Aqueous liquid embolic agents

Abstract

Described are aqueous liquid embolic compositions and uses thereof.

Description

1956788.00438AQUEOUS LIQUID EMBOLIC AGENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 707,682, filed October 15, 2024, and U.S. Provisional Patent Application No. 63 / 891 ,838, filed October 1, 2025, the entire contents of which are incorporated herein by reference.FIELD

[0002] This disclosure is generally related to aqueous liquid embolic agents that can be used for vascular and neurovascular embolization.BACKGROUND

[0003] Embolization is a minimally invasive procedure used to treat vascular malformations. Recently, embolization has been used for treating subdural hematoma. A currently used device for treatment of subdural hematomas utilizes DMSO in the embolic composition. This DMSO-based device may pose some concerns, as DMSO has been associated with rare but serious complications in some patients.

[0004] Traditional embolic agents rely on either non-soluble contrast agents or covalently bound radiopacifiers for fluoroscopic visualization. Non-radiopaque embolic agents are often formulated with non-soluble rad io pacifiers, such as barium sulfate, bismuth compounds, and tantalum. These radiopacifiers are heavier in density and insoluble in the embolic medium. It is common practice to suspend the radiopaque material by agitating the formulation immediately before injection, adding an extra step to the medical procedure. Additionally, the radiopacifier begins to precipitate from the embolic shortly after agitation, which can lead to sedimentation in the syringe or catheter during injection. Moreover, tantalum is known to generate artifacts and excessive shielding during fluoroscopic monitoring.

[0005] Covalently bound radiopacifiers have been synthesized with the embolic agents (polymers or copolymers) without the need for pre-mixing. However, whether the embolic agents employ non-soluble or covalently bound radiopacifiers, a disadvantage is that the precipitated embolic cast remains permanently radiopaque, which hinders visualization during follow-up procedures.

[0006] There is a need for improved embolic compositions that can overcome the drawbacks of existing products.1602617836.1 11956788.00438SUMMARY

[0007] In a first aspect, provided herein is a liquid embolic comprising a copolymer, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; andD) a fourth monomer, comprising a pH-sensitive functional group; wherein the liquid embolic is an aqueous-based liquid embolic.

[0008] In a second aspect, provided herein is a liquid embolic comprising a copolymer and a water-soluble visualization agent, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; andD) a fourth monomer, comprising a pH-sensitive functional group.

[0009] In a third aspect, provided herein is a liquid embolic comprising a copolymer and a water-soluble visualization agent, wherein the copolymer is a reaction product of: a methacrylate having a hydroxyl group; and a monomer having a pH-sensitive functional group. wherein the liquid embolic is an aqueous-based liquid embolic.

[0010] Also provided are methods of using the liquid embolics described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows fluoroscopic images taken for Testing Example 8. From left to right 0 min, 3 min, and 10 min.

[0012] FIG. 2 shows fluoroscopic images taken for Testing Example 9. From left to right 0 min, 3 min, and 10 min.DETAILED DESCRIPTION

[0013] A currently marketed non-adhesive liquid embolic agent includes ethylene vinyl alcohol copolymer, and requires dissolution of the copolymer in DMSO (dimethyl sulfoxide). The embolic agent further includes suspended micronized tantalum powder to provide1602617836.1 21956788.00438 contrast for visualization under fluoroscopy. Despite vigorous mixing, sedimentation of tantalum powder may compromise visual control during prolonged injections. Moreover, tantalum may generate artifacts and cause excessive shielding during fluoroscopic monitoring, which is particularly disadvantageous when repeated embolization reinterventions are needed. Moreover, the use of barium oxide as a contrast agent is also problematic, as it can produce toxic effects.

[0014] Another marketed liquid embolic agent includes a polymer of hydroxymethylacrylate (PHEMA) dissolved in DMSO, and further includes covalently bonded iodine. When the contrast agent is covalently bonded, the embolic stays radiopaque for longer periods of time which may compromise visual control during follow up visits with the patients.

[0015] Described herein are embolic compositions that alleviate some of the problems noted above. In one aspect, the embolic compositions described herein are substantially free of DMSO, i.e., they include water soluble polymers or copolymers. In some embodiments, the embolic compositions described herein include water soluble visualization agents. The water soluble contrast agents can gradually diffuse out of the embolic cast, thereby providing better visual control during follow up visits with the patients. In some embodiments, the embolic compositions described herein include a combination of water soluble visualization agents and water insoluble visualization agents. Advantageously, using appropriate ratios of monomers can provide copolymers that can form a solid cast, which does not adhere to the catheter and does not shear or disperse during injection.Definitions

[0016] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” As used herein the terms "about" and “approximately” means within 10 to 15%, preferably within 5 to 10%. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of 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 as1602617836.1 31956788.00438 precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0017] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0018] As used herein, “visualization agent” is used interchangeably with and / or includes and is not limited to contrast agents, radiopacifiers, radiolabels, and / or any other agent which improves visibility and / or imaging of vessels or tissues that have embolic agents injected or administered or cast therein. In some embodiments, a visualization agent enhances radiodensity in a target vessel or tissue. In some embodiments, a visualization agent is not transparent to X-rays or other forms of radiation (radiopaque). In some embodiments, a visualization agent is transparent to X-rays or other forms of radiation (radiolucent).

[0019] An “aqueous liquid embolic” or an “aqueous-based liquid embolic” is substantially free of any solvent other than water. In some embodiments, an aqueous-based liquid embolic is substantially free of DMSO.

[0020] “Substantially free of’ a solvent means, in some embodiments, that the aqueousbased liquid embolic includes no more than 1%, or 2% of a solvent (e.g., DMSO). In some embodiments, substantially free of a solvent means that the aqueous-based liquid embolic includes no more than 3%, 4%, or 5% of a solvent (e.g., DMSO). In some embodiments, substantially free of a solvent means that the aqueous-based liquid embolic includes no more than 6%, 7%, 8%, 9%, or 10% of a solvent (e.g., DMSO).1602617836.1 41956788.00438

[0021] “Substantially constant” radiopacity over a period of time means that the embolized composition is capable of being imaged over the period of time without any loss in image intensity, for example, no more than about 1% - 10%, about 1% - 20%, loss in image intensity such that detection of the embolized composition is not impacted.

