Composition of thermosensitive hydrogel having altered reversible sol-gel transition property, and use thereof

Abstract

To overcome the limitation of application fields caused by the reversible transition according to the temperature change after gel formation by changing the sol-gel transition property of thermosensitive phosphazene-based polymers.SOLUTION: The present invention relates to a thermosensitive hydrogel composition with an altered reversible sol-gel transition character, comprising a polyphosphazene-based polymer that comprises an amino acid ester, polyethylene glycol with controlled length and content, and groups comprising a functional group for the introduction of a functional moiety at an end thereof at a predetermined ratio.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a thermosensitive hydrogel composition having altered reversible sol-gel transition properties, which comprises a polyphosphazene-based polymer containing an amino acid ester, polyethylene glycol, and a group containing a functional group at the end for introducing a functional moiety, in predetermined proportions, with the length and content of the polyethylene glycol contained therein being controlled, and a medical hydrogel composition or 3D printing ink composition containing the polyphosphazene-based polymer. [Background technology]

[0002] Thermosensitive polymer hydrogels maintain a liquid phase (e.g., sol) at low temperatures, but exhibit a sol-gel phase transition, changing to a gel as the temperature rises. Because they are injected in liquid form, they can be uniformly distributed over the lesion, regardless of the shape of the tissue to be applied. They also rapidly form a three-dimensional gel at body temperature, allowing them to effectively adapt to the application site. This gives them great potential as injectable drug reservoir hydrogels and tissue adhesives. However, their low strength and thermosensitivity, which can lead to hydrogel loss or morphological changes, limit their use in medical applications.

[0003] The present inventors have confirmed through previous research that phosphazene-based polymers obtained by substituting amino acid esters and methoxypolyethylene glycol into dichlorophosphazene linear polymers exist in a solution state below a certain temperature, but when the temperature exceeds a certain temperature, they have the properties of a thermosensitive polymer that exhibits a sol-gel phase transition into a three-dimensional gel state (Korean Patent Registration No. 10-0259367 (Patent Document 1), No. 10-0315630 (Patent Document 2)).

[0004] However, hydrogels containing such thermosensitive polymers as active ingredients have the advantage of being able to be mixed with various substances that function in tissue regeneration or drugs that require long-term administration. However, their temperature-sensitive sol-gel phase transition properties have been mainly utilized under conditions where they can maintain their three-dimensional structure within the human body after injection, and are sufficient for use as drug delivery systems in locations where body temperature homeostasis is well maintained. However, their other reversible thermosensitive properties limit their application fields. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Korean Patent No. 10-0259367 [Patent Document 2] Korean Patent Registration No. 10-0315630 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted extensive research and development to overcome the limited application field due to the reversible transition caused by temperature change after gel formation by changing the sol-gel transition characteristics of thermosensitive polyphosphazene polymers. As a result, they have confirmed that by adjusting the proportion of polyethylene glycol moieties substituted on the polyphosphazene skeleton within an appropriate range depending on the length of the skeleton, a solution containing the same remains in a liquid phase from low to room temperature, gels at around 37°C, which is body temperature, and maintains the strength and / or shape of the formed gel without reversibly transitioning back to a solution even when the temperature drops back to room temperature, thereby completing the present invention. [Means for solving the problem]

[0007] A first aspect of the present invention provides a thermosensitive hydrogel composition having altered reversible sol-gel transition properties, comprising a polyphosphazene-based polymer, the polyphosphazene skeleton of which is represented by the following chemical formula 1, and which comprises, on a phosphorus atom thereof, an amino acid ester first moiety represented by the following chemical formula 2; a polyethylene glycol second moiety represented by the following chemical formula 3; and a third moiety comprising a functional group at its terminal for introducing a functional moiety, in a ratio of a:b:c, respectively:

[0008] [ka]

[0009] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[0010] A second aspect of the present invention provides a composition for tissue regeneration containing the polyphosphazene polymer.

[0011] A third aspect of the present invention provides a drug delivery system comprising the polyphosphazene polymer and a functional substance.

[0012] A fourth aspect of the present invention provides an ink composition for 3D printing, which contains the polyphosphazene-based polymer.

[0013] A fifth aspect of the present invention provides a composition containing the polyphosphazene polymer for use in tissue regeneration.

[0014] A sixth aspect of the present invention provides a use of a composition containing the polyphosphazene-based polymer as an ink for 3D printing. [Effects of the Invention]

[0015] The thermosensitive hydrogel composition containing the polyphosphazene polymer of the present invention can change the sol-gel transition characteristics of the hydrogel formed therefrom according to the temperature by adjusting the content of the moiety, particularly polyethylene glycol, bound thereto. After gelling at a predetermined temperature, the hydrogel can maintain its shape without rapidly changing back to a solution phase even when the temperature is changed again. Therefore, the composition can be designed to gel at body temperature and used as an in vivo implant, or can be used as a tissue repair or regeneration structure and / or drug delivery system by further incorporating drugs, physiologically active substances, etc. [Brief explanation of the drawings]

[0016]

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Figure 2

Figure 3

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Figure 9

Figure 10

[0017] A first aspect of the present invention provides a thermosensitive hydrogel composition having altered reversible sol-gel transition properties, comprising a polyphosphazene-based polymer, the polyphosphazene skeleton of which is represented by the following chemical formula 1, and which comprises, on a phosphorus atom thereof, an amino acid ester first moiety represented by the following chemical formula 2; a polyethylene glycol second moiety represented by the following chemical formula 3; and a third moiety comprising a functional group at its terminal for introducing a functional moiety, in a ratio of a:b:c, respectively:

[0018] [ka]

[0019] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[0020] A second aspect of the present invention provides a composition for tissue regeneration containing the polyphosphazene polymer.

[0021] A third aspect of the present invention provides a drug delivery system comprising the polyphosphazene polymer and a functional substance.

[0022] A fourth aspect of the present invention provides an ink composition for 3D printing, which contains the polyphosphazene-based polymer.

[0023] A fifth aspect of the present invention provides a composition containing the polyphosphazene polymer for use in tissue regeneration.

[0024] A sixth aspect of the present invention provides a use of a composition containing the polyphosphazene-based polymer as an ink for 3D printing.

[0025] The present invention will be described in detail below.

[0026] Generally, thermosensitive polymers are polymers that exhibit a sudden change in solubility with temperature. As temperature increases, the hydrogen bonds between the polymer and the solvent weaken, dehydration occurs, and the hydrophobic attraction between the polymers strengthens, resulting in a more hydrophobic structure. At the low critical solution temperature (LCST), polymer-polymer and water-water interactions are favored over hydrogen bonds between the polymer and water, resulting in rapid dehydration from the polymer and a more hydrophobic structure. The critical temperature of a thermosensitive polymer changes depending on the balance of hydrophobic and hydrophilic groups attached to the polymer backbone. Generally, the phase transition temperature increases as the content of hydrophilic groups increases, and decreases as the content of hydrophobic groups increases.

[0027] Among these thermosensitive polymers, those based on a polyphosphazene backbone maintain a solution state at room temperature due to their thermosensitivity, gel at body temperature upon injection into the body, and form a three-dimensional structure. Their biodegradability allows them to be gradually degraded within the body, allowing them to be injected into the desired site in the form of an injection to form a transplant, or to be mixed with a drug and injected, if necessary, to slowly release the drug as the structure degrades, thereby making them useful as drug delivery systems. However, due to their reversibility, in which they transition back to a solution state upon temperature change when removed from the body's environment, their application is limited to internal injections. Furthermore, when used in areas highly susceptible to external temperature, such as the face, hands, and feet, under thin skin membranes, open wounds, gums, and implant sites, the injected hydrogels lose their shape due to loss of body temperature due to the external environment, resulting in ineffective transplants. Furthermore, if a drug is contained in the hydrogel, excessive drug release may occur, resulting in side effects.

[0028] The present invention was devised to overcome the limitations on the applications of the thermosensitive polyphosphazene polymer due to its reversible sol-gel transition property. It was discovered that when the essential constituent moieties constituting the polymer are present in a specific proportion, the polymer solution undergoes a reversible sol-gel transition due to temperature changes below a certain temperature, but after exposure to a specific temperature or higher, this rapid reversible transition property is lost and the gel form is maintained for a long period of time. Specifically, the aforementioned property is exhibited only when a specific proportion of substituents is introduced into the polyphosphazene backbone, and such property changes can be achieved depending on the proportion of substituents introduced during the initial polymer synthesis, regardless of the polymer concentration and / or composition in the aqueous polymer solution.

