Iquid embolic material

Abstract

To provide a liquid embolic material that is inherently radiopaque, available in both a radiostable form and a radioactive form, and capable of delivering a pharmaceutical drug or therapeutic agent to a vascular site.SOLUTION: An embolic composition comprising a substantially stable biocompatible polymer comprising a reaction product of a first monomer including a polymerizable moiety having a biodegradable or biostable linkage to a visualization agent having at least one aromatic ring including at least one iodine atom, and a second monomer including a polymerizable moiety and at least one hydroxyl group, and a non-physiological solution containing a pharmaceutical drug or therapeutic agent, wherein the substantially stable biocompatible polymer is soluble in the non-physiological solution and insoluble in a physiological solution.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 990,812, filed March 17, 2020, which is incorporated herein by reference in its entirety.

[0002] (Technical field) Disclosed herein are drug treatments, and more particularly, liquid-to-solid transition solutions for use in the embolization of cerebral arteriovenous malformations (AVMs) and solid tumors. [Background technology]

[0003] Liquid embolic materials are introduced through a microcatheter in a liquid state and transition to a solid state once inside the body. This transition is generally controlled by either reaction or precipitation. In reaction-activated materials, the material is introduced in a liquid state and undergoes a chemical reaction to transition to a solid state. In some embolic materials, a pharmaceutical or therapeutic agent is dissolved in one of two components that combine to form the solidified liquid embolic material. In precipitation-activated materials, the material is introduced under non-physiological conditions and transitions to a solid state upon exposure to physiological conditions. Non-physiological conditions include water-miscible organic solvents, temperature, and pH.

[0004] Liquid embolic materials that function by precipitation have been widely investigated. Precipitation from water-miscible organic solvents has been utilized to control the transition from the liquid state to the solid state. Some examples provide a water-insoluble polymer, ethylene vinyl acetate, in combination with the water-miscible organic solvent, dimethyl sulfoxide. Another example provides a water-insoluble polymer that is inherently radiopaque in combination with the water-miscible organic solvent, dimethyl sulfoxide. Yet another example provides an alternative water-insoluble polymer that is inherently radiopaque in combination with the water-miscible organic solvent, dimethyl sulfoxide. Upon exposure to the bloodstream, all three polymers precipitate from the water-miscible organic solvent, forming an insoluble mass to occlude the bloodstream.

[0005] Radioactivity enhances the functionality of liquid embolic agents, which are designed to occlude blood flow as part of an effort to destroy unwanted tissue, such as AVMs and solid tumors. Radioactivity can destroy tissue. For example, several radioisotope-coated stents are provided that supplement the mechanical support of the stent with mechanisms to destroy arterial plaque. Radioactivity has also been investigated in conjunction with liquid embolic agents. Another example provides the water-insoluble polymer ethylene vinyl acetate supplemented with a water-insoluble radioisotope used in conjunction with the water-miscible organic solvent dimethyl sulfoxide. Summary of the Invention [Problem to be solved by the invention]

[0006] In some embodiments, liquid embolic agents are described that are inherently radiopaque, available in radiostable and radioactive forms, and that deliver pharmaceutical or therapeutic agents to a vascular site.

[0007] In some embodiments, a liquid embolic solution or formulation is described that can be deployed within the vasculature using standard techniques and a microcatheter / catheter to occlude blood flow. In some embodiments, the liquid embolic formulation comprises a biocompatible polymer having a biostable or biodegradable bond to an aromatic ring containing multiple (radiostable and / or radioactive) iodine atoms, and a water-miscible, non-aqueous solvent that dissolves the biocompatible polymer and contains a pharmaceutical or therapeutic agent.

[0008] In one embodiment, the biodegradable linkage is susceptible to hydrolytic cleavage. In another embodiment, the biodegradable linkage is susceptible to enzymatic cleavage. In another embodiment, the linkage is biostable.

[0009] In one embodiment, described herein is an embolic composition comprising a substantially stable biocompatible polymer comprising the reaction product of a first monomer comprising a polymerizable moiety having a biodegradable or biostable linkage to a visualization agent having at least one aromatic ring containing at least one iodine atom and a second monomer comprising a polymerizable moiety and at least one hydroxyl group, and a non-physiological solution containing a pharmaceutical or therapeutic agent. In some embodiments, the substantially stable biocompatible polymer is soluble in the non-physiological solution and insoluble in physiological solution.

[0010] In some embodiments, at least one of the iodine atoms contained in the liquid embolic materials described herein is a radioisotope. 123 I, 124 I, 125 I, 131 I, or a combination of these.

[0011] In one embodiment, the stable or radiostable iodine isotope is 127 I, the radioactive iodine isotope 123 I, 124 I, 125 I, or 131 I.

[0012] In one embodiment, the pharmaceutical or therapeutic agent is doxorubicin, irinotecan, sunitinib, sorafenib, paclitaxel, temozolomide, carmustine, cyclophosphamide, vincristine, and / or an antibody.

[0013] Methods of treatment are also described. In one embodiment, the method of treatment can include delivering an embolic composition described herein to a treatment site. In some embodiments, this delivery results in precipitation of a substantially stable biocompatible polymer in physiological solution. The treatment site can be within a lumen, such as, but not limited to, a blood vessel. [Brief explanation of the drawings]

[0014] [Figure 1]1 shows the kinetics of paclitaxel elution from a liquid embolic solution. [Figure 2] 1 shows the elution kinetics of irinotecan from a liquid embolic solution. [Figure 3] 1 shows the kinetics of doxorubicin elution from a liquid embolic solution. [Figure 4] Figure 1 shows the elution kinetics of sunitinib from a liquid embolic solution. [Figure 5] 1 shows the kinetics of sorafenib elution from a liquid embolic solution. [Figure 6] 1 shows the kinetics of elution of gemcitabine from a liquid embolic solution. [Figure 7] 1 shows the kinetics of oxaliplatin elution from a liquid embolic solution. [Figure 8] 1 shows the kinetics of elution of cyclophosphamide from a liquid embolic solution. [Figure 9] 1 shows the kinetics of elution of temozolomide from a liquid embolic solution. [Figure 10] 1 shows the kinetics of elution of carmustine from a liquid embolic solution. [Figure 11] Post-embolization angiogram showing good penetration into the distal hepatic vasculature. [Figure 12] Quantitation of irinotecan in blood showing a rapid rise and decline to baseline over the timescale of the experiment is shown. [Figure 13] Post-embolization angiogram showing good penetration into the distal hepatic vasculature. [Figure 14] Quantitation of doxorubicin in blood showing a rapid rise and decline to baseline is shown. [Figure 15] Post-embolization angiogram showing good penetration into the distal hepatic vasculature. [Figure 16] Quantitation of oxaliplatin in blood showing a rapid rise and decline to baseline over the timescale of the experiment is shown. DETAILED DESCRIPTION OF THE INVENTION

[0015] Described herein are drug treatment solutions that transition from a liquid state to a solid state for use in embolizing cerebral arteriovenous malformations (AVMs) and solid tumors. Methods using such solutions are also described. Some embodiments described herein include a biocompatible polymer having one or more covalently attached (radiostable and / or radioactive) iodine isotopes and a non-physiological solution containing a pharmaceutical or therapeutic agent. Precipitation of the liquid embolic material within the vascular abnormality can induce blood pooling, followed by delivery of pharmaceuticals from the solidified liquid embolic material to surrounding tissue with reduced washout.

