Radiopaque polymers

Patent metadata

Field	Value
Publication number	US-11744916-B2
Application number	US-202016933042-A
Country	US
Kind code	B2
Filing date	Jul 20, 2020
Priority date	Jul 18, 2019
Publication date	Sep 5, 2023
Grant date	Sep 5, 2023

Abstract

The present disclosure relates to radiopaque PVA polymers where the PVA has a first pendant group and a second pendant group, wherein the first pendant group comprises a first phenyl group bearing 1 to 5 iodine atoms, and the second pendant group comprises either (a) a second phenyl group bearing 1 to 3 substituents selected from the group W and optionally 1 to 4 iodine substituents, the group(s) W and the optional iodines being the sole substituents of the second phenyl group. Each W is selected from —OH, —COOH, —SO 3 H, —OPO 3 H 2 , —O—(C 1-4 alkyl), —O—(C 1-4 alkyl)OH, —O—(C 1-4 alkyl)R 2 , —O—(C 2 H 5 O) q R 1 —(C═O)—O—C 1-4 alkyl and —O—(C═O)C 1-4 alkyl; wherein R 1 is H or C 1-4 alkyl; R 2 is —COOH, —SO 3 H, or —OPO 3 H 2 ; q is an integer from 1 to 4; wherein the group W may be in the form of a pharmaceutically acceptable salt; or (b) a pyridyl group; which is optionally in the form of a pyridinium ion.

First claim

The invention claimed is:

1. A polymer comprising polyvinyl alcohol (PVA), the PVA having a first pendant group and a second pendant group, wherein the first pendant group comprises a first phenyl group bearing 1 to 5 iodines as the sole substituent(s) of the first phenyl group, and wherein the second pendant group comprises a second phenyl group bearing 1 to 3 substituents selected from the group W and optionally 1 to 4 iodine substituents, the group(s) W and the optional iodines being the sole substituents of the second phenyl group;
wherein each W is independently selected from —SO 3 H, —OPO 3 H 2 , and —O—(C 1-4 alkyl)R 2 ,
wherein R 2 is —SO 3 H, or
—OPO 3 H 2 ; and wherein the group W may be in the form of a pharmaceutically acceptable salt.

2. A polymer according to claim 1 , wherein the first pendant group is coupled to the PVA through an ether, ester, amide or 1,3 dioxane group and/or wherein the second pendant group is coupled to the PVA through an ether, ester, amide or 1,3 dioxane group.

3. A polymer according to claim 1 , wherein the first pendant group is a group according to formula 1A or 1B

wherein
G is a coupling group through which the group of the formula 1A is coupled to the PVA and is selected from ether, ester and amide;
X is independently either a bond or is a linking group having a chain of 1 to 6 atoms selected from C, N, S and O, provided that the chain contains no more than one atom selected from N, S and O;
wherein C is optionally substituted by a group selected from C 1-4 alkyl; wherein N is substituted by R 3 , wherein R 3 is selected from H and C 1-4 alkyl; and wherein S is either an —S(O)— or —S(O) 2 — group; and
n is an integer from 1 to 5.

4. A polymer according to claim 1 , wherein the second pendant group is of the formula 2A or 2B

wherein
G is a coupling group through which the group of the formula 2A is coupled to the polyvinyl alcohol and is selected from ether, ester and amide;
X is independently either a bond or is a linking group having a chain of 1 to 6 atoms selected from C, N, S and O, provided that the chain contains no more than one atom selected from N, S and O;
wherein C is optionally substituted by a group selected from C 1-4 alkyl; wherein N is substituted by R 3 , wherein R 3 is selected from H and C 1-4 alkyl; and wherein S is either an —S(O)— or —S(O) 2 — group;
W is independently selected from —SO 3 H, —OPO 3 H 2 , and —O—(C 1-4 alkyl)R 2 ; wherein R 2 is —SO 3 H, or —OPO 3 H 2 ;and wherein the group W may be in the form of a pharmaceutically acceptable salt;
n2 is an integer from 0 to 4;
p is an integer from 1 to 3; and
n2+p is an integer from 1 to 5.

