Suspension of radiopaque cross-linked hydrogel particles in carrier fluid containing biocompatible hydrophilic polymer

Abstract

In some embodiments, the present disclosure relates to an injectable suspension containing radiopaque cross-linked hydrogel particles in a carrier fluid comprising one or more linear hydrophilic polymers. In some embodiments, the present disclosure relates to kits comprising a syringe preloaded with an injectable suspension containing radiopaque cross-linked hydrogel particles in a carrier fluid comprising one or more linear hydrophilic polymers. In some embodiments, the present disclosure relates to methods of treatment comprising injecting an injectable suspension containing radiopaque cross-linked hydrogel particles in a carrier fluid comprising one or more linear hydrophilic polymers into a subject.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 462,852, filed April 28, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention relates to cross-linked hydrogel particles and carrier fluids containing biocompatible hydrophilic polymers, which can be used to form suspensions of cross-linked hydrogel particles. Suspensions of cross-linked hydrogel particles can be used, for example, in various medical applications. Background Technology

[0004] Bioabsorbable hydrogels with a rapid in vivo cross-linking reaction rate (trade name SpaceOAR®) have become an important biomaterial, achieving clinical success in creating space between the prostate and rectum, significantly improving patient safety during cancer treatment. Further improvements based on this application involve functionalizing some 8-arm PEG branches with 2,3,5-triiodobenzamide (TIB) groups, replacing partially activated ester end groups, namely succinimidyl glutarate (SG), to provide the hydrogel itself with inherent radiopaqueness for CT visibility. This hydrogel, traded as SpaceOAR Vue®, represents the next generation of SpaceOAR® for prostate medical applications.

[0005] While the above method is effective, several issues arise due to the introduction of the TIB functional group. First, to functionalize TIB on the 8-arm PEG, each functionalized arm requires sacrificing a succinimide glutarate (SG) binding site, thereby reducing the capacity and efficiency of the in vivo cross-linking reaction. Furthermore, the SG group can begin to degrade in acidic pH environments, potentially leading to longer gelation times and faster dissipation of the cross-linked hydrogel in vivo. Additionally, co-injection of the functionalized 8-arm PEG with trilysine as a cross-linking agent limits the ability to pause the injection process and necessitates a dual-tube syringe.

[0006] For these and other reasons, alternative strategies for forming radiopaque injectable hydrogels are needed. Summary of the Invention

[0007] This disclosure provides alternative methods to the above-described methods.

[0008] In some embodiments, this disclosure relates to an injectable suspension containing radiopaque cross-linked hydrogel particles in a carrier fluid comprising one or more linear hydrophilic polymers.

[0009] In some embodiments, the linear hydrophilic polymer is selected from poly-2-oxazoline, polyvinylpyrrolidone, polyacrylamide, polysaccharides, peptides, polyvinyl alcohol, and poly(2-hydroxyethyl methacrylate).

[0010] In some embodiments that can be used in conjunction with the above embodiments, the weight-average molecular weight (M) of the linear hydrophilic polymer is... w The range is from 1 kDa to 60 kDa.

[0011] In some embodiments that can be used in conjunction with the above embodiments, the carrier fluid contains 1 wt% to 35 wt% of one or more linear hydrophilic polymers.

[0012] In some embodiments that can be used in conjunction with the above embodiments, the radiopaque crosslinked hydrogel particles comprise one or more radiopaque atoms selected from Br, I, Bi, Ba, Gd, Ta, Zn, W, and Au.

[0013] In some embodiments that can be used in conjunction with the above embodiments, the radiopaque cross-linked hydrogel particles contain covalently linked iodine atoms.

[0014] In some embodiments that can be used in conjunction with the above embodiments, the radiopaque cross-linked hydrogel particles comprise a cross-linked polymer comprising one or more of the following: poly(epoxyalkylene) chains, poly(N-vinylpyrrolidone) chains, poly(2-oxazoline) chains, polyacrylamide chains, polysaccharide chains, polypeptide chains, polyvinyl alcohol chains, and poly(2-hydroxyethyl methacrylate) chains.

[0015] In some embodiments that can be used in conjunction with the above embodiments, the radiopaque cross-linked hydrogel particles comprise a cross-linked polymer having a core region and a plurality of polymer arms connected to the core region, each polymer arm comprising a hydrophilic polymer chain.

[0016] In some embodiments that can be used in conjunction with the above embodiments, a portion of the polymer arm includes a portion containing radiopaque atoms at its end.