[0016] Delivery of medicinal or therapeutic agents can be additive to the performance of liquid embolic materials. In some embodiments, embolic materials with medicinal or therapeutic agents can be used when the goal is to eliminate vasculature and / or tissue, such as AVMs and vascularly rich tumors. The addition of medicinal or therapeutic agents to the stagnant blood flow can be induced by solidifying liquid embolic materials, further enhancing the effectiveness of liquid embolic materials in treating vascular disease.

[0017] The liquid embolic materials described herein may include (i) a biocompatible polymer having an aromatic ring with multiple iodine atoms attached via a biodegradable or biostable bond, and (ii) a water-miscible solvent that dissolves the biocompatible polymer and dissolves or suspends a pharmaceutical or therapeutic agent.

[0018] In some embodiments, the liquid embolic material described herein can be a precipitating hydrophobic injection solution (PHIL®, MicroVention, Inc., Aliso Viejo, Calif.). In some embodiments, the embolic composition includes an iodine-based contrast agent bound to a polymer to render the polymer radiopaque.

[0019] The primary function of a liquid embolic material polymer may be to coagulate within a vasculature or other anatomical structure upon contact with blood or other physiological fluids, occluding the vessel or structure, and to allow visualization of the polymer when imaged using medically relevant techniques. Solubility of the liquid embolic material polymer can be achieved by judiciously selecting the composition of the polymer to ensure that it is essentially insoluble under physiological conditions. In some embodiments, the liquid embolic material polymer is prepared from a monomer containing a visualization species, or optionally from the monomer and other monomers. The ratio of the monomer containing the visualization species to the other monomers may depend on the structure of the monomers.

[0020] The one or more monomers having a visualization species can impart visibility to the liquid embolic material polymer when imaged using a medically relevant imaging technique, such as fluoroscopy or computed tomography (CT). The monomer having a visualization species can be characterized by a core that is visible under the medically relevant imaging technique and one or more polymerizable moieties attached to the core by biodegradable bonds.

[0021] Visibility of the polymer under fluoroscopy and CT imaging can be achieved by using a monomer having an iodine-containing core, particularly a core containing an aromatic ring with multiple iodine atoms. A preferred iodine-containing core is triiodophenol. The iodine concentration for making the liquid embolic material visible using fluoroscopy or CT imaging can range from about 20 wt% to about 50 wt% of the liquid embolic solution.

[0022] In some embodiments, the polymerizable moiety is capable of free radical polymerization and includes acrylates, methacrylates, acrylamides, methacrylamides, vinyl groups, and derivatives thereof. Alternatively, other reactive species can be employed to polymerize the liquid embolic material polymer, including, but not limited to, nucleophile / N-hydroxysuccinimide esters, nucleophile / halogen compounds, vinyl sulfone / acrylates, or maleimide / acrylates. In one embodiment, the polymerizable moiety is an acrylate or acrylamide.

[0023] Biodegradable linkages allow for the separation of the visualization core from the polymer. After separation from the polymer, the core is removed by diffusion or by cells, including a foreign body reaction to the polymer. Biodegradable linkages can be divided into two types: hydrolytically susceptible and enzymatically susceptible. Hydrolytically susceptible linkages are generally esters or polyesters. Esters can be introduced by reacting hydroxyl groups with strained anhydrides (e.g., succinic or glutaric anhydrides) or cyclic esters (e.g., lactide, glycolide, ε-caprolactone, and trimethylene carbonate). The degradation rate can be controlled by the choice of ester and the number of esters inserted into the biodegradable linkage. Enzymatically susceptible linkages are generally peptides that are degraded by specific enzymes (e.g., matrix metalloproteinases, collagenases, elastases, and cathepsins). Peptide sequences degraded by matrix metalloproteinases include Gly-Pro-Gln-Gly-Ile-Ala-Ser-Gln, Gly-Pro-Gln-Gly\Pro-Ala-Gly-Gln, Lys-Pro-Leu-Gly-Leu-Lys-Ala-Arg-Lys, Gly-Pro-Gln-Ile-Trp-Gly-Gln, and Gln-Pro-Gln-Gly-Leu-Ala-Lys. Peptide sequences degraded by cathepsins include Gly-Phe-Gln-Gly-Val-Gln-Phe-Ala-Gly-Phe, Gly-Phe-Gly-Ser-Val-Gln-Phe-Ala-Gly-Phe, and Gly-Phe-Gly-Ser-Thr-Phe-Phe-Ala-Gly-Phe. Peptide sequences degraded by collagenase include Gly-Gly-Leu-Gly-Pro-Ala-Gly-Gly-Lys and Ala-Pro-Gly-Leu. Peptide sequences degraded by papain include Gly-Phe-Leu-Gly. Peptide sequences degraded by caspase-3 include Asp-Glu-Val-Asp-Thr. The degradation rate can be controlled by peptide sequence selection.

[0024] Other monomers may contain polymerizable moieties and have structures conducive to desired solubility characteristics. Preferred polymerizable moieties may be those capable of free radical polymerization and may include acrylates, methacrylates, acrylamides, methacrylamides, vinyl groups, and their derivatives. Alternatively, other reactive species may be employed to polymerize the liquid embolic material polymer, including, but not limited to, nucleophile / N-hydroxysuccinimide esters, nucleophile / halogen compounds, vinyl sulfone / acrylates, or maleimide / acrylates. In one embodiment, the polymerizable moieties are acrylates and acrylamides. In some embodiments, other monomers may supplement the monomers with visualization species. If the prepared polymer is too hydrophobic to dissolve in water-miscible solvents, more hydrophilic monomers may be introduced to alter solubility. If the prepared polymer is too hydrophilic to be soluble in water, more hydrophobic monomers may be introduced to alter solubility. Other monomers include hydroxyethyl methacrylate, t-butyl acrylate, t-butyl acrylamide, n-octyl methacrylate, and methyl methacrylate.

[0025] In some embodiments, the liquid embolic material polymer is polymerized from a solution containing the monomers described herein, including the visualization species, and optionally other monomers. The solvent used to dissolve the monomers can be any solvent that dissolves the desired monomers. In some embodiments, the solvent can be aqueous, non-aqueous, or water-miscible. In some embodiments, the solvent can include methanol and / or acetonitrile.

[0026] A polymerization initiator can be used to initiate polymerization of the monomers in the solution. Polymerization can be initiated by oxidation-reduction, radiation, heat, or any other method known in the art. Radiation crosslinking of the prepolymer solution can be achieved by ultraviolet or visible light in conjunction with an appropriate initiator, or by ionizing radiation (e.g., electron beam or gamma radiation) without an initiator. Polymerization can be achieved by the application of heat, either by conventionally heating the solution using a heat source such as a heated well, or by applying infrared radiation to the prepolymer solution.

[0027] In one embodiment, the polymerization initiator is azobisisobutyronitrile (AIBN) or a water-soluble AIBN derivative (2,2'-azobis(2-methylpropionamidine) dihydrochloride). Other initiators may include, but are not limited to, AIBN derivatives such as 4,4'-azobis(4-cyanovaleric acid), N,N,N',N'-tetramethylethylenediamine, ammonium persulfate, benzoyl peroxides, and combinations thereof, including azobisisobutyronitriles. In some embodiments, the initiator concentration is less than 0.5 wt% of the prepolymer solution. The polymerization reaction may be carried out at elevated temperatures, such as, but not limited to, about 80°C. After polymerization is complete, the liquid embolic material polymer may be recovered by precipitation in a non-solvent and dried under vacuum.