[0022] “Bismuth subcarbonate” refers to (BiO)2CO3, sometimes written as Bi2O2(CO3), and is a chemical compound of bismuth containing both oxide and carbonate anions. Bismuth is in the +3 oxidation state. Bismuth subcarbonate occurs naturally as the mineral bismutite.Compositions

[0023] In an embodiment, provided is a liquid embolic comprising a copolymer, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; andD) a fourth monomer, comprising a pH-sensitive functional group; wherein the liquid embolic is an aqueous-based liquid embolic.

[0024] In some embodiments, as further described herein, the molar ratio of the monomers affects the properties of the copolymer such as adhesion to catheter and / or disperse or shearing of the polymer during injection.

[0025] In some embodiments, the liquid embolic further includes a non-soluble visualization agent. In some embodiments, the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.

[0026] In some embodiments, the liquid embolic precipitates in physiological medium, and the radiopacity of the precipitated liquid embolic remains visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.

[0027] In some other embodiments, the liquid embolic further includes a soluble visualization agent. In some embodiments, the soluble visualization agent is selected from an iodinated or a brominated compound. In some embodiments, the soluble visualization agent is selected from iohexol, iomeprol, iotalamic acid, iodinated tyrosine, diatrizoic acid, 3,5-diiodo-4- pyridone-N-acetic acid, or derivatives thereof.

[0028] In some embodiments, the liquid embolic includes both a soluble visualization agent and a non-soluble visualization agent.1602617836.1 51956788.00438

[0029] In some embodiments of the liquid embolic, the first monomer is selected from tertbutyl acrylate, n-butyl acrylate, isopropyl acrylate, n-propyl acrylate, pentyl acrylate, hexyl acrylate, phenyl acrylate, benzyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate or decyl acrylate, or combinations thereof.

[0030] In some embodiments of the liquid embolic, the second monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof. In some embodiments of the liquid embolic, the second monomer is selected from hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof.

[0031] In some embodiments of the liquid embolic, the third monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof. In some embodiments of the liquid embolic, the third monomer is selected from hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.

[0032] In some embodiments of the liquid embolic, the fourth monomer is an acrylamide or a methacrylamide comprising a side chain having a carboxylic acid, sulfonic acid, phosphonic acid, a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.

[0033] In some embodiments of the liquid embolic, the fourth monomer is selected from 3- aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3-methylpyridine )acrylamide or a salt thereof, N-(2-(4-aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4- imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.

[0034] In some embodiments of the liquid embolic, the molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 4-8 : 1-9 : 9-1 : 1.

[0035] In some embodiments of the liquid embolic, the molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 6 : 1-9 : 9-1 : 1.

[0036] In some embodiments of the liquid embolic, the molar ratio of the second monomer : third monomer ranges from about 2-8 : 8-2 (equivalent to about 1-4 : 4-1), or from about 2.5 - 7.5 : 7.5 - 2.5 (equivalent to about 1-3 : 3-1). In some embodiments of the liquid embolic,1602617836.1 61956788.00438 the molar ratio of the second monomer : third monomer ranges from about 2.4 - 7.4 : 7.4 - 2.4 (equivalent to about 1-3 : 3-1).

[0037] In some embodiments of the liquid embolic, the first monomer is tert-butyl acrylate, the second monomer is hydroxypropyl acrylate, the third monomer is hydroxypropyl methacrylate, and the fourth monomer is 3-aminopropyl methacrylamide hydrochloride.

[0038] In some embodiments, the liquid embolic forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.

[0039] In some embodiments, provided herein is a liquid embolic comprising a copolymer and a water-soluble visualization agent, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; andD) a fourth monomer, comprising a pH-sensitive functional group.

[0040] In some embodiments, the water-soluble visualization agent is selected from an iodinated or a brominated compound.

[0041] In some embodiments, the water-soluble visualization agent is selected from iohexol, iomeprol, iotalamic acid, iodinated tyrosine, diatrizoic acid, 3,5-diiodo-4-pyridone-N-acetic acid, or derivatives thereof.

[0042] In some embodiments, the liquid embolic precipitates in physiological medium, and the radiopacity of the precipitated liquid embolic remains substantially constant for at least about 1 min to about 40 min after precipitation of the embolic.

[0043] In some embodiments, the liquid embolic having a soluble visualization agent further includes a non-soluble visualization agent. In some embodiments, the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.

[0044] In some embodiments, when the liquid embolic having a soluble visualization agent further includes a non-soluble visualization agent, the liquid embolic precipitates in physiological medium, and the radiopacity of the precipitated liquid embolic is visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.

[0045] In some embodiments, the first monomer is selected from tert-butyl acrylate, n-butyl acrylate, isopropyl acrylate, n-propyl acrylate, pentyl acrylate, hexyl acrylate, phenyl acrylate,1602617836.1 71956788.00438 benzyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate or decyl acrylate, or combinations thereof.

[0046] In some embodiments of the liquid embolic, the second monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof. In some embodiments of the liquid embolic, the second monomer is selected from hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof.

[0047] In some embodiments of the liquid embolic, the third monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof. In some embodiments of the liquid embolic, the third monomer is selected from hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.

[0048] In some embodiments, the fourth monomer is an acrylamide or a methacrylamide including a side chain having a carboxylic acid, sulfonic acid, phosphonic acid, a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.

[0049] In some embodiments, the fourth monomer is selected from 3-aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3- methylpyridine )acrylamide or a salt thereof, N-(2-(4-aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4-imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.

[0050] In some embodiments, the liquid embolic having a soluble visualization agent has a molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 4-8 : 1-9 : 9-1 : 1.

[0051] In some embodiments, the liquid embolic having a soluble visualization agent has a molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 6 : 1-9 : 9-1 : 1 .

