CN1455677A - 皮肤创伤愈合促进剂 - Google Patents
皮肤创伤愈合促进剂 Download PDFInfo
- Publication number
- CN1455677A CN1455677A CN01815486A CN01815486A CN1455677A CN 1455677 A CN1455677 A CN 1455677A CN 01815486 A CN01815486 A CN 01815486A CN 01815486 A CN01815486 A CN 01815486A CN 1455677 A CN1455677 A CN 1455677A
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- Prior art keywords
- phe
- insulin
- growth factor
- gln
- skin
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/046—Tachykinins, e.g. eledoisins, substance P; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明提供了皮肤创伤如割裂、擦伤、外科手术切口、皮肤溃疡和烧伤的愈合促进剂。Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2或Phe-Gly-Leu-Met-NH2与胰岛素样生长因子-I的共存对皮肤创伤的愈合表现出明显的促进作用。因此,联合施用至少一种P物质类似物或其可药用盐和胰岛素样生长因子对表皮伸展表现出促进作用并且对皮肤创伤的愈合也表现出促进作用。
Description
技术领域
本发明涉及皮肤创伤愈合促进剂,该促进剂包含至少一种P物质类似物或其可药用盐和胰岛素样生长因子作为活性成分。
背景技术
皮肤创伤是表面组织的损伤,如割裂、擦伤、外科手术切口、皮肤溃疡或烧伤。这些皮肤创伤的一般性治疗是紧急处理创伤部位,然后等待由于机体恢复力的自动愈合。
但是,这类自身恢复需要较长时间才能达到康复,并且疼痛也会继续。因此,需要对创伤部位施用创伤治疗剂,积极促进创伤愈合。
由于新的表皮和结缔组织在创伤愈合过程中通过细胞的迁移和增殖形成,因此促进或刺激参与创伤愈合之细胞的迁移、分化和增殖的药物可以作为创伤治疗剂。已知溶菌酶氯化物、血活素(solcoseryl)等是这类创伤治疗剂。
但现有的创伤治疗剂存在着治疗剂对创伤愈合没有足够的促进作用并且不能在短时间内使创伤完全恢复的问题。据认为,这些问题是由于这些治疗剂对于作为创伤愈合过程中的重要因素的表皮的康复、胶原的合成、外周循环的改善、颗粒形成、血管生成等的贡献较小。
P物质类似物是由3-12个氨基酸组成的多肽,它们具体公开于美国专利3862114中,并且已知这些多肽具有降压作用。作为P物质类似物之一的P物质是由神经末端释放和形成的多肽,它是由式Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2所示的11个氨基酸组成的多肽,并已知其表现血管扩张、平滑肌收缩、促进唾液腺分泌、利尿等作用。在眼科领域,有关于P物质改善眼病中结膜杯形细胞的异常分泌的作用(WO 95/13087)、P物质在炎症如角膜炎中的动力学(J.Jpn.Ophthalmol.Soc.,91,982-987(1987);J.Jpn.Ophthalmol.Soc.,92,448-452(1988))等的报道。此外,日本专利申请特许公开17489/1998公开了Phe-Gly-Leu-Met-NH2(下文称之为“FGLM”),它是P物质C末端一侧的四肽,用作角膜疾病治疗剂。
另一方面,胰岛素样生长因子是调节正常人体细胞生长的因子之一,如表皮生长因子、成纤维细胞生长因子、血小板衍生的生长因子和转化生长因子,它们可分为两组,即胰岛素样生长因子-I(下文称之为IGF-I)和胰岛素样生长因子-II(下文称之为IGF-II)。据报道,IGF-I刺激甲状腺细胞的增殖(J.Biol.Chem.,264,18485-18488(1989)),IGF-II调节肌肉的生长和分化(Hum.Mol.Genet.,3,1117-1121(1994))等。
但没有关于P物质类似物和胰岛素样生长因子对皮肤疾病作用的报道。
基于这些事实,为研究对表皮伸展的促进作用和对皮肤创伤愈合的促进作用,将P物质类似物与胰岛素样生长因子结合并对表皮进行药理学试验是一个有趣的课题。
发明内容
