Injectable compositions for reducing or preventing blood flow in a neurovascular vessel

Abstract

Described herein are methods for reducing or preventing blood flow in a neurovascular blood vessel of a subject. The method involves injecting a composition composed of water, one or more polycationic polyelectrolytes and anionic counterions and one or more one polyanionic polyelectrolytes and cationic counterions, wherein the composition has an ion concentration that is (i) sufficient to prevent association of the polycationic polyelectrolytes and the polyanionic polyelectrolytes in water and (ii) greater than the concentration of ions in the subject. Upon introduction of the composition into a subject, a solid is produced in situ. The injectable compositions have unique distal penetration properties, which make the injectable compositions described herein very useful as embolics for neurovascular blood vessels.

Description

ATTORNEY DOCKET NO.: 930601-2120INJECTABLE COMPOSITIONS FOR REDUCING OR PREVENTING BLOOD FLOW IN A NEUROVASCULAR VESSELCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 762,118, filed on February 24, 2025, the contents of which are incorporated by reference herein in their entireties.BACKGROUND

[0002] Chronic subdural hematoma is one of the most common neurosurgical conditions affecting older people. It can occur after an injury or medical problem that causes bleeding between the dura and the brain, an area known as the subdural space. Subdural hematomas can cause a range of symptoms, including headaches, confusion, loss of balance, and weakness on one side of the body. If untreated, the increasing pressure on the brain can lead to seizures, coma and even death.

[0003] The traditional treatment for chronic subdural hematoma is surgical. The procedure generally involves drilling two holes into the skull and a hollow tube is inserted to drain the blood. The operation can be risky, and patients have to stay in intensive care for a few days while the hematoma is draining. Furthermore, patients can have recurring symptoms shortly after the procedure within a month and must return to the hospital for additional treatment.

[0004] One approach is to inject an embolic agent into a neurovascular blood vessel such as the middle meningeal artery (MMA) to stop blood from leaking into the brain. Introducing embolic agents into neurovascular vessels has several challenges. Neurovascular vessels have very small diameters requiring catheters with even smaller diameters. Current embolic agents require additional handling and equipment to ensure the embolic once administered has sufficient distal penetration and blood flow is blocked in the neurovascular vessel and prevent further bleeding into the brain.

[0005] Vascular tumors of the head, neck and central nervous system (CNS) constitute an uncommon and heterogenous group of tumors ranging from benign toATTORNEY DOCKET NO.: 930601-2120malignant. Surgical resection is the standard of care when the tumor is accessible. Radiation therapy is commonly used to treat both accessible tumors before resection and non-accessible tumors. Clinical monitoring is often the preferred method for benign tumors causing mild symptoms.

[0006] One approach is to inject an embolic agent into a neurovascular blood vessel that supplies a vascular tumor of the head, neck and CNS to devascularize the tumor. This can be performed preoperatively to minimize blood loss during and decrease operating time during surgical resection. Other benefits are improved visualization of the tumor volume, reduced risk of occurrence, reduce damage to adjacent tissue, and provide palliative treatment to non-operable patients.

[0007] Brain tumors can develop in any part of the brain or skull. There are >120 different types of brain tumors that can develop depending on their tissue of origin. Metastatic brain tumors originate in other parts of the body and spread to the brain and are more common than tumors that originate in the brain.

[0008] The traditional treatments for brain tumors include surgical resection via craniotomy, endoscopy and laser ablation. Chemotherapy and radiation therapy are used to shrink the tumor and / or slow growth.

[0009] One approach is to inject an embolic agent into a neurovascular blood vessel that supplies a brain tumor to devascularize the tumor. This can be performed preoperatively to reduce blood loss and facilitate removal during surgical resection. This can be performed preoperatively to minimize blood loss during and decrease operating time during surgical resection. Other benefits are improved visualization of the tumor volume, reduced risk of occurrence, reduce damage to adjacent tissue, and provide palliative treatment to non-operable patients.SUMMARY

[0010] Described herein are methods for reducing or preventing blood flow in a neurovascular blood vessel of a subject. The method involves injecting a composition composed of water, one or more polycationic polyelectrolytes and anionic counterions and one or more one polyanionic polyelectrolytes and cationic counterions, wherein the composition has an ion concentration that is (i) sufficient to prevent association of theATTORNEY DOCKET NO.: 930601-2120polycationic polyelectrolytes and the polyanionic polyelectrolytes in water and (ii) greater than the concentration of ions in the subject. Upon introduction of the composition into a subject, a solid is produced in situ. The injectable compositions have unique distal penetration properties, which make the injectable compositions described herein very useful as embolics for neurovascular blood vessels.

[0011] The advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below.

[0013] Figure 1 shows viscosity vs. weight percent of the polymer present in the injectable composition.

[0014] Figure 2 shows the occlusion zones when measuring the magnitude of occlusion of the arterial lumen.

[0015] Figure 3 shows a representative example of arterial occlusion and distal penetration by an injectable composition described herein in Zone 3. Complete occlusion of pre-glomerular arteries (e.g., white arrowheads) and evidence of test product in glomerular capillaries (i.e., dashed circles) was observed.

[0016] Figure 4 shows a variety of artery sizes (0.03mm - 0.60mm) are filled with injectable composition described herein. All 3 animals treated with the injectable composition exhibited embolization down to arteries sized 0.03 mm - 1.2 mm in diameter compared to Onyx-18 (0.25mm - 1.3mm diameter. The injectable composition exhibited distal penetration into 5x smaller arteries than Onyx-18.

[0017] Figure 5 shows distal penetration of IC-LV. Full occlusion of pre-glomerularATTORNEY DOCKET NO.: 930601-2120arteries (e.g., arrowheads) at the farthest edge of cortex and evidence of IC-LV in glomerular capillaries (e.g., within dashed circles) was observed.DETAILED DESCRIPTION

[0018] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0019] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0020] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0021] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0022] All publications mentioned herein are incorporated herein by reference toATTORNEY DOCKET NO.: 930601-2120disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0023] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0024] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0025] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0026] Definitions

[0027] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the termsATTORNEY DOCKET NO.: 930601-2120“consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.

[0028] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” include, but are not limited to, mixtures or combinations of two or more such excipients, and the like.

[0029] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0030] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “xto y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0031] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only theATTORNEY DOCKET NO.: 930601-2120numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. Thus, for example, if a component is in an amount of about 1%, 2%, 3%, 4%, or 5%, where any value can be a lower and upper endpoint of a range, then any range is contemplated between 1% and 5% (e.g., 1% to 3%, 2% to 4%, etc.).

[0032] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0033] A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. Weight percent includes and covers weight / volume percent and weight / weight percent.ATTORNEY DOCKET NO.: 930601-2120

[0034] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0035] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxy a Iky I” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxy a Iky I” and the like.

[0036] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties,ATTORNEY DOCKET NO.: 930601-2120the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0037] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0038] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized IT electrons above and below the plane of the molecule, where the TT clouds contain (4n+2) TT electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0039] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is includedATTORNEY DOCKET NO.: 930601-2120in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl. Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated.

[0040] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0041] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, orthiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[c / ]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1 ,2-b]pyridazinyl, imidazo[1 ,2-a]pyrazinyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0042] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systemsATTORNEY DOCKET NO.: 930601-2120in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1 ,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1 ,2,3-triazole, 1.3.4-triazole, tetrazole, including 1 ,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1 ,2,4-triazine and 1,3,5-triazine, tetrazine, including 1, 2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0043] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1 , 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1 ,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 3.4-dihydro-2H-chromenyl, 1 H-pyrazolo[4,3-c]pyridin-3-yl; 1 H-pyrrolo[3,2-b]pyridin-3-yl; and 1 H-pyrazolo[3,2-b]pyridin-3-yl.ATTORNEY DOCKET NO.: 930601-2120

[0044] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0045] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0046] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) and — N(-alkyl)2, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0047] The term “treat” as used herein is defined as maintaining or reducing the symptoms of a pre-existing condition when compared to the same symptoms in the absence of the injectable composition. The term “prevent” as used herein is the ability of the injectable compositions described herein to completely eliminate the activity or reduce the activity when compared to the same activity in the absence of the injectable composition. The term “inhibit” as used herein refers to the ability of the injectable composition to slow down or prevent a processATTORNEY DOCKET NO.: 930601-2120

[0048] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.

[0049] As used herein, the term “reduce” or “reducing” refers to deceasing the degree or amount of an event. For example, reducing biofilm formation can mean lower the amount of biofilm formation when using the compositions described herein when compared to the amount of biofilm formation when the compositions described herein are not used.

[0050] “Subject” refers to mammals including, but not limited to, humans, non-human primates, sheep, dogs, rodents (e.g., mouse, rat, guinea pig, etc.), cats, rabbits, cows, horses, and non-mammals including vertebrates, birds, fish, amphibians, and reptiles.

[0051] The term “salt” as used herein is defined as a dry solid form of a water-soluble compound that possesses cations and anions. When the salt is added to water, the salt dissociates into cations and anions. A polycationic salt is a compound having a plurality of cationic groups with anionic counterions. A polyanionic salt is a compound having a plurality of anionic groups with cationic counterions.

[0052] The term “polyelectrolytes” as used herein is defined as polymers with ionized functional groups, where the ionized functional groups can incorporated in the polymer backbone, a sidechain of the polymer, or a combination thereof. Polycations and polyanions are produced when a polycationic salt or a polyanionic salt is dissolved in water.

[0053] The term "molecular weight" is used herein to refer to the average molecular mass of an ensemble of synthetic polymers that contains a distribution of molecular masses. Unless otherwise noted, values reported herein are weight-average molecular weight (Mw).

[0054] The term “stable solution” as used herein is defined as a liquid composition of oppositely charged polyelectrolytes that do not interact electrostatically. The polyelectrolyte solutions do not separate into macroscopically distinct phases.

[0055] The term “solid” as used herein is defined as a non-fluid, viscoelastic materialATTORNEY DOCKET NO.: 930601-2120that has a substantially higher elastic modulus and viscous modulus than the initial fluid form of the injectable composition used to produce the solid.

[0056] The term "transient" as used herein with respect to the contrast agent is defined herein as the ability of the contrast agent to diffuse or escape over time the solid produced by the injectable compositions described herein.

[0057] The term "temporary contrast" as used herein occurs when the majority of the transient contrast agent diffuses from the solid such that the transient contrast agent cannot be detected in the subject by imaging techniques such as, for example, fluoroscopy or CT.

[0058] The term "critical ion concentration" is the concentration of ions above which a specific combination of polycations and polyanions do not associate electrostatically, thus preventing liquid-liquid or liquid-sold phase separation. The critical ion concentration for a specific composition depends on multiple factors, including the molecular weight and concentration of the polyelectrolyte pairs, the mol% of polymeric ions, the polymeric ion species, the free ion species, and pH. The counterions that dissociate from the polymeric salts upon dissolution in water contribute to the total ion concentration of the solution. In most cases, for the polyelectrolyte pairs and concentrations described herein, the concentration of dissociated counterions is above the critical ion concentration for the specific composition. In some cases, additional ions (e.g., monovalent ions such as NaCI) can be added to increase the total ion concentration to above the critical ion concentration for the specific composition.

[0059] ‘‘Physiological conditions” refers to conditions such as osmolality, ion concentrations, pH, temperature, etc. within a particular area of the subject. For example, the normal blood sodium concentration range is between 135 and 145 mMol / L in a human.

[0060] As used herein, a plurality (i.e., more than one) of items, structural elements, compositional elements, and / or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of any such list should be construed as a de facto equivalent of any other member of the same list based solely on its presentation in a common group, without indications to theATTORNEY DOCKET NO.: 930601-2120contrary.

[0061] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0062] Applications of the Injectable Compositions

[0063] The injectable compositions described herein are useful for reducing or preventing blood flow in a neurovascular blood vessel of a subject. The term “neurovascular blood vessel” is any vessel in the head or neck region of a subject, In one aspect, the neurovascular blood vessel is a capillary bed. In another aspect, the neurovascular blood vessel supplies a tumor. In another aspect, the neurovascular blood vessel is the middle meningeal artery (MMA).

[0064] Upon introduction of the injectable composition into the neurovascular blood vessel of the subject, the counterions present in the injectable composition diffuse out from the composition. Diffusion of ions out of the injectable composition allows electrostatic interactions between polycations and polyanions present in the composition, resulting in conversion of the polyelectrolytes into a non-fluid, water-insoluble solid in situ. The solid produced in situ is a stiff cohesive material that remains positioned at the site of solidification within the subject.

[0065] The injectable compositions can be injected into neurovascular blood vessels using very small catheters without the use of special equipment such as, for example, pressurized systems. By varying the amount of the polycationic and polyanionic polyelectrolytes in the injectable composition, the injectable composition can be injected through a number of different catheters with varying diameters.

