KR100964604B1 - 산소 친화도가 높은 개질된 헤모글로빈을 포함하는 산소 전달용 조성물 및 방법 - Google Patents
산소 친화도가 높은 개질된 헤모글로빈을 포함하는 산소 전달용 조성물 및 방법 Download PDFInfo
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- KR100964604B1 KR100964604B1 KR1020047010847A KR20047010847A KR100964604B1 KR 100964604 B1 KR100964604 B1 KR 100964604B1 KR 1020047010847 A KR1020047010847 A KR 1020047010847A KR 20047010847 A KR20047010847 A KR 20047010847A KR 100964604 B1 KR100964604 B1 KR 100964604B1
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Abstract
Description
조혈(Hematopoiesis). 인공혈액은 조혈과정 동안 새로운 헤모글로빈을 합성하는데 사용되는 헴과 철의 기원으로서 제공될 수 있다.
테스트 | 세부 사항 |
헤모글로빈 농도(g/dl) | 4.2±0.2 |
메트헤모글로빈(%) | <10 |
pH | 7.4±0.4 |
전도율(mS/cm) | 12±4 |
내독소(EU/mL) | <0.5 |
FPLC 머무름 시간(분) | 43±3 |
절반 높이에서 FPLC 피크 넓이(분) | 6±2 |
점도(cPs) | 2.5±1.0 |
COP(mmHg) | 50±20 |
P50(torr) | 6±2 |
힐 넘버(Hill number, P50에서) | 1.2±0.5 |
무균상태 | 통과 |
혈액 | SFH | MalPEG-Hb | |
P50 (torr) | 28 | 15 | 5 |
N50 (힐 넘버) | 2.9 | 2.9 | 1.2 |
보어 효과(ΔLog P50/ΔpH) | -- | -0.46 | -0.20 |
점도(cPs)1 | 4.0 | 0.9 | 2.5 |
COP(mm Hg)1 | 27 | 16 | 50 |
MW (kD)2 | N/A | 65 | 90 |
분자 반경(nm) | 4000 | 3.22 | 9 |
PHP | POE | |
Hb, g/dl | 8.0 | 8.3 |
점도 (cP) | 2.8 | 2.8 |
COP, mm Hg | 62.7 | 56.5 |
*a1(×10-1) | 1.368 | 2.228 |
*a2(×10-3) | 9.680 | 21.070 |
*a3(×10-5) | 0.752 | 46.500 |
*a4(×10-5) | 1.537 | 8.766 |
P50 | 19.7 | 12.2 |
n50 | 1.48 | 1.49 |
WT(g) | *혈액부피(ml) | 출혈부피(ml) | 출혈부피(%) | 사망시간(분) | ||
PHP | n | 18 | 18 | 18 | 18 | 18 |
PHP | 291 | 18.89 | 11.10 | 58.79 | 93 | |
sd | 24 | 1.59 | 0.90 | 0.35 | 29 | |
POE | n | 11 | 11 | 11 | 11 | 11 |
POE | 334 | 21.74 | 12.78 | 58.77 | 116 | |
sd | 41 | 2.65 | 1.60 | 0.39 | 12 | |
P | 0.001 | 0.001 | 0.001 | 0.915 | 0.020 |
n | PHP | sem | n | POE | sem | P | ||
HCT | 기준선 | 17 | 39.80 | 0.57 | 10 | 43.15 | 0.23 | 0.0032 |
ET 후 | 17 | 17.89 | 0.43 | 10 | 19.25 | 0.62 | 0.3568 | |
60분 | 15 | 13.29 | 0.47 | 10 | 15.85 | 0.14 | 0.0015 | |
HB | 기준선 | 17 | 13.59 | 0.22 | 10 | 15.08 | 0.17 | 0.0057 |
ET 후 | 17 | 8.70 | 0.18 | 10 | 9.74 | 0.07 | 0.0007 | |
60분 | 15 | 6.34 | 0.21 | 10 | 7.38 | 0.06 | 0.0016 | |
PLHB | 기준선 | 16 | 0.00 | 0.00 | 10 | 0.00 | 0.00 | |
ET 후 | 16 | 2.86 | 0.07 | 10 | 2.99 | 0.09 | 0.6785 | |
60분 | 15 | 1.93 | 0.07 | 10 | 2.47 | 0.02 | 0.0001 | |
LACT | 기준선 | 9 | 0.70 | 0.06 | 7 | 2.68 | 0.16 | 0.0001 |
ET 후 | 9 | 1.59 | 0.10 | 7 | 4.21 | 0.24 | 0.0004 | |
60분 | 9 | 10.62 | 0.89 | 7 | 17.27 | 1.18 | 0.0360 | |
BE | 기준선 | 17 | 6.22 | 1.28 | 9 | 5.41 | 0.08 | 0.6530 |
ET 후 | 17 | 6.20 | 1.41 | 5 | 5.60 | 0.13 | 0.8101 | |
60분 | 15 | -4.02 | 1.60 | 6 | -1.60 | 0.53 | 0.4678 |
Claims (19)
- 표면-개질된 산화 헤모글로빈을 포함하고,상기 표면-개질된 산화 헤모글로빈은 헤모글로빈이 산화된 상태에 있는 동안 헤모글로빈 분자 표면에 노출된 아미노산 측쇄(side-chain)의 표면 티올기(thiol group)를 통하여 폴리에틸렌 글리콜이 공유결합으로 부착되어 있는 헤모글로빈이고,상기 폴리에틸렌 글리콜은 알킬기를 통해 결합되고,상기 표면-개질된 산화 헤모글로빈은 동일한 조건하에서 측정하였을 때 동일한 동물 소스(source) 유래의 천연 무지질(stroma-free) 헤모글로빈의 P50의 2/3이하의 P50을 갖는 것을 특징으로 하는 인공 혈액제.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 제1항에 있어서,표면-개질된 산화 헤모글로빈을 포함하고,상기 표면-개질된 산화 헤모글로빈은 하기 일반식을 갖고:Hb-(S-Y-R-CH2-CH2-[O-CH2-CH2]n-O-CH3)m상기 식에서,Hb는 사량체(tetrameric) 헤모글로빈이고;S는 표면 티올기(thiol group)이고;Y는 숙신이미딜(succinimidyl) 공유 결합(covalent link)이고;R은 알킬기(alkyl group)이고;n은 중합체(polymer)의 길이를 의미하는 것이며, 4 이상이고;m은 헤모글로빈의 표면에 부착된 PEG 중합체의 개수이고;상기 표면-개질된 산화 헤모글로빈은 동일한 조건하에서 측정하였을 때 동일한 동물 소스(source) 유래의 천연 무지질(stroma-free) 헤모글로빈의 P50의 2/3이하의 P50을 갖는 것을 특징으로 하는 인공 혈액제.
- 제7항에 있어서,상기 m은 4 내지 5인 것을 특징으로 하는 인공 혈액제.
- 제1항 또는 제7항에 있어서,상기 표면 개질 이전에 상기 헤모글로빈이 티올화(thiolated) 된 것을 특징으로 하는 인공 혈액제.
- 제1항 또는 제7항에 있어서,0.10 미만의 메트헤모글로빈(methemoglobin)/총 헤모글로빈의 비를 갖는 것을 특징으로 하는 인공 혈액제.
- 제1항 또는 제7항에 있어서,상기 표면 개질된 산화 헤모글로빈은 10 토르(torr)(1333 Pa) 미만의 P50을 갖는 것을 특징으로 하는 인공 혈액제.
- 제1항 또는 제7항에 있어서,상기 표면 개질된 산화 헤모글로빈은 7 토르(torr)(933 Pa) 미만의 P50을 갖는 것을 특징으로 하는 인공 혈액제.
- 제1항 또는 제7항에 있어서,PEG-헤모글로빈 접합체(conjugate)를 포함하여 24℃에서 자동산화(autooxidation)에 대해 안정하고, 상기 메트헤모글로빈/총 헤모글로빈의 비는 0.10 미만이고, 상기 PEG-헤모글로빈 접합체(conjugate)는 10 토르(torr)(1333 Pa) 미만의 P50을 갖는 것을 특징으로 하는 인공 혈액제.
- 제1항에 있어서,상기 헤모글로빈은 말(horse) 헤모글로빈인 것을 특징으로 하는 인공 혈액제.
- 수용성 희석제(aqueous diluent) 중에 제1항 또는 제7항에 따른 인공 혈액제를 포함하는 인공 혈액용 조성물.
- 제15항에 있어서,상기 헤모글로빈의 농도는 0.1 내지 4.0 g/㎗인 것을 특징으로 하는 인공 혈액용 조성물.
- 제1항 또는 제7항에 있어서,인간 또는 동물체의 치료 방법에 유용한 것을 특징으로 하는 인공 혈액제.
- 제1항에 있어서,상기 인공 혈액제는 외상(trauma), 빈혈(ischemia), 혈액희석(hemodilution), 패혈증 쇼크(septic shock), 암(cancer), 만성빈혈증(chronic anemia), 겸상 적혈구 빈혈증(sickle-cell anemia), 심장마비(cardioplegia) 또는 저산소증(hypoxia)의 치료를 위한 약제 제조에 사용되는 것을 특징으로 하는 인공 혈액제.
- 제1항에 있어서,상기 인공 혈액제는 상해로 인한 혈액손실(loss of blood due to injury), 용혈성 빈혈증(haemolytic anemia), 전염성 빈혈증(equine infectious anemia), 고양이 전염성 빈혈증(feline infectious anemia), 박테리아 감염(bacterial infection), 인자 IV 분열(factor IV fragmentation), 비대증(hypersplenation)과 비종대(splenomegaly), 가금류에서의 출혈증후군(hemorrhagic syndrome in poultry), 발육부전성 빈혈(hypoplastic anemia), 재생불량성 빈혈(aplastic anemia), 본태성 면역 용혈 상태(idiopathic immune haemolytic condition), 철 결핍(iron deficiency), 동족면역 용혈성 빈혈(isoimmune haemolytic anemia), 미세혈관성 용혈성 빈혈(microangiopahtic haemolytic anemia) 또는 기생(parasitism)의 수의학적 치료를 위한 약제 제조에 사용되는 것을 특징으로 하는 인공 혈액제.
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US60/347,741 | 2002-01-11 | ||
US10/114,400 US20030153491A1 (en) | 2002-01-11 | 2002-04-01 | Methods and compositions for oxygen transport comprising a high oxygen affinity modified hemoglobin |
US10/114,400 | 2002-04-01 | ||
PCT/US2003/000696 WO2003059363A1 (en) | 2002-01-11 | 2003-01-10 | Methods and compositions for oxygen transport comprising a high oyzgen affinity |
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JP2005515225A (ja) | 2005-05-26 |
CA2473662A1 (en) | 2003-07-24 |
AU2003207504B2 (en) | 2007-05-24 |
JP5149480B2 (ja) | 2013-02-20 |
ATE382358T1 (de) | 2008-01-15 |
US20030153491A1 (en) | 2003-08-14 |
US20050026816A1 (en) | 2005-02-03 |
DE60318388D1 (de) | 2008-02-14 |
JP2010138197A (ja) | 2010-06-24 |
KR20040081451A (ko) | 2004-09-21 |
CN103203013A (zh) | 2013-07-17 |
PT1465643E (pt) | 2008-03-27 |
CA2473662C (en) | 2009-12-22 |
EP1465643A4 (en) | 2004-10-20 |
US6844317B2 (en) | 2005-01-18 |
CN1630527A (zh) | 2005-06-22 |
MXPA04006733A (es) | 2005-12-05 |
EP1465643B1 (en) | 2008-01-02 |
DE60318388T2 (de) | 2008-12-24 |
US20030162693A1 (en) | 2003-08-28 |
AU2003207504A1 (en) | 2003-07-30 |
EP1465643A1 (en) | 2004-10-13 |
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