[0029] Therefore, the present invention provides a thermosensitive hydrogel composition having altered reversible sol-gel transition properties, comprising a polyphosphazene-based polymer, the polyphosphazene skeleton of which is represented by the following chemical formula 1, and which comprises, on a phosphorus atom thereof, an amino acid ester first moiety represented by the following chemical formula 2; a polyethylene glycol second moiety represented by the following chemical formula 3; and a third moiety containing a functional group at the end for introducing a functional moiety, in a ratio of a:b:c, respectively:

[0030] [ka]

[0031] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[0032] In the hydrogel composition of the present invention, the functional group for introducing a functional moiety in the third moiety contained in the polyphosphazene-based polymer can be selected from the group consisting of an amino acid, a peptide, a depsipeptide, a depsipeptide ester, an amide group, an amino group, a sulfate group, a thiol group, a vinyl group, an aldehyde group, an acrylate group, a methacrylate group, a hydroxy group, and a carboxyl group.

[0033] For example, in the above formula, R1 can be methyl, ethyl, propyl, butyl, benzyl, or 2-propenyl.

[0034] For example, but not limited to, R3 in the above formula may be methyl.

[0035] The third moiety may further comprise a fourth moiety to which one or more functional moieties selected from the group consisting of a substance capable of adjusting the degradation rate of the polymer, a substituent containing an ionic group capable of adjusting the degradation rate, a crosslinkable substituent, an additional compound capable of inducing tissue bonding, a physiologically active substance, and a composite substance formed by linearly linking two or more of these functional substances are bound, either directly or via a linker, to a part or all of the functional groups of the third moiety.

[0036] In this case, the fourth moiety may include one or more selected from the group consisting of folic acid, hyaluronic acid, cyclodextrin, imidazole compounds, anticancer drugs, histidine, lysine, arginine, cysteine, thiolarylamine, spermine, spermidine, polyethyleneimine, polyhistidine, polylysine, polyarginine, protamine, heparin, chitosan, and a peptide consisting of 1 to 20 amino acids.

[0037] The thermosensitive hydrogel composition having altered reversible sol-gel transition characteristics of the present invention may be a solution in which the polyphosphazene polymer is dissolved in a solvent at a concentration of 1 to 50 wt %.

[0038] In this case, the solvent may be at least one selected from the group consisting of water, a buffer solution, an acidic solution, a basic solution, a salt solution, physiological saline, water for injection, a cell culture medium, and a glucose saline solution, but is not limited thereto.

[0039] For example, the thermosensitive hydrogel composition of the present invention having altered reversible sol-gel transition properties exhibits sol-gel behavior in the range of 5 to 70°C and can form a hydrogel at a predetermined temperature.

[0040] Furthermore, the thermosensitive hydrogel composition of the present invention having altered reversible sol-gel transition properties may be designed to gel when applied to a living body or in an ex vivo environment, but to lose its thermosensitivity at a predetermined temperature and maintain the gel state regardless of temperature changes.

[0041] The present invention also provides a composition for tissue regeneration comprising a polyphosphazene-based polymer, the composition comprising, on a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, an amino acid ester first moiety represented by the following chemical formula 2; a polyethylene glycol second moiety represented by the following chemical formula 3; and a third moiety comprising a functional group at the end for introducing a functional moiety, in a ratio of a:b:c, respectively:

[0042] [ka]

[0043] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[0044] The present invention also provides a tissue regeneration application of a composition containing the polyphosphazene polymer.

[0045] As described above, the tissue regeneration composition of the present invention may be designed to gel when applied to a living body or in an ex vivo environment, but to lose its thermosensitivity at a predetermined temperature and maintain its gel state regardless of temperature changes.

[0046] The present invention also provides a drug delivery system comprising a polyphosphazene-based polymer and a functional substance, the polyphosphazene skeleton of which is represented by the following chemical formula 1, and which comprises, on a phosphorus atom thereof, an amino acid ester first moiety represented by the following chemical formula 2; a polyethylene glycol second moiety represented by the following chemical formula 3; and a third moiety containing a functional group at its terminal for introduction of a functional moiety, in a ratio of a:b:c, respectively:

[0047] [ka]

[0048] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[0049] For example, the drug delivery system of the present invention may include, as the functional substance, a drug, a cell, a nanoparticle, a microparticle, a physiologically active substance, or a combination thereof.

[0050] The functional substances include preosteoblasts, chondrocytes, umbilical vein endothelial cells (UVECs), osteoblasts, adult stem cells, scwann cells, oligodendrocytes, hepatocytes, and mural cells. cells: treated in combination with UVEC), myoblasts, insulin-secreting cells, endothelial cells, smooth nuscle cells, fibroblasts, beta cells, endodermal cells, hepatic stem cells, juxraglomerular cells, skeletal muscle cells cell), keratinocyte, melanocyte, langerhans cell Cells such as dermal fibroblasts, Merkel cells, dermal fibroblasts, and preadipocytes; genes such as short interfering ribonucleic acid (siRNA), plasmid DNA, and antisense oligodeoxynucleotides (AS-ODN); exendin-4, erythropoietin, interferon-alpha, interferon-beta, interferon-gamma, growth hormone, growth hormone-releasing factor, nerve growth factor, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and macrophage-colony stimulating factor (M-CSF).factor), blood coagulation factors, insulin, oxytocin, vasopressin, adrenocorticotropic hormone, fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, insulin-like growth factor, vascular endothelial growth factor, transforming growth factor, cranial nerve growth factor, neurotrophin-3 (NT-3), neurotrophin-4 / 5, prolactin, luliberin, luteinizing hormone-releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone release inhibitory factor (somatostatin), glucagon, interleukin-2 (IL-2), interleukin-11 (IL-11), gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalin, endorphins, angiotensin, thyrotropin-releasing hormone, tumor necrosis factor, tumor necrosis factor-related apoptosis-inducing ligand, heparin-degrading enzyme, bone morphogenetic protein, human atrial nucleoside peptide (hANP) natriuretic peptide), glucagon-like peptide, renin, bradykinin, bacitracin, polymyxin, colistin, tyrocidine, gramicidin, cyclosporine, neurotensin, tachykinin, neuropeptide Y, peptide YY,Proteins, peptides, or polypeptides such as vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, and their specific antibodies, enzymes, and / or cytokines; vaccines such as hepatitis vaccine; hormones such as testosterone, estradiol, progesterone, and prostaglandins; paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, tegafur, irinotecan, docetaxel, cyclophosphamide, gemcitabine, ifosfamide, mitomycin C C), vincristine, etoposide, methotrexate, topotecan, tamoxifen, vinorelbine, camptothecin, daunorubicin, chlorambucil, bryostatin-1, calicheamicin, maytansine, levamisole, DNA recombinant interferon alfa-2a, mitoxantrone, nimustine, interferon alpha-2a alfa-2a, doxifluridine, formestane, leuprolide acetate, megestrol acetateacetate, carmofur, teniposide, bleomycin, carmustine, heptaplatin, exemestane, anastrozole, estramustine, capecitabine, goserelin acetate, polysaccharide potassium, medroxyprogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, actinomycin D Anticancer drugs such as cyclosporine, anastrozole, belotecan, imatinib, floxuridine, gemcitabine, hydroxyurea, zoledronate, flutamide, valrubicin, streptozocin, and polyethylene glycol-bound anticancer drugs thereof; Clodronate, 6-deoxy-6-demethyl-4-dedimethylaminotetracycline (COL-3), doxycycline, marimastat, 2-methoxyestradiol, squalamine, thalidomide, TNP-470, combretastatin A4, soy isoflavonesIsoflavone, Enzastaurin, Revimid, Celecoxib, Vandetanib, Halofuginone Hydrobromide, Interferon-alpha, Bevacizumab, Shark Cartilage Extract, Interleukin-12, Vascular Endothelial Growth Factor Trap (VEFG-trap), Cetuximab, Revimastat, Matrix Metalloproteinase (MMP) Inhibitors, Protein Kinase C beta Inhibitors, Endostatin, Vatalanib, Sunitinib Malate malate, cilengitide, humanized monoclonal antibodies, volociximab, angiogenesis inhibitors such as integrin alpha-5-beta-1 antagonists; or combinations thereof.

[0051] Specifically, the drug delivery system of the present invention comprises one or more cationic polymers selected from the group consisting of polyarginine, polylysine, polyethylene glycol, polyethyleneimine, chitosan, and protamine, each having a weight-average molecular weight of 200 to 750,000; one or more anionic polymers selected from the group consisting of polyvinyl acetate, hyaluronic acid, chondroitin sulfate, heparin, and alginate, each having a weight-average molecular weight of 200 to 750,000; and one or more additives selected from the group consisting of amino acids, peptides, proteins, fatty acids, phospholipids, vitamins, polyethylene glycol esters, steroids, amine compounds, acrylic copolymers, organic solvents, preservatives, sugars, polyols, sugar-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicates, metal salts, and ammonium salts, in an amount of 1×10 -6 It may further be included in an amount of up to 30% by weight.

