Hydrolysis-resistant hydrogels and methods of treatment using the same

Abstract

In some aspects, the present disclosure provides systems for forming a hydrogel comprising (i) a reactive multi-arm polymer comprising three or more polymer arms linked to a core region, each arm comprising a polyether segment and a reactive moiety comprising a cyclic imide carboxy-C1-C5-alkyl ester end group, or each arm comprising a polyether segment and a reactive moiety comprising a C2-C6- isocyanoalkyl end group, and (ii) a polyamino compound comprising at least two amino groups (-NH2), wherein the reactive multi-arm polymer and the polyamino compound react to form a crosslinked hydrogel that is free of ester groups and has long-term stability in vivo. In some aspects, the present disclosure provides therapeutic methods using such systems and hydrolysis-resistant crosslinked hydrogels formed from such systems.

Description

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 567,758, filed March 20, 2024, the disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to hydrolysis-resistant hydrogels, crosslinkable systems for forming such hydrolysis-resistant hydrogels, and treatment methods using such hydrolysis-resistant hydrogels. Background Technology

[0003] SpaceOAR® is a rapidly crosslinked hydrogel that polymerizes in vivo within seconds. It is based on a multi-arm polyethylene glycol (PEG) polymer with a polyol core, functionalized with succinimidyl glutarate as a reactive end group, which then reacts with trilysine to form a crosslink. This product has become a highly successful clinical biomaterial in prostate cancer treatment. A further improvement to this structure is the replacement of a portion of the succinimidyl glutarate end group with a 2,3,5-triiodobenzamide group, thereby providing radiopacity. This hydrogel, known by the trade name SpaceOAR Vue®, is a radiopaque version of SpaceOAR® for prostate medical applications. Above a specific pH, the succinimidyl glutarate groups of SpaceOAR® and SpaceOAR Vue® react rapidly in vivo with a trilysine crosslinking agent to form a hydrogel. The hydrogel decomposes in vivo within approximately 6–9 months. This decomposition primarily occurs through the hydrolysis of the ester bonds in the glutarate groups.

[0004] This disclosure provides implantable hydrogel alternatives to SpaceOAR® and SpaceOAR Vue® that are hydrolysis resistant and have long-term stability, thereby expanding the range of medical applications for hydrogels. Summary of the Invention

[0005] In some aspects, this disclosure provides a system for forming a hydrogel comprising (i) a reactive multi-arm polymer comprising three or more polymer arms connected to a core region, each arm comprising a polyether segment and a reactive portion comprising a cyclic imide carboxyl-C1-C5-alkyl ester end group, or each arm comprising a polyether segment and a reactive portion comprising a C2-C6-isocyanoalkyl end group, and (ii) a polyamine compound comprising at least two amino groups (-NH2), wherein the reactive multi-arm polymer and the polyamine compound react to form an ester-free crosslinked hydrogel that has long-term stability in vivo.

[0006] In some embodiments, the reactive portion is a cyclic imide carboxyl-C1-C5-alkyl ester group or a C2-C6-isocyanoalkyl group, and the reactive portion is directly bonded to the polyether segment.

[0007] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the reactive multi-arm polymer is formed from a multi-arm polymer comprising three or more polymer arms connected to a core region, each arm comprising a polyether segment and a C2-C6-hydroxyalkyl end group. In some of these embodiments, the reactive multi-arm polymer is formed by a method comprising: oxidizing the C2-C6-hydroxyalkyl end group to form a C2-C6-carboxyalkyl end group, and reacting the C2-C6-carboxyalkyl end group with an N-hydroxycyclic imide compound in an ester coupling reaction to form a cyclic imide carboxy-C1-C5-alkyl ester end group. In some of these embodiments, the reactive multi-arm polymer is formed by a method comprising: converting the C2-C6-hydroxyalkyl end group to a C2-C6-aminoalkyl end group, and reacting the C2-C6-aminoalkyl end group with phosgene to form a C2-C6-isocyanoalkyl end group.

[0008] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the polyether segment is a polyoxyethylene segment.

[0009] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the C2-C6-isocyanoalkyl terminal group is an isocyanoethyl terminal group.

[0010] In some embodiments that can be used in conjunction with the above aspects and embodiments, the cyclic imide carboxyl-C1-C5-alkyl ester end group is a cyclic imide carboxylmethyl ester end group. In a specific embodiment, the cyclic imide carboxyl-C1-C5-alkyl ester end group is a succinimide carboxylmethyl ester end group.

[0011] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, each polyether segment contains 10 to 1000 monomer residues.

[0012] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the core region comprises polyol residues.

[0013] In some implementation schemes that can be used in conjunction with the above aspects and implementation schemes, the core region is an iodination core region.

[0014] In some embodiments that can be used in conjunction with the above aspects and embodiments, the polyamino compound comprises a plurality of basic amino acid residues.

[0015] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the polyamino compound is an iodinated polyamino compound.

[0016] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the system includes a first composition comprising the polyamine compound in a first container and a second composition comprising the reactive multi-arm polymer in a second container. In some of these embodiments, the first and second containers are independently selected from vials and syringes. In some of these embodiments, the first container is a syringe and the second container is a vial.

[0017] In some embodiments that can be used in conjunction with the foregoing aspects and implementations, the system further includes a delivery device. In some of these embodiments, the delivery device is a dual-tube syringe.

[0018] In other respects, this disclosure relates to hydrolysis-resistant crosslinked hydrogels produced by systems according to any of the foregoing aspects and embodiments.

[0019] In some embodiments, the radiation-resistant crosslinked hydrogel has a radiation impermeability greater than 100 Hounsfield units (HU).

[0020] In some embodiments that can be used in conjunction with the above aspects and implementations, the hydrolysis-resistant crosslinked hydrogel is in particulate form, which can be delivered, for example, from a single syringe tube in suspension form.

[0021] In some aspects, this disclosure relates to a treatment method comprising administering to a subject a mixture comprising: (i) a reactive multi-arm polymer comprising three or more polymer arms connected to a core region, each arm comprising a polyether segment and a reactive moiety comprising a cyclic imide carboxyl-C1-C5-alkyl ester end group, or each arm comprising a polyether segment and a reactive moiety comprising a C2-C6-isocyanoalkyl end group, and (ii) a polyamino compound comprising at least two amino groups (-NH2), wherein the mixture is administered under conditions such that the polyamino compound and the reactive multi-arm polymer react upon administration to form a crosslinked hydrogel, and wherein the crosslinked hydrogel is ester-free and has long-term stability in vivo.

[0022] In some embodiments, the method includes administering to a subject: (a) a first fluid composition comprising the polyamine compound and the reactive multi-arm polymer, wherein the reactive portion comprises a cyclic imide carboxyl-C1-C5-alkyl ester end group; and (b) a second fluid composition comprising a promoter that accelerates the reaction between the polyamine compound and the reactive multi-arm polymer. In some of these embodiments, the first fluid composition and the second fluid composition are delivered using a dual-tube syringe.

[0023] In some embodiments, the method includes administering to a subject: (a) a first fluid composition comprising the polyamine compound and a non-aqueous solvent, and (b) a second fluid composition comprising the reactive multi-arm polymer and a non-aqueous solvent, wherein the reactive portion comprises the C2-C6-isocyanoalkyl terminal group. In some of these embodiments, the first fluid composition and the second fluid composition are delivered using a dual-tube syringe.

[0024] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the mixture is injected into the body's sphincter muscles.

[0025] In some embodiments that can be used in conjunction with the foregoing aspects and implementations, the mixture is injected into the urethral sphincter. In some of these embodiments, the mixture is injected into the bladder neck of the subject via a transurethral route through the urethral wall.

[0026] The above and other aspects, implementations, features and benefits of this disclosure will become apparent from the following detailed description. Attached Figure Description

[0027] Figure 1 The formation of an 8-arm PEG with a hydroxyl-terminated core of a tripentaerythritol residue is schematically illustrated according to one embodiment of the present disclosure.

[0028] Figure 2 The formation of a hydroxyl-terminated 3-arm PEG having a 1,3,5-triiodo-2,4,6-tri-hydroxymethylbenzene residue core is schematically illustrated according to one embodiment of the present disclosure.

[0029] Figure 3 The formation of a succinimide-carboxymethyl ester-terminated multi-arm PEG according to one embodiment of the present disclosure is illustrated schematically.

[0030] Figure 4 The formation of an isocyanomethyl-terminated multiarm PEG according to one embodiment of the present disclosure is illustrated schematically.

[0031] Figure 5The diagram schematically illustrates the formation of a crosslinked polymer network by reacting trilysine with succinimide-carboxymethyl ester-terminated eight-arm PEG according to one embodiment of the present disclosure.

[0032] Figure 6 A delivery device according to one embodiment of the present disclosure is illustrated schematically.

