Carbamoylphenylboronic acid-containing acrylic monomer and its uses

Abstract

The present invention generally relates to a water-soluble hydrophilic copolymer comprising one (carbamoylphenyl)boronic acid and an acrylamido monomer having a pKa of about 6.4 to about 7.6, and repeating units of such acrylamido monomer.

Description

Technology Field

[0001] The present invention generally relates to a class of acrylamido monomers, each of which contains (carbamoylphenyl)boronic acid and has a pKa of about 6.4 to about 7.8. Background Technology

[0002] Phenylboronic acid derivatives are known to be usable as receptors and sensors for carbohydrates and small molecules due to their ability to form cyclic boronate esters, primarily with cis-diols (see, e.g., SD Bull, et al., Acc. Chem. Res. 2013, 46 (2), 312-326; JA Peters, Coord. Chem. Rev. 2014, 268, 1-22). Recently, aryl boronic acid-containing vinyl monomers have been developed and used to prepare aryl boronic acid-containing polymers (e.g., T. Konno & K. Ishihara, Biomater. 2007, 28, 1770-1777; Z. Liu & H. He, Acc. Chem. Rev. 2017, 50, 2185-2193; WLA Brook & BS Summerlin, Chem. Rev. 2016, 116, 1375-1397; Z. Huang, et al., Biomater. Sci. 2018, 6, 2487-2495; JN Cambre & BS Summerlin, Polymer 2011, 52, 4631-4643; ZH Farooqi, et al., [Macromol. Chem. Phys. 2011, 212, 1510-1514]; [S. Roy, et al., Designed Monomers and Polymers 2009, 12, 483-495]; [D. Zhang & R. Pelton, Langmuir 2012, 28, 3112-3119]; [G. Vancoillie & R. Hoogenboom, Polym. Chem. 2016, 7, 5484-5495] see references).

[0003] These aryl boronic acid-containing polymers can form complexes with mucin, particularly epithelial mucin, by having an aryl boronic acid moiety. As such, aryl boronic acid-containing polymers have been reported to be usable in ophthalmic devices and ophthalmic compositions (see, e.g., U.S. Patents No. 7988988, 8419792, 8534031, 8631631, 8668736, 6596267, 8802075, 9244196, 10962803, 11439661; U.S. Patent Application Publication No. 2021-0077385). However, the vinyl aryl boronic acid monomers used in the manufacture of aryl boronic acid-containing polymers may have a pKa that is too high to ensure that the aryl boronic acid-containing polymers have strong interactions with mucin.

[0004] Therefore, there is still a need for arylboronic acid-containing vinyl monomers with low pKa.

[0005] In one embodiment, the present invention provides an acrylamido monomer comprising an acrylamido group and (carbamoylphenyl)boronic acid covalently bonded to the acrylamido group through bonding, wherein the acrylamido monomer has a pKa of about 6.4 to about 7.6.

[0006] In another aspect, the present invention provides a water-soluble hydrophilic copolymer comprising: (a) repeating monomer units of at least one acrylamido monomer of the present invention; (b) repeating units of at least one hydrophilic vinyl monomer; and optionally (c) repeating units of at least one hydrophilic vinyl crosslinker (provided that components (a) and (b) are present in the water-soluble hydrophilic copolymer in a total amount of at least 90 mol%).

[0007] In a further embodiment, the present invention provides an ophthalmic composition comprising: a water-soluble hydrophilic copolymer of the present invention. Specific details for implementing the invention

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. In general, the nomenclature and laboratory procedures used herein are well known and commonly used in the art. Conventional methods, such as those provided in the art and various general references, are used for these procedures. Where a term is provided in the singular form, the inventors also consider the plural form of the term. The nomenclature used herein and the laboratory procedures described below are well known and commonly used in the art.

[0009] As used herein, “about” means that the number referred to as “about” includes 1 to 10% of the cited number added to or subtracted from the cited number.

[0010] "Optional" or "optionally" means that the event or situation described subsequently may or may not occur, and implies that the description includes cases where the event or situation occurs and cases where it does not occur.

[0011] "Vinyl monomer" refers to a compound having a single ethylene-based unsaturated group.

[0012] With respect to a compound or substance in a solvent, the term "soluble" means that the compound or substance can be dissolved in the solvent to provide a solution at a concentration of at least about 0.1 weight% at room temperature (i.e., about 20°C to about 30°C).

[0013] With respect to a compound or substance in a solvent, the term "insoluble" means that the compound or substance is dissolved in the solvent and can provide a solution at a concentration of less than 0.005 weight% at room temperature (as defined above).

[0014] The term "ethylene-based unsaturated group" is used herein in a broad sense and is intended to encompass any group containing at least one >C=C< group. An exemplary ethylene-based unsaturated group is (meth)acryloyl ( and / or ), allyl, vinyl( ), 1-methylethenyl( Includes ), styrenyl, etc. without limitation.

[0015] The term "(meth)acrylamide" refers to methacrylamide and / or acrylamide.

[0016] The term "(meth)acrylate" refers to methacrylates and / or acrylates.

[0017] As used herein, "hydrophilic vinyl monomer" refers to a vinyl monomer that is water-soluble or can be polymerized to form a homopolymer capable of absorbing at least 10 weight percent of water.

[0018] "Hydrophobic vinyl monomer" refers to a vinyl monomer that is insoluble in water and can be polymerized to form a homopolymer capable of absorbing less than 10 weight percent of water.

[0019] "Acrylic monomer" refers to a vinyl monomer having a single (meth)acryloyl group.

[0020] "Acrylamido monomer" is a vinyl monomer having a single (meth)acrylamido group ( and / or It refers to ).

[0021] As used in this application, the term "vinylic crosslinker" refers to a compound having at least two ethylene-based unsaturated groups. "Vinylic crosslinker" refers to a vinyl crosslinker having a molecular weight of about 700 daltons or less.

[0022] As used in this application, the term "polymer" refers to a material formed by polymerizing or crosslinking one or more monomers, macromonomers, or prepolymers.

[0023] "Vinyl copolymer" refers to a copolymer of at least two different vinyl monomers.

[0024] As used in this application, the term “molecular weight” of a polymeric material (including monomeric or macromonomeric materials) refers to the weight-average molecular weight unless specifically stated otherwise or test conditions otherwise indicated.

[0025] The term "alkyl" refers to a monovalent radical obtained by removing a hydrogen atom from a linear or branched alkane compound. The alkyl group (radical) form forms one bond with another group in an organic compound.

[0026] The terms "alkylene divalent radical," "alkylene diradical," or "alkyl diradical" are interchangeably used to refer to a divalent radical obtained by removing one hydrogen atom from an alkyl group. An alkylene divalent group forms two bonds with another group in an organic compound.

[0027] The term "alkyl triradical" refers to a trivalent radical obtained by removing two hydrogen atoms from an alkyl group. Alkyl triradicals form three bonds with other groups in organic compounds.

[0028] The term "alkoxy" or "alkoxyl" refers to a monovalent radical obtained by removing a hydrogen atom from the hydroxyl group of a linear or branched alkyl alcohol. The alkoxy group (radical) form forms one bond with one other group in an organic compound.

[0029] In this application, the term “substituted” in relation to alkyl diradicals or alkyl radicals means that the alkyl diradicals or alkyl radicals replace one hydrogen atom of the alkyl diradicals or alkyl radicals and comprise at least one substituent selected from the group consisting of hydroxy (-OH), carboxyl (-COOH), -NH2, sulfhydryl (-SH), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio(alkyl sulfide), C1-C4 acylamino, C1-C4 alkylamino, di-C1-C4 alkylamino, halogen atom (Br or Cl), and combinations thereof.

[0030] In this application, "aryl boronic acid-containing vinyl monomer" refers to a vinyl monomer comprising one single aryl boronic acid group connected to its single ethylene-based unsaturated group through a single bond.

[0031] In this application, the "Arylborono" device It refers to the monovalent radical (where R1 is a monovalent radical (preferably H, NO2, F, Cl, Br, CF3, CH2OH, or CH2NR). o R o and, here, R o and R o ' are independently H or C1-C4 alkyl)). R1 ​​is CH2OH or CH2NR o R o In this case, it is understood that it is located at the ortho-position of boronic acid and can lower the pKa of boronic acid by forming intramolecular BO or BN coordination.

[0032] In this application, "phosphorylcholine-containing vinyl monomer" refers to a vinyl monomer comprising one single arylvorono group connected to its single ethylene unsaturated group through one bond.

[0033] As used in this application, the term "phosphorylcholine" is It refers to a monovalent zwitterionic group (where t1 is an integer from 1 to 5, and T1, T2 and T3 are independently C1-C8 alkyl or C1-C8 hydroxyalkyl).

[0034] The term "azlactone" is It refers to a monovalent radical, wherein p is 0 or 1; and T4 and T5 are independently 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, an arenyl group having 6 to 26 carbons and 0 to 3 sulfur, nitrogen and / or oxygen atoms, or T4 and T5 may be taken together with the carbons to which they are bonded to form a carbon-cyclic ring containing 5 to 8 ring atoms.

[0035] In this application, "(carbamoylphenyl)boronic acid" is It refers to the monovalent radical (where R1 is a monovalent radical (preferably H, NO2, F, Cl, Br, CF3, CH2OH, or CH2NR). o R o and, here, R o and R o ' are independently H or C1-C4 alkyl)). R1 ​​is CH2OH or CH2NR o R o In this case, it is understood that it is located at the ortho-position of boronic acid and can lower the pKa of boronic acid by forming intramolecular BO or BN coordination.

[0036] "Mucoaddhesive polymer" refers to a polymer capable of binding to mucus or mucosa that adheres to epithelial surfaces (e.g., gastrointestinal tract, lungs, eyes, etc.), as is known to those skilled in the art. It should be noted that mucoddhesive polymers are widely described in the literature. For example, refer to the paper titled "Mucoadhesive Drug Delivery System: A Review" (Dharmendra et al., Int. J. Pharm. Biol. Arch. 2012, 3(6):1287-1291) and the paper titled "Polymers in Mucoadhesive Drug-Delivery Systes: A Brief Note" (published in Roy et al., Designed Monomers and Polymers 2009, 12(6):483-495).

[0037] Generally, the present invention provides a class of acrylamido monomers, each having one (carbamoylphenyl)boronic acid and a pKa of about 6.4 to about 7.8. It has been found that these acrylamido monomers can be prepared from relatively inexpensive starting materials according to a well-known coupling reaction in the presence of a coupling agent.