[0052] Furthermore, the present invention provides an ink composition for 3D printing comprising a polyphosphazene-based polymer, the polyphosphazene-based polymer comprising, on a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, an amino acid ester first moiety represented by the following chemical formula 2; a polyethylene glycol second moiety represented by the following chemical formula 3; and a third moiety comprising a functional group at the end for introducing a functional moiety; in a ratio of a:b:c, respectively:

[0053] [ka]

[0054] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[0055] The present invention also provides a use of a composition containing the polyphosphazene-based polymer as an ink for 3D printing.

[0056] For example, the ink composition for 3D printing of the present invention maintains a liquid state at room temperature, and gels upon printing at or above a predetermined temperature at which it loses its temperature sensitivity, and the printed product maintains its gel state regardless of temperature changes.

[0057] For example, the 3D printing ink composition of the present invention can further contain one or more types of cells to prepare a bioanalog for transplantation or a bioanalog for drug testing. Specifically, because the 3D printing ink composition of the present invention exhibits the properties of a thermosensitive hydrogel with the aforementioned altered reversible sol-gel transition characteristics, the cells to be used can be mixed with a polymer solution at a temperature that maintains the solution state, injected into a 3D printing cartridge, and printed into a desired shape. The mixture can then be solidified by gelation by increasing the temperature, and then cultured in a culture medium to form a desired 3D shape. In a specific example of the present invention, cells were added to the 3D printing ink composition of the present invention as described above, and the 3D-printed structure was cultured in a cell culture medium. The cell viability was measured, and it was confirmed that a viability of nearly 100% was maintained even after long-term culture for up to 21 days without any side effects such as toxicity (Figure 4).

[0058] An embodiment of the present invention may be any of the inventions shown in [1] to

[17] . [1] On a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, an amino acid ester first moiety represented by the following chemical formula 2: a polyethylene glycol second moiety represented by formula 3: a third moiety containing a functional group at the end for introducing a functional moiety; in the proportions a:b:c, respectively; Thermosensitive hydrogel compositions containing polyphosphazene-based polymers with altered reversible sol-gel transition properties:

[0059] [ka]

[0060] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%. [2] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to [1], wherein the functional group for introducing a functional moiety in the third moiety is selected from the group consisting of an amino acid, a peptide, a depsipeptide, a depsipeptide ester, an amide group, an amino group, a sulfate group, a thiol group, a vinyl group, an aldehyde group, an acrylate group, a methacrylate group, a hydroxyl group, and a carboxyl group. [3] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to [1] or [2], wherein R1 is methyl, ethyl, propyl, butyl, benzyl, or 2-propenyl. [4] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to any one of [1] to [3], wherein R3 is methyl. [5] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to any one of [1] to [4], further comprising a fourth moiety to which one or more functional moieties selected from the group consisting of a substance capable of adjusting the degradation rate of a polymer, a substituent containing an ionic group capable of adjusting the degradation rate, a crosslinkable substituent, an additional compound capable of inducing tissue bonding, a physiologically active substance, and a composite substance formed by linearly linking two or more of these functional substances are bound, directly or via a linker, to a part or all of the functional groups of the third moiety. [6] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to [5], wherein the fourth moiety comprises one or more selected from the group consisting of folic acid, hyaluronic acid, cyclodextrin, imidazole compounds, anticancer drugs, histidine, lysine, arginine, cysteine, thiolarylamine, spermine, spermidine, polyethyleneimine, polyhistidine, polylysine, polyarginine, protamine, heparin, chitosan, and peptides consisting of 1 to 20 amino acids. [7] The thermosensitive hydrogel composition having altered reversible sol-gel transition characteristics according to any one of [1] to [6], wherein the polyphosphazene polymer is dissolved in a solvent at a concentration of 1 to 50% by weight. [8] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to [7], wherein the solvent is at least one selected from the group consisting of water, a buffer solution, an acidic solution, a basic solution, a salt solution, physiological saline, water for injection, a cell culture medium, and a glucose-saline solution. [9] The thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to any one of [1] to [8], which exhibits sol-gel behavior in the range of 5 to 70°C and forms a hydrogel at a predetermined temperature.

[10] A thermosensitive hydrogel composition having altered reversible sol-gel transition properties according to any one of [1] to [9], which is designed to gel when applied to a living body or in an ex vivo environment, but lose its thermosensitivity at a predetermined temperature and maintain a gel state regardless of temperature changes.

[11] On a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, an amino acid ester first moiety represented by the following chemical formula 2: a polyethylene glycol second moiety represented by formula 3: a third moiety containing a functional group at the end for introducing a functional moiety; in the proportions a:b:c, respectively; Composition for tissue regeneration comprising a polyphosphazene-based polymer:

[0061] [ka]

[0062] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[12] A tissue regeneration composition according to

[11] , which is designed to gel when applied to a living body or in an ex vivo environment, but loses its thermosensitivity at a predetermined temperature and maintains its gel state regardless of changes in temperature.

[13] On a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, an amino acid ester first moiety represented by the following chemical formula 2: a polyethylene glycol second moiety represented by formula 3: a third moiety containing a functional group at the end for introducing a functional moiety; in the proportions a:b:c, respectively; Drug delivery systems containing polyphosphazene-based polymers and functional materials:

[0063] [ka]

[0064] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[14] The drug delivery system described in

[13] , wherein the functional substance is a drug, a cell, a nanoparticle, a microparticle, a physiologically active substance, or a combination thereof.

[15] On a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, an amino acid ester first moiety represented by the following chemical formula 2: a polyethylene glycol second moiety represented by formula 3: a third moiety containing a functional group at the end for introducing a functional moiety; in the proportions a:b:c, respectively; 3D printing ink composition comprising a polyphosphazene-based polymer:

[0065] [ka]

[0066] In the above chemical formulas 1 to 3, R1 is C 1-6 Alkyl, (C 1-6 alkenyl) or C 6-10 Aryl-C 1-6 is alkyl, R2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl, or 2-indolylmethyl; R3 is C 1-6 is alkyl, n is an integer from 3 to 100,000, p is an integer from 1 to 23, Based on the total bonding sites of polyphosphazene, a+b is 80 to 99%, and c is 1 to 20%; i) When p is 1 to 13, b is less than 25 to 40%; ii) When p is 14-17, b is 10-20%; iii) When p is 18-23, b is 10-15%.

[16] The ink composition for 3D printing described in

[15] , which maintains a liquid state at room temperature and gels when printed at or above a predetermined temperature at which it loses its temperature sensitivity, and the printed result maintains its gel state regardless of changes in temperature.

[17] The 3D printing ink composition according to

[15] or

[16] , further comprising one or more types of cells for producing a biological analogue for transplantation or a biological analogue for drug testing.

[0067] The present invention will be described in more detail below with reference to examples. These examples are intended solely to more specifically explain the present invention, and the scope of the present invention is not limited to these examples. [Example]

[0068] <Identification of compounds> In the following examples, carbon, hydrogen, and nitrogen elemental analyses were performed using a Perkin-Elmer C, H, N analyzer at the Korea Advanced Institute of Science and Technology's Characterization Center to identify the synthesized polymers. Furthermore, hydrogen and phosphorus nuclear magnetic resonance spectra were measured using a Varian Gemini-300, and weight-average molecular weights (Mw) were measured using gel permeation chromatography with a Waters 1515 pump and 2410 differential refractometer.

[0069] Example 1: Poly[(isoleucine ethyl ester)] 1.19 (Aminomethoxypolyethylene glycol 550) 0.79 (Ethyl-2-(O-glycyl)lactate) 0.02 Phosphazene] n Manufacturing Dry isoleucine ethyl ester hydrochloride (IleOEt.HCl, 20.09 g) was dissolved in anhydrous tetrahydrofuran (THF) containing triethylamine. A solution of polydichlorophosphazene (10 g) dissolved in anhydrous tetrahydrofuran was added dropwise to the solution using dry ice-acetone-rich water, and the temperature was gradually raised to 40-50°C, allowing the reaction to proceed for 24 hours. After the reaction mixture was cooled to room temperature, dry ethyl-2-(O-glycyl)lactate ammonium oxalate (0.52 g) was added to the reaction mixture in anhydrous acetonitrile containing triethylamine, and the reaction was continued at 40-50°C for 24 hours.

