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(12) Patent Application Publication (10) Pub. No.: US 2014/0271461 A1 Reb Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0271461 A1 Reb Et Al US 20140271461A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0271461 A1 Reb et al. (43) Pub. Date: Sep. 18, 2014 (54) COMPOSITIONS AND ASSOCATED Publication Classification METHODS FOR RADIOSOTOPE-BINDING MCROPARTICLES (51) Int. Cl. A615 L/2 (2006.01) (71) Applicant: Biosphere Medical, Inc., South Jordan, (52) U.S. Cl. UT (US) CPC .................................. A61K 51/1244 (2013.01) USPC ........................... 424/1.37: 525/360; 428/402 (72) Inventors: Philippe Reb, Themericourt (FR); Celine Chaix, Clichy la Garenne (FR) (57) ABSTRACT (73) Assignee: Biosphere Medical, Inc., South Jordan, The present disclosure relates to polymeric materials that UT (US) may be labeled with a radioisotope, to processes for produc ing the labeled polymeric material, and to methods of using (21) Appl. No.: 14/207,219 the materials in analytical and therapeutic applications. Spe cifically, the disclosure relates to injectable and implantable (22) Filed: Mar 12, 2014 microparticles. Such as microspheres, which are associated with radioisotopes such that the microparticles are both thera Related U.S. Application Data peutic and detectable. The radioisotope-containing micropar (60) Provisional application No. 61/779,712, filed on Mar. ticles are useful for embolization and other therapeutic medi 13, 2013. cal applications. Patent Application Publication Sep. 18, 2014 Sheet 1 of 11 US 2014/0271461 A1 FIG. 1 Patent Application Publication Sep. 18, 2014 Sheet 2 of 11 US 2014/0271461 A1 FIG. 2 Patent Application Publication Sep. 18, 2014 Sheet 3 of 11 US 2014/0271461 A1 FIG 3 Patent Application Publication Sep. 18, 2014 Sheet 4 of 11 US 2014/0271461 A1 FIG. 4 Patent Application Publication Sep. 18, 2014 Sheet 5 of 11 US 2014/0271461 A1 FIG. 5 Patent Application Publication Sep. 18, 2014 Sheet 6 of 11 US 2014/0271461 A1 F.G. 6 Patent Application Publication Sep. 18, 2014 Sheet 7 of 11 US 2014/0271461 A1 FIG. 7 Patent Application Publication Sep. 18, 2014 Sheet 8 of 11 US 2014/0271461 A1 FIG. 8 Patent Application Publication Sep. 18, 2014 Sheet 9 of 11 US 2014/0271461 A1 FIG. 9 Patent Application Publication Sep. 18, 2014 Sheet 10 of 11 US 2014/0271461 A1 FIG. 10 Patent Application Publication Sep. 18, 2014 Sheet 11 of 11 US 2014/0271461 A1 FIG. 11 US 2014/0271461 A1 Sep. 18, 2014 COMPOSITIONS AND ASSOCATED under imaging control to position solid or liquid embolic METHODS FOR RADIOSOTOPE-BINDING agents in a target blood vessel. MICROPARTICLES 0016 Embolization can be used to occlude, partially or completely, vessels of a variety of organs including the brain, CROSS-REFERENCE TO RELATED liver, and spinal cord, which results in reduced blood flow or APPLICATIONS complete occlusion of the vessels. One application of embo 0001. This application claims the benefit of U.S. Provi lization is to stop or reduce blood flow in hemorrhagic situa sional Application No. 61/779,712, filed on Mar. 13, 2013, tions. Another application is to stop delivery of blood Supply titled COMPOSITIONS AND ASSOCIATED METHODS and nutrients to tissue, for instance, to reduce or deny blood FOR RADIOISOTOPE-BINDING MICROPARTICLES, Supply to a solid tumor. In the case of vascular malformations, the disclosure of which is incorporated herein by reference in embolization may enable the blood flow to the normal tissue, its entirety. aid in Surgery and limit the risks of hemorrhage. Depending on the pathological condition, embolization can be used for TECHNICAL FIELD temporary as well as permanent therapeutic objectives. 0017 Embolization has been performed with a variety of 0002 The present disclosure relates generally to compo materials, such as Small pieces of durable goods, including sitions of microparticles containing radioisotopes, methods glass, polyvinyl alcohol particles, gelatin particles, liquid for their delivery, methods for their therapeutic use, and kits embolic products and spherical Solid hydrogels. Commer thereof. In certain aspects, the present disclosure relates to cially available embolic materials may be difficult to see or to compositions and methods for delivery of polymeric micro trace in vivo because they are relatively transparent, cannot be spheres containing radioisotopes for the treatment of certain seen clearly with normal light before and during administra CaCCS. tion, or are difficult to detect after administration because they are not radiopaque and lack features that render them detect BRIEF DESCRIPTION OF THE FIGURES able using magnetic resonance imaging, ultrasound, or 0003 FIG. 1 is a microscope image of microparticles of nuclear medicine procedures. Example 4 after lyophilization and prior to coupling to a 0018. The labeling of biocompatible