Polysaccharides with improved radiocontrast 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 in the carboxyl-containing polysaccharide chain 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 methods comprising introducing such medical compositions into or between tissues of a patient, and medical kits comprising such medical compositions.

Description

[0001] priority

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 130,950, filed on December 28, 2020, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] In other aspects, the present disclosure relates to medical compositions comprising iodinated polysaccharide compounds having radiocontrast properties, methods of preparing such iodinated polysaccharide compounds, medical compositions comprising such iodinated polysaccharide compounds, and medical methods of using such iodinated polysaccharide compounds. Background Art

[0004] Injectable hydrogels are an emerging class of materials with a variety of medical uses. As a specific example, injectable hydrogels have been used to create or maintain space between tissues to reduce the side effects of off-target radiation therapy. The use of spacer materials in conjunction with prostate radiotherapy is schematically shown in Figures 1A and 1B. Figure 1A shows a cross-section of a human male anatomy including a prostate 110 and a rectal wall 112. When radiotherapy is used to treat the prostate, there is a higher dose area 114 near the prostate that is subjected to high dose radiation, and a lower dose area 116 is formed as it moves away from the prostate 110. As shown in Figure 1B, 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.

[0005] However, for a variety of applications, including the use of injectable hydrogels as spacers near tumor sites prior to radiation therapy, it would be useful for the material to additionally have some persistent radiocontrast properties. Tungsten particles can be added, but these do not biodegrade and may settle out of the hydrogel, making this not an ideal strategy. Iodinated contrast agents can also be added immediately prior to injection. However, there are three problems with this approach: 1) images need to be taken within hours of implantation, otherwise the implant will not be visible, 2) subsequent imaging will not have any perceptible contrast, and 3) the iodine is not bound to the hydrogel, so it is possible that the contrast agent imaged is not the hydrogel, but rather contrast agent that diffuses out of the hydrogel.

[0006] Thus, in the biomedical field, there is a continuing need for, among other needs, new materials having radiocontrast properties and methods of making and using such materials. Summary of the invention

[0007] In some aspects, the disclosure relates to an iodinated polysaccharide compound comprising a polysaccharide backbone comprising a plurality of carboxyl groups and a plurality of iodinated side groups. In certain embodiments, the polysaccharide backbone comprises a carboxyl-containing polysaccharide chain to which the iodinated side groups are attached. In certain embodiments, the carboxyl-containing polysaccharide chain comprises one or more residues selected from one or more of a glucuronic acid residue, a mannuronic acid residue, or a galacturonic acid residue.

[0008] In some aspects, the present disclosure relates to iodinated polysaccharide compounds, wherein at least a portion of the carboxyl groups present in the carboxyl-containing polysaccharide chains are functionalized with a plurality of iodinated side groups. In certain embodiments, the carboxyl-containing polysaccharide chains comprise one or more residues selected from glucuronic acid residues, mannuronic acid residues, or galacturonic acid residues.

[0009] In some embodiments that can be used in combination with the aforementioned aspects and embodiments, the iodinated side group can include an iodinated aryl, wherein one or more hydrogens of the aryl are replaced by iodine, and one or more hydrogens of the aryl are replaced by a hydrophilic group. In some of these embodiments, the aryl can be a phenyl. In some of these embodiments, the hydrophilic group can include a polyhydroxyl group.

[0010] In some embodiments that can be used in combination with the foregoing aspects and embodiments, the iodinated side groups can include iodinated aromatic groups and hydrophilic groups. In some of these embodiments, the iodinated aromatic side groups can include monoiodophenyl, diiodophenyl, triiodophenyl, or tetraiodophenyl. In some of these embodiments, the hydrophilic group can include polyhydroxy groups, for example, polyhydroxy-C 1 -C 6 -alkyl groups, polyhydroxy groups, etc.

[0011] In some embodiments that may be used in combination with the preceding aspects and embodiments, the iodinated side groups may comprise 2,4,6-triiodophenyl groups, wherein at least one of the hydrogens at the 3 and 5 positions is replaced by a polyhydroxyl group, such as a polyhydroxy-C 1 -C 6 -alkyl groups, polyhydroxy groups, etc.