[0052] In some embodiments, the liquid embolic having a soluble visualization agent has a molar ratio of the second monomer : third monomer ranges from about 2-8 : 8-2 (equivalent to about 1-4 : 4-1), or from about 2.5 - 7.5 : 7.5 - 2.5 (equivalent to about 1-3 : 3-1). In some embodiments of the liquid embolic having a soluble visualization agent, the molar ratio of the1602617836.1 81956788.00438 second monomer third monomer ranges from about2.4 - 7.4 : 7.4 - 2.4 (equivalent to about 1-3 : 3-1).

[0053] In some embodiments, in a liquid embolic having a soluble visualization agent, the first monomer is tert-butyl acrylate, the second monomer is hydroxypropyl acrylate, the third monomer is hydroxypropyl methacrylate, and the fourth monomer is 3-aminopropyl methacrylamide hydrochloride.

[0054] In some embodiments, the liquid embolic having a soluble visualization agent is an aqueous-based liquid embolic.

[0055] In some embodiments, the liquid embolic having a soluble visualization agent forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.Methods

[0056] Provided herein is a method of treating a vascular condition in a subject including inserting a catheter in the subject and injecting a liquid embolic described herein in the catheter.

[0057] In some embodiments, the vascular condition is selected from pseudoaneurysms, tumors, cerebral arteriovenous malformations (AVM), dural arteriovenous fistulae, or subdural hematomas.General methods for preparation of copolymers

[0058] In some embodiments, to prepare a polymer, two or more monomers and an initiator are dissolved in a solvent. In general, any solvent that dissolves the two or more monomers and the initiator can be used. Solvents can include methanol / water, ethanol / water, isopropanol / water, dioxane / water, tetrahydrofuran / water, dimethyl formamide / water, dimethyl sulfoxide and / or water, and combinations thereof. With carboxylic acid and hydroxyl containing monomers, a wider range of solvents can be utilized, including toluene, xylene, dimethyl sulfoxide, dioxane, tetrahydrofuran, methanol, ethanol, and dimethyl formamide.

[0059] Polymerization initiators can be used to start the polymerization of the monomers in the solution. The polymerization can be initiated by reduction-oxidation, radiation, heat, or any other method known in the art. Radiation polymerization of the monomer solution can be achieved with ultraviolet light or visible light with suitable initiators or ionizing radiation (e g. electron beam or gamma ray) without initiators. Polymerization can be achieved by application1602617836.1 91956788.00438 of heat, either by conventionally heating the solution using a heat source such as a heating well, or by application of infrared light to the monomer solution.

[0060] In one embodiment, the polymerization initiator is azobisisobutyronitrile (A TRN) or a water soluble Al BN derivatives (2,2'-azobis(2- methylpropionamidine) dihydrochloride), or 4,4'-azobis(4-cyanopentanoic acid). Other initiators can include N,N,N',N'- tetramethylethylenediamine, ammonium persulfate, benzoyl peroxides, and combinations thereof, including azobisisobutyronitriles. Concentrations of the initiator can range from about 0.25% to about 2% w / w of the mass of the monomers in solution.

[0061] Initiators can include Norrish Type I initiators, Norrish Type II initiators, and combinations thereof. The initiator concentration in the solvent ranges from about 0.1 % w / w to about 6% w / w, preferably about 0.3% w / w. Examples of suitable Norrish Type I or free- radical photo-initiators are benzoin derivatives, methylolbenzoin and 4-benzoyl-1 ,3-dioxolane derivatives, benzilketals, a,a-dialkoxyacetophenones, a-hydroxy alkylphenones, a- aminoalkylphenones, acylphosphine oxides, bisacylphosphine oxides, acylphosphine sulphides, halogenated acetophenone derivatives, and the like.

[0062] Other suitable Norrish Type I photoinitiators are Irgacure 2959 (2-hydroxy-4'-(2- hydroxyethoxy)-2-methyl propiophenone), Irgacure 651 (benzildimethyl ketal or 2,2- dimethoxy-1 ,2-diphenylethanone) (Ciba-Geigy), Irgacure 184 (1-hydroxycyclohexyl-phenyl ketone as the active component) (Ciba-Geigy), Darocur 1173 (2-hydroxy-2-methyl-1- phenylpropan-1-one as the active component) (Ciba-Geigy), Irgacure 907 (2-methyl-1-[4- (methylthio)phenyl]-2-morpholino propan-1-one) (CibaGeigy), Irgacure 369 (2-benzyl-2- dimethylamino-1-(4-morpholinophenyl)-butan-1-one as the active component) (Ciba-Geigy), Esacure KIP 150 (poly {2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}) (Fratelli Lamberti), Esacure KIP 100 F (blend of poly{2-hydroxy-2-methyl-1-[4-(1- methylvinyl)phenyl]propan-1-one} and 2-hydroxy-2-methyl-1-phenyl-propan-1-one) (Fratelli Lamberti), Esacure KTO 46 (blend of poly {2-hydroxy-2-methyl-1-[4-(1- methylvinyl)phenyl]propan-1-one}, 2,4,6-trimethylbenzoyldiphenyl-phosphine oxide, and methylbenzophenone derivatives) (Fratelli Lamberti), acylphosphine oxides such as Lucirin TPO (2,4,6-trimethylbenzoyl di phenyl phosphine oxide) (BASF), Irgacure 819 (bis(2,4,6- trimethylbenzoyl)-phenylphosphine-oxide) (Ciba-Geigy), Irgacure 1700 (25:75% blend of bis(2,6-dimethoxybenzoyl)-2,4,4-trimethyl-pentyl phosphine oxide, and 2-hydroxy-2-methyl-1- phenyl-propan-1-one) (Ciba-Geigy), and the like. Also, mixtures of type I photo-initiators can be used.1602617836.1 101956788.00438

[0063] Norrish Type II photo-initiators that can be used include aromatic ketones such as benzophenone, xanthone, derivatives of benzophenone (e.g. chlorobenzophenone), blends of benzophenone and benzophenone derivatives (e.g. Photocure 81, a 50 / 50 blend of 4- methyl-benzophenone and benzophenone), Michler's Ketone, Ethyl Michler's Ketone, thioxanthone and other xanthone derivatives like Quantacure ITX (isopropyl thioxanthone), benzil, anthraquinones (e.g. 2-ethyl anthraquinone), coumarin, or chemical derivatives or combinations of these photoinitiators.

