Therapeutic hydrogels

Abstract

To provide therapeutic hydrogels.SOLUTION: The present disclosure pertains to therapeutic hydrogels that comprise an anionic polysaccharide crosslinked by a branched polyamine, wherein the branched polyamine comprises at least two primary amine groups, more typically at least three primary amine groups. The present disclosure also pertains to medical compositions that comprise such therapeutic hydrogels and to methods of medical treatment in which such therapeutic hydrogels are delivered to a patient in need of medical treatment.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to therapeutic hydrogels. [Background technology]

[0002] A variety of therapeutic hydrogels are known in the medical field and can be used in a wide variety of medical applications. The present disclosure relates to polysaccharide-based therapeutic hydrogels that can be used in a variety of medical applications, such as in conjunction with embolic agents, tissue sealants, tissue spacers, tissue augmentation compositions, scaffolds for tissue regeneration and / or cell growth, surgical adhesion barriers, and implantable wound dressings, among other applications. Summary of the Invention [Problem to be solved by the invention]

[0003] An object of the present invention is to provide a therapeutic hydrogel. [Means for solving the problem]

[0004] The present disclosure relates to therapeutic hydrogels comprising ionic polysaccharides and branched polyamines. The present disclosure relates to therapeutic polysaccharide-based hydrogels that can be used in a variety of medical applications. In some embodiments, the present disclosure relates to therapeutic hydrogels comprising anionic polysaccharides crosslinked by branched polyamines containing at least three primary amine groups.

[0005] In some embodiments, the present disclosure relates to a therapeutic hydrogel comprising (a) an anionic polysaccharide and (b) a branched polyamine, wherein the anionic polysaccharide is negatively charged at the pH of the therapeutic hydrogel, and the branched polyamine is positively charged at the pH of the therapeutic hydrogel and comprises two or more positively charged primary amine groups, and wherein the branched polyamine ionically crosslinks the anionic polysaccharide.

[0006] In some embodiments that can be used in combination with any of the preceding embodiments, the therapeutic hydrogel can have a pH in the range of 5.5 to 7.5. In some embodiments that can be used in combination with any of the preceding embodiments, the branched polyamine may be in the form of an organic acid salt or an inorganic salt, the branched polyamine may have a molecular weight of less than 2000, the branched polyamine may be an oligomeric branched polyamine having 2 to 10 monomer residues, or the branched polyamine may have any combination of the foregoing properties.

[0007] In some embodiments, which may be used in combination with any of the preceding embodiments, the anionic polysaccharide may be a linear anionic polysaccharide or a branched anionic polysaccharide.

[0008] In some embodiments that can be used in combination with any of the preceding embodiments, the therapeutic hydrogel is a flowable therapeutic hydrogel, or the therapeutic hydrogel has a free-standing three-dimensional shape.

[0009] In some embodiments, which may be used in combination with any of the preceding embodiments, the therapeutic hydrogel further comprises an imaging agent, which may be selected from, for example, a fluorescent dye, a magnetic resonance imaging (MRI) contrast agent, an ultrasound contrast agent, a radiological contrast agent, and a near-infrared (NIR) contrast agent.

[0010] In some embodiments, which can be used in combination with any of the preceding embodiments, the therapeutic hydrogel further comprises a cation selected from Group I metal cations and Group II metal cations.

[0011] In some embodiments, which may be used in combination with any of the preceding embodiments, the therapeutic hydrogel further comprises chitosan. In some embodiments that can be used in combination with any of the preceding embodiments, the therapeutic hydrogel further comprises a therapeutic agent. For example, a therapeutic agent delivery depot can be provided that comprises such a therapeutic hydrogel.

[0012] In some embodiments, the present disclosure provides medical compositions comprising a therapeutic hydrogel according to any of the foregoing embodiments, including, for example, embolic agents, tissue sealants, tissue spacers, tissue augmentation compositions, scaffolds for tissue regeneration and / or cell growth, surgical adhesion barriers, and implantable wound dressings.

