1. A poly(organophosphazene) with a physiologically active substance covalently-bonded thereto, which is chemically-crosslinkable and has Chemical Formula 1 as follows:
wherein,
p is from 7 to 50,
in NHCH(R1)CO2R2, R1 is selected from the group consisting of H, CH3, CH2SH, CH2OH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2NH2C6H4, and R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5 and CH2CHCH2
in NH(R3)(R4)(R5), R3 is CH(W), R4 is selected from the group consisting of CO2, CONHCH(Q)CO2CO2, CH2CO2 and CO2CH(CH3)CO2, R5 is selected from the group consisting of H, CH3 and C2H5, in which each of W and Q is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3, and CH2SH,
in XR6, X represents N or O, and R6 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenol derivative compound, NH(R7)(R8)(R9) represents a substituent having a functional group, in which R7 is CH(Y), R8 is selected from the group consisting of CH2, C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, CH2OCOCH2CH2CO, CH2OCOCH2CH2CH2CO, CH2OCOCH2CH2CH2CH2CO, CH2CH2OCOCH2CH2CO, CH2CH2OCOCH2CH2CH2CO, CH2CH2OCOCH2CH2CH2CH2CO, O, CONHCH(Z)O, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(N)CONHCH(L)O, CO, CO2, S, CONHCH(Z)S, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, N, CONHCH(Z)N, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, CON, COCHNH(Z)CON, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, CONHCH(Z)CO, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, CONHCH(Z)CO2, COCHNH(Z)CONHCH(M)CO2, COCHNH(Z)CONHCH(M)CONHCH(L)CO2, OCH(CH3)COq, (OCH2CO)q, (OCH(CH3)COq, OCO(CH2)8COq, OCOC6H5O(CH2)3OC6H5COq and OCOC6H5O(CH2)6OC6H5COq, and R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)qH, NHCH(C4H8NH2)COqOH, NHCH(CH2)3C(\u2550NH)(NH2)COqOH, folic acid, hyaluronic acid, cyclodextrin, an imidazole compound, histidine, lysine, arginine, cysteine, thioalkyl amine, spermine, spermidine, TAT peptide, polyethyleneimine, polyhistidine, polylysine, polyarginine, heparin, chitosan, protamine, and a typical protecting group of a functional group, in which each of Y, Z, M, and L is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3 and CH2SH, and q represents the number of the repeating unit ranging from 1 to 18000,
R10 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative,
R11 represents a physiologically active substance and is at least one selected from the group consisting of a protein, a polypeptide, a peptide, a fusion protein, an antibody, a hormone, a vaccine, a gene, an anticancer drug, and an angiogenesis inhibitor that have at least one functional group selected from the group consisting of a hydroxyl, an amide, an amino, a carboxyl, a thiol, a vinyl, an aldehyde, a halogen, and a ketone groups,
a, b, c, d, e, f, g, h, and i represent a content of each substituent, in which a and b range from 0.01 to 1.9, respectively, c, d, e, f, g, h, and i range from 0 to 1.9, respectively, d and f cannot be simultaneously zero, and g, h, and i cannot be simultaneously zero, and a+b+c+d+e+f+g+h+i=2.0, and
n represents a degree of polymerization of the poly(organophosphazene), ranging from 5 to 100000.
2. The poly(organophosphazene) with a physiologically active substance covalently-bonded thereto in accordance with claim 1, wherein the protein, the polypeptide, the peptide, the fusion protein, and the antibody are at least one selected from the group consisting of erythropoietin (EPO), interferon-\u03b1, interferon-\u03b2, interferon-\u03b3, a growth hormone releasing factor, a nerve growth factor (NGF), Granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), a blood clotting factor, insulin, albumin, botulinum toxin, oxytocin, vasopressin, a fibroblast growth factor (FGF), a epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), a keratinocyte growth factor, an insulin-like growth factor (IGF), a vascular endothelial growth factor (VEGF), a transforming growth factor-beta (TGF-\u03b2), a nerve growth factor, a brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-45, prolactin, luliberin, LHRH agonists, LHRH antagonists, glucagon, interleukin-2 (IL-2), interleukin-11 (IL-11), gastrin, tetragastrin, pentagastrin, urogastrone, secretin, enkephalins, endorphins, angiotensins, tumor necrosis factor (TNF), tumor necrosis factor related apoptosis inducing ligand (TRAIL), heparinase, bone morphogenic proteins (BMPs), a human atrial natriuretic peptide (hANP), a glucagon-like peptide (GLP-1), exnatide, calcitonin (human or salmon), teriparatide, coagulation factors, hirudin, anakinra, renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins, neurotensin, tachykinin, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), pituitray adenylate cyclase-activating polypeptide (PACAP) and synthetic analogues thereof, RGD, collagens, fibronectin, laminin, vitronectin, proteoglycan, monoclonal antibodies, fusion proteins, \u03b2-glucocerebrosidase, lactase, alglucosidase-\u03b1,\u03b1-galactosidase A, lipase, amylase, protease, hyaluronidase, L-asparaginase and cytokines,
the hormone is at least one selected from the group consisting of growth hormones, somatotropins, luteinizing hormone releasing hormone (LHRH), somatostatin, thyrotropin releasing hormone (TRH), adrenocorticotropic hormone, follicle-stimulating hormone (FSH), human chorionic gonadotropin (HCG), lutropin-\u03b1, testosterone, estradiol, progesterones, prostaglandins, and their synthetic analogues, and modified or equivalent efficacy substances,
the vaccine is at least one selected from the group consisting of a hepatitis vaccine, an HPV vaccine, and a lime disease vaccine.
