JP2013150796A - Temperature-sensitive material and hemostatic agent - Google Patents
Temperature-sensitive material and hemostatic agent Download PDFInfo
- Publication number
- JP2013150796A JP2013150796A JP2012283090A JP2012283090A JP2013150796A JP 2013150796 A JP2013150796 A JP 2013150796A JP 2012283090 A JP2012283090 A JP 2012283090A JP 2012283090 A JP2012283090 A JP 2012283090A JP 2013150796 A JP2013150796 A JP 2013150796A
- Authority
- JP
- Japan
- Prior art keywords
- temperature
- polymer
- sensitive
- cloud point
- tris
- 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.)
- Granted
Links
- 239000000463 material Substances 0.000 title claims abstract description 29
- 229940030225 antihemorrhagics Drugs 0.000 title claims description 9
- 239000002874 hemostatic agent Substances 0.000 title claims description 9
- 229920000642 polymer Polymers 0.000 claims abstract description 78
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000002861 polymer material Substances 0.000 claims abstract description 28
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 14
- 239000007983 Tris buffer Substances 0.000 description 34
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 239000013033 iniferter Substances 0.000 description 18
- 238000005259 measurement Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000178 monomer Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 230000002209 hydrophobic effect Effects 0.000 description 12
- -1 N, N-dimethylaminoethyl Chemical group 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 7
- 230000001070 adhesive effect Effects 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229920001519 homopolymer Polymers 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 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 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002091 cationic group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005227 gel permeation chromatography Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 3
- 239000003973 paint Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 238000002834 transmittance Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000001879 gelation Methods 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 238000010550 living polymerization reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000003505 polymerization initiator Substances 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 229920005604 random copolymer Polymers 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- XJOUCILNLRXRTF-UHFFFAOYSA-N 1,2,3,4,5,6-hexakis(bromomethyl)benzene Chemical compound BrCC1=C(CBr)C(CBr)=C(CBr)C(CBr)=C1CBr XJOUCILNLRXRTF-UHFFFAOYSA-N 0.000 description 1
- UTXIKCCNBUIWPT-UHFFFAOYSA-N 1,2,4,5-tetrakis(bromomethyl)benzene Chemical compound BrCC1=CC(CBr)=C(CBr)C=C1CBr UTXIKCCNBUIWPT-UHFFFAOYSA-N 0.000 description 1
- GHITVUOBZBZMND-UHFFFAOYSA-N 1,3,5-tris(bromomethyl)benzene Chemical compound BrCC1=CC(CBr)=CC(CBr)=C1 GHITVUOBZBZMND-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XGXQZMDBRWCHOK-UHFFFAOYSA-N 2-dimethylarsanylsulfanylethanol Chemical compound C[As](C)SCCO XGXQZMDBRWCHOK-UHFFFAOYSA-N 0.000 description 1
- LBSXSAXOLABXMF-UHFFFAOYSA-N 4-Vinylaniline Chemical class NC1=CC=C(C=C)C=C1 LBSXSAXOLABXMF-UHFFFAOYSA-N 0.000 description 1
- GQWAOUOHRMHSHL-UHFFFAOYSA-N 4-ethenyl-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(C=C)C=C1 GQWAOUOHRMHSHL-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010053649 Vascular rupture Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012986 chain transfer agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000011557 critical solution Substances 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HOXINJBQVZWYGZ-UHFFFAOYSA-N fenbutatin oxide Chemical compound C=1C=CC=CC=1C(C)(C)C[Sn](O[Sn](CC(C)(C)C=1C=CC=CC=1)(CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C=1C=CC=CC=1)(CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C1=CC=CC=C1 HOXINJBQVZWYGZ-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 229940088644 n,n-dimethylacrylamide Drugs 0.000 description 1
- YLGYACDQVQQZSW-UHFFFAOYSA-N n,n-dimethylprop-2-enamide Chemical compound CN(C)C(=O)C=C YLGYACDQVQQZSW-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920005749 polyurethane resin Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Compositions Of Macromolecular Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
本発明は、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とする温度感応性ポリマー材料の曇点（ＬＣＳＴ（Ｌｏｗｅｒ Ｃｒｉｔｉｃａｌ Ｓｏｌｕｔｉｏｎ Ｔｅｍｐｅｒａｔｕｒｅ）を低下させた温度感応性材料に関する。また、本発明は、この温度感応性材料よりなる止血剤に関する。 The present invention relates to a temperature-sensitive material having a low cloud point (LCST (Low Critical Solution Temperature)) of a temperature-sensitive polymer material containing 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof as a polymerization main component. The present invention also relates to a hemostatic agent comprising this temperature sensitive material.
曇点より低い温度では親水性であり、曇点より高い温度では疎水性となる温度感応性を示す温度感応性ポリマーとして、Ｎ−イソプロピルアクリルアミドのポリマー及び２−（Ｎ，Ｎ−ジメチルアミノエチル）メタクリレートのポリマーが公知である（特許文献１，２）。 N-isopropylacrylamide polymer and 2- (N, N-dimethylaminoethyl) are temperature-sensitive polymers that are hydrophilic at temperatures below the cloud point and hydrophobic at temperatures above the cloud point. Polymers of methacrylate are known (Patent Documents 1 and 2).
特許文献１の通り、ポリ（Ｎ−イソプロピルアクリルアミド）が３７℃付近では疎水性であり、２５℃付近では親水性である特性を利用して培養皿から培養細胞を剥離することができる。細胞は、疎水性の表面に接着するため、３７℃でポリ（Ｎ−イソプロピルアクリルアミド）が疎水性のときには、これが付着した培養皿に細胞が培養される。２５℃でポリ（Ｎ−イソプロピルアクリルアミド）が親水性となると、培養細胞は培養皿から剥離する。この現象を利用して培養皿から細胞シートを剥離させて回収することができる。 As described in Patent Document 1, poly (N-isopropylacrylamide) is hydrophobic at around 37 ° C. and is hydrophilic at around 25 ° C., whereby cultured cells can be detached from the culture dish. Since the cells adhere to the hydrophobic surface, when poly (N-isopropylacrylamide) is hydrophobic at 37 ° C., the cells are cultured in a culture dish to which the poly (N-isopropylacrylamide) is attached. When poly (N-isopropylacrylamide) becomes hydrophilic at 25 ° C., the cultured cells are detached from the culture dish. Utilizing this phenomenon, the cell sheet can be detached from the culture dish and recovered.
特許文献２には、ポリ[２−（Ｎ，Ｎ−ジメチルアミノエチル）メタクリレート]の温度感応性を利用した、Ｎ，Ｎ−ジアルキルジチオカルバミルメチル基を同一分子内に３個以上有する化合物をイニファターとし、このイニファターに対して、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を光照射リビング重合してなるスター型ポリマーよりなる遺伝子導入剤が記載されている。この遺伝子導入剤は、分岐鎖を構成する２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体が、僅かながらカチオン性を有する。そのため、このカチオン性の２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート単位は、核酸との結合に寄与し、遺伝子導入剤の核酸担持量が多くなる。また、この遺伝子導入剤は、分岐鎖が感温性を有しており、温度を上昇させることにより、遺伝子導入剤が疎水性に変化する。 Patent Document 2 discloses a compound having three or more N, N-dialkyldithiocarbamylmethyl groups in the same molecule utilizing the temperature sensitivity of poly [2- (N, N-dimethylaminoethyl) methacrylate]. As an iniferter, a gene transfer agent comprising a star-type polymer obtained by subjecting the iniferter to light irradiation living polymerization of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof is described. In this gene introduction agent, 2-N, N-dimethylaminoethyl methacrylate and / or its derivative constituting a branched chain have a slight cationic property. Therefore, this cationic 2-N, N-dimethylaminoethyl methacrylate unit contributes to the binding with the nucleic acid, and the amount of the nucleic acid carried by the gene introduction agent increases. Further, in this gene introduction agent, the branched chain has a temperature sensitivity, and the gene introduction agent changes to hydrophobic by raising the temperature.