[0017] In some embodiments that can be used in conjunction with the above embodiments, the radiopaque crosslinked hydrogel particles comprise the following crosslinking reaction products: (a) a reactive multiarm polymer containing a plurality of first reactive moieties comprising electrophilic groups, and (b) a reactive compound having a plurality of second reactive moieties comprising nucleophilic groups.

[0018] In some embodiments that can be used in conjunction with the above embodiments, the injectable suspension contains 1 wt% to 25 wt% (dry weight) of radiopaque cross-linked hydrogel particles relative to the total weight of the suspension.

[0019] In some embodiments that can be used in conjunction with the above embodiments, the radiopaque cross-linked hydrogel particles range from 10 to 1500 micrometers in their longest dimension.

[0020] In some embodiments that can be used in conjunction with the above embodiments, the carrier fluid contains an acidic buffer and has a pH range of 3 to 6.5.

[0021] In some embodiments that can be used in conjunction with the above embodiments, the carrier fluid also contains a therapeutic agent.

[0022] In some embodiments that can be used in conjunction with the above embodiments, the injectable suspension has a radiation impermeability of greater than 100 Hounsfield units (HU).

[0023] In some implementations, the injectable suspension according to any of the above implementations is pre-filled into the syringe.

[0024] In some embodiments, this disclosure relates to a kit comprising a syringe and a delivery device pre-loaded with an injectable suspension according to any of the above embodiments.

[0025] In some implementations, the delivery device includes a catheter and / or a needle.

[0026] In some embodiments, this disclosure relates to treatment methods, including injecting an injectable suspension according to any of the above embodiments into a subject.

[0027] In some implementations, the hydrogel particle suspension is injected to provide spacers between tissues, injected to provide a reference marker, injected for tissue augmentation or regeneration, injected as a filler or replacement for soft tissue, injected to provide mechanical support for damaged tissue, injected as a scaffold, and / or injected as a carrier for one or more therapeutic agents.

[0028] Potential benefits associated with this disclosure include one or more of the following: physicians can pause the injection process without any risk of needle blockage, and only one syringe is used. Furthermore, radiographic efficacy and in vivo persistence are achieved.

[0029] The above and other aspects, implementations, features and benefits of this disclosure will become apparent from the following detailed description. Attached Figure Description

[0030] Figure 1 A conduit and syringe loaded with a suspension of hydrogel particles are schematically shown according to one embodiment of the present disclosure. Detailed Implementation

[0031] This disclosure relates to a suspension of radiopaque cross-linked hydrogel particles in a carrier fluid. The carrier fluid contains one or more linear hydrophilic polymers that act as lubricants and significantly improve the injectability of the radiopaque cross-linked hydrogel particles by reducing injection force.

[0032] The linear hydrophilic polymers according to this disclosure can be selected from a variety of synthetic, natural, or synthetic-natural hybrid hydrophilic polymers. Examples of linear hydrophilic polymers include linear homopolymers and linear copolymers formed from one or more of the following hydrophilic monomers: ethylene oxide, propylene oxide, N-vinylpyrrolidone, oxazoline monomers (e.g., 2-alkyl-2-oxazoline, such as 2-(C1-C6 alkyl)-2-oxazoline, including various isomers such as 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, 2-propyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2-n-butyl-2-oxazoline, 2-n-hexyl-2-oxazoline, etc., and 2-phenyl-2-oxazoline), vinyl alcohol, allyl alcohol, hydroxyethyl acrylate, hydroxyethyl methacrylate, acrylamide, N-isopropylacrylamide, and amino acids.

[0033] The linear hydrophilic polymer may be selected from, for example, any one or a combination of the following homopolymers and copolymers: polyethers, including polyepoxides, such as polyethylene oxide (PEO) (also known as polyethylene glycol or PEG), polypropylene oxide, polyethylene oxide-co-propylene oxide, poly(N-vinylpyrrolidone), poly-2-oxazoline, including poly(2-C1-C6-alkyl-2-oxazoline), such as poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), poly(2-propyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), and poly(2-n-butyl-2-oxazoline), poly(2-phenyl-2-oxazoline), polyvinyl alcohol, polyallyl alcohol, hydroxyethyl polyacrylate, polyhydroxyethyl methacrylate, polyacrylamide and its derivatives, such as poly(N-isopropylacrylamide), and peptides.

