JPH0555531B2 - - Google Patents
Info
- Publication number
- JPH0555531B2 JPH0555531B2 JP27827786A JP27827786A JPH0555531B2 JP H0555531 B2 JPH0555531 B2 JP H0555531B2 JP 27827786 A JP27827786 A JP 27827786A JP 27827786 A JP27827786 A JP 27827786A JP H0555531 B2 JPH0555531 B2 JP H0555531B2
- Authority
- JP
- Japan
- Prior art keywords
- amino acid
- acid polymer
- hydroxyl group
- side chain
- polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229920000642 polymer Polymers 0.000 claims description 47
- 150000001413 amino acids Chemical class 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 150000001768 cations Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- -1 cyclic phosphate ester Chemical class 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 description 38
- 229940024606 amino acid Drugs 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 125000005210 alkyl ammonium group Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000009102 absorption Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- QQJDHWMADUVRDL-UHFFFAOYSA-N didodecyl(dimethyl)azanium Chemical compound CCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCC QQJDHWMADUVRDL-UHFFFAOYSA-N 0.000 description 2
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000013269 sustained drug release Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- MEALETCBCJNEFX-LURJTMIESA-N (2s)-5-amino-2-(3-hydroxypropylamino)-5-oxopentanoic acid Chemical compound NC(=O)CC[C@@H](C(O)=O)NCCCO MEALETCBCJNEFX-LURJTMIESA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- HYLUGFQIEIXIFQ-UHFFFAOYSA-N 2-chloro-1,3,2$l^{5}-dioxaphosphinane 2-oxide Chemical compound ClP1(=O)OCCCO1 HYLUGFQIEIXIFQ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000000978 circular dichroism spectroscopy Methods 0.000 description 1
- 238000001142 circular dichroism spectrum Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- XRWMGCFJVKDVMD-UHFFFAOYSA-M didodecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCC XRWMGCFJVKDVMD-UHFFFAOYSA-M 0.000 description 1
- PSLWZOIUBRXAQW-UHFFFAOYSA-M dimethyl(dioctadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC PSLWZOIUBRXAQW-UHFFFAOYSA-M 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000002270 phosphoric acid ester group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000155 polyglutamine Polymers 0.000 description 1
- 108010040003 polyglutamine Proteins 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000007785 strong electrolyte Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CHYBTAZWINMGHA-UHFFFAOYSA-N tetraoctylazanium Chemical compound CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC CHYBTAZWINMGHA-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Polyamides (AREA)
Description
【発明の詳細な説明】
〔技術分野〕
本発明は、下記一般式（）で表わされる構造
のリン酸エステル基の側鎖を有するアミノ酸重合
体（以下、本発明の重合体とも言う）及びその製
造方法に関するものである。Detailed Description of the Invention [Technical Field] The present invention relates to an amino acid polymer (hereinafter also referred to as the polymer of the present invention) having a structure represented by the following general formula () and a side chain of a phosphate ester group, and its This relates to a manufacturing method.
（式中、Ｒは炭化水素基であり、Ｍは水素原子又
は塩形成性陽イオンである）
〔従来技術〕
アミノ酸重合体は、コラーゲンなどの生体タン
パク質に類似した物質のため医用材料としての研
究開発が行われている。しかし、各種の誘導体が
知られているにもかかわらず、強電解質の性質を
もつリン酸基を側鎖に有するアミノ酸重合体は知
られていない。アミノ酸重合体は生体内分解性が
期待できることから、体内埋込型の薬物除放性担
体に適しているが、そのような用途においては、
薬物の放出速度を制御し得ることが望ましい。例
えば、従来、水酸基のみを有するアミノ酸重合体
は知られているが、このようなアミノ酸重合体を
前記薬物除放性担体として用いる場合、その薬物
の放出速度を制御するのが困難であり、また一般
有機溶媒に体する親和性に劣るという問題もあ
る。 (In the formula, R is a hydrocarbon group, and M is a hydrogen atom or a salt-forming cation.) [Prior art] Amino acid polymers have been studied as medical materials because they are similar to biological proteins such as collagen. Development is underway. However, although various derivatives are known, an amino acid polymer having a phosphate group in its side chain with strong electrolyte properties is unknown. Amino acid polymers are expected to be biodegradable, so they are suitable for use as sustained-release drug carriers that can be implanted in the body.
