Systems and methods for accelerating hydrolysis of polysaccharide-based hydrogels

Abstract

In some aspects, the present disclosure provides a kit for delivering and hydrolyzing a crosslinked polysaccharide hydrogel, the kit comprising: (a) a hydrogel delivery system configured to deliver a crosslinked polysaccharide hydrogel to a subject, the crosslinked polysaccharide hydrogel comprising polysaccharide molecules crosslinked by crosslinks comprising hydrolysable ester bonds, and (b) a hydrogel hydrolysis system configured to deliver a hydrolysis-accelerating catalytic composition to the subject, the hydrolysis-accelerating catalytic composition being suitable for accelerating hydrolysis of the hydrolysable ester bonds in the crosslinked polysaccharide hydrogel. In other aspects, the present disclosure provides methods of using the system.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 620,056, filed January 11, 2024, the disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to systems and methods for accelerating the hydrolysis of polysaccharide-based hydrogels. Such systems and methods can be used, for example, to remove hydrogels from a patient. Background Technology

[0003] Injectable hydrogels are a newly emerging class of materials with a variety of medical applications. As a specific example, injectable hydrogels have been used to create or maintain spaces between tissues to reduce the side effects of radiation therapy that deviates from its target. The hydrogel forms a space between the rectum and prostate, removing the rectum from the treatment area. This can help reduce radiation exposure to the rectum and / or provide other desired benefits.

[0004] An example of a hydrogel-based perirectal septum material is an injectable hyaluronic acid hydrogel, available as Barrigel®. Barrigel® is crosslinked with 1,4-butanediol diglycidyl ether (BDDE) under alkaline conditions, thereby creating ether bonds between the hyaluronic acid chains and generating a three-dimensional network. However, the covalent bonds generated by this method do not have tunable degradation capability.

[0005] exist Figure 1A and 1B The image schematically illustrates the use of a hydrogel-based perirectal septum material combined with prostate radiotherapy. Figure 1A A cross-section of the human male anatomy, including the prostate 110 and the rectal wall 112, is shown. When the prostate is treated with radiation therapy, a higher dose region 114 exists near the prostate receiving high-dose radiation, which becomes a lower dose region 116 as it moves away from the prostate 110. Figure 1B As shown, a spacer material 118 can be injected between the prostate 110 and the rectal wall 112, which can push the rectal wall from the higher dose area 114 to the lower dose area 116, thereby reducing damage to the rectal wall.

[0006] Those skilled in the art will understand that inserting spacers into a patient can lead to complications such as patient discomfort, hydrogel seepage into the rectal wall, and urinary retention. Furthermore, improper placement of the spacer may reduce its effectiveness. Although these complications are extremely rare, there is clinical interest in potentially reversing the placement if necessary. This document discloses systems and methods for improving patient comfort, improving spacer effectiveness, resolving improper spacer placement, combinations thereof, and / or other benefits. For example, such systems can be used to accelerate the hydrolysis of hydrogels, including accelerating the hydrolysis of hydrogel-based spacers. Summary of the Invention

[0007] In some aspects, this disclosure provides a kit for delivering and hydrolyzing cross-linked polysaccharide hydrogels, the kit comprising: (a) a hydrogel delivery system configured to deliver a cross-linked polysaccharide hydrogel to a subject, the cross-linked polysaccharide hydrogel containing polysaccharide molecules cross-linked by cross-linking bonds comprising hydrolyzable ester bonds; and (b) a hydrogel hydrolysis system configured to deliver a hydrolysis-accelerating catalytic composition to a subject, the hydrolysis-accelerating catalytic composition being adapted to accelerate the hydrolysis of the hydrolyzable ester bonds in the cross-linked polysaccharide hydrogel.

[0008] In some embodiments, the hydrolysis-accelerating catalytic composition comprises a hydrolysis-accelerating catalyst selected from hydroxide catalysts and enzyme proteins.

[0009] In some embodiments that can be used in conjunction with the above aspects and implementations, the hydrolysis accelerating catalytic composition is pre-packaged in a hydrolysis injector system.

[0010] In some embodiments that can be used in conjunction with the above aspects and implementations, the hydrogel hydrolysis system further includes a needle, a flexible tube, or both, and wherein the hydrolysis injector system is configured to be coupled to the needle, flexible tube, or both.

[0011] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the hydrogel delivery system comprises a pre-formed cross-linked polysaccharide hydrogel. In some of these embodiments, the pre-formed cross-linked polysaccharide hydrogel comprises cross-linked polysaccharide hydrogel particles, which may, for example, be pre-packaged in a delivery syringe system. In some of these embodiments, the hydrogel delivery system may further comprise a needle, a flexible tube, or both, and the delivery syringe system may be configured to engage with the needle, flexible tube, or both.

[0012] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the hydrogel delivery system comprises a carboxylated polysaccharide, a polyol, and an ester coupling agent. In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the hydrogel delivery system is configured to form a mixture of the carboxylated polysaccharide, the polyol, and the ester coupling agent, and to deliver the mixture to a subject, whereby the carboxylated polysaccharide and the polyol form the crosslinks with each other. In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the hydrogel delivery system comprises a delivery syringe system configured to form a mixture of the carboxylated polysaccharide, the polyol, and the ester coupling agent, and to deliver the mixture to a subject, whereby the carboxylated polysaccharide and the polyol form the crosslinks with each other. For example, the delivery syringe system may include a dual-tube syringe device for preparing and delivering the mixture of the carboxylated polysaccharide, the polyol, and the ester coupling agent.

[0013] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the hydrogel delivery system comprises a hydroxyl polysaccharide, a polycarboxylic acid molecule, and an ester coupling agent. In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the hydrogel delivery system is configured to form a mixture of the hydroxyl polysaccharide, the polycarboxylic acid molecule, and the ester coupling agent, and to deliver the mixture to a subject, whereby the hydroxyl polysaccharide and the polycarboxylic acid molecule form cross-links with each other. In some of these embodiments, the hydrogel delivery system comprises a delivery syringe system configured to form a mixture of the hydroxyl polysaccharide, the polycarboxylic acid molecule, and the ester coupling agent, and to deliver the mixture to a subject, whereby the hydroxyl polysaccharide and the polycarboxylic acid molecule form the cross-links with each other. For example, the delivery syringe system may include a dual-tube syringe device for preparing and delivering the mixture of the hydroxyl polysaccharide, the polycarboxylic acid molecule, and the ester coupling agent.

[0014] Other aspects of this disclosure relate to a method comprising the steps of: (a) delivering a cross-linked polysaccharide hydrogel to a subject, the cross-linked polysaccharide hydrogel containing polysaccharide molecules cross-linked by cross-linking bonds comprising hydrolyzable ester bonds; and (b) delivering a hydrolysis-accelerating catalytic composition to the subject, such that the hydrolysis-accelerating catalytic composition contacts the cross-linked polysaccharide hydrogel, the hydrolysis-accelerating catalytic composition acting to accelerate the hydrolysis of the hydrolyzable ester bonds in the cross-linked polysaccharide hydrogel.

[0015] In some embodiments, the method includes: delivering the cross-linked polysaccharide hydrogel to a subject via a delivery syringe system coupled to a needle; disconnecting the delivery syringe system from the needle; connecting a hydrolysis syringe system to the needle, the hydrolysis syringe system including a hydrolysis-accelerating catalytic composition disposed in a syringe tube; and injecting the hydrolysis-accelerating catalytic composition into the subject.

[0016] In some embodiments that can be used in conjunction with the foregoing aspects and implementation methods, the method further includes observing complications associated with the delivery of the cross-linked polysaccharide hydrogel to the subject prior to the injection of the hydrogel hydrolysate into the subject. For example, the complications may include improper placement of the cross-linked polysaccharide hydrogel and / or subject discomfort.

[0017] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the method further includes delivering an alternative cross-linked polysaccharide hydrogel into the subject.

