CN100467058C - 含有plgf-1的药物和化妆品组合物 - Google Patents
含有plgf-1的药物和化妆品组合物 Download PDFInfo
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- CN100467058C CN100467058C CNB038051532A CN03805153A CN100467058C CN 100467058 C CN100467058 C CN 100467058C CN B038051532 A CNB038051532 A CN B038051532A CN 03805153 A CN03805153 A CN 03805153A CN 100467058 C CN100467058 C CN 100467058C
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Abstract
本发明涉及含有胎盘生长因子(PLGF)的治疗和化妆品组合物的制备,其能够增加皮肤、皮下和内脏***的血管生成。这样的组合物适合用于通过皮肤层新血管的形成或再生而治疗病理或自然状态,例如硬皮病、其各种征候、皮肤老化或脱发。
Description
发明领域
本发明涉及含有胎盘生长因子(PLGF)的治疗和化妆品组合物的制备,其能够增加皮肤、皮下和内脏器官***的血管生成。这样的组合物适合用于通过皮肤层新血管的形成或再生而治疗病理或自然状态,例如各种表现形式的硬皮病、皮肤老化或脱发。
本领域状况
胎盘生长因子(PLGF)是调节血管生成的同二聚体糖蛋白.Maglione和Persico在专利BP-B-0 550 519(WO-A-92/06194)中描述了编码PLGF蛋白的完整多核苷酸序列。PGLF RNA的选择性剪接产生三种同源形式,即PLGF-1、PLGF-2和PLGF-3,它们具有不同的多肽序列并都在文献中进行了描述。
在本领域现有技术中描述了或只是假设了PLGF-1的治疗应用。专利EP-B-0 550 519假设了PLGF用于治疗一般性炎症状态、创伤、烧伤、溃疡和手术后阶段。国际申请WO-A-01/56593描述了在治疗和预防脑、心肌和外周缺血中VEGF和PLGF因子的肠胃外全身性使用.在“I1Farmaco”(Vol.55,2000,165-167页,Maglione等人)上发表的科学文章也描述了PLGF-1对于预防心肌缺血和降低梗死严重性的效用.最后,Faille等人在“Journal Invest.Dermatol.”(115(3),Sep.2000,388-395页)中报道了在创伤组织修复过程所涉及的角膜细胞中引起PLGF的产生。可是,现有技术教导没有使得能够断定PLGF-1在预防性或治愈性治疗涉及皮肤、皮下和内脏器官***的疾病或者病理变化中是有效的。特别地,现有技术教导没有使得能够断定局部施用外源性PLGF能够在体内影响与病理状态以及与自然状况相关的皮肤的血管形成。在根据本发明进行施用外源性PLGF之后所获得的促进血管生成(特别是促进皮肤血管形成)的效用在处理病理或生理状态中是特别有利的,这些病理或生理状态由于得到更有效的血液供应而易得到改善。
发明概述
本发明是基于一个意外的发现,即在组成皮肤的组织中特别是在***中增加PLGF-1的水平将伴随出现皮肤血管形成的增加.同样地,已经观察到该组织PLGF-1水平的增加可以有利地通过根据本发明肠胃外或局部使用组合物而施用外源性PLGF-1来获得.血管生成刺激经证实对于下列情况的处理是有用的,即皮肤、皮下和内脏***的典型病理状态,例如具有不同表现形式的硬皮病如局部性硬皮病、渐进性全身性硬皮病和全身性硬化症,和修复皮肤损伤和溃疡、自然和病理性脱发,或者只是生理状态如皮肤老化,特别是由于暴露于日光或暴露于空气/环境侵袭性试剂所产生的皮肤老化。
本申请的目标是使用PLGF特别是1型PLGF(PLGF-1)来制备治疗或化妆品组合物,该组合物可在预防性或治愈性治疗涉及皮肤、皮下和内脏***和/或血管***的疾病或者自然或病理变化,从而促进血管生成。
特别地,本发明的目标是使用PLGF-1来制备治疗组合物以用于治疗硬皮病,特别是局限性硬皮病、进行性全身性硬皮病和全身性硬化症,和治疗由于暴露于空气/环境侵袭剂或暴露于日光辐射而引起的病理性皮肤老化,以及治疗病理原因的脱发。
本发明的进一步目标为在用于预防性或治愈性治疗脱发和皮肤老化的化妆品中使用PLGF-1。
本发明的进一步目标也为用于局部和肠胃外使用的药物组合物,以及用于局部使用的化妆品组合物,它们含有PLGF-1和在药物与化妆品组合物领域中通常使用的赋形剂。
发明详述
在组成皮肤的组织中特别是在角质形成细胞中增加PLGF-1的水平会伴随出现皮肤血管形成的局部增加.这种组织中PLGF-1水平的增加可以通过全身性以及区城性施用外源性PLGF-1来获得。
检测
PLGF-1的血管生成作用通过已知的在体内或体外进行的方法来测定,例如兔角膜血管形成检测或鸡尿囊绒膜血管形成检测.根据本发明,按照Streit等人(Proc.Natl.Acad.Sci.USA 1999,Dec.21st,96(26),14888-14893)的描述通过皮肤样品的计算机化形态测量分析来检查皮肤的血管形成。将从根据本发明进行处理或未处理的实验动物中分离得到的皮肤切片使用所用动物的抗CD31单克隆抗体进行免疫组织化学染色.经这样处理的切片用电子显微镜进行分析,组织的形态测量分析用IP-LAB程序(Scanalytics公司)来进行。按照Streit等人的描述来测定每mm2的血管数目、它们的平均大小和它们所占据的相关区域。
在经处理的动物中,用外源性PLGF-1进行局部处理引起如实施例中举例说明的血管参数的显著增加。
用于评测根据本发明的组合物的血管生成活性的第二种方法是体内毛细管显微镜检查和毛细管显微镜测量。该已知的技术涉及皮肤的直接显微镜观察,优选地用增加透明度的物质如凡士林或植物油进行预处理。优选的分析区域为肢体指甲壁。通过毛细管显微镜检查和毛细管显微镜测量所获得的数据的分析可以合适地通过使用照相记录***和计算机化数据再处理***来进行。值得考虑的参数为血管形态学、血管周围组织形态学和流变学状况。形态学观察记录了任何血管形成的增加或减少、毛细管口径和每mm2的毛细管密度。组织观察评测了***透明度以及毛细血管周围出血或者液体或硬化胶原沉积的存在。特别地,血管周围***的观察强调了,在正常条件下,毛细血管袢由颜色较浅的晕所环绕,该晕称为毛细管晕,其是由富含葡糖胺聚糖的松弛组织所组成的。这种晕的消失或减少是***的深度结构变化的征兆。其他变化类型为伴随硬皮病出现的组织透明度的降低。流变学状况评测了流速或红细胞凝集或血栓形成的存在。
按照Yamamoto T.等人在Arch.Dermatol.Res.(Nov.2000,292(11),535-541页)中的描述,在动物模型上评测本发明的组合物在治疗硬皮病中的活性。在C3H小鼠中通过用博来霉素(100mcg/ml)处理而诱导产生硬皮病状态,博来霉素是通过每日进行皮下注射并持续3星期而进行施用的。在3星期之后,处死动物并将经处理的区域的皮肤样品进行组织学分析。治疗的效用表现在归因于博来霉素引起的皮肤硬化的组织学表现,特别是皮肤变厚和高的羟脯氨酸水平。
PLGF
本发明中使用的1型胎盘生长因子(PLGF-1)可以是提取来源的,或者作为来自经遗传修饰的宿主细胞的表达产物而获得.在本发明的优选实施方案中,高度纯化的因子以基本上同二聚体或多聚体形式进行使用,这种形式是根据本发明者在国际申请PCT/IT 02/00065中所揭示的方法而获得的。特别地,所使用的产物含有不低于98.5%的二聚体和多聚体活性形式、不低于70%的二聚体形式或无论如何不高于1.5%的单体形式。在功能上具有活性的PLGF-1片段同样也可以在本发明的范围内使用。具有纯化因子的至少30%的比活性或者优选地至少50%或更好地至少90%的片段可以认为其在功能上相当于天然因子。
疾病
硬皮病治疗分别是本发明的一个方面和本发明的组合物的一个方面。
硬皮病是涉及微血管***和皮肤、皮下与内脏***的疾病.该疾病引起成纤维细胞的活化和胶原的过多产生及在组织和血管周围的沉积,这在很大程度上影响着纤维化和钙化区城的形成,因此影响着疾病引起的症状的表现。特别地,在毛细管显微镜检查中观察到大量的硬化胶原环绕在皮肤的血管周围,从而引起血管口径的变窄。
皮肤参与的局限性硬皮病与进行性全身性硬皮病是有区别的,前者的特征在于由于过多的和不适当的胶原沉积所造成的皮肤***和变厚,而在后者中血管的参与和具有内脏损伤的全身性硬化与皮肤纤维化有关。在手指和手上的皮肤都出现***、变厚和水肿。此外,疾病还表现在具有心机能不全的心肌水平上,和表现在肺、胃肠、肾和骨-肌肉***水平上。此外,一些患者形成皮肤纤维化引起的给关节活动性造成巨大困难的侵蚀性关节病.
关于其他的血管生成药物,已经报道了,由于用这些有益于疾病的病史的药物进行治疗而促进了血管生成,特别是促进了皮肤的血管生成。特别地,用血管生成因子治疗受全身性硬化症影响的患者,这种患者的皮肤表面的体内毛细管显微镜检查证实了在密度以及平均血管口径上有统计学上显著的血管形成的增加。此外,新血管没有硬化的胶原,因此能够改善组织的血液供应.这一增加伴随着病理表现的部分缓解。
不是想将本发明束缚于或限制于科学理论,假设在治疗全身性硬化症中PLGF-1对于动物模型所发挥的治疗效用是由伴随着体内血管生成的血管舒张作用来介导的。事实上,已经证实PLGF-1引起的一种效用为刺激了一氧化氮(NO)的产生,有许多科学证据表明NO是重要的血管舒张媒介物。
基于PLGF-1在治疗硬皮病和其伴随的表现中所引起的效用而假设的作用机制与到目前为止这些病理状况的治疗相一致。事实上,这种治疗依赖于不同药物的联合使用,在这些药物中有着具有血管(主要是血管舒张)作用的药剂。
本发明的第二个方面涉及皮肤老化的典型表象的治疗。这种治疗虽然认为本质上是属于化妆品的,但是当考虑由于延长暴露于日光辐射(光老化)、其他辐射或其他环境/空气侵袭剂所造成的皮肤组织的过早退化现象时,其具有治疗的含义。
对于光损伤皮肤样品的电子显微镜观察揭示了典型的微血管形态学,除了其他表现之外,其特征在于存在病理性扩张的毛细管,这些毛细管顺弹性蛋白排列或者被密集的无定形物质包围。也观察到存在活化的内皮细胞,这些细胞具有增加了数量的胞质细胞器和胞饮泡。已经观察到,由根据本发明施用PLGF-1所引起的对新皮肤血管形成的刺激在自然以及过早老化的皮肤中产生了对于细胞外基质的调节效用,这些细胞外基质影响着皮肤张力和厚度.在用本发明的组合物进行延长的局部治疗之后,毛细血管的形成增加了,这伴随着成纤维细胞的增加和新胶原的产生,随后总体改善了皮肤的外观。
本发明的另一个方面涉及脱发.
改善的皮肤血管形成伴随着进一步的治疗以及美容价值的表现,即皮肤附属物(毛发等等)的生长的调节,意指脱落预防和再生促进.
生长阶段(即相当于毛发生长阶段)伴随着毛囊血管形成的自然增加。局部施用的PLGF-1的血管生成作用促进了这种血管的增加和随之发生的毛发的生长.用本发明的组合物处理动物,其靠近毛囊的皮肤切片的计算机化形态测量分析揭示了不只在毛细管口径大小和毛细管密度上有增加(由此在毛囊周围的血管形成上有大体的增加),而且在毛球的尺寸和毛发本身的直径上有增加。
预防脱发或者促进其再生长的效用不仅可用于自然脱发的情况,而且可用于由于临床相关状态如脱发症、激素紊乱、化疗、放疗或药物施用所造成的脱发。
适合于治疗药剂的全身性或区域性施用的任何配剂可以根据本发明使用。用于区域性使用的配剂在化妆品应用的领域中使用。
特别地,PLGF-1因子可以通过具有全身性或区域性(local)效应的肠胃外途径进行施用,或者通过主要具有区域性效应的局部途径(topic)施用于皮肤或粘膜。虽然腹膜内或肌肉内施用也是合适的,但是全身性效用主要是通过静脉内施用来获得的.区域性效用通过局部或者肠胃外的肌肉内、皮下、关节间施用而获得。同样地,PLGF-1因子可以通过电转运或离子电泳进行局部施用。当希望延迟的释放时,皮下植入物同样是可用的。虽然因子的口服施用也是可行的,但是鉴于活性产物的易腐性其是较不合适的.
用于肠胃外、全身性或区域性使用的组合物包括溶液、悬浮液、脂质体悬浮液、W/O或O/W乳浊液.用于局部使用的组合物包括溶液、洗液、悬浮液、脂质体悬浮液、W/O或O/W乳浊液、凝胶、软膏、霜剂、润发油和糊剂.在优选的实施方案中,活性物质以冻干的形式进行配制,其混合了合适的冻干添加剂,并易于用治疗上可用的稀释剂进行再溶解。可用的冻干添加剂为:缓冲液、多糖、蔗糖、甘露醇、肌醇、多肽、氨基酸和其他任何与活性物质可相容的添加剂.在本发明的优选实施方案中,将活性物质以这样的数量溶解在磷酸缓冲液(NaH2PO4/H2O-Na2HPO4/2H2O)中,即在冻干之后PLGF-1/磷酸盐的比例位于1:1和1:2之间.适合于肠胃外使用的稀释剂为:水、生理溶液、糖溶液、水醇溶液(hydroalcoholic solution)、油性稀释剂、多元醇(如甘油、乙二醇或聚乙二醇),或者任何可与施用方法例如无菌状态、pH、离子强度和粘度相匹配的其他稀释剂。
在乳浊液或悬浮液的情况下,组合物可以含有通常在药物配剂中使用的合适的非离子、两性离子、阴离子或阳离子型表面活性剂。油/水(O/W)亲水性乳浊液对于肠胃外全身性使用是优选的,然而水/油(W/O)亲脂性乳浊液对于区域性或局部使用是优选的。
此外,本发明的组合物可以含有可选择的添加剂如等渗试剂,例如糖或多元醇、缓冲液、螯合剂、抗氧化剂、抗菌剂。
用于局部使用的组合物具有液体形式或半固体形式。液体形式包括溶液或洗液。这些可以是含水的、水醇的如乙醇/水或者含醇的,并可以通过溶解冻干的物质来获得。
作为另一种选择,活性物质溶液可以通过添加已知的胶凝剂而以凝胶形式进行配制,如:淀粉、甘油、聚乙二醇或聚丙二醇、聚(甲基)丙烯酸酯、异丙醇、羟基硬脂酸酯。
用于局部使用的其他类型的组合物为润发油、糊剂、霜剂形式的乳浊液或悬浮液.W/O乳浊液是优选的,其提供了更快的吸收。亲脂性赋形剂的例子为:液体石蜡、无水羊毛脂、白凡士林、鲸蜡醇、硬脂醇、植物油、矿物油。有利地可以使用增加皮肤渗透性并由此促进吸收的试剂。这种试剂的例子为生理上可用添加剂如聚乙烯醇、聚乙二醇或二甲亚砜(DMSO)。
在局部组合物中使用的其他添加剂为等渗试剂,例如糖或多元醇、缓冲液、螯合剂、抗氧化剂、抗菌剂、增稠剂、分散剂。
同样地,可以使用用于区域性或全身性使用的延迟释放的组合物,其含有聚合物如聚乳酸酯、聚(甲基)丙烯酸酯、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素和本领域中已知的其他物质.以基于例如聚乳酸酯或其他生物可降解聚合物的皮下植入物的形式存在的延迟释放组合物也可以使用。
虽然活性物质优选地以经冻干因此稳定的形式进行包装,但是药物组合物有利地含有将PLGF-1稳定于有活性的二聚体-多聚体形式的物质。这种稳定剂抑制了分子间二硫键的形成,因此防止了活性物质的多聚化.可是,应当小心地调节稳定剂的数量,从而预防活性物质还原成无活性的单体形式.这样的物质的例子为:半胱氨酸、半胱胺或还原形式的谷胱甘肽.
剂量
剂量取决于施用途径和所选择的配剂.对于肠胃外施用,数量从1mcg/kg/天至500mcg/kg/天变化,优选地从10mcg/kg/天至200mcg/kg/天变化.这种施用可用这样数量的药物组合物来获得,即每个单个剂量单位含有大约50mcg-30mg,优选地每个剂量单位含有大约500mcg-10mg.对于局部治疗应用,在每克组合物含有0.1-10mg的数量经证明是有效的。用于治疗皮肤老化或脱发的局部化妆品组合物优选地在每克组合物中含有0.01-0.09mg的活性物质.
治疗的时间长短依赖于病理状态或所希望的效果而变化。在治疗硬皮病的情况下,施用时间根据病理严重性而从1天至12个月变化。在抗自然或过早皮肤老化的治疗的情况下,施用时间从1天至400天变化,优选地持续至少30天。同样地,在用于预防脱发或用于促进毛发再生的处理的情况下,施用时间从1天至400天变化。
实施例1
用于肠胃外使用的溶液:
将含有25mg纯PLGF-1和33mg磷酸缓冲剂(10mg NaH2PO4/H2O和23mg Na2HPO4/2H2O)的58mg冻干物质和大约125ml用于肠胃外使用的生理溶液分别装入预置的烧瓶中,用于在使用之前快速混合冻干的产物和稀释剂.活性物质的溶解后浓度为大约0.2mg/ml。
实施例2
用于局部应用的W/O乳浊液
将含有20mg活性物质的一些冻干物质置于含有10%DMSO的5ml10%乙醇水醇溶液中。将该溶液在用于皮肤应用的无菌植物油中进行乳化,这是通过使用具有<10HLB系数的适合于W/O乳浊液的表面活性剂来进行的。该乳浊液含有的活性物质等于大约2mg/gr组合物.
实施例3
O/W乳浊液
将含有大约20mg活性物质的一些冻干物质溶解在含有30%DMSO的5ml水醇溶液中,并用合适的表面活性剂在基于植物油的亲脂性溶剂中进行乳化。结果所得的O/W乳浊液含有浓度为大约3mg/gr组合物的活性物质。
实施例4
凝胶形式的局部组合物
将含有10mg活性物质的一些冻干物质置于含有20% DMSO的20ml10%乙醇水醇溶液中。然后,向溶液中添加聚乙二醇(400-4000)和聚丙二醇的混合物。活性物质以等于2mg/gr组合物的数量存在。该凝胶适合于化妆品应用。
实施例5
将4只SKH-1无毛小鼠每天用50μl实施例1中所描述的溶液(0.2mg/ml)进行处理并持续20天,该溶液是通过背部区域的一组皮肤表面(1cm2)进行肠胃外皮下途径来施用的。其他4只SKH-1小鼠用实施例2中所描述的组合物(2mg/gr)通过局部途径处理30天。4只同样种类的小鼠只用用于肠胃外使用的赋形剂进行处理,其他4只小鼠只用用于局部使用的赋形剂进行处理,这都是依照同样的施用规程来进行的。被处死动物的皮肤样品通过Streit等人(如上)描述的计算机化形态测量分析来进行检查。详细地说,将皮肤切片(5微米)用单克隆抗鼠CD31抗体进行免疫组织化学染色。经这样处理的切片用电子显微镜进行分析,并用IP-LAB程序(Scanalytics公司)实施组织的形态测量分析.所考虑的参数为血管覆盖区域(%/mm2)和平均血管大小(μm2).结果报告在表1中。
表1
参数 | 肠胃外安慰剂 | 局部安慰剂 | 肠胃外PLGF-1 | 局部PLGF-1 |
血管区域(mm<sup>2</sup>)(%) | 4.3±0.2% | 4.1±0.2% | 6.2±0.3% | 5.2±0.6% |
血管大小(μm<sup>2</sup>) | 180±9 | 176±9 | 279±14 | 235±12.7 |
在表中所报告的值表明,肠胃外处理和局部处理都显示出统计学上显著的增加,虽然局部处理的增加的显著性较小。
实施例6
在该实施例中,使用Yamamoto等人(如上)所描述的博来霉素诱导的硬皮病的动物模型。
第一组C3H小鼠用博来霉素(100mcg/ml)通过每天皮下注射并持续3星期而进行处理.其他3组C3H小鼠像第一组一样进行处理,但是对于它们的每日注射分别以0.1、1和10mcg/ml的剂量加入PLGF-1。在处理3星期之后处死动物,然后收集经处理区域的皮肤并进行组织学分析。用1和10mcg/ml但不是0.1mcg/ml的PLGF-1进行处理的效果强调出归因于博来霉素诱导的皮肤硬化的组织学表现的显著减少。特别地,相对于用单独博来霉素处理的小鼠,皮肤变厚和羟脯氨酸水平显著减少了。
实施例7
一些年龄在50-60岁的健康成年个体常常明显地暴露于环境侵袭剂和日光辐射,将这样的个体的左手背用实施例4中所描述的以凝胶形式存在的组合物通过皮肤局部应用进行处理。所使用的数量为每天1gr凝胶,相当于0.2mg活性物质,并在夏季持续60天。处理的效果照如下进行评估,即进行毛细管显微镜检查和毛细管显微镜测量分析,以及进行观察得到的数据的存储和计算机化再处理。未处理的表面的分析强调出皮肤过早光老化的典型图像,其特征在于存在病理性扩张的毛细管,这些毛细管顺弹性蛋白排列或者被密集的无定形物质包围。
在宏观水平上,处理产生了皮肤张力和外观的总体改善.
特别地,毛细管显微镜检查分析强调出毛细血管形成的增加在毛发毛囊周围区域是特别明显的。通过毛细管显微镜测量来比较用正在研究的组合物处理或未用正在研究的组合物处理的表面的毛囊周围区域,其结果强调出每mm2的血管数量有大约35.0%的增加。由于知道毛囊血管形成的增加刺激其生长,因此此处所报告的数据证明用PLGF-1进行局部处理不只对于抗皮肤老化有效,而且也促进毛细管/毛发的生长。
Claims (16)
1.1型胎盘生长因子(PLGF-1)在制备药物中的应用,该药物在预防性或治愈性治疗以下病症中促进血管生成:
-涉及皮肤或皮下***的疾病或病理变化,或
-硬皮病,或
-由于暴露于空气侵袭性试剂或延长的日光辐射而造成的过早皮肤老化。
2.根据权利要求1所述的1型胎盘生长因子(PLGF-1)的应用,其中所述疾病为局限性硬皮病或进行性全身性硬皮病。
3.根据权利要求2所述的1型胎盘生长因子(PLGF-1)的应用,其中局限性硬皮病为皮肤硬皮病,进行性全身性硬皮病为心肌硬皮病。
4.根据权利要求1的应用,其中所含PLGF-1的数量适合于1-500μg/kg体重/天的施用。
5.根据权利要求1的应用,其中药物以适合于产生区域性或全身性效用的形式存在。
6.根据权利要求5的应用,其中药物以适合于静脉内、肌肉内、关节内、皮下施用、局部施用或者皮下植入物或离子电泳施用的形式存在。
7.根据权利要求1所述的1型胎盘生长因子(PLGF-1)在制备药物中的应用,该药物在预防性或治愈性治疗由于脱发症、激素紊乱、化疗、放疗或药物施用所造成的病理性脱发中促进血管生成。
8.1型胎盘生长因子(PLGF-1)在制备组合物中的应用,所述组合物在预防和美容性治疗自然皮肤老化中促进皮肤或皮下血管生成。
9.1型胎盘生长因子(PLGF-1)在制备组合物中的应用,所述组合物在预防和美容性治疗自然脱发中促进毛囊周围血管生成。
10.根据权利要求8或9中任何一项所述的应用,其中将PLGF-1配制成用于局部施用的化妆品组合物。
11.含有PLGF-1作为活性成分以及药物可用的赋形剂的药物组合物,其特征在于至少98.5%的PLGF-1以二聚体和多聚体形式存在、至少70%以二聚体形式存在或不多于1.5%以单体形式存在,并且该药物组合物用于肠胃外使用,所含PLGF-1的量为50μg-30mg/单位剂型。
12.含有PLGF-1作为活性成分以及药物可用的赋形剂的药物组合物,其特征在于至少98.5%的PLGF-1以二聚体和多聚体形式存在、至少70%以二聚体形式存在或不多于1.5%以单体形式存在,并且该药物组合物用于局部使用,所含PLGF-1的量为0.1-10mg/g组合物。
13.含有PLGF-1作为活性成分和化妆品可用的赋形剂的化妆品组合物,其特征在于至少98.5%的PLGF-1以二聚体和多聚体形式存在、至少70%以二聚体形式存在或不多于1.5%以单体形式存在,并且所含PLGF-1的量为0.01-0.09mg/g组合物。
14.根据权利要求11-13中任一项的组合物,其特征在于所述PLGF-1是遗传修饰的原核宿主细胞的表达产物。
15.根据权利要求11-13中任一项的组合物,其特征在于其用于局部或全身性使用并以溶液、W/O乳浊液、O/W乳浊液、或凝胶剂形式存在。
16.根据权利要求11-13中任何一项所述的组合物,其含有一种或多种能够使活性二聚体-多聚体形式的PLGF-1稳定的物质。
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