[0012] In some embodiments that may be used in combination with the preceding aspects and embodiments, the iodinated side groups may comprise -N,N'-bis(polyhydroxy-C 1 -C 6 -alkyl)-2,4,6-triiodophenyl-3,5-dicarboxamide group.

[0013] In some aspects, the invention relates to a method of forming an iodinated polysaccharide compound according to any one or embodiment of the aforementioned aspects and embodiments. In some embodiments, the method comprises forming an amide bond by a coupling reaction, wherein an amino group of an amino-containing iodinated compound reacts with a carboxyl group of a carboxyl-containing polysaccharide chain.

[0014] In some embodiments that can be used in combination with the aforementioned aspects and embodiments, the coupling is performed in aqueous solution in the presence of a coupling agent. For example, the coupling agent can be a carbodiimide coupling agent or the like.

[0015] In some embodiments that may be used in conjunction with the preceding aspects and embodiments, the amino-containing iodinated compound comprises an aromatic group in which one or more hydrogens are replaced by an amino-containing group, one or more hydrogens are replaced by iodine, and one or more hydrogens are replaced by a hydrophilic group, such as a hydrophilic group selected from those described above.

[0016] In some aspects, the present disclosure relates to a medical composition comprising an iodinated polysaccharide compound according to any aspect or embodiment of the foregoing aspects and embodiments.

[0017] In some embodiments, the medical composition is a hydrogel. In certain of these embodiments, the hydrogel is an injectable hydrogel.

[0018] In some embodiments that may be used in combination with the preceding aspects and embodiments, the medical composition further comprises a therapeutic agent.

[0019] In some aspects, the present disclosure relates to a medical method comprising introducing a medical composition according to any one or more of the foregoing aspects and embodiments into or between tissues of a patient.

[0020] In some embodiments, the medical method further comprises imaging the medical composition using an X-ray based imaging technique.

[0021] In some embodiments that may be used in conjunction with the foregoing aspects and embodiments, the medical method is selected from a method of implanting a reference marker comprising an iodinated polysaccharide compound, a method of implanting a tissue regeneration scaffold comprising an iodinated polysaccharide compound, a method of implanting a tissue support comprising an iodinated polysaccharide compound, a method of implanting a tissue bulking agent comprising an iodinated polysaccharide compound, a method of implanting a reservoir containing a therapeutic agent comprising an iodinated polysaccharide compound, a method of tissue augmentation comprising implanting a medical composition, a method of introducing a medical composition between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0022] In some aspects, the present disclosure relates to a medical kit comprising a medical composition according to any one of the preceding aspects and embodiments or embodiments in a container and one or more of: (a) an injectable degradation composition in a container, the degradation composition being used to decompose the iodinated polysaccharide compound, (b) a catheter or other delivery device, (d) a needle, or (e) a dilution fluid suitable for injection (e.g., water for injection or saline).

[0023] In addition to the foregoing, further aspects and embodiments of the present disclosure will become apparent by reading the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] 1A and 1B schematically illustrate a cross-section of the human male anatomy including the prostate and rectal wall before and after injection of a spacer material.

[0025] Figure 2 A method of forming a radiopaque polysaccharide compound according to an embodiment of the present disclosure is schematically illustrated. DETAILED DESCRIPTION

[0026] In various aspects, the present disclosure provides an iodinated polysaccharide compound comprising a polysaccharide backbone comprising a plurality of carboxyl groups and a plurality of iodinated side groups. In various embodiments, the polysaccharide backbone comprises a carboxyl-containing polysaccharide chain to which the iodinated side groups are attached. In various aspects, the present disclosure provides an iodinated polysaccharide compound wherein at least a portion of the carboxyl groups present in the carboxyl-containing polysaccharide chain are functionalized with a plurality of iodinated side groups.