[0018] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the cross-linked polysaccharide hydrogel provides spacing between the subject's tissues, and the method further includes treating the subject with radiotherapy.

[0019] The above and other aspects, implementations, features and benefits of this disclosure will become apparent from the following detailed description. Attached Figure Description

[0020] Figure 1A and 1B The use of a hydrogel-based perirectal septum material combined with prostate radiotherapy is illustrated schematically according to the prior art.

[0021] Figure 2A The diagram schematically illustrates the formation of a cross-linked polysaccharide having ester-containing cross-linking bonds according to one embodiment of the present disclosure.

[0022] Figure 2B This schematically illustrates one embodiment of the present disclosure, using esterase acceleration. Figure 2A Hydrolysis of cross-linked polysaccharides.

[0023] Figure 3 A method for forming a non-iodinated polymeric polyol according to one embodiment of the present disclosure is illustrated schematically.

[0024] Figure 4 A method for forming iodinated polymeric polyols according to one embodiment of the present disclosure is illustrated schematically.

[0025] Figure 5The diagram schematically illustrates the formation of an iodinated cross-linked polysaccharide having ester-containing cross-linking bonds according to one embodiment of the present disclosure.

[0026] Figure 6 This is a diagram of a region of the human body.

[0027] Figure 7 It shows Figure 6 Placement of cross-linked polysaccharide hydrogel spacers in the human body region shown.

[0028] Figure 8 The delivery of the hydrolysis-accelerating catalytic composition to... Figure 7 Cross-linked polysaccharide hydrogel spacers.

[0029] Figure 9 This demonstrates the effect after accelerated hydrolysis of the cross-linked polysaccharide hydrogel spacer. Figure 8 The human body region.

[0030] Figure 10 A pre-filled syringe containing an injectable hydrolysis-accelerating catalytic composition is schematically shown according to one embodiment of the present disclosure.

[0031] Figure 11 A delivery device for delivering cross-linked polysaccharide hydrogels is schematically illustrated according to one embodiment of the present disclosure.

[0032] Figure 12 A delivery device for in-situ formation of cross-linked polysaccharides is schematically illustrated according to one embodiment of the present disclosure. Detailed Implementation

[0033] In some aspects, this disclosure relates to a method for accelerating the hydrolysis and degradation of cross-linked polysaccharide hydrogels in situ (i.e., within a subject). The cross-linked polysaccharide hydrogel comprises cross-linking bonds between polysaccharide chains within the hydrogel, the cross-linking bonds comprising hydrolyzable ester bonds. The method includes contacting the cross-linked polysaccharide hydrogel with a hydrolysis-accelerating catalytic composition suitable for accelerating the hydrolysis of ester bonds within the cross-linking bonds. Contact may include, for example, applying the hydrolysis-accelerating catalytic composition to a surface of the cross-linked polysaccharide hydrogel, injecting the hydrolysis-accelerating catalytic composition into the cross-linked polysaccharide hydrogel, etc.

[0034] As used herein, a "hydrogel" is a cross-linked polymer that contains or is able to absorb water but does not dissolve when placed in water.

[0035] Preferred subjects include mammalian subjects, especially human subjects.

[0036] In some of these embodiments, cross-linked polysaccharides are provided, wherein the carboxylic acid-containing polysaccharide is covalently linked to a polyol via an ester group. For example, cross-linked polysaccharides can be formed via an esterification reaction between the carboxylic acid group of the carboxylic acid-containing polysaccharide and the hydroxyl group of the polyol, with the polyol acting as the cross-linking agent for the carboxylic acid-containing polysaccharide. The ester coupling between the carboxylic acid group and the hydroxyl group can be carried out in the presence of a suitable coupling agent, such as a carbodiimide coupling agent, like N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or N,N'-diisopropylcarbodiimide (DIC). The formed ester bond is hydrolyzable.

[0037] For example, now refer to Figure 2A In the presence of a suitable coupling agent (such as DCC or EDC), during ester coupling, the carboxyl group of a carboxylic acid (particularly hyaluronic acid (212)) can react with the hydroxyl group of a polyol molecule (particularly linear dihydroxyl-terminated polyethylene glycol (PEG) molecule (214)) to form a cross-linked polysaccharide (216), wherein the hyaluronic acid chains are cross-linked to each other by PEG-containing cross-linking bonds (216b) containing hydrolyzable ester bonds. Such a cross-linked polysaccharide hydrogel (216) can be formed in vivo or in vitro and subsequently delivered to the subject.

[0038] In cases where it is necessary to remove cross-linked polysaccharides from a subject (e.g., due to discomfort caused by the cross-linked polysaccharides, due to improper placement of the cross-linked polysaccharides, etc.), the cross-linked polysaccharides can be contacted with a hydrolysis-accelerating catalytic composition suitable for breaking down the ester bonds in the cross-links. For example, see reference. Figure 2B ,like Figure 2A The cross-linked polysaccharide hydrogel (216) can be contacted with a hydrolysis-accelerating catalyst (specifically, an esterase) that breaks down the ester bonds (216b) in the PEG-containing cross-links, thereby releasing hyaluronic acid (212) and linearly dihydroxy-terminated polyethylene glycol (PEG) (214) from each other. The degradation products shown are non-toxic, biocompatible, and bioabsorbable. Although in Figure 2B The diagram shows 100% ester bond (216b) breakage, but fundamental decomposition of the hydrogel can be achieved by breaking less than 100% of the ester bonds (216b). For example, in some embodiments, any range from 1% to 100%, preferably 10% to 100%, of the ester bonds (216b) can be broken.

[0039] The hydrolysis acceleration catalytic compositions used in this disclosure comprise one or more hydrolysis acceleration catalytic compositions. Exemplary hydrolysis acceleration catalysts include hydroxides (such as NaOH and KOH) that accelerate ester bond hydrolysis at low concentrations, and enzyme proteins (such as esterases) that break down ester bonds. Esterases may be nonspecific and capable of hydrolyzing a variety of ester bonds, or esterases may exhibit selective binding to specific types of ester bonds. Enzyme proteins can be selected from suitable members such as: carboxylesterases, peptidases, amidases, acetylcholinesterases, bile salt-activated esterases, protein glutamate methylesterases, cholinesterases, carboxymethylene-butenolidases, crystal proteins, keratinases, cAMP-regulated D2 proteins, 2-hydroxymucosamide hemialdehyde hydrolases, intestinal esterases, esterase B1, hepatic carboxylesterases, esterase 1, esterase B2, esterase 4, esterase 5, esterase 6, arginine esterases, esterase 5A, esterase 5B, esterase 5C, esterase D, juvenile hormone esterases, esterase P, Pi 6.1 esterases, and phosphatidylcholine-sterol acyltransferases. Acyltransferases), porcine pancreatic lipase, lipase 1, lipase 2, lipase 3, lipase 4, lipase 5, triacylglycerol lipase, lipoprotein lipase, pancreatic lipase, hormone-sensitive lipase, lactone lipase, mono- and diacylglycerol lipase, 6-methylsalicylic acid synthase, betaine hydrolase, poly(3-hydroxyalkyl ester) depolymerase, 2-hydroxy-6-oxo-2,4-heptadienoic acid hydrolase, tropine esterase, vitellogenin I, vitellogenin II, vitellogenin III, 2-hydroxymuconic acid semialdehyde hydrolase, acetylesterase, protein-glutamate methyl esterase, S-acyl fatty acid synthase thioesterase, acetyl hydrolase, erythromycin synthase, gramic acid peptide S biosynthesis GRST protein, triglyceride lipase-cholesterol esterase, Candida Antarctica B lipase and / or analogues.

[0040] In addition to one or more hydrolysis accelerating catalysts, the hydrolysis accelerating catalytic compositions disclosed herein may also contain additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters, as detailed below.