[0064] The polymerization reaction can be performed at elevated temperatures, such as in the range from about 65°C to about 85°C. For example, in embodiments the polymerization reaction is performed at 65°C, 70°C, 75°C, 80°C, or 85°C. After the polymerization is completed, the polymer is recovered by precipitation in a non-solvent and dried under vacuum. The molecular weight of the copolymer can range from about 500 g / mole to about 100,000 g / mole, or from about 1 ,000 g / mole to about 40,000 g / mole.EMBODIMENTS

[0065] Embodiment 1. A liquid embolic comprising a copolymer, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; andD) a fourth monomer, comprising a pH-sensitive functional group; wherein the liquid embolic is an aqueous-based liquid embolic.Embodiment 2. The liquid embolic of embodiment 1 , further comprising a non-soluble visualization agent.Embodiment 3. The liquid embolic of embodiment 2, wherein the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.Embodiment 4. The liquid embolic of embodiment 2 or embodiment 3, wherein the liquid embolic precipitates in physiological medium, and the radiopacity of the precipitated liquid embolic remains visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.1602617836.1 111956788.00438Embodiment 5. The liquid embolic of embodiment 1 , further comprising a soluble visualization agent.Embodiment 6. The liquid embolic of embodiment 4, wherein the soluble visualization agent is selected from an iodinated or a brominated compound.Embodiment 7. The liquid embolic of embodiment 4, wherein the soluble visualization agent is selected from iohexol, iomeprol, iotalamic acid, iodinated tyrosine, diatrizoic acid, 3,5-diiodo-4- pyridone-N-acetic acid, or derivatives thereof.Embodiment 8. The liquid embolic of embodiment 1 , further comprising a soluble visualization agent and a non-soluble visualization agent.Embodiment 9. The liquid embolic of any one embodiments 1-8, wherein the first monomer is selected from tert-butyl acrylate, n-butyl acrylate, isopropyl acrylate, n-propyl acrylate, pentyl acrylate, hexyl acrylate, phenyl acrylate, benzyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate or decyl acrylate, or combinations thereof.Embodiment 10. The liquid embolic of any one of embodiments 1-9, wherein the second monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof.Embodiment 11 . The liquid embolic of any one of embodiments 1-10, wherein the third monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.Embodiment 12. The liquid embolic of any one of embodiments 1-11 , wherein the fourth monomer is an acrylamide or a methacrylamide comprising a side chain having a carboxylic acid, sulfonic acid, phosphonic acid, a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.Embodiment 13. The liquid embolic of any one of embodiments 1-12, wherein the fourth monomer is selected from 3-aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3-methylpyridine )acrylamide or a salt thereof, N-(2-(4-1602617836.1 121956788.00438 aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4-imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.Embodiment 14. The liquid embolic of any one of embodiments 1-13, wherein the molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 4-8 : 1-9 : 9-1 : 1.Embodiment 15. The liquid embolic of any one of embodiments 1-13, wherein the molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 6 : 1- 9 : 9-1 : 1.Embodiment 16. The liquid embolic of any one of embodiments 1-13, wherein the molar ratio of the second monomer : third monomer ranges from about 2-8 : 8-2.Embodiment 17. The liquid embolic of any one of embodiments 1-13, wherein the molar ratio of the second monomer : third monomer ranges from about 2.4 - 7.4 : 7.4 - 2.4.Embodiment 18. The liquid embolic of any one of embodiments 1-17, wherein the first monomer is tert-butyl acrylate, the second monomer is hydroxypropyl acrylate, the third monomer is hydroxypropyl methacrylate, and the fourth monomer is 3-aminopropyl methacrylamide hydrochloride.Embodiment 19. The liquid embolic of any one of embodiments 1-18, wherein the liquid embolic forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.Embodiment 20. A method of treating a vascular condition in a subject comprising inserting a catheter in the subject and injecting the liquid embolic of any one of claims 1-19 in the catheter.Embodiment 21. The method of embodiment 20, wherein the vascular condition is selected from pseudoaneurysms, tumors, cerebral arteriovenous malformations (AVM), dural arteriovenous fistulae, and subdural hematomas.Embodiment 22. A liquid embolic comprising a copolymer and a water-soluble visualization agent, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; and1602617836.1 131956788.00438D) a fourth monomer, comprising a pH-sensitive functional group.Embodiment 23. The liquid embolic of embodiment 22, wherein the water-soluble visualization agent is selected from an iodinated or a brominated compound.Embodiment 24. The liquid embolic of embodiment 22, wherein the water-soluble visualization agent is selected from iohexol, iomeprol, iotalamic acid, iodinated tyrosine, diatrizoic acid, 3,5- diiodo-4-pyridone-N-acetic acid, or derivatives thereof.Embodiment 25. The liquid embolic of any one of embodiments 22-24, wherein the liquid embolic precipitates in physiological medium, and the radiopacity of the precipitated liquid embolic remains substantially constant for at least about 1 min to about 40 min after precipitation of the embolic.Embodiment 26. The liquid embolic of embodiment 22 further comprising a non-soluble visualization agent.Embodiment 27. The liquid embolic of embodiment 26, wherein the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.Embodiment 28. The liquid embolic of embodiment 26 or embodiment 27, wherein the liquid embolic precipitates in physiological medium, and the radiopacity of the precipitated liquid embolic is visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.Embodiment 29. The liquid embolic of any one of embodiments 22-28, wherein the first monomer is selected from tert-butyl acrylate, n-butyl acrylate, isopropyl acrylate, n-propyl acrylate, pentyl acrylate, hexyl acrylate, phenyl acrylate, benzyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate or decyl acrylate, or combinations thereof.Embodiment 30. The liquid embolic of any one of embodiments 22-29, wherein the second monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N- (4-hydroxyphenyl)methacrylamide, hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof.Embodiment 31 . The liquid embolic of any one of embodiments 22-30, wherein the third monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4-1602617836.1 141956788.00438 hydroxyphenyl)methacrylamide, hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.Embodiment 32. The liquid embolic of any one of embodiments 22-31 , wherein the fourth monomer is an acrylamide or a methacrylamide comprising a side chain having a carboxylic acid, sulfonic acid, phosphonic acid, a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.Embodiment 33. The liquid embolic of any one of embodiments 22-32, wherein the fourth monomer is selected from 3-aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3-methylpyridine )acrylamide or a salt thereof, N-(2-(4- aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4-imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.Embodiment 34. The liquid embolic of any one of embodiments 22-33, wherein the molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 4-8 : 1-9 : 9-1 : 1.Embodiment 35. The liquid embolic of any one of embodiments 22-33, wherein the molar ratio of the first monomer : second monomer : third monomer : fourth monomer ranges from about 6 : 1- 9 : 9-1 : 1.Embodiment 36. The liquid embolic of any one of embodiments 22-33, wherein the molar ratio of the second monomer : third monomer ranges from about 2-8 : 8-2.Embodiment 37. The liquid embolic of any one of embodiments 22-33, wherein the molar ratio of the second monomer : third monomer ranges from about 2.4 - 7.4 : 7.4 - 2.4.Embodiment 38. The liquid embolic of any one of embodiments 22-37, wherein the first monomer is tert-butyl acrylate, the second monomer is hydroxypropyl acrylate, the third monomer is hydroxypropyl methacrylate, and the fourth monomer is 3-aminopropyl methacrylamide hydrochloride.Embodiment 39. The liquid embolic of any one of embodiments 22-38, wherein the liquid embolic is an aqueous-based liquid embolic.1602617836.1 151956788.00438Embodiment 40. The liquid embolic of any one of embodiments 22-39, wherein the liquid embolic forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.Embodiment 41. A method of treating a vascular condition in a subject comprising inserting a catheter in the subject and injecting the liquid embolic of any one of embodiments 22-40 in the catheter.Embodiment 42. The method of embodiment 41 , wherein the vascular condition is selected from pseudoaneurysms, tumors, cerebral arteriovenous malformations (AVM), dural arteriovenous fistulae, and subdural hematomas.Embodiment 43. A liquid embolic comprising a copolymer wherein the copolymer is a reaction product of: a methacrylate having a hydroxyl group; and a monomer having a pH-sensitive functional group; wherein the liquid embolic is an aqueous-based liquid embolic.Embodiment 44. The liquid embolic of embodiment 43 further comprising a non-soluble visualization agent.Embodiment 45. The liquid embolic of embodiment 44, wherein the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.Embodiment 46. The liquid embolic of embodiments 43 or 44, wherein the liquid embolic precipitates in physiological medium, and radiopacity of the precipitated liquid embolic is visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.Embodiment 47. The liquid embolic of embodiments 43 or 44, wherein the methacrylate having a hydroxyl group is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4-hydroxyphenyl)methacrylamide, hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.Embodiment 48. The liquid embolic of embodiments 43 or 44, wherein the monomer having a pH- sensitive functional group is selected from 3-aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3-methylpyridine)acrylamide or a salt thereof, N-1602617836.1 161956788.00438(2-(4-aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4-imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.Embodiment 49. The liquid embolic of embodiments 43 or 44, the methacrylate having a hydroxyl group is hydroxypropyl methacrylate, and monomer having a pH-sensitive functional group is 3- aminopropyl methacrylamide hydrochloride.Embodiment 50. The liquid embolic of embodiments 43 or 44, wherein the liquid embolic forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.Embodiment 51. A method of treating a vascular condition in a subject comprising inserting a catheter in the subject and injecting the liquid embolic of embodiment 43 or embodiment 44, in the catheter.Embodiment 52. The method of embodiment 51 , wherein the vascular condition is selected from pseudoaneurysms, tumors, cerebral arteriovenous malformations (AVM), dural arteriovenous fistulae, and subdural hematomas.EXAMPLES