the gene is at least one selected from the group consisting of small interfernce RNA (siRNA), small hairpin RNA (shRNA), micro RNA (miRNA), aptamer, plasmid DNA, and antisense oligodeoxynucleotide (AS-ODN),
the anticancer drug is at least one selected from the group consisting of paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, tegafur, irinotecan, docetaxel, cyclophosphamide, cemcitabine, ifosfamide, mitomycin C, vincristine, etoposide, methotrexate, topotecan, tamoxifen, vinorelbine, camptothecin, danuorubicin, chlorambucil, bryostatin-1, calicheamicin, mayatansine, levamisole, DNA recombinant interferon alfa-2a, mitoxantrone, nimustine, interferon alfa-2a, doxifluridine, formestane, leuprolide acetate, megestrol acetate, carmofur, teniposide, bleomycin, carmustine, heptaplatin, exemestane, anastrozole, estramustine, capecitabine, goserelin acetate, polysaccharide potassium, medroxypogexterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, actinomycin D, anasterozole, belotecan, imatinib, floxuridine, gemcitabine, hydroxyurea, zoledronate, vincristine, flutamide, valrubicin, streptozocin, silibinin, polyethyleneglygol conjugated anticancer drug, and synthetic analogues thereof, and modified or equivalent efficacy substances, and
the angiogenesis inhibitor is at least one selected from the group consisting of BMS-275291 (Bristol-Myers Squibb, New York, N.Y.), clodronate, 6-deoxy-6-demethyl-4-dedimethylaminotetracycline (COL-3), doxycycline, marimastat, 2-methoxyestradiol, squalamine, SU5164, thalidomide, TNP-470, combretastatin A4, soy isoflavone, enzastaurin, CC 5013 (Revimid; Celgene Corp, Warren, N.J.), celecoxib, ZD 6474 (inhibitor of vascular endothelial growth factor receptor tyrosine kinase), halofuginone hydrobromide, interferon-\u03b1, bevacizumab, AE-941 (Neovastat), interleukin-12, vascular endothelial growth factor-trap (VEFG-trap), cetuximab, rebimastat, matrix metalloproteinases (MMP) inhibitor, protein kinase C beta inhibitor, endostatin, vatalanib (PTK787ZK 222584), sunitinib malate (SU11248), cilenqitide (EMD-121974), humanized monoclonal antibody MEDI-522, EOS-200-4, integrin alpha-5-beta-1-antagonist (ATN-161), and their synthetic analogs, and modified or equivalent efficacy substances.