[0027] By attaching iodinated side groups to the polysaccharide chain, radiopacity is rendered to the polysaccharide chain, allowing the iodinated polysaccharide compounds to be used, for example, in radiocontrast settings.

[0028] The carboxyl-containing polysaccharide chain may generally be any carboxyl-containing polysaccharide of natural origin, synthetic origin or a combination thereof. Specific examples of the carboxyl-containing polysaccharide chain include the following: polymers containing glucuronic acid residues, including polyglucuronic acid homopolymers and polyglucuronic acid copolymers, such as hyaluronic acid (which includes D-glucuronic acid residues and N-acetyl-D-glucosamine residues) and various carboxyl-containing gums, including gums with glucuronic acid residues, such as gellan gum (which includes D-glucuronic acid residues, D-glucose residues and L-rhamnose residues) and xanthan gum (which includes D-glucuronic acid residues, D-glucose residues and D-mannose residues); polymers containing mannuronic acid residues, including polymannuronic acid homopolymers and polymannuronic acid copolymers, such as Alginic acid (which includes D-mannuronic acid residues and L-glucuronic acid residues); and polymers containing galacturonic acid residues, which include polygalacturonic acid homopolymers and polygalacturonic acid copolymers including pectin family members, which, in addition to D-galacturonic acid residues, may also include D-glucuronic acid residues and one or more selected from D-xylose residues (e.g., xylogalacturonan), D-celeryose residues (e.g., celery galacturonan), α-L-rhamnose residues (rhamnogalacturonan), D-galacturonic acid residues, D-galactose residues, L-arabinose residues and D-xylose residues). Other specific examples of carboxyl-containing polysaccharide chains include carboxylated cellulose, carboxymethyl cellulose, carboxylated starch, carboxymethyl starch, N-carboxymethyl chitosan or N,O-carboxymethyl chitosan.

[0029] In various embodiments, the iodinated side groups of the iodinated polysaccharide compound comprise iodinated aryl groups, wherein one or more hydrogens of the aryl group are replaced by iodine, and one or more hydrogens of the aryl group are replaced by a hydrophilic group. In these embodiments, the aryl group may be selected from phenyl or naphthalene, etc.

[0030] In various embodiments, the iodinated side group comprises an iodinated aryl and at least one hydrophilic group. In these embodiments, the iodinated aryl can be selected from iodinated phenyl or iodinated naphthyl, etc. In a specific embodiment, the iodinated aryl can comprise a mono-iodophenyl, a di-iodophenyl, a tri-iodophenyl or a tetra-iodophenyl. In certain embodiments, the iodinated side group can comprise a 2,4,6-tri-iodophenyl group, wherein at least one hydrogen at the 3 and 5 positions is replaced by a hydrophilic group.

[0031] The at least one hydrophilic group may be selected from, for example, a polyhydroxyl group, etc. For example, the at least one polyhydroxyl group may include, for example, a polyhydroxy-C 1 -C 6 -alkyl groups, or polyhydroxy-C 1 -C 6 -alkyl-carboxamide groups.

[0032] In certain embodiments, the iodinated side groups may comprise —N,N′-bis(polyhydroxy-C 1 -C 6 -alkyl)-2,4,6-triiodophenyl-3,5-dicarboxamide radical, of which -N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophenyl-3,5-dicarboxamide is an example.

[0033] Other aspects of the present disclosure relate to methods of forming iodinated polysaccharide compounds, such as those described above. In some embodiments, these methods include forming an amide bond that connects the iodinated side group to the polysaccharide backbone by a coupling reaction in which the amino group of the amino-containing iodinated compound reacts with the carboxyl group of the carboxyl-containing polysaccharide chain. By coupling the amino-containing iodinated compound to the polysaccharide, radiopacity is imparted to the polysaccharide.