[0028] The substitution of stable iodine with radioactive iodine can be performed at any step within the synthesis process. In one embodiment, this step can be performed after the preparation of the liquid embolic polymer is complete. After the liquid embolic polymer is prepared, it is redissolved in dimethyl sulfoxide, and the sodium salt of radioactive iodine is added. After the sodium salt is dissolved (e.g., completely dissolved), 30% hydrogen peroxide is added. Optionally, the reaction solution can be heated to facilitate the substitution. Upon completion of the reaction, the liquid embolic polymer is purified by repeated precipitation in water and dissolution in dimethyl sulfoxide. Alternatively, the substitution can be performed on a monomer containing a polymerizable moiety with a biostable or biodegradable linkage to an aromatic ring containing multiple iodine atoms. The same reaction method described for the liquid embolic polymer can be used for the monomer.

[0029] In some embodiments, the iodine radioisotope is 123 I, 124 I, 125 I, 131 I, or a combination thereof. Each isotope has distinct properties that allow for tissue ablation and imaging. In one embodiment, the isotope is selected from the group consisting of: I, ... 131 I.

[0030] A water-miscible non-aqueous solvent can be used to dissolve the liquid embolic material polymer and to dissolve or suspend the pharmaceutical or therapeutic agent. The concentration of the liquid embolic material polymer in the aqueous solution can range from about 2.5% to about 25%, from about 5% to about 15%, or from about 2.5% to about 10%.

[0031] In one embodiment, a method for preparing a liquid embolic material can include dissolving a liquid embolic material polymer in a water-miscible, non-aqueous solvent and adding it to a syringe, vial, or other container. Sterilization before use can be achieved by autoclaving or gamma irradiation. Pharmaceutical or therapeutic agents can be added prior to sterilization during the manufacturing process or immediately prior to use by reconstitution in the liquid embolic solution.

[0032] In one embodiment, the liquid embolic agent solvent is dimethyl sulfoxide.

