CN102665765A - 促进创伤愈合的组合物 - Google Patents
促进创伤愈合的组合物 Download PDFInfo
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- CN102665765A CN102665765A CN2010800499024A CN201080049902A CN102665765A CN 102665765 A CN102665765 A CN 102665765A CN 2010800499024 A CN2010800499024 A CN 2010800499024A CN 201080049902 A CN201080049902 A CN 201080049902A CN 102665765 A CN102665765 A CN 102665765A
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- wound healing
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- peptide
- silicone oil
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Abstract
本发明提供一种脂质层形成创伤愈合促进组合物，其包含挥发性硅油、极性脂质、C2-C4脂肪醇和创伤愈合促进剂，具体说，是小的至中等大小的天然肽或合成肽。还提供在创伤上形成这种脂质层的方法，和提供这种组合物的医用贴片。
Description
发明领域
本发明涉及一种能在创面上形成一层包含药学有效量的创伤愈合促进剂的促进创伤愈合组合物，该组合物的制造方法，和其使用方法。
发明背景
创伤愈合促进剂，具体说，短链肽或中等链长的肽是本领域已知的。以下提供几个例子。
美国专利5,015,629披露了加速创伤组织上皮再形成的方法，向创伤施加八肽血管紧张素II能有效地加速创伤愈合。
皮下注射甲状旁腺素(1-34)或其氨基末端片段可促进绝经后妇女破裂脊椎骨的愈合(R M Neer等.“甲状旁腺素(1-34)对骨质疏松绝经后妇女骨折和骨矿物质密度的影响(Effect of Parathyroid Hormone(1-34)on Fractures and Bone Mineral Density inPostmenopausal Women with Osteoporosis)”，NEJM 344：19(2001)1434-1441)。
美国专利7,452,864公开了一种局部用于促进上皮细胞再生的药物组合物，包含至少25个氨基酸的新型创伤愈合肽以及包含其中可分散所述肽的半乳糖脂的形成双层脂质的载体。
WO 2008/084253A1揭示了一种含有半乳糖脂材料和另一种活性成分用于创伤治疗的药物组合物。
WO 01/87344A1揭示了一种包含一种或多种药学或美容学活性剂、一种或多种基于低聚或多聚有机二硅氧烷的有机硅化合物和一种或多种磷脂的药学或美容学组合物。当将其施加到植物上皮时，WO 01/87344A1的组合物可在短时间内直接渗入用其治疗的植物外层而不能被擦掉，因为它已被迅速地吸收入植物内部。这种组合物可用于人和动物局部使用，其中的有机硅化合物在大气压下的沸点为15-150℃。
然而，给予创伤，特别是皮肤创伤的创伤愈合促进剂仍存在问题。
发明目的
本发明的一个目的是提供一种用于哺乳动物包括人的创伤的给予创伤愈合促进剂，具体说是短链或中等链长的肽的组合物，其中，所述肽是溶解形式，易于施加到创伤上以在创伤上形成粘附层。
本发明另一目的是提供不会刺激创伤的这类组合物。
本发明还有一个目的是提供施加于皮肤后不会引起肿胀的这类组合物。
本发明还有一个目的是提供施加于皮肤后不会产生烧灼感的这类组合物。
可从阅读以下本发明的概述、实施例所描述的优选实施方式、某些优选实施方式的附图说明以及权利要求书附件明白本发明的其他目的。
发明概述
本发明披露的上述类型组合物包含极性脂质、挥发性硅油、低级醇和创伤愈合促进剂或基本上由它们组成，具体说创伤愈合促进剂是可溶于该组合物中的短肽和中等链长的肽。本发明的组合物由单一相组成。该组合物的粘度低而允许通过喷雾给予创伤。喷雾时，本发明的组合物通过其中的溶剂蒸发或相对于醇的蒸发能在创伤上面形成粘附层并部分被创伤组织吸收。
本发明的创伤愈合促进剂是一种肽，具体说是短肽和中等链长的肽，更优选6-120个氨基酸长度的肽，最优选8-45个氨基酸的肽。本发明的肽可以是天然产生的肽或合成肽。本发明的肽可以由天然氨基酸组成，或包含天然氨基酸和非天然氨基酸。本发明优选的创伤愈合促进剂包括：血管紧张素II及其创伤愈合片段、类似物或衍生物，人甲状旁腺素及其创伤愈合片段、类似物或衍生物，和采用纳入本文作参考的美国专利7,452,864中公开的抗菌肽(cathelicidin)LL37及其创伤愈合片段、类似物或衍生物。
根据本发明的一个优选方面内容，本发明的创伤愈合促进剂是纳入本文作参考的美国专利7,427,589公开的促炎细胞因子的抑制剂。
