JPH0676333B2 - ヘモグロビン―ポリオキシアルキレン結合体 - Google Patents

ヘモグロビン―ポリオキシアルキレン結合体

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Publication number
JPH0676333B2
JPH0676333B2 JP61142302A JP14230286A JPH0676333B2 JP H0676333 B2 JPH0676333 B2 JP H0676333B2 JP 61142302 A JP61142302 A JP 61142302A JP 14230286 A JP14230286 A JP 14230286A JP H0676333 B2 JPH0676333 B2 JP H0676333B2
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Prior art keywords
hemoglobin
polyoxyalkylene
polyoxyethylene
solution
molecular weight
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JPS6289630A (ja
Inventor
敬治 岩崎
健俊 岡見
晃徳 権正
昭 矢吹
雄二 岩下
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Ajinomoto Co Inc
Fujirebio Inc
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Ajinomoto Co Inc
Fujirebio Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/795—Porphyrin- or corrin-ring-containing peptides
    • C07K14/805—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

【発明の詳細な説明】 産業上の利用分野 本発明は、代用血液中に必要な酸素運搬物質として使用
する新規なヘモグロビン−ポリオキシアルキレン結合体
に関する。
従来の技術 代用血液に使用する酸素運搬物質としてヘモグロビン−
ポリオキシアルキレン結合体が血流内寿命を大幅に延ば
すことができる点で優れていることは既に明らかにされ
ている（特開昭56-12308号,57-206622号明細書参
照。）。
発明が解決しようとする問題点 ヘモグロビンが生体成分であるところから、ポリオキシ
アルキレンを結合させることによりヘモグロビンが変性
したり酸素親和性を減少させたりする問題があった。さ
らに、得られたヘモグロビン−ポリオキシアルキレン結
合体の保存性特にポリオキシアルキレン−ヘモグロビン
間の結合の安定性にも問題があった。
問題点を解決するための手段 本発明者はこのような問題点を解決するべく種種検討の
結果、末端にエーテル結合を介してカルボキシル基を有
するポリオキシアルキレンを用いてこれにヘモグロビン
をアミド結合させて得られた結合体は前記問題点を解決
したものであることを見出して本発明を完成するに至っ
た。
すなわち、本発明は、ポリオキシアルキレン末端とヘモ
グロビンのアミノ基との結合部分が下記の構造式よりな
るヘモグロビン−ポリオキシアルキレン結合体に関する
ものである。
‐CH2‐O-(CH2)n‐CONH-Hb （式中、Hbはヘモグロビンを表わし、ｎ＝１〜７であ
る。） 本発明で用いられるポリオキシアルキレンは、例えばポ
リオキシエチレン（エチレンオキサイドの重合体でポリ
エチレングリコールともいう。）、ポリオキシプロピレ
ンあるいはエチレンオキサイドとプロピレンオキサイド
との共重合体等水溶性の高い重合物であり、その分子量
