KR100259367B1 - Thermosensitive degradable polyphosphagens and their preparation method - Google Patents
Thermosensitive degradable polyphosphagens and their preparation method Download PDFInfo
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- KR100259367B1 KR100259367B1 KR1019980023695A KR19980023695A KR100259367B1 KR 100259367 B1 KR100259367 B1 KR 100259367B1 KR 1019980023695 A KR1019980023695 A KR 1019980023695A KR 19980023695 A KR19980023695 A KR 19980023695A KR 100259367 B1 KR100259367 B1 KR 100259367B1
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- 238000002360 preparation method Methods 0.000 title description 23
- 229920000642 polymer Polymers 0.000 claims abstract description 51
- -1 environment Substances 0.000 claims abstract description 37
- 229920002627 poly(phosphazenes) Polymers 0.000 claims abstract description 22
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 239000000047 product Substances 0.000 claims description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- 235000001014 amino acid Nutrition 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002244 precipitate Substances 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 238000000502 dialysis Methods 0.000 claims description 6
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical group NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 claims description 4
- 235000003704 aspartic acid Nutrition 0.000 claims description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 claims description 3
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000002861 polymer material Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- 229940000635 beta-alanine Drugs 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 150000001804 chlorine Chemical class 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 235000013922 glutamic acid Nutrition 0.000 claims 1
- 239000004220 glutamic acid Substances 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 239000011557 critical solution Substances 0.000 abstract description 10
- 230000035945 sensitivity Effects 0.000 abstract description 8
- 238000000354 decomposition reaction Methods 0.000 abstract description 6
- 238000012377 drug delivery Methods 0.000 abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 3
- 239000002537 cosmetic Substances 0.000 abstract description 2
- 239000012567 medical material Substances 0.000 abstract description 2
- CSCSROFYRUZJJH-UHFFFAOYSA-N 1-methoxyethane-1,2-diol Chemical compound COC(O)CO CSCSROFYRUZJJH-UHFFFAOYSA-N 0.000 description 42
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 23
- 229920002632 poly(dichlorophosphazene) polymer Polymers 0.000 description 22
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 8
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229920006237 degradable polymer Polymers 0.000 description 3
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 3
- 238000005227 gel permeation chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001309 chloro group Chemical class Cl* 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000009477 glass transition Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- OIOXLUPGUCZKSV-UHFFFAOYSA-N sodium;2-(2-methoxyethoxy)ethanolate Chemical compound [Na+].COCCOCC[O-] OIOXLUPGUCZKSV-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- WJKJXKRHMUXQSL-UHFFFAOYSA-N benzyl glycinate 4-methylbenzenesulfonate salt Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.NCC(=O)OCC1=CC=CC=C1 WJKJXKRHMUXQSL-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000000160 carbon, hydrogen and nitrogen elemental analysis Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- GLFVNTDRBTZJIY-UHFFFAOYSA-N diethyl 2-aminopropanedioate;hydron;chloride Chemical compound Cl.CCOC(=O)C(N)C(=O)OCC GLFVNTDRBTZJIY-UHFFFAOYSA-N 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- RJCGNNHKSNIUAT-UHFFFAOYSA-N ethyl 3-aminopropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)CCN RJCGNNHKSNIUAT-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000012719 thermal polymerization Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
- C08G79/02—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing phosphorus
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
- C08L83/10—Block- or graft-copolymers containing polysiloxane sequences
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
Abstract
다음 화학식 1로 표시되는 폴리포스파젠계 고분자 및 그의 제조방법이 제공된다.The polyphosphazene-based polymer represented by the following formula (1) and a manufacturing method thereof are provided.
[화학식 1][Formula 1]
본 발명에 따른 폴리포스파젠계 고분자는 온도감응성과 생체분해성을 동시에 가지므로 약물전달시스템을 중심으로 하는 의료용재료분야, 환경분야 및 화장품분야와 같은 다양한 분야에서 응용이 가능하며, 분자내 메톡시폴리에틸렌 및 아미노산에스테르의 조성, 메톡시폴리에틸렌글리콜의 분자량, 아미노산에스테르의 종류에 따라 폴리포스파젠계 고분자의 저임계용액온도와 분해속도를 응용목적에 맞게 조절할 수 있다.Since the polyphosphazene polymer according to the present invention has both temperature sensitivity and biodegradability, the polyphosphazene-based polymer can be applied in various fields such as medical materials, environment, and cosmetics centered on drug delivery system. And according to the composition of the amino acid ester, the molecular weight of methoxy polyethylene glycol, the type of amino acid ester can be adjusted to the low-critical solution temperature and decomposition rate of the polyphosphazene-based polymer according to the application purpose.
Description
본 발명은 온도감응성과 분해성을 갖는 신규 폴리포스파젠계 고분자와 그 제조방법에 관한 것이다. 더욱 구체적으로는 다음 화학식 1로 표시되는 온도감응성 및 분해성을 동시에 갖는 폴리포스파젠계 고분자와 그 제조방법에 관한 것이다.The present invention relates to a novel polyphosphazene-based polymer having a temperature sensitivity and degradability and a method of manufacturing the same. More specifically, the present invention relates to a polyphosphazene-based polymer having both temperature sensitivity and degradability represented by the following Chemical Formula 1 and a method of manufacturing the same.