3. The poly(organophosphazene) in accordance with claim 1, wherein in the definition of R6 and R10,
the acrylate compound is an acrylate; an acrylate having a C1 to C30, substituted or unsubstituted, linear or branched alkyl group unsubstituted or substituted with at least one selected from the group consisting of a halogen atom, a C1 to C12 alkoxy, an acryloyloxy, and an amino acid; an acrylate having an amino acid group; ethyleneglycol acrylate; or polyethyleneglycol acrylate having polyethyleneglycol of the weight-average molecular weight of 200 to 2,500,
the methacrylate compound is a methacrylate; a methacrylate having a C1 to C30, substituted or unsubstituted, linear or branched alkyl group unsubstituted or substituted with at least one selected from the group consisting of a halogen atom, a C1 to C12 alkoxy, an acryloyloxy, and an amino acid; a methacrylate having an amino acid group; ethyleneglycol methacrylate; or polyethyleneglycol methacrylate having polyethyleneglycol of the weight-average molecular weight of 200 to 2,500,
the acrylamide compound is an acryl amide; an acryl amide having a C1 to C30, substituted or unsubstituted, linear or branched alkyl group unsubstituted or substituted with at least one selected from the group consisting of a halogen atom, a C1 to C12 alkoxy, acryloyloxy, and an amino acid; an acryl amide having an amino acid group; ethyleneglycol acrylamide; or polyethyleneglycol amide having polyethyleneglycol of the weight-average molecular weight of 200 to 2,500,
the vinyl sulfone compound is a vinyl sulfone, vinyl sulfone-ethyleneglycol, vinyl sulfone-polyethyleneglycol having polyethyleneglycol of the weight-average molecular weight of 200 to 2,500, a vinyl sulfone-alkylate having a C1 to C30 alkyl group, a vinyl sulfone-amino acid, or a vinyl sulfone-peptide,
the thiol compound is thiol-polyethylene glycol having polyethylene glycol of the weight-average molecular weight of 200 to 2,500, or a thiol-alkylate having a C1 to C30 alkyl group,
the cysteine compound is cysteine, N-acetyl-cysteine, or an N-acetyl-cysteine alkyl ester having a C1 to C30 alkyl group,
the cisteamine compound is cisteamine, or N-acetyl-cisteamine,
the mercaptic acid compound is 2-mercapto succinic acid,
the allyl pyrimidine compound is 1-allyl-2-amino-pyridinium, or 1-allyl-6-amino-3-ethyl-5-nitrosouracil,
the tyramine compound is tyramine, or 3-methoxytyramine,
the tyrosine compound is tyrosine, or tyrosine methylester, or tyrosine ethylester, and
the phenol compounds is 2-amino-4-phenylphenol, 2-amino-4-teriaryamylphenol, 2-amino-4-tert-butylphenol, 8-amino-2-naphthol, 5-amino-1-naphthol, 4-amino-1-naphthol, 3-amino-2-naphthol, 1-amino-2-naphthol, 4-amino 2,5 dimethylphenol, 5-amino-2-methoxyphenol, 5-amino-2-methylphenol, 4-amino-3-methylphenol, 4-amino-2-methylphenol, 2-amino-5-methylphenol, 2-amino-4-methylphenol, 2-amino-3-methylphenol, 2,4-diaminophenol, 2,3-diaminophenol, 4-aminophenol, 3-aminophenol, 2-aminophenol, 4-amino-3-nitrophenol, 4-amino-2-nitrophenol, 2-amino-5-nitrophenol, 2-amino-4-nitrophenol, 2-amino-4-fluorophenol, 4-amino-3-chlorophenol, 4-amino-2-chlorophenol, 3-amino-4-chlorophenol, 2-amino-5-chlorophenol, 2-amino-4-chlorophenol, 5-amino-2,4-dichlorophenol, 4-amino-3,6-dichlorophenol, 2-amino-4-chloro-6-nitrophenol, or 4-amino-2,6-dibromophenol.
4. A process for preparing the poly(organophosphazene) according to claim 1, which comprises the steps of:
(1) polymerizing a phosphazene trimer to obtain dichlorophosphazene linear polymers of Chemical Formula 3;
(where, n ranges from 1 to 100000)
(2) subjecting the compound of Chemical Formula 3 prepared in Step (1) to a reaction with 0.01 to 1.9 equiv. of an amino acid ester having Chemical Formula 4 or a salt thereof;
NH2CH(R1)CO2R2\u2003\u2003Chemical Formula 4
(3) subjecting the product of Step (2) to a reaction with 0 to 1.9 equiv. of an amino acid, a peptide, or a depsipeptide ester represented by Chemical Formula 5 or salts thereof;
NH2(R3)(R4)(R5)\u2003\u2003Chemical Formula 5
(4) subjecting the product of Step (3) to a reaction with 0.01 to 1.9 equiv. of a crosslinkable substituent represented by Chemical Formula 6 or a salt thereof;
NH2(R6) or OH(R6)\u2003\u2003Chemical Formula 6
(5) subjecting the product of Step (3) or the product of Step (4) to a reaction with 0.01 to 1.9 equiv. of a substituent having a functional group of the Chemical Formula 7 or a salt thereof;
NH2(R7)(R8)(R9)\u2003\u2003Chemical Formula 7
(6) subjecting the product of Step (4) or Step (5) to a reaction with aminomethoxy polyethyleneglycol of Chemical Formula 8 or a salt thereof;
NH2(CH2CH2O)pCH3\u2003\u2003Chemical Formula 8
(7) subjecting the compound obtained as above to a reaction with a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative compound, and
(8) covalently-bonding at least one functional group of R6, R9, and R10 of the product obtained as above selected from the group consisting of a hydroxyl group, an amide group, an amino group, a carboxyl group, a thiol group, and a vinyl group to at least one physiologically active substance selected from the group consisting of a protein, a polypeptide, a peptide, a fusion protein, an antibody, a hormone, a vaccine, a gene, an anticancer drug, and an angiogenesis inhibitor having various functional groups such as a hydroxyl group, an amide group, an amino group, a carboxyl group, a thiol group, a vinyl group, an aldehyde group, a halogen group, or a keton group; and
