Patent Description:
Embolization is widely used to treat vascular malformations, such as aneurysms, arteriovenous malformations, fistulas, and tumors. These malformations can be treated with a variety of different products, including metallic coils, polymer-metal hybrid coils, microparticles, glues, and foams. However, there remains a need for products that can minimize the risks associated with embolization. <CIT> relates to a polymer solution for treatment of angiopathy and forming an artificial embolism. <CIT> relates to liquified embolic materials capable of sol-gel phase transition for use in therapy.

The invention provides a vascular treatment composition comprising: a polymer comprising a reaction product of: a first monomer comprising aminopropyl methacrylamide, aminoethyl methacrylamide, N-(<NUM>-methylpyridine)acrylamide, N-(<NUM>-(<NUM>-aminophenyl)ethyl acrylamide, N-(<NUM>-aminobenzyl)acrylamide, or N-(<NUM>-<NUM>-imidazolyl)ethyl)acrylamide or a combination thereof; and a second monomer comprising an acrylate, an acrylamide, or a combination thereof; an aqueous solution with a non-physiological pH; and a visualization agent; wherein the polymer is soluble in the aqueous solution and insoluble at a physiological pH at a treatment site.

In embodiments, the visualization agent has a concentration of <NUM> % w/w to <NUM> % w/w. In embodiments, the visualization agent is an iodinated compound, barium sulfate, tantalum, superparamagnetic iron oxide, gadolinium molecules or a combination thereof.

In embodiments, the polymer comprises a reaction product of two or more different monomers.

In embodiments, the non-physiological pH is a pH of less than <NUM>. In embodiments, the non-physiological pH is a pH of greater than <NUM>.

In embodiments, the polymer has a concentration of <NUM>% w/w to about <NUM>% w/w.

In embodiments, the visualization agent is a particulate visualization agent that has a concentration of <NUM> % w/w to <NUM> % w/w.

In embodiments, the visualization agent is a particulate. In embodiments, the visualization agent is an iodinated compound or barium sulfate.

In embodiments, the polymer comprises a reaction product of two different monomer. In embodiments, the polymer comprises a reaction product of three different monomers.

In embodiments, the second monomer comprises t-butyl acrylate, t-butyl acrylamide, n-octyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, or hydroxybutyl methacrylate, or a combination thereof.

The invention also provides the vascular treatment composition according to the invention for use in the treatment of vascular disorders, wherein the vascular treatment composition is injected through a delivery device into a vessel to be treated.

Described herein generally are vascular treatment compositions comprising (i) a polymer that can be soluble in solutions at non-physiological pH and insoluble at a physiological pH or when subjected to a physiological pH, (ii) an aqueous solution with a non-physiological pH, and (iii) an opacification agent(s) that can permit visualization in vivo. These compositions can be introduced through a delivery device in the liquid state and transition to the solid state once in the body at subjected to a physiological pH. In one embodiment, the aqueous solution does not include an organic solvent.

When the polymer is soluble, it can be deployed through a delivery device. A delivery device can be any device suitable to deliver the liquid embolic polymers described herein. For example, a delivery device can be a catheter or a microcatheter that is deployed to a delivery site and/or treatment site. However, once precipitated out of solution, the polymer can be much more difficult to deploy. For example, once precipitated, the polymer can in some instances reduce the ability to deliver the polymer through a delivery device. As such, the compositions and medical uses described herein can provide a polymer treatment solution that can be deployed to a treatment site and having it precipitate once at the location of interest; the precipitated product would generally not be deliverable.

Treatment site and/or delivery site as used herein can be any site within a living creature. The creature is a mammal such as a human. Human sites can include blood vessels, renal lumens, fatty tissue, muscle, connective tissue, cerebral spinal fluid, brain tissue, repertory tissue, nerve tissue, subcutaneous tissue, intra atria tissue, gastrointestinal tissue, and the like. As a skilled artisan understands, the physiological pH of different tissues and lumens within a mammalian body such as a human can vary. A polymeric solution can be customized for a particular delivery site pH. For example, if the polymer solution is to be delivered to the stomach, where pHs tend to be acidic, the polymeric solution can be formed in as an alkaline solution.

