Claims for Patent: 8,075,916

Summary for Patent: 8,075,916

Title:	Poly(organophosphazene) hydrogels for drug delivery, preparation method thereof and use thereof
Abstract:	A biodegradable and thermosensitive poly(organophosphazene) with a functional group, a preparation method thereof, and a use thereof for delivery of bioactive substances are provided.
Inventor(s):	Song; Soo-Chang (Namyangju-si, KR), Park; Mi-Ran (Seoul, KR), Lee; Sun-Mi (Seoul, KR)
Assignee:	Korea Institute of Science and Technology (Hawolgok-Dong, Seongbuk-Gu, Seoul, KR)
Application Number:	12/122,665
Patent Claims:	1. A poly(organophosphazene) represented by Chemical Formula 1a: ##STR00006## wherein p is the number of repeating units of ethylene glycol ranging from 7 to 50; NHCH(R.sup.1)CO.sub.2R.sup.2 is a hydrophobic amino acid ester, wherein R.sup.1 is selected from the group consisting of H, CH.sub.3, CH.sub.2SH, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.6H.sub.4OH, and CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, and R.sup.2 is selected from the group consisting of CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5, and CH.sub.2CHCH.sub.2; NH(R.sup.3)(R.sup.4)(R.sup.5) is an amino acid, peptide, or depsipeptide ester, wherein R.sup.3 is CH(W), R.sup.4 is selected from the group consisting of CO.sub.2, CO.sub.2CH.sub.2CO.sub.2, CO.sub.2CH(CH.sub.3)CO.sub.2, and CONHCH(X)CO.sub.2, R.sup.5 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, and W and X are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2NH.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH; NH(R.sup.6)(R.sup.7)(R.sup.8) and NH(R.sup.6)(R.sup.7)(R.sup.9) are substituents having a functional group, wherein R.sup.6 is CH(Y), R.sup.7 is selected from the group consisting of CH.sub.2, C.sub.2H.sub.4CO.sub.2, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(L)CONHCH(L)O, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, COCHNH(Z)CONHCH(M)CO.sub.2, and COCHNH(Z)CONHCH(M)CONHCH(L)CO.sub.2, R.sup.8 is selected from the group consisting of OH, SH, H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5 CH.sub.2CHCH.sub.2, and a protecting group, Y, Z, L, and M are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2NH.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH, R.sup.9 is selected from the group consisting of OH, SH, H, NH.sub.2, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5, CH.sub.2CHCH.sub.2, NHCH(SH)CO.sub.2H, NH(CH.sub.2).sub.qSH, NH(CH.sub.2CH.sub.2NH).sub.rH, [NHCH(C.sub.4H.sub.8NH.sub.2)CO].sub.rOH, [NHCH[(CH.sub.2).sub.3C(.dbd.NH)(NH.sub.2)]CO].sub.rOH, folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, chitosan, and protamines, and q is the number of repeating units of methylene ranging from 1 to 20; r is the number of repeating units of ethylenimine, lysine, or arginine, ranging from 1 to 18,000; a.sub.1, a.sub.2, b, c, d, and e respectively represent the content of each substituent, wherein a.sub.1, a.sub.2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a.sub.1+a.sub.2+b+c+d+e=2.0; and n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000. 2. A poly(organophosphazene) represented by Chemical Formula 1b: ##STR00007## wherein, p is the number of repeating units of ethylene glycol ranging from 7 to 50; NHCH(R.sup.1)CO.sub.2R.sup.2 is a hydrophobic amino acid ester, wherein R.sup.1 is selected from the group consisting of H, CH.sub.3, CH.sub.2SH, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.6H.sub.4OH, and CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, and R.sup.2 is selected from the group consisting of CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5, and CH.sub.2CHCH.sub.2; NH(R.sup.3)(R.sup.4)(R.sup.5) is an amino acid, peptide, or depsipeptide ester, wherein R.sup.3 is CH(W), R.sup.4 is selected from the group consisting of CO.sub.2, CO.sub.2CH.sub.2CO.sub.2, CO.sub.2CH(CH.sub.3)CO.sub.2, and CONHCH(X)CO.sub.2, R.sup.5 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, and W and X are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.6, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH; NH(R.sup.6)(R.sup.7)(R.sup.8) and NH(R.sup.6)(R.sup.7)(R.sup.9) are substituents having a functional group, wherein R.sup.6 is CH(Y), R.sup.7 is selected from the group consisting of