[0070] After the reaction mixture was cooled to room temperature, dried polyethylene glycol (37.49 g) having a molecular weight of 550 was dissolved in anhydrous THF, and a solution containing triethylamine was added to the reaction mixture. The temperature was then raised to 40-50°C and the mixture was allowed to react for 24 hours.

[0071] The reaction solution was filtered to remove the triethylamine hydrochloride produced, and the reaction filtrate was concentrated under reduced pressure until only a small amount of solvent remained. The concentrated solution was dissolved in anhydrous THF, and an excess amount of hexane was added to induce precipitation. This process was repeated 2-3 times, and the precipitate was again dissolved in a small amount of methanol and placed in a MWCO 12000 membrane (Spectrum Laboratories, Inc.). It was dialyzed against methanol at room temperature for 4 days, then against distilled water for 4 days, and dried at low temperature to obtain a polyphosphazene polymer containing isoleucine ethyl ester, aminomethoxypolyethylene glycol, and ethyl-2-(O-glycyl) lactate [NP(IleOEt)] 1.19 (AMPEG550) 0.79 (GlyLacOEt) 0.02 ] n obtained.

[0072] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.3-1.5(b,-NHCH2COOCH(CH3)COOCH2C H 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ1.6-1.7(b,-NHCH2COOCH( CH 3) COOCH2CH3), δ2.67-3.2(b,-NH(CH2CH2O) 11 CH 3), δ3.4(s,-NH(CH2CH2O) 11 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 11CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), δ4.0-4.4(b,-NH CH 2COOCH(CH3)COO CH 2CH3), δ5.2-5.4(b,-NHCH2COO CH (CH3)COOCH2CH3), Average molecular weight (M w ):23,000 Example 2: Poly[(isoleucine ethyl ester)] 1.56 (Aminomethoxypolyethylene glycol 750) 0.39 (Ethyl-2-(O-glycyl)lactate) 0.05 Phosphazene] n Manufacturing In the same manner as in Example 1, isoleucine ethyl ester hydrochloride (26.34 g), polydichlorophosphazene (10 g), ethyl-2-(O-glycyl) lactate ammonium oxalate The final product [NP(IleOEt) 1.56 (AMPEG750) 0.39 (GlyLacOEt) 0.05 ] n obtained.

[0073] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.3-1.5(b,-NHCH2COOCH(CH3)COOCH2C H 3), δ1.4-1.8(b,-NH CH (CH (CH3)CH2CH3)COOCH2CH3), δ1.6-1.7(b,-NHCH2COOCH( CH 3) COOCH2CH3), δ2.67-3.2(b,-NH(CH2CH2O) 11 CH 3), δ3.4(s,-NH(CH2CH2O) 16 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 16 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), δ4.0-4.4(b,-NH CH 2COOCH(CH3)COO CH 2CH3), δ5.2-5.4(b,-NHCH2COO CH (CH3)COOCH2CH3), Average molecular weight (M w ):19,000 Example 3: Poly[(isoleucine ethyl ester)] 1.77 (Aminomethoxypolyethylene glycol 1000) 0.21 (Ethyl-2-(O-glycyl)lactate) 0.02 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 1 using isoleucine ethyl ester hydrochloride (29.88 g), polydichlorophosphazene (10 g), ethyl-2-(O-glycyl)lactate ammonium oxalate (52 g), and polyethylene glycol having a molecular weight of 1,000 (18.12 g). 1.77 (AMPEG1000) 0.21 (GlyLacOEt) 0.02 ] n obtained.

[0074] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.3-1.5(b,-NHCH2COOCH(CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ1.6-1.7(b,-NHCH2COOCH( CH 3) COOCH2CH3), δ2.67-3.2(b,-NH(CH2CH2O) 20 CH 3), δ3.4(s,-NH(CH2CH2O) 20 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 20 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), δ4.0-4.4(b,-NH CH 2COOCH(CH3)COO CH 2CH3), δ5.2-5.4(b,-NHCH2COO CH (CH3)COOCH2CH3), Average molecular weight (M w ): 48,000 Example 4: Poly[(isoleucine ethyl ester)] 1.29 (Aminomethoxypolyethylene glycol 550) 0.50 (aminoethanol) 0.21 Phosphazene] n Manufacturing Isoleucine ethyl ester hydrochloride (21.61 g), polydichlorophosphazene (10 g), aminoethanol (1.21 g), and polyethylene glycol having a molecular weight of 550 (23.25 g) were reacted in the same manner as in Example 1, except that THF was used instead of anhydrous acetonitrile when adding aminoethanol, to obtain the final product [NP(IleOEt)]. 1.29 (AMPEG550) 0.50 (Aminoethanol) 0.21 ] n obtained.

[0075] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 11 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 11 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 11 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), Average molecular weight (M w ):8,800 Example 5: Poly[(isoleucine ethyl ester)] 1.45 (Aminomethoxypolyethylene glycol 750) 0.32 (aminoethanol) 0.23 Phosphazene] n Manufacturing Isoleucine ethyl ester hydrochloride (24.48 g), polydichlorophosphazene (10 g), aminoethanol (1.21 g), and polyethylene glycol having a molecular weight of 750 (20.70 g) were reacted in the same manner as in Example 1, except that THF was used instead of anhydrous acetonitrile when adding aminoethanol, to obtain the final product [NP(IleOEt)]. 1.45 (AMPEG750) 0.32 (Aminoethanol) 0.23 ] n obtained.

[0076] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 16 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 16 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 16 CH3,-NH CH(CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), Average molecular weight (M w ): 7,900 Example 6: Poly[(isoleucine ethyl ester)] 1.70 (Aminomethoxypolyethylene glycol 1000) 0.20 (aminoethanol) 0.10 Phosphazene] n Manufacturing Isoleucine ethyl ester hydrochloride (28.70 g), polydichlorophosphazene (10 g), aminoethanol (0.52 g), and polyethylene glycol having a molecular weight of 1000 (17.25 g) were reacted in the same manner as in Example 1, except that THF was used instead of anhydrous acetonitrile when adding aminoethanol, to obtain the final product [NP(IleOEt)]. 1.70 (AMPEG1000) 0.20 (Aminoethanol) 0.10 ] n obtained.

[0077] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 20 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 20 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 20 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), Average molecular weight (M w ):14,000 Example 7: Poly[(isoleucine ethyl ester)] 1.21 (Aminomethoxypolyethylene glycol 550) 0.61 (aminoethyl succinic acid) 0.18 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 4 using isoleucine ethyl ester hydrochloride (20.43 g), polydichlorophosphazene (10 g), aminoethanol (0.94 g), polyethylene glycol having a molecular weight of 550 (28.94 g), succinic anhydride (4.00 g), and dimethylaminopyridine (4.00 g). 1.21 (AMPEG550) 0.61 (Aminoethylsuccinate) 0.18 ] n obtained.

[0078] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCOCH 2CH2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 11 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 11 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 11 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3,-NHCH2 [[ID=管理]] 2OCOCH2CH2COOH), Average molecular weight (M w ):8,400 Example 8: Poly[(isoleucine ethyl ester)] 1.48 (Aminomethoxypolyethylene glycol 750) 0.33 (aminoethyl succinic acid) 0.19 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 7 using isoleucine ethyl ester hydrochloride (24.99 g), polydichlorophosphazene (10 g), aminoethanol (1.00 g), polyethylene glycol having a molecular weight of 750 (21.35 g), succinic anhydride (4.00 g), and dimethylaminopyridine (4.00 g). 1.48 (AMPEG750) 0.33 (Aminoethylsuccinate) 0.19 ] n obtained.

[0079] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCO CH 2CH2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 16 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 16 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 16 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3,-NHCH2 CH 2OCOCH2CH2COOH), Average molecular weight (M w ):6,700 Example 9: Poly[(isoleucine ethyl ester)] 1.70 (Aminomethoxypolyethylene glycol 1000) 0.20 (aminoethyl succinic acid) 0.10 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 7 using isoleucine ethyl ester hydrochloride (28.70 g), polydichlorophosphazene (10 g), aminoethanol (0.52 g), polyethylene glycol having a molecular weight of 1000 (17.25 g), succinic anhydride (4.00 g), and dimethylaminopyridine (4.00 g).1.70 (AMPEG1000) 0.20 (Aminoethylsuccinate) 0.10 ] n obtained.

[0080] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCO CH 2CH2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 20 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 20 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 20 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3,-NHCH2 CH 2OCOCH2CH2COOH), Average molecular weight (M w ):14,600 Example 10: Poly[(isoleucine ethyl ester)] 1.23 (Aminomethoxypolyethylene glycol 550) 0.68(aminoethyl glutarate) 0.09 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 7 using isoleucine ethyl ester hydrochloride (20.76 g), polydichlorophosphazene (10 g), aminoethanol (0.47 g), polyethylene glycol having a molecular weight of 550 (32.27 g), glutaric anhydride (8.00 g), and dimethylaminopyridine (8.00 g). 1.23 (AMPEG550) 0.68 (Aminoethyl Glutarate) 0.09 ] n obtained.

