Imageable polymers

Patent metadata

Field	Value
Publication number	US-10925979-B2
Application number	US-202016733405-A
Country	US
Kind code	B2
Filing date	Jan 3, 2020
Priority date	Sep 6, 2013
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

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

The invention claimed is:

1. Hydrogel polymer microspheres wherein the hydrogel polymer comprises: a polyvinyl alcohol (PVA) backbone comprising 1,3 diol groups and further comprises at least two pendant groups having cross-linkable ethylenically unsaturated functional groups which are cross linked by a vinylic co-monomer;
wherein at least a portion of the 1,3 diol groups of the PVA backbone are acetalised with a radiopaque species which is coupled to the hydrogel polymer through a cyclic acetal group, the radiopaque species comprising one or more covalently bound iodines and wherein the hydrogel polymer microspheres comprise at least 50 mg of iodine per milliliter of fully hydrated microspheres when measured as a packed volume.

2. Hydrogel polymer microspheres according to claim 1 , wherein the pendant chains comprising cross-linkable ethylenically unsaturated functional groups are attached to 1,3-diol groups of the PVA backbone via cyclic acetal linkages.

3. Hydrogel polymer microspheres according to claim 1 , wherein the vinylic co-monomer is 2-acrylamido-2-methylpropanesulfonic acid.

4. Hydrogel polymer microspheres according to claim 1 , wherein the ethylenically unsaturated functional groups are acrylate groups.

5. Hydrogel polymer microspheres according to claim 1 , wherein the radiopaque species comprises an iodinated phenyl group.

6. Hydrogel polymer microspheres according claim 1 , wherein the radiopaque species is coupled to the hydrogel polymer through a cyclic acetal group, such that the hydrogel polymer comprises a structure according to the general formula I:

wherein X is a group of the formula:

wherein
Z is a linking group bonded to the cyclic acetal, 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 iodines.

7. Hydrogel polymer microspheres according to claim 6 , wherein, Z is (i) a methylene or ethylene group or is (ii) a group —(CH 2 ) p —O—(CH 2 ) q — wherein q is 0, 1 or 2 and p is 1 or 2 or is (iii) absent.

8. Hydrogel polymer microspheres according to claim 6 , wherein, Z is
—CH 2 O—, —(CH 2 ) 2 O—, —CH 2 OCH 2 —, —(CH 2 ) 2 O(CH 2 ) 2 — or is absent.

9. Hydrogel polymer microspheres according to claim 6 , wherein Hal is 3 or 4 iodines.

10. Hydrogel polymer microspheres according to claim 6 , wherein Hal is 2,3,5 triiodo, 2,4,6 triiodo or 2,3,4,6 tetraiodo.

11. Hydrogel polymer microspheres according to claim 1 , wherein the radiopaque species is coupled to the hydrogel polymer through a cyclic acetal group, such that the hydrogel polymer comprises a structure according to any of the general formulas Ia to Ie

12. Hydrogel polymer microspheres according to claim 1 , wherein the hydrogel polymer has a net charge at pH 7.4.

13. Hydrogel polymer microspheres according to claim 12 , wherein the hydrogel polymer has a net negative charge at pH 7.4.

14. Hydrogel polymer microspheres according to claim 1 , having a mean diameter size range of from 10 to 2000 μm.

15. A composition comprising hydrogel polymer microspheres according to claim 1 , and a therapeutic agent, wherein the therapeutic agent is electrostatically held within the hydrogel matrix.

16. The composition according to claim 15 , wherein the therapeutic agent is selected from the group consisting of camptothecins, anthracyclines, antiangiogenic agents, microtubule assembly inhibitors, aromatase inhibitors, platinum drugs and nucleoside analogues.

17. The composition according to claim 15 , wherein the therapeutic agent is selected from the group consisting of irinotecan, topotecan, doxorubicin, daunorubicin, idarubicin, epirubicin, axitinib, bortezomib, bosutinib, canertinib, dovitinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, masutinib, mubitinib, pazopanib, pazopanib, semaxanib, sorafenib, sunitinib, tandutinib, vandetanib, vatalanib, vismodegib, vinblastine, vinorelbine, vincristine, anastrazole, cisplatin, oxaliplatin, carboplatin, miriplatin, 5-FU, cytarabine, fludarabine, gemcitabine, paclitaxel, docetaxel, mitomycin, mitoxantrone, bleomycin, pingyangmycin, abiraterone, amifostine, buserelin, degarelix, folinic acid, goserelin, lanreotide, lenalidomide, letrozole, leuprorelin, octreotide, tamoxifen, triptorelin, bendamustine, chlorambucil, dacarbazine, melphalan, procarbazine, temozolomide, rapamycin, zotarolimus, everolimus, umirolimus, sirolimus, methotrexate, pemetrexed and raltitrexed.

18. A composition according to claim 17 , wherein the therapeutic agent is selected from irinotecan, topotecan, doxorubicin, epirubicin, sorafenib, sunitinib, vandetanib, and miriplatin.

Assignees

• Biocompatibles Uk Ltd

Inventors

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

Classifications

• A61P9/14

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

• A61L2430/36

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

• A61L2400/06

  Flowable or injectable implant compositions · CPC title

• A61L2300/622

  Microcapsules · CPC title

• A61L2300/416

  Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus · CPC title