[0033] Figure 7A and 7B The illustration schematically depicts the injection of a cross-linked polymer network into the bladder neck of a patient according to one embodiment of the present disclosure.

[0034] Figure 8 A delivery device according to another embodiment of this disclosure is shown. Detailed Implementation

[0035] In some aspects of this disclosure, a hydrolysis-resistant hydrogel is provided, comprising (a) a crosslinking reaction product of a polyamine compound and (b) a reactive polymer, the reactive polymer comprising a reactive moiety capable of reacting with the amino group of the polyamine compound, wherein the crosslinking reaction product is free of esters or other easily hydrolyzed groups that would cause the crosslinking reaction product to decompose after implantation. Such a hydrogel exhibits long-term stability after implantation, opening up a variety of medical applications.

[0036] As used herein, a "hydrogel" is a cross-linked polymer that contains or can absorb water but does not dissolve when placed in water. As used herein, an implanted hydrogel is considered to have "long-term stability" if it undergoes less than 25 wt%, preferably less than 10 wt%, of bioreabsorption within at least 5 years, preferably 10 years, after implantation in a subject.

[0037] The reactive polymers used in this disclosure include reactive multi-arm polymers comprising a plurality of polymer arms connected to a core region, wherein said polymer arms comprise hydrophilic polymer segments. In some embodiments, a first end of the hydrophilic polymer segment is covalently connected to the core region, and a reactive portion is covalently connected to a second end (opposite end) of the hydrophilic polymer segment.

[0038] The reactive polymers according to this disclosure include polymers having 3 to 100 arms (e.g., any value in the range of 3 to 4 to 5 to 6 to 7 to 8 to 10 to 12 to 15 to 20 to 25 to 50 to 75 to 100 arms).

[0039] The reactive portion includes a portion containing an electrophilic group and a portion containing an isocyanate group.

[0040] The electrophilic group can be selected from, for example, cyclic imide ester groups (e.g., succinimide ester groups, Maleimide ester group, glutarimide ester group, diethylene glycol imide ester group, phthalimide ester group and bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide ester group, ), imidazole ester group, imidazole carboxylic ester group and benzotriazole ester group, etc.

[0041] Electrophilic groups or isocyanate groups can be attached to hydrophilic polymer segments through any suitable hydrolysis-resistant linker, which may be selected from, for example, linkers containing C1-C6 alkyl groups, linkers containing ether groups, linkers containing amide groups, linkers containing urethan groups, linkers containing urea groups, or linkers containing a combination of two or more of the aforementioned groups.

[0042] In some embodiments, the cyclic imide ester group is a cyclic imide carboxyl-C1-C6-alkyl ester group, including succinimide carboxyl-C1-C6-alkyl ester group, maleimide carboxyl-C1-C6-alkyl ester group, glutarimide carboxyl-C1-C6-alkyl ester group, diethylene glycol imide carboxyl-C1-C6-alkyl ester group, phthalimide carboxyl-C1-C6-alkyl ester group, and bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide carboxyl-C1-C6-alkyl ester group, as well as other possible groups. Specific embodiments described below include succinimide carboxymethyl ester group, succinimide carboxyethyl ester group, and succinimide carboxypropyl ester group.

[0043] In some embodiments, the cyclic imide carboxyl-C1-C5-alkyl ester group is directly bonded to the hydrophilic polymer segment.

[0044] The hydrophilic polymer segment used for the polymer arm can be selected from a variety of synthetic, natural, or synthetic-natural hybrid hydrophilic polymer segments. Examples of hydrophilic polymer segments include those formed from one or more hydrophilic monomers selected from: C1-C6-epoxides (e.g., ethylene oxide, propylene oxide, tetramethylene oxide, etc.), and polar aprotic vinyl monomers (e.g., N-vinylpyrrolidone, acrylamide, N-methacrylamide, N-isopropylacrylamide, dimethacrylamide, N-vinylimidazolium, 4-vinylimidazolium, sodium 4-vinylbenzenesulfonate, etc.).

[0045] The hydrophilic polymer segments can be selected from, for example, the following polymer segments: polyether segments, including poly(C1-C6-epoxyalkylene) segments, such as poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG) segments, poly(propylene oxide) segments, poly(ethylene oxide-co-propylene oxide) segments, and polymer segments formed from one or more polar aprotic vinyl monomers, including poly(N-vinylpyrrolidone) segments, poly(acrylamide) segments, poly(N-methacrylamide) segments, poly(N-isopropylacrylamide) segments, poly(dimethacrylamide) segments, poly(N-vinylimidazolium) segments, poly(4-vinylimidazolium) segments, and poly(4-vinylbenzenesulfonate) segments.

[0046] The polymer segments used in the multi-arm polymers of this disclosure typically contain 10 to 1000 monomer units or more.

[0047] In some embodiments, the core region includes residues of a non-iodinated or iodinated polyol containing three or more hydroxyl groups for forming the polymer arm. In some advantageous embodiments, the core region includes residues of a polyol containing 3 to 100 hydroxyl groups (e.g., any number of hydroxyl groups in the range of 3 to 4 to 5 to 6 to 7 to 8 to 9 to 10 to 11 to 12 to 15 to 20 to 25 to 50 to 75 to 100).

[0048] In some embodiments of this disclosure, non-iodinated or iodinated polyols (such as one of those described below) can be used as multifunctional initiators for polymer chain growth. For example, non-iodinated or iodinated polyols can be used as initiators for the ring-opening polymerization of ethylene oxide to form a polyethylene oxide (PEO) segment (also referred to as a polyethylene glycol or PEG segment) at each of the hydroxyl groups of the polyol. Depending on the desired water solubility of the resulting multi-arm polymer, the resulting hydroxyl-terminated PEG segments have tunable hydrophilicity; for example, increasing the PEG segment length results in increased hydrophilicity.

[0049] exist Figure 1 In the specific embodiment shown, commercially available tripentaerythritol (110) (CAS# 78-24-0) can be used as an octafunctional initiator, which undergoes ring-opening polymerization with ethylene oxide (111). The polymerization process results in the growth of poly(ethylene oxide) (PEG) chains at each of the eight hydroxyl groups of tripentaerythritol, thereby forming an 8-arm PEG (112) with hydroxyl-terminated cores of tripentaerythritol residues. Figure 1 In this context, n is an integer representing the number of monomer units in each polymer chain segment shown.

[0050] Figure 1 The strategies shown are widely applicable and can be used in combination with a range of polyols, including those described below. Figure 2In the specific embodiment shown, an iodinated polyol (specifically 1,3,5-triiodo-2,4,6-tris(hydroxymethylbenzene) (210)) is used as an initiator, which undergoes ring-opening polymerization with ethylene oxide (211). The polymerization process results in the growth of poly(ethylene oxide) (PEG) chains at each of the three hydroxyl groups of 1,3,5-triiodo-2,4,6-tris(hydroxymethylbenzene) (210). The resulting multi-arm polymer (212) contains three PEG arms extending from a core of 1,3,5-triiodo-2,4,6-tris(hydroxymethylbenzene) residues. Each PEG arm has a terminal hydroxyl group. Figure 2 In this context, n is an integer representing the number of monomer units in each polymer chain segment shown.

[0051] Other illustrative non-iodinated and iodinated polyols used in this disclosure are described below. Such polyols can be used to form multi-arm polymeric polyols, for example, as described above. Figure 1 and 2 As stated above.

[0052] Non-iodinated polyols can be selected from, for example, sugars (monosaccharides, disaccharides, trisaccharides, etc.), sugar alcohols, calixarenes, cyclodextrins, polyhydroxylated polymers, catechins, flavanols, anthocyanins, stilbenes, and polyphenols.

[0053] Non-iodinated polyols can be selected from, for example, straight-chain, branched, and cyclic aliphatic polyols, including straight-chain, branched, and cyclic polyhydroxy alkanes, straight-chain, branched, and cyclic polyhydroxy ethers (including polyhydroxy polyethers), straight-chain, branched, and cyclic polyhydroxy alkyl ethers (including polyhydroxy alkyl polyethers), straight-chain, branched, and cyclic sugars and sugar alcohols. Specific examples include methyltriol, glycerol, trimethylolpropane, phloroglucinol, mannitol, sorbitol, inositol, xylitol, styraxyl alcohol, threitol, arabinol, erythritol, pentaerythritol, dipentaerythritol, tripentaerythritol, arabinol, arabinol, hexamethylenetetramine, galactitol, fucose, ribose, arabinose, xylose, lysolose, rhamnose, galactose, glucose, fructose, sorbitol, mannose, pyranose, azurose, tarose, tagatose, pyranoside, sucrose, and lactose. Polymers of straight-chain, branched, and cyclic sugars and sugar alcohols (defined herein as two or more units) (including oligomers of straight-chain, branched, and cyclic sugars and sugar alcohols (defined herein as two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers, and decamers), sugars and sugar alcohols including the aforementioned sugars and sugar alcohols, starch, amylose, dextrin, cyclodextrin, catechins, flavanols, anthocyanins, stilbene, polyphenols, and polyhydroxy crown ethers and polyhydroxyalkyl crown ethers). Exemplary polyols also include aromatic polyols (including 1,1,1-tris(4'-hydroxyphenyl)alkanes, such as 1,1,1-tris(4-hydroxyphenyl)ethane and 2,6-bis(hydroxyalkyl)cresol, etc.).