[0033] The pharmaceutical or therapeutic agent can be any chemical that can be dissolved or suspended in the liquid embolic solution. In one embodiment, the pharmaceutical or therapeutic agent can be one used to treat cancer. Cancer therapeutic agents include, but are not limited to, abemaciclib, abiraterone acetate, Abraxane (an albumin-stabilized nanoparticle formulation of paclitaxel), ABVD, ABVE, ABVE-PC, AC, acalabrutinib, AC-T, Actemra (tocilizumab), Adcetris (brentuximab), and others. Vedotin), ADE, ado-trastuzumab emtansine, Adriamycin (doxorubicin hydrochloride), afatinib dimaleate, Afinitor (everolimus), Aquinzeo (netupitant-palonosetron hydrochloride), Aldara (imiquimod), aldesleukin, Alecensa (alectinib), alectinib, alemtuzumab, Alimta (pemetrexed disodium), Alicopa (copanlisib hydrochloride), Alkeran for injection (melphalan hydrochloride), Alkeran tablets (melphalan hydrochloride) Faran), Aloxi (palonosetron hydrochloride), alpelisib, Alunbrig (brigatinib), Amels (aminolevulinic acid hydrochloride), amifostine, aminolevulinic acid hydrochloride, anastrozole, apalutamide, aprepitant, Aranesp (darbepoetin alfa), Aredia (pamidronate disodium), Arimidex (anastrozole), Aromasin (exemestane), Alanon (nelarabine), arsenic trioxide, Arzera (ofatumumab), asparaginase Erwinia chrysanthemi, Asparagase (calaspargase pegol-mknl), atezolizumab, Avastin (bevacizumab), avelumab, axicarbagene ciloreucel, axitinib, azacitidine, Azedra (iobenguane I131), Barbasa (erdafitinib), Bavencio (avelumab), BEACOPP, Beleodac (belinostat), belinostat, bendamustine hydrochloride, Bendeca (bendamustine hydrochloride), BEP, Besponsa (inotuzumab) Ozogamicin), bevacizumab, bexarotene, bicalutamide, BiCNU (carmustine), binimetinib, bleomycin sulfate, blinatumomab, Blincyto (blinatumomab), bortezomib, Bosulif (bosutinib), bosutinib,Braftobi (encorafenib), brentuximab vedotin, brigatinib, Brukinsa (zanubrutinib), BuMel, busulfan, Busulfex (busulfan), cabazitaxel, Cabryvi (caplacizumab-yhdp), Cabometyx (cabozantinib s-malate), cabozantinib s-malate, CAF, calaspargase pegol-mknl, Calquence (acalabrutinib), Camptosar (irinotecan hydrochloride), capecitabine, caps lacizumab-yhdp, CAPOX, Carac (topical fluorouracil), carboplatin, carboplatin-taxol, carfilzomib, carmustine, carmustine implant, Casodex (bicalutamide), CEM, cemiplimab-rwlc, ceritinib, Cerbidine (daunorubicin hydrochloride), Cervarix (recombinant HPV bivalent vaccine), cetuximab, CEV, chlorambucil, chlorambucil-prednisolone Zon, CHOP, cisplatin, cladribine, clofarabine, Clolar (clofarabine), CMF, cobimetinib, Cometrik (cabozantinib s-malate), copanlisib hydrochloride, COPDAC, Copictra (duvelisib), COPP, COPP-ABV, Cosmegen (dactinomycin), Cotellic (cobimetinib), crizotinib, CVP, cyclophosphamide, Cyramza (ramucirumab), cytarabine, Dabrafenib mesylate, dacarbazine, Dacogen (decitabine), dacomitinib, dactinomycin, daratumumab, darbepoetin alfa, darolutamide, Darzalex (daratumumab), dasatinib, daunorubicin hydrochloride, daunorubicin hydrochloride / liposomal cytarabine, Daurismo (glasdegib maleate), decitabine, defibrotide sodium, Defitelio (defibrotide sodium), degarelix, denileukin Diftitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel, Doxil (doxorubicin hydrochloride liposomal), doxorubicin hydrochloride, doxorubicin hydrochloride liposomal, durvalumab, duvelisib, Efudex (fluorouracil - topical), Eligard (leuprolide acetate), ERYTECH (rasburicase),Elence (epirubicin hydrochloride), elotuzumab, Eloxatin (oxaliplatin), eltrombopag olamine, Erzonris (taglaxofusp - erzs), emapalumab - lzsg, Emend (aprepitant), Empliciti (elotuzumab), enasidenib mesylate, encorafenib, entrectinib, enzalutamide, epirubicin hydrochloride, EPOCH, epoetin alfa, Epogen (epoetin alfa), Erbitux (cetuximab), erdafitinib, eribulin mesylate, Erivedge (vismodegib), Erleada (apalutamide), erlotinib hydrochloride, Erwinase (asparaginase) Erwinia chrysanthemi, Ethiol (amifostine), Etopofos (etoposide phosphate), etoposide, etoposide phosphate, everolimus, Evista (raloxifene hydrochloride), Evomela (melphalan hydrochloride), exemestane, 5-FU (fluorouracil injection), 5-FU (fluorouracil - topical), Fareston (toremifene), Farydak (panobinostat), Fasolodex (fulvestrant), FEC, fedratinib hydrochloride, Femara (letrozole), filgrastim, Filmagon (degarelix), fludarabine phosphate, Fluoroplex (fluorouracil - topical), fluorouracil injection, fluorouracil - topical, flutamide, FOLFIRI, FOLFIRI-bevacizumab, FOLFIRI-setuximab Cimab, FOLFIRINOX, FOLFOX, Folotin (pralatrexate), fostamatinib disodium, FU-LV, fulvestrant, Gamifant (emapalmab-lzsg), ​​Gardasil (recombinant HPV quadrivalent vaccine), Gardasil 9 (recombinant HPV nonavalent vaccine), Gazyva (obinutuzumab), gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin, Gemzar (gemcitabine hydrochloride), Geotrif (afatinib dimaleate), gilteritinib fumarate, glasdegib maleate, Glivec (imatinib mesylate), Gliadel wafer (carmustine implant), glucarpidase, goserelin acetate, granisetron, granisetron hydrochlorideGranix (filgrastim), Halaven (eribulin mesylate), Hemandiol (propranolol hydrochloride), Herceptin Hylecta (trastuzumab and hyaluronidase-oysk), Herceptin (trastuzumab), recombinant HPV bivalent vaccine, recombinant HPV nonavalent vaccine, recombinant HPV quadrivalent vaccine, Hycamtin (topotecan hydrochloride), Hydrea (hydroxyurea), hydroxyurea, Hyper-CVAD, Ibrance (palbociclib), ibritumomab Tiuxetan, ibrutinib, ICE, Iclusig (ponatinib hydrochloride), idamycin, PFS (idarubicin hydrochloride), idarubicin hydrochloride, idelalisib, Idifa (enasidenib mesylate), Ifex (ifosfamide), ifosfamide, Il-2 (aldesleukin), imatinib mesylate, Imbruvica (ibrutinib), Imfinzi (durvalumab), imiquimod, Imlygic (talimogene laherparepvec), Inrita (axitinib), inotuzumab ozogamicin, Inlevic (fedratinib hydrochloride), recombinant interferon alfa-2b, interleukin-2 (aldesleukin), Intron A (recombinant interferon alfa-2b), iobenguan I131, ipilimumab, Iressa (gefitinib), irinotecan hydrochloride, irinotecan hydrochloride liposomal, Istodax (romidepsin), ivosidenib, ixabepilone, ixazomib citrate, Ixempra (ixabepilone), Jakafi (ruxolitinib), JES, Jevtana (cabazitaxel), Kadsila (ado-trastuzumab emtansine), Kepivance (palifermin), Keytruda (pembrolizumab), Kisqali (ribociclib), Kymriah (tisagenlecleucel), Kyprolis Lanreotide acetate, lapatinib ditosylate, larotrectinib sulfate, lenalidomide, lenvatinib mesylate, Lenvima (lenvatinib mesylate), letrozole, leucovorin calcium, Leukeran (chlorambucil), leuprolide acetate, Levlankerastic (aminolevulinic acid hydrochloride), Libtayo (cemiplimab-rwlc), lomustine, Lonsurf (trifluridine and tipiracil hydrochloride),Lobrena (lorlatinib), lorlatinib, Lumoxiti (moxetumomab-pasudotox-tdfk), Lupron (leuprolide acetate), Lupron Depot (leuprolide acetate), Lutatera (lutetium Lu177 dotatate), lutetium Lu177 dotatate, Lynparza (olaparib) (carfilzomib), Markivo (vincristine sulfate liposomal), Matulane (procarbazine hydrochloride), mechlorethamine hydrochloride, megence acetate Strol, Mekinist (trametinib), Mektovi (binimetinib), melphalan, melphalan hydrochloride, mercaptopurine, mesna, Mesnex (mesna), methotrexate, methylnaltrexone bromide, midostaurin, mitomycin C, mitoxantrone hydrochloride, mogamulizumab-kpkc, moxetumomab-pasudotox-tdfk, Mozovir (plelixafor), Mustagen (mechlorethamine hydrochloride), MVAC, Mvasi (bevacizumab), Maile Myleran (busulfan), Mylotarg (gemtuzumab ozogamicin), microparticulate paclitaxel (albumin-stabilized nanoparticle formulation of paclitaxel), Navelbine (vinorelbine tartrate), necitumumab, nelarabine, neratinib maleate, Nerlinx (neratinib maleate), netupitant and palonosetron hydrochloride, Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (sorafenib tosylate), Niland LON (nilutamide), nilotinib, nilutamide, NINLARO (ixazomib citrate), niraparibut tosylate monohydrate, nivolumab, N-Plate (romiplostim), Nubeka (darolutamide), obinutuzumab, Odomzo (sonidegib), OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, Oncaspar (pegaspargase), ondansetron hydrochloride, Onivyde (irinotecan hydrochloride liposomal), Ontak (denileukin-10) Diftitox), Opdivo (nivolumab), OPPA, osimertinib mesylate, oxaliplatin, paclitaxel, albumin-stabilized nanoparticle formulation of paclitaxel, PAD, palbociclib, palifermin, palonosetron hydrochloride,Palonosetron hydrochloride and netupitant, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, PCV, PEB, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pegIntron (peginterferon alfa-2b), pembrolizumab, pemetrexed dihydrate, Um, Perjeta (pertuzumab), pertuzumab, Picley (alpelisib), plerixafor, polatuzumab vedotin-piiq, Poliv (polatuzumab vedotin-piiq), pomalidomide, Pomalyst (pomalidomide), ponatinib hydrochloride, Portraza (necitumumab), Potelizio (mogamulizumab-kpkc), pralatrexate, prednisone, procarbazine hydrochloride, Procrit (epoetin alfa), Proleukin (aldesleukin), Prolia (denosumab), Promacta (eltrombopag) Olamine), propranolol hydrochloride, Provenge (Sipuleucel-T), Purinetol (mercaptopurine), Purixan (mercaptopurine), radium-223 dichloride, raloxifene hydrochloride, ramucirumab, rasburicase, ravulizumab-cwvz, R-CHOP, R-CVP, recombinant human papillomavirus (HPV) bivalent vaccine, recombinant human papillomavirus (HPV) nonavalent vaccine, recombinant human papillomavirus (HPV) quadrivalent vaccine, recombinant interferon alfa-2b, regorafenib, Relistol (methylnaltrexone bromide), R-EPOCH, Retacrit (epoetin alfa) α), Revlimid (lenalidomide), Rheumatrex (methotrexate), ribociclib, R-ICE, Rituxan (rituximab), Rituxan Hythera (rituximab and human hyaluronidase), rituximab, rituximab and human hyaluronidase, rolapitant hydrochloride, romidepsin, romiplostim, Rozlytrek (entrectinib), Rubidomycin (daunorubicin hydrochloride), Rubraca (rucaparib camsylate), rucaparib camsylate, ruxolitinib phosphate, Rydapt (midostaurin), Sancuso (granisetron), Sclerosol intrapleural aerosol Intrapleural Aerosol) (talc), selinexor, siltuximab, sipuleucel-T, Somatuline Depot (lanreotide acetate), sonidegib, sorafenib tosylate, Sprycel (dasatinib), STANFORD V, sterile talc powder (talc), Steritalc (talc), Stivarga (regorafenib), sunitinib malate,Sustol (granisetron), Sutent (sunitinib malate), Silatron (peginterferon alfa-2b), Silvant (siltuximab), Synribo (omacetaxine mepesuccinate), Tabloid (thioguanine), TAC, Tafinlar (dabrafenib mesylate), tagraxofusp-erzs, Tagrisso (osimertinib mesylate), talazoparib tosilate, talc, talimogene laherparepvec, Tarzenna (talazoparib tosilate), tamoxifen citrate, Tarceva (erlotinib) fostamatinib hydrochloride), Targretin (bexarotene), Tasigna (nilotinib), Tavarisse (fostamatinib disodium), Taxol (paclitaxel), Taxotere (docetaxel), Tecentriq (atezolizumab), Temodar (temozolomide), temozolomide, temsirolimus, thalidomide, Thalomid (thalidomide), thioguanine, thiotepa, Tibsovo (ivosidenib), tisagenlecleucel, tocilizumab, Tolak (fluorouracil-topical), topotecan hydrochloride, toremifene, Tolicel (temsirolimus) , Totect (dexrazoxane hydrochloride), TPF, trabectedin, trametinib, trastuzumab, trastuzumab and hyaluronidase-oysk, Treanda (bendamustine hydrochloride), Trexall (methotrexate), trifluridine and tipiracil hydrochloride, Trisenox (arsenic trioxide), Truxima (rituximab), Tykerb (lapatinib ditosylate), Ultomiris (ravulizumab-cwvz), Unituxin (dinutuximab), uridine triacetate, VAC, valrubicin, Valstar (valrubicin), vandetanib, VAMP, Varubi (rolapitant hydrochloride), Vectibix (panitumumab), VeIP, Velcade (bortezomib), vemurafenib, Venclexta (venetoclax), venetoclax, Verzenio (abemaciclib), Vidaza (azacitidine), vinblastine sulfate, vincristine sulfate, vincristine sulfate liposomal, vinorelbine tartrate, VIP, vismodegib, Vistogard (uridine triacetate), Vitrakvi (larotrectinib sulfate),Vizinpro (dacomitinib), Voraxaze (glucarpidase), vorinostat, Votrient (pazopanib hydrochloride), Vyxeos (daunorubicin hydrochloride / liposomal cytarabine), Xalkori (crizotinib), Xeloda (capecitabine), XEURI, XELOX, Xgeva (denosumab), Xofigo (radium-223 dichloride), Xospata (gilteritinib fumarate), Expovio (selinexor), Xtandi (enzalutamide), Yervoy (ipilimumab), Yescarta (axicabtagene) These may include cyclosporine (Cirolucel), Yondelis (trabectedin), Zaltrap (div-aflibercept), zanubrutinib, Zarxio (filgrastim), Zedula (niraparibut tosilate monohydrate), Zelboraf (vemurafenib), Zevalin (ibritumomab tiuxetan), Zinecard (dexrazoxane hydrochloride), ziv-aflibercept, Zofran (ondansetron hydrochloride), Zoladex (goserelin acetate), zoledronic acid, Zolinza (vorinostat), Zometa (zoledronic acid), Zydelig (idelalisib), Zykadia (ceritinib), Zytiga (abiraterone acetate), and combinations thereof.