本发明阻断的优选促炎细胞因子具体选自：肿瘤坏死因子(TNF)、白介素1(IL-1)、白介素6(IL-6)、白介素8(IL-8)、白介素12(IL-12)、白介素15(IL-15)、白介素17(IL-17)、白介素18(IL-1)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、巨噬细胞集落刺激因子(M-CSF)、单核细胞趋化蛋白-1(MCP-1)、巨噬细胞炎性蛋白1(MIP-1)、RANTES(调节活性，正常T-细胞表达和推测分泌的)、表皮细胞衍生的中性白细胞吸引剂-78(ENA-78)、制瘤素-M(OSM)、成纤维细胞生长因子(FGF)、血小板衍生的生长因子(PDGF)和血管内皮生长因子(VEGF)；特别优选TNF(也称为TNF-α)和IL-1(包括IL-1α和IL-1β。
本发明优选的促炎细胞因子抑制剂是：(a)特异性TNF阻断剂，如单克隆抗体，例如英夫利昔单抗、CDP-571(HumicaderTM)、D2E7和CDP-870；可溶性细胞因子受体，如依那西普(etanercept)、来那西普(lenercept)、PEG化TNF-1型受体、TBP-1；TNF-受体拮抗剂；反义寡核苷酸，如ISIS-104838；(b)非特异性TNF阻断物质，如(b1)MMP抑制剂(即基质金属蛋白酶抑制剂或TACE-抑制剂)，如TNF-α转换酶抑制剂；四环素类，如多西霉素、赖甲环素、氧代四环素、四环素、米诺环素和合成的四环素衍生物，如CMT，即化学修饰的四环素；普林司他(AG3340)、巴马司他、马马司他；B-R7785、TIMP-1、TIMP-2和TIMP-1(腺病毒递送的TIMP-1)及TIMP-2(腺病毒递送的TIMP-2)；(b2)喹诺酮类，如诺氟沙星、左氧氟沙星、依诺沙星、司帕沙星、替马沙星、莫西沙星、加替沙星、吉米沙星、格帕沙星、曲伐沙星、氧氟沙星、环丙沙星、培氟沙星、洛美沙星、替马沙星；(b3)沙利度胺衍生物，如SelCID(即选择性细胞因子抑制剂)、CC-1088、CDC-501、CDC-801和利诺胺(Roquininex
)；(b4)拉扎洛依，如非糖皮质激素21-氨基类固体醇，如U-74389G(16-去甲基替拉扎特)和U-74500；(b4)前列腺素；伊洛前列腺素(前列腺环素)；(b5)环孢霉素；(b6)己酮可可碱衍生物；(b7)异羟肟酸衍生物；(b8)呢吡林；(b9)磷酸二酯酶I、II、III和V-抑制剂，如CC-1088、Ro 20-1724、咯利普兰、氨吡酮、匹莫苯、维纳林酮、SB 207499(Ariflo
)；(b10)黑素皮质素(melancortin)激动剂，如HP-228；(c)其他TNF阻断物质，如：(c1)乳铁蛋白及其衍生肽(参见纳入本文作参考的美国专利7,253,143B1)；(c2)CT3、ITF-2357、PD-168787、CLX-1100、M-PGA、NCS-700、PMS-601、RDP-58、TNF-484A、PCM-4、CBP-1011、SR-31747、AGT-1、索利司他、CH-3697、NR58-3.14.3、RIP-3、Sch-23863、Yissum方案11649号药物，Pharma方案6181、6019和4657、SH-636号药物；(d)特异性IL-la和IL-Iβ阻断物质，如单克隆抗体、可溶性细胞因子的受体、IL-1型和II型受体(诱饵RII)拮抗剂；IL-lra(Orthogen
，Orthokir)，反义寡核苷酸；(e)非特异性IL-la和IL-Iβ阻断物质，如：(e1)MMP抑制剂(即基质金属蛋白酶抑制剂)；(e2)四环素类，如多西霉素、曲伐沙星、赖甲环素、氧代四环素、四环素、米诺环素和合成的四环素衍生物，如CMT，即化学修饰的四环素；(e3)普林司他(AG3340)、巴马司他、马马司他、KB-R7785、TIMP-1、TIMP-2、adTIMP-1、adTIMP-2；(e4)喹诺酮类，如诺氟沙星、左氧氟沙星、依诺沙星、司帕沙星、替马沙星、莫西沙星、加替沙星、吉米沙星、格帕沙星、曲伐沙星、氧氟沙星、环丙沙星、培氟沙星、洛美沙星、替马沙星；(e5)前列腺素类；伊洛前列腺素(前列腺环素)；(e7)己酮可可碱衍生物； (e8)异羟肟酸衍生物；(e9)磷酸二酯酶I、II、III和V-抑制剂、CC-1088、Ro 20-1724、咯利普兰、氨吡酮、匹莫苯、维纳林酮、SB 207499；(f)特异性IL-6阻断物质，如：(f1)单克隆抗体；(f2)可溶性细胞因子受体；(f3)受体拮抗剂；(f4)反义寡核苷酸；(g)非特异性IL-6阻断物质，如：(g1)MMP抑制剂(即基质金属蛋白酶抑制剂)，如四环素类，例如多西霉素、赖甲环素、氧代四环素、四环素、米诺环素和合成的四环素衍生物，如CMT，即化学修饰的四环素；普林司他(AG3340)、巴马司他、马马司他、KB-R7785、TIMP-1、TIMP-2、adTIMP-1、adTIMP-2；(g2)喹诺酮类，如诺氟沙星、左氧氟沙星、依诺沙星、司帕沙星、替马沙星、莫西沙星、加替沙星、吉米沙星、格帕沙星、曲伐沙星、氧氟沙星、环丙沙星、培氟沙星、洛美沙星、替马沙星； (g3)己酮可可碱衍生物；(g4)环孢霉素；(g5)己酮可可碱衍生物；(g6)异羟肟酸衍生物；(g7)磷酸二酯酶I、II、III和V-抑制剂、CC-1088、Ro 20-1724、咯利普兰、氨吡酮、匹莫苯、维纳林酮、SB 207499； (g8)黑色素和黑色素皮质激素激动剂、HP-228；(h)非特异性IL-8阻断物质，如单克隆抗体、可溶性细胞因子受体、受体拮抗剂、反义寡核苷酸；(i)非特异性IL-8阻断物质，如：(i1)喹诺酮类，如诺氟沙星、左氧氟沙星、依诺沙星、司帕沙星、替马沙星、莫西沙星、加替沙星、吉米沙星、格帕沙星、曲伐沙星、氧氟沙星、环丙沙星、培氟沙星、洛美沙星、替马沙星；(i2)沙利度胺衍生物，如SelCID(即选择性细胞因子抑制剂)，如CC-1088、CDC-50l、CDC-80l和利诺胺(Roquininex