5. A polymer according to claim 3 wherein X is selected from the group consisting of a bond, C 1-6 a 1 kylene groups; C 1-5 alkoxylene groups, groups of the formula —(CH 2 ) y —O—(CH 2 ) z — wherein y and z are, independently, 1, 2 or 3, and y+z is an integer from 2 to 5; and groups of the formula —N(R 3 )(CH 2 ) n3 — wherein n3 is an integer from 1 to 4, wherein R 3 is H or C 1-4 alkyl.

6. A polymer according to claim 3 wherein X is selected from the group consisting of a bond, methylene, ethylene, oxymethylene and oxyethylene, —CH 2 —O—CH 2 — and —NH(CH 2)—.

7. A polymer according claim 1 wherein W is, independently in each case, selected from —SO 3 H and —O—(C 1-4 alkyl)R 2 ; and wherein R 2 is —SO 3 H.

8. A polymer according to claim 1 wherein W is, independently in each case, selected from —SO 3 H.

9. A polymer according to claim 1 , wherein W is, independently in each case, selected from —O—(C 1-4 alkyl)R 2 ; wherein R 2 is —SO 3 H.

10. A polymer according to claim 1 , wherein either the first pendant group is coupled to the PVA through an ether linkage and the second pendant group is coupled to the PVA through a 1,3 dioxane group or both the first pendant group and the second pendant group are coupled to the PVA through a 1,3 dioxane group.

11. A polymer according to claim 1 , wherein the first pendant group is of the formula 4A and the second pendant group is of the formula 4B:

wherein n is an integer from 1 to 4; n2 is an integer from 1 to 4; W is selected from —SO 3 H and —O—(C 1-4 a 1 kyl)SO 3 H; p is 1 or 2.

12. A polymer according to claim 1 , wherein the first pendant group is of the formula 4A and the second pendant group is of the formula 4D:

wherein n is an integer from 1 to 4; W is —SO 3 H; and p is 1 or 2.

13. A polymer according to claim 3 wherein n is 2 or 3.

14. A polymer according to claim 4 wherein p is one.

15. A polymer according to claim 1 wherein the PVA without the first and second pendant groups has a weight average molecular weight of 1 kDa to 250 kDa.

16. A polymer according to claim 1 wherein the PVA without the first and second pendant groups has a weight average molecular weight of 10 kDa to 100 kDa.

17. A polymer according to claim 1 having an iodine content of at least 10% dry weight and/or having an iodine content of at least 10 mg/ml.

18. A polymer according to claim 1 , having a radiodensity of at least 500 HU.

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

20. A composition comprising a polymer according to claim 1 , dissolved in a solvent.

21. A method of treatment comprising delivering a polymer according to claim 1 to a blood vessel of a subject in need thereof, such as to form an embolus in the blood vessel.

22. A polymer according to claim 1 , wherein the first pendant group is of the formula 4A and wherein the second pendant group is of the formula 4B or 4D:

wherein n is an integer from 1 to 4; n2 is an integer from 1 to 4; W is selected from —SO 3 H and —O—(C 1-4 alkyl)SO 3 H; p is 1 or 2.

Assignees

• Biocompatibles Uk Ltd

Inventors

• Ashrafi Koorosh
• Britton Hugh
• Cuda Francesco
• Lewis Andrew Lennard
• Parisi Cristian
• Tang Yiqing
• Willis Sean Leo

Classifications

• A61L24/06 Primary

  obtained by reactions only involving carbon-to-carbon unsaturated bonds {(A61L24/043, A61L24/046 take precedence)} · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C08F216/10

  Carbocyclic compounds · CPC title

• A61L2430/36

  for embolization or occlusion, e.g. vaso-occlusive compositions or devices · CPC title

• C08F8/48 Primary

  Isomerisation; Cyclisation · CPC title