[화학식 1][Formula 1]
(식 중, NHA는 아미노산기로서 글라이신기(-NHCH2COO-), 알라닌기(-NHCH(CH3)COO-), β-알라닌기(-NHCH2CH2COO-), 아미노말론산기(-NHCH(COO-)2), 아스파르트산기(-NHCH(CH2COO-)COO-), 및 글루타민산기(-NHCH(CH2COO-)COO-)중에서 선택되며, R은 메틸기, 에틸기 및 벤질기중에서 선택되고, m은 폴리에틸렌글리콜의 반복단위로서 2, 7 및 16중에서 선택된 정수이고, x는 폴리에틸렌글리콜의 몰 함량으로서 0.2∼1.8의 값을 가지며, n은 폴리포스파젠의 중합도로서 10∼100의 값을 갖는다. 본 발명자들은 폴리디클로로포스파젠을 폴리에틸렌글리콜과 아미노산에스테르로 치환함으로써 얻어지는 폴리포스파젠계 고분자들이 일정온도 이하에서는 물에 녹지만 일정온도를 초과하면 물에 용해되지 않는 온도감응성을 나타내며 수용액중에서 서서히 수분해됨을 발견하였다. 온도감응성 고분자라 함은 수용액중에서 온도변화에 따른 급격한 고분자의 용해도 차이에 의해 상이 전이되는 고분자를 말하는데 액상에서 고체 또는 액상에서 겔로 변한다. 이때 일정 온도이하에서는 액상이고 그 온도를 초과하며 고체 또는 겔로 변할 때 이 때의 온도를 저임계용액온도(LCST)라고 하며, 이와 반대로 일정 온도 이상에서 액상이고 그 온도 미만에서 고체 또는 겔로 변할 때 이때의 온도를 고임계용액온도(UCST)라고 하는데, 주로 LCST형태의 고분자가 주류를 이루고 있다 (K. Park, Controlled Drug Delivery, 485 (1997)). 온도감응성 고분자는 고분자골격에 결합되어 있는 소수성기와 친수성기의 균형에 따라 저임계용액온도가 변하며 일반적으로 친수성기의 함량이 증가하면 상전이 온도가 올라가고 소수성기가 증가하면 반대로 상전이 온도가 내려간다. 이러한 온도감응성 고분자는 약물전달시스템을 중심으로 하는 의료용 재료분야, 환경 분야, 화장품 분야등 다양한 분야에서 응용연구가 활발히 진행되고 있다. 예를 들면 온도감응성 고분자겔에 각종 약물을 담지시킨 후에 온도를 변화시킴으로써 약물의 방출속도를 제어하는 연구(T. Okano외, Controlled Release, 11, 255 (1990)), 온도감응성 고분자를 효소에 결합시켜 온도감응성 효소를 제조하여 효소반응 후에 온도를 변화시킴으로써 생성물과 효소를 쉽게 분리할 수 있음에 따라 반응효율을 높이는 연구(Z. Ding외, Bioconjugate Chem, 7, 121 (1996)) 등을 들 수 있다. 현재까지 수십 종류의 온도감응성 고분자들이 보고되어 있다. 폴리(N-이소프로필 아크릴아미드) 또는 이들의 공중합체는 가장 널리 연구되어지고 있는 온도감응성 고분자 재료로 저임계용액온도가 33.2℃이기 때문에 약물전달체계에 많이 응용되고 있다 (E. Kokufuta외, Macromolecules, 26, 1053(1993)). 이외에도 폴리에틸렌옥시드 공중합체, 히드록시계 고분자 그리고 몇 종류의 폴리포스파젠계 고분자도 보고되었다. 그러나 이들 거의 대부분이 비분해성 고분자로서 약물전달시스템용 재료로서 응용되기에는 한계가 있다는 지적을 받고 있다. 그 이유는 비분해성 고분자를 인체에 투여했을 경우 분해되지 않고 인체에 축적되기 때문에 독성을 나타낼 가능성이 있기 때문이다. 따라서 생체내에서 분해될 수 있는 온도감응성 고분자의 개발이 요구되어 왔다.(In the formula, glycine is NHA group (-NHCH 2 COO as amino group-), alanine group (-NHCH (CH 3) COO -), β- alanine group (-NHCH 2 CH 2 COO -) , amino malonic acid ( -NHCH (COO -) 2), aspartic acid (-NHCH (CH 2 COO -) COO -) , and the glutamate group (-NHCH (CH 2 COO -) COO -) is selected from, R represents a methyl group, an ethyl group, and benzyl M is an integer selected from 2, 7 and 16 as repeating units of polyethylene glycol, x has a value of 0.2 to 1.8 as the molar content of polyethylene glycol, and n is 10 to 100 as the degree of polymerization of polyphosphazene. The present inventors have shown that the polyphosphazene-based polymers obtained by substituting polydichlorophosphazene with polyethylene glycol and amino acid esters dissolve in water below a certain temperature but do not dissolve in water above a certain temperature. It was found to hydrolyze slowly in aqueous solution. A sensitized polymer is a polymer whose phase transitions due to the rapid change in solubility of the polymer in an aqueous solution, which changes from liquid to solid or from liquid to gel under a certain temperature. The temperature at this time is called the low critical solution temperature (LCST). On the contrary, the temperature at this time is called the high critical solution temperature (UCST) when the liquid is above a certain temperature and becomes solid or gel below that temperature. (K. Park, Controlled Drug Delivery, 485 (1997)). The temperature sensitive polymer has a low critical solution temperature that varies with the balance of hydrophobic and hydrophilic groups bound to the polymer backbone. If this increases, the phase transition temperature rises, and if the hydrophobic group increases, the phase transition temperature decreases. Such temperature-sensitive polymers is becoming an Applied actively in various fields such as medical materials field, environmental field, cosmetic field as a drug delivery system. For example, studies on controlling the release rate of drugs by varying the temperature after supporting various drugs in a thermosensitive polymer gel (T. Okano et al., Controlled Release, 11, 255 (1990)), combining thermosensitive polymers with enzymes To increase the reaction efficiency as the product can be easily separated from the enzyme by changing the temperature after the enzymatic reaction (Z. Ding et al., Bioconjugate Chem, 7, 121 (1996)). have. Dozens of temperature sensitive polymers have been reported to date. Poly (N-isopropyl acrylamide) or copolymers thereof are the most widely studied temperature-sensitive polymer materials and are widely used in drug delivery systems because of the low critical solution temperature of 33.2 ° C (E. Kokufuta et al., Macromolecules , 26, 1053 (1993). In addition, polyethylene oxide copolymers, hydroxy polymers and several types of polyphosphazene polymers have also been reported. However, most of them are pointed out that there is a limit to being applied as a material for drug delivery system as a non-degradable polymer. The reason is that when non-degradable polymers are administered to the human body, they may be toxic because they do not decompose and accumulate in the human body. Therefore, the development of a temperature-sensitive polymer that can be degraded in vivo has been required.
따라서, 본 발명의 목적은 온도감응성을 가지면서 생체분해성이 있는 새로운 폴리포스파젠계 고분자를 제공하는 것이다.Accordingly, an object of the present invention is to provide a new polyphosphazene-based polymer having temperature sensitivity and biodegradability.
더욱 구체적으로 본 발명의 목적은 폴리디클로로포스파젠을 메톡시폴리에틸렌글리콜과 아미노산에스테르로 치환함으로써 온도감응성과 생체분해성이 동시에 부여됨과 함께, 이들 특성의 제어가 가능한 폴리포스파젠계 고분자 및 그 제조방법을 제공하는 것이다.More specifically, an object of the present invention is to provide a polyphosphazene-based polymer and a method of manufacturing the same, which are endowed with temperature sensitivity and biodegradability by substituting polydichlorophosphazene with methoxy polyethylene glycol and amino acid ester, and which can control these characteristics. To provide.
이같은 목적을 달성하기 위해 본 발명자들은 폴리디클로로포스파젠을 서로 다른 분자량의 친수성 메톡시폴리에틸렌 글리콜을 먼저 반응시킨 다음 여러 종류의 소수성 아미노산에스테르를 친핵치환반응시켜 다양한 온도감응성과 분해성을 동시에 갖는 폴리스파젠계 고분자를 합성할 수 있음을 발견하였다. 특히 본 발명에 따른 이들 폴리파스포젠계 고분자의 저임계용액온도와 분해속도는 메톡시폴리에틸렌 및 아미노산에스테르의 조성, 메톡시폴리에틸렌글리콜의 분자량, 아미노산에스테르의 종류등에 따라 달라지기 때문에 폴리포스파젠계 고분자의 저임계용액온도와 분해속도를 응용목적에 맞게 조절할 수 있다.In order to achieve the above object, the present inventors first react polydichlorophosphazene with hydrophilic methoxypolyethylene glycol having different molecular weight and then nucleophilic substitution reaction of various hydrophobic amino acid esters to have various temperature sensitivity and degradability simultaneously. It has been found that polymers can be synthesized. In particular, the low-critical solution temperature and decomposition rate of these polypaspogen-based polymers according to the present invention depend on the composition of the methoxy polyethylene and amino acid esters, the molecular weight of the methoxy polyethylene glycol, the type of the amino acid ester, and the like. The low critical solution temperature and decomposition rate can be adjusted to suit the application.
