Polymeric biomaterials derived from monomers comprising hydroxyacids and phenol compounds and their medical uses

Patent metadata

Field	Value
Publication number	US-10329379-B2
Application number	US-201414454073-A
Country	US
Kind code	B2
Filing date	Aug 7, 2014
Priority date	Aug 7, 2013
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present invention provides new classes of phenolic compounds derived from hydroxyacids and tyrosol or tyrosol analogs, useful as monomers for preparation of biocompatible polymers, and the biocompatible polymers prepared from these monomeric hydroxyacid-phenolic compounds, including novel biodegradable and/or bioresorbable polymers. These biocompatible polymers or polymer compositions with enhanced bioresorbabilty and processability are useful in a variety of medical applications, such as in medical devices and controlled-release therapeutic formulations. The invention also provides methods for preparing these monomeric hydroxyacid-phenolic compounds and biocompatible polymers.

First claim

What is claimed is:

1. A biocompatible implantable polymer, consisting essentially of tissue compatible and bioresorbable recurring units including recurring units of formula:

wherein
y1 is 0, 1, 2, 3, or 4;
X 1 is bromine (Br) or iodine (I);
X 2 and X 3 are;
R 1 is selected from the group consisting of linear or branched C 1 -C 12 alkylene;
A is selected from the group consisting of linear or branched C 1 -C 24 alkylene;
R 2 is selected from the group consisting of linear or branched C 1 -C 24 alkylene;
n1 and n2 are independently numbers from 0 to 100, and are average values which can be fractional, where the sum of n1 and n2 is at least 1;
p is zero or 1; and
A 1 is a linking group selected from:

wherein R 8 is selected from a bond, C 1 -C 30 alkylene, C 2 -C 30 alkenylene, C 2 -C 30 alkynylene; C 1 -C 30 heteroalkylene, C 2 -C 30 heteroalkenylene, C 2 -C 30 heteroalkynylene, C 7 -C 30 heteroalkylarylene, C 8 -C 30 heteroalkynylarylene, C 8 -C 30 heteroalkynylarylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene; and
R 9 and R 10 are each independently selected from H, C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 2 -C 30 heteroalkenyl, and C 2 -C 30 heteroalkynyl;
wherein each said alkyl and alkylene can be substituted with one or more of hydroxy, alkoxy, halogen, nitro, cyano, CO 2 R, where R is defined above, phenyl, aryl, heteroaryl, cycloalkyl, mercapto, or alkylthio;
wherein said biocompatible polymer is tissue compatible and bioresorbable when implanted in vivo.

2. The biocompatible polymer of claim 1 , wherein R 1 is C 1 -C 4 alkylene.

3. The biocompatible polymer of claim 2 , wherein R 1 is —CH 2 CH 2 —.

4. The biocompatible polymer of claim 1 , wherein A 1 is carbonyl.

5. The biocompatible polymer of claim 1 , wherein n1 is zero and n2 is an average value between 1 and 6.

6. The biocompatible polymer of claim 5 , wherein n2 is an average value between 1 and 2.

7. The biocompatible polymer of claim 1 , wherein said recurring unit is of formula:

8. The biocompatible polymer of claim 1 , wherein said recurring unit is of formula:

wherein R 3 is selected from the group consisting of hydrogen and linear or branched C 1 -C 23 alkyl.

9. The biocompatible polymer of claim 8 , wherein said recurring unit is of formula:

10. The biocompatible polymer of claim 9 , wherein R 3 is hydrogen or methyl.

11. The biocompatible polymer of claim 1 , further comprising a macromeric recurring unit.

12. An implantable polymer composition comprising a biocompatible implantable polymer according to claim 1 .

13. An implantable medical device comprising a biocompatible implantable polymer according to claim 1 .

14. The medical device of claim 13 , further comprising a biologically active compound.

15. The medical device of claim 14 , wherein the biologically active compound is selected from the group consisting of a chemotherapeutic agent, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory, and a wound healing agent.

16. The medical device of claim 13 , wherein the medical device is a stent.

17. A biocompatible implantable polymer, comprising tissue compatible and bioresorbable recurring units including recurring units of formula:

wherein
y1 is 0, 1, 2, 3, or 4;
X 1 is bromine (Br) or iodine (I);
X 2 and X 3 are independently selected from O, S and NR, where R is H or lower alkyl;
R 1 is selected from the group consisting of linear or branched C 1 -C 12 alkylene;
A is selected from the group consisting of linear or branched C 1 -C 24 alkylene;
R 2 is selected from the group consisting of linear or branched C 1 -C 24 alkylene;
n1 and n2 are independently numbers from 0 to 100, and are average values which can be fractional, where the sum of n1 and n2 is at least 1;
p is zero or 1; and
A 1 is a linking group selected from:

wherein R 8 is selected from a bond, C 1 -C 30 alkylene, C 2 -C 30 alkenylene, C 2 -C 30 alkynylene; C 1 -C 30 heteroalkylene, C 2 -C 30 heteroalkenylene, C 2 -C 30 heteroalkynylene, C 7 -C 30 heteroalkylarylene, C 8 -C 30 heteroalkynylarylene, C 8 -C 30 heteroalkynylarylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene; and
R 9 and R 10 are each independently selected from H, C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 2 -C 30 heteroalkenyl, and C 2 -C 30 heteroalkynyl;
wherein each said alkyl and alkylene can be substituted with one or more of hydroxy, alkoxy, halogen, nitro, cyano, CO 2 R, where R is defined above, phenyl, aryl, heteroaryl, cycloalkyl, mercapto, or alkylthio; wherein said biocompatible polymer is tissue compatible and bioresorbable when implanted in vivo; and
further comprising a recurring unit of the formula:

wherein B is —O—((CHR) p —O) q —; each R is independently H or C 1 to C 3 alkyl; p and q are each independently an integer in the range of from 1 to 100; and A 1 is as defined above, independently from any other A 1 .

18. The biocompatible polymer of claim 17 , wherein R is H and p is 2.

19. The biocompatible polymer of claim 1 , further comprising a tyrosol recurring unit characterized by the formula:

wherein A 1 is as defined in claim 1 , independently from any other A 1 .

20. A biocompatible implantable polymer, consisting essentially of tissue compatible and bioresorbable recurring units including recurring units of formula:

wherein
y1 is 0, 1, 2, 3, or 4;
X 1 is bromine (Br) or iodine (I);
R 1 is selected from the group consisting of linear or branched C 1 -C 12 alkylene;
A is selected from the group consisting of linear or branched C 1 -C 24 alkylene;
n1 and n2 are independently numbers from 0 to 100, and are average values which can be fractional, where the sum of n1 and n2 is at least 1;
p is zero or 1; and
A 1 is a linking group selected from:

wherein R 8 is selected from a bond, C 1 -C 30 alkylene, C 2 -C 30 alkenylene, C 2 -C 30 alkynylene; C 1 -C 30 heteroalkylene, C 2 -C 30 heteroalkenylene, C 2 -C 30 heteroalkynylene, C 7 -C 30 heteroalkylary

Assignees

• Univ Rutgers
• Reva Medical Inc

Inventors

• Bolikal Durgadas
• Kohn Joachim B
• Kabalnova Lioubov

Classifications

• A61L2300/41

  Anti-inflammatory agents, e.g. NSAIDs · CPC title

• C08G64/0233

  containing halogens · CPC title

• C08G64/1608

  saturated · CPC title

• A61L31/148

  Materials at least partially resorbable by the body · CPC title

• A61L2300/40

  characterised by a specific therapeutic activity or mode of action · CPC title