[0066] In one aspect, the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent. In another aspect, the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is 10 weight percent, 15 weight percent, 20 weight percent, 25 weight percent, 30 weight percent, 35 weight percent, 40 weight percent, 45 weight percent, 50 weight percent, or less than 55 weight percent, where any value can be a lower and upper end-point of a range (e.g., 20 weight percent to 50 weight percent, etc.).ATTORNEY DOCKET NO.: 930601-2120

[0067] In one aspect, the injectable composition has a viscosity of less than 140 centipoise. In another aspect, the injectable composition has a viscosity of 10 centipoise, 20 centipoise, 30 centipoise, 40 centipoise, 50 centipoise, 60 centipoise, 70 centipoise, 80 centipoise, 90 centipoise, 100 centipoise, 110 centipoise, 120 centipoise, 130 centipoise, or less than 140 centipoise, where any value can be a lower and upper end-point of a range (e.g., 40 centipoise to 90 centipoise, etc.).

[0068] In one aspect, the injectable compositions can be injected into the neurovascular blood vessel using a syringe and catheter. In one aspect, the catheter has an inner diameter of 0.008 inches to 0.021 inches, or 0.008 inches, 0.009 inches, 0.010 inches, 0.011 inches, 0.012 inches, 0.013 inches, 0.014 inches, 0.015 inches, 0.016 inches, 0.017 inches, 0.018 inches, 0.019 inches, 0.020 inches, or 0.021 inches, where any value can be a lower and upper end-point of a range (e.g., 0.009 inches to 0.016 inches, etc.).

[0069] In one aspect, when the solution viscosity of the injectable composition is less than 140 cP, the composition can be delivered in a neurovascular catheter having an inner diameter of 0.017” inner diameter at clinically relevant delivery rates. In another aspect, when the solution viscosity of the injectable composition is less than 45 cP, the composition can be delivered in a neurovascular catheter having an inner diameter of 0.013” inner diameter at clinically relevant delivery rates.

[0070] The injectable compositions described herein have unique distal penetration properties, which make the injectable compositions very useful as embolics for neurovascular blood vessels. Current embolics such as n-BCA and Onyx require further manipulation in order to be injected into small vessels such as neurovascular vessels. For example, n-BCA and Onyx requires off-label dilution to promote distal penetration. n-BCA and Onyx further require supplemental or unique equipment to create a ‘‘pressurized” system, where the embolic material is delivered with backstop to block proximal flow and promote distal penetration. Finally, for the delivery of n-BCA and Onyx in the MMA, the catheter needs to be wedged in the MMA artery to block proximal flow and promote distal penetration.ATTORNEY DOCKET NO.: 930601-2120

[0071] Not wishing to be bound by theory, the unique distal penetration properties of the injectable compositions described herein reduce the time to resolution of the patients’ subdural hematoma. Additionally, the unique distal penetration properties the injectable compositions described herein improve devascularization of the tumor and therefore minimize blood loss and time during surgical resection, improve visualization of the tumor volume during surgical resection, reduce the risk of occurrence, reduce damage to adjacent tissue, and provide palliative treatment to non-operable patients.

[0072] The injectable compositions described herein consistently exhibit higher luminal occlusion than other embolic materials such as n-BCA and Onyx. As demonstrated herein, the injectable compositions consistently occlude a higher proportion of vessels in each zone of the neurovascular vessel when compared to n-BCA and Onyx. The injectable compositions described herein do not require any subsequent handling or manipulation as required with the commercial embolics n-BCA and Onyx to achieve high distal penetration into the vessel. Moreover, the injectable compositions can consistently penetrate neurovascular vessels regardless of the delivery technique.

[0073] The ability of the injectable compositions described herein to be injected into neurovascular vessels with increased distal penetration and luminal occlusion provides numerous benefits and biomedical applications. In one aspect, the injectable compositions and solids produced therefrom can be used to reduce or inhibit blood flow in a neurovascular blood vessel of a subject. In this aspect, the solid produced from the injectable composition creates an artificial embolus within the neurovascular blood vessel. Thus, the injectable compositions described herein can be used as synthetic embolic agents. In this aspect, the injectable composition is injected into the neurovascular blood vessel followed by formation of the solid in order to partially or completely block the neurovascular blood vessel.

[0074] In one aspect, the injectable compositions and solids produced therefrom can be used to diminish / stop blood flow in a neurovascular blood vessel in the subject. In one aspect, the injectable composition can be injected into a neurovascular vessel at a sufficient amount to diminish / stop blood flow. For example, the injectable composition and solid produced therefrom can be injected into the MMA to stop blood flow from the MMAATTORNEY DOCKET NO.: 930601-2120and resolve a subdural hematoma.

[0075] In one aspect, the injectable compositions and solids produced therefrom can be used to reduce or prevent blood flow in a neurovascular blood vessel that supplies a head or neck tumor in the subject. Examples of head and neck tumors include, but are not limited to, nasal, paranasal, and skull base tumors, nasopharyngeal tumors, hypopharyngeal, laryngeal, tracheal, and parapharyngeal tumors, salivary gland tumors, oral cavity and mobile tongue tumors, oropharyngeal tumors, odontogenic and maxillofacial bone tumors, ear tumors, soft tissue tumors, haematolymphoid proliferations and neoplasia, melanocytic tumors, tumors and tumor-like lesions of the neck and lymph nodes, germ cell tumors, metastasis, neuroendocrine neoplasms and paraganglioma, and genetic tumor syndromes involving the head and neck.

[0076] In one aspect, the injectable compositions and solids produced therefrom can be used to reduce or prevent blood flow in a neurovascular blood vessel that supplies a brain tumor in the subject. Examples of brain tumors include, but are not limited to

[0077] Gliomas, glioneuronal tumors, and neuronal tumors, adult-type diffuse gliomas, astrocytoma, IDH-mutant oligodendroglioma, IDH-mutant and 1p / 19q-codeleted glioblastoma, IDH-wildtype pediatric-type diffuse low-grade gliomas, diffuse astrocytoma, MYB- or MYBL1 -altered, angiocentric glioma, polymorphous low-grade neuroepithelial tumor of the young, diffuse low-grade glioma, MAPK pathway-altered Pediatric-type diffuse high-grade gliomas, diffuse midline glioma, H3 K27-altered diffuse hemispheric glioma, H3 G34-mutant diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype infant-type hemispheric glioma, circumscribed astrocytic gliomas, pilocytic astrocytoma high-grade astrocytoma with piloid features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, astroblastoma, M / V1-altered glioneuronal and neuronal tumors, ganglioglioma desmoplastic infantile ganglioglioma, desmoplastic infantile astrocytoma, dysembryoplastic neuroepithelial tumor, diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, papillary glioneuronal tumor, rosetteforming glioneuronal tumor, myxoid glioneuronal tumor, diffuse leptomeningeal glioneuronal tumor, gangliocytoma, multinodular and vacuolating neuronal tumor,ATTORNEY DOCKET NO.: 930601-2120dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), central neurocytoma, extraventricular neurocytoma, cerebellar liponeurocytoma, ependymal tumors, supratentorial ependymoma, supratentorial ependymoma, ZFTA fusion-positive, supratentorial ependymoma, YAP1 fusion-positive posterior fossa ependymoma Posterior fossa ependymoma, group PFA, posterior fossa ependymoma, group PFB, spinal ependymoma, spinal ependymoma, MYC / V-amplified, myxopapillary ependymoma, subependymoma, choroid plexus tumors, choroid plexus papilloma Atypical choroid plexus papilloma Choroid plexus carcinoma, embryonal tumors, medulloblastoma, medulloblastomas, molecularly defined medulloblastoma, WNT-activated medulloblastoma, SHH-activated and TP53-wildtype medulloblastoma, SHH-activated and 7F53-mutant medulloblastoma, non-WNT / non-SHH medulloblastomas, atypical teratoid / rhabdoid tumor, Cribriform neuroepithelial tumor, embryonal tumor with multilayered rosettes CNS neuroblastoma, FOXR2-activated CNS tumor with BCOR internal tandem duplication, CNS embryonal tumor, pineal tumors, pineocytoma, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, papillary tumor of the pineal region, desmoplastic myxoid tumor of the pineal region, SMARCB1 -mutant, cranial and paraspinal nerve tumors, schwannoma neurofibroma perineurioma, hybrid nerve sheath tumor, malignant melanotic nerve sheath tumor, malignant peripheral nerve sheath tumor, paraganglioma meningiomas, meningioma mesenchymal, non-meningothelial tumors, fibroblastic and myofibroblastic tumors, solitary fibrous tumor, vascular tumors, hemangiomas and vascular malformations, hemangioblastoma, Rhabdomyosarcoma, uncertain differentiation Intracranial mesenchymal tumor, FET-CREB fusion-positive C / C-rearranged sarcoma, primary intracranial sarcoma, D / CER1-mutant Ewing sarcoma, chondro-osseous tumors, chondrogenic tumors, mesenchymal chondrosarcoma, notochordal tumors chordoma (including poorly differentiated chordoma), melanocytic tumors, diffuse meningeal melanocytic neoplasms, meningeal melanocytosis and meningeal melanomatosis, circumscribed meningeal melanocytic neoplasms, meningeal melanocytoma and meningeal melanoma, hematolymphoid tumors, lymphomas, CNS lymphomas, primary diffuse large B-cell lymphoma of the CNS, immunodeficiency-associated CNS lymphoma, lymphomatoid granulomatosis, intravascular large B-cellATTORNEY DOCKET NO.: 930601-2120lymphoma, miscellaneous rare lymphomas in the CNS, MALT lymphoma of the dura, anaplastic large cell lymphoma (ALK+IALK-), T-cell and NK / T-cell lymphomas, histiocytic tumors, Erdheim-Chester disease, Rosai-Dorfman disease, juvenile xanthogranuloma, langerhans cell histiocytosis, histiocytic sarcoma, germ cell tumors, mature teratoma Immature teratoma, teratoma with somatic-type malignancy, germinoma embryonal carcinoma, yolk sac tumor, choriocarcinoma, mixed germ cell tumor, tumors of the sellar region, adamantinomatous craniopharyngioma, papillary craniopharyngioma, pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma, pituitary adenoma / PitNET, pituitary blastoma, metastases to the CNS, metastases to the brain and spinal cord parenchyma, or metastases to the meninges.

[0078] In one aspect, the injectable compositions and solids produced therefrom can be used to deliver a bioactive agent in addition to reducing or preventing blood flow in a neurovascular blood vessel. For example, the injectable composition can include an anticancer agent when the composition is injected into a neurovascular vessel that supplies the tumor.

[0079] Each component used to produce the injectable compositions described herein as well as methods for making the injectable compositions is provided below.

[0080] Polvcationic Salts

[0081] The polycationic salt is compound having a plurality of cationic groups and pharmaceutically-acceptable counterions, where there is a 1:1 stoichiometric ratio of the cationic groups to anionic counterions. In one aspect, the polycationic salt is a polymer having a polymer backbone with a plurality of cationic groups and pharmaceutically-acceptable anionic counterions. The cationic groups can be pendant to the polymer backbone and / or incorporated within the polymer backbone.

[0082] In one aspect, the polycationic polyelectrolyte is derived by dissolving a polycationic salt in water. In one aspect, the polycationic salt is a polycationic hydrochloride salt, wherein upon mixing with water produces the polycationic polyelectrolyte and chloride ions. In another aspect, the polycationic salts described herein can be produced by combining a polymer with a plurality of basic groups (e.g., amino groups) with an acid to produce the corresponding cationic groups. In various aspects, acids which may beATTORNEY DOCKET NO.: 930601-2120employed to form pharmaceutically acceptable polycationic salts include inorganic acids as hydrochloric acid, acetic acid, or other monovalent carboxylic acids.

[0083] Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

[0084] In other aspects, when the polycationic salt is a polymer, the polycationic salt can be produced by the polymerization of one or more monomers, where the monomers possess one or more cationic groups with corresponding counterion. Non-limiting procedures for making the polycationic salts using this approach are provided in the Examples. In one aspect, once the polycation has been prepared, excess ions can be removed from the polycation by filtration or dialysis prior to drying (e.g., lyophilization) to produce the polycationic salt with stoichiometric amounts of anionic counterions relative to the number of cationic groups.

[0085] In one aspect, the counterion of the polycationic salt is a monovalent ion such as, for example, chloride, pyruvate, acetate, tosylate, benzenesulfonate, benzoate, lactate, salicylate, glucuronate, galacturonate, nitrite, mesylate, trifluoroacetate, nitrate, gluconate, glycolate, formate, or any combination thereof. In one aspect, the counterion of the polycationic salt is a multivalent ion such as, for example, sulfate or phosphate.

[0086] In one aspect, the polycationic salt is a pharmaceutically-acceptable salt of a polyamine. The amino groups of the polyamine can be branched or part of the polymer backbone. In one aspect, the polyamine comprises two or more pendant amino groups, wherein the amino group comprises a primary amino group, a secondary amino group, tertiary amino group, a quaternary amine, an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazolyl, or an aromatic group substituted with one or more amino groups.

[0087] In one aspect, the pharmaceutically-acceptable salt of the polyamine can include an aryl group having one or more amino groups directly or indirectly attached to the aromatic group. Alternatively, the amino group can be incorporated in the aromaticATTORNEY DOCKET NO.: 930601-2120ring. For example, the aromatic amino group is a pyrrole, an isopyrrole, a pyrazole, imidazole, a triazole, or an indole. In another aspect, the aromatic amino group includes the isoimidazole group present in histidine. In another aspect, the biodegradable polyamine can be gelatin modified with ethylenediamine.

