Polysaccharides with improved radiographic contrast properties

Abstract

The present disclosure relates to iodinated polysaccharide compounds comprising a polysaccharide backbone comprising a plurality of carboxyl groups and a plurality of iodinated side groups. The present disclosure also relates to iodinated polysaccharide compounds wherein at least a portion of the carboxyl groups present on the carboxyl-containing polysaccharide chains are functionalized with a plurality of iodinated side groups. Other aspects of the present disclosure relate to methods of forming iodinated polysaccharide compounds, medical compositions comprising iodinated polysaccharide compounds, medical procedures comprising introducing such medical compositions into or between the tissues of a patient, and medical kits comprising such medical compositions.

Description

Technical Field

[0001] Priority This application claims the benefit of U.S. Provisional Patent Application No. 63 / 130,950, filed Dec. 28, 2020, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Among several aspects, the present disclosure relates to a medical composition comprising an iodinated polysaccharide compound having radiopaque properties, a method of making such an iodinated polysaccharide compound, a medical composition comprising such an iodinated polysaccharide compound, and a medical treatment using such an iodinated polysaccharide compound.

Background Art

[0002] Injectable hydrogels are a newly emerging class of materials with various medical applications. As one specific example, injectable hydrogels are used to create or maintain interstitial spacing to reduce the side effects of off-target radiation therapy. A schematic of the use of a spacer material in prostate radiation therapy is shown in FIGS. 1A and 1B. FIG. 1A shows a cross-section of the anatomical structure of a human male including the prostate 110 and the rectal wall 112. When the prostate is treated using radiation therapy, there is a high-dose region 114 adjacent to the prostate that is subjected to a high dose of radiation, but it becomes a low-dose region 116 as it moves further away from the prostate 110. As shown in FIG. 1B, a spacing material 118 can be injected between the prostate 110 and the rectal wall 112, which can reduce damage to the rectal wall by pushing the rectal wall from the high-dose region 114 to the low-dose region 116.

[0003] However, various applications include using hydrogels for injection before radiotherapy as spacers near tumor sites, and it is also beneficial if the material has some sustained radio-enhancing properties. Tungsten particles can also be added, however, these do not biodegrade and may settle from the hydrogel, making it not an ideal strategy. Iodized contrast agents can also be added immediately before injection. However, this approach has three problems: 1) images must be acquired within a few hours of implantation, otherwise the implant will not be visible; 2) follow-up imaging does not have enough contrast agent to be perceived; and 3) since iodine does not bind to hydrogel, the contrast agent being imaged may be the contrast agent diffused from the hydrogel, rather than the hydrogel itself. Therefore, in the field of biomedicine, among the many demands, there is a continuous need for novel materials with radiographic contrast properties, as well as methods for producing and using such materials. [Overview of the Initiative]

[0004] In some embodiments, the disclosure relates to iodized polysaccharide compounds comprising a polysaccharide skeleton containing a plurality of carboxyl groups and a plurality of iodizing side groups. In certain embodiments, the polysaccharide skeleton comprises a carboxyl-containing polysaccharide chain to which the iodizing side groups are attached. In certain embodiments, the carboxyl-containing polysaccharide chain comprises one or more residues selected from one or more glucuronic acid residues, mannuronic acid residues, or galacturonic acid residues. In some embodiments, the disclosure relates to iodized polysaccharide compounds in which at least some of the carboxyl groups present in the carboxyl-containing polysaccharide chain are functionalized with a plurality of iodized side groups. In certain embodiments, the carboxyl-containing polysaccharide chain comprises one or more residues selected from glucuronic acid residues, mannuronic acid residues, or galacturonic acid residues. In some embodiments that may be used in connection with prior art and embodiments, the iodized side group may include an iodized aromatic group in which one or more hydrogens of the aromatic group are substituted with iodine and one or more hydrogens of the aromatic group are substituted with a hydrophilic group. In some of these embodiments, the aromatic group may be a phenyl group. In some of these embodiments, the hydrophilic group may include a polyhydroxylated group.