は300〜20,000、製造される結合体の粘度等の観点から
好ましくは750〜10,000、特に好ましくは1000〜6000、
の範囲内にあるものである。
ポリオキシアルキレンの末端とカルボキシル基部分との
間の結合にはエステル結合、アミド結合、エーテル結合
等が考えられる。これらの結合のうちで特にエーテル結
合が有効であることを見出してなされたのが本発明であ
る。従って、本発明のヘモグロビン−ポリオキシアルキ
レン結合体の合成に使用されるポリオキシアルキレンは
ヘモグロビンを結合させる末端が‐O-(CH2)n‐COOHに変
換されているものである。ｎは１〜10程度であり、１〜
７程度、特に１〜３程度のものが選択されることが多
い。
ポリオキシアルキレンの末端をこのような形に変換する
方法としては、白金、パラジウムの炭素担持触媒を用い
て末端炭素を酸化する方法、活性化二酸化マンガンで末
端のオキシメチル基を酸化してアルデヒドに変え、過酸
化水素でさらに酸化してカルボン酸にする方法、塩基の
存在下でポリオキシアルキレンにハロゲン化脂肪酸を反
応させる方法、ジアゾ基を有する脂肪酸とポリオキシア
ルキレンを反応させる方法などを利用すればよい。
このようにカルボキシル基を付与されたポリオキシアル
キレンとヘモグロビンの反応に際して、例えばＮ−ヒド
ロキシコハク酸イミド、Ｎ−ヒドロキシフタル酸イミ
ド、ｐ−ニトロフェノール、ペンタクロロフェノール等
通常のペプチド合成におけるカルボン酸活性化剤により
活性エステルとし、これとヘモグロビンと反応させてア
ミド交換することもできるし、塩化チオニル等ハロゲン
化剤を作用させてポリオキシアルキレンの酸ハロゲン化
物とし、これとヘモグロビンとを反応させることもでき
る。
本発明に使用するヘモグロビンは、ヒト、ウシ、ブタ、
ヒツジ、ウマ、イヌ、サル、ウサギ、ニワトリ等ヘモグ
ロビンを有する動物由来のものであればよい。本明細書
でいうヘモグロビンとは、いわゆる異常ヘモグロビン
（K.Imai,Alloaterle Effects in Haemoglobin,Cambrid
ge University Press,1980参照）あるいはピリドキサー
ル−リン酸例えば、ピリドキサール−５′−リン酸、２
−ノル−２−ホルミルピリドキサール−５′−リン酸、
ピリドキサール−硫酸、例えばピリドキサール−５′−
硫酸、グリセリンリン酸類、例えばグリセリン−2,3−
ジリン酸、糖リン酸、例えばグルコース−６−リン酸、
アデノシン−５′−リン酸等のヘモグロビン誘導体であ
ってもよい。
ヘモグロビンの反応時の濃度は、0.5〜20％（重量）程
度、好ましくは0.5〜10％（重量）程度である。しかし
ながら、アミノ酸等が共存せずヘモグロビン濃度が４％
を越えた場合には、架橋反応が進んで高分子化しゲル化
しやすくなるので反応の管理に注意を要する。一方、ヘ
モグロビンが低濃度になると反応容器が大型化するとと
もに反応後に濃縮が必要になるので好ましくない。
ポリオキシアルキレンの使用量は、ヘモグロビン１モル
に対して１〜50モル程度、好ましくは２〜10モル程度で
ある。
ポリオキシアルキレンとヘモグロビンとの結合反応にお
いてアミノ酸又はアミンを共存させることにより、生成
するヘモグロビン−ポリオキシアルキレン結合体の分子
量をコントロールすることができる。これはポリオキシ
アルキレンの活性化されたカルボキシル基の一部にアミ
ノ酸又はアミンを結合させてヘモグロビンへの結合を阻
止することによる。この方法により、ヘモグロビンを希
薄溶液としなくとも好ましい結合体を得ることができ
る。
反応時に存在せしめるアミノ酸は、例えば蛋白質の構成
アミノ酸を使用すればよく、リジン、アルギニン、ヒス
チジン等の塩基性アミノ酸、グリシン、フェニルアラニ
ン等の中性アミノ酸、グルタミン酸、アスパラギン酸等
の酸性アミノ酸が例示される。一方、アミンはアンモニ
ア、脂肪族アミン、芳香族アミンのいずれでもよいが、
本物質が血流内に投与される関係から安全性の高いもの