)；(i3)拉扎洛依； (i4)环孢霉素A；(i5)己酮可可碱衍生物。
本发明也采用纳入本文作参考的美国专利7,253,143公开的基于人乳铁蛋白的肽。
按照本发明第二优选方面，所述创伤愈合促进剂是人纤溶酶原，包括其变体和/或另一血浆组分，如肝素，包括肝素的创伤愈合促进片段。
按照本发明第三优选方面，所述创伤愈合促进剂是激肽拮抗剂，具体说，是缓激肽拮抗剂或血管舒张素拮抗剂，这类激肽拮抗剂选自HOE140、NPC17751、NPC349、CP0127、NPC-1776、WIN 64338、des-Arg9-缓激肽、des-Arg9-D-精氨酸-缓激肽和纳入本文作参考的美国专利6,221,845公开的Sar4-des-Arg9-缓激肽。
按照本发明第四优选方面，所述创伤愈合促进剂是链球菌M蛋白、纤维蛋白素原与β2整联蛋白之间相互作用的抑制剂，如四肽Gly-Pro-Arg-Pro。
按照本发明第五优选方面，所述创伤愈合促进剂是以下一组物质的成员：美国专利6,063,757公开的治疗慢性创伤的重组人2.5S β-神经生长因子，US 20030092682A1公开的治疗口腔感冒疮、口疮、癌创伤、手术创伤、褥疮、足癣的多西霉素和/或头孢克洛；EP 1300138A2公开的治疗湿疹、痤疮、疱疹、牛皮癣、皮肤病的类黄酮和任选的肉桂酸衍生物；美国专利7,049,294公开的治疗慢性皮肤溃疡，如糖尿病溃疡的凝血酶衍生物；US 20090069307A1公开的治疗皮肤道病损的吡啶类化合物；美国专利7,247,620公开的治疗皮肤创伤、皮肤溃疡、褥疮、特应性皮炎的载体编码的肝细胞生长因子；US 20020065286A1公开的治疗非糖尿病慢性创伤和急性创伤的环鸟苷3’，5’-单磷酸5型磷酸二脂酶抑制剂；美国专利6,455,565公开的治疗唇疱疹、感冒疮、光照性皮炎、热灼伤、褥疮的组胺；美国专利6,682,732公开的治疗皮肤病损的黄嘌呤氧化还原酶；EP 1013280A1公开的治疗溃疡，包括褥疮的纤毛亲神经因子；US 20060166885A1公开的治疗褥疮的红细胞生成素；US 20080188546A1公开的治疗褥疮的N-乙酰羟基脯氨酸；US 20090192088A1公开的促进创伤愈合的血管内皮生长因子2多肽或其活性片段；US 20090215884A1公开的促进创伤愈合的一种巨大戟醇；US 20060286157A1公开的治疗创伤。如糖尿病溃疡的从骨中分离或重组方法产生的含生长因子，如骨形态发生生长因子，包括BMP-2、PMP-3、BMP-4、BMP-5、BMP-7、TGF-β1、TGF-β2、TGF-β3、FGF-2中的二种或多种的蛋白质混合物；US 20080241210A1公开的治疗急性创伤，如撕裂伤、擦伤、血肿和皮肤病的人蛋白质1556A；美国专利6,495,532公开的促进创伤愈合的溶血磷脂酸；EP 1658855A2公开的促进创伤愈合的P物质；US 20090220450A1公开的促进创伤愈合的抗-联结蛋白43制剂与能有效促进创伤愈合的肽或蛋白，如表皮生长因子联用方法；US 20090170910A1公开的促进创伤愈合的p38细胞分裂素活化的蛋白激酶抑制剂；美国专利5,525,335公开的促进创伤愈合的转谷氨酰胺酶；US20070161625A1公开的促进创伤愈合的吩噻嗪鎓(phenotiazinium)化合物。
本发明组合物能促进愈合的创伤，例如有，切割引起的浅或深的创伤、皮肤磨损或其他损伤；热烧伤或皮肤烫伤，或皮肤化学灼伤引起的创伤，还有骨折或细菌或病毒感染或褥疮引起的皮肤创伤。此外，本发明组合物能促进愈合的皮肤创伤还包括：刺激、炎症、烧灼或机械损伤的皮肤。本说明书中所用的术语“皮肤创伤”包括，例如细菌或病毒感染或过热引起的大水疱。术语“皮肤创伤”还包括湿疹、皮炎和牛皮癣引起的皮肤病。
按照本发明第六优选方面，所述创伤愈合剂是能有效治疗湿疹和/或皮炎和/或牛皮癣的创伤愈合剂，如杜松焦油、樟脑、薄荷醇、苯佐卡因、苦味酸氨苯丁酯、地布卡因、盐酸地布卡因、盐酸二甲异喹、盐酸达克罗宁、利多卡因、间甲酚、盐酸利多卡因、盐酸丙马卡因、丁卡因、盐酸丁卡因、苯甲醇、樟脑间甲酚、苯酚、苯酚钠、间苯二酚、盐酸苯海拉明；皮质类固醇，如氢化可的松和乙酸氢化可的松，及它们的组合。其他有用的皮质类固醇是：四氢皮质醇、泼尼松、去氢氢化可的松、6α-甲基氢化泼尼松、氟氢可的松、11-脱氧可的松、可的松、皮质酮、去炎松、帕拉米松、倍他米松、地塞米松、醋酸脱氧皮质酮、三甲醋酸脱氧皮质酮、醋酸氟氢可的松、氟甲基氢化泼尼松、甲基强的松、甲基氢化泼尼松、醋酸对氟米松。
