Injectable shear thinning composition and its use

Abstract

In some embodiments, the disclosure relates to an injectable shear thinning composition comprising (a) one or more polymers, (b) one or more microparticles, and (c) water. In some embodiments, the disclosure relates to a kit comprising (a) one or more containers containing an injectable shear thinning composition comprising one or more polymers, one or more microparticles, and water, and (b) a delivery device. In some embodiments, the disclosure relates to a medical procedure comprising administering an injectable shear thinning composition comprising one or more polymers, one or more microparticles, and water to a subject.

Description

[Technical Field]

[0001] This disclosure relates to injectable shear-thinning compositions, as well as methods for preparing and using injectable shear-thinning compositions. Injectable shear-thinning compositions are useful, for example, in various medical procedures. [Background technology]

[0002] Injectable shea-thinning compositions are attractive because they represent a minimally invasive delivery procedure for compositions, offering reduced healing time, less scarring, a lower risk of infection, and ease of delivery compared to surgically implanted materials. Injectable shea-thinning compositions are particularly useful in applications where the final form and shape are not critical, or where the final form and shape are determined by the void or space into which the composition is injected. Due to the ease of delivery of compositions, injectable shea-thinning compositions are potentially useful in several areas, such as providing structural or space-filling functions, acting as embolizers to bypass or block blood flow, acting as tissue engineering compositions, and drug delivery. In addition, injectable shea-thinning compositions provide higher drug concentrations at the desired site of action while minimizing systemic drug concentrations and associated side effects.

[0003] Novel injectable shear thinning compositions are currently needed in the biomedical field. [Overview of the project]

[0004] In some embodiments, the present disclosure relates to an injectable shear thinning composition comprising (a) one or more polymers, (b) one or more fine particles, and (c) water.

[0005] In some embodiments, the injectable shea-thinning composition is a physically crosslinked hydrogel composition. In some embodiments that can be used in conjunction with the above embodiments, the one or more polymers include a polymer having a net negative charge and / or a polymer having a net positive charge.

[0006] In some embodiments that can be used in conjunction with the above embodiments, the one or more polymers are selected from polysaccharides, proteins, polypeptides, and synthetic polymers.

[0007] In some embodiments that can be used in combination with the above embodiments, the one or more polymers are selected from non-animal-derived proteins and non-animal-derived polysaccharides. In some embodiments that can be used in combination with the above embodiments, the one or more types of fine particles are selected from metal fine particles, metal oxide fine particles, carbon-based fine particles, silicate fine particles, lipid fine particles, and crosslinked charged polymer fine particles.

[0008] In some embodiments that can be used in combination with the above embodiments, the one or more types of fine particles include fine particles having a net negative charge and / or fine particles having a net positive charge.

[0009] In some embodiments that can be used in conjunction with the above embodiments, the one or more types of fine particles have a maximum size ranging from 10 nm to 50 μm. In some embodiments that can be used in combination with the above embodiments, the one or more polymers include a polymer having a first net charge, and the one or more fine particles include fine particles having a second net charge opposite in sign to the first net charge.

[0010] In some embodiments that can be used in conjunction with the above embodiments, the injectable shea-thinning composition further comprises one or more additional agents selected from therapeutic agents, imaging agents, colorants, isotonic agents, suspension agents, wetting agents, and pH adjusters.

[0011] In some embodiments that can be used in conjunction with the above embodiments, the injectable shear thinning composition is a sterile composition. In some embodiments that can be used in conjunction with the above embodiments, the injectable shear thinning composition is provided in a container.

[0012] In some embodiments that can be used in conjunction with the above embodiments, the injectable shear thinning composition is provided pre-filled in a syringe. In some embodiments, the present disclosure relates to a kit comprising (a) one or more containers containing the injectable shear thinning composition according to any of the embodiments described above, and (b) a delivery device.

[0013] In some embodiments, the delivery device includes a syringe, a needle, and optionally a catheter. In some embodiments, the present disclosure relates to a medical procedure involving administering an injectable shear thinning composition according to any of the above embodiments to a subject.

[0014] In some embodiments, the method includes injecting an injectable shear thinning composition into a subject. In some embodiments that can be used in combination with the above embodiments, the administration includes parenteral administration.

[0015] In some embodiments that can be used in conjunction with the above embodiments, the administration is performed using a catheter or syringe. In some embodiments that can be used in conjunction with the above embodiments, the administration is performed under image guidance.