[0041] The carboxylic acid-containing polysaccharides used in this disclosure include those containing one or more uronic acid substances (such as galacturonic acid, glucuronic acid, and / or iduronic acid). Specific examples of carboxylic acid-containing polysaccharides include alginic acid, hyaluronic acid, pectin, agar, carrageenan, gellan gum, gum arabic, guar gum, xanthan gum, and carboxymethyl cellulose fractions. In some embodiments, the number average molecular weight of the carboxylic acid-containing polysaccharide can be from 1 kDa to 8000 kDa, for example, any range from 1 kDa to 2.5 kDa to 5 kDa to 10 kDa to 25 kDa to 50 kDa to 100 kDa to 250 kDa to 500 kDa to 1000 kDa to 2000 kDa to 8000 kDa (in other words, the range between any two of the foregoing values).

[0042] Polyols used in this disclosure include polyols having two or more hydroxyl groups, for example, containing 2 to 100 hydroxyl groups (e.g., having 3 to 4 to 5 to 6 to 7 to 8 to 9 to 10 to 12 to 15 to 20 to 25 to 30 to 40 to 50 to 60 to 70 to 80 to 90 to 100 hydroxyl groups).

[0043] The polyols used in this disclosure include polymeric polyols and nonpolymeric polyols.

[0044] The polyols used in this disclosure include small-molecule polyols and large-molecule polyols. As used herein, "small molecule" is a molecule with a molecular weight of less than 2500, less than 1000 in some embodiments, and less than 500 in some embodiments. "Large molecule" as used herein is a molecule with a molecular weight of 2500 or greater.

[0045] Polymeric polyols include linear polymers that comprise one or more polymer segments and have hydroxyl-containing moieties connected at each end; specific examples are... Figure 2A Linear dihydroxy-terminated polyethylene glycol (PEG).

[0046] Polymer polyols also include multi-arm polymers having a core region and multiple polymer arms, each polymer arm containing one or more polymer segments, each polymer arm having a fixed end connected to the core region and a relatively free end connected to the hydroxyl-containing portion.

[0047] In some embodiments, the core region of the multi-arm polymer includes residues of a polyol containing two or more hydroxyl groups for forming the polymer arms. In some advantageous embodiments, the core region includes residues of a polyol containing 2 to 100 hydroxyl groups.

[0048] The polymer segments used in the linear and multi-arm polymers described herein may be selected from any of a variety of synthetic, natural, or synthetic-natural hybrid polymer segments. Examples of polymer segments include those formed from one or more monomers selected from: C1-C6-epoxide monomers (e.g., ethylene oxide, propylene oxide, tetramethylene oxide, etc.), cyclic ester monomers (e.g., glycolide, lactide, β-propiolactone, β-butyrolactone, γ-butyrolactone, γ-valerolactone, δ-valerolactone, ε-caprolactone, etc.), and oxazoline monomers (e.g., oxazoline and 2-alkyl-2-oxazoline, such as 2-(C1-C6 alkyl)-2-oxazoline, including various isomers, such as 2-methyl-2-oxazoline). Phosphorus, 2-ethyl-2-oxazoline, 2-n-propyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2-n-butyl-2-oxazoline, 2-isobutyl-2-oxazoline, 2-hexyl-2-oxazoline, etc.), 2-phenyl-2-oxazoline, polar aprotic vinyl monomers (such as N-vinylpyrrolidone, acrylamide, N-methylacrylamide, dimethylacrylamide, N-vinylimidazolium, 4-vinylimidazolium, sodium 4-vinylbenzenesulfonate, etc.), dioxanehexanone, N-isopropylacrylamide, amino acids and sugars.

[0049] The polymer segments used for the polymer arm can be selected, for example, from the following polymer segments: polyether segments, including poly(C1-C6-epoxyalkylene) segments, such as poly(ethylene oxide) (PEO) segments (also known as polyethylene glycol segments or PEG segments), poly(propylene oxide) segments, and poly(ethylene oxide-co-propylene oxide) segments; polyester segments, including polyglycolic acid segments, polylactide segments, poly(lactide-co-glycolic acid) segments, poly(β-propiolactone) segments, poly(β-butyrolactone) segments, poly(γ-butyrolactone) segments, poly(γ-valerolactone) segments, poly(δ-valerolactone) segments, and poly(ε-caprolactone) segments; polyoxazoline segments, including poly(2-C1-C6-alkyl-2-oxazoline) segments, such as poly(2-methyl-2-oxazoline) segments. Poly(2-ethyl-2-oxazoline) segments, poly(2-propyl-2-oxazoline) segments, poly(2-isopropyl-2-oxazoline) segments, poly(2-n-butyl-2-oxazoline) segments, and poly(2-phenyl-2-oxazoline) segments; polymer segments formed from one or more polar aprotic vinyl monomers, including poly(N-vinylpyrrolidone) segments, poly(acrylamide) segments, poly(N-methacrylamide) segments, poly(dimethacrylamide) segments, poly(N-vinylimidazolium) segments, poly(4-vinylimidazolium) segments, and poly(4-vinylbenzenesulfonate) segments; polydioxane-1,2-oxazoline segments, poly(N-isopropylacrylamide) segments, polypeptide segments, and polysaccharide segments.

[0050] Each polymer segment in the polymers used in this disclosure may contain 2 to 1,000 or more monomer units, for example, in the range of 2 to 5 to 10 to 30 to 70 to 100 to 300 to 700 to 1,000 monomer units (i.e., in the range of any two of the foregoing values).

[0051] In some embodiments of this disclosure, pre-formed polymer segments can be linked to nucleating molecules.

[0052] In some embodiments of this disclosure, non-iodinated or iodinated polyols, such as one or more described below, can be used as multifunctional initiators for polymer chain growth, resulting in hydroxyl-terminated multi-arm polymers. For example, non-iodinated or iodinated polyols can be used as initiators for the ring-opening polymerization of ethylene oxide to form poly(ethylene oxide) (PEG) segments on each hydroxyl group 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.

[0053] exist Figure 3 In the specific embodiment shown, commercially available tripentaerythritol (310) (CAS# 78-24-0) can be used as an octafunctional initiator, which undergoes ring-opening polymerization with ethylene oxide (311). This polymerization process results in the growth of a polyethylene oxide (PEG) chain on each of the eight hydroxyl groups of the tripentaerythritol, thereby forming an eight-arm PEG (312) with hydroxyl-terminated cores of tripentaerythritol residues. Figure 3 In this context, n is an integer representing the number of monomer units in each polymer segment shown. In other cases, only a single monomer unit exists and n=1.

[0054] Figure 3 The strategy shown is widely applicable and can be used in combination with a range of polyols, including those mentioned above. Figure 4 In the specific embodiment shown, the iodinated polyol 1,3,5-triiodo-2,4,6-tris(hydroxymethyl)benzene (410) is used as an initiator for ring-opening polymerization with ethylene oxide. The polymerization process results in the growth of a poly(ethylene oxide) chain on each of the three hydroxyl groups of 1,3,5-triiodo-2,4,6-tris(hydroxymethyl)benzene (410). The resulting multi-arm polymer (412) comprises three PEG arms extending from a core of 1,3,5-triiodo-2,4,6-tris(hydroxymethyl)benzene residues. Each PEG arm has a terminal hydroxyl group. Figure 4 In this context, n is an integer representing the number of monomer units in each polymer segment shown. In other cases, only a single monomer unit exists and n=1.

[0055] Further exemplary polyols used in this disclosure are described below. Such polyols can be used to form multi-arm polymeric polyols, such as those described above. Figure 3 and Figure 4 As described above. Such polyols can also be used directly as crosslinking agents, for example, in conjunction with the following... Figure 5 As stated above.

[0056] Further polyols can be selected from, for example, sugars (monosaccharides, disaccharides, trisaccharides, etc.), sugar alcohols, calixarenes, polyhedral oligosemisilsesquioxanes (POSS), cyclodextrins, polyhydroxylated polymers, catechins, flavanols, anthocyanins, stilbenes, and polyphenols.