[0005] In some embodiments that may be used in connection with prior art and embodiments, the iodized side group may include an iodized aromatic group and a hydrophilic group. In some of these embodiments, the iodized aromatic side group may include a monoiodophenyl group, a diiodophenyl group, a triiodophenyl group, or a tetraiodophenyl group. In some of these embodiments, the hydrophilic group may include, among many others, a polyhydroxylated group, such as a polyhydroxylated C1-C6 alkyl-containing group. In some embodiments that may be used in connection with prior art and embodiments, the 2,4,6-triiodobenzene group may be contained in the iodizing side group, and at least one of the hydrogens at positions 3 and 5 is substituted with a polyhydroxylation group, among many others, such as a polyhydroxylation group containing a polyhydroxylated C1-C6-alkyl group. In some embodiments that may be used in connection with prior art and embodiments, the iodizing side group may include a -N,N'-bis(polyhydroxy-C1-C6-alkyl)-2,4,6-triiodobenzene-3,5-dicalboxamide group.

[0006] In some embodiments, the present disclosure relates to a method for forming iodized polysaccharide compounds according to any of the prior embodiments and models. In some embodiments, the method includes forming an amide bond by a coupling reaction in which the amino group of an amino-containing iodized compound reacts with the carboxyl group of a carboxyl-containing polysaccharide chain. In some embodiments that may be used in connection with prior art and embodiments, the coupling is carried out in an aqueous solution in the presence of a coupling agent. For example, the coupling agent may be a carbodiimide coupling agent, among many others. In some embodiments that can be used in connection with prior art and embodiments, the aromatic group is contained in an amino-containing iodized compound, in which one or more hydrogens are substituted with an amino-containing group, one or more hydrogens are substituted with iodine, and one or more hydrogens are substituted with a hydrophilic group, for example, a hydrophilic group selected from those described above.

[0007] In some aspects, the present disclosure relates to a medical composition comprising an iodized polysaccharide compound according to any of the preceding aspects and embodiments. In some embodiments, the medical composition is a hydrogel. In certain embodiments of these embodiments, the hydrogel is an injectable hydrogel. In some embodiments that may be used in connection with prior art and embodiments, the medical composition further includes a therapeutic agent. In some aspects, the present disclosure relates to a medical procedure that involves introducing a medical composition according to any of the prior aspects and embodiments into or between the tissues of a patient. In some embodiments, the medical procedure further includes imaging the medical composition using an X-ray-based imaging technique.

[0008] In some embodiments that may be used in connection with prior art and embodiments, the medical procedure is selected from a procedure for implanting a reference marker containing an iodized polysaccharide compound, a procedure for implanting a tissue regeneration scaffold containing an iodized polysaccharide compound, a procedure for implanting a tissue support containing an iodized polysaccharide compound, a procedure for implanting a tissue expander containing an iodized polysaccharide compound, a procedure for implanting a therapeutic agent-containing depot containing an iodized polysaccharide compound, a tissue augmentation procedure including implanting a medical composition, and a procedure for introducing a medical composition between a first tissue and a second tissue to create a gap between the first tissue and the second tissue. In some aspects, the present disclosure relates to a medical composition in a container according to any of the preceding embodiments and models, and a medical kit comprising one or more of the following: (a) an injectable degradable composition in a container that acts to degrade an iodized polysaccharide compound, (b) a catheter or other delivery device, (d) a needle, or (e) a diluent suitable for infusion (e.g., water or saline for infusion). In addition to the foregoing, further aspects and embodiments of this disclosure will readily become apparent upon closer examination of the following detailed description. [Brief explanation of the drawing]

[0009] [Figure 1A-1B] Figures 1A and 1B are schematic diagrams showing cross-sections of human male anatomical structures, including the prostate and rectal wall, before and after injection of the spacer material. [Figure 2] Figure 2 is a schematic diagram showing a method for forming a radiopaque polysaccharide compound according to an embodiment of the present disclosure. [Modes for carrying out the invention]

