Biodegradable and Thermosensitive Poly(Organophosphazene) Hydrogel, Preparation Method Thereof and Use Thereof
First Claim
1. A poly(organophosphazene) represented by the following Chemical Formula 1:
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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.
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Citations
57 Claims
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1. A poly(organophosphazene) represented by the following Chemical Formula 1:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 22, 23, 24, 25, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)
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2. The poly(organophosphazene) according to claim 1, selected from the group consisting of poly[(phenylalanineethylester)(aminomethoxypolyethyleneglycol350)(lysineethylester)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(lysineethylester)phosphazene], poly[(phenylalanineethylester)(ethyl-2-(O-glycyl)lactate)(aminomethoxypolyethyleneglycol550)], poly[(isoleucineethylester)(ethyl-2-(O-glycyl)glycolate)(aminomethoxyethyleneglycol550)(lysineethylester)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol350)(glycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol350)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycine)phosphazene], poly[(isoleucineethylester)(ethyl-2-(O-glycyl)lactate)(aminomethoxypolyethyleneglycol750)(glycylglycine)phosphazene], and poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)(glycylglycylpolyethyleneimine)phosphazene].
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3. A method for preparing the poly(organophosphazene) according to claim 1, comprising the steps of:
(1) thermopolymerizing a phosphazene trimer represented by the following Chemical Formula 2, to prepare a linear polymer of dichloro phosphazene represented by the following Chemical Formula 3
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4. The method according to claim 3, further comprising a step (6) of dehydrogenating or de-allylesterificating the product of said step (5), when the product of said step (5) contains R8 in Chemical Formula 6 selected from the group consisting of CH2C6H5 and CH2CHCH2.
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5. The method according to claim 3, further comprising a step (7) of reacting the product of said step (5) with one or more selected from lysine, arginine, cystein, thiol alkylamine, polyethyleneimine, polylysine, polyarginine, and protamine.
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6. The method according to claim 3, wherein said step (1) is performed by thermopolymerizing the phosphazene trimer of Chemical Formula 2 with 0.1 to 10 wt % of AlCl3.
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7. The method according to claim 3, wherein in said step (2), said salt of the amino acid ester of Chemical Formula 4 is sulfate or chlorohydrate.
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8. The method according to claim 3, wherein in said step (3), said salt of the compound of Chemical Formula 5 is selected from the group consisting of oxalate, chlorohydrate, and trifluoro acid salt.
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9. The method according to claim 3, wherein in said step (4), said salt of the substituent of Chemical Formula 6 is selected from the group consisting of oxalate, chlorohydrate, and trifluoro acid salt.
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10. The method according to claim 3, wherein after completing step (5), the polyphosphazene molecule is substituted with methoxypolyethyleneglycol through an amine bond.
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11. The method according to claim 4, wherein R8 in Chemical Formula 6 is CH2C6H5, and the dehydrogenation step (6) is performed by dissolving the product of step (5) in ethylalcohol or methylalcohol, adding 50 to 90 wt % of palladium/charcoal or palladium black, and reacting under the presence of 30 to 80 psi of hydrogen gas at 10 to 35°
- C. for 1 to 24 hours to generate a side chain of hydrogen on R8 in Chemical Formula 6 and to prepare the poly(organophosphazene) with carboxylic acid.
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12. The method according to claim 4, wherein R8 in Chemical Formula 6 is CH2CHCH2, and the de-allylesterification step (6) is performed by dissolving the product of step (5) in ethyl tetrahydrofuran and conducting the reaction under the presence of 10 to 20 mol % of tetrakis triphenylphosphin palladium(0) and 10 to 20 equivalents of morpholine at 0°
- C. to 25°
C. for about 1 to 24 hours to generate a side chain of hydrogen on R8 in Chemical Formula 6 and to prepare the poly(organophosphazene) with carboxylic acid.