[0088] The amino group of the polyamine can be protonated at a pH of from about 6 to about 9 (e.g., physiological pH) to produce cationic ammonium groups with a pharmaceutically-acceptable counterion.

[0089] In general, the polyamine salt is a polymer with a large excess of positive charges relative to negative charge at or near physiological pH. For example, the polycationic salt can have from 10 to 90 mole %, 10 to 80 mole %, 10 to 70 mole %, 10 to 60 mole %, 10 to 50 mole %, 10 to 40 mole %, 10 to 30 mole %, or 10 to 20 mole % protonated amino groups. In another aspect, all of the amino groups of the polyamine are protonated.

[0090] In one aspect, the polycationic salt can have a protonated residue of lysine, histidine, or arginine. For example, arginine has a guanidinyl group, where the guanidinyl group is a suitable amino group that can be converted to a cationic group useful herein.

[0091] In another aspect, the polyamine can be a biodegradable synthetic polymer or naturally-occurring polymer. The mechanism by which the polyamine can degrade will vary depending upon the polyamine that is used. In the case of natural polymers, they are biodegradable because there are enzymes that can hydrolyze the polymer chain. For example, proteases can hydrolyze natural proteins like gelatin. In the case of synthetic biodegradable polyamines, they also possess chemically labile bonds. For example, □-aminoesters have hydrolyzable ester groups.

[0092] In one aspect, the polyamine includes a polysaccharide, a protein, peptide, or a synthetic polyamine. Polysaccharides bearing two or more amino groups can be used herein. In one aspect, the polysaccharide is a natural polysaccharide such as chitosan or chemically modified chitosan. Similarly, the protein can be a synthetic or naturally-occurring compound. In another aspect, the polyamine is a synthetic polyamine such as poly(D-aminoesters), polyester amines, poly(disulfide amines), mixed poly(ester and amide amines), and peptide crosslinked polyamines.ATTORNEY DOCKET NO.: 930601-2120

[0093] In one aspect, the pharmaceutically-acceptable salt of the polyamine can be an amine-modified natural polymer. For example, the amine-modified natural polymer can be gelatin modified with one or more alkylamino groups, heteroaryl groups, or an aromatic group substituted with one or more amino groups. Examples of alkylamino groups are depicted in Formulae IV-VI-NRI3(CH2)SNR14R15IV-NR13(CjH2)tN(CH2)uNR17R18VR16wherein R13-R22are, independently, hydrogen, an alkyl group, or a nitrogen containing substituent;s, t, u, v, w, and x are an integer from 1 to 10; andA is an integer from 1 to 50,where the alkylamino group is covalently attached to the natural polymer. In one aspect, if the natural polymer has a carboxyl group (e.g., acid or ester), the carboxyl group can be reacted with an alkyldiamino compound to produce an amide bond and incorporate the alkylamino group into the polymer. Thus, referring to formulae IV-VI, the amino group NR13is covalently attached to the carbonyl group of the natural polymer.

[0094] As shown in formula IV-VI, the number of amino groups can vary. In one aspect, the alkylamino group is-NHCH2NH2, -NHCH2CH2NH2, -NHCH2CH2CH2NH2, -NHCH2CH2CH2CH2NH2, -NHCH2CH2CH2CH2CH2NH2,-NHCH2NHCH2CH2CH2NH2,-NHCH2CH2NHCH2CH2CH2NH2,ATTORNEY DOCKET NO.: 930601-2120-NHCH2CH2CH2NHCH2CH2CH2CH2NHCH2CH2CH2NH2, -NHCH2CH2NHCH2CH2CH2CH2NH2, -NHCH2CH2NHCH2CH2CH2NHCH2CH2CH2NH2, or -NHCH2CH2NH(CH2CH2NH)dCH2CH2NH2, where d is from 0 to 50.

[0095] In one aspect, the pharmaceutically-acceptable salt of the amine-modified natural polymer can include an aryl group having one or more amino groups directly or indirectly attached to the aromatic group. Alternatively, the amino group can be incorporated in the aromatic ring. For example, the aromatic amino group is a pyrrole, an isopyrrole, a pyrazole, imidazole, a triazole, or an indole. In another aspect, the aromatic amino group includes the isoimidazole group present in histidine. In another aspect, the biodegradable polyamine can be gelatin modified with ethylenediamine.

[0096] In other aspects, the polycationic salt can be a dendrimer. The dendrimer can be a branched polymer, a multi-armed polymer, a star polymer, and the like. In one aspect, the dendrimer is a polyalkylimine dendrimer, a mixed amino / ether dendrimer, a mixed amino / amide dendrimer, or an amino acid dendrimer. In another aspect, the dendrimer is poly(amidoamine), or PAMAM. In one aspect, the dendrimer has 3 to 20 arms, wherein each arm comprises an amino group.

[0097] In one aspect, the polycationic salt includes a polyacrylate having one or more pendant protonated amino groups. For example, the backbone of the polycationic salt can be derived from the polymerization of acrylate monomers including, but not limited to, acrylates, methacrylates, acrylamides, methacrylamides, and the like. In one aspect, the polycationic salt backbone is derived from polyacrylamide. In other aspects, the polycationic salt is a random co-polymer. In other aspects, the polycationic salt is a block copolymer, where segments or portions of the co-polymer possess cationic groups or neutral groups depending upon the selection of the monomers and method used to produce the co-polymer.

[0098] In another aspect, the polycationic salt is a pharmaceutically-acceptable salt of a protamine. Protamines are polycationic, arginine-rich proteins that play a role in condensation of chromatin into the sperm head during spermatogenesis. As by-products of the fishing industry, commercially available protamines, purified from fish sperm, areATTORNEY DOCKET NO.: 930601-2120readily available in large quantity and are relatively inexpensive. A non-limiting example of a protamine useful herein is salmine. In another aspect, the protamine is clupein.

[0099] In one aspect, the polycationic salts is a polymer with a plurality of guanidinyl groups. In one aspect, the guanidinyl groups are pendant to the polymer backbone. The number of guanidinyl groups present on the polycation ultimately determines the charge density of the polycation. In one aspect, the guanidinyl group can be derived from a residue of arginine attached to a polymer backbone.

[0100] The polyguanidinyl polymer can be a homopolymer or copolymer having a plurality of guanidinyl groups. In one aspect, the polyguanidinyl copolymer is a synthetic compound prepared by the free radical polymerization between a monomer such as an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof, and a guanidinyl monomer of formula Iwherein R1is a hydrogen or an alkyl group, X is oxygen or NR5, where R5is a hydrogen or an alkyl group, and m is from 1 to 10, or the pharmaceutically acceptable salt thereof. In one aspect, when the neutral compound of formula I is used to produce the polymer, the resulting polymer can be subsequently reacted with an acid such as, for example, hydrochloric acid or ammonium chloride, to produce the polycationic salt.ATTORNEY DOCKET NO.: 930601-2120

[0101] In one aspect, in the compound of formula I, R1is methyl, X is NH, and m is 3. In another aspect, the monomer is methacrylamide, methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), A / -[3-(AT-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), A / -(3-aminopropyl)methacrylamide, A / -(1,3-dihydroxypropan-2-yl) methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof.

[0102] In a further aspect, the mole ratio of the guanidinyl monomer of formula I to the monomer is from 1:20 to 20:1, or is 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1, where any ratio can be a lower and upper end-point of a range (e.g., 2:1 to 5:1 , etc.). In one aspect, the mole ratio of the guanidinyl monomer of formula I to the monomer is from 3:1 to 4:1. In another aspect, the polyguanidinyl polymer is a homopolymer derived from the guanidinyl monomer of formula I.

[0103] The polyguanidinyl copolymer can be synthesized using polymerization techniques known in the literature such as, for example, RAFT polymerization (i.e., reversible addition-fragmentation chain-transfer polymerization) or other methods such as free radical polymerization. In one aspect, the polymerization reaction can be carried out in an aqueous environment. As discussed above, the polyguanidinyl copolymer can be prepared initially as a neutral polymer followed by treatment with an acid to produce the pharmaceutically-acceptable salt.

[0104] In another aspect, multiple copolymers with controlled Mwand narrow polydispersity indices (PDIs) can be synthesized by RAFT polymerization. In one aspect, the pharmaceutically-acceptable salt of the polyguanidinyl copolymer has an average molecular weight (Mw) from about 1 kDa to about 100 kDa, or can be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 kDa, where any value can be a lower and upper end-point of a range (e.g., 10 to 25 kDa, etc.).

[0105] In another aspect, the pharmaceutically-acceptable salt of the polyguanidinyl copolymer is a multimodal polyguanidinyl copolymer. The term “multimodal polyguanidinyl copolymer” is a polyguanidinyl copolymer with a molecular mass distribution curve beingATTORNEY DOCKET NO.: 930601-2120the sum of at least two or more molecular mass unimodal distribution curves. In one aspect, the polyguanidinyl copolymer has a multimodal distribution of polyguanidinyl copolymer molecular mass with modes between 5 and 100 kDa, or can be about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 kDa, where any value can be a lower and upper end-point of a range (e.g., 10 to 30 kDa, etc.).

[0106] In another aspect, the number of guanidinyl side groups in the pharmaceutically-acceptable salt of the polyguanidinyl copolymer can vary from about 10 to about 100 mol % of the. total polymer sidechains, or can be about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mol %, where any value can be a lower and upper end-point of a range (e.g., 60 to 90 mol %, etc.). In one aspect, the guanidinyl side groups are from about 70 to about 80 mol % of the polyguanidinyl copolymer. Conversely, comonomer concentration can vary from about 50 to about 0 mol %, or can be about 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, orO mol %, where any value can be a lower and upper end-point of a range (e.g., 10 to 40 mol %, etc.). In one aspect, the Mn, PDI, and structures of the copolymers can be verified by size exclusion chromatography (SEC),1H NMR, and13C NMR or other common techniques. Exemplary procedures for preparing and characterizing copolymers useful herein are provided in the Examples below.

[0107] The concentration of the of the polycationic salt in the injectable compositions described herein can vary depending upon the application of the composition. In one aspect, the concentration of the of the polycationic salt used to produce the injectable compositions described herein is from 100 mg / mL to 1,000 mg / mL, or 100 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, 600 mg / mL, 650 mg / mL, 700 mg / mL, 750 mg / mL, 800 mg / mL, 850 mg / mL, 900 mg / mL, 950 mg / mL, 1,000 mg / mL, where any value can be a lower and upper end-point of a range (e.g., 200 mg / mL to 500 mg / mL, etc.).

[0108] Polyanionic Salts

[0109] The polyanionic salt is a compound with a plurality of anionic groups and pharmaceutically-acceptable cationic counterions, where there is a 1 :1 stoichiometric ratio of the anionic groups to cationic counterions.ATTORNEY DOCKET NO.: 930601-2120

[0110] In one aspect, the polyanionic polyelectrolyte is derived by dissolving a polyanionic salt in water. In one aspect, the polyanionic salts described herein can be produced by adjusting the pH of a solution of a compound with a plurality of acidic groups (e.g., carboxylic acid groups) with the addition of a base to produce the corresponding anionic groups. In various aspects, bases which may be employed to form pharmaceutically acceptable polyanionic salts include alkali metal hydroxides, carbonates, acetate, etc. In one aspect, once the polyanion has been prepared, excess ions can be removed from the polyanion by filtration or dialysis prior to drying (e.g., lyophilization) to produce the polyanionic salt with stoichiometric amounts of cationic counterions relative to the number of anionic groups.

[0111] In one aspect, the cationic counterions of the polyanionic salt are monovalent cations such as, for example, sodium, potassium or ammonium ions. In another aspect, the counterions of the polyanionic salt are multivalent ion such as, for example, calcium, magnesium ions, or mixtures thereof.

[0112] In one aspect, the polyanionic salt is composed of a polymer backbone with a plurality of anionic groups and pharmaceutically-acceptable cationic counterions. The anionic groups can be pendant to the polymer backbone and / or incorporated within the polymer backbone. In certain aspects, (e.g., biomedical applications), the polyanionic salt is any biocompatible polymer possessing anionic groups.

[0113] In one aspect, the polyanionic salt can be a pharmaceutically-acceptable salt of a synthetic polymer or naturally-occurring polymer. Examples of naturally-occurring polyanions include glycosaminoglycans such as chondroitin sulfate, heparin, heparin sulfate, dermatan sulfate, keratin sulfate, and hyaluronic acid. In other aspects, proteins having a net negative charge at neutral pH or proteins with a low pl can be used as naturally-occurring polyanions described herein. The anionic groups can be pendant to the polymer backbone and / or incorporated in the polymer backbone.