화학식 1로 표시되는 대표적인 폴리포스파젠계 고분자의 제조방법을 좀 더 구체적으로 설명하면 다음과 같다. 화학식 1의 최종제품은 공기중의 수분에 대하여 매우 안정하지만 중간체들은 대부분 특히 수분에 민감하므로 모든 제조 과정은 수분이 들어가지 않도록 진공 및 질소 라인을 이용하여 수행하였으며, 반응에 사용한 용매, 테트라히드로퓨란, 벤젠, 또는 톨루엔도 수분을 철저히 제거한 후 사용하였다. 먼저 화학식 2의 포스파젠 삼합체 (N=PCl2)3로부터 문헌의 방법으로 (Y. S. Sohn 외, Macromolecules, 28, 7566 (1955)) 열중합시켜 화학식 3의 폴리디클로로포스파젠 선형중합체를 얻는다.Hereinafter, a method for preparing a representative polyphosphazene polymer represented by Chemical Formula 1 will be described in more detail. The final product of Formula 1 is very stable against moisture in the air, but most of the intermediates are particularly sensitive to moisture, so all the manufacturing processes were carried out using vacuum and nitrogen lines to prevent moisture from entering. The solvent used for the reaction, tetrahydrofuran , Benzene, or toluene was also used after thoroughly removing moisture. First, a polydichlorophosphazene linear polymer of formula 3 is obtained by thermal polymerization of phosphazene trimer (N = PCl 2 ) 3 of formula ( 2 ) by the method of literature (YS Sohn et al., Macromolecules, 28, 7566 (1955)).
[화학식 2][Formula 2]
[화학식 3][Formula 3]
(식 중, n은 중합도로서 10∼100임)(Wherein n is 10 to 100 as the degree of polymerization)
한편, 화학식 4의 폴리에틸렌글리콜모노메틸에테르를 벤젠과 함께 70∼80℃에서 공비하여 과량의 물을 제거한 후 80∼90℃의 기름 중탕에서 진공으로 3일 동안 건조시킨 후 반응에 사용하였다.Meanwhile, the polyethyleneglycol monomethyl ether of Formula 4 was azeotrope with benzene at 70 to 80 ° C. to remove excess water, and then dried in vacuum in an oil bath at 80 to 90 ° C. for 3 days, and then used for the reaction.
[화학식 4][Formula 4]
(식 중 m은 2, 7 및 16 중에서 선택된 정수임)(Where m is an integer selected from 2, 7 and 16)
[화학식 5][Formula 5]
(식 중 m은 2, 7 및 16 중에서 선택된 정수임)(Where m is an integer selected from 2, 7 and 16)
이렇게 건조된 화학식 4의 화합물을 트리에틸아민 존재하에 화학식 3의 화합물과 직접 반응시키거나 또는 화학식 4의 화합물을 알카리금속인 나트륨과 반응시켜 화학식 5의 알콕시드형으로 만든 후 화학식 3의 화합물과 반응시킨다. 화학식 5에서 m은 화학식 1의 화합물에 대해 정의한 바와 같다. 화학식 3 및 화학식 4의 화합물을 직접반응시킬 경우 원하는 공중합체의 조성에 따라 폴리포스파젠단위체에 대하여 0.2∼1.8당량의 화학식 4의 화합물을 가한 후 화학식 4의 화합물 2 당량에 해당하는 트리에틸아민을 넣고 상온에서 10∼24시간 반응시킨다. 화학식 3의 화합물과 화학식 5의 알콕시드형 화합물을 반응시킬 경우에는 화학식 4의 화합물을 1.5당량의 나트륨 또는 수소화나트륨과 테트라히드로퓨란(THF), 벤젠 또는 톨루엔용매에서 반응시켜 화학식 5의 알콕시드형 화합물로 만든 후 이것을 같은 용매에 녹인 화학식 3의 폴리디클로로포스파젠 용액에 적가하여 상온에서 약3∼15시간동안 반응시킨다. 여기에 미치환된 염소에 대하여 2당량의 화학식 6의 아미노산에스테르와 3당량의 트리에틸아민을 같은 용매에 녹인 용액을 적가하여 상온에서 약 3∼15시간 동안 반응시킨다. 여기에 미치환된 염소에 대하여 2당량의 화학식 6의 아미노산에 스테르와 3당량의 트리에틸아민을 같은 용매에 녹인 용액을 적가하여 상온에서 1일 반응시킨 후 계속해서 50℃에서 1∼3일 정도 반응시킨다. 화학식 6에서 NHA와 R은 화학식 1에서 정의한 바와 같다.The dried compound of formula 4 is reacted directly with the compound of formula 3 in the presence of triethylamine, or the compound of formula 4 is reacted with sodium, which is an alkali metal, to form an alkoxide form of formula 5 and then reacted with the compound of formula 3 . M in Formula 5 is as defined for the compound of Formula 1. In the case of directly reacting the compound of Formula 3 and Formula 4, 0.2-1.8 equivalents of the compound of Formula 4 is added to the polyphosphazene unit according to the composition of the desired copolymer, and then triethylamine corresponding to 2 equivalents of the compound of Formula 4 is added. Put and react for 10 to 24 hours at room temperature. When the compound of Formula 3 is reacted with the alkoxide compound of Formula 5, the compound of Formula 4 is reacted with 1.5 equivalents of sodium or sodium hydride in tetrahydrofuran (THF), benzene or toluene solvent to give an alkoxide compound of Formula 5 After making it, it was added dropwise to the polydichlorophosphazene solution of Formula 3 dissolved in the same solvent and reacted at room temperature for about 3 to 15 hours. To the unsubstituted chlorine, a solution of 2 equivalents of the amino acid ester of Formula 6 and 3 equivalents of triethylamine in the same solvent is added dropwise and reacted at room temperature for about 3 to 15 hours. To the unsubstituted chlorine, 2 equivalents of an amino acid represented by the formula (6) was added dropwise with a solution of sterol and 3 equivalents of triethylamine in the same solvent, followed by 1 day of reaction at room temperature, followed by 1-3 days at 50 ° C. React to degree. In Formula 6, NHA and R are as defined in Formula 1.
[화학식 6][Formula 6]
(식 중, NHA와 R은 화학식 1에서 정의된 바와 같다)Wherein NHA and R are as defined in formula (1)
반응용액을 원심분리 또는 여과하여 생성된 과량의 침전물들(Et3NㆍHCl 또는 NaCl)을 제거하고 여액은 용매가 조금 남을때까지 감압농축한다. 여기에 과량의 에테르 또는 헥산을 가하여 침전을 유도한다. 이 과정을 2∼3회 반복한 후 침전물을 소량의 증류수에 녹여 투석막(MWCO:3500)으로 2일 동안 증류수에서 투석한 다음 화학식 1의 최종고분자 생성물을 얻는다. 본 발명의 제조공정을 다음에 반응식 1로 표시하였다.The reaction solution is centrifuged or filtered to remove excess precipitates (Et 3 N.HCl or NaCl) and the filtrate is concentrated under reduced pressure until some solvent remains. Excess ether or hexane is added thereto to induce precipitation. After repeating this process 2 to 3 times, the precipitate is dissolved in a small amount of distilled water and dialyzed in distilled water for 2 days with a dialysis membrane (MWCO: 3500) to obtain a final polymer product of Chemical Formula 1. The manufacturing process of the present invention is represented by the following Scheme 1.
