Imageable Polymers

Patent metadata

Field	Value
Publication number	US-2016193367-A1
Application number	US-201414916472-A
Country	US
Kind code	A1
Filing date	Sep 5, 2014
Priority date	Sep 6, 2013
Publication date	Jul 7, 2016
Grant date	—

Abstract

This invention relates to imageable polymers, particularly those comprising poly vinylalcohol and to methods for making them as well as to embolic microspheres comprising the polymers. The microspheres are imageable during embolization procedures and can be loaded with drugs or other therapeutic agents to provide an imageable drug delivery system.

First claim

1 . A hydrogel comprising 1,2-diol or 1,3-diol groups acetalised with a radiopaque species the radiopaque species comprising one or more covalently bound radiopaque halogens, the radiopaque species being coupled to the polymer through a cyclic acetal group.

2 . A hydrogel according to claim 1 comprising 1,2-diol or 1,3-diol groups acetalised with a radiopaque species such that that the polymer comprises an iodinated aromatic group covalently bound to the polymer through cyclic acetal linkage.

3 . A hydrogel according to claim 1 wherein the hydrogel is a cross-linked polymer network.

4 . A hydrogel according to claim 1 wherein the polymer comprises polyvinyl alcohol (PVA) or copolymers of polyvinyl alcohol containing a 1,3-diol skeleton

5 . A hydrogel according to claim 1 wherein the hydrogel comprises polyvinyl alcohol (PVA) in which the PVA comprises pendent actetate groups formed from the acetalisation of PVA with N-acryloyl-aminoacetaldehyde dimethylacetal and which is cross-linked with 2-acrylamido-2-methylpropanesulfonic acid (PVA-AMPS).

6 . A hydrogel according to claim 1 wherein the radiopaque species is selected from iodine and bromine.

7 . A hydrogel according to claim 6 wherein the radiopaque species comprises an iodinated or brominated phenyl group.

8 . A hydrogel according to claim 6 wherein the hydrogel comprises greater than 10% iodine by dry weight.

9 . A hydrogel according to claim 1 wherein the hydrogel is in the form of microparticles or microspheres.

10 . A hydrogel according to claim 9 wherein the hydrogel is in the form of microspheres with a mean diameter size range of from 10 to 2000 μm.

11 . A hydrogel according to claim 1 in the form of microspheres or microparticles having a mean radiopacity of 500 HU or greater.

12 . A hydrogel according to claim 1 wherein the hydrogel has a net charge at physiological pH

13 . A hydrogel according to claim 1 comprising a structure of the general formula I or II

wherein X is a group substituted by one or more halogens and preferably one or more iodine moieties and J is a group of the formula —CH 2 — or is a bond.

14 . A hydrogel according to claim 13 wherein X is a group of the formula

wherein Z is a linking group, or is absent, such that the phenyl group is bonded to the cyclic acetal;
if Z is present, then Z is C 1-6 alkylene, C 1-6 alkoxylene or C 1-6 alkoxyalkylene;
Hal is 1, 2, 3 or 4 covalently attached radiopaque halogens

15 . A composition comprising a hydrogel according to claim 1 and a therapeutic agent wherein the therapeutic agent is absorbed into the hydrogel matrix.

16 . A composition according to claim 15 wherein the therapeutic agent is electrostatically held in the hydrogel and elutes from the hydrogel in electrolytic media.

17 . A method of making a radiopaque polymer comprising reacting a polymer comprising 1,2-diol or 1,3-diol groups with a radiopaque species capable of forming a cyclic acetal with said 1,2-diol or 1,3 diols under acidic conditions.

18 . A method according to claim 17 wherein the polymer is cross-linked.

19 . A method according to claim 17 wherein the polymer comprises polyvinyl alcohol (PVA) or copolymers of PVA.

20 . A method according to claim 17 wherein the radiopaque species is an organic molecule or organometallic complex, which provides a radiopacity>1 HU, and which comprises a reactive moiety selected from the group consisting of aldehydes, acetals, hemiacetals thioacetals and dithioacetals.

21 . A method according to claim 17 in which the radiopaque species comprises iodine or bromine

22 . A method according to claim 21 wherein the radiopaque species is an iodinated aldehyde.

23 . A method according to claim 22 wherein the radiopaque species is an iodinated benzyl aldehyde, iodinated phenyl aldehyde or an iodinated phenoxyaldehyde

24 . A method of making a radiopaque hydrogel microsphere comprising the steps of:
(a) swelling a pre-formed hydrogel microsphere comprising a polymer with 1,2-diol or 1,3-diol groups in a solvent capable of swelling said microsphere; and (b) mixing the swollen beads with a solution of a radiopaque species capable of forming a cyclic acetal with said 1,2 or 1,3 diols under acidic conditions; and (c) extracting the microspheres.

25 . A method according to claim 24 which further comprises the step of drying the extracted microspheres.

26 . A method according to claim 24 in which the reaction is conducted in polar organic solvent and at elevated temperature.

27 . A method according to claim 24 in which the radiopaque species comprises a functional group selected from the group consisting of aldehydes, acetals, hemiacetals, thioacetals and dithioacetals.

28 . A method according to claim 24 in which the radiopaque species comprises iodine.

29 . A method according to claim 28 wherein the radiopaque species is an iodinated aldehyde.

30 . A method according to claim 28 wherein the radiopaque species is an iodinated benzyl aldehyde, an iodinated phenyl aldehyde or an iodinated phenoxyaldehyde

31 . A method according to claim 30 wherein the radiopaque species is 2,3,5-triiodobenzaldehyde, 2,3,4,6-tetraiodobenzyaldehyde or 2-(2,4,6-triiodophenoxy)acetaldehyde

32 . A method according to claim 24 in which the preformed hydrogel microsphere comprises PVA with pendent actetate groups formed from the acetalisation of PVA with N-acryloyl-aminoacetaldehyde dimethylacetal and which is cross-linked with 2-acrylamido-2-methylpropanesulfonic acid.

33 . A method of treatment in which a hydrogel according to claim 1 is administered into a blood vessel of a patient to embolise said blood vessel.

34 . A method according to claim 33 in which the blood vessel is associated with solid tumour.

35 . A method according to claim 34 in which the tumour is hepatocellular carcinoma.

36 .- 37 . (canceled)

Assignees

• Biocompatibles Uk Ltd

Inventors

• Hohn Stéphane
• Lewis Andrew Lennard
• Willis Sean Leo
• Dreher Matthew R
• Ashrafi Koorosh
• Tang Yiqing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61L2400/06

  Flowable or injectable implant compositions · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61L24/06

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

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title