[0034] In some embodiments, the linear hydrophilic polymer is PEG. However, some patients are allergic to PEG. Therefore, in other embodiments, a non-PEG hydrophilic polymer is used. In a particularly advantageous embodiment, the linear hydrophilic polymer may be selected from poly-2-oxazoline (which has various side groups that regulate its hydrophilicity), polyvinylpyrrolidone, polyacrylamide, poly(N-isopropylacrylamide), or peptides.

[0035] The length of the linear hydrophilic polymer according to the invention can vary, but typically has a weight-average molecular weight (M) in the range of 1 kDa to 60 kDa. wFor example, any value in the range of 1 kDa to 2 kDa to 5 kDa to 10 kDa to 15 kDa to 20 kDa to 30 kDa to 40 kDa to 50 kDa to 60 kDa (i.e., between any two of the aforementioned values), and other possible values.

[0036] The concentration of one or more linear hydrophilic polymers in the carrier fluid can vary, but typically comprises 1 wt% to 35 wt% relative to the weight of the carrier fluid, for example, in the range of 1 wt% to 2.5 wt% to 5 wt% to 10 wt% to 0.15 wt% to 20 wt% to 25 wt% to 30 wt% to 35 wt%.

[0037] In some implementations, the carrier fluid contains a buffer that can, for example, stabilize particles, maintain gel lifetime, and / or reduce the required injection force.

[0038] For example, in some embodiments, the carrier fluid comprises an acidic buffer solution with a pH range of 3 to 6.5, such as 3.5 to 4.5. Any biocompatible and injectable buffer solution can be used; sodium dihydrogen phosphate is a specific example.

[0039] The carrier fluid may further contain water, which may be in the form of, for example, water for injection, saline, or phosphate-buffered saline.

[0040] The concentration of water in the carrier fluid can vary, but it is typically at least 65 wt% relative to the weight of the carrier fluid.

[0041] The concentration of radiopaque crosslinked hydrogel particles in the suspension can vary, but the suspension typically contains 1 wt% to 25 wt% (dry weight) of radiopaque crosslinked hydrogel particles relative to the total weight of the suspension (e.g., in the range of 1 wt% to 2.5 wt% to 5 wt% to 10 wt% to 15 wt% to 20 wt% to 25 wt%).

[0042] The size of the radiopaque crosslinked hydrogel particles can vary and typically ranges from 10 to 1500 μm in its longest dimension (e.g., the diameter of spherical particles, the length of elongated or rod-shaped particles, the maximum width of plate-shaped particles, etc.) (e.g., ranging from 10 μm to 25 μm to 50 μm to 100 μm to 250 μm to 500 μm to 1000 μm to 1500 μm).

[0043] In some implementations, the suspension may further contain additives, examples of which will be discussed further below.

[0044] The radiopaque crosslinked hydrogel particles of this disclosure include the following crosslinking reaction products: (a) a reactive multiarm polymer containing a plurality of first reactive moieties comprising electrophilic groups, and (b) a reactive compound having a plurality of second reactive moieties comprising nucleophilic groups.

[0045] Reactive multi-arm polymers used to form radiopaque crosslinked hydrogel particles include polymers comprising multiple polymer arms connected to a core region. Some or all of the polymer arms of a reactive multi-arm polymer comprise hydrophilic polymer chains connected to a core region and reactive portions located at the ends of the polymer arms. Reactive multi-arm polymers include polymers having three, four, five, six, seven, eight, nine, ten, fifteen, twenty, or more arms.

[0046] In some embodiments, the reactive multi-arm polymer further comprises one or more radiopaque atoms, which may be selected from, for example, Br, I, Bi, Ba, Gd, Ta, Zn, W, and Au. The one or more radiopaque atoms may be disposed in the core of the reactive multi-arm polymer, between the core and at least one hydrophilic polymer chain, within at least one hydrophilic polymer chain, between at least one hydrophilic polymer chain and a reactive portion at the end of the polymer arm, or at the end of at least one polymer arm. In some cases, the first portion of the polymer arm will each contain a portion containing radiopaque atoms at the end of the polymer arm, and the remaining portions of the polymer arm will each contain a reactive portion at the end of the polymer arm.