A function of the polymer, e.g. liquid embolic polymer, can be to precipitate when coming in contact with blood or other physiological fluid at a physiological pH at the intended site of treatment. Physiological pH of the blood stream can be a pH of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. In another embodiment, physiological pH of the stomach can be a pH of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>. In still another embodiment, physiological pH of the intestines can depend on the location within the intestines, but generally can be a pH of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>. Ranges of pH for any of the lists above can be created between any set of values listed. Precipitation of the polymer at a physiological pH can be used to occlude a biological structure and/or a tissue. Control of the liquid embolic polymer's solubility can be achieved by selection of the composition of the polymer.

The vascular treatment compositions can comprise a solution at a non-physiological pH. The solution may be aqueous. The solution can include a polymer soluble in the solution at non-physiological pH but insoluble in a physiological pH. Further included in the solution can be a visualization agent. This change in solubility can be a result in a changing viscosity of the polymer within the solution. In other embodiments, this change in solubility can result in a change in density of the polymer in solution.

The polymer can be prepared with monomers having ionizable moieties. In some embodiments, the polymers can be a reaction product of two different monomers, three different monomers, four different monomers, five different monomers or more. A hydrophobic polymer can be constructed with a minimum amount of ionizable moieties to render the polymer soluble in non-physiological pH solutions. The ratio of monomers with ionizable moieties and other monomers can be dependent on the structure of the monomers and can be determined experimentally.

Amine-containing liquid embolic polymers can be dissolved in a low pH solution, the amines may be substantially protonated and can enhance the solubility of the polymer. The resulting solution can be placed in conditions with a physiological pH and the amines can deprotonate and render the polymer insoluble. Conversely, carboxylic acid-containing polymers can be dissolved in a high pH solution, the carboxylic acids can be substantially deprotonated and enhance the solubility of the polymer. The resulting solution can be placed in conditions with a physiological pH and the carboxylic acids can protonate and render the polymer insoluble.

Monomers with ionizable moieties can contain a polymerizable moiety and can contain an ionizable moiety. Polymerizable moieties can be those that permit free radical polymerization, including but not limited to acrylates, methacrylates, acrylamides, methacrylamides, vinyl groups, combinations thereof and derivatives thereof. Alternatively, other reactive chemistries can be employed to polymerize the polymer, such as but not limited to nucleophile/N-hydroxysuccinimide esters, nucleophile/halide, vinyl sulfone/acrylate or maleimide/acrylate. A polymerizable moiety can be an acrylate and/or an acrylamide.

Ionizing moieties can be added to impart the pH-sensitive solubility to the polymer. Ionizable moieties can include carboxylic acids, amines, and derivatives thereof. Alternatively or additionally, amines protected using any suitable technique, such as t-Boc, may be used in the synthesis of the liquid embolic polymer. Molecules containing polymerizable and ionizable moieties can include acrylic acid, methacrylic acid, aminopropyl methacrylamide, aminoethyl methacrylamide, N-(<NUM>-methylpyridine)acrylamide, N-(<NUM>-(<NUM>-aminophenyl)ethyl)acrylamide, N-(<NUM>-aminobenzyl)acrylamide, N-(<NUM>-(<NUM>-imidazolyl)ethyl)acrylamide, deverivatives thereof and combinations thereof.

Other monomers can contain a polymerizable moiety and have a structure that facilitates the desired performance in dissolution or in precipitation. Polymerizable moieties can be those that permit free radical polymerization, including acrylates, methacrylates, acrylamides, methacrylamides, vinyl groups, and derivatives thereof. Alternatively or additionally, other reactive chemistries can be employed to polymerize the polymer, such as but not limited to nucleophile/N-hydroxysuccinimde esters, nucleophile/halide, vinyl sulfone/acrylate or maleimide/acrylate. In one embodiment, polymerizable moieties may be acrylates and acrylamides.

Less hydrophobic monomers can require less ionizable monomer to be copolymerized with it to have the desired solubility characteristics. Likewise, more hydrophobic monomers can require more ionizable monomer to be copolymerized with it to have the desired solubility characteristics. Monomers containing moieties available for hydrogen bonding, such as hydroxyl groups, can increase the cohesiveness of the precipitated polymer. Monomers used can include acrylates and acrylamides such as alkyl acrylates, alkyl alkacrylates, alkyl alkacrylamides, and alkyl acrylamides. Acrylates and acrylamides can include but are not limited to t-butyl acrylate, t-butyl acrylamide, n-octyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxybutyl methacrylate, derivatives thereof and combinations thereof.