[0081] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO CH 2 CH 2CH2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 11 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 11 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 11 CH3,-NH CH(CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3,-NHCH2 CH 2OCOCH2CH2CH2COOH), Average molecular weight (M w ):8,400 Example 11: Poly[(isoleucine ethyl ester)] 1.38 (Aminomethoxypolyethylene glycol 750) 0.38 (aminoethyl glutarate) 0.24 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (23.30 g), polydichlorophosphazene (10 g), aminoethanol (1.26 g), polyethylene glycol having a molecular weight of 750 (24.59 g), glutaric anhydride (8.00 g), and dimethylaminopyridine (8.00 g). 1.38 (AMPEG750) 0.38 (Aminoethyl Glutarate) 0.24 ] n obtained.

[0082] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO CH 2 CH 2CH2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O)16 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 CH 2COOH), δ3.4(s,-NH(CH2CH2O) 16 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 16 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3,-NHCH2 CH 2OCOCH2CH2CH2COOH), Average molecular weight (M w ):9,400 Example 12: Poly[(isoleucine ethyl ester)] 1.61 (Aminomethoxypolyethylene glycol 1000) 0.22 (aminoethyl glutarate) 0.17 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (27.18 g), polydichlorophosphazene (10 g), aminoethanol (0.89 g), polyethylene glycol having a molecular weight of 1000 (18.98 g), glutaric anhydride (8.00 g), and dimethylaminopyridine (8.00 g). 1.61 (AMPEG1000) 0. 22 (Aminoethyl Glutarate) 0.17 ] n obtained.

[0083] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO CH 2 CH 2CH2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 20 CH 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 [[ID=管理]] 2COOH), δ3.4(s,-NH(CH2CH2O) 20 CH 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 20 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), Average molecular weight (M w ):17,500 Example 13: Poly[(isoleucine ethyl ester)] 1.48 (Aminomethoxypolyethylene glycol 750) 0.34 (Aminoethyl glutarate beta cyclodextrin) 0.18 Phosphazene] n Manufacturing In the same manner as in Example 10, a polymer was obtained using isoleucine ethyl ester hydrochloride (24.99 g), polydichlorophosphazene (10 g), aminoethanol (0.94 g), polyethylene glycol having a molecular weight of 750 (22.00 g), glutaric anhydride (8.00 g), and dimethylaminopyridine (8.00 g), and then aminobeta-cyclodextrin (10 g) was added and reacted to obtain the final product [NP(IleOEt)]. 1.48 (AMPEG750) 0.34 (AminoethylGlutaric Beta-CD) 0.18 ] n obtained.

[0084] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO ​ 2 ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), δ4.7-4.8(b,-NHCH2 ​ , Average molecular weight (M w ): 7,500 Example 14: Poly[(isoleucine ethyl ester)] 1.51 (Aminomethoxypolyethylene glycol 750) 0.25 (aminoethyl adipate) 0.24 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (25.49 g), polydichlorophosphazene (10 g), aminoethanol (1.26 g), polyethylene glycol having a molecular weight of 750 (22.00 g), adipic anhydride (7.00 g), and dimethylaminopyridine (7.00 g). 1.51 (AMPEG750) 0.25 (Aminoethyl Adipate) 0.24 ] n obtained.

[0085] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ1.52-1.64(b,-NHCH2CH2OCOCH2 ​ 2 ​ 2CH2COOH), δ2.3-2.32(b,-NHCH2CH2OCO ​ 2CH2CH2​ 2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.94.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), Average molecular weight (M w ):4,530 Example 15: Poly[(isoleucine ethyl ester)] 1.18 (Aminomethoxypolyethylene glycol 550) 0.72 (aminoethyl sulfate) 0.10 Phosphazene] n Manufacturing The final product, [NP(IleOEt)], was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (19.92 g), polydichlorophosphazene (10 g), aminoethanol (0.52 g), polyethylene glycol having a molecular weight of 550 (34.17 g), and sulfa trioxide pyridine complex (5.00 g). 1.18 (AMPEG550) 0.72 (Aminoethylsulfate) 0.10 ] n obtained.

[0086] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 ​ 2SO4,-NH(CH2CH2O) 11 ​ 3), δ3.4(s,-NH(CH2CH2O) 11 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 11 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), Average molecular weight (M w ):8,600 Example 16: Poly[(isoleucine ethyl ester)] 1.40 (Aminomethoxypolyethylene glycol 750) 0.30 (aminoethyl sulfate) 0.30 Phosphazene] n Manufacturing The final product, [NP(IleOEt)], was prepared in the same manner as in Example 15 using isoleucine ethyl ester hydrochloride (23.63 g), polydichlorophosphazene (10 g), aminoethanol (1.58 g), polyethylene glycol having a molecular weight of 750 (19.41 g), and sulfa trioxide pyridine complex (8.00 g). 1.40 (AMPEG750) 0.30 (Aminoethylsulfate) 0.30 ] n obtained.

[0087] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 ​ 2SO4,-NH(CH2CH2O) 16 ​ 3), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), Average molecular weight (M w ):7,700 Example 17: Poly[(isoleucine ethyl ester)] 1.40 (Aminomethoxypolyethylene glycol 750) 0.30 (aminoethyl methacrylate) 0.30 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 1 using isoleucine ethyl ester hydrochloride (23.63 g), polydichlorophosphazene (10 g), polyethylene glycol having a molecular weight of 750 (19.41 g), and amino methacrylate hydrochloride (3.00 g) dissolved in dimethylformamide. 1.40 (AMPEG750) 0.30 (AminoethylMethacrylate) 0.30 ] n obtained.

[0088] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4~1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ1.9(s,-NHCH2CH2O2C( ​ 3)C=CH2), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9~4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), δ5.5(s,-NHCH2CH2O2C(CH3)C= ​ 2), δ6.1(s,-NHCH2CH2O2C(CH3)C= ​ 2), Average molecular weight (M w ):14,500 Example 18: Poly[(isoleucine ethyl ester)] 1.11 (Aminomethoxypolyethylene glycol 550) 0.75 (aminoethyl acrylate) 0.14 Phosphazene] n Manufacturing The final product, [NP(IleOEt)], was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (18.74 g), polydichlorophosphazene (10 g), aminoethanol (0.73 g), polyethylene glycol having a molecular weight of 550 (35.59 g), and acrylic acid (3.00 g) dissolved in THF. 1.11 (AMPEG550) 0.75(Aminoethyl Acrylate) 0.14 ] n obtained.

[0089] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4~1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ1.9(s,-NHCH2CH2O2C( ​ 3)C=CH2), δ3.4(s,-NH(CH2CH2O) 11 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 11 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9~4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), δ5.5~6.5(s,-NHCH2CH2O2 ​ ), Average molecular weight (M w ):26,500 Example 19: Poly[(isoleucine ethyl ester)] 1.55 (Aminomethoxypolyethylene glycol 750) 0.38 (Aminoethylsuccinic acid imidazole) 0.07 Phosphazene] n Manufacturing The final product, [NP(IleOEt)], was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (26.17 g), polydichlorophosphazene (10 g), aminoethanol (0.36 g), polyethylene glycol having a molecular weight of 750 (24.59 g), succinic anhydride (4.00 g), dimethylaminopyridine (4.00 g), diisopropylcarboimidazole (15.00 g), hydroxysuccinimide (15.00 g), and 1-(3-aminopropylimidazole) (10.00 g) dissolved in THF. 1.55 (AMPEG750) 0.38 (AminoethylsuccinateImidazole) 0.07 ] n obtained.

[0090] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCO ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​(CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2COOH), δ6.8-7.8(b,-NHCH2CH2OCO ​ 2CH2CONH-Imi), Average molecular weight (M w ):9,700 Example 20: Poly[(isoleucine ethyl ester)] 1.51 (Aminomethoxypolyethylene glycol 750) 0.40 (aminoethyl succinic acid polypeptide) 0.09 Phosphazene] n Manufacturing The final product, [NP(IleOEt)], was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (25.15 g), polydichlorophosphazene (10 g), aminoethanol (0.47 g), polyethylene glycol having a molecular weight of 750 (27.18 g), succinic anhydride (4.00 g), hexylamine (4.00 g), and the polypeptide dissolved in dimethyl sulfur monoxide (3.00 g). 1.51 (AMPEG750) 0.40 (AminoethylsuccinateCRRRRHHHHHHGGGGGRGDS) 0.09 ] n The polypeptide was quantified using the amino acid quantification method.