が好ましい。アミノ酸及びアミンは１種であってもよ
く、２種以上であってもよい。アミノ酸又はアミンのア
ミノ基が第３級である場合には活性エステルの分解を触
媒することによりヘモグロビンと結合していないポリオ
キシアルキレンの末端は‐O-(CH2)n‐COOHの形をとる。
一方、第１級又は第２級の場合には末端が‐O-(CH2)n‐
CONHRとなり、Ｒの種類によってヘモグロビン表面の電
荷や疎水性を変えることができる。これによって本発明
の結合体を代用血液に用いた場合に生体内の血液との混
合によって接する赤血球、白血球、血漿タンパク等との
相互作用を変えて免疫的認識等を好ましい方向に変える
ことができる。アミノ酸の使用量はヘモグロビン１モル
に対し１〜100モル程度、好ましくは５〜20モル程度で
ある。
ヘモグロビンとポリオキシアルキレンとを結合させる反
応時に、酸素不存在か酸素低濃度とするのが好ましい、
酸素分圧として０〜30mmHg程度を選択すればよい。上記
酸素濃度以外の反応条件は、ヘモグロビンの変性を伴わ
ない条件であればいずれであってもよい。
酸素の濃度を低下させるには、窒素、アルゴン、ヘリウ
ム等の不活性ガスで反応容器中の空気を置換する方法、
容器中の酸素を還元剤（NaBH4、Na2S2O3等）によって還
元し除去する方法、ポンプ等で脱ガスしアルゴン等の不
活性ガスで置換する方法等、公知の方法を採用すること
ができる。
このようにして得られたヘモグロビン−ポリアルキレン
結合体は通常は凍結乾燥して製剤化する。
作用 本発明のヘモグロビン−ポリオキシアルキレン結合体
は、エーテル結合を介してカルボン酸が結合した形のポ
リオキシアルキレンを用いることによって、ヘモグロビ
ンの酸素親和力を低下させないばかりでなく、安定性の
高い結合体になっている。
例えばポリオキシエチレン4000の末端が-OCO(CH2)2COO
H、-NHCO(CH2)2COOH、-O-CH2COOHの３種のポリオキシエ
チレンを調製し、これらのポリオキシエチレンと結合さ
せた３種のポリオキシエチレン−ヘモグロビン結合体の
加水分解反応に対する抵抗性を比較したところ次のよう
な結果が得られた。すなわち、上記エステル型（Ｉ）、
アミド型（II）、エーテル型（III）の各々５％水溶液
（pH7.0 0.1規定リン酸緩衝液）を35℃で１週間インキ
ュベートし、分解によって生じたポリオキシエチレンを
定量したところ、III＞II＞Ｉの順となった。そこで、
最も安定性が秀れているのがエーテル型である事が明ら
かとなった。
以下実施例で本発明の詳細を説明する。
なお、これらの実施例において、生成物の分子量はプレ
パックドゲル（Prepacked）型カラムSW3000G（東洋ソー
ダ（株）、日本）を用い高速液体クロマトグラフィーよ
り測定した。
なお用いた展開溶媒は0.1Mリン酸緩衝液（pH＝6.8）を
使用し、分子量はファルマシア社製（Pharmacia Fine C
hem.,Sweden）の分子量決定のための標準タンパク質キ
ットを用いて検量線を求め、溶出量より推定した。
またヘモグロビン１分子当りの結合ポリアルキレン分子
数は、限外過により完全に塩類と未反応ポリオキシア
ルキレンを除去して、凍結乾燥（脱水）した後、重量測
定し、その後吸光度より算出して当該サンプル中のヘモ
グロビン量を差引く事によって求めた。
またえられた安定化ヘモグロビンの酸素解離曲線の測定
はpH7.4の0.1Mリン酸緩衝液を用い、今井らの方法（K.I
mai.H.Morimoto,M.Kotani,H.Waka,M.Kuroda,Biochim.Bi
ophys.Acta.,200,189〜196(1970)）によっておこなっ
た。
実施例１ 分子量1000ダルトンのポリオキシエチレン（Aldrich Ch
emical Co.,USA）30g（30mモル）と３−クロロプロピオ
ン酸エチル16.4g（120mモル）を乾燥したジメチルホル
ムアミド700mlに溶解し、これに20gの酸化銀を加え70°