[0114] When the polyanionic salt is a synthetic polymer, it is generally any polymer possessing anionic groups or groups that can be ionized to anionic groups. Examples of groups that can be converted to anionic groups include, but are not limited to, carboxylate, sulfonate, boronate, sulfate, borate, phosphonate, or phosphate.ATTORNEY DOCKET NO.: 930601-2120

[0115] In one aspect, the polyanionic salt is a polyphosphate. In another aspect, the polyanionic salt is a polyphosphate compound having from 5 to 90 mole % phosphate groups. In another aspect, the polyanionic salt has from 10 to 1,000 phosphate groups, or 10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1 ,000 phosphate groups, where any value can be a lower and upper endpoint of a range (e.g., 100 to 300, etc.)

[0116] In one aspect, the polyphosphate can be a naturally-occurring compound such as, for example, DNA, RNA, or highly phosphorylated proteins like phosvitin (an egg protein), dentin (a natural tooth phosphoprotein), casein (a phosphorylated milk protein), or bone proteins (e.g. osteopontin).

[0117] In another aspect, the polyanionic salt can be a synthetic polypeptide made by polymerizing the amino acid serine and then chemically or enzymatically phosphorylating the polypeptide. In another aspect, the polyanionic salt can be produced by the polymerization of phosphoserine. In one aspect, the polyphosphate can be produced by chemically or enzymatically phosphorylating a protein (e.g., natural serine- or threonine-rich proteins). In a further aspect, the polyphosphate can be produced by chemically phosphorylating a polyalcohol including, but not limited to, polysaccharides such as cellulose or dextran. The polyanionic polymers can subsequently be converted to pharmaceutically-acceptable salts.

[0118] In another aspect, the polyphosphate can be a synthetic compound. For example, the polyphosphate can be a polymer with pendant phosphate groups attached to the polymer backbone and / or present in the polymer backbone, (e.g., a phosphodiester backbone).

[0119] In one aspect, the polyanionic salt includes a polyacrylate having one or more pendant phosphate groups. For example, the polyanionic salt can be derived from the polymerization of acrylate monomers including, but not limited to, acrylates, methacrylates, acrylamides, methacrylamides, and the like. In other aspects, the polyanionic salt is a block co-polymer, where segments or portions of the co-polymer possess anionic groups and neutral groups depending upon the selection of the monomers used to produce the co-polymer. In one aspect, the anionic group can be a plurality of carboxylate, sulfate,ATTORNEY DOCKET NO.: 930601-2120sulfonate, borate, boronate, phosphonate, or phosphate groups.

[0120] In one aspect, the polyanionic salt is a polymer having a plurality of fragments of formula XIwherein R4is hydrogen or an alkyl group;n is from 1 to 10;Y is oxygen, sulfur, or NR30, wherein R30is hydrogen, an alkyl group, or an aryl group; Z’ is a pharmaceutically-acceptable salt of an anionic group.

[0121] In one aspect, Z’ in formula XI is carboxylate, sulfate, sulfonate, borate, boronate, a substituted or unsubstituted phosphate, or a phosphonate. In another aspect, Z’ in formula XI is sulfate, sulfonate, borate, boronate, a substituted or unsubstituted phosphate, or a phosphonate, and n in formulae XI is 2.

[0122] In one aspect, the polyanionic salt can be an inorganic polyphosphate including a cyclic inorganic polyphosphate having the formula (PnO3n)n', a linear inorganic polyphosphate having the formula (PnO3n+i)n+2’, or a combination thereof. In one aspect, the polyanionic salt is an inorganic polyphosphate possessing a plurality of phosphate groups (e.g., NaPO3)n, where n is 10to 1,000 or 10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1 ,000 phosphate groups, where any value can be a lower and upper end-point of a range (e.g., 100 to 300, etc.). Examples of inorganic phosphates include, but are not limited to, Graham salts, hexametaphosphateATTORNEY DOCKET NO.: 930601-2120salts, and triphosphate salts. The counterions of these salts can be monovalent cations such as, for example, Na+, K+, NH4+, or a combination thereof. In one aspect, the polyanionic salt is sodium hexametaphosphate.

[0123] In another aspect, the polyanionic salt is an organic polyphosphate. In one aspect, polymers with phosphodiester backbones connecting organic moieties (e.g., DNA or synthetic phosphodiesters) are organic polyphosphates useful herein.

[0124] In another aspect, the polyanionic salt is a pharmaceutically-acceptable salt of a phosphorylated sugar. The sugar can be a hexose or pentose sugar. Additionally, the sugar can be partially or fully phosphorylated. In one aspect, the phosphorylated sugar is inositol hexaphosphate (IP6).

[0125] The concentration of the of the polyanionic salt in the injectable compositions described herein can vary depending upon the application of the composition. In one aspect, the concentration of the of the polyanionic salt used to produce the injectable compositions described herein is from 100 mg / mL to 1,000 mg / mL, or 100 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, 600 mg / mL, 650 mg / mL, 700 mg / mL, 750 mg / mL, 800 mg / mL, 850 mg / mL, 900 mg / mL, 950 mg / mL, 1,000 mg / mL, where any value can be a lower and upper end-point of a range (e.g., 200 mg / mL to 500 mg / mL, etc.).

[0126] Reinforcing Component

[0127] In another aspect, the injectable compositions described herein also include a reinforcing component. The term “reinforcing component” is defined herein as any component that enhances or modifies one or more mechanical or physical properties of the solids produced herein (e.g., cohesiveness, fracture toughness, elastic modulus, dimensional stability after curing, color, visibility etc.). The mode in which the reinforcing component can enhance the mechanical properties of the solid can vary and will depend on the selection of the components used to prepare the injectable composition and reinforcing component. Examples of reinforcing component useful herein are provided below.

[0128] In one aspect, the reinforcing component is a coil or fiber. In a further aspect, the coil or fiber can be platinum, plastic, nylon, another natural or synthetic fiber, aATTORNEY DOCKET NO.: 930601-2120polymerizable monomer, a nanostructure, a micelle, a liposome, a water-insoluble filler, or any combination thereof. In one aspect, the coil or fiber is administered concurrently with the injectable composition. In another aspect, the coil or fiber is administered sequentially either before or after the injectable composition.

[0129] In other aspects, the reinforcing component can be a water-insoluble filler. The filler can have a variety of different sizes and shapes, ranging from particles (micro and nano) to fibrous materials. The selection of the filler can vary depending upon the application of the injectable composition.

[0130] The fillers useful herein can be composed of organic and / or inorganic materials. In one aspect, the nanostructures can be composed of organic materials like carbon or inorganic materials including, but not limited to, boron, molybdenum, tungsten, silicon, titanium, copper, bismuth, tungsten carbide, aluminum oxide, titanium dioxide, molybdenum disulphide, silicon carbide, titanium diboride, boron nitride, dysprosium oxide, iron (III) oxide-hydroxide, iron oxide, manganese oxide, titanium dioxide, boron carbide, aluminum nitride, or any combination thereof.

[0131] In one aspect, the filler comprises a metal oxide, a ceramic particle, or a water insoluble inorganic salt. Examples of fillers useful herein include those manufactured by SkySpring Nanomaterials, Inc., which is listed below.

[0132] Metals and Non-metal ElementsAg, 99.95%, 100 nmAg, 99.95%, 20-30 nmAg, 99.95%, 20-30 nm, PVP coatedAg, 99.9%, 50-60 nmAg, 99.99%, 30-50 nm, oleic acid coatedAg, 99.99%, 15 nm, 10wt%, self-dispersibleAg, 99.99%, 15 nm, 25wt%, self-dispersibleAl, 99.9%, 18 nmATTORNEY DOCKET NO.: 930601-2120Al, 99.9%, 40-60 nmAl, 99.9%, 60-80 nmAl, 99.9%, 40-60 nm, low oxygenAu, 99.9%, 100 nmAu, 99.99%, 15 nm, 10wt%, self-dispersibleB, 99.9999%B, 99.999%B, 99.99%B, 99.9%B, 99.9%, 80 nmDiamond, 95%, 3-4 nmDiamond, 93%, 3-4 nmDiamond, 55-75 %, 4-15 nmGraphite, 93%, 3-4 nmSuper Activated Carbon, 100 nmCo, 99.8%, 25-30 nmCr, 99.9%, 60-80 nmCu, 99.5%, 300 nmCu, 99.5%, 500 nmCu, 99.9%, 25 nmCu, 99.9%, 40-60 nmCu, 99.9%, 60-80 nmCu, 5-7 nm, dispersion, oil solubleFe, 99.9%, 20 nmATTORNEY DOCKET NO.: 930601-2120Fe, 99.9%, 40-60 nmFe, 99.9%, 60-80 nmCarbonyl-Fe, micro-sizedMo, 99.9%, 60-80 nmMo, 99.9%, 0.5-0.8 mNi, 99.9%, 500 nm (adjustable)Ni, 99.9%, 20 nmNi coated with carbon, 99.9%, 20 nmNi, 99.9%, 40-60 nmNi, 99.9%, 60-80 nmCarbonyl-Ni, 2-3 pmCarbonyl-Ni, 4-7 pmCarbonyl-Ni-AI (Ni Shell, Al Core)Carbonyl-Ni-Fe AlloyPt, 99.95%, 5 nm, 10wt%, self-dispersibleSi, Cubic, 99%, 50 nmSi, Polycrystalline, 99.99995%, lumpsSn, 99.9%, <100 nmTa, 99.9%, 60-80 nmTi, 99.9%, 40-60 nmTi, 99.9%, 60-80 nmW, 99.9%, 40-60 nmW, 99.9%, 80-100 nmZn, 99.9%, 40-60 nmATTORNEY DOCKET NO.: 930601-2120Zn, 99.9%, 80-100 nm

[0133] Metal OxidesAIOOH, 10-20nm, 99.99%AI2O3alpha, 98+%, 40 nmAI2O3 alpha, 99.999%, 0.5-10 pmAI2O3 alpha, 99.99%, 50 nmAI2O3 alpha, 99.99%, 0.3-0.8 pmAI2O3 alpha, 99.99%, 0.8-1.5 pmAI2O3 alpha, 99.99%, 1.5-3.5 pmAI2O3 alpha, 99.99%, 3.5-15 pmAI2O3 gamma, 99.9%, 5 nmAI2O3 gamma, 99.99%, 20 nmAI2O3 gamma, 99.99%, 0.4-1.5 pmAI2O3 gamma, 99.99%, 3-10 pmAI2O3 gamma, ExtrudateAI2O3 gamma, ExtrudateAI(OH)3, 99.99%, 30-100 nmAI(OH)3, 99.99%, 2-10 pmAluminium Iso-Propoxide (AIP), C9H21O3AI, 99.9%AIN, 99%, 40 nmBaTiO3, 99.9%, 100 nmBBr3, 99.9%B2O3, 99.5%, 80 nmBN, 99.99%, 3-4 pmATTORNEY DOCKET NO.: 930601-2120BN, 99.9%, 3-4 mB4C, 99%, 50 nmBi2C>3, 99.9%, <200 nmCaCO3, 97.5%, 15-40 nmCaCO3, 15-40 nmCa3(PO4)2, 20-40 nmCa10(PO4)6(OH)2, 98.5%, 40 nmCeO2, 99.9%, 10-30 nmCoO, <100 nmCo203, <100 nmCo304, 50 nmCuO, 99+%, 40 nmEr2O3, 99.9%, 40-50 nmFe2O3alpha, 99%, 20-40 nmFe2O3gamma, 99%, 20-40 nmFe3O4, 98+%, 20-30 nmFe3O4, 98+%, 10-20 nmGd2O3, 99.9%<100 nmHfO2, 99.9%, 100 nmln203:Sn02=90:10, 20-70 nmln2O3, 99.99%, 20-70 nmln(OH)3, 99.99%, 20-70 nmLaB6, 99.0%, 50-80 nmLa2O3, 99.99%, 100 nmATTORNEY DOCKET NO.: 930601-2120LiFePO4, 40 nmMgO, 99.9%, 10-30 nmMgO, 99%, 20 nmMgO, 99.9%, 10-30 nmMg(OH)2, 99.8%, 50 nmMn2O3, 98+%, 40-60 nmMoCI5, 99.0%Nd2O3, 99.9%, <100 nmNiO, <100 nmNi2O3, <100 nmSb2O3, 99.9%, 150 nmSiO2, 99.9%, 20-60 nmSiO2, 99%, 10-30 nm, treated with Silane Coupling AgentsSiO2, 99%, 10-30 nm, treated with HexamethyldisilazaneSiO2, 99%, 10-30 nm, treated with Titanium EsterSiO2, 99%, 10-30 nm, treated with SilanesSiO2, 10-20 nm, modified with amino group, dispersibleSiO2, 10-20 nm, modified with epoxy group, dispersibleSiO2, 10-20 nm, modified with double bond, dispersibleSiO2, 10-20 nm, surface modified with double layer, dispersibleSiO2, 10-20 nm, surface modified, super-hydrophobic & oleophilic, dispersible SiO2, 99.8%, 5-15 nm, surface modified, hydrophobic & oleophilic, dispersible SiO2, 99.8%, 10-25 nm, surface modified, super-hydrophobic, dispersibleSiC, beta, 99%, 40 nmATTORNEY DOCKET NO.: 930601-2120SiC, beta, whisker, 99.9%Si3N4, amorphous, 99%, 20 nmSi3N4alpha, 97.5-99%, fiber, 100nmX800 nmSnO2, 99.9%, 50-70 nmATO, Sn02:Sb203=90:10, 40 nmTiO2anatase, 99.5%, 5-10 nmTiO2Rutile, 99.5%, 10-30 nmTiO2Rutile, 99%, 20-40 nm, coated with SiO2, highly hydrophobicTiO2Rutile, 99%, 20-40 nm, coated with SiO2 / AI2O3TiO2Rutile, 99%, 20-40 nm, coated with AI2O3, hydrophilicTiO2Rutile, 99%, 20-40 nm, coated with SiO2 / AI2O3 / Stearic AcidTiO2Rutile, 99%, 20-40 nm, coated with Silicone Oil, hydrophobicTiC, 99%, 40 nmTiN, 97+%, 20 nmWO3, 99.5%, <100 nmWS2, 99.9%, 0.8 pmWCI6, 99.0%Y2O3, 99.995%, 30-50 nmZnO, 99.8%, 10-30 nmZnO, 99%, 10-30 nm, treated with silane coupling agentsZnO, 99%, 10-30 nm, treated with stearic acidZnO, 99%, 10-30 nm, treated with silicone oilZnO, 99.8%, 200 nmZrO2, 99.9%, 100 nmATTORNEY DOCKET NO.: 930601-2120ZrO2, 99.9%, 20-30 nmZrO2-3Y, 99.9%, 0.3-0.5 pmZrO2-3Y, 25 nmZrO2-5Y, 20-30 nmZrO2-8Y, 99.9%, 0.3-0.5 pmZrO2-8Y, 20 nmZrC, 97+%, 60 nm

[0134] In one aspect, the filler is nanosilica. Nanosilica is commercially available from multiple sources in a broad size range. For example, aqueous Nexsil colloidal silica is available in diameters from 6-85 nm from Nyacol Nanotechnologies, Inc. Amino-modified nanosilica is also commercially available, from Sigma Aldrich for example, but in a narrower range of diameters than unmodified silica.

