Inherently radiopaque polymeric products for embolotherapy

Patent metadata

Field	Value
Publication number	US-10206946-B2
Application number	US-201715714302-A
Country	US
Kind code	B2
Filing date	Sep 25, 2017
Priority date	Sep 25, 2003
Publication date	Feb 19, 2019
Grant date	Feb 19, 2019

Abstract

Preferred embodiments relate to compositions of inherently radiopaque, biocompatible, bioresorbable polymeric particles and methods of using them for embolizing a body lumen.

First claim

What is claimed is:

1. An embolotherapy product, comprising a particulate formulation comprising a biocompatible, bioresorbable polymer comprising one or more units of Formula (I):

and optionally including stereoisomers thereof,
wherein X═I or Br; Y1 and Y2 independently=0, 1, 2, 3 or 4; provided that at least one iodine atom is present, or, in the absence of at least one iodine atom, at least two bromine atoms are present;
wherein f is between 0 and less than 1; g is between 0 and 1, inclusive; and f+g is between 0 and 1, inclusive;
wherein A is selected from the group consisting of:

wherein R 1 is independently H or an alkyl group having 1 to about 18 carbon atoms and containing 0 to 5 heteroatoms selected from O and N; and R 3 is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkylaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N;
wherein B is an aliphatic linear or branched diol or a poly(alkylene glycol) unit; and
wherein R and R 2 are independently selected from:

wherein R 7 is selected from the group consisting of —CH═CH—, —CHJ 1 -CHJ 2 - and (—CH 2 -)a; wherein R 8 is selected from the group consisting of —CH═CH—, —CHJ 1 -CHJ 2 - and (—CH 2 -)n; wherein a and n are independently between 0 and 8 inclusive; J 1 and J 2 are independently Br or I; and wherein Q for R 2 comprises a free carboxylic acid group and Q for each R is independently selected from the group consisting of hydrogen, carboxylic acid esters and carboxylic acid amides, wherein said esters and amides are selected from the group consisting of esters and amides of alkyl and alkylaryl groups containing up to 18 carbon atoms, and esters and amides of biologically active compounds;
wherein the embolotherapy product is inherently radiopaque.

2. The embolotherapy product of claim 1 , wherein said polymer further comprises a homopolymer, a heteropolymer, or a blend thereof.

3. The embolotherapy product of claim 1 , wherein R and R 2 are selected from the groups:

wherein for each R, R 1 is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N and for each R 2 , R 1 is H;
wherein j and m are independently integers from 1 to 8 inclusive; and
wherein Z is independently either 0 or S.

4. The embolotherapy product of claim 1 , wherein said polymer is copolymerized with a poly(C 1 -C 4 alkylene glycol).

5. The embolotherapy product of claim 4 , wherein said poly(C 1 -C 4 alkylene glycol) is present in a weight fraction of less than about 75 wt %.

6. The embolotherapy product of claim 5 , wherein said poly(alkylene glycol) is poly(ethylene glycol).

7. The embolotherapy product of claim 4 , wherein between about 0.01 and about 0.99 percent of said polymer units comprise a pendant —COOH group.

8. The embolotherapy product of claim 1 , wherein said polymer comprises one or more units of Formula (IV):

wherein each X is independently I or Br, Y1 and Y2 for each diphenol unit are independently between 0 and 4, inclusive, and Y1+Y2 for each diphenol unit is between 1 and 8, inclusive;
each R and R 2 are independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, wherein R 2 further comprises a pendant carboxylic acid group;
wherein A is either:

wherein R 3 is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkylaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; and
wherein P is a poly(C 1 -C 4 alkylene glycol) unit having a weight fraction of about 75% or less; f is between 0 and less than 1; g is between 0 and 1, inclusive; and f+g is between 0 and 1, inclusive.

9. The embolotherapy product of claim 8 , wherein P is a poly(ethylene glycol) that is present in a weight fraction of about 50% or less.

10. The embolotherapy product of claim 8 , wherein both R and R 2 comprise a pendant COOR 1 group;
wherein for R, the subgroup R 1 is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N; and
wherein for R 2 , the subgroup R 1 is a hydrogen atom.

11. The embolotherapy product of claim 8 , wherein each R and R 2 independently has the structure:

wherein R 7 is selected from the group consisting of —CH═CH—, —CHJ 1 -CHJ 2 - and (—CH 2 -)a, wherein R 8 is selected from the group consisting of —CH═CH—, —CHJ 1 -CHJ 2 - and (—CH 2 -)n, wherein a and n are independently between 0 and 8 inclusive; and J 1 and J 2 are independently Br or I; and wherein, for each R 2 , Q comprises a free carboxylic acid group, and, for each R, Q is independently selected from the group consisting of hydrogen and carboxylic acid esters and amides, wherein said esters and amides are selected from the group consisting of esters and amides of alkyl and alkylaryl groups containing up to 18 carbon atoms and esters and amides of biologically active compounds.

12. The embolotherapy product of claim 8 , wherein each R 2 independently has the structure:

wherein R 5a is an alkyl group containing up to 18 carbon atoms and from 0 to 5 heteroatoms selected from O and N; wherein m is an integer from 1 to 8 inclusive; and wherein, for each R 2 , R 1 is hydrogen, and, for each R, R 1 is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N.

13. The embolotherapy product of claim 8 , wherein each R 2 independently has the structure:

wherein j and m are independently an integer from 1 to 8, inclusive, and wherein, for each R 2 , R 1 is hydrogen, and, for each R, R 1 is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N.

14. The embolotherapy product of claim 8 , wherein R 3 of said polymer is a moiety selected from the group consisting of —CH 2 —C(═O)—, —CH 2 —CH 2 —C(═O)—, —CH═CH— and (—CH 2 -)z, wherein z is an integer from 1 to 8, inclusive.

15. The embolotherapy product of claim 8 , wherein all X groups are ortho-directed.

16. The embolotherapy product of claim 8 , wherein Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4.

17. The embolotherapy product of claim 16 , wherein all X groups are iodine.

18. The embolotherapy product of claim 8 , wherein f is greater than 0.1 to about 0.3.

19. The embolotherapy product of claim 8 ,

Assignees

• Univ Rutgers

Inventors

• Brandom Donald K
• Schmid Eric
• Zeltinger Joan
• Bolikal Durgadas
• Kohn Joachim B

Classifications

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P35/00

  Antineoplastic agents · CPC title