本发明者通过上述试验发现,当P物质类似物(典型代表是P物质或FGLM)与胰岛素样生长因子(典型代表是IGF-I)共存时,显著增强这些药物促进表皮伸展和皮肤创伤愈合的效果,并且还对难治的糖尿病性皮肤溃疡的愈合表现出出色的效果。即,本发明的包含至少一种P物质类似物或其可药用盐和胰岛素样生长因子作为活性成分的皮肤创伤愈合促进剂,对于皮肤创伤和疾病的愈合具有促进作用,所述创伤是例如割裂、擦伤、外科手术切口、皮肤溃疡(包括糖尿病性皮肤溃疡)和烧伤,所述疾病是例如源于这些皮肤创伤的坏疽。可以向皮肤创伤愈合促进剂中加入抗坏血酸、抗坏血酸酯、抗坏血酸盐、泛酸、泛酸盐等,它们的创伤愈合作用已得到公认。
P物质类似物的实例是Tyr-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2,Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2(P物质),Arg-Pro-Lys-Pro-Gln-Gln-Phe-Tyr-Gly-Leu-Met-NH2,Tyr-Pro-Gln-Gln-Phe-Phe-Gly-Gln-Met-NH2,Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2,Pro-Gln-Gln-Phe-Tyr-Gly-Leu-Met-NH2,Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2,Asp-Ala-Phe-Tyr-Gly-Leu-Met-NH2,Gln-Phe-Phe-Gly-Leu-Met-NH2,Ala-Phe-Tyr-Gly-Leu-Met-NH2,Phe-Phe-Gly-Leu-Met-NH2,Tyr-Phe-Gly-Leu-Met-NH2,Gly-Phe-Gly-Leu-Met-NH2,Phe-Gly-Leu-Met-NH2(FGLM)和Tyr-Gly-Leu-Met-NH2.
P物质类似物的优选实例是P物质和FGLM。
P物质类似物的氨基酸结构有L-、D-和DL-形式的,它们均包括在本发明中。本发明的优选形式是其中所有立体结构均是L-形式的多肽。
P物质类似物、P物质和FGLM的可药用盐的实例是盐酸盐、硫酸盐、磷酸盐、乳酸盐、马来酸盐、富马酸盐、草酸盐、甲磺酸盐和对甲苯磺酸盐。
本发明的皮肤创伤愈合促进剂可通过已广泛使用的技术制备。其制剂形式的实例是软膏剂、凝胶剂、泥敷剂、涂敷剂、洗剂、霜剂、喷雾剂、气雾剂、硬膏剂、混悬剂、乳液、片剂和丸剂,并且促进剂也可通过选择适宜的溶剂以液体制剂形式使用。为制备皮肤创伤愈合促进剂,可根据剂型形式加入填充剂、赋形剂、基质、崩解剂、松散填料、粘合剂、成膜剂、润滑剂、着色剂、pH调节剂、增溶剂、助悬剂、缓冲剂、稳定剂、防腐剂、抗菌剂、表面活性剂、抗氧剂、分散剂、乳化剂、溶解试剂或增溶试剂等。
上述制剂的载体或基质的实例是白软石蜡、液体石蜡、凝固烃、鲸蜡醇、聚乙二醇、明胶、玉米淀粉、藻酸钠、甲基纤维素、羟乙基纤维素、羧甲基纤维素、亲水性塑性基质、明胶、糊精、鲸蜡醇、硬脂醇、聚乙二醇、聚乙烯醇、甲氧基亚乙基-马来酸酐共聚物、聚乙烯基醚、包含乙烯基吡咯烷酮作为聚合组分的聚合物和共聚物、硬脂酸钠、硬脂酸镁、苯扎氯胺、脂肪和油(如橄榄油、山茶油和豆油)、乳糖和水。
皮肤创伤愈合促进剂中包含的各种P物质类似物及其可药用盐的量为0.001-10%重量,优选0.005-5%重量。皮肤创伤愈合促进剂中包含的胰岛素样生长因子的量为0.0001-5%重量,优选0.001-1%重量。
本发明提供了一种治疗皮肤创伤的方法,该方法包括给需此治疗的患者施用一种组合物,该组合物包含治疗有效量的P物质类似物或其可药用盐和胰岛素样生长因子以及可药用添加剂。
本发明还提供P物质类似物或其可药用盐和胰岛素样生长因子在制备皮肤创伤治疗剂中的应用。
本发明的皮肤创伤愈合促进剂可以以各种形式施用,这取决于创伤的部位和创伤的程度。例如,当促进剂作为外用制剂使用时,只需将其直接涂抹、喷雾或涂敷到所需皮肤部位(创面)。
本发明的皮肤创伤愈合促进剂的剂量可根据症状、年龄、剂型等适当选择。与胰岛素样生长因子联合(混合)的P物质类似物及其可药用盐的日常规剂量是0.01-5000mg,优选0.1-1000mg,该剂量可一次性地或分数次给药。与至少一种P物质类似物及其可药用盐联合(混合)的胰岛素样生长因子的日常规剂量为0.001-1000mg,优选0.01-500mg,该剂量可一次性地或分数次给药。本发明的皮肤愈合促进剂每日可给药一次至五次。
下面显示了本发明的制剂实例和药理学试验结果。这些实施例不限制本发明的范围,而旨在使本发明更清楚和易于理解。
实施发明的最佳方式
制剂
下面给出本发明的代表性制剂实例。
实施例1(软膏剂A-1)
100克中
P物质 100mg
IGF-I 10mg
液体石蜡 10g
白软石蜡 适量
改变P物质的量,可制备浓度为0.2%(w/w)(软膏剂A-2)、0.5%(w/w)(软膏剂A-3)和1.0%(w/w)(软膏剂A-4)的软膏剂。
实施例2(软膏剂B-1)
100克中
FGLM 100mg
IGF-I 5mg
液体石蜡 10g
白软石蜡 适量
改变FGLM的量,可制备浓度为0.3%(w/w)(软膏剂B-2)、1%(w/w)(软膏剂B-3)和2%(w/w)(软膏剂B-4)的软膏剂。