[0057] Further polyols may 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. Examples include: C1-C8 alkyldiols, including α,ω-C2-C8 alkyldiols, such as 1,2-ethylene glycol (i.e., ethylene glycol), 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, etc.; triols, such as methyltriol, glycerol, trimethylolpropane, phloroglucinol, mannitol, sorbitol, inositol, xylitol, styritol, arabinose, erythritol, pentaerythritol, dipentaerythritol, tripentaerythritol, arabinose, hexamethylenetetramine, galactitol, fucose, ribose, arabinose, xylose, lysolose, rhamnose, galactose, glucose, fructose, sorbitol, etc. Polymers of sugars, mannose, pyranose, azoose, tarose, tagatose, pyranoside, sucrose, lactose, and maltose (defined herein as two or more units), including oligomers of sugars and sugar alcohols (defined herein as two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers, and decamers), starch, amylose, dextrin, cyclodextrin, polyhedral oligosilsesquioxanes (POSS), catechins, flavanols, anthocyanins, stilbenes, 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.

[0058] Other polyols include iodinated polyols, which may be ideal where radiopaqueness is required. Iodinated polyols include iodinated aromatic polyols, examples of which are compounds containing two 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 further substituted with two or more hydroxyl groups, which can be directly substituted to the aromatic group or can be provided in the form of hydroxyalkyl groups (e.g., C1-C4-hydroxyalkyl groups containing 1, 2, 3, or 4 carbon atoms and containing 1, 2, 3, or 4 or more hydroxyl groups). The hydroxyalkyl group can be attached to the aromatic group directly or through any suitable linking moiety selected from, for example, amide, amino, ether, ester, or carbonate groups.

[0059] Specific examples of iodinated polyols used in this disclosure include iodinated polyols known for use as iodinated contrast agents, whose biocompatibility has been demonstrated to be quite tolerable. Specific examples of iodinated polyols include commercially available 1,3,5-triiodo-2,4,6-tris(hydroxymethyl)benzene (CAS# 178814-33-0). Iodixanol (CAS# 92339-11-2) Iodritolam (CAS# 79770-24-4) Iohexol (CAS# 66108-95-0) Iodophorol (CAS# 87771-40-2) Iopamidol (CAS# 60166-93-0) Iohexol Impurity J (CAS#76801-93-9) And iopromide (CAS# 73334-07-3) wait.

[0060] As mentioned above, the aforementioned polyols can be directly used as cross-linking agents for carboxylic acid-containing polysaccharides. For example, now refer to... Figure 5 In the presence of a suitable coupling agent (such as DCC or EDC), during the ester coupling reaction, the carboxyl group of the carboxylic acid polysaccharide (specifically, hyaluronic acid (512)) can react with the hydroxyl group of the polyol (specifically, 1,3,5-triiodo-2,4,6-trihydroxymethylbenzene ((514))) to form a cross-linked polysaccharide (516), in which the hyaluronic acid chains are cross-linked with each other by iodine-containing cross-linking bonds containing hydrolyzable ester bonds (516b).

[0061] Such cross-linked polysaccharide hydrogels (516) can be formed in vivo or in vitro and subsequently delivered to the subject. Such cross-linked polysaccharide hydrogels (516) can also be contacted with hydrolysis-accelerating catalytic compositions suitable for breaking down ester bonds in the cross-linking bonds, such as... Figure 2B As shown.

[0062] The aforementioned implementation scheme involves cross-linked polysaccharides, wherein the carboxylic acid polysaccharides are covalently linked to polyols via ester groups.

[0063] In other embodiments, cross-linked polysaccharides can be formed via an esterification reaction between the hydroxyl groups of the hydroxyl-containing polysaccharide and the carboxyl groups of the polycarboxylic acid molecule. Because all polysaccharides contain hydroxyl groups, the range of polysaccharides that can be used in these embodiments extends to polysaccharides other than those containing carboxylic acids. Examples of such other cross-linkable polysaccharides include cellulose derivatives (including alkyl celluloses, such as methylcellulose and ethylcellulose, and hydroxyalkyl celluloses, such as hydroxyethylcellulose and hydroxypropylcellulose), starches (e.g., corn starch, potato starch, cassava starch, and cationic starch), chitosan, and gelatin-polysaccharide composites, etc.

[0064] As described above, ester coupling between the carboxylic acid group and the hydroxyl group can be carried out in the presence of suitable coupling agents, such as carbodiimide coupling agents, such as N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or N,N'-diisopropylcarbodiimide (DIC). The resulting ester bond is hydrolyzable.

[0065] The polycarboxylic acid molecules used according to this disclosure include polycarboxylic acid molecules having two or more carboxylic acid groups, for example containing 2 to 100 carboxylic acid groups (e.g., having 3 to 4 to 5 to 6 to 7 to 8 to 9 to 10 to 12 to 15 to 20 to 25 to 30 to 40 to 50 to 60 to 70 to 80 to 90 to 100 carboxylic acid groups).

[0066] The polycarboxylic acid molecules used in this disclosure include polymeric polycarboxylic acid molecules and non-polymeric polycarboxylic acid molecules.

[0067] The polycarboxylic acid molecules used in this disclosure include small molecule polycarboxylic acid molecules and large molecule polycarboxylic acid molecules.

[0068] Polymeric polycarboxylic acid molecules include linear polymers containing one or more polymer segments and having connected carboxylic acid-containing moieties at each end.

[0069] Polymeric polycarboxylic acid molecules also include multi-arm polymers having a core region and multiple polymer arms, each polymer arm containing one or more polymer segments, and each arm having a fixed end connected to the core region and a relatively free end connected to the carboxylic acid multipartite.

[0070] The polymer segments used for linear polymerization of polycarboxylic acid molecules and multi-arm polymerization of polycarboxylic acid molecules include those described above.

[0071] In some embodiments, the core region contains residues of iodinated or non-iodinated polyols, which contain two or more hydroxyl groups and can be used to form polymer arms as described above.

[0072] In some embodiments, the polymeric polycarboxylic acid molecule can be formed from linear and multi-arm polymeric polyols as described above. This is achieved by reacting the terminal hydroxyl groups of the polymeric polyol with cyclic anhydrides (e.g., glutaric anhydride, succinic anhydride, malonic anhydride, adipic anhydride, diethylene glycol anhydride, 1,3-acetone dicarboxylic anhydride, etc.) to form carboxylic acid-terminated linear and multi-arm polymers, such as glutaric acid-terminated linear and multi-arm polymers, succinic acid-terminated linear and multi-arm polymers, malonic acid-terminated linear and multi-arm polymers, adipic acid-terminated linear and multi-arm polymers, diethylene glycol-terminated linear and multi-arm polymers, 1,3-acetone dicarboxylic acid-terminated linear and multi-arm polymers, etc. The aforementioned cyclic anhydrides can react with hydroxyl-terminated polymers under alkaline conditions to form carboxylic acid-terminated polymers containing carboxylic acid terminal groups, which are connected to the polymer arms via hydrolyzable ester bonds (other than the hydrolyzable ester bonds described elsewhere herein).

[0073] Further polycarboxylic acid molecules can be selected from, for example, non-iodinated polycarboxylic acid molecules having two or more carboxylic acid groups, including dicarboxylic acids (e.g., C1-C8 alkane dicarboxylic acids, including α,ω-C2-C8 alkane dicarboxylic acids, such as 1,2-ethanedicarboxylic acid, 1,3-propanedicarboxylic acid, 1,4-butanedicarboxylic acid, 1,5-pentanedicarboxylic acid, 1,6-hexanedicarboxylic acid, etc.), tricarboxylic acids (e.g., propane-1,2,3-tricarboxylic acid, benzene-1,3,5-tricarboxylic acid), tetracarboxylic acids, pentacarboxylic acids, hexacarboxylic acids, heptacarboxylic acids, octacarboxylic acids, etc. Non-iodinated polycarboxylic acid molecules having two or more carboxylic acid groups can also be formed from any of the above-mentioned non-iodinated polyols having two or more hydroxyl groups by reacting the hydroxyl groups of the polyol with cyclic anhydrides to form carboxylic acid groups.