[0135] In another aspect, the filler can be composed of calcium phosphate. In one aspect, the filler can be hydroxyapatite, which has the formula Ca5(PO4)3OH. In another aspect, the filler can be a substituted hydroxyapatite. A substituted hydroxyapatite is hydroxyapatite with one or more atoms substituted with another atom. The substituted hydroxyapatite is depicted by the formula M5X3Y, where M is Ca, Mg, Na; X is PO4or CO3; and Y is OH, F, Cl, or CO3. Minor impurities in the hydroxyapatite structure may also be present from the following ions: Zn, Sr, Al, Pb, Ba. In another aspect, the calcium phosphate comprises a calcium orthophosphate. Examples of calcium orthophosphates include, but are not limited to, monocalcium phosphate anhydrate, monocalcium phosphate monohydrate, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, octacalcium phosphate, beta tricalcium phosphate, alpha tricalcium phosphate, super alpha tricalcium phosphate, tetracalcium phosphate, amorphous tricalcium phosphate, or any combination thereof. In other aspects, the calcium phosphate can also include calcium-deficient hydroxyapatite, which can preferentially adsorb bone matrix proteins.

[0136] In certain aspects, the filler can be functionalized with one or more amino or activated ester groups. In this aspect, the filler can be covalently attached to the polycation or polyanion. For example, aminated silica can be reacted with the polyanion possessingATTORNEY DOCKET NO.: 930601-2120activated ester groups to form new covalent bonds.

[0137] Contrast Agents

[0138] The injectable compositions described herein can include one or more contrast agents that permit the visualization of the injectable composition after it has been administered to the subject.

[0139] In one aspect, the contrast agent is a radiographic contrast agent. Further in this aspect, the radiographic contrast agent can be tantalum metal particles (Ta), gold particles, or an iodide salt (e.g., sodium iodide). In one aspect, up to 30 % (w / w) of Ta can be included in the formulations. In one aspect, inclusion of Ta can be beneficial to interventional radiologists in the operating room. In another aspect, the contrast agent can be a fluoroscopic contrast agent. Further in this aspect, the fluoroscopic contrast agent can be tantalum oxide (TaC>2, Ta2Os) particles. In one aspect, the contrast agent can be tantalum particles having a particle size from 0.5 pm to 50 pm, 1 pm to 25 pm, 1 pm to 10 pm, or 1 pm to 5 pm. In another aspect, contrast agent is tantalum particles in the amount of 10% to 60%, 20% to 50%, or 20% to 40%.

[0140] The injectable compositions described herein include one or more transient contrast agents, where the contrast agent readily diffuses out of the injectable composition upon administration to the subject, providing temporary contrast.

[0141] In one aspect, the transient contrast agent is a non-ionic compound. In another aspect, the transient contrast agent is water-soluble. In one aspect, the transient contrast agent is an iodinated organic compound, where one or more iodine atoms are covalently bonded to the organic compound. Iodinated organic contrast agents are a class of iodine-containing organic compounds. This set of compounds are derivatives of 2,3,5-triidobenzoic acid to produce different commercially available compounds, such as iopamidol, iodixanol, iohexol, iopromide, iobtiridol, iomeprol, iopentol, iopamiron, ioxilan, iotrolan, iotrol and ioversol, iopanoate, diatrizoic acid, iothalamate, and ioxaglate, various side chains are added to the parent compound. These sidechains modify the solubility, toxicity, and osmolality of the compound. Iodixanol is a dimer of the parent compound, producing a molecule with 6 iodine atoms. In another aspect, the iodinated organic compound is an iodinated oil such as, for example, ethiodized poppyseed oil (Lipiodol).ATTORNEY DOCKET NO.: 930601-2120

[0142] The concentration of the transient contrast agent in the injectable compositions can vary depending upon the application. In one aspect, the concentration of the transient contrast agent in the injectable compositions is from 10 mgl / mL to 1 ,000 mgl / mL, or is 10 mgl / mL, 25 mgl / mL, 50 mgl / mL, 75 mgl / mL, 100 mgl / mL, 125 mgl / mL, 150 mgl / mL, 175 mgl / mL, 200 mgl / mL, 225 mgl / mL, 250 mgl / mL, 275 mgl / mL, 300 mgl / mL, 325 mgl / mL, 350 mgl / mL, 375 mgl / mL, 400 mgl / mL, 425 mgl / mL, 450 mgl / mL, 475 mgl / mL, 500 mgl / mL, 525 mgl / mL, 550 mgl / mL, 575 mgl / mL, 600 mgl / mL, 625 mgl / mL, 650 mgl / mL, 675 mgl / mL, 700 mgl / mL, 725 mgl / mL, 750 mgl / mL, 775 mgl / mL, 800 mgl / mL, 825 mgl / mL, 850 mgl / mL, 875 mgl / mL, 900 mgl / mL, 925 mgl / mL, 950 mgl / mL, 975 mgl / mL, or 1,000 mgl / mL, 100 mgl / mL, 100 mgl / mL, 100 mgl / mL, 100 mgl / mL, 100 mgl / mL, 100 mgl / mL, where any value can be a lower and upper end-point of a range (e.g., 400 mgl / mL to 600 mgl / mL, etc.).

[0143] In one aspect, the majority of the transient contrast agent that diffuses from the injectable composition is such that the transient contrast agent cannot be detected by imaging techniques such as, for example, fluoroscopy or CT. In one aspect, up to 70%, up to 80%, up to 90%, up to 95%, or up to 100% of the transient contrast agent diffuses out of the solid from 5 minutes to 48 hours once the solid is produced in situ, or 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours, 2 days, 5 days, 10 days, 15 days, 20 days, 25 days, or 30 days, where any value can be a lower and upper end-point of a range (e.g., 1 hour to 3 hours, etc.).

[0144] Bioactive Agents

[0145] The injectable compositions described herein can include one or more bioactive agents. In one aspect, the bioactive agent is an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, an anti-angiogenic agent, a receptor antagonist, a nucleic acid, or any combination thereof.

[0146] In one aspect, the bioactive agent is an FDA-approved anti-angiogenic agent. In one aspect, the anti-angiogenic agent is a tyrosine kinase inhibitor (TKI). Not wishingATTORNEY DOCKET NO.: 930601-2120to be bound by theory, angiogenesis is, in large part, initiated and maintained by cell signaling through receptor tyrosine kinases (RTKs). In one aspect, RTKs include receptors for several angiogenesis promoters, including VEGF, which stimulates vascular permeability, proliferation, and migration of endothelial cells; PDGF, which recruits pericytes and smooth muscle cells that support the budding endothelium; and FGF, which stimulates proliferation of endothelial cells, smooth muscle cells, and fibroblasts. In one aspect, the anti-angiogenic agent is a TKI such as sunitinib malate (SUN), pazopanib hydrochloride (PAZ), sorafenib tosylate (SOR), vandetanib (VAN), cabozantinib, or any combination thereof.

[0147] In another aspect, the bioactive agent can be humanized anti- VEGF and anti-VEGFR Fab' fragments. In this aspect, electrostatic interactions can control release kinetics. In one aspect, the native charge of the Fab' fragment is sufficient to interact with the polyelectrolyte components in the injectable composition. In another aspect, the native charge of the Fab' fragment is insufficient to interact with the polyelectrolyte components in the injectable composition and the Fab' fragment is modified to increase charge density by attaching a short polyelectrolyte to reactive sulfhydryl groups using maleamide conjugation chemistries.

[0148] In one aspect, the anti-angiogenic agent is an anti-VEGF antibody. In a still further aspect, the anti-VEGF antibody is bevacizumab or is a biosimilar anti-VEGF antibody, or is an anti-VEGF antibody derivative such as, for example, ranibizumab.

[0149] Kits

[0150] Described herein are kits for making the injectable compositions. In one aspect, the kit includes (a) a composition comprising a mixture of at least one polycationic salt and at least one polyanionic salt, (b) and instructions for making the injectable composition. In another aspect, the kit includes (a) at least one polycationic salt, (b) at least one polyanionic salt, (c) a contrast agent, and (d) instructions for making the injectable composition.

[0151] The polycationic salt and polyanionic salt used herein can be stored as dry powders for extended periods of time. In one aspect, the kit can include dry powders of the polycationic salt and polyanionic salt as separate components in separate vials, or aATTORNEY DOCKET NO.: 930601-2120mixture of the polycationic salt and polyanionic salt as a dry powder or solid in a single container. In other aspects, the kit can include aqueous solutions of the polycationic salt and polyanionic salt as separate components (e.g., in separate vials) or a mixture of the polycationic salt and polyanionic salt in water.

[0152] In one aspect, the kit can include a contrast as a dry powder or solid. In another aspect, the contrast agent can be in an aqueous solution or an oil.

[0153] The kits also include instructions for making the injectable compositions. As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can include one or multiple documents and are meant to include future updates.

[0154] The kits can also include additional components as described herein (e.g., reinforcing components, bioactive agents, etc.). In other aspects, the kits can include optional mechanical components such as, for example, syringes, microcatheters, and other devices for mixing and delivering the injectable compositions to a subject.

[0155] Preparation of the Injectable Compositions

[0156] The preparation of the injectable compositions described herein can be performed using a number of techniques and procedures. Exemplary techniques for producing the injectable compositions are provided in the Examples. In one aspect, a powder composed of a mixture of the at least one polycationic salt and the at least one polyanionic salt are mixed in water for a sufficient time to produce an injectable composition.

[0157] In one aspect, one or more additional agents (e.g., reinforcing agent, contrast agent, bioactive agent) can be added after the injectable composition has been formed. In another aspect, the one or more additional agents (e.g., reinforcing agent, contrastATTORNEY DOCKET NO.: 930601-2120agent, or bioactive agent) can be added during the formation of the injectable composition.

[0158] In one aspect, the pH of the injectable composition is from 6 to 9, 6.5 to 8.5, 7 to 8, or 7 to 7.5. In another aspect, the pH of the composition is 7.2, which is the normal physiological pH in blood.

[0159] The injectable compositions described herein are stable solutions (i.e., a liquid composition of polyelectrolytes with no distinguishable separation into distinct phases). Although the components used to produce the injectable composition can be used in dry powder form then subsequently mixed with water, the injectable compositions can be formulated as water-borne formulations and stored for future use. In certain aspects, one or more additional salts can be added to the injectable composition to prevent association of the polycationic polyelectrolytes and the polyanionic polyelectrolytes in the injectable composition. In one aspect, the salt is a monovalent salt. For example, sodium chloride can be added to the injectable composition to produce a stable composition as defined herein. The concentration of the monovalent salt can vary depending upon the molecular weight, concentration, and charge ratio of the polycationic and polyanionic salts. In other aspects, additional monovalent salt is not needed to produce the injectable compositions as stable solutions.

[0160] Aspects

[0161] Aspect 1. A method for reducing or preventing blood flow in a neurovascular blood vessel of a subject comprising introducing into the neurovascular blood vessel an injectable composition,wherein the injectable composition comprises water, one or more polycationic polyelectrolytes and anionic counterions and one or more one polyanionic polyelectrolytes and cationic counterions, wherein the composition has an ion concentration that is (i) sufficient to prevent association of the polycationic polyelectrolytes and the polyanionic polyelectrolytes in water and (ii) greater than the concentration of ions in the subject, whereupon introduction of the composition into the subject a solid is produced in situ.