[0054] Exemplary non-iodinated polyols also include polyhydroxylated polymers. For example, in some embodiments, the core region comprises polyhydroxylated polymer residues, such as polyvinyl alcohol residues, polyallyl alcohol, hydroxyethyl polyacrylate residues, or hydroxyethyl polymethacrylate residues. The length of such polyhydroxylated polymer residues can range, for example, from 3 to 100 monomer units.

[0055] Iodinated polyols are desirable where radiopaqueness is required. Iodinated polyols include iodinated aromatic polyols, examples of which are compounds comprising three or more hydroxyl groups and one or more iodinated aromatic groups. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as iodine-substituted phenyl, iodine-substituted naphthyl, iodine-substituted anthraceneyl, iodine-substituted phenanthryl, and iodine-substituted tetraphenyl, etc. The aromatic group can be substituted with one, two, three, four, five, six, or more iodine atoms. In various embodiments, the aromatic group is also substituted with two or more hydroxyl groups, which can directly replace the aromatic group or can be provided in the form of a hydroxyalkyl group (e.g., a C1-C4-hydroxyalkyl group containing one, two, three, or four carbon atoms and containing one, two, three, or four or more hydroxyl groups). The hydroxyalkyl group can be directly or via any suitable linking moiety selected from, for example, amide groups, ether groups, alkyl groups, and combinations thereof.

[0056] In addition to the aforementioned 1,3,5-triiodo-2,4,6-tri-hydroxymethylbenzene, other iodinated polyols used in this disclosure include iodinated polyols known as iodinated contrast agents, whose biocompatibility has been demonstrated to be quite good tolerable. Specific examples of iodinated polyols include commercially available 1,3,5-triiodo-2,4,6-trihydroxymethylbenzene (CAS# 178814-33-0), iodixanol (CAS# 92339-11-2), iotrolan (CAS# 79770-24-4), iohexol (CAS# 66108-95-0), ioversol (CAS# 87771-40-2), iopamidol (CAS# 60166-93-0), iohexol impurity J (CAS# 76801-93-9), and iopramide (CAS# 73334-07-3), etc.

[0057] The reactive multi-arm polymer according to the invention can be formed from a hydroxyl-terminated precursor multi-arm polymer having arms comprising one or more hydroxyalkyl terminal groups. In an initial step, the hydroxyalkyl terminal groups of the hydroxyl-terminated precursor multi-arm polymer can be oxidized to form a carboxylic acid-terminated intermediate multi-arm polymer having arms each comprising one or more carboxylic acid terminal groups. The reactive portion can then be attached to the carboxylic acid-terminated intermediate multi-arm polymer.

[0058] In some embodiments, the electrophilic portion can be attached to a carboxylic acid-terminated precursor polymer. For example, N-hydroxycyclic imide compounds (e.g., N-hydroxysuccinimide, N-hydroxymaleimide, N-hydroxyglutarimide, N-hydroxyphthalimide, or N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, also known as N-hydroxybicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid imide (HONB), etc.) can be coupled in a suitable coupling agent (e.g., a carbodiimide coupling agent, such as N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- In the presence of (3-dimethylpropyl)carbodiimide (EDC), N-hydroxybenzotriazole (HOBt), BOP reagent, and / or other coupling agents, it reacts with a carboxylic acid-terminated precursor polymer to form a reactive cyclic imide ester (e.g., succinimide ester group, maleimide ester group, glutarimide ester group, phthalimide ester group, diethylene glycol imide ester group, bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide ester group, etc.), which is attached to a hydrophilic polymer segment. In this way, a variety of reactive ester groups can be formed.

[0059] In one specific embodiment, the intermediate multiarm polymer can be formed by oxidizing the hydroxyalkyl terminal group (e.g., C2-C6-hydroxyalkyl terminal group) of the hydroxyl-terminated multiarm precursor polymer with an oxidizing agent (e.g., potassium dichromate (VI) or potassium permanganate), thereby forming a carboxylalkyl terminal group (e.g., C2-C6-carboxylalkyl terminal group) at the site previously occupied by the hydroxyalkyl terminal group.

[0060] exist Figure 3In one embodiment shown, an intermediate multi-arm polymer comprising a core region and multiple polyethylene oxide (PEO) arms with carboxylic acid end groups is formed by oxidizing the hydroxyalkyl end groups of a multi-arm polymer having a core region comprising polyol residues and multiple hydroxyl-terminated polyethylene oxide arms. Specifically, a hydroxyl-terminated 8-arm PEG (310) (where R comprises tripentaerythritol or hexaglycerol polyol residues, and n ranges from 30 to 140 (only one polymer arm is shown, and R represents polyol residues and the remaining seven arms)) is oxidized by reacting with potassium dichromate (VI) to produce a carboxylic acid-terminated 8-arm PEO (320). Then, in a subsequent step, the carboxylic acid-terminated 8-arm PEO (320) reacts with N-hydroxysuccinimide (325) in the presence of a coupling agent (specifically N,N'-dicyclohexylcarbodiimide (DCC)) to form a succinimide ester-terminated 8-arm polymer (330), wherein the succinimide ester group is attached to the PEO segment via a methylene group, also referred herein as a succinimide carboxymethyl ester group or a succinimide-carboxymethyl ester group. In embodiments using multi-arm polypropylene oxide, a similar product is formed, except that the succinimide ester group is attached to the polypropylene oxide segment via an ethylidene group, also referred herein as a succinimide carboxyethyl ester group or a succinimide-carboxyethyl ester group. In embodiments using multi-arm polytetramethylene oxide, a similar product will be formed, except that the succinimide ester group will be attached to the polytetramethylene oxide segment via a propylene (i.e., trimethylene) group, also referred to herein as a succinimide carboxypropyl ester group or a succinimide carboxypropyl ester group.

[0061] Reactive multiarm polymers having reactive moieties containing isocyanate groups can also be formed from hydroxyl-terminated precursor multiarm polymers having arms containing one or more hydroxyl end groups.

[0062] In some embodiments, a multi-arm polymer having an isocyanoalkyl terminal group (e.g., a C2-C6-isocyanoalkyl terminal group) can be formed from a multi-arm polymer having a hydroxyalkyl terminal group (e.g., a C2-C6-hydroxyalkyl terminal group).

[0063] refer to Figure 4A multi-armed polymer comprising a core region and multiple isocyanate-terminated polyethylene oxide (PEO) arms is formed by reacting the hydroxyl-terminated alkyl end groups of a multi-armed polymer having a core region comprising polyol residues and multiple hydroxyl-terminated polyethylene oxide arms. More specifically, a hydroxyl-terminated 8-armed PEG (410) (where R comprises tripentaerythritol or hexaglycerol polyol residues, and n ranges from 30 to 140 (only one polymer arm is shown; polyol residues and the remaining seven arms are represented by R)) is first treated with methanesulfonyl chloride (CAS#124-63-0) to form an intermediate polymer, wherein the hydroxyl groups of iodixanol are converted to methanesulfonate groups, which are then reacted with ammonia, followed by treatment with hydrochloric acid to convert the methanesulfonate groups to amino groups (in ammonium salt form), thereby forming an amino-terminated multi-armed PEO (420). The amino-terminated multi-armed PEO (420) is then reacted with phosgene to form an isocyanate-terminated multi-armed PEO (430). More generally, these reaction steps can be used to form isocyanoalkyl terminal groups (e.g., C2-C6-isocyanoalkyl terminal groups) from aminoalkyl terminal groups (e.g., C2-C6-aminoalkyl terminal groups) at sites previously occupied by the aforementioned hydroxyalkyl terminal groups (e.g., C2-C6-hydroxyalkyl terminal groups).

[0064] As previously stated, in some aspects, this disclosure provides hydrolysis-resistant crosslinking hydrogels comprising (a) a polyamine compound and (b) a hydrolysis-resistant crosslinking reaction product of a reactive polymer, said reactive polymer comprising a reactive portion capable of reacting with the amino group of the polyamine compound.

[0065] Such polyamino compounds include non-iodinated polyamino compounds and iodinated polyamino compounds.

