Injectable tissue supplement

Patent metadata

Field	Value
Publication number	US-2016263278-A1
Application number	US-201615159184-A
Country	US
Kind code	A1
Filing date	May 19, 2016
Priority date	Nov 20, 2013
Publication date	Sep 15, 2016
Grant date	—

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.

First claim

What is claimed is:

1 . A polymer synthesized in situ or ex situ, wherein the polymer comprises one or more monomers selected from sugar molecules and polyethylene glycols comprising an ethylenically unsaturated group, compounds of Formula I-XIV, compounds of Formula XVII-XXXVII, or any combinations thereof, wherein compounds of Formulas I-XIV are:

compounds of Formulas XVII-XXXVII are:

wherein:
R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, H, halide, ether-linked alkyl, ether-linked alkenyl, ether-linked alkynyl;
R 3 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, S, Se, or NH;
X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently selected from the group consisting of OH, OSO 3 H, OSO 3 − J + , OPO 3 H 2 , OPO 3 H − J + , OPO 3 2− 2J + , OPO 3 2− Z 2+ , NH 2 , and NC(O)CH 3 ;
Y is independently for each occurrence H, CH 2 OH, COOH, COO − J + , CH 2 OSO 3 H, CH 2 OSO 3 − J + , CH 2 OPO 3 H 2 , CH 2 OPO 3 H − J + , CH 2 OPO 3 2− 2J + , or CH 2 OPO 3 2− Z 2+ ;
J + is a monovalent cation;
Z 2+ is a divalent cation;
Q 1 , Q 2 and Q 3 are each independently selected from the group consisting of C, Si, or ethylene glycol, or a hydrophilic monomer;
E 1 , E 2 , E 3 , E 4 , E 5 are each independently selected from the group consisting of O, S, Se, or NH;
n and m can each independently range from 0-14; and
a is an integer from 0-1200.

2 . The polymer 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.

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

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

5 . The polymer of claim 1 , wherein the monomer is selected from the group consisting of N,N-dimethyl-N-acryloyloxyethyl-N-(3-sulfopropyl)-ammonium betaine, N,N-dimethyl-N-acrylamidopropyl-N-(2-carboxymethyl)-ammonium betaine, N,N-dimethyl-N-acrylamidopropyl-N-(3-sulfopropyl)-ammonium betaine, N,N-dimethyl-N-acrylamidopropyl-N-(2-carboxymethyl)-ammonium betaine, 2-(methylthio)ethyl methacryloyl-S-(sulfopropyl)-sulfonium betaine, 2-[(2-acryloylethyl)dimethylammonio]ethyl 2-methyl phosphate, 2-(acryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphate, [(2-acryloylethyl)dimethylammonio]methyl phosphonic acid, 2-methacryloyloxyethyl phosphorylcholine (MPC), 2-[(3-acrylamidopropyl)dimethylammonio]ethyl 2′-isopropyl phosphate (AAPI), 1-vinyl-3-(3-sulfopropyl)imidazolium hydroxide, (2-acryloxyethyl)carboxymethyl methylsulfonium chloride, 1-(3-sulfopropyl)-2-vinylpyridinium betaine, N-(4-sulfobutyl)-N-methyl-N,N-diallylamine ammonium betaine (MDABS), N,N-diallyl-N-methyl-N-(2-sulfoethyl)ammonium betaine, and any combination thereof.

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

7 . The polymer of claim 6 , wherein the cross-linker is selected from a compound of Formula XV or XVI:

and any combination thereof, wherein:
R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, H, halide, ether-linked alkyl, ether-linked alkenyl, ether-linked alkynyl;
R 3 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 1 and X 2 are each independently selected from O, S, Se, and NH;
Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently C, Si, ethylene glycol, or a hydrophilic monomer;

E 1 , E 2 , E 3 , E 4 , E 5 , and E 6 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.

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

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

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

11 . 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.

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

13 . 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.

14 . 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.

15 . The method of claim 9 , wherein polymer is in a pharmaceutical composition comprising the polymer and a pharmaceutically acceptable ex

Assignees

• Univ Boston

Inventors

• Grinstaff Mark
• Cooper Benjamin Goldman

Classifications

• A61L2430/06

  for cartilage reconstruction, e.g. meniscus · CPC title

• A61K9/06

  Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} · CPC title

• A61L2430/34

  for soft tissue reconstruction · CPC title

• A61L27/52

  Hydrogels or hydrocolloids · CPC title

• A61L27/54

  Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} · CPC title