本发明的依据是，发现特定类型的溶剂、挥发性硅油、任选与低级脂肪醇联用，可用于形成含极性脂质的组合物，特别适合在其中掺入短肽或中等链长的肽。将本发明的组合物施加到创伤表面形成的不稳定极性脂质层，通过挥发性硅油、低级脂肪醇(如果存在)的迅速蒸发，留下基本上由含创伤愈合促进剂的极性脂质组成的稳定的极性油脂层。本发明组合物的粘度低似乎是由于极性脂质不能形成溶致液晶，例如高粘度的层状、六角和各种立方相。本发明的组合物甚至当其中的极性脂质含量高达20重量％时仍澄清和粘度低。
相反，与本发明组合物相对应的用相应含量的水代替硅油的极性脂质组合物，在膜脂浓度低时呈现为略为粘稠的分散液，或在最高的膜脂质受试浓度，膜脂重量占该组合物20％时呈现为稠厚凝胶。后一种组合物粘度高因而不允许喷涂给药。采用挥发性硅油代替水作稀释剂有可能掺入令人惊讶的高含量极性脂质，同时对粘度的影响只是微不足道。
本领域知晓可用于本发明的药用级硅油。这种硅油可以是环硅氧烷，即环甲硅油或短的直链硅氧烷，即二甲基硅油。特别有用的硅油包括：十甲基环五硅氧烷[道康宁345液(Dow Corning
345Fluid)]和十二甲基环六硅氧烷(道康宁
246液(Dow Corning
246Fluid))。虽然优选五硅氧烷和六硅氧烷，但四-、七-和八硅氧烷也有潜在用途。本发明所用的硅油是纯化形式或混和形式。
除了化学性质不活泼外，本发明所用的硅油还取决于其挥发性能。尽管本发明所用的硅油沸点高，在180℃以上，特别是在200℃以上，但本发明的硅油容易蒸发。这是由于这类化合物的低蒸发热。在本发明中，尤其有用的是在25℃的蒸发热(kj/kg)为约100-300kJ/kg的硅油，更优选约120-200kJ/kg，甚至更优选25℃的蒸发热为约140-180kJ/kg的硅油。
用本发明的硅油提供的本发明组合物至少具有以下优点：i)能够掺入高含量的极性脂质材料，ii)形成热力学稳定的溶液，iii)形成的溶液粘度低使其适合喷雾、浸渍、涂覆或滴注。
本发明的低级脂肪醇是C2-C4醇或混和醇，具体用的醇选自C2-C4醇或叔丁醇。特别优选乙醇。
按照本发明的一个优选方面，所述C2-C4包括1，2-丙二醇和/或甘油，它们的具体含量占组合物重量最高达5％或15％。
本发明的极性脂质优选膜脂，如磷脂、糖脂、鞘脂或它们的混合物。特别优选的磷脂是磷脂酰胆碱。其他优选的磷脂有磷脂酰乙醇胺和磷脂酰肌醇。特别优选的糖脂是半乳糖脂。一种优选的半乳糖脂是二半乳糖基-1，2-二酰基甘油，或它与其他半乳糖脂和/或磷脂和/或鞘脂的混和物。
本发明采用的技术上大规模生产的商品化极性脂质可能含有大量非极性脂质，非极性脂质的重量可最高达约50或60％。因此，根据本发明另一优选方面，本发明组合物的极性脂质组分包含的非极性脂质含量可最高达30重量％或更高，例如最高达50重量％或60重量％，甚至最高达75重量％。优选的非极性脂质包括：甘油一酯、甘油二酯和甘油三酯及其混合物。作为本发明极性脂质的一种组分，可以容忍的非极性脂质中，与甘油三酯相应含量相比，甘油一酯和甘油二酯含量较高，尤其是甘油一酯。本发明的非极性脂质也可包括脂肪酸及其盐、脂肪酸酯、脂肪酸酰胺、脂肪醇、脂肪胺和它们的混合物。
用低级脂肪醇，如无水乙醇溶解本发明的极性油脂，特别有利的是采用链熔温度低的脂质。所述链熔温度，是在过量水中膜脂的酰基链经过相转变从类似固体的状态变为熔融态或类似液体的状态的温度。膜脂材料，例如，类脂S75、类脂S45、类磷脂50(Phospholipon 50)、类脂S100和DOPC，它们所有的链熔温度均在0℃以下，因此易溶于无水乙醇，浓度可最高达50重量％，甚至更高。
为了制备本发明的载脂组合物，可将极性脂质，尤其是膜脂混合物，如卵磷脂或分馏燕麦油溶于低级脂肪醇，然后用本发明的挥发性硅油稀释产生低粘稠的可喷雾的均匀液体。分馏燕麦油获自粗燕麦油，富含极性脂质。其通常包含约50重量％的非极性脂质，如三酰基甘油和二酰基甘油，和约50重量％的极性脂质，如磷脂和糖脂。一般，分馏燕麦油中的二半乳糖二酰基甘油的含量约为20重量％。例如，在WO 99/44585A1中公开了合适的分馏燕麦油。
类似于磷脂酰乙醇胺的脂质，具体是二油酰磷脂酰乙醇胺(DOPE)也可用作本发明极性脂质组分，或者与其他极性脂质混和。在水中，DOPE的链熔温度约为-16℃，可在无水乙醇中溶解至50重量％，升高温度(＞60℃)溶解得更多。用挥发性硅油，如DC345稀释这种溶液可产生澄清的低粘度液体。
虽然可容忍少量的水，如1重量％或2重量％甚至最高达约5重量％的水，但本发明的创伤愈合促进组合物宜基本上无水，具体说，水含量低于5重量％，优选低于2重量％或1重量％，甚至低于0.5重量％，或低于0.2重量％。
按照一优选方面，本发明的创伤愈合促进组合物包含：约10-30重量％的膜脂，约10-30重量％的乙醇，约0.01-5重量％的创伤愈合剂，其余是挥发性硅油，前提条件是挥发性硅油含量为40重量％或更高。
按照本发明公开的药物运载组合物的另一优选方面，本发明的运载组合物不含本发明的创伤愈合促进剂，但适合掺入这种试剂。所述运载组合物包含约30-90重量％的硅油，约5-45重量％的极性脂质，约5-45重量％的C2-C4醇，具体是乙醇，任选地5重量％或更低的水。
按照本发明公开的另一优选方面，所述创伤愈合促进剂运载组合物基本上由图3的相位图中区域F所示重量百分比例的极性脂质、挥发性硅油和乙醇组成，任选地包含5重量％或更低的水。