It would be desirable to be able to control the rate of drug release. For example, amino acid polymers having only hydroxyl groups have been known, but when such amino acid polymers are used as sustained drug release carriers, it is difficult to control the release rate of the drug, and There is also the problem that they have poor affinity with common organic solvents.
本発明は、親水性にすぐれると共に、薬物除放
性担体として適用した場合に、その薬物の放出速
度を環境のPH変化で制御することができ、かつ一
般有機溶媒に対する親和性にすぐれた新規なアミ
ノ酸重合体を提供することを目的とする。
The present invention is a novel drug that has excellent hydrophilicity, can control the release rate of the drug by changing the pH of the environment when applied as a drug sustained release carrier, and has excellent affinity for general organic solvents. The purpose is to provide amino acid polymers that are
本発明によれば、分子量１万〜50万の水酸基を
側鎖に有するアミノ酸重合体において、該水酸基
からなる側鎖の少なくとも一部が下記一般式
（）で表わされるリン酸エステル基の側鎖で置
換されていることを特徴とするアミノ酸重合体が
提供される。
According to the present invention, in an amino acid polymer having a hydroxyl group in a side chain having a molecular weight of 10,000 to 500,000, at least a part of the side chain consisting of the hydroxyl group is a side chain of a phosphate ester group represented by the following general formula (). Provided is an amino acid polymer characterized in that it is substituted with.
前記式中、Ｒは炭化水素基であり、炭素数２〜
４、好ましくは２〜３のアルキレン基が一般的で
ある。Ｍは水素原子又はリン酸の水酸基と反応し
て塩を形成し得る陽イオンであり、この場合の塩
を形成し得る陽イオンとしては、例えば、ナトリ
ウム、カリウム、リチウム等のアルカリ金属イオ
ン、アンモニウムイオン、又はジメチルジオクタ
デシルアンモニウムや、ジメチルジドデシルアン
モニウム、テトラプロピルアンモニウム、テトラ
オクチルアンモニウム等のアルキルアンモニウ
ム、殊に炭素数１〜６の低級アルキル基と炭素数
８〜24の高級アルキル基を含むアルキルアンモニ
ウム等である。 In the above formula, R is a hydrocarbon group having 2 to 2 carbon atoms.
Four, preferably two to three, alkylene groups are common. M is a cation that can react with a hydrogen atom or a hydroxyl group of phosphoric acid to form a salt; examples of cations that can form a salt include alkali metal ions such as sodium, potassium, and lithium; ions, or alkylammoniums such as dimethyldioctadecylammonium, dimethyldidodecylammonium, tetrapropylammonium, and tetraoctylammonium, especially alkyl containing a lower alkyl group having 1 to 6 carbon atoms and a higher alkyl group having 8 to 24 carbon atoms. Ammonium etc.
本発明の重合体を製造するには、出発物質とし
て、水酸基を側鎖に有する従来公知のアミノ酸重
合体を用いる。このようなアミノ酸重合体には、
セリン、スレオニン、チロシン、Ｎ−ヒドロキシ
プロピルグルタミン、Ｎ−ヒドロキシエチルアス
パラギン等がある他、これらの水酸基を有するア
ミノ酸成分相互の共重合体及び水酸基を有するア
ミノ酸成分と他のアミノ酸成分との共重合体、さ
らにこのようなアミノ酸重合体の主鎖同志を架橋
させた重合体等が包含されている。このアミノ酸
重合体の分子量は、通常、１万〜50万の範囲であ
る。反応に供するアミノ酸重合体の形態は、粉
末、フイルム、繊維及び溶液等の任意の形態であ
ることができる。 To produce the polymer of the present invention, a conventionally known amino acid polymer having a hydroxyl group in its side chain is used as a starting material. Such amino acid polymers include
Serine, threonine, tyrosine, N-hydroxypropylglutamine, N-hydroxyethyl asparagine, etc., as well as copolymers of these hydroxyl group-containing amino acid components and copolymers of hydroxyl group-containing amino acid components and other amino acid components , and further includes polymers in which the main chains of such amino acid polymers are crosslinked. The molecular weight of this amino acid polymer is usually in the range of 10,000 to 500,000. The form of the amino acid polymer subjected to the reaction can be any form such as powder, film, fiber, and solution.
