Claims for Patent: 9,526,699

Summary for Patent: 9,526,699

Title:	Biodegradable and thermosensitive poly(organophosphazene) hydrogel, preparation method thereof and use thereof
Abstract:	The present invention relates to a biodegradable and thermosensitive poly(organophosphazene) with a functional group, a preparation method thereof, and a use thereof for delivery of bioactive substances. According to the present invention, poly(organophosphazene) is a phosphagen-based polymer showing biodegradability, thermosensitivity, and sol-gel phase transition depending on temperature change, whereby when administered into a living body with bioactive substances such as drugs, the poly(organophosphazene) forms a gel-phase at body temperature to be capable of controlled release of the bioactive substances. Further, the poly(organophosphazene) has functional groups to chemically bind with bioactive substances through an ionic bond, covalent bond, or coordinate covalent bond to be capable of a sustained release of the bioactive substances due to its good binding property. Therefore, the poly(organophosphazene) is useful as a delivery material for bioactive substances.
Inventor(s):	Song; Soo-Chang (Namyangju, KR), Lee; Sun-Mi (Busan, KR), Kim; Chang-Won (Seoul, KR), Park; Mi-Ran (Seoul, KR)
Assignee:	KIST (Seoul, KR)
Application Number:	11/568,851
Patent Claims:	1. A poly(organophosphazene) selected from the group consisting of: poly[(isoleucineethylester).sub.a1(isoleucineethylester).sub.a2(aminometh- oxypolyethyleneglycol350).sub.b(glycine).sub.dphosphazene].sub.n, poly[(isoleucineethylester).sub.a1(isoleucineethylester).sub.a2(aminometh- oxypolyethyleneglycol550).sub.b(glycylleucine).sub.dphosphazene].sub.n, poly[(isoleucineethylester).sub.a1(isoleucineethylester).sub.a2(aminometh- oxypolyethyleneglycol550).sub.b(glycine).sub.dphosphazene].sub.n, poly[(isoleucineethylester).sub.a1(isoleucineethylester).sub.a2(ethyl-2-(- O-glycyl)lactate).sub.c(aminomethoxypolyethyleneglycol750).sub.b(glycylgly- cine).sub.dphosphazene].sub.n, and poly[isoleucineethylester).sub.a1(isoleucineethylester).sub.a2(aminometho- xypolyethyleneglycol550).sub.b(glycylglycine).sub.d(glycylglycylpolyethyle- neimine).sub.ephosphazene].sub.n, wherein a1, a2, b, c, d, and e respectively represent the content of each substituent, a1, a2, b, and d are independently selected from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a1+a2+b+c+d+e=2.0, and n is from 5 to 100000. 2. A poly(organophosphazene) hydrogel containing the poly(organophosphazene) of claim 1 dissolved in one or more solvents and showing sol-gel phase transition depending on temperature change. 3. The hydrogel according to claim 2, wherein the solvent is one or more selected from the group consisting of water, buffer solution, acid solution, basic solution, salt solution, saline solution, water for injection, and glucose salt solution, and the concentration of the poly(organophosphazene) is from 1 to 50 wt %. 4. A bioactive substance delivery composition containing one or more poly(organophosphazene)s according to claim 1. 5. The bioactive substance delivery composition according to claim 4, wherein the bioactive substance is a drug selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, and angiogenesis inhibitors. 6. The bioactive substance delivery composition according to claim 4, further comprising one or more additives in the amount of 1.times.10.sup.-6 to 30 wt %. 7. The bioactive substance delivery composition according to claim 6, wherein the additive is one or more selected from the group consisting of cationic polymers having the molecular weight from 200 to 750,000, poly(N-vinyl-2-pyrrolidone), polyvinylacetate (PVA), hyaluronic acid, chondroitin sulfate, heparin, alginate, amiloride, procainamide, acetyl-beta-methylcholine, spermine, spermidine, lysozyme, fibroin, albumin, collagen, growth factors, bone morphogenetic proteins (BMPs), dexamethason, fibronectin, fibrinogen, thrombin, proteins, cremophor EL, dexrazoxane, leucovorin, ricinoleic acid, phospholipid, small intestinal submucosa, vitamin E, polyglycerol ester of fatty acid, Labrafil, Labrafil M1944CS, citric acid, glutamic