Multi-arm polymers containing free radical polymerizable monomers

Abstract

In some aspects, this disclosure relates to a multi-arm polymer comprising a core and a plurality of polymer segments having a first end covalently bonded to the core and a second end comprising a group containing a reactive group, wherein the polymer segments comprise one or more radically polymerizable monomers. In some aspects, a system is provided comprising a first composition and a second composition, the first composition comprising such a multi-arm polymer and the second composition comprising a multifunctional compound including functional groups reactive with the reactive groups of the multi-arm polymer. In some aspects, a system is provided comprising a crosslinking reaction product of such a multi-arm polymer and such a multifunctional compound.

Description

[0001] (Case number 202080058760.1)

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 892,786, filed August 28, 2019, entitled “Multi-arm Polymers and Compositions Containing Radical Polymerizable Monomers, Systems and Methods for Preparing the Compositions,” the entire disclosure of which is incorporated herein by reference. Technical Field

[0004] This disclosure relates to multi-armed polymers, compositions containing the multi-armed polymers, methods for preparing multi-armed polymers, methods for using multi-armed polymers, and other aspects. The multi-armed polymers of this disclosure can be used for various biomedical applications, for example. Background Technology

[0005] Bio-soluble injectable hydrogels are a newly emerging type of material with a variety of medical applications.

[0006] As a concrete example, in In the case of (a long-term bio-erosive injectable hydrogel based on multi-arm PEG), this product is used to create or maintain spaces between tissues, thereby reducing the side effects of off-target radiotherapy. See “Augmenix Announces Positive Results from Three-Year SpaceOAR Clinical Trial,” Imaging Technology News, October 27, 2016. As another concrete example, Augmenix has developed… Hydrogel, a bio-erodible, injectable synthetic hydrogel primarily composed of water and iodinated crosslinked polyethylene glycol (PEG), is visible under computed tomography (CT), cone-beam, ultrasound, and magnetic resonance (MR) imaging and can be used as a tissue marker (e.g., for targeted radiotherapy). See “Augmenix Receives FDA Market Access Approval Letter for Marketing Its TraceIT™ Tissue Marker,” Business Wire, January 28, 2013. The hydrogel remains stable and visible in tissues for up to three months (long enough for radiation therapy), after which it is absorbed and cleared from the body.

[0007] In the biomedical field, there is a continuous demand for other hydrogels (including biosoluble injectable hydrogels), precursors of such hydrogels, methods for preparing such hydrogels and precursors, methods for using such hydrogels and precursors, systems for forming such hydrogels, and other related needs. Summary of the Invention

[0008] In some respects, this disclosure relates to multi-armed polymers comprising a core, a plurality of polymer segments having a first end covalently bonded to the core and a second end comprising a group (segment, portion) containing a reactive group, wherein the polymer segments comprise one or more radical polymerizable monomers.

[0009] In some embodiments, the polymer segment comprises one or more hydrophilic aprotic monomers. For example, the polymer segment may comprise one or more monomers selected from N-vinylpyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate, and many other monomers.

[0010] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the core of the multi-arm polymer can be a polyol residue core.

[0011] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the reactive group is an electrophile. For example, the reactive group may be selected from N-hydroxysuccinimide esters, imidazole esters, imidazole carboxylic esters, and benzotriazole esters, etc.

[0012] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the reactive group can be a nucleophile. For example, the reactive group can be an amino group or a thiol group, etc.

[0013] In some embodiments that can be used in combination with the above aspects and implementation schemes, the group containing the reactive group may also contain a hydrolyzable ester group.

[0014] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the group containing the reactive group may comprise a diester. For example, the diester may be selected from malondiacrylate, succinic acid diester, glutaric acid diester, and adipate diester, etc.

[0015] In other aspects, systems are provided comprising (a) a first composition comprising a multi-arm polymer according to the foregoing aspects and embodiments, and (b) a second composition comprising a multifunctional compound containing functional groups reactive to the reactive groups of the multi-arm polymer.