[0047] In some embodiments, the first reactive moiety containing the electrophilic group may be selected from succinimidyl ester groups, imidazole ester groups, imidazole carboxylic acid ester groups, and benzotriazole ester groups, etc. In some embodiments, the reactive moiety may be covalently linked to the polymer arm via a hydrolyzable ester group. For example, the reactive moiety may include a diester. In specific examples, the diester may be selected from malonic acid-based diesters, succinic acid-based diesters, glutaric acid-based diesters, and adipic acid-based diesters. In some embodiments, the succinimidyl group is attached to one ester of the diester, and the other ester of the diester is attached to the hydrophilic polymer chain. Specific examples of such reactive moieties include succinimidyl malonic acid ester moieties, succinimidyl succinate moieties, succinimidyl glutaric acid ester moieties, and succinimidyl adipate moieties.

[0048] Hydrophilic polymer chains can be selected from a variety of synthetic, natural, or synthetic-natural hybrid hydrophilic polymer chains. Examples of hydrophilic polymer chains include homopolymer chains and copolymer chains formed from one or more of the following hydrophilic monomers: ethylene oxide, propylene oxide, N-vinylpyrrolidone, oxazoline monomers (e.g., 2-alkyl-2-oxazoline, such as 2-(C1-C6 alkyl)-2-oxazoline, including various isomers such as 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, 2-propyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2-n-butyl-2-oxazoline, 2-n-hexyl-2-oxazoline, etc., and 2-phenyl-2-oxazoline), vinyl alcohol, allyl alcohol, hydroxyethyl acrylate, hydroxyethyl methacrylate, N-isopropylacrylamide, amino acids, and sugars.

[0049] The hydrophilic polymer chain can be selected from, for example, the following copolymer chains: polyether chains, including polyepoxide chains, such as polyethylene oxide (PEO) (also known as polyethylene glycol or PEG) chains, polypropylene oxide chains, polyethylene oxide-co-propylene oxide chains, poly(N-vinylpyrrolidone) chains, polyoxazoline chains, including poly(2-C1-C6-alkyl-2-oxazoline) chains, such as poly(2-methyl-2-oxazoline) chains, poly(2-ethyl-2-oxazoline) chains, poly(2-propyl-2-oxazoline) chains, poly(2-isopropyl-2-oxazoline) chains and poly(2-n-butyl-2-oxazoline) chains, poly(2-phenyl-2-oxazoline) chains, polyvinyl alcohol chains, polyallyl alcohol chains, polyhydroxyethyl acrylate chains, polyhydroxyethyl methacrylate chains, and poly(N-isopropylacrylamide) chains.

[0050] The hydrophilic polymer chains used in the multi-arm polymers of this disclosure typically contain 10 to 2000 monomer units (e.g., 10 to 20 to 50 to 100 to 200 to 500 to 1000 to 2000 monomer units). In some embodiments, the hydrophilic polymer chains have the same monomer composition as linear hydrophilic polymers.

[0051] The core region may be selected from residues of a polyol containing two or more hydroxyl groups, which are used to form the copolymer arm. In some advantageous embodiments, the core region includes residues of a polyol containing two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more hydroxyl groups.

[0052] Exemplary polyols may be selected from, for example, linear, branched, and cyclic aliphatic polyols (including linear, branched, and cyclic polyhydroxy alkanes), linear, branched, and cyclic polyhydroxy ethers (including polyhydroxy polyethers), linear, branched, and cyclic polyhydroxy alkyl ethers (including polyhydroxy alkyl polyethers), linear, branched, and cyclic sugars and sugar alcohols (e.g., glycerol, mannitol, sorbitol, inositol, xylitol, styraxyl alcohol, threitol, arabinol, erythritol, pentaerythritol, dipentaerythritol, tripentaerythritol, arabinol, hexaglycerol, galactitol, fucose, ribose, arabinose, xylose, etc.). Polyols include threose, rhamnose, galactose, glucose, fructose, sorbitol, mannose, pyranose, atroose, tarose, tagatose, pyranoside, sucrose, lactose, and maltose; polymers of linear, branched, and cyclic sugars and sugar alcohols (defined herein as two or more units) (including oligomers of linear, branched, and cyclic sugars and sugar alcohols (defined herein as two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptomers, octamers, nonamerms, and decamers); sugars and sugar alcohols include the aforementioned sugars and sugar alcohols, starch, amylose, dextrin, cyclodextrin, 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. Exemplary polyols also include polyhydroxylated polymers. For example, in some embodiments, the core region comprises polyhydroxylated polymer residues, such as poly(vinyl alcohol) residues, poly(allyl alcohol), polyhydroxyethyl acrylate residues, or polyhydroxyethyl methacrylate residues. The length of such polyhydroxylated polymer residues can range from, for example, 5 to 1000 units, and is typically 10 to 25 units.