acid, hydroxypropyl methylcellulose, gelatin, isopropyl myristate, Eudragit, tego betain, dimyristoylphosphatidylcholine, scleroglucan, ethanol, dimethyl sulfoxide, preservatives, sugars, polyols, sugar-containing polyols, amino acids, polymer-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicate, NaCl, KCl, NaBr, NaI, LiCl, n-Bu.sub.4NBr, n-Pr.sub.4NBr, Et.sub.4NBr, Mg(OH).sub.2, Ca(OH).sub.2, ZnCO.sub.3, Ca.sub.3(PO.sub.4).sub.2, ZnCl.sub.2, (C.sub.2H3O.sub.2).sub.2Zn, ZnCO.sub.3, CdCl.sub.2, HgCl.sub.2, CoCl.sub.2, (CaNO.sub.3).sub.2, BaCl.sub.2, MgCl.sub.2, PbCl.sub.2, AlCl.sub.3, FeCl.sub.2, FeCl.sub.3, NiCl.sub.2, AgCl, AuCl.sub.3, CuCl.sub.2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide. 8. A bioactive substance delivery system containing one or more bioactive substances and one or more poly(organophosphazene)s according to claim 1. 9. The bioactive substance delivery system according to claim 8, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells. 10. The bioactive substance delivery system according to claim 9, wherein the drug is selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, and angiogenesis inhibitors and the content of the drug is from 1.times.10.sup.-8 to 50 vol %. 11. The bioactive substance delivery system according to claim 10, wherein the protein, polypeptide, or peptide is one or more selected from the group consisting of erythropoietin (EPO), interferon-alpha, interferon-beta, interferon-gamma, growth hormone (human, pig, cow, etc.), 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, epidermal growth factor, platelet-derived growth factor (PDGF), 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 and synthetic analogs thereof, monoclonal antibody, antibody, a substance which is modified or shows the same effect of a drug, ferment, and cytokines; the vaccine is one or more selected from the group consisting of hepatitis vaccine; the gene is one or more selected from the group consisting of small interference RNA (siRNA), plasmid DNA, and antisense oligodeoxynucleotide (AS-ODN); the hormone is one or more selected from the group consisting of testosterone, estradiol, progesterone, prostaglandins and synthetic analogs thereof, and a substance which is modified or shows the same effect of a drug; 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, medroxypogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, actinomycin D, polyethylene glycol conjugated protein, and synthetic analogs thereof, and a substance which is modified or shows the same effect of a drug; and the angiogenesis inhibitor is one or more selected from the group consisting of BMS-275291, Clodronate, 6-deoxy-6-demethyl-4-dedimethylaminotetracycline, Doxycycline, Marimastat, 2-Methoxyestradiol, Squalamine, SU5164, Thalidomide, TNP-470, Combretastatin A4, Soy Isoflavone, Enzastaurin, CC 5013, Celecoxib, ZD 6474, Halofuginone hydrobromide, interferon-alpha, Bevacizumab, AE-941, Interleukin-12, VEFG-trap, Cetuximab, and synthetic analogs thereof, and a substance which is modified or shows the same effect of a drug. 12. The bioactive substance delivery system according to claim 9, wherein the therapeutic cell is one or more selected from the group consisting of preosteoblast, chondrocyte, umbilical vein endothelial cell (UVEC), osteoblast, adult stem cell, schwann cell, oligodendrocyte, hepatocyte, mural cell (used in combination with UVEC), 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. 13. The bioactive substance delivery system according to claim 8, further comprising one or more additives in the amount of 1.times.10.sup.-6 to 30 wt % based on the total weight. 14. The bioactive substance delivery system according to claim 13, wherein the additive is one or more selected from the group consisting of cationic polymers having the molecular weight from 200 to 750,000, poly(N-vinyl-2-pyrrolidone), polyvinylacetate (PVA), hyaluronic acid, chondroitin sulfate, heparin, alginate, amiloride, procainamide, acetyl-beta-methylcholine, spermine, spermidine, lysozyme, fibroin, albumin, collagen, growth factors, bone morphogenetic proteins (BMPs), dexamethason, fibronectin, fibrinogen, thrombin, proteins, cremophor EL, dexrazoxane, leucovorin, ricinoleic acid, phospholipid, small intestinal submucosa, vitamin E, polyglycerol ester of fatty acid, Labrafil, Labrafil M1944CS, citric acid, glutamic acid, hydroxypropyl methylcellulose, gelatin, isopropyl myristate, Eudragit, tego betain, dimyristoylphosphatidylcholine, scleroglucan, ethanol, dimethyl sulfoxide, preservatives, sugars, polyols, sugar-containing polyols, amino acids, polymer-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicate, NaCl, KCl, NaBr, NaI, LiCl, n-Bu.sub.4NBr, n-Pr.sub.4NBr, Et.sub.4NBr, Mg(OH).sub.2, Ca(OH).sub.2, ZnCO.sub.3, Ca.sub.3(PO.sub.4).sub.2, ZnCl.sub.2, (C.sub.2H3O.sub.2).sub.2Zn, ZnCO.sub.3, CdCl.sub.2, HgCl.sub.2, CoCl.sub.2, (CaNO.sub.3).sub.2, BaCl.sub.2, MgCl.sub.2, PbCl.sub.2, AlCl.sub.3, FeCl.sub.2, FeCl.sub.3, NiCl.sub.2, AgCl, AuCl.sub.3, CuCl.sub.2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide. 15. The bioactive substance delivery system according to claim 8, wherein an administration route for delivery is selected from the group consisting of oral administration, buccal administration, mucosal administration, nasal administration, intraperitoneal administration, hypodermic injection, muscular injection, percutaneous administration, and intratumoral administration. 16. A bioactive substance delivery composition containing one or more poly(organophosphazene) hydrogels according to claim 2. 17. The bioactive substance delivery composition according to claim 16, wherein the bioactive substance is a drug selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, and angiogenesis inhibitors. 18. The bioactive substance delivery composition according to claim 16, further comprising one or more additives in the amount of 1.times.10.sup.-6 to 30 wt %. 19. The bioactive substance delivery composition according to claim 18, wherein the additive is one or more selected from the group consisting of cationic polymers having the molecular weight from 200 to 750,000, poly(N-vinyl-2-pyrrolidone), polyvinylacetate (PVA), hyaluronic acid, chondroitin sulfate, heparin, alginate, amiloride, procainamide, acetyl-beta-methylcholine, spermine, spermidine, lysozyme, fibroin, albumin, collagen, growth factors, bone morphogenetic proteins (BMPs), dexamethason, fibronectin, fibrinogen, thrombin, proteins, cremophor EL, dexrazoxane, leucovorin, ricinoleic acid, phospholipid, small intestinal submucosa, vitamin E, polyglycerol ester of fatty acid, Labrafil, Labrafil M1944CS, citric acid, glutamic acid, hydroxypropyl methylcellulose, gelatin, isopropyl myristate, Eudragit, tego betain, dimyristoylphosphatidylcholine, scleroglucan, ethanol, dimethyl sulfoxide, preservatives, sugars, polyols, sugar-containing polyols, amino acids, polymer-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicate, NaCl, KCl, NaBr, NaI, LiCl, n-Bu.sub.4NBr, n-Pr.sub.4NBr, Et.sub.4NBr, Mg(OH).sub.2, Ca(OH).sub.2, ZnCO.sub.3, Ca.sub.3(PO.sub.4).sub.2, ZnCl.sub.2, (C.sub.2H3O.sub.2).sub.2Zn, ZnCO.sub.3, CdCl.sub.2, HgCl.sub.2, CoCl.sub.2, (CaNO.sub.3).sub.2, BaCl.sub.2, MgCl.sub.2, PbCl.sub.2, AlCl.sub.3, FeCl.sub.2, FeCl.sub.3, NiCl.sub.2, AgCl, AuCl.sub.3, CuCl.sub.2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide. 20. A bioactive substance delivery system containing one or more bioactive substances and one or more poly(organophosphazene) hydrogels according to claim 2. 21. The bioactive substance delivery system according to claim 20, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells. 22. The bioactive substance delivery system according to claim 21, wherein the drug is selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, and angiogenesis inhibitors and the content of the drug is from 1.times.10.sup.-8 to 50 vol %. 23. The bioactive substance delivery system according to claim 22, wherein the protein, polypeptide, or peptide is one or more selected from the group consisting of erythropoietin (EPO), interferon-alpha, interferon-beta, interferon-gamma, growth hormone (human, pig, cow), 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, epidermal growth factor, platelet-derived growth factor (PDGF), 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 and synthetic analogs thereof, monoclonal antibody, antibody, a substance which is modified or shows the same effect of a drug, ferment, and cytokines; the vaccine is one or more selected from the group consisting of hepatitis vaccine; the gene is one or more selected from the group consisting of small interference RNA (siRNA), plasmid DNA, and antisense oligodeoxynucleotide (AS-ODN); the hormone is one or more selected from the group consisting of testosterone, estradiol, progesterone, prostaglandins and synthetic analogs thereof, and a substance which is modified or shows the same effect of a drug; 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, medroxypogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, actinomycin D, polyethylene glycol conjugated protein, and synthetic analogs thereof, and a substance which is modified or shows the same effect of a drug; and the angiogenesis inhibitor is one or more selected from the group consisting of BMS-275291, Clodronate, 6-deoxy-6-demethyl-4-dedimethylaminotetracycline, Doxycycline, Marimastat, 2-Methoxyestradiol, Squalamine, SU5164, Thalidomide, TNP-470, Combretastatin A4, Soy Isoflavone, Enzastaurin, CC 5013, Celecoxib, ZD 6474, Halofuginone hydrobromide, interferon-alpha, Bevacizumab, AE-941, Interleukin-12, VEFG-trap, Cetuximab, and synthetic analogs thereof, and a substance which is modified or shows the same effect of a drug. 24. The bioactive substance delivery system according to claim 21, wherein the therapeutic cell is one or more selected from the group consisting of preosteoblast, chondrocyte, umbilical vein endothelial cell (UVEC), osteoblast, adult stem cell, schwann cell, oligodendrocyte, hepatocyte, mural cell (used in combination with UVEC), 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. 25. The bioactive substance delivery system according to claim 20, further comprising one or more additives in the amount of 1.times.10.sup.-6 to 30 wt % based on the total weight. 26. The bioactive substance delivery system according to claim 25, wherein the additive is one or more selected from the group consisting of cationic polymers having the molecular weight from 200 to 750,000, poly(N-vinyl-2-pyrrolidone), polyvinylacetate (PVA), hyaluronic acid, chondroitin sulfate, heparin, alginate, amiloride, procainamide, acetyl-beta-methylcholine, spermine, spermidine, lysozyme, fibroin, albumin, collagen, growth factors, bone morphogenetic proteins (BMPs), dexamethason, fibronectin, fibrinogen, thrombin, proteins, cremophor EL, dexrazoxane, leucovorin, ricinoleic acid, phospholipid, small intestinal submucosa, vitamin E, polyglycerol ester of fatty acid, Labrafil, Labrafil M1944CS, citric acid, glutamic acid, hydroxypropyl methylcellulose, gelatin, isopropyl myristate, Eudragit, tego betain, dimyristoylphosphatidylcholine, scleroglucan, ethanol, dimethyl sulfoxide, preservatives, sugars, polyols, sugar-containing polyols, amino acids, polymer-containing polyols, sugar-containing amino acids, surfactants, sugar-containing ions, silicate, NaCl, KCl, NaBr, NaI, LiCl, n-Bu.sub.4NBr, n-Pr.sub.4NBr, Et.sub.4NBr, Mg(OH).sub.2, Ca(OH).sub.2, ZnCO.sub.3, Ca.sub.3(PO.sub.4).sub.2, ZnCl.sub.2, (C.sub.2H3O.sub.2).sub.2Zn, ZnCO.sub.3, CdCl.sub.2, HgCl.sub.2, CoCl.sub.2, (CaNO.sub.3).sub.2, BaCl.sub.2, MgCl.sub.2, PbCl.sub.2, AlCl.sub.3, FeCl.sub.2, FeCl.sub.3, NiCl.sub.2, AgCl, AuCl.sub.3, CuCl.sub.2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide. 27. The bioactive substance delivery system according to claim 20, wherein an administration route for delivery is selected from the group consisting of oral administration, buccal administration, mucosal administration, nasal administration, intraperitoneal administration, hypodermic injection, muscular injection, percutaneous administration, and intratumoral administration.

Details for Patent 9,526,699

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Hoffmann-la Roche Inc.	ROFERON-A	interferon alfa-2a	For Injection	103145	06/04/1986		2026-01-18
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2026-01-18
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2026-01-18
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2026-01-18