in the above formulae, p is from 7 to 50,
in NHCH(R1)CO2R2, R1 is selected from the group consisting of H, CH3, CH2SH, CH2OH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5 and CH2CHCH2
in NH(R3)(R4)(R5), R3 is CH(W), R4 is selected from the group consisting of CO2, CONHCH(Q)CO2CO2, CH2CO2 and CO2CH(CH3)CO2, R5 is selected from the group consisting of H, CH3 and C2H5, wherein each of W and Q is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3, and CH2SH,
in XR6, X represents N or O, and R6 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative compound, NH(R7)(R8)(R9) is a substituent having a functional group, in which R7 is CH(Y), R8 is selected from the group consisting of CH2, C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, CH2OCOCH2CH2CO, CH2OCOCH2CH2CH2CO, CH2OCOCH2CH2CH2CH2CO, CH2CH2OCOCH2CH2CO, CH2CH2OCOCH2CH2CH2CO, CH2CH2OCOCH2CH2CH2CH2CO, O, CONHCH(Z)O, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(N)CONHCH(L)O, CO, CO2, S, CONHCH(Z)S, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, N, CONHCH(Z)N, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, CON, COCHNH(Z)CON, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, CONHCH(Z)CO, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, CONHCH(Z)CO2, COCHNH(Z)CONHCH(M)CO2, COCHNH(Z)CONHCH(M)CONHCH(L)CO2, OCH(CH3)COq, (OCH2CO)q, (OCH(CH3)COq, OCO(CH2)8COq, OCOC6H5O(CH2)3OC6H5COq and OCOC6H5O(CH2)6OC6H5COq, and R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)qH, NHCH(C4H8NH2)COqOH, NHCH(CH2)3C(\u2550NH)(NH2)COqOH, folic acid, hyaluronic acid, cyclodextrin, an imidazole compound, histidine, lysine, arginine, cysteine, thioalkyl amine, spermine, spermidine, TAT peptide, polyethyleneimine, polyhistidine, polylysine, polyarginine, protamine, heparin, chitosan, and a typical protecting group of a functional group, in which each of Y, Z, M, and L is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3 and CH2SH, and q represents the number of the repeating unit ranging from 1 to 18000,
R10 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a cysteine compound, a thiol compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or a vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative compound,
R11 represents a physiologically active substance and is at least one selected from the group consisting of a protein, a polypeptide, a peptide, a fusion protein, an antibody, a hormone, a vaccine, a gene, an anticancer drug, and an angiogenesis inhibitor that have at least one functional group selected from the group consisting of a hydroxyl, an amide, an amino, a carboxyl, a thiol, a vinyl, an aldehyde, a halogen, and a ketone groups,
a, b, c, d, e, f, g, h, and i represent a content of each substituent, in which a and b range from 0.01 to 1.9, respectively, c, d, e, f, g, h, and i range from 0 to 1.9, respectively, d and f cannot be simultaneously zero, and g, h, and i cannot be simultaneously zero, and a+b+c+d+e+f+g+h+i=2.0, and
n represents a degree of polymerization of the poly(organophosphazene), ranging from 5 to 100000.
5. A hydrogel comprising a chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto, wherein it comprises a solution of a poly(organophosphazene) according to claim 1 and, it has chemical crosslinkings formed within or between the poly(organophosphazene)(s) by at least one treatment selected from the group consisting of
1) UV irradiation; 2) addition of at least one crosslinker selected from the group consisting of a thiol-based crosslinker and a vinyl-based crosslinker; 3) addition of at least one additive selected from the group consisting of a pH regulator, a catalyst, and an organic solvent; 4) addition of an enzyme; and 5) using as the solution of the poly(organophosphazene) a mixture of a solution of at least one poly(organophosphazene) solution including a thiol group and a solution of at least one poly(organophosphazene) including a vinyl group;
and it shows sol-gel behavior depending on a temperature.
6. The hydrogel according to claim 5, wherein at least one poly(organophosphazene) whose R6 and R10 has a vinyl group and at least one poly(organophosphazene) whose R6 and R10 has a thiol group are mixed together to form crosslinkings by a reaction between the vinyl group and the thiol group.
7. The hydrogel according to claim 5, wherein it further comprises at least one photoinitiator selected from the group consisting of ketone compounds, phosphine oxide compounds, alkyl ester compounds, benzoyl compounds, titanate salts, iodonium salts, dibenzoyl compounds, thiocarbonate compounds, dion compounds, and potassium sulfates in an amount of 1\xd710\u22126 to 10 wt % based on the weight of the chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto, and wherein the crosslinkings are formed by UV irradiation.