で24時間反応したのち沈殿物を過により除去した。
えられた液は3lの冷却したエチルエーテル中にそそ
ぎ、ポリオキシエチレン誘導体を沈殿させた。
沈殿物はエチルエーテルで洗浄後乾燥し、水300mlに再
び溶かし、１規定水酸化ナトリウム水溶液をpH11以上に
なるまで加え、60℃で一夜攪拌してエステルの加水分解
をおこなった。
１規定塩酸で反応液を中和してpH5とし、濃縮、乾固し
た。
えられた生成物は塩化メチレン−エーテルの1:1混合溶
液200mlに溶かし不溶物を別したのち濃縮し、白色粉
末を沈殿によってえた。
えられた固型物を水100mlに溶解したのち強塩基性イオ
ン交換樹脂Bio-Rad AGIX2（Bio-Rad Laboratories,US
A）にかけ、吸着物を0.05規定塩酸で溶離した。
生成物は18gの白色結晶であった。
この生成物（ポリオキシエチレンのジカルボン酸誘導
体）10gとＮ−ヒドロキシコハク酸イミド6.5g（56.5ミ
リモル）をジメチルホルムアミド200mlに溶かし、ジシ
クロヘキシルカルボジイミドで脱水縮合してポリオキシ
エチレン1000の活性エステル9.8gをえた。
一方ウシの新鮮赤血球100mlを0.9％食塩水に浮遊させ遠
心分離機を用いて４℃で４回洗浄した。
ウシ洗浄赤血球60mlを同容の注射薬用蒸留水を用いて溶
血し孔径0.22μのフィルター（Millipore Co.,USA）を
用いて膜成分を除いた。さらに残存する膜成分は遠心分
離機で6000回転１時間遠心分離して除いた。
えられたウシヘモグロビン溶液10gを200mlのホウ酸0.1
モル緩衝液pH7.0に溶解し、えられた溶液（0.15ミリモ
ル）に活性ポリオキシエチレン4.7g（3.5ミリモル）と
リジン212mg（1.45ミリモル）を加え、アルゴンで酸素
分圧1mmHgまで引下げたあと４℃で２時間反応させた。
えられた反応液は分画分子量10,000ダルトンの限外過
膜YM-10（Amicon Co,UAS）で未反応ポリオキシエチレン
が100ppm以下になるまでくり返し精製した。
生成した反応液のゲル過クロマトグラフィーにおける
ピークの面積比から原料ヘモグロビンは、ほとんど残存
せず、第１図に例示するような単量体型（Ａ），二重体
型（Ｂ），三重体型（Ｃ）がほぼ5:3:1で混合している
事が判明した。尚、図中丸４つでヘモグロビン分子を表
わし、カギ形はポリオキシエチレンを表わしている。
またヘモグロビン分子１個あたりについているポリオキ
シエチレンの結合分子数は6.3個であった。
またP50即ち酸素解離曲線において50％の酸素が化学修
飾ヘモグロビンに配位する時の酸素分圧は25℃で13.7mm
Hgであった。また、結合ポリオキシエチレンの末端にリ
ジン基が存在する事が加水分解物のアミノ酸分析より明
らかにされた。
実施例２ 特開昭53-141219（川研ファインケミカル（株））に述
べられている方法で調製した白金パラジウム炭素触媒20
gと市販のポリオキシエチレン（日本油脂（株），日
本）（Macrogoal 4000）200gを含む水溶液500mlを1.5l
オートクレーブ中に入れ、加圧空気を導入して圧力を10
kg/cm2とし、90℃で10時間反応させた。
反応生成物は過により触媒を除去したのち、活性炭で
処理し、さらに水から再結晶し180gの両末端にカルボキ
シル基を有するポリオキシエチレンの酸誘導体（α−カ
ルボキシメチル−ω−カルボメトキシポリ（エチレンオ
キシド））をえた。
この分子量約4000のポリオキシエチレンの酸誘導体20g
（５ミリモル）、Ｎ−ヒドロキシコハク酸イミド4g及び
ジシクロヘキシルカルボジイミド（DCC）7gをジメチル
ホルムアミド100mlに溶かし一夜攪拌した。生成した結
晶のジシクロヘキシル尿素を分離したのち、エチルエー
テル400mlを加えてポリオキシエチレンの活性化エステ
ル17gを沈殿させ、別後更にエーテルで洗浄した。一
方期限切れ輸血用血液より得られたヒト赤血球50mlを0.
