EP-4739355-A1 - CROSSLINKED HYDROGELS WITH ENHANCED RADIOPACITY FOR MEDICAL APPLICATIONS

EP4739355A1EP 4739355 A1EP4739355 A1EP 4739355A1EP-4739355-A1

Abstract

Disclosed herein are radiopaque, reactive multi-arm polymers that comprise an iodine-containing core region, a plurality of polymer arms comprising a plurality of polymer segments linked to the iodine-containing core region, and a plurality of reactive moieties linked to the plurality of polymer segments. Also disclosed are methods of forming such radiopaque, reactive multi-arm polymers, systems for forming hydrogel compositions that comprise (a) such radiopaque, reactive multi-arm polymers and (b) multifunctional crosslinking compounds comprising a plurality of complementary reactive moieties that are reactive with the reactive moieties of the radiopaque, reactive multi-arm polymers, as well as reaction products of such systems and methods of treatment using such systems.

Inventors

HSU, YEN-HAO
DELANEY, JR., Joseph Thomas
DORN, Rick
PARISI, Cristian
GURUNG, Niraj
HOBBS, Claire

Assignees

Boston Scientific Scimed, Inc.

Dates

Publication Date: 20260513
Application Date: 20240702

Claims (1)

BSC File No.23-0119WO01 Atty. Docket No.2001.3158111 CLAIMS: 1. A radiopaque, reactive multi-arm polymer comprising an iodine-containing core region, a plurality of polymer arms comprising a plurality of polymer segments linked to the iodine-containing core region, and a plurality of reactive moieties linked to the plurality of polymer segments. 2. The radiopaque, reactive multi-arm polymer of claim 1, further comprising a plurality of hydrolysable ester groups positioned between the plurality of reactive moieties and the plurality of polymer segments. 3. The radiopaque, reactive multi-arm polymer of any one of claims 1-2, wherein the plurality of polymer segments comprise one or more monomer residues selected from C 1 -C 4 -alkylene oxide residues, oxazoline monomer residues, cyclic ester monomer residues and propylene oxide and fumarate comonomers (that can generate degradable copolymer). 4. The radiopaque, reactive multi-arm polymer of any one of claims 1-3, wherein the polymer segments contain between 10 and 1000 monomer residues. 5. The radiopaque, reactive multi-arm polymer of any one of claims 1-4, wherein the reactive moieties are selected from reactive moieties that comprise electrophilic groups, reactive moieties that comprise nucleophilic groups, reactive moieties that comprise diene groups, reactive moieties that comprise dieneophile groups, reactive moieties that comprise alkenyl-containing groups, reactive moieties that comprise strained alkyne groups, and reactive moieties that comprise azide groups. 6. The radiopaque, reactive multi-arm polymer of any of claims 1-5, wherein the iodine-containing core region comprises one or more iodinated aromatic groups and/or the iodine-containing core region comprises a chain of two or more iodinated aromatic groups. 7. The radiopaque, reactive multi-arm polymer of claim 6 wherein the iodinated aromatic groups are directly linked together or linked together by a linking moiety that comprises an ether group, an ester group, an amide group, an amine group, a carbonate group. BSC File No.23-0119WO01 Atty. Docket No.2001.3158111 8. The radiopaque, reactive multi-arm polymer of any of claims 1-5, wherein the iodine-containing core region comprises two or more iodinated aromatic groups, the two or more iodinated aromatic groups each being linked to a central moiety though amide linkages. 9. The radiopaque, reactive multi-arm polymer of claim 8, wherein the two or more iodinated aromatic groups are each linked to a residue of a polyamine compound through an amide linkage or wherein the two or more iodinated aromatic groups are each linked to a residue of a polyacid compound through an amide linkage. 10. The radiopaque, reactive multi-arm polymer of any of claims 1-5, wherein the iodinated aromatic groups are iodine-substituted monocyclic aromatic groups or iodine-substituted multicyclic aromatic groups. 11. The radiopaque, reactive multi-arm polymer of any of claims 1-10, wherein the iodine-containing core region comprises a residue of an iodinated polyhydroxylated initiator having a plurality of hydroxyl groups and wherein the plurality of polymer arms correspond in number the number of hydroxyl groups in the iodinated polyhydroxylated initiator. 12. A method of forming the radiopaque, reactive multi-arm polymer of claim 11, comprising conducting a ring-opening polymerization reaction in the presence of the iodinated polyhydroxylated initiator to form one of the plurality of polymer segments at each of the hydroxyl groups. 13. A system for forming a hydrogel composition that comprises (a) a radiopaque, reactive multi-arm polymer in accordance with any one of claims 1-11 and (b) multifunctional crosslinking compound comprising a plurality of complementary reactive moieties that are reactive with the reactive moieties of the radiopaque, reactive multi-arm polymer. 14. The system of claim 13, wherein the system comprises a first composition that comprises the radiopaque, reactive multi-arm polymer and a second composition that comprises the multifunctional crosslinking compound or wherein the system comprises a first composition that comprises the radiopaque, reactive multi-arm BSC File No.23-0119WO01 Atty. Docket No.2001.3158111 polymer and the multifunctional crosslinking compound and a second composition that comprises an accelerant. 15. A crosslinked reaction product of (a) a radiopaque, reactive multi-arm polymer in accordance with any one of claims 1-11 and (b) multifunctional crosslinking compound comprising a plurality of complementary reactive moieties that are reactive with the reactive moieties of the radiopaque, reactive multi-arm polymer. 1/9 SUBSTITUTE SHEET (RULE 26) 2/9 SUBSTITUTE SHEET (RULE 26) 3/9 FIG. 3 SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26) FIG.7 9/9 FIG.9 SUBSTITUTE SHEET RULE 26

