# US 2019/0167838 A1 · Phosphorylated poly (ester-urea) based degradable bone adhesives

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- Number: US 2019/0167838 A1
- Document ID: US20190167838A1
- Status: Published application
- Kind: A1
- Application number: 16/095,718
- Filed: 2017-04-25
- Published: 2019-06-06
- Earliest claimed: 2016-04-28
- Assignees: The University of Akron
- Applicants: The University of Akron
- Inventors: Matthew BECKER; Vrushali Dinkar BHAGAT
- Web page: https://patentgrep.com/patent/US20190167838A1

## CPC

- A61L 24/0042: {Materials resorbable by the body}
- A61L 24/046: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds (A61L24/043 takes precedence)}
- C08K 3/16: Halogen-containing compounds
- C08L 75/02: Polyureas
- C08L 77/04: Polyamides derived from alpha-amino carboxylic acids (C08L77/10 takes precedence)
- C08K 2003/162: {Calcium, strontium or barium halides, e.g. calcium, strontium or barium chloride}
- C08K 2003/166: {Magnesium halide, e.g. magnesium chloride}
- C08K 2003/168: {Zinc halides}
- C08L 2203/02: for biomedical use
- 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)
- C08K: Use of inorganic or non-macromolecular organic substances as compounding ingredients (paints, inks, varnishes, dyes, polishes, adhesives C09)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

In various aspects, the present invention provides a degradable and resorbable novel phosphate functionalized amino acid-based poly(ester urea) adhesive and related methods for its synthesis and use. These adhesives are formed from phosphate functionalized PEU polymers and copolymers crosslinked using one or more divalent metal crosslinking agents. The phosphate functionalized amino acid-based poly(ester urea) adhesives of various embodiments of the present invention have been found particularly effective in bonding bone to either bone or metal and have demonstrated adhesive strengths on bone samples that were significant and comparable to commercially available poly(methyl methacrylate) bone cement.

## Claims

### Claim 1

A poly(ester urea) (PEU) based adhesive comprising:
a PEU polymer backbone having one or more side chains comprising a phosphate group; and
a crosslinking agent comprising a divalent metal salt.

### Claim 2 (depends on 1)

The PEU based adhesive of claim 1 wherein said PEU polymer chain comprises the residue of an amino acid selected from the group consisting of alanine (ala—A), glycine (gly—G), isoleucine (ile—I), leucine (leu—L), methionine (met—M), phenylalanine (phe—F), threonine (thr—T), tryptophan (trp—W), tyrosine (tyr—Y), or valine (val—V).

### Claim 3 (depends on 1)

The PEU based adhesive of claim 1 wherein said PEU polymer chain comprises the residue of one or more phosphorylated L-serine molecules.

### Claim 4 (depends on 1)

The PEU based adhesive of claim 1 wherein said PEU polymer backbone having one or more side chains comprising a phosphate group further comprises:
a residue of a first amino acid based polyester monomer comprising two phosphorylated amino acids separated by from 2 to 20 carbon atoms; and
a residue of a second amino acid based polyester monomer comprising two amino acids separated by from 2 to 20 carbon atoms.

### Claim 5 (depends on 4)

The PEU based adhesive of claim 4 wherein said first amino acid based polyester monomer comprises two phosphorylated L-serine molecules.

### Claim 6 (depends on 4)

The PEU based adhesive of claim 4 wherein said first amino acid based polyester monomer has the formula:
where a is an integer from about 1 to about 20.

### Claim 7 (depends on 4)

The PEU based adhesive of claim 4 wherein said second amino acid based polyester monomer comprises two amino acids selected from the group consisting of alanine (ala—A), glycine (gly—G), isoleucine (ile—I), leucine (leu—L), methionine (met—M), phenylalanine (phe—F), threonine (thr—T), tryptophan (trp—W), tyrosine (tyr—Y), or valine (val—V).

### Claim 8 (depends on 4)

The PEU based adhesive of claim 4 wherein said second amino acid based polyester monomer comprises valine or isoleucine.