[0010] In various embodiments, the disclosure provides iodized polysaccharide compounds comprising a polysaccharide skeleton containing a plurality of carboxyl groups and a plurality of iodizing side groups. In various embodiments, the polysaccharide skeleton comprises a carboxyl-containing polysaccharide chain to which the iodizing side groups are attached. In various embodiments, the disclosure provides iodized polysaccharide compounds in which at least a portion of the carboxyl groups present in the carboxyl-containing polysaccharide chain are functionalized with a plurality of iodizing side groups. By attaching iodized side groups to polysaccharide chains, radiopaqueness is imparted to the polysaccharide chains, making iodized polysaccharide compounds useful, for example, in radiation contrast imaging settings.

[0011] Carboxyl-containing polysaccharides can generally be any carboxyl-containing polysaccharide of natural, synthetic, or combination thereof. Specific examples of carboxyl-containing polysaccharides include: polyglucuronic acid homopolymers and polyglucuronic acid copolymers, such as hyaluronic acid (containing D-glucuronic acid residues and N-acetyl-D-glucosamine residues), and various carboxyl-containing gums including gums containing glucuronic acid residues such as gellan gum (containing D-glucuronic acid residues, D-glucose residues, and L-rhamnose residues) and xanthan gum (containing D-glucuronic acid residues, D-glucose residues, and D-mannose residues); polymannuronic acid homopolymers and polymannuronic acid copolymers, such as alginic acid (containing D-mannuronic acid residues); Polymers containing mannuronic acid residues, including D-glucuronic acid residues and L-glucuronic acid residues; polygalacturonic acid homopolymers; and galacturonic acid residue-containing polymers, including polygalacturonic acid copolymers containing members of the pectin family, which may similarly contain, in addition to D-galacturonic acid residues, one or more additional residues selected from D-glucuronic acid residues and D-xylose residues (e.g., xylogalacturonan), D-apiose residues (e.g., apiogalacturonan), α-L-rhamnose residues (rhamnogalacturonan pectin), D-galacturonic acid residues, D-galactose residues, L-arabinose residues, and D-xylose residues. Other specific examples of carboxyl-containing polysaccharides include carboxylated cellulose, carboxymethylcellulose, carboxylated starch, carboxymethyl starch, N-carboxymethyl chitosan, or N,O-carboxymethyl chitosan.

[0012] In various embodiments, the iodized side group of the iodized polysaccharide compound includes an iodized aromatic group in which one or more hydrogens of the aromatic group are substituted with iodine and one or more hydrogens of the aromatic group are substituted with a hydrophilic group. In these embodiments, the aromatic group can be selected from among several groups, such as a phenyl group or a naphthalene group. In various embodiments, the iodized side group comprises an iodized aromatic group and at least one hydrophilic group. In these embodiments, the iodized aromatic group may be selected from among several, an iodized phenyl group or an iodized naphthalene group. In certain embodiments, the iodized aromatic group may include a monoiodophenyl group, a diiodophenyl group, a triiodophenyl group, or a tetraiodophenyl group. In certain embodiments, the iodized side group may include a 2,4,6-triiodobenzene group in which at least one of the hydrogen atoms at positions 3 and 5 is substituted with a hydrophilic group.

[0013] At least one hydrophilic group can be selected from among many, for example, from polyhydroxylated groups. For example, at least one polyhydroxylated group may include, for example, a polyhydroxylated C1-C6-alkyl-containing group or a polyhydroxylated C1-C6-alkyl-carboxamide group. In certain embodiments, the iodized side group may include a -N,N'-bis(polyhydroxy-C1-C6-alkyl)-2,4,6-triiodobenzene-3,5-dicarboxamide group, of which -N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-3,5-dicarboxamide is one example.

[0014] Other aspects of this disclosure relate to methods for forming iodized polysaccharide compounds as described above. In some embodiments, these methods include forming an amide bond that links the iodized side group to the polysaccharide skeleton by a coupling reaction in which the amino group of the amino-containing iodized compound reacts with the carboxyl group of the carboxyl-containing polysaccharide chain. Radiopaqueness is imparted to the polysaccharide by coupling the amino-containing iodized compound with the polysaccharide.