[0074] Further polycarboxylic acid molecules include iodinated polycarboxylic acid molecules. Iodinated polycarboxylic acid molecules include iodinated aromatic polycarboxylic acid molecules, examples of which are compounds comprising two or more carboxylic acid 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 may be substituted with one, two, three, four, five, six, or more iodine atoms. In various embodiments, the aromatic group is further substituted with two or more carboxylic acid groups, which may directly replace the aromatic group or may be provided in the form of a carboxyalkyl group (e.g., a C1-C4 carboxyalkyl group containing one, two, three, or four carbon atoms and containing one, two, three, or four or more carboxylic acid groups). The hydroxyalkyl group may be attached to the aromatic group directly or through any suitable linking moiety selected from, for example, amide, amino, ether, ester, or carbonate groups.

[0075] Iodinated polycarboxylic acid molecules having two or more carboxylic acid groups can be formed by reacting the hydroxyl groups of any of the above-mentioned iodinated polyols having two or more hydroxyl groups with cyclic anhydrides to form carboxylic acid groups.

[0076] Specific examples of iodinated polycarboxylic acid molecules used in this invention include 2,4,6-triiodobenzene-1,3,5-tricarboxylic acid. 2,4,6-Triiodio-1,3-Benzenedicarboxylic acid (CAS# 53451-54-0) And 2,4,5,6-tetraiodo-1,3-benzenediacarboxylic acid (CAS# 162321-54-2) .

[0077] As previously stated, this disclosure relates to compositions, apparatus, systems, and methods for accelerating the hydrolysis (and thus degradation) of cross-linked polysaccharide hydrogels in vivo in subjects. In various embodiments, the cross-linking bonds between polysaccharide molecules in the cross-linked polysaccharide hydrogel contain hydrolyzable ester bonds. The method includes contacting the cross-linked polysaccharide hydrogel with a hydrolysis-accelerating catalytic composition suitable for accelerating the hydrolysis of ester bonds within the cross-linking bonds.

[0078] Figure 6 and 7 The placement of such a cross-linked polysaccharide hydrogel between the prostate and rectum of a subject is shown. Figure 6 This is a schematic diagram depicting regions of the human body, including, for example, the bladder 12, the prostate 14, and the rectum 16. In this example, the prostate 14 may include a tumor 18. In some cases, radiation therapy may be necessary to treat the tumor 18.

[0079] Prior to radiotherapy, it may be necessary to place a cross-linked polysaccharide hydrogel spacer 20 inside the body. For example... Figure 7 As shown, a pre-loaded syringe (in which an injectable cross-linked polysaccharide hydrogel composition 715 is disposed within a delivery syringe system including a syringe tube 712 and a plunger 714) can be connected to a needle 748, the distal end of which is located between the prostate 14 and the rectum 16. The plunger 714 can be used to deliver the cross-linked polysaccharide hydrogel composition 715 to form a cross-linked polysaccharide hydrogel spacer 20. With the prostate 14 separated from the rectum 16, radiotherapy can be used to treat the tumor 18.

[0080] In cases where hydrolysis of the cross-linked polysaccharide hydrogel spacer 20 is required, a catalytic composition for accelerating hydrolysis can be brought into contact with the cross-linked polysaccharide hydrogel spacer 20 to accelerate its hydrolysis. For example... Figure 8 As shown, a pre-loaded syringe (in which the hydrolysis-accelerating catalytic composition 1015 is disposed within a hydrolysis syringe system including a syringe tube 1012 and a plunger 1014) can be connected to a needle 1048, the end of which is positioned within the cross-linked polysaccharide hydrogel spacer 20. The plunger 1014 can be used to deliver the hydrolysis-accelerating catalytic composition 1015 to the cross-linked polysaccharide hydrogel spacer 20, as... Figure 8 As illustrated. The hydrolysis-accelerating catalytic composition 1015 can accelerate the hydrolysis of the cross-linked polysaccharide hydrogel spacer 20, such as... Figure 9 As shown schematically.

[0081] It should be noted that in some cases (e.g., when it is immediately discovered that the cross-linked polysaccharide hydrogel spacer 20 is improperly placed), the needle 1048 may be the same as the needle 748 originally used to introduce the cross-linked polysaccharide hydrogel spacer 20, thereby allowing the pre-loaded syringe 710 to be disconnected from the needle 748 and the pre-loaded syringe 1010 to be connected to the needle 748 without having to remove the needle 748 from the subject.

[0082] In some aspects, this disclosure relates to a system comprising: (a) an injectable or implantable composition comprising a pre-formed cross-linked polysaccharide hydrogel containing cross-links between polysaccharide molecules containing hydrolyzable ester bonds; and (b) a hydrolysis-accelerating catalytic composition adapted to accelerate the hydrolysis of hydrolyzable ester bonds.

[0083] Various catalytic compositions for accelerating hydrolysis are described above and include at least one hydrolysis accelerating catalyst. The hydrolysis accelerating catalytic compositions can be provided in suitable reservoirs, such as syringes, vials, or ampoules. Whether provided in syringes, vials, ampoules, or other reservoirs, the hydrolysis accelerating catalytic compositions can be provided in, for example, a dry form (e.g., powder form), a fluid form (e.g., solution form), a multiphase fluid (e.g., a particulate suspension of at least one hydrolysis accelerating catalyst), or an oil / water or water / oil emulsion form, wherein the hydrolysis accelerating catalyst is primarily present in an oil phase or an aqueous phase. The hydrolysis accelerating catalytic compositions may further comprise one or more additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below.

[0084] Figure 10 A syringe 1010 is shown for injecting the hydrolysis-accelerating catalytic composition as described above. The syringe 1010 may include a tube 1012, a plunger 1014, and one or more stoppers 1016. The tube 1012 may include a Luer adapter (or other suitable adapter / connector) at its distal end 1018 for attachment to an injection needle or flexible catheter. The syringe tube 1012 may function as a reservoir containing the hydrolysis-accelerating catalytic composition 1015 for injection (e.g., via a needle or catheter) into a subject.

[0085] The pre-formed cross-linked polysaccharide hydrogel can be formed by ester coupling between the carboxylic acid group of a carboxylic acid polysaccharide (such as one of the aforementioned) and the hydroxyl group of a polyol (such as one of the aforementioned).

[0086] In various embodiments, such cross-linked polysaccharide hydrogels have a radiation impermeability greater than 100 Hounsfield units (HU), advantageously in the range of 100 HU to 500 HU to 750 HU to 1000 HU or greater, for example, when measured on a desktop miniature CT system such as the Xtreme Ct or similar system from Scanco Medical (Wangen-brüttisellen, Switzerland).

[0087] X-ray impermeability can be provided, for example, by forming a cross-linked polysaccharide hydrogel from an iodide as described above, or by including a separate contrast agent.

[0088] The pre-formed cross-linked polysaccharide hydrogel can be in any desired form, including plates, cylinders, coatings, or granules. In some embodiments, the cross-linked polysaccharide is dried and then granulated into particles of a suitable size. Granulation can be performed by any suitable method, such as homogenization, forced sieving, grinding (including cryogenic grinding), crushing, milling, or pulverizing. The particles can be sorted and separated using sieving or other known techniques. The size of the cross-linked polysaccharide particles formed using the above and other techniques can vary considerably, for example, with an average size of 50 to 950 micrometers.

[0089] In addition to the cross-linked polysaccharide hydrogels described above, the cross-linked polysaccharide hydrogel compositions according to this disclosure may contain additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below.