Description

BSC File No.23-0119WO01 Atty. Docket No.2001.3158111 CROSSLINKED HYDROGELS WITH ENHANCED RADIOPACITY FOR MEDICAL APPLICATIONS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.63/525,223 filed on July 6, 2023, the disclosure of which is incorporated herein by reference. FIELD [0002] The present disclosure relates radiopaque hydrogels and to crosslinkable systems for forming radiopaque hydrogels, among other aspects. The radiopaque hydrogels and crosslinkable systems for forming the same are useful, for example, in various medical applications. BACKGROUND [0003] SpaceOAR®, a rapid crosslinking hydrogel that polymerizes in vivo within seconds, is based on a multi-arm polyethylene glycol (PEG) polymer functionalized with succinimidyl glutarate as activated end groups which further react with trilysine to form crosslinks. This product has become a very successful, clinically-used biomaterial in prostate cancer therapy. A further improvement based on this structure is that a portion the succinimidyl glutarate end groups have been functionalized with 2,3,5-triiiodobenzamide groups, providing radiopacity. This hydrogel, known by the trade name of SpaceOAR Vue®, is the radiopaque version of SpaceOAR® for prostate medical applications. [0004] While the above approach is effectual, some issues arise as a result of the incorporation of the TIB functional group. First, in order to functionalize TIB on 8-arm PEG, one succinimidyl glutarate binding site is sacrificed for each TIB- functionalized arm. Moreover, the entire functionalization process involves multiple steps, typically five steps, from commercially available hydroxyl- terminated 8-arm PEG to its functionalized form with two different end groups (2,3,5-triiiodobenzamide and succinimidyl glutarate groups). This complex process of synthesizing the 8-arm PEG results in a significant increase of the product cost, decreased hydrogel persistence, and difficulties in product quality BSC File No.23-0119WO01 Atty. Docket No.2001.3158111 control. Furthermore, each added 2,3,5-triiiodobenzamide group occupies one arm of the star-PEG, reducing capacity and efficiency of the crosslinking reaction. [0005] For these and other reasons, alternative strategies for forming iodine-labelled crosslinked hydrogels that provide enhanced radiopacity while maintaining crosslink density per polymer molecule are desired. SUMMARY [0006] The present disclosure provides an alternative approach to that described above. [0007] In some aspects, the present disclosure provides radiopaque, reactive multi- arm polymers that comprise an iodine-containing core region, a plurality of polymer arms comprising a plurality of polymer segments linked to the iodine- containing core region, and a plurality of reactive moieties linked to the plurality of polymer segments. [0008] In some embodiments, radiopaque, reactive multi-arm polymer further comprises a plurality of hydrolysable ester groups positioned between the plurality of reactive moieties and the plurality of polymer segments. [0009] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the radiopaque, the plurality of polymer segments comprise one or more monomer residues selected from C1-C4-alkylene oxide residues, oxazoline monomer residues, cyclic ester monomer residues and propylene oxide and fumarate comonomers (that can generate degradable copolymer). [0010] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the polymer segments contain between 10 and 1000 monomer residues. [0011] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the reactive moieties are selected from reactive moieties that comprise electrophilic groups, reactive moieties that comprise nucleophilic groups, reactive moieties that comprise diene groups, reactive moieties that comprise dieneophile groups, reactive moieties that comprise BSC File No.23-0119WO01 Atty. Docket No.2001.3158111 alkenyl-containing groups, reactive moieties that comprise strained alkyne groups, and reactive moieties that comprise azide groups. [0012] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the iodine-containing core region comprises one or more iodinated aromatic groups. [0013] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the iodine-containing core region comprises a chain of two or more iodinated aromatic groups. For example, the iodinated aromatic groups may be directly linked together or may be linked together by a linking moiety that comprises an ether group, an ester group, an amide group, an amine group, a carbonate group. [0014] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the iodine-containing core region comprises two or more iodin