[0015] This coupling can be facilitated by the use of a coupling agent in aqueous and non-aqueous solutions. Suitable coupling agents may be selected from, for example, the following: (a) carbodiimides, e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-cyclohexyl-3-(2-morpholinyl-4-ethyl)carbodiimidemethyl p-toluenesulfonate (CMC), or 1-cyclohexyl-3-(2-morpholio(ethyl))carbodiimidemeth-4-toluenesulfonate (CDI); (b) phosphonium reagents, e.g., BOP (benzotriazole-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), PyBOPR (benzotriazole-1-yloxy-tripyroxene (c) Lidino-phosphonium hexafluorophosphate, PyBrOPR (bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-aza-benzotriazole-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate), PyOxim (ethylcyano(hydroxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), DEPBT (3-(diethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H)-one), (c) Amium / uronium-imonium reagent, e.g., 2-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethylaminium tetrafluoroborate / hexafluorophosphate (TBTU, BF4) - Anions) / HBTU, PF6 -Anion), HCTU (2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N-oxide), 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium tetrafluoroborate / hexafluorophosphate (TATU, BF4) - Anions / HATU, PF6 -Anions), COMU (1-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-oxypyridine-2-yl)-1,1,3,3-tetramethylisothiouronium tetrafluoroborate), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), (d) additional Coupling agents include, for example, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), T3P (2-propanephosphonic anhydride), DMTMM and related compounds (4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium salt), BTC (bis-trichloromethylcarbonate or "triphosgene"), and CDI (1,1'-carbonyldiimitazole). Additives are commonly used to form amide bonds using carbodiimides to increase reactivity while simultaneously reducing the formation of epimers and N-acylureas. Examples of additives include HOBt (1-hydroxybenzotriazole), HOBt-6-sulfonamidemethyl resin·HCl (1-hydroxybenzotriazole-6-sulfonamidemethyl resin·HCl), HOOBT (HODhbt) (hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine), HOSu (N-hydroxysuccinimide), HOAt (1-hydroxy-7-aza-1H-benzotriazole), Oxyma Pure (ethyl 2-cyano-2-(hydroxymino(hydroximino))acetate), and DMAP (4-(N,N-dimethylamino)pyridine). The above coupling agents and additives are available from suppliers such as Bachem Americas, Inc., Torrance, CA, USA, etc.

[0016] The carboxyl-containing polysaccharide compound for use in such coupling methods can be selected from homopolymers and copolymers of polyglucuronic acid, homopolymers and copolymers of polymannuronic acid, homopolymers and copolymers of polygalacturonic acid, carboxylated cellulose, carboxymethyl cellulose, carboxylated starch, carboxymethyl starch, N-carboxymethyl chitosan, or N,O-carboxymethyl chitosan, as described above.

[0017] In various embodiments, the amino-containing iodinated compound can be water-soluble. In various embodiments, the amino-containing iodinated compound can be a water-soluble iodinated aromatic amine, for example, an iodinated aromatic amine substituted with one or more hydrophilic groups. In various embodiments, an aromatic group can be included in the amino-containing iodinated compound, one or more hydrogens are substituted with amino-containing groups, one or more hydrogens are substituted with iodine, and one or more hydrogens are substituted with hydrophilic groups. For example, a benzene group can be included in the amino-containing iodinated compound, at least one hydrogen is substituted with an amino-containing group, at least one hydrogen is substituted with an iodine group, and at least one hydrogen is substituted with a hydrophilic group.

[0018] In various embodiments, an iodinated aromatic group can be included in the amino-containing iodinated compound, one or more hydrogens are substituted with amino-containing groups, and one or more hydrogens are substituted with hydrophilic groups. For example, an iodinated benzene group can be included in the amino-containing iodinated compound, at least one hydrogen is substituted with an amino-containing group, and at least one hydrogen is substituted with a hydrophilic group. In certain embodiments, a 2,4,6-triiodobenzene group can be included in the amino-containing iodinated compound, at least one hydrogen is substituted with an amino-containing group at the 1, 3, and 5 positions, and at least one hydrogen is substituted with a hydrophilic group at the 1, 3, and 5 positions. Examples of hydrophilic groups include, among others, polyhydroxylated groups. Certain amino-containing iodinated compounds include 5-amino-N,N'-bis(polyhydroxy-C1-C6-alkyl)-2,4,6-triiodobenzene-1,3-dicarboxamide compounds, among which 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide is an example.