[0162] Aspect 2. The method of Aspect 1 , wherein the injectable composition is introduced into the neurovascular blood vessel by a catheter having an inner diameter ofATTORNEY DOCKET NO.: 930601-21200.008 inches to 0.017 inches.

[0163] Aspect 3. The method of Aspect 1 or 2, wherein the injectable composition has a viscosity of less than 140 centipoise.

[0164] Aspect 4. The method of any one of Aspects 1 to 3, wherein the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent.

[0165] Aspect 5. The method of any one of Aspects 1 to 3, wherein the injectable composition penetrates to arteries and arterioles less than 10 pM in diameter in the vasculature bed of the target vessel, independent of delivery technique.

[0166] Aspect 6. The method of Aspect 5, wherein the injectable composition exhibits near complete to complete occlusion of the vessels within the vasculature bed to complete occlusion of the vessels and reduce the risk of recanalization.

[0167] Aspect 7. The method of any one of Aspects 1 to 6, wherein the injectable composition penetrates more completely (e.g., greater than 75%) the vasculature bed of the target vessel, independent of delivery technique.

[0168] Aspect 8. The method of any one of Aspects 1 to 7, wherein the injectable composition is introduced into the neurovascular blood vessel having a diameter greater than the diameter of the catheter, wherein the blood circulation carries the injectable composition into the vasculature bed.

[0169] Aspect 9. The method of any one of Aspects 1 to 8, wherein the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent.

[0170] Aspect 10. The method of any one of Aspects 1 to 9, wherein the neurovascular blood vessel is the middle meningeal artery (MMA).

[0171] Aspect 11. The method of any one of Aspects 1 to 9, wherein the neurovascular blood vessel supplies a brain tumor.

[0172] Aspect 12. The method of any one of Aspects 1 to 9, wherein the neurovascular blood vessel supplies a head, neck, or central nervous system tumor.ATTORNEY DOCKET NO.: 930601-2120

[0173] Aspect 13. The method of any one of Aspects 1 to 9, wherein the subject has a subdural hematoma.

[0174] Aspect 14. The method of any of Aspects 1 to 9, wherein the subject has a brain tumor.

[0175] Aspect 15. The method of any one of Aspects 1 to 9, wherein the method reduces or stops bleeding from the neurovascular blood vessel.

[0176] Aspect 16. An injectable composition comprises water, one or more polycationic polyelectrolytes and anionic counterions and one or more one polyanionic polyelectrolytes and cationic counterions, wherein the composition has an ion concentration that is (i) sufficient to prevent association of the polycationic polyelectrolytes and the polyanionic polyelectrolytes in water and (ii) greater than the concentration of ions in the subject, whereupon introduction of the composition into the subject a solid is produced in situ, whereinthe injectable composition has a viscosity of less than 110 centipoise, and the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent.

[0177] Aspect 17. The method and composition of any one of Aspects 1 to 16, wherein the counterions comprise sodium and chloride ions.

[0178] Aspect 18. The method and composition of any one of Aspects 1 to 17, wherein the ion concentration in the injectable composition is 1.5 to 20 times greater than the ion concentration in the subject.

[0179] Aspect 19. The method and composition of any one of Aspects 1 to 18, wherein the polycationic polyelectrolyte is derived by dissolving a polycationic salt in water.

[0180] Aspect 20. The method and composition of any one of Aspects 1 to 19, wherein the polycationic polyelectrolyte is derived from a polycationic hydrochloride salt in water.

[0181] Aspect 21. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a polyamine.

[0182] Aspect 22. The method and composition of Aspect 21 , wherein the polyamineATTORNEY DOCKET NO.: 930601-2120comprises two or more pendant amino groups, wherein the amino group comprises a primary amino group, a secondary amino group, tertiary amino group, a quaternary amine, an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazolyl, or an aromatic group substituted with one or more amino groups.

[0183] Aspect 23. The method and composition of Aspect 21, wherein the pharmaceutically-acceptable salt of the polyamine comprises a dendrimer having 3 to 20 arms, wherein each arm comprises a terminal amino group.

[0184] Aspect 24. The method and composition of Aspect 19, wherein the polycationic salt comprises a polyacrylate comprising two or more pendant amino groups, wherein the amino group comprises a primary amino group, a secondary amino group, tertiary amino group, a quaternary amine, an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazolyl, or an aromatic group substituted with one or more amino groups.

[0185] Aspect 25. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a biodegradable polyamine.

[0186] Aspect 26. The method and composition of Aspect 25, wherein the pharmaceutically-acceptable salt of the biodegradable polyamine comprises a polysaccharide, a protein, a peptide, a recombinant protein, a synthetic polyamine, a protamine, a branched polyamine, or an amine-modified natural polymer.

[0187] Aspect 27. The method and composition of Aspect 26, wherein the pharmaceutically-acceptable salt of the biodegradable polyamine comprises gelatin modified with an alkyldiamino compound.

[0188] Aspect 28. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a protamine.

[0189] Aspect 29. The method and composition of Aspect 19, wherein the polycationic salt is a pharmaceutically-acceptable salt of salmine or clupein.

[0190] Aspect 30. The method of Aspect 9, wherein the polycationic salt is a pharmaceutically-acceptable salt of natural polymer or a synthetic polymer containing two or more guanidinyl sidechains.

[0191] Aspect 31. The method and composition of Aspect 19, wherein the polycationicATTORNEY DOCKET NO.: 930601-2120salt comprises a pharmaceutically-acceptable salt of a polyacrylate comprising two or more pendant guanidinyl groups.

[0192] Aspect 32. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a homopolymer comprising pendant guanidinyl groups.

[0193] Aspect 33. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a copolymer comprising two or more pendant guanidinyl groups.

[0194] Aspect 34. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a synthetic polyguanidinyl copolymer comprising an acrylate, methacrylate, acrylamide, or methacrylamide backbone and two or more guanidinyl groups pendant to the backbone.

[0195] Aspect 35. The method and composition of Aspect 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a synthetic polyguanidinyl copolymer comprising the polymerization product between a monomer selected from the group consisting of an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof and a pharmaceutically-acceptable salt of compound of formula IATTORNEY DOCKET NO.: 930601-2120wherein R1is hydrogen or an alkyl group, X is oxygen or NR5, where R5is hydrogen or an alkyl group, and m is from 1 to 10.

[0196] Aspect 36. The method and composition of Aspect 35, wherein the polycationic salt comprises a copolymerization product between the compound of formula I and an acrylate, a methacrylate, an acrylamide, or a methacrylamide,

[0197] Aspect 37. The method and composition of Aspect 35, wherein the polycationic salt comprises a copolymerization product between the compound of formula I and methacrylamide, / V-(2-hydroxypropyl)methacrylamide (HPMA), / V-[3-( / V-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), / V-(3-aminopropyl)methacrylamide, A / -(1,3-dihydroxypropan-2-yl) methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof.

[0198] Aspect 38. The method and composition of Aspect 35, wherein R1is methyl, X is NH, m is 3.

[0199] Aspect 39. The method and composition of Aspect 35, wherein the mole ratio of the guanidinyl monomer of formula I to the comonomer is from 1:20 to 20:1.

[0200] Aspect 40. The method and composition of Aspect 35, wherein the polyguanidinyl copolymer has an average molar mass from 1 kDa to 1 ,000 kDa.

[0201] Aspect 41. The method and composition of any one of Aspects 1 to 40, wherein the polyanionic polyelectrolyte is derived by dissolving a polyanionic salt in water.

[0202] Aspect 42. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a synthetic polymer or a naturally-occurring polymer.

[0203] Aspect 43. The method and composition of Aspect 41 , wherein the polyanionic salt comprises two or more carboxylate, sulfate, sulfonate, borate, boronate, phosphonate, or phosphate groups.

[0204] Aspect 44. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a glycosaminoglycan or an acidic protein.ATTORNEY DOCKET NO.: 930601-2120

[0205] Aspect 45. The method and composition of Aspect 44, wherein the glycosaminoglycan comprises chondroitin sulfate, heparin, heparin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid.

[0206] Aspect 46. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a protein having a net negative charge at a pH of 6 or greater.

[0207] Aspect 47. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a polymer comprising anionic groups pendant to the backbone of the polymer, incorporated in the backbone of the polymer backbone, or a combination thereof.

[0208] Aspect 48. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a homopolymer or copolymer comprising two or more anionic groups.

[0209] Aspect 49. The method and composition of Aspect 41 , wherein the polyanionic salt is a copolymer comprising two or more fragments having the formula XIwherein R4is hydrogen or an alkyl group;n is from 1 to 10;Y is oxygen, sulfur, or NR30, wherein R30is hydrogen, an alkyl group, or an aryl group; Z’ is a pharmaceutically-acceptable salt of an anionic group.ATTORNEY DOCKET NO.: 930601-2120

[0210] Aspect 50. The method and composition of Aspect 49, wherein Z’ is carboxylate, sulfate, sulfonate, borate, boronate, a substituted or unsubstituted phosphate or phosphonate.

[0211] Aspect 51. The method and composition of Aspect 50, wherein n is 2.

[0212] Aspect 52. The method and composition of Aspect 41, wherein the polyanionic salt comprises a polyphosphate.

[0213] Aspect 53. The method and composition of Aspect 52, wherein the polyphosphate comprises a natural polymer or a synthetic polymer.

[0214] Aspect 54. The method and composition of Aspect 53, wherein the polyphosphate comprises polyphosphoserine.

[0215] Aspect 55. The method and composition of Aspect 53, wherein the polyphosphate comprises a polyacrylate comprising two or more pendant phosphate groups.

[0216] Aspect 56. The method and composition of Aspect 53, wherein the polyphosphate is the copolymerization product between a phosphate acrylate and / or phosphate methacrylate with one or more additional polymerizable monomers.

[0217] Aspect 57. The method and composition of Aspect 41, wherein the polyanionic salt has from 10 to 1,000 phosphate groups.

[0218] Aspect 58. The method and composition of Aspect 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of an inorganic polyphosphate, an organic polyphosphate, ora phosphorylated sugar.

[0219] Aspect 59. The method and composition of Aspect 58, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of inositol hexaphosphate.

[0220] Aspect 60. The method and composition of Aspect 58, wherein the polyanionic salt comprises a hexametaphosphate salt.

[0221] Aspect 61. The method and composition of Aspect 58, wherein the polyanionic salt comprises sodium hexametaphosphate.

[0222] Aspect 62. The method and composition of Aspect 41 , wherein the polyanionicATTORNEY DOCKET NO.: 930601-2120salt comprises a pharmaceutically-acceptable salt of cyclic inorganic polyphosphate, a linear inorganic polyphosphate, or a combination thereof.

[0223] Aspect 63. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a polyacrylate comprising two or more pendant phosphate groups.

[0224] Aspect 64. The method and composition of Aspect 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of the copolymerization product between a phosphate or phosphonate acrylate or phosphate or phosphonate methacrylate with one or more additional polymerizable monomers.

[0225] Aspect 65. The method and composition of any one of Aspects 1 to 64, wherein the composition further comprises a reinforcing component, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.

[0226] Aspect 66. The method and composition of Aspect 65, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.

[0227] Aspect 67. The method and composition of any one of Aspects 1 to 66, wherein the composition further comprises one or more bioactive agents, wherein the bioactive agent comprises an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, a receptor antagonist, a nucleic acid, a chemically-modified nucleic acid, or any combination thereof.

[0228] Aspect 68. The method and composition of any one of Aspects 1 to 67, wherein the total positive / negative charge ratio of the polycationic polyelectrolytes to the polyanionic polyelectrolytes is from 4 to 0.25 and the ion concentration in the composition is from 0.5 M to 2.0 M.

[0229] Aspect 69. The method and composition of any one of Aspects 1 to 68, wherein the concentration of the polycationic polyelectrolytes and the polyanionic polyelectrolytes is sufficient to yield a charge ratio of polycationic polyelectrolytes to polyanionicATTORNEY DOCKET NO.: 930601-2120polyelectrolytes from 0.5:1 to 2:1.

[0230] Aspect 70. The method and composition of any one of Aspects 1 to 69, wherein the composition has a pH of 6 to 9.

[0231] Aspect 71. The method and composition of any one of Aspects 1 to 70, wherein the composition further comprises a contrast agent.

[0232] Aspect 72. The method and composition of Aspect 71, wherein the contrast agent is a radiographic contrast agent.

[0233] Aspect 73. The method and composition of Aspect 71, wherein the contrast agent is tantalum metal particles, gold particles, or tantalum oxide particles.

[0234] Aspect 74. The method and composition of Aspect 71, wherein the contrast agent is a transient contrast agent.

[0235] Aspect 75. The method and composition of Aspect 74, wherein the transient contrast agent comprises an iodinated organic compound.

[0236] Aspect 76. The method and composition of Aspect 75, wherein the iodinated organic compound comprises iopamidol, iodixanol, iohexol, iopromide, iobtiridol, iomeprol, iopentol, iopamiron, ioxilan, iotrolan, iotrol and ioversol, iopanoate, diatrizoic acid, iothalamate, ioxaglate, or any combination thereof.

