Imageable embolic microsphere
Inventors
Dreher, Matthew R. • Wood, Bradford J. • Negussie, Ayele H. • LEWIS, Andrew Leonard • Tang, Yiqing
Assignees
Boston Scientific Medical Device Ltd • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-10307493-B2
Publication Date
2019-06-04
Expiration Date
2034-03-14
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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.
Core Innovation
This invention concerns imageable, radiopaque embolic beads that are particularly useful for monitoring embolization procedures by enhancing X-ray imaging in real-time or near real-time without requiring additional contrast agents. The beads comprise iodine-containing compounds covalently incorporated into the polymer network of preformed hydrogel beads and can be loaded with chemotherapeutic agents to facilitate embolization of hyperplastic tissue or solid tumors.
The problem addressed arises from the limitations of existing embolic materials and contrast agents, such as the lack of reproducibility and risks associated with viscous liquid embolics or instability when mixing non-radiopaque beads with radiopaque contrast agents. There is a need for radiopaque embolic beads that combine reproducible embolization properties with stable and permanent radiopacity, enabling effective visualization during and after embolization procedures while facilitating drug loading and controlled elution for chemoembolization.
The invention provides a method for post-processing pre-formed hydrogel microspheres, typically made from polyvinyl alcohol (PVA) or related copolymers, by activating them towards nucleophilic substitution using carbonyldiimidazole or carbodiimide. Subsequently, iodinated compounds reactive towards the activated groups are covalently attached, resulting in stable radiopaque microspheres that retain size, shape, compressibility, and drug loading properties of the original beads. This approach allows manufacturing flexibility, size selection prior to activation, and ensures long-lived radiopacity suitable for clinical follow-up.
Claims Coverage
The patent includes a set of independent claims focusing on compositions and methods for producing radiopaque hydrogel microspheres with covalently bound aromatic iodine containing compounds and their use with pharmacologically active agents.
Radiopaque hydrogel microsphere with activated PVA and covalently bound aromatic iodine compound
A radiopaque hydrogel microsphere comprising functional groups on a preformed crosslinked polyvinyl alcohol (PVA) hydrogel microsphere activated towards nucleophilic substitution with carbonyl diimidazole or carbodiimide, configured to react with an aromatic iodine containing compound and covalently bind it to the microsphere.
Use of iodinated benzyl or phenyl alcohol or iodinated benzoic acid as iodine containing compound
The iodine containing compound covalently bound to the hydrogel microsphere is an iodinated benzyl or phenyl alcohol or an iodinated benzoic acid, including 2,3,5-triiodobenzoic acid.
Hydrogel microsphere pre-formed from PVA with alcoholic hydroxyl substituents or acylated derivatives
The hydrogel microsphere is pre-formed from a polymer having alcoholic hydroxyl substituents or acylated derivatives thereof, specifically from crosslinked polyvinyl alcohol formed by copolymerizing ethylenically unsaturated PVA macromer with an ethylenically unsaturated comonomer.
Incorporation of pharmacologically active agent within the radiopaque microsphere
The radiopaque hydrogel microsphere further comprises a pharmacologically active agent absorbed within it, such as antiangiogenic or chemotherapeutic drugs including doxorubicin.
The independent claims cover radiopaque hydrogel microspheres prepared by activating preformed crosslinked PVA beads for covalent attachment of iodinated aromatic compounds to impart stable radiopacity, including specific chemical compositions and methods for incorporating therapeutic agents for medical embolization applications.
Stated Advantages
The radiopaque hydrogel beads provide permanent or long-lived radiopacity that allows accurate monitoring of embolization procedures and clinical follow-up.
The post-processing method preserves physical properties of the beads such as size, shape, compressibility, and drug loading efficiency, facilitating reproducible embolization.
Manufacturing flexibility is enhanced by enabling activation and iodination after size selection of preformed beads, allowing precise control over bead size and radiopacity.
The covalent incorporation of iodine-containing compounds ensures stable radiopacity without the instability issues of mixed contrast agent suspensions.
Documented Applications
Use of radiopaque hydrogel beads for embolization of blood vessels to reduce blood flow to tumors or hyperplastic tissues.
Use in chemoembolization procedures by loading with chemotherapeutic agents such as doxorubicin and irinotecan for localized drug delivery.
Monitoring embolization procedures using X-ray imaging techniques, including clinical and micro computed tomography (CT), to ensure precise delivery and localization of embolic beads.
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