[0066] Synthesis Example 1 - Synthesis of Copolymer 1

[0067] To a 500 mL amber jar was added tert-butyl acrylate (8.36 g, 65.3 mmol), a mixture of hydroxypropyl acrylate isomers (3.59 g, 27.5 mmol), 2-hydroxypropyl methacrylate (11.91 g, 82.6 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (2.00 g, 11.2 mmol), AIBN (0.236 g, 1.44 mmol), and methanol (52.87 g). The content was mixed well and sparged for 1 min with dry argon. The jar was capped, placed in a 65 °C oil bath, and left to react for about 24 hours. To work up, the jar was removed from the oil bath, and the polymer was precipitated in MTBE (500 mL). Kept the precipitate and discarded the supernatant. Poured an additional portion of MTBE (300 mL) over the precipitate and stirred. Kept the precipitate and discarded the supernatant. Dissolved the precipitate in water (150 mL) and lyophilized the resulting solution for 72 hours to afford dry copolymer.

[0068] Synthesis Example 2 - Synthesis of Copolymer 2

[0069] To a 500 mL amber jar was added tert-butyl acrylate (8.37 g, 65.3 mmol), a mixture of hydroxypropyl acrylate isomers (2.87 g, 22.0 mmol), 2-hydroxypropyl methacrylate (12.71 g, 88.1 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (2.00 g, 11.2 mmol), AIBN (0.236 g, 1 .44 mmol), and methanol (53.06 g). The contents were mixed well and sparged for1602617836.1 171956788.004381 min with dry argon. The jar was capped, placed in a 65 °C oil bath, and left to react for about 24 hours. To work up, the jar was removed from the oil bath, and the content was precipitated in MTBE (800 ml_). Kept the precipitate and discarded the supernatant. Dissolved the precipitate in water (150 ml_) and lyophilized the resulting solution for 72 hours to afford dry copolymer.