[0034] The use of coupling agents can facilitate such coupling in aqueous and non-aqueous solutions. For example, suitable coupling agents can be selected from the following: (a) carbodiimides, such as 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-cyclohexyl-3-(2-morpholinyl-4-ethyl)carbodiimide methyl p-toluenesulfonate (CMC) or 1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide methyl-4-toluenesulfonate ( CDI), (b) phosphonium reagents, such as BOP (benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), PyBOPR (benzotriazol-1-yloxy-tripyrrolidinyl-phosphonium hexafluorophosphate), PyBrOPR (bromo-tripyrrolidinyl-phosphonium hexafluorophosphate), PyAOP (7-aza-benzotriazol-1-yloxy-tripyrrolidinylphosphonium hexafluorophosphate), PyOxim (ethyl cyano(hydroxyimino)acetate-O 2 )-tris-(1-pyrrolidinyl)-phosphonium hexafluorophosphate). DEPBT (3-(diethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H)-one), (c) ammonium / urea-imine reagents, such as 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylammonium tetrafluoroborate / hexafluorophosphate (TBTU, BF 4 - Anion) / HBTU, PF 6 -anion), HCTU (2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylammonium 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′-tetramethylammonium tetrafluoroborate / hexafluorophosphate (TATU, BF 4 - Anion / HATU, PF 6 - anion), COMU (1-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino]-urea hexafluorophosphate), TOTT (2-(1-oxy-pyridin-2-yl)-1,1,3,3-tetramethylisothiourea tetrafluoroborate), TFFH (tetramethylfluorourea hexafluorophosphate), (d) other coupling agents such as EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), T3P (2-propylphosphonic anhydride), DMTMM and related compounds (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium salt), BTC (bistrichloromethyl carbonate or "triphosgene") and CDI (1,1'-carbonyldiimidazole). Additives are often used to form amide bonds with carbodiimides to increase reactivity and reduce the formation of diastereomers and N-acylureas. Additives include HOBt (1-hydroxybenzotriazole), HOBt-6-sulfonamidomethyl resin HCl (1-hydroxybenzotriazole-6-sulfonamidomethyl 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-(oximino)acetate), DMAP (4-(N,N-dimethylamino)pyridine). The aforementioned coupling agents and additives can be obtained from suppliers such as Bachem Americas, Inc., Torrance, CA, USA.

[0035] The carboxyl-containing polysaccharide compound used in this coupling method can be selected from polyglucuronic acid homopolymers and copolymers, polymannuronic acid homopolymers and copolymers, polygalacturonic acid homopolymers and copolymers, carboxylated cellulose, carboxymethyl cellulose, carboxylated starch, carboxymethyl starch, N-carboxymethyl chitosan or N,O-carboxymethyl chitosan as described above.

[0036] In various embodiments, the amino-containing iodinated compound may be water soluble.

[0037] 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.

[0038] In various embodiments, the amino-containing iodinated compound may comprise an aryl 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 hydrophilic group. For example, the amino-containing iodinated compound may comprise a phenyl group in which 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.

[0039] In various embodiments, the amino-containing iodinated compound may include an iodinated aryl group, wherein one or more hydrogens are replaced by an amino-containing group, and one or more hydrogens are replaced by a hydrophilic group. For example, the amino-containing iodinated compound may include an iodinated phenyl group, wherein at least one hydrogen is replaced by an amino-containing group, and at least one hydrogen is replaced by a hydrophilic group. In certain embodiments, the amino-containing iodinated compound may include a 2,4,6-triiodophenyl group, wherein at least one hydrogen at positions 1, 3, and 5 is replaced by an amino-containing group, and at least one hydrogen at positions 1, 3, and 5 is replaced by a hydrophilic group.

[0040] Examples of the hydrophilic group include a polyhydroxy group and the like.

[0041] Specific amino-containing iodinated compounds include 5-amino-N,N′-bis(polyhydroxy-C 1 -C 6 -alkyl)-2,4,6-triiodophenyl-1,3-dicarboxamide compounds, of which 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophenyl-1,3-dicarboxamide is an example.

