CN1362883A - 包含表皮生长因子作为活性成分的稳定组合物 - Google Patents
包含表皮生长因子作为活性成分的稳定组合物 Download PDFInfo
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- CN1362883A CN1362883A CN01800267A CN01800267A CN1362883A CN 1362883 A CN1362883 A CN 1362883A CN 01800267 A CN01800267 A CN 01800267A CN 01800267 A CN01800267 A CN 01800267A CN 1362883 A CN1362883 A CN 1362883A
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Abstract
本发明涉及一种稳定组合物,它包含表皮生长因子(下文中称作“EGF”)活性成分和羧乙烯基聚合物基质。本发明人已确定包含EGF活性成分和酸性聚合物诸如羧乙烯基聚合物基质的EGF制剂具有与使用诸如纤维素基聚合物基质或中性聚合物基质的在先技术相比显著的稳定性。因此,本发明的组合物可用于眼用制剂、皮肤用的局部制剂和美容制剂等等。
Description
技术领域
本发明涉及包含表皮生长因子(下文中称作“EGF”)作为活性成分的稳定组合物。更具体地说,本发明涉及包含具有生物活性的EGF和能显著增加水溶液中EGF的稳定性的羧乙烯基聚合物基质的稳定组合物。
EGF(即尿抑胃素)是由53个氨基酸残基组成并包括3个二硫键的、分子量为6045的多肽。EGF被认为是皮肤和角膜的伤口愈合剂以及胃溃疡愈合剂,因为它表现出良好的刺激各种细胞包括表皮细胞和间充质细胞的有丝分裂及其生长和控制胃酸分泌的活性。(美国专利第140998号;Carpenter,实验细胞研究,164:1-10,1986)。
尽管EGF显示出良好的在体外刺激表皮细胞分化的活性,但开发用于治疗皮肤和角膜伤口的含有EGF的局部制剂是非常困难的,原因是当EGF临床应用于伤口时只有很小的治疗伤口的作用。
EGF是生物学上不稳定的和物理化学上非同质的,所以它的愈合作用不充分且它的分解产物可能诱导变态反应。因此EGF在应用于活体时不能显示出充分的治疗伤口的作用。EGF在室温下非常不稳定,特别是在水分的存在下。尽管伤口上DNA的合成需要约8至12小时的延滞时间,但EGF具有非常短的、约为1小时的半衰期,因而无法获得所需作用。另外,EGF在室温下、甚至在冷藏状态下长时间储存时会产生物理化学变性。当EGF施用到皮肤上时,因伤口中存在蛋白水解酶而引起的EGF的变性、分解、凝缩和沉淀导致EGF丧失生物活性(Manning等,药学研究,6:903-917,1989)。
为了克服EGF的生物不稳定性和提供其期望的伤口愈合作用,报道了在对于伤口愈合来说最重要的治疗的最初几天时间里将EGF连续施用到伤口上,以不断地保持EGF的有效浓度(Frankline等,实验与临床医学杂志,108:103-108,1986)。在这点上,已研究了一些EGF持续释放制剂,它们可以连续地提供EGF到伤口上。
结果,美国专利第4,944,948号公开了使用中性磷脂、负电荷磷脂和胆固醇连续地将EGF提供到伤口的EGF/脂质体凝胶制剂;EP出版物第312208号公开了包含药学上可接受的各种水溶性或水膨胀性聚合物基质的、能连续释放EGF的含水制剂。但是,尽管上述在先技术公开了能连续12小时或更久释放EGF的制剂,但它们不适合在工业领域中生产,因为这些制剂长期储存时不稳定。因此,一直以来都需要能长时间地保持EGF的生物活性及其物理化学稳定性诸如纯度和同质性,以提供EGF作为药物的足够的伤口愈合作用。
