Degradable amino acid-based poly (ester urea) copolymer adhesives

Patent metadata

Field	Value
Publication number	US-10414864-B2
Application number	US-201515328983-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Jul 22, 2014
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

The present invention is directed to a novel group of amino acid-based poly(ester urea)s (PEUs) for use in biodegradable adhesive and related methods for their making and use. These novel amino acid-based PEUs have a wide variation in mechanical properties and degradation behavior that can be tuned by varying the amino acids and polyols used to form the polyester monomers that form the PEUs. Importantly, these novel PEUs have been shown to be non-toxic in vitro and in vivo and may be suitable to a wide variety of biomedical and other uses. In some embodiments, the adhesive properties of these degradable amino acid-based poly(ester urea) adhesives has been further improved by the incorporation of controlled amounts of catechol functional groups into the side chains of the PEU via post-polymerization functionalization chemistry.

First claim

What is claimed is:

1. A biodegradable tissue adhesive comprising an amino acid-based poly(ester urea) having one or more catechol functional groups wherein said amino acid-based poly(ester urea) further comprises two or more polyester monomer segments; wherein each of said two or more polyester monomer segments comprise the residue of two or more amino acids separated by the residue of a diol or polyol having from 2 to 20 carbon atoms.

2. The biodegradable tissue adhesive of claim 1 , wherein said amino acid-based poly(ester urea) further comprises a residue of phenylalanine or tyrosine.

3. The biodegradable tissue adhesive of claim 1 wherein the two or more amino acids in said two or more monomer segments are each selected from the group consisting of alanine (ala—A), arginine (arg—R), asparagine (asn—N), aspartic acid (asp—D), cysteine (cys—C), glutamine (gln—Q), glutamic acid (glu—E), glycine (gly—G), histidine (his—H), isoleucine (ile—I), leucine (leu—L), lysine (lys—K), methionine (met—M), phenylalanine (phe—F), serine (ser—S), threonine (thr—T), tryptophan (trp—W), tyrosine (tyr—Y), valine (val—V), benzyl protected tyrosine, BOC protected tyrosine and combinations thereof.

4. The biodegradable tissue adhesive of claim 1 wherein said at least one of said two or more polyester monomer segments contains a catechol functionalized phenylalanine or tyrosine residue.

5. The biodegradable tissue adhesive of claim 1 wherein said at least one of said two or more polyester monomer segments is branched.

6. The biodegradable tissue adhesive of claim 1 , wherein said amino acid-based poly(ester urea) is a copolymer comprising:
one or more first monomer segments containing two or more catechol-functionalized amino acid residues separated by the residue of a diol or polyol having from 2 to 20 carbon atoms; and
one or more second monomer segments containing two or more amino acid residues separated by the residue of a diol or polyol having from 2 to 20 carbon atoms.

7. The biodegradable tissue adhesive of claim 6 wherein said one or more first monomer segments has the formula:

wherein a is an integer from 1 to 20 and b is an integer from 1 to 6.

8. The biodegradable tissue adhesive of claim 6 wherein the two amino acid residues of said one or more second monomer segments are residues of amino acids selected from the group consisting of alanine (ala—A), arginine (arg—R), asparagine (asn—N), aspartic acid (asp—D), cysteine (cys—C), glutamine (gln—Q), glutamic acid (glu—E), glycine (gly—G), histidine (his—H), isoleucine (ile—I), leucine (leu—L), lysine (lys—K), methionine (met—M), phenylalanine (phe—F), serine (ser—S), threonine (thr—T), tryptophan (trp—W), tyrosine (tyr—Y), valine (val—V), and combinations thereof.

9. The biodegradable tissue adhesive of claim 6 wherein said one or more second monomer segments has the formula:

wherein R′ is —CH 3 , —(CH 2 ) 3 NHC(NH 2 )C═NH, —CH 2 CONH 2 , —CH 2 COOH, —CH 2 SH, —(CH 2 ) 2 COOH, —(CH 2 ) 2 CONH 2 , —NH 2 , —CH 2 C═CH—N═CH—NH, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 SCH 3 , —CH 2 Ph, —CH 2 OH, —CH(OH)CH 3 , —CH 2 —C═CH—NH-Ph, —CH 2 -Ph-OH, or —CH(CH 3 ) 2 ; and a′ is an integer from 1 to 20.