In one embodiment, liquid embolic polymers can be polymerized from solutions, mixtures, prepolymer solutions of monomers with ionizable moieties and other monomers. The solvent used to dissolve the monomers can be any solvent that dissolves or substantially dissolves the chosen monomers. Solvents can include methanol, acetonitrile, dimethyl formamide, and dimethyl sulfoxide.

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 cross-linking 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 application 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.

In one embodiment, the polymerization initiator can azobisisobutyronitrile (AIBN) or a water soluble AIBN derivative (<NUM>,<NUM>'-azobis(<NUM>-methylpropionamidine) dihydrochloride). Other initiators can include N,N,N',N'-tetramethylethylenediamine, ammonium persulfate, benzoyl peroxides, azobisisobutyronitriles and combinations thereof. Initiator concentrations can range from about <NUM>% w/w to about <NUM>% w/w, about <NUM>% w/w to about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, of the mass of the monomers in solution or any range or value within the listed percentages. The polymerization reaction can be performed at elevated temperatures, of about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. After the polymerization is completed, the polymer can be recovered by precipitation in a non-solvent and dried under vacuum.

The aqueous solution with non-physiological pH can dissolve the liquid embolic polymer. In one embodiment, the aqueous solution does not include an organic solvent. Concentrations of the polymer in the aqueous solution can range from about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% or any percentage or range of percentages bound by the above percentages. The aqueous solution can contain the minimum amount of buffer to maintain the non-physiologic pH after dissolution of the liquid embolic polymer, but not adversely affect the pH of the patient after administration. Buffer concentrations range from about <NUM> to about <NUM>, abouot <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or any concentration or range of concentrations within the values listed. In other embodiments, the buffer concentration can be less than about <NUM> or even not used. In one embodiment, the buffer concentration can be about <NUM>.

For liquid embolic polymers containing amines, buffers can include citrate and acetate and solution pH's can be from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. For liquid embolic polymers containing carboxylic acids, buffers can include carbonate, N-cyclohexyl-<NUM>-aminoethanesulfonic acid (CHES), N-cyclohexyl-<NUM>-hydroxyl-<NUM>-aminopropanesulfonic acid (CAMPSO), N-cyclohexyl-<NUM>-aminopropanesulfonic acid (CAPS), <NUM>-[<NUM>-(<NUM>-Hydroxyethyl)-<NUM>-piperazinyl]propanesulfonic acid (HEPPS or EPPS), <NUM>-(N-morpholino)propanesulfonic acid (MOPS), <NUM>-(<NUM>-hydroxyethyl)-<NUM>-piperazineethanesulfonic acid (HEPES), <NUM>-(N-morpholino)ethanesulfonic acid (MES) and <NUM>-amino-<NUM>-methyl-<NUM>-propanol (AMP) and solution pH's can be from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>.

Particulate visualization and/or opacification agent or agents can impart visibility to the liquid embolic polymer when imaged using a medically relevant imaging technique such as fluoroscopy, computed tomography, or magnetic resonance techniques. Visualization of the polymer under fluoroscopy can be imparted by the incorporation of solid particles of radiopaque materials such as barium, bismuth, tantalum, platinum, gold, and other dense metals suspended in the non-physiological pH solution of the liquid embolic polymer. In one embodiment, the visualization agent for fluoroscopy can be barium sulfate. Visualization of the polymer under computed tomography imaging can be imparted by incorporation of solid particles of barium or bismuth. In one embodiment, the visualization agent for computed tomography imaging can be barium sulfate. Concentrations of barium sulfate to render the liquid embolic visible using fluoroscopic and computed tomography imaging can be from about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>% w/w, about <NUM>% to about <NUM>% w/w, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% about <NUM>% of the non-physiological pH solution or any concentration or range of concentrations within the values listed.

In another embodiment, the visualization agent for fluoroscopy can be tantalum. Concentrations of tantalum to render the liquid embolic visible using fluoroscopic and/or computed tomography imaging can be from about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>% w/w, about <NUM>% to about <NUM>% w/w, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% about <NUM>% of the non-physiological pH solution or any concentration or range of concentrations within the values listed.

