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US-12624204-B2 - Ultra-high molecular weight polymers and methods of using the same

US12624204B2US 12624204 B2US12624204 B2US 12624204B2US-12624204-B2

Abstract

The present disclosure provides for compositions including at least one type of water-soluble polymer, methods of making the water-soluble polymer, structures having the water-soluble polymer disposed thereof, and methods of use thereof.

Inventors

  • Cullen L. Davidson
  • Wallace G. Sawyer
  • Brent S. Sumerlin
  • Juan M. Urueña Vargas

Assignees

  • UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC.

Dates

Publication Date
20260512
Application Date
20220830

Claims (20)

  1. 1 . A composition comprising: an ophthalmic aqueous solution including a first water-soluble polymer, wherein the first water-soluble polymer includes a plurality of backbone units and at least one first type of a mucin-binding unit, wherein the backbone units comprise greater than 50% of the first water-soluble polymer based on molecular weight, wherein the first type of mucin-binding unit comprises of 1 unit up to 50% of the first water-soluble polymer based on molecular weight, wherein the first type of mucin-binding unit comprises monomer units, copolymers that include the monomer units, or both, wherein the monomer unit includes a boronic acid group, wherein the first water-soluble polymer includes a second type of mucin-binding unit, wherein the second type of mucin-binding unit comprises monomer units, copolymers that include the monomer units, or both, wherein the monomer unit is selected from the group consisting of: acrylic acid, methacrylic acid, 4-vinylbenzoic acid, 4-(acrylamido)phenylboronic acid, 3-(acrylamido)phenylboronic acid, (2-(3-acrylamidopropanamido)phenyl) boronic acid (APAPBA), 2-(acrylamido)phenylboronic acid, 4-vinylphenylboronic acid, 3-vinylphenylboronic acid, 2-vinylphenylboronic acid, 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, pyridyl disulfide ethyl acrylate, pyridyl disulfide ethyl acrylamido, pyridyl disulfide alkyl (e.g. ethyl) methacrylamido, 2-(pyridin-2-yldisulfaneyl)ethyl acrylate, 2-(pyridin-2-yldisulfaneyl)ethyl acrylamido, 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, or 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, N-(2-(tritylthio)ethyl) acrylamide, a monomer including one or more boronic acid groups, a monomer containing one or more disulfide-forming groups, a halogenated versions of each of these, or a derivative of any one of these or copolymer of anyone of these, wherein the first type of mucin-binding unit is different than the second type of mucin-binding unit; wherein the first type of mucin binding unit comprises 1 functional unit to about 5% of the first water-soluble polymer based on molecular weight; wherein the second type of mucin binding unit comprises 1 functional unit to about 5% of the first water-soluble polymer based on molecular weight.
  2. 2 . The composition of claim 1 , wherein the backbone unit comprises monomer units, copolymers including the monomer units, or both the monomer units and the copolymers, wherein the monomer unit is selected from the group consisting of: an acrylamide monomer, a methacrylamide monomer, an acrylate monomer, a methacrylate monomer, a styrenic monomer, a vinyl pyridine monomer, a maleimide monomer, a maleic anhydride-derived monomer, a vinyl ester monomer, a vinyl ether monomer, a vinyl amide monomer, a vinyl amine monomer, a vinyl halide monomer, or a derivative of anyone of these.
  3. 3 . The composition of claim 1 , wherein the backbone unit comprises a monomer unit, a copolymer including the monomer unit or both, wherein the monomer unit is selected from the group consisting of: acrylamide, N,N-dimethylacrylamide, N,N-dialkylacrylamides, N-alkylacrylamides, N,N-dialkyl methacrylamides, N-alkyl methacrylamides, poly(ethlylene glycol) acrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) acrylamide, and poly(ethylene glycol) methacrylamide.