作为保持EGF的物理化学稳定性和抑制EGF活性下降的方法,EP公开第205051号提供了皮肤和眼用膏霜形式的药物组合物,它包含0.0001-0.005%(w/w)的EGF,1-10%(w/w)的表面活性剂,5-45%(w/w)的脂肪物质和0.3-0.8%(w/w)的防腐剂。EP出版物第267015号和美国专利第4717717号提供了通过向EGF中加入水溶性纤维素衍生物使其稳定的含有EGF的组合物。EP出版物第398615号和美国专利第5130298号提供了通过将EGF与药学上可接受的金属阳离子诸如锌混合来稳定EGF的方法,锌能够防止EGF在水溶液中降解,因为EGF与锌发生离子键合。
然而,尽管加入了上述稳定剂,但EGF的稳定性在4℃下只能维持约2个月。因此,当在临床上将EGF的皮肤用局部制剂应用于伤口时,它们不适合在工业领域中采用,因为它们具有很小的伤口愈合作用且制剂的稳定性降低。
因此,非常希望开发出用于治疗不能治愈的病状等诸如在没有特定治疗剂的情形下的皮肤溃疡或角膜损伤等的EGF的成品制剂,它们能充分地显示出伤口愈合作用,具有能对抗生物活性损失的保护的EGF,并且当其应用时能从载体中快速地释放出EGF到伤口上。
因此,本发明人已进行了很多研究来研制具有足够的伤口愈合作用和良好稳定性的EGF的局部制剂。结果,我们发现包含EGF作为活性成分和酸性聚合物诸如羧乙烯基聚合物作为基质的局部制剂可以显示出所需的良好的伤口愈合作用和与使用诸如纤维素基聚合物基质或中性聚合物基质的在先技术相比的显著的稳定性。
发明的公开
因此本发明的目的是提供含有EGF的生物学和物理化学稳定的组合物,它包含EGF作为活性成分和羧乙烯基(carboxyvinyl)聚合物作为基质(base)。
本发明的组合物包含EGF活性成分和羧乙烯基聚合物基质。EGF活性成分可以是从天然来源分离的或者使用重组DNA技术生产。EGF在组合物中的含量以制剂的总重计在0.001至1,000μg/g范围内,优选在0.1至100μg/g范围内,以使EGF是药理学上有效的。本发明组合物的pH优选在4至8的范围内,更优选在5至7的范围内,以保持EGF溶解但没有变性。
在本发明中用作基质的羧乙烯基聚合物是分子量为1×106至4×106的均聚物。羧乙烯基聚合物是丙烯酸和芳基蔗糖的交联产物,它是分散于1%水溶液中时pH显示为2.5至3.0的酸性聚合物。甚至在小于1%的低浓度下,它也有宽范围的粘度,所以它可广泛地用作用于口服、洗液、膏霜和凝胶制剂的悬浮体的基质。另外,不管聚合物的种类如何,羧乙烯基聚合物含有56.0至68.0%比例的羧酸残基(carboxylicresidue),包括卡波姆(Carbomer)934、卡波姆934P、卡波姆940、卡波姆941或卡波姆947P。羧乙烯基聚合物的含量以组合物的总重计在0.001至50wt%范围内,优选为0.005至25wt%,更优选为0.01至10wt%。
本发明的组合物可以进一步含有药学上可接受的添加剂,例如稳定剂、赋形剂、各向同性剂、增湿剂、pH控制剂等等。
本发明人已进行了稳定性试验,对按照本发明的含有羧乙烯基聚合物的EGF制剂与含有另一种聚合物基质的EGF制剂在4℃和25℃下6个月的稳定性进行了比较。在这种情况下,将溶于10mM磷酸盐缓冲剂的EGF用作对照,用ELISA法分析EGF的含量。结果,按照本发明的含有羧乙烯基聚合物基质的EGF制剂与含有另一种基质的EGF制剂以及溶于磷酸盐缓冲剂的EGF相比在各种浓度下都显示出显著的稳定化。从这个结果可以确定:在按照本发明的EGF制剂中的EGF通过加入羧乙烯基聚合物(不管其含量如何)得以稳定,于是该聚合物可以根据使用目的用作可任选地控制其粘度的基质和作为稳定剂加入。
按照本发明的含有EGF的组合物可以用于眼用制剂、皮肤用的局部制剂诸如霜剂、油膏、凝胶、贴敷片(patch)等,并且该组合物可以通过涂敷或摊开在棉质平坦表面的纱布上使用,且该组合物可以冷冻干燥形式储存,然后在需要使用时溶于合适的溶剂。此外,皮肤用局部制剂可以用于美容制剂。
本发明通过下列实施例作更具体的说明。但是,应当理解本发明不以任何方式限于这些实施例。
实施例1
含有卡波姆(0.1%)的滴眼剂
EGF卡波姆934P甘露糖醇对羟基苯甲酸甲酯对羟基苯甲酸丙酯氢氧化钠注射用蒸馏水 | 0.5mg0.1g5g0.04g0.01g适量适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将甘露糖醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯溶于适量的注射用蒸馏水中,向该溶液中加入卡波姆934P(BFGoodrich,美国)并搅拌使其分散。然后,用氢氧化钠控制该溶液的pH后将其灭菌,并与EGF(Daewoong Pharm.,韩国)在注射用蒸馏水中的经过过滤和灭菌的溶液混合得到100g制剂。
实施例2
含有EGF的10mM磷酸盐缓冲剂
EGF磷酸氢钠氯化钠20%磷酸 | 0.5mg0.14g0.88g适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将磷酸氢钠和氯化钠溶于适量的注射用蒸馏水,用20%磷酸控制该溶液的pH后将其灭菌,并与EGF在注射用蒸馏水中的经过过滤和灭菌的溶液混合得到100g制剂。
实施例3
含有羧甲基纤维素钠(0.5%)的滴眼剂
EGF羧甲基纤维素钠(Sod.CMC)山梨糖醇对羟基苯甲酸甲酯氢氧化钠注射用蒸馏水 | 0.5mg0.5g5.47g0.05g适量适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将山梨糖醇和对羟基苯甲酸甲酯溶于适量的注射用蒸馏水中,向该溶液中加入羧甲基纤维素钠并搅拌使其分散。然后,用氢氧化钠控制该溶液的pH后将其灭菌,并与EGF在注射用蒸馏水中的经过过滤和灭菌的溶液混合得到100g制剂。
实施例4
含有卡波姆(1%)的局部凝胶制剂
EGF卡波姆934P对羟基苯甲酸甲酯丙二醇氢氧化钠注射用蒸馏水 | 5mg1g0.2g20g适量适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将对羟基苯甲酸甲酯溶于适量的注射用蒸馏水中,向该溶液中加入卡波姆934P并搅拌使其分散。然后,用氢氧化钠控制该溶液的pH,将该溶液与丙二醇掺合并通过加热灭菌。之后向其中加入EGF在注射用蒸馏水中的经过过滤和灭菌的溶液而得到100g制剂。
实施例5
含有泊洛沙姆(Poloxamer)(15%)的局部制剂
EGF泊洛沙姆407对羟基苯甲酸甲酯磷酸氢钠氯化钠磷酸丙二醇注射用蒸馏水 | 5mg15g0.2g272.18mg666.22mg适量20g适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,使用所给用量的磷酸氢钠、氯化钠和磷酸制备磷酸盐缓冲剂。将对羟基苯甲酸甲酯防腐剂溶于磷酸盐缓冲剂中。向该溶液中加入泊洛沙姆407(BASF,德国)并搅拌使其分散。然后将该溶液与丙二醇掺合,并向其中加入EGF活性成分,得到100g制剂。
实施例6
含有卡波姆(0.1%)的霜制剂
EGF甘油对羟基苯甲酸甲酯对羟基苯甲酸丙酯卡波姆940硬脂醇鲸蜡醇司盘#60硬脂酸#40聚烃氧基酯三乙醇胺注射用蒸馏水 | 0.05mg4.5g0.15g0.05g0.1g1.75g4.00g0.50g2.00g适量适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将甘油和对羟基苯甲酸甲酯溶于适量的注射用蒸馏水中,向该溶液中加入卡波姆940(BF Goodrich,美国)并搅拌使其分散。然后向该溶液中加入对羟基苯甲酸丙酯和其他组分并通过熔化使其乳化。之后,用三乙醇胺控制该溶液的pH后将其灭菌,并与EGF(Daewoong Pharm.,韩国)在注射用蒸馏水中的经过过滤和灭菌的溶液混合得到100g制剂。
实施例7
含有卡波姆(0.1%)的软膏剂
EGF对羟基苯甲酸甲酯对羟基苯甲酸丙酯卡波姆940蜂蜡矿物油硼砂微晶蜡石蜡注射用蒸馏水 | 0.5mg0.10g0.05g0.1g5g45g0.2g7.00g10g适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和卡波姆940(BF Goodrich,美国)溶解并分散于适量的注射用蒸馏水中。向该溶液中加入剩余的蜡并在抬高的温度下乳化。然后,该溶液通过乳化灭菌,并与EGF(DaewoongPharm.,韩国)在注射用蒸馏水中的经过过滤和灭菌的溶液混合得到100g制剂。
实施例8
含有卡波姆(1%)的贴敷片制剂
EGF聚乙烯醇聚乙烯吡咯烷酮卡波姆940聚乙二醇4000甘油注射用蒸馏水 | 1.0mg20g15g1g5g3g适量 |
总量 | 100g |
使用所给用量的上述组分按照常规方法制成制剂。具体地说,将卡波姆940(BF Goodrich,美国)、聚乙烯醇、聚乙烯吡咯烷酮、PEG400、甘油溶解并分散于适量的注射用蒸馏水中。该溶液在抬高的温度下灭菌,并与EGF(Daewoong Pharm.,韩国)在注射用蒸馏水中的经过过滤和灭菌的溶液混合得到100g制剂。然后,将该溶液倒入模子里形成贴敷片(patch)。
实验1
滴眼剂的稳定性测试
测试在实施例1中制备的含有卡波姆的滴眼剂的稳定性,并与已知会稳定EGF的在实施例2中制备的含有羧甲基纤维素的制剂进行比较。进行该试验来估计每种制剂在4℃和25℃下储存时随着时间的消逝(2、4、8和18周)后EGF的含量。将溶于10mM磷酸盐缓冲剂的实施例2的样品用作标准样品,并通过Quantikine EGF ELISA试剂盒(R&D,美国)的ELISA法来估计EGF的含量。
表1显示了含有EGF的滴眼剂与标准样品相比的在4℃下的稳定性的结果,表2显示了含有EGF的滴眼剂与标准样品相比的在25℃下的稳定性的结果。
从下表1中可以看出,磷酸盐缓冲剂中的EGF的含量在4℃下8周内下降了约10%,而在卡波姆和羧甲基纤维素中的EGF的含量直到8周都没有变化。但是,在4℃条件下储存18周时,磷酸盐缓冲剂和卡波姆制剂中的EGF的含量都没有变化,而在羧甲基纤维素中的EGF的含量在18周里下降到87.3%。
表1
样品 | 起始浓度(%) | 4℃下的浓度(%) | |||
2周 | 4周 | 8周 | 18周 | ||
实施例10.1%卡波姆 | 100±2.5 | 99.2±3.2 | 102.0±4.3 | 103.7±1.2 | 101.6±3.5 |
实施例210mM磷酸盐缓冲剂 | 100±1.9 | 98.4±5.4 | 96.8±14.0 | 91.6±10.3 | 92.5±5.9 |
实施例30.5%羧甲基纤维素钠 | 100±2.1 | 104.9±3.4 | 99.7±6.0 | 102.7±2.3 | 87.3±3.1 |
从下表2中可以看出,当相同的制剂在25℃下储存时,在磷酸盐缓冲剂样品中的EGF的含量在2周内下降了约20%,而在羧甲基纤维素的情况下经过4周后EGF的含量不断下降。但是,在实施例1制剂中的EGF的含量直到8周也几乎没有变化。并且,当实施例1制剂在室温下储存18周时,EGF的含量仅下降了约13%。因此可以确定:含有卡波姆的制剂甚至在室温下储存时EGF的稳定性也显著提高了。
表2
样品 | 起始浓度(%) | 25℃下的浓度(%) | |||
2周 | 4周 | 8周 | 18周 | ||
实施例10.1%卡波姆 | 100±2.5 | 98.2±2.5 | 101.8±2.4 | 101.8±2.4 | 87.6±5.2 |
实施例210mM磷酸盐缓冲剂 | 100±1.9 | 81.6±3.6 | 88.4±6.9 | 81.3±1.7 | 72.5±3.3 |
实施例30.5%羧甲基纤维素钠 | 100±2.1 | 93.5±6.5 | 88.4±0.2 | 78.5±2.7 | 48.7±9.3 |
实验2
局部凝胶制剂的稳定性测试
测试在实施例4中制备的局部凝胶制剂的稳定性,并与含有广泛用作局部制剂基质的中性聚合物、且已知能使水溶液中介电常数降低而导致蛋白质稳定的泊洛沙姆的局部制剂进行比较。进行该试验来估计每种制剂在4℃和25℃下储存18周过程中EGF的含量。将溶于10mM磷酸盐缓冲剂的样品用作标准样品,并通过Quantikine EGF ELISA试剂盒(R&D,美国)的ELISA法来估计EGF的含量。
表3和表4分别显示了每种局部凝胶制剂在4℃和25℃下的稳定性。从下表3中可以看出,含有卡波姆或泊洛沙姆的制剂的EGF含量在冷藏条件下直到8周仍没有变化。然而,储存18周时,含有泊洛沙姆的制剂的EGF含量下降了约10%。从下表4中可以看出,含有1%卡波姆的制剂的EGF含量直到18周也几乎没有变化,而含有泊洛沙姆的制剂或磷酸盐缓冲剂制剂的EGF含量在8周内下降了约20%,然后直到18周仍不断下降。就含有泊洛沙姆的制剂而言,下降的程度更大。正如从滴眼剂可看出的那样,当聚合物用作基质时,EGF的含量随时间进一步下降,还不如磷酸盐缓冲剂,这是因为在长期储存时聚合物可进一步促进EGF的降解。最后可以确定:制剂中EGF的稳定性可以通过使用卡波姆作为基质必然得到改善。
表3
样品 | 起始浓度(%) | 4℃下的浓度(%) | |||
2周 | 4周 | 8周 | 18周 | ||
实施例210mM磷酸盐缓冲剂 | 100±1.9 | 98.4±5.4 | 96.8±14.0 | 91.6±10.3 | 92.5±5.9 |
实施例41%卡波姆 | 100±1.8 | 104.5±14.2 | 102.3±2.6 | 101.2±0.8 | 100.3±2.3 |
实施例415%泊洛沙姆 | 100±2.8 | 103.5±9.3 | 95.7±0.8 | 94.2±4.2 | 90.5±4.5 |
表4
样品 | 起始浓度(%) | 25℃下的浓度(%) | |||
2周 | 4周 | 8周 | 18周 | ||
实施例210mM磷酸盐缓冲剂 | 100±1.9 | 81.6±3.6 | 88.4±6.9 | 81.3±1.7 | 72.5±3.3 |
实施例41%卡波姆 | 100±1.8 | 107.3±2.0 | 92.5±0.5 | 101.8±2.4 | 99.5±4.5 |
实施例515%泊洛沙姆 | 100±2.8 | 90.3±41.4 | 79.5±5.0 | 78.5±2.7 | 66.4±2.6 |
实验3
霜剂、软膏剂和贴敷片制剂的稳定性测试
为了评估在实施例6、7和8中制备的含有卡波姆的制剂的稳定性,进行该试验来估计每种制剂在4℃和25℃下储存时随着时间的消逝(2、4、8和18周)后EGF的含量。将溶于10mM磷酸盐缓冲剂的实施例2的样品用作标准样品,并通过Quantikine EGF ELISA试剂盒(R&D,美国)的ELISA法来估计EGF的含量。
表5和表6分别显示了每种霜剂、软膏剂和贴敷片制剂在4℃和25℃下的稳定性。从下表5中可以看出,在冷藏条件下EGF含量没有变化。从下表6中可以看出,在室温下EGF含量几乎没有变化。因此可以确定:不管制剂的类型如何,制剂中EGF的稳定性可以通过使用卡波姆基质得到改善。
表5
样品 | 起始浓度(%) | 4℃下的浓度(%) | |||
2周 | 4周 | 8周 | 18周 | ||
实施例60.1%卡波姆霜剂 | 100±2.9 | 99.6±5.2 | 102.5±7.2 | 101.4±1.9 | 97.9±6.4 |
实施例70.1%卡波姆软膏剂 | 100±2.3 | 97.0±9.5 | 100.1±5.7 | 98.9±2.1 | 98.5±3.3 |
实施例81%卡波姆贴敷片 | 100±3.5 | 98.5±6.5 | 97.4±8.6 | 98.4±2.7 | 97.5±5.8 |
表6
样品 | 起始浓度(%) | 25℃下的浓度(%) | |||
2周 | 4周 | 8周 | 18周 | ||
实施例60.1%卡波姆霜剂 | 100±2.9 | 100.1±6.2 | 100.5±3.3 | 96.7±2.5 | 95.2±4.5 |
实施例70.1%卡波姆软膏剂 | 100±2.3 | 99.5±6.3 | 102.1±5.1 | 94.8±1.8 | 96.2±8.9 |
实施例81%卡波姆贴敷片 | 100±3.5 | 100.2±12.3 | 96.5±9.4 | 97.2±8.8 | 95.7±8.4 |
如上述实验中得到的结果所示,本发明提供了稳定的EGF组合物,它包含羧乙烯基聚合物作为基质和在生物学和物理化学上确保其稳定性的生物活性EGF。
Claims (16)
1、一种稳定组合物,它包含生物活性表皮生长因子(下文中称作“EGF”)作为活性成分和羧乙烯基聚合物作为基质。
2、按照权利要求1的稳定组合物,其中生物活性EGF从天然来源分离或者使用重组DNA技术生产。
3、按照权利要求1的稳定组合物,其中EGF的含量以制剂的总重计在0.001至1,000μg/g范围内。
4、按照权利要求1的稳定组合物,其中EGF的含量以制剂的总重计在0.1至100μg/g范围内。
5、按照权利要求1的稳定组合物,其中该组合物在水溶液中的pH在4至8范围内。
6、按照权利要求1的稳定组合物,其中羧乙烯基聚合物选自卡波姆934、卡波姆934P、卡波姆940、卡波姆941或卡波姆947P。
7、按照权利要求1的稳定组合物,其中羧乙烯基聚合物的含量以该组合物的总重计在0.001至50(w/w)%范围内。
8、按照权利要求1的稳定组合物,其中羧乙烯基聚合物的含量以该组合物的总重计在0.005至25(w/w)%范围内。
9、按照权利要求1的稳定组合物,其中羧乙烯基聚合物的含量以该组合物的总重计在0.01至10(w/w)%范围内。
10、按照权利要求1的稳定组合物,它是眼用制剂。
11、按照权利要求1的稳定组合物,它是局部制剂。
12、按照权利要求11的稳定组合物,它是霜制剂。
13、按照权利要求11的稳定组合物,它是软膏剂。
14、按照权利要求11的稳定组合物,它是凝胶制剂。
15、按照权利要求11的稳定组合物,它是贴敷片制剂。
16、按照权利要求11的稳定组合物,其中该组合物摊开在棉质平坦表面或纱布上。
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CN103443276A (zh) * | 2011-03-08 | 2013-12-11 | 加的夫大学学院咨询有限公司 | 用于愈合或治疗伤口的分子靶标 |
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KR100366439B1 (ko) * | 2000-02-21 | 2003-01-09 | 주식회사 대웅 | 상피세포 성장인자를 유효성분으로 하는 안정한 약제학적조성물 |
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KR100748390B1 (ko) * | 2005-11-14 | 2007-08-10 | 주식회사 대웅 | 상피세포성장인자를 포함하는 상처치료용 서방성 필름 제형 |
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JP5303322B2 (ja) * | 2009-03-13 | 2013-10-02 | ピアス株式会社 | 皮膚外用組成物 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100571773C (zh) * | 2002-03-12 | 2009-12-23 | 生物键有限公司 | 采用表皮生长因子治疗皮肤伤口的方法和组合物 |
CN103443276A (zh) * | 2011-03-08 | 2013-12-11 | 加的夫大学学院咨询有限公司 | 用于愈合或治疗伤口的分子靶标 |
CN103443276B (zh) * | 2011-03-08 | 2016-09-28 | 加的夫大学学院咨询有限公司 | 用于愈合或治疗伤口的分子靶标 |
CN104644464A (zh) * | 2015-02-06 | 2015-05-27 | 深圳唯美度生物科技有限公司 | 一种提高细胞活力的防干燥油及其制备方法 |
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