Imageable embolic microsphere

Patent metadata

Field	Value
Publication number	US-2020155711-A1
Application number	US-202016749370-A
Country	US
Kind code	A1
Filing date	Jan 22, 2020
Priority date	Mar 15, 2013
Publication date	May 21, 2020
Grant date	—

Abstract

This invention concerns imageable, radiopaque embolic beads, which are particularly useful for monitoring embolization procedures. The beads comprise iodine containing compounds which are covalently incorporated into the polymer network of a preformed hydrogel bead. The beads are prepared by activating pre-formed hydrogel beads towards nucleophilic attack and then covalently attaching iodinated compounds into the polymer network. The radiopaque beads may be loaded with chemotherapeutic agents and used in methods of embolizing hyperplastic tissue or solid tumors.

First claim

1 - 36 . (canceled)

37 . A method of making a radiopaque hydrogel bead, comprising:
preforming hydrogel beads; selecting a particular size or size range of preformed beads; and reacting functional groups on the selected preformed hydrogel beads with an aromatic iodine containing compound.

38 . A method according to claim 37 , wherein the aromatic iodine containing compound is an iodinated benzyl or phenyl alcohol or is an iodinated benzoic acid.

39 . A method according to claim, wherein the aromatic iodine containing compound is 2,3,5-triiodobenzoic acid.

40 . A method according to claim 37 , comprising preforming the hydrogel bead from a polymer which has alcoholic hydroxyl substituents or acylated derivatives thereof.

41 . A method as claimed in claim 37 ,
characterized in that the hydrogel beads have been reacted with carbonyl diimidazole or carbodiimide so as to be activated towards nucleopilic substitution reaction; and characterized in that the beads are covalently coupled with an iodinated compound which is reactive towards the imidazole or diimide functionality of the activated beads.

42 . A method according to claim 41 , wherein the hydrogel comprises a cross-linked polyhydroxy polymer selected from polyvinyl alcohol (PVA) or a copolymer of vinyl alcohol.

43 . A method according to claim 41 , wherein the hydrogel has a polymer backbone with a 1,2-diol and/or a 1,3-diol structure to enable crosslinking with an acrylic monomer.

44 . A method according to claim 43 , herein the acrylic monomer is 2-acrylamido-2-methylpropane sulfonic acid (AMPS).

45 . A method according to claim 41 , wherein hydroxyl moieties on and/or within a preformed hydrogel bead are activated by reaction with carbonyldiimidazole,

46 . A method according to claim 41 , wherein the iodinated compound is an iodinated alcohol, an iodinated amine, or an iodinated carboxylic acid.

47 . A method according to claim 41 , wherein the iodinated compound is an iodinated alcohol.

48 . A method according to claim 47 , wherein the iodinated alcohol is a triiodobenzyl alcohol or a triiodophenyl alcohol.

49 . A method according to claim 41 , having coupled to its imide or imidazole function, a terminally bifunctional linker which comprises an aliphatic carbon chain with at least 2 carbons.

50 . A method according to claim 49 , wherein both functionalities of the terminally bifunctional linker are reactive with imide or imidazole

51 . A method according to claim 49 , wherein the functionality or reactive moieties of the bifunctional linker comprise one or more of an amine, carboxylic acid and alcohol.

52 . A method according to claim 49 , wherein the bifunctional linker is a diamino alkane, optionally wherein bifunctional linker has general formula H 2 N(CH 2 ) n NH 2 wherein n includes any number between 2 and 20, 2 and 10, or 2 and 4.

53 . A method according to claim 49 wherein the iodinated compound is covalently coupled through the bifunctional linker.

54 . A method according to claim 37 , further comprising absorbing a pharmacologically active agent within the bead.

55 . A method of making a bead according to claim 41 , comprising the steps of:
preforming a bead, comprising: (i) suspending hydrogel beads in organic solvent until they have swollen, wherein the hydrogel comprises a polyhydroxy polymer, optionally cross-linked; characterized in that the method further comprises (ii) adding carbonyidiimidazole or a carbodiimide to the suspension of swollen beads in solvent, in the presence of a catalytic amount of a base and under anhydrous conditions to react with the hydrogel such that it is activated towards nucleophilic substitution; and
covalently coupling the preformed bead with the iodinated compound which is reactive towards the imidazole or diimide functionality of the activated bead; and optionally further comprises
(iii) filtering and washing the beads with organic solvent to provide purified activated beads.

56 . A method according to claim 55 , wherein the hydrogel comprises a cross-linked polyhydroxy polymer selected from polyvinyl alcohol (PVA) or a copolymer of vinyl alcohol.

Assignees

• Biocompatibles Uk Ltd

Inventors

• Dreher Matthew R
• Wood Bradford J
• Negussie Ayele H
• Lewis Andrew Lennard
• Tang Yiqing

Classifications

• A61K49/0476

  Particles, beads, capsules, spheres · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C08L29/04

  Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids · CPC title

• A61K49/0442 Primary

  Polymeric X-ray contrast-enhancing agent comprising a halogenated group · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title