Visualization of the liquid embolic polymer under magnetic resonance imaging can be imparted by the incorporation of solid particles of superparamagnetic iron oxide or gadolinium molecules polymerized into the polymer structure or encased into the polymeric structure once precipitated. One example visualization agent for magnetic resonance can be superparamagnetic iron oxide with a particle size of <NUM> microns. Concentrations of superparamagnetic iron oxide particles to render the hydrogel visible using magnetic resonance imaging range from about <NUM>% w/w to about <NUM>% w/w, about <NUM>% w/w to about <NUM>% w/w, or about <NUM>% w/w to about <NUM>% w/w of the polymerization solution.

Further, an iodinated compound can be used to impart visibility of the liquid embolic polymer when imaged using fluoroscopy or computer tomography. Dissolution of iohexol, iothalamate, diatrizoate, metrizoate, ioxaglate, iopamidol, ioxilan, iopromide, or iodixanol in the aqueous solution with non-physiological pH can render the radiopaque. Suspension of ethiodol, iodophenylundecylic acid, or both in the aqueous solution with non-physiological pH can render the liquid embolic polymer radiopaque.

In other embodiments, lipiodol ultra fluid which can include ethyl esters of iodized fatty acids of poppy seed oil qs ad for one ampoule with an iodine content of about <NUM>% (i.e. <NUM> per mL). Additionally, in some embodiments, the use of iodinated compounds can provide temporary radiopacity of the polymer because the iodinated compounds can diffuse or otherwise be carried away from the embolization site by in vivo processes.

Polymer visualization under magnetic resonance imaging can be imparted by the incorporation of solid particles of superparamagnetic iron oxide or water soluble gadolinium compounds. In one embodiment, the visualization agent for magnetic resonance can be superparamagnetic iron oxide with a particle size of about <NUM>, about <NUM> or about <NUM>. Concentrations of superparamagnetic iron oxide particles with any of the above particle sizes to render the liquid embolic visible using magnetic resonance imaging can be from about <NUM>% w/w to about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w, about <NUM>% w/w of the non-physiological pH solution or any concentration or range of concentrations within the values listed.

If a particulate visualization agent is utilized, it can be prepared by dissolving the liquid embolic polymer in the aqueous solution with non-physiologic pH and adding the particulate agent. If a soluble visualization agent is utilized, it can be prepared by dissolving the liquid embolic polymer and water soluble visualization agent in an aqueous solution with non-physiologic pH.

The liquid embolic polymers, solutions and mixtures described herein can be sterilized without substantially degrading the polymer. After sterilization, at least about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% about <NUM>% or about <NUM>% of the polymer can remain intact. In one embodiment, the sterilization method can be autoclaving and can be utilized before administration of the polymer.

The liquid embolic polymer formulation can be removed from the vial using a needle and syringe, the syringe to be later connected to a delivery catheter. To prevent premature liquid embolic polymer deposition, the delivery catheter can be primed with a bolus of the same aqueous solution with non-physiologic pH as was used to dissolve the liquid embolic polymer. This flushing can prevent clogging of the delivery catheter with the liquid embolic polymer. The syringe containing the liquid embolic formulation can then be connected to the proximal end of a delivery catheter, such as a microcatheter, cannula, or the like, and positioned in the desired vascular or other anatomic site.

As the liquid embolic formulation is injected, it can push the aqueous solution with non-physiologic pH flushing solution out of the microcatheter. The rate of injection can provide differing precipitation amounts and/or precipitation performance. For example, a slower injection rate can achieve a more distal penetration of the liquid embolic polymer and a faster injection rate can achieve a more proximal penetration. In other embodiments, the opposite can be true. In yet another embodiment, a slower injection rate can result in more precipitation whereas a faster injection rate can result in less precipitation. In other embodiments, the opposite effect may occur. The speed of precipitation can be fast and in some cases can be immediate, e.g. faster than the human eye can discern. In other embodiments, the polymer can precipitate in less than about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or any range encompassed by any of these values. For example, in one embodiment, the polymer can precipitate in between about <NUM> and about <NUM>.