[반응식 1]Scheme 1
다음에 실시예를 들어 본 발명을 더욱 상세히 설명하나 본 발명의 범위는 특허청구의 범위를 벗어나지 않는 한 이들 실시예로 한정되지 않는다.The present invention will be described in more detail with reference to the following Examples, but the scope of the present invention is not limited to these Examples unless the claims depart from the scope of the claims.
본 발명의 화합물에 대한 탄소, 수소, 질소 원소분석은 본원 특성분석센터의 Perkin-Elmer C, H, N 분석기에 의해 수행하였다. 한편, 수소 및 인 핵자기 공명 스펙트럼은 Varian Gemini-300을, 유리전이온도(Tg)는 Du Pont 1090 시차열분석를, 평균분자량(Mw)은 Waters 510펌프 및 410 미분굴절계의 겔투과크로마토그래피를, 저임계용액온도는 Perkin-Elmer Lamda18 UV/VIS 스펙트로미터를 각각 사용하여 측정하였다.Carbon, hydrogen and nitrogen elemental analysis of the compound of the present invention was performed by Perkin-Elmer C, H, N analyzer of the characterization center of the present application. Hydrogen and phosphorus nuclear magnetic resonance spectra were Varian Gemini-300, glass transition temperature (T g ) was analyzed by Du Pont 1090 differential thermal analysis, and average molecular weight (Mw) was gel permeation chromatography of Waters 510 pump and 410 fine refractometer. The low critical solution temperature was measured using a Perkin-Elmer Lamda18 UV / VIS spectrometer, respectively.
[실시예 1]Example 1
폴리[2-(2'-메톡시에톡시)에톡시)(글라이신에틸에스테르)포스파젠],Poly [2- (2'-methoxyethoxy) ethoxy) (glycineethylester) phosphazene],
[NP(OCH2CH2)2OCH3)1.10(NHCH2COOC2H5)0.90]n의 제조Preparation of [NP (OCH 2 CH 2 ) 2 OCH 3 ) 1.10 (NHCH 2 COOC 2 H 5 ) 0.90 ] n
2-(2'-메톡시에톡시)에톡시드 나트륨염은 2-(2'-메톡시에톡시)에탄올(2.07g, 17.26mmol)과 나트륨금속조각(0.59g, 25.84mmol)을 건조된 테트라히드로퓨란용매에 넣고 질소 기류하에서 48시간 환류하여 제조 하였다. 폴리(디클로로포스파젠)(2.00g, 17.26mmol)을 같은 용매에 녹인 다음 드라이아이스-아세톤중탕에 넣고 앞서 제조된 2-(2'-메톡시에톡시)에톡시드 나트륨염용액을 적가하였다. 30분 후 드라이아이스-아세톤 중탕을 제거하고 상온에서 5시간 반응시킨 다음 이 용액에 트리에틸아민(10.48g, 103.59mmol)을 넣고 글라이신에틸에스테르의 염화수소염(4.82g, 34.52mmol)을 가한 후 상온에서 12시간 반응시킨 후 다시 50℃로 올려 48시간 반응시켰다. 반응용액을 원심분리 또는 여과하여 생서된 과량의 침전물들(Et3NㆍHCl 또는 NaCl)을 제거하고 여액은 용매가 조금 남을때까지 감압농축한다. 여기에 과량의 에테르 또는 헥산을 가하여 침전을 유도한다. 이 과정을 2∼3회 반복한 후 침전물을 소량의 증류수에 녹여 투석막(MWCO:3500)으로 2일 동안 증류수에서 투석한 다음 동결건조하여 최종고분자 생성물 [NP(OCH2CH2)2OCH3)1.10(NHCH2COOC2H5)0.90]n를 2.64g(수율, 55.5%) 얻었다.2- (2'-methoxyethoxy) ethoxide sodium salt was prepared by drying 2- (2'-methoxyethoxy) ethanol (2.07 g, 17.26 mmol) and sodium metal flakes (0.59 g, 25.84 mmol). In a hydrofuran solvent it was prepared by refluxing for 48 hours under a nitrogen stream. Poly (dichlorophosphazene) (2.00 g, 17.26 mmol) was dissolved in the same solvent, and then put into dry ice-acetone bath, and a 2- (2'-methoxyethoxy) ethoxide sodium salt solution prepared above was added dropwise. After 30 minutes, the dry ice-acetone bath was removed and reacted at room temperature for 5 hours. Then, triethylamine (10.48g, 103.59mmol) was added to the solution, and hydrogen chloride (4.82g, 34.52mmol) of glycine ethyl ester was added thereto. After reacting for 12 hours at 50 ° C., the reaction was carried out for 48 hours. The reaction solution is centrifuged or filtered to remove excess precipitates (Et 3 N.HCl or NaCl) and the filtrate is concentrated under reduced pressure until some solvent remains. Excess ether or hexane is added thereto to induce precipitation. After repeating this process 2-3 times, the precipitate was dissolved in a small amount of distilled water and dialyzed in distilled water for 2 days with a dialysis membrane (MWCO: 3500), followed by freeze drying to obtain the final polymer product [NP (OCH 2 CH 2 ) 2 OCH 3 ). 1.10 (NHCH 2 COOC 2 H 5 ) 0.90 ] n was obtained at 2.64 g (yield, 55.5%).