[0066] Non-iodinated polyamine compounds suitable for use in this disclosure include, for example, polyamines containing at least two amino (-NH2) groups (e.g., in some embodiments, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino groups). Non-iodinated polyamine compounds suitable for use in this disclosure include those containing a plurality of -(CH2) groups. x Those with -NH2 groups (where x is 0, 1, 2, 3, 4, 5, or 6). Non-iodinated polyamine compounds suitable for use in this disclosure include polyamine compounds comprising basic amino acid residues, said basic amino acid residues including amino acid residues having two or more primary amine groups, such as lysine and ornithine, for example, polyamines comprising 2 to 10 lysine residues and / or ornithine amino acid residues (e.g., dilysine, trilysine, tetralysine, pentalysine, diornithine, triornithine, tetraornithine, pentaornithine, etc.).

[0067] Other examples of non-iodinated polyamino compounds that can be used as polyfunctional compounds include ethylenetriamine, diethylenetriamine, hexamethylenetriamine, di(heptamethyl)triamine, di(trimethylene)triamine, bis(hexamethylene)triamine, triethylenetetramine, tripropylenetetramine, tetraethylenepentamine, hexamethyleneheptamine, pentaethylenehexamine, dimethyloctylamine, dimethyldecylamine, and JEFFAMINE polyetheramine and poly(allylamine) purchased from Huntsman Corporation.

[0068] In cases where additional radiation impermeability is required in cross-linked hydrogels, iodinated polyamine compounds can be used.

[0069] In some embodiments, the iodinated polyamino compound comprises a polyamino moiety connected to a carboxyl-substituted iodinated moiety via an amide group. The iodinated polyamino compound may comprise a peptide oligomer containing 2 to 10 lysine and / or ornithine amino acid residues and one or more iodinated amino acid residues. The carboxyl-substituted iodinated moiety may comprise iodinated amino acid residues.

[0070] Examples of iodinated amino acid residues include iodinated α-amino acid residues, iodinated β-amino acid residues, iodinated γ-amino acid residues, and iodinated δ-amino acid residues. Examples of iodinated amino acid residues include amino acid residues containing an iodinated aromatic group. Examples of iodinated aromatic groups include iodophenyl and iodonaphthyl. In a specific embodiment, the iodinated amino acid residue includes an amino acid residue containing a hydroxyiodoaromatic group (e.g., hydroxyiodophenyl or hydroxyiodonaphthyl). More specific examples of hydroxyiodoaromatic groups include hydroxyiodophenyl selected from the following: monohydroxy monoiodophenyl, monohydroxy diiodophenyl, monohydroxy triiodophenyl, monohydroxy tetraiodophenyl, dihydroxy monoiodophenyl, dihydroxy diiodophenyl, dihydroxy triiodophenyl, trihydroxy monoiodophenyl, and trihydroxy diiodophenyl, as previously described.

[0071] Specific examples of iodinated amino acid residues include the following iodinated amino acid residue: iodophenylalanine, It contains monoiodophenyl; monoiodotyrosine, It contains monoiodophenyl (specifically monohydroxy monoiodophenyl); diiodotyrosine, It contains monohydroxydiiodophenyl; diiodothyronine, It contains diiodophenyl and hydroxyphenyl; triiodothyronine, also known as T3, It contains diiodophenyl and monohydroxy monoiodophenyl; tetraiodothyronine, also known as thyroxine or T4. It contains diiodophenyl and monohydroxydiiodophenyl; iodophenylalanine; and 6-iodo-L-DOPA, which contains dihydroxymonoiodophenyl, etc.

[0072] Iodinated polyamino compounds can be formed by an amide coupling reaction between (a) an iodinated amino acid derivative (e.g., a C1-C5-alkyl ester of an iodinated amino acid, preferably a methyl ester of an iodinated amino acid) and (b) a carboxyl-substituted polyamino compound (selected from those described below, for example, after amino protection). Examples of such iodinated amino acid derivatives include any of the aforementioned C1-C5-alkyl esters of iodinated amino acids. After coupling, the protecting group on the residue of the carboxyl-substituted polyamino compound is removed, and the C1-C5-alkyl ester can be converted into the corresponding carboxylic acid or anionic carboxylic acid ester group, thereby providing the final iodinated polyamino compound.

[0073] In various embodiments, the iodinated polyamino compound comprises a polyamino moiety having a plurality of amino groups (two, three, four, five, six, seven, eight, nine, ten, or more). For example, the polyamino moiety may comprise a plurality of (two, three, four, five, six, seven, eight, nine, ten, or more) -(CH2). x -NH2 groups, where x is 0, 1, 2, 3, 4, 5, or 6. In some of these embodiments, the polyamino moiety may include multiple -(CH2) groups arranged along the polymer moiety (defined herein as a moiety containing 2, 3, 4, 5, 6, 7, 8, 9, 10, or more monomer residues). x -NH2 group.

[0074] In some embodiments, the polyamino moiety of the iodinated polyamino compound may correspond to the residues of a carboxyl-substituted polyamino compound (a compound comprising a carboxyl group and multiple amino groups). Examples of carboxyl-substituted polyamino compounds include peptides containing 2 to 10 lysine and / or ornithine amino acid residues, including polylysines (e.g., dilysine, trilysine, tetralysine, pentalysine, etc.) and carboxyl-terminated polyamines (e.g., carboxyl-terminated poly(allylamine), carboxyl-terminated poly(ethyleneamine), or carboxyl-terminated chitosan).

[0075] Commercially available examples of carboxyl-substituted polyamino compounds also include 16-amino-3-[2-[(4-aminobutyl)(3-aminopropyl)amino]-2-oxoethyl]-12-(3-aminopropyl)-6,9-bis(carboxymethyl)-11-oxo-3,6,9,12-tetraazahexadecanoic acid, L-ornityl-L-ornithine, and N... 2 -[1-[N 2 -[N 2-(NL-valine-L-alanyl)-L-lysyl]-L-lysyl]-L-prolyl]-L-lysine, L-lysyl-L-tryptophanyl-L-lysyl-L-lysine, N 2 N 5 N 5 -Tris(3-aminopropyl)-L-ornithine, L-lysyl-L-ornithine-L-lysine, D-lysyl-D-lysyl-D-lysine, glycyl-L-lysyl-glycyl-L-lysine, N 2 -[N 4 -[N-[N-(N-glycylglycyl)glycyl]glycyl]-L-lysyl]-L-lysine, L-lysyl-L-threonyl-L-lysyl-L-lysine, glycylglycyl-L-lysyl-L-lysylglycyl-L-cysteine, L-lysyl-L-arginyl-L-lysyl-L-lysine, L-arginyl-L-lysyl-L-lysyl-L- Lysine, L-leucyl-L-lysyl-L-seryl-L-lysyl-L-lysine, L-alanyl-L-methionylglycyl-L-lysyl-L-lysine, L-lysyl-L-lysyl-L-lysyl-L-arginyl-L-glutamine, L-seryl-L-isoleucyl-L-lysyl-L-lysyl-L-lysyl-L-lysine, N 2 -(N 2 -L-ornithine-L-lysyl)-L-lysine, lysyllysyl-lysine, and L-lysyl-L-lysyl-L-alanine.

[0076] Iodinated polyamino compounds can be formed by reacting the carboxyl group of a carboxyl-substituted polyamino compound (e.g., those mentioned above, after protecting the amino group of the carboxyl-substituted polyamino compound with a suitable protecting agent, for example, by reacting with di-tert-butyl carbonate or another protecting agent) with the amino group of an iodinated amino acid C1-C5-alkyl ester (e.g., those mentioned above) to form an amide bond between the two residues. Specific compounds formed, for example, by amide coupling between a tBoc-protected trilysine and a diiodotyrosine methyl ester (after tBoc deprotection and methyl ester hydrolysis) are shown here: .

[0077] Other examples of iodinated polyamino compounds include those formed by replacing the hydroxyl groups of the polyhydroxylated iodide compound with amino groups (-NH2 groups) using various suitable techniques. In one process, similar to... Figure 4In the first step shown, the hydroxyl groups of the polyhydroxylated iodide compound are converted to methanesulfonate groups, which are then reacted with ammonia and treated with hydrochloric acid to convert the methanesulfonate groups to amino groups (in the form of an ammonium salt). As another example, the hydroxyl groups of the polyhydroxylated iodide compound are converted to methanesulfonate groups, which are then reacted with sodium amide (NaNH2, also known as sodium azanide) and treated with hydrochloric acid to convert the methanesulfonate groups to amino groups (in the form of an ammonium salt).

[0078] Using these and other techniques, various iodinated polyamino compounds can be formed from iodinated polyhydroxylated compounds by substituting all or part of the amino groups with iodinated polyhydroxylated compounds. Such iodinated polyamino compounds can contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more amino groups.