设计的本发明组合物能以所需方式控制水分丧失，即大大减少原本无限制或几乎无限制的水分丧失，例如，每单位时间减少50％或更高的水分丧失。控制水分丧失对创伤愈合是一种至关重要的因素。控制水分丧失可加强本发明组合物给予创伤愈合促进剂的治疗效果。
现在可通过参见一些带有插图的实施例更详细地说明本发明。
附图说明
图1.说明实施例1组合物的三元相位图。
图2.是可施加于皮肤浅层创伤含本发明组合物的医用贴片的代表性截面图。
图3.是本发明脂质形成组合物的另一种三元相位图，包括创伤愈合促进剂的运载组合物和含创伤愈合促进剂的组合物。
图4.本发明创伤愈合促进剂运载组合物如何控制经表皮水分丧失的图解说明。
优选实施方式的描述
材料
表1.配方实验用的硅油和脂质
该配方实验中用的醇是乙醇99.9％(″EtOH″，VWR)、2-丙醇HPLC级(″IPA″，拉斯布公司(Rathburn))、甘油99.5％(″Gro″，VWR)和1，2-丙二醇Ph.Eur.(″PD″，Fluka/西格玛-奥德里奇公司)。该配方实验中用的材料由以下供应商提供：美国密歇根州米德兰的道康宁公司；德国路德维希港的类脂有限公司(Lipoid GmbH)；瑞典卡尔莎的奥尔胡斯卡尔莎有限公司(Aarhus Karlshamn)；瑞典卡尔莎的LTP类脂技术供应商(LTP LipidTechnologies Provider AB)；瑞典韦若巴卡的瑞典燕麦纤维公司(Swedish Oat Fiber AB)；美国密苏里州圣路易斯的西格玛-奥德里奇公司(Sigma-Aldrich)；英国东约克郡古尔的克劳德公司(Croda，Goole)；英国苏格兰沃克布的拉斯布化学有限公司(Rathburn ChemicalsLtd，Walkerburn)；瑞典斯潘达的VWR国际公司(VWR International AB，Spanga)；丹麦希勒勒的多肽实验室公司(Polypeptide Laboratories A/S，
Denmark)；瑞典隆德的德马吉公司(Dermagen AB，Dermagen AB，Lund，Sweden)。
创伤愈合促进组合物
实施例1.人甲状旁腺素(PTH)制剂
将磷脂溶于无水乙醇，浓度50.0％(w/w)。将预先称取量的人甲状旁腺素加入50％(w/w)磷脂乙醇溶液中。在约40℃水浴型超声器中短时超声使磷脂完全溶解并轻轻混和。用硅油稀释溶液得到的澄清黄色溶液，室温贮存在气密气体瓶中。
实施例2.血管紧张素II制剂
按实施例1所述，将预先称取量的血管紧张素II加入50％(w/w)磷脂乙醇溶液中。在约35℃水浴型超声器中超声处理后获得澄清溶液。用挥发性硅油稀释该溶液得到澄清亮棕色至黄色溶液，室温贮存在气密气体瓶中。在室温下一个月该制剂外观无变化，即无相分离或沉淀现象，随后未观察到沉降，表明物理稳定性优良。
实施例3.抗微生物的抗菌多肽(cathelicidin)LL37制剂
按实施例1所述，将预先称取量的LL37加入33％(w/w)磷脂乙醇(重量比1∶1)溶液中。在约35℃水浴型超声器中超声处理后获得澄清溶液。用挥发性硅油稀释该溶液得到澄清亮棕色至黄色溶液，室温贮存在气密气体瓶中。在室温下一个多月该组合物外观无变化，即无相分离或沉淀现象，随后未观察到沉降，表明物理稳定性优良。
实施例4.细胞因子抑制剂创伤愈合组合物
将预先称取量的环孢菌素加入28.5％(w/w)磷脂乙醇溶液中，在约35℃水浴型超声器中超声处理后获得澄清溶液。用挥发性硅油稀释该溶液得到澄清亮棕色至黄色溶液，室温贮存在气密气体瓶中。在室温下一个多月该组合物外观无变化。
实施例5.在硅油/脂质运载体中的DPK-060创伤愈合促进肽的组合物
将精确称量的DPK-060肽在40℃搅拌下溶于脂质、甘油、1，2-丙二醇和乙醇混合液，加入硅油和异丙醇。40℃温和搅拌混合液直到获得均匀澄清和无色至棕黄色液体。
表2.在硅油/脂质运载体中的DPK-060肽的组合物
*DPK-060占组合物非挥发性组分的浓度，％w/w。
实施例6.在硅油/脂质运载体中的LL-37肽的组合物
将精确称量的LL-37肽在40℃搅拌下溶于脂质、甘油和乙醇混合液，加入硅油(DC 345)和异丙醇。40℃温和搅拌混合液直到获得均匀澄清的浅黄至棕黄色液体。表3提供了LL-37组合物的代表性示范例。
表3.LL-37肽的硅油/脂质运载组合物
*LL-37占组合物非挥发性组分的浓度，％w/w。
创伤愈合促进剂的运载组合物
实施例7.基于磷脂的运载组合物
将磷脂溶于DC345挥发性硅油和水的混合液中。精确称取脂质与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清和无色的液体或浅黄色液体。表4a显示基于磷脂酰胆碱的组合物，表4b是基于磷脂酰乙醇胺的组合物。
表4a.基于磷脂酰胆碱的运载组合物
表4b.基于磷脂酰乙醇胺的运载组合物
实施例8.基于酰基甘油的运载组合物
商品化购得的单甘油酯产品是单酰基-、双酰基和少量三酰基甘油的混合物。将该酰基甘油产品溶于DC345与挥发性硅油和醇的混合液中。精确称取脂质与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清和无色液体。表5显示基于酰基甘油组合物的示范例。