[0038] The acrylamido monomer of the present invention has a pKa of approximately neutral pH (7.0 to 7.2) and can form a stable cycloboronate ester with a cis-diol. This is advantageously used in combination with one or more hydrophilic vinyl monomers in preparing a vinyl copolymer that is a mucoadhesive polymer capable of strongly interacting with mucus or mucosa attached to an epithelial surface. Additionally, the acrylamido monomer of the present invention has at least two hydrogen bond donors. It is believed that a mucoadhesive polymer containing repeating units of such acrylamido monomer can have additional interactions with mucin through hydrogen bonding.

[0039] In one embodiment, the present invention provides an acrylamido monomer of the following formula 1:

[0040] [Chemical Formula 1]

[0041]

[0042] (wherein R0 is H or CH3, R2 is NO2, F, Cl, Br, CF3, CCl3, or CH2N(CH3)2, L1 is a C2-C6 alkylene divalent radical or a divalent radical -R3-X1-R4-, X1 is an amide bond of -C(O)NH-, R3 and R4 are independently C2-C3 alkylene divalent radicals optionally substituted with one or more hydroxyl groups, and the acrylamido monomer has a pKa of about 6.4 to about 7.8 (preferably about 6.4 to about 7.6). Preferably, the boronic acid is at the para position.

[0043] The acrylamido monomer of Formula 1, in which L1 is a C2-C6 alkylene divalent radical, is the following starting material: (1) amino-C2-C6-alkyl (meth)acrylamide; and (2) a phenylboronic acid compound of Formula 2 below:

[0044] [Chemical Formula 2]

[0045]

[0046] From (where R2 is Cl or NO2), it can be prepared according to a known coupling reaction between a carboxylic acid and an amine in the presence of a zero-length coupling agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, N,N'-diisopropylcarbodiimide (DIC) or a mixture thereof) and an activator (e.g., N-hydroxysuccinimide (NHS)) to form an amide bond as known in the art. As an exemplary example, the acrylamido monomer of Formula 1 can be prepared as exemplified in Reaction Scheme I.

[0047] [Reaction Equation I]

[0048]

[0049] Similarly, an acrylamido monomer of Formula 1 can be prepared in which L1 is a divalent radical -R3-X1-R4-, X1 is an amide bond of -C(O)NH-, and R3 and R4 are independently C2-C6 alkylene divalent radicals optionally substituted with one or more hydroxyl groups, which is obtained from (1) a carboxy-containing (meth)acrylamide or azlactone-containing vinyl monomer, (2) a phenylboronic acid compound of Formula 2, and (3) a diamine (preferably a mono-Boc-protected diamine), through the amino-carboxy coupling reaction (forming an amide bond) described above and the ring-opening coupling reaction (-C(O)NH-CT4T5-(CH2) p It can be manufactured according to the formation of an alkylene-diamido link of -C(O)NR'-.

[0050] Examples of preferred phenylboronic acid compounds of Formula 2 include, without limitation, 4-carboxy-3-chlorophenylboronic acid, 4-carboxy-2-chlorophenylboronic acid, 4-carboxy-3-nitrophenylboronic acid, 4-carboxy-2-nitrophenylboronic acid, 3-carboxy-4-chlorophenylboronic acid, 3-carboxy-5-chlorophenylboronic acid, 3-carboxy-2-chlorophenylboronic acid, 3-carboxy-5-nitrophenylboronic acid, 5-carboxy-2-chlorophenylboronic acid, 2-carboxy-4-chlorophenylboronic acid, 2-carboxy-5-chlorophenylboronic acid, and combinations thereof. These preferred phenylboronic acid compounds of Formula 2 may be obtained from commercial sources.

[0051] Examples of preferred amino-C2-C6-alkyl (meth)acrylamides are without limitation

[0052] N-(2-aminoethyl)(meth)acrylamide, N-(3-aminopropyl)(meth)acrylamide, N-(2-aminoisopropyl)(meth)acrylamide, N-(4-aminobutyl)(meth)acrylamide, N-(5-aminopentyl)(meth)acrylamide, N-(6-aminohexyl)(meth)acrylamide, and combinations thereof are included.

[0053] Examples of preferred carboxy-containing (meth)acrylamides include, without limitation, N-(2-carboxypropyl)(meth)acrylamide, N-(3-carboxypropyl)(meth)acrylamide, N-2-acrylamidoglycolic acid, and combinations thereof.

[0054] Preferred examples of azlactone-containing vinyl monomers include, without limitation, 2-vinyl-4,4-dimethyl-1,3-oxazolin-5-one, 2-isopropen-4,4-dimethyl-1,3-oxazolin-5-one, 2-vinyl-4-methyl-4-ethyl-1,3-oxazolin-5-one, 2-isopropen-4-methyl-4-butyl-1,3-oxazolin-5-one, 2-vinyl-4,4-dibutyl-1,3-oxazolin-5-one, 2-isopropen-4-methyl-4-dodecyl-1,3-oxazolin-5-one, 2-isopropen-4,4-diphenyl-1,3-oxazolin-5-one, 2-isopropen-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 (2-vinyl-4,4-dimethyl-1,3-oxazolin-5-one (VDMO) as the most preferred azlactone-containing vinyl monomer) and It includes 2-isopropenyl-4,4-dimethyl-1,3-oxazolin-5-one (IPDMO).

[0055] Examples of preferred diamines include, without limitation, N,N'-bis(hydroxyethyl)-ethylenediamine, N,N'-dimethylethylenediamine, ethylenediamine, N,N'-dimethyl-1,3-propanediamine, N,N'-diethyl-1,3-propanediamine, propane-1,3-diamine, butane-1,4-diamine, pentane-1,5-diamine, hexamethylenediamine, and combinations thereof.

[0056] In a preferred embodiment, in Formula 1, L1 is a C2-C6 alkylene divalent radical. This preferred acrylamido monomer can be prepared from inexpensive starting materials in a one-step coupling reaction. Examples of this preferred acrylamido monomer of Formula 1 include, without limitation, the following:

[0057]

[0058] The acrylamido monomer of Formula 1 as defined above (including the preferred embodiments described above) may find specific uses in preparing copolymers comprising repeating monomer units of the acrylamido monomer of Formula 1 and repeating monomer units of at least one hydrophilic vinyl monomer. Such copolymers can interact strongly and reversibly with membrane-bound mucin in the eye. As such, it can act as an active ingredient / lubricant and a mucoadhesive hydrophilic copolymer, and can also be used in ophthalmic compositions containing emollients and drugs / comfort agents to extend the retention of emollients and drugs / comfort agents.

[0059] In another aspect, the present invention provides a water-soluble hydrophilic copolymer comprising: (a) repeating monomer units of at least one acrylamido monomer of Formula 1 (as defined above); (b) repeating units of at least one hydrophilic vinyl monomer; and optionally (c) repeating units of at least one hydrophilic vinyl crosslinker (provided that components (a) and (b) are present in the water-soluble hydrophilic copolymer in a total amount of at least 90 mol% (preferably at least 93 mol%, more preferably at least 96 mol%, even more preferably at least 99 mol%)).

[0060] According to the present invention, the water-soluble hydrophilic copolymer of the present invention may be a linear or branched polymer as long as it is soluble in water.

[0061] Any suitable hydrophilic vinyl monomer can be used in the manufacture of the hydrophilic copolymer of the present invention.

[0062] Examples of preferred hydrophilic vinyl monomers include alkyl (meth)acrylamide (as described below), hydroxyl-containing acrylic monomers (as described below), amino-containing acrylic monomers (as described below), carboxyl-containing acrylic monomers (as described below), N-vinylamide monomers (as described below), methylene-containing pyrrolidone monomers (i.e., pyrrolidone derivatives having a methylene group connected to a pyrrolidone ring at the 3- or 5-position, respectively) (as described below), acrylic monomers having C1-C4 alkoxyethoxy groups (as described below), vinyl ether monomers (as described below), allyl ether monomers (as described below), and phosphorylcholine-containing vinyl monomers (as described below). There are N-2-hydroxyethyl vinyl carbamate, N-carboxyvinyl-β-alanine (VINAL), N-carboxyvinyl-α-alanine, and combinations thereof.

[0063] Examples of alkyl (meth)acrylamides include, without limitation, (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N-ethyl (meth)acrylamide, N,N-diethyl (meth)acrylamide, N-propyl (meth)acrylamide, N-isopropyl (meth)acrylamide, N-3-methoxypropyl (meth)acrylamide, and combinations thereof.

[0064] Examples of hydroxyl-containing acrylic monomers include, without limitation, N-2-hydroxylethyl (meth)acrylamide, N,N-bis(hydroxyethyl)(meth)acrylamide, N-3-hydroxypropyl (meth)acrylamide, N-2-hydroxypropyl (meth)acrylamide, 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, di(ethylene glycol)(meth)acrylate, tri(ethylene glycol)(meth)acrylate, tetra(ethylene glycol)(meth)acrylate, poly(ethylene glycol)(meth)acrylate with a number average molecular weight of 1500 or less, poly(ethylene glycol)ethyl (meth)acrylamide with a number average molecular weight of 1500 or less, and combinations thereof.

[0065] Examples of amino-containing acrylic monomers include, without limitation, N-2-aminoethyl (meth)acrylamide, N-2-methylaminoethyl (meth)acrylamide, N-2-ethylaminoethyl (meth)acrylamide, N-2-dimethylaminoethyl (meth)acrylamide, N-3-aminopropyl (meth)acrylamide, N-3-methylaminopropyl (meth)acrylamide, N-3-dimethylaminopropyl (meth)acrylamide, 2-aminoethyl (meth)acrylate, 2-methylaminoethyl (meth)acrylate, 2-ethylaminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, 3-methylaminopropyl (meth)acrylate, 3-ethylaminopropyl (meth)acrylate, 3-amino-2-hydroxypropyl (meth)acrylate, trimethylammonium 2-hydroxypropyl (meth)acrylate hydrochloride, Dimethylaminoethyl (meth)acrylate and combinations thereof are included.

[0066] Examples of carboxyl-containing acrylic monomers include, without limitation, 2-(meth)acrylamidoglycolic acid, (meth)acrylic acid, ethylacrylic acid, propylacrylic acid, 3-(meth)acrylamidopropionic acid, 4-(meth)acrylamidobutanoic acid, 5-(meth)acrylamido-pentanoic acid, 3-(meth)acryloyloxypropanoic acid, 4-(meth)acryloyloxybutanoic acid, 5-(meth)acryloyloxypentanoic acid, and combinations thereof.