[0053] In other embodiments, the core region comprises a silsesquioxane. A silsesquioxane is a compound having a cage-like silicon-oxygen core composed of Si-O-Si bonds and tetrahedral Si vertices. -H groups or external organic groups may be covalently attached to the cage-like silicon-oxygen core. In this disclosure, the organic groups include copolymer arms. Silsesquioxanes used in this disclosure include silsesquioxanes with 6 Si vertices, silsesquioxanes with 8 Si vertices, silsesquioxanes with 10 Si vertices, and silsesquioxanes with 12 Si vertices, which can serve as the core of 6-arm, 8-arm, 10-arm, and 12-arm polymers, respectively. The silicon-oxygen core is sometimes referred to as a T6, T8, T10, and T12 cage-like silicon-oxygen core (where T = the number of tetrahedral Si vertices). In all cases, each Si atom is bonded to three O atoms, while the oxygen atom is bonded to other Si atoms. Silsesquioxanes include those with the chemical formula [RSiO]. 3 / 2 ] nCompounds, where n is an integer of at least 6, typically 6, 8, 10, or 12 (thus having T6, T8, T... respectively). 10 or T 12 The T8 cage-like siloxane core (R8) is selected from a series of organic functional groups, such as alkyl, aryl, alkoxy, and polymer arms. The T8 cage-like siloxane core has been extensively studied, and its formula is [RSiO8]. 3 / 2 ]8, or equivalently R8Si8O 12 The structure is as follows: In this disclosure, the R group includes the polymer arm described herein.

[0054] As previously described, the radiopaque crosslinked hydrogel particles of this disclosure comprise crosslinking reaction products of the following substances: (a) a reactive multi-arm polymer containing a plurality of first reactive moieties comprising electrophilic groups, such as those described above, and (b) a reactive compound having a plurality of second reactive moieties comprising nucleophilic groups (e.g., amine moieties and / or thiol moieties, etc.), wherein at least one of the reactive multi-arm polymer and the reactive compound having a plurality of second reactive moieties comprising nucleophilic groups comprises one or more radiopaque atoms.

[0055] In various embodiments, the reactive compound having multiple second reactive moieties comprising nucleophilic groups is a polyamine compound. Typically, polyamine compounds suitable for this disclosure include, for example, small molecule polyamines (e.g., containing at least two amino groups, e.g., 3 to 20 or more amino groups in some embodiments), polymers having amine side groups, and branched polymers having amine terminal groups, including dendritic polymers with amine terminal groups. Polyamine compounds suitable for this disclosure include those containing multiple -(CH2) groups. x Those with -NH2 groups, where x is 0, 1, 2, 3, 4, 5, or 6. Polyamine compounds suitable for use in this disclosure include those comprising basic amino acid residues (including amino acid residues having two or more primary amino groups, such as lysine and ornithine), for example, polyamines comprising 2 to 10 lysine and / ornithine amino acid residues (e.g., dilysine, trilysine, tetralysine, pentalysine, diornithine, triornithine, tetraornithine, pentaornithine, etc.).

[0056] Specific examples of 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, chitosan and its derivatives and poly(allylamine), which are available from Huntsman Corporation.

[0057] In some embodiments, the reactive compound having a plurality of second reactive moieties containing nucleophilic groups further comprises one or more radiopaque atoms, selected from, for example, Br, I, Bi, Ba, Gd, Ta, Zn, W, and Au.

[0058] Whether provided in a reactive multi-arm polymer containing multiple first reactive moieties comprising electrophilic groups and / or in a reactive compound having multiple second reactive moieties comprising nucleophilic groups, in some embodiments, one or more radiopaque atoms are iodine atoms, which may be provided in the covalently linked iodide moieties. In some of these embodiments, the iodide moieties comprise iodinated aromatic groups. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as phenyl iodide, naphthyl iodide, anthraceneyl iodide, phenanthrene iodide, or tetraphenyl iodide. The iodinated aromatic group may be substituted with one, two, three, four, five, six, or more iodine atoms. In some of these embodiments, the aromatic group may be further substituted with one or more hydrophilic groups, such as one, two, three, four, five, six, or more hydrophilic groups. The hydrophilic group may be a hydroxyl-containing group, which may be selected, for example, hydroxyl and hydroxyalkyl (e.g., hydroxyalkyl containing one, two, three, four, or more carbons).