Ｎ−イソプロピルアクリルアミドや２−（Ｎ，Ｎ−ジメチルアミノエチル）メタクリレートのいずれのポリマーも水溶液中で３２℃付近にＬＣＳＴがあり、哺乳類動物の体温領域で疎水性、室温で親水性を示す特徴を利用してＤＤＳ（ドラッグデリバリーシステム）や細胞培養の分野が利用されている。この現象はポリマー側鎖の運動エネルギーと側鎖分子団の水分子との親和性の関係で３０℃付近でグロビュール構造とコイル構造の転移を起すことで現れるものである。 Both N-isopropylacrylamide and 2- (N, N-dimethylaminoethyl) methacrylate polymers have LCST in the aqueous solution at around 32 ° C., and are characterized by being hydrophobic in the body temperature range of mammals and hydrophilic at room temperature. Utilizing the field of DDS (drug delivery system) and cell culture. This phenomenon appears by causing a transition between the globule structure and the coil structure at around 30 ° C. due to the relationship between the kinetic energy of the polymer side chain and the affinity of the water molecule of the side chain molecular group.
ポリ［２−（Ｎ，Ｎ−ジメチルアミノエチル）メタクリレート］は親水性⇔疎水性と同時にカチオン性⇔無電荷の性質の変化も起しているため、種々の用途（例えば止血材）に踏襲できることが期待される。 Poly [2- (N, N-dimethylaminoethyl) methacrylate] has both hydrophilic and hydrophobic properties as well as changes in the properties of cationic and uncharged, so it can be used for various applications (eg hemostatic materials). There is expected.
止血材としては、臨床の現場では外科的処置の際に血管破裂や誤切断などにより出血した際に、２液反応性のポリウレタン樹脂や瞬間接着剤で緊急の止血を検討することがある。他に医薬品としてヘビ毒などから抽出分離した天然組成物なども公知である。 As a hemostatic material, emergency hemostasis may be examined with a two-component reactive polyurethane resin or an instantaneous adhesive when bleeding due to vascular rupture or miscutting during a surgical procedure in clinical practice. In addition, natural compositions extracted from snake venom and the like as pharmaceuticals are also known.
感温性ポリマーとして知られるＮ−イソプロピルアクリルアミドもポリ［２−（Ｎ，Ｎ−ジメチルアミノエチル）メタクリレート］は、曇点が３２℃程度であり、生体内へ埋入して体温と平衡となるまで静置すれば疎水性の性質を発現する。しかしながら、この感温性ポリマーを体表面（切開した場合も含む）へ滴下した場合は、体表面温度は室温に近い３２℃程度であり、この感温性ポリマーは親水性のままであることが多い。従って、この感温性ポリマーを体表面へ滴下した場合は、ゲル化せずに流出してしまうなどの問題がある。感温性ポリマーの曇点が２５℃以下、特に２０℃以下であれば、体表面へ滴下した場合に速やかにゲル化し、体表面に固着すると考えられる。 N-isopropylacrylamide, also known as a thermosensitive polymer, is poly [2- (N, N-dimethylaminoethyl) methacrylate], which has a cloud point of about 32 ° C. and is embedded in the living body to be in equilibrium with body temperature. Hydrophobic properties are manifested if left still. However, when this temperature-sensitive polymer is dropped onto the body surface (including when it is cut open), the body surface temperature is about 32 ° C., which is close to room temperature, and this temperature-sensitive polymer may remain hydrophilic. Many. Therefore, when this thermosensitive polymer is dropped onto the body surface, there is a problem that it flows out without gelation. If the cloud point of the temperature-sensitive polymer is 25 ° C. or less, particularly 20 ° C. or less, it is considered that when it drops onto the body surface, it gels quickly and adheres to the body surface.
本発明は、温度感応性ポリマーとして２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とするポリマー材料に曇点降下剤を添加してその曇点を低下させた温度感応性材料と、この温度感応性材料よりなる止血剤を提供することを目的とする。 The present invention relates to a temperature sensitive compound in which a cloud point depressant is added to a polymer material mainly composed of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof as a temperature sensitive polymer to lower its cloud point. It is an object of the present invention to provide a hemostatic agent comprising an adhesive material and this temperature sensitive material.
本発明（請求項１）の温度感応性材料は、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とする温度感応性ポリマー材料に対し、２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールを添加してなることを特徴とするものである。 The temperature-sensitive material of the present invention (Claim 1) is a 2-amino-2-hydroxy compound with respect to a temperature-sensitive polymer material containing 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof as a polymerization main component. It is characterized by adding methyl-1,3-propanediol.
請求項２の温度感応性材料は、請求項１において、前記ポリマー材料は、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とする分岐鎖を複数本有する分岐型重合体であることを特徴とするものである。 The temperature-sensitive material according to claim 2 is the branched heavy weight according to claim 1, wherein the polymer material has a plurality of branched chains mainly composed of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof. It is a combination.
請求項３の温度感応性材料は、請求項２において、前記分岐鎖１本当りの２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体単位の分子量が、該分岐鎖１本当りの分子量の９０％以上であることを特徴とするものである。 The temperature sensitive material according to claim 3 is the temperature sensitive material according to claim 2, wherein the molecular weight of 2-N, N-dimethylaminoethyl methacrylate and / or its derivative unit per one branched chain is the molecular weight per one branched chain. It is characterized by being 90% or more.
請求項４の温度感応性材料は、請求項２又は３において、前記分岐鎖は、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体単位のみからなることを特徴とするものである。 The temperature-sensitive material according to claim 4 is characterized in that, in claim 2 or 3, the branched chain consists only of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative unit thereof.
本発明（請求項５）の止血剤は、請求項１ないし４のいずれか１項に記載の温度感応性材料よりなるものである。 The hemostatic agent of the present invention (Claim 5) is made of the temperature-sensitive material according to any one of Claims 1 to 4.
温度感応性ポリマーである、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とするポリマー材料に、２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールを加えることにより、この温度感応性ポリマーの曇点が若干ではあるが低下する。２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールの添加量が多くなるほど曇点以上の温度で凝集したポリマー材料が曇点以下の温度で溶解するまでの時間を遅延させる効果があるので、この添加量を調整することにより、曇点以下でポリマー材料が再溶解するまでの時間を任意に調整することができる。 2-amino-2-hydroxymethyl-1,3-propanediol is added to a polymer material mainly composed of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof, which is a temperature-sensitive polymer. As a result, the cloud point of this temperature-sensitive polymer is slightly reduced. As the amount of 2-amino-2-hydroxymethyl-1,3-propanediol added increases, there is an effect of delaying the time until the polymer material aggregated at a temperature above the cloud point dissolves at a temperature below the cloud point. By adjusting this addition amount, the time until the polymer material is redissolved below the cloud point can be arbitrarily adjusted.
また、この温度感応性材料よりなる止血剤は、見かけ上の曇点が低いので、わずかな温度低下で流出してしまうことがなく、安定して生体面（切開面を含む。）に固着させることができる。 In addition, the hemostatic agent made of this temperature-sensitive material has a low apparent cloud point, so that it does not flow out with a slight temperature drop, and is stably adhered to the living body surface (including the incision surface). be able to.
以下に、本発明の実施の形態を詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
本発明では、２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とするポリマー材料に対し、２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールを添加して該ポリマー材料の曇点を低下させる。
ただし、本発明でいうポリマー材料の『曇点』とは、厳密な意味で『ポリマー材料が、ある一定の温度未満で水に溶解するが、その温度以上では不溶化して疎水凝集するために水溶液懸濁する時の温度』を指すものではない。これは、ポリマー材料の水溶液を冷却・加温する速度、水溶液を入れる容器のサイズと伝熱効率、ポリマー材料の濃度などの人為的因子が測定値に影響するするために厳密な『曇点』が測定がしにくい事情を考慮してのことであり、従って、本発明では、３７℃で不溶化凝集させたポリマー材料が所定の温度未満の条件とした際に該ポリマー材料が再溶解する際の所要時間が数分以上かかる場合にその所定の温度を曇点と呼ぶも場合もある。
In the present invention, 2-amino-2-hydroxymethyl-1,3-propanediol is added to a polymer material containing 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof as a main component for polymerization. Reduce the cloud point of the polymeric material.