本発明では、前記の如き水酸基を持つアミノ酸
重合体に、環状リン酸エステルのハロゲン化物を
反応させる。この環状リン酸エステルのハロゲン
化物は、下記一般式（）で表わされる。 In the present invention, an amino acid polymer having a hydroxyl group as described above is reacted with a halide of a cyclic phosphoric acid ester. This cyclic phosphoric acid ester halide is represented by the following general formula ().
（式中、Ｒは前記と同じ意味を有し、Ｘはハロゲ
ンを示す。）
このような環状リン酸エステルのハロゲン化物
の具体例としては、例えば、２−クロロ−２−オ
キソ−１，３，２−ジオキサホスホラン、２−ク
ロロ−２−オキソ−１，３，２−ジオキサホスホ
リナン等が挙げられる。 (In the formula, R has the same meaning as above, and X represents a halogen.) Specific examples of halides of such cyclic phosphoric esters include, for example, 2-chloro-2-oxo-1,3 , 2-dioxaphosphorane, 2-chloro-2-oxo-1,3,2-dioxaphosphorinane, and the like.
前記反応においては、原料アミノ酸重合体の水
酸基の水素と、環状リン酸エステルのハロゲン化
物のハロゲン原子とが脱ハロゲン化水素反応を起
し、アミノ酸重合体中に環状リン酸エステル基が
導入される。この反応は、トリエチルアミンやピ
リジン等の第３級アミンの共存下、Ｎ，Ｎ−ジメ
チルアセトアミドやＮ−メチルピロリドン等の溶
媒中において、−10〜−20℃で10〜20時間反応さ
せることによつて行われる。反応後、均一溶液反
応の場合は、反応により脱離したハロゲン化水素
をアミン塩酸基として除去した後、その溶液状の
まま、あるいはアセトンや、酢酸エチル、アルコ
ール等に生成物を沈殿させて分離し、次の反応に
用いる。また、アミノ酸重合体をフイルム等の固
形物の形で用いた不均一系の反応の場合は、その
固形状アミノ酸重合体を、ジメチルアセトアミド
や、ジメチルスルホキシド、アルコール等で洗浄
して次の反応に用いる。 In the above reaction, the hydrogen of the hydroxyl group of the raw material amino acid polymer and the halogen atom of the halide of the cyclic phosphate ester cause a dehydrohalogenation reaction, and a cyclic phosphate ester group is introduced into the amino acid polymer. . This reaction is carried out in the presence of a tertiary amine such as triethylamine or pyridine in a solvent such as N,N-dimethylacetamide or N-methylpyrrolidone at -10 to -20°C for 10 to 20 hours. It is carried out at the same time. After the reaction, in the case of a homogeneous solution reaction, the hydrogen halide released by the reaction is removed as an amine hydrochloric acid group, and then the product is separated either in solution form or by precipitating the product in acetone, ethyl acetate, alcohol, etc. and used in the next reaction. In addition, in the case of a heterogeneous reaction using an amino acid polymer in the form of a solid material such as a film, the solid amino acid polymer should be washed with dimethylacetamide, dimethyl sulfoxide, alcohol, etc. before the next reaction. use
次に、前記の反応で得られた反応生成物に、水
酸化ナトリウムや水酸化カリウム、水酸化リチウ
ム等の水酸化アルカリの水溶液を反応させると、
前記式（）の構造（但し、Ｍはアルカリ金属）
の側鎖を有する本発明のアミノ酸重合体を得るこ
とができる。この場合の反応条件は室温で10〜30
時間程度である。 Next, when the reaction product obtained in the above reaction is reacted with an aqueous solution of an alkali hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide,
Structure of the above formula () (where M is an alkali metal)
It is possible to obtain an amino acid polymer of the present invention having a side chain of The reaction conditions in this case are 10-30 at room temperature.
It takes about an hour.
このようにして得られたアミノ酸重合体には、
従来公知の種々の変性処理を施して、前記式
（）で示される構造の側鎖において、Ｍがアル
キルアンモニウムや、水素原子を有するもの等を
得ることができる。例えば、Ｍがアルキルアモニ
ウムであるものを得るには、前記で得たアミノ酸
重合体水溶液と、アルキルアンモニウム塩水溶液
と混合すればよく、これにより目的の生成物を沈
殿物として得ることができる。この場合、アルキ
ルアンモニウム塩の陰イオンは、塩素、臭素、ヨ
ウ素等であり、アルキルアンモニウム塩の水溶液
の濃度は0.5〜10重量％である。このようにして
得られるアミノ酸重合体（Ｍ：アルキルアンモニ
ウム）は水に溶解しないが、メタノールや、エタ
ノール、２−プロパノール、クロロホルム等に溶
解する。従つて、このアミノ酸重合体は、これら
の溶媒に溶解して、フイルムや粒子等の任意の形
状に成形することができる。また、式（）にお
いてＭが水素原子を有するものを得るには、先の
アミノ酸重合体を0.1〜2Mの塩酸や、陽イオン交
換樹脂で処理すれば良い。 The amino acid polymer obtained in this way has
By performing various conventionally known modification treatments, it is possible to obtain a structure in which M has an alkyl ammonium or a hydrogen atom in the side chain of the structure represented by the above formula (). For example, to obtain a product in which M is alkylammonium, the amino acid polymer aqueous solution obtained above may be mixed with an alkyl ammonium salt aqueous solution, thereby obtaining the desired product as a precipitate. In this case, the anion of the alkylammonium salt is chlorine, bromine, iodine, etc., and the concentration of the aqueous solution of the alkylammonium salt is 0.5 to 10% by weight. The amino acid polymer (M: alkylammonium) obtained in this way does not dissolve in water, but dissolves in methanol, ethanol, 2-propanol, chloroform, etc. Therefore, this amino acid polymer can be dissolved in these solvents and formed into any desired shape such as a film or particles. Further, in order to obtain a compound in which M has a hydrogen atom in formula (), the above amino acid polymer may be treated with 0.1 to 2M hydrochloric acid or a cation exchange resin.
次に本発明を実施例によりさらに詳細に説明す
る。
Next, the present invention will be explained in more detail with reference to Examples.
実施例 １
ポリグルタミン酸ベンジル（4.04ｇ）をプロパ
ノールアミン（65ml）に浸せきし、60℃で２日間
攪拌し、ポリ（Ｎ−ヒドロキシプロピル）グルタ
ミンにし、アセトン600mlに沈殿させ、沈殿を濾
取した。この沈殿をメタノール80mlにとかし、ア
セトン500mlに沈殿させこの沈澱を乾燥させた。
このポリ（Ｎ−ヒドロキシプロピル）グルタミン
の分子量を粘度報（「バイオポリマーズ」第３巻、
第625頁（1965））によつて測定したところ、
93000であつた。乾燥したポリ（Ｎ−ヒドロキシ
プロピル）グルタミン（0.50ｇ）をＮ−メチル−
２−ピロリドン10mlに溶解させ、トリエチルアミ
ン0.37mlを加え、−15℃にした。ここへ２−クロ
ロ−２−オキソ−１，３，２−ジオキサホスホラ
ン0.26mlを滴下し、２時間攪拌して反応させた。
次に室温にして、10時間攪拌した。この溶液を遠
心分離して、トリエチルアミン塩酸塩を除き、上
澄に1M水酸化ナトリウム３mlを加え、室温で22
時間攪拌し、混合物をアセトン150mlに沈殿させ
た。沈殿をメタノール20mlにとかして、酢酸エチ
ル150mlに沈殿させた。Example 1 Benzyl polyglutamate (4.04 g) was soaked in propanolamine (65 ml), stirred at 60°C for 2 days to form poly(N-hydroxypropyl)glutamine, precipitated in 600 ml of acetone, and the precipitate was collected by filtration. This precipitate was dissolved in 80 ml of methanol, precipitated in 500 ml of acetone, and the precipitate was dried.
The molecular weight of this poly(N-hydroxypropyl)glutamine was determined by the viscosity report ("Biopolymers" Vol. 3,
625 (1965)),
It was 93000. Dry poly(N-hydroxypropyl)glutamine (0.50g) was mixed with N-methyl-
The mixture was dissolved in 10 ml of 2-pyrrolidone, added with 0.37 ml of triethylamine, and heated to -15°C. 0.26 ml of 2-chloro-2-oxo-1,3,2-dioxaphosphorane was added dropwise thereto, and the mixture was stirred for 2 hours to react.
The mixture was then brought to room temperature and stirred for 10 hours. This solution was centrifuged to remove triethylamine hydrochloride, 3 ml of 1M sodium hydroxide was added to the supernatant, and the mixture was heated at room temperature for 22
After stirring for an hour, the mixture was precipitated into 150 ml of acetone. The precipitate was dissolved in 20 ml of methanol and precipitated into 150 ml of ethyl acetate.
目的のリン酸基（Ｍ：ナトリウム）を有するポ
リグルタミンを0.603ｇ得た。この物質は、メタ
ノール、水、1M塩酸に可溶であつた。またこの
物質の赤外線吸収スペクトルにおいては、1237cm
-1及び1084cm-1のリン酸基に特有の吸収ピークが
現われた。 0.603 g of the desired polyglutamine having a phosphate group (M: sodium) was obtained. This material was soluble in methanol, water, and 1M hydrochloric acid. Also, in the infrared absorption spectrum of this material, 1237cm
-1 and 1084 cm -1 absorption peaks specific to phosphate groups appeared.
実施例 ２
実施例１で得られたアミノ酸重合体5.62mgを
1M塩酸5.62mlに溶解し、円偏光二色性スペクト
ルを測定した。222nｍに谷をもつスペクトルが
得られ、重合体がα−ヘリツクス構造をとつてい
ることがわかつた。塩酸ではなく、水に溶解した
場合は216nｍに山をもつスペクトルが得られ、
ランダム構造であつたが、塩酸処理によりα−ヘ
リツクス構造にかわつたのは側鎖のリン酸基がナ
トリウム塩ではなく、水素を有する酸型のものに
なつたためである。このようにして構造式（）
中のＭが水素の重合体が得られた。Example 2 5.62 mg of the amino acid polymer obtained in Example 1 was
It was dissolved in 5.62 ml of 1M hydrochloric acid and the circular dichroism spectrum was measured. A spectrum with a valley at 222 nm was obtained, indicating that the polymer had an α-helical structure. When dissolved in water instead of hydrochloric acid, a spectrum with a peak at 216 nm is obtained.
Although it had a random structure, it changed to an α-helical structure by treatment with hydrochloric acid because the phosphate group in the side chain became an acid type having hydrogen instead of a sodium salt. In this way, the structural formula ()
A polymer in which M is hydrogen was obtained.
実施例 ３
実施例１で得たアミノ酸重合体26mgを水2.6ml
に溶解させた。ジメチルジオクタデシルアンモニ
ウムブロマイド50mgを水５mlに溶解させた。両液
をはげしく攪拌しながら混合した。白色の沈殿が
生じた。沈殿を濾別し乾燥した。44mgが得られ
た。この物質の赤外線吸収スペクトルにおいて
は、2917、2850、1471、719cm-1のメチレン基の
吸収が明りように現われており、アンモニウムが
とりこまれていることを示した。このアミノ酸重
合体はメタノール、エタノール、２−プロパノー
ル、クロロホルムに可溶であつた。酢酸エチルに
は不溶であつた。このようにして、Ｍがジメチル
ジオクタデシルアンモニウムの重合体が得られ
た。Example 3 26 mg of the amino acid polymer obtained in Example 1 was added to 2.6 ml of water.