[0059] Specific examples of the iodination moiety include those comprising one or more monocyclic or polycyclic aromatic structures, which are substituted by (a) one or more iodine groups (e.g., one, two, four, five, six or more iodine atoms) and (b) optionally one or more hydroxyl groups, said hydroxyl groups being independently selected from one or more hydroxyl groups and / or one or more C1-C4-hydroxyalkyl groups (e.g., C1-C4-monohydroxyalkyl, C1-C4-dihydroxyalkyl, C1-C4-trihydroxyalkyl, C1-C4-tetrahydroxyalkyl, etc.), wherein the C1-C4-hydroxyalkyl group may be directly or via any suitable linking moiety selected from, for example, ether, ester, amide, amino, or carbonate groups.

[0060] Transmissive crosslinked hydrogel particles can be provided by first combining (a) a reactive multi-arm polymer containing a plurality of first reactive moieties comprising electrophilic groups (e.g., as described above) and (b) a reactive compound having a plurality of second reactive moieties comprising nucleophilic groups (e.g., as described above) under conditions that cause the electrophilic and nucleophilic groups to crosslink with each other. In some embodiments, those conditions include an environment with an alkaline pH, for example, a pH range of about 9 to about 11.

[0061] Crosslinking reactions produce radiopaque crosslinked hydrogels, which can be broken down into hydrogel particles. For example, radiopaque crosslinked hydrogels can be granulated into radiopaque crosslinked hydrogel particles of suitable size. Granulation can be performed by any suitable method, such as processing the radiopaque crosslinked hydrogel in a homogenizer, grinding (including cryogenic grinding), crushing, milling, or pulverizing. The radiopaque crosslinked hydrogel particles can be classified and graded using sieving or other known techniques. The size of the radiopaque crosslinked hydrogel particles formed using the above and other techniques can vary considerably, for example, as mentioned above, with an average size of 10-1500 μm.

[0062] Examples of radiopaque cross-linked hydrogel particles used in this disclosure also include polysaccharide particles containing one or more cross-linked polysaccharides and one or more radiopaque atoms. Specific examples of cross-linked polysaccharide particles include hydrogel particles containing cross-linked anionic polysaccharides, cross-linked cationic polysaccharides, and cross-linked neutral polysaccharides.

[0063] Anionic polysaccharides include carboxylic acid polysaccharides containing one or more uronic acids, such as galacturonic acid, glucuronic acid, and / or iduronic acid. Specific examples of carboxylic acid polysaccharides include pectin, agarose gel, carrageenan, gellan gum, gum arabic, guar gum, xanthan gum, alginic acid, hyaluronic acid, and carboxymethyl cellulose. In embodiments where the carboxylic acid polysaccharide is hyaluronic acid, the carboxylic acid polysaccharide can be a non-animal-derived stable hyaluronic acid. Another specific example of anionic polysaccharides is agar, which is a polysaccharide mixture containing agarose (a neutral polysaccharide) and agarose gel (a charged sulfated polysaccharide). Other specific examples of anionic polysaccharides include carboxyalkyl cellulose, such as carboxymethyl cellulose. Cationic polysaccharides include polysaccharides containing positively charged functional groups such as amine functional groups, including primary, secondary, tertiary, and quaternary amino groups. Specific examples of cationic polysaccharides include chitosan and cationic starch. Neutral polysaccharides include cellulose derivatives, including alkyl cellulose (such as methylcellulose and ethylcellulose) and hydroxyalkyl cellulose (such as hydroxyethylcellulose and hydroxypropylcellulose). Neutral polysaccharides also include starches, such as corn starch, potato starch, and tapioca starch.

[0064] The radiopaque atoms used for crosslinking polysaccharide particles can be selected from, for example, Br, I, Bi, Ba, Gd, Ta, Zn, W, and Au. In some embodiments, when one or more radiopaque atoms are iodine atoms, the one or more iodine atoms can be provided in the form of a covalently linked iodide moiety. In some of these embodiments, the iodide moiety includes aryl iodide, examples of which are described above.

[0065] As previously described, in various embodiments, the injectable hydrogel particle suspension of this disclosure contains one or more additives. Examples of such additives include therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, and wetting agents.