[0070] Synthesis Example 3 - Synthesis of Copolymer 3

[0071] To a 500 mL amber jar was added tert-butyl acrylate (8.40 g, 65.3 mmol), a mixture of hydroxypropyl acrylate isomers (7.17 g, 55.0 mmol), 2-hydroxypropyl methacrylate (7.96 g, 55.0 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (2.01 g, 11.2 mmol), AIBN (0.236 g, 1 .44 mmol), and methanol (52.20 g). The contents were mixed well and sparged for 1 min with dry argon. The jar was capped, placed in a 65 °C oil bath, and left to react for about 24 hours. To work up, the jar was removed from the oil bath, and the content was precipitated in MTBE (800 mL). Kept the precipitate and discarded the supernatant. Dissolved the precipitate in water (150 mL) and lyophilized the resulting solution for 72 hours to afford dry copolymer.

[0072] Synthesis Example 4 - Synthesis of Copolymer 4

[0073] To a 500 mL amber jar was added tert-butyl acrylate (8.39 g, 65.3 mmol), a mixture of hydroxypropyl acrylate isomers (10.74 g, 82.6 mmol), 2-hydroxypropyl methacrylate (3.97 g, 27.5 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (1.99 g, 11.2 mmol), AIBN (0.236 g, 1 .44 mmol), and methanol (51.30 g). The contents were mixed well and sparged for 1 min with dry argon. The jar was capped, placed in a 65 °C oil bath, and left to react for about 24 hours. To work up, the jar was removed from the oil bath, and the contents were precipitated in MTBE (500 mL). Poured MTBE (300 mL) over the precipitate. Stirred and decanted the supernatant. Kept the precipitate and discarded the supernatant. Dissolved the precipitate in water (150 mL) and lyophilized the resulting solution for 72 hours to afford dry copolymer.

[0074] Synthesis Example 5 - Synthesis of Copolymer 5

[0075] To a 500 mL amber jar was added tert-butyl acrylate (12.59 g, 98.0 mmol), 2- hydroxypropyl methacrylate (23.8 g, 165.1 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (3.00 g, 16.8 mmol), AIBN (0.355 g, 2.15 mmol), and methanol (80.4 g). The contents were mixed well and sparged for 1 min with dry argon. The jar was capped, placed in a 65 °C oil bath, and left to react for about 24 hours. To work up, the jar was removed from1602617836.1 181956788.00438 the oil bath, and the content was precipitated in MTBE (800 mL). Kept the precipitate and discarded the supernatant. Dissolved the precipitate in water (300 mL) and lyophilized the resulting solution for 72 hours to afford dry copolymer.

[0076] Synthesis Example 6 - Synthesis of Copolymer 6

[0077] To a 32 oz. amber jar was added tert-butyl acrylate (41 g, 320 mmol), hydroxypropyl acrylate (mixture of isomers, 69 g, 530 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (10.00 g, 56.0 mmol), AIBN (1.2 g, 7.30 mmol), and methanol (250 g). The contents were mixed well and sparged for 1 min with dry argon. The jar was capped, placed in a 65 °C oil bath, and left to react for about 72 hours. To work up, the jar was removed from the oil bath, and the content was precipitated in MTBE (4 L). Kept the precipitate and discarded the supernatant, poured MTBE over the precipitate, and stirred for about 15 min. Repeated this step for a second time. Placed the solid under reduced pressure for about 3 hours to remove the residual MTBE. Dissolved the precipitate in water (2 L) and precipitated in PBS (4 L). Discarded the supernatant and kept the precipitate. Dissolved the precipitate in water (2 L) and lyophilized the resulting solution to afford a dry copolymer.

[0078] Synthesis Example 7 - Synthesis of Copolymer 7

[0079] To a 120 mL amber jar was added 2-Hydroxypropyl methacrylate (13.27 g, 92.0 mmol), A / -(3-Dimethylaminopropyl) methacrylamide (1.00 g, 6.0 mmol), AIBN (0.124 g, 0.75 mmol), and dimethylformamide (28.93 g). The contents were mixed well and sparged for 1 min with dry argon. The jar was capped, placed in an 80 °C oil bath, and left to react for about 24 hours. To work up, the jar was removed from the oil bath, and the content was precipitated in MTBE (300 mL). Kept the precipitate and discarded the supernatant. The precipitate was vacuum-dried at room temperature for 12 hours to afford dry copolymer.

[0080] Formulation Example 1

[0081] Copolymer 1 Formulated with iohexol at 150 mgl / mL (mgl is defined as mg iodide per mL): Copolymer 1 was dissolved in water for injection to reach a 20% concentration (wt / v). Added to this solution (6.3 mL) was iohexol (2.04 g) to reach a concentration of 150 mgl / mL. The viscosity of this sample was measured on a Brookfield DV2T viscometer (Table 1).

[0082] Formulation Example 2

[0083] Copolymer 1 Formulated with iohexol at 300 mgl / mL: Copolymer 1 was dissolved in water for injection to reach a 20% concentration (wt / v). Added to this solution (5.8 mL) was1602617836.1 191956788.00438 iohexol (3.77 g) to reach a concentration of 300 mgl / mL. The viscosity of this sample was measured on a Brookfield DV2T viscometer (Table 1).

[0084] Formulation Example 3

[0085] Copolymer 2 Formulated with iohexol at 150 mgl / mL: Copolymer 2 was prepared as an embolic agent following the procedure described in Formulation Example 1. The viscosity of this sample was measured on a Brookfield DV2T viscometer (Table 1).

[0086] Formulation Example 4

[0087] Copolymer 2 Formulated with iohexol at 300 mgl / mL: Copolymer 2 was prepared as an embolic agent following the procedure described in Formulation Example 1. The viscosity of this sample was measured on a Brookfield DV2T viscometer (Table 1).

[0088] Table 1. Summary of Viscosity

[0089] Formulation Example 5

[0090] Copolymer 1 Formulated with iohexol at 150 mgl / mL and barium sulfate at 25%: Added to the solution from Formulation Example 1 was BaSCk to achieve a BaSO4:polymer solution ratio of 1:3 (wt:wt). The delivery force of this sample was measured on an Instron tester. Maximum delivery force = 8.12 N.