인 핵자기 공명 스펙트럼(acetone-d6, ppm) : δ23.11Phosphorus nuclear magnetic resonance spectrum (acetone-d 6 , ppm): δ 23.11
유리전이온도(Tg) : -60.6℃Glass transition temperature (T g ): -60.6 ℃
저임계용액온도 : 39.5℃Low critical solution temperature: 39.5 ℃
[실시예 2]Example 2
폴리[폴리(메톡시에틸렌글리콜)(글라이신메틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine methyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.00(NHCH2COOCH3)1.00]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.00 (NHCH 2 COOCH 3 ) 1.00 ] n
먼저 폴리(메톡시에틸렌글리콜)에톡시드 나트륨염을 분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.44g, 18.98mmol)을 건조된 테트라히드로퓨란용매에 넣고 질소 기류하에서 48시간 환류하여 제조 하였다. 폴리(디클로로포스파젠)(2.00g, 17.26mmol)을 테트라히드로퓨란용매에 녹인 다음 드라이아이스-아세톤 중탕에 넣고 앞서 제조된 폴리(메톡시에틸렌글리콜)에톡시드 나트륨염용액을 적가하였다. 30분 후 드라이아이스-아세톤 중탕을 제거하고 상온에서 5시간 반응시킨 다음 이 용액에 트리에틸아민(10.47g, 130.46mmol)을 넣고 글라이신 메틸에스테르 염화수소염(4.33g, 34.52mmol)을 가한 후 상온에서 12시간 반응시킨 후 다시 50℃로 올려 48시간 반응시켰다. 반응용액을 원심분리 또는 여과하여 생성된 과량의 침전물들((Et3NㆍHCl 또는 NaCl)을 제거하고 여액은 용매가 조금 남을때까지 감압농축하였다. 여기에 과량의 에테르 또는 헥산을 가하여 침전을 유도한다. 이 과정을 2∼3회 반복한 후 침전물을 소량의 증류수에 녹여 투석막(MWCO:3500)으로 2일 동안 증류수에서 투석한 다음 동결건조하여 최종 고분자 생성물[NP(OCH2CH2)7OCH3)1.00(NHCH2COOCH3)1.00]n를 5.20g(수율, 62.0%) 얻었다.First, poly (methoxyethylene glycol) ethoxide sodium salt was added to poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) and sodium metal fragment (0.44 g, 18.98 mmol) having a molecular weight of 350 in a dried tetrahydrofuran solvent. It was prepared by refluxing for 48 hours under a nitrogen stream. Poly (dichlorophosphazene) (2.00 g, 17.26 mmol) was dissolved in a tetrahydrofuran solvent and then placed in a dry ice-acetone bath, and the poly (methoxyethylene glycol) ethoxide sodium salt solution prepared above was added dropwise. After 30 minutes, dry ice-acetone bath was removed and reacted at room temperature for 5 hours. Triethylamine (10.47g, 130.46mmol) was added to this solution, and glycine methyl ester hydrogen chloride (4.33g, 34.52mmol) was added thereto. After reacting for 12 hours, the reaction mixture was further heated to 50 ° C. for 48 hours. Excess precipitates (Et 3 N.HCl or NaCl) were removed by centrifugation or filtration of the reaction solution, and the filtrate was concentrated under reduced pressure until some solvent was left. Excess ether or hexane was added thereto to induce precipitation. After repeating this process 2-3 times, the precipitate was dissolved in a small amount of distilled water, dialyzed in distilled water for 2 days with dialysis membrane (MWCO: 3500), and then lyophilized to obtain the final polymer product [NP (OCH 2 CH 2 ) 7 OCH. 3 ) 1.00 (NHCH 2 COOCH 3 ) 1.00 ] n was obtained by 5.20 g (yield, 62.0%).
[실시예 3]Example 3
폴리[폴리(메톡시에틸렌글리콜)(글라이신에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine ethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.30(NHCH2COOC2H5)1.70]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.30 (NHCH 2 COOC 2 H 5 ) 1.70 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(1.21g, 3.45mmol)과 나트륨금속조각(0.12g, 5.19mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(18.86g, 186.34mmol), 글라이신에틸에스테르 염화수소염(8.67g, 62.13mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물[NP(OCH2CH2)7OCH3)0.30(NHCH2COOC2H5)1.70]n를 2.14g(수율, 37.0%) 얻었다.Poly (methoxyethylene glycol) ethanol (1.21 g, 3.45 mmol) with a molecular weight of 350, sodium metal chips (0.12 g, 5.19 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (18.86 g, 186.34 mmol), glycine ethyl ester hydrogen chloride (8.67 g, 62.13 mmol) in the same manner as in Example 2 the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.30 (NHCH 2 COOC 2 H 5 ) 1.70 ] n was obtained in 2.14 g (yield, 37.0%).
[실시예 4]Example 4
폴리[폴리(메톡시에틸렌글리콜)(글라이신에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine ethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.50(NHCH2COOC2H5)1.50]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.50 (NHCH 2 COOC 2 H 5 ) 1.50 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(1.21g, 3.45mmol)과 나트륨금속조각(0.29g, 12.9mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(15.72g, 155.39mmol), 글라이신에틸에스테르 염화수소염(7.23g, 51.77mmol)을 사용하여 실시예 2와 같은 방법으로 [NP(OCH2CH2)7OCH3)0.50(NHCH2COOC2H5)1.50]n를 5.82g(수율, 88.9%) 얻었다.Poly (methoxyethylene glycol) ethanol (1.21 g, 3.45 mmol) with a molecular weight of 350, sodium metal chips (0.29 g, 12.9 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (15.72 g, 155.39 mmol), glycine ethyl ester hydrogen chloride (7.23 g, 51.77 mmol) was obtained in the same manner as in Example 2 [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.50 (NHCH 2 COOC 2 H 5 ) 1.50 ] n 5.82 g (yield, 88.9%) was obtained.
[실시예 5]Example 5
폴리[폴리(메톡시에틸렌글리콜)(글라이신에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine ethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.01(NHCH2COOC2H5)0.99]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.01 (NHCH 2 COOC 2 H 5 ) 0.99 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol), 나트륨금속조각(0.44g, 18.98mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.48g, 103.59mmol), 글라이신에틸에스테르 염화수소염(4.82g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 [NP(OCH2CH2)7OCH3)1.01(NHCH2COOC2H5)0.99]n를 4.58g(수율, 52.9%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal chips (0.44 g, 18.98 mmol), 2.00 g (17.26 mmol) of poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol), glycine ethyl ester hydrogen chloride (4.82 g, 34.52 mmol) was prepared in the same manner as in Example 2 [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.01 (NHCH 2 COOC 2 H 5 ) 0.99 ] n 4.58 g (yield, 52.9%) was obtained.
[실시예 6]Example 6
폴리[폴리(메톡시에틸렌글리콜)(글라이신에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine ethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.30(NHCH2COOC2H5)0.70]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.30 (NHCH 2 COOC 2 H 5 ) 0.70 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(9.06g, 25.89mmol)과 나트륨금속조각(0.79g, 34.52mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(2.61g, 25.79mmol), 글라이신에틸에스테르 염화수소염(1.20g, 8.63mmol)을 사용하여 실시예 2와 같은 방법으로 [NP(OCH2CH2)7OCH3)1.30(NHCH2COOC2H5)0.70]n를 7.96g(수율, 80.0%) 얻었다.Poly (methoxyethylene glycol) ethanol (9.06 g, 25.89 mmol) with a molecular weight of 350, sodium metal chips (0.79 g, 34.52 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (2.61 g, 25.79 mmol), glycine ethyl ester hydrogen chloride (1.20 g, 8.63 mmol) was prepared in the same manner as in Example 2 [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.30 (NHCH 2 COOC 2 H 5 ) 0.70 ] n 7.96 g (yield, 80.0%) was obtained.
[실시예 7]Example 7
폴리[폴리(메톡시에틸렌글리콜)(글라이신메틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine methyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.40(NHCH2COOC2H5)0.60]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.40 (NHCH 2 COOC 2 H 5 ) 0.60 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(10.75g, 30.20mmol)과 나트륨금속조각(0.67g, 29.34mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(5.24g, 51.79mmol), 글라이신에틸에스테르 염화수소염(2.41g, 17.26mmol)을 사용하여 실시예 2와 같은 방법으로 [NP(OCH2CH2)7OCH3)1.40(NHCH2COOC2H5)0.60]n를 4.93g(수율, 47.6%) 얻었다.Poly (methoxyethylene glycol) ethanol (10.75 g, 30.20 mmol) with a molecular weight of 350, sodium metal chips (0.67 g, 29.34 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (5.24 g, 51.79 mmol), glycineethylester hydrogen chloride (2.41 g, 17.26 mmol) was used in the same manner as in Example 2 [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.40 (NHCH 2 COOC 2 H 5 ) 0.60 ] n 4.93 g (yield, 47.6%) was obtained.
[실시예 8]Example 8
폴리[폴리(메톡시에틸렌글리콜)(글라이신벤질에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine benzyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.99(NHCH2COOCH2C6H5)1.01]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.99 (NHCH 2 COOCH 2 C 6 H 5 ) 1.01 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.44g, 18.98mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.47g, 103.51mmol), 글라이신벤질에스테르 p-톨루엔술폰산염(11.64g, 34.5mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)0.99(NHCH2COOCH2C6H6)1.01]n를 7.74g(수율, 79.5%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal fragment (0.44 g, 18.98 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (10.47 g, 103.51 mmol), and glycinebenzyl ester p-toluenesulfonate (11.64 g, 34.5 mmol) in the same manner as in Example 2 to obtain the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.99 (NHCH 2 COOCH 2 C 6 H 6 ) 1.01 ] n obtained 7.74 g (yield, 79.5%).
[실시예 9]Example 9
폴리[폴리(메톡시에틸렌글리콜)(글라이신에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (glycine ethyl ester) phosphazene],
[NP(OCH2CH2)16OCH3)1.00(NHCH2COOC2H5)1.00]n의 제조Preparation of [NP (OCH 2 CH 2 ) 16 OCH 3 ) 1.00 (NHCH 2 COOC 2 H 5 ) 1.00 ] n
분자량750의 폴리(메톡시에틸렌글리콜)에탄올(12.94g, 17.26mmol)과 나트륨금속조각(0.59g, 25.88mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.48g, 103.59mmol), 글라이신에틸에스테르 염화수소염(4.82g, 34.52mmol)를 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)16OCH3)1.00(NHCH2COOC2H5)1.00]n를 11.84g(수율, 76.4%) 얻었다.Poly (methoxy ethylene glycol) ethanol (12.94 g, 17.26 mmol) with a molecular weight of 750, sodium metal chips (0.59 g, 25.88 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol), glycine ethyl ester hydrogen chloride (4.82 g, 34.52 mmol) in the same manner as in Example 2 the final polymer product [NP (OCH 2 CH 2 ) 16 OCH 3 ) 1.00 (NHCH 2 COOC 2 H 5 ) 1.00 ] n was obtained 11.84g (yield, 76.4%).
[실시예 10]Example 10
폴리[폴리(메톡시에틸렌글리콜)(알라닌에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (alanine ethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.96(NHCH(CH3)COOC2H5)1.04]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.96 (NHCH (CH 3 ) COOC 2 H 5 ) 1.04 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.48g, 103.59mmol), 알라닌에틸에스테르 염화수소염(5.31g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)0.96(NHCH(CH3)COOC2H5)1.04]n를 6.77g(수율, 76.1%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal fragment (0.59 g, 25.89 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol) and alanine ethyl ester hydrogen chloride (5.31 g, 34.52 mmol) in the same manner as in Example 2 to obtain the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.96 (NHCH (CH 3 ) COOC 2 H 5 ) 1.04 ] n obtained 6.77 g (yield, 76.1%).
[실시예 11]Example 11
폴리[폴리(메톡시에틸렌글리콜)(알라닌에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (alanine ethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.03(NHCH2COOC2H5)0.97]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.03 (NHCH 2 COOC 2 H 5 ) 0.97 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.48g, 103.59mmol), β-알라닌에틸에스테르 염화수소염(5.31g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.03(NHCH2COOC2H5)0.97]n를 4.27g(수율, 48.0%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal fragment (0.59 g, 25.89 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol), β-alanine ethyl ester hydrogen chloride (5.31 g, 34.52 mmol) in the same manner as in Example 2 the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.03 (NHCH 2 COOC 2 H 5 ) 0.97 ] n was obtained 4.27 g (yield, 48.0%).
[실시예 12]Example 12
폴리[폴리(메톡시에틸렌글리콜)(아미노말로네이토일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (aminomalonytoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.03(NHCH(COOC2H5)2)0.97]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.03 (NHCH (COOC 2 H 5 ) 2 ) 0.97 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.59g, 25.88mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(10.48g, 103.59mmol), 아미노말로네이트디에틸에스테르 염화수소염(7.30g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.03(NHCH(COOC2H5)2)0.97]n를 7.13g(수율, 72.0%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal chips (0.59 g, 25.88 mmol), poly (dichlorophosphazene) (2.00 g, 17.26 mmol), triethylamine (10.48 g) , 103.59 mmol), the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.03 (NHCH (COOC) in the same manner as in Example 2 using aminomalonate diethyl ester hydrogen chloride (7.30 g, 34.52 mmol) 2 H 5 ) 2 ) 0.97 ] n to obtain 7.13 g (yield, 72.0%).
[실시예 13]Example 13
폴리[2-(2'-메톡시에톡시)에톡시(L-아스파르토일디에틸에스테르)포스파젠],Poly [2- (2'-methoxyethoxy) ethoxy (L-aspartoyldiethylester) phosphazene],
[NP(OCH2CH2)2OCH3)1.00(NHCH(COOC2H5)COOC2H5)1.00]n의 제조Preparation of [NP (OCH 2 CH 2 ) 2 OCH 3 ) 1.00 (NHCH (COOC 2 H 5 ) COOC 2 H 5 ) 1.00 ] n
2-(2'-메톡시에톡시)에탄올(2.07g, 17.26mmol)과 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(10.48g, 103.59mmol), L-아스파르토일디에틸에스테르 염화수소염(7.79g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)2OCH3)1.00(NHCH(CH2COOC2H5)COOC2H5)1.00]n를 2.43g(수율, 41.5%) 얻었다.2- (2'-methoxyethoxy) ethanol (2.07g, 17.26mmol), sodium metal chips (0.59g, 25.89mmol), poly (dichlorophosphazene) (2.00g, 17.26mmol), triethylamine (10.48 g, 103.59 mmol), and L-aspartoyldiethyl ester hydrogen chloride (7.79 g, 34.52 mmol) in the same manner as in Example 2 to obtain the final polymer product [NP (OCH 2 CH 2 ) 2 OCH 3 ) 1.00 ( NHCH (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.00 ] n was obtained in 2.43 g (yield, 41.5%).
[실시예 14]Example 14
폴리[폴리(메톡시에틸렌글리콜)(L-아스파르토일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-aspartoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.00(NHCH(CH2COOCH3)COOCH3)1.00]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.00 (NHCH (CH 2 COOCH 3 ) COOCH 3 ) 1.00 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol), 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(10.48g, 103.59mmol), L-아스파르토일디에틸에스테르 염화수소염(6.82g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.00(NHCH(CH2COOCH3)COOCH3)1.00]n를 7.73g(수율, 80.0%) 얻었다.Molecular weight 350 poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol), sodium metal chips (0.59 g, 25.89 mmol), poly (dichlorophosphazene) (2.00 g, 17.26 mmol), triethylamine (10.48 g , 103.59 mmol), the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.00 (NHCH) in the same manner as in Example 2 using L-aspartoyldiethylester hydrogen chloride (6.82 g, 34.52 mmol) (CH 2 COOCH 3) COOCH 3 ) 1.00] n to obtain 7.73g (yield, 80.0%).
[실시예 15]Example 15
폴리[폴리(메톡시에틸렌글리콜)(L-아스파르토일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-aspartoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.50(NHCH(CH2COOC2H5)COOC2H5)1.50]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.50 (NHCH (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.50 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(3.02g, 8.63mmol)과 나트륨금속조각(0.29g, 12.90mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(15.72g, 155.32mmol), L-아스파르토일디에틸에스테르 염화수소염(11.68g, 51.77mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)0.50(NHCH(CH2COOC2H5)COOC2H5)1.50]n를 5.39g(수율, 61.5%) 얻었다.Poly (methoxyethylene glycol) ethanol (3.02 g, 8.63 mmol) with a molecular weight of 350, sodium metal chips (0.29 g, 12.90 mmol), poly (dichlorophosphazene) (2.00 g, 17.26 mmol), triethylamine (15.72 g) , 155.32 mmol), the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.50 (NHCH) in the same manner as in Example 2 using L-aspartoyldiethylester hydrogen chloride (11.68 g, 51.77 mmol) 5.39 g (yield, 61.5%) of (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.50 ] n was obtained.
[실시예 16]Example 16
폴리[폴리(메톡시에틸렌글리콜)(L-아스파르토일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-aspartoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.01(NHCH(CH2COOC2H5)COOC2H5)0.99]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.01 (NHCH (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.99 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.48g, 103.59mmol), L-아스파르토일디에틸에스테르 염화수소염(7.79g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.01(NHCH(CH2COOC2H5)COOC2H5)0.99]n를 7.79g(수율, 77.6%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal fragment (0.59 g, 25.89 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol), the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.01 (NHCH () using the L-aspartoyldiethyl ester hydrogen chloride (7.79 g, 34.52 mmol) in the same manner as in Example 2. CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.99 ] n to obtain 7.79 g (yield, 77.6%).
[실시예 17]Example 17
폴리[폴리(메톡시에틸렌글리콜)(L-아스파르토일디벤질에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-aspartoyldibenzylester) phosphazene],
[NP(OCH2CH2)7OCH3)1.10(NHCH(CH2COOCH2C6H5)COOCH2C6H5)0.90]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.10 (NHCH (CH 2 COOCH 2 C 6 H 5 ) COOCH 2 C 6 H 5 ) 0.90 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)과 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) 2.00g(17.26mmol), 트리에틸아민(10.48g, 103.59mmol), L-아스파르토일디벤질에스테르-p-톨루엔술폰산염(16.76g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.10(NHCH(CH2COOCH2C6H5)COOCH2C6H5)0.90]n를 3.56g(수율, 29.1%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal fragment (0.59 g, 25.89 mmol), 2.00 g (17.26 mmol) poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol), the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) in the same manner as in Example 2 using L-aspartoyldibenzylester-p-toluenesulfonate (16.76 g, 34.52 mmol) 1.10 (NHCH (CH 2 COOCH 2 C 6 H 5 ) COOCH 2 C 6 H 5 ) 0.90 ] n was obtained 3.56 g (yield, 29.1%).
[실시예 18]Example 18
폴리[폴리(메톡시에틸렌글리콜)(L-아스파르토일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-aspartoyldiethyl ester) phosphazene],
[NP(OCH2CH2)16OCH3)1.10(NHCH(CH2COOC2H5)COOC2H5)0.90]n의 제조Preparation of [NP (OCH 2 CH 2 ) 16 OCH 3 ) 1.10 (NHCH (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.90 ] n
분자량750의 폴리(메톡시에틸렌글리콜)에탄올(12.94g, 17.26mmol)과 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(10.48g, 103.59mmol), L-아스파르토일디에틸에스테르 염화수소염(7.79g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)16OCH3)1.10(NHCH(CH2COOC2H5)COOC2H5)0.90]n를 9.24g(수율, 54.5%) 얻었다.Poly (methoxyethylene glycol) ethanol (12.94 g, 17.26 mmol) with a molecular weight of 750, sodium metal chips (0.59 g, 25.89 mmol), poly (dichlorophosphazene) (2.00 g, 17.26 mmol), triethylamine (10.48 g) , 103.59 mmol), the final polymer product [NP (OCH 2 CH 2 ) 16 OCH 3 ) 1.10 (NHCH) in the same manner as in Example 2 using L-aspartoyldiethylester hydrogen chloride (7.79 g, 34.52 mmol) (CH 2 COOC 2 H 5) COOC 2 H 5) 0.90] n to obtain 9.24g (yield, 54.5%).
[실시예 19]Example 19
폴리[폴리(메톡시에틸렌글리콜)(L-글루타모일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-glutamoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.60(NHCH(CH2COOC2H5)COOC2H5)1.40]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.60 (NHCH (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.40 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(3.62g, 10.35mmol), 나트륨금속조각(0.36g, 15.53mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(12.57g, 124.25mmol), L-글루타모일디에틸에스테르 염화수소염(9.43g, 41.42mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)0.60(NHCH(CH2COOC2H5)COOC2H5)1.40]n를 4.31g(수율, 41.3%) 얻었다.Poly (methoxy ethylene glycol) ethanol (3.62 g, 10.35 mmol), molecular weight 350 (0.36 g, 15.53 mmol), poly (dichlorophosphazene) (2.00 g, 17.26 mmol), triethylamine (12.57 g) , 124.25 mmol), the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.60 (NHCH) in the same manner as in Example 2 using L-glutamoyldiethyl ester hydrogen chloride (9.43 g, 41.42 mmol) 4.31 g (yield, 41.3%) of (CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.40 ] n was obtained.
저임계용액온도 : 25.0℃Low critical solution temperature: 25.0 ℃
[실시예 20]Example 20
폴리[폴리(메톡시에틸렌글리콜)(L-글루타모일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-glutamoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.00(NHCH(CH2CH2COOC2H5)COOC2H5)1.00]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.00 (NHCH (CH 2 CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.00 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol), 나트륨금속조각(0.59g, 25.89mmol), 폴리(디클로로포스파젠) 2.00g (17.26mmol), 트리에틸아민(10.48g, 103.59mmol), L-글루타모일디에틸에스테르 염화수소염(7.79g, 34.52mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.00(NHCH(CH2CH2COOC2H5)COOC2H5)1.00]n를 6.29g(수율, 66.4%) 얻었다.Poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) with a molecular weight of 350, sodium metal chips (0.59 g, 25.89 mmol), 2.00 g (17.26 mmol) of poly (dichlorophosphazene), triethylamine (10.48 g, 103.59 mmol), and the final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.00 (NHCH () using L-glutamoyldiethyl ester hydrogen chloride (7.79 g, 34.52 mmol) in the same manner as in Example 2. CH 2 CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 1.00 ] n was obtained 6.29 g (yield, 66.4%).