[0066] Examples of therapeutic agents include antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, anticancer drugs, antiproliferative agents, anti-inflammatory agents, proliferative inhibitors, antirestenosis agents, steroids, antiallergic agents, hemostatic agents, smooth muscle cell inhibitors, antibiotics, antibacterial agents, antifungal agents, analgesics, anesthetics, immunosuppressants, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, antiangiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T-cell agonists, and STING (interferon gene stimulator) agonists, etc.

[0067] Other specific 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, and (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. (d) Contrast agents used in conjunction with near-infrared (NIR) imaging, which may be selectively used to impart near-infrared fluorescence to the hydrogel particle suspension of this disclosure, thereby allowing 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, such as partially oxidized carbon nanotubes), dye-containing nanoparticles, such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots, etc., and NIR-sensitive dyes, such as cyanine dyes. (e) Imageable radioactive isotopes, including 99mTc, 201Th, 51Cr, 67Ga, 68Ga, 111In, 64Cu, 89Zr, 59Fe, 42K, 82Rb, 24Na, 45Ti, 44Sc, 51Cr and 177Lu, and (f) radiocontrast agents (excluding radiopaque atoms in cross-linked polysaccharide particles), such as metal particles, such as tantalum, tungsten, rhenium, niobium, molybdenum and their alloys, wherein the metal particles 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®).

[0068] Examples of colorants include Brilliant Blue (e.g., Brilliant Blue FCF, also known as FD&C Blue 1), Indigo Carmine (also known as FD&C Blue 2), Indigo Carmine Lake, FD&C Blue 1 Lake, and Methylene Blue (also known as Methylene Blue Chloride), etc.

[0069] Examples of additives also 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 and wetting agents.

[0070] In various embodiments, the hydrogel particle suspensions of this disclosure are visible under fluorescence fluoroscopy. In various embodiments, the hydrogel particle suspensions have a radiation impermeability greater than 100 Huntsfield units (HU), advantageously in the range of 100 HU to 250 HU to 500 HU to 750 HU to 1000 HU to 2000 HU or higher (in other words, within the range between any two of the aforementioned values). Such hydrogel particle suspensions are applicable to a variety of biomedical applications, including implants, medical devices, and pharmaceutical compositions. The hydrogel particle suspensions of this disclosure can be stored and transported in a sterile form. The hydrogel particle suspensions can be transported via, for example, syringes, catheters, vials, ampoules, or other containers.

[0071] In various embodiments, kits are provided that include one or more delivery devices for delivering a suspension of hydrogel particles to a subject. Such kits may include one or more of the following: a syringe tubing, which may or may not contain the carrier fluid and / or radiopaque cross-linked hydrogel particles described herein; a vial, which may or may not contain the carrier fluid and / or radiopaque cross-linked hydrogel particles described herein; a needle; a flexible tube (e.g., adapted to connect the needle to the syringe fluid); and an injectable liquid, such as water for injection, physiological saline, or phosphate-buffered saline. The carrier fluid is typically provided in a syringe or vial. Whether provided in the form of a syringe, vial, or other reservoir, the radiopaque cross-linked hydrogel particles may be provided in a dry form (e.g., powder form) or in a ready-for-injection form (e.g., as a suspension of radiopaque cross-linked hydrogel particles in a carrier fluid).

[0072] For example, Figure 1An exemplary syringe 10 is shown, providing a reservoir for the hydrogel particle suspension described herein. 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 connector (or other suitable 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 examples, the tube 12 may be directly connected to the injection needle 50. The injection tube 12 can be used as a reservoir for containing a hydrogel particle suspension 15 for injection via the needle 50.

[0073] The hydrogel particle suspension described in this article can be used for a variety of purposes.

[0074] For example, in applications such as the treatment of diseases and cancers, as well as tissue repair and regeneration, hydrogel particle suspensions can be injected to provide spacers between tissues, hydrogel particle suspensions (e.g., in the form of bubbles) can be injected to provide reference markers, hydrogel particle suspensions can be injected for tissue enlargement or regeneration, hydrogel particle suspensions can be used as fillers or substitutes for soft tissues, hydrogel particle suspensions can be injected to provide mechanical support for damaged tissues, hydrogel particle suspensions can be injected as scaffolds, and / or hydrogel particle suspensions can be injected as carriers of therapeutic agents.

[0075] After application, the hydrogel particle suspension of this disclosure can be imaged using suitable imaging techniques.