[0019] Here, a specific example of a method for forming an iodinated polysaccharide according to the present disclosure will be described. In this method, at least a part of the carboxyl groups present in the hyaluronic acid-containing polysaccharide chain is functionalized with an iodinated side group so that radiopacity is imparted to the polysaccharide chain. In one advantageous embodiment, the carboxyl groups of non-animal stabilized hyaluronic acid (NASHA) are functionalized with an iodinated side group. At a sufficiently high concentration, the NASHA solution forms a physically cross-linked hydrogel, which is biocompatible and suitable for injection. Furthermore, the NASHA hydrogel also has the additional attractive feature that it can be easily dissolved by administering hyaluronidase under mild conditions to catalyze hydrolysis. The NASHA polymer is functionalized with a water-soluble iodinated side group. Referring to Figure 2, the carboxyl groups of the D-glucuronic acid subunits of NASHA and the available amino groups of the compound 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (CAS#76801-93-9) can be coupled to obtain a water-soluble radiopaque moiety. This coupling can be facilitated using a suitable coupling agent such as EDC in an aqueous solution.

[0020] Another aspect of the present disclosure relates to a composition comprising the iodinated polysaccharide compound of the present disclosure. The composition comprising the iodinated polysaccharide compound of the present disclosure can be used in a variety of biomedical applications including use in injectables, implants, and medical devices. Examples of such compositions include hydrogel compositions comprising the iodized polysaccharide compounds and water of the present disclosure. Hydrogels according to the present disclosure can be crosslinked physically or chemically (e.g., covalently). In some embodiments, hydrogels according to the present disclosure can form a smooth coating. In some embodiments, hydrogels according to the present disclosure may be injection hydrogels.

[0021] As mentioned above, by attaching iodized side groups to carboxyl-containing polysaccharide chains, radiopaqueness is imparted to the polysaccharide chains, resulting in iodized polysaccharide compounds that are useful in radiation contrast imaging settings. In some embodiments, compositions comprising the iodized polysaccharide compounds of this disclosure may include one or more therapeutic agents, such as small molecule drugs, cells, proteins, and bioactive molecules.

[0022] In some embodiments, the therapeutic agent may be selected from: anesthetics; analgesics selected from acetaminophen, ibuprofen, flurbiprofen, ketoprofen, Voltaren®, phenacetin and salicylamide; anti-inflammatory agents selected from naproxen and indomethacin; chlorpheniramine maleate, phenindamine tartrate, pyriramine maleate, doxylamine succinate, phenyltroxamine citrate and diphenhydramine Antihistamines selected from hydrochloride, promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fumarate, and triprolidine; antitussives selected from dextromethorphan hydrobromide and guaifenesin; expectorants; decongestants selected from phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; amoebicides, broad-spectrum and intermediate-spectrum fungal agents. Antibiotics selected from monobactams and antivirals; bronchodilators selected from theophylline, albuterol and terbutaline; cardiovascular preparations selected from diltiazem, propranolol, nifedipine, clonidine, α-adrenergic receptor agonists, α-receptor blockers, α and β-receptor blockers, antiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers and cardiac glycosides; central nervous system drugs selected from thioridazine, diazepam, meclizine, ergoloid mesylate, chlorpromazine, carbidopa and levodopa; potassium chloride and lithium carbonate Selected metal salts; inorganic substances selected from the group consisting of iron, chromium, molybdenum, and potassium; immunomodulators; immunosuppressants selected from minocycline and cyclosporine A; thyroid preparations selected from synthetic thyroid hormones and thyroxine sodium; peptides and glycoprotein hormones and analogs selected from human chorionic gonadotropin (HCG), corticotropin, human growth hormone (HGH-somatotropin), erythropoietin (EPO), basic fibroblast growth factor (FGF) including FGF1 and FGF2, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), angiopoietin 1, and angiopoietin 2;Steroids and hormones selected from ACTH, anabolic agents, androgens and estrogens in combination, androgens, corticoids and analgesics, estrogens, glucocorticoids, gonadotropins, gonadotropin-releasing agents, hypocalcemia agents, menotropins, parathyroid agents, progesterone, progestogens, progestogens and estrogens in combination, somatostatin-like compounds, urofolitropin, vasopressin, methylprednisolone, GM1 ganglioside, and cAMP; vitamins and veterinary preparations selected from water-soluble vitamins; growth factors selected from EGF, FGF2, and neurotrophins; peptides, peptide mimetic and other protein preparations; DNA; and small interfering RNA.