[0016] In some embodiments, the reactive group of the multi-arm polymer can be selected from one of an electrophilic group and a nucleophilic group, and the functional group of the multifunctional compound can be selected from another of an electrophilic group and a nucleophilic group. For example, in some embodiments, the reactive group can be an electrophilic group (e.g., N-hydroxysuccinimide ester group, and many other groups), and the functional group can be a nucleophilic group (e.g., an amino group or a thiol group, and many other groups).

[0017] In some embodiments that can be used in combination with the above aspects and implementation schemes, the second composition comprises a polyamine.

[0018] In some embodiments that can be used in combination with the above aspects and implementation methods, the polyamine contains three or more amino groups.

[0019] In some embodiments that can be used in conjunction with the foregoing aspects and implementations, the system may further include a conveying device. For example, the conveying device may include a first reservoir containing a first composition and a second reservoir containing a second composition.

[0020] In many other respects, this disclosure provides (a) crosslinking reaction products of multi-arm polymers according to the foregoing aspects and embodiments and (b) multifunctional compounds according to the foregoing aspects and embodiments.

[0021] In addition to the above, other aspects and embodiments of this disclosure will become readily understood upon reading the following detailed description. Attached Figure Description

[0022] Figure 1 This is a schematic diagram of a method for preparing a reactive multi-arm polymer according to one embodiment of the present disclosure.

[0023] Figure 2 This is a schematic diagram of a method for crosslinking a reactive multi-arm polymer with a multifunctional crosslinking agent according to one embodiment of the present disclosure.

[0024] Figure 3A This is a schematic diagram of a method for forming a multi-arm poly(vinylpyrrolidone) polymer having terminal RAFT polymer groups according to one embodiment of the present disclosure.

[0025] Figure 3B This is a schematic diagram of a method for forming a multi-arm poly(vinylpyrrolidone) with reactive succinimide glutarate groups capped according to one embodiment of the present disclosure. Detailed Implementation

[0026] In various respects, this disclosure relates to a method for polymerizing at least one type of unsaturated, radical polymerizable monomer from a suitable multifunctional initiator molecule.

[0027] The unsaturated radical polymerizable monomers used in this disclosure may be selected from at least the following unsaturated monomers: (a) vinyl monomers, including vinylpyrrolidone, vinyl alcohol, halogenated vinyl compounds (such as vinyl chloride and vinyl fluoride, vinyl imidazole, vinyl ethers, vinyl esters (such as vinyl acetate), acrylonitrile, and vinyl aromatic monomers (such as substituted and unsubstituted styrene); (b) olefin monomers and derivatives, such as ethylene, propylene (e.g., α-propylene, isopropylene), butene (e.g., α-butene, β-butene, isobutene), pentene, etc.; (c) fluorinated unsaturated monomers, including fluorinated olefin monomers (e.g., tetrafluoroethylene, trifluorochloroethylene, vinylidene fluoride, etc.); (d) (meth)acrylate monomers. The monomers and their derivatives, such as acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, glyceryl acrylate, glyceryl methacrylate, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, PEG acrylates and PEG methacrylates, such as PEG methyl ether acrylate and PEG methyl ether methacrylate, acrylamide, methacrylamide, ethyl acrylamide, etc.; (e) nitriles, including acrylonitrile and methacrylonitrile; and (f) diene monomers (such as 1,3-butadiene, chloroprene, and isoprene), and combinations of the aforementioned monomers.

[0028] In specific implementations, the unsaturated radical polymerizable monomer is selected from monomers that are hydrophilic, aprotic, biocompatible, and capable of polymerization via a living polymerization mechanism, enabling controlled polymer construction. Specific examples of such unsaturated radical polymerizable monomers include N-vinylpyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate, etc.