[0013] In some embodiments, the present disclosure provides methods of treatment comprising delivering to a patient a therapeutic hydrogel according to any of the foregoing embodiments, such as, for example, methods of local or systemic therapeutic agent release, methods of tissue embolization, methods of spacing a first tissue from a second tissue, methods of tissue sealing, methods of preventing surgical adhesions, methods of tissue augmentation, methods of tissue regeneration, and methods of hemostasis, among others. [Effects of the Invention]

[0014] According to the present invention, a therapeutic hydrogel can be provided. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the cumulative % release of IgG as a function of time from a therapeutic hydrogel, according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure relates to therapeutic hydrogels comprising ionic polysaccharides and branched polyamines. The therapeutic hydrogels can be used in a variety of medical applications. In various embodiments, the therapeutic hydrogels of the present disclosure comprise an ionic polysaccharide crosslinked by a branched polyamine, the branched polyamine having at least three primary amine groups. In some of these embodiments, the branched polyamine has 3, 4, 5, 6, 7, 8, 9, 10, or more primary amine groups per molecule. In some of these embodiments, the branched polyamine can have 3-25, 3-20, 3-15, 3-10, or 3-5 primary amine groups.

[0017] In various embodiments, the therapeutic hydrogels of the present disclosure comprise (a) an anionic polysaccharide and (b) a branched polyamine, wherein the branched polyamine is positively charged at the pH of the therapeutic hydrogel and has two or more positively charged primary amine groups, such that the branched polyamine ionically crosslinks the anionic polysaccharide. In some of these embodiments, the branched polyamine has three or more positively charged primary amine groups per molecule at the pH of the therapeutic hydrogel. In some of these embodiments, the branched polyamine has 3, 4, 5, 6, 7, 8, 9, 10, or more positively charged primary amine groups per molecule at the pH of the therapeutic hydrogel. In some of these embodiments, the branched polyamine has 3-25, 3-20, 3-15, 3-10, or 3-5 positively charged primary amine groups per molecule at the pH of the therapeutic hydrogel.

[0018] In some embodiments, the pH of the therapeutic hydrogel of any of the foregoing embodiments may range from 5.5 to 7.5. In some embodiments, the branched polyamine of the therapeutic hydrogel of any of the foregoing embodiments can have a molecular weight that is less than 2000 g / mol. For example, the branched polyamine can have a molecular weight ranging from 100 g / mol, to 250 g / mol, to 500 g / mol, to 750 g / mol, to 1000 g / mol, to 1250 g / mol, to 1500 g / mol, to 2000 g / mol (in other words, the molecular weight of the branched polyamine can range between any two of the foregoing values).

[0019] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may contain from 0.005 w / w% or less to 5 w / w% or more of branched polyamine, for example, in the range of from 0.005 w / w% to 0.01 w / w%, to 0.025 w / w%, to 0.05 w / w%, to 0.10 w / w%, to 0.25 w / w%, to 0.5 w / w%, to 1.0 w / w%, to 2.5 w / w%, to 5 w / w% branched polyamine.

[0020] In some embodiments, the branched polyamine of the therapeutic hydrogel of any of the foregoing embodiments can be an oligomeric branched polyamine having 2 to 10 monomer residues. For example, the oligomeric branched polyamine can be a branched peptide oligomer containing multiple lysine residues, or the oligomeric branched polyamine can be a branched polyethyleneimine oligomer, among other possibilities.

[0021] In some embodiments, the branched polyamine of the therapeutic hydrogel of any of the foregoing embodiments may be selected from trilysine (molecular weight 402.5 g / mol), tetralysine (molecular weight 530.7 g / mol), pentalysine (molecular weight 658.9 g / mol), tris(aminoalkyl)amines (e.g., tris(2-aminoethyl)amine (molecular weight 146.2 g / mol)), or tris(aminoalkyl)alkanes (e.g., 1,1,1-tris(aminomethyl)ethane (molecular weight 117.2 g / mol)), among other possibilities.

[0022] In some embodiments, the branched polyamine of the therapeutic hydrogel of any of the foregoing embodiments may be in the form of an organic acid salt, for example, the organic acid salt may be selected from formate, acetate, propionate, butyrate, oxalate, malonate, succinate, maleate, glutarate, glycolate, lactate, malate, citrate, or gluconate, among others.

[0023] In some embodiments, the branched polyamine of the therapeutic hydrogel of any of the foregoing embodiments may be in the form of an inorganic salt, for example, the inorganic salt may be selected from a halide salt, a nitrate salt, a phosphate salt, a sulfate salt, or a sulfonate salt, among others.

[0024] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may contain anionic polysaccharides in a range of from 0.1 w / w% or less to 10 w / w% or more, for example, from 0.10 w / w% to 0.25 w / w%, to 0.5 w / w%, to 1.0 w / w%, to 2.5 w / w%, to 5 w / w%, to 10 w / w%.