8. The hydrogel according to claim 5, wherein it further comprises at least one crosslinker selected from the group consisting of a vinyl-based crosslinker and a thiol-based crosslinker in an amount of 1\xd710\u22126 to 30 wt % based on the weight of the chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto, and wherein the crosslinkings are formed by a reaction between a vinyl or thiol group of the crosslinker and a thiol or vinyl group in the poly(organophosphazene).
9. The hydrogel according to claim 5, wherein it further comprises at least one additive selected from the group consisting of at least one pH regulator selected from the group consisting of sodium hydroxide, ammonia, potassium hydroxide, triethyl amine, sodium phosphate, trisbase, and HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); at least one catalyst selected from the group consisting of hydrogen peroxide and ammonium peroxide; and an organic solvent in an amount of 1\xd710\u22126 to 30 wt % based on the weight of the chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto, and wherein the additive causes the crosslinkings to be formed between the polymer having a thiol group and the polymer having a vinyl group or the polymer having a thiol group.
10. The hydrogel according to claim 5, wherein it further comprises oxydoreductase in an amount of 1\xd710\u22126 to 200 wt % based on the weight of the chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto, and wherein the crosslinkings are formed by a reaction between the enzyme and tyramine, tyrosine, or a phenyl derivative in the poly(organophosphazene).
11. The hydrogel according to claim 5, wherein the solution comprises the chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto at a concentration of 1 to 50 wt %.
12. A process for preparing the hydrogel of claim 5, which comprises the steps of preparing a solution of at least one poly(organophosphazene) in accordance with claim 1; and forming chemical crosslinkings to the polymer, and
wherein the formation of the chemical crosslinkings is carried out by at least one of five methods as follows:
1) using a solution mixture of at least one poly(organophosphazene) having a thiol group and at least one poly(organophosphazene) having a vinyl group as the solution of the poly(organophosphazene); 2) UV irradiation; 3) addition of at least one crosslinker selected from the group consisting of a vinyl-based crosslinker and a thiol-based crosslinker; 4) addition of at least one additive selected from the group consisting of a pH regulator, a catalyst, and an organic solvent; 5) addition of oxydoreductase.
13. The process according to claim 12, wherein a solution mixture of at least one poly(organophosphazene) whose R6 and R10 has a vinyl group and at least one poly(organophosphazene) whose R6 and R10 has a vinyl group are used to form crosslinkings by a reaction between the vinyl group and the thiol group.
14. The process according to claim 12, wherein a photoinitiator forming a radical by light irradiation that is selected from the group consisting of ketone compounds, phosphine oxide compounds, alkylester compounds, benzoyl compounds, titanium salts, iodonium salts, dibenzoyl compounds, thiocarbonate compounds, dion compounds, and potassium sulfates is further added in an amount of 1\xd710\u22126 to 10 wt % based on the total weight of the polymer and the crosslinkings are formed by UV irradiation.
15. The process according to claim 12, wherein at least one crosslinker selected from the group consisting of a vinyl-based crosslinker and a thiol-based crosslinker that have two or more vinyl or thiol groups is added in an amount of 1\xd710\u22126 to 30 wt % based on the weight of a chemically crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto to form crosslinkings by a reaction between a vinyl or thiol group of the crosslinker and a vinyl or thiol group of the poly(organophosphazene).
16. The process according to claim 12, wherein it is treated with at least one additive selected from the group consisting of at least one pH regulator selected from the group consisting of sodium hydroxide, ammonia, potassium hydroxide, triethyl amine, sodium phosphate, trisbase, and HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); at least one catalyst selected from the group consisting of hydrogen peroxide and ammonium peroxide; and an organic solvent in an amount of 1\xd710\u22126 to 30 wt % based on the weight of a chemically crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto to form crosslinkings between the poly(organophosphazene) having a thiol group and the poly(organophosphazene) having a vinyl group or the polymer having a thiol group.
17. The process according to claim 12, wherein it is treated with oxidoreductase in an amount of 1\xd710\u22126 to 200 wt % based on the weight of the chemically-crosslinkable, poly(organophosphazene) with a physiologically active substance covalently-bonded thereto so that the crosslinkings are formed by a reaction between the enzyme and tyramine or tyrosine in the poly(organophosphazene).