[0029] In various embodiments, reversible addition fragmentation transfer (RAFT) polymerization of at least one type of unsaturated radical polymerizable monomer is performed. In these embodiments, the multifunctional initiator molecule may contain a multifunctional core having multiple RAFT polymerizable groups. Examples of RAFT polymerizable groups include thiocarbonyl thio groups. In some embodiments, the RAFT polymer group may include a dithioester group, a trithiocarbonate group, a dithiocarbonate group (including O-esters of dithiocarbonates (xanthate esters) such as ethyl xanthate), a dithiocarbamate group, and a dithiobenzoate group.

[0030] In some embodiments of this disclosure, multifunctional initiators can be formed by methods including coupling a plurality of RAFT polymeric groups to a polyol molecule. For example, multifunctional initiator molecules can be formed by methods including condensing a polyol with a compound containing a carboxyl group and a thiocarbonyl thio group, or reacting a polytoluenesulfonate with a xanthate. Specific examples of such compounds include 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid, 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, and 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid, etc. In other embodiments, the RAFT polymer group can be coupled to the polyol molecule via, for example, amide coupling, Diels-Alder coupling reaction, etc.

[0031] Illustrative polyols used to form alkoxyamine molecules include, for example: linear, branched, and cyclic aliphatic polyols (including linear, branched, and cyclic polyhydroxy alkanes); linear, branched, and cyclic polyhydroxy ethers and polyhydroxy polyethers; linear, branched, and cyclic polyhydroxy alkyl ethers; and polyhydroxy alkyl polyethers; linear, branched, and cyclic sugars and sugar alcohols, such as glycerol, mannitol, sorbitol, inositol, xylitol, leucosterol, threitol, arabinol, erythritol, arbutinol, euonymus alcohol, fucose, ribose, arabinose, xylose, lysose, rhamnose, galactose, glucose, fructose, sorbitol, mannose, pyranose, arbutin, and taraxerol. Oligomers (defined herein as having two to ten units, including dimers, trimers, tetramers, pentamers, nonamers, or decanters) and polymers (defined herein as having eleven or more units) of linear, branched, and cyclic sugars and sugar alcohols, including the aforementioned sugars and sugar alcohols; starch, amylose, dextrin, cyclodextrin; polyhydroxy crown ethers or polyhydroxy alkyl crown ethers; and 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. In some embodiments, the polyol is an oligomer of a sugar alcohol (such as glycerol, mannitol, sorbitol, inositol, xylitol, or erythritol). In some embodiments, polyols containing two or more hydroxyl groups (e.g., in some cases, between 4 and 12 hydroxyl groups) may be selected.

[0032] In some embodiments, polymerization of at least one type of unsaturated radical polymerizable monomer from a suitable multifunctional initiator molecule can be enhanced by carrying out polymerization in the presence of a radical initiator. Examples of radical initiators include, for example, hydrogen peroxide, organic peroxides (such as di-tert-butyl peroxide, benzoyl peroxide, or methyl ethyl ketone peroxide, etc.), and azo compounds (such as azobisisobutyronitrile (AIBN), or 1,1′-azobis(cyclohexanecarbonitrile) (ABCN), etc.

[0033] Using the above and other techniques, multi-armed polymers with RAFT polymeric end groups (e.g., polymers having 2, 3, 4, 5, 6, 7, 8, 9, 10 or more arms) can be formed. Using the above and other techniques, multi-armed polymers comprising a core (e.g., residues of a polyol) and multiple polymer segments (each having a first end and a second end and each formed by polymerization of at least one type of unsaturated radical polymerizable monomer, wherein the first end is connected to the core and the second end is connected to a RAFT polymeric group) can be formed.

[0034] Following polymerization, in various embodiments, the RAFT polymeric group can be removed to form, for example, a hydroxyl-terminated multiarm polymer. In various embodiments, the RAFT polymeric group can be removed, for example, through a nucleophilic substitution reaction.