表5.基于酰基甘油的运载组合物
实施例9.基于胆固醇的运载组合物
通过与DC345挥发性硅油和醇混合制备含胆固醇的组合物。精确称取脂质与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清的无色液体。表6显示基于胆固醇组合物的示范例。
表6.基于胆固醇的运载组合物
实施例10.基于富含半乳糖脂的运载组合物
采用二种示范的富含半乳糖脂材料制备与DC345挥发性硅油和醇的混合液。精确称取脂质，与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清和浅黄色至棕黄色液体。表7显示基于富含半乳糖脂的脂质的示范性组合物。
表7.基于富含半乳糖脂材料的运载组合物
实施例11.基于脂质组合的运载组合物
测试了在挥发性硅油/醇混和物混和物中脂质以不同比例组合的能力。精确称取脂质材料，与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清和无色液体或浅黄色液体。表8显示基于不同脂质组合的组合物的示范例。
表8.基于脂质组合的运载组合物
实施例12.基于商品化购得的卵磷脂的运载组合物
商品化购得的卵磷脂产品是极性脂质(主要是磷脂)和非极性脂质(主要是甘油三酯)的混合物。以下示范例所用的材料都获自大豆，包含极性脂质磷脂酰胆碱作为主要的极性脂质。精确称取脂质，与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清黄色或棕黄色液体。表9显示基于卵磷脂的组合物的示范例。
表9.基于卵磷脂的运载组合物
实施例16.不同硅油的运载组合物
通过用二种其他硅油DC 245和DC 246替换DC 345测试了采用其他挥发性硅油的可能性。称取脂质，与硅油和醇混合。40℃温和搅拌混合液直到获得均匀澄清和无色液体。表10显示含DC 245和DC 246的组合物的示范例。
表10.含挥发性硅油DC 245和DC 246的运载组合物
实施例13.基于脂质和少量水的运载组合物
测试了在本发明的运载体中加入少量水的可能性。精确称取脂质与硅油和醇混合。加入少量水和任选的异丙醇。40℃温和搅拌混合液直到获得均匀澄清和无色或棕黄色液体。表11显示含少量水的组合物示范例。
表11.含少量水的运载组合物
实施例14.混溶性能测试
表12提供了磷脂乙醇溶液与挥发性硅油或水的混溶性数据。低含量磷脂乙醇溶液与硅油混合制备后立即具有澄清外观，但在室温一个月内分离。另一方面，含浓度20％磷脂乙醇溶液的制剂与挥发性硅油易混溶，在此期间外观无变化，可认为物理稳定。
表12.磷脂乙醇(PL；类脂S75)溶液分别与挥发性硅油(DC 345)和水的稀释液，所有百分比是重量百分比。
表12中的磷脂是类脂S75，由德国路德维希港的类脂有限公司(Lipoid GmbH)制造。从大豆提取的此磷脂材料含约68-73％的磷脂酰胆碱[PC]。其他合适的磷脂材料有，例如类脂S45、类磷脂50(Phospholipon 50)和类脂S100，所有均由类脂有限公司从大豆制得，PC含量范围约50％-100％。其他有用的磷脂是合成的二油酰磷脂酰胆碱[DOPC]、二肉豆蔻酰磷脂酰胆碱[DMPC]和二棕榈酰磷脂酰胆碱[DPPC]。
实施例15.医用贴片
图2.说明将含有实施例3的组合物施加到充满创伤血清和凝血块皮肤浅创伤的示意图。此圆形贴片(可以是圆形、方形其他任何合适的形状)包括用实施例3组合物浸湿的棉纱垫3。棉纱垫3的前部对着创面1。棉纱垫3的后部附着于可弯曲聚合物的背衬4，该聚合物允许硅油蒸气和醇蒸气渗透。背衬4的面积比安置在背衬4中心的纱布垫3大。背衬4的前部外围5没有纱布垫3覆盖，而有一医用粘附膜6，可将该医用贴片附着于伤口1周围尚完整的皮肤上。施加组合物前，撕掉保护粘附膜6的箔片(图中未显示)。施加到伤口1后，通过醇和挥发性硅油的蒸发，在薄层纱布3与伤口1之间形成含有纱布垫3提供的LL37肽的稳定极性脂质层。LL37肽可从脂质层漏入伤口血清促进创伤1愈合。本发明的医用贴片装在无菌的、不允许溶剂蒸气透过的聚合物密封容器中提供。
实施例16.创伤愈合测试
用一滴实施例13的制剂治疗左手大拇指切伤志愿者(男，66岁)。在创伤表面，液滴容易散开，溶剂迅速蒸发，留下一层含创伤愈合肽的薄层脂质。溶剂蒸发时创伤没有任何冷感觉，对周围皮肤也没有刺激。创伤在二天内愈合。按该志愿者所说，否则这种创伤愈合需要较长时间(多达二周)。
实施例17.控制经表皮的水分丧失
控制经表皮的水分丢失
测试了称为A、B、C(表13)的本发明三种脂质层形成组合物防止皮肤表面经表皮水分丢失(TEWL)的效果。将它们的效果与防止TEWL的常规制剂白凡士林(ACOhud公司，瑞典)作比较。将组合物施加到证明无皮肤疾病的平均年龄34±18岁的10位健康个体(五男五女)皮肤上。施加前用浸泡纯酒精的纸巾快速清洁他们前臂掌侧皮肤。用笔在前臂标记出五块面积各2x2cm的方形区域，检测其基础TEWL。将组合物与凡士林随机施加上述区域，一个区域留置作为不处理对照。研究了两种剂量：3μl/cm2和6μl/cm2。凡士林用半量，即1.5μl/cm2和3μl/cm2。对右前臂施加高剂量，左前臂低剂量。用可更换吸头的微量移液管(Gilson)将产品分配到皮肤表面。以小液滴将各组合物施加到所述区域；向表面轻轻吹气促进蒸发。凡士林则用手指尖涂敷散开。