实施例3(软膏剂C-1)
100克中
FGLM 50mg
IGF-I 10mg
抗坏血酸 3mg
液体石蜡 10g
亲水性塑性基质 适量
改变FGLM的量,可制备浓度为0.3%(w/w)(软膏剂C-2)、1%(w/w)(软膏剂C-3)和3%(w/w)(软膏剂C-4)的软膏剂。
药理学试验
(1)对表皮伸展的作用
对大鼠(Spraque-Dawley)施用过量的戊巴比妥,然后制备约2×4mm的耳组织切片。在60mm有盖培养皿中加入18ml各包含表1中的试验药物[P物质、FGLM、IGF-I、P物质+IGF-I和FGLM+IGF-I]的TCM 199培养基,并在每个有盖培养皿中加入三片组织切片(12个样品:每组三份)。将组织切片在CO2培养箱(37℃,5%CO2)中培养24小时,将组织切片用乙醇-乙酸(体积比95∶5)固定以按照常规方法将每个组织切片制成三个组织部分。这些组织部分用苏木精-曙红进行染色,然后测定超出切割表面的表皮细胞层的长度。将组织切片在与上述相同的条件下,使用不含试验药物的培养基进行培养,作为对照。这些结果示于表1。表中的数值是12个样品的平均值。
表1
试验药物 | 表皮伸长的长度(μm) |
对照P物质(20μm)FGLM(20μm)IGF-I(10ng/ml)P物质(20μm)+IGF-I(10ng/ml)FGLM(20μm)+IGF-I(10ng/ml) | 63.0272.5755.3750.68156.04138.24 |
(2)对皮肤创伤愈合的作用
在乙醚吸入麻醉下,将溶于柠檬酸缓冲液的链脲霉素(70mg/kgBW)静脉注射到大鼠(Wistar)尾部,以制备糖尿病大鼠(DM Rat)(每组5只大鼠)。将等量的仅仅是柠檬酸缓冲液静脉注射到大鼠(Wistar)中,以制备非糖尿病大鼠(非DM Rat)(每组5只)。静脉注射后四周,在乙醚吸入麻醉后,用剃刀剃净所有大鼠的背部,并用脱毛膏脱去毛发。24小时后,使用直径为5mm的皮肤活检用环锯在背部皮肤上以相等间隔制作五处全厚度(即表皮和真皮)伤口。证实出血,将表2和3中的各种软膏剂涂敷在伤口上,每日一次。在每日一次涂敷软膏剂之前,对背部伤口进行照相,并测定它们的面积。表2显示了非糖尿病大鼠(非DM Rat)的面积测定结果,表3显示了糖尿病大鼠的面积测定结果(DM Rat)。这些表中的数值是5个样品的平均值。
表2
软膏组 | 非糖尿病大鼠的皮肤创伤面积(%) | |||
第1天 | 2天后 | 4天后 | 6天后 | |
对照(PBS) | 100 | 93 | 87 | 64 |
P物质(2.5mg/ml) | 100 | 88 | 74 | 59 |
IGF-I(1μg/ml) | 100 | 81 | 66 | 43 |
P物质(2.5mg/ml)+IGF-I(1μg/ml) | 100 | 72 | 50 | 32 |
表3
软膏组 | 糖尿病大鼠的皮肤创伤面积(%) | ||||
第1天 | 1天后 | 4天后 | 7天后 | 10天后 | |
对照(PBS) | 100 | 96 | 91 | 84 | 60 |
P物质(2.5mg/ml) | 100 | 90 | 77 | 68 | 44 |
IGF-I(1μg/ml) | 100 | 89 | 64 | 52 | 27 |
P物质(2.5mg/ml)+IGF-I(1μg/ml) | 100 | 81 | 50 | 18 | 1 |
表1清楚地显示出,即使单独使用P物质、FGLM或IGF-I培养组织切片,表皮的延伸长度几乎与使用对照的情况一样(没有添加剂),但当组织切片在P物质或FGLM与IGF-I共同存在下进行培养时,延伸长度比单独使用这些药物时要长2-2.5倍(协同效果)。表2显示含有P物质和IGF-I的软膏剂与其中单独含有P物质或IGF-I的软膏剂相比显著地促进皮肤创伤愈合。表3显示含有P物质和IGF-I的软膏剂对难治的糖尿病性大鼠(DM Rat)也表现出出色的作用。因此,联合(混合)施用至少一种P物质类似物(典型代表是P物质和FGLM)或可药用盐与胰岛素样生长因子(典型代表是IGF-I)可通过这些药物的增效作用有效促进皮肤创伤的愈合,所述创伤是例如割裂、擦伤、外科手术切口、皮肤溃疡(特别是难治的糖尿病患者的皮肤溃疡)和烧伤。
工业实用性
本发明提供了包含至少一种P物质类似物或其可药用盐和胰岛素样生长因子作为活性成分的皮肤创伤愈合促进剂。
Claims (12)
1.一种皮肤创伤愈合促进剂,其包含P物质类似物或其可药用盐和胰岛素样生长因子作为活性成分。
2.一种皮肤创伤愈合促进剂,其包含0.001-10%重量的P物质类似物或其可药用盐和0.0001-5%重量的胰岛素样生长因子作为活性成分。
3.一种皮肤创伤愈合促进剂,其包含Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2、Phe-Gly-Leu-Met-NH2及其可药用盐中的至少一种和胰岛素样生长因子-I作为活性成分。
