# US 9,872,936 B2 · Injectable tissue supplement

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- Number: US 9,872,936 B2
- Document ID: US9872936B2
- Status: Granted
- Kind: B2
- Application number: 15/159,184
- Filed: 2016-05-19
- Published: 2016-09-15
- Granted: 2018-01-23
- Earliest claimed: 2013-11-20
- Assignees: Trustees of Boston University
- Applicants: Trustees of Boston University
- Inventors: Mark Grinstaff; Benjamin Goldman Cooper
- Web page: https://patentgrep.com/patent/US9872936B2

## CPC

- A61L 27/50: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials}
- A61L 27/18: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
- A61L 27/52: Hydrogels or hydrocolloids
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- C08F 230/02: containing phosphorus
- C08L 43/02: Homopolymers or copolymers of monomers containing phosphorus
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61L 2400/06: Flowable or injectable implant compositions
- A61L 2400/10: Materials for lubricating medical devices
- A61L 2430/06: for cartilage reconstruction, e.g. meniscus
- A61L 2430/34: for soft tissue reconstruction
- 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)
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- 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)

## Abstract

The present invention provides polymers which can be used as tissue supplements or lubricants in vivo. The inventive polymers can be used as tissue-interpenetrating hydrogel supplements, viscosupplements, tribosupplements, viscoelastics, tissue space fillers, and/or anti-adhesive agents. Also provided are pharmaceutical compositions comprising the inventive polymers and methods of using them including, for example, in the treatment of arthritic and injured synovial joints; in reconstruction or cosmetic procedures, intervertebral disc repair, treatment of vocal cord problems, treatment of urinary incontinence, and prevention of adhesion formation following abdominal or gynecological surgery or malfunction of naturally lubricious mucosal tissue.

## Claims

### Claim 1

An aqueous solution comprising a polymer dissolved therein, wherein the polymer in the aqueous solution comprises: (a) one or more monomers selected from compounds of Formulas I and II; and (b) one or more monomers selected from compounds of Formula XXXV, wherein compounds of Formulas I and II are:
wherein:
R1, R2, R4, R5, R6, R7, R11, R12, R13, and R14 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, H, halide, ether-linked alkyl, ether-linked alkenyl, ether-linked alkynyl;
R8, R9 and R10 are independently alkyl;
R3 is selected from the group consisting of hydrogen, a straight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, methoxy, ethoxy, amino, or fluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain is optionally substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents;
X is O;
Q1, Q2 and Q3 are each C;
E1, E2, E3, E4, E5 are each O;
n and m can each independently range from 0-14; and
m is 1-14;
compounds of Formulas XXXV are:
wherein:
R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, H, halide, ether-linked alkyl, ether-linked alkenyl, ether-linked alkynyl;
R3 is selected from the group consisting of hydrogen, a straight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, methoxy, ethoxy, amino, or fluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain is optionally substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents;
Q1, Q2, Q3 and Q4 are each C;
E1 and E2 are each O; and
a is an integer from 0-1200.

### Claim 2 (depends on 1)

The solution of claim 1, wherein the monomer comprises a functional group selected from the group consisting of carboxylic acid, carboxylate, sulfate, sulfonate, sulfuric acid, phosphate, phosphonate, phosphoric acid, amine, ammonium, phosphine, phosphonium, and ether.

### Claim 3 (depends on 1)

The solution of claim 1, wherein the monomer comprises a betaine.

### Claim 4 (depends on 1)

The solution of claim 1, wherein the monomer comprises a phosphorylcholine.

### Claim 5 (depends on 1)

The solution of claim 1, wherein the monomer is selected from the group consisting of
2-methacryloyloxyethyl phosphorylcholine (MPC),
and any combination thereof.

### Claim 6 (depends on 1)

The solution of claim 1, further comprising one or more cross-linkers.

### Claim 7 (depends on 6)

The solution of claim 6, wherein the cross-linker is selected from a compound of Formula XV or XVI:
and any combination thereof, wherein:
R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, H, halide, ether-linked alkyl, ether-linked alkenyl, ether-linked alkynyl;
R3 is selected from the group consisting of hydrogen, a straight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, methoxy, ethoxy, amino, or fluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain is optionally substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents;
X1 and X2 are each independently selected from O, S, Se, and NH;
Q1, Q2, Q3, Q4, and Q5 are each independently C, Si, ethylene glycol, or a hydrophilic monomer;
E1, E2, E3, E4, E5, and E6 are each independently selected from the group consisting of O, S, Se, or NH;
n, m, and p are integers, each independently ranging from 0-15.

### Claim 8 (depends on 7)

The solution of claim 7, wherein the cross-linker is ethylene glycol dimethacrylate (EGDMA) or methacryloyloxyethyl-N-(2-methacryloyloxyethyl phosphorylcholine).

### Claim 9 (depends on 1)

A method of treating a tissue in a subject, the method comprising administering to the subject a composition comprising the solution of claim 1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the tissue is diseased, injured, suboptimal, or defective.

### Claim 11 (depends on 9)

The method of claim 9, wherein the tissue is selected from group consisting of synovial joint, cartilage, tendon, ligament, vocal cord, urinary system, dermal tissue, epidermal tissue, intervertebral disc, abdominal tissue, ophthalmic tissue, gynecological tissue, epithelial tissue, and any combination thereof.

### Claim 12 (depends on 9)

The method of claim 9, further comprising administering an effective amount of at least one bioactive agent to the subject.

### Claim 13 (depends on 12)

The method of claim 12, wherein the bioactive agent is selected from the group consisting of small or large organic or inorganic molecules, monosaccharides, disaccharides, trisaccharides, oligosaccharides, polysaccharides, glycosaminoglycans, peptides, proteins, peptide analogs and derivatives thereof, peptidomimetics, polyclonal antibodies and antigen binding fragments thereof, monoclonal antibodies and antigen binding fragments thereof, lipids, nucleic acids, nucleic acid analogs and derivatives, an extract made from biological materials, naturally occurring or synthetic compositions, and any combination thereof.

### Claim 14 (depends on 12)

The method of claim 12, wherein the bioactive agent is selected from the group consisting of a growth factor, a cytokine, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an anti-inflammatory agent, an antioxidant, an antiseptic agent, and any combination thereof.

### Claim 15 (depends on 9)

The method of claim 9, wherein polymer is in a pharmaceutical composition comprising the polymer and a pharmaceutically acceptable excipient or carrier.

### Claim 16 (depends on 1)

The solution of claim 1, wherein the solution can be easily passed through a thin 27 gauge needle.

### Claim 17 (depends on 1)

The solution of claim 1, wherein the solution has a viscosity of 100 to 106 centipose.

### Claim 18 (depends on 17)

The solution of claim 17, wherein the polymer is present in a concentration of less than 10% (w/v).

### Claim 19 (depends on 1)

The solution of claim 1, wherein the polymer in the solution comprises monomer of Formula I and monomer of Formula XXXV.