[0079] Specific examples of iodinated polyamino compounds include, for instance, iopromide, in which at least some of the hydroxyl groups (specifically, four hydroxyl groups) have been substituted with amino groups, resulting in N,N'-bis(2,3-diaminopropyl)-2,4,6-triiodo-5-(2-methoxyacetamide)-N-methylisophthalamide. Iopamidol, wherein at least some of the hydroxyl groups (specifically, all five hydroxyl groups) have been replaced by amino groups, yields N,N'-bis(2-amino-1-(aminomethyl)ethyl)-2,4,6-triiodo-5-lactamyl isophthalamide. Iomeprol, in which at least some of the hydroxyl groups (specifically, all five hydroxyl groups) have been replaced by amino groups, yields N,N'-bis(2,3-aminopropyl)-5-(2-amino-N-methylacetamide)-2,4,6-triiodoisophthalamide. Ioforol, wherein at least some of the hydroxyl groups (specifically, all six hydroxyl groups) have been replaced by amino groups, yields N,N'-bis(2,3-diaminopropyl)-5-(2-amino-N-(2-amino)acetamide)-2,4,6-triiodoisophthalamide. Iobitridol, in which at least some of the hydroxyl groups (specifically, all six hydroxyl groups) have been replaced by amino groups, yields N,N'-bis(2,3-diaminopropyl)-5-((5-amino-2-(aminomethyl)-1-oxopropyl)amino)-2,4,6-triiodo-N,N'-dimethyl-1,3-phenylenediamide. Iodixanol, in which at least some of the hydroxyl groups (specifically eight out of nine hydroxyl groups) have been replaced by amino groups, yields 5,5'-((2-hydroxytrimethylene)bis(acetylimino))bis(N,N'-bis(2,3-diaminopropyl)-2,4,6-triiodoisophthalamide). ; and iodotram, in which at least some of the hydroxyl groups (specifically 12 hydroxyl groups) have been replaced by amino groups, resulting in 5,5'-((1,3-dioxo-1,3-propanediyl)bis(methylimino))bis(N,N'-bis(2,3-diamino-1-(aminomethyl)propyl)-2,4,6-triiodo-1,3-phenylenediamide), In some implementations, the iodinated polyamino compound does not need to be formed from an iodinated polyhydroxylated compound. An example of such an iodinated polyamino compound is CA. 4+ : .

[0080] As previously stated, in some aspects, this disclosure provides hydrogels comprising (a) a hydrolysis-resistant crosslinking product of a polyamine compound (such as those described above) and (b) a reactive polymer (such as those described above), the reactive polymer comprising a reactive portion capable of reacting with the amino group of the polyamine compound.

[0081] Figure 5 A specific embodiment is shown, schematically illustrating a polyamino compound (specifically, trilysine (520)) and a reactive polymer having a reactive portion comprising a reactive cyclic imide ester group (specifically, an eight-arm PEG (530) having a reactive succinimide carboxymethyl ester (SA) group, having a core region comprising a polyol residue (e.g., a tripentaerythritol polyol residue or a hexaglycerol polyol residue), where R represents a polyol residue and n ranges from 30 to 140). The reactive polymer (530) and the polyamino compound (520) are mixed under conditions that cause the succinimide ester group of the reactive polymer (530) to react with the amino group of the polyamino compound (520) to form an amide bond, simultaneously releasing an N-hydroxysuccinimide, resulting in a crosslinked polymer network (540). The amide bond formation eliminates the ester group, resulting in an ester-free amide bond, making the crosslinked polymer network (540) resistant to hydrolysis. In some embodiments, the reaction between the succinimide ester group and the amino group is carried out at a weakly basic pH (e.g., pH range of 7.4 to 11), wherein the amino group of the polyamino compound is deprotonated / neutralized, and amide bond formation can occur spontaneously at body temperature.

[0082] Although not shown, in another specific embodiment, the polyamine compound as described herein can react with a reactive multi-arm polymer having a reactive portion comprising an isocyanate group (e.g., an eight-arm PEG having a reactive isocyanate group and a core region comprising the aforementioned tripentaerythritol or hexaglycerol residues). The reactive multi-arm polymer and the polyamine compound can be combined under conditions that cause the isocyanate group of the reactive hydrophilic polymer to react with the primary amine group of the polyamine compound to form a urea bond, thereby forming a cross-linked polymer network. In various embodiments, a non-aqueous solution of the reactive isocyanate multi-arm polymer reacts with a non-aqueous solution of the polyamine compound to form a cross-linked polymer network. Examples of non-aqueous solutions include dimethyl sulfoxide (DMSO) solutions.

[0083] It should be understood that the crosslinking density of the hydrolysis-resistant crosslinked hydrogels described herein can be adjusted, for example, (a) by changing the number of primary amine groups in the polyamine compound, (b) by changing the number of arms in the reactive multiarm polymer, or (c) both.

[0084] In some embodiments, the hydrolysis-resistant crosslinked hydrogel is visible under fluorescence fluoroscopy. The radiation opacity of the hydrolysis-resistant crosslinked hydrogel can be greater than 100 Hounsfield units (HU), advantageously any value in the range of 100 HU to 250 HU to 500 HU to 750 HU to 1000 HU or higher (in other words, within the range of any two of the aforementioned values), for example, when measured on a benchtop miniature CT system (e.g., Scanco Medical's XtremeCT from Wangen-brüttisellen, Switzerland) or a similar system.

[0085] In some aspects of this disclosure, a system is provided comprising (a) a first composition comprising a polyamine compound as described herein, and (b) a second composition comprising a reactive polymer comprising a reactive portion as described herein, wherein the system is configured to deliver the reactive polymer and the polyamine compound under conditions such that a covalent crosslink is formed between the reactive polymer and the polyamine compound.

[0086] For example, when the reactive polymer is a reactive polymer containing a reactive isocyanate moiety, the first composition may be a first fluid composition containing a polyamine compound and a suitable non-aqueous solvent (e.g., DMSO), or the first composition may be a first dry composition containing a polyamine compound, to which a suitable non-aqueous solvent may be added to form the first fluid composition. In addition to the polyamine compound, the first composition may also contain other agents (including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below). The second composition may be a second fluid composition containing a reactive polymer containing a reactive isocyanate moiety and a suitable non-aqueous solvent (e.g., DMSO), or the second composition may be a second dry composition containing a reactive polymer containing a reactive isocyanate moiety, to which a suitable non-aqueous solvent may be added to form the second fluid composition. In addition to the reactive polymer, the second composition may also contain other agents (including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below).

[0087] When the reactive polymer is a reactive polymer containing a reactive electrophilic moiety, the first composition may be a first fluid composition containing a polyamine compound or a first dry composition containing a polyamine compound. A suitable fluid (e.g., water for injection, saline, etc.) may be added to the first dry composition to form a first fluid composition. In addition to the polyamine compound, the first composition may also contain other reagents (including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below). The second composition may be a second fluid composition containing a reactive polymer containing a reactive electrophilic moiety or a second dry composition containing a reactive polymer containing a reactive electrophilic moiety. A suitable fluid (e.g., water for injection, saline, etc.) may be added to the second dry composition to form a second fluid composition. In addition to the reactive polymer containing a reactive electrophilic moiety, the second composition may also contain other reagents (including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below).

[0088] In some embodiments, the system is configured to mix a first fluid composition comprising a polyamine compound with a second fluid comprising a reactive polymer. During mixing of the first and second fluid compositions, the polyamine compound crosslinks with the reactive polymer to form a crosslinked product. The first and second fluid compositions can be combined to form a hydrolysis-resistant crosslinked hydrogel.

[0089] In some embodiments, the polyamine compound initially binds to the reactive polymer under conditions where crosslinking between the reactive polymer and the polyamine compound is inhibited (e.g., acidic pH in the case where the reactive polymer contains a reactive electrophilic portion). Then, when crosslinking is required, the conditions are changed to increase crosslinking (e.g., in some embodiments, from acidic pH to alkaline pH), resulting in crosslinking between the polyamine compound and the reactive polymer, thereby forming a crosslinked product. The first fluid composition and the second fluid composition can be combined to form a hydrolysis-resistant crosslinked hydrogel.

[0090] In some of these embodiments, the system includes (a) a first composition comprising a polyamine compound, (b) a second composition comprising a reactive polymer comprising a reactive electrophilic moiety as described above, and (c) a third composition, specifically, an accelerator composition containing an accelerator configured to accelerate the crosslinking reaction between the polyamine compound and the reactive polymer comprising a reactive electrophilic moiety.