polymeric materials, chelating agent. including emboli for vascular occlusion, is useful to properly 0004 FIG. 2 is a microscope image of microparticles of detect, control, and/or study the effect of the implanted or Example 4 after the first procedure for coupling to a chelating injected material. Chemical dyes, magnetic resonance agents, agent and prior to Sonication. and contrasting/radiopaque agents have all been used to serve 0005 FIG. 3 is a microscope image of microparticles of Such purposes. Radiopaque labeling of polymeric materials, Example 4 after the first procedure for coupling to a chelating which constitute the vast majority of implanted materials, has agent and after Sonication. received the most attention. To improve the radio-visibility of 0006 FIG. 4 is a microscope image of microparticles of the polymers, heavy elements may be incorporated into the Example 4 after the second procedure for coupling to a chelat polymers to increase the average electron density and specific ing agent and prior to Sonication. gravity. A radiopaque polymeric material, however, is only 0007 FIG. 5 is a microscope image of microparticles of visible by X-rays, which may not be appropriate for use in Example 4 after the second procedure for coupling to a chelat specific medical situations. An additional method for labeling ing agent and after Sonication. biocompatible polymeric materials would be beneficial. 0008 FIG. 6 is a microscope image of microparticles of 0019. One potential method is via isotopic labeling, Example 5 before lyophilization and prior to coupling to a including labeling with radioactive isotopes. Biocompatible chelating agent. polymeric material labeled with a radioisotope may be useful 0009 FIG. 7 is a microscope image of microparticles of therapeutically, Such as to treat tumors, as well as for analyti Example 5 after lyophilization and prior to coupling to a cal or diagnostic purposes. chelating agent. 0020 Attachment of certain radioactive isotopes to poly 0010 FIG. 8 is a microscope image of microparticles of meric microparticles, however, is challenging. A balance Example 6 after coupling to a chelating agent. must be found between the activity of the isotope used for the 0011 FIG. 9 is a microscope image of microparticles of label, and the type of polymeric material chosen, as the radio Example 7 after coupling to a chelating agent. activity may affect the physical stability of the polymer. In Some instances, use of an isotope which degrades the poly 0012 FIG. 10 is a microscope image of microparticles of meric material may be advantageous, such as, for example, Example 7 after coupling to a chelating agent and after siev with biodegradable polymeric materials. In other instances, 1ng. use of more durable polymeric material is favored. The man 0013 FIG. 11 is an additional microscope image of micro ner (i.e., covalent or ionic) and timing (i.e. immediately prior particles of Example 7 after coupling to a chelating agent and to injection/implantation or during polymerization of the after sieving. microparticle) of the association of the radioisotope with the microparticle should be considered, as well, and will also DETAILED DESCRIPTION likely be use-dependent. 0014. The present disclosure provides compositions of 0021. In addition, the development of microparticles, microparticles containing radioisotopes, methods for their including microspheres, for radionuclide therapy is compli delivery, methods for their therapeutic use, and kits thereof. cated by the difficulty in determining the in vivo biodistribu 0015 Therapeutic vascular embolization procedures are tion of the microspheres. The biodistribution of micropar used to treat or prevent certain pathological situations in vivo. ticles is significant for radiotherapy because the microparticle Generally, they are carried out using catheters or syringes should be in close physical proximity to the tumor or physi US 2014/0271461 A1 Sep. 18, 2014 ological area being treated. It would be useful to associate a Hence embolization of the tumoral vascular bed with radio material with the microparticle that is capable of emitting a active microparticles allows for delivery of a large radiation detectable, non-hazardous signal, which would allow for the dose directly to the tumor, while minimizing radiation dam determination of the radiation dose distribution in the tissue. age to Surrounding tissues. In situ radiation can also palliate Thus, any tumor tissue that escaped effective radiotherapy recanalization, a drawback associated with particle emboliza ("cold spots”) could be detected, and would indicate retreat tion. This type of treatment provides a highly selective appli ment. An example of Such a signal is a Y-photon (gamma cation of suitable radioactive particles (such as, for example, photon) of
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