4.一种皮肤创伤愈合促进剂,其包含0.001-10%重量的Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2、Phe-Gly-Leu-Met-NH2及其可药用盐的中至少一种和0.0001-5%重量的胰岛素样生长因子-I作为活性成分。
5.权利要求1-4任一项的皮肤创伤愈合促进剂,其中皮肤创伤是割裂、擦伤、外科手术切口、皮肤溃疡或烧伤。
6.皮肤创伤愈合促进剂,其中权利要求5中所述的皮肤溃疡是糖尿病性皮肤溃疡。
7.一种表皮伸展促进剂,其包含P物质类似物或其可药用盐和胰岛素样生长因子作为活性成分。
8.一种表皮伸展促进剂,其包含0.001-10%重量的P物质类似物或其可药用盐和0.0001-5%重量的胰岛素样生长因子作为活性成分。
9.一种治疗皮肤创伤的方法,包括给需此治疗的患者施用一种组合物,该组合物包含治疗有效量的P物质类似物或其可药用盐和胰岛素样生长因子,以及可药用添加剂。
10.一种治疗皮肤创伤的方法,包括给需此治疗的患者施用一种组合物,该组合物包含治疗有效量的Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2、Phe-Gly-Leu-Met-NH2及其可药用盐中的至少一种和胰岛素样生长因子-I,以及可药用添加剂。
11.P物质类似物或其可药用盐与胰岛素样生长因子在制备皮肤创伤治疗剂中的应用。
12.Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2、Phe-Gly-Leu-Met-NH2及其可药用盐中的至少一种与胰岛素样生长因子-I在制备皮肤创伤治疗剂中的应用。
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JP242489/00 | 2000-08-10 | ||
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JP361388/2000 | 2000-11-28 | ||
JP2000361388 | 2000-11-28 | ||
JP361388/00 | 2000-11-28 |
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CN1455677A true CN1455677A (zh) | 2003-11-12 |
CN1228083C CN1228083C (zh) | 2005-11-23 |
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CNB018154867A Expired - Fee Related CN1228083C (zh) | 2000-08-10 | 2001-08-10 | 皮肤创伤愈合促进剂 |
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US (1) | US7071166B2 (zh) |
EP (1) | EP1308165B1 (zh) |
CN (1) | CN1228083C (zh) |
AT (1) | ATE470449T1 (zh) |
AU (2) | AU7776701A (zh) |
CA (1) | CA2418976C (zh) |
DE (1) | DE60142341D1 (zh) |
WO (1) | WO2002013853A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104771785A (zh) * | 2015-04-03 | 2015-07-15 | 周宏志 | 具有神经多肽诱导陈骨活性的骨修复材料的制造方法 |
CN107789216A (zh) * | 2016-09-07 | 2018-03-13 | 新田明胶株式会社 | 表皮细胞间功能强化剂 |
CN112316110A (zh) * | 2020-11-12 | 2021-02-05 | 温州大学 | 促进皮肤创伤修复的药物制剂及其制备方法 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI305778B (en) * | 2001-12-03 | 2009-02-01 | Nishida Teruo | Peptides of an expressing unit for igf-i minimal activity and their pharmaceutical use |
KR100593397B1 (ko) * | 2004-10-27 | 2006-06-28 | 한국원자력연구소 | 중배엽 줄기세포 및/또는 p 물질을 함유하는 상처 치유또는 상처 치유 촉진제, 또는 세포 치료제 |