  4. 4 . The composition of claim 1 , wherein the backbone unit is N,N-dimethylacrylamide.
  5. 5 . The composition of claim 1 , wherein the first water-soluble polymer includes a second type of mucin-binding unit, wherein the second type of mucin-binding unit comprises monomer units, copolymers that include the monomer units, or both, wherein the monomer unit is selected from the group consisting of: acrylic acid, methacrylic acid, 4-vinylbenzoic acid, 4-(acrylamido)phenylboronic acid, 3-(acrylamido)phenylboronic acid, (2-(3-acrylamidopropanamido)phenyl) boronic acid (APAPBA), 2-(acrylamido)phenylboronic acid, 4-vinylphenylboronic acid, 3-vinylphenylboronic acid, 2-vinylphenylboronic acid, 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, pyridyl disulfide ethyl acrylate, pyridyl disulfide ethyl acrylamido, pyridyl disulfide alkyl (e.g. ethyl) methacrylamido, 2-(pyridin-2-yldisulfaneyl)ethyl acrylate, 2-(pyridin-2-yldisulfaneyl)ethyl acrylamido, 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, or 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, N-(2-(tritylthio)ethyl) acrylamide, a monomer including one or more boronic acid groups, a monomer containing one or more disulfide-forming groups, a halogenated versions of each of these, or a derivative of any one of these or copolymer of anyone of these, wherein the first type of mucin-binding unit is different than the second type of mucin-binding unit.
  6. 6 . The composition of claim 5 , wherein the first water-soluble polymer includes a third type of mucin-binding unit, wherein the third type of mucin-binding unit comprises monomer units, copolymers that include the monomer units, or both, wherein the monomer unit is selected from the group consisting of: acrylic acid, methacrylic acid, 4-vinylbenzoic acid, 4-(acrylamido)phenylboronic acid, 3-(acrylamido)phenylboronic acid, (2-(3-acrylamidopropanamido)phenyl) boronic acid (APAPBA), 2-(acrylamido)phenylboronic acid, 4-vinylphenylboronic acid, 3-vinylphenylboronic acid, 2-vinylphenylboronic acid, 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, pyridyl disulfide ethyl acrylate, pyridyl disulfide ethyl acrylamido, pyridyl disulfide alkyl (e.g. ethyl) methacrylamido, 2-(pyridin-2-yldisulfaneyl)ethyl acrylate, 2-(pyridin-2-yldisulfaneyl)ethyl acrylamido, 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, or 2-(pyridin-2-yldisulfaneyl)ethyl methacrylate, N-(2-(tritylthio)ethyl) acrylamide, a monomer including one or more boronic acid groups, a monomer containing one or more disulfide-forming groups, a halogenated versions of each of these, or a derivative of any one of these or copolymer of anyone of these, wherein the first type of mucin-binding unit is different than the second type of mucin-binding unit, wherein the second type of mucin-binding unit is different than the third type of mucin-binding unit monomer including one or more pyridyl disulfide groups, or a derivative of any one of these.
  7. 7 . The composition of claim 6 , wherein the first type of mucin binding unit comprises 1 functional unit to about 5% of the first water-soluble polymer based on molecular weight; wherein the second type of mucin binding unit comprises 1 functional unit to about 5% of the first water-soluble polymer based on molecular weight; wherein the third type of mucin binding unit comprises 1 functional unit to about 5% of the first water-soluble polymer based on molecular weight.
  8. 8 . The composition of claim 1 , wherein the first water-soluble polymer has a structure that is linear or non-linear, wherein the non-linear structure is selected from the group consisting of star-like, branched, hyperbranched, cyclic, graph copolymer, or bottle brush-like.
  9. 9 . The composition of claim 1 , wherein the first type of mucin binding unit is located solely at one or both terminal ends of the first water-soluble polymer.
  10. 10 . The composition of claim 1 , wherein the first water-soluble polymer is selected from the group consisting of: a block copolymer, a random copolymer, a statistical copolymer, an alternative copolymer, or a gradient copolymer.