C.sub.2H.sub.4, C.sub.3H.sub.6, C.sub.4H.sub.8, CH.sub.2C.sub.6H.sub.4, CH.sub.2CO.sub.2, O, CONHCH(Z)O, CO, CO.sub.2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO.sub.2, R.sup.8 is selected from the group consisting of OH, SH, H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5 CH.sub.2CHCH.sub.2, and a protecting group, Y and Z are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH, and R.sup.9 is selected from the group consisting of folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, and chitosan; a.sub.1, a.sub.2, b, c, d, and e respectively represent the content of each substituent, wherein a.sub.1, a.sub.2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a.sub.1+a.sub.2+b+c+d+e=2.0; and n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000. 3. The poly(organophosphazene) according to claim 1, selected from the group consisting of: poly[(glycine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycinephenylalanineleucine)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycylglycine)(glycylglycylprotamine)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycylglycine)(glycylglycyl ethylene heparin)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycylglycine)(glycylglycyl ethylene hyaluronic acid)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)(aminoethylsuccinate PEI)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycinephenylalanineleucine)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)(aminoethylsuccinate ethylene heparin)phosphazene; and poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)(aminoethylsuccinate ethylene hyaluronic acid)phosphazene. 4. A poly(organophosphazene) hydrogel showing sol-gel phase transition depending on temperature and biodegradability, wherein the poly(organophosphazene) according to claim 1 is dissolved in one or more solvents selected from the group consisting of water, a buffer solution, an acid solution, a basic solution, a salt solution, a saline solution, water for injection, and a glucose salt solution, at a concentration of 1 to 50 wt %. 5. A poly(organophosphazene) hydrogel showing sol-gel phase transition depending on temperature and biodegradability, wherein the poly(organophosphazene) according to claim 2 is dissolved in one or more solvents selected from the group consisting of water, a buffer solution, an acid solution, a basic solution, a salt solution, a saline solution, water for injection, and a glucose salt solution, at a concentration of 1 to 50 wt %. 6. A delivery system of a bioactive substance comprising: poly(organophosphazene) according to claim 1, or a poly(organophosphazene) hydrogel comprising a solution where the poly(organophosphazene) according to claim 1 is dissolved in one or more solvents selected from the group consisting of water, a buffer solution, an acid solution, a basic solution, a salt solution, a saline solution, water for injection, and a glucose salt solution, at a concentration of 1 to 50 wt %; and a bioactive substance selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, angiogenesis inhibitors, treating cells, and a combination thereof. 7. The delivery system of a bioactive substance according to claim 6, wherein the proteins, polypeptides, and peptides are one or more selected from the group consisting of erythropoietin (EPO), interferon-alpha, interferon-beta, interferon-gamma, growth hormone, growth hormone releasing factor, nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), blood clotting factor, insulin, oxytocin, vasopressin, adrenocorticotropic hormone, fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-.beta.), nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5, prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, somatostatin, glucagon, interleukin-2 (IL-2), interleukin-11 (IL-11), gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), tumor necrosis factor related apoptosis inducing ligand (TRAIL), heparinase, bone morphogenic protein (BMP), human atrial natriuretic peptide (hANP), glucagon-like peptide (GLP-1), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins, neurotensin, tachykinin, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP), and their synthetic analogs, monoclonal antibodies, antibodies; enzymes; and cytokines. 8. The delivery system of a bioactive substance according to claim 6, wherein the vaccine is hepatitis vaccine. 