CN1058149A - 稳定的成纤维细胞生长因子组合物 - Google Patents
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Abstract
本发明提供了使成纤维细胞生长因子(FGF)在
热、酸和/或蛋白分解环境中稳定的方法。这类方法
包括用蔗糖八硫酸(SOS)盐,尤其是用其铝盐(硫糖
铝)或钾盐来结合或络合FGF。本发明还提供了含
有SOS和FGF的稳定性FGF组合物。这些组合
物可用于包括创伤和胃肠道溃疡性疾患在内的FGF
反应性疾病的治疗。本发明还提供了应用SOS以及
带有SOS成分的诊断性试剂盒的多种诊断性方案。
最后,本发明提供了用SOS纯化FGF的方法。
Description
本发明提供了一种通过将FGF与蔗糖八硫酸(SOS)盐,尤其是与其铝盐硫糖铝(Sucralfate)或钾盐结合或络合使成纤维细胞生长因子(FGF)在热、酸和/或分解蛋白的环境中稳定存在的方法。本发明还涉及含有SOS和FGF的稳定的FGF组合物。该组合物可以用于FGF反应性疾病包括对创伤及胃肠道溃疡的治疗。本发明还涉及SOS在各种诊断方案中的应用及其用作诊断试剂盒中的一种成分。最后,本发明涉及使用SOS纯化FGF。
胃肠道的溃疡性疾病通常指的是消化性溃疡,它是一种胃肠道表皮细胞存在缺损的疾病。这种缺损是盐酸和胃蛋白酶联合作用的结果。从定义上讲,消化性溃疡至少穿透到粘膜下;较浅表的损害称为糜烂。消化性溃疡可发生于胃肠道的多个部位,包括胃、十二指肠或食管,Meckel′s憩室、外科术形成的吻合口处,但罕见于近端空肠。
二十年前,消化性溃疡的治疗包括卧床休息、进清淡饮食、使用抗酸剂和/或对罹患区行手术切除。最近,H2-受体拮抗剂已用于治疗消化性溃疡,两种最常用的H2-受体拮抗剂是呋喃硝胺和甲氰咪胍,两者的治疗作用都是抑制胃酸的分泌。对这两种拮抗剂的疗效及付作用已进行了广泛的研究(如Thomas et al.,in Clinics in Gastroenterology,Volume13,Number2,p501-529)。
尽管这两种拮抗剂已广泛用于临床治疗并相当成功,但是许多消化性溃疡对H2-受体拮抗剂疗法却并无反应。例如,在用甲氰咪胍或呋喃硝胺治疗十二指肠溃疡四至六周后,有20~30%的溃疡没有愈合,其原因尚不清楚。而且,用H2-受体拮抗剂治疗后,溃疡复发不是罕见的。
硫糖铝已被用作一种具有最小付作用的溃疡治疗剂。据认为,硫糖铝影响胃肠道的保护和修复/愈合多种机理,包括:ⅰ)胃蛋白酶及胆酸的吸附;ⅱ)胃刺激时使胃粘膜产生碳酸氢盐分泌和粘液分泌的细胞保护作用;ⅲ)保护prolifactine区以免遭受损害;ⅳ)保护血管的完整性。尽管在理解硫糖铝如何防止糜烂和溃疡发生方面取得了重大进展,然而,在认识它是如何加速溃疡愈合以及解释该药物慢性治疗作用方面还存在很大的差距。
业已证明成纤维细胞生长因子(FGF)将成为一种有潜力的拮抗因子,尤其是主司创伤愈合过程中的新血管形成。FGF有两种类型,即酸性成纤维细胞生长因子(aFGF)和碱性成纤维细胞生长因子(bFGF)。但是,aFGF和bFGF均具有酸和/或热不稳定性。因此,当在治疗消化性溃疡这样的酸和/或热的环境中应用FGF时,需要它对于该环境稳定的以致最大限度增加它每微升的治疗体积(vo/ul)。
最近,一个PCT申请号为PCT/US8903467(1990.3.8.公开)的申请(其内容被参考结合在本文中)公开了一种抗酸性FGF组合物,它包括重组FGF和下列成分的结合:ⅰ)促稳定剂,如葡萄胺聚糖、硫酸聚糖及硫酸化的环糊精;ⅱ)抗分泌剂,如H2-受体拮抗剂;ⅲ)细胞保护剂;以及ⅳ)抗酸剂。这些新型组合物据称对于FGF将是一个很有效的药物但又必须经受酸和/或热的环境的疾病极为有效。
然而,还需要寻找一些新的途径来进一步稳定FGF;以使它在治疗胃肠道疾病,创伤等疾患时发挥其诊断和治疗潜力。
本发明提供了一种稳定FGF的方法,它包括将FGF与蔗糖八硫酸盐(SOS),特别是其铝盐(硫糖铝)或钾盐,结合或络合。这里所说的“SOS”包括蔗糖八硫酸盐,它包括但不限制于其铝盐和钾盐,本发明的稳定的FGF组合物可用于治疗哺乳动物实质上患有的任何FGF反应性疾病,尤其是用于治疗那些存在酸性或热环境的疾病或者存在蛋白分解因子的疾病。具体地说,本发明的组合物可通过给病人施用有效量的与SOS结合了的FGF以及药用载体、赋形剂或稀释剂用以治疗胃肠道的溃疡性疾病。该组合物也可以用于存在干扰FGF治疗价值的蛋白分解因子的创伤的治疗。
本发明的另一方面是发现了SOS对FGF具有较高的亲和力。因此,这就使得SOS可用于FGF的纯化,同时它在对于FGF存在与否和/或存在的量的多少是关键的诊断应用中也是有用的。
图1说明高温对于有或没有SOS的情况下bFGF的影响。
图2说明酸对于有或没有SOS的bFGF的影响。
图3说明胃蛋白酶对于有或没有硫糖铝的rhbFGF突变蛋白CS23的影响。
图4以2MNacl作为对比,通过SOS对肝素中的未偶联bFGF结合能力说明SOS对bFGF的亲和力。
图5说明用硫糖铝-琼脂糖柱从液体样品中纯化bFGF的情况。
本发明提供了新的稳定的FGF组合物,它用于哺乳动物中对FGF治疗有反应性的疾病的治疗和/或预防。本发明还提供了纯化FGF的方法以及必须确定FGF存在及其含量的诊断性应用。
治疗FGF反应性疾病方法最简单方式,包括给哺乳动物施用有效量的稳定的FGF组合物或其药用盐,其中的稳定的组合物包括与FGF。结合的SOS。
例如,可以给哺乳动物施用有效量的稳定的FGF组合物以治疗消化道的各种溃疡性疾病。这类溃疡性疾病包括局灶性回肠炎,溃疡性结肠炎和消化性溃疡(包括十二指肠的或胃的)。
本发明的稳定的FGF组合物也可用于治疗哺乳动物中在酸性,热和/或蛋白分解环境存在而对FGF治疗有反应性的其它疾病。例如,在膀胱癌的放射治疗和化学治疗中,常导致相应器官的组织形成溃疡,如果发现FGF在膀胱酸性环境中能稳定存在,那么就可用FGF治疗该处的溃疡。创伤同样也能形成一个酸性和/或蛋白分解的环境,但对本发明的稳定化FGF组合物具有反应性。其它具有酸性,热或蛋白分解环境的疾病和对FGF治疗有反应性的其它疾病对于本领域技术人员是显而易见的,它们包括:
ⅰ)组织损伤、烧伤、创伤、术后组织、血栓形成,动脉粥样硬化;
ⅱ)肌肉-骨胳疾病,如骨折、韧带和肌腱修复,肌腱炎和滑囊炎,皮肤疾病,如不严重的烧伤、割伤、撕裂伤,褥疮,缓慢愈合和慢性溃疡,如见于糖尿病患者和缺血及心肌梗死中的组织的修复;
ⅲ)眼视网膜病,包括糖尿病性视网膜病和新血管性青光眼,皮肤疾病,包括牛皮癣和晶状体后纤维组织形成、慢性炎症、风湿性关节炎,有高度血管源性的某些肿瘤,如某种良性和恶性肿瘤的生长,例如,hemagiomas和血管纤维瘤和实质性肿瘤。
本发明的稳定化FGF组合物可以是SOS与aFGF或bFGF的组合物。用于实施本发明的aFGF和bFGF可有许多来源,包括人、牛、猴、猪和马等哺乳动物。
优选的稳定化FGF组合物是一种包括例如纯化的重组人类碱性FGF(rhbFGF)蛋白之类的经修饰的FGF的组合物。在rhbFGF中,经过将存在于成熟蛋白质中氨基酸残基的25、69、87和92位点上的四个半胱氨酸中的一个或几个改变成丝氨酸而诱发突变(“突变蛋白”)。在计算构成人类bFGF的氨基酸时,N-末端的脯氨酸构成第一个氨基酸。最优选的FGF是rhbFGF突变蛋白CS23,有关其结构的更详细的描述见于Senoo et,al,Biochemical and Biophysical Research Communications,Vol,151,No.2,701-708(1988)及申请号为161,123美国专利(申请日为1988,2,18),该专利相应于欧洲专利EP281,822A2,这些文献的描述均被参考结合在本申请中。其它可用于实施本发明并也在上述参考文献中描述过的突变蛋白包括那些增加了氨基酸和结构氨基酸存在缺失或替换的突变蛋白。
已经发现,本发明的稳定的FGF组合物在酸、热及蛋白分解环境中具有高度的稳定性。天然的哺乳类FGF和上述经重组修饰而具抗酸性的FGF均具有很低的毒性。
可用于稳定FGF的蔗糖八硫酸盐的两种优选形式是SOS钾和SOS铝(硫糖铝)。选用哪一种形式的蔗糖八硫酸盐制备优选的稳定化FGF组合物将有赖于包括给药途径,增溶需要等多种因素。对于治疗胃肠道疾病而言,优选的SOS是SOS铝(硫糖铝),因为它不会被吸收到血流中。
本发明稳定化FGF组合物的优选给药途径也依赖于诸如所存在的治疗条件和病人方便与否等多种因素。例如,在治疗由于例如放射治疗和化学治疗所诱发的膀胱溃疡性创伤时,稳定的FGF组合物可经尿道导管给药。在治疗胃肠道的溃疡性创伤时,优选的给药途径是通过例如片剂、胶囊、锭剂或咀嚼的口服。对于胃肠道疾病的其它给药途径包括通过灌肠直肠给药和肠道外途径。
作为给药用的稳定化FGF组合物的制备是通过常规技术完成的。例如,片剂和胶囊是通过加用如药用载体(如:乳糖、谷类淀粉、轻质硅酐、微晶纤维素、蔗糖)、粘合剂(如α-型淀粉,甲基纤维素、羧甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、聚乙烯吡咯烷酮)、崩解剂(如:羟甲基纤维素钙、淀粉、低级取代的羟丙基纤维素)、表面活性剂(如:吐温80(kao-λtlas),PluronicF68(Asahi Denka Japan))、聚氧乙烯-聚氧丙烯共聚物、抗氧化剂(如:L-丝氨酸、亚硫酸钠、抗坏血酸钠)、润滑剂(如硬脂酸镁、滑石)等等添加剂来制备的。
直肠的制剂也是通过常规技术来完成的。例如,应用一种油性基质如高级脂肪酸甘油脂(如天然可可脂,Witepsols(一种半合成基质,(Dynamite Nobel,Federal Republic of Gemnany)),中级脂肪酸甘油酯(如Miglyols(Dynamite Nobel))或植物油(如芝麻油、豆油、玉米油、棉籽油、橄榄油)。
当把组合物配制成为可注射的水溶液时,该溶液是通过应用一种溶剂如水溶剂(如:蒸馏水,生理盐水,林格氏液)或油性溶剂(如:芝麻油、橄榄油)按常规方法进行制备的。如果需要的话,可以加用一种或多种添加剂。这些添加剂包括助溶剂(如水杨酸钠,乙酸钠)、缓冲剂(如柠檬酸钠,甘油),等渗剂(如葡萄糖、转化糖)、稳定剂(如:人血浆白蛋白、聚乙烯乙二醇)、防腐剂(如苄基醇、苯酚)或止痛剂(如氯化苄烷胺,普鲁卡因盐酸化物)。考虑到溶解度,当SOS静脉使用时,优先选用其钾盐。
当把组合物配制成固体制剂时,其制备可以应用如稀释剂(如蒸馏水,生理盐水,葡萄糖、赋形剂(如羧甲基纤维素(CMC)、精氨酸钠)、防腐剂(如苄基醇、氯化苄烷胺、苯酚)或止痛剂(如:葡萄糖、葡萄糖酸钙、盐酸普鲁卡因)等按常规方法进行。优选的使用形式是硫糖铝。
当与其它药剂如H2受体阻断剂相比时,组合物中FGF成分的含量明显地要少,并且依赖于多种因素包括所治疗状况,组合物是单独使用还是与抗分泌剂、细胞保护剂和制酸剂联用,以及病人的进食量。
例如,当用于治疗成年人胃肠道的溃疡性疾病时,进行口服给药的该组合物中FGF蛋白的含量一般为每天大约0.1μg-30mg,优选含量为每天约0.1μg-10mg,较优选含量为每天约1.0μg-3mg,最优选含量为每天约10μg-300μg,对于口服给药而言,可将10μg-150μg的rhbFGF突变蛋白CS23或其盐类与硫糖铝(通常为约10mg~1000mg)与药用载体、稀释剂或其它适宜的赋形剂配制成片剂或胶囊一起使用。这样的配方有利于每天给药1-4次,以达到优选剂量范围。
对于胃肠道较下部位的某些疾病,如消化性溃疡和溃疡性结肠炎,优选的稳定化FGF组合物外包有一种肠共聚物如羟丙基甲基纤维素邻苯二甲酸酯,乙酸纤维素邻苯二甲酸酯或异丁烯酸共聚物以进一步保护该稳定的FGF不受酸和消化性酶类如胃蛋白酶的损害。这种包衣的组合物因此得以进入胃肠道如消化道和营养通道,以使其治疗效果最佳化。
稳定的FGF组合物中用以稳定FGF成分的SOS的含量依赖于包括溶解度在内的若干因素。用于人类的硫糖铝的剂量也就是本发明所指示的一般用量。例如,对于口服给药而言,每天约0.1~6g(最好分次给药)的SOS可以与稳定化组合物中的FGF联用。
本发明的SOS成分也可以是其它的盐类形式。可用的其它盐类包括药用阳离子,如钠、铵、三甲基铵等等。
当FGF蛋白成分放到水介质中与硫化的二糖接触时,SOS与FGF蛋白成分的重量比范围为1/1~10,000/1(重量)。
SOS在水介质中的优选浓度范围为约0.4mg/ml-400mg/ml更优选的范围是4mg/ml~400mg/ml,更优选的范围是4mg/ml~40mg/ml。FGF在水性介质中的优选浓度范围为约1ng/ml~5,000ng/ml,较优选的范围约为10ng/ml~500ng/ml。
对于将FGF蛋白成分置入水性介质中与SOS接触而言,仅仅将这些物质在水性介质中混合即可达到目的,优选的水性介质是由蒸馏水、生理盐水、葡萄糖液、缓冲液如磷酸缓冲液和三羟甲基氨基甲烷-盐酸缓冲液组成。稳定的FGF在它未经分离或回收时就可如此应用。
通过上述方法可以获得高度稳定的FGF组合物,这种组合物可安全用于治疗哺乳动物,如人类、大鼠、豚鼠、狗、小鼠等等。
没有必要受理论的束缚,据信,硫糖铝(SOS的铝盐)对胃和十二指肠溃疡的治疗效果依赖于它作为内源性bFGF持续释放的载体和稳定剂的能力。根据本发明可以认为,硫糖铝从正常的粘膜和细胞外间质中获取到bFGF,并以其生物活性形式将bFGF携带到胃肠道的溃疡面或其它损伤区。早已知道,在细胞外间质中贮存有大量的bFGF(参见Vlodavsky et al.,P.N.A.S.(USA)64:2292-2296(1987)及Folkman et al.,Amer.J.Pathol.130:393-400(1988)。这与早期有关施用外源性酸稳定bFGF有利于所诱发的慢性十二指肠溃疡迅速愈合的报道相一致。(参见Szabo et al.,Dig.Dis.Sci.:34:1323(1989)及上文引用的专利申请No.PCT/US/03467)。因此,根据本发明可以认为,经SOS稳定的FGF在延长FGF的生物活性以治愈创伤、烧伤、溃疡等方面是有效的。
本发明的另外一个实施方案提供了从样品中分离、纯化和鉴定对硫糖铝有亲和力的化合物,如FGF的方法。
一般说来,该方法包括将含有FGF(或其它与硫糖铝结合或络合的化合物)的样品与含有SOS作为它的一个成分的柱接触。存在于样本中的任何FGF都将结合到柱的硫糖铝成分上。FGF因此可用一种合适的高浓度盐或酸从柱中洗脱下来。
对这一实施方案进行改变,FGF就可以用在PCT申请号为PCTUS88/01660,国际公开号为WO89/08144的专利文献(其说明已被参考结合在本文中)中描述的双亲和型柱进行处理,其中,硫糖铝为双亲和柱中的肝素成分所替代。
在优选实施方案中,硫糖铝琼脂糖柱是通过将硫糖铝和琼脂糖粉以大约1/10的重量比进行混合制得的。
用于实施本发明的洗脱液依赖于是否应用了标准的亲和柱或者是否应用了双亲和柱。一般说来,高浓度的盐溶液,如氯化钠用于从标准亲和柱中洗脱FGF。其它的洗脱液包括乙酸。优选的洗脱液通常是含有生理盐水和适宜缓冲物质的水溶液,使PH值维持在7左右。优选的缓冲组合物是浓度为大约10mm的Tris。对于象上方引用的PCT专利申请文献中讨论的双亲和柱而言,其中所述及的洗脱液均可应用。
本发明的另外一个实施方案提供了硫糖铝和FGF在多种诊断应用中的用途。例如,患膀胱癌时伴有尿中肝素结合内皮生长活性量的增加(Chodak,G.W.et al.,Cancer Res.45:690-694,1985,以及46:5507-5510,1986)。因此,在标本瓶中应用SOS将这些存在于样品中的活性得以稳定,以使得FGF作为癌症指示剂的敏感性和可靠性增加。
同样,脑脊液中的FGF与脑部肿瘤的发生相关。如上所述,SOS可通过稳定存在于脑脊液中的FGF而增加脑部肿瘤试验的敏感性和可靠性。
这类试验的最简单的形式包括将疑为含有FGF的样本液与SOS接触,然后分析样本液中SOS与FGF的复合体。该分析可以通过测定BALB/C小鼠3T3细胞中摄入[H3]胸腺嘧啶的DNA来进行(Klagsbrun et al.,PHAS 82:805-809,1985,该文献被参考结合在本文中)。
已经发现在多种组织培养中SOS均可用于稳定FGF,并且发现直到400μ/ml浓度的SOS对离体细胞也无毒性。因此,可以添加SOS作为一种组织培养成分来稳定组织培养细胞中的任何内源性FGF。
下面实施例Ⅰ和Ⅱ中所用的重组人类碱性FGF(rhbFGF)是按照EP-237,966中的实施例1,3,6或8所描述的方法,应用转化子E.colik12MM294/pTB669(IEP14532,FERM BP-1281)进行生产的。
下面实施例Ⅰ中所使用的rbhFGF突变蛋白CS23是按照上述参考文献Biochemical and Biophysical Research Communicatio-n Vol。151,701-708页(1988)以及美国专利申请161,123(相应于Ep-281,822A2)中参考实施例1,2和实施例1,6,7和24所描述的方法,应用转化子E.coli MM294/pTB762(IFO14613,FERM BP-1645)进行生产的。
下面的实施例将有助于理解和进一步解释本发明,但不能解释为本发明的限制。
实施例Ⅰ用硫糖铝稳定FGF
A热稳定性
将0.25μg人bFGF与含20μgBSA的50μlTris缓冲液混合制得含FGF的溶液。该溶液在未加入SOS和加入2mgSOS钾后于60℃温育10分钟。在温育结束时,用含BAS(1mg/ml)的Tris缓冲液将bFGF样品稀释20倍,然后按Klagzburn等人(Klagzburn et al,P.N.A.S.(USA)82:805-809(1985),该文内容通过参考结合于文本)描述的方法,通过测定BALB/C小鼠3T3细胞DNA中[H3]胸腺嘧啶的结合量来分析生长因子的活性。
如图1所示,SOS钾使FGF在高温下稳定。图中空白条表示将温度控制在4℃时回收的活性物。
B,酸稳定性
将0.5μgFGF与含有20μgBSA的1.5M乙酸60μl混和制得含FGF的酸性溶液。该溶液pH约为2.2在加入2mgSOS钾和完全不加SOS钾的情况下将溶液置于37℃下温育30分钟。在温育结束时,用含BAS(1mg/ml)的Tris缓冲液将bFGF样品稀释和中和,然后按上例的方法分析生长因子的活性。当bFGF样品被酸化时,它变得不可溶,因此而可通过离心使之澄清。离上清液和沉淀团溶解于含BSA(1mg/ml)的Tris缓冲液中,然后再进行生长因子活性分析。
如图2所示,SOS钾可以使FGF在象胃肠道一样的酸性环境中稳定。图中的空白条表示在对照值pH(pH7)时回收的活性物。
C对蛋白分解因子的稳定性
rhbFGF突变蛋白CS23溶液(200μg/ml)与硫糖铝一起在胃蛋白酶(4μg/ml)存在情况下于pH2.3和37℃下温育20小时。硫糖铝按1∶10的摩尔比加入。用牛胎心脏内皮细胞ATCC CRL1395来确定残留的有丝分裂活性。
如图3所示,硫糖铝保护rhbFGF突变蛋白CS23不受胃蛋白酶的蛋白分解作用。
实施例Ⅱ FGF硫糖铝的亲和性
A、肝素亲和色谱
用Pharmacia公司的快速操作液相色谱(FPLC)系统证明FGF对硫糖铝的亲和性:将2.5μgbFGF加入含0.1mgBAS的0.1ml盐水中,然后上样到TSK-GEL肝素5PW柱上(内径为3.5cm×8mm产自Tosohaas,Phil,PA).该柱用0.6MNacl,10mMTris-HCL,pH7(Tris缓冲剂)预平衡。上样后,用10ml含0.6MNacl的Tris缓冲液冲洗色谱柱,用4ml含2MNacl或含78mMSOS铝的Tris缓冲液以0.5ml/min的流速对结合的活性物进行洗脱。收集每1ml的馏分,然后按实施例Ⅰ的方法分析生长因子活性。
如图4示所示,78mM的SOS钾在肝素一琼脂糖柱中不与bFGF偶连。它进一步还表明了由SOS所致的有丝分裂活性的恢复至少可与2MNacl(图4上格)的同一作用相比。早先的研究已经表明bFGF能牢固地粘附于固定的肝素之上(参见Shing et al.,Science 223:1296-1298(1984)及Klagsburn et al.,同上文)并能用高度浓度的Nacl(如1.5m)洗脱下来,很显然,与bFGF同肝素的亲和力相比,bFGF同硫糖铝具有相等或更大的亲和力。
B、硫糖铝-琼脂糖色谱
硫糖铝-琼脂糖柱是通过将0.1g硫糖铝与0.8ml(柱床体积)溶有琼脂糖CL-6B(Pharmacia)并含有0.6NNacl的Tris缓冲液混合而制得。将2μgbFGF加入含0.1mgBAS的0.2ml盐水中,然后上样到硫糖铝柱。用含0.6MNacl的Tris缓冲液10ml冲洗柱,然后再用下列洗脱液以15ml/hr的低流速进行洗脱:ⅰ)0.6~3M梯度浓度的Nacl(80ml);ⅱ)20ml3MNacl;ⅲ)30ml1.5M乙酸(pH2.2)。以2ml为馏分进行收集,用Tris缓冲液将每一等份试样稀释、中和、然后按实施例Ⅰ的方法分析生长因子活性。
如图5所示,当含bFGF的样品预先上样到由硫糖铝和琼脂糖粉形成的柱中,用直至3M梯度浓度的Nacl也无法将bFGF洗脱下来。用1.5M的乙酸(pH2.2)从柱中回收具有生物活性的bFGF,并按实施例Ⅰ描述的试验方法分析其活性。这就进一步表明FGF对硫糖铝具有更强的亲和力以及硫糖铝可用于从液态样品中纯化FGF。
Claims (24)
1、一种治疗哺乳动物FGF反应性疾病的方法,它包括给哺乳动物施用有效量的一种用SOS稳定的FGF组合物。
2、一种治疗哺乳动物胃肠道溃疡性疾病的方法,它包括给哺乳动物施用有效量的一种用SOS稳定的FGF组合物。
3、根据权利要求1或2的方法,其中的组合物中的FGF成分选自天然FGF或重组FGF。
4、根据权利要求3的方法,其中的重组FGF含有rhbFGF突变蛋白CS23。
5、根据权利要求2的方法,其中的胃肠道溃疡性疾病包括局灶性回肠炎。
6、根据权利要求2的方法,其中的胃肠道溃疡性疾病包括溃疡性结肠炎。
7、根据权利要求2的方法,其中的胃肠道溃疡性疾病包括消化性溃疡。
8、根据权利要求7的方法,其中的消化性溃疡是十二指肠性溃疡。
9、根据权利要求7的方法,其中的消化性溃疡是胃溃疡。
10、根据权利要求3的方法,其中的哺乳动物是人,该组合物经口服给药并且是组合物中FGF蛋白成分的用量是每天约0.1μg~30mg。
11、根据权利要求10的方法,其中FGF蛋白成分的量是每天约1μg~3mg。
12、根据权利要求10的方法,其中FGF蛋白成分的量是每天约10μg~300μg。
13、根据权利要求3的方法,其中的哺乳动物是人,该组合物经口服给药,组合物中SOS成分的量为0.1~6g/day,分次施用。
14、一种药用组合物,它含有FGF和SOS以及一种药用载体、赋形剂或稀释剂。
15、根据权利要求14的药用组合物,其中的FGF选自天然FGF或重组FGF。
16、根据权利要求15的药用组合物,其中的重组FGF是rhbFGF突变蛋白CS23。
17、根据权利要求16的药用组合物,其中SOS与FGF的重量比为约1∶1-10,000∶1。
18、一种测定FGF在液体样品中存在的方法,它包括:
a)将SOS与液体样品接触;
b)分析液体样本中被稳定的FGF的存在情况。
19、根据权利要求18的方法,其中的液体样品是尿液。
20、根据权利要求18的方法,其中的液体样品是脑脊液。
21、一种从液体样品中分离FGF的方法,它包括:
a)用含有SOS的柱与液体样品接触;
b)用一种能洗脱FGF的洗脱液与柱接触。
22、根据权利要求21的方法,其中的柱进一步还包括琼脂糖粉。
23、根据权利要求21的方法,其中的洗脱液是选自Nacl和乙酸。
24、一种稳定组织培养中FGF的方法,它包括将结合的SOS作为一种组织培养成分。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/524.144 | 1990-05-15 | ||
US07/524,144 US5202311A (en) | 1988-08-19 | 1990-05-15 | Stabilized fgf composition |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1058149A true CN1058149A (zh) | 1992-01-29 |
Family
ID=24087954
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN91103961A Pending CN1058149A (zh) | 1990-05-15 | 1991-05-14 | 稳定的成纤维细胞生长因子组合物 |
Country Status (13)
Country | Link |
---|---|
US (1) | US5202311A (zh) |
EP (1) | EP0457223A1 (zh) |
JP (1) | JPH04330017A (zh) |
KR (1) | KR910019637A (zh) |
CN (1) | CN1058149A (zh) |
AU (1) | AU637904B2 (zh) |
CA (1) | CA2042569A1 (zh) |
FI (1) | FI912348A (zh) |
HU (1) | HU208635B (zh) |
IE (1) | IE911655A1 (zh) |
IL (1) | IL98040A0 (zh) |
NO (1) | NO911861L (zh) |
RU (1) | RU2070722C1 (zh) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5260071A (en) * | 1989-12-18 | 1993-11-09 | Lemelson Jerome H | Drug units and methods for using same |
US6077823A (en) * | 1991-03-11 | 2000-06-20 | Creative Biomolecules, Inc. | Method for reducing tissue damage associated with ischemia-reperfusion or hypoxia injury |
US5482929A (en) * | 1991-12-26 | 1996-01-09 | Kaken Pharmaceutical Co., Ltd. | Composition of stabilized fibroblast growth factor |
WO1994028020A1 (en) * | 1993-05-18 | 1994-12-08 | Bukh Meditec A/S | A method for the preparation of interferons |
JP3639593B2 (ja) * | 1993-05-31 | 2005-04-20 | 科研製薬株式会社 | 塩基性線維芽細胞増殖因子含有架橋ゼラチンゲル製剤 |
US5783568A (en) * | 1994-06-10 | 1998-07-21 | Sugen, Inc. | Methods for treating cancer and other cell proliferative diseases |
JP3263598B2 (ja) * | 1995-11-01 | 2002-03-04 | 有限会社ドット | 経鼻吸収用生理活性ペプチド組成物 |
US20110207666A1 (en) * | 1996-03-05 | 2011-08-25 | Depuy Spine, Inc. | Method of promoting bone growth with hyaluronic acid and growth factors |
US6645945B1 (en) | 1996-03-05 | 2003-11-11 | Depuy Acromed, Inc. | Method of treating diseased, injured or abnormal cartilage with hyaluronic acid and growth factors |
US5942499A (en) * | 1996-03-05 | 1999-08-24 | Orquest, Inc. | Method of promoting bone growth with hyaluronic acid and growth factors |
US6221854B1 (en) | 1996-03-05 | 2001-04-24 | Orquest, Inc. | Method of promoting bone growth with hyaluronic acid and growth factors |
US7598224B2 (en) | 2002-08-20 | 2009-10-06 | Biosurface Engineering Technologies, Inc. | Dual chain synthetic heparin-binding growth factor analogs |
US8227411B2 (en) | 2002-08-20 | 2012-07-24 | BioSurface Engineering Technologies, Incle | FGF growth factor analogs |
US20080227696A1 (en) * | 2005-02-22 | 2008-09-18 | Biosurface Engineering Technologies, Inc. | Single branch heparin-binding growth factor analogs |
CA2555583A1 (en) * | 2004-02-20 | 2005-09-09 | Biosurface Engineering Technologies, Inc. | Positive modulator of bone morphogenic protein-2 |
JP2009541358A (ja) | 2006-06-22 | 2009-11-26 | バイオサーフェス エンジニアリング テクノロジーズ,インク. | 骨形成を強化するためにbmp−2増幅因子/共活性化因子を送達するための組成物および方法 |
GB0622688D0 (en) | 2006-11-14 | 2006-12-27 | Diosamine Dev Corp | Novel compounds |
AU2007234612B2 (en) * | 2006-12-14 | 2013-06-27 | Johnson & Johnson Regenerative Therapeutics, Llc | Protein stabilization formulations |
US7678764B2 (en) | 2007-06-29 | 2010-03-16 | Johnson & Johnson Regenerative Therapeutics, Llc | Protein formulations for use at elevated temperatures |
JP5323832B2 (ja) | 2007-08-07 | 2013-10-23 | アドバンスト・テクノロジーズ・アンド・リジェネレイティブ・メディスン・エルエルシー | 酸性水溶液中にgdf−5を含むタンパク質製剤 |
US7947649B2 (en) * | 2008-04-14 | 2011-05-24 | Advanced Technologies And Regenerative Medicine, Llc | Liquid buffered GDF-5 formulations |
US9347037B2 (en) * | 2013-02-11 | 2016-05-24 | Evan Masataka Masutani | Methods and apparatus for building complex 3D scaffolds and biomimetic scaffolds built therefrom |
SG11201804402WA (en) | 2015-11-27 | 2018-06-28 | Univ Masarykova | Thermostable fgf2 polypeptide, use thereof |
WO2020188019A1 (en) * | 2019-03-20 | 2020-09-24 | Reponex Pharmaceuticals A/S | Targeting biological agents to mucosal defects of the gastrointestinal tract |
EP4183796A1 (en) | 2021-11-19 | 2023-05-24 | Enantis s.r.o. | Thermostable fgf10 polypeptide or fragment thereof use thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU607690B2 (en) * | 1985-12-24 | 1991-03-14 | Marion Laboratories, Inc. | Use of synthetic sulfated saccharides to enhance wound healing |
US4912093A (en) * | 1986-10-01 | 1990-03-27 | Marion Laboratories, Inc. | Use of synthetic sulfated saccharides to enhance wound healing |
DE3628829C1 (de) * | 1986-08-25 | 1988-02-11 | Pantelis Bozoglou | Naehmaschine zum Annaehen eines Gummibandes |
DK505488D0 (da) * | 1987-12-21 | 1988-09-09 | Bar Shalom Daniel | Middel og anvendelse af samme |
AU614137B2 (en) * | 1988-06-06 | 1991-08-22 | Takeda Chemical Industries Ltd. | Stabilized fgf composition and production thereof |
US5100668A (en) * | 1988-06-14 | 1992-03-31 | Massachusetts Institute Of Technology | Controlled release systems containing heparin and growth factors |
US5175147A (en) * | 1988-08-19 | 1992-12-29 | Takeda Chemical Industries, Ltd | Acid-resistant fgf composition and method of treating ulcerating diseases of the gastrointestinal tract |
DE3900198A1 (de) * | 1989-01-05 | 1990-07-12 | Merck Patent Gmbh | Topisch anwendbare pharmazeutische zubereitung |
FR2644066B1 (fr) * | 1989-03-09 | 1994-05-13 | Therapeutiques Substitutives | Compositions stabilisees comprenant des fgfs, leur procede d'obtention et leurs applications therapeutiques, chirurgicales et cosmetologiques |
CA2020654A1 (en) * | 1989-07-07 | 1991-01-08 | Yohko Akiyama | Stabilized fgf composition and production thereof |
-
1990
- 1990-05-15 US US07/524,144 patent/US5202311A/en not_active Expired - Fee Related
-
1991
- 1991-05-02 IL IL98040A patent/IL98040A0/xx unknown
- 1991-05-11 EP EP91107682A patent/EP0457223A1/en not_active Withdrawn
- 1991-05-14 CN CN91103961A patent/CN1058149A/zh active Pending
- 1991-05-14 AU AU77030/91A patent/AU637904B2/en not_active Ceased
- 1991-05-14 RU SU914895442A patent/RU2070722C1/ru active
- 1991-05-14 FI FI912348A patent/FI912348A/fi not_active Application Discontinuation
- 1991-05-14 CA CA002042569A patent/CA2042569A1/en not_active Abandoned
- 1991-05-14 NO NO91911861A patent/NO911861L/no unknown
- 1991-05-14 IE IE165591A patent/IE911655A1/en unknown
- 1991-05-14 HU HU911613A patent/HU208635B/hu not_active IP Right Cessation
- 1991-05-15 JP JP3110430A patent/JPH04330017A/ja not_active Withdrawn
- 1991-05-15 KR KR1019910007897A patent/KR910019637A/ko not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
AU637904B2 (en) | 1993-06-10 |
KR910019637A (ko) | 1991-12-19 |
AU7703091A (en) | 1991-11-21 |
NO911861D0 (no) | 1991-05-14 |
NO911861L (no) | 1991-11-18 |
FI912348A0 (fi) | 1991-05-14 |
EP0457223A1 (en) | 1991-11-21 |
HU208635B (en) | 1993-12-28 |
US5202311A (en) | 1993-04-13 |
HUT57061A (en) | 1991-11-28 |
JPH04330017A (ja) | 1992-11-18 |
RU2070722C1 (ru) | 1996-12-20 |
FI912348A (fi) | 1991-11-16 |
IE911655A1 (en) | 1991-11-20 |
CA2042569A1 (en) | 1991-11-16 |
IL98040A0 (en) | 1992-06-21 |
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