[0090] Pre-formed cross-linked polysaccharide hydrogel compositions can be provided in any suitable packaging. When the cross-linked polysaccharide hydrogel composition is provided in an injectable form (e.g., where the cross-linked polysaccharide hydrogel composition comprises injectable cross-linked polysaccharide hydrogel particles, beads, pellets, etc.), the cross-linked polysaccharide hydrogel composition can be provided in a reservoir, such as a syringe, vial, or ampoule. Whether provided in a syringe, vial, ampoule, or other reservoir, the pre-formed cross-linked polysaccharide hydrogel composition can be provided, for example, in a dry form (e.g., as a powder containing cross-linked polysaccharide hydrogel particles) or in a fluid form (e.g., as a suspension containing cross-linked polysaccharide hydrogel particles).

[0091] The pre-formed cross-linked polysaccharide hydrogel composition can be delivered to subjects using a suitable delivery device. Preferred subjects include mammalian subjects, especially human subjects.

[0092] Figure 11 An exemplary delivery device is illustrated, showing a syringe 1110 that provides a reservoir for a pre-formed cross-linked polysaccharide hydrogel composition as described above. The syringe 1110 may include a tube 1112, a plunger 1114, and one or more stoppers 1116. The tube 1112 may include, for example, a Luer adapter (or other suitable adapter / connector) at its distal end 1118 for attachment to an injection needle 1150 via a flexible conduit 1129. The proximal end of the conduit 1129 may include a suitable connector 1120 for receiving the tube 1112. In other examples, the tube 1112 may be directly connected to the injection needle 1150. The syringe tube 1112 may serve as a reservoir containing a pre-formed cross-linked polysaccharide hydrogel composition 1115 for injection via the needle 1150.

[0093] In some embodiments, the cross-linked polysaccharide hydrogel composition of this disclosure can be imaged after application using a suitable imaging technique, such as ultrasound or X-ray-based imaging techniques, such as computed tomography or X-ray fluorescence fluoroscopy.

[0094] Because the cross-linked polysaccharide hydrogel composition of this disclosure has ester-containing cross-linking bonds, the degradation rate of the cross-linked polysaccharide hydrogel composition will be adjusted from slow degradation over time in aqueous body fluids to faster degradation based on the ester bond density.

[0095] However, when needed, the hydrolysis of the cross-linked polysaccharide hydrogel composition of this disclosure can be accelerated by contacting the cross-linked polysaccharide hydrogel composition with the hydrolysis-accelerating catalytic composition described herein.

[0096] The cross-linked polysaccharide hydrogel compositions described herein can be used for a variety of medical purposes.

[0097] For example, in applications such as the treatment of diseases and cancer, as well as tissue repair and regeneration, cross-linked polysaccharide hydrogel compositions can be injected to provide spacers between tissues; cross-linked polysaccharide hydrogel compositions can be injected to provide reference markers; cross-linked polysaccharide hydrogel compositions can be injected for tissue enlargement or regeneration (including cosmetic tissue enlargement); cross-linked polysaccharide hydrogel compositions can be injected as fillers or substitutes for soft tissues; cross-linked polysaccharide hydrogel compositions can be injected to provide mechanical support for damaged tissues; cross-linked polysaccharide hydrogel compositions can be injected as scaffolds; cross-linked polysaccharide hydrogel compositions can be injected as lifting agents for internal cyst removal; and / or cross-linked polysaccharide hydrogel compositions can be injected as carriers for therapeutic agents. Cross-linked polysaccharide hydrogel compositions can also be injected into the left atrial appendage during left atrial appendage closure. In some embodiments, the cross-linked polysaccharide hydrogel composition can be injected into the left atrial appendage after the introduction of a closure device (such as the Watchman® left atrial appendage closure device available from Boston Scientific).

[0098] The cross-linked polysaccharide hydrogel composition disclosed herein can be used in various medical procedures, including: procedures for implanting a reference marker comprising cross-linked polysaccharide hydrogel, procedures for implanting a tissue regeneration scaffold comprising cross-linked polysaccharide hydrogel, procedures for implanting a tissue support comprising cross-linked polysaccharide hydrogel, procedures for implanting a tissue bulking agent comprising cross-linked polysaccharide hydrogel, procedures for implanting a therapeutic agent depot comprising cross-linked polysaccharide hydrogel, tissue enlargement procedures comprising implanting cross-linked polysaccharide hydrogel, and procedures for introducing cross-linked polysaccharide hydrogel between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0099] Cross-linked polysaccharide hydrogel compositions can be injected with various medical procedures, including: septal injections between the prostate or vagina and rectum in radiotherapy for rectal cancer; septal injections between the rectum and prostate in radiotherapy for prostate cancer; subcutaneous injections for palliative treatment of prostate cancer; transurethral or submucosal injections for female stress urinary incontinence; intravesical injections for urinary incontinence; intrauterine injections for Asherman's syndrome; submucosal injections for anal incontinence; percutaneous injections for heart failure; intramyocardial injections for heart failure and dilated cardiomyopathy; injections for closure of atrial septal defects; transendocardial injections for myocardial infarction; intra-articular injections for osteoarthritis; spinal injections for spinal fusion and spinal, maxillofacial, and orthopedic trauma surgery; spinal injections for posterolateral lumbar fusion; and intradiscal injections for degenerative disc disease. 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; 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 to stimulate natural collagen production.

[0100] In various embodiments, a kit is provided comprising one or more delivery devices for delivering the pre-formed cross-linked polysaccharide hydrogel composition and the hydrolysis-accelerating catalytic composition described herein to a subject. Such a kit may include any of the following: one or more syringes, which may or may not contain the pre-formed cross-linked polysaccharide hydrogel composition or the hydrolysis-accelerating catalytic composition; one or more vials, which may or may not contain the pre-formed cross-linked polysaccharide hydrogel composition or the hydrolysis-accelerating catalytic composition; one or more needles (compatible with both a delivery syringe system for delivering the pre-formed cross-linked polysaccharide hydrogel composition and a hydrolysis syringe system for delivering the hydrolysis-accelerating catalytic composition); one or more flexible tubes (compatible with both a syringe for delivering the pre-formed cross-linked polysaccharide hydrogel composition and a syringe for delivering the hydrolysis-accelerating catalytic composition); and an injectable liquid, such as water for injection, physiological saline, or phosphate-buffered saline. Whether provided in a syringe, vial, or other reservoir, the pre-formed cross-linked polysaccharide hydrogel composition and the hydrolysis-accelerating catalytic composition may be provided independently in a dry form (e.g., powder form) or in a fluid form, said fluid form being ready for injection.

[0101] In some aspects, this disclosure relates to a system comprising: (a) a composition for forming a cross-linked polysaccharide hydrogel in a subject, the cross-linked polysaccharide hydrogel comprising polysaccharide molecules and cross-linking bonds containing hydrolyzable ester bonds between the polysaccharide molecules; and (b) a hydrolysis-accelerating catalytic composition adapted to accelerate the hydrolysis of the hydrolyzable ester bonds.

[0102] In various embodiments, the cross-linked polysaccharide hydrogel formed in the subject has a radiation impermeability greater than 100 Hounsfield units (HU), advantageously in the range of 100 HU to 500 HU to 750 HU to 1000 HU or greater, for example, when measured on a benchtop miniature CT system such as the Xtreme Ct or similar system from Scanco Medicalbrüttisellen, Switzerland.

[0103] As described above, the hydrolysis accelerating catalytic composition can be provided in a suitable reservoir, such as a syringe, vial, or ampoule. Regardless of whether it is provided in a syringe, vial, ampoule, or other reservoir, the hydrolysis accelerating catalytic composition can be provided in, for example, a dry form (e.g., powder form), a fluid form (e.g., solution form), a multiphase fluid (e.g., a particulate suspension of at least one hydrolysis accelerating catalyst), or an oil / water or water / oil emulsion form, wherein the hydrolysis accelerating catalyst is primarily present in an oil phase or an aqueous phase. The hydrolysis accelerating catalytic composition may further comprise one or more additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described above. Figure 10 A specific embodiment of providing a hydrolysis-accelerating catalytic composition 1015 within a syringe 1010 is shown.