[0034] Additionally, pharmaceuticals and therapeutic agents unrelated to cancer treatment may be incorporated into the liquid embolic material. These may include, but are not limited to, anti-angiogenic factors, anti-inflammatory drugs, analgesics, anticoagulants, clotting agents, thrombogenic agents, local anesthetics, etc. Any combination of the pharmaceuticals and therapeutic agents described may be used.

[0035] In some embodiments, the embolic formulations described herein may deliver a pharmaceutical or therapeutic agent at a particular rate or with a particular release profile. In some embodiments, the release profile may be first order, second order, third order, etc. In some embodiments, the profile may be a rapid release followed by a plateau steady release.

[0036] In some embodiments, a particular drug or therapeutic agent may have a logarithmic or near-logarithmic curve, with a rapid increase over a first period followed by a plateau during a second period.

[0037] In some embodiments, the first period of time is about 90 minutes, about 80 minutes, about 70 minutes, about 65 minutes, about 60 minutes, or between about 90 minutes and about 60 minutes, between about 80 minutes and about 60 minutes, between about 90 minutes and about 80 minutes, between about 70 minutes and about 60 minutes, or between about 80 minutes and about 70 minutes.

[0038] In some embodiments, the second period of time is about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 50 minutes, or between about 2 minutes and about 50 minutes, between about 2 minutes and about 10 minutes, between about 20 minutes and about 50 minutes, between about 2 minutes and about 5 minutes, or between about 5 minutes and about 10 minutes.

[0039] In one embodiment, the pharmaceutical or therapeutic agent is paclitaxel.

[0040] In one embodiment, the paclitaxel is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, the paclitaxel is released exponentially over the first about 9 minutes.

[0041] In one embodiment, the pharmaceutical or therapeutic agent is irinotecan.

[0042] In one embodiment, irinotecan is released or eluted from the liquid embolic agent at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, irinotecan is released exponentially over the first about 9 minutes.

[0043] In one embodiment, the pharmaceutical or therapeutic agent is doxorubicin.

[0044] In one embodiment, doxorubicin is released or eluted from the liquid embolic agent at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, doxorubicin is released exponentially over the first about 14 minutes.

[0045] In one embodiment, the pharmaceutical or therapeutic agent is sunitinib.

[0046] In one embodiment, sunitinib is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 65 minutes. In some embodiments, sunitinib is released exponentially over the first about 2 minutes.

[0047] In one embodiment, the pharmaceutical or therapeutic agent is sorafenib.

[0048] In one embodiment, sorafenib is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, sorafenib is released exponentially over the first about 2 minutes.

[0049] In one embodiment, the pharmaceutical or therapeutic agent is gemcitabine.

[0050] In one embodiment, gemcitabine is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, gemcitabine is released exponentially over the first about 9 minutes.

[0051] In one embodiment, the pharmaceutical or therapeutic agent is oxaliplatin.

[0052] In one embodiment, the oxaliplatin is released or eluted from the liquid embolic agent at a logarithmic rate. In one embodiment, the rate is over about 80 minutes. In some embodiments, the oxaliplatin is released exponentially over about the first 15 minutes.

[0053] In one embodiment, the pharmaceutical or therapeutic agent is cyclophosphamide.

[0054] In one embodiment, the cyclophosphamide is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, the cyclophosphamide is released exponentially over the first about 35 minutes.

[0055] In one embodiment, the pharmaceutical or therapeutic agent is temozolomide.

[0056] In one embodiment, temozolomide is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, temozolomide is released exponentially over the first about 35 minutes.

[0057] In one embodiment, the pharmaceutical or therapeutic agent is carmustine.

[0058] In one embodiment, carmustine is released or eluted from the liquid embolic material at a logarithmic rate. In one embodiment, the rate is over about 90 minutes. In some embodiments, carmustine is released exponentially over the first about 35 minutes.

[0059] In one embodiment, the pharmaceutical or therapeutic agent is doxorubicin, irinotecan, sunitinib, sorafenib, paclitaxel, temozolomide, oxaliplatin, gemcitabine, carmustine, cyclophosphamide, vincristine, and / or an antibody.

[0060] The liquid embolic formulation may be formulated as a solution and supplied in a syringe or vial. In another embodiment, the formulation may be prepared as a dry powder or lyophilizate that must be reconstituted before use. In some embodiments, pharmaceutical or therapeutic agents may be added to the liquid embolic material prior to use or may be formulated into the liquid embolic material as it is formed.

[0061] In some embodiments, the liquid embolic agent may then be formulated into a solution and mixed with a pharmaceutical or therapeutic agent in a vial or syringe, which may be a liquid or powder requiring reconstitution.

[0062] In some embodiments, the liquid embolic formulation can be removed from the vial using a needle and syringe. To prevent premature liquid embolic polymer deposition, the delivery catheter is flushed with a rapid dose of the same water-miscible solvent used to dissolve the liquid embolic polymer. This flushing prevents the delivery catheter from clogging with the liquid embolic polymer. The syringe containing the liquid embolic formulation is then connected to the proximal end of a delivery catheter, such as a microcatheter or cannula, positioned within the desired vessel or other anatomical site.

[0063] As the liquid embolic formulation is injected, it pushes the water-miscible solvent flushing solution out of the microcatheter. The progress of the liquid embolic formulation within the delivery catheter can be monitored using imaging techniques compatible with the selected visualization species. As the injection continues, the liquid embolic formulation can advance to the target delivery site.

[0064] The solidified liquid embolic material polymer can provide long-term occlusion of the target site. Over time, the biodegradable bonds connecting the visualization species to the liquid embolic material polymer are cleaved, causing the visualization of the liquid embolic material polymer to diminish.