[0076] As described above, the hydrogel particle suspension of this disclosure can be used in various medical procedures, including the following: procedures for implanting a reference marker containing a radiopaque cross-linked hydrogel; procedures for implanting a tissue regeneration scaffold containing a radiopaque cross-linked hydrogel; procedures for implanting a tissue support containing a radiopaque cross-linked hydrogel; procedures for implanting a tissue bulking agent containing a radiopaque cross-linked hydrogel; procedures for implanting a therapeutic agent depot containing a radiopaque cross-linked hydrogel; tissue enlargement procedures involving the implantation of a radiopaque cross-linked hydrogel; and procedures for introducing a radiopaque cross-linked hydrogel between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0077] Hydrogel particle suspensions can be injected with various medical procedures, including: interstitial injection between the prostate or vagina and rectum in radiotherapy for rectal cancer; interstitial 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; transendocardial injection for myocardial infarction; intra-articular injection for osteoarthritis; spinal injection for spinal fusion and spinal, maxillofacial, and orthopedic trauma surgery; and spinal injection for posterolateral lumbar fusion. Intradiscal injection for degenerative disc diseases; inter-pancreatic and duodenal injection for pancreatic cancer imaging; resection bed injection for oropharyngeal cancer imaging; peritumoral injection for bladder cancer imaging; submucosal injection for gastrointestinal tumors and polyps; visceral pleural injection for lung biopsy; renal injection for type 2 diabetes and chronic kidney disease; renal cortical injection for chronic kidney disease with congenital abnormalities from the kidneys and urethra; intravitreal injection for neovascular age-related macular degeneration; intratympanic injection for sensorineural hearing loss; correction of 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 injection to stimulate natural collagen production.

Claims

1. An injectable suspension comprising radiopaque cross-linked hydrogel particles in a carrier fluid, said carrier fluid comprising one or more linear hydrophilic polymers.

2. The injectable suspension according to claim 1, wherein the linear hydrophilic polymer is selected from poly-2-oxazoline, polyvinylpyrrolidone, and polyacrylamide.

3. The injectable suspension according to claim 1 or claim 2, wherein the linear hydrophilic polymer has a weight-average molecular weight (M... w The range is from 1 kDa to 60 kDa.

4. The injectable suspension according to any one of claims 1-3, wherein the carrier fluid contains 1 wt% to 35 wt% of the one or more linear hydrophilic polymers.

5. The injectable suspension according to any one of claims 1-4, wherein the radiopaque cross-linked hydrogel particles comprise covalently linked iodine atoms.

6. The injectable suspension according to any one of claims 1-5, wherein the radiopaque cross-linked hydrogel particles comprise a cross-linked polymer, the cross-linked polymer comprising one or more of the following: poly(epoxyalkylene) chains, poly(N-vinylpyrrolidone) chains, poly(2-oxazoline) chains, polyacrylamide chains, polysaccharide chains, polypeptide chains, polyvinyl alcohol chains, and poly(2-hydroxyethyl methacrylate) chains.

7. The injectable suspension according to any one of claims 1-6, wherein the radiopaque crosslinked hydrogel particles comprise a crosslinked polymer having a core region and a plurality of polymer arms connected to the core region, each polymer arm comprising a hydrophilic polymer chain.

8. The injectable suspension of claim 7, wherein a portion of the polymer arm comprises a portion containing radiopaque atoms at its end.

9. The injectable suspension according to any one of claims 1-8, wherein the radiopaque crosslinked hydrogel particles comprise the following crosslinking reaction products: (a) a reactive multiarm polymer containing a plurality of first reactive moieties comprising electrophilic groups, and (b) a reactive compound having a plurality of second reactive moieties comprising nucleophilic groups.

10. The injectable suspension according to any one of claims 1-9, wherein the injectable suspension contains 1 wt% to 25 wt% (dry weight) of radiopaque cross-linked hydrogel particles relative to the total weight of the suspension.

11. The injectable suspension according to any one of claims 1-10, wherein the radiopaque cross-linked hydrogel particles range from 10 to 1500 micrometers in their longest dimension.

12. The injectable suspension according to any one of claims 1-11, wherein the carrier fluid contains an acidic buffer and has a pH range of 3 to 6.

5.

13. The injectable suspension according to any one of claims 1-12, wherein the injectable suspension has a radiation impermeability of greater than 100 Huntsfield units (HU).

14. The injectable suspension according to any one of claims 1-13, pre-filled in a syringe.

15. A kit comprising a syringe pre-loaded with the injectable suspension of any one of claims 1-14 and a delivery device.

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