[0104] The composition for forming a cross-linked polysaccharide hydrogel in a subject is as described above, and includes the carboxylic acid polysaccharide, the polyol, and the ester coupling agent as described above.

[0105] Carboxylic acid polysaccharides, polyols, or combinations thereof can be provided in suitable reservoirs, such as syringes, vials, or ampoules. Whether provided in syringes, vials, ampoules, or other containers, carboxylic acid polysaccharides, polyols, or combinations thereof can be provided in, for example, a dry form (e.g., powder) or a fluid form (e.g., solution). Furthermore, compositions containing carboxylic acid polysaccharides, polyols, or both may further comprise one or more additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below.

[0106] Ester coupling agents can also be provided in suitable reservoirs, such as syringes, vials, or ampoules. Whether provided in syringes, vials, ampoules, or other containers, ester coupling agents can be provided in, for example, dry form (e.g., powder form) or fluid form (e.g., solution form). Furthermore, ester coupling agents may further comprise one or more additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below.

[0107] In some implementations, a carboxylated polysaccharide, a polyol, and an ester coupling agent are simultaneously administered to the subject, after which cross-linking bonds are formed between the carboxylated polysaccharide, the polyol, and the ester coupling agent.

[0108] In some embodiments, a system is provided comprising a delivery device including a first reservoir and a second reservoir. The first reservoir contains a first fluid composition comprising the carboxylated polysaccharide and the polyol, and the second reservoir contains a second fluid composition comprising the ester coupling agent. When the first and second fluid compositions are mixed, cross-linking occurs between the carboxylated polysaccharide and the polyol. During operation, the first and second fluid compositions are dispensed from and bound together from the first and second reservoirs, thereby cross-linking the carboxylated polysaccharide and the polyol with each other to form a cross-linked polysaccharide hydrogel in the body of a subject.

[0109] In various embodiments, a kit is provided comprising one or more delivery devices for delivering to a subject (a) the carboxylated polysaccharide, the polyol, and the ester coupling agent described herein, and (b) the hydrolysis-accelerating catalytic composition described herein. Such a kit may include any of the following: a syringe, vial, or other container containing the carboxylated polysaccharide; a syringe, vial, or other container containing the polyol; a syringe, vial, or other container containing both the carboxylated polysaccharide and the polyol; a syringe, vial, or other container containing the ester coupling agent; a syringe, vial, or other container containing the hydrolysis accelerator composition; one or more needles (compatible with both hydrolysis syringe systems for delivering the hydrolysis accelerator composition and delivery syringe systems for delivering carboxylated polysaccharide, polyol, and ester coupling agent); one or more flexible tubes (compatible with both hydrolysis syringe systems for delivering the hydrolysis accelerator composition and delivery syringe systems for delivering carboxylated polysaccharide, polyol, and ester coupling agent); and injectable liquids, such as water for injection, physiological saline, or phosphate-buffered saline, which may be provided in a syringe, vial, or other container.

[0110] The composition for forming a cross-linked polysaccharide hydrogel in a subject further comprises the carboxylic acid polysaccharide as described above, the polycarboxylic acid molecule as described above, and the ester coupling agent as described above.

[0111] Hydroxypolysaccharides, polycarboxylic acid molecules, or combinations thereof can be provided in suitable reservoirs, such as syringes, vials, or ampoules. Whether provided in syringes, vials, ampoules, or other reservoirs, hydroxypolysaccharides, polycarboxylic acid molecules, or combinations thereof can be provided in, for example, a dry form (e.g., powder) or a fluid form (e.g., solution). Furthermore, compositions containing hydroxypolysaccharides, polycarboxylic acid molecules, or both may further comprise one or more additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below.

[0112] As previously mentioned, ester coupling agents can also be provided in suitable reservoirs, such as syringes, vials, or ampoules. Whether provided in syringes, vials, ampoules, or other containers, ester coupling agents can be provided in, for example, a dry form (e.g., powder form) or a fluid form (e.g., solution form). Furthermore, ester coupling agents may further comprise one or more additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described below.

[0113] In some implementations, a hydroxyl polysaccharide, a polycarboxylic acid molecule, and an ester coupling agent are simultaneously administered to the subject, after which cross-linking bonds are formed between the hydroxyl polysaccharide, the polycarboxylic acid molecule, and the ester coupling agent.

[0114] In some embodiments, a system is provided comprising a delivery device including a first reservoir and a second reservoir. The first reservoir contains a first fluid composition comprising molecules of the hydroxyl polysaccharide and the polycarboxylic acid, and the second reservoir contains a second fluid composition comprising the ester coupling agent. When the first and second fluid compositions are mixed, cross-linking occurs between the hydroxyl polysaccharide and the polycarboxylic acid molecules. During operation, the first and second fluid compositions are dispensed from and bound together from the first and second reservoirs, thereby cross-linking the hydroxyl polysaccharide and the polycarboxylic acid molecules to form a cross-linked polysaccharide hydrogel in the body of a subject.

[0115] In various embodiments, a kit is provided comprising one or more delivery devices for delivering to a subject (a) the hydroxy polysaccharide, the polycarboxylic acid molecule, and the ester coupling agent described herein, and (b) the hydrolysis-accelerating catalytic composition described herein. Such a kit may include any of the following: a syringe, vial, or other container containing the hydroxy polysaccharide; a syringe, vial, or other container containing the polycarboxylic acid molecule; a syringe, vial, or other container containing both the hydroxy polysaccharide and the polycarboxylic acid molecule; a syringe, vial, or other container containing the ester coupling agent; a syringe, vial, or other container containing the hydrolysis accelerator composition; one or more needles (compatible with both hydrolysis syringe systems for delivering the hydrolysis accelerator composition and delivery syringe systems for delivering the hydroxy polysaccharide, polycarboxylic acid molecule, and ester coupling agent); one or more flexible tubes (compatible with both hydrolysis syringe systems for delivering the hydrolysis accelerator composition and delivery syringe systems for delivering the hydroxy polysaccharide, polycarboxylic acid molecule, and ester coupling agent); and injectable liquids, such as water for injection, physiological saline, or phosphate-buffered saline, which may be provided in a syringe, vial, or other container.

[0116] In the specific implementation plan, and referring to Figure 12 The syringe delivery system may include a delivery device 1210 comprising a dual-tube syringe, the syringe including a first tube 1212a having a first tube outlet 1214a (the first tube containing one of the aforementioned first fluid compositions and a first plunger 1219a movable within the first tube 1212a), a second tube 1212b having a second tube outlet 1214b (the second tube 1212b containing one of the aforementioned second fluid compositions and a second plunger 1219b movable within the second tube 1212b). In some embodiments, the device 1210 may further include a mixing section 1218 having a first mixing section inlet 1218ai in fluid communication with the first tube outlet 1214a, a second mixing section inlet 1218bi in fluid communication with the second tube outlet, and a mixing section outlet 1218o. Also shown is a syringe holder 1222 configured to maintain a fixed relationship between the first and second syringe tubes 1212a, 1212b, and a plunger cap 1224 configured to maintain a fixed relationship between the first and second plungers 1219a, 1219b. In some embodiments, the delivery device may further include a needle or catheter configured to receive a first fluid composition and a second fluid composition from the first and second tubes. For example, the needle or catheter may be configured to form a fluid connection with the outlet of the mixing section by attaching a cannula or catheter to the outlet of the mixing section (e.g., via a suitable fluid connector such as a Luer connector).