9％の食塩水50mlで遠心分離機を用いて４℃で４回洗浄
した。
上記の操作でえられた洗浄赤血球40mlを注射薬用蒸留水
40mlに加えて溶血したあと、20mlのトルエンにて膜成分
を抽出した。えられたヘモグロビン液は8000回転で１時
間遠心分離を行う事によって更に膜成分とヘモグロビン
を分離した。
ヘモグロビン溶液は0.1Mリン酸緩衝液に溶解し濃度を6g
/dl（0.088mM）,pH7.0とした。ついでこのヘモグロビン
溶液1.00mlに酸素分圧が2mmHg以下になるまで激しくア
ルゴンをふき込む事により脱酸素したのち、ベネシェら
の方法（R.Benesch,R.Benesch,S.Kwong,A.Acharya,J.Ma
nning,J.Biol.Chem 257(3)1320-24(1982)）によりピリ
ドキサール−５′−リン酸を付加し、ピリドキサール化
ヘモグロビン（6g/dl）をえた。
これにグリシン160mlを加えた後、上記の方法でえたポ
リオキシエチレンの活性化エステル7.2gを加え、30分４
℃で反応した。ついで、１規定水酸化ナトリウム水溶液
を加えpH7.8にしたのち更に30分反応させた。
反応液は分子量分画３万の限外過膜YM30（Amicon社,U
SA）により限外過をくり返し、未反応のポリオキシエ
チレンの濃度が100ppm以下にした。
実施例１で述べたゲルタイプの充填カラムを用いた高速
液体クロマトグラフィーから生成物の分子量は約9.8万
ダルトンと推定された。なおポリオキシエチレンのヘモ
グロビンと結合していない方の末端にはグリシンが結合
している。
実施例３ 市販のプルロニック（Pluronic）P123,分子量4000ダル
トン（エチレンオキサイドとプロピレンオキサイドのブ
ロック共重体（BASF Wayandotte Co,USA））20g（５ミ
リモル）をよく脱水したジオキサン中1gの金属ナトリウ
ムと反応させ、プルロニックの２ナトリウム塩をえた。
沈殿物を過後、この過液に、モノクロロ酢酸エチル
エステル2mlを滴下し50℃で24時間反応させた。
えられた反応液は実施例１で述べた方法により、エステ
ルを加水分解後、沈殿をくり返す事により精製した。
更にプルロニックの両末端にカルボキシル基を有するこ
のポリアルキレングリコール誘導体は実施例２で述べた
方法を用いてＮ−ヒドロキシコハク酸イミドと反応させ
活性エステルとした。
一方実施例２の方法によってえられたヒトヘモグロビン
の６％溶液（0.09ミリモル）100ml（pH7.4のホウ酸緩衝
溶液）に窒素ガスを吸込む事により酸素分圧を5mmHgに
下げたのち、上記によってえられたプルロニックの活性
エステル7g（1.7ミリモル）とＬ−アラニン250mg（2.8
ミリモル）を加え４℃で１時間反応させた。
次いでpH7.8に上げ更に30分攪拌し実施例１の方法で精
製した。
高速液体クロマトグラフィーによって推定した分子量は
95,000ダルトン，ヘモグロビン分子１個あたりのプルロ
ニック結合数は4.8であった。また酸素解離曲線より推
定された50％酸素解離圧（P50）は25℃で6.1mmHgであっ
た。
実施例４ ポリオキシエチレンメチルエーテル分子量1900（Aldric
h Chemical Co.USA）15g（7.9ミリモル）を乾燥したジ
クロロメタンに溶解し、30gの活性化二酸化マンガンを
加え、室温で一夜攪拌し反応させた。
過により触媒を分離したのち、アルデヒド型に酸化さ
れたポリオキシエチレン誘導体は、溶媒を減圧下で留去
