# US 11,440,976 B2 · Functionalized and crosslinked polymers

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- Number: US 11,440,976 B2
- Document ID: US11440976B2
- Status: Granted
- Kind: B2
- Application number: 16/643,438
- Filed: 2018-09-01
- Published: 2020-06-18
- Granted: 2022-09-13
- Earliest claimed: 2017-09-01
- Assignees: Pmidg, LLC
- Applicants: Pmidg, LLC
- Inventors: David Gravett; Kara Bethany Acampora; Prabhjot Saini
- Web page: https://patentgrep.com/patent/US11440976B2

## CPC

- C08B 37/0072: {Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates}
- C08J 3/075: Macromolecular gels
- A61K 31/728: Hyaluronic acid
- A61L 26/0023: {Polysaccharides}
- A61L 26/0066: {Medicaments; Biocides}
- A61L 27/20: Polysaccharides
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61L 29/085: {Macromolecular materials}
- A61L 31/042: {Polysaccharides}
- A61L 31/10: Macromolecular materials
- C08L 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- C09D 105/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0034: {Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 33/38: Silver; Compounds thereof
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 38/4893: {Botulinum neurotoxin (3.4.24.69)}
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61L 29/16: Biologically active materials, e.g. therapeutic substances {(A61L29/048 takes precedence)}
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- B33Y 70/00: Materials specially adapted for additive manufacturing
- B33Y 80/00: Products made by additive manufacturing
- C08J 2305/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)
- C08J: WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H (working, e.g. shaping, of plastics B29)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- C09D: COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR (cosmetics A61K; processes for applying liquids or other fluent materials to surfaces, in general, B05D; staining wood B27K5/02; glazes or vitreous enamels C03C; natural resins, French polish, drying-oils, driers, turpentine, per se, C09F; polishing compositions other than French polish, ski waxes C09G; adhesives or use of materials as adhesives C09J; materials for sealing or packing joints or covers C09K3/10; materials for stopping leaks C09K3/12; processes for the electrolytic or electrophoretic production of coatings C25D)
- B33Y: ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING

## Abstract

Polyhydric polymers may be converted to derivatives thereof by reaction with divinyl sulfone to provide vinyl sulfone substituted polymers, where the polymers may additionally be further derivatized, including crosslinked, and the crosslinked and non-crosslinked derivatives may be used in biomedical and other applications.

## Claims

### Claim 1

A hyaluronic acid polymer derivative comprising one or more modified hydroxyl groups, wherein the hyaluronic acid polymer derivative has the formula:
A) HA-(OCH2CH2SO2CH2CH2—X—R1—Y)n, where HA is hyaluronic acid, X is S or NH, R1 is an aromatic moiety, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n is the number of modified hydroxyl groups where n≥1; or
B) (Y—R2—X—CH2CH2SO2CH2CH2O)m,—HA-(OCH2CH2SO2CH2CH2—X—R1—Y)n, where HA is hyaluronic acid, X is S or NH, R1 and R2 are each a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety, wherein R1 and R2 are different from each other, Y may be the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, or an amine group, and n≥1 and m≥1; or
C) (CH2═CH—SO2CH2CH2O)m—HA-(OCH2CH2SO2CH2CH2—X—R1—Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n≥1 and m≥1.

### Claim 2 (depends on 1)

A process for making a derivative polymer of claim 1, comprising:
a) reacting hydroxyl groups of hyaluronic acid (HA) polymer, with divinyl sulfone (DVS) to provide a first HA derivative; and
b) reacting the first HA derivative with a nucleophile of a formula X′—R1—Y, or X′—R2—Y, or both to provide a second HA derivative; wherein R1 and R2 are different and each is a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety, X′ is a nucleophilic group of SH or NH2, and Y is the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group.

### Claim 3 (depends on 2)

The process of claim 2, further comprising step c) derivatizing the second HA derivative polymer by repeating, one or more times, step a) or step a) and step b).