[0091] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCO ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2COOH), Average molecular weight (M w ):13,700 Comparative Example 1: Poly[(isoleucine ethyl ester)] 1.12 (Aminomethoxypolyethylene glycol 550) 0.85 (Ethyl-2-(O-glycyl)lactate) 0.03 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 1 using isoleucine ethyl ester hydrochloride (19.75 g), polydichlorophosphazene (10 g), ethyl-2-(O-glycyl)lactate ammonium oxalate (0.52 g), and polyethylene glycol having a molecular weight of 550 (37.96 g). 1.12 (AMPEG550) 0.85 (GlyLacOEt) 0.03 ] n obtained.

[0092] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.3-1.5(b,-NHCH2COOCH(CH3)COOCH2C H 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ1.6-1.7(b,-NHCH2COOCH( ​ 3) COOCH2CH3), δ2.67-3.2(b,-NH(CH2CH2O) 11 ​ 3), δ3.4(s,-NH(CH2CH2O) 11 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 11 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), δ4.0-4.4(b,-NH ​ 2COOCH(CH3)COO ​ 2CH3), δ5.2-5.4(b,-NHCH2COO ​ (CH3)COOCH2CH3), Average molecular weight (M w ):69,000 Comparative Example 2: Poly[(isoleucine ethyl ester)] 1.32 (Aminomethoxypolyethylene glycol 750) 0.65 (Ethyl-2-(O-glycyl)lactate) 0.03 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 1 using isoleucine ethyl ester hydrochloride (22.28 g), polydichlorophosphazene (10 g), ethyl-2-(O-glycyl)lactate ammonium oxalate (0.52 g), and polyethylene glycol having a molecular weight of 750 (42.06 g). 1.32 (AMPEG750) 0.65 (GlyLacOEt) 0.03 ] n obtained.

[0093] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.3-1.5(b,-NHCH2COOCH(CH3)COOCH2C H 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ1.6-1.7(b,-NHCH2COOCH( ​ 3) COOCH2CH3), δ2.67-3.2(b,-NH(CH2CH2O) 16 ​ 3), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), δ4.0-4.4(b,-NH ​ 2COOCH(CH3)COO​ 2CH3), δ5.2-5.4(b,-NHCH2COO ​ (CH3)COOCH2CH3), Average molecular weight (M w ):58,000 Comparative Example 3: Poly[(isoleucine ethyl ester)] 1.30 (Aminomethoxypolyethylene glycol 750) 0.42 (aminoethanol) 0.28 Phosphazene] n Manufacturing Isoleucine ethyl ester hydrochloride (21.95 g), polydichlorophosphazene (10 g), aminoethanol (1.58 g), and polyethylene glycol having a molecular weight of 750 (25.88 g) were used in the same manner as in Example 1, except that THF was used instead of anhydrous acetonitrile when adding aminoethanol, to obtain the final product [NP(IleOEt)]. 1.30 (AMPEG750) 0.42 (Aminoethanol) 0.28 ] n obtained.

[0094] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 11 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 11​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 11 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3), Average molecular weight (M w ): 5,900 Comparative Example 4: Poly[(isoleucine ethyl ester)] 1.07 (Aminomethoxypolyethylene glycol 550) 0.81 (aminoethyl succinic acid) 0.12 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 4 using isoleucine ethyl ester hydrochloride (18.06 g), polydichlorophosphazene (10 g), aminoethanol (0.63 g), polyethylene glycol having a molecular weight of 550 (38.44 g), succinic anhydride (4.00 g), and dimethylaminopyridine (4.00 g). 1.07 (AMPEG550) 0.81 (Aminoethylsuccinate) 0.12 ] n obtained.

[0095] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCO ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 11 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 11 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 11 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2COOH), Average molecular weight (M w ):13,200 Comparative Example 5: Poly[(isoleucine ethyl ester)] 1.39 (Aminomethoxypolyethylene glycol 750) 0.41 (aminoethyl succinic acid) 0.20 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 4 using isoleucine ethyl ester hydrochloride (23.47 g), polydichlorophosphazene (10 g), aminoethanol (1.05 g), polyethylene glycol having a molecular weight of 750 (26.53 g), succinic anhydride (4.00 g), and dimethylaminopyridine (4.00 g). 1.39 (AMPEG750) 0.41 (Aminoethylsuccinate) 0.20 ] n obtained.

[0096] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.5-2.7(b,-NHCH2CH2OCO ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2COOH), Average molecular weight (M w ):41,200 Comparative Example 6: Poly[(isoleucine ethyl ester) 1.05 (Aminomethoxypolyethylene glycol 550) 0.81 (aminoethyl glutarate) 0.14 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 7 using isoleucine ethyl ester hydrochloride (17.72 g), polydichlorophosphazene (10 g), aminoethanol (0.73 g), polyethylene glycol having a molecular weight of 550 (38.44 g), glutaric anhydride (7.00 g), and dimethylaminopyridine (7.00 g). 1.05 (AMPEG550)0.81 (Aminoethyl Glutarate) 0.14 ] n obtained.

[0097] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO ​ 2 ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 11 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 11 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 11 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), Average molecular weight (M w ): 7,900 Comparative Example 7: Poly[(isoleucine ethyl ester)] 1.32 (Aminomethoxypolyethylene glycol 750) 0.42(aminoethyl glutarate) 0.26 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 7 using isoleucine ethyl ester hydrochloride (22.28 g), polydichlorophosphazene (10 g), aminoethanol (1.58 g), polyethylene glycol having a molecular weight of 750 (24.59 g), glutaric anhydride (8.00 g), and dimethylaminopyridine (8.00 g). 1.32 (AMPEG750) 0.42 (Aminoethyl Glutarate) 0.26 ] n obtained.

[0098] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO ​ 2 ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​(CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), Average molecular weight (M w ):5,800 Comparative Example 8: Poly[(isoleucine ethyl ester)] 1.61 (Aminomethoxypolyethylene glycol 1000) 0.34 (aminoethyl glutarate) 0.05 Phosphazene] n Manufacturing In the same manner as in Example 7, isoleucine ethyl ester hydrochloride (29.54 g), polydichlorophosphazene (10 g), aminoethanol (0.26 g), polyethylene glycol having a molecular weight of 1,000, The final product [NP(IleOEt)] was prepared using 17.25 g of methylparaben, 8.00 g of glutaric anhydride, and 8.00 g of dimethylaminopyridine. 1.61 (AMPEG1000) 0.34 (Aminoethyl Glutarate) 0.05 ] n obtained.

[0099] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO ​ 2 ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​2OH,-NH(CH2CH2O) 20 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 20 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 20 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), Average molecular weight (M w ):9,800 Comparative Example 9: Poly[(isoleucine ethyl ester) 1.33 (Aminomethoxypolyethylene glycol 750) 0.47 (Aminoethyl glutarate beta cyclodextrin) 0.20 Phosphazene] n Manufacturing In the same manner as in Example 10, a polymer was obtained using isoleucine ethyl ester hydrochloride (22.45 g), polydichlorophosphazene (10 g), aminoethanol (1.05 g), polyethylene glycol having a molecular weight of 750 (30.41 g), glutaric anhydride (8.00 g), and dimethylaminopyridine (8.00 g), and then aminobeta-cyclodextrin (16.00 g) was added and reacted to obtain the final product [NP(IleOEt)]. 1.33 (AMPEG750) 0.47 (AminoethylGlutaric Beta-CD) 0.20 ] n obtained.

[0100] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 ​ 3), δ1.4-1.8(b,-NH ​ ( ​ (CH3)CH2CH3)COOCH2CH3), δ2.1-2.32(b,-NHCH2CH2OCO ​ 2 ​ 2CH2COOH), δ2.67-3.2(b,-NHCH2 ​ 2OH,-NH(CH2CH2O) 16 ​ 3), δ2.9-3.2(b,-NHCH2CH2OCOCH2CH2 ​ 2COOH), δ3.4(s,-NH(CH2CH2O) 16 ​ 3), δ3.4-3.9(b,-NH( ​ 2 ​ 2O) 16 CH3,-NH ​ (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO ​ 2CH3,-NHCH2 ​ 2OCOCH2CH2CH2COOH), δ4.7-4.8(b,-NHCH2 ​ , Average molecular weight (M w ):15,500 Comparative Example 10: Poly[(isoleucine ethyl ester) 1.48 (Aminomethoxypolyethylene glycol 750) 0.42 (aminoethyl adipate) 0.10 Phosphazene] n Manufacturing The final product [NP(IleOEt)] was prepared in the same manner as in Example 10 using isoleucine ethyl ester hydrochloride (24.99 g), polydichlorophosphazene (10 g), aminoethanol (0.52 g), polyethylene glycol having a molecular weight of 750 (27.18 g), adipic anhydride (8.00 g), and dimethylaminopyridine (8.00 g). 1.48 (AMPEG750) 0.42 (Aminoethyl Adipate) 0.10 ] n obtained.