表13.测试组合物控制经表皮水分丢失(％重量)
| 组合物 | MCM | 极性脂质 | EtOH | DC345 |
| 1 | 15(S75) | 10 | 75 | |
| 2 | 9 | 1(胆固醇) | 10 | 80 |
| 3 | 5(DOPE) | 10 | 85 |
用DermaLab仪(开放室，CT公司(Cortex Technology)，海松(Hadsund)，丹麦)检测施加前和施加后30分钟的TEWL。图4显示所记录到的经表皮水分丧失减少。本发明的组合物1效果与白凡士林相当，而本发明的组合物2和3显示对TEWL无显著影响。
实施例18.含DPK-060的本发明组合物对细菌生长的抑制作用。
用辐射状扩散试验检测了组合物KL-DPK-40、-42、-43、-45、-47和KL-DPK-49到-53(表2)对培养的大肠杆菌ATCC 25922、绿脓杆菌ATCC 27853和金黄色葡萄球菌ATCC29213生长的抑制作用。组合物KL-DPK-40、-42、-43、-45、-47、-49、-52和-53显示了优良的抑制作用，特别是KL-DPK-45和-49，而安慰剂KL-DPK-50和-51显示无效。
Claims (28)
1.一种脂质层形成创伤愈合促进组合物，其包含挥发性硅油、极性脂质、C2-C4脂肪醇、创伤愈合促进剂。
2.如权利要求1所述的组合物，其特征在于，所述组合物基本上由挥发性硅油、极性脂质、任选的C2-C4脂肪醇、创伤愈合促进剂组成。
3.如权利要求1或2所述的组合物，其特征在于，所述极性脂质包括膜脂，或就是膜脂。
4.如权利要求3所述的组合物，其特征在于，所述膜脂选自：磷脂、糖脂、鞘脂和它们的混合物。
5.如权利要求1-4所述的组合物，其特征在于，所述C2-C4脂肪醇是乙醇。
6.如权利要求1-5所述的组合物，其特征在于，所述低级脂肪醇是或包括占醇最高达10重量％的1，2-丙二醇和甘油。
7.如权利要求1-6任何一项所述的组合物，其特征在于，还包含低于5重量％的水，特别是低于1重量％的水。
8.如权利要求1-7任何一项所述的组合物，其特征在于，所述硅油是硅氧烷，具体是十甲基环五硅氧烷、十二甲基环六硅氧烷或它们的混合物。
9.如权利要求1-8任何一项所述的组合物，其特征在于，所述硅油的沸点在180℃以上，特别是在200℃以上。
10.如权利要求1-8任何一项所述的组合物，其特征在于，所述硅油在25℃的蒸发热(kJ/kg)约为100-300kJ/kg，具体说为120-200kJ/kg，最具体说为140-180kJ/kg。
11.如权利要求1-10任何一项所述的组合物，其特征在于，所述创伤愈合促进剂是肽。
12.如权利要求11所述的组合物，其特征在于，所述肽是短肽或中等链长的肽，具体是6-120个氨基酸的肽，特别是8-45个氨基酸的肽。
13.如权利要求11所述的组合物，其特征在于，所述肽选自：血管紧张素II及血管紧张素II的创伤愈合片段、类似物或衍生物，人甲状旁腺素及人甲状旁腺素的创伤愈合片段、类似物或衍生物，抗菌多肽LL37及抗菌多肽LL37的创伤愈合片段、类似物或衍生物，DPK-060。
14.一种在创伤上形成含创伤愈合促进剂的稳定极性脂质层的方法。该方法包括：
提供如权利要求1-13任何一项所述的组合物，
将所需量的所述组合物施加到创伤上，形成含有硅油和任选的C2-C4脂肪醇的脂质层；通过在所述创伤表面的温度下让硅油和如果存在的C2-C4脂肪醇蒸发，在创伤上形成稳定的极性脂质层。
15.如权利要求14所述的方法，其特征在于，所述施加是通过喷雾施加。
16.如权利要求14或15所述的方法，其特征在于，通过选择组合物的施加量可获得厚度1μm-500μm的稳定极性脂质层。
17.一种制备创伤愈合促进组合物的方法，包括：
提供药学有效量的创伤愈合促进剂；
将该创伤愈合促进剂溶于C2-C4脂肪醇，形成含创伤愈合促进剂的醇溶液；
混和该醇溶液与极性脂质和硅油，形成所述的创伤愈合促进组合物。
18.如权利要求17所述的方法，其特征在于，在20℃-50℃温度下通过超声促进所述混和。
19.如权利要求17或18所述的方法，其特征在于，所述硅油的沸点在180℃以上，特别是在200℃以上。
20.如权利要求17-19任何一项所述的方法，其特征在于，所述创伤愈合促进剂是短肽或中等链长的肽。
21.一种浸润了权利要求1-13任何一项所述创伤愈合促进组合物的创伤敷料。
22.如权利要求21所述的创伤敷料，其特征在于，包括浸润了所述创伤愈合促进组合物的贴片和背衬，所述背衬多孔以允许硅油蒸气和醇蒸气透过。
23.如权利要求21或22所述的创伤敷料，其特征在于，用气密性聚合物包覆材料密封。
24.如权利要求1-13任何一项所述的组合物促进创伤愈合的应用。
25.如权利要求24所述的应用，其特征在于，所述创伤是皮肤切口或磨损造成的创伤。
26.如权利要求24所述的应用，其特征在于，所述创伤是皮肤热灼伤或烫伤。
27.如权利要求24所述的应用，其特征在于，所述创伤是皮肤化学烧伤。
28.如权利要求24所述的应用，其特征在于，所述创伤是细菌或病毒感染造成的皮肤创伤。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0901408 | 2009-11-03 | ||