[0237] Aspect 77. The method and composition of Aspect 75, wherein the iodinated organic compound comprises an iodinated oil.

[0238] Aspect 78. The method and composition of any one of Aspects 71 to 77, wherein the concentration of the transient contrast agent in the injectable composition is from 10 mgl / mLto 1,000 mgl / mL.

[0239] Aspect 79. The method and composition of any one of Aspects 71 to 78, wherein up to 100% of the transient contrast agent diffuses out of the solid or gel from 5 minutes to 30 days.EXAMPLES

[0240] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions,ATTORNEY DOCKET NO.: 930601-2120and methods described herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. Numerous variations and combinations of reaction conditions, e.g. component concentrations, desired solvents, solvent mixtures, temperatures, pressures, and other reaction ranges and conditions can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0241] Example 1

[0242] Preparation of Poly N-(3-methacrylaminopropyl) guanidinium chloride (pGPMA-HCI)

[0243] A flask was charged with / V-(3-aminopropyl) methacrylamide hydrochloride (APMA-HCI) and the inhibitor 4-methoxyphenol (1 wt.%, relative to APMA). DMF was added to dissolve APMA HCI at a concentration of 1 M. Triethylamine (TEA) (2.5 equivalents) was added to the flask and the mixture was stirred for 5 minutes under N2before 1H-pyrazole-1-carboxamidine hydrochloride (1 equivalent) was added. The reaction proceeded at 20°C under N2. After 16 h, TEA- HCI salts were separated from the reaction mixture by vacuum filtration. The GPMA monomer was extracted with diethyl ether 4 times and recovered as a dense oil. Finally, the monomer was dried under vacuum. The product was confirmed by proton and carbon NMR.1H NMR (400 MHz, D2O): 5 (ppm) 1.68 (q, CH2-CH2- CH2), 1.77 (s, CH3), 3.08 (m, CH2-N), 3.18 (m, CH2-N), 5.30 (s, =CH2), 5.55 (s, =CH2).13C NMR: (400 MHz, D2O) 6 (ppm) 17.74 (CH3), 27.62 (CH2), 36.62 (CH2-N), 38.71 (CH2-N), 121.13 (C=CH2), 138.83 (CH2=C), 156.6 2(C), 171.55 (C=O). Formation of GPMA was also verified by ESI mass spectroscopy (185.1 Da).

[0244] A random copolymer of GPMA- HCI and methacrylamide (MA) was synthesized by free radical polymerization with a molar feed ratio of 60:40 (GPMA:MA). GPMA HCI and MA monomers were dissolved in a 60:40 v:v water methanol mixture at a totalATTORNEY DOCKET NO.: 930601-2120monomer concentration of 1 M. 4,4'-Azobis(4-cyanovaleric acid was added as the initiator at 1-5% (w:v), depending on the desired molecular weight. The resulting mixture was septum sealed and degassed by bubbling for 1 hr with N2. The reaction proceeded under N2. The temperature was varied from 70-82° C depending on the target Mw. The resulting solution was cooled, exposed to air, the polymer precipitated in acetone, then dissolved in water. The pH of the solution was adjusted to less than pH 6 using HCI. The polymer was purified by tangential flow filtration with deionized water. This process formed the hydrochloride salt at approximately a 1 :1 stochiometric ratio of guanidinium to HCI. The polymer Mwwas characterized by aqueous size exclusion chromatography (SEC) on an Aglient HPLC 1260 Infinity equipped with refractive index detector and a Wyatt miniDAWN TREOS light scattering detector. An elutent of 1 wt% acetic acid in 0.1 M LiBr (pH=3.3) was run at 1 mL / min on an Eprogen CATSEC 300 column. For Mwanalysis using light scattering, the dn / dc value for p(GPMA-co-MA) was determined by injecting known stock solutions of PG ranging from 0.25-2 mg / mL at 1 mL / min into the Wyatt miniDAWN TREOS light scattering detector and measuring changes in intensity in response to concentration. The mole percent (mol%) GPMA was determined by relative integration of the CH2-N groups (5=2.8-3.2 ppm) on GPMA (4 total H) and the saturated hydrocarbon groups (5=0.4-2.2 ppm) in the polymer backbone (5 total H’s on both GPMA and MA) and polymer sidechain (2 H’s on GPMA).

[0245] P(GPMA-HCI) was also synthesized using an alternative method with equivalent results. First, a random copolymer of A / -(3-aminopropyl) methacrylamide hydrochloride (APMA HCI) and methacrylamide (MA) was synthesized by free radical polymerization at a fixed molar feed ratio of 60:40 (APMA:MA). The APMA-HCI and MA monomers were dissolved in a 60:40 v:v water methanol mixture at a total monomer concentration of 1 M. 4,4'-Azobis(4-cyanovaleric acid was added as the initiator at 1-5% (w:v), depending on the targeted polymer molecular weight. Reactions were done under N2, with the reaction temperature varied from 70-82°C, depending on the target polymer Mw. The resulting solution was cooled, exposed to air, the p(APMA-co-MA-HCI) copolymer precipitated in acetone, then dissolved in water. Second, the sidechain primary amines of the p(APMA-co-MA) HCI copolymer were converted to guanidinium groups. The copolymer, p(APMA HCI -co-MA), was dissolved in water at a concentration of ~1 M. 1H-ATTORNEY DOCKET NO.: 930601-2120pyrazole-1-carboxamidine hydrochloride (1.15 equivalents relative to initial APMA) was added. Sodium carbonate was added to raise the pH of the reaction mixture to ~9. The reaction proceeded for 14-28 hrs under N2at 25°C. Conversion of the APMA HCI side chains to GPMA HCI was >99% as determined using1H NMR. The product was then acidified to pH<6 with HCI, and tangential flow filtration with deionized water was used to purify the copolycation and associated counterions prior to lyophilization to produce the dry Cl- salt with approximately a 1 :1 stoichiometric ratio of Cl- ions to guanidinium+sidechains.

[0246] Preparation of Sodium Hexametaphosphate

[0247] Commercial sodium hexametaphosphate (NanMP) is a mixture of inorganic phosphate oligomers in sodium salt form, both cyclic and linear, usually containing 10-20 phosphorous atoms per chain [40-43], In their fully ionized form, cyclic inorganic polyphosphates have the formula (PnO3n)n_, while the linear form comprises (PnO3n+i)n+2'. Regardless of the whether the polyphosphate is linear or cyclic, each phosphorus atom has one weakly associated proton, with a pKa of ~4.5 or less [40,44], The end group protons of linear polyphosphates are dissociated between pH 4.5 and 9.5. Therefore, the charge density of NanMP at physiological pH (7.2-7.4) was calculated as one negative charge per phosphorous atom. Commercial NanMP was pH adjusted to 8.3-8.7 before preparation of the injectable composition.

[0248] Preparation of Injectable Compositions

[0249] Solutions of (poly)GPMA HCIn-co-MA (PG-HCIn) and sodium hexametaphosphate (NanMP) were prepared by the addition of water to a mixture of dry PG HCln and NanMP salts. Sequentially dissolving the polymers before mixing, as an alternative preparation method, resulted in final compositions with equivalent properties. Unless otherwise noted, solutions were prepared with 1 :1 polymeric charge ratios, corresponding to a 2.65:1 PG-HCInto NanMP mass ratio. Solutions were prepared in which the PG-HCInconcentrations were varied from 300-750 mg / mL using PG-HCIncopolymers with average molecular weights (Mw) ranging from 19 to 53 kDa. The Cl- and. Na+concentrations of the solutions can be calculated from the concentrations (mol / L) and charge densities (mol / g) of the polymeric salts, PG-HCInand NanMP, respectively.ATTORNEY DOCKET NO.: 930601-2120Compositions with different amounts (poly)GPMA HCIn-co-MA (PG-HCIn) and sodium hexametaphosphate (NanMP) were prepared and evaluated.

[0250] Liquid State Properties

[0251] Viscosities of injectable compositions (ICs) were measured at 25° C using a Brookfield Amrtek DV2T Viscometer with a small sample cup adaptor and CPA-41Z spindle. All solutions were prepared with NanMP at a 1:1 polymeric charge ratio. The viscosity of the ICs ranged from 50 cP to 350 cP and increased with the amount of (PG-HCIn) present in the composition (Figure 1).

[0252] Referring to Figure 1, a solution viscosity of less than 110 cP viscosity is required to for delivery through a common 150 cm, 0.016” inner diameter neurovascular catheter at clinically relevant delivery rates. A solution viscosity of less than 45 cP viscosity is required for delivery through a common 150cm, 0.013” inner diameter neurovascular catheter at clinically relevant delivery rates. Figure 1 demonstrates that to achieve a viscosity of less than 110 cP, the polymer content is less than 55 weight percent.

[0253] Degree of Occlusion and Distal Penetration Studies

[0254] The magnitude of occlusion of the arterial lumen of all examined materials was assessed based on the relative filling of the arterial lumen by the embolized material, and / or its proximate apposition to the arterial wall, and by the presence of residual red blood cells (RBCs) within the lumen of the treated artery, which could imply RBC ‘entrapment’ in the interstices of the embolized material and / or evidence of continued, active ‘blood flow’ through the embolized artery.

[0255] The injectable composition (IC) described herein occludes (i.e., mostly to completely occluded) the lumen of the treated arteries / branches (FIG. 5). The injectable composition exhibited an overall (i.e., on average) increased luminal occlusion compared to NBCA: Lipiodol (Control), which was also frequently associated with the presence of residual RBCs amongst the embolized material. The injectable composition occluded vessels through each zone similarly (i.e., similar incidence of complete occlusion scores) with > 90% of vessels observed to be near completely to completely occluded, regardless of material (Figure 2 and Table 1). In Zone 1, near complete-to-complete occlusion was observed in 90% of vessels treated with the injectable composition. Vessels treated withATTORNEY DOCKET NO.: 930601-2120injectable composition exhibited near-complete to complete occlusion (98%) in both Zone 2 and Zone 3. Comparatively, NBCA: Lipiodol and Onyx-18 materials exhibited less near complete to complete of the vessels in more distal zones (i.e., Zone 2 and Zone 3) and a generally decreased incidence of complete occlusion in the more distal zones as well.Table 1Arterial Occlusion Scores by ZoneTable 2ATTORNEY DOCKET NO.: 930601-2120

[0256] The injectable composition described herein can embolize the distal aspect of the renal cortical vasculature (Table 2). The composition after administration was observed in arterial vasculature having an inner diameter of less than 10 pm, including the afferent arterioles of the glomerulus and / or within the glomerular vasculature (FIG. 4). NBCA-Lipiodol and Onyx-18 materials were not observed in distal cortical arterial vasculature with an inner diameter of less than 40 pm.Table 3

[0257] Example 2

[0258] Swine kidney in-vivo distal penetration study

[0259] Solutions of (poly)GPMA HCIn-co-MA (PG-HCIn) and sodium hexametaphosphate (NanMP) were prepared by the addition of water to a mixture of dry PG HCIn and NanMP salts. IC-LV represents 400 mg / mL PG HCIn and 151 mg / mL NanMP salt and IC-HV represents 500 mg / mL PG HCInand 189 mg / mL NanMP salt. 20mg / mL of dry sodium chloride (NaCI) was dissolved to provide additional Ch and Na+for the 350 mg / mL PG-HCInsolution and 30% weight dry tantalum powder <5 pm was added to all solutions for radiopacity.

[0260] IC-HV and IC-LV were compared to 40 pm Embozene in-vivo using a swineATTORNEY DOCKET NO.: 930601-2120kidney model. Two domestic swine weighing 35-55 kg underwent general anesthesia and the femoral artery was catheterized to gain access to the renal arterial vasculature. Solutions were delivered via microcatheter into distinct regions of the renal arterial vasculature by the surgeon. Following surgery, animals were euthanized, and the kidneys were fixed in 10% neutral buffered formalin. The kidneys were evaluated by a board-certified veterinary pathologist for degree of arterial occlusion.

[0261] To characterize the distal penetration of the different materials examined, the following steps were performed. First, the kidney sections were divided into three (3) anatomically based zones as approximated in Figure 2. Given the general inversely proportional relationship between arterial size and distance from the hilum, these zones were determined to reflect the overall distal penetration of the products considered.

[0262] IC-LV and IC-HV predominantly associated with complete occlusion of the vascular lumen of treated arteries which was overall (i.e., on average) mildly increased relative to the Embozene treated arteries (Table 4 and Figure 5).Table 4

[0263] An IC described herein was compared to Onyx-18 in the swine middle meningeal artery (MMA). The IC is composed of (poly)GPMA HCIn-co-MA (PG-HCIn) and sodium hexametaphosphate (NanMP) and was prepared by the addition of water to aATTORNEY DOCKET NO.: 930601-2120mixture of dry PG HCIn and NanMP salts, 350 mg / mL PG HCIn and 132 mg / mL NanMP salt. 20mg / ml_ of dry sodium chloride (NaCI) was dissolved to provide additional Ck and Na+and 30% weight dry T antalum powder <5 pm was added to all solutions for radiopacity.