[0025] In some embodiments, the anionic polysaccharide of the therapeutic hydrogel of any of the foregoing embodiments may be a linear anionic polysaccharide, for example, the anionic polysaccharide may be selected from alginate, gellan gum, pectin, agaropectin, and carrageenan, among others.

[0026] In some embodiments, gellan gum is preferred. Gellan gum is a high molecular weight, anionic polysaccharide gum, typically produced by microbial fermentation. The polysaccharide is primarily composed of a tetrasaccharide repeating unit of one rhamnose, one glucuronic acid, and two glucose units. Along the polysaccharide backbone, there is substitution of acyl groups (glycerate and acetate) on the glucose residues. Direct recovery of the polysaccharide from fermentation yields what is known as high-acyl gellan gum. Deacylation (e.g., by alkaline treatment) yields what is known as low-acyl gellan gum.

[0027] In some embodiments, alginate is preferred. Alginate is a linear polysaccharide composed of mannuronic acid and guluronate residues. Alginate is typically produced by marine algae and some bacteria.

[0028] In some embodiments, the anionic polysaccharide of the therapeutic hydrogel of any of the foregoing embodiments may be a branched anionic polysaccharide. For example, the anionic polysaccharide may be selected from guar gum, tragacanth gum, karaya gum, gum arabic, and xanthan gum, among others.

[0029] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may further comprise a pH adjusting agent (i.e., a buffering agent). For example, the pH adjusting agent can maintain the pH of the therapeutic hydrogel between 5.5 and 7.5, among other values.

[0030] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may further comprise an imaging agent. Examples of imaging agents include radiological contrast agents, fluorescent dyes, magnetic resonance imaging (MRI) contrast agents, ultrasound contrast agents, and near-infrared (NIR) imaging contrast agents. Specific examples of radiological contrast agents include non-ionic radiological contrast agents such as iohexol, iodixanol, ioversol, iopamidol, ioxilan, or iopromide, among others; ionic radiological contrast agents such as diatrizoate, iothalamate, metrizoate, or ioxaglate, among others; and iodized oils, including, for example, ethiodized poppyseed oil (available as Lipiodol®). Further specific examples of imaging agents include, among others: (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, or cyan fluorescent proteins); (b) Gd (III) , Mn (II) , Fe(III) (c) contrast agents for use with ultrasound imaging comprising organic and inorganic echogenic particles (i.e., particles that result in an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that result in a decrease in reflected ultrasound energy); and (d) contrast agents for use in connection with near-infrared (NIR) imaging, comprising: Among these are NIR-sensitive nanoparticles such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots, and NIR-sensitive dyes such as cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives, and boron dipyrromethane (BODIPY) analogs, which can be selected to impart near-infrared fluorescence to the hydrogels of the present disclosure, enabling deep tissue imaging and device marking.

[0031] In some embodiments, the therapeutic hydrogel of any of the preceding embodiments comprises a Group I metal cation (Li + , Na + , K. + , Rb + , Cs + , Fr + ) and group II metal cations (Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Ra 2+For example, such metal cations may act as competitors for the branched polyamine, reducing the degree of crosslinking and, in some embodiments, making the therapeutic hydrogel more fluid and / or softening the therapeutic hydrogel.

[0032] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may further comprise a linear polysaccharide crosslinker, such as chitosan, which in some embodiments has a cationic charge at the pH of the gel.

[0033] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may further comprise a therapeutic agent. In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may include a charged and / or uncharged therapeutic agent. Charged therapeutic agents may be loaded into the therapeutic hydrogel by an ion exchange mechanism. Charged therapeutic agents may be electrostatically retained in the therapeutic hydrogel and may elute from the hydrogel in an electrolyte medium (e.g., saline (0.90% w / v NaCl)) or in vivo (e.g., in blood or tissue) to provide sustained release of the therapeutic agent over hours, days, or even weeks. Therapeutic agents that are uncharged at physiological pH can also be loaded into the therapeutic hydrogel. This may be particularly advantageous, for example, when rapid elution or a "burst effect" is desired (e.g., for rapid delivery of the therapeutic agent to tissue) or when the low solubility of the therapeutic agent under physiological conditions, rather than ionic interactions, determines the release profile.