However, the “cloud point” of the polymer material in the present invention is, in a strict sense, “the polymer material dissolves in water at a temperature lower than a certain temperature, but becomes insoluble and hydrophobic aggregates above that temperature. It does not indicate the temperature when suspended. This is due to the fact that artificial factors such as the rate at which the aqueous solution of the polymer material is cooled and heated, the size and heat transfer efficiency of the container containing the aqueous solution, and the concentration of the polymer material affect the measurement value. Therefore, in the present invention, when the polymer material insolubilized and agglomerated at 37 ° C. is set to a temperature lower than a predetermined temperature, it is necessary to re-dissolve the polymer material. When the time is several minutes or more, the predetermined temperature may be called a cloud point.
２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体を重合主成分とする温度感応性ポリマー材料は、線形ポリマーであってもよく、前述のスター型ポリマーのような非線形ポリマーであってもよく、これらの混合物であってもよい。スター型ポリマーとしては、Ｎ，Ｎ−ジ置換ジチオカルバミルメチル基を同一分子内に３個以上有する化合物をイニファターとし、このイニファターに少なくとも２−Ｎ，Ｎ−ジメチルアミノエチルメタクリレート及び／又はその誘導体（以下、これらを「ＤＭＡＥＭ」と称す場合がある。）を光照射リビング重合させたものが好ましい。 The temperature-sensitive polymer material containing 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof as a polymerization main component may be a linear polymer or a non-linear polymer such as the aforementioned star polymer. It may be a mixture thereof. As the star polymer, a compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule is used as an iniferter, and at least 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof is included in the iniferter. (Hereinafter, these may be referred to as “DMAEM”.) Those subjected to light irradiation living polymerization are preferred.
このイニファターとは、光照射によりラジカルを発生させる重合開始剤、連鎖移動剤としての機能と共に、成長末端と結合して成長を停止する機能、さらに光照射が停止すると重合を停止させる重合開始・重合停止剤として機能する分子である。 This iniferter is a polymerization initiator that generates radicals by light irradiation, a function as a chain transfer agent, a function to stop growth by binding to the growth terminal, and a polymerization start / polymerization that stops polymerization when light irradiation stops A molecule that functions as a terminator.
イニファターとなるＮ，Ｎ−ジ置換ジチオカルバミルメチル基を同一分子内に３個以上有する芳香族化合物としては、ベンゼン環に該Ｎ，Ｎ−ジ置換ジチオカルバミルメチル基、好ましくはＮ，Ｎ−ジアルキルジチオカルバミルメチル基が３個以上分岐鎖として結合しているものが好適であり、具体的には次が例示される。即ち、３分岐鎖化合物としては、１，３，５−トリ（ブロモメチル）ベンゼンとＮ，Ｎ−ジアルキルジチオカルバミン酸ナトリウム（ナトリウムＮ，Ｎ−ジアルキルジチオカルバメート）とをエタノール中で付加反応させて得られる１，３，５−トリ（Ｎ，Ｎ−ジアルキルジチオカルバミルメチル）ベンゼンであり、４分岐鎖化合物としては、１，２，４，５−テトラキス（ブロモメチル）ベンゼンとＮ，Ｎ−ジアルキルジチオカルバミン酸ナトリウム（ナトリウムＮ，Ｎ−ジアルキルジチオカルバメート）とをエタノール中で付加反応させて得られる１，２，４，５−テトラキス（Ｎ，Ｎ−ジアルキルジチオカルバミルメチル）ベンゼンであり、６分岐鎖化合物としては、ヘキサキス（ブロモメチル）ベンゼンとＮ，Ｎ−ジアルキルジチオカルバミン酸ナトリウム（ナトリウムＮ，Ｎ−ジアルキルジチオカルバメート）とをエタノール中で付加反応させて得られるヘキサキス（Ｎ，Ｎ−ジアルキルジチオカルバミルメチル）ベンゼンが挙げられる。なお、ここで、Ｎ，Ｎ−ジアルキルジチオカルバミルメチル基に含まれるジアルキル部分のアルキル基としては、エチル基等の炭素数２〜１８個のアルキル基が好ましいが、アルキル基に限らず、フェニル基など芳香族系の炭化水素基であっても構わない。即ち、Ｎ，Ｎ−ジアルキルジチオカルバミルメチル基に限らず、Ｎ，Ｎ−ジアリールジチオカルバミルメチル基等を含む、脂肪族炭化水素基及び／又は芳香族炭化水素基で置換されたＮ，Ｎ−ジ置換ジチオカルバミルメチル基であれば目的を達成することができる。 As an aromatic compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule as an iniferter, the N, N-disubstituted dithiocarbamylmethyl group, preferably N, N A compound in which three or more dialkyldithiocarbamylmethyl groups are bonded as a branched chain is preferable, and specific examples are as follows. That is, the tri-branched compound is obtained by addition reaction of 1,3,5-tri (bromomethyl) benzene and sodium N, N-dialkyldithiocarbamate (sodium N, N-dialkyldithiocarbamate) in ethanol. 1,3,5-tri (N, N-dialkyldithiocarbamylmethyl) benzene, and four-branched compounds include 1,2,4,5-tetrakis (bromomethyl) benzene and N, N-dialkyldithiocarbamic acid 1,2,4,5-tetrakis (N, N-dialkyldithiocarbamylmethyl) benzene obtained by addition reaction of sodium (sodium N, N-dialkyldithiocarbamate) in ethanol, 6-branched compound As hexakis (bromomethyl) benzene and N, N-dialkyldithio Rubamin sodium (sodium N, N-dialkyldithiocarbamate) and the hexakis obtained by addition reaction in ethanol (N, N-dialkyldithiocarbamate carbamylmethyl) include benzene. Here, the alkyl group of the dialkyl moiety contained in the N, N-dialkyldithiocarbamylmethyl group is preferably an alkyl group having 2 to 18 carbon atoms such as an ethyl group, but is not limited to an alkyl group. It may be an aromatic hydrocarbon group such as a group. That is, not only N, N-dialkyldithiocarbamylmethyl group but also N, N-substituted by aliphatic hydrocarbon group and / or aromatic hydrocarbon group including N, N-diaryldithiocarbamylmethyl group and the like. A di-substituted dithiocarbamylmethyl group can achieve the object.
上記のイニファターは、アルコール等の極性溶媒に対しては殆ど不溶であるが、非極性溶媒には易溶である。この非極性溶媒としては炭化水素、ハロゲン化アルキル又はハロゲン化アルキレンが好適であり、特に、ベンゼン、トルエン、クロロホルム又は塩化メチレン特にトルエンが好適である。 The above iniferter is almost insoluble in polar solvents such as alcohol, but is easily soluble in nonpolar solvents. The nonpolar solvent is preferably a hydrocarbon, an alkyl halide or an alkylene halide, particularly preferably benzene, toluene, chloroform or methylene chloride, especially toluene.
イニファターと上記ＤＭＡＥＭとを反応させるには、イニファター、及びＤＭＡＥＭを含んでなる原料溶液を調製し、これに光照射することによって、イニファターに対し、ＤＭＡＥＭが結合した反応生成物を生成させる。 In order to react the iniferter with the DMAEM, a raw material solution containing the iniferter and the DMAEM is prepared and irradiated with light to thereby generate a reaction product in which DMAEM is bound to the iniferter.
該原料溶液中のＤＭＡＥＭの濃度は０．５Ｍ以上、例えば０．５Ｍ〜２．５Ｍが好適であり、イニファターの濃度は１〜２０ｍＭ程度が好適である。 The concentration of DMAEM in the raw material solution is preferably 0.5 M or more, for example, 0.5 M to 2.5 M, and the concentration of iniferter is preferably about 1 to 20 mM.