[0023] Examples of settings in which the injectable hydrogels pursuant to this disclosure may be used include, among many others, injections to create interstitial space between tissues, injections to provide reference markers (e.g., in the form of blebs), injections for tissue augmentation or regeneration, injections as fillers or replacements for soft tissues, injections to provide mechanical support to damaged tissues, injections as scaffolds, and injections as carriers for therapeutic agents in the treatment of tissue diseases, cancer, repair, and regeneration.

[0024] The present invention encompasses various methods for administering the compositions of this disclosure in connection with various medical procedures. Those skilled in the art can determine the most desirable method of administering the compositions depending on several factors, particularly the type of treatment and the patient's condition. Methods of administration include, for example, percutaneous methods and other effective routes of administration. For example, the compositions of the present invention can be delivered via a syringe, or via a catheter, such as a microcatheter, stabilizable microcatheter, or flow-direct microcatheter, which can be advanced along a guidewire. In various embodiments, the medical procedure provided involves the insertion of a medical composition comprising the iodized polysaccharide compound of this disclosure into or between the tissues of a patient. In various embodiments, the injected medical composition is then imaged using external or internal imaging techniques. Typically, the imaging technique is an X-ray based imaging technique, such as computed tomography or fluoroscopy.

[0025] In certain embodiments, the medical procedure may be one of the following: a procedure to implant a reference marker containing an iodized polysaccharide; a procedure to implant a tissue regeneration scaffold containing an iodized polysaccharide; a procedure to implant a tissue support containing an iodized polysaccharide; a procedure to implant a tissue expander containing an iodized polysaccharide; a procedure to implant a therapeutic agent-containing depot containing an iodized polysaccharide; a tissue augmentation procedure including implanting a medical composition; a procedure to introduce a medical composition between a first tissue and a second tissue to create a gap between the first tissue and the second tissue.

[0026] Compositions according to this disclosure (e.g., hydrogels) can be injected at various sites in various medical procedures, including: injection between the prostate or vagina and rectum in intermittent radiotherapy for rectal cancer; injection between the rectum and prostate in intermittent radiotherapy for prostate cancer; subcutaneous injection in elective treatment for prostate cancer; transurethral or submucosal injection in female stress urinary incontinence; intravesical injection in urinary incontinence; intrauterine injection in Asherman's syndrome; submucosal injection in anal incontinence; percutaneous injection in heart failure; intramyocardial injection in heart failure and dilated cardiomyopathy; transendocardial injection in myocardial infarction; intraarticular injection in osteoarthritis; spinal fusion and spinal, oral, maxillofacial and orthopedic trauma surgery; spinal fusion in posterolateral lumbar spinal fusion; degenerative vertebrae Intradiscal injection for intervertebral disc disease; injection between the pancreas and duodenum for imaging of pancreatic adenocarcinoma; injection into the resection bed for imaging of oropharyngeal cancer; injection around the tumor bed for imaging of bladder cancer; submucosal injection for gastrointestinal tumors and polyps; visceral pleural injection for lung biopsy; kidney injection for type 2 diabetes and chronic kidney disease; renal cortical injection for chronic kidney disease resulting from congenital anomalies of the kidneys and urinary tract; intravitreous injection for neovascular age-related macular degeneration; intratympanic injection for sensorineural hearing loss; correction of wrinkles, creases and folds; correction of signs of fat loss, volume loss and shallow to deep contour deficiency in the face; correction of depressed skin scars; correction of perioral wrinkles; correction of lip augmentation; correction of facial adipose tissue atrophy; dermal injection for stimulation of natural collagen production.