[0034] In some embodiments, the therapeutic hydrogels of any of the foregoing embodiments may contain one or more therapeutic agents in a range of from 0.01 mg / ml or less to 10 mg / ml or more, for example, from 0.01 mg / ml to 0.025 mg / ml, to 0.05 mg / ml, to 0.10 mg / ml, to 0.25 mg / ml, to 0.5 mg / ml, to 1 mg / ml, to 2.5 mg / ml, to 5 mg / ml, to 10 mg / ml.

[0035] Examples of therapeutic agents (which may also be referred to herein as pharmaceutically active ingredients) that can be incorporated into the therapeutic hydrogels of any of the foregoing embodiments include small molecule therapeutic agents (defined herein as therapeutic agents having a molecular weight of less than 2000 g / mol, typically less than 1500 g / mol, and more typically less than 1000 g / mol) and biomolecules (e.g., polypeptides, including proteins and protein fragments, such as antibodies and antibody fragments and oligopeptides, and polynucleotides and oligonucleotides, including nucleic acids and nucleic acid analogs, such as deoxyribonucleic acid, ribonucleic acid, peptide nucleic acid, and fragments thereof).

[0036] Examples of therapeutic agents include anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T cell agonists, and STING (stimulator of interferon genes) agonists, among others.

[0037] Examples of therapeutic agents include, among others, checkpoint inhibitors, including inhibitors of the binding between PD-1 and PD-L1, inhibitors of the binding between CTLA-4 and CD80 and / or CD86, inhibitors of the binding between TIGIT and CD-112, and inhibitors of the binding between LAG-3 and MHC class II molecules; anti-PD-1 inhibitors (e.g., pembrolizumab, nivolumab, donbanalimab, etc.), anti-PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab, etc.), anti-PD-3 inhibitors (e.g., lelatrimab, antibodies or antigen-binding fragments thereof that bind to TIM-3 (e.g., LY3321367, MBG453, TSR-022, etc.), TIGIT (e.g., etigilimab, tiragolumab, vibostolimab, etc.), or CTLA-4 (e.g., ipilimumab, tremelimumab, etc.); CD3, CD19, CD20, CD22, CD52, CD79B, CD30, CD33, CD38, CD52, CD79B, HER2, EGFR, VEGF, VEGFR2, EPCAM / CD3, G Antibodies or antigen-binding fragments thereof that bind to D2, IL-6, RANKL, SLAMF7, CCR4, PDGFRα, nectin-4, or TROP2; immunomodulatory cytokines such as IL-2, IL-12, IL-15, IL-23, interferon gamma (IFN-γ), and gm-CSF (granulocyte-macrophage colony-stimulating factor); TLR3 agonists (polyinosinic acid:polycytidylic acid, double-stranded RNA, etc.), TLR7 agonists (TMX-202, gardikimod, imiquimod, etc.), and TLR8 agonists. These include T cell agonists such as agonists (e.g., VTX-2337), TLR7 / 8 agonists (e.g., MEDI9197, R848, resiquimod), TLR9 agonists (e.g., lefitolimod (MGN1703), tilsotolimod, CpG oligodeoxynucleotides (e.g., agatolimod), etc.); and STING agonists such as GSK532, cyclic dinucleotides (e.g., cyclic guanosine monophosphate-adenosine monophosphate), CRD5500 (LB-061), E7766, ADU-S100, SB11285 MSA2, MK1454, and TTI-10001.

[0038] Further examples of therapeutic agents include camptothecins (e.g., irinotecan and topotecan), anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin), angiogenesis inhibitors (vascular endothelial growth factor receptor (VEGFR) inhibitors, e.g., axitinib, bortezomib, bosutinib, canertinib, dovitinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, masitinib, mubritinib, pazopanib, and rituximab). semaxanib, sorafenib, sunitinib, tanjutinib, vandetanib, vatalanib, and vismodegib), microtubule formation inhibitors (e.g., vinblastine, vinorelbine, and vincristine), aromatase inhibitors (e.g., anastrozole), platinum agents (e.g., cisplatin, oxaliplatin, carboplatin, and miriplatin), nucleoside analogs (e.g., 5-FU, cytarabine, fludarabine, and gemcitabine), paclitaxel, docetaxel, mitomycin, mitoxantrone, bleomycin, pinocytopenic acid (PCA), These include pingyangmycin, abiraterone, amifostine, buserelin, degarelix, folinic acid, goserelin, lanreotide, lenalidomide, letrozole, leuprolide, octreotide, tamoxifen, triptorelin, bendamustine, chlorambucil, dacarbazine, melphalan, procarbazine, temozolomide, rapamycin (and analogs such as zotarolimus, everolimus, umirolimus, and sirolimus), methotrexate, pemetrexed, or raltitrexed.