[0016] Potential advantages of the present disclosure include, among others, one or more of the following: reduced injection force, improved cohesion in larger or high-flow vasculature, improved thixotropic behavior allowing for more distal penetration when used as an embolic agent, improved therapeutic agent release profile, and enhanced radiopacity. Brief Description of the Drawings

[0017] [Figure 1] A syringe and catheter filled with an injectable thixotropic composition according to an embodiment of the present disclosure are schematically shown. Modes for Carrying Out the Invention

[0018] In some aspects, the present disclosure relates to an injectable thixotropic composition comprising (a) one or more polymers, (b) one or more microparticles, and (c) water. A composition is shear-thinning if its viscosity decreases as the shear rate increases.

[0019] In some embodiments, the injectable thixotropic composition of the present disclosure is a physically crosslinked hydrogel composition. In some embodiments, the injectable thixotropic composition of the present disclosure flows when a pressure greater than the yield stress of the injectable thixotropic composition is applied.

[0020] Polymers used in the injectable thixotropic composition of the present disclosure include uncharged and charged polymers selected from anionic polymers and cationic polymers. An anionic polymer may contain one or more functional groups having a negative charge, such as carboxylate groups, sulfate groups, sulfonate groups, phosphonate groups, phosphate groups, or any combination of these functional groups. A cationic polymer may contain one or more functional groups having a positive charge, such as amine functional groups including primary amine functional groups, secondary amine functional groups, tertiary amine functional groups, and quaternary amine functional groups.

[0021] The polymers used in the injectable shear thinning compositions of this disclosure include polymers having a net negative charge, polymers having a net positive charge, or polymers having a neutral charge. Net negative charge polymers include polymers containing negative charge functional groups such as carboxylate groups, sulfate groups, sulfonic acid groups, phosphonic acid groups, phosphate groups, or any combination of these functional groups. Net negative charge polymers used in this disclosure typically have a net negative charge at pH 8.0 or higher. However, in some embodiments, net negative charge polymers used in this disclosure have a net negative charge at pH 7.0, pH 6.5, pH 6.0, pH 5.5, pH 5.0, pH 4.5, or even pH 4.0. Net positive charge polymers include polymers containing positive charge functional groups such as amine functional groups including primary amine functional groups, secondary amine functional groups, tertiary amine functional groups, and quaternary amine functional groups. Net positive charge polymers used in this disclosure typically have a net positive charge at pH 6.0 or lower. However, in some embodiments, the net positively charged polymers used in this disclosure have a net positive charge at pH 6.5, pH 7.0, pH 7.5, pH 8.0, pH 8.5, pH 9.0, pH 9.5, or even pH 10.0.

[0022] For example, polymers used in the injectable shear thinning compositions of this disclosure include polysaccharides that may have a net negative charge, polysaccharides that may have a net positive charge, or polysaccharides that may have a neutral charge. Net negative charge polysaccharides include polysaccharides containing negatively charged functional groups such as carboxylate groups, sulfate groups, sulfonic acid groups, phosphonic acid groups, phosphate groups, or any combination thereof. The net negative charge polysaccharides used in this disclosure typically have a net negative charge at pH 8.0 or higher. In some embodiments, the net negative charge polysaccharides used in this disclosure have a net negative charge at pH 7.0, pH 6.5, pH 6.0, pH 5.5, pH 5.0, pH 4.5, or even pH 4.0.

[0023] Specific examples of polysaccharides having a net negative charge include carboxylic acid-containing polysaccharides containing one or more uronic acid species such as galacturonic acid, glucuronic acid, and / or iduronic acid. Specific examples of carboxylic acid-containing polysaccharides include pectin, agaropectin, carrageenan, gellan gum, gum arabic, guar gum, xanthan gum, alginic acid, hyaluronic acid, and carboxymethylcellulose. In embodiments where the carboxylic acid-containing polysaccharide is hyaluronic acid, the carboxylic acid-containing polysaccharide may be non-animal-derived stabilized hyaluronic acid. Another specific example of a polysaccharide having a net negative charge is agar, which is a mixture of polysaccharides containing agarose, a neutral polysaccharide, and agaropectin, a charged sulfated polysaccharide. Other specific examples of polysaccharides having a net negative charge include carboxyalkylcelluloses such as carboxymethylcellulose.

[0024] Net positively charged polysaccharides include polysaccharides containing positively charged functional groups such as amine functional groups including primary, secondary, tertiary, and quaternary amine functional groups. The net positively charged polysaccharides used in this disclosure typically have a net positive charge at pH 6.0 or below. In some embodiments, the net positively charged polysaccharides used in this disclosure have a net positive charge at pH 6.5, pH 7.0, pH 7.5, pH 8.0, pH 8.5, pH 9.0, pH 9.5, or even pH 10.0. Specific examples of net positively charged polysaccharides include chitosan and cationic starch.