  11. 11 . The composition of claim 10 , wherein the block copolymer is an AB diblock copolymer or an ABA triblock copolymer, optionally wherein the mucin-binding units are isolated on the A block of the AB diblock copolymer or A block of the ABA triblock copolymer.
  12. 12 . The composition of claim 1 , wherein the first water-soluble polymer has the following chemical structure: wherein unit a is the backbone unit and m is greater than 50% of the first water-soluble polymer based on molecular weight, wherein unit b is the first type of mucin binding unit and n is 1 unit to about 50% of the first water-soluble polymer based on molecular weight, wherein unit a and unit b are different from one another, R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R b3 , and R b4 , independently of one another, are selected from: H, —OR 1 , —NR 1 R 2 , —N + (R 1 ) 3 , —N + (R 1 ) 2 (R 2 ), —N + (R 1 ) (R 2 )(R 3 ), —S(O) 2 R 1 , —S(O) 2 OR 1 , —S(O) 2 NR 1 R 2 , —NR 1 S(O) 2 R 2 , —NR 1 C(O)R 2 , —C(O)R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)NR 1 S(O) 2 NR 1 R 2 , catechol, a boronic acid group, and a pyridyl disulfide group, where each R 1 , R 2 , and R 3 is independently H or a linear or branched C 1-18 alkyl as well as —C(O)OCH 2 CH 2 —OH, —C(O)OCH 2 CH 2 —N(CH 3 ) 2 , —C(O)OCH 2 CH 2 —N + (CH 3 ) 3 , —C(O)OCH 2 CH 2 —OSO 3 —, —C(O)OCH 2 CH 2 —OSO 3 H, —C(O)OCH 2 CH 2 —SO 3 , —C(O)OCH 2 CH 2 —SO 3 H, and —C(O)N(H)C((CH 3 ) 2 )CH 2 SO 3 , —C(O)N(H)C((CH 3 ) 2 )CH 2 SO 3 H, wherein one of R b1 , R b2 , R b3 , R b4 , is a boronic acid group, wherein X is C, and wherein Y is C.
  13. 13 . The composition of claim 1 , wherein the first water-soluble polymer has the following chemical structure: wherein unit a is the backbone unit and m is greater than 50% of the first water-soluble polymer based on molecular weight, wherein unit b is the first type of mucin binding unit and n is 1 unit to about 50% of the first water-soluble polymer based on molecular weight, wherein unit c is the second type of mucin binding unit and o is 1 unit to about 50% of the first water-soluble polymer based on molecular weight, wherein unit a and unit b are different from one another, R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R b3 , R b4 , R c1 , R c2 , R c3 , and R c4 , independently of one another, can be H, —OR 1 , —NR 1 R 2 , —N + (R 1 ) 3 , —N + (R 1 ) 2 (R 2 ), —N + (R 1 )(R 2 )(R 3 ), —S(O) 2 R 1 , —S(O) 2 OR 1 , —S(O) 2 NR 1 R 2 , —NR 1 S(O) 2 R 2 , —NR 1 C(O)R 2 , —C(O)R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)NR 1 S(O) 2 NR 1 R 2 , catechol, a boronic acid group, and a pyridyl disulfide group, where each R 1 , R 2 , and R 3 is independently H or linear or branched C 1-18 alkyl as well as —C(O)OCH 2 CH 2 —OH, —C(O)OCH 2 CH 2 —N(CH 3 ) 2 , —C(O)OCH 2 CH 2 —N + (CH 3 ) 3 , —C(O)OCH 2 CH 2 —OSO 3 —, —C(O)OCH 2 CH 2 —OSO 3 H, —C(O)OCH 2 CH 2 —SO 3 —, —C(O)OCH 2 CH 2 —SO 3 H, and —C(O)N(H)C((CH 3 ) 2 ) CH 2 SO 3 —, —C(O)N(H)C((CH 3 ) 2 ) CH 2 SO 3 H, wherein one of R b1 , R b2 , R b3 , R b4 , is a boronic acid group, wherein X is C, wherein Y is C, and wherein Z is C.
  14. 14 . The composition of claim 13 , wherein unit a, unit b, and unit c are different from one another.
  15. 15 . The composition of claim 1 , wherein the first water-soluble polymer has chemical structure as shown below: wherein unit a is the backbone unit and m is greater than 50% of the first water-soluble polymer based on molecular weight, wherein unit b is the first type of mucin binding unit and n is 1 unit to about 50% of the first water-soluble polymer based on molecular weight, wherein unit c is the second type of mucin binding unit and o is 1 unit to about 50% of the first water-soluble polymer based on molecular weight, wherein unit d is the second type of mucin binding unit and o is 1 unit to about 50% of the first water-soluble polymer based on molecular weight, wherein unit a and unit b are different from one