[0039] In some embodiments, the therapeutic hydrogel of any of the foregoing embodiments may further comprise a therapeutic and / or imageable radioisotope. Therapeutic hydrogels containing therapeutic radioisotopes can be used, for example, in selective internal radiation therapy (SIRT) or brachytherapy, such as in cancer treatment, and can be delivered in any of the manners described elsewhere herein in connection with other therapeutic hydrogel embodiments. In one approach, the radioisotope can be bound to the gel through ionic interactions or covalently attached, for example, via a carrier (e.g., a chelator). In some embodiments, the radioisotope can be incorporated into the gel in particles, which contain the radioisotope. Such particles may be in the form of microspheres, typically with a maximum diameter in the range of 5 μm to 500 μm, particularly less than 100 μm. The particles may be, for example, polymeric or ceramic. One such ceramic is yttrium aluminosilicate ceramic (see, for example, U.S. Pat. No. 4,789,501). Further examples of ceramic microspheres are described in WO 16082045 and WO 05087274. Therapeutic radioisotopes include, but are not limited to: 177 Lu, 90 Y, 131 I, 89 Sr, 153 Sm, 223 Ra, 224 Ra, 211 At, 225 Ac, 227 Th, 212 Bi, 213 Bi, and / or 212 In some embodiments, the therapeutic radioisotope is 177 Lu, 90 Y, 131 I, 89 Sr, 153 Sm, and / or 223 In some embodiments, the therapeutic radioisotope is one or more of 90Y. Imagable radioisotopes include, but are not limited to: 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 In some embodiments, the imageable isotope is 99m Tc, 67 Ga, 68 Ga, 64 Cu, or 89 In some embodiments, the imageable isotope is 99m In some embodiments, the imageable isotope is 89 It is Zr.

[0040] One particular example of ceramic particles is described in US Pat. No. 4,789,501 and is commercially available as TheraSphere® (Biocompatibles UK Ltd).

[0041] The therapeutic hydrogel of any of the foregoing embodiments may be provided in a sterile form. The therapeutic hydrogel of any of the foregoing embodiments can be provided in several different forms. In some cases, the therapeutic hydrogel can be in the form of a flowable therapeutic hydrogel that can be injectable, for example, from a container (e.g., a syringe barrel, vial, ampoule, etc.) through a needle or catheter tubing. In some instances, the therapeutic hydrogel can be in the form of a free-standing three-dimensional shape. For example, the therapeutic hydrogel can be in the form of microparticles or microspheres, or in the form of larger implantable dosage forms such as beads, pellets, plugs, discs, etc.

[0042] Another embodiment of the present disclosure relates to a medical composition comprising the therapeutic hydrogel of any of the foregoing embodiments. For example, in some embodiments, the medical composition is a therapeutic drug delivery depot comprising a therapeutic hydrogel of any of the foregoing embodiments, such that the therapeutic drug delivery depot can release a therapeutic drug in a controlled manner for local, systemic, or targeted therapeutic drug delivery.

[0043] In some embodiments, the medical composition is an embolic agent comprising a therapeutic hydrogel of any of the preceding embodiments. In some embodiments, the medical composition is a tissue sealant comprising the therapeutic hydrogel of any of the preceding embodiments.

[0044] In some embodiments, the medical composition is a tissue spacer comprising the therapeutic hydrogel of any of the preceding embodiments. In some embodiments, the medical composition is a tissue augmentation composition (including dermal fillers) comprising the therapeutic hydrogel of any of the preceding embodiments.

[0045] In some embodiments, the medical composition is a scaffold for tissue regeneration and / or cell growth comprising the therapeutic hydrogel of any of the foregoing embodiments. In some embodiments, the medical composition is a surgical adhesion barrier comprising a therapeutic hydrogel of any of the preceding embodiments.

[0046] In some embodiments, the medical composition is an implantable wound dressing comprising the therapeutic hydrogel of any of the foregoing embodiments. Yet other embodiments of the present disclosure relate to medical procedures using the therapeutic hydrogel or medical composition of any of the foregoing embodiments.