[0091] The first composition may be a first fluid composition containing a polyamine compound buffered to an acidic pH or a first dry composition containing a polyamine compound. A suitable fluid (e.g., water for injection, saline, acid buffer solution, etc.) may be added to the first dry composition to form a first fluid composition containing a polyamine compound buffered to an acidic pH. For example, in some embodiments, the acid buffer composition may include sodium dihydrogen phosphate, etc. The pH range of the first fluid composition containing the polyamine compound may be, for example, from about 3 to about 6.5, typically from about 3 to about 5. In addition to the polyamine compound, the first composition may also contain other agents (including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below).

[0092] The second composition may be a second fluid composition comprising a reactive polymer containing a reactive electrophilic moiety or a second dry composition comprising a reactive polymer containing a reactive electrophilic moiety, wherein the fluid composition is formed from the second dry composition, for example by adding a suitable fluid (e.g., water for injection, saline, or a first fluid composition comprising a polyamine compound buffered to an acidic pH). In addition to the reactive polymer, the second composition may also contain other agents (including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below).

[0093] In one particular embodiment, the first composition is a first fluid composition containing a polyamine compound buffered to an acidic pH, and the second composition comprises a dry composition containing a reactive polymer having a reactive electrophilic moiety. The first and second compositions can then be mixed to provide a prepared fluid composition buffered to an acidic pH and containing both the polyamine compound and the reactive polymer. In one specific example, a syringe containing the first fluid composition containing the polyamine compound buffered to an acidic pH can be provided, and a vial containing the dry composition (e.g., powder) containing the reactive polymer can also be provided. The first fluid composition can then be injected into the vial containing the reactive polymer using the syringe to form the prepared fluid composition buffered to an acidic pH and containing both the polyamine compound and the reactive polymer, which can then be aspirated back into the syringe for administration.

[0094] The accelerator composition can be a liquid accelerator composition buffered to an alkaline pH, or a dry composition containing an alkaline buffer composition. A suitable fluid (e.g., water for injection, saline, etc.) can be added to the dry composition to form a fluid accelerator composition buffered to an alkaline pH. For example, the alkaline buffer composition may include sodium borate and disodium hydrogen phosphate, etc. The pH range of the fluid accelerator composition can be, for example, from about 8.5 to about 12, typically from about 9 to about 11. In addition to the above, the fluid accelerator composition may also contain other reagents, including those described below.

[0095] The prepared fluid composition, which is buffered to an acidic pH and contains a polyamine compound and a reactive polymer containing a reactive electrophilic moiety as described above, and the fluid accelerator composition, which is buffered to an alkaline pH as described above, can be combined to form a hydrolysis-resistant crosslinked hydrogel.

[0096] Other agents used in the compositions described herein include therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters.

[0097] Examples of therapeutic agents include antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, proliferation inhibitors, anti-restenosis agents, smooth muscle cell inhibitors, antibiotics, antibacterial agents, analgesics, anesthetics, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T-cell agonists, STING (interferon gene stimulator) agonists, antimetabolites, alkylating agents, microtubule inhibitors, hormones, hormone antagonists, monoclonal antibodies, antimitotic agents, immunosuppressants, tyrosine and serine / threonine kinases, proteasome inhibitors, matrix metalloproteinase inhibitors, Bcl-2 inhibitors, DNA alkylating agents, spindle poisons, poly(DP-ribose) polymerase (PARP) inhibitors, and combinations thereof.

[0098] Examples of imaging agents include (a) fluorescent dyes, such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, and blue-green fluorescent proteins); (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including contrast agents containing elements that form paramagnetic ions, such as Gd(III), Mn(II), Fe(III), and compounds containing them (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid; (c) contrast agents used in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in increased reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that result in decreased reflected ultrasound energy); and (d) contrast agents used in conjunction with near-infrared (NIR) imaging, which can be selectively used to impart near-infrared fluorescence to the hydrogels of this disclosure, thereby allowing for deep tissue imaging and device labeling, such as NIR-sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derived with hydroxyl or carboxyl groups). Examples include partially oxidized carbon nanotubes, dye-containing nanoparticles (e.g., dye-doped nanofibers and dye-encapsulated nanoparticles), and semiconductor quantum dots, as well as NIR-sensitive dyes (e.g., cyanine dyes, squaranes, phthalocyanines, porphyrin derivatives, and borodipyrrole methylene analogs), (e) imageable radioactive isotopes, including 99mTc, 201Th, 51Cr, 67Ga, 68Ga, 111In, 64Cu, 89Zr, 59Fe, 42K, 82Rb, 24Na, 45Ti, 44Sc, 51Cr, and 177Lu, and (f) radioactive contrast agents, such as particles of tantalum, tungsten, rhenium, niobium, molybdenum, and their alloys, which may be spherical or non-spherical. Other examples of contrast agents include nonionic contrast agents such as iohexol, iodixanol, iofluoxetine, iopamidol, ioxilan, or iopromide; ionic contrast agents such as diatrizoate, iothalamate, metrizoate, or ioxaglate; and iodized oils, including ethiodized poppyseed oil (available as Lipiodol®).

[0099] Examples of colorants include brilliant blue (e.g., brilliant blue FCF, also known as FD&C blue 1), indigocarmine (also known as FD&C blue 2), indigocarmine lake, FD&C blue 1 lake, and methylene blue (also known as methylene blue chloride), etc.

[0100] Examples of other reagents include tension modifiers such as sugars (e.g., glucose, lactose, etc.), polyols (e.g., glycerol, propylene glycol, mannitol, sorbitol, etc.) and inorganic salts (e.g., potassium chloride, sodium chloride, etc.), suspending agents including various surfactants, wetting agents and polymers (e.g., albumin, PEO, polyvinyl alcohol, block polymers, etc.), and pH adjusters including various buffer solutes.

[0101] In various embodiments, a system is provided that includes one or more delivery devices for delivering a first composition and a second composition to a subject.

[0102] In some embodiments, the system may include a delivery device comprising a first reservoir and a second reservoir, the first reservoir containing a first fluid composition comprising a polyamino compound as described herein, and the second reservoir containing a second fluid composition comprising a reactive polymer as described herein, wherein the first fluid composition and the second fluid composition, upon mixing, form a crosslinked product.

[0103] In some embodiments, the system may include a delivery device comprising a first reservoir and a second reservoir, the first reservoir containing a first fluid composition (e.g., the aforementioned prepared fluid composition) comprising a polyamino compound as described herein and a reactive polymer containing a reactive electrophilic moiety as described herein and buffered to an acidic pH, and the second reservoir containing a second fluid composition (e.g., the fluid accelerator composition described herein).

[0104] In either case, during operation, the first fluid composition and the second fluid composition are dispensed from the first reservoir and the second reservoir and mixed, whereby the polyamine compound and the reactive polymer crosslink with each other to form a hydrolysis-resistant crosslinked hydrogel.

[0105] In the specific implementation plan, and referring to Figure 6The system may include a delivery device 610 comprising a dual-tube syringe, the dual-tube syringe including a first tube 612a having a first tube outlet 614a (the first tube contains a first fluid composition as described above), a first plunger 619a movable within the first tube 612a, a second tube 612b having a second tube outlet 614b (the second tube 612b contains a second fluid composition as described above), and a second plunger 619b movable within the second tube 612b. In some embodiments, the device 610 may further include a mixing section 618 having a first mixing section inlet 618a1 in fluid communication with the first tube outlet 614a, a second mixing section inlet 618b in fluid communication with the second tube outlet 614b, and a mixing section outlet 618o. Also shown is a syringe holder 622 configured to maintain a fixed relationship between the first syringe tube 612a and the second syringe tube 612b, and a plunger cap 624 configured to maintain a fixed relationship between the first plunger 619a and the second plunger 619b. In some embodiments, the delivery device may further include a needle or conduit configured to receive a first fluid composition and a second fluid composition from a first tube and a second tube. For example, the needle or conduit may be configured to form a fluid connection with the outlet of the mixing section by attaching the needle or conduit to the outlet of the mixing section (e.g., via a suitable fluid connector such as a Luer connector).

[0106] In some embodiments, the delivery device may further include a cannula or conduit configured to receive a first fluid composition and a second fluid composition from a first tube and a second tube. For example, the cannula or conduit may be configured to form a fluid connection with the outlet of the mixing section by attaching the cannula or conduit to the outlet of the mixing section (e.g., via a suitable fluid connector such as a Luer connector).

[0107] As another example, the catheter may be a multi-lumen catheter including a first lumen and a second lumen, the proximal end of the first lumen being configured to form a fluid connection with a first tube outlet, and the proximal end of the second lumen being configured to form a fluid connection with a second tube outlet. In some embodiments, the multi-lumen catheter may include a mixing portion having a first mixing portion inlet in fluid communication with the distal end of the first lumen, a second mixing portion inlet in fluid communication with the distal end of the second lumen, and a mixing portion outlet.

[0108] During operation, when the first and second plungers are depressed, a first fluid composition and a second fluid composition are dispensed from the first and second tubes, whereby the first and second fluid compositions mix and ultimately crosslink to form a hydrolysis-resistant crosslinked hydrogel, which is then applied to or within the subject's tissue. For example, the first and second fluid compositions can enter a mixing section from the first and second tubes via a first mixing section inlet and a second mixing section inlet, whereby the first and second fluid compositions mix to form a mixture, which exits the mixing section via a mixing section outlet. In some embodiments, a cannula or catheter is attached to the mixing section outlet, thereby allowing the mixture to be applied to the subject after passing through the cannula or catheter.

[0109] As another example, a first fluid composition may enter the first lumen of a multi-lumen catheter from a first tube outlet, and a second fluid composition may enter the second lumen of the multi-lumen catheter from a second tube outlet. In some embodiments, the first fluid composition and the second fluid composition may enter a mixing section at the distal end of the multi-lumen catheter from the first lumen and the second lumen, respectively, via a first mixing section inlet and a second mixing section inlet, whereby the first fluid composition and the second fluid composition are mixed in the mixing section to form a mixture, which exits the mixing section via a mixing section outlet.

[0110] In a specific embodiment, the system may include (a) a pre-loaded first syringe filled with a polyamine solution also containing a polyamine compound as described herein and buffered to an acidic pH, for example, a trilysine solution buffered to a pH range of 3.8 to 4.2; (b) a vial containing a powder comprising a reactive polymer (e.g., an eight-arm PEG, wherein the polymer arms contain terminal succinimide carboxymethyl ester groups, the number-average molecular weight of the reactive polymer being, for example, 10,000 to 20,000 Daltons); and (c) a pre-loaded second syringe containing a fluid accelerator composition buffered to an alkaline pH (e.g., a pH range of about 9.8 to 10.4). In use, the first syringe may be used to inject the polyamine solution into the vial to form a prepared fluid composition buffered to an acidic pH and containing the polyamine compound and the multi-arm polymer, which may be aspirated back into the first syringe for administration. The prepared solution may also contain, for example, 0.1 to 1.0 wt% lysine and 0.5 to 12 wt% octagonal PEG. The system may also include components similar to... Figure 6 The delivery device may be loaded with a first syringe containing a prepared fluid composition and a second syringe containing a fluid promoter composition, and may be used to simultaneously inject and mix the prepared fluid composition and the fluid promoter composition.

[0111] Regardless of the type of system used to mix the first and second fluid compositions, or how the first and second fluid compositions are mixed, after the mixture of the first and second fluid compositions is formed, the mixture is initially in a fluid state and can be applied to a subject (e.g., a mammal, particularly a human) using a variety of techniques. Alternatively, the first and second fluid compositions can be applied to the subject independently, and the fluid mixture of the first and second fluid compositions is formed inside or on the surface of the subject. In either method, the fluid mixture of the first and second fluid compositions is formed and used in a variety of medical procedures.

[0112] For example, in some embodiments, the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected as a filler. For example, the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected to increase the coaptation of body sphincters (e.g., the anal sphincter or urethral sphincter in fecal incontinence). Figure 7A and 7B A portion of human anatomy is shown, including the lower part of the bladder wall 712, the upper part of the urethra 714, and the bladder neck 716, a group of muscles connecting the bladder to the urethra. A fluid mixture of the first fluid composition and the second fluid composition is delivered using a suitable delivery device (e.g., Figure 6 The delivery device shown, in which a catheter (not shown) and needle 724 are attached to the mixing portion outlet 618 of the delivery device 610, allows injection via the transurethral route. In the illustrated embodiment, injection is performed by means of a cystoscope 722 penetrating the urethral wall 718 to the bladder neck 716, which increases the engagement of the urethral sphincter. After injection, the polyamine compounds and reactive polymers in the fluid mixture crosslink to form a hydrolysis-resistant hydrogel 730. In cases where the liquid mixture contains a non-aqueous solvent (e.g., DMSO), the non-aqueous solvent is eventually replaced by water from the surrounding bodily fluids.

[0113] In other instances, for applications such as the treatment of diseases and cancers, and the repair and regeneration of tissues, the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected as fillers into the tissue surrounding the ureteral orifice to treat vesicoureteral reflux; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected for tissue enlargement or regeneration, including cosmetic tissue enlargement; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected to provide interstitial spacers; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected (e.g., in the form of vesicles) to provide reference markers; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected as fillers or replacements for soft tissues; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected to provide mechanical support for damaged tissues; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected as scaffolds; the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected as embolic compositions, and / or the first fluid composition and the second fluid composition, or fluid mixtures thereof, can be injected as carriers of therapeutic agents. The first fluid composition and the second fluid composition, or fluid mixtures thereof, can also be injected into the left atrial appendage during left atrial appendage occlusion procedures, or injected for the occlusion of atrial septal defects. In some embodiments, the first fluid composition and the second fluid composition, or a fluid mixture thereof, may be injected into the left atrial appendage after the introduction of an occlusion device (such as the Watchman® left atrial appendage occlusion device from Boston Scientific Corporation).

[0114] Upon application of the compositions disclosed herein (either as a first fluid composition and a second fluid composition mixed in vivo, or as a fluid mixture of the first fluid composition and the second fluid composition), a hydrolysis-resistant crosslinked hydrogel is ultimately formed at the application site.

[0115] During and / or after application, the compositions of this disclosure can be imaged using suitable imaging techniques. Typically, the imaging techniques are X-ray based techniques, such as computed tomography or X-ray fluorescence fluoroscopy, or near-IR fluorescence spectroscopy techniques.

[0116] As can be seen from the above, the compositions disclosed herein can be used in a variety of medical procedures, including: procedures for implanting a reference marker comprising a cross-linked product of a first fluid composition and a second fluid composition; procedures for implanting a tissue regeneration scaffold comprising a cross-linked product of a first fluid composition and a second fluid composition; procedures for implanting a tissue support comprising a cross-linked product of a first fluid composition and a second fluid composition; procedures for implanting a tissue filler comprising a cross-linked product of a first fluid composition and a second fluid composition for controlling reproductive health / family planning; procedures for occluding the vas deferens or fallopian tube with a cross-linked product of a first fluid composition and a second fluid composition; procedures for implanting an embolization composition comprising a cross-linked product of a first fluid composition and a second fluid composition; procedures for implanting a left atrial appendage occlusion composition comprising a cross-linked product of a first fluid composition and a second fluid composition; procedures for implanting a depot containing a therapeutic agent comprising a cross-linked product of a first fluid composition and a second fluid composition; procedures for tissue enlargement including implanting a cross-linked product of a first fluid composition and a second fluid composition; and procedures for introducing a cross-linked product of a first fluid composition and a second fluid composition between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0117] The first fluid composition and the second fluid composition, a fluid mixture of the first fluid composition and the second fluid composition, or a crosslinked product of the first fluid composition and the second fluid composition can be injected in combination with a variety of medical procedures including: septal injection between the prostate or vagina and rectum in radiotherapy for rectal cancer; septal injection between the rectum and prostate in radiotherapy for prostate cancer; subcutaneous injection for palliative treatment of prostate cancer; transurethral or submucosal injection for female stress urinary incontinence; intravesical injection for urinary incontinence; intrauterine injection for Asherman's syndrome; submucosal injection for anal incontinence; percutaneous injection for heart failure; intramyocardial injection for heart failure and dilated cardiomyopathy; injection for closure of atrial septal defects; transendocardial injection for myocardial infarction; intra-articular injection for osteoarthritis; and injection for spinal fusion and spinal, maxillofacial, and orthopedic procedures. Spinal injections for surgical trauma, spinal injections for posterolateral lumbar fusion, intradiscal injections for degenerative disc diseases, injections between the pancreas and duodenum for pancreatic cancer imaging, resection bed injections for oropharyngeal cancer imaging, peritumoral injections for bladder cancer imaging, submucosal injections for gastrointestinal tumors and polyps, visceral pleural injections for lung biopsies, injections for vas deferens obstruction, injections for fallopian tube obstruction, renal injections for type 2 diabetes and chronic kidney disease, renal cortical injections for chronic kidney disease with congenital abnormalities from the kidneys and urethra, intravitreal injections for neovascular age-related macular degeneration, intratympanic injections for sensorineural hearing loss, and dermal injections to correct wrinkles, creases and folds, signs of facial fat loss, volume reduction, superficial to deep contour defects, correction of depressed skin scars, perioral wrinkles, lip augmentation, facial fat atrophy, and stimulate natural collagen production.

[0118] In some embodiments, the hydrolysis-resistant crosslinked hydrogel is formed in vitro. In this case, the hydrolysis-resistant crosslinked hydrogel can be in any desired form, including sheets, columns, coatings, or particles. In some embodiments, the hydrolysis-resistant crosslinked hydrogel is dried and then granulated into particles of suitable size. Granulation can be carried out by any suitable method, such as by grinding (including cryogenic grinding), homogenization, crushing, milling, pulverizing, extruding through a screen, etc. The particles can be sorted and separated using sieving or other known techniques. The size of the hydrogel particles formed using the above and other techniques can vary considerably, for example, with an average size of 50 to 950 micrometers.

[0119] In addition to hydrolysis-resistant crosslinked hydrogels formed in vitro, hydrogel compositions according to the present disclosure may be provided, which contain other agents, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents and pH adjusters as described above.

[0120] In various embodiments, a kit is provided that includes one or more delivery devices for delivering such a hydrogel composition to a subject. Such a system may include one or more of the following: a syringe tubing that may or may not contain the hydrogel composition; a vial that may or may not contain the hydrogel composition; a needle; a flexible tube (e.g., adapted for fluid connection of the needle to a syringe); and an injectable liquid, such as water for injection, physiological saline, or phosphate-buffered saline. Whether provided in the form of a syringe, vial, or other reservoir, the hydrogel composition may be delivered in a dry form (e.g., powder form) or in a ready-for-injection form, such as an injectable hydrogel form (e.g., a suspension of hydrogel particles).

[0121] Figure 8 A syringe 10 is shown, which provides a reservoir for a hydrogel composition according to the present disclosure. The syringe 10 may include a tube 12, a plunger 14, and one or more stoppers 16. The tube 12 may include, for example, a Luer adapter (or other suitable adapter / connector) at its distal end 18 for attachment to an injection needle 50 via a flexible conduit 29. The proximal end of the conduit 29 may include a suitable connector 20 for receiving the tube 12. In other instances, the tube 12 may be directly connected to the injection needle 50. The syringe tube 12 may serve as a reservoir for containing a hydrogel composition 15 to be injected via the needle 50.

[0122] The hydrogel compositions described herein (e.g., suspensions of hydrogel particles, which may also optionally contain the other reagents described above) can be used for a variety of purposes.

[0123] For example, in applications such as the treatment of diseases and cancers, as well as the repair and regeneration of tissues, hydrogel compositions can be injected to provide spacers between tissues, can be injected (e.g., in the form of vesicles) to provide reference markers, can be injected for tissue enlargement or regeneration, can be injected as fillers or substitutes for soft tissues, can be injected for tissue filling, can be injected for occlusion of cavities, can be injected to provide mechanical support for damaged tissues, can be injected as scaffolds, and / or can be injected as carriers of therapeutic agents.

[0124] During or after application, the hydrogel compositions of this disclosure can be imaged using suitable imaging techniques.

[0125] As can be seen from the above, the hydrogel composition disclosed herein can be used in a variety of medical procedures, including the following: procedures for implanting a reference marker containing hydrogel, procedures for implanting a tissue regeneration scaffold containing hydrogel, procedures for implanting a tissue support containing hydrogel, procedures for implanting a tissue filler containing cross-linked hydrogel, procedures for occluding cavities, procedures for implanting a therapeutic reservoir containing hydrogel, tissue enlargement procedures including implantation of hydrogel, procedures for introducing hydrogel between a first tissue and a second tissue to separate the first tissue from the second tissue, etc.

[0126] The hydrogel composition can be injected in conjunction with a variety of medical procedures, including: injection as a septum between the prostate or vagina and rectum in radiotherapy for rectal cancer; injection as a septum between the rectum and prostate in radiotherapy for prostate cancer; subcutaneous injection for palliative treatment of prostate cancer; transurethral or submucosal injection for female stress urinary incontinence; intravesical injection for urinary incontinence; intrauterine injection for Asherman's syndrome; submucosal injection for anal incontinence; percutaneous injection for heart failure; intramyocardial injection for heart failure and dilated cardiomyopathy; transendocardial injection for myocardial infarction; intra-articular injection for osteoarthritis; spinal injection for spinal fusion and spinal, maxillofacial, and orthopedic trauma surgery; spinal injection for posterolateral lumbar fusion; intradiscal injection for degenerative disc disease; and pancreatic and duodenal fusion for pancreatic cancer imaging. Interdigital injections; resection bed injections for oropharyngeal cancer imaging; peritumoral injections for bladder cancer imaging; submucosal injections for gastrointestinal tumors and polyps; visceral pleural injections for lung biopsies; renal injections for type 2 diabetes and chronic kidney disease; renal cortical injections for chronic kidney disease with congenital abnormalities from the kidneys and urethra; injections to increase the engagement of body sphincters (e.g., anal sphincter or urethral sphincter); injections for vas deferens occlusion; injections for fallopian tube occlusion; injections for seminal vesicle duct occlusion; intravitreal injections for neovascular age-related macular degeneration; intratympanic injections for sensorineural hearing loss; injections for correcting wrinkles, creases and folds; signs of facial fat loss; volume reduction; superficial to deep contour defects; correction of depressed skin scars; perioral wrinkles; lip augmentation; facial fat atrophy; dermal injections to stimulate natural collagen production.

[0127] The hydrogel compositions according to this disclosure include smooth compositions for medical applications, compositions for the release of therapeutic agents (e.g., by including one or more therapeutic agents in the matrix of the hydrogel), and implants (which may be formed in vitro or in vivo) (e.g., compositions used as tissue markers, compositions acting as spacers to reduce the side effects of off-target radiation therapy, cosmetic compositions, etc.).

[0128] It should be understood that this disclosure is merely illustrative in many respects and that changes in detail may be made without departing from the scope of this disclosure. This may, to appropriate extent, include using any feature of one embodiment in other embodiments.

Claims

1. A system for forming a hydrogel, the system comprising (i) a reactive multi-arm polymer comprising three or more polymer arms connected to a core region, each arm comprising a polyether segment and a reactive moiety comprising a cyclic imide carboxyl-C1-C5-alkyl ester end group, or each arm comprising a polyether segment and a reactive moiety comprising a C2-C6-isocyanoalkyl end group, and (ii) a polyamine compound comprising at least two amino groups (-NH2), wherein the reactive multi-arm polymer and the polyamine compound react to form an ester-free crosslinked hydrogel having long-term stability in vivo.

2. The system according to claim 1, wherein the reactive portion is a cyclic imide carboxyl-C1-C5-alkyl ester group or a C2-C6-isocyanoalkyl group, and wherein the reactive portion is directly bonded to the polyether segment.

3. The system according to claim 1 or 2, wherein the reactive multi-arm polymer is formed of a multi-arm polymer comprising three or more polymer arms connected to a core region, each arm comprising a polyether segment and a C2-C6-hydroxyalkyl end group.

4. The system of claim 3, wherein the reactive multi-arm polymer is formed by a method comprising: oxidizing the C2-C6-hydroxyalkyl end group to form a C2-C6-carboxyalkyl end group, and reacting the C2-C6-carboxyalkyl end group with an N-hydroxycyclic imide compound in an ester coupling reaction to form the cyclic imide carboxy-C1-C5-alkyl ester end group.

5. The system according to any one of claims 1-4, wherein the polyether segment is a polyethylene oxide segment, and the cyclic imide carboxyl-C1-C5-alkyl ester end group is a cyclic imide carboxylmethyl ester end group.

6. The system according to any one of claims 1-5, wherein the cyclic imide carboxyl-C1-C5-alkyl ester end group is a succinimide carboxylmethyl ester end group.

7. The system of claim 3, wherein the reactive multi-arm polymer is formed by a method comprising: converting the C2-C6-hydroxyalkyl end group to a C2-C6-aminoalkyl end group, and reacting the C2-C6-aminoalkyl end group with phosgene to form the C2-C6-isocyanoalkyl end group.

8. The system according to any one of claims 1-3 and 7, wherein the polyether segment is a polyoxyethylene segment and the C2-C6-isocyanoalkyl end group is an isocyanoethyl end group.

9. The system according to any one of claims 1-8, wherein each of the polyether segments contains 10 to 1000 monomer residues.

10. The system according to any one of claims 1-9, wherein the core region comprises polyol residues.

11. The system according to any one of claims 1-10, wherein the core region is an iodinated core region.

12. The system according to any one of claims 1-11, wherein the polyamino compound comprises a plurality of basic amino acid residues.

13. The system according to any one of claims 1-12, wherein the polyamino compound is an iodinated polyamino compound.

14. The system according to any one of claims 1-13, comprising a first composition containing the polyamine compound in a first container and a second composition containing the reactive multi-arm polymer in a second container.

15. The system according to any one of claims 1-14, further comprising a delivery device.

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