[0101] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( ​ 3) CH2 ​ 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) ​ 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ1.52-1.64(b,-NHCH2CH2OCOCH2 CH 2 CH 2CH2COOH), δ2.3-2.32(b,-NHCH2CH2OCO CH 2CH2CH2 CH 2COOH), δ2.67-3.2(b,-NHCH2 CH 2OH,-NH(CH2CH2O) 16 CH 3), δ3.4(s,-NH(CH2CH2O) 16 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 16 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.94.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3,-NHCH2 CH 2OCOCH2CH2CH2COOH), Average molecular weight (M w ): 4,600 Comparative Example 11: Poly[(isoleucine ethyl ester)] 1.49 (Aminomethoxypolyethylene glycol 750) 0.44 (aminoethyl sulfate) 0.07 Phosphazene] n Manufacturing The final product, [NP(IleOEt)], was prepared in the same manner as in Example 15 using isoleucine ethyl ester hydrochloride (25.15 g), polydichlorophosphazene (10 g), aminoethanol (0.36 g), polyethylene glycol having a molecular weight of 750 (28.47 g), and sulfa trioxide pyridine complex (5.00 g). 1.49 (AMPEG750) 0.44 (Aminoethylsulfate) 0.07 ] n obtained.

[0102] Hydrogen nuclear magnetic resonance spectrum (CDCl3, ppm): δ0.8-1.1(b,-NHCH(CH( CH 3) CH2 CH 3) COOCH2CH3), δ1.1-1.4(b,-NHCH(CH(CH3) CH 2CH3)COOCH2 CH 3), δ1.4-1.8(b,-NH CH ( CH (CH3)CH2CH3)COOCH2CH3), δ2.67-3.2(b,-NHCH2 CH 2SO4,-NH(CH2CH2O) 16 CH 3), δ3.4(s,-NH(CH2CH2O) 16 CH 3), δ3.4-3.9(b,-NH( CH 2 CH 2O) 16 CH3,-NH CH (CH(CH3)CH2CH3)COOCH2CH3), δ3.9-4.3(b,-NHCH(CH(CH3)CH2CH3)COO CH 2CH3), Average molecular weight (M w ):8,800 [Experimental Example 1: Sol-gel transition of polyphosphazene polymers exhibiting reversible-irreversible properties due to temperature change] The various polyphosphazene-based polymers prepared according to Examples 1 to 20 and Comparative Examples 1 to 11 were dissolved in phosphate buffered saline (pH 7.4) at 4°C at a concentration of 10 wt%. The solution was placed in the chamber of an automatically controlled water bath (TC-501) to observe the sol-gel behavior with temperature. Specifically, the solution was placed in the chamber of a Brookfield DB-III+ rheometer equipped with an automatically controlled water bath (TC-501). The sol-gel behavior with temperature was observed by increasing the temperature by 0.33°C per minute at a shear rate of 0.1 to 1.7 / sec. The viscosity onset temperature and the maximum strength of the hydrogel were measured, and the results are shown in Table 1.

[0103] [Table 1]

[0104] JPEG2025168555000013.jpg194169

[0105] JPEG2025168555000014.jpg38169

[0106] As shown in Table 1, the polyphosphazene polymer solutions (10 wt%) of Examples 1 to 20 and Comparative Examples 1 to 11 were all in a flowable solution state below the initial gel temperature, but converted to a gel state above 37°C, which is the temperature condition in the body. Even when re-cooled to about 10°C, they still maintained the gel state, whereas the hydrogels made of the compositions of Comparative Examples 1 to 11 all converted back to a flowable sol state.

[0107] [Experimental Example 2: Evaluation of rheological properties of aqueous polyphosphazene polymer solutions exhibiting reversible-irreversible properties through temperature changes] To observe whether the polyphosphazene-based polymer solution of the present invention loses its reversible sol-gel transition property after being exposed to a certain temperature or higher, the temperature was repeatedly changed and the rheological properties of the polymer solution were observed. The results are shown in Figure 1. Similarly to Experimental Example 1, polyphosphazene-based polymer solutions (10 wt%) of Example 4 and Comparative Example 3 were prepared. A strain of 5% and a frequency of 0.8 Hz were applied to each of the prepared polyphosphazene-based polymer solutions of Example 4 and Comparative Example 3, and the storage modulus and loss modulus were measured with respect to temperature. As a result, the polyphosphazene-based polymer solution of Example 4 existed in a solution state with a lower storage modulus than the loss modulus at low temperatures. As the temperature increased, the storage modulus became higher than the loss modulus, forming a hydrogel. Furthermore, the polymer solution of Example 4 lost its reversible property change before 40°C. Therefore, even when the temperature was gradually lowered after increasing to 40°C, the storage modulus remained significantly higher than the loss modulus, and the hydrogel state was maintained. On the other hand, the polyphosphazene-based polymer solution of Comparative Example 3 existed in a solution state at low temperatures, with the storage modulus lower than the loss modulus. With increasing temperature, the storage modulus became higher than the loss modulus, forming a hydrogel. However, when the temperature was increased to 40°C and then gradually cooled again, the storage modulus again became lower than the loss modulus, returning to a solution state. Furthermore, when the temperature was gradually increased and then decreased again, the reversible sol-gel transition with temperature change was clearly demonstrated.

[0108] [Experimental Example 3: Observation of the sol-gel transition of polyphosphazene-based polymers exhibiting reversible-irreversible properties] After exposing the polyphosphazene-based polymer solution of the present invention to a certain temperature or higher, the temperature was changed to observe with the naked eye whether the solution lost its reversible sol-gel transition property with a temperature change. The results are shown in Figure 2. Similarly to Experimental Example 1, polyphosphazene-based polymer solutions (10 wt%) of Example 8 and Comparative Example 5 were prepared. Both the polyphosphazene-based polymer solutions of Example 8 and Comparative Example 5 were in a solution state at 4°C. After exposure to body temperature (37°C) for more than 3 minutes, they exhibited a hydrogel state that did not flow in the direction of gravity even when the vial was placed on them. When the hydrogels formed from the polyphosphazene-based polymer solutions of Example 8 and Comparative Example 5 were then exposed to 4°C again, Comparative Example 5 was observed to return to a solution state within 1 minute, while the hydrogel of Example 8 maintained its hydrogel state that did not flow in the direction of gravity even after exposure for more than 6 hours at 4°C.

[0109] [Experimental Example 4: 3D printing application of polyphosphazene-based polymers exhibiting reversible-irreversible properties] Based on the reversible-irreversible properties of the polyphosphazene-based polymer of the present invention, its applicability as a 3D printing ink was confirmed. Similar to Experimental Example 1, polyphosphazene-based polymer solutions (10 wt %) were prepared for Examples 10 and 11 and Comparative Examples 6 and 7. To more easily distinguish the morphology of the 3D printed objects, the polyphosphazene-based polymer solution of Example 11 was mixed with a red dye, and the polyphosphazene-based polymer solution of Comparative Example 7 was mixed with a blue dye at less than 0.1%. The solution was filled into a 3D printer cartridge at 4°C and printed at a viscosity range that allowed for the formation of a weak gel above the initial gel temperature. The bottom of the printed object was heated to a temperature at which the reversible properties are lost during printing (e.g., 37°C, which is body temperature in this invention) to solidify the morphology. The printed object was then exposed to room temperature to observe whether it maintained its shape and / or returned to a solution phase.

[0110] Figure 3 shows photographs of the morphological changes observed when structures formed by 3D printing using the polyphosphazene-based polymer solutions (10 wt%) of Examples 10 and 11 and Comparative Examples 6 and 7 were gelled and then exposed to room temperature. The 3D printed structures produced using the polymer solutions of Examples 10 and 11 maintained their printed 3D shapes without converting to a solution state even when exposed to room temperature after solidifying with a hydrogel. In contrast, the 3D printed structures produced using the polymer solutions of Comparative Examples 6 and 7 were solidified with a hydrogel and then reversibly converted to a sol state immediately after exposure to room temperature, resulting in a change in the strength of the 3D structures and a collapse of their shape.