### Claim 4 (depends on 2)

The process of claim 2 wherein the second HA derivative is HA-(OCH2 CH2SO2CH2CH2—X—R1—Y)n (HA-DVS-N), wherein HA is hyaluronic acid, X is S or NH, wherein R1 is a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety; Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n≥1.

### Claim 5 (depends on 2)

The process of claim 2 wherein 0.25-50% of the hydroxyl groups present on the HA polymer are derivatized to —OCH2CH2SO2CH2CH2—X—R1—Y groups, wherein X is S or NH; wherein R1 is a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety; and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group.

### Claim 6 (depends on 2)

The process of claim 2 wherein 0.25-50% of the hydroxyl groups present on the HA polymer are derivatized to —OCH2CH2SO2CH2CH2—X—R1—Y and —OCH2CH2SO2CH2CH2—X—R2—Y groups, wherein R1 and R2 are different, and each is a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety, X is S or NH; and Y is the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group.

### Claim 7 (depends on 2)

The process of claim 2 wherein 0.25-50% of the hydroxyl groups present on the HA polymer are converted to oxyethyl ethenyl sulfone groups of the formula —OCH2CH2—SO2CH═CH2.

### Claim 8 (depends on 2)

The process of claim 2 wherein 0.25-50% of the hydroxyl groups present on the HA polymer are converted to oxyethyl ethenyl sulfone groups of the formula —OCH2CH2—SO2CH═CH2 and —OCH2CH2SO2CH2CH2—X—R1—Y, wherein R1 is a substituted or unsubstituted C1-C20 aliphatic or aromatic moiety, X is S or NH; and Y is the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group.

### Claim 9 (depends on 2)

The process of claim 2 wherein the first HA derivative is an oxyethyl ethenyl sulfone derivative of hyaluronic acid with the formula: HA-(OCH2CH2SO2CH═CH2)n (HA-DVS), wherein n≥1.

### Claim 10 (depends on 2)

The process of claim 2 further comprising reacting a product of step b) with a crosslinking agent to provide a crosslinked polymer.

### Claim 11 (depends on 2)

A derivative of hyaluronic acid prepared by the process of claim 2.

### Claim 12 (depends on 10)

A crosslinked polymer prepared by the process of claim 10.

### Claim 13 (depends on 1)

A composition comprising a hyaluronic acid polymer derivative of claim 1 and at least one of a pharmaceutically acceptable excipient, a synthetic polymer, thermosreversible polymer, biodegradable polymer, buffer, complexing agent, tonicity modulator, ionic strength modifier, solvent, anti-oxidant, preservative, viscosity modifier, pH modifier, surfactant, emulsifier, phospholipid, stabilizer or porogen.

### Claim 14 (depends on 1)

A method comprising administering to a subject in need thereof an effective amount of hyaluronic acid polymer derivative of claim 1, wherein the amount is effective to achieve at least one of treating a wound of the subject, filling a void in the subject, relieving joint pain in the subject, preventing surgical adhesions in the subject, sealing tissue in the subject, treating bacterial vaginosis in the subject, treating an ocular condition of the subject, treating mucocitis of the subject, and treating an ear infection of the subject.

### Claim 15 (depends on 1)

A method of drug delivery to a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a hyaluronic acid polymer derivative according to claim 1, and the drug.

### Claim 16 (depends on 1)

A method of supporting tissue growth in a subject in need thereof comprising implanting in the subject a tissue scaffold comprising a hyaluronic acid polymer derivative according to claim 1.

### Claim 17 (depends on 1)

A medical device comprising a derivative of hyaluronic acid according to claim 1.

### Claim 18 (depends on 1)

A method for additive manufacturing comprising producing, with an additive manufacturing apparatus, an article comprising a derivative of hyaluronic acid according to claim 1.

### Claim 19 (depends on 1)

A method for producing an electrospun material or article, comprising producing, with an electrospinning device, a material or an article comprising a derivative of hyaluronic acid according to claim 1.