[0091] Formulation Example 6

[0092] Copolymer 2 Formulated with iohexol at 150 mgl / mL and barium sulfate at 25%: Added to the solution from Formulation Example 3 was BaSCU to achieve a BaSO4:polymer solution ratio of 1:3 (wt:wt). The delivery force of this sample was measured on an Instron tester. Maximum delivery force = 12.46 N.1602617836.1 201956788.00438

[0093] Formulation Example 7

[0094] Copolymer 1 Formulated with iohexol at 300 mgl / mL and barium sulfate at 25%: Copolymer 1 was dissolved in water for injection to reach a 18% concentration (wt / v). Added to this solution was iohexol to achieve a final iodine concentration of 300 mgl / mL. BaSC>4 was added to this solution to achieve a BaSC polymer solution ratio of 1 :3 (wt:wt). The delivery force of this sample was measured on an Instron tester. Maximum delivery force = 8.63 N.

[0095] Formulation Example 8

[0096] Copolymer 2 Formulated with iohexol at 300 mgl / mL and barium sulfate at 25%: Copolymer 2 was dissolved in water for injection to reach a 18% concentration (wt / v). Added to this solution was iohexol to achieve a final iodine concentration of 300 mgl / mL. BaSC was added to this solution to achieve a BaSCM: polymer solution ratio of 1 :3 (wt:wt). The delivery force of this sample was measured on an Instron tester. Maximum delivery force = 9.48 N.

[0097] Testing Example 1

[0098] In vitro simulated testing of Copolymer 1 in an arteriovenous malformation (AVM) Flow Model: Polymer 1 was dissolved in water for injection. The resulting solution was adjusted with water for injection so that the viscosity was between 20-28 cps. To a speed mixer cup was added this aqueous solution and barium sulfate powder to achieve a 3:1 ratio (embolic solution / barium sulfate, wt / wt). The sample was further degassed and mixed to remove dissolved air and to suspend the barium powder. The resulting embolic agent was loaded into a 1 mL syringe. Meanwhile, a silicone model simulating arteriovenous malformation was connected to a 37 °C constant flow of phosphate buffer saline. A Headway Duo catheter flushed with dextrose solution was inserted into the model and positioned for injection. The syringe was attached to the catheter via an adaptor, and the embolic agent was injected into the model under the constant flow of 37 °C phosphate buffer saline. After the model was embolized and a reflux was achieved around the tip of the catheter (maximum reflux distant ~3 cm), injection came to a full stop and a countdown of 3 min was set. After 3 min, the catheter was withdrawn from the model, and the adhesion of the polymer at the tip of the catheter was evaluated. Results are shown in Table 2.

[0099] Testing Example 2

[0100] In vitro simulated testing of Copolymer 2 in an AVM Flow Model.

[0101] Polymer 2 was tested following the procedure shown in Testing Example 1. Results are shown in Table 2.1602617836.1 211956788.00438

[0102] Testing Example 3

[0103] In vitro simulated testing of Copolymer 3 in an AVM Flow Model.

[0104] Copolymer 3 was tested following the procedure shown in Testing Example 1 . Results are shown in Table 2.

[0105] Testing Example 4

[0106] In vitro simulated testing of Copolymer 4 in an AVM Flow Model.

[0107] Copolymer 4 was tested following the procedure shown in Testing Example 1. Results are shown in Table 2.

[0108] Testing Example 5

[0109] In vitro simulated testing of Copolymer 5 in an AVM Flow Model.

[0110] Copolymer 5 was tested following the procedure shown in Testing Example 1. Results are shown in Table 2.

[0111] Testing Example 6

[0112] In vitro simulated testing of Copolymer 6 in an AVM Flow Model.

[0113] Copolymer 6 was tested following the procedure shown in Testing Example 1. Results are shown in Table 2.

[0114] Testing Example 7

[0115] In vitro simulated testing of Copolymer 7 in a subdural hematoma (SDH) Flow Model: Copolymer 7 was dissolved in water for injection. The resulting solution was adjusted with water for injection so that the viscosity was between 20-28 cps. To a speed mixer cup was added this aqueous solution and barium sulfate powder to achieve a 3:1 ratio (embolic solution / barium sulfate, wt / wt). The sample was further degassed and mixed to remove dissolved air and to suspend the barium powder. The resulting embolic agent was loaded into a 1 mL syringe. Meanwhile, a silicone model simulating subdural hematoma was connected to a 37 °C constant flow of phosphate buffer saline. A Headway Duo catheter flushed with dextrose solution was inserted into the model and positioned for injection. The syringe was attached to the catheter via an adaptor, and the embolic agent was injected into the model under the constant flow of 37 °C phosphate buffer saline. After the model was embolized and a reflux was achieved around the tip of the catheter (maximum reflux distant ~3 cm), injection came to a full stop and a countdown of 3 min was set. After 3 min, the catheter was withdrawn1602617836.1 221956788.00438 from the model, and the adhesion of the polymer at the tip of the catheter was evaluated. Results are shown in Table 2.

[0116] Table 2 In vitro simulated testing results.

[0117] The properties of the copolymers were found to be sensitive to the molar ratios of the second monomer (including an acrylate having a hydroxyl group) to the third monomer (including a methacrylate having a hydroxyl group). The data in Table 2 shows that copolymer 1 (ratio of second monomer : third monomer of about 2.4:7.4 (equivalent to a ratio of about 1 : 3)) and copolymer 4 (ratio of second monomer : third monomer of about 7.4:2.4 (equivalent to a ratio of about 3:1)) had minimal or no disperse or shearing at injection, and none to minimal adhesion at withdrawal. By contrast, copolymer 2 (ratio of second monomer : third monomer of about 1.9:7.8 (equivalent to a ratio of about 1 :4)), for example, had significant adhesion to the catheter.1602617836.1 231956788.00438

[0118] Testing Example 8

[0119] A silicone model simulating arteriovenous malformation was connected to a 37 °C constant flow of phosphate buffer saline. A Headway Duo catheter flushed with dextrose solution was inserted into the model and positioned for injection. A syringe was loaded with the embolic agent described in Formulation Example 1. The syringe was attached to the catheter via an adaptor, and the embolic agent was injected into the model under the flow of phosphate buffer saline. Fluoroscopic image was taken as soon as the model was nearly fully embolized. After this first time point (t=0 min), subsequent images were taken at different time intervals, up to 10 min. After a reflux was achieved around the tip of the catheter (max. 3 cm of reflux), injection came to a full stop, and a countdown of 3 min was set. After 3 min, the catheter was withdrawn from the model, and adhesion of the embolic to the catheter was evaluated. No adhesion was observed at 0 min, 3 min, or 10 min. The fluoroscopic images are shown in FIG. 1.