[0035] Although the above-described process employs RAFT polymerization, other types of polymerization can also be used to form multi-arm polymers. As an example, such multi-arm polymers can be formed by nitroxide-mediated polymerization (NMP) of at least one type of unsaturated radical polymerizable monomers, for example, where polymerization is carried out from a multifunctional initiator molecule having multiple nitroxy groups, as described in the concurrently pending attorney's patent application No. 8150.0584Z. As another example, such multi-arm polymers can be formed by atom transfer radical polymerization (ATRP) of at least one type of unsaturated radical polymerizable monomers, for example, where polymerization is carried out from a multifunctional initiator molecule having multiple haloalkyl groups in the presence of a copper catalyst. When RAFT is used to form polymer segments, the polymer product can be identified using a measurable amount of residual sulfur. In the case of using NMP to form polymer segments, the polymer product can be identified using a measurable amount of nitroxide radicals. In the case of using ATRP to form polymer segments, the polymer product can be identified using a measurable amount of copper.

[0036] Figure 1The diagram schematically illustrates the formation of such a multi-armed polymer, wherein a core molecule 110 (e.g., a polyol core, etc.) is used to form a multifunctional initiator molecule having multiple polymeric groups 120 (e.g., an initiator molecule containing multiple RAFT polymeric groups, multiple NMP polymeric groups, or multiple ATRP polymeric groups). Subsequently, a suitable unsaturated radical polymerizable monomer 125 (e.g., vinylpyrrolidone, etc.) is polymerized from the multifunctional initiator molecule to form the multi-armed polymer, which includes a core 110 (e.g., a polyol residue, etc.) and multiple polymer segments 130, each polymer segment 130 having a first end and a second end, wherein the first end is connected to the core 110. In the illustrated embodiment, the second end of each polymer segment 130 contains a polymeric group 120 (e.g., a RAFT polymeric group).

[0037] In various embodiments, a reactive multi-armed polymer can be formed, comprising a core and a plurality of polymer segments (each polymer segment having a first end and a second end and each being formed from at least one type of unsaturated radical polymerizable monomer, wherein the first end is connected to the core and the second end contains a reactive group). For example, such as Figure 1 The diagram schematically illustrates that reactive groups 140 may be present at the second end of each polymer segment 130. In some embodiments, the second end comprises a hydrolyzable ester group located between the reactive group and the polymer segment. As described above, when RAFT is used to form the polymer segment, a measurable amount of residual sulfur can be used to identify the reactive multi-arm polymer; when NMP is used to form the polymer segment, a measurable amount of nitroxide radicals can be used to identify the reactive multi-arm polymer; and when ATRP is used to form the polymer segment, a measurable amount of copper can be used to identify the reactive multi-arm polymer.

[0038] The reactive group of the reactive multi-arm polymer can be, for example, an electrophilic group or a nucleophilic group. In some embodiments, the reactive group of the reactive multi-arm polymer can be an electrophilic group selected from imidazole esters, imidazole carboxylic esters, benzotriazole esters, and imide esters (including N-hydroxysuccinimide esters). In some embodiments, the reactive group of the reactive multi-arm polymer can be a nucleophilic group selected from amine and thiol groups.

[0039] In a specific embodiment, the reactive multi-arm polymer can be formed by reacting (a) a polymer comprising a core (e.g., a polyol residue, etc.) and a plurality of polymer segments (each having a first end and a second end, and formed from at least one type of unsaturated radical polymerizable monomer, wherein the first end is connected to the core and the second end contains a hydroxyl group) with (b) a cyclic anhydride (e.g., glutaric anhydride, succinic anhydride, malonic anhydride, etc.) to form a reaction product (c) in the form of a polymer comprising a core and a plurality of polymer segments, wherein the first end of the polymer segments is connected to the core and the second end comprises a moiety (segment, group) comprising a carboxylic acid group and a hydrolyzable ester group located between the carboxylic acid group and the polymer segment. Next, the reaction product (c) can be treated with a coupling agent (e.g., a carbodiimide coupling agent, such as N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxybenzotriazole (HOBt), BOP reagent, and / or another coupling agent) and N-hydroxysuccinimide (NHS) to obtain a multi-arm polymer comprising succinimide end groups, specifically comprising an arm polymer comprising a core and multiple polymer segments, wherein the first end of the polymer segments is connected to the core and the second end comprises a group comprising a hydrolyzable ester group and a succinimide ester group.

