Imageable embolic microsphere
Inventors
Dreher, Matthew R. • Wood, Bradford J. • Negussie, Ayele H. • Lewis, Andrew Lennard • Tang, Yiqing
Assignees
Boston Scientific Medical Device Ltd • US Department of Health and Human Services
Publication Number
US-11672876-B2
Publication Date
2023-06-13
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 relates to imageable, radiopaque embolic microspheres particularly useful for monitoring embolization procedures. The beads comprise iodine-containing compounds covalently incorporated into the polymer network of preformed hydrogel beads. These beads are prepared by activating preformed 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 embolizing hyperplastic tissue or solid tumors.
The problem addressed by this invention is the difficulty in real-time visualization of drug-loaded microspheres during chemoembolization procedures, which is important to ensure precise delivery at the target site. Existing techniques either use inherently radiopaque materials with drawbacks such as precipitation or mix embolic particles with radiopaque contrast agents which lead to instability and lack of co-localization. There is a clear need for radiopaque embolics that combine efficient embolization and reproducibility with permanent or long-lived radiopacity suitable for clinical follow-up, and that also allow efficient drug loading and elution for chemoembolization monitoring.
The core innovation involves a method to post-process pre-formed hydrogel microspheres by activation towards nucleophilic substitution using carbonyldiimidazole or carbodiimides, followed by covalent coupling with iodinated organic materials such as iodinated aryl alcohols, especially 2,3,5-triiodobenzyl alcohol. This renders the microspheres permanently radiopaque without adversely affecting their physical properties critical for embolization like size, shape, water content, swellability, and compressibility. This chemistry also permits loading with pharmacologically active agents including chemotherapeutic drugs while preserving drug loading and elution properties.
Claims Coverage
The claims include one independent claim describing a method for making a radiopaque hydrogel bead with several inventive features covering activation, iodination, and functionalization steps.
Method of activating preformed hydrogel bead with carbonyldiimidazole or carbodiimide
The method involves reacting a preformed hydrogel bead with carbonyldiimidazole or a carbodiimide to form an activated hydrogel bead that is susceptible to nucleophilic substitution.
Covalent coupling of activated hydrogel bead with iodinated aromatic compound
Functional groups on the activated bead are reacted with an iodinated aromatic iodine-containing compound, such as iodinated benzyl or phenyl alcohol or iodinated benzoic acid to render the bead radiopaque.
Use of bifunctional aliphatic carbon chain linker for further functionalization
A terminally bifunctional linker comprising an aliphatic carbon chain (at least 2 carbons) reactive with imide or imidazole functions is coupled to the bead, allowing subsequent covalent coupling of iodinated compounds through the linker.
Preparation of preformed hydrogel bead from cross-linked polyhydroxy polymer
The preformed hydrogel bead is made from polymers with alcoholic hydroxyl substituents such as cross-linked polyvinyl alcohol or vinyl alcohol copolymers, optionally including polymers with 1,2-diol or 1,3-diol structures for crosslinking with acrylic monomers like 2-acrylamido-2-methylpropane sulfonic acid (AMPS).
Incorporation of pharmacologically active agents within radiopaque beads
The radiopaque hydrogel beads may further comprise pharmacologically active agents absorbed within them, including antiangiogenic or chemotherapeutic drugs.
Activation and reaction performed in swollen bead suspensions under anhydrous conditions
The method includes adding activating agents to suspensions of swollen preformed beads in organic solvents with catalytic base under anhydrous conditions to activate beads towards nucleophilic substitution, followed by covalent coupling with iodinated compounds reactive towards imidazole or diimide functionalities.
The claims cover a method to produce radiopaque hydrogel beads by activating preformed hydrogel beads chemically, then covalently bonding iodinated aromatic compounds either directly or through bifunctional linkers. The method also encompasses bead preparation from specific polymers and incorporation of active pharmaceutical agents, with detailed process conditions ensuring bead functionality and radiopacity.
Stated Advantages
The radiopaque beads provide permanent or sufficiently long-lived radiopacity allowing real-time and follow-up imaging of embolization procedures without the need for additional contrast agents.
The post-processing method preserves critical bead physical properties such as size, spherical shape, high water content, swellability, and compressibility.
The beads maintain or improve drug loading and elution properties compared to non-radiopaque beads, facilitating effective chemoembolization.
The method allows flexible manufacturing processes to prepare both radiopaque and non-radiopaque beads, enabling size selection prior to post-processing.
The combination of radiopaque beads with traditional contrast agents offers clinicians enhanced discrimination in imaging embolic compositions.
Documented Applications
Use of radiopaque microspheres for embolization of blood vessels, such as in treatment of solid tumors including liver tumors and uterine fibroids.
Use in chemoembolization procedures where the microspheres are loaded with chemotherapeutic drugs for localized drug delivery while monitoring by imaging.
Monitoring embolization procedures in real time and clinical follow-up using X-ray or CT imaging based on the radiopacity of the beads themselves.
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