[0067] Examples of preferred N-vinyl amide monomers include, without limitation, N-vinylpyrrolidone (also known as N-vinyl-2-pyrrolidone), N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-6-methyl-2-pyrrolidone, N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinylpiperidone (also known as N-vinyl-2-piperidone), N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl caprolactam (also known as N-vinyl-2-caprolactam), N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-caprolactam, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, N-vinyl-N-methylacetamide, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl-N-ethyl acetamide, N-vinyl-N-ethyl formamide, and mixtures thereof are included. Preferably, the N-vinyl amide monomer is N-vinylpyrrolidone, N-vinyl-N-methyl acetamide, or a combination thereof.

[0068] Examples of preferred methylene-containing (=CH2) pyrrolidone monomers include, without limitation, 1-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, 1-n-propyl-3-methylene-2-pyrrolidone, 1-n-propyl-5-methylene-2-pyrrolidone, 1-isopropyl-3-methylene-2-pyrrolidone, 1-isopropyl-5-methylene-2-pyrrolidone, 1-n-butyl-3-methylene-2-pyrrolidone, 1-tert-butyl-3-methylene-2-pyrrolidone, and combinations thereof.

[0069] Examples of preferred acrylic monomers having a C1-C4 alkoxyethoxy group include, without limitation, ethylene glycol methyl ether (meth)acrylate, di(ethylene glycol) methyl ether (meth)acrylate, tri(ethylene glycol) methyl ether (meth)acrylate, tetra(ethylene glycol) methyl ether (meth)acrylate, C1-C4-alkoxy poly(ethylene glycol) (meth)acrylate having a weight average molecular weight of 1500 daltons or less, methoxy-poly(ethylene glycol)ethyl (meth)acrylamide having a number average molecular weight of 1500 daltons or less, and combinations thereof.

[0070] Examples of preferred vinyl ether monomers include, without limitation, ethylene glycol monovinyl ether, di(ethylene glycol) monovinyl ether, tri(ethylene glycol) monovinyl ether, tetra(ethylene glycol) monovinyl ether, poly(ethylene glycol) monovinyl ether, ethylene glycol methyl vinyl ether, di(ethylene glycol) methyl vinyl ether, tri(ethylene glycol) methyl vinyl ether, tetra(ethylene glycol) methyl vinyl ether, poly(ethylene glycol) methyl vinyl ether, and combinations thereof.

[0071] Examples of preferred allyl ether monomers include, without limitation, allyl alcohol, ethylene glycol monoallyl ether, di(ethylene glycol) monoallyl ether, tri(ethylene glycol) monoallyl ether, tetra(ethylene glycol) monoallyl ether, poly(ethylene glycol) monoallyl ether, ethylene glycol methylallyl ether, di(ethylene glycol) methylallyl ether, tri(ethylene glycol) methylallyl ether, tetra(ethylene glycol) methylallyl ether, poly(ethylene glycol) methylallyl ether, and combinations thereof.

[0072] Examples of preferred phosphorylcholine-containing vinyl monomers include, without limitation, (meth)acryloyloxyethyl phosphorylcholine (also known as MPC or 2-((meth)acryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate), (meth)acryloyloxypropyl phosphorylcholine (also known as 3-((meth)acryloyloxy)propyl-2'-(trimethylammonio)ethyl phosphate), 4-((meth)acryloyloxy)butyl-2'-(trimethylammonio)ethyl phosphate, 2-[(meth)acryloylamino]-ethyl-2'-(trimethylammonio)-ethyl phosphate, 3-[(meth)acryloylamino]propyl-2'-(trimethyl-ammonio)ethyl phosphate, 4-[(meth)acryloylamino]butyl-2'-(trimethylammonio)ethyl-phosphate, 5-((meth)acryloyloxy)pentyl-2'-(trimethylammonio)ethyl phosphate, 6-((meth)acryloyloxy)hexyl-2'-(trimethylammonio)-ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(triethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(tripropylammonio)ethyl-phosphate, 2-((meth)acryloyloxy)ethyl-2'-(tributylammonio)ethyl phosphate, 2-((meth)acryloyloxy)propyl-2'-(trimethylammonio)-ethyl phosphate, 2-((meth)acryloyloxy)-butyl-2'-(trimethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)pentyl-2'-(trimethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)hexyl-2'-(trimethylammonio)ethyl phosphate, 2-(vinyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(vinyloxycarbonyl)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxycarbonyl)ethyl-2'-(trimethylammonio)-ethyl phosphate, 2-(vinylcarbonylamino)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxycarbonylamino)-ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(butenoyloxy)ethyl-2'-(trimethylammonio)-ethyl phosphate, and combinations thereof are included.

[0073] Any suitable hydrophilic vinyl-based crosslinker may be used in the present invention. Examples of preferred hydrophilic vinyl-based crosslinkers include, without limitation, ethylene glycol di-(meth)acrylate, diethylene glycol di-(meth)acrylate, triethylene glycol di-(meth)acrylate, tetraethylene glycol di-(meth)acrylate, polyethylene glycol di-(meth)acrylate having a number average molecular weight of 200 to 1,000 daltons, glycerol di-(meth)acrylate, glycerol 1,3-diglycerolate di-(meth)acrylate, ethylenebis[oxy(2-hydroxypropane-1,3-diyl)] di-(meth)acrylate, bis[2-(meth)acryloxyethyl] phosphate, diacrylamide (i.e., N-(1-oxo-2-propenamide)-2-propenamide), and dimethacrylamide (i.e., N-(1-oxo-2-methyl-2-propenamide)-2-methyl-2-propenamide), N,N-di(meth)acryloyl-N-methylamine, N,N-di(meth)acryloyl-N-ethylamine, N,N'-methylene bis(meth)acrylamide, N,N'-ethylene bis(meth)acrylamide, N,N'-dihydroxy-ethylene bis(meth)acrylamide, N,N'-propylene bis(meth)acrylamide, N,N'-2-hydroxy-propylene bis(meth)acrylamide, N,N'-2,3-dihydroxybutylene bis(meth)acrylamide, 1,3-bis(meth)acrylamide-propane-2-yl dihydrogen phosphate (i.e., N,N'-2-phosphonyoxy-propylene bis(meth)acrylamide), Piperazine diacrylamide (or 1,4-bis(meth)acryloylpiperazine) and combinations thereof are included (more preferably ethylene glycol di-(meth)acrylate, diethylene glycol di-(meth)acrylate, triethylene glycol di-(meth)acrylate, tetraethylene glycol di-(meth)acrylate, polyethylene glycol di-(meth)acrylate having a number average molecular weight of 200 to 1000 daltons, N,N-di(meth)acryloyl-N-methylamine, N,N-di(meth)acryloyl-N-ethylamine, N,N'-methylene bis(meth)acrylamide, N,N'-ethylene bis(meth)acrylamide, N,Selected from the group consisting of N'-dihydroxyethylene bis(meth)acrylamide, N,N'-propylene bis(meth)acrylamide, N,N'-2-hydroxypropylene bis(meth)acrylamide, N,N'-2,3-dihydroxybutylene bis(meth)acrylamide, and combinations thereof).

[0074] In a preferred embodiment, the water-soluble hydrophilic copolymer of the present invention comprises (a) repeating monomer units of at least one acrylamido monomer of Formula 1 (as defined above), in an amount of about 0.1 mol% to about 10 mol% (preferably about 0.5 mol% to about 8 mol%, more preferably about 1 mol% to about 6 mol%, even more preferably about 1 mol% to about 5 mol%), (b) repeating monomer units of at least one hydrophilic vinyl monomer, in an amount of about 85 mol% to about 99.9 mol% (preferably about 90 mol% to about 99.9 mol%, more preferably about 95 mol% to about 99.9 mol%), and (c) repeating monomer units of at least one hydrophilic vinyl crosslinker, in an amount of 0 mol% to about 0.20 mol% (preferably 0 to about 0.15 mol%, more preferably 0 mol% to about 0.1 mol%). Includes (provided that the sum of the molar percentages of components (a), (b), (c) and other components not listed above is 100%). In a preferred embodiment, the acrylamido monomer of Formula 1 has a pKa of about 6.5 to 7.5, preferably about 6.8 to about 7.5, more preferably about 6.9 to about 7.4.

[0075] In another preferred embodiment, the water-soluble hydrophilic copolymer of the present invention comprises (a) repeating monomer units of at least one acrylamido monomer of Formula 1 (as defined above) in an amount of about 0.1 mol% to about 10 mol% (preferably about 0.5 mol% to about 8 mol%, more preferably about 1 mol% to about 6 mol%, even more preferably about 1 mol% to about 5 mol%), (b)(1) repeating monomer units of at least one zwitterionic vinyl monomer (preferably at least one phosphorylcholine-containing vinyl monomer) in an amount of about 5 mol% to about 35 mol% (preferably about 10 mol% to about 30 mol%), and (b)(2) about 60 mol% to about 94.9 mol% (more preferably about 65 mol% to about 94 mol%, even more preferably about 70 mol% to about 93 mol%), It comprises at least one repeating unit of a hydrophilic vinyl monomer without a zwitterionic group, and (c) at least one repeating unit of a hydrophilic vinyl crosslinker in an amount of 0 mol% to about 0.20 mol% (preferably 0 mol% to about 0.15 mol%, more preferably 0 mol% to about 0.1 mol%) (provided that the sum of the molar percentages of components (a), (b)(1), (b)(2), (c) and other components not listed above is 100%). In a preferred embodiment, the acrylamido monomer of Formula 1 has a pKa of about 6.5 to 7.5, preferably about 6.8 to about 7.5, more preferably about 6.9 to about 7.4.

[0076] According to the present invention, the molar percentage of each type of repeating monomer unit (i.e., monomer unit) of the water-soluble hydrophilic copolymer of the present invention can be determined based on the molar percentage of the vinyl monomer from which such a repeating unit is derived in the polymerizable composition for forming the water-soluble hydrophilic copolymer of the present invention.

[0077] According to the present invention, the water-soluble hydrophilic copolymer of the present invention has a number average molecular weight of about 10,000 daltons to about 5,000,000 daltons, preferably about 25,000 daltons to 2,000,000 daltons, more preferably about 50,000 daltons to about 1,000,000 daltons.

[0078] A method for preparing the water-soluble hydrophilic copolymer of the present invention according to any known polymerization technique is well known to those skilled in the art. For example, this can be obtained by thermal polymerization or chemical beam polymerization of a polymerizable composition comprising all required polymerizable components, a free radical initiator (thermal initiator or photoinitiator), and optionally (but preferably) a chain transfer agent. A chain transfer agent (containing at least one thiol group) is used to control the molecular weight of the resulting copolymer.