[실시예 21]Example 21
폴리[폴리(메톡시에틸렌글리콜)(L-글루타모일디에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-glutamoyldiethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)1.10(NHCH(CH2CH2COOC2H5)COOC2H5)0.90]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 1.10 (NHCH (CH 2 CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.90 ] n
폴리(디클로로포스파젠) (2.00g, 17.26mmol)을 벤젠에 녹인 다음 드라이아이스-아세톤 중탕에 넣고 트리에틸아민(3.49g, 34.52mmol)을 넣는다. 이 용액에 분자량350의 폴리(메톡시에틸렌글리콜)에탄올(6.04g, 17.26mmol)을 벤젠용매에 녹인 용액을 적가하였다. 30분 후 드라이아이스-아세톤 중탕을 제거하고 상온에서 10∼15시간 반응시킨 다음 이 용액에 트리에틸아민(10.48g, 103.59mmol)을 넣고 L-글루타모일디에틸에스테르 염화수소염(7.79g, 34.52mmol)을 가한 후 상온에서 12시간 반응시킨 후 다시 50℃로 올려 48시간 반응시켰다. 반응용액을 원심분리 또는 여과하여 생성된 과량의 침전물들(Et3NㆍHCl 또는 NaCl)을 제거하고 여액은 용매가 조금 남았을때 까지 감압농축하였다. 여기에 과량의 에테르 또는 헥산을 가하여 침전을 유도하였다. 이 과정을 2∼3회 반복한 후 침전물을 소량의 증류수에 녹여 투석막(MWCO:3500)으로 2일 동안 증류수에서 투석한 다음 동결건조하여 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)1.10(NHCH(CH2CH2COOC2H5)COOC2H5)0.90]n를 7.01g(수율, 74.0%) 얻었다.Poly (dichlorophosphazene) (2.00g, 17.26mmol) is dissolved in benzene and placed in dry ice-acetone bath and triethylamine (3.49g, 34.52mmol). To this solution was added dropwise a solution of poly (methoxyethylene glycol) ethanol (6.04 g, 17.26 mmol) having a molecular weight of 350 in a benzene solvent. After 30 minutes, the dry ice-acetone bath was removed and reacted at room temperature for 10-15 hours. Then, triethylamine (10.48 g, 103.59 mmol) was added to the solution, and L-glutamoyldiethyl ester hydrogen chloride (7.79 g, 34.52) was added. mmol) was added thereto, followed by reaction at room temperature for 12 hours, and then heated to 50 ° C. for 48 hours. The reaction solution was centrifuged or filtered to remove excess precipitates (Et 3 N.HCl or NaCl) and the filtrate was concentrated under reduced pressure until some solvent remained. Excess ether or hexane was added thereto to induce precipitation. After repeating this process 2-3 times, the precipitate was dissolved in a small amount of distilled water, dialyzed in distilled water for 2 days with a dialysis membrane (MWCO: 3500), and then lyophilized to obtain a final polymer product [NP (OCH 2 CH 2 ) 7 OCH 3 ). 1.10 (NHCH (CH 2 CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.90 ] n was obtained at 7.01 g (yield, 74.0%).
[실시예 22]Example 22
폴리[폴리(메톡시에틸렌글리콜)(L-글루타모일디에틸에스테르)(글라이신에틸에스테르)포스파젠],Poly [poly (methoxyethylene glycol) (L-glutamoyldiethyl ester) (glycineethyl ester) phosphazene],
[NP(OCH2CH2)7OCH3)0.59(NHCH(CH2CH2COOC2H5)COOC2H5)0.40(NHCH2COOC2H5)1.01]n의 제조Preparation of [NP (OCH 2 CH 2 ) 7 OCH 3 ) 0.59 (NHCH (CH 2 CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.40 (NHCH 2 COOC 2 H 5 ) 1.01 ] n
분자량350의 폴리(메톡시에틸렌글리콜)에탄올(3.02g, 8.63mmol), 나트륨금속조각(0.30g, 12.94mmol), 폴리(디클로로포스파젠) (2.00g, 17.26mmol), 트리에틸아민(11.79g, 116.49mmol), L-글루타모일디에틸에스테르 염화수소염(3.10g, 12.94mmol), 글라이신에틸에스테르 염화수소염(3.61g, 25.89mmol)을 사용하여 실시예 2와 같은 방법으로 최종 고분자 생성물 [NP(OCH2CH2)7OCH3)0.59(NHCH(CH2CH2COOC2H5)COOC2H5)0.40(NHCH2COOC2H5)1.01]n를 6.05g(수율, 85.2%) 얻었다.Poly (methoxyethylene glycol) ethanol (3.02 g, 8.63 mmol) with a molecular weight of 350, sodium metal chips (0.30 g, 12.94 mmol), poly (dichlorophosphazene) (2.00 g, 17.26 mmol), triethylamine (11.79 g) , 116.49 mmol), L-glutamoyldiethyl ester hydrogen chloride (3.10 g, 12.94 mmol), glycine ethyl ester hydrogen chloride (3.61 g, 25.89 mmol) in the same manner as in Example 2 6.05 g (yield, 85.2%) of (OCH 2 CH 2 ) 7 OCH 3 ) 0.59 (NHCH (CH 2 CH 2 COOC 2 H 5 ) COOC 2 H 5 ) 0.40 (NHCH 2 COOC 2 H 5 ) 1.01 ] n .
[온도감응성 폴리포스파젠계 고분자의 분해실험의 예][Example of Decomposition Experiment of Temperature-Sensitive Polyphosphazene Polymer]
본 발명의 온도감응성 폴리포스파젠계 고분자들에 대한 분해실험을 다음과 같이 실시하였다. 폴리포스파젠계 고분자를 pH=5, 7.4, 10인 완충용액에 녹인 후 36℃수조에서 방치하고 방치기간에 따른 분자량의 감소를 겔투과크로마토그래피(GPC)를 이용하여 측정하였으며 그 결과를 표 1에 나타내었다. 그리고 일정기간 분해가 진행된 용액을 성분분석한 결과 인산염, 암모니아, 에탄올 등이 검출되었으며 따라서 고분자들은 인체에 무해한 인산염, 암모니아, 아미노산, 에탄올등으로 분해되는 것으로 추정된다.The decomposition experiments for the temperature sensitive polyphosphazene polymers of the present invention were carried out as follows. The polyphosphazene-based polymer was dissolved in a buffer solution of pH = 5, 7.4, and 10 and left in a 36 ° C water bath. The decrease in molecular weight was measured using gel permeation chromatography (GPC). Shown in As a result of the component analysis of the solution which has been decomposed for a certain period of time, phosphate, ammonia, ethanol, etc. were detected. Therefore, it is estimated that the polymers are decomposed into phosphate, ammonia, amino acid, ethanol, which are harmless to the human body.
[표 1]TABLE 1
본 발명에 따라 온도감응성을 갖는 분해성 고분자가 제공된다. 본 발명의 폴리포스파젠계 고분자는 온도감응성과 분해성을 동시에 가지며 감응온도 및 분해속도를 자유로이 조절할 수 있다. 따라서 본 발명의 고분자는 앞으로 의약전달체용 재료를 포함하는 여러 분야에 응용될 수 있을 것으로 기대된다.According to the present invention there is provided a degradable polymer having temperature sensitivity. The polyphosphazene-based polymer of the present invention has both temperature sensitivity and degradability, and can freely adjust the temperature and the decomposition rate. Therefore, the polymer of the present invention is expected to be applicable to various fields including the drug carrier material in the future.
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