18. A biomaterial which comprises
a poly(organophosphazene) having a structure of Chemical Formula 1-1; or
a poly(organophosphazene)-containing hydrogel wherein it comprises a solution comprising the poly(organophosphazene) at a concentration of 1 to 50 wt %, and it has chemical crosslinkings formed within or between the poly(organophosphazene)(s) by at least one treatment selected from the group consisting of UV irradiation; addition of at least one crosslinker selected from the group consisting of a thiol-based crosslinker and a vinyl-based crosslinker; addition of at least one additive selected from the group consisting of a pH regulator, a catalyst and an organic solvent; addition of an enzyme; and using as the solution of the poly(organophosphazene) a mixture of a solution of at least one poly(organophosphazene) comprising a thiol group and a solution of at least one poly(organophosphazene) comprising a vinyl group:
in the above formula,
p is from 7 to 50,
in NHCH(R1)CO2R2, R1 is selected from the group consisting of H, CH3, CH2SH, CH2OH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5 and CH2CHCH2,
in NH(R3)(R4)(R5), R3 is CH(W), R4 is selected from the group consisting of CO2, CONHCH(X)CO2CO2, CH2CO2 and CO2CH(CH3)CO2, R5 is selected from the group consisting of H, CH3 and C2H5, wherein each of W and X is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3, and CH2SH,
in XR6, X represents N or O, and R6 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenol derivative compound,
NH(R7)(R8)(R9) is a substituent having a functional group, in which R7 is CH(Y), R8 is selected from the group consisting of CH2, C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, CH2OCOCH2CH2CO, CH2OCOCH2CH2CH2CO, CH2OCOCH2CH2CH2CH2CO, CH2CH2OCOCH2CH2CO, CH2CH2OCOCH2CH2CH2CO, CH2CH2OCOCH2CH2CH2CH2CO, O, CONHCH(Z)O, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(N)CONHCH(L)O, CO, CO2, S, CONHCH(Z)S, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, N, CONHCH(Z)N, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, CON, COCHNH(Z)CON, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, CONHCH(Z)CO, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, CONHCH(Z)CO2, COCHNH(Z)CONHCH(M)CO2, COCHNH(Z)CONHCH(M)CONHCH(L)CO2, OCH(CH3)COq, (OCH2CO)q, (OCH(CH3)COq, OCO(CH2)8COq, OCOC6H5O(CH2)3OC6H5COq and OCOC6H5O(CH2)6OC6H5COq, and R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)qH, NHCH(C4H8NH2)COqOH, NHCH(CH2)3C(\u2550NH)(NH2)COqOH, folic acid, hyaluronic acid, cyclodextrin, an imidazole compound, histidine, lysine, arginine, cysteine, thioalkyl amine, spermine, spermidine, TAT peptide, polyethyleneimine, polyhistidine, polylysine, polyarginine, heparin, chitosan, protamine, and a typical protecting group of a functional group, wherein each of Y, Z, M, and L is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3 and CH2SH, and q represents the number of the repeating unit ranging from 1 to 18000,
R10 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative,
R11 is at least one selected from the group consisting of a protein, a polypeptide, a peptide, a fusion protein, an antibody, a hormone, a vaccine, a gene, an anticancer drug, and an angiogenesis inhibitor that have at least one functional group selected from the group consisting of a hydroxyl, an amide, an amino, a carboxyl, a thiol, a vinyl, an aldehyde, a halogen, and a ketone groups,
a, b, c, d, e, f, g, h, and i represent a content of each substituent, in which a and b range from 0.01 to 1.9, respectively, c, d, e, f, g, h, and i range from 0 to 1.9, respectively, d and f cannot be simultaneously zero, and a+b+c+d+e+f+g+h+i=2.0, and
n represents a polymerization degree of polyphosphazene, ranging from 5 to 100000.
19. The biomaterial according to claim 18, wherein the biomaterial is at least one selected from the group consisting of materials for plastic surgery and orthopedics, tissue engineering biomaterials, dental materials, materials for preventing stenosis, and vasoocclusion materials.
20. The biomaterial according to claim 19, wherein the materials for plastic surgery and orthopedics are a filler, the tissue engineering biomaterials are an artificial cartilage, and the materials for preventing stenosis are a stent.
21. A composition for delivering a physiologically active substance, which comprises a poly(organophosphazene) with a physiologically active substance covalently-bonded thereto in accordance with claim 1 or a hydrogel comprising a poly(organophosphazene) with a physiologically active substance covalently-bonded thereto in accordance with claim 5 and wherein the content of the physiologically active substance ranges from 1\xd710\u22128 to 50 volume % based on the total volume of the composition.
22. The composition for delivering a physiologically active substance according to claim 21, wherein at least one selected from the group consisting of an additional physiologically active substance, a cell and an additive is simply mixed therein.
23. The composition for delivering a physiologically active substance according to claim 21, further comprising at least one additive selected from the group consisting of neutral, cationic, and anionic polymers having the weight-average molecular weight of 200 to 750,000, amino acids, peptides, proteins, fatty acids, phospholipids, vitamins, drugs, polyethyleneglycol 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\xd710\u22126 to 30 wt % based on the total weight of the composition.