[0120] Testing Example 9

[0121] Formulation Example 2 was tested, and fluoroscopic images (see FIG. 2) were taken following the procedure described in Test Example 1. No adhesion was observed at 0 min, 3 min, and 10 min.

[0122] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0123] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.1602617836.1 241956788.00438

[0124] Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.

[0125] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.1602617836.1 25

Claims

1956788.00438CLAIMS1. A liquid embolic comprising a copolymer, wherein the copolymer is a reaction product of:A) a first monomer, comprising an acrylate with a hydrophobic side chain;B) a second monomer, comprising an acrylate having a hydroxyl group;C) a third monomer, comprising a methacrylate having a hydroxyl group; andD) a fourth monomer, comprising a pH-sensitive functional group; wherein the liquid embolic is an aqueous-based liquid embolic.

2. The liquid embolic of claim 1 , further comprising a non-soluble visualization agent.

3. The liquid embolic of claim 2, wherein the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.

4. The liquid embolic of claim 2 or 3, wherein the liquid embolic precipitates in physiological medium, and radiopacity of the precipitated liquid embolic remains visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.

5. The liquid embolic of claim 1 , further comprising a soluble visualization agent.

6. The liquid embolic of claim 4, wherein the soluble visualization agent is selected from an iodinated or a brominated compound.

7. The liquid embolic of claim 4, wherein the soluble visualization agent is selected from iohexol, iomeprol, iotalamic acid, iodinated tyrosine, diatrizoic acid, 3,5-diiodo-4-pyridone-N- acetic acid, or derivatives thereof.

8. The liquid embolic of claim 1 , further comprising a soluble visualization agent and a non- soluble visualization agent.

9. The liquid embolic of claim 1 or 2, wherein the first monomer is selected from tert-butyl acrylate, n-butyl acrylate, isopropyl acrylate, n-propyl acrylate, pentyl acrylate, hexyl acrylate, phenyl acrylate, benzyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate or decyl acrylate, or combinations thereof.1602617836.1 261956788.0043810. The liquid embolic of claim 1 or 2, wherein the second monomer is selected from hydroxyl ethyl acrylate, hydroxypropyl acrylate, or hydroxybutyl acrylate, or combinations thereof.

11. The liquid embolic of claim 1 or 2, wherein the third monomer is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyl)methacrylamide, hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.

12. The liquid embolic of claim 1 or 2, wherein the fourth monomer is selected from 3- aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3- methylpyridine )acrylamide or a salt thereof, N-(2-(4-aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4-imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.

13. The liquid embolic of claim 1 or 2, wherein the molar ratio of the second monomer : third monomer ranges from about 1-3 : 3-1 .

14. The liquid embolic of claim 1 or 2, wherein the first monomer is tert-butyl acrylate, the second monomer is hydroxypropyl acrylate, the third monomer is hydroxypropyl methacrylate, and the fourth monomer is 3-aminopropyl methacrylamide hydrochloride.

15. The liquid embolic of claim 1 or 2, wherein the liquid embolic forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.

16. A method of treating a vascular condition in a subject comprising inserting a catheter in the subject and injecting the liquid embolic of claim 1 or claim 2 in the catheter.

17. The method of claim 16, wherein the vascular condition is selected from pseudoaneurysms, tumors, cerebral arteriovenous malformations (AVM), dural arteriovenous fistulae, and subdural hematomas.

18. A liquid embolic comprising a copolymer wherein the copolymer is a reaction product of: a methacrylate having a hydroxyl group; and a monomer having a pH-sensitive functional group;1602617836.1 271956788.00438 wherein the liquid embolic is an aqueous-based liquid embolic.

19. The liquid embolic of claim 18 further comprising a non-soluble visualization agent.

20. The liquid embolic of claim 19, wherein the non-soluble visualization agent is selected from barium sulfate, tantalum powder, or bismuth subcarbonate.

21. The liquid embolic of claim 18 or 19, wherein the liquid embolic precipitates in physiological medium, and radiopacity of the precipitated liquid embolic is visible on a fluoroscope for at least about two months after injection and precipitation of the embolic.

22. The liquid embolic of claim 18 or 19, wherein the methacrylate having a hydroxyl group is selected from glycerol monomethacrylate, 3-chloro-2-hydroxypropyl methacrylate, N-(4- hydroxyphenyljmethacrylamide, hydroxyl ethyl methacrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or combinations thereof.

23. The liquid embolic of claim 18 or 19, wherein the monomer having a pH-sensitive functional group is selected from 3-aminopropyl methacrylamide or a salt thereof, aminoethyl methacrylamide or a salt thereof, N-(3-methylpyridine)acrylamide or a salt thereof, N-(2-(4- aminophenyl)ethyl)acrylamide or a salt thereof, N-(4-aminobenzyl)acrylamide or a salt thereof, or N-(2-(4-imidazolyl)ethyl)acrylamide or a salt thereof, or combinations thereof.

24. The liquid embolic of claim 18 or 19, the methacrylate having a hydroxyl group is hydroxypropyl methacrylate, and monomer having a pH-sensitive functional group is 3- aminopropyl methacrylamide hydrochloride.

25. The liquid embolic of claim 18 or 19, wherein the liquid embolic forms a solid cast that does not adhere to a catheter and does not shear or disperse during an injection.

26. A method of treating a vascular condition in a subject comprising inserting a catheter in the subject and injecting the liquid embolic of claim 18 or claim 19, in the catheter.1602617836.1 281956788.0043827. The method of claim 26, wherein the vascular condition is selected from pseudoaneurysms, tumors, cerebral arteriovenous malformations (AVM), dural arteriovenous fistulae, and subdural hematomas.1602617836.1 29

Images