[0065] Additionally, the solidified liquid embolic material polymer can provide for the delivery of a pharmaceutical or therapeutic agent to a target site. Over time, the pharmaceutical or therapeutic agent can elute from the liquid embolic material polymer as described herein.

[0066] In some embodiments, the formulations described herein may be used to treat cancer.

[0067] In some embodiments, the formulations described herein may be used to treat tumors.

[0068] In some embodiments, the formulations described herein may be used to treat unwanted growths.

[0069] In some embodiments, the formulations described herein may be used to treat tissue proliferation.

[0070] Example 1 (Preparation of Iodine-Containing Monomers) To 250 milliliters of toluene, 15 grams of triiodophenol, 22.9 grams of 3,6-dimethyl-1,4-dioxane-2,5-dione, and 25 microliters of stannous octoate are added. The solution is refluxed for 18 hours. After the solution is cooled to 25°C, 3 milliliters of acryloyl chloride and 5.2 milliliters of triethylamine dissolved in 50 milliliters of toluene are added. The mixture is stirred for 5 hours, filtered, washed with water, and dried under vacuum.

[0071] Example 2 (Preparation of Iodine-Containing Polymers) To 3 mL of dimethyl sulfoxide was added 1.8 g of acrylate-capped triiodophenol, an average of 5 lactide units extended, 0.2 g of hydroxyethyl methacrylate, and 10 mg of azobisisobutyronitrile. After all components were completely dissolved, the solution was placed at 80°C for 4 hours. After cooling to room temperature, the polymer was recovered by precipitation in ethyl ether and dried under vacuum.

[0072] Example 3 (Exchange of iodine on iodine-containing polymers) To the dimethyl sulfoxide solution of the iodine-containing polymer of Example 2, Na 131 I is added. 131After I is completely dissolved, hydrogen peroxide (30% aqueous solution) is added. The reaction is optionally heated to accelerate the exchange process. After a reaction time of 10 minutes (or longer if desired), the DMSO solution is poured into distilled water to precipitate the iodine-containing polymer. The precipitate is filtered, then redissolved in DMSO and reprecipitated two more times in deionized water. The solid is then lyophilized to remove the water, yielding the product as a solid.

[0073] Example 4 (Preparation of Liquid Embolic Formulation) To 9 g of dimethyl sulfoxide, 1 g of the polymer of Example 3 is added. The liquid embolic formulation is then dispensed into vials, which are then capped. The vials are autoclaved at 121° C. for 15 minutes.

[0074] Example 5 In vitro dissolution of pharmaceutical agents 50 mg of paclitaxel was dissolved in 1 mL of a 25 wt% PHIL® solution containing triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / paclitaxel solution was precipitated in 199 mL of dissolution medium consisting of 45:55 acetonitrile / 10 mM potassium phosphate buffer (pH 4.5) at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0075] The concentration of paclitaxel in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase consisted of 50% acetonitrile and 50% 5% acetonitrile in water, delivered at 1 mL / min. The injection volume was 10 μL, and the UV detector wavelength was 227 nm. A calibration curve was prepared from 5 to 500 ppm paclitaxel. The amount and relative percentage of released paclitaxel were calculated from the concentration data.

[0076] The kinetics of paclitaxel elution from PHIL® solution is shown in Figure 1. The resulting elution curve was nearly logarithmic over a 90-minute period, with a rapid increase of 30 mg within the first 9 minutes, followed by a gradual plateau over the 90-minute period. The total amount of paclitaxel eluted during the first 90 minutes was 38 mg per mL of PHIL®.

[0077] Example 6 In vitro dissolution of pharmaceutical agents 50 mg of irinotecan hydrochloride was dissolved in 1 mL of a 25 wt% PHIL® solution containing triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / irinotecan solution was precipitated in 99 mL of dissolution medium consisting of 10 mM potassium phosphate buffer (pH 4.0) at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0078] The concentration of irinotecan in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase consisted of 18% acetonitrile and 82% 10 mM potassium phosphate buffer (pH 3, containing 5% acetonitrile and 7.2 mM triethylamine) delivered at 1 mL / min. The injection volume was 2 μL, and the UV detector wavelength was 223 nm. A calibration curve was prepared from 10 to 1000 ppm irinotecan. The amount and relative percentage of irinotecan released were calculated from the concentration data.

[0079] The kinetics of irinotecan elution from PHIL® solution is shown in Figure 2. The resulting elution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 24 mg within the first 9 minutes, followed by a gradual plateau over the 90-minute period. The total amount of irinotecan eluted during the first 90 minutes is 31 mg per mL of PHIL®.

[0080] Example 7 In vitro dissolution of pharmaceutical agents 50 mg of doxorubicin hydrochloride was dissolved in 1 mL of 25 wt% PHIL® solution, which contained triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / doxorubicin solution was precipitated in 99 mL of dissolution medium containing 10 mM potassium phosphate buffer (pH 4.0) at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0081] The concentration of doxorubicin in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase consisted of 18% acetonitrile and 82% 10 mM potassium phosphate buffer (pH 3, containing 5% acetonitrile and 7.2 mM triethylamine) delivered at 1 mL / min. The injection volume was 3 μL, and the UV detector wavelength was 234 nm. A calibration curve was prepared from 10 to 1000 ppm doxorubicin. The amount and relative percentage of released doxorubicin were calculated from the concentration data.

[0082] The kinetics of doxorubicin elution from PHIL® solution is shown in Figure 3. The resulting elution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 29 mg within the first 14 minutes, followed by a gradual plateau over the 90-minute period. The total amount of doxorubicin eluted during the first 90 minutes is 38 mg per mL of PHIL®.

[0083] Example 8 In vitro dissolution of pharmaceutical agents 50 mg of sunitinib malate was dissolved in 1 mL of 25 wt% PHIL® solution, which contained triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / sunitinib solution was precipitated in 999 mL of dissolution medium containing phosphate-buffered saline. At 2, 5, 9, 14, 20, 27, 35, 44, 54, and 65 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0084] The concentration of sunitinib in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase consisted of 22% acetonitrile and 78% 10 mM potassium phosphate buffer (pH 3, containing 5% acetonitrile and 7.2 mM triethylamine) delivered at 1 mL / min. The injection volume was 3 μL, and the UV detector wavelength was 429 nm. A calibration curve was prepared from 1 to 100 ppm sunitinib. The amount and relative percentage of released sunitinib were calculated from the concentration data.

[0085] The kinetics of sunitinib elution from PHIL® solution is shown in Figure 4. The resulting elution curve is nearly logarithmic over a 65 minute period, with a rapid increase of 11 mg within the first 2 minutes, followed by a gradual plateau over the 65 minutes. The total amount of sunitinib eluted during the first 65 minutes is 16 mg per mL of PHIL®.

[0086] Example 9 In vitro dissolution of pharmaceutical agents 50 mg of sorafenib was dissolved in 1 mL of a 25 wt% PHIL® solution containing triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / sorafenib solution was precipitated in 999 mL of dissolution medium containing 70:30 acetonitrile / 10 mM potassium phosphate buffer (pH 4.3) at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0087] The concentration of sorafenib in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase consisted of 50% acetonitrile and 50% 10 mM potassium phosphate buffer (pH 3, containing 5% acetonitrile and 7.2 mM triethylamine) delivered at 1 mL / min. The injection volume was 3 μL, and the UV detector wavelength was 263 nm. A calibration curve was prepared from 1 to 100 ppm sorafenib. The amount and relative percentage of sorafenib released were calculated from the concentration data.