24. A poly(organophosphazene)-containing hydrogel comprising chemical crosslinkings, which comprises a solution of a poly(organophosphazene) having a structure of Chemical Formula 1-2, and
wherein the concentration of the poly(organophosphazene) in the solution of the poly(organophosphazene) is from 1 to 50 wt %, and
wherein the crosslinkings between the poly(organophosphazene) having a thiol group and the poly(organophosphazene) having a vinyl group or the polymer having a thiol group are formed by treating it with at least one additive selected from the group consisting of at least one pH regulator selected from the group consisting of sodium hydroxide, ammonia, potassium hydroxide, triethyl amine, sodium phosphate, trisbase, and HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); at least one catalyst selected from the group consisting of hydrogen peroxide and ammonium peroxide; and an organic solvent in an amount of 1\xd710\u22126 to 30 wt % based on the total weight of the polymer:
in the above formula,
p is from 7 to 50,
in NHCH(R1)CO2R2, R1 is selected from the group consisting of H, CH3, CH2SH, CH2OH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5 and CH2CHCH2,
in NH(R3)(R4)(R5), R3 is CH(W), R4 is selected from the group consisting of CO2, CONHCH(X)CO2CO2, CH2CO2 and CO2CH(CH3)CO2, R5 is selected from the group consisting of H, CH3 and C2H5, wherein each of W and X is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3, and CH2SH,
in XR6, X represents N or O, and R6 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenol derivative compound,
NH(R7)(R8)(R9) is a substituent having a functional group, in which R7 is CH(Y), R8 is selected from the group consisting of CH2, C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, CH2OCOCH2CH2CO, CH2OCOCH2CH2CH2CO, CH2OCOCH2CH2CH2CH2CO, CH2CH2OCOCH2CH2CO, CH2CH2OCOCH2CH2CH2CO, CH2CH2OCOCH2CH2CH2CH2CO, O, CONHCH(Z)O, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(N)CONHCH(L)O, CO, CO2, S, CONHCH(Z)S, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, N, CONHCH(Z)N, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, CON, COCHNH(Z)CON, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, CONHCH(Z)CO, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, CONHCH(Z)CO2, COCHNH(Z)CONHCH(M)CO2, COCHNH(Z)CONHCH(M)CONHCH(L)CO2, OCH(CH3)COq, (OCH2CO)q, (OCH(CH3)COq, OCO(CH2)8COq, OCOC6H5O(CH2)3OC6H5COq and OCOC6H5O(CH2)6OC6H5COq and R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)qH, NHCH(C4H8NH2)COqOH, NHCH(CH2)3C(\u2550NH)(NH2)COqOH, folic acid, hyaluronic acid, cyclodextrin, an imidazole compound, histidine, lysine, arginine, cysteine, thioalkyl amine, spermine, spermidine, TAT peptide, polyethyleneimine, polyhistidine, polylysine, polyarginine, heparin, chitosan, protamine, and a typical protecting group of a functional group,
wherein each of Y, Z, M, and L is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3 and CH2SH, and q represents the number of the repeating unit ranging from 1 to 18000,
R10 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or a vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative,
a, b, c, d, e, f, g, h, and i represent a content of each substituent, in which a and b range from 0.01 to 1.9, respectively, c, d, e, f, g, h, and i range from 0 to 1.9, respectively, d and f cannot be simultaneously zero, and g, h, and i are simultaneously zero, and a+b+c+d+e+f+g+h+i=2.0, and
n represents a polymerization degree of polyphosphazene, ranging from 5 to 100000.
25. A process for preparing a poly(organophosphazene)-containing hydrogel comprising chemical crosslinkings, which comprises the steps of:
preparing a solution of a poly(organophosphazene) having a structure of Chemical Formula 1-2; and forming chemical crosslinkings in the polymers,
wherein the concentration of the poly(organophosphazene) in the solution of the poly(organophosphazene) ranges from 1 to 50 wt %, and
wherein the chemical crosslinkings are formed between the poly(organophosphazene) having a thiol group and the poly(organophosphazene) having a vinyl group or the polymer having a thiol group by a treatment with at least one additive selected from the group consisting of at least one pH regulator selected from the group consisting of sodium hydroxide, ammonia, potassium hydroxide, triethyl amine, sodium phosphate, trisbase, and HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); at least one catalyst selected from the group consisting of hydrogen peroxide and ammonium peroxide; and an organic solvent in an amount of 1\xd710\u22126 to 30 wt % based on the total weight of the polymer:
in the above formula,
p is from 7 to 50,
in NHCH(R1)CO2R2, R1 is selected from the group consisting of H, CH3, CH2SH, CH2OH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5 and CH2CHCH2,
in NH(R3)(R4)(R5), R3 is CH(W), R4 is selected from the group consisting of CO2, CONHCH(X)CO2CO2, CH2CO2 and CO2CH(CH3)CO2, R5 is selected from the group consisting of H, CH3 and C2H5, wherein each of W and X is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3, and CH2SH,