[0042] A specific example of a method of forming an iodinated polysaccharide according to the present disclosure will now be described, wherein at least a portion of the carboxyl groups present in the hyaluronic acid-containing polysaccharide chains are functionalized with iodinated side groups to render the polysaccharide chains radiopaque. In one beneficial embodiment, the carboxyl groups of non-animal stabilized hyaluronic acid (NASHA) are functionalized with iodinated side groups. At sufficiently high concentrations, NASHA solutions form physically cross-linked hydrogels that are suitable for injection and have good biocompatibility. In addition, NASHA hydrogels have the additional attractive feature that they can be readily dissolved under mild conditions by administering hyaluronidase to catalyze their hydrolysis. NASHA polymers are functionalized with water-soluble iodinated side groups. Reference Figure 2The available amino group of the compound 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (CAS#76801-93-9) can be coupled with the carboxyl group of the D-glucuronic acid subunit of NASHA to provide a water-soluble, radiopaque moiety. This coupling can be promoted in aqueous solution with a suitable coupling agent such as EDC.

[0043] Other aspects of the present disclosure relate to compositions comprising the iodinated polysaccharide compounds of the present disclosure.Compositions comprising the iodinated polysaccharide compounds of the present disclosure can be used in a variety of biomedical applications, including for injections, implants, and medical devices.

[0044] Such compositions include hydrogel compositions comprising iodinated polysaccharide compounds of the present disclosure and water. According to the hydrogel of the present disclosure, it can be physically or chemically (e.g., covalently) cross-linked. In some embodiments, according to the hydrogel of the present disclosure, a smooth coating can be formed. In some embodiments, according to the hydrogel of the present disclosure, it can be an injectable hydrogel.

[0045] As previously described, radiopacity is rendered to the polysaccharide chains by attaching iodinated side groups to the carboxyl-containing polysaccharide chains, thereby producing iodinated polysaccharide compounds useful in radiocontrast settings.

[0046] In some embodiments, compositions comprising the iodinated polysaccharide compounds of the present disclosure may include one or more therapeutic agents, such as small molecule drugs, cells, proteins, and bioactive molecules.

[0047] In some embodiments, the therapeutic agent may be selected from the following: an anesthetic; an analgesic selected from acetaminophen, ibuprofen, flurbiprofen, ketoprofen, Phenacetin and salicylamide; anti-inflammatory agents selected from naproxen and indomethacin; antihistamines selected from chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine 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; antibiotics selected from antiamoebic drugs (broad-spectrum and medium-spectrum), fungal drugs, monolactams and antiviral agents; bronchodilators selected from the group consisting of theophylline, salbutamol and terbutaline; cardiovascular agents selected from the group consisting of diltiazem, propranolol, nifedipine, clonidine, alpha adrenergic receptor agonists, alpha receptor blockers, alpha and beta receptor blockers, angiotensin converting enzyme inhibitors, beta blockers, calcium channel blockers and cardiac glycosides; central nervous system drugs selected from the group consisting of thioridazine, diazepam, meclizine, lysergic acid esters, chlorpromazine, carbidopa and levodopa; metal salts selected from the group consisting of potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressants selected from the group consisting of minocycline, cyclosporine A; thyroid preparations selected from synthetic thyroid hormones and thyroxine sodium; peptide and glycoprotein hormones and analogs selected from human chorionic gonadotropin (HCG), adrenocorticotropic hormone, human growth hormone (HGH-somatropin), 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, synthetic steroids (anab olics), androgen and estrogen combinations, androgens, corticosteroids and analgesics, estrogens, glucocorticoids, gonadotropins, gonadotropin-releasing, hypocalcemia, fertility hormones, parathyroid hormone, progesterone, progesterone, progesterone and estrogen combinations, somatostatin-like compounds, urofollicle-stimulating hormone, vasopressin, methylprednisolone, GM1 ganglioside, cAMP, etc.; vitamins selected from water-soluble vitamins and veterinary preparations; growth factors selected from EGF, FGF2 and neurotrophins; peptides, peptide mimetics and other protein preparations; DNA; and small interfering RNA.