[0025] Examples of neutral polysaccharides include cellulose derivatives containing alkylcelluloses such as methylcellulose and ethylcellulose, and hydroxyalkylcelluloses such as hydroxyethylcellulose and hydroxypropylcellulose. Neutral polysaccharides also include starches such as corn starch, potato starch, and tapioca starch.

[0026] The polymers used in the injectable shea-thinning compositions of this disclosure also include animal-derived proteins such as collagen and gelatin, where collagen includes bovine collagen, porcine collagen and horse collagen, and gelatin includes porcine gelatin (e.g., type A porcine gelatin, porcine skin-derived gelatin, porcine bone-derived gelatin), bovine gelatin (e.g., type B bovine gelatin, bovine skin-derived gelatin, bovine bone-derived gelatin), horse gelatin, avian gelatin and fish gelatin.

[0027] The polymers used in the injectable shea-thinning compositions of this disclosure further comprise non-animal proteins, including plant-derived and microbial-derived proteins, which include spider silk protein known as spidroin, expressed by bacteria and exhibiting gelation via α-helix to β-sheet conversion upon temperature increase (37°C). His-NT2RepCT, a recombinant minispidroin consisting of an N-terminus (NT), a short repeat region, a C-terminus (CT), and a His6-tag for purification, has comparable solubility in aqueous buffer to that of natural spider silk protein and possesses the key characteristics of natural spider silk. See T. Arndt et al., "Spidroin N-terminal domain forms amyloid-like fibril based hydrogels and provides a protein immobilization platform" (Nat Commun 13, 4695 (2022)), and T. Arndt et al., "Native-like Flow Properties of a Artificial Spider Silk Dope" (ACS Biomater Sci Eng. February 8, 2021; (2): 462-471).

[0028] Polymers used in the injectable shea-thinning compositions of this disclosure include cationic polypeptides containing cationic amino acids such as lysine, arginine, and ornithine, the cationic polypeptides include polylysine, polyarginine, polyornithine, and polypeptides containing two or more of lysine, arginine, and ornithine.

[0029] Polymers used in the injectable shear thinning compositions of this disclosure include anionic polypeptides containing anionic amino acids such as aspartic acid and glutamic acid, and anionic polypeptides include polyaspartic acid, polyglutamic acid, and polypeptides containing aspartic acid and glutamic acid.

[0030] The polymers used in the injectable shear thinning compositions of this disclosure further include synthetic polymers having a net negative charge, such as polymethacrylic acid, polyacrylic acid, polyitaconic acid, or poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (polyAMPS), as well as synthetic polymers having a net positive charge, such as poly(di-C1~C6-alkylaminoethanol acrylate) and poly(di-C1~C6-alkylaminoethanol methacrylate).

[0031] In some embodiments, the injectable shea thinning compositions of the present disclosure comprise any two, three, or more types of the polymers listed above. In some of these embodiments, the injectable shea thinning compositions of the present disclosure comprise a net positively charged polymer, for example, selected from the above, in combination with a net negatively charged polymer, for example, selected from the above. In some of these embodiments, the injectable shea thinning compositions of the present disclosure comprise gelatin and one or more other polymers listed above.

[0032] In some embodiments, the injectable shear thinning compositions of the present disclosure contain one or more polymers in amounts ranging from 0.05% by mass to 60.0% by mass. For example, the injectable shear thinning compositions of the present disclosure contain one or more polymers in any amount from 0.05% by mass to 0.10% by mass, up to 0.25% by mass, up to 0.5% by mass, up to 1% by mass, up to 2.5% by mass, up to 5% by mass, up to 10% by mass, up to 25% by mass, up to 50% by mass, and up to 60% by mass (i.e., within a range between any two of the aforementioned values).

[0033] The microparticles used in the injectable shear thinning compositions of this disclosure include metal microparticles, metal oxide microparticles, carbon-based microparticles, silicate microparticles, lipid microparticles, and crosslinked charged polymer microparticles.

[0034] Examples of metal nanoparticles used in the injectable shear thinning compositions of this disclosure include transition metal nanoparticles such as titanium nanoparticles, tantalum nanoparticles, gold nanoparticles, silver nanoparticles, copper nanoparticles, and iron nanoparticles; Group II metal nanoparticles such as magnesium nanoparticles; and alloy nanoparticles such as brass nanoparticles, steel nanoparticles, cobalt-chromium nanoparticles, and platinum-chromium nanoparticles.