CA2585265A1 (en) * | 2004-10-27 | 2006-05-04 | Immuneregen Biosciences, Inc. | Method to promote wound healing |
US20070154448A1 (en) | 2005-11-22 | 2007-07-05 | Ted Reid | Methods and compositions using Substance P to promote wound healing |
US7834153B2 (en) * | 2006-06-05 | 2010-11-16 | University Of South Florida | Combination of insulin and ascorbate to enhance wound healing |
WO2007145934A1 (en) * | 2006-06-05 | 2007-12-21 | University Of South Florida | Combination of insulin and ascorbate to enhance wound healing |
US8575089B2 (en) | 2009-08-17 | 2013-11-05 | University-Industry Cooperation Group Of Kyung Hee | Composition for preventing or treating inflammation |
US10279007B2 (en) | 2010-11-15 | 2019-05-07 | Oxygenetix Institute, Inc. | Topical treatment method for healing wounds, disinfecting, covering and concealing the wound until healing occurs |
BR102013025813A2 (pt) * | 2013-10-04 | 2015-08-25 | Sanofi Aventis Farmacêutica Ltda | Composição para tratamento de úlceras diabéticas, processo de preparação da composição e seu uso |
CN104523341B (zh) * | 2014-12-18 | 2017-06-20 | 中国人民解放军第四军医大学 | 具有牙周生物活性的即刻种植牙的制造方法 |
KR101825041B1 (ko) * | 2016-04-07 | 2018-02-02 | 주식회사 바이오솔루션 | 물질 p를 포함하는 상처치유용 약학 조성물 |
KR102158969B1 (ko) * | 2018-10-19 | 2020-09-23 | 주식회사 바이오솔루션 | 물질 p를 포함하는 난치성 궤양 치료용 조성물 |
Family Cites Families (8)
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GB1412730A (en) * | 1971-11-16 | 1975-11-05 | Mapac Packaging Ltd | Wrapping machine |
US3862114A (en) * | 1971-11-22 | 1975-01-21 | Ici Australia Ltd | Analogs of substance p |
US4885163A (en) | 1987-02-24 | 1989-12-05 | Eli Lilly And Company | Topical use of IGF-II for wound healing |
US5616562A (en) * | 1990-04-27 | 1997-04-01 | Murphy; Christopher J. | Methods and compositions using substance P to promote wound healing |
US5360789A (en) | 1990-11-20 | 1994-11-01 | Kowa Co., Ltd. | Therapeutic agent for skin or corneal disease |
GR1002610B (el) * | 1991-01-02 | 1997-02-20 | Johnson & Johnson Consumer Products Inc. | Θεραπευτικες συνθεσεις πληγων που περιεχουν παραγοντα αναπτυξης ινοβλαστων και ασκορβικον οξυ. |