[0111] [Experimental Example 5: Observation of morphological maintenance in cell culture after 3D printing of polyphosphazene-based polymers with reversible property changes] In Experimental Example 4, the shape retention ability of 3D-printed products was examined with temperature changes. Therefore, to confirm the applicability of the polyphosphazene-based polymer to 3D cell culture, its biocompatibility was considered and the morphology retention ability was examined by exposing it to cell culture medium. Similar to Experimental Example 4, 3D-printed gelled structures were immersed in cell culture medium, and the morphological changes over time were observed and shown in Figure 4. The 3D structures fabricated using the polymer solutions of Examples 11 and 13 maintained their shape without structural collapse even after immersion in cell culture medium for more than one week. In contrast, the 3D structure fabricated using the polyphosphazene-based polymer solution of Comparative Example 7 began to show changes in strength and / or morphology immediately after gelation and exposure to room temperature. Upon immersion in cell culture medium, the structure quickly dissolved into the cell culture medium, causing rapid structural collapse that was too rapid to photograph.

[0112] [Experimental Example 6: Evaluation of cell viability after 3D printing of polyphosphazene-based polymers with reversible property changes] The applicability of 3D structures fabricated using the polymer solutions of the Examples, whose morphology-maintaining ability in cell culture medium was confirmed in Experimental Example 5, as cell culture scaffolds was confirmed. Specifically, the polymer solution (10 wt%) of Example 11 was prepared and mixed with human adipose-derived mesenchymal stem cells (hADMSCs) at 4°C. The solution was then loaded into a 3D printer cartridge. This was printed at a viscosity range above the initial gel temperature, which would result in a weak gel. The bottom was heated to 37°C, a temperature at which the reversible properties are lost, to solidify the printed shape. The structures were then immersed in cell culture medium for 3 weeks, and the viability of the cells contained therein was evaluated. The results are shown in Figure 5. ADMSCs were loaded into the polyphosphazene-based polymer solution of Example 11, and the 3D-printed structures were cultured in cell culture medium for 3 weeks. The viability was confirmed to be nearly 100% even up to 3 weeks.

[0113] [Experimental Example 7: Observation of deformation of a hydrogel structure made of a polyphosphazene-based polymer with reversible properties when implanted into an exposed wound] Based on the reversible property changes and / or drug loading and release capabilities of the polyphosphazene-based polymers of the present invention, their applicability as implants for tissue repair or regeneration in wounds exposed to an external environment where relatively frequent and highly variable temperature changes are expected was confirmed. Specifically, the polyphosphazene polymer solutions of Example 13 and Comparative Example 8 were applied to the wounds of 6-week-old male rats with severe back injuries to form hydrogels, and the maintenance of the hydrogels at the exposed wounds was examined, with the results shown in Figure 6. As shown in Figure 6, the hydrogel made from the polymer solution of Example 13 maintained its shape for more than two weeks, whereas the hydrogel made from the polymer solution of Comparative Example 8 did not maintain its shape for a long period of time, running off or being absorbed within one day.

[0114] [Experimental Example 8: Observation of the deformation of a hydrogel structure made of a polyphosphazene-based polymer that changes reversible properties upon exposure to an external environment] To confirm the potential use of the polyphosphazene-based polymers of the present invention as drug delivery systems and / or therapeutic agents for tissue repair or regeneration based on their reversible property changes, the shape retention ability of hydrogels formed by injecting them into the body was evaluated in response to environmental changes. Specifically, the polyphosphazene polymer solutions (10 wt%) of Example 11 and Comparative Example 7 were subcutaneously injected into the backs of 6-week-old male rats to form hydrogels. After one day, the backs of the rats were opened to observe the degradation of the hydrogels. The immediate changes in their state upon exposure to the external environment were observed, and the results are shown in Figure 7. As shown in Figure 7, the hydrogel formed by injecting the polymer solution of Example 13 maintained its shape even when opened and was easily separated outside the body. However, the hydrogel formed by injecting the polymer solution of Comparative Example 7 weakened upon exposure to the external environment when opened, causing it to lose its shape and making it difficult to separate outside the body.

[0115] [Experimental Example 9: Observation of self-tissue regeneration due to cell penetration and survival after attachment when polyphosphazene-based polymer hydrogel with reversible sol-gel properties is injected into the body] Based on the reversible property changes of the polyphosphazene-based polymers of the present invention, we have confirmed their potential for use as polymer hydrogels themselves as therapeutic agents for tissue repair and autologous tissue regeneration without the addition of drugs or cells. Polymer hydrogels with reversible sol-gel properties maintain a significantly enhanced hydrophobic state above a certain temperature due to the disruption of their hydrophilic-hydrophobic balance with temperature changes, resulting in persistent hydrophobic cohesion. This property allows cells that have infiltrated into the hydrogel to attach to the hydrogel's structural network and survive. Over time, the polymer hydrogel biodegrades, but the autologous tissue generated by the infiltrated and surviving cells remains at the implantation site, maintaining a certain volume or greater. Specifically, the polyphosphazene polymer solutions (10 wt%) of Example 5 and Comparative Example 7 were subcutaneously injected into the backs of 6-week-old male rats to form hydrogels. After 4 weeks, the backs were incised to observe the hydrogel degradation and autologous tissue regeneration results. The injected sites were then observed and evaluated. The results are shown in Figure 8. As shown in Figure 8, the area where the hydrogel was formed by injecting the polymer solution of Comparative Example 7 was completely biodegraded and disappeared after four weeks, while the hydrogel formed by injecting the polymer solution of Example 5 maintained approximately 80% or more of its hydrogel morphology even after four weeks. The hydrogel area was peeled off and observed using various staining methods, confirming that it had been replaced with autologous tissue. Hematoxylin & Eosin, Oil Red O, and Masson's trichrome staining were used. The results confirmed that the hydrogel-formed area was completely filled with infiltrated cells and consisted of blood vessels, adipose tissue, and / or extracellular matrix.

[0116] [Experimental Example 10: Observation of the improved drug delivery and tissue regeneration capabilities of polyphosphazene-based polymer hydrogels with reversible property changes] The reversible property change of the polyphosphazene-based polymer of the present invention significantly delayed the biodegradation time of the hydrogel, thereby significantly increasing the drug delivery period. Furthermore, when delivering cytokines related to cell survival and differentiation, the gradual drug release over a long period of time maximized tissue regeneration. Specifically, polyphosphazene polymer solutions (10 wt%) of Comparative Example 5, Example 16, and Example 14 were prepared, and 7 μg of bone morphogenetic protein-2 (BMP-2) was added to each solution at the same dose. The drug release over time was observed in vitro. The hydrogels were then subcutaneously injected into the backs of 6-week-old male rats to form hydrogels. The extent of newly formed bone was then observed 8 weeks later. The results are shown in Figures 9 and 10, respectively. As shown in Figure 9, the osteogenic protein released from Comparative Example 5 was released rapidly, whereas the osteogenic protein was released slowly over a period of approximately two months from the polymer hydrogels of Examples 16 and 14. As shown in Figure 10, the hydrogels containing osteogenic protein were injected subcutaneously into the back of animals. After eight weeks, the injected hydrogels were isolated and evaluated using X-ray and μ-CT to determine whether they had been replaced by bone tissue. When the osteogenic protein-containing polymer hydrogel of Comparative Example 5 was injected, the bone formed was less than 40% of the injected hydrogel's volume, or bone formation was insufficient, due to the biodegradation of the hydrogel over time and / or the hydrophilic properties of the hydrogel. However, when the osteogenic protein-loaded polymer hydrogels of Examples 16 and 14 were injected, the biodegradation properties of the hydrogel were reduced and the hydrophobic properties were maintained at a maximum. This phenomenon allowed replacement by newly formed bone, maintaining more than 80% of the volume of the hydrogel at the time of initial injection, even after eight weeks. Furthermore, it was confirmed that the newly formed bone tissue was well filled inward.

Claims

[Claim 1] On a phosphorus atom of a polyphosphazene skeleton represented by the following chemical formula 1, An amino acid ester first moiety represented by the following chemical formula 2: a polyethylene glycol second moiety represented by formula 3: a third moiety containing a functional group at the end for the introduction of a functional moiety; in the proportions a:b:c, respectively; 3D printing ink composition comprising a polyphosphazene-based polymer: 【Chemistry 1】 In the above Chemical Formulas 1 to 3, R １ is C １－６ Alkyl, (C １－６ alkenyl) or C ６－１０ Aryl-C １－６ is alkyl, R ２ is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxybenzyl or 2-indolylmethyl; R ３ is C １－６ is alkyl, n is an integer from 3 to 100,000; p is an integer from 1 to 23, a+b is 80 to 99% and c is 1 to 20% based on the total bonding sites of the polyphosphazene; i) when p is 1 to 13, b is 25 to less than 40%; ii) when p is 14 to 17, b is 10 to 20%; iii) When p is 18 to 23, b is 10 to 15%.

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