another, R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R b3 , R b4 , R c1 , R c2 , R c3 , R c4 , R d1 , R d2 , R d3 , and R d4 , independently of one another, can be H, —OR 1 , —NR 1 R 2 , —N + (R 1 ) 3 , —N + (R 1 ) 2 (R 2 ), —N + (R 1 ) (R 2 ) (R 3 ), —S(O) 2 R 1 , —S(O) 2 OR 1 , —S(O) 2 NR 1 R 2 , —NR 1 S(O) 2 R 2 , —NR 1 C(O)R 2 , —C(O)R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)NR 1 S(O) 2 NR 1 R 2 , catechol, a boronic acid group, and a pyridyl disulfide group, where each R 1 , R 2 , and R 3 is independently H or linear or branched C 1-18 alkyl as well as —C(O)OCH 2 CH 2 —OH, —C(O)OCH 2 CH 2 —N(CH 3 ) 2 , —C(O)OCH 2 CH 2 —N + (CH 3 ) 3 , —C(O)OCH 2 CH 2 —OSO 3 —, —C(O)OCH 2 CH 2 —OSO 3 H, —C(O)OCH 2 CH 2 —SO 3 —, —C(O)OCH 2 CH 2 —SO 3 H, and —C(O)N(H)C((CH 3 ) 2 ) CH 2 SO 3 , —C(O)N(H)C((CH 3 ) 2 ) CH 2 SO 3 H, wherein one of R b1 , R b2 , R b3 , R b4 , is a boronic acid group, wherein X is C, wherein Y is C, wherein Z is C, and wherein Q is C.
  16. 16 . The composition of claim 15 , wherein unit a, unit b, unit c, and unit d are different from one another.
  17. 17 . A synthetic method of making the first water-soluble polymer of claim 1 , comprising: polymerizing a backbone unit and at least one mucin-binding unit to form the first water-soluble polymer of claim 1 .
  18. 18 . A composition comprising: an ophthalmic aqueous solution including a first water-soluble polymer, wherein the first water-soluble polymer includes a plurality of backbone units and at least one first type of a mucin-binding unit, wherein the backbone units comprise greater than 50% of the first water-soluble polymer based on molecular weight, wherein the first type of mucin-binding unit comprises of 1 unit up to 50% of the first water-soluble polymer based on molecular weight, wherein the first type of mucin-binding unit comprises monomer units, copolymers that include the monomer units, or both, wherein the monomer unit includes a boronic acid group, wherein the first type of mucin binding unit is located solely at one or both terminal ends of the first water-soluble polymer.
  19. 19 . The composition of claim 18 , wherein the backbone unit comprises monomer units, copolymers including the monomer units, or both the monomer units and the copolymers, wherein the monomer unit is selected from the group consisting of: an acrylamide monomer, a methacrylamide monomer, an acrylate monomer, a methacrylate monomer, a styrenic monomer, a vinyl pyridine monomer, a maleimide monomer, a maleic anhydride-derived monomer, a vinyl ester monomer, a vinyl ether monomer, a vinyl amide monomer, a vinyl amine monomer, a vinyl halide monomer, or a derivative of anyone of these.
  20. 20 . The composition of claim 18 , wherein the backbone unit comprises a monomer unit, a copolymer including the monomer unit or both, wherein the monomer unit is selected from the group consisting of: acrylamide, N,N-dimethylacrylamide, N,N-dialkylacrylamides, N-alkylacrylamides, N,N-dialkyl methacrylamides, N-alkyl methacrylamides, poly(ethlylene glycol) acrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) acrylamide, and poly(ethylene glycol) methacrylamide.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 63/239,027, having the title “ULTRA-HIGH MOLECULAR WEIGHT POLYMERS AND METHODS OF USING THE SAME” filed Aug. 31, 2021, the disclosure of which is incorporated herein in by reference in its entirety. BACKGROUND The eye's first line of defense against the external environment is a thin stratified layer of moist epithelial cells at the surface of the cornea which are shielded by an aqueous and mucinous tear film. Ocular health, durability, and comfort are inexorably linked to the ability of these epithelial cells to produce mucins to form the glycocalyx and stabilize the tear film. Ocular mucins contribute to homeostasis on the ocular surface, maintain clarity of the cornea and the tear film, and provide a physical barrier of protection against foreign debris (e.g., pathogens, toxins, and particles) while