[0088] The kinetics of sorafenib elution from PHIL® solution is shown in Figure 5. The resulting elution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 38 mg within the first 2 minutes, followed by a gradual plateau over the 90-minute period. The total amount of sorafenib eluted during the first 90 minutes is 42 mg per mL of PHIL®.

[0089] Example 10 In vitro dissolution of pharmaceutical agents 50 mg of gemcitabine was dissolved in 1 mL of a 25 wt% PHIL® solution containing triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / gemcitabine solution was precipitated in 99 mL of dissolution medium containing phosphate-buffered saline (PBS) at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0090] The concentration of gemcitabine in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase included HPLC water (containing 5% acetonitrile) delivered at 1 mL / min. The injection volume was 3 μL, and the UV detector wavelength was 275 nm. A calibration curve was prepared from 10 to 1000 ppm gemcitabine. The amount and relative percentage of gemcitabine released were calculated from the concentration data.

[0091] The kinetics of gemcitabine elution from PHIL® solution is shown in Figure 6. The resulting elution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 34 mg within the first 9 minutes, followed by a gradual plateau over the 90-minute period. The total amount of gemcitabine eluted during the first 90 minutes is 43 mg per mL of PHIL®.

[0092] Example 11 In vitro dissolution of pharmaceutical agents 50 mg of oxaliplatin was dissolved in 1 mL of 25 wt% PHIL® solution, which contained triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / oxaliplatin solution was precipitated in 50 mL of dissolution medium containing phosphate-buffered saline (PBS) at room temperature. At 4.5, 15, 24.5, 34.5, 47.5, 60, and 80 minutes, 10 mL of the supernatant was pipetted into a 15 mL centrifuge tube. The remaining supernatant was poured off, and the precipitate was mixed with 50 mL of fresh dissolution medium at room temperature.

[0093] For ICP-MS analysis to measure platinum concentrations in the supernatant, samples are prepared by mixing a 1 mL sample portion with 4 mL of 2% nitric acid (5-fold diluted) or a 2.5 mL sample portion with 0.05 mL of 2% nitric acid (undiluted). A calibration curve is prepared from 0.5 to 100 ppm platinum. The amount and relative percentage of platinum released is calculated from the concentration data.

[0094] The kinetics of oxaliplatin elution from PHIL® solution is shown in Figure 7. The resulting elution curve is nearly logarithmic over an 80 minute period, with a rapid increase of 37 mg within the first 15 minutes, followed by a gradual plateau over 34.5 minutes. The total amount of oxaliplatin eluted during the first 80 minutes is 41 mg per mL of PHIL®.

[0095] Example 12 In vitro dissolution of pharmaceutical agents 50 mg of cyclophosphamide was dissolved in 1 mL of 25 wt% PHIL® solution, which contained triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / cyclophosphamide solution was precipitated in 99 mL of dissolution medium containing distilled water at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0096] The concentration of cyclophosphamide in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on a Primesep 100 column (3.2 mm x 50 mm, 3 μm). The mobile phase consisted of 5% acetonitrile and 95% HPLC water (containing 5% acetonitrile) delivered at 1 mL / min. The injection volume was 25 μL, and the UV detector wavelength was 197 nm. A calibration curve was prepared from 10 to 1000 ppm cyclophosphamide. The amount and relative percentage of cyclophosphamide released were calculated from the concentration data.

[0097] The kinetics of cyclophosphamide elution from PHIL® solution is shown in Figure 8. The resulting elution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 35 mg within the first 35 minutes, followed by a gradual plateau over the 90-minute period. The total amount of cyclophosphamide eluted during the first 90 minutes is 38 mg per mL of PHIL®.

[0098] Example 13 In vitro dissolution of pharmaceutical agents 50 mg of temozolomide was dissolved in 1 mL of 25 wt% PHIL® solution, which contained triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / temozolomide solution was precipitated in 99 mL of elution solvent containing HLPC water (containing 0.5% acetic acid) at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0099] The concentration of temozolomide in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on an Agilent Extended-C18 column (4.6 mm x 50 mm, 3.5 μm). The mobile phase consisted of 10% methanol and 90% HPLC water (containing 0.5% acetic acid) delivered at 1 mL / min. The injection volume was 3 μL, and the UV detector wavelength was 330 nm. A calibration curve was prepared from 10 to 1000 ppm temozolomide. The amount and relative percentage of temozolomide released were calculated from the concentration data.

[0100] The kinetics of temozolomide elution from PHIL® solution is shown in Figure 9. The resulting elution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 34 mg within the first 35 minutes, followed by a gradual plateau over the 90-minute period. The total amount of temozolomide eluted during the first 90 minutes is 39 mg per mL of PHIL®.

[0101] Example 14 In vitro dissolution of pharmaceutical agents 50 mg of carmustine was dissolved in 1 mL of a 25 wt% PHIL® solution containing triiodophenol-(lactide-co-glycolide) acrylate and hydroxyethyl methacrylate in dimethyl sulfoxide. 1 mL of the 25 wt% PHIL® / carmustine solution was precipitated in 99 mL of dissolution medium containing distilled water at room temperature. At 2, 5, 9, 14, 20, 27, 35, 44, 54, 65, and 90 minutes, 1 mL of the supernatant was pipetted into an HPLC vial.

[0102] The concentration of carmustine in each sample was determined using an Agilent 1100 HPLC system. Chromatographic analysis was performed on a Primesep 100 column (3.2 mm x 50 mm, 3 μm). The mobile phase consisted of 10% methanol and 90% 10 mM potassium phosphate buffer (pH 3, containing 5% acetonitrile and 7.2 mM triethylamine) delivered at 1 mL / min. The injection volume was 3 μL, and the UV detector wavelength was 230 nm. A calibration curve was prepared from 10 to 1000 ppm carmustine. The amount and relative percentage of carmustine released were calculated from the concentration data.

[0103] The kinetics of carmustine dissolution from PHIL® solution are shown in Figure 10. The resulting dissolution curve is nearly logarithmic over a 90-minute period, with a rapid increase of 21 mg within the first 35 minutes, followed by a gradual plateau over the 90-minute period. The total amount of carmustine dissolved during the first 90 minutes is 26 mg per mL of PHIL®.

[0104] Example 15 In vivo evaluation of PHIL LV liquid embolic material containing irinotecan in the canine liver Dogs were anesthetized, and a 6Fr sheath was inserted into the femoral artery through an incision. A 6Fr GlideCath was advanced retrograde into the celiac trunk and then the hepatic artery. Following angiography, a Scepter balloon (4 mm x 10 mm) was advanced through the GlideCath into the hepatic artery bifurcation. The balloon was inflated, and 1.5 mL of PHIL LV loaded with 75 mg of irinotecan was injected into the hepatic artery bifurcation. Blood samples were taken at 5, 15, 30, 60, and 120 minutes after embolization for irinotecan quantification.

[0105] The post-embolization angiogram shown in Figure 11 demonstrates good penetration into the distal hepatic vasculature. No reflux into other branches of the hepatic vasculature is observed.

[0106] Quantitative determination of irinotecan in blood shows a rapid rise to approximately 300 ppb and a decline to baseline over the timescale of the experiment, as shown in FIG.

[0107] Example 16 In vivo evaluation of PHIL 25 liquid embolic material containing doxorubicin in the canine liver. Dogs were anesthetized, and a 6Fr sheath was inserted into the femoral artery through an incision. A 6Fr GlideCath was advanced retrograde into the celiac trunk and then the hepatic artery. Following angiography, a Scepter balloon (4 mm x 10 mm) was advanced through the GlideCath into the hepatic artery bifurcation. The balloon was inflated, and 1.6 mL of PHIL 25 loaded with 80 mg of doxorubicin was injected into the hepatic artery bifurcation. Blood samples were taken at 5, 15, 30, 60, and 60 minutes after embolization for doxorubicin quantification.