[0027] In other embodiments, the Disclosure relates to a medical kit comprising a composition comprising an iodized polysaccharide compound according to the Disclosure, in a suitable container. The composition comprising the iodized polysaccharide may be in a dry form (e.g., in the form of dry particles) or in the form of a pre-made hydrogel. The container for the composition comprising the iodized polysaccharide may be, for example, a vial or a syringe. The syringe may have an opening at its proximal end to receive a plunger, such that the interior of the syringe is fluidly connected to the interior of a needle or catheter, and may have a fitting (e.g., a Luer fitting or another suitable fitting) at its distal end for direct or indirect engagement with the needle or catheter. The syringe may also have a flange at its proximal end for facilitating engagement and a graduation for determining the volume of fluid remaining in the syringe. The capacity of a suitable syringe may be, for example, in the range of 5cc or less to 50cc or more, typically 5cc to 15cc. In addition to the composition containing iodized polysaccharides, the medical kit may include one or more of the following: (a) an injectable degradable composition in a container that degrades iodized polysaccharides (e.g., hyaluronidase for hyaluronic acid-containing polysaccharides) (e.g., in a dry or readily injectable form); (b) a catheter or other delivery device; (b) a needle; or (d) a diluent suitable for injection (e.g., water or saline for injection). Preferred embodiments of the present invention are as follows: [1] An iodized polysaccharide compound comprising a polysaccharide skeleton containing multiple carboxyl groups and multiple iodized side groups. [2] The iodized polysaccharide compound according to [1], wherein the polysaccharide skeleton comprises a carboxyl-containing polysaccharide chain to which an iodized side group is attached, and the carboxyl-containing polysaccharide chain comprises one or more residues selected from one or more glucuronic acid residues, mannuronic acid residues, or galacturonic acid residues. [3] An iodized polysaccharide compound in which at least some of the carboxyl groups present in the carboxyl-containing polysaccharide chain are functionalized with multiple iodized side groups. [4] The iodized polysaccharide compound according to [3], wherein the carboxyl-containing polysaccharide chain comprises one or more residues selected from glucuronic acid residues, mannuronic acid residues, or galacturonic acid residues. [5] An iodized polysaccharide compound according to any one of [1] to [4] above, wherein the iodized side group comprises an iodized aromatic group in which one or more hydrogens of the aromatic group are substituted with iodine and one or more hydrogens of the aromatic group are substituted with a hydrophilic group. [6] The iodized polysaccharide compound described in [5] above, wherein the aromatic group is a phenyl group. [7] An iodized polysaccharide compound according to any one of [1] to [4] above, wherein the iodized side group includes an iodized aromatic group and a hydrophilic group. [8] The iodized polysaccharide compound according to [7] above, wherein the iodized aromatic side group comprises a monoiodophenyl group, a diiodophenyl group, a triiodophenyl group, or a tetraiodophenyl group. [9] An iodized polysaccharide compound according to any one of [5] to [8] above, wherein the hydrophilic group includes a polyhydroxylation group.

[10] The iodized polysaccharide compound according to any one of [1] to [4] above, wherein the iodizing side group comprises a 2,4,6-triiodobenzene group in which at least one hydrogen at the 3rd and 5th positions is substituted with a polyhydroxyl group.

[11] Polyhydroxylated group, polyhydroxylated C 1 -C 6 - An iodized polysaccharide compound according to [9] or

[10] above, comprising an alkyl-containing group.

[12] The iodized side group is -N,N'-bis(polyhydroxy-C 1 -C 6 An iodized polysaccharide compound according to any one of [1] to [4] above, comprising an alkyl)-2,4,6-triiodobenzene-3,5-dicalboxamide group.