### Claim 9 (depends on 4)

The PEU based adhesive of claim 4 wherein said second amino acid based polyester monomer has the formula:
where R is —CH3, H, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —(CH2)2SCH3, —CH2Ph-, —CH(OH)CH3, —CH2—C═CH—NH-Ph, —CH2-Ph-OH, —CH(CH3)2 and a is an integer from 1 to 20.

### Claim 10 (depends on 1)

The PEU based adhesive of claim 1 having the formula:
where R is —CH3, H, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —(CH2)2SCH3, —CH2Ph-, —CH(OH)CH3, —CH2—C═CH—NH-Ph, —CH2-Ph-OH, —CH(CH3)2; a is an integer from 1 to 20; m is a mole percent of from about 1% to about 20%; and n is a mole percent from about 80% to about 99%.

### Claim 11 (depends on 1)

The PEU based adhesive of claim 1 wherein said crosslinking agent is a divalent salt of a metal selected from the group consisting of calcium, magnesium, strontium, barium, zinc, and combinations thereof.

### Claim 12 (depends on 1)

The PEU based adhesive of claim 1 wherein said crosslinking agent comprises from about 1 mole percent to about 20 mole percent of said PEU based adhesive.

### Claim 13 (depends on 1)

A method of making the poly(ester urea) (PEU) based adhesive of claim 1 comprising:
A. preparing a PEU polymer having one or more side chains comprising a phosphate group;
B. adding a crosslinking agent comprising a divalent metal salt.

### Claim 14 (depends on 13)

The method of claim 13 wherein molar ratio of said PEU polymer having one or more side chains comprising a phosphate group to said crosslinking agent comprising a divalent metal salt is from about 1:1 to about 10:1

### Claim 15 (depends on 13)

The method of claim 13 wherein said PEU polymer having one or more side chains comprising a phosphate group has the formula:
where R is —CH3, H, —CH (CH3)CH2CH3, —CH2CH(CH3)2, —(CH2)2SCH3, —CH2Ph-, —CH(OH)CH3, —CH2—C═CH—NH-Ph, —CH2-Ph-OH, —CH(CH3)2; a is an integer from 1 to 20; m is a mole percent of from about 1% to about 20%; and n is a mole percent from about 80% to about 99%.

### Claim 16 (depends on 13)

The method of claim 13 wherein the step of preparing a PEU polymer (step A) further comprises:
1. preparing a first amino acid based polyester monomer comprising two phosphorylated amino acids separated by from 1 to 20 carbon atoms;
2. preparing a second amino acid based polyester monomer comprising two amino acids separated by from 2 to 20 carbon atoms;
3. reacting said first amino acid based polyester monomer and said second amino acid based polyester monomer with phosgene, diphosgene or triphosgene to introduce urea bonds between and among said first and second amino acid based polyester monomer to form the PEU polymer of step A.

### Claim 17 (depends on 16)

The method of claim 16 wherein the said first amino acid based polyester monomer comprises two phosphorylated serine molecules separated by from 2 to 20 carbon atoms.

### Claim 18 (depends on 16)

The method of claim 16 wherein the said second amino acid based polyester monomer comprises two amino acids selected from the group consisting of alanine (ala—A), glycine (gly—G), isoleucine (ile—I), leucine (leu—L), methionine (met—M), phenylalanine (phe—F), threonine (thr—T), tryptophan (trp—W), tyrosine (tyr—Y), or valine (val—V), separated by from 2 to 20 carbon atoms.

### Claim 19 (depends on 16)

The method of claim 16 wherein the said second amino acid based polyester monomer comprises valine or isoleucine molecules.

### Claim 20 (depends on 1)

A method of bonding bone to bone or bone to metal using the poly(ester urea) (PEU) based adhesive of claim 1 comprising:
A. preparing a first surface and second surface to be joined;
B. preparing a PEU polymer having one or more side chains comprising a phosphate group;
C. mixing a crosslinking agent comprising a divalent metal salt into the PEU polymer of step A to form the poly(ester urea) (PEU) based adhesive of claim 1;
D. applying the PEU polymer/crosslinking agent mixture of step C to one or both of said first and second surfaces to be joined;
E. placing said first and said second surfaces to be joined in contact with each other; and
F. allowing the poly(ester urea) (PEU) based adhesive of claim 1 to crosslink, forming a bond between said first surface and said second surface.