[0035] Examples of metal oxide nanoparticles used in the injectable shear thinning compositions of this disclosure include iron oxide nanoparticles, titanium oxide nanoparticles, cobalt oxide nanoparticles (including cobalt(II) oxide, cobalt(III) oxide, and cobalt(II,III) oxide nanoparticles), gold(III) oxide nanoparticles, and tungsten oxide nanoparticles.

[0036] Examples of carbon-based microparticles used in the injectable shear thinning compositions of this disclosure include activated carbon microparticles and graphite microparticles, including exfoliated graphite nanoparticles and exfoliated graphite platelets.

[0037] Examples of silicate microparticles used in the injectable shear thinning compositions of this disclosure include natural and synthetic silicate microparticles. Specific examples of silicate microparticles include natural and synthetic silicate layered clays. Examples of natural silicate layered clays include montmorillonite, saponite, hectorite, kaolinite, palygorskite, and sepiolite. Synthetic silicate layered clays include Laponite®-based silicate nanoplatelets (for example, Laponite® XLG-based silicate nanoplatelets, Laponite® XLS-based silicate nanoplatelets, Laponite® XL2I-based silicate nanoplatelets, and Laponite® D-based silicate nanoplatelets), lithium magnesium sodium silicates such as Sumecton® SWN and Lucentite® SWN, magnesium aluminum silicates such as Sumecton® SA, sodium magnesium silicates such as Optigel® SH and SUPLITE-MP, and fluoromica such as Somasif® ME100.

[0038] Examples of crosslinked charged polymer microparticles used in the injectable shear thinning compositions of this disclosure include crosslinked poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (polyAMPS), gelatin, and chitosan.

[0039] The microparticles used in the injectable shear thinning compositions of this disclosure may have various regular and irregular shapes and may include spherical microparticles (e.g., regular spherical microparticles, flattened spherical microparticles, elongated spherical microparticles), regular geometric microparticles (e.g., cubic microparticles, tetrahedral microparticles, rhombohedral microparticles, hexagonal microparticles, octahedral microparticles, dodecahedral microparticles, icostetrahedral microparticles, prismatic microparticles, etc.), plate-like microparticles, and rod-like microparticles.

[0040] The fine particles used in the injectable shear thinning composition of this disclosure may have a maximum dimension (e.g., diameter of a sphere, length of a rod, maximum width of a platelet, etc.) ranging from 10 nm or less to 600 μm or more, for example, any size within the range of 10 nm to 25 nm, up to 50 nm, up to 100 nm, up to 250 nm, up to 500 nm, up to 1 μm, up to 2.5 μm, up to 5 μm, up to 10 μm, up to 25 μm, up to 50 μm, up to 100 μm, up to 250 μm, and up to 600 μm.

[0041] The microparticles used in the injectable shear thinning compositions of this disclosure include neutrally charged microparticles, net positively charged microparticles, and net negatively charged microparticles. In some embodiments, the fine particles originally have a net positive charge or a net negative charge.

[0042] In some embodiments, the microparticles are surface-modified to have a net positive charge or a net negative charge. For example, to give the microparticles a net positive charge, the microparticles may be surface-modified to include positively charged functional groups such as primary amine functional groups, secondary amine functional groups, tertiary amine functional groups, and quaternary amine functional groups, or any combination of the aforementioned functional groups. To give the microparticles a net negative charge, the microparticles may be surface-modified to include negatively charged functional groups such as carboxylate groups, sulfate groups, sulfonic acid groups, phosphonic acid groups, phosphate groups, or any combination of the aforementioned functional groups.

[0043] Fine particles having a net positive charge may be formed, for example, by covalently bonding an organic molecule containing a positively charged functional group to the surface of the fine particles. Fine particles having a net negative charge may be formed, for example, by covalently bonding an organic molecule containing a negatively charged functional group to the surface of the fine particles.

[0044] Fine particles having a net positive charge may also be formed by, for example, non-covalently bonding organic molecules containing positively charged functional groups to the surface of the fine particles. Similarly, fine particles having a net negative charge may be formed by, for example, non-covalently bonding organic molecules containing negatively charged functional groups to the surface of the fine particles.

[0045] For example, fine particles having a net positive charge may be formed by adsorbing a cationic surfactant onto the surface of fine particles. Examples of cationic surfactants include cetyltrimethylammonium bromide, i.e., "CTAB" (e.g., cetrimide), cetyltrimethylammonium chloride (CTAC), benzalkonium chloride, benzethonium chloride, didodecyldimethylammonium bromide (DDAB), dioleoyl-3-trimethylammonium-propane (DOTAP), benzalkonium chloride, hexadecyltrimethylammonium chloride, dimethyidodecylaminopropane, N-cetyl-N-ethylmorpholinium ethosulfate, lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, and cetylpyridinium chloride.

[0046] Alternatively, fine particles having a net negative charge may be formed by adsorbing anionic surfactants onto the surface of fine particles. Examples of anionic surfactants include sodium dodecyl sulfate (SDS), sodium lauryl sulfate (SLS), disulfosuccinate (DSS), sulfated fatty alcohols, sodium and potassium salts of fatty acids, glycerol esters of fatty acids, polyoxyl stearate, polyoxyethylene lauryl ether, sorbitan sesquioleate, and triethanolamine.

[0047] In some embodiments, the injectable shear thinning compositions of the present disclosure include any two, three or more types of microparticles selected from, for example, the microparticles listed above. In some of these embodiments, the injectable shear thinning compositions of the present disclosure include, as silicate microparticles, lithium magnesium sodium silicate such as Laponite® silicate nanoplatelets, and one or more of the other microparticles listed above. In some of these embodiments, the injectable shear thinning compositions of the present disclosure include, as metallic microparticles, tantalum microparticles, and one or more of the other microparticles listed above.

[0048] In some embodiments, the injectable shear thinning composition of the present disclosure contains one or more types of fine particles in an amount ranging from 1% by mass to 50% by mass (for example, any range from 1% by mass to 2.5% by mass, up to 5% by mass, up to 10% by mass, up to 25% by mass, and up to 50% by mass).

[0049] The water in the injectable shear thinning composition of this disclosure may be provided in the form of ultrapure water, water for injection, physiological saline, phosphate-buffered saline, or high-ion content water. In some embodiments, the injectable shear thinning composition of the present disclosure contains 5% by mass to 90% by mass of water (for example, any range from 5% by mass to 10% by mass, up to 25% by mass, up to 50% by mass, up to 75% by mass, and up to 90% by mass).

[0050] The injectable shear-thinning compositions of this disclosure may be formed by various methods. One or more polymers, one or more particulate matter, and water may be mixed in any order. For example, one or more polymers and one or more particulate matter may be mixed first and then combined with water. Another example is to mix one or more polymers and water first and then combine them with one or more particulate matter. Another example is to mix one or more particulate matter and water first and then combine them with one or more polymers. Yet another example is to mix one or more particulate matter, one or more polymers, and water simultaneously. Mixing may be carried out by any suitable mixing technique, including, for example, centrifugal mixing, manual mixing, high shear dispersion, vacuum mixing, vortex and / or syringe-to-syringe mixing.

[0051] The injectable shear thinning composition of this disclosure may be sterilized by any preferred method. For example, the composition may be autoclaved in a reservoir such as a syringe barrel, vial, or ampoule, by heating the mixture to a temperature of about 121°C or to a temperature of 121°C. Alternatively or additionally, the composition may be sterilized by sterile filtration and / or by supercritical CO2, gamma rays, X-rays, or electron beam irradiation.

[0052] In various embodiments, the injectable shear thinning compositions of this disclosure contain one or more polymers, one or more particulate matter, and water, in addition to one or more agents. Examples of such additional agents include therapeutic agents, imaging agents, colorants, tonicity adjusting agents, suspending agents, wetting agents, and pH adjusters.

[0053] Examples of therapeutic drugs include antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, antibodies, anticancer agents, antiproliferative agents, anti-inflammatory agents, hyperplasia inhibitors, restenosis inhibitors, steroids, antiallergic agents, hemostatic agents, smooth muscle cell inhibitors, antibiotics, antibacterial agents, antifungal agents, analgesics, anesthetics, immunosuppressants, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T cell agonists, and STING (interferon-stimulating factor) agonists.

[0054] Examples of imaging agents include (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, cyan fluorescent proteins), and (b) contrast agents for use in combination with magnetic resonance imaging (MRI), wherein Gd (III) Mn (II) Fe (III) (c) A contrast agent containing elements that form paramagnetic ions, and compounds containing these (including chelates) (such as gadolinium ions chelated with diethylenetriaminepentaacetic acid); (d) A contrast agent for use in combination with ultrasound imaging, comprising organic and inorganic echogenic particles (i.e., particles that increase reflected ultrasound energy) or organic and inorganic echo-transmissive particles (i.e., particles that decrease reflected ultrasound energy); (e.g., a contrast agent for use in connection with near-infrared (NIR) imaging, wherein near-infrared fluorescence is imparted to the injectable shear-thinning composition of the Disclosure, for example For example, contrast agents that may be selected to enable deep tissue imaging or device marking include NIR-sensitive nanoparticles such as gold nanoshells and carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, e.g., partially oxidized carbon nanotubes), dye-containing nanoparticles (e.g., dye-doped nanofibers and dye-encapsulated microparticles), semiconductor quantum dots, and NIR-sensitive dyes such as cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives, and boron dipyromethane (BODIPY) analogs, (e) 99m Tc, 201 Th,51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr and 177 imageable radioisotopes such as Lu, and (f) radiopaque agents such as metal particles such as particles of tantalum, tungsten, rhenium, niobium, molybdenum, and their alloys, said metal particles being spherical or non-spherical, are included. Additional examples of radiopaque agents include non-ionic radiopaque agents (e.g., iohexol, iodixanol, iobendazole, iopamidol, ioxilan, or iopromide), ionic radiopaque agents (e.g., diatrizoate, iothalamate, metrizoate, or ioxaglate), and iodinated oils (including ethiodized poppyseed oil (available as Lipiodol®)).

[0055] Examples of colorants include brilliant blue (brilliant blue FCF, also known as FD&C blue 1), indigocarmine (also known as FD&C blue 2), indigocarmine lake, FD&C blue 1 lake, and methylene blue (also known as methylthioninium chloride).

[0056] Examples of additional agents include isotonic agents such as sugars (e.g., dextrose, lactose), polyhydric alcohols (e.g., glycerol, propylene glycol, mannitol, sorbitol), and inorganic salts (e.g., potassium chloride, sodium chloride), as well as suspending agents containing various surfactants, wetting agents, polymers (e.g., albumin, PEO, polyvinyl alcohol, block copolymers), and pH adjusters containing various buffer solutes.

[0057] In various embodiments, the injectable shear thinning compositions according to this disclosure have radiopaqueness greater than 100 Houndsfield units (HU), preferably in any range from 100 HU to 250 HU, up to 500 HU, up to 750 HU, 1000 HU or more. Radiopaqueness can be provided in various ways. For example, one or more types of fine particles in the injectable shear thinning composition may provide radiopaqueness, one or more types of polymers (e.g., iodized polymers) in the injectable shear thinning composition may provide radiopaqueness, and / or one or more ionic and / or nonionic contrast agents (e.g., those listed above) may provide radiopaqueness.

[0058] The injectable shear thinning composition of this disclosure may be stored and transported in a sterile form. The injectable shear thinning composition can be transported in containers such as syringes, catheters, vials, ampoules, etc.

[0059] Kits are provided that may include one or more containers and other components of the shea-thinning compositions described herein in various embodiments. For example, a kit may include one or more delivery devices (e.g., syringes, catheters, or tube sets) for delivering the injectable shea-thinning composition to a subject. In some embodiments, a kit may include the shea-thinning composition described herein, pre-filled in a catheter and / or syringe barrel, and / or in a container such as a vial or ampoule. Kits may be provided that include one or more accessory devices, such as a guidewire, as an alternative or in addition. Kits may be provided that include one or more containers of liquid materials (e.g., contrast agents, sterile water for injection, saline, phosphate buffer). As an alternative or in addition, a kit may further include additional therapeutic agents, which may be selected from, for example, those described above. Instructions indicating the amount of composition to be administered and / or guidelines for administration may also be included in the kits provided herein as inserts or labels. In some embodiments, the instructions include instructions for performing one or more of the methods provided herein.

[0060] The injectable shea-thinning compositions described herein can be administered by various routes depending on the desired medical outcome. In some embodiments, administration involves injecting the injectable shea-thinning composition. In some embodiments, the injectable shea-thinning composition is administered by parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion. In some embodiments, administration involves image-guided procedures to deliver the composition using computed tomography, fluoroscopy, or ultrasound imaging. In some embodiments, administration involves injecting the injectable shea-thinning composition into the vascular system of a subject. In some embodiments, administration involves injecting the injectable shea-thinning composition into the cancer of a subject or into the vascular structures supplying the cancer of a subject. In some embodiments, administration is carried out using a catheter or syringe.

[0061] Figure 1 shows an exemplary syringe 10 providing a reservoir for the shearing composition as described above. The syringe 10 may comprise a barrel 12, a plunger 14, and one or more stoppers 16. The barrel 12 may include a Luer adapter (or other suitable adapter / connector), which may be provided at the distal end 18 of the barrel 12 for attachment to a needle 50 via a flexible catheter 29, for example. The proximal end of the catheter 29 may include a suitable connector 20 for receiving the barrel 12. In other examples, the barrel 12 may be directly connected to the needle 50. The syringe barrel 12 can function as a reservoir for containing the shearing composition 15 for injection through the needle 50.

[0062] The injectable shea-thinning compositions described herein can be administered to a patient to achieve several medical outcomes. The injectable shea-thinning compositions described herein can be visualized during and / or after administration using any suitable method (e.g., in mammals). For example, the injectable shea-thinning compositions provided herein can be visualized using imaging techniques such as ultrasound, computed tomography, magnetic resonance imaging, and / or fluoroscopy.

[0063] Injectable shear thinning compositions can be injected to provide space between multiple tissues, to provide reference markers (for example in the form of blebs), to provide tissue augmentation or regeneration, to provide fillers or substitutes for soft tissues, to provide mechanical support for compromised tissues, to provide scaffolds, and / or to provide carriers for therapeutic agents in the treatment of diseases and cancer, as well as in tissue repair and regeneration, among other uses.

[0064] The injectable shearing compositions of this disclosure can be used in a variety of medical procedures, including, in particular, procedures for implanting reference markers containing radiopaque particles; procedures for implanting tissue regeneration scaffolds containing radiopaque particles; procedures for implanting tissue supports containing radiopaque particles; procedures for implanting bulking agents containing radiopaque particles; procedures for implanting therapeutic drug-containing depots containing radiopaque particles; tissue augmentation procedures involving the implantation of radiopaque particles; procedures for embolizing tissues including benign tumors, malignant tumors and other abnormal tissues; procedures for controlling bleeding; and procedures for separating a first tissue from a second tissue by introducing radiopaque particles between the first and second tissues.

[0065] Injectable sheathing compositions can be injected in conjunction with various medical procedures and include: injection into the space between the prostate or vagina and rectum to create space during radiotherapy for rectal cancer; injection into the space between the rectum and prostate to create space during radiotherapy for prostate cancer; subcutaneous injection for palliative care of prostate cancer; transurethral or submucosal injection for stress urinary incontinence in women; intravesical injection for urinary incontinence; intrauterine injection for Asherman's syndrome; submucosal injection for fecal incontinence; percutaneous injection for heart failure; intramyocardial injection for heart failure and dilated cardiomyopathy; transendocardial injection for myocardial infarction; intraarticular injection for osteoarthritis; spinal injection for spinal fusion; and spinal injection for spinal trauma surgery, oral and maxillofacial trauma surgery and orthopedic trauma surgery; spinal injection for posterolateral lumbar fusion; and for intervertebral disc degeneration. This includes intradiscal injections, injections between the pancreas and duodenum for imaging of pancreatic adenocarcinoma, injections into the resection bed for imaging of oropharyngeal cancer, injections around the tumor bed for imaging of bladder cancer, submucosal injections for gastrointestinal tumors and polyps, injections into the visceral pleura for lung biopsy, renal injections for type 2 diabetes and chronic kidney disease, renal cortical injections for chronic kidney disease resulting from renal and urinary tract anomalies, intravitreous injections for neovascular age-related macular degeneration, intratympanic injections for sensorineural hearing loss, correction of wrinkles, folds and skin folds, improvement of facial fat loss findings, improvement of volume loss, correction of contour defects from shallow to deep, correction of depressed skin scars, improvement of perioral wrinkles, improvement of lip augmentation, improvement of facial fat atrophy, and dermal injections for promoting natural collagen production.

[0066] Injectable shea-thinning compositions may be injected for permanent or temporary occlusion of blood vessels and may therefore be useful for managing various diseases and conditions. For example, injectable shea-thinning compositions can be used for the controlled and selective elimination of blood supply to benign and malignant tumors, including the treatment of solid tumors such as kidney cancer, bone cancer, brain tumors, liver cancer, breast cancer, prostate cancer, benign prostatic hyperplasia, esophageal cancer, colon cancer, endometrial cancer, bladder cancer, uterine cancer, uterine fibroids (leiomyomas), ovarian cancer, lung cancer, sarcomas, pancreatic cancer, and gastric cancer. The idea behind this treatment is to shrink the tumor by blocking the blood flow that nourishes it. Embolization may be performed as an augmentation of chemotherapy or radiotherapy. The treatment may be augmented in this disclosure by including therapeutic agents (e.g., antineoplastic agents / antiproliferative agents / anti-mitotic agents, toxins, ablation agents) in the particulate composition.

[0067] The shearing compositions of this disclosure may also be used to treat various other diseases, conditions and disorders, including the following treatments: arteriovenous fistulas and arteriovenous malformations, such as aneurysms including neurovascular aneurysms and aortic aneurysms, pulmonary pseudoaneurysms, intracerebral arteriovenous fistulas, cavernous sinus dural arteriovenous fistulas and portal venous fistulas, varicose veins, chronic venous insufficiency, varicocele, abscesses, pelvic congestion syndrome, gastrointestinal bleeding, renal bleeding, urinary tract bleeding, varicose bleeding, venous congestion disorders, bleeding (including uterine bleeding), and severe bleeding from the nose (epistaxis). Furthermore, these include preoperative embolization (to reduce blood loss during surgical procedures) and occlusion of saphenous vein branches in saphenous vein bypass grafting procedures. As elsewhere in this specification, treatments may be enhanced in this disclosure by including therapeutic agents in the particulate compositions.

[0068] The shear thinning compositions according to this disclosure may be further used in tissue bulking applications, for example, as augmentative materials in the treatment of urinary incontinence, vesicoureteral reflux, fecal incontinence, intrinsic sphincteric insufficiency (ISD), or gastroesophageal reflux disease, or as augmentative materials for aesthetic improvement. For example, a common method for treating patients with urinary incontinence is via periurethral or transperineal injection of the bulking material. In this regard, the method of injecting the bulking agent generally requires, for example, positioning a needle in a periurethral or transperineal treatment area. The bulking agent is injected at multiple locations with the assistance of visual aids to join the urethral endometrium. Further application of the bulking agent may be required in some cases. Treatment may be enhanced by including therapeutic agents (e.g., pro-inflammatory agents, sclerosing agents) in the particulate composition.

[0069] Various embodiments are specifically illustrated and described herein, but it should be understood that modifications and variations of this disclosure are covered by the teachings above and are within the scope of any appended claims without departing from the technical idea and intended scope of this disclosure.

Claims

1. An injectable shear thinning composition comprising (a) one or more polymers, (b) one or more fine particles, and (c) water.

2. The injectable shea thinning composition according to claim 1, wherein the injectable shea thinning composition is a physically crosslinked hydrogel composition.

3. The injectable shear thinning composition according to claim 1 or 2, wherein the one or more polymers include a polymer having a net negative charge and / or a polymer having a net positive charge.

4. The injectable shear thinning composition according to any one of claims 1 to 3, wherein the one or more polymers are selected from polysaccharides, proteins, polypeptides, and synthetic polymers.

5. The injectable shear thinning composition according to any one of claims 1 to 3, wherein the one or more polymers are selected from non-animal-derived proteins and non-animal-derived polysaccharides.

6. The injectable shear thinning composition according to any one of claims 1 to 5, wherein the one or more types of fine particles are selected from metal fine particles, metal oxide fine particles, carbon-based fine particles, silicate fine particles, lipid fine particles, and crosslinked charged polymer fine particles.

7. The injectable shear thinning composition according to any one of claims 1 to 6, wherein the one or more types of fine particles include fine particles having a net negative charge and / or fine particles having a net positive charge.

8. The injectable shear thinning composition according to any one of claims 1 to 7, wherein the one or more types of fine particles have a maximum size ranging from 10 nm to 50 μm.

9. The injectable shear thinning composition according to any one of claims 1 to 8, wherein the one or more polymers include a polymer having a first net charge, and the one or more fine particles include fine particles having a second net charge opposite in sign to the first net charge.

10. The injectable shear thinning composition according to any one of claims 1 to 9, further comprising one or more additional agents selected from therapeutic agents, imaging agents, colorants, isotonic agents, suspension agents, wetting agents and pH adjusters.

11. The injectable shear thinning composition according to any one of claims 1 to 10, wherein the injectable shear thinning composition is a sterilization composition.

12. The injectable shear thinning composition according to any one of claims 1 to 11, wherein the injectable shear thinning composition is provided in a container.

13. The injectable shear thinning composition according to any one of claims 1 to 11, wherein the injectable shear thinning composition is provided in a state where it is pre-filled in a syringe.

14. A kit comprising one or more containers containing the injectable shear thinning composition according to any one of claims 1 to 13, and a delivery device.

15. The kit according to claim 14, wherein the delivery device includes a syringe, a needle, and optionally a catheter.

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