The pH of the aqueous solution can then rapidly change to physiological pH as a result of the large buffering capacity of the body's tissues and fluids. Also, a low buffer strength of the solution can lead to the rapid change of pH. The progress of the liquid embolic formulation inside the delivery catheter can be observed using an imaging technique compatible with the particulate agent or agents selected. With continued injection, the liquid embolic formulation can enter a target delivery site or treatment site.

The large buffering capacity of the body's tissues can cause the fluids to rapidly deprotonate or protonate the ionizable moieties present on the liquid embolic polymer, thus reducing the solubility of the liquid embolic polymer and causing it to precipitate from solution. The precipitated liquid embolic polymer can entrap the particulate agents and can provide occlusion of the target site.

The precipitated liquid embolic polymer can be a solid mass of precipitate. In some embodiments, the mass can have less than about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>, or about <NUM>% fragmentation. In some embodiments, the precipitated polymer can be cohesive and remain substantially a solid mass.

The precipitated liquid embolic polymer can remain substantially stable once implanted. For example, the liquid embolic polymer can remain greater than about <NUM>%, about <NUM>% about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% or about <NUM>% intact after about <NUM> days, about <NUM> weeks, about <NUM> month, about <NUM> months, about <NUM> months, about <NUM> months, about a year, about <NUM> years, about <NUM> years, about <NUM> years or about <NUM> years.

In some embodiments, however, it may be desirable for the precipitated liquid embolic polymer to degrade over time. In such embodiments, the liquid embolic polymer can degrade to less than about <NUM>%, about <NUM>% about <NUM>%, about <NUM>%, about <NUM>% or about <NUM>% intact after about <NUM> days, about <NUM> weeks, about <NUM> month, about <NUM> months, about <NUM> months, about <NUM> months, about a year, about <NUM> years, about <NUM> years, or about <NUM> years.

Further, the liquid embolic polymers once precipitated can be cohesive enough to stick to the tissue and/or remain in place through friction with the tissues. In other embodiments, the precipitated polymer can act as a plug in a vessel held in place by the flow and pressure of the blood itself.

To <NUM> of methanol, <NUM> t-butyl acrylate, <NUM> of aminoethyl methacrylate, and <NUM> of azobisisobutyronitrile were added. Upon complete dissolution, the solution was placed at <NUM> for <NUM> hr. Then, after cooling to room temperature, the polymer was recovered by precipitation in ethyl ether and dried under vacuum.

To <NUM> of distilled water, <NUM> sodium chloride and <NUM> potassium phosphate monobasic were added. Upon complete dissolution, the pH of the solution was adjusted to <NUM> using phosphoric acid.

To <NUM> of the liquid of Example <NUM>, <NUM> of the polymer of Example <NUM> was added. Dissolution of the polymer was aided by incubating at <NUM> for <NUM> hr. After complete dissolution, <NUM> of barium sulfate was added. The liquid embolic polymer formulation was then aliquoted into vials and capped. The vials were autoclaved at <NUM> for <NUM>.

Using the techniques described in Examples <NUM> and <NUM>, the polymers described in Table <NUM> were prepared. The solubility of the polymers was investigated in aqueous solutions at pH <NUM> (non-physiological) and at pH <NUM> (physiological).

The results of Table <NUM> show how the solubility of the liquid embolic polymer can be controlled by the amount of ionizable moieties present in the polymer.

The liquid embolic polymer formulation prepared according to the techniques of Examples <NUM>, <NUM>, and <NUM> was utilized for the embolization of five rabbit kidneys. Angiographic occlusion was obtained in all five kidneys. The kidneys remained occluded angiographically at the follow-up evaluation at <NUM> month (n=<NUM>, <FIG> months (n=<NUM>). Histological evaluation of the kidneys demonstrated good penetration of the liquid embolic polymer into the vasculature and substantial tissue destruction from the removal of the blood supply by the liquid embolic polymer (<FIG>).

The liquid embolic polymer formulation prepared according to the techniques of Examples <NUM>, <NUM>, and <NUM> was utilized for the embolization of a rete in an acute pig. At the end of the procedure, angiographic occlusion of the rete was obtained and can be seen when comparing the pre-treatment angiogram in <FIG> and the post-treatment angiogram in <FIG>.

