (v) combinations thereof.
[0019]
19. Method, according to claim 17 or 18, characterized by the fact that the heating step is carried out by autoclaving the hydrogel silicone contact lens immersed in a packaging solution in a sealed lens packaging at a temperature of 118 ° C to 125 ° C for 20 to 90 minutes.
[0020]
20. Method, according to any one of claims 17 to 19, characterized by the fact that it also comprises a step of applying a main coating of a fixing polymer on the hydrogel silicone contact lens, in which the polymer is acidic polyacrylic; polymethacrylic acid; polyethylacrylic acid, polypropylacrylic acid; a copolymer of at least two vinyl monomers selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid, and propylacrylic acid; polymalleic acid, a maleic acid copolymer and one or more vinyl monomers; a copolymer composed of 0.05% to 20 mol% of a vinyl monomer containing azetidinium and 80% to 99.95 mol% of one or more vinyl monomers containing carboxyl selected from the group consisting of acrylic acid, methacrylic acid, ethylacrylic acid , propylacrylic acid, and a combination thereof; a reaction product of an azetidinium compound of where T7 and T8 independent of each other are C1 to C14 alkyl groups with polymalic anhydride or a maleic anhydride copolymer and one or more vinyl monomers where the molar ratio of the azetidinium compound to maleic anhydride is 0.25 or less, or a combination thereof.

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法律状态:
2020-03-10| B25A| Requested transfer of rights approved|Owner name: ALCON INC. (CH) |

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2020-05-19| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-11-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-01-05| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/06/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261659592P| true| 2012-06-14|2012-06-14|

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US61/659,592|2012-06-14|

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PCT/US2013/044938|WO2013188274A2|2012-06-14|2013-06-10|Azetidinium-containing copolymers and uses thereof|

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