[0048] Examples of settings in which injectable hydrogels according to the present disclosure may be used include injections for providing intertissue spacing, injections for providing fiducial markers (e.g., in the form of bubbles), injections for tissue augmentation or regeneration, injections as fillers or replacements for soft tissue, injections to provide mechanical support for damaged tissue, injections as scaffolds, injections as carriers of therapeutic agents in disease and cancer treatment and in the repair and regeneration of tissue, and the like.

[0049] The present invention includes various modes of administration of the disclosed compositions combined with various medical methods. Among other factors, those skilled in the art can also determine the most ideal mode of administration of the compositions according to the type of treatment and the patient's condition. The administration method includes, for example, percutaneous techniques and other effective administration routes. For example, the compositions of the present invention can be delivered by a syringe or a catheter (e.g., a microcatheter), which can be advanced on devices such as guidewires, manipulable microcatheters, or flow-guided microcatheters.

[0050] In various aspects, a medical method is provided in which a medical composition comprising an iodinated polysaccharide compound of the present disclosure is inserted into or between tissues of a patient. In various embodiments, the injected medical composition is then imaged using an external or internal imaging technique. Typically, the imaging technique is an X-ray-based imaging technique, such as computed tomography or X-ray fluoroscopy.

[0051] In certain embodiments, the medical method may be one of the following methods: a method of implanting a fiducial marker comprising iodinated polysaccharide, a method of implanting a tissue regeneration scaffold comprising iodinated polysaccharide, a method of implanting a tissue support comprising iodinated polysaccharide, a method of implanting a tissue filler comprising iodinated polysaccharide, a method of implanting a reservoir containing a therapeutic agent comprising iodinated polysaccharide, a method of tissue augmentation comprising implanting a medical composition, a method of introducing a medical composition between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0052] The compositions (e.g., hydrogels) according to the present disclosure can be injected at different sites in various medical procedures, including the following: injection between the prostate or vagina and rectum to maintain the interval in radiotherapy for rectal cancer, injection between the rectum and prostate to maintain the interval 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, injection for Asherman's syndrome (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 trauma surgery for spine, oral and maxillofacial, and orthopedic surgery, spinal injection for posterolateral lumbar fusion, intradiscal injection for degenerative disc disease, interpancreatic and duodenal injection for imaging of pancreatic cancer, resection bed injection for imaging of oropharyngeal cancer, peri-tumor bed injection for imaging of bladder cancer, and intra-articular injection for gastrointestinal tumors and urinary tract infections. Submucosal injections for meat, visceral pleural injections for lung biopsy, renal injections for type 2 diabetes and chronic kidney disease, renal cortical injections for chronic kidney disease caused by congenital kidney and urinary tract anomalies, intravitreal injections for neovascular age-related macular degeneration, intratympanic injections for sensorineural hearing loss, dermal injections for correction of wrinkles, creases and folds, facial fat loss, signs of volume loss, contour defects from superficial to deep, correction of sunken skin scars, perioral wrinkles, lip augmentation, facial fat atrophy, stimulation of natural collagen production.

[0053] In other respects, the present disclosure relates to a medical kit of a composition included in a suitable container, the composition comprising an iodinated polysaccharide compound according to the present disclosure. The composition comprising the iodinated polysaccharide can be a dry form (e.g., dry granular form) or a prefabricated hydrogel form. The container comprising the composition of the iodinated polysaccharide can be, for example, a vial or a syringe barrel. The syringe barrel can have an opening to receive a plunger at its proximal end, and have an accessory (e.g., a Luer interface (luer) accessory or another suitable accessory) at its distal end, for direct or indirect engagement with a needle or catheter, so that the inside of the syringe barrel is communicated with the internal fluid of the needle or catheter. The barrel can also be provided with a flange at its proximal end, so as to engage, and for determining the scale of the residual fluid volume in the barrel. The scope of a suitable syringe volume can be, for example, from 5cc or less to 50cc or more, typically from 5cc to 15cc. In addition to the composition comprising the iodinated polysaccharide, the medical kit may also include one or more of the following: (a) an injectable, degradable composition in a container (e.g., in dry form or in a form ready for injection), which degradable composition is a composition that decomposes the iodinated polysaccharide (e.g., hyaluronidase for hyaluronic acid containing polysaccharide), (b) a catheter or other delivery device, (b) a needle, or (d) a diluent suitable for injection (e.g., water for injection or saline).