| SE0901408-5 | 2009-11-03 | ||
| SE1000022-2 | 2010-01-12 | ||
| SE1000022 | 2010-01-12 | ||
| PCT/SE2010/000269 WO2011056116A1 (en) | 2009-11-03 | 2010-11-03 | Composition for promoting wound healing |
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| CN102665765A true CN102665765A (zh) | 2012-09-12 |
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| CN2010800499024A Pending CN102665765A (zh) | 2009-11-03 | 2010-11-03 | 促进创伤愈合的组合物 |
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| US (1) | US20120213843A1 (zh) |
| EP (1) | EP2496264A4 (zh) |
| JP (1) | JP2013510085A (zh) |
| CN (1) | CN102665765A (zh) |
| AU (1) | AU2010316006B2 (zh) |
| CA (1) | CA2779433A1 (zh) |
| IL (1) | IL219439A0 (zh) |
| WO (1) | WO2011056116A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105939726A (zh) * | 2013-11-19 | 2016-09-14 | 利波佩普泰德公司 | 慢性溃疡的新治疗 |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2699267A4 (en) * | 2011-04-18 | 2014-11-12 | Lipidor Ab | LIQUID CARRIER FOR THE ORAL DELIVERY OF A PHARMACOLOGICAL ACTIVE SUBSTANCE |
| SE1300709A1 (sv) * | 2013-11-14 | 2015-05-15 | Lipidor Ab | Komposition och metod för topikal behandling |
| CA2834301A1 (en) * | 2011-05-02 | 2012-11-08 | Lipidor Ab | Treatment of psoriasis |
| BR112015027436A8 (pt) * | 2013-05-03 | 2018-01-16 | Lipidor Ab | composição tópica e veículo para administração de ingredientes farmaceuticamente ou cosmeticamente ativos |
| AU2014349256B2 (en) * | 2013-11-14 | 2020-04-30 | Lipidor Ab | Sprayable topical carrier and composition comprising phosphatidylcholine |
| WO2016170382A1 (en) * | 2015-04-23 | 2016-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Pharmaceutical compositions comprising a bradykinin 2 receptor antagonist for prevention or treatment of impaired skin wound healing |
| US10496949B2 (en) * | 2017-01-04 | 2019-12-03 | Christopher Zoumalan | Compositions and methods for treating cutaneous conditions |
| CN111450310A (zh) * | 2020-03-03 | 2020-07-28 | 劳龙斯(上海)医药科技有限公司 | 一种新型液体伤口敷料及其制备方法 |
| DE102020211387A1 (de) * | 2020-09-10 | 2022-03-10 | Beiersdorf Aktiengesellschaft | Wirkstoffhaltige Wundverschlusszubereitung |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030170194A1