[0047] For example, in some embodiments, the medical treatment is a method of local or systemic therapeutic agent delivery comprising delivering (e.g., by injecting, implanting, spraying, etc.) a therapeutic hydrogel or medical composition of any of the foregoing embodiments to a patient (e.g., onto, into, between the patient's tissue, etc.).

[0048] In some embodiments, the medical procedure is a method of treatment comprising delivering (e.g., by injecting, implanting, spraying, etc.) a therapeutic hydrogel or medical composition of any of the foregoing embodiments into or onto a tumor in a patient, and the therapeutic agent is released into the tumor.

[0049] In some embodiments, the medical procedure is a method of tissue embolization comprising delivering a therapeutic hydrogel or medical composition of any of the foregoing embodiments to one or more blood vessels (e.g., feeder arteries) that supply nutrients to the tissue.

[0050] In some embodiments, the medical procedure is a method of spacing a first tissue from a second tissue, comprising delivering (e.g., injecting, implanting, etc.) a therapeutic hydrogel or medical composition of any of the foregoing embodiments between the first tissue and the second tissue (e.g., between prostate tissue and rectal tissue).

[0051] In some embodiments, the medical procedure is a method of sealing tissue comprising applying a therapeutic hydrogel or medical composition of any of the preceding embodiments onto the tissue, the method comprising topically applying the therapeutic hydrogel or medical composition to tissue at a surgical site in an amount effective to seal the tissue.

[0052] In some embodiments, the medical procedure is a method for preventing surgical adhesions comprising applying a therapeutic hydrogel or medical composition of any of the preceding embodiments to tissue at a surgical site, thereby inhibiting post-operative adhesions at a surgical site in a patient. The method comprises topically applying the therapeutic hydrogel to tissue at the surgical site in an amount effective to inhibit adhesion formation during healing.

[0053] In some embodiments, the medical procedure is a method of tissue augmentation comprising delivering (e.g., by injecting, implanting, etc.) a therapeutic hydrogel or medical composition of any of the foregoing embodiments into or between tissues of a patient (e.g., to alter tissue contour, increase tissue volume).

[0054] In some embodiments, the medical procedure is a method of regenerating tissue in a patient, comprising delivering (e.g., by injecting, implanting, spraying, etc.) to a patient (e.g., into, on, or between tissues of the patient), a tissue scaffold comprising the therapeutic hydrogel or medical composition of any of the foregoing embodiments.

[0055] In some embodiments, the medical procedure is a method of hemostasis in a patient comprising delivering (e.g., by injecting, implanting, spraying, etc.) a therapeutic hydrogel or medical composition of any of the foregoing embodiments to the patient (e.g., onto a tissue of the patient, into a tissue of the patient, including within a blood vessel of the patient).

[0056] In still further embodiments, the present disclosure relates to the use of a therapeutic hydrogel or pharmaceutical composition of any of the foregoing embodiments in the manufacture of a medicament for the treatment of diseases such as cancer, particularly solid tumors, including, but not limited to, cancers of the liver (hepatocellular carcinoma and distant tumor metastasis to the liver, e.g., metastatic colorectal cancer, neuroendocrine tumors, metastatic Barrett's esophagus, etc.), lung, breast, kidney, head and neck, esophagus, skin, pancreas, adrenal gland, brain, stomach, and intestine.

[0057] The present disclosure also relates to the use of any of the pharmaceutically active ingredients described herein in the manufacture of a medicament for the treatment of such diseases, wherein the active ingredient is incorporated into a hydrogel of any of the above-described embodiments. The present disclosure also relates to the use of any of the active ingredients described herein in the treatment of such diseases, wherein the active ingredient is incorporated into a hydrogel of any of the above-described embodiments. The therapeutic hydrogels and compositions may be particularly useful when the hydrogel is delivered by injection, implantation, spraying, etc.

[0058] In embodiments, a therapeutic hydrogel for localized delivery of a therapeutic agent is formed, comprising: (a) 0.5-2.5 wt.% anionic polysaccharide (e.g., gellan gum (low or high acyl, depending on the degree of acyl substitution) or alginate), (b) 0.01-3.0 wt.% branched polyamine (e.g., acetate forms of polylysine, including trilysine acetate, tetralysine acetate, pentalysine acetate, etc.), (c) a therapeutic agent, and (d) optionally, other active agents, such as a pH adjuster, a preservative, and / or a contrast agent, among others.