The liquid embolic polymer formulation prepared according to the techniques of Examples <NUM>, <NUM>, and <NUM> was utilized for the embolization of the renal vasculature of rabbits. The liquid embolic formulation was opacified with barium sulfate. At the end of the procedure, the rabbit was imaged using a CT scanner and differences can be seen when comparing the pre-treatment angiogram in <FIG> and the post-treatment CT angiogram in <FIG>.

The liquid embolic polymer formulation prepared according to the techniques of Examples <NUM>, <NUM>, and <NUM> was utilized for the embolization of the renal vasculature of rabbits. The liquid embolic formulation was opacified with either tantalum or barium sulfate. At the end of the procedure, the rabbits were imaged using a MR scanner and differences can be seen when comparing the pre-treatment angiogram in <FIG> and the post-treatment MR angiogram in <FIG>.

To <NUM> of methanol, <NUM> t-butyl acrylate, <NUM> hydroethyl methacrylate, <NUM> of aminoethyl methacrylate, and <NUM> of azobisisobutyronitrile were added. Upon dissolution of all components, the solution was placed at <NUM> for <NUM> hr. After cooling to room temperature, the polymer was recovered by precipitation in ethyl ether and dried under vacuum.

To <NUM> of distilled water, <NUM> sodium chloride, <NUM> potassium phosphate monobasic, and <NUM> iohexol were added. Upon dissolution of all components, the pH of the solution was adjusted to <NUM> using phosphoric acid.

To <NUM> of the liquid of Example <NUM>, <NUM> of the polymer of Example <NUM> was added. Dissolution of the polymer was aided by incubating at <NUM> for several hours. After dissolution of the liquid embolic polymer, the liquid embolic polymer formulation was then aliquoted into vials and capped. The vials were autoclaved at <NUM> for <NUM>.

The liquid embolic polymer formulations of Examples <NUM> and <NUM> were evaluated by adding each formulation drop wise into excess phosphate buffered saline at pH <NUM>. The speed of precipitation and cohesiveness of the precipitate were evaluated. Results are included in Table <NUM>.

To <NUM> of methanol, <NUM> t-butyl acrylate, <NUM> of aminoethyl methacrylate, and <NUM> of azobisisobutyronitrile were added. Upon dissolution of components, the solution was placed at <NUM> for <NUM> hr. After cooling to room temperature, the polymer was recovered by precipitation in ethyl ether and dried under vacuum. To <NUM> of distilled water, <NUM> sodium chloride and <NUM> potassium phosphate monobasic were added. Upon dissolution of components, the pH of the solution was adjusted to <NUM> using phosphoric acid.

To <NUM> of the liquid, one gram of the polymer was added. Dissolution of the polymer was aided by incubating at <NUM> for <NUM> hr. After dissolution of the liquid embolic polymer, <NUM> of barium sulfate was added to the solution. The liquid embolic formulation was then aliquoted into vials and capped. The vials were autoclaved at <NUM> for <NUM>.

Such a liquid embolic formulation can be implanted as described herein into intestines or other high pH environments where the polymer precipitates.

To <NUM> of methanol, <NUM> n-octyl methacrylate, <NUM> of methacrylic acid, and <NUM> of azobisisobutyronitrile were added. Upon dissolution of components, the solution was placed at <NUM> for <NUM> hr. After cooling to room temperature, the polymer was recovered by precipitation in ethyl ether and dried under vacuum. To <NUM> of distilled water, <NUM> sodium chloride and <NUM> sodium bicarbonate were added. Upon dissolution of components, the pH of the solution was adjusted to <NUM> using sodium hydroxide.

Such a liquid embolic formulation can be implanted as described herein into a stomach or other low pH environments where the polymer precipitates.

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. " 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. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Claim 1:
A vascular treatment composition comprising:
a polymer comprising a reaction product of:
a first monomer comprising aminopropyl methacrylamide, aminoethyl methacrylamide, N-(<NUM>-methylpyridine)acrylamide, N-(<NUM>-(<NUM>-aminophenyl)ethyl)acrylamide, N-(<NUM>-aminobenzyl)acrylamide, or N-(<NUM>-(<NUM>-imidazolyl)ethyl)acrylamide or a combination thereof; and
a second monomer comprising an acrylate, an acrylamide, or a combination thereof;
an aqueous solution with a non-physiological pH; and
a visualization agent;
wherein the polymer is soluble in the aqueous solution and insoluble at a physiological pH at a treatment site.