[0264] Animals were anesthetized and femoral artery access was obtained. Heparin was administered with a target ACT of 250-350 seconds. IC and Onyx-18 were delivered into either the right or left swine MMA and the extent of embolization and targeted occlusion was determined by the surgeon. Following a 12-14 day recovery the animals were terminated and tissues were harvested and preserved in 10% neutral buffered formalin. The dura matter and adjacent brain were evaluated by a board-certified veterinary pathologist.

[0265] Figure 4 shows a variety of artery sizes (0.03mm - 0.60mm) are filled with injectable composition described herein. All 3 animals treated with the injectable composition exhibited embolization down to arteries sized 0.03 mm - 1.2 mm in diameter compared to Onyx-18 (0.25mm - 1.3mm diameter. The injectable composition exhibited distal penetration into 5x smaller arteries than Onyx-18.

[0266] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the compounds, compositions, and methods described herein.

[0267] Various modifications and variations can be made to the compounds, compositions, and methods described herein. Other aspects of the compounds, compositions, and methods described herein will be apparent from consideration of the specification and practice of the compounds, compositions, and methods disclosed herein. It is intended that the specification and examples be considered as exemplary.

Claims

ATTORNEY DOCKET NO.: 930601-2120What is claimed:

1. A method for reducing or preventing blood flow in a neurovascular blood vessel of a subject comprising introducing into the neurovascular blood vessel an injectable composition,wherein the injectable composition comprises water, one or more polycationic polyelectrolytes and anionic counterions and one or more polyanionic polyelectrolytes and cationic counterions, wherein the composition has an ion concentration that is (i) sufficient to prevent association of the polycationic polyelectrolytes and the polyanionic polyelectrolytes in water and (ii) greater than the concentration of ions in the subject, whereupon introduction of the composition into the subject a solid is produced in situ.

2. The method of claim 1, wherein the injectable composition is introduced into the neurovascular blood vessel by a catheter having an inner diameter of 0.008 inches to 0.017 inches.

3. The method of claim 1, wherein the injectable composition has a viscosity of less than 140 centipoise.

4. The method of claim 1, wherein the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent.

5. The method of claim 1, wherein the injectable composition penetrates to arteries and arterioles less than 10 pM in diameter in the vasculature bed of the target vessel, independent of delivery technique.

6. The method of claim 5, wherein the injectable composition exhibits near complete to complete occlusion of the vessels within the vasculature bed to complete occlusion of the vessels and reduce the risk of recanalization.

7. The method of claim 1, wherein the injectable composition penetrates more completely the vasculature bed of the target vessel, independent of delivery technique.ATTORNEY DOCKET NO.: 930601-21208. The method of claim 1, wherein the injectable composition is introduced into the neurovascular blood vessel having a diameter greater than the diameter of the catheter, wherein the blood circulation carries the injectable composition into the vasculature bed.

9. The method of claim 1, wherein the sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent.

10. The method of claim 1 , wherein the neurovascular blood vessel is the middle meningeal artery (MMA).

11. The method of claim 1 , wherein the neurovascular blood vessel supplies a brain tumor.

12. The method of claim 1 , wherein the neurovascular blood vessel supplies a head, neck, or central nervous system tumor.

13. The method of claim 1 , wherein the subject has a subdural hematoma.

14. The method of claim 1 , wherein the subject has a brain tumor.

15. The method of claim 1 , wherein the method reduces or stops bleeding from the neurovascular blood vessel.

16. An injectable composition comprising water, one or more polycationic polyelectrolytes and anionic counterions and one or more one polyanionic polyelectrolytes and cationic counterions, wherein the composition has an ion concentration that is (i) sufficient to prevent association of the polycationic polyelectrolytes and the polyanionic polyelectrolytes in water and (ii) greater than the concentration of ions in the subject, whereupon introduction of the composition into the subject a solid is produced in situ, whereinthe injectable composition has a viscosity of less than 110 centipoise, andthe sum of the polycationic polyelectrolytes and polyanionic polyelectrolytes in the injectable composition is less than 55 weight percent.ATTORNEY DOCKET NO.: 930601-212017. The method and composition of any one of claims 1 to 16, wherein the counterions comprise sodium and chloride ions.

18. The method and composition of any one of claims 1 to 16, wherein the ion concentration in the injectable composition is 1.5 to 20 times greater than the ion concentration in the subject.

19. The method and composition of any one of claims 1 to 16, wherein the polycationic polyelectrolyte is derived by dissolving a polycationic salt in water.

20. The method and composition of any one of claims 1 to 16, wherein the polycationic polyelectrolyte is derived from a polycationic hydrochloride salt in water.

21. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a polyamine.

22. The method and composition of claim 21, wherein the polyamine comprises two or more pendant amino groups, wherein the amino group comprises a primary amino group, a secondary amino group, tertiary amino group, a quaternary amine, an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazolyl, or an aromatic group substituted with one or more amino groups.

23. The method and composition of claim 21 , wherein the pharmaceutically- acceptable salt of the polyamine comprises a dendrimer having 3 to 20 arms, wherein each arm comprises a terminal amino group.

24. The method and composition of claim 19, wherein the polycationic salt comprises a polyacrylate comprising two or more pendant amino groups, wherein the amino group comprises a primary amino group, a secondary amino group, tertiary amino group, a quaternary amine, an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazolyl, or an aromatic group substituted with one or more amino groups.

25. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a biodegradable polyamine.ATTORNEY DOCKET NO.: 930601-212026. The method and composition of claim 25, wherein the pharmaceutically- acceptable salt of the biodegradable polyamine comprises a polysaccharide, a protein, a peptide, a recombinant protein, a synthetic polyamine, a protamine, a branched polyamine, or an amine-modified natural polymer.

27. The method and composition of claim 26, wherein the pharmaceutically- acceptable salt of the biodegradable polyamine comprises gelatin modified with an alkyldiamino compound.

28. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a protamine.

29. The method and composition of claim 19, wherein the polycationic salt is a pharmaceutically-acceptable salt of salmine or clupein.

30. The method of claim 9, wherein the polycationic salt is a pharmaceutically- acceptable salt of natural polymer or a synthetic polymer containing two or more guanidinyl sidechains.

31. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a polyacrylate comprising two or more pendant guanidinyl groups.

32. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a homopolymer comprising pendant guanidinyl groups.

33. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a copolymer comprising two or more pendant guanidinyl groups.

34. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a synthetic polyguanidinyl copolymer comprising an acrylate, methacrylate, acrylamide, or methacrylamide backbone and two or more guanidinyl groups pendant to the backbone.ATTORNEY DOCKET NO.: 930601-212035. The method and composition of claim 19, wherein the polycationic salt comprises a pharmaceutically-acceptable salt of a synthetic polyguanidinyl copolymer comprising the polymerization product between a monomer selected from the group consisting of an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof and a pharmaceutically-acceptable salt of compound of formula Iwherein R1is hydrogen or an alkyl group, X is oxygen or NR5, where R5is hydrogen or an alkyl group, and m is from 1 to 10.

36. The method and composition of claim 35, wherein the polycationic salt comprises a copolymerization product between the compound of formula I and an acrylate, a methacrylate, an acrylamide, or a methacrylamide,37. The method and composition of claim 35, wherein the polycationic salt comprises a copolymerization product between the compound of formula I and methacrylamide, A / -(2-hydroxypropyl)methacrylamide (HPMA), / V-[3-( / \f- dicarboxymethyl)aminopropyl]methacrylamide (DAMA), N-(3- aminopropyl)methacrylamide, A / -(1 ,3-dihydroxypropan-2-yl) methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof.ATTORNEY DOCKET NO.: 930601-212038. The method and composition of claim 35, wherein R1is methyl, X is NH, m is 3.

39. The method and composition of claim 35, wherein the mole ratio of the guanidinyl monomer of formula I to the comonomer is from 1 :20 to 20:

1.

40. The method and composition of claim 35, wherein the polyguanidinyl copolymer has an average molar mass from 1 kDa to 1 ,000 kDa.

41. The method and composition of any one of claims 1 to 16, wherein the polyanionic polyelectrolyte is derived by dissolving a polyanionic salt in water.

42. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a synthetic polymer or a naturally-occurring polymer.

43. The method and composition of claim 41, wherein the polyanionic salt comprises two or more carboxylate, sulfate, sulfonate, borate, boronate, phosphonate, or phosphate groups.

44. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a glycosaminoglycan or an acidic protein.

45. The method and composition of claim 44, wherein the glycosaminoglycan comprises chondroitin sulfate, heparin, heparin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid.

46. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a protein having a net negative charge at a pH of 6 or greater.

47. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a polymer comprising anionic groups pendant to the backbone of the polymer, incorporated in the backbone of the polymer backbone, or a combination thereof.ATTORNEY DOCKET NO.: 930601-212048. The method and composition of claim 41 , wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a homopolymer or copolymer comprising two or more anionic groups.

49. The method and composition of claim 41 , wherein the polyanionic salt is a copolymer comprising two or more fragments having the formula XIwherein R4is hydrogen or an alkyl group;n is from 1 to 10;Y is oxygen, sulfur, or NR30, wherein R30is hydrogen, an alkyl group, or an aryl group;Z’ is a pharmaceutically-acceptable salt of an anionic group.

50. The method and composition of claim 49, wherein Z’ is carboxylate, sulfate, sulfonate, borate, boronate, a substituted or unsubstituted phosphate or phosphonate.

51. The method and composition of claim 50, wherein n is 2.

52. The method and composition of claim 41 , wherein the polyanionic salt comprises a polyphosphate.

53. The method and composition of claim 52, wherein the polyphosphate comprises a natural polymer or a synthetic polymer.ATTORNEY DOCKET NO.: 930601-212054. The method and composition of claim 53, wherein the polyphosphate comprises polyphosphoserine.

55. The method and composition of claim 53, wherein the polyphosphate comprises a polyacrylate comprising two or more pendant phosphate groups.

56. The method and composition of claim 53, wherein the polyphosphate is the copolymerization product between a phosphate acrylate and / or phosphate methacrylate with one or more additional polymerizable monomers.

57. The method and composition of claim 41 , wherein the polyanionic salt has from 10 to 1 ,000 phosphate groups.

58. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of an inorganic polyphosphate, an organic polyphosphate, or a phosphorylated sugar.

59. The method and composition of claim 58, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of inositol hexaphosphate.

60. The method and composition of claim 58, wherein the polyanionic salt comprises a hexametaphosphate salt.

61. The method and composition of claim 58, wherein the polyanionic salt comprises sodium hexametaphosphate.

62. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of cyclic inorganic polyphosphate, a linear inorganic polyphosphate, or a combination thereof.

63. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of a polyacrylate comprising two or more pendant phosphate groups.

64. The method and composition of claim 41, wherein the polyanionic salt comprises a pharmaceutically-acceptable salt of the copolymerization product between a phosphate or phosphonate acrylate or phosphate or phosphonate methacrylate with one or more additional polymerizable monomers.ATTORNEY DOCKET NO.: 930601-212065. The method and composition of any one of claims 1 to 16, wherein the composition further comprises a reinforcing component, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.

66. The method and composition of claim 65, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.

67. The method and composition of any one of claims 1 to 16, wherein the composition further comprises one or more bioactive agents, wherein the bioactive agent comprises an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, a receptor antagonist, a nucleic acid, a chemically-modified nucleic acid, or any combination thereof.

68. The method and composition of any one of claims 1 to 16, wherein the total positive / negative charge ratio of the polycationic polyelectrolytes to the polyanionic polyelectrolytes is from 4 to 0.25 and the ion concentration in the composition is from 0.5 M to 2.0 M.

69. The method and composition of any one of claims 1 to 16, wherein the concentration of the polycationic polyelectrolytes and the polyanionic polyelectrolytes is sufficient to yield a charge ratio of polycationic polyelectrolytes to polyanionic polyelectrolytes from 0.5:1 to 2:1.

70. The method and composition of any one of claims 1 to 16, wherein the composition has a pH of 6 to 9.

71. The method and composition of any one of claims 1 to 16, wherein the composition further comprises a contrast agent.

72. The method of claim 71 , wherein the contrast agent is a radiographic contrast agent.ATTORNEY DOCKET NO.: 930601-212073. The method of claim 71 , wherein the contrast agent is tantalum metal particles, gold particles, or tantalum oxide particles.

74. The method of claim 71, wherein the contrast agent is a transient contrast agent.

75. The method of claim 74, wherein the transient contrast agent comprises an iodinated organic compound.

76. The method of claim 75, wherein the iodinated organic compound comprises iopamidol, iodixanol, iohexol, iopromide, iobtiridol, iomeprol, iopentol, iopamiron, ioxilan, iotrolan, iotrol and ioversol, iopanoate, diatrizoic acid, iothalamate, ioxaglate, or any combination thereof.

77. The method of claim 75, wherein the iodinated organic compound comprises an iodinated oil.

78. The method of claim 71, wherein the concentration of the transient contrast agent in the injectable composition is from 10 mgl / mLto 1,000 mgl / mL.

79. The method of claim 71, wherein up to 100% of the transient contrast agent diffuses out of the solid or gel from 5 minutes to 30 days.

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