[13] A method for forming an iodized polysaccharide compound according to any one of [1] to

[12] above, comprising the step of forming an amide bond by a coupling reaction in which the amino group of an amino-containing iodized compound is reacted with the carboxyl group of a carboxyl-containing polysaccharide chain.

[14] A medical composition comprising an iodized polysaccharide compound as described in any of [1] to

[12] above.

[15] A medical procedure comprising the step of introducing the medical composition described in

[14] into or between the tissues of a patient.

Claims

1. A hydrogel composition comprising water and an iodized polysaccharide compound comprising a polysaccharide skeleton comprising a plurality of carboxyl groups and a plurality of iodized side groups, wherein the polysaccharide skeleton comprises a carboxyl-containing polysaccharide chain to which the iodized side groups are attached, the carboxyl-containing polysaccharide chain comprises one or more residues selected from one or more glucuronic acid residues or galacturonic acid residues, and the iodized side groups comprise iodized aromatic groups in which one or more hydrogens of the aromatic group are substituted with iodine and one or more hydrogens of the aromatic group are substituted with a polyhydroxylated group comprising a polyhydroxylated C1-C6-alkyl-containing group.

2. A hydrogel composition comprising water and an iodized polysaccharide compound comprising a polysaccharide skeleton containing a plurality of carboxyl groups and a plurality of iodized side groups, wherein at least a portion of the carboxyl groups present in the carboxyl-containing polysaccharide chain are functionalized with a plurality of iodized side groups, wherein the carboxyl-containing polysaccharide chain comprises one or more residues selected from glucuronic acid residues or galacturonic acid residues, and the iodized side groups comprise iodized aromatic groups in which one or more hydrogens of the aromatic group are substituted with iodine and one or more hydrogens of the aromatic group are substituted with a polyhydroxylated group containing a polyhydroxylated C1-C6-alkyl group.

3. The hydrogel composition according to claim 1 or claim 2, wherein the aromatic group is a phenyl group.

4. The hydrogel composition according to claim 1 or claim 2, wherein the iodized side group comprises a monoiodophenyl group, a diiodophenyl group, a triiodophenyl group, or a tetraiodophenyl group.

5. The hydrogel composition according to claim 1 or claim 2, wherein the iodized side group comprises a 2,4,6-triiodobenzene group in which at least one of the hydrogen atoms at the 3rd and 5th positions is substituted with a polyhydroxylated C1-C6-alkyl-containing group.

6. The iodized side group is -N,N'-bis(polyhydroxy-C) 1 -C 6 A hydrogel composition according to claim 1 or claim 2, comprising an alkyl-2,4,6-triiodobenzene-3,5-dicalboxamide group.

7. The hydrogel composition according to any one of claims 1 to 6, wherein the carboxyl-containing polysaccharide chain comprises a D-glucuronic acid residue and an N-acetyl-D-glucosamine residue.

8. A hydrogel composition according to any one of claims 1 to 7, wherein the components are covalently crosslinked.

9. A method for forming a hydrogel composition according to any one of claims 1 to 8, comprising the step of forming an iodized polysaccharide compound by forming an amide bond through a coupling reaction in which the amino group of an amino-containing iodized compound reacts with the carboxyl group of a carboxyl-containing polysaccharide chain.

10. The method according to claim 9, wherein the amino-containing iodized compound comprises an aromatic group in which one or more hydrogens are substituted with an amino-containing group, one or more hydrogens are substituted with iodine, and one or more hydrogens are substituted with a polyhydroxylated group containing a polyhydroxylated C1-C6-alkyl group.

11. The method according to claim 10, wherein the aromatic group comprises a 2,4,6-triiodobenzene group in which at least one hydrogen at the 3rd and 5th positions is substituted with a polyhydroxylation group.

12. A medical composition comprising the hydrogel composition according to any one of claims 1 to 8.

13. The medical composition according to claim 12 for use in reducing side effects of off-target radiotherapy.

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