US5545617A (en) | 1993-11-12 | 1996-08-13 | The Schepens Eye Research Institute, Inc. | Therapeutic regulation of abnormal conjunctival goblet cell mucous secretion |
JP3191038B2 (ja) | 1996-06-26 | 2001-07-23 | 輝夫 西田 | 眼科用医薬組成物 |
-
2001
- 2001-08-10 AT AT01955679T patent/ATE470449T1/de not_active IP Right Cessation
- 2001-08-10 WO PCT/JP2001/006933 patent/WO2002013853A1/ja active Application Filing
- 2001-08-10 US US10/344,199 patent/US7071166B2/en not_active Expired - Fee Related
- 2001-08-10 EP EP01955679A patent/EP1308165B1/en not_active Expired - Lifetime
- 2001-08-10 AU AU7776701A patent/AU7776701A/xx active Pending
- 2001-08-10 CA CA2418976A patent/CA2418976C/en not_active Expired - Fee Related
- 2001-08-10 CN CNB018154867A patent/CN1228083C/zh not_active Expired - Fee Related
- 2001-08-10 AU AU2001277767A patent/AU2001277767B2/en not_active Ceased
- 2001-08-10 DE DE60142341T patent/DE60142341D1/de not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104771785A (zh) * | 2015-04-03 | 2015-07-15 | 周宏志 | 具有神经多肽诱导陈骨活性的骨修复材料的制造方法 |
CN107789216A (zh) * | 2016-09-07 | 2018-03-13 | 新田明胶株式会社 | 表皮细胞间功能强化剂 |
CN112316110A (zh) * | 2020-11-12 | 2021-02-05 | 温州大学 | 促进皮肤创伤修复的药物制剂及其制备方法 |
CN112316110B (zh) * | 2020-11-12 | 2023-06-23 | 温州大学 | 促进皮肤创伤修复的药物制剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2418976C (en) | 2011-08-02 |
CN1228083C (zh) | 2005-11-23 |
DE60142341D1 (de) | 2010-07-22 |
US7071166B2 (en) | 2006-07-04 |
EP1308165A4 (en) | 2004-04-21 |
WO2002013853A1 (fr) | 2002-02-21 |
ATE470449T1 (de) | 2010-06-15 |
AU7776701A (en) | 2002-02-25 |
AU2001277767B2 (en) | 2006-08-31 |
EP1308165A1 (en) | 2003-05-07 |
CA2418976A1 (en) | 2003-02-07 |
US20030181386A1 (en) | 2003-09-25 |
EP1308165B1 (en) | 2010-06-09 |
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Effective date of registration: 20151030 Address after: Tokyo, Japan, Japan Patentee after: R-Tech Ueno, Ltd. Patentee after: Nishida Teruo Address before: Osaka Japan Patentee before: Santen Pharmaceutical Co., Ltd. Patentee before: Nishida Teruo |
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