9. The delivery system of a bioactive substance according to claim 6, wherein the gene is one or more selected from the group consisting of small interference RNA (siRNA), plasmid DNA, and antisense oligodeoxynucleotide (AS-ODN). 10. The delivery system of a bioactive substance according to claim 6, wherein the hormone is one or more selected from the group consisting of testosterone, estradiol, progesterone, prostaglandins. 11. The delivery system of a bioactive substance according to claim 6, wherein the anti-cancer drug is one or more selected from the group consisting of paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, tegafur, irinotecan, docetaxel, cyclophosphamide, cemcitabine, ifosfamide, mitomycin C, vincristine, etoposide, methotrexke, 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, medroxyprogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, actinomycin D, anasterozole, belotecan, imatinib, floxuridine, gemcitabine, hydroxyurea, zoledronate, vincristine, flutamide, valrubicin, streptozocin, polyethylene glycol conjugated anti-cancer agent. 12. The delivery system of a bioactive substance according to claim 6, wherein the angiogenesis inhibitor is one or more selected from the group consisting of BMS-275291, 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, halofuginone hydrobromide, interferon-alpha, bevacizumab, AE-941, interleukin-12, vascular endothelial growth factor-trap (VEFG-trap), cetuximab, rebimastat, S-3304, LY317615, endostatin, vatalanib (PTK787/ZK 222584), sunitinib malate (SU11248), cilenqitide (EMD-121974), humanized monoclonal antibody MEDI-522, EOS-200-4, integrin alpha-5-beta-1 antagonist (ATN-161). 13. The delivery system of a bioactive substance according to claim 6, wherein the treating cell is one or more selected from the group consisting of preosteoblast, chondrocyte, umbilical vein endothelial cell, osteoblast, adult stem cell, schwann cell, oligodendrocyte, hepatocyte, mural cell, myoblast, insulin-secreting cell, endothelial cell, smooth muscle cell, fibroblast, .beta. cell, endodermal cell, hepatic stem cell, juxraglomerular cell, skeletal muscle cell, keratinocyte; melanocyte, Langerhans cell, Merkel cell, dermal fibroblast, and preadipocyte. 14. The delivery system of a bioactive substance according to claim 6, additionally comprising one or more additives selected from the group consisting of cationic polymers having a molecular weight of 200 to 750,000, anionic polymers having a molecular weight of 200 to 750,000, amino acids, peptides, proteins, fatty acids, phospholipids, vitamins, drugs, polyethyleneglycol esters, steroids, amines, acryl-based copolymers, organic solvents, preservatives, sugars, polyols, sugar-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicates, metal salts, and ammonium salts, in the amount of 1.times.10.sup.-6 to 30 wt % based on the total weight of the bioactive substance delivery system. 15. A delivery system of a bioactive substance, comprising: the poly(organophosphazene) represented by Chemical Formula 1b, or a poly(organophosphazene) hydrogel comprising a solution where the poly(organophosphazene) represented by Chemical Formula 1a is dissolved in one or more solvents selected from the group consisting of water, a buffer solution, an acid solution, a basic solution, a salt solution, a saline solution, water for injection, and a glucose salt solution, at a concentration of 1 to 50 wt %; and a bioactive substance selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, angiogenesis inhibitors, treating cells, and a combination thereof: ##STR00008## wherein p is the number of repeating units of ethylene glycol ranging from 7 to 50; NHCH(R.sup.1)CO.sub.2R.sup.2 is a hydrophobic amino acid ester, wherein R.sup.1 is selected from the group consisting of H, CH.sub.3, CH.sub.2SH, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.6H.sub.4OH, and CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, and R.sup.2 is selected from the group consisting of CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.2, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5, and CH.sub.2CHCH.sub.2; NH(R.sup.3)(R.sup.4)(R.sup.5) is an amino acid, peptide, or depsipeptide ester, wherein R.sup.3 is CH(W), R.sup.4 is selected from the group consisting of