[0040] exist Figure 3A In a specific example schematically shown, hexaglycerol (a polyol having eight hydroxyl groups) is condensed with 4-cyano-4-(phenylthiocarbonylthio)valerate to form a multifunctional initiator containing multiple RAFT polymerization groups. See, for example, Wei, Z., Hao, X., Gan, Z., Hughes, TC, “One-pot synthesis of hyperbranched glycerol polymers by RAFT polymerization”, Journal of Polymer Chemistry Part A, 2012, 50(12), 2378-2388. Next, an unsaturated radical polymerizable monomer (N-vinylpyrrolidone) is added along with a radical initiator (AIBN), and the mixture is allowed to react to form an 8-arm PVP, wherein the PVP segments are capped with RAFT polymerization groups. Then, as... Figure 3B The diagram illustrates (that is) Figure 3A(Continued), the thiocarbonyl thio group of the 8-arm PVP is removed via a nucleophilic substitution reaction and a succinimide glutarate group is added using glutaric anhydride and N-hydroxysuccinimide as reactants. See, for example, Willcock, H., O'Reilly, RK, "Removal and Modification of End Groups in RAFT Polymers", Polym. Chem. 2010, 1(2), 149-157; and Lopez-Perez, PM, da Silva, RMP, Strehin, I., Kouwer, PHJ, Leeuwenburgh, SCG; Messersmith, PB, "Self-Healing Hydrogels Formed by Complexation Between Calcium Ions and Bisphosphonate-Functionalized Star Polymers", Macromolecular, 2017, 50(21), 8698-8706.

[0041] The reactive multi-arm polymer formed in the manner described above can be water-soluble. Furthermore, the reactive multi-arm polymer formed in the manner described above can be crosslinked with a suitable crosslinking agent in vivo or in vitro to form a crosslinked hydrogel.

[0042] In some embodiments, the reactive multi-arm polymer can be crosslinked with a multifunctional compound having a functional group reactive to the reactive group of the multi-arm polymer. For example, in some embodiments, the reactive group of the reactive multi-arm polymer is a nucleophilic group, and the functional group of the multifunctional compound is an electrophilic group. In some embodiments, the reactive group of the reactive multi-arm polymer is an electrophilic group, and the functional group of the multifunctional compound is a nucleophilic group. For example, the functional group of the multifunctional compound can be an electrophilic group selected from imidazole esters, imidazole carboxylic esters, benzotriazole esters, and imide esters (including N-hydroxysuccinimide esters). As another example, the functional group of the multifunctional compound can be a nucleophilic group selected from amine and / or thiol groups.

[0043] In some embodiments, the reactive groups of the reactive multi-arm polymer react with the functional groups of the multifunctional compound via an amide coupling reaction.

[0044] In various respects, this disclosure relates to a crosslinkable system comprising: (a) a first composition comprising a reactive multi-arm polymer as described above, the reactive multi-arm polymer comprising a core (e.g., a polyol residue, etc.) and a plurality of polymer segments, each polymer segment having a first end and a second end, and each polymer segment being formed from at least one type of unsaturated radical polymerizable monomer, wherein the first end is connected to the core, and the second end comprises a moiety (moiety, fragment, group) containing a reactive group and, optionally, a hydrolyzable ester group located between the reactive group and the polymer segment; and (b) a second composition comprising a multifunctional compound as described above, the multifunctional compound comprising a functional group reactive with respect to the reactive group. In some embodiments, the reactive group of the reactive multi-arm polymer is an electrophilic group, and the functional group of the multifunctional compound is a nucleophilic group. In some embodiments, the reactive group of the reactive multi-arm polymer reacts with the functional group of the multifunctional compound via an amide coupling reaction.