It was dissolved in 50 mg of dimethyldioctadecylammonium bromide was dissolved in 5 ml of water. Both solutions were mixed with vigorous stirring. A white precipitate formed. The precipitate was filtered off and dried. 44 mg was obtained. In the infrared absorption spectrum of this substance, methylene group absorptions at 2917, 2850, 1471, and 719 cm -1 clearly appeared, indicating that ammonium was incorporated. This amino acid polymer was soluble in methanol, ethanol, 2-propanol, and chloroform. It was insoluble in ethyl acetate. In this way, a polymer in which M was dimethyldioctadecylammonium was obtained.
実施例 ４
実施例１で得たアミノ酸重合体26mgを水2.6ml
に溶解させた。ジメチルジドデシルアンモニウム
ブロマイド36mgを水3.6mlに溶解させた。両液を
はげしく攪拌しながら混合した。白色の沈殿が生
じた。沈殿を濾別し、乾燥した。20mgが得られ
た。この物質の赤外線スペクトルにおいては、
2922、2853、1469、720cm-1のメチレン基の吸収
が明瞭に現われておりアンモニウムがとりこまれ
たことを確認した。このようにして、Ｍがジメチ
ルジドデシルアンモニウムの重合体を得た。Example 4 26 mg of the amino acid polymer obtained in Example 1 was added to 2.6 ml of water.
It was dissolved in 36 mg of dimethyldidodecylammonium bromide was dissolved in 3.6 ml of water. Both solutions were mixed with vigorous stirring. A white precipitate formed. The precipitate was filtered off and dried. 20 mg was obtained. In the infrared spectrum of this material,
Absorption of methylene groups at 2922, 2853, 1469, and 720 cm -1 clearly appeared, confirming that ammonium was incorporated. In this way, a polymer in which M was dimethyldidodecylammonium was obtained.
本発明のアミノ酸重合体は、その側鎖として前
記一般式（）で示したリン酸エステル基を有
し、生体細胞膜を構成するリン脂質と類似構造を
有するため、生体細胞との特異的親和性を有する
ものである。また、このアミノ酸重合体は、この
側鎖のリン酸エステル基の構造を変化させること
により、親水性に著しく富む構造のもの（Ｍ：ア
ルカリ金属）から、有機溶媒に対する溶解性に著
しくすぐれたもの（Ｍ：アルキルアミンニウム）
等その物性を大幅に変化させることができるとい
う特徴を有する。また、本発明のアミノ酸重合体
は、リン酸エステル基の側鎖を有し、PH値により
その溶解性又は立体構造が変化するため、薬物除
放性担体として用いた場合に、その薬物放出速度
を環境のPH変化により制御することができるとい
う大きな特徴を有する。即ち、本発明のリン酸エ
ステル基を有するアミノ酸重合体は、PHによつて
そのリン酸エステル基における陽イオンＭの溶
解、非解離を行ない、その際にアミノ酸重合体の
立体構造が変化するという特徴を有する。従つ
て、本発明のアミノ酸重合体を架橋化して得たフ
イルムにおいては、その透過性をPH変化によつて
制御することができる。この立体構造の変化を円
二色性スペクトルで測定したところ、酸性ではα
−ヘリツクス構造を示し、中性ではランダムコイ
ル構造を示し、そのフイルムの透過性が大幅に変
化することが認識された。
The amino acid polymer of the present invention has a phosphoric acid ester group represented by the above general formula () as a side chain, and has a structure similar to that of the phospholipids that constitute biological cell membranes, so it has a specific affinity with biological cells. It has the following. In addition, by changing the structure of the phosphate ester group in the side chain, this amino acid polymer can be changed from a structure with extremely high hydrophilicity (M: alkali metal) to a structure with extremely high solubility in organic solvents. (M: alkylaminenium)
It has the characteristic that its physical properties can be changed significantly. In addition, the amino acid polymer of the present invention has a side chain of a phosphate ester group, and its solubility or steric structure changes depending on the pH value, so when it is used as a sustained drug release carrier, the drug release rate is It has the great feature that it can be controlled by changing the pH of the environment. That is, in the amino acid polymer having a phosphate ester group of the present invention, the cation M in the phosphate ester group is dissolved and non-dissociated by pH, and the three-dimensional structure of the amino acid polymer changes at this time. Has characteristics. Therefore, in the film obtained by crosslinking the amino acid polymer of the present invention, its permeability can be controlled by changing the pH. When this change in steric structure was measured using circular dichroism spectroscopy, it was found that in acidic conditions α
- It was recognized that the film exhibits a helical structure, and in neutrality it shows a random coil structure, and the permeability of the film changes significantly.