10. The biodegradable tissue adhesive of claim 1 having the formula:

wherein R is —OCOO(CH 2 ) 2 C 6 H(OH) 2 , —OCOO(CH 2 ) 2 C 6 H 3 (OH) 2 , —OCOO(CH 2 ) 3 C 6 H 3 (OH) 2 , —OCOO(CH 2 ) 4 C 6 H 3 (OH) 2 , —OCOO(CH 2 ) 5 C 6 H 3 (OH) 2 , —OCOO(CH 2 ) 6 C 6 H 3 (OH) 2 , and —OCOO(CH 2 ) 7 C 6 H 3 (OH) 2 ; R′ is —CH 3 , —(CH 2 ) 3 NHC(NH 2 )C═NH, —CH 2 CONH 2 , —CH 2 COOH, —CH 2 SH, —(CH 2 ) 2 COOH, —(CH 2 ) 2 CONH 2 , —NH 2 , —CH 2 C═CH—N═CH—NH, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 SCH 3 , —CH 2 Ph, —CHOH, —CH(OH)CH 3 , —CH 2 —C═CH—NH-Ph, —CH 2 -Ph-OH, or —CH(CH 3 ) 2 ; a and a′ are each an integer from about 1 to about 20; and m and n are mole fractions.

11. The biodegradable tissue adhesive of claim 1 having a formula selected from the group consisting of:

wherein R′ is —CH 3 , —(CH 2 ) 3 NHC(NH 2 )C═NH, —CH 2 CONH 2 , —CH 2 COOH, —CH 2 SH, —(CH 2 ) 2 COOH, —(CH 2 ) 2 CONH 2 , —NH 2 , —CH 2 C═CH—N═CH—NH, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 SCH 3 , —CH 2 Ph, —CH 2 OH, —CH(OH)CH 3 , —CH 2 —C═CH—NH-Ph, —CH 2 -Ph-OH, or —CH(CH 3 ) 2 ; a and a′ are each integers from 1 to 20; b is an integer from 1 to 6; m is a mole fraction from 0.01 to 0.30; and n is a mole fraction from 0.70 to 0.99.

12. The biodegradable tissue adhesive of claim 1 further comprising an oxidative cross linker.

13. A method for making the biodegradable tissue adhesive of claim 1 comprising:
A. preparing a first counter-ion protected polyester monomer, wherein said first counter-ion protected polyester monomer comprises two benzyl protected tyrosine residues separated by from 2 to 20 carbon atoms;
B. preparing a second counter-ion protected polyester monomer, wherein said second counter-ion protected polyester monomer comprises two amino acid residues separated by from 2 to 20 carbon atoms;
C. reacting said first counter-ion protected polyester monomer and second counter-ion protected polyester monomer with a poly(ester urea) forming compound to form a first amino acid-based poly(ester urea) intermediate having a first segment comprising the residue of said first counter-ion protected polyester monomer and a second segment comprising the residue of said second counter-ion protected polyester monomer;
D. removing the protecting benzyl groups from the tyrosine residues of said first segment of said first amino acid-based poly(ester urea) intermediate to form a tyrosine-based poly(ester urea) adhesive;
E. preparing a carboxyl functionalized protected catechol compound, said carboxyl functionalized protected catechol compound comprising a protected catechol group and a carboxyl group;
F. reacting said carboxyl functionalized protected catechol compound with the hydroxyl groups of the tyrosine-based poly(ester urea) adhesive, thereby coupling said protected catechol group to said tyrosine-based poly(ester urea) adhesive to form a second amino acid-based poly(ester urea) intermediate having one or more protected catechol groups; and
G. deprotecting the one or more protected catechol groups on said second poly(ester urea) intermediate to produce a degradable amino acid-based poly(ester urea) tissue adhesive having catechol functional groups.

14. The method of claim 13 wherein one or both of said first counter-ion protected polyester monomer and said second counter-ion protected polyester monomer are branched.

15. The method of claim 13 wherein, said second counter-ion protected polyester monomer comprises the residues of two amino acids selected from the group consisting of alanine (ala—A), arginine (arg—R), asparagine (asn—N), aspartic acid (asp—D),

Assignees

• Univ Akron

Inventors

• Becker Matthew
• Zhou Jinjun
• Defante Adrian
• Dhinojwala Ali

Classifications

• A61Q1/025

  Semi-permanent tattoos, stencils, e.g. "permanent make-up" · CPC title

• A61K8/85

  Polyesters · CPC title

• A61K8/0204

  Specific forms not provided for by any of groups A61K8/0208 - A61K8/14 · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K9/0014 Primary

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title