[0117] Regardless of the type of apparatus used to mix the first fluid composition and the second fluid composition, or how the first fluid composition and the second fluid composition are mixed, after the mixture of the first fluid composition and the second fluid composition is formed, the mixture may initially be in a fluid state and may be applied to a subject (e.g., a mammal, particularly a human) by various techniques. Alternatively, the first fluid composition and the second fluid composition may be applied to the subject independently, and the fluid mixture of the first fluid composition and the second fluid composition may be formed inside or on the surface of the subject.

[0118] In either method, a fluid blend of the first and second fluid compositions is produced, which leads to the formation of a cross-linked polysaccharide hydrogel composition in the subject's body.

[0119] In some embodiments, the cross-linked polysaccharide hydrogel composition of this disclosure can be imaged after application using a suitable imaging technique, such as ultrasound or X-ray-based imaging techniques, such as computed tomography or X-ray fluorescence fluoroscopy.

[0120] Furthermore, because the cross-linked polysaccharide hydrogel compositions of this disclosure have ester-containing cross-linking bonds, they will slowly degrade in aqueous body fluids over time due to hydrolysis. However, when desired, the hydrolysis of the cross-linked polysaccharide hydrogel compositions of this disclosure can be accelerated by contacting the cross-linked polysaccharide hydrogel compositions with the hydrolysis-accelerating catalytic compositions described herein.

[0121] In either method, for various medical purposes, the first and second fluid compositions or fluid mixtures thereof are introduced into the patient.

[0122] For example, in applications such as the treatment of diseases and cancers, as well as tissue repair and regeneration, the first fluid composition and the second fluid composition, or a mixture thereof, can be injected to provide spacers between tissues; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected to provide reference markers; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected for tissue enlargement or regeneration; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected as fillers or substitutes for soft tissues; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected to provide mechanical support for damaged tissues; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected as scaffolds; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected as embolic compositions; the first fluid composition and the second fluid composition, or a mixture thereof, can be injected as lifting agents for the removal of internal cysts; and / or the first fluid composition and the second fluid composition, or a mixture thereof, can be injected as carriers of therapeutic agents. The first fluid composition and the second fluid composition, or a mixture thereof, can also be injected into the left atrial appendages during left atrial appendage closure or during injection for atrial septal defect closure. 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 a closure device, such as the Watchman® left atrial appendage closure device available from Boston Scientific.

[0123] 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 cross-linked polysaccharide hydrogel is ultimately formed at the application site.

[0124] After application, the compositions disclosed herein can be imaged using suitable imaging techniques, such as ultrasound or X-ray-based imaging techniques, such as computed tomography or X-ray fluorescence fluoroscopy.

[0125] As described 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 polysaccharide hydrogel composition; procedures for implanting a tissue regeneration scaffold comprising a cross-linked polysaccharide hydrogel composition; procedures for implanting a tissue support comprising a cross-linked polysaccharide hydrogel composition; procedures for implanting a tissue filler comprising a cross-linked polysaccharide hydrogel composition; procedures for implanting an embolization composition comprising a cross-linked polysaccharide hydrogel composition; procedures for implanting a lifting agent comprising a cross-linked polysaccharide hydrogel composition; procedures for introducing a left atrial appendage occlusion composition comprising a cross-linked polysaccharide hydrogel composition; procedures for implanting a therapeutic reservoir comprising a cross-linked polysaccharide hydrogel composition; procedures for tissue enlargement comprising implanting a cross-linked polysaccharide hydrogel composition; and procedures for introducing a cross-linked polysaccharide hydrogel composition between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0126] The first and second fluid compositions, or fluid mixtures thereof, can be administered in combination 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; and intradiscal injection for degenerative disc disease. 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; 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 to stimulate natural collagen production.

[0127] As described above, other agents used in the compositions described herein include therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters.

[0128] Examples of therapeutic agents include antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, proliferative 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 drugs, immunosuppressants, tyrosine and serine / threonine kinases, proteasome inhibitors, mRNA, matrix metalloproteinase inhibitors, Bcl-2 inhibitors, DNA alkylating agents, spindle poisons, poly(DP-ribose) polymerase (PARP) inhibitors, and combinations thereof.

[0129] 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 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, 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) radioactive contrast agents, such as particles of 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®).

[0130] 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.

[0131] 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, wetting agents and polymers (e.g., albumin, PEO, polyvinyl alcohol, block polymers, etc.), and pH adjusters including various buffer solutes.

Claims

1. A kit for delivering and hydrolyzing cross-linked polysaccharide hydrogels, the kit comprising: (a) a hydrogel delivery system configured to deliver a cross-linked polysaccharide hydrogel to a subject, the cross-linked polysaccharide hydrogel containing polysaccharide molecules cross-linked by cross-linking bonds comprising hydrolyzable ester bonds; and (b) a hydrogel hydrolysis system configured to deliver a hydrolysis-accelerating catalytic composition to a subject, the hydrolysis-accelerating catalytic composition being adapted to accelerate the hydrolysis of the hydrolyzable ester bonds in the cross-linked polysaccharide hydrogel.

2. The kit according to claim 1, wherein the hydrolysis acceleration catalytic composition comprises a hydrolysis acceleration catalyst selected from hydroxide catalysts and enzyme proteins.

3. The kit according to any one of claims 1-2, wherein the hydrolysis acceleration catalytic composition is pre-packaged in a hydrolysis syringe system.

4. The kit according to any one of claims 1-3, wherein the hydrogel hydrolysis system further comprises a needle, a flexible tube, or both, and wherein the hydrolysis syringe system is configured to be coupled to the needle, the flexible tube, or both.

5. The kit according to any one of claims 1-4, wherein the hydrogel delivery system comprises a pre-formed cross-linked polysaccharide hydrogel.

6. The kit according to claim 5, wherein the pre-formed cross-linked polysaccharide hydrogel comprises cross-linked polysaccharide hydrogel particles.

7. The kit according to claim 6, wherein the pre-formed cross-linked polysaccharide hydrogel particles are pre-packaged in a delivery syringe system.

8. The kit according to any one of claims 1-4, wherein the hydrogel delivery system comprises a carboxylic acid polysaccharide, a polyol, and an ester coupling agent.

9. The kit of claim 8, wherein the hydrogel delivery system is configured to form a mixture of the carboxylated polysaccharide, the polyol and the ester coupling agent, and to deliver the mixture to a subject, wherein the carboxylated polysaccharide and the polyol form the crosslinking bonds with each other.

10. The kit of claim 8, wherein the hydrogel delivery system comprises a delivery syringe system configured to form a mixture of the carboxylated polysaccharide, the polyol and the ester coupling agent, and to deliver the mixture to a subject, wherein the carboxylated polysaccharide and the polyol form the crosslinks with each other.

11. The kit of claim 10, wherein the delivery syringe system comprises a dual-tube syringe device for preparing and delivering the mixture containing the carboxylic polysaccharide, the polyol, and the ester coupling agent.

12. The kit according to any one of claims 1-4, wherein the hydrogel delivery system comprises a hydroxy polysaccharide, a polycarboxylic acid molecule, and an ester coupling agent.

13. The kit of claim 12, wherein the hydrogel delivery system is configured to form a mixture of the hydroxy polysaccharide, the polycarboxylic acid molecule and the ester coupling agent, and to deliver the mixture to a subject, wherein the hydroxy polysaccharide and the polycarboxylic acid molecule form the crosslinking bond with each other.

14. The kit of claim 12, wherein the hydrogel delivery system comprises a delivery syringe system configured to form a mixture of the hydroxy polysaccharide, the polycarboxylic acid molecule and the ester coupling agent, and to deliver the mixture to a subject, wherein the hydroxy polysaccharide and the polycarboxylic acid molecule form the crosslinks with each other.

15. The kit of claim 14, wherein the delivery syringe system comprises a dual-tube syringe device for preparing and delivering the mixture of the hydroxy polysaccharide, the polycarboxylic acid molecule and the ester coupling agent.

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