照射する光の波長は２５０〜４００ｎｍが好適であり、例えば蛍光灯、ショートアークキセノンランプ、低圧水銀灯、高圧水銀灯などを用いることができる。光の照射時間は照射強度にも依存するが、１〜９０分程度が好適であり、１μＷ／ｃｍ２〜１０ｍＷ／ｃｍ２程度の低い照射強度で１〜６０分程度が特に好適である。市販の蛍光灯を用いて光照射を行う場合には、１〜１００時間程度光照射を行うことが好ましい。 The wavelength of the irradiated light is preferably 250 to 400 nm. For example, a fluorescent lamp, a short arc xenon lamp, a low pressure mercury lamp, a high pressure mercury lamp, or the like can be used. The irradiation time of the light depends on the irradiation intensity, about 1 to 90 minutes are preferred, about 1 to 60 minutes at a low irradiation intensity of about 1μW / cm 2 ~10mW / cm 2 is particularly preferred. When light irradiation is performed using a commercially available fluorescent lamp, it is preferable to perform light irradiation for about 1 to 100 hours.
この光照射により、反応液中に目的とする分岐型重合体が生成するので、必要に応じ精製することにより、分岐鎖部分にＤＭＡＥＭ単位よりなるポリマー鎖が導入され、分岐鎖の末端がＮ，Ｎ−ジ置換ジチオカルバミルメチル基であるホモポリマーを得る。 By this light irradiation, the target branched polymer is produced in the reaction solution. Therefore, by purifying as necessary, a polymer chain composed of DMAEM units is introduced into the branched chain portion, and the end of the branched chain is N, A homopolymer which is an N-disubstituted dithiocarbamylmethyl group is obtained.
このスター型ポリマーの分岐鎖の１本当たりの分子量としては、１００〜６０，０００程度、特に２００〜３０，０００程度が好ましい。この分子量は、光照射の時間を制御することにより調整することができる。即ち、反応時間を長くすることにより、重合反応を進行させて分子量の大きい分岐型重合体を得ることができる。 The molecular weight per one branched chain of this star polymer is preferably about 100 to 60,000, particularly about 200 to 30,000. This molecular weight can be adjusted by controlling the light irradiation time. That is, by extending the reaction time, the polymerization reaction can be advanced to obtain a branched polymer having a large molecular weight.
なお、本明細書において、分子量とは、ＧＰＣ（ゲルパーミエーションクロマトグラフィー）によるポリエチレングリコール換算の数平均分子量をさす。 In addition, in this specification, molecular weight means the number average molecular weight of polyethylene glycol conversion by GPC (gel permeation chromatography).
ポリマー材料の分岐鎖は、前述のＤＭＡＥＭをモノマーとする１種のモノマーのみからなるホモポリマーであることが好ましいが、ＤＭＡＥＭとＤＭＡＥＭとは異なる１種以上のモノマーを導入したブロックコポリマー又はランダムコポリマーであってもよい。 The branched chain of the polymer material is preferably a homopolymer consisting of only one monomer having the above-mentioned DMAEM as a monomer, but is a block copolymer or a random copolymer into which one or more monomers different from DMAEM and DMAEM are introduced. There may be.
この場合の他のモノマーとしては、アクリル酸誘導体、スチレン誘導体等のビニル系モノマーが好適であり、具体的には、Ｎ，Ｎ−ジメチルアクリルアミド、メトキシエチル（メタ）アクリレート、３−Ｎ，Ｎ−ジメチルアミノプロピルアクリルアミドＣＨ２＝ＣＨＣＯＮＨＣ３Ｈ６Ｎ（ＣＨ３）２、４−Ｎ，Ｎ-ジメチルアミノスチレン、及び４−アミノスチレンの誘導体からなる群から選択される少なくとも１種のビニル系モノマーが挙げられ、特に、３−Ｎ，Ｎ−ジメチルアミノプロピルアクリルアミドＣＨ２＝ＣＨＣＯＮＨＣ３Ｈ６Ｎ（ＣＨ３）２等のカチオン性ビニル系モノマーが好ましい。これらのビニル系モノマーは１種を単独で用いてもよく、２種以上を混合して用いてもよい。 As other monomers in this case, vinyl monomers such as acrylic acid derivatives and styrene derivatives are suitable. Specifically, N, N-dimethylacrylamide, methoxyethyl (meth) acrylate, 3-N, N- Dimethylaminopropylacrylamide CH 2 = CHCONHC 3 H 6 N (CH 3 ) 2 , 4-N, N-dimethylaminostyrene, and at least one vinyl monomer selected from the group consisting of 4-aminostyrene derivatives In particular, cationic vinyl monomers such as 3-N, N-dimethylaminopropylacrylamide CH 2 ═CHCONHC 3 H 6 N (CH 3 ) 2 are preferable. These vinyl monomers may be used alone or in combination of two or more.
イニファターとＤＭＡＭＥとＤＭＡＥＭとは異なるモノマーとを反応させるには、前述のイニファターとＤＭＡＥＭとを反応させる場合と同様に、イニファター、ＤＭＡＥＭ、及びＤＭＡＥＭ以外のモノマーを含んでなる原料溶液を調製し、これに光照射することによって、イニファターに対し、ＤＭＡＥＭ及びＤＭＡＥＭ以外のモノマーが結合したランダムコポリマーを得る。 In order to react an iniferter with a monomer different from DMAME and DMAEM, a raw material solution containing monomers other than the iniferter, DMAEM, and DMAEM is prepared in the same manner as in the case of reacting the iniferter with DMAEM. Is irradiated with light to obtain a random copolymer in which monomers other than DMAEM and DMAEM are bonded to the iniferter.
また、上記イニファターに対し、まず、ＤＭＡＥＭをブロック重合させて、ホモポリマーを形成し、その後、このホモポリマーに３−Ｎ，Ｎ−ジメチルアミノプロピルアクリルアミドをブロック重合させ、分岐鎖の基端側をＤＭＡＥＭのブロックポリマー、分岐鎖の先端側を３−Ｎ，Ｎ−ジメチルアミノプロピルアクリルアミドブロックポリマーで構成した分岐鎖としてもよい。このように、分岐鎖を２種類以上のモノマーのブロックコポリマーとする場合、イニファターに対する重合の順序は任意である。 In addition, to the above iniferter, first, DMAEM is block-polymerized to form a homopolymer, and then 3-N, N-dimethylaminopropylacrylamide is block-polymerized to the homopolymer, and the base end side of the branched chain is The block polymer of DMAEM may be a branched chain composed of 3-N, N-dimethylaminopropylacrylamide block polymer on the tip side of the branched chain. Thus, when making a branched chain into a block copolymer of two or more types of monomers, the order of polymerization with respect to the iniferter is arbitrary.
いずれの場合も分岐鎖の末端は、Ｎ，Ｎ−ジ置換ジチオカルバミルメチル基となる。 In either case, the end of the branched chain is an N, N-disubstituted dithiocarbamylmethyl group.
また、ポリマー材料の分子量としては、５，０００〜５００，０００程度、特に２５，０００〜１５０，０００程度が好ましい。 In addition, the molecular weight of the polymer material is preferably about 5,000 to 500,000, particularly about 25,000 to 150,000.