in XR6, X represents N or O, and R6 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenol derivative compound,
NH(R7)(R8)(R9) is a substituent having a functional group, in which R7 is CH(Y), R8 is selected from the group consisting of CH2, C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, CH2OCOCH2CH2CO, CH2OCOCH2CH2CH2CO, CH2OCOCH2CH2CH2CH2CO, CH2CH2OCOCH2CH2CO, CH2CH2OCOCH2CH2CH2CO, CH2CH2OCOCH2CH2CH2CH2CO, O, CONHCH(Z)O, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(N)CONHCH(L)O, CO, CO2, S, CONHCH(Z), CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, N, CONHCH(Z)N, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, CON, COCHNH(Z)CON, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, CONHCH(Z)CO, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, CONHCH(Z)CO2, COCHNH(Z)CONHCH(M)CO2, COCHNH(Z)CONHCH(M)CONHCH(L)CO2, OCH(CH3)COq, (OCH2CO)q, (OCH(CH3)COq, OCO(CH2)8COq, OCOC6H5O(CH2)3OC6H5COq and OCOC6H5O(CH2)6OC6H5COq, and R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)qH, NHCH(C4H8NH2)COqOH, NHCH(CH2)3C(\u2550NH)(NH2)COqOH, folic acid, hyaluronic acid, cyclodextrin, an imidazole compound, histidine, lysine, arginine, cysteine, thioalkyl amine, spermine, spermidine, TAT peptide, polyethyleneimine, polyhistidine, polylysine, polyarginine, heparin, chitosan, protamine, and a typical protecting group of a functional group,
wherein each of Y, Z, M, and L is independently selected from the group consisting of H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(\u2550NH)NH2, CH2C3N2H3 and CH2SH, and q represents the number of the repeating unit ranging from 1 to 18000,
R10 is a compound that has a thiol group, a vinyl group, tyramine, tyrosine or a phenyl derivative, and is selected either from the group consisting of an acrylate compound, a methacrylate compound, an acrylamide compound, a vinyl sulfone compound, a thiol compound, a cysteine compound, a cisteamine compound, a mercaptic acid compound, an allyl pyrimidine compound and, a compound belonging to one of the foregoing compounds and having a thiol or a vinyl group protected by a protecting group, or from the group consisting of a tyramine compound, a tyrosine compound, and a phenyl derivative,
a, b, c, d, e, f, g, h, and i represent a content of each substituent, in which a and b range from 0.01 to 1.9, respectively, c, d, e, f, g, h, and i range from 0 to 1.9, respectively, d and f cannot be simultaneously zero, and g, h, and i are simultaneously zero, and a+b+c+d+e+f+g+h+i=2.0, and
n represents a polymerization degree of polyphosphazene, ranging from 5 to 100000.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A curved glass pane, comprising float glass,
wherein
an area of a main face is greater than 1.5 m2,
a product of two depths of bending of the glass pane is greater than 3000 mm2,
a point located on the normal to a surface passing through the center of gravity of the glass pane has a radius of curvature of less than 3 m in any direction, and
a variation in the thickness of the glass pane in the longitudinal float direction is less than 10 \u03bcm over 500 mm.
2. The pane of claim 1, wherein the variation in the thickness is less than 7 \u03bcm over 500 mm in the longitudinal float direction.
3. The pane of claim 1, wherein the area of a main face is greater than 1.8 m2.
4. The pane of claim 1, wherein
the product of two depths of bending is greater than 6000 mm2, and
the point located on the normal to a surface passing through the center of gravity has a radius of curvature of less than 2 m in any direction.
5. The pane of claim 1, wherein a thickness of the glass pane ranges from 1.1 to 2.8 mm.
6. A laminated glazing assembly, comprising at least two glass panes of claim 1, wherein float directions of the at least two glass panes are mutually concordant.
7. The glazing assembly of claim 6, wherein a measured level of double imaging:
through the point on the normal to a surface passing through the center of gravity; and
at a viewing angle of 20\xb0,
is at most 7 minutes.
8. A windshield, comprising the glazing of claim 7.
9. A motor vehicle, comprising the windshield of claim 8, wherein a transverse float direction is horizontal.
10. A process for manufacturing the curved glass pane of claim 1, the process comprising bending a pane against a solid mold to give the pane at least 50% of each of the two depths of bending.
11. The process of claim 10, wherein a temperature of the pane at the point located on the normal to a surface passing through the center of gravity is between 590 and 615\xb0 C. during the bending.
12. The process of claim 11, further comprising cooling directly after the bending.
13. The process of claim 10, further comprising a gravity bending before the bending of the pane against the solid mold.
14. The process of claim 13, wherein, during the gravity bending, a temperature of the pane at the point located on the normal to a surface passing through the center of gravity is between 610 and 640\xb0 C.
15. The process of claim 10, wherein at least two superposed glass panes are bent simultaneously.