[0059] In one particular approach to the embodiments described herein, the therapeutic hydrogel is gellan gum crosslinked with trilysine, which may be prepared as described above.

[0060] Hydrogels are typically formed by heating a solution of anionic polysaccharide to a temperature suitable for hydrating the polysaccharide, which is typically in the range of 62°C to 90°C. The polysaccharide may be allowed to hydrate for a period typically ranging from 30 minutes to 3 hours. If desired, the solution may be agitated, for example, by an impeller suitable for mixing high-viscosity materials (otherwise phase separation may occur).

[0061] After hydration of the anionic polysaccharide, the gel may be cooled to a temperature that prevents possible damage to any active ingredients that may be incorporated. Temperatures below 40°C are generally suitable. At this point, the therapeutic agent can be added, followed by the crosslinker, if used. The therapeutic agent and crosslinker may be added with continuous agitation at a controlled temperature (e.g., in a jacketed, temperature-controlled mixing vessel).

[0062] The components may be sterilized prior to formulation, they may be filled in an aseptic manner, or they may be sterilized (e.g., while warm) after filling the composition into a syringe or other container. [Example]

[0063] The therapeutic hydrogel was formed from the following: 1.5 w / w% low-acyl gellan gum, water for injection (WFI) as the solvent, and 0.03 w / w% trilysine acetate (TLA) as the cross-linker. The gellan gum was added to the WFI at a temperature above 80°C. Continuous stirring with an impeller was used for the high viscosity material. After a hydration period of 2 hours, the mixture was cooled. IgG was added at a temperature of 38°C. At this stage, a small amount of the gel was transferred to a beaker equipped with a magnetic stir bar. The IgG was then added, followed by TLA after 1 minute of mixing. The loaded cross-linked mixture was stirred for an additional 3 minutes and then loaded into a syringe. The syringe was refrigerated below 5°C overnight, and the sample was then tested for drug release properties.

[0064] IgG was loaded into the therapeutic hydrogel as a surrogate for the active ingredient in the anti-PD1-loaded gel. The release profile was measured by pouring 1 g of hydrogel sample into a well plate. 6 ml of calcium-free Dulbecco's PBS solution was used as the collection medium. 100 μl of sample was withdrawn from the PBS at the designated time points, and the sample was transferred to a 96-well plate. The release profile was measured using absorbance measurements at 280 nm using a BioTek Microplate Reader (BioTek Instruments, Inc., Winooski, VT, USA). The results are shown in Figure 1, which shows the cumulative release percentage as a function of time for IgG. Release is believed to be primarily controlled by diffusion.

[0065] Therapeutic agent-loaded therapeutic hydrogels can be injected submucosally or used for local treatment (e.g., intratumorally for localized delivery and sustained release of anti-cancer drugs). The technical concepts that can be understood from the above-described embodiment will be described below as supplementary notes.

[0066] [Appendix 1] A therapeutic hydrogel comprising (a) an anionic polysaccharide and (b) a branched polyamine, wherein the anionic polysaccharide is negatively charged at the pH of the therapeutic hydrogel, and the branched polyamine is positively charged at the pH of the therapeutic hydrogel and comprises two or more positively charged primary amine groups, and the branched polyamine ionically crosslinks the anionic polysaccharide.

[0067] [Appendix 2] The therapeutic hydrogel described in Appendix 1, wherein the branched polyamine contains three or more positively charged primary amine groups at the pH of the therapeutic hydrogel. [Appendix 3] The therapeutic hydrogel described in Appendix 1, wherein the branched polyamine contains 3 to 10 positively charged primary amine groups at the pH of the therapeutic hydrogel.

[0068] [Appendix 4] A therapeutic hydrogel comprising an anionic polysaccharide crosslinked by a branched polyamine, wherein the branched polyamine contains at least three primary amine groups.

[0069] [Appendix 5] The therapeutic hydrogel according to Appendix 4, wherein the branched polyamine contains 3 to 10 primary amine groups. [Appendix 6] The therapeutic hydrogel according to any one of Appendices 1 to 5, wherein the therapeutic hydrogel has a pH in the range of 5.5 to 7.5.

[0070] [Appendix 7] The therapeutic hydrogel according to any one of Appendices 1 to 6, wherein the branched polyamine is in the form of an organic acid salt or an inorganic salt. [Appendix 8] The therapeutic hydrogel according to any one of Appendices 1 to 7, wherein the branched polyamine is an oligomeric branched polyamine having 2 to 10 monomer residues.