Claims (1)
ミノ酸重合体において、該水酸基の少なくとも一
部が一般式 （式中、Ｒは炭化水素基であり、Ｍは水素原子又
はリン酸の水酸基と反応して塩を形成し得る陽イ
オンである） で表わされるリン酸エステル基の側鎖で置換され
ていることを特徴とするアミノ酸重合体。 ２ 分子量１万〜50万の水酸基を側鎖に有するア
ミノ酸重合体において、該水酸基の少なくとも一
部が一般式 （式中、Ｒは炭化水素基であり、Ｍは水素原子又
はリン酸の水酸基と反応して塩を形成し得る陽イ
オンである） で表わされるリン酸エステル基の側鎖で置換され
ているアミノ酸重合体を製造するにあたり、水酸
基を有するアミノ酸重合体に環状リン酸エステル
のハロゲン化物を反応させた後、水酸化アルカリ
を反応させることによつて前記一般式においてＭ
がアルカリ金属である側鎖を有する反応生成物を
得、次いで、必要に応じて得られた反応生成物に
水素イオン又はリン酸の水酸基と反応して塩を形
成し得る陽イオンを反応させることを特徴とする
方法。[Scope of Claims] 1. An amino acid polymer having a hydroxyl group in its side chain with a molecular weight of 10,000 to 500,000, at least a part of which has the general formula (In the formula, R is a hydrocarbon group, and M is a cation that can react with a hydrogen atom or a hydroxyl group of phosphoric acid to form a salt.) An amino acid polymer characterized by: 2. In an amino acid polymer having a hydroxyl group in its side chain with a molecular weight of 10,000 to 500,000, at least a portion of the hydroxyl group has the general formula (In the formula, R is a hydrocarbon group, and M is a cation that can react with a hydrogen atom or a hydroxyl group of phosphoric acid to form a salt.) In producing an amino acid polymer, after reacting an amino acid polymer having a hydroxyl group with a halide of a cyclic phosphate ester, M in the above general formula is reacted with an alkali hydroxide.
obtaining a reaction product having a side chain in which is an alkali metal, and then optionally reacting the obtained reaction product with a hydrogen ion or a cation capable of reacting with the hydroxyl group of phosphoric acid to form a salt. A method characterized by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27827786A JPS63130629A (en) | 1986-11-21 | 1986-11-21 | Amino acid polymer having phosphate group as side chain and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27827786A JPS63130629A (en) | 1986-11-21 | 1986-11-21 | Amino acid polymer having phosphate group as side chain and its production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63130629A JPS63130629A (en) | 1988-06-02 |
| JPH0555531B2 true JPH0555531B2 (en) | 1993-08-17 |
Family
ID=17595105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27827786A Granted JPS63130629A (en) | 1986-11-21 | 1986-11-21 | Amino acid polymer having phosphate group as side chain and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63130629A (en) |
-
1986
- 1986-11-21 JP JP27827786A patent/JPS63130629A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63130629A (en) | 1988-06-02 |
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