CN1323724C - 获得2-18f-氟-2-脱氧-d-葡萄糖(18f-fdg)溶液的方法 - Google Patents
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Abstract
本发明涉及改进18F-氟-脱氧-葡萄糖(18F-FDG)溶液的一或多种理化性质的方法,如降低辐射分解,以及高压灭菌能力,该方法包括步骤a)制备18F-氟-脱氧-葡萄糖(18F-FDG)溶液,b)加入至少一种基于弱酸的缓冲液。本发明还涉及通过高压灭菌制备无菌18F-氟-脱氧-葡萄糖(18F-FDG)溶液的方法。
Description
发明领域
本发明涉及获得2-[18F]-氟-2-脱氧-D-葡萄糖(18F-FDG)溶液的方法(也描述为18F-氟-脱氧-葡萄糖或18F-FDG)溶液,其具有改进的理化性质,即放射化学稳定性,如此可得到无菌的,18F-FDG溶液。
技术背景
近些年来,在核医学领域,化合物18F-FDG,除用于心脏病学和神经病学的重要用途外,还表现出可用于检测常规方法不能检测的癌组织,或纠正这些疾病的误诊。这是利用当它们变得恶性时发生在细胞中的基本变化;癌细胞失去了它们有效转化葡萄糖为能量的能力。结果,它们需要更多葡萄糖,高达20到50倍。
18F-FDG通常利用全自动合成仪制备。因为该化合物需要注射到患者,注射前含该化合物的溶液需要灭菌。但是,通过标准高压灭菌步骤化合物的放射化学纯度显著降低,这样的化合物将不能符合欧洲和美国药典的规定。此外,合成后,由于辐射分解(radiolysis)和放射性同位素的半衰期18F-FDG快速丧失其放射化学纯度,这样就限制了该化合物的使用期限。
发明内容
本发明意图提供可高压灭菌的18F-氟-脱氧-葡萄糖或(FDG)溶液,其仍符合生产后8小时放射化学纯度高于95%的规定。此外,本发明还提供降低,合成后,溶液中18F-FDG的辐射分解效果。
本发明研究发现,缓冲18F-FDG溶液对理化性质,例如放射稳定性,有强影响。令人惊奇地是发现基于弱酸的缓冲液改进了18F-FDG溶液理化性质,即放射稳定性,其可以进行高压灭菌并保持至少95%的放射化学纯度。
按照本发明可通过以下步骤实现:
a)准备18F-氟-脱氧-葡萄糖(18F-FDG)溶液,
b)向该18F-氟-脱氧-葡萄糖(18F-FDG)溶液中添加至少一种基于弱酸的缓冲液。
所述弱酸缓冲液必须是生理可接受的,并优选柠檬酸缓冲液,乙酸缓冲液,抗坏血酸缓冲液或这样缓冲液的组合。
当柠檬酸缓冲液低于5.5,具体2和5.5之间可以获得改进的理化性质。对于乙酸缓冲液,可在pH3.0到5.5之间获得这些性质。抗坏血酸缓冲液的使用pH类似于乙酸缓冲液,在3.0到5.5之间。
(18F-FDG)溶液的高压灭菌在110Ec和150EC之间进行,优选130-140EC,更优选134EC。考虑18F-FDG溶液稳定性和放射同位素半衰期,发现这些温度是优化的。18F-FDG溶液的高压灭菌在1-30分钟之间进行,优选1-10分钟,更优选2-5分钟。考虑18F-FDG溶液稳定性和放射同位素半衰期,其是109.8分钟,这些范围是优化的。
具体实施方式
本发明由以下实施例进一步说明,但它们并非对本发明的限制:
实施例1:在pH4.5-5.5对18F-FDG溶液进行高压灭菌
进行3个试验轮次研究用弱酸缓冲的18F-氟-2-脱氧-葡萄糖(FDG)溶液的放射化学纯度,与盐水中非缓冲溶液对比。
生产后,用盐水稀释18F-氟-脱氧-葡萄糖(FDG)溶液至在ART(ActivityRefeence Time)(t=0)放射活性浓度3mCi/ml。生产2小时后,制备有0.5ml 18F-氟-脱氧-葡萄糖(FDG)溶液的小瓶,混合0.1ml缓冲液(10mM),然后高压灭菌。
表1表明不同缓冲的18F-氟-脱氧-葡萄糖(FDG)溶液在134℃5分钟高压灭菌后的放射化学纯度。采用KAVO SterimasterTM在高压灭菌后直接进行。
表1
在pH 4.5到5.5对18F-FDG溶液进行高压灭菌
18F-FDG的放射化学纯度(%) | |||
试验1 | 试验2 | 试验3 | |
未高压灭菌 | 98.85 | 96.41 | 95.9 |
高压灭菌的缓冲液/pH | |||
抗坏血酸/4.5 | 94.5 | 95.0 | 94.7 |
抗坏血酸/5.5 | 94.1 | 94.4 | 94.5 |
柠檬酸/4.5 | 97.3 | 96.5 | 96.3 |
柠檬酸/5.5 | 94.5 | 95.3 | 94.1 |
乙酸/4.5 | 96.5 | 94.6 | 94.5 |
乙酸/5.5 | 94.5 | 92.5 | 92.5 |
NaCl/6.2(参照) | 92.4 | 90.9 | 91.1 |
所有测试缓冲液相对未缓冲参照样品NaCL/pH6.2获得高的放射化学纯度。得到最佳结果的缓冲液是pH4.5的柠檬酸缓冲液。与未高压灭菌样品相比,三个试验中只有一个表现出放射化学纯度降低1%(试验1)。
实施例2:低pH范围(pH2-3)18F-FDG溶液的高压灭菌
进行2轮试验研究用弱酸缓冲到pH2-3的18F-氟-脱氧-葡萄糖(FDG)溶液的放射化学纯度。
用盐水将18F-氟-脱氧-葡萄糖(FDG)溶液在生产后直接稀释到在ART(12:00h)放射化学纯度3mCi/ml。生产2小时后,制备有0.5ml 18F-氟-脱氧-葡萄糖(FDG)溶液的小瓶,其混有0.1ml缓冲液(100mM),然后高压灭菌。
表2表明了不同缓冲的18F-氟-脱氧-葡萄糖(FDG)溶液在134℃5分钟高压灭菌后的放射化学纯度。
缓冲液 | pH | 18F-FDG的放射化学纯度(%) | |
试验1 | 试验2 | ||
抗坏血酸 | 3.0 | 97.8 | 98.0 |
柠檬酸 | 2.0 | 98.7 | 98.5 |
乙酸 | 3.0 | 97.4 | 97.3 |
NaCl(参照) | 6.2 | 90.9 | 91.1 |
所有测试缓冲液较未缓冲参照样品NaCl/pH6.2表现出高的放射化学纯度。与对照样品相比(放射化学纯度降低9%),用弱酸缓冲的样品观察到2-3%的降低。对于所有缓冲液(抗坏血酸,柠檬酸,乙酸),与未高压灭菌样品(表1)相比,没有显著的放射化学纯度降低。
实施例3:18F-FDG的辐射分解
在约8.5小时的时期内测定18F-FDG的放射性浓度。在ART(t=0)放射性浓度为3mCi/ml。
测试2个缓冲液,并与0.9%NaCl/pH6.9中的参照样品相对比。第一个缓冲液是柠檬酸缓冲液pH4.5,第二个缓冲液是抗坏血酸缓冲液pH4.5。在间隔中进行样品放射化学纯度的5个测定。结果见表3。
表3:18F-氟-脱氧-葡萄糖(FDG)溶液的辐射分解
缓冲液/pH | 测定时间(min) | 18F-FDG百分比 |
柠檬酸缓冲液pH4.5 | 0 | 98.98 |
46 | 98.03 | |
203 | 96.18 | |
317 | 95.31 | |
495 | 94.73 | |
抗坏血酸缓冲液pH 4.5 | 0 | 98.98 |
64 | 97.96 | |
213 | 97.55 | |
327 | 97.37 | |
505 | 97.28 | |
0.9%NaCl pH6.90 | 0 | 98.98 |
94 | 96.51 | |
230 | 94.74 | |
340 | 94.13 | |
516 | 93.59 |
在两个测试缓冲液辐射分解较0.9%NaCl样品降低。当采用抗坏血酸缓冲液观察到最大降低。8.5小时后只有2%活性降低。对于柠檬酸缓冲液和0.9%NaCl分别是4%和6%。结论是,与不加缓冲液相比,在加入抗坏血酸或柠檬酸缓冲液后,18F-FDG更稳定。
实施例4:18F-氟-脱氧-葡萄糖(FDG)溶液的高压灭菌和辐射分解
18F-FDG的辐射分解在高压灭菌样品后约7.5小时时期内进行。测试两个缓冲液,并与0.9%NaCl pH6.90向对照。第一个是柠檬酸缓冲液pH4.5,第二个缓冲液是抗坏血酸缓冲液pH4.5。在间隔进行样品放射化学纯度的三个测定。结果见表4。
表4
18F-氟-脱氧-葡萄糖(FDG)溶液的高压灭菌和辐射分解
18F-FDG的放射化学纯度(%) | ||||
高压灭菌 | 未高压灭菌 | |||
测定时间(min) | 柠檬酸 | 抗坏血酸 | NaCl | NaCl |
0 | 97.37 | 95.56 | 89.56 | 97.49 |
240 | 95.55 | 94.65 | 87.49 | 95.30 |
453 | 95.35 | 94.50 | 86.77 | 94.61 |
加入弱酸缓冲液后,18F-FDG在高压灭菌下更稳定。不加该缓冲液,样品的放射化学纯度显著降低到低于90%。与抗坏血酸相比,柠檬酸缓冲液产生更好的稳18F-FDG定性效果。此外,辐射分解,在高压灭菌后,与NaCl样品对照,测试的两个缓冲液都显著降低。采用抗坏血酸缓冲液时,观察到最大的降低。7.5小时后只有1%的活性降低。对于柠檬酸缓冲液和NaCl样品此降低分别是2%和3%。结论是,加入抗坏血酸和柠檬酸后,与不加这些缓冲液相比,在高压灭菌中更为稳定。高压灭菌后,两个缓冲液中的18F-FDG溶液的辐射分解都降低。
Claims (15)
1.改进18F-氟-脱氧-葡萄糖溶液的一或多种理化性质的方法,该方法包括如下步骤:
a)准备18F-氟-脱氧-葡萄糖溶液,
b)向该18F-氟-脱氧-葡萄糖溶液中添加至少一种基于弱酸的缓冲液,其中所述至少一种缓冲液选自柠檬酸,乙酸,抗坏血酸,或其组合。
2.权利要求1的方法,其中所述改进的理化性质是18F-氟-脱氧-葡萄糖溶液的高压灭菌能力,从而使该溶液适于医疗用途。
3.权利要求1的方法,其中所述改进的理化性质是在18F-氟-脱氧-葡萄糖溶液中降低的辐射分解。
4.权利要求1的方法,其中所述柠檬酸缓冲液pH低于5.5。
5.权利要求4的方法,其中所述柠檬酸缓冲液pH在2和5.5之间。
6.权利要求1的方法,其中所述乙酸缓冲液的pH在3和5.5之间。
7.权利要求1的方法,其中所述抗坏血酸缓冲液的pH在3和5.5之间。
8.制备无菌18F-氟-脱氧-葡萄糖溶液的方法,所述方法在至少一种基于弱酸的缓冲液的存在下,在110℃到145℃之间的温度下,对18F-氟-脱氧-葡萄糖溶液进行高压灭菌,其中所述至少一种缓冲液选自柠檬酸,乙酸,抗坏血酸,或其组合。
9.权利要求8的制备无菌18F-氟-脱氧-葡萄糖溶液的方法,其中在130℃到140℃之间的温度下,对18F-氟-脱氧-葡萄糖溶液进行高压灭菌。
10.权利要求9的制备无菌18F-氟-脱氧-葡萄糖溶液的方法,其中在134℃的温度下,对18F-氟-脱氧-葡萄糖溶液进行高压灭菌。
11.权利要求8的方法,其中所述高压灭菌过程为1到30分钟。
12.权利要求8的方法,其中所述高压灭菌过程为1到10分钟。
13.权利要求8的方法,其中所述高压灭菌过程为2到5分钟。
14.由权利要求1的方法得到的具有改进的理化性质的18F-氟-脱氧-葡萄糖溶液。
15.权利要求8的方法得到的无菌18F-氟-脱氧-葡萄糖溶液。
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EP02076638A EP1356827A1 (en) | 2002-04-24 | 2002-04-24 | Method for obtaining a 2-18F-fluor-2-deoxy-D-glucose (18F-FDG)-solution |
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EP2218463A1 (en) * | 2007-10-30 | 2010-08-18 | Nihon Medi-Physics Co., Ltd. | Use of novel compound having affinity for amyloid, and process for production of the same |
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BR112013015396B1 (pt) | 2010-12-29 | 2021-11-03 | Ge Healthcare Limited | Método para a preparação de 18f para uso em uma reação de radiofluoração, reação de radiofluoração e cassete para a realização da reação de radiofluoração |
US20130004414A1 (en) * | 2011-06-30 | 2013-01-03 | General Electric Company | Devices and methods for reducing radiolysis of radioisotopes |
US20130005958A1 (en) * | 2011-06-30 | 2013-01-03 | General Electric Company | Devices and methods for reducing radiolysis of radioisotopes |
US11534494B2 (en) | 2011-12-21 | 2022-12-27 | Ge Healthcare Limited | Formulation and method of synthesis |
AU2012356846B2 (en) * | 2011-12-21 | 2017-07-27 | Ge Healthcare Limited | 18F - Fluciclovine compositions in citrate buffers |
GB201411569D0 (en) | 2014-06-30 | 2014-08-13 | Ge Healthcare Ltd | Novel formulation and method of synthesis |
GB201202420D0 (en) * | 2012-02-13 | 2012-03-28 | Ge Healthcare Ltd | Radiotracer compositions |
US10695450B2 (en) | 2016-07-26 | 2020-06-30 | Laboratoires Cyclopharma | Synthesis of a radioactive agent composition |
FR3054445B1 (fr) * | 2016-07-26 | 2019-07-05 | Laboratoires Cyclopharma | Synthese d'une composition d'agent radioactif |
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- 2003-04-23 AT AT03721834T patent/ATE422903T1/de not_active IP Right Cessation
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AU2003225124B2 (en) | 2007-06-14 |
NO329160B1 (no) | 2010-08-30 |
JP2006500319A (ja) | 2006-01-05 |
KR20050005456A (ko) | 2005-01-13 |
EP1356827A1 (en) | 2003-10-29 |
CN1646175A (zh) | 2005-07-27 |
NO20045070L (no) | 2004-11-22 |
CA2483181A1 (en) | 2003-11-06 |
WO2003090789A1 (en) | 2003-11-06 |
AU2003225124A1 (en) | 2003-11-10 |
PL371682A1 (en) | 2005-06-27 |
DE60326220D1 (de) | 2009-04-02 |
IL164805A (en) | 2009-06-15 |
EP1496946A1 (en) | 2005-01-19 |
CA2483181C (en) | 2011-06-28 |
JP2010248244A (ja) | 2010-11-04 |
US8182788B2 (en) | 2012-05-22 |
US20050175536A1 (en) | 2005-08-11 |
JP5132869B2 (ja) | 2013-01-30 |
ATE422903T1 (de) | 2009-03-15 |
EP1496946B1 (en) | 2009-02-18 |
IL164805A0 (en) | 2005-12-18 |
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