[0071] [Appendix 9] A therapeutic hydrogel according to any one of Appendices 1 to 8, wherein the therapeutic hydrogel is a fluid therapeutic hydrogel or the therapeutic hydrogel has a self-supporting three-dimensional shape.

[0072] [Appendix 10] The therapeutic hydrogel according to any one of Appendices 1 to 9, further comprising an imaging agent selected from a fluorescent dye, a magnetic resonance imaging (MRI) contrast agent, an ultrasound contrast agent, a radiological contrast agent, and a near-infrared (NIR) contrast agent.

[0073] [Appendix 11] The therapeutic hydrogel according to any one of Appendices 1 to 10, further comprising a cation selected from a Group I metal cation and a Group II metal cation.

[0074] [Appendix 12] A therapeutic hydrogel according to any one of Appendices 1 to 11, further comprising chitosan. [Appendix 13] The therapeutic hydrogel described in any one of Appendices 1 to 12, further comprising a therapeutic agent.

[0075] [Appendix 14] A medical composition comprising the therapeutic hydrogel according to any one of Appendices 1 to 13. [Appendix 15] The medical composition according to Appendix 14, selected from an embolic agent, a tissue sealant, a tissue spacer, a tissue augmentation composition, a scaffold for tissue regeneration and / or cell growth, a surgical adhesion barrier, or an implantable wound dressing.

Claims

1. 1. A therapeutic hydrogel comprising: (a) an anionic polysaccharide and (b) a branched polyamine, wherein the anionic polysaccharide is negatively charged at the pH of the therapeutic hydrogel; and the branched polyamine has a molecular weight of less than 2000 g / mol and is positively charged at the pH of the therapeutic hydrogel and comprises two or more positively charged primary amine groups, and wherein the branched polyamine ionically crosslinks the anionic polysaccharide.

2. 10. The therapeutic hydrogel of claim 1, wherein said branched polyamine comprises three or more positively charged primary amine groups at the pH of said therapeutic hydrogel.

3. 10. The therapeutic hydrogel of claim 1, wherein said branched polyamine contains 3 to 10 positively charged primary amine groups at the pH of said therapeutic hydrogel.

4. The therapeutic hydrogel of claim 3 , wherein the branched polyamine is a branched peptide oligomer containing multiple lysine residues.

5. 5. The therapeutic hydrogel of claim 4, wherein the branched polyamine is selected from trilysine, tetralysine, and pentalysine.

6. The therapeutic hydrogel of any one of claims 1 to 5, wherein the therapeutic hydrogel has a pH in the range of 5.5 to 7.

5.

7. The therapeutic hydrogel according to any one of claims 1 to 5, wherein the branched polyamine is in the form of an organic acid salt.

8. The therapeutic hydrogel of any one of claims 1 to 5, wherein the branched polyamine is an oligomeric branched polyamine having 2 to 10 monomer residues.

9. The therapeutic hydrogel of any one of claims 1 to 5, wherein the therapeutic hydrogel is a flowable therapeutic hydrogel or the therapeutic hydrogel has a free-standing three-dimensional shape.

10. 6. The therapeutic hydrogel of any one of claims 1 to 5, further comprising an imaging agent selected from a fluorescent dye, a magnetic resonance imaging (MRI) contrast agent, an ultrasound contrast agent, a radiological contrast agent, and a near-infrared (NIR) contrast agent.

11. The therapeutic hydrogel of any one of claims 1 to 5, further comprising a cation selected from Group I metal cations and Group II metal cations.

12. The therapeutic hydrogel of any one of claims 1 to 5, further comprising chitosan.

13. The therapeutic hydrogel of any one of claims 1 to 5, wherein the therapeutic hydrogel further comprises a therapeutic agent.

14. 10. The therapeutic hydrogel of claim 1, wherein the anionic polysaccharide is gellan gum.

15. The therapeutic hydrogel of claim 14, wherein the branched polyamine is an organic acid salt of trilysine.

16. A medical composition comprising the therapeutic hydrogel according to any one of claims 1 to 5.

17. 17. The medical composition of claim 16, selected from an embolic agent, a tissue sealant, a tissue spacer, a tissue augmentation composition, a scaffold for tissue regeneration and / or cell growth, a surgical adhesion barrier, or an implantable wound dressing.

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