[0079] As is known to those skilled in the art, the polymerizable composition for preparing the copolymer of the present invention may be a solution in which all necessary components are dissolved in an inert solvent (i.e., one that does not interfere with the reaction between reactants in the mixture), such as water, an organic solvent, or a mixture thereof.

[0080] Examples of suitable solvents include, without limitation, water, tetrahydrofuran, tripropylene glycol methyl ether, dipropylene glycol methyl ether, ethylene glycol n-butyl ether, ketones (e.g., acetone, methyl ethyl ketone, etc.), diethylene glycol n-butyl ether, diethylene glycol methyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, propylene glycol methyl ether acetate, dipropylene glycol methyl ether acetate, propylene glycol n-propyl ether, dipropylene glycol n-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 glycol, polypropylene glycol, and ethyl Acetate, butyl acetate, amyl acetate, methyl lactate, ethyl lactate, i-propyl lactate, methylene chloride, 2-butanol, 1-propanol, 2-propanol, 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, tert-butanol, tert-amyl, alcohol, 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-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,Includes 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-pentanol, 1-ethoxy-2-propanol, 1-methyl-2-propanol, t-amyl alcohol, isopropanol, 1-methyl-2-pyrrolidone, N,N-dimethylpropionamide, dimethylformamide, dimethylacetamide, dimethylpropionamide, N-methylpyrrolidinone, and mixtures thereof.

[0081] The copolymerization of the polymerizable composition for producing the copolymer of the present invention may be induced photochemically or, preferably, thermally. Suitable thermal polymerization initiators are known to those skilled in the art and include, for example, peroxides, hydroperoxides, azo-bis(alkyl- or cycloalkylnitrile), persulfates, percarbonates, or mixtures thereof. Examples include benzoyl peroxide, tert.-butyl peroxide, di-tert.-butyl-diperoxyphthalate, tert.-butyl hydroperoxide, azo-bis(isobutyronitrile) (AIBN), 1,1-azodiisobutyramidine, 1,1'-azo-bis(1-cyclohexanecarbonitrile), 2,2'-azo-bis(2,4-dimethylvaleronitrile), etc. Polymerization is conveniently carried out in the aforementioned solvent at an elevated temperature, for example, 25 to 100°C, preferably 40 to 80°C. The reaction time may vary within a wide range, but is conveniently, for example, 1 to 24 hours or preferably 2 to 12 hours. It is advantageous to degas the components and solvent used in the polymerization reaction beforehand and to carry out the copolymerization reaction under an inert atmosphere, for example, under a nitrogen or argon atmosphere. By copolymerization, an optically transparent copolymer with a clear structure can be obtained, which can be post-treated in a conventional manner using techniques such as extraction, precipitation, and ultrafiltration.

[0082] The water-soluble hydrophilic copolymer of the present invention may find special uses in developing ophthalmic compositions for topical application, particularly artificial tear compositions comprising compounds that lubricate and protect the surface of the eye. In the context of dry eye disorders, artificial tear compositions can prevent symptoms such as pain and discomfort, prevent friction-induced bioadhesion and tissue damage, and promote the natural healing and recovery of previously damaged tissues.

[0083] Ophthalmic compositions are typically developed to have a target viscosity to ensure they are comfortable for the user and do not cause undesirable side effects, such as blurred vision. A suitable viscosity can help ensure that ophthalmic compositions used for dry eye disorders alleviate dry eye-related symptoms and / or treat the underlying disorder. In drug delivery applications, the viscosity of an ophthalmic composition may be selected to ensure that the agent contained in the composition remains in the eye, preferably for a longer period of time.

[0084] Natural polymers or chemically modified derivatives thereof exhibiting thixotropic and viscoelastic properties are well known and have been used as lubricants and ocular surface protectants in many ophthalmic compositions in the prior art. Examples of such polymers include hydroxypropyl methylcellulose, galactomannan, e.g. guar and hydroxypropyl guar, carboxymethylcellulose, hyaluronic acid, sodium alginate, polyvinyl alcohol, etc. The shear thinning and viscoelastic profiles of these polymers play an important role when mixed with the tear film.

[0085] The copolymer of the present invention is believed to be able to form cycloboronate ester linkages with the 1,2-diol and 1,3-diol moiety present in these polymers to impart gel-forming behavior to ophthalmic compositions.

[0086] The ophthalmic composition may include one or more additional pharmaceutical active agents. In some embodiments, one or more pharmaceutical active agents may be selected from the group of phospholipids, ocular lubricants, anti-decongestants, e.g., brimonidine tartrate, tetrahydrozoline, naphazoline, cooling agents, e.g., menthol, steroids and non-steroidal anti-inflammatory drugs for relieving ocular pain and inflammation, antibiotics, antihistamines, e.g., olopatadine, antivirals for infectious conjunctivitis, antibiotics and antibacterial agents, anti-muscarinic agents for the treatment of myopia, e.g., atropine and derivatives thereof, and glaucoma drug delivery, e.g., prostaglandins and prostaglandin analogs, e.g., travoprost, and therapeutically suitable combinations thereof.

[0087] Although various embodiments of the present invention have been described using specific terms, devices, and methods, such description is for illustrative purposes only. The words used are descriptive, not limiting. It should be understood that modifications and variations may be made by those skilled in the art without departing from the spirit or scope of the invention as set forth in the following claims. Furthermore, it should be understood that aspects of various embodiments may be interchangeable, in whole or in part, or combined and / or used together in any manner, as illustrated below:

[0088] 1. Acrylamido monomer of the following chemical formula 1:

[0089] [Chemical Formula 1]

[0090]

[0091] (wherein R0 is H or CH3, R2 is NO2, F, Cl, Br, CF3, CCl3, or CH2N(CH3)2, L1 is a C2-C6 alkylene divalent radical or a divalent radical -R3-X1-R4-, X1 is an amide bond of -C(O)NH-, R3 and R4 are independently C2-C6 alkylene divalent radicals optionally substituted with one or more hydroxyl groups, and the acrylamido monomer has a pKa of about 6.4 to about 7.8).

[0092] 2. In Embodiment 1, an acrylamido monomer, wherein in Formula 1, L1 is a divalent radical -R3-X1-R4-, X1 is an amide bond of -C(O)NH-, and R3 and R4 are independently C2-C6 alkylene divalent radicals selectively substituted with one or more hydroxyl groups.

[0093] 3. In Embodiment 1, in Formula 1, L1 is an acrylamido monomer in which L1 is a C2-C6 alkylene divalent radical.

[0094] 4. In Embodiment 1, an acrylamido monomer selected from the group consisting of the following:

[0095]

[0096]

[0097] 5. In any one of embodiments 1 to 4, the acrylamido monomer is an acrylamido monomer having a pKa of about 6.5 to 7.5.

[0098] 6. In any one of embodiments 1 to 4, the acrylamido monomer is an acrylamido monomer having a pKa of about 6.8 to about 7.5.

[0099] 7. In any one of embodiments 1 to 4, the acrylamido monomer is an acrylamido monomer having a pKa of about 6.9 to about 7.4.

[0100] 8. As a water-soluble hydrophilic copolymer,

[0101] (a) a repeating monomer unit of at least one acrylamido monomer of any one of embodiments 1 to 7;

[0102] (b) at least one repeating unit of a hydrophilic vinyl monomer; and optionally

[0103] (c) repeating unit of at least one hydrophilic vinyl crosslinker

[0104] Includes,

[0105] However, components (a) and (b) are present in the water-soluble hydrophilic copolymer in a total amount of at least 90 mol%.

[0106] 9. In embodiment 8, components (a) and (b) are present in a total amount of at least 93 mol%, more preferably at least 96 mol%, and even more preferably at least 99 mol% in the water-soluble hydrophilic copolymer.

[0107] 10. In Embodiment 8, components (a) and (b) are present in a total amount of at least 96 mol% in the water-soluble hydrophilic copolymer.

[0108] 11. In Embodiment 8, components (a) and (b) are present in a total amount of at least 99 mol% in the water-soluble hydrophilic copolymer, the water-soluble hydrophilic copolymer.

[0109] 12. In any one of embodiments 8 to 11, the water-soluble hydrophilic copolymer comprises (a) about 0.1 mol% to about 10 mol% of repeating monomer units of the at least one acrylamido monomer and (b) about 85 mol% to about 99.9 mol% of repeating monomer units of the at least one hydrophilic vinyl monomer.

[0110] 13. In Embodiment 12, the water-soluble hydrophilic copolymer comprises about 0.5 mol% to about 8 mol% of repeating monomer units of the at least one acrylamido monomer.

[0111] 14. In Embodiment 12, the water-soluble hydrophilic copolymer comprises about 1 mol% to about 6 mol% of repeating monomer units of the at least one acrylamido monomer.

[0112] 15. In Embodiment 12, the water-soluble hydrophilic copolymer comprises about 1 mol% to about 5 mol% of repeating monomer units of the at least one acrylamido monomer.

[0113] 16. In any one of embodiments 12 to 15, the water-soluble hydrophilic copolymer comprises about 90 mol% to about 99.9 mol% of repeating monomer units of the at least one hydrophilic vinyl monomer.

[0114] 17. In any one of embodiments 12 to 15, the water-soluble hydrophilic copolymer comprises about 95 mol% to about 99.9 mol% of repeating monomer units of the at least one hydrophilic vinyl monomer.

[0115] 18. In any one of embodiments 12 to 17, the water-soluble hydrophilic copolymer comprises about 0 mol% to about 0.20 mol% of repeating monomer units of at least one hydrophilic vinyl-based crosslinking agent.

[0116] 19. In any one of embodiments 12 to 17, the water-soluble hydrophilic copolymer comprises about 0 mol% to about 0.15 mol% of repeating monomer units of at least one hydrophilic vinyl-based crosslinking agent.

[0117] 20. In any one of embodiments 12 to 17, the water-soluble hydrophilic copolymer comprises about 0 mol% to about 0.1 mol% of repeating monomer units of at least one hydrophilic vinyl-based crosslinking agent.