CO.sub.2, CO.sub.2CH.sub.2CO.sub.2, CO.sub.2CH(CH.sub.3)CO.sub.2, and CONHCH(X)CO.sub.2, R.sup.5 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, and W and X are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH; NH(R.sup.6)(R.sup.7)(R.sup.8) and NH(R.sup.6)(R.sup.7)(R.sup.9) are substituents having a functional group, wherein R.sup.6 is CH(Y), R.sup.7 is selected from the group consisting of CH.sub.2, C.sub.2H.sub.4CO.sub.2, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(L)CONHCH(L)O, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, COCHNH(Z)CONHCH(M)CO.sub.2, and COCHNH(Z)CONHCH(M)CONHCH(L)CO.sub.2, R.sup.8 is selected from the group consisting of OH, SH, H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5CH.sub.2CHCH.sub.2, and a protecting group, Y, Z, L, and M are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH, R.sup.9 is selected from the group consisting of OH, SH, H, NH.sub.2, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH.sub.2C.sub.6H.sub.5, CH.sub.2CHCH.sub.2, NHCH(SH)CO.sub.2H, NH(CH.sub.2).sub.qSH, NH(CH.sub.2CH.sub.2NH).sub.rH, [NHCH(C.sub.4H.sub.8NH.sub.2)CO].sub.rOH, [NHCH[(CH.sub.2).sub.3C(.dbd.NH)(NH.sub.2)]CO].sub.rOH, folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, chitosan, and protamines, and q is the number of repeating units of methylene ranging from 1 to 20; r is the number of repeating units of ethylenimine, lysine, or arginine, ranging from 1 to 18,000; a.sub.1, a.sub.2, b, c, d, and e respectively represent the content of each substituent, wherein a.sub.1, a.sub.2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a.sub.1+a.sub.2+b+c+d+e=2.0; and n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000, ##STR00009## wherein, p is the number of repeating units of ethylene glycol ranging from 7 to 50; NHCH(R.sup.1)CO.sub.2R.sup.2 is a hydrophobic amino acid ester, wherein R.sup.1 is selected from the group consisting of H, CH.sub.3, CH.sub.2SH, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.6H.sub.4OH, and CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, and R.sup.2 is selected from the group consisting of CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5, and CH.sub.2CHCH.sub.2; NH(R.sup.3)(R.sup.4)(R.sup.5) is an amino acid, peptide, or depsipeptide ester, wherein R.sup.3 is CH(W), R.sup.4 is selected from the group consisting of CO.sub.2, CO.sub.2CH.sub.2CO.sub.2, CO.sub.2CH(CH.sub.3)CO.sub.2, and CONHCH(X)CO.sub.2, R.sup.5 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, and W and X are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH; NH(R.sup.6)(R.sup.7)(R.sup.8) and NH(R.sup.6)(R.sup.7)(R.sup.9) are substituents having a functional group, wherein R.sup.6 is CH(Y), R.sup.7 is selected from the group consisting of C.sub.2H.sub.4, C.sub.3H.sub.6, C.sub.4H.sub.8, CH.sub.2C.sub.6H.sub.4, CH.sub.2CO.sub.2, O, CONHCH(Z)O, CO, CO.sub.2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO.sub.2, R.sup.8 is selected from the group consisting of OH, SH, H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5 CH.sub.2CHCH.sub.2, and a protecting group, Y and Z are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH, and R.sup.9 is selected from the group consisting of folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, and chitosan; a.sub.1, a.sub.2, b, c, d, and e respectively represent the content of each substituent, wherein a.sub.1, a.sub.2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a.sub.1+a.sub.2+b+c+d+e=2.0; and n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000. 16. The delivery system of a bioactive substance according to claim 15, wherein the proteins, polypeptides, and peptides are one or more selected from the group consisting of erythropoietin (EPO), interferon-alpha, interferon-beta, interferon-gamma, growth hormone, growth hormone releasing factor, nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), blood clotting factor, insulin, oxytocin, vasopressin, adrenocorticotropic hormone, fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-.beta.), nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5, prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, somatostatin, glucagon, interleukin-2 interleukin-11 (IL-11), gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), tumor necrosis factor related apoptosis inducing ligand (TRAIL), heparinase, bone morphogenic protein (BMP), human atrial natriuretic peptide (hANP), glucagon-like peptide (GLP-1), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins, neurotensin, tachykinin, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP), and their synthetic analogs, monoclonal antibodies, antibodies; enzymes; and cytokines. 17. The delivery system of a bioactive substance according to claim 15, wherein the vaccine is hepatitis vaccine. 18. The delivery system of a bioactive substance according to claim 15, wherein the gene is one or more selected from the group consisting of small interference RNA (siRNA), plasmid DNA, and antisense oligodeoxynucleotide (AS-ODN). 19. The delivery system of a bioactive substance according to claim 15, wherein the hormone is one or more selected from the group consisting of testosterone, estradiol, progesterone, prostaglandins, and their synthetic analogs. 20. The delivery system of a bioactive substance according to claim 15, wherein the anti-cancer drug is one or more 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, medroxyprogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, actinomycin D, anasterozole, belotecan, imatinib, floxuridine, gemcitabine, hydroxyurea, zoledronate, vincristine, flutamide, valrubicin, streptozocin, polyethylene glycol conjugated anti-cancer agent, and their synthetic analogs. 21. The delivery system of a bioactive substance according to claim 15, wherein the angiogenesis inhibitor is one or more selected from the group consisting of BMS-275291, 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, halofuginone hydrobromide, interferon-alpha, bevacizumab, AE-941, interleukin-12, vascular endothelial growth factor-trap (VEFG-trap), cetuximab, rebimastat, S-3304, LY317615, endostatin, vatalanib (PTK787/ZK 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. 22. The delivery system of a bioactive substance according to claim 15, wherein the treating cell is one or more selected from the group consisting of preosteoblast, chondrocyte, umbilical vein endothelial cell, osteoblast, adult stem cell, schwann cell, oligodendrocyte, hepatocyte, mural cell, myoblast, insulin-secreting cell, endothelial cell, smooth muscle cell, fibroblast, .beta. cell, endodermal cell, hepatic stem cell, juxraglomerular cell, skeletal muscle cell, keratinocyte, melanocyte, Langerhans cell, Merkel cell, dermal fibroblast, and preadipocyte. 23. The delivery system of a bioactive substance according to claim 6, additionally comprising one or more additives selected from the group consisting of cationic polymers having a molecular weight of 200 to 750,000, anionic polymers having a molecular weight of 200 to 750,000, amino acids, peptides, proteins, fatty acids, phospholipids, vitamins, drugs, polyethyleneglycol ester, steroids, amines, acryl-based 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.times.10.sup.-6 to 30 wt % based on the total weight of the bioactive substance delivery system. 24. A delivery system of a bioactive substance containing a bioactive substance, and a poly(organophosphazene) represented by the following Chemical Formula 1c, or a hydrogel containing a solution of the poly(organophosphazene) represented by following Chemical Formula 1c, wherein the bioactive substance is one or more selected from the group consisting of: one or more proteins, polypeptides, or peptides selected from the group consisting of exendin-4, fibroblast growth factor (FGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-.beta.), nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5, neurotensin, tachykinin, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and their synthetic analogs, monoclonal antibodies, and antibodies; one or more anti-cancer drugs selected from the group consisting of imatinib, floxuridine, gemcitabine, hydroxyurea, zoledronate, flutamide, valrubicin, and streptozocin; one or more angiogenesis inhibitors selected from the group consisting of rebimastat, matrix metalloproteinases (MMPs) inhibitor (S-3304), protein kinase C beta inhibitor (LY317615), endostatin, vatalanib (PTK787/ZK 222584), sunitinib malate (SU11248), cilenqitide (EMD-121974), humanized monoclonal antibody MEDI-522, EOS-200-4, and integrin alpha-5-beta-1 antagonist (ATN-161); and synthetic analogs thereof, ##STR00010## wherein p ranges from 7 to 50; NHCH(R.sup.1)CO.sub.2R.sup.2 is a hydrophobic amino acid ester, wherein R.sup.1 is selected from the group consisting of H, CH.sub.3, CH.sub.2SH, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.6H.sub.4OH, and CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, and R.sup.2 is selected from the group consisting of CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.5, CH.sub.2C.sub.6H.sub.5, and CH.sub.2CHCH.sub.2; NH(R.sup.3)(R.sup.4)(R.sup.5) is an amino acid, peptide, or depsipeptide ester, wherein R.sup.3 is CH(W), R.sup.4 is selected from the group consisting of CO.sub.2, CO.sub.2CH.sub.2CO.sub.2, CO.sub.2CH(CH.sub.3)CO.sub.2, and CONHCH(X)CO.sub.2, R.sup.5 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, and W and X are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH; NH(R.sup.6)(R.sup.7)(R.sup.8) and NH(R.sup.6)(R.sup.7)(R.sup.9) are substituents having a functional group, wherein R.sup.6 is CH(Y), R.sup.7 is selected from the group consisting of C.sub.2H.sub.4, C.sub.3H.sub.6, C.sub.4H.sub.8, CH.sub.2C.sub.6H.sub.4, CH.sub.2CO.sub.2, O, CONHCH(Z)O, CO, CO.sub.2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO.sub.2, R.sup.8 is selected from the group consisting of OH, SH, H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5 CH.sub.2CHCH.sub.2, and a protecting group, Y and Z are independently selected from the group consisting of H, HCH.sub.2, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2C.sub.6H.sub.5, CH.sub.2C.sub.2H.sub.2C.sub.6H.sub.4, CO.sub.2C.sub.2H.sub.5, (CH.sub.2).sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2OH, CH(CH.sub.3)OH, CH.sub.2C.sub.6H.sub.4OH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CONH.sub.2, C.sub.4H.sub.8NH.sub.2, C.sub.3H.sub.6NHC(.dbd.NH)NH.sub.2, CH.sub.2C.sub.3N.sub.2H.sub.3, and CH.sub.2SH, R.sup.9 is selected from the group consisting of OH, SH, H, NH.sub.2, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.2, C.sub.4H.sub.9, CH.sub.2C.sub.6H.sub.5, CH.sub.2CHCH.sub.2, NHCH(SH)CO.sub.2H, NH(CH.sub.2).sub.qSH, NH(CH.sub.2CH.sub.2NH).sub.rH, [NHCH(C.sub.4H.sub.8NH.sub.2)CO].sub.rOH, [NHCH[(CH.sub.2).sub.3C(.dbd.NH)(NH.sub.2)]CO].sub.rOH, and protamine, q ranges from 1 to 20, and r ranges from 1 to 18,000; a.sub.1, a.sub.z, b, c, d, and e respectively represent the content of each substituent, wherein a.sub.1, a.sub.2, b, and d are independently 0.01 to 1.9, c and e are independently 0 to 1.9, and a.sub.1+a.sub.2+b+c+d+e=2.0; and n ranges from 5 to 100,000. 25. The delivery system of a bioactive substance according to claim 24, additionally comprising one or more additives selected from the group consisting of cationic polymers having a molecular weight of 200 to 750,000, anionic polymers having a molecular weight of 200 to 750,000, amino acids, peptides, proteins, fatty acids, phospholipids, vitamins, drugs, polyethyleneglycol ester, steroids, amines, acryl-based copolymers, organic solvents, preservatives, sugars, polyols, sugar-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicates, metal salts, and ammonium salts, in the amount of 1.times.10.sup.-6 to 30 wt % based on the total weight of the bioactive substance delivery system. 26. The poly(organophosphazene) according to claim 2, selected from the group consisting of: poly[(glycine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycinephenylalanineleucine)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycylglycine)(glycylglycylprotamine)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550))(glycylglycine)(glycylglycyl ethylene heparin)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycylglycine)(glycylglycyl ethylene hyaluronic acid)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)(aminoethylsuccinate PEI)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(glycinephenylalanineleucine)phosphazene; poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)(aminoethylsuccinate ethylene heparin)phosphazene; and poly[(isoleucine ethyl ester)(aminomethoxy polyethylene glycol 550)(aminoethylsuccinate)(aminoethylsuccinate ethylene hyaluronic acid)phosphazene.

Details for Patent 8,075,916

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2027-06-14
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2027-06-14
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2027-06-14