Claims

1. A hydrogel composition, comprising water and an iodinated polysaccharide compound, wherein the iodinated polysaccharide compound comprises a polysaccharide backbone, wherein the polysaccharide backbone comprises a plurality of carboxyl groups and a plurality of iodinated side groups, wherein the polysaccharide backbone comprises a carboxyl-containing polysaccharide chain to which the iodinated side groups are attached, wherein the carboxyl-containing polysaccharide chain comprises one or more residues selected from one or more of glucuronic acid residues or galacturonic acid residues, and wherein the iodinated polysaccharide compound is formed by a method comprising forming an amide bond by a coupling reaction, wherein an amino group of the amino-containing iodinated compound reacts with a carboxyl group of the carboxyl-containing polysaccharide.

2. A hydrogel composition comprising water and an iodinated polysaccharide compound, wherein at least a portion of the carboxyl groups present in the carboxyl-containing polysaccharide chains are functionalized with a plurality of iodinated side groups, wherein the carboxyl-containing polysaccharide chains comprise one or more residues selected from glucuronic acid residues or galacturonic acid residues, and wherein the iodinated polysaccharide compound is formed by a process comprising forming an amide bond by a coupling reaction, in which the amino groups of the amino-iodinated compound react with the carboxyl groups of the carboxyl-containing polysaccharide.

3. The hydrogel composition of claim 1 or 2, wherein the iodinated side groups comprise iodinated aryl groups, wherein one or more hydrogens of the aryl groups are replaced by iodine, and one or more hydrogens of the aryl groups are replaced by a hydrophilic group. The hydrogel composition according to claim 3 , wherein the aryl group is a phenyl group.

5. The hydrogel composition of claim 1 or 2, wherein the iodinated side groups comprise iodinated aromatic groups and hydrophilic groups.

6. The hydrogel composition of claim 5, wherein the iodinated aryl side groups comprise mono-iodinated phenyl, di-iodinated phenyl, tri-iodinated phenyl, or tetra-iodinated phenyl.

7. The hydrogel composition of claim 3, wherein the hydrophilic group comprises a polyhydroxyl group.

8. The hydrogel composition of claim 1 or 2, wherein the iodinated side groups comprise 2,4,6-triiodophenyl groups, wherein at least one of the hydrogens at the 3- and 5-positions is replaced by a polyhydroxy group.

9. The hydrogel composition according to claim 7, wherein the polyhydroxyl group comprises polyhydroxy-C 1 -C 6 -alkyl group.

10. The hydrogel composition of claim 1 or 2, wherein the iodinated side groups comprise -N,N'-bis(polyhydroxy-C 1 -C 6 -alkyl)-2,4,6-triiodophenyl-3,5-dicarboxamide group.

11. The hydrogel composition of claim 10, wherein the amino-containing iodinated 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 hydrophilic group.

12. The hydrogel composition of claim 11, wherein the aryl group comprises a 2,4,6-triiodophenyl group in which at least one hydrogen at the 3-position and the 5-position is substituted with a hydrophilic group.

13. The hydrogel composition of claim 11, wherein the hydrophilic group comprises a polyhydroxy group.

14. The hydrogel composition according to claim 13, wherein the polyhydroxyl group comprises polyhydroxy-C 1 -C 6 -alkyl group.

15. The hydrogel composition according to claim 1 or 2, wherein the carboxyl group-containing polysaccharide chain comprises a D-glucuronic acid residue and an N-acetyl-D-glucosamine residue.

16. The hydrogel composition of claim 1 or 2, wherein the hydrogel composition is covalently cross-linked.

17. A medical composition comprising the hydrogel composition according to any one of claims 1 to 16.

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