したのち３％の過酸化水素水500mlに溶解し24時間反応
させた。
反応液はBio-Rad AGI×２を充填したカラムを通し中性
物を除去したのち0.02M HClで末端にカルボキシル基を
有するポリオキシエチレン誘導体を分離した。
この酸誘導体5g（2.6ミリモル）を乾燥したジメチルホ
ルムアミド100mlに溶解し0.8g（7.0ミリモル）のＮ−ヒ
ドロキシコハク酸イミドと1.5g（7.2ミリモル）のジシ
クロヘキシルカルボジイミドを加えて一夜室温で反応さ
せた。
不溶物を別後、乾燥エーテルを沈殿が生成するまで加
え活性化エステルをえた。
一方、実施例２により調製したヒトヘモグロビンの６％
溶液300mlを20倍過剰のグリオキザール酸とHEPES緩衝液
中でディドナートらの方法（A.DiDonato,W.Fartl,A.Ach
arya,J.Manning,J.Biol,Chem.258(19)11890〜895(198
3)）で反応させひきつづきNaBH3CNで還元した。
えられたカルボキシメチル化したヘモグロビンはセファ
デックスG-100で低分子物質を除き、さらに0.1Mのリン
酸緩衝液で5.2g/100mlの溶液とし、4.8gの上記の手法に
よってえられたポリオキシエチレンモノメチルエーテル
の活性化エステルと５℃２時間反応させた。
生成物は実施例１の限外過の手法で精製した。前記の
高速液体クロマトグラフィーで測定した分子量は8.2万
ダルトン、P50＝12mmHg（25℃,pH7.4）であった。
実施例５ ポリオキシエチレン平均分子量8,000ダルトン（Aldrich
Chemical Co.USA）20g（2.5ミリモル）を用い実施例２
で示した方法で該当するポリオキシエチレンの両末端に
‐O-CH2‐CO2Hを持つカルボン酸をえた。
このカルボン酸をBio-Rad AGI×２の樹脂で精製したあ
と実施例２の方法でＮ−ヒドロキシコハク酸イミドと反
応させ活性エステルとした。一方実施例１で示した方法
によってえられたウシヘモグロビン7gを用い、これをpH
7.4のリン酸緩衝液に溶解して0.1M溶液（100ml）を作
り、前記ベネシェらの方法でピリドキサール−５′−リ
ン酸と反応させ、ひきつづき水素化ホウ素ナトリウム
（NaBH4）で還元した。
この溶液を高純度窒素で脱酸素後、Ｎ−ジメチルグリシ
ン1500mgと4.8gの活性化ポリオキシエチレンエステルを
加え４℃の低温で１時間反応させた。
反応液は実施例１で述べた方法を用いて低分子量の物質
を除き精製した。
シアンメトヘモグロビン法でヘモグロビン濃度を測定し
た。収率はウシヘモグロビンから計算して63％であっ
た。
また平均分子量12万ダルトン,6％のヘモグロビン濃度の
溶液の粘度は2.8cpsであった。
今井の方法（前述）で測定した酸素解離曲線からP50＝1
9mmHg（25℃,pH＝7.4）がえられた。
実施例６ 10.9％のヒトヘモグロビン溶液20ml（0.034ミリモル）
を0.122Mのトリス緩衝液（pH6.8）90mlに溶解した液に
容量200mlの三つ口フラスコに入れ、アルゴンガスを１
時間通気した。
引き続き、アルゴンガスを通気しつつ、ピリドキサール
５リン酸エステル−水和物33mg（0.125ミリモル）を加
え、さらに１時間アルゴンガスを通気した後、水素化ホ
ウ素ナトリウム（NaBH4）25mg（0.66ミリモル）を加え
てさらに１時間アルゴンガスを通気し、溶液１を得た。
一方、ポリオキシエチレン（Aldrich Chemical Co.US
A、平均分子量3400）をジョーンズ試薬で酸化し、両端
にカルボキシメチル基を有するポリオキシエチレンを調
整し、これとＮ−ヒドロキシコハク酸イミドとを反応さ
せて活性化ポリオキシエチレン（α−カルボキシメチル
−ω−カルボメトキシポリ（エチレンオキシド）のＮ−
ヒドロキシコハク酸イミドエステル）を得た。
溶液１に活性化ポリオキシエチレン3.29g（0.91ミリモ
ル）を加えて４℃で一夜攪拌した後に分子量阻止30,000
の限外過膜により限外過を繰り返し、未反応の活性
エステルまたはその分解物を除去することにより、4.5
％の修飾ヘモグロビン溶液41mlを得た。これを標準修飾
ヘモグロビン溶液とする。なお、この修飾ヘモグロビン
は分子量約86,000ダルトン、置換度6.2であってP50（リ
ン酸緩衝液、pH7.40、25℃）は11.0mmHgであった。
発明の効果 本発明のヘモグロビン−ポリオキシアルキレン結合体は
ヘモグロビンを変性させず酸素親和力を損なわない。ま
た、安定性が高く、製剤化工程及び保存時においてその
活性を長く維持する。
【図面の簡単な説明】
第１図は本発明のヘモグロビン−ポリオキシアルキレン
結合物の単量体、二重体及び三重体を模式的に示した図
である。
───────────────────────────────────────────────────── フロントページの続き (72)発明者 矢吹 昭 神奈川県川崎市川崎区鈴木町１−１ 味の 素株式会社中央研究所内 (72)発明者 岩下 雄二 神奈川県川崎市川崎区鈴木町１−１ 味の 素株式会社中央研究所内 審査官 松浦 新司 (56)参考文献 特開 昭59−104323（ＪＰ，Ａ) 特開 昭59−89629（ＪＰ，Ａ) 特開 昭57−206622（ＪＰ，Ａ) 特開 昭61−53223（ＪＰ，Ａ)

Claims (6)

    【特許請求の範囲】
  1. 【請求項１】ポリオキシアルキレン末端とヘモグロビン
    のアミノ基との結合部分が下記の構造式よりなるヘモグ
    ロビン−ポリオキシアルキレン結合体。 ‐CH2‐O-(CH2)n‐CONH-Hb （式中、Hbはヘモグロビンを表わし、ｎ＝１〜７であ
    る。）
  2. 【請求項２】ポリオキシアルキレンのヘモグロビンが結
    合されていない末端の少なくとも50％にアミノ酸がアミ
    ド結合されている請求項１記載のヘモグロビン−ポリオ
    キシアルキレン結合体。
  3. 【請求項３】アミノ酸が蛋白質の構成アミノ酸のいずれ
    かである請求項２記載のヘモグロビン−ポリオキシアル
    キレン結合体。
  4. 【請求項４】ポリオキシアルキレンがポリオキシエチレ
    ン、ポリオキシプロピレン又はエチレンオキサイドとプ
    ロピレンオキサイドの共重合体のいずれかである請求項
    １記載のヘモグロビン−ポリオキシアルキレン結合体。
  5. 【請求項５】ポリオキシアルキレンの分子量が1000〜60
    00の範囲内にある請求項４記載のヘモグロビン−ポリオ
    キシアルキレン結合体。
  6. 【請求項６】代用血液用酸素運搬剤の有効成分として存
    する請求項１記載のヘモグロビン−ポリオキシアルキレ
    ン結合体。
JP61142302A 1985-06-19 1986-06-18 ヘモグロビン―ポリオキシアルキレン結合体 Expired - Lifetime JPH0676333B2 (ja)

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