線形ポリマーよりなる温度感応性ポリマー材料は、モノマーとして少なくともＤＭＡＥＭを用い、ＡＩＢＮ（アゾビスイソブチロニトリル）等の重合開始剤の存在下に常法に従って重合を行うことにより製造することができる。また、上記のスター型ポリマーの製造において、イニファターを用いないこと以外は同様にして光照射を行って製造することもできる。この線形ポリマーについても、上述のスター型ポリマーを製造する際に用いられると同様の他のモノマーを用いてもよいが、ＤＭＡＥＭによる温度感応性を十分に得るために、線形ポリマーの分子量の９０％以上、特に９５以上とりわけ１００％がＤＭＡＥＭ単位よりなることが好ましい。 A temperature-sensitive polymer material comprising a linear polymer can be produced by performing polymerization according to a conventional method in the presence of a polymerization initiator such as AIBN (azobisisobutyronitrile) using at least DMAEM as a monomer. In addition, in the production of the above star-type polymer, it can also be produced by performing light irradiation in the same manner except that the iniferter is not used. For this linear polymer, other monomers similar to those used in the production of the star polymer described above may be used, but in order to obtain sufficient temperature sensitivity by DMAEM, 90% of the molecular weight of the linear polymer. In particular, it is preferable that 95% or more, particularly 100%, is composed of DMAEM units.
また、この線形ポリマーの分子量についても、５，０００〜５００，０００程度、特に２５，０００〜１５０，０００程度が好ましい。 Also, the molecular weight of this linear polymer is preferably about 5,000 to 500,000, particularly about 25,000 to 150,000.
本発明では、上記の温度感応性ポリマー材料の水溶液に２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールを添加することにより、温度感応性ポリマー材料の曇点を低下させる。この２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールの添加量が少ない程、温度感応性材料ポリマーの曇点低下量が少なく、２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールの添加量が多くなるほど温度感応性ポリマー材料の曇点は低いものとなる。従って、この２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールの添加量は、温度感応性材料の曇点が目標とする曇点を有するように決定する。 In the present invention, the cloud point of the temperature-sensitive polymer material is lowered by adding 2-amino-2-hydroxymethyl-1,3-propanediol to the aqueous solution of the temperature-sensitive polymer material. The smaller the amount of 2-amino-2-hydroxymethyl-1,3-propanediol added, the less the cloud point lowering amount of the temperature sensitive material polymer, and 2-amino-2-hydroxymethyl-1,3-propane The higher the amount of diol added, the lower the cloud point of the temperature sensitive polymer material. Therefore, the amount of 2-amino-2-hydroxymethyl-1,3-propanediol added is determined so that the cloud point of the temperature-sensitive material has the target cloud point.
本発明では、温度感応性ポリマー材料の水溶液へ２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオールを加えることでポリマーの曇点を室温以下へ降下させることができる。そのため、このように曇点を室温以下、例えば１０〜２５℃、特に１０〜２０℃に低下させた温度感応性ポリマー材料よりなる温度感応性材料は、止血剤として好適である。この止血剤は、３２℃程度の体表面（切開面を含む）などに滴下された場合でも、速やかにゲル化し、安定して固着する。 In the present invention, the cloud point of the polymer can be lowered to room temperature or lower by adding 2-amino-2-hydroxymethyl-1,3-propanediol to an aqueous solution of a temperature sensitive polymer material. Therefore, a temperature-sensitive material made of a temperature-sensitive polymer material having a cloud point lowered to room temperature or lower, for example, 10 to 25 ° C., particularly 10 to 20 ° C. is suitable as a hemostatic agent. Even when this hemostatic agent is dropped on a body surface (including an incision surface) of about 32 ° C., it quickly gels and adheres stably.
本発明の温度感応性材料は、感温性粘着剤としても利用することができる。曇点以下の温度に保持したこの感温性粘着剤を生体と被着物との一方又は双方に塗布して両者を当接させ、感温性粘着剤の曇点以上の温度に昇温させると、両者が感温性粘着剤によって付着する。その後、冷水などの冷媒体を用いて付着部位を冷却して感温性粘着剤を曇点よりも低温にすると、この付着が解除される。 The temperature sensitive material of the present invention can also be used as a temperature sensitive adhesive. When this temperature-sensitive adhesive kept at a temperature below the cloud point is applied to one or both of the living body and the adherend, both are brought into contact with each other, and the temperature is raised to a temperature above the cloud point of the temperature-sensitive adhesive. Both are adhered by the temperature sensitive adhesive. Thereafter, when the adhering site is cooled using a refrigerant body such as cold water and the temperature-sensitive adhesive is set to a temperature lower than the cloud point, this adhesion is released.
また、本発明の温度感応性材料と顔料とを混合して身体装飾用ペイント（塗料）としてもよい。このペイントは、温度感応性材料の曇点以下の温度で身体に塗布される。このペイントを塗布した身体表面を冷水で洗うことによりペイントを洗い流すことができる。 The temperature-sensitive material of the present invention and a pigment may be mixed to form a body decoration paint. The paint is applied to the body at a temperature below the cloud point of the temperature sensitive material. The body surface to which the paint is applied can be washed away with cold water.
以下に実施例を挙げて本発明をより具体的に説明するが、本発明はその要旨を超えない限り、以下の実施例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist.
＜実施例１＞
ｉ）感温性カチオン性ホモポリマーの光重合による合成
２−（Ｎ，Ｎ−ジメチルアミノエチル）メタクリレート７．０ｇを５０ｍＬ容の透明軟質ガラス製のバイアル瓶へ加えてマグネットスタラーで混合し、高純度窒素ガスで１０分間パージした後に、丸型ブラック蛍光灯で紫外線を２１時間照射した。約５時間で増粘し、１５時間で固化した。光照射物をクロロホルムへ溶解して回収し、ｎ−ヘキサンで重合物を再沈殿させ、クロロホルム／ｎ−ヘキサン系で６回再沈殿を繰り返して精製し、ｎ−ヘキサンを蒸散させた後に少量のベンゼンへ溶解し、０．２μｍフィルターで濾過してから凍結乾燥させて感温性カチオン性ホモポリマーを得た。
<Example 1>
i) Synthesis of thermosensitive cationic homopolymer by photopolymerization 7.0 g of 2- (N, N-dimethylaminoethyl) methacrylate was added to a 50 mL transparent soft glass vial and mixed with a magnetic stirrer. After purging with high purity nitrogen gas for 10 minutes, ultraviolet rays were irradiated for 21 hours with a round black fluorescent lamp. The viscosity increased in about 5 hours and solidified in 15 hours. The light irradiated product is dissolved in chloroform and collected, and the polymer is reprecipitated with n-hexane, purified by repeating
ポリエチレングリコールを標準物質とした数平均分子量は、ＧＰＣにより１２０，０００（Ｍｗ／Ｍｎ＝２．４）と測定された。続いて、１Ｈ−ＮＭＲ（ｉｎ ＣＤ3ＯＤ）の測定結果は、δ０．８−１．２ｐｐｍ（ｂｒ，３Ｈ，−ＣＨ２−ＣＨ３−），δ１．６−２．０ｐｐｍ（ｂｒ，２Ｈ，−ＣＨ２−ＣＨ３−），δ２．２−２．４ｐｐｍ(ｂｒ，６Ｈ，Ｎ−ＣＨ３)，δ２．５−２．７ｐｐｍ（ｂｒ，２Ｈ，ＣＨ２−Ｎ），δ４．０−４．２ｐｐｍ（ｂｒ，２Ｈ，Ｏ−ＣＨ２）となった。 The number average molecular weight using polyethylene glycol as a standard substance was measured by GPC as 120,000 (Mw / Mn = 2.4). Subsequently, the measurement result of 1 H-NMR (in CD 3 OD) was δ0.8-1.2 ppm (br, 3H, —CH 2 —CH 3 —), δ 1.6-2.0 ppm (br, 2H). , —CH 2 —CH 3 —), δ 2.2-2.4 ppm (br, 6H, N—CH 3 ), δ 2.5-2.7 ppm (br, 2H, CH 2 —N), δ 4.0— 4.2ppm was (br, 2H, O-CH 2) and.