[0108] The post-embolization angiogram shown in Figure 13 demonstrates good penetration into the distal hepatic vasculature. No reflux into other branches of the hepatic vasculature is observed.

[0109] Quantitative results for doxorubicin in the blood show a rapid rise to approximately 600 ppb within 5 minutes and a decline to baseline over 2 hours, as shown in FIG.

[0110] Example 17 In vivo evaluation of PHIL LV liquid embolic material containing oxaliplatin in porcine livers The pig was anesthetized, and a 6Fr sheath was inserted into the femoral artery through the incision. A 6Fr GlideCath was advanced retrograde into the celiac trunk and then the hepatic artery. Following angiography, a Scepter balloon (4 mm x 10 mm) was advanced through the GlideCath into the hepatic artery bifurcation. The balloon was inflated, and 1.5 mL of PHIL LV loaded with 30 mg of oxaliplatin was injected into the hepatic artery bifurcation. Blood samples were taken at 5, 15, 30, 60, and 60 minutes after embolization for doxorubicin quantification.

[0111] The post-embolization angiogram shown in Figure 15 demonstrates good penetration into the distal hepatic vasculature. No reflux into other branches of the hepatic vasculature is observed.

[0112] Quantitative determination of oxaliplatin in blood shows a rapid rise to approximately 1300 ppb within 5 minutes and a decline to baseline over the timescale of the experiment, as shown in FIG.

[0113] Unless otherwise indicated, all numbers used in the specification and claims expressing quantities of ingredients, properties such as molecular weights, reaction conditions, and the like, are to be understood as being modified by the word "about." Accordingly, unless contradictory, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. While not limiting the application of the doctrine of equivalents to the scope of the claims, at the very least, each numerical parameter should be construed as at least partially based on the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0114] When describing the present invention (particularly in the claims), terms referring to the singular should be construed to include both the singular and the plural unless otherwise indicated herein and clearly contradicted by context. Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value encompassed within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein and clearly contradicted by context. Any examples or illustrative statements (e.g., statements such as "etc.") described herein are intended merely to further clarify the invention and are not intended to limit the scope of any claims. The description of the invention should not be construed as referring to any element essential to the practice of the invention not recited in the claims.

[0115] Groupings of alternative elements or embodiments described herein should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or elements described herein. For purposes of convenience and / or patentability, one or more members of a group may be added to or deleted from a group. When such additions or deletions occur, the specification is considered to include the group so modified, thereby satisfying the description requirement of all Markush groups used in the claims.

[0116] Several embodiments are described herein, including the best mode contemplated by the inventors for carrying out the invention. Of course, variations on the embodiments described herein will be apparent to those skilled in the art in light of the foregoing description. The inventors expect that those skilled in the art will adopt such variations as appropriate, and intend that the invention may be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the claimed subject matter as permitted by applicable law. Moreover, any combination of the above-described elements is contemplated in all possible variations of the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0117] Additionally, numerous citations to patents and printed publications are made throughout this application. Each of the above cited patents and printed publications is herein individually incorporated by reference.

[0118] Finally, it should be understood that the embodiments described herein are intended to illustrate the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not limitation, alternative embodiments may be employed in accordance with the teachings herein. Accordingly, the claims should not be limited to the precise embodiments shown and disclosed.

[0119] [Note] [Appendix 1] a substantially stable biocompatible polymer comprising the reaction product of a first monomer comprising a polymerizable moiety having a biodegradable or biostable linkage to a visualization agent having at least one aromatic ring containing at least one iodine atom, and a second monomer comprising a polymerizable moiety and at least one hydroxyl group; a non-physiological solution containing a pharmaceutical or therapeutic agent; Including, The substantially stable biocompatible polymer is soluble in the non-physiological solution and insoluble in the physiological solution. Embolic compositions.

[0120] [Appendix 2] At least one of the at least one iodine atom is a radioisotope. 2. The embolic composition of claim 1.

[0121] [Appendix 3] The radioisotope is 123 I, 124 I, 125 I, 131 I, or a combination of these, 10. The embolic composition of claim 2.

[0122] [Appendix 4] the pharmaceutical or therapeutic agent is doxorubicin, irinotecan, sunitinib, sorafenib, paclitaxel, temozolomide, oxaliplatin, gemcitabine, carmustine, cyclophosphamide, vincristine, an antibody, or a combination thereof; 2. The embolic composition of claim 1.

[0123] [Appendix 5] the pharmaceutical or therapeutic agent is paclitaxel; 2. The embolic composition of claim 1.

[0124] [Appendix 6] The pharmaceutical or therapeutic agent is irinotecan. 2. The embolic composition of claim 1.

[0125] [Appendix 7] the pharmaceutical or therapeutic agent is doxorubicin; 2. The embolic composition of claim 1.

[0126] [Appendix 8] The pharmaceutical or therapeutic agent is sunitinib. 2. The embolic composition of claim 1.

[0127] [Appendix 9] The pharmaceutical or therapeutic agent is sorafenib. 2. The embolic composition of claim 1.

[0128] [Appendix 10] the pharmaceutical or therapeutic agent is gemcitabine; 2. The embolic composition of claim 1.

[0129] [Appendix 11] The pharmaceutical or therapeutic agent is oxaliplatin. 2. The embolic composition of claim 1.

[0130] [Appendix 12] the pharmaceutical or therapeutic agent is cyclophosphamide; 2. The embolic composition of claim 1.

[0131] [Appendix 13] the pharmaceutical or therapeutic agent is temozolomide; 2. The embolic composition of claim 1.

[0132] [Appendix 14] the pharmaceutical or therapeutic agent is carmustine; 2. The embolic composition of claim 1.

[0133] [Appendix 15] delivering to a treatment site an embolic composition comprising: a substantially stable biocompatible polymer comprising the reaction product of a first monomer comprising a polymerizable moiety having a biodegradable or biostable linkage to a visualization agent having at least one aromatic ring containing at least one iodine atom and a second monomer comprising a polymerizable moiety and at least one hydroxyl group; and a non-physiological solution containing a pharmaceutical or therapeutic agent, wherein the substantially stable biocompatible polymer is soluble in the non-physiological solution and insoluble in physiological solution; treating a condition present at the treatment site; and A method of treatment comprising:

[0134] [Appendix 16] the delivery results in precipitation of the substantially stable biocompatible polymer in the physiological solution. The method described in Appendix 15.

[0135] [Appendix 17] The treatment site is within the lumen. The method described in Appendix 15.

[0136] [Appendix 18] The condition is a cancer, a tumor, an unwanted growth, a proliferation of tissue, or a combination thereof. The method described in Appendix 15.

[0137] [Appendix 19] said delivery resulting in elution of said pharmaceutical or therapeutic agent; The method described in Appendix 15.

[0138] [Appendix 20] The elution is logarithmic. 19. The method described in Appendix 19.

Claims

[Claim 1] a substantially stable biocompatible polymer comprising the reaction product of a first monomer comprising a polymerizable moiety having a biodegradable or biostable linkage to a visualization agent having at least one aromatic ring containing at least one iodine atom, and a second monomer comprising a polymerizable moiety and at least one hydroxyl group; a non-physiological solution containing a pharmaceutical or therapeutic agent; Including, The substantially stable biocompatible polymer is soluble in the non-physiological solution and insoluble in the physiological solution. Embolic compositions.

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