[0118] 21. In any one of embodiments 8 to 17, the at least one hydrophilic vinyl monomer is (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N-ethyl (meth)acrylamide, N,N-diethyl (meth)acrylamide, N-propyl (meth)acrylamide, N-isopropyl (meth)acrylamide, N-3-methoxypropyl (meth)acrylamide, N-2-hydroxyethyl (meth)acrylamide, N,N-bis(hydroxyethyl) (meth)acrylamide, N-3-hydroxypropyl (meth)acrylamide, N-2-hydroxypropyl (meth)acrylamide, 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, di(ethylene glycol) (meth)acrylate, Tri(ethylene glycol) (meth)acrylate, tetra(ethylene glycol) (meth)acrylate, poly(ethylene glycol) (meth)acrylate with a number average molecular weight of 1500 or less, poly(ethylene glycol)ethyl (meth)acrylamide with a number average molecular weight of 1500 or less, N-2-aminoethyl (meth)acrylamide, N-2-methylaminoethyl (meth)acrylamide, N-2-ethylaminoethyl (meth)acrylamide, N-2-dimethylaminoethyl (meth)acrylamide, N-3-aminopropyl (meth)acrylamide, N-3-methylaminopropyl (meth)acrylamide, N-3-dimethylaminopropyl (meth)acrylamide, 2-aminoethyl (meth)acrylate, 2-methylaminoethyl (meth)acrylate, 2-ethylaminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, 3-methylaminopropyl (Met)acrylate, 3-ethylaminopropyl (meth)acrylate, 3-amino-2-hydroxypropyl (meth)acrylate, trimethylammonium 2-hydroxypropyl (meth)acrylate hydrochloride, dimethylaminoethyl (meth)acrylate, 2-(meth)acrylamidoglycolic acid, (meth)acrylic acid, ethylacrylic acid, propylacrylic acid, 3-(meth)acrylamidopropionic acid, 4-(meth)acrylamidobutanoic acid, 5-(meth)acrylamidopentanoic acid,3-(meth)acryloyloxypropanoic acid, 4-(meth)acryloyloxybutanoic acid, 5-(meth)acryloyloxypentanoic acid, N-vinylpyrrolidone, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-6-methyl-2-pyrrolidone, N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinylpiperidone, N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl caprolactam, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-caprolactam, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, N-vinyl-N-methylacetamide, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl-N-ethyl acetamide, N-vinyl-N-ethyl formamide, 1-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, 1-n-propyl-3-methylene-2-pyrrolidone, 1-n-propyl-5-methylene-2-pyrrolidone, 1-isopropyl-3-methylene-2-pyrrolidone, 1-isopropyl-5-methylene-2-pyrrolidone, 1-n-butyl-3-methylene-2-pyrrolidone, 1-tert-butyl-3-methylene-2-pyrrolidone, ethylene glycol methyl ether (meth)acrylate, di(ethylene glycol) methyl ether (meth)acrylate, tri(ethylene glycol) methyl ether (meth)acrylate, tetra(ethylene glycol) methyl ether (meth)acrylate,C1-C4-alkoxy poly(ethylene glycol) (meth)acrylate with a weight average molecular weight of 1500 or less, methoxy-poly(ethylene glycol)ethyl (meth)acrylamide with a number average molecular weight of 1500 or less, ethylene glycol monovinyl ether, di(ethylene glycol) monovinyl ether, tri(ethylene glycol) monovinyl ether, tetra(ethylene glycol) monovinyl ether, poly(ethylene glycol) monovinyl ether, ethylene glycol methyl vinyl ether, di(ethylene glycol) methyl vinyl ether, tri(ethylene glycol) methyl vinyl ether, tetra(ethylene glycol) methyl vinyl ether, poly(ethylene glycol) methyl vinyl ether, allyl alcohol, ethylene glycol monoallyl ether, di(ethylene glycol) monoallyl ether, tri(ethylene glycol) monoallyl ether, tetra(ethylene glycol) monoallyl A water-soluble hydrophilic copolymer comprising ethers, poly(ethylene glycol) monoallyl ethers, ethylene glycol methylallyl ethers, di(ethylene glycol) methylallyl ethers, tri(ethylene glycol) methylallyl ethers, tetra(ethylene glycol) methylallyl ethers, poly(ethylene glycol) methylallyl ethers, phosphorylcholine-containing vinyl monomers, N-2-hydroxyethyl vinyl carbamate, N-carboxyvinyl-β-alanine (VINAL), N-carboxyvinyl-α-alanine, or combinations thereof.

[0119] 22. In any one of embodiments 8 to 21, the at least one hydrophilic vinyl-based crosslinking agent is ethylene glycol di-(meth)acrylate, diethylene glycol di-(meth)acrylate, triethylene glycol di-(meth)acrylate, tetraethylene glycol di-(meth)acrylate, polyethylene glycol di-(meth)acrylate having a number average molecular weight of 200 to 1,000 daltons, glycerol di-(meth)acrylate, glycerol 1,3-diglycerolate di-(meth)acrylate, ethylenebis[oxy(2-hydroxypropane-1,3-diyl)] di-(meth)acrylate, bis[2-(meth)acryloxyethyl] phosphate, diacrylamide (i.e., N-(1-oxo-2-propenamide)-2-propenamide), dimethacrylamide (i.e., N-(1-oxo-2-methyl-2-propenamide)-2-methyl-2-propenamide), N,N-di(meth)acryloyl-N-methylamine, N,N-di(meth)acryloyl-N-ethylamine, N,N'-methylene bis(meth)acrylamide, N,N'-dihydroxyethylene bis(meth)acrylamide, N,N'-propylene bis(meth)acrylamide, N,N'-2-hydroxypropylene bis(meth)acrylamide, N,N'-2,3-dihydroxybutylene bis(meth)acrylamide, 1,3-bis(meth)acrylamide-propane-2-yl dihydrogen phosphate (i.e., N,N'-2-phosphonyoxypropylene bis(meth)acrylamide), piperazine Diacrylamide (or 1,4-bis(meth)acryloylpiperazine), and combinations thereof, more preferably comprising ethylene glycol di-(meth)acrylate, diethylene glycol di-(meth)acrylate, triethylene glycol di-(meth)acrylate, tetraethylene glycol di-(meth)acrylate, polyethylene glycol di-(meth)acrylate having a number average molecular weight of 200 to 1000 daltons, N,N-di(meth)acryloyl-N-methylamine, N,N-di(meth)acryloyl-N-ethylamine, N,N'-methylene bis(meth)acrylamide, N,N'-ethylene bis(meth)acrylamide, N,N'-dihydroxyethylene bis(meth)acrylamide,A water-soluble hydrophilic copolymer selected from the group consisting of N,N'-propylene bis(meth)acrylamide, N,N'-2-hydroxypropylene bis(meth)acrylamide, N,N'-2,3-dihydroxybutylene bis(meth)acrylamide, and combinations thereof.

[0120] 23. In any one of embodiments 8 to 22, the water-soluble hydrophilic copolymer comprises about 5 mol% to about 35 mol% of repeating monomer units of at least one phosphorylcholine-containing vinyl monomer and about 60 mol% to about 94.9 mol% of repeating units of at least one hydrophilic vinyl monomer other than the phosphorylcholine-containing vinyl monomer.

[0121] 24. In Embodiment 23, the water-soluble hydrophilic copolymer comprises about 10 mol% to about 30 mol% of repeating monomer units of at least one phosphorylcholine-containing vinyl monomer.

[0122] 25. In embodiment 23 or 24, the water-soluble hydrophilic copolymer comprises about 65 mol% to about 94 mol% of repeating units of at least one hydrophilic vinyl monomer other than the phosphorylcholine-containing vinyl monomer.

[0123] 26. In embodiment 23 or 24, the water-soluble hydrophilic copolymer comprises about 70 mol% to about 93 mol% of repeating units of at least one hydrophilic vinyl monomer other than the phosphorylcholine-containing vinyl monomer.

[0124] 27. In any one of embodiments 23 to 26, the at least one phosphorylcholine-containing vinyl monomer is (meth)acryloyloxyethyl phosphorylcholine, (meth)acryloyloxypropyl phosphorylcholine, 4-(meth)acryloyloxy)butyl-2'-(trimethylammonio)ethyl phosphate, 2-[(meth)acryloylamino]ethyl-2'-(trimethylammonio)-ethyl phosphate, 3-[(meth)acryloylamino]propyl-2'-(trimethylammonio)ethyl phosphate, 4-[(meth)acryloylamino]butyl-2'-(trimethylammonio)ethyl phosphate, 5-(meth)acryloyloxy)pentyl-2'-(trimethylammonio)ethyl phosphate, 6-((meth)acryloyloxy)hexyl-2'-(trimethylammonio)-ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(triethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(tripropylammonio)ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(tributylammonio)ethyl phosphate, 2-((meth)acryloyloxy)propyl-2'-(trimethylammonio)-ethyl phosphate, 2-((meth)acryloyloxy)butyl-2'-(trimethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)pentyl-2'-(trimethylammonio)ethyl phosphate, A water-soluble hydrophilic copolymer selected from the group consisting of 2-((meth)acryloyloxy)hexyl-2'-(trimethylammonio)ethyl phosphate, 2-(vinyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(vinyloxycarbonyl)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxycarbonyl)ethyl-2'-(trimethylammonio)-ethyl phosphate, 2-(vinylcarbonylamino)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxycarbonylamino)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(butenoyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, and combinations thereof.

[0125] 28. In any one of embodiments 8 to 27, the at least one hydrophilic vinyl monomer is (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N-ethyl (meth)acrylamide, N,N-diethyl (meth)acrylamide, N-propyl (meth)acrylamide, N-isopropyl (meth)acrylamide, N-3-methoxypropyl (meth)acrylamide, N-2-hydroxyethyl (meth)acrylamide, N,N-bis(hydroxyethyl) (meth)acrylamide, N-3-hydroxypropyl (meth)acrylamide, N-2-hydroxypropyl (meth)acrylamide, poly(ethylene glycol)ethyl (meth)acrylamide having a number average molecular weight of 1500 or less, N-2-aminoethyl (meth)acrylamide, N-2-methylaminoethyl (meth)acrylamide, N-2-ethylaminoethyl A water-soluble hydrophilic copolymer comprising at least one hydrophilic acrylamido monomer selected from the group consisting of (meth)acrylamide, N-2-dimethylaminoethyl (meth)acrylamide, N-3-aminopropyl (meth)acrylamide, N-3-methylaminopropyl (meth)acrylamide, N-3-dimethylaminopropyl (meth)acrylamide, 2-(meth)acrylamidoglycolic acid, 3-(meth)acrylamidopropionic acid, 4-(meth)acrylamidobutanoic acid, 5-(meth)acrylamidopentanoic acid, and combinations thereof.

[0126] 29. In any one of embodiments 8 to 27, the at least one hydrophilic vinyl monomer is 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, di(ethylene glycol) (meth)acrylate, tri(ethylene glycol) (meth)acrylate, tetra(ethylene glycol) (meth)acrylate, poly(ethylene glycol) (meth)acrylate having a number average molecular weight of 1500 or less, poly(ethylene glycol)ethyl (meth)acrylamide having a number average molecular weight of 1500 or less, 2-aminoethyl (meth)acrylate, 2-methylaminoethyl (meth)acrylate, 2-ethylaminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, 3-methylaminopropyl (meth)acrylate, 3-ethylaminopropyl A water-soluble hydrophilic copolymer comprising a hydrophilic acrylic monomer selected from the group consisting of (meth)acrylate, 3-amino-2-hydroxypropyl (meth)acrylate, trimethylammonium 2-hydroxypropyl (meth)acrylate hydrochloride, dimethylaminoethyl (meth)acrylate, (meth)acrylic acid, ethylacrylic acid, propylacrylic acid, 3-(meth)acryloyloxypropanoic acid, 4-(meth)acryloyloxybutanoic acid, 5-(meth)acryloyloxypentanoic acid, and combinations thereof.

[0127] 30. A water-soluble hydrophilic copolymer in any one of embodiments 8 to 27, wherein the at least one hydrophilic vinyl monomer comprises a vinyl monomer selected from the group consisting of N-vinylpyrrolidone, N-vinyl-N-methylacetamide, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl-N-ethylacetamide, N-vinyl-N-ethyl formamide, and mixtures thereof.

[0128] 31. In any one of embodiments 8 to 30, the water-soluble hydrophilic copolymer is a water-soluble hydrophilic copolymer having a number average molecular weight of about 10,000 daltons to about 10,000,000 daltons.

[0129] 32. In any one of embodiments 1 to 37, the water-soluble hydrophilic copolymer is a water-soluble hydrophilic copolymer having a number average molecular weight of about 25,000 daltons to about 5,000,000 daltons.

[0130] 33. In any one of embodiments 1 to 37, the water-soluble hydrophilic copolymer is a water-soluble hydrophilic copolymer having a number average molecular weight of about 50,000 daltons to about 2,000,000 daltons.

[0131] 34. An ophthalmic composition comprising a water-soluble hydrophilic copolymer of any one of embodiments 8 to 33.

[0132] The foregoing disclosure will enable those skilled in the art to practice the invention. Various modifications, variations, and combinations of the various embodiments described herein may be made. To enable the reader to better understand specific embodiments and their advantages, it is suggested to refer to the following examples. This specification and examples are intended to be regarded as exemplary.

[0133] abbreviation

[0134] The following abbreviations are used in the embodiments described below: CPBA represents (4-(2-acrylamidoethyl)carbamoyl)-3-chlorophenyl)boronic acid; AA represents acrylic acid; APBA represents 3-(acrylamido)phenylboronic acid; MBA represents N,N-methylenebis(acrylamide); MPC represents 2-methacryloyloxyethylphosphorylcholine; DMA represents N,N-dimethylacrylamide; HEAm represents N-(2-hydroxyethyl)acrylamide; NHS represents N-hydroxysuccinimide; DIC represents diisopropylcarbodiimide; EtOAc represents ethyl acetate; DMF represents dimethylformamide; and DIPEA is N , N - represents diisopropylethylamine; DMSO represents dimethyl sulfoxide; MeOH represents methanol; mmole represents millimole; TLC represents thin-layer chromatography; CHCl3 represents chloroform; NMR represents nuclear magnetic resonance; Hz represents Hertz; MHz represents megahertz; VAZO 56 represents 2,2'-azobis(2-methylpropionamidine) dihydrochloride; PBS represents phosphate buffered brine containing about 0.044 wt% NaH2PO4·H2O, about 0.388 wt% Na2HPO4·2H2O, and about 0.79 wt% NaCl, with a pH of 7.2±0.2 at 25°C; DI water represents deionized water; wt% (weight basis %) represents weight percentage; w / v% indicates weight / volume percentage concentration (i.e., grams of solute per 100 mL of solution); min indicates minutes; MW indicates molecular weight; UF indicates ultrafiltration; cP indicates centipoise; meq indicates milliequivalent; MUC2 indicates porcine gastric mucin (type III) (Sigma-Aldrich, catalog number M1778); and DPBS indicates Dulbecco phosphate buffered saline.

[0135] Example 1

[0136] (4-(2-acrylamidoethyl)carbamoyl)-3-chlorophenyl)boronic acid (CPBA) is prepared according to the procedure shown in Reaction Scheme 1.

[0137] [Reaction Equation 1]

[0138]

[0139] 3-3-chloro-4-carboxyphenylboronic acid (0.51 g, 2.52 mmol) and N-hydroxysuccinimide, NHS (0.32 g, 2.78 mmol) are loaded into a 40 mL vial equipped with a magnetic stirrer and a rubber diaphragm. Ethyl acetate (15 mL) is added through the diaphragm using a syringe. The contents of the vial are cooled to 0°C in an ice bath. 2 mL of diisopropyl-carbodiimide, DIC (0.35 g, 2.77 mmol) dissolved in ethyl acetate is added dropwise to the cooled solution of 3-chloro-4-carboxyphenylboronic acid and NHS in ethyl acetate. After 30 minutes, the ice bath is removed, and the reaction mixture is left to be stirred overnight at room temperature. The formed urea precipitate is removed by filtration, and the ethyl acetate is evaporated. The active ester was redissolved in DMF (10 mL), 2-(aminoethyl)-acrylamide xHCl (0.45 g, 2.99 mmol) was added, and the mixture was stirred for 10 minutes until all solids were dissolved. The contents of the reaction flask were cooled to 0°C in an ice bath. N,N-diisopropylethylamine, DIPEA (0.93 g, 7.20 mmol) combined with 2 mL of DMF was added dropwise to the vial containing the NHS-ester and 2-(aminoethyl)acrylamide xHCl. After 10 minutes, the ice bath was removed, and the reaction mixture was left to be stirred at room temperature for 5 hours. TLC showed the consumption of the NHS-ester. DMF was removed overnight using a high-vacuum pump, and the crude reaction mixture was purified by silica gel column chromatography (1.5 in × 12 in; CHCl3 → CHCl3:MeOH 100 → 90:10). The solvent was removed by rotary evaporation, and the final product was purified by crystallization from a MeOH / water mixture. A white solid was produced through crystallization at room temperature over 3 days, and this It was collected by filtering through a funnel. This was transferred to a vial and dried overnight under vacuum with an oil pump to obtain 0.372 g (1.25 mmol, 50% yield) of the final product as a white solid.

[0140] 1 H-NMR (600 MHz, DMSO-d6+ DO): δ=8.45 (s, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 7.73 (d, 2H, J = 8.0 Hz), 7.41 (d, 2H, J = 8.0 Hz), 6.20 (dd, 1H, J = 17.0, 10.0 Hz), 6.09 (d, 1H, J = 17.0 Hz), 5.60 (d, 1H, J = 10.0 Hz), 3.48 (s, 4H).

[0141] Example 2

[0142] In current Systane products, the mechanism of action relies on the formation of a hydroxypropyl-gua (HP-gua) gel using borates to extend the retention of demulcants, such as polyethylene glycol and propylene glycol, in the eye. This helps reduce the symptoms of dry eye by protecting the ocular surface. The challenge is that the current retention time of the demulcants in the eye is not long enough for patients to experience.

[0143] The water-soluble hydrophilic copolymer of the present invention is believed to be capable of cross-linking with mucin present in membrane-bound mucin primarily through reversible cyclo-boronate-ester bonds formed between one substituted (carbamoylphenyl)boronic acid of the hydrophilic copolymer and one of the cis-diol moiety of mucin, respectively, and secondarily through non-covalent interactions such as hydrogen bonds formed between the hydrophilic copolymer and mucin. As such, the water-soluble hydrophilic copolymer of the present invention can act as an active ingredient / lubricant and will effectively bind to membrane-bound mucin.

[0144] In addition, when a solution of the water-soluble hydrophilic polymer of the present invention is mixed with a solution of mucin of the eye, the interaction between the water-soluble hydrophilic polymer of the present invention and the mucin present in the membrane-bound mucin is believed to provide an improved viscosity compared to the sum of the viscosities of the two solutions. This improved viscosity may be a quantitative measure of the polymer-mucin interaction and is indicated in this application as a polymer-mucin interaction synergy.

[0145] The mucin selected for evaluating the interaction between the water-soluble hydrophilic copolymer and the mucin is porcine mucin due to its similarity to human eye mucin. Porcine stomach mucin, type III, is ordered from Sigma-Aldrich (catalog number M1778). The obtained mucin is purified by ultrafiltration before use for evaluating these polymer-mucin interactions.

[0146] In this application, the polymer-mucin-interaction synergy (indicated as PMIS) of the water-soluble hydrophilic copolymer of the present invention is calculated according to Formula 1:

[0147] [Equation 1]

[0148]

[0149] Here, is the viscosity of a first copolymer solution containing 1.0 wt% of a water-soluble hydrophilic copolymer in a phosphate buffered brine, and is the viscosity of a first mucin solution containing 0.6 wt% of porcine gastric mucin type III in phosphate buffered saline, and is the viscosity of the copolymer-mucin solution obtained by mixing the second copolymer solution with an equal volume of the second mucin solution, wherein the second copolymer solution contains 2.0 wt% of a water-soluble hydrophilic copolymer in phosphate buffered brine and the second mucin solution contains 1.2 wt% of porcine gastric mucin type III in phosphate buffered brine.

[0150] analyze

[0151] A stock solution (2 wt%) of the water-soluble hydrophilic copolymer of the present invention is prepared by dissolving freeze-dried MUC2 in DPBS using a speed mixer (1500~2000 RPM / 10 min / 2~3 times). A stock solution (2 wt%) of the water-soluble hydrophilic copolymer of the present invention is prepared by reconstituting and homogenizing the water-soluble hydrophilic copolymer in DPBS using a speed mixer (1500~2000 RPM / 10 min / 2~3 times).

[0152] A 1.2 wt% MUC2 solution is prepared by diluting a 2 wt% MUC2 stock solution with DPBS.

[0153] Equal volumes (1 mL) of 1.2 wt% MUC2 solution and DPBS are mixed in a 20 mL scintillation vial to form a 0.6 wt% MUC2 solution. The prepared 0.6 wt% MUC2 solution is tested for viscosity according to the procedure described below.

[0154] An equal volume (1 mL) of a 2 wt% hydrophilic copolymer solution and DPBS are mixed in a 20 mL scintillation vial to form a 1 wt% copolymer solution. The prepared 1 wt% copolymer solution is tested for viscosity according to the procedure described below.

[0155] Add 2 mL of 2.0% copolymer solution to a 20 mL scintillation vial equipped with a stirring bar. Place the vial on a stirring plate set to 500–600 RPM. Dropwise add 2 mL of 1.2% MUC2 solution over 10–20 seconds. Verify that the mixed solution exhibits free flow as a uniform viscous solution free of clusters or solidified gels. Mix the solution at 500–600 RPM for 30 minutes, then reduce the mixing speed to 150–200 RPM for 20–30 minutes to eliminate air bubbles.

[0156] Perform viscosity measurements on a DVNext Wells-Brookfield Cone / Plate Rheometer as follows. Place approximately 0.5 mL of sample into the sample cup. All viscosities are measured at room temperature using a size 40 spindle.

[0157] Example 3

[0158] Copolymer synthesis

[0159] A desired amount of CPBA is dissolved in DMSO to prepare a stock solution of CPBA (4 wt%); and a desired amount of Vazo-56, MBA, or MPC is dissolved in deionized water to prepare a stock solution of Vazo-56 (1 wt%), MBA (1 wt%), and MPC (17 wt%).

[0160] The stock solution is directly combined in a jacketed reactor equipped with an overhead stirrer, a condenser, a thermocouple, and a nitrogen gas dispersion frit tube to satisfy the target amount as shown in Table 1. Subsequently, the remainder is filled with water to produce a final 5% solid solution ([Vazo-56] = 2,2'-azobis(2-methylpropionamidine) dihydrochloride).

[0161] [Table 1]

[0162]

[0163] The first value represents weight %, and the value in parentheses represents mole %.

[0164] Oxygen is removed from the polymerizable composition by purging with nitrogen. The frit of the gas dispersion tube is left over the polymerizable composition, and a nitrogen flow of approximately 50 mL / min is maintained throughout the polymerization. The temperature of the polymerizable composition is increased from 16°C to 56°C over 2 hours. After 10 hours, the temperature is lowered from 56°C to 20°C over 2 hours. The crude polymer solution is purified by ultrafiltration using a 1 M Dalton cutoff membrane to remove residual monomers, low MW polymers, and any residual solvent. For further characterization and testing, the purified polymer is freeze-dried.

[0165] The purified polymer is characterized. The results are provided in Table 2.

[0166] [Table 2]

[0167]

[0168] * Content of phenylboronic acid; the value in parentheses is a theoretical value based on the composition of the polymerizable composition.

[0169] Example 4

[0170] A water-soluble hydrophilic copolymer is prepared and characterized according to the procedure described in Example 3. The composition of the polymerizable composition for preparing the copolymer and the results of the characterization are reported in Table 3.

[0171] [Table 3]

[0172]

[0173] The first value represents weight %, and the value in parentheses represents mole %.

[0174] Example 5

[0175] A water-soluble hydrophilic copolymer is prepared and characterized according to the procedure described in Example 3. The composition of the polymerizable composition for preparing the copolymer and the results of the characterization are reported in Table 4.

[0176] [Table 4]

[0177]

[0178] The first value represents weight %, and the value in parentheses represents mole %.

[0179] Example 6

[0180] A water-soluble hydrophilic copolymer is prepared and characterized according to the procedure described in Example 3. The composition of the polymerizable composition for preparing the copolymer and the results of the characterization are reported in Table 5.

[0181] [Table 5]

[0182]

[0183] The first value represents weight %, and the value in parentheses represents mole %.

[0184] Example 7

[0185] The polymer-mucin-interaction synergy (PMIS) of the water-soluble hydrophilic copolymer prepared in Example 3 is determined according to the procedure described in Example 2. The results are reported in Tables 6 and 7.

[0186] [Table 6]

[0187]

[0188] [Table 7]

[0189]

[0190] Table 6 shows a comparison of the strength of polymer-mucin interactions of the copolymer of the present invention (having repeating monomer units of CPBA with a pKa of about 7.2) and the strength of the control copolymer (having repeating monomer units of APBA with a pKa of about 8.1). The water-soluble hydrophilic copolymer of the present invention has stronger mucin interactions than the control copolymer.

[0191] Table 7 shows DMA (N H-결합 공여체 - N H-결합 수용체= 0 -1=-1) is HEAm (N H-결합 공여체 - N H-결합 수용체 It is shown that replacing with =2-2=0) significantly enhances polymer-mucin interactions. Viscosity increases from 46 cP (DMA) to 141 cP (HEAm), corresponding to PMIS of 426% and 1739%, respectively. These results may be due to the formation of hydrogen bonds between the HEAm-containing copolymer and mucin caused by the presence of H-bond donors in HEAm. On the other hand, the addition of MPC (20 mol%) to either copolymer reduces PMIS, i.e., polymer-mucin interactions (Table 7). While 2-methacryloyloxyethylphosphorylcholine (MPC) can weaken mucin interactions, HEAm appears to help restore interaction strength.

[0192] Example 8

[0193] The polymer-mucin-interaction synergy (PMIS) of the water-soluble hydrophilic copolymer prepared in Example 4 is determined according to the procedure described in Example 2. The results are reported in Table 8.

[0194] [Table 8]

[0195]

[0196] Table 8 shows the effect of repeat monomer unit content of CPBA on the PMIS (polymer-mucin interaction strength) of poly(DMA-MPC-CPBA). As the CPBA content increases, the PMIS increases (i.e., the polymer-mucin interaction is stronger).

[0197] Example 9

[0198] The polymer-mucin-interaction synergy (PMIS) of the water-soluble hydrophilic copolymer prepared in Example 5 is determined according to the procedure described in Example 2. The results are reported in Table 9.

[0199] [Table 9]

[0200]

[0201] Table 9 shows the effect of repeat monomer unit content of CPBA on the PMIS (polymer-mucin interaction strength) of poly(HEAm-MPC-CPBA). As the CPBA content increases, the PMIS increases (i.e., the polymer-mucin interaction is stronger).

[0202] Example 10

[0203] The polymer-mucin-interaction synergy (PMIS) of the water-soluble hydrophilic copolymer prepared in Example 6 is determined according to the procedure described in Example 2. The results are reported in Table 10.

[0204] [Table 10]

[0205]

[0206] Table 10 shows the effect of repeat monomer unit content of MPC on the PMIS (polymer-mucin interaction strength) of poly(HEAm-MPC-CPBA). As the MPC content increases, the PMIS decreases (i.e., the polymer-mucin interaction is stronger).

[0207] All publications, patents, and patent application publications cited herein by reference are incorporated herein by reference in their entirety.

Claims

Claim 1 Acrylamido monomer of the following chemical formula 1: [Chemical Formula 1] (wherein R0 is H or CH3, R2 is NO2, F, Cl, Br, CF3, CCl3, or CH2N(CH3)2, L1 is a C2-C6 alkylene divalent radical or a divalent radical -R3-X1-R4-, X1 is an amide bond of -C(O)NH-, R3 and R4 are independently C2-C6 alkylene divalent radicals optionally substituted with one or more hydroxyl groups, and the acrylamido monomer has a pKa of about 6.4 to about 7.8). Claim 2 The acrylamido monomer according to claim 1, wherein in Formula 1, L1 is a divalent radical -R3-X1-R4-, X1 is an amide bond of -C(O)NH-, and R3 and R4 are independently C2-C6 alkylene divalent radicals selectively substituted with one or more hydroxyl groups. Claim 3 In claim 1, in Chemical Formula 1, L1 is an acrylamido monomer in which L1 is a C2-C6 alkylene divalent radical. Claim 4 In paragraph 1, an acrylamido monomer selected from the group consisting of the following: Claim 5 In any one of claims 1 to 4, the acrylamido monomer is an acrylamido monomer having a pKa of about 6.5 to 7.

5. Claim 6 A water-soluble hydrophilic copolymer comprising: (a) about 0.1 mol% to about 10 mol% of repeating monomer units of at least one acrylamido monomer of any one of claims 1 to 5; (b) about 85 mol% to about 99.9 mol% of repeating units of at least one hydrophilic vinyl monomer; and optionally (c) 0% to about 0.20 mol% of repeating units of at least one hydrophilic vinyl crosslinking agent, provided that components (a) and (b) are present in the water-soluble hydrophilic copolymer in a total amount of at least 90 mol%. Claim 7 In claim 6, the at least one hydrophilic vinyl monomer is (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N-ethyl (meth)acrylamide, N,N-diethyl (meth)acrylamide, N-propyl (meth)acrylamide, N-isopropyl (meth)acrylamide, N-3-methoxypropyl (meth)acrylamide, N-2-hydroxyethyl (meth)acrylamide, N,N-bis(hydroxyethyl)(meth)acrylamide, N-3-hydroxypropyl (meth)acrylamide, N-2-hydroxypropyl (meth)acrylamide, 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, di(ethylene glycol)(meth)acrylate, tri(ethylene glycol) (Met)acrylate, tetra(ethylene glycol) (meth)acrylate, poly(ethylene glycol) (meth)acrylate with a number average molecular weight of 1500 or less, poly(ethylene glycol)ethyl (meth)acrylamide with a number average molecular weight of 1500 or less, N-2-aminoethyl (meth)acrylamide, N-2-methylaminoethyl (meth)acrylamide, N-2-ethylaminoethyl (meth)acrylamide, N-2-dimethylaminoethyl (meth)acrylamide, N-3-aminopropyl (meth)acrylamide, N-3-methylaminopropyl (meth)acrylamide, N-3-dimethylaminopropyl (meth)acrylamide, 2-aminoethyl (meth)acrylate, 2-methylaminoethyl (meth)acrylate, 2-ethylaminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, 3-methylaminopropyl (Met)acrylate, 3-ethylaminopropyl (meth)acrylate, 3-amino-2-hydroxypropyl (meth)acrylate, trimethylammonium 2-hydroxypropyl (meth)acrylate hydrochloride, dimethylaminoethyl (meth)acrylate, 2-(meth)acrylamidoglycolic acid, (meth)acrylic acid, ethylacrylic acid, propylacrylic acid, 3-(meth)acrylamidopropionic acid, 4-(meth)acrylamidobutanoic acid, 5-(meth)acrylamidopentanoic acid, 3-(meth)acryloyloxypropanoic acid,4-(meth)acryloyloxybutanoic acid, 5-(meth)acryloyloxypentanoic acid, N-vinylpyrrolidone, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-6-methyl-2-pyrrolidone, N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinylpiperidone, N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl caprolactam, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-caprolactam, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, N-vinyl-N-methylacetamide, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-Vinyl-N-Ethyl Acetamide, N-Vinyl-N-Ethyl Formamide, 1-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, 1-n-Propyl-3-Methylene-2-Pyrrolidone, 1-n-Propyl-5-Methylene-2-Pyrrolidone, 1-Isopropyl-3-Methylene-2-Pyrrolidone, 1-Isopropyl-5-Methylene-2-Pyrrolidone, 1-n-Butyl-3-Methylene-2-Pyrrolidone, 1-tert-Butyl-3-Methylene-2-Pyrrolidone, Ethylene Glycol methyl ether (meth)acrylate, di(ethylene glycol) methyl ether (meth)acrylate, tri(ethylene glycol) methyl ether (meth)acrylate, tetra(ethylene glycol) methyl ether (meth)acrylate,C1-C4-alkoxy poly(ethylene glycol) (meth)acrylate with a weight average molecular weight of 1500 or less, methoxy-poly(ethylene glycol)ethyl (meth)acrylamide with a number average molecular weight of 1500 or less, ethylene glycol monovinyl ether, di(ethylene glycol) monovinyl ether, tri(ethylene glycol) monovinyl ether, tetra(ethylene glycol) monovinyl ether, poly(ethylene glycol) monovinyl ether, ethylene glycol methyl vinyl ether, di(ethylene glycol) methyl vinyl ether, tri(ethylene glycol) methyl vinyl ether, tetra(ethylene glycol) methyl vinyl ether, poly(ethylene glycol) methyl vinyl ether, allyl alcohol, ethylene glycol monoallyl ether, di(ethylene glycol) monoallyl ether, tri(ethylene glycol) monoallyl ether, tetra(ethylene glycol) monoallyl A water-soluble hydrophilic copolymer comprising ethers, poly(ethylene glycol) monoallyl ethers, ethylene glycol methylallyl ethers, di(ethylene glycol) methylallyl ethers, tri(ethylene glycol) methylallyl ethers, tetra(ethylene glycol) methylallyl ethers, poly(ethylene glycol) methylallyl ethers, phosphorylcholine-containing vinyl monomers, N-2-hydroxyethyl vinyl carbamate, N-carboxyvinyl-β-alanine (VINAL), N-carboxyvinyl-α-alanine, or combinations thereof. Claim 8 In claim 6 or 7, the at least one hydrophilic vinyl-based crosslinking agent is ethylene glycol di-(meth)acrylate, diethylene glycol di-(meth)acrylate, triethylene glycol di-(meth)acrylate, tetraethylene glycol di-(meth)acrylate, polyethylene glycol di-(meth)acrylate having a number average molecular weight of 200 to 1,000 daltons, glycerol di-(meth)acrylate, glycerol 1,3-diglycerolate di-(meth)acrylate, ethylenebis[oxy(2-hydroxypropane-1,3-diyl)] di-(meth)acrylate, bis[2-(meth)acryloxyethyl] phosphate, diacrylamide (i.e., N-(1-oxo-2-propenamide)-2-propenamide), dimethacrylamide (i.e., N-(1-oxo-2-methyl-2-propenamide)-2-methyl-2-propenamide), N,N-di(meth)acryloyl-N-methylamine, N,N-di(meth)acryloyl-N-ethylamine, N,N'-methylene bis(meth)acrylamide, N,N'-dihydroxyethylene bis(meth)acrylamide, N,N'-propylene bis(meth)acrylamide, N,N'-2-hydroxypropylene bis(meth)acrylamide, N,N'-2,3-dihydroxybutylene bis(meth)acrylamide, 1,3-bis(meth)acrylamide-propane-2-yl dihydrogen phosphate (i.e., N,N'-2-phosphonyoxypropylene bis(meth)acrylamide), piperazine Diacrylamide (or 1,4-bis(meth)acryloylpiperazine), and combinations thereof, more preferably comprising ethylene glycol di-(meth)acrylate, diethylene glycol di-(meth)acrylate, triethylene glycol di-(meth)acrylate, tetraethylene glycol di-(meth)acrylate, polyethylene glycol di-(meth)acrylate having a number average molecular weight of 200 to 1000 daltons, N,N-di(meth)acryloyl-N-methylamine, N,N-di(meth)acryloyl-N-ethylamine, N,N'-methylene bis(meth)acrylamide, N,N'-ethylene bis(meth)acrylamide, N,N'-dihydroxyethylene bis(meth)acrylamide, N,A water-soluble hydrophilic copolymer selected from the group consisting of N'-propylene bis(meth)acrylamide, N,N'-2-hydroxypropylene bis(meth)acrylamide, N,N'-2,3-dihydroxybutylene bis(meth)acrylamide, and combinations thereof. Claim 9 A water-soluble hydrophilic copolymer according to any one of claims 6 to 8, wherein the water-soluble hydrophilic copolymer comprises about 5 mol% to about 35 mol% of repeating monomer units of at least one phosphorylcholine-containing vinyl monomer and about 60 mol% to about 94.9 mol% of repeating units of at least one hydrophilic vinyl monomer other than the phosphorylcholine-containing vinyl monomer. Claim 10 In claim 9, the water-soluble hydrophilic copolymer comprises about 65 mol% to about 94 mol% of repeating units of at least one hydrophilic vinyl monomer other than the phosphorylcholine-containing vinyl monomer. Claim 11 In claim 9 or 10, the at least one phosphorylcholine-containing vinyl monomer is (meth)acryloyloxyethyl phosphorylcholine, (meth)acryloyloxypropyl phosphorylcholine, 4-((meth)acryloyloxy)butyl-2'-(trimethylammonio)ethyl phosphate, 2-[(meth)acryloylamino]ethyl-2'-(trimethylammonio)-ethyl phosphate, 3-[(meth)acryloylamino]propyl-2'-(trimethylammonio)ethyl phosphate, 4-[(meth)acryloylamino]butyl-2'-(trimethylammonio)ethyl phosphate, 5-((meth)acryloyloxy)pentyl-2'-(trimethylammonio)ethyl phosphate, 6-((meth)acryloyloxy)hexyl-2'-(trimethylammonio)-ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(triethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(tripropylammonio)ethyl phosphate, 2-((meth)acryloyloxy)ethyl-2'-(tributylammonio)ethyl phosphate, 2-((meth)acryloyloxy)propyl-2'-(trimethylammonio)-ethyl phosphate, 2-((meth)acryloyloxy)butyl-2'-(trimethylammonio)ethyl phosphate, 2-((meth)acryloyloxy)pentyl-2'-(trimethylammonio)ethyl phosphate, A water-soluble hydrophilic copolymer selected from the group consisting of 2-((meth)acryloyloxy)hexyl-2'-(trimethylammonio)ethyl phosphate, 2-(vinyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(vinyloxycarbonyl)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxycarbonyl)ethyl-2'-(trimethylammonio)-ethyl phosphate, 2-(vinylcarbonylamino)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(allyloxycarbonylamino)ethyl-2'-(trimethylammonio)ethyl phosphate, 2-(butenoyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, and combinations thereof. Claim 12 In any one of claims 6 to 11, the at least one hydrophilic vinyl monomer is (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N-ethyl (meth)acrylamide, N,N-diethyl (meth)acrylamide, N-propyl (meth)acrylamide, N-isopropyl (meth)acrylamide, N-3-methoxypropyl (meth)acrylamide, N-2-hydroxyethyl (meth)acrylamide, N,N-bis(hydroxyethyl) (meth)acrylamide, N-3-hydroxypropyl (meth)acrylamide, N-2-hydroxypropyl (meth)acrylamide, poly(ethylene glycol)ethyl (meth)acrylamide having a number average molecular weight of 1500 or less, N-2-aminoethyl (meth)acrylamide, N-2-methylaminoethyl (meth)acrylamide, N-2-ethylaminoethyl A water-soluble hydrophilic copolymer comprising at least one hydrophilic acrylamido monomer selected from the group consisting of (meth)acrylamide, N-2-dimethylaminoethyl (meth)acrylamide, N-3-aminopropyl (meth)acrylamide, N-3-methylaminopropyl (meth)acrylamide, N-3-dimethylaminopropyl (meth)acrylamide, 2-(meth)acrylamidoglycolic acid, 3-(meth)acrylamidopropionic acid, 4-(meth)acrylamidobutanoic acid, 5-(meth)acrylamidopentanoic acid, and combinations thereof. Claim 13 In any one of claims 6 to 11, the at least one hydrophilic vinyl monomer is 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, di(ethylene glycol) (meth)acrylate, tri(ethylene glycol) (meth)acrylate, tetra(ethylene glycol) (meth)acrylate, poly(ethylene glycol) (meth)acrylate having a number average molecular weight of 1500 or less, poly(ethylene glycol)ethyl (meth)acrylamide having a number average molecular weight of 1500 or less, 2-aminoethyl (meth)acrylate, 2-methylaminoethyl (meth)acrylate, 2-ethylaminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, 3-methylaminopropyl (meth)acrylate, 3-ethylaminopropyl A water-soluble hydrophilic copolymer comprising a hydrophilic acrylic monomer selected from the group consisting of (meth)acrylate, 3-amino-2-hydroxypropyl (meth)acrylate, trimethylammonium 2-hydroxypropyl (meth)acrylate hydrochloride, dimethylaminoethyl (meth)acrylate, (meth)acrylic acid, ethylacrylic acid, propylacrylic acid, 3-(meth)acryloyloxypropanoic acid, 4-(meth)acryloyloxybutanoic acid, 5-(meth)acryloyloxypentanoic acid, and combinations thereof. Claim 14 A water-soluble hydrophilic copolymer according to any one of claims 6 to 11, wherein the at least one hydrophilic vinyl monomer comprises a vinyl monomer selected from the group consisting of N-vinylpyrrolidone, N-vinyl-N-methylacetamide, N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl-N-ethylacetamide, N-vinyl-N-ethyl formamide, and mixtures thereof. Claim 15 In any one of claims 6 to 14, the water-soluble hydrophilic copolymer is a water-soluble hydrophilic copolymer having a number average molecular weight of about 10,000 daltons to about 10,000,000 daltons. Claim 16 An ophthalmic composition comprising a water-soluble hydrophilic copolymer according to any one of claims 6 to 15.

Images