ii）曇点の測定
ｉ）で合成した感温性カチオン性ホモポリマー（以下、単に「ポリマー」と称す。）の３重量％（以下、「％」は「重量％」を示す。）水溶液（以下、単に「ポリマー溶液」と称す。）を調製し、６６０ｎｍでの吸光度の温度依存性を２０℃〜４０℃の間で測定した。なお、このii）での測定は、４０℃で懸濁させたポリマーの水溶液を毎分１℃の速度で２０℃まで降温させて行き、溶液が透明となった時の温度を曇点とした。その結果、３２℃付近に曇点を有することが分かった。
ii) Measurement of cloud point 3% by weight (hereinafter, “%” indicates “% by weight”) of the thermosensitive cationic homopolymer synthesized in i) (hereinafter simply referred to as “polymer”) Hereinafter, it was simply referred to as “polymer solution”), and the temperature dependence of absorbance at 660 nm was measured between 20 ° C. and 40 ° C. In this measurement of ii), the temperature of the aqueous solution of the polymer suspended at 40 ° C. was lowered to 20 ° C. at a rate of 1 ° C. per minute, and the temperature when the solution became transparent was taken as the cloud point. . As a result, it was found that it had a cloud point near 32 ° C.
iii）Ｔｒｉｓ９９９添加効果の測定例Ｉ
２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオール（和光純薬製、Ｔｒｉｓ９９９、以下「Ｔｒｉｓ」と記載する。）の顆粒をii）で調製したポリマー溶液と混合し、水を加えて終濃度を１ｍＭ〜１０００ｍＭの範囲に調整した。ポリマーの終濃度は０．０１％〜２．５％の範囲で調整した。
iii) Measurement example I of Tris999 addition effect I
The granules of 2-amino-2-hydroxymethyl-1,3-propanediol (manufactured by Wako Pure Chemical Industries, Tris 999, hereinafter referred to as “Tris”) are mixed with the polymer solution prepared in ii), and water is added. The final concentration was adjusted to a range of 1 mM to 1000 mM. The final concentration of the polymer was adjusted in the range of 0.01% to 2.5%.
室温において、Ｔｒｉｓの顆粒をポリマー溶液へ混合した瞬間にポリマー溶液は懸濁を開始し、ポリマー濃度０．５％以上では溶液全体がゲル化し、ポリマー濃度０．２％未満では凝集したポリマー塊が水と相分離して沈殿した。Ｔｒｉｓ顆粒の濃度としては１０ｍＭ未満では凝集したポリマー塊が水と相分離して沈殿し、１００ｍＭ以上では溶液全体がゲル化した。ポリマー側鎖と２−アミノ−２−ヒドロキシメチル−１，３−プロパンジオール分子が定量的に架橋性の結合を起すことによりポリマー材料が凝集しやすくなっているものと考えられる。ポリマー塊が凝集相分離した系、ゲル化した系ともに冷蔵庫中へ移すと速やかに溶解して無色透明な水溶液となり、室温へ戻すと応答性良くポリマー塊が凝集相分離した系かゲル化した系へ戻り、繰り返しこの操作を行なっても応答性に変化はなく可逆的に相転移する現象が起こることが確認された。 At room temperature, the polymer solution starts to be suspended as soon as the Tris granules are mixed into the polymer solution. When the polymer concentration is 0.5% or more, the whole solution is gelled, and when the polymer concentration is less than 0.2%, the aggregated polymer mass is It was separated from water and precipitated. When the concentration of Tris granules was less than 10 mM, the aggregated polymer mass was phase-separated from water and precipitated, and when it was 100 mM or more, the entire solution was gelled. The polymer side chain and the 2-amino-2-hydroxymethyl-1,3-propanediol molecule are considered to be easily aggregated by quantitatively causing a crosslinkable bond. Both the system in which the polymer mass is separated into agglomerated phase and the gelled system quickly dissolves into a colorless and transparent aqueous solution when it is transferred to the refrigerator. It was confirmed that even when this operation was repeated, there was no change in responsiveness and a phenomenon of reversible phase transition occurred.
上記ii）と同様にして曇点を測定した結果を表１に示す。 Table 1 shows the results of measuring the cloud point in the same manner as in ii) above.
iv）Ｔｒｉｓ添加効果の測定例II
上記ｉ）で合成したポリマーとＴｒｉｓを水に溶解し、終濃度をポリマー０．１％、Ｔｒｉｓはポリマーとの重量比で０、０．５、１．０、２．０、４．０又は８．０となるように調整した。なお、０はＴｒｉｓを添加しなかったものである。
iv) Measurement example of Tris addition effect II
The polymer synthesized in i) and Tris are dissolved in water, the final concentration is 0.1% polymer, and Tris is 0, 0.5, 1.0, 2.0, 4.0 or 4.0 by weight ratio with the polymer. It adjusted so that it might be set to 8.0. In addition, 0 is what added no Tris.
各水溶液２ｍＬを１０ｍｍ×１０ｍｍ角石英セル（厚み１ｍｍ）へ入れ、３７℃の水浴で加温して白濁させた。 2 mL of each aqueous solution was put into a 10 mm × 10 mm square quartz cell (thickness 1 mm) and heated in a 37 ° C. water bath to be clouded.
２５℃の恒温室に設置した吸光度計に各セルをセットし、波長６００ｎｍの光透過率の経時変化を測定した。結果を図１に示す。 Each cell was set in an absorptiometer installed in a thermostatic chamber at 25 ° C., and a change with time in light transmittance at a wavelength of 600 nm was measured. The results are shown in FIG.
図１の通り、Ｔｒｉｓの添加量が多くなるほど白濁液が透明になるまでの時間が長くなる。これは、Ｔｒｉｓの添加量が多くなるほど、ポリマー材料が凝集し易くなるためであると考えられる。
上記iii）の実験は、曇点以上の温度環境で凝集させたポリマー溶液が速やかに透明になる時の温度を測定した評価系であり、このiv）の実験は、凝集させたポリマーを２５℃に維持した際に溶解するまでの時間を測定した評価系であり、いずれの場合も『曇点』と呼んで良いと考えられるが、測定方法によって差異が生じることが分かる。
As shown in FIG. 1, as the amount of Tris increases, the time until the cloudy liquid becomes transparent becomes longer. This is considered to be because the polymer material tends to aggregate as the amount of Tris added increases.
The experiment of the above iii) is an evaluation system that measures the temperature when the polymer solution aggregated in a temperature environment above the cloud point quickly becomes transparent. It is an evaluation system that measures the time until dissolution when it is maintained, and in any case it can be called a “cloud point”, but it can be seen that there is a difference depending on the measurement method.
ｖ）Ｔｒｉｓ添加効果の測定例III
上記ｉ）で合成したポリマーとＴｒｉｓを水に溶解し、終濃度をポリマー０．１％、Ｔｒｉｓはポリマーとの重量比で０、０．５、１．０、２．０、４．０又は８．０となるように調整した。なお、０はＴｒｉｓを添加しなかったものである。
v) Measurement example III of Tris addition effect
The polymer synthesized in i) and Tris are dissolved in water, the final concentration is 0.1% polymer, and Tris is 0, 0.5, 1.0, 2.0, 4.0 or 4.0 by weight ratio with the polymer. It adjusted so that it might be set to 8.0. In addition, 0 is what added no Tris.
各水溶液２ｍＬを１０ｍｍ×１０ｍｍ角石英セル（厚み１ｍｍ）へ入れた。 2 mL of each aqueous solution was put into a 10 mm × 10 mm square quartz cell (thickness 1 mm).
２０℃の恒温室に設置した吸光度計に各セルをセットし、４０分経過後、波長６００ｎｍの光透過率を測定した。 Each cell was set in an absorptiometer installed in a constant temperature room at 20 ° C., and light transmittance at a wavelength of 600 nm was measured after 40 minutes.
また、温度を２１℃、２２℃、・・・又は３７℃（１℃刻み）としたこと以外は上記と同じ測定を行った。結果を表２に示す。
なお、上記iv）の実験の結果から、水溶液の温度を一定に維持した場合、約３０〜４０分後にポリマーの状態が安定化することが分かっているため、このｖ）の実験での測定値が外的因子の影響を受けにくい『曇点』であると言える。
Further, the same measurement as described above was performed except that the temperature was 21 ° C., 22 ° C.,..., Or 37 ° C. (in increments of 1 ° C.). The results are shown in Table 2.