permitting the rapid passage of selected gases, fluids, ions, and nutrients. The cornea and conjunctiva express lower molecular weight membrane-spanning mucins (MUC1, MUC4, MUC16, and MUC20), which anchor the secretory and gel-forming mucins (MUC2, MUC5AC) produced by goblet cells found in the conjunctival epithelia. The mucins present in the tear film (MUC1, MUC2, MUC4, MUC5AC, and MUC16) together form a gel layer that serves to maintain hydration and clarity of the ocular surface, provide lubrication, and resist adhesion between the corneal and conjunctival epithelia during an eyeblink. These mucins create a gel-spanning hydrogel network, called the glycocalyx, which stabilizes the tear film and prevents dewetting. This gel network is primarily crosslinked through physical crosslinks, as opposed to chemical crosslinks. Critically, the weak physical crosslinks and the large mesh-size of mucin gels result in a surface with an intrinsically low shear stress during sliding and a low yield stress. The physical crosslinks break and heal dynamically under conditions when the yield stress is exceeded (e.g., during blinking); the gel spanning mucin network acts like a mechanical fuse limiting the potentially damaging level of stress that can be transmitted to the underlying epithelial cells. Table 1 (FIG. 1) shows a list of the mucins found in the ocular environment. This wide array of mucins function as a system to create a gel spanning network with finite yield stress, shear thinning, and maintain a smooth and uniform film thickness across the optical interface. Gel-forming and soluble mucins are not formed by corneal epithelial cells. The eyes are rarely at rest during waking hours and blink about 20,000 times in a day. During a blink, the eyelid wiper accelerates to a maximum speed of approximately 100 mm/s, approaches the lower eyelid, and then retracts back; the entire process takes place in ˜100 milliseconds. The contact pressure exerted on the cornea by the eyelid during this activity has not been directly measured but is thought to be on the order of 1-5 kPa. A schematic of the corneal epithelium, tear film, mucins associated with the ocular surface, including mucin MUC20 secreted between cells, and the waxy lipid layer is shown schematically in the inset of FIG. 2. The homeostasis in the healthy eye is a dynamic equilibrium that requires low shear stress across the cornea and conjunctiva. This achieved through the maintenance of a tear film comprised of mucins, salts, proteins, and a complex array of cytokines, chemokines, and growth factors. Defects in the composition of the tear film can lead to elevated levels dehydration and shear stress. Both tissues are highly innervated with pain receptors and shear stresses above physiologically “normal” level can produce the perception of pain. The tear film (˜5 μm thickness) covers the corneal epithelial cells of the ocular surface (˜55 μm thickness). The lipid rafts (50-100 nm in thickness) are produced by meibomian glands at the rim of the eyelids and are thought to impede evaporation of the tear film and prevent fine dust and debris from entering the ocular environment. The inset also illustrates the large molecular weight and complex structure of secretory and gel-forming mucins, as well as soluble, tear film mucins. The ultrastructure of the corneal epithelium and detail of the microvilli on the surface of the stratified squamous epithelium increase the surface area for secreting membrane-bound mucins MUC1, MUC4, and MUC16. Together these mucins anchor the secretory and soluble mucins and form a bio-polymer hydrogel, called the glycocalyx, which stabilizes the tear film and prevents dewetting. Dry eye discomfort may have an underlying etiology that involves frictional shear stresses exceeding physiological levels that can be well tolerated. The quality of the tear film is critically important for both of these applications. SUMMARY The present disclosure provides for compositions including at least one type of water-soluble pol