- C. to 25°
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13. The method according to claim 5, wherein step (7) is performed by reacting the product with carboxylic acid obtained in step (5) or step (6) with one or more selected from lysine, arginine, cystein, thiol alkylamine, polyethyleneimine, polylysine, polyarginines, and protamine having various molecular weights under the presence of 1 to 3 equivalents of dicyclohexyl carbodiimide and 1 to 3 equivalents of hydroxy succinimide at 0°
- C. to 25°
C. for about 1 to 48 hours to prepare the poly(organophosphazene) with a functional group.
- C. to 25°
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14. The method according to claim 3, after respectively completing said step (5), further comprising a purification step comprising the steps of:
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adding ethyl ether, hexane, or a mixed solvent of ethyl ether and hexane to the obtained reaction mixture to form precipitates; filtering the precipitates; dissolving the resulting product in methylalcohol or ethylalcohol; dialyzing the resulting product with methylalcohol or ethylalcohol at 25°
C. for 3 to 10 days,dialyzing the resulting product with distilled water at 4°
C. to 25°
C. for 3 to 10 days;drying the resulting product; and collecting the obtained pure poly(organophosphazene).
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22. A bioactive substance delivery composition containing one or more poly(organophosphazene)s according to claim 1.
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23. The bioactive substance delivery composition according to claim 22, 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.
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24. The bioactive substance delivery composition according to claim 22, further comprising one or more additives in the amount of 1×
- 10−
6 to 30 wt %.
- 10−
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25. The bioactive substance delivery composition according to claim 24, 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-Bu4NBr, n-Pr4NBr, Et4NBr, Mg(OH)2, Ca(OH)2, ZnCO3, Ca3(PO4)2, ZnCl2, (C2H3O2)2Zn, ZnCO3, CdCl2, HgCl2, CoCl2, (CaNO3)2, BaCl2, MgCl2, PbCl2, AlCl3, FeCl2, FeCl3, NiCl2, AgCl, AuCl3, CuCl2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide.
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34. A bioactive substance delivery system containing one or more bioactive substances and one or more poly(organophosphazene)s according to claim 1.
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35. The bioactive substance delivery system according to claim 34, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells.
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36. The bioactive substance delivery system according to claim 35, 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×
- 10−
8 to 50 vol %.
- 10−
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37. The bioactive substance delivery system according to claim 36, 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 may be 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.
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38. The bioactive substance delivery system according to claim 35, 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, β
- -cell, endodermal cell, hepatic stem cell, juxraglomerular cell, skeletal muscle cell, keratinocyte, melanocyte, langerhans cell, merkel cell, dermal fibroblast, and preadipocyte.
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39. The bioactive substance delivery system according to claim 34, further comprising one or more additives in the amount of 1×
- 10−
6 to 30 wt % based on the total weight.
- 10−
-
40. The bioactive substance delivery system according to claim 39, 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-Bu4NBr, n-Pr4NBr, Et4NBr, Mg(OH)2, Ca(OH)2, ZnCO3, Ca3(PO4)2, ZnCl2, (C2H3O2)2Zn, ZnCO3, CdCl2, HgCl2, CoCl2, (CaNO3)2, BaCl2, MgCl2, PbCl2, AlCl3, FeCl2, FeCl3, NiCl2, AgCl, AuCl3, CuCl2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide.
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41. The bioactive substance delivery system according to claim 34, administered through an administration route 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.
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42. The method according to claim 4, further comprising a step (7) of reacting the product of said step (6) with one or more selected from lysine, arginine, cystein, thiol alkylamine, polyethyleneimine, polylysine, polyarginine, and protamine.
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43. The method according to claim 4, after respectively completing said step (6), further comprising a purification step comprising the steps of:
-
adding ethyl ether, hexane, or a mixed solvent of ethyl ether and hexane to the obtained reaction mixture to form precipitates; filtering the precipitates; dissolving the resulting product in methylalcohol or ethylalcohol; dialyzing the resulting product with methylalcohol or ethylalcohol at 25°
C. for 3 to 10 days,dialyzing the resulting product with distilled water at 4°
C. to 25°
C. for 3 to 10 days;drying the resulting product; and collecting the obtained pure poly(organophosphazene).
-
-
44. The method according to claim 5, after respectively completing said step (7), further comprising a purification step comprising the steps of:
-
adding ethyl ether, hexane, or a mixed solvent of ethyl ether and hexane to the obtained reaction mixture to form precipitates; filtering the precipitates; dissolving the resulting product in methylalcohol or ethylalcohol; dialyzing the resulting product with methylalcohol or ethylalcohol at 25°
C. for 3 to 10 days,dialyzing the resulting product with distilled water at 4°
C. to 25°
C. for 3 to 10 days;drying the resulting product; and collecting the obtained pure poly(organophosphazene).
-
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45. The method according to claim 42, after respectively completing said step (7), further comprising a purification step comprising the steps of:
-
adding ethyl ether, hexane, or a mixed solvent of ethyl ether and hexane to the obtained reaction mixture to form precipitates; filtering the precipitates; dissolving the resulting product in methylalcohol or ethylalcohol; dialyzing the resulting product with methylalcohol or ethylalcohol at 25°
C. for 3 to 10 days,dialyzing the resulting product with distilled water at 4°
C. to 25°
C. for 3 to 10 days;drying the resulting product; and collecting the obtained pure poly(organophosphazene).
-
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2. The poly(organophosphazene) according to claim 1, selected from the group consisting of poly[(phenylalanineethylester)(aminomethoxypolyethyleneglycol350)(lysineethylester)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(lysineethylester)phosphazene], poly[(phenylalanineethylester)(ethyl-2-(O-glycyl)lactate)(aminomethoxypolyethyleneglycol550)], poly[(isoleucineethylester)(ethyl-2-(O-glycyl)glycolate)(aminomethoxyethyleneglycol550)(lysineethylester)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol350)(glycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol350)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)phosphazene], poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycine)phosphazene], poly[(isoleucineethylester)(ethyl-2-(O-glycyl)lactate)(aminomethoxypolyethyleneglycol750)(glycylglycine)phosphazene], and poly[(isoleucineethylester)(aminomethoxypolyethyleneglycol550)(glycylglycine)(glycylglycylpolyethyleneimine)phosphazene].
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15. A poly(organophosphazene) hydrogel containing poly(organophosphazene) of the following Chemical Formula 1-1 dissolved in one or more solvents and showing sol-gel phase transition depending on temperature change:
- View Dependent Claims (16, 46, 47, 48, 49)
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16. The hydrogel according to claim 15, 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 %.
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46. A bioactive substance delivery composition containing one or more poly(organophosphazene) hydrogels according to claim 15.
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47. The bioactive substance delivery composition according to claim 46, 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.
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48. The bioactive substance delivery composition according to claim 46, further comprising one or more additives in the amount of 1×
- 10−
6 to 30 wt %.
- 10−
-
49. The bioactive substance delivery composition according to claim 48, 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-Bu4NBr, n-Pr4NBr, Et4NBr, Mg(OH)2, Ca(OH)2, ZnCO3, Ca3(PO4)2, ZnCl2, (C2H3O2)2Zn, ZnCO3, CdCl2, HgCl2, CoCl2, (CaNO3)2, BaCl2, MgCl2, PbCl2, AlCl3, FeCl2, FeCl3, NiCl2, AgCl, AuCl3, CuCl2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide.
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16. The hydrogel according to claim 15, 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 %.
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17. A bioactive substance delivery composition containing biodegradable polymer or a polymer hydrogel containing the biodegradable polymer, and one or more additives,
wherein the biodegradable polymer forms a gel-phase at body temperature, and the polymer hydrogel is biodegradable and forms a gel-phase at body temperature and contains the polymer dissolved in a solvent selected from the group consisting of water, buffer solution, acid solution, basic solution, salt solution, saline solution, water for injection, and glucose salt solution with the concentration of 1 to 50 wt %. - View Dependent Claims (18, 19, 20, 21, 50, 51, 52, 53, 54, 55, 56, 57)
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18. The bioactive substance delivery composition according to claim 17, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells.
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19. The bioactive substance delivery composition according to claim 18, wherein the drug is selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, and angiogenesis inhibitors.
-
20. The bioactive substance delivery composition according to claim 17, wherein the content of the one or more additives is 1×
- 10−
6 to 30 wt % based on the total weight of the composition.
- 10−
-
21. The bioactive substance delivery composition according to claim 20, 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-Bu4NBr, n-Pr4NBr, Et4NBr, Mg(OH)2, Ca(OH)2, ZnCO3, Ca3(PO4)2, ZnCl2, (C2H3O2)2Zn, ZnCO3, CdCl2, HgCl2, CoCl2, (CaNO3)2, BaCl2, MgCl2, PbCl2, AlCl3, FeCl2, FeCl3, NiCl2, AgCl, AuCl3, CuCl2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide.
-
50. A bioactive substance delivery system containing one or more bioactive substances and one or more poly(organophosphazene) hydrogels according to claim 19.
-
51. The bioactive substance delivery system according to claim 50, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells.
-
52. The bioactive substance delivery system according to claim 51, 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×
- 10−
8 to 50 vol %.
- 10−
-
53. The bioactive substance delivery system according to claim 52, 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 may be 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.
-
-
54. The bioactive substance delivery system according to claim 51, 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, β
- -cell, endodermal cell, hepatic stem cell, juxraglomerular cell, skeletal muscle cell, keratinocyte, melanocyte, langerhans cell, merkel cell, dermal fibroblast, and preadipocyte.
-
55. The bioactive substance delivery system according to claim 50, further comprising one or more additives in the amount of 1×
- 10−
6 to 30 wt % based on the total weight.
- 10−
-
56. The bioactive substance delivery system according to claim 55, 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-Bu4NBr, n-Pr4NBr, Et4NBr, Mg(OH)2, Ca(OH)2, ZnCO3, Ca3(PO4)2, ZnCl2, (C2H3O2)2Zn, ZnCO3, CdCl2, HgCl2, CoCl2, (CaNO3)2, BaCl2, MgCl2, PbCl2, AlCl3, FeCl2, FeCl3, NiCl2, AgCl, AuCl3, CuCl2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide.
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57. The bioactive substance delivery system according to claim 50, administered through an administration route 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.
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18. The bioactive substance delivery composition according to claim 17, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells.
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26. A bioactive substance delivery system containing the biodegradable polymer or a polymer hydrogel containing the biodegradable polymer, a bioactive substance, and one or more additives,
wherein the biodegradable polymer forms a gel-phase at body temperature, and the polymer hydrogel is biodegradable and forms a gel-phase at body temperature and contains the polymer dissolved in a solvent selected from the group consisting of water, buffer solution, acid solution, basic solution, salt solution, saline solution, water for injection, and glucose salt solution with the concentration of 1 to 50 wt %. - View Dependent Claims (27, 28, 29, 30, 31, 32, 33)
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27. The bioactive substance delivery system according to claim 26, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells.
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28. The bioactive substance delivery system according to claim 27, 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×
- 10−
8 to 50 vol %.
- 10−
-
29. The bioactive substance delivery system according to claim 28, 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 may be 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.
-
-
30. The bioactive substance delivery system according to claim 27, 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, β
- -cell, endodermal cell, hepatic stem cell, juxraglomerular cell, skeletal muscle cell, keratinocyte, melanocyte, langerhans cell, merkel cell, dermal fibroblast, and preadipocyte.
-
31. The bioactive substance delivery system according to claim 26, wherein the content of the one or more additives is from 1×
- 10−
6 to 30 wt % based on the total weight.
- 10−
-
32. The bioactive substance delivery system according to claim 31, 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-Bu4NBr, n-Pr4NBr, Et4NBr, Mg(OH)2, Ca(OH)2, ZnCO3, Ca3(PO4)2, ZnCl2, (C2H3O2)2Zn, ZnCO3, CdCl2, HgCl2, CoCl2, (CaNO3)2, BaCl2, MgCl2, PbCl2, AlCl3, FeCl2, FeCl3, NiCl2, AgCl, AuCl3, CuCl2, sodium tetradecyl sulfate, dodecyltrimethylammonium bromide, dodecyltrmethylammonium chloride, and tetradecyltrimethylammonium bromide.
-
33. The bioactive substance delivery system according to claim 26, administered through an administration route 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.
-
27. The bioactive substance delivery system according to claim 26, wherein the bioactive substance is one or more selected from the group consisting of drugs and therapeutic cells.
Specification
- Resources
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Current AssigneeKIST
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Original AssigneeKIST
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InventorsPark, Mi-Ran, Song, Soo-Chang, Lee, Sun-Mi, Kim, Chang-Won
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current424/85.200
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CPC Class CodesA61K 47/34 Macromolecular compounds ob...A61K 47/6903 the form being semi-solid, ...A61K 9/0024 Solid, semi-solid or solidi...A61K 9/06 Ointments; Bases therefor; ...A61K 9/08 Solutions composition of so...A61P 35/00 Antineoplastic agentsC08G 79/025 Polyphosphazenes