In addition, from the result of the experiment of the above iv), it is known that the polymer state is stabilized after about 30 to 40 minutes when the temperature of the aqueous solution is kept constant. Can be said to be a “cloud point” that is not easily affected by external factors.
表２の通り、このポリマーの曇点は３２℃であり、Ｔｒｉｓを添加することにより曇点が低下すること、Ｔｒｉｓの添加量と曇点低下量との間には緩い相関があることが認められた。 As shown in Table 2, the cloud point of this polymer is 32 ° C., and it is recognized that the cloud point is lowered by adding Tris, and there is a loose correlation between the amount of Tris added and the cloud point drop amount. It was.
vi）Ｔｒｉｓ添加効果の測定例IV
上記ｉ）で合成したポリマーとＴｒｉｓを重水に溶解し、終濃度をポリマー０．１％、Ｔｒｉｓはポリマーとの重量比で０．６５、１．３、２．６又は５．８となるように調整した。
vi) Measurement example IV of Tris addition effect IV
The polymer synthesized in i) and Tris are dissolved in heavy water so that the final concentration is 0.1% of the polymer, and Tris is 0.65, 1.3, 2.6, or 5.8 by weight ratio with the polymer. Adjusted.
各Ｔｒｉｓ／ポリマー溶液について、４℃、２５℃又は３７℃の各温度でＮＭＲを測定し、ポリマー側鎖の−Ｎ（ＣＨ３）２の１Ｈ積分値とＴｒｉｓ中の−ＣＨ２−の１Ｈ積分値との比を算出し、結果を図２に示した。 Each Tris / polymer solution, 4 ℃, 25 ℃ or 37 NMR measurement at each temperature of ° C., -N polymer side chains (CH 3) 2 The 1 H integrated value and -CH 2 in Tris - 1 The ratio with the H integrated value was calculated, and the results are shown in FIG.
図２より明らかなように、ポリマー側鎖の−Ｎ（ＣＨ３）２の１Ｈの積分値とＴｒｉｓ中の−ＣＨ２−の１Ｈの積分値の比は、４℃では配合比通りとなっているが、２５℃ではＴｒｉｓ添加量が多い領域で理論値からはずれてゆき、３７℃ではポリマー側鎖のピークは検出されない。これは、疎水凝集によるミセル形成によって遮蔽された結果であると考えられる。 As apparent from FIG. 2, -CH 2 of the polymer side -N chain (CH 3) integral value of 2 of the 1 H and in Tris - the ratio of the integrated value of the 1 H of a street at 4 ° C. compounding ratio However, at 25 ° C., it deviates from the theoretical value in a region where the amount of Tris added is large, and at 37 ° C., no polymer side chain peak is detected. This is considered to be a result of shielding by micelle formation by hydrophobic aggregation.
vii）Ｔｒｉｓ添加効果の測定例Ｖ
上記ｉ）で合成したポリマーとＴｒｉｓを水に溶解し、終濃度をポリマー０．１％、Ｔｒｉｓはポリマーとの重量比で０、０．５、１．０、２．０、４．０又は８．０となるように調整した。なお、０はＴｒｉｓを添加しなかったものである。
vii) Measurement example V of Tris addition effect
The polymer synthesized in i) and Tris are dissolved in water, the final concentration is 0.1% polymer, and Tris is 0, 0.5, 1.0, 2.0, 4.0 or 4.0 by weight ratio with the polymer. It adjusted so that it might be set to 8.0. In addition, 0 is what added no Tris.
各Ｔｒｉｓ／ポリマー溶液について、それぞれ４０℃で凝固させたものを瞬時に２５℃まで冷却して維持した際の微分ＤＳＣ曲線を測定し、結果を図３に示した。図３より、Ｔｒｉｓ配合量の増大に伴い、吸熱が起こる（疎水凝集体が溶解する）までの時間に遅延が生じることが分かる。 For each Tris / polymer solution, a differential DSC curve was measured when each solidified at 40 ° C. was instantaneously cooled to 25 ° C. and maintained, and the results are shown in FIG. From FIG. 3, it can be seen that a delay occurs in the time until endotherm occurs (hydrophobic aggregate dissolves) as the Tris content increases.
以上の実験の通り、３つの原理の異なる測定、即ち、
測定例II：水中凝集による光透過性(濁り)
測定例IV：水中での疎水凝集による磁場遮蔽
測定例Ｖ：再溶解時の熱エネルギー変化
の測定結果から、Ｔｒｉｓを配合することによって、Ｔｒｉｓ／ポリマー組成物の熱的応答性が変化することが確認された。
この結果から、本発明によれば、Ｔｒｉｓ配合によって、２５℃での操作中にポリマーのコーティング層が溶出してしまうことを防ぎ、温度感応的に形成された凝集層の目的を十分に発揮できるという効果が得られることが分かる。
As described above, the three principles have different measurements:
Measurement Example II: Light transmission due to aggregation in water (turbidity)
Measurement Example IV: Magnetic Field Shielding by Hydrophobic Aggregation in Water Measurement Example V: From the measurement result of change in thermal energy at the time of redissolution, the thermal responsiveness of the Tris / polymer composition can be changed by adding Tris. confirmed.
From this result, according to the present invention, the Tris compound prevents the coating layer of the polymer from eluting during the operation at 25 ° C., and can fully exhibit the purpose of the temperature-sensitive aggregated layer. It can be seen that the effect is obtained.
viii）体表面（室温）へ滴下したポリマー
ラット背部皮膚の一部を切開して表皮を切除して露出させた。
viii) Polymer dropped on the body surface (room temperature) A part of the rat dorsal skin was incised to expose the epidermis.
２．５％ポリマー溶液（１００ｍＭ Ｔｒｉｓと、視認しやすくする目的で少量転換したエオシン色素を含む）を冷蔵庫から出して速やかに露出部位へ滴下した。体表面温度はほとんど室温であったが、液垂れすることなく、滴下部位で硬化した。さらに室温で保管した生理食塩水で洗浄したが、硬化したポリマーは流出することなく滴下部位へ留まった。室温でも水溶液とならずにゲル化状態を維持することが確認された。 A 2.5% polymer solution (containing 100 mM Tris and eosin dye converted in a small amount for the purpose of facilitating visual recognition) was taken out of the refrigerator and quickly dropped onto the exposed site. The body surface temperature was almost room temperature, but cured at the dropping site without dripping. Furthermore, although it wash | cleaned with the physiological saline stored at room temperature, the hardened | cured polymer remained in the dripping site | part, without flowing out. It was confirmed that the gelled state was maintained without becoming an aqueous solution even at room temperature.
ix）止血剤としての使用
ウサギ腹部動脈を露出させ、枝血管を切除して出血させた。上記iv）で調製したポリマーを出血部位へ滴下すると、ポリマーは出血部位でゲル化して固着した。さらにポリマーが僅かに帯電している陽電荷の効果で血液の凝集が起こり出血を止めることができた。
ix) Use as a hemostatic agent Rabbit abdominal arteries were exposed, branch vessels were excised and bled. When the polymer prepared in the above iv) was dropped onto the bleeding site, the polymer gelled and fixed at the bleeding site. Furthermore, blood aggregation occurred due to the effect of the positive charge in which the polymer was slightly charged, and bleeding could be stopped.