[0045] In addition to reactive multi-arm polymers, the first composition may also contain, for example, therapeutic agents and / or contrast agents, and other possibilities. In addition to multifunctional compounds, the second composition may also contain, for example, therapeutic agents and / or contrast agents, and other possibilities.

[0046] In various embodiments, the system will include one or more delivery devices for delivering the first and second fluid compositions to a subject. For example, the system may include a delivery device comprising a first reservoir containing the first composition (e.g., a first liquid composition comprising a reactive multi-armed polymer, or a first dry composition comprising a reactive multi-armed polymer compound, to which a suitable fluid (e.g., water for injection, saline, etc.) may be added to form a fluid composition) and a second reservoir containing the second composition (e.g., a second fluid composition comprising a multifunctional compound, or a second dry composition comprising a multifunctional compound, to which a suitable fluid (e.g., water for injection, saline, etc.) may be added to form a fluid composition). During operation, the first and second compositions are dispensed from the first and second reservoirs, and subsequently the first and second compositions interact and crosslink to form a hydrogel.

[0047] In a specific embodiment, the system may include a delivery device comprising a dual-barrel syringe, the dual-barrel syringe comprising a first cylinder having a first cylindrical outlet (the first cylinder containing a first fluid composition), a second cylinder having a second cylindrical outlet (the second cylinder containing a second fluid composition), a first plunger movable in the first cylinder, and a second plunger movable in the second cylinder.

[0048] In some embodiments, the apparatus may further include: a mixing section (the mixing section having a first mixing section inlet in fluid communication with the outlet of the first cylinder), a second mixing section inlet in fluid communication with the outlet of the second cylinder, and a mixing section outlet. In some embodiments, the apparatus may further include a sleeve or conduit configured to receive first and second fluid compositions from the first and second cylinders. For example, the sleeve or conduit may be configured to form a fluid connection with the outlet of the mixing section by attaching the sleeve or conduit to the outlet of the mixing section, for example via a suitable fluid connector (such as a Luer connector).

[0049] As another example, the catheter may be a multi-lumen catheter including a first lumen and a second lumen; the distal end of the first lumen is configured to form a fluid connection with a first cylindrical outlet, and the proximal end of the second lumen is configured to form a fluid connection with a second cylindrical outlet. In some embodiments, the multi-lumen catheter may include a mixing section (the mixing section having a first mixing section inlet in fluid communication with the distal end of the first lumen), a second mixing section inlet in fluid communication with the distal end of the second lumen, and a mixing section outlet.

[0050] During operation, when the first and second plungers are pressed, first and second fluid compositions are dispensed from the first and second cylinders. The first and second fluid compositions then interact and crosslink to form a hydrogel, which is applied to or enters the subject's tissue. For example, the first and second fluid compositions may enter a mixing chamber from the first and second cylinders via first and second mixing chamber inlets, whereby the first fluid composition is mixed with a second fluid composition to form a mixture, which exits the mixing chamber via a mixing chamber outlet. In some embodiments, a cannula or catheter is attached to the mixing chamber outlet, thereby allowing the mixture to be administered to the subject after passing through the cannula or catheter.

[0051] As another example, a first fluid composition may enter a first lumen of a multi-lumen conduit from a first cylindrical outlet, and a second fluid composition may enter a second lumen of the multi-lumen conduit from a second cylindrical outlet. In some embodiments, the first and second fluid compositions may respectively enter a mixing section at the distal end of the multi-lumen conduit from the first and second lumens via first and second mixing section inlets, and then the first and second fluid compositions are mixed in the mixing section to form a mixture, which exits the mixing section via a mixing section outlet.

[0052] In other respects, this disclosure relates to (a) a crosslinked product of a reactive multi-armed polymer as described above and (b) a multifunctional compound as described above; said reactive multi-armed polymer comprising a core and a plurality of polymer segments, each polymer segment having a first end and a second end, and each polymer segment being formed from at least one type of unsaturated radical polymerizable monomer, wherein the first end is connected to the core and the second end comprises a group including a reactive group and optionally a hydrolyzable group located between the reactive group and the polymer segment; said multifunctional compound comprising a functional group reactive to the reactive group. Such a crosslinked product may be formed in vivo (e.g., using a delivery device as described above), or such a crosslinked product may be formed ex vivo and subsequently administered to a subject.

[0053] In various embodiments, the reaction products of the functional groups of the multifunctional compounds having reactive groups of reactive multiarm polymers include amide bonds.

[0054] In some advantageous embodiments, the reactive groups of the first composition used in the above-described system and apparatus and the reactive multi-arm polymer used to form the above-described crosslinking product (i.e., the crosslinking product of the multi-arm polymer described herein and the multifunctional compound described herein) may be selected from imidazole esters, benzotriazole esters, imide esters (including N-hydroxysuccinimide esters), and imidazole carboxylic esters, etc.

[0055] In various embodiments, the multifunctional compound used in the above-described systems and apparatus and in the second composition for forming the above-described crosslinked product can be a polyamine. Generally, suitable polyamines for use in this disclosure include, for example, small molecule polyamines (e.g., containing at least two amino groups, such as 3 to 20 amino groups in some embodiments), comb polymers having amine side groups, and branched polymers having amine end groups (including dendritic polymers having amine end groups).

[0056] Specific examples of polyfunctional amines that can be used as polyfunctional compounds include: trilysine, ethylenetriamine, diethylenetriamine, hexamethyltriamine, di(heptamethyl)triamine, di(trimethylene)triamine, bis(hexamethylene)triamine, triethylenetetramine, tripropylenetetramine, tetraethylenepentamine, hexamethyleneheptylamine, pentaethylenehexamine, dimethyln-octylamine, dimethyldecylamine, and polyetheramines available from Huntsman Corporation, etc. Other specific examples of polyfunctional amines include peptides, including poly(L-lysine), chitosan, and poly(allylamine), etc.

[0057] like Figure 2The diagram schematically illustrates that a reactive multi-arm polymer 210 (e.g., comprising a core and a plurality of PVP segments capped with succinimide groups) as described above is crosslinked with a multifunctional compound 220 (e.g., a polyamine, such as trilysine) containing functional groups that are reactive with the reactive groups of the multi-arm polymer 210 to form a crosslinked product 230.

[0058] Compositions comprising multi-arm polymers as described herein, and compositions comprising crosslinked polymers as described herein (i.e., crosslinked products of multi-arm polymers as described herein and multifunctional compounds as described herein), can be used for a wide range of biomedical applications, including medical devices, implants, and pharmaceutical compositions.

[0059] In various embodiments, compositions comprising the multi-arm polymer described herein and one or more other chemical agents can be formed. In various embodiments, compositions comprising the crosslinked polymer described herein and one or more other chemical agents can be formed.

[0060] Examples of other chemical agents include therapeutic agents and imaging agents, etc.

[0061] Examples of imaging agents include: (a) fluorescent dyes, such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, and cyan fluorescent proteins); and (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including those containing elements that form paramagnetic ions (such as Gd). (III) Mn (II) Fe (III) (c) Contrast agents containing these elements (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid; (d) Contrast agents used in conjunction with ultrasound imaging, comprising organic and inorganic echogenic particles (i.e., particles that increase reflected ultrasound energy) or organic and inorganic anechoic particles (i.e., particles that decrease reflected ultrasound energy); (e) Contrast agents used in conjunction with X-ray fluoroscopy, comprising metals and metal compounds (e.g., metal salts, metal oxides, etc.), such as barium compounds, bismuth compounds and tungsten, and iodide compounds, etc.; (e) Radioactive contrast agents, such as those based on clinically important isotopes 9. 9m Tc contrast agents, as well as other gamma emitters, such as 123 I, 125 I, 131 I, 111 In、 57 Co、 153 Sm、 133 Xe, 51 Cr 81m Kr、 201 Tl、 67 Ga and 75Se, etc.; (f) Positron emitters, such as 18 F, 11 C 13 N、 15 O and 68 Ga, etc., can be used to obtain functionalized radioactive tracer coatings; and (g) contrast agents used in conjunction with near-infrared (NIR) imaging, which can be selectively used to impart near-infrared fluorescence to the coatings disclosed herein, thereby enabling deep tissue imaging and device labeling, such as near-infrared (NIR) sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derived with hydroxyl or carboxyl groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles, such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots, etc. Near-infrared (NIR) sensitive dyes include cyanine dyes, squaric acid cyanine, phthalocyanines, porphyrin derivatives, and borodipyrrolidine methane (BODIPY) analogs, etc.

[0062] The compositions according to this disclosure include: smooth compositions for medical use, compositions for the release of therapeutic agents (e.g., by including one or more therapeutic agents in a matrix of a cross-linked polymer, by encapsulating one or more therapeutic agents with the cross-linked polymer, etc.), and implants (which may be formed ex vivo or in vivo) (e.g., compositions used as tissue markers, compositions acting as spacers for reducing off-target radiation therapy side effects, cosmetic compositions, etc.).

Claims

1. A crosslinking reaction product of (a) a multi-arm polymer and (b) a multifunctional compound, said multi-arm polymer comprising a core and a plurality of polymer arms, each polymer arm having a polymer segment, said arm having a first end covalently connected to said core and a second end containing a reactive group, said polymer segment comprising one or more monomers selected from N-vinylpyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate, and said second end comprising a hydrolyzable ester group located between said reactive group and said polymer segment, said multifunctional compound comprising a functional group reactive to said reactive group.

2. The crosslinking reaction product of claim 1, wherein the reactive group is an electrophilic group and the functional group is a nucleophilic group.

3. The crosslinking reaction product of claim 2, wherein the reactive group is selected from N-hydroxysuccinimide ester, imidazole ester, imidazole carboxylic ester, and benzotriazole ester.

4. The crosslinking reaction product of claim 2, wherein the reactive group is N-hydroxysuccinimide ester.

5. The crosslinking reaction product of any one of claims 1-4, wherein the second end comprises a diester.

6. The crosslinking reaction product of claim 5, wherein the diester is selected from malondiol diester, succinic acid diester, glutaric acid diester and adipate diester.

7. The crosslinking reaction product of any one of claims 2-4, wherein the nucleophilic group is selected from amino and thiol groups.

8. The crosslinking reaction product of claim 7, wherein the nucleophilic group is an amino group.

9. The crosslinking reaction product of claim 8, wherein the polyfunctional compound is a polyamine.

10. The crosslinking reaction product of claim 9, wherein the polyamine comprises three or more amino groups.

11. The crosslinking reaction product of claim 9, wherein the polyamine is triphenylamine.

12. A crosslinking reaction product of (a) a multi-arm polymer and (b) a multifunctional compound, said multi-arm polymer comprising a core and a plurality of polymer segments having a first end covalently bonded to said core and a second end comprising a reactive group, wherein said polymer segments comprise one or more monomers selected from N-vinylpyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate, wherein said reactive group is selected from N-hydroxyethyl methacrylate. The polyfunctional compound comprises a functional group that is reactive to the reactive group of the multi-arm polymer, wherein the polyfunctional compound is a small molecule polyamine selected from trilysine, ethylenetriamine, diethylenetriamine, hexamethylenetriamine, di(heptamethyl)triamine, di(trimethylene)triamine, bis(hexamethylene)triamine, triethylenetetramine, tripropylenetetramine, tetraethylenepentamine, hexamethyleneheptamine, pentaethylenehexamine, dimethyln-octylamine, and dimethyldecylamine.

13. The crosslinking reaction product according to claim 12, wherein the reactive group is N-hydroxysuccinimide ester.

14. The crosslinking reaction product according to claim 12, wherein the small molecule polyamine is trilysine.

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