＜比較例１＞
上記ｉ）で合成したポリマーの２．５％水溶液へ、（Ａ）何も加えないか、（Ｂ）１００ｍＭＴｒｉｓ緩衝溶液（等モル塩酸塩）を加えること以外は上記viii）と同様の実験を行うと、Ａ，Ｂいずれの材料も体表面へ固着することなく液垂れして流出し、生理食塩水の洗浄で、完全に除去された。曇点が体表面の温度（室温に近い）以上であり、疎水性の凝集（ゲル化）が起こらないためである。
<Comparative Example 1>
The same experiment as in viii) above is performed except that (A) nothing is added or (B) 100 mM Tris buffer solution (equimolar hydrochloride) is added to the 2.5% aqueous solution of the polymer synthesized in i) above. Then, both the materials A and B drip out without adhering to the body surface, and were completely removed by washing with physiological saline. This is because the cloud point is not less than the temperature of the body surface (close to room temperature) and hydrophobic aggregation (gelation) does not occur.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012283090A JP6032483B2 (en) | 2011-12-28 | 2012-12-26 | Temperature sensitive materials and hemostatic agents |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011287593 | 2011-12-28 | ||
| JP2011287593 | 2011-12-28 | ||
| JP2012283090A JP6032483B2 (en) | 2011-12-28 | 2012-12-26 | Temperature sensitive materials and hemostatic agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013150796A true JP2013150796A (en) | 2013-08-08 |
| JP6032483B2 JP6032483B2 (en) | 2016-11-30 |
Family
ID=49047690
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012283090A Expired - Fee Related JP6032483B2 (en) | 2011-12-28 | 2012-12-26 | Temperature sensitive materials and hemostatic agents |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6032483B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013136660A (en) * | 2011-12-28 | 2013-07-11 | National Cerebral & Cardiovascular Center | Temperature-sensitive material |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20230257686A1 (en) * | 2020-07-03 | 2023-08-17 | National University Corporation Okayama University | Method for producing cartilage tissue |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58127753A (en) * | 1982-01-25 | 1983-07-29 | Pilot Pen Co Ltd:The | Reversible thermowhitening composition |
| JP2006043204A (en) * | 2004-08-05 | 2006-02-16 | National Cardiovascular Center | Wound healing promoter |
| JP2008274151A (en) * | 2007-05-01 | 2008-11-13 | Teika Seiyaku Kk | Wound-covering composition and wound-covering material |
| CN101348570A (en) * | 2008-09-03 | 2009-01-21 | 东华理工大学 | A kind of preparation method of self-assembled nanomicelle of star copolymer |
| WO2013099924A1 (en) * | 2011-12-28 | 2013-07-04 | 独立行政法人国立循環器病研究センター | Method for producing cell having nucleic acid introduced therein |
| JP2013135623A (en) * | 2011-12-28 | 2013-07-11 | National Cerebral & Cardiovascular Center | Nucleic acid transfer agent, method for transferring nucleic acid and cell |
| JP5852880B2 (en) * | 2011-12-28 | 2016-02-03 | 国立研究開発法人国立循環器病研究センター | Temperature sensitive material |
-
2012
- 2012-12-26 JP JP2012283090A patent/JP6032483B2/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58127753A (en) * | 1982-01-25 | 1983-07-29 | Pilot Pen Co Ltd:The | Reversible thermowhitening composition |
| JP2006043204A (en) * | 2004-08-05 | 2006-02-16 | National Cardiovascular Center | Wound healing promoter |
| JP2008274151A (en) * | 2007-05-01 | 2008-11-13 | Teika Seiyaku Kk | Wound-covering composition and wound-covering material |
| CN101348570A (en) * | 2008-09-03 | 2009-01-21 | 东华理工大学 | A kind of preparation method of self-assembled nanomicelle of star copolymer |
| WO2013099924A1 (en) * | 2011-12-28 | 2013-07-04 | 独立行政法人国立循環器病研究センター | Method for producing cell having nucleic acid introduced therein |
| JP2013135623A (en) * | 2011-12-28 | 2013-07-11 | National Cerebral & Cardiovascular Center | Nucleic acid transfer agent, method for transferring nucleic acid and cell |
| JP5852880B2 (en) * | 2011-12-28 | 2016-02-03 | 国立研究開発法人国立循環器病研究センター | Temperature sensitive material |
Non-Patent Citations (3)
| Title |
|---|
| JPN6016010278; Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅ， ２００９， Ｖｏｌ．９８（１２）， ｐ．４７１１-４７２３ * |
| JPN6016010279; ｅ-Ｐｏｌｙｍｅｒｓ， ２００５， Ｎｏ．０５７， ｐ．１-１１ＵＲＬ：ｈｔｔｐ：／／ｗｗｗ．ｄｅｇｒｕｙｔｅｒ．ｃｏｍ／ｖｉｅｗ／ｊ／ｅｐｏｌｙ．２００５．５．ｉｓｓｕｅ-１／ｅｐｏｌｙ．２００５． * |
| JPN6016010281; Ｊｏｕｒｎａｌ ｏｆ Ｃｏｌｌｏｉｄ ａｎｄ Ｉｎｔｅｒｆａｃｅ Ｓｃｉｅｎｃｅ， ２００９， Ｖｏｌ．３２９， ｐ．２４４-２５２ * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013136660A (en) * | 2011-12-28 | 2013-07-11 | National Cerebral & Cardiovascular Center | Temperature-sensitive material |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6032483B2 (en) | 2016-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yin et al. | Poly (N-isopropylacrylamide-co-propylacrylic acid) copolymers that respond sharply to temperature and pH | |
| Ning et al. | Synthesis of highly stretchable, mechanically tough, zwitterionic sulfobetaine nanocomposite gels with controlled thermosensitivities | |
| Xia et al. | End group effect on the thermal response of narrow-disperse poly (N-isopropylacrylamide) prepared by atom transfer radical polymerization | |
| JP5439551B2 (en) | Block copolymer coating | |
| Li et al. | Synthesis and characterization of biocompatible thermo-responsive gelators based on ABA triblock copolymers | |
| Qiao et al. | Biocompatible thermoresponsive polymers with pendent oligo (ethylene glycol) chains and cyclic ortho ester groups | |
| O’Lenick et al. | Rheological properties of aqueous micellar gels of a thermo-and pH-sensitive ABA triblock copolymer | |
| JP5746240B2 (en) | Temperature-responsive polymer manufacturing method, temperature-responsive polymer, cell culture device manufacturing method, and cell culture device | |
| US20190263973A1 (en) | Cucurbituril-based hydrogels | |
| Ziółkowski et al. | Thermoresponsive poly (ionic liquid) hydrogels | |
| Tsitsilianis et al. | Thermoresponsive hydrogels based on telechelic polyelectrolytes: from dynamic to “frozen” networks | |
| CN106496568B (en) | A kind of cleaning and antifouling amphiphilic copolymer network and preparation method thereof | |
| Li et al. | Preparation and characterization of thermoresponsive PEG-based injectable hydrogels and their application for 3D cell culture | |
| Sugihara et al. | Design of hydroxy-functionalized thermoresponsive copolymers: improved direct radical polymerization of hydroxy-functional vinyl ethers | |
| JP6375358B2 (en) | Cell culture composition and cell culture vessel | |
| Rikkou-Kalourkoti et al. | Synthesis and characterization of end-linked amphiphilic copolymer conetworks based on a novel bifunctional cleavable chain transfer agent | |
| Wang et al. | Thermoresponsive degradable poly (ethylene glycol) analogues | |
| JP6032483B2 (en) | Temperature sensitive materials and hemostatic agents | |
| CN108164655A (en) | A kind of application of n-isopropyl acrylamide copolymer of the side chain containing azo pyridine | |
| CN108299591A (en) | A kind of preparation method of n-isopropyl acrylamide copolymer of the side chain containing azo pyridine | |
| Deng et al. | Synthesis of well-defined poly (N-isopropylacrylamide)-b-poly (L-glutamic acid) by a versatile approach and micellization | |
| EP3269747B1 (en) | Antithrombotic block copolymer | |
| JP6718610B2 (en) | Cell culture substrate, method for producing the same, and method for controlling physical properties of cell culture substrate | |
| US20220411591A1 (en) | Cucurbituril-based hydrogels | |
| WO2023013410A1 (en) | Polymer composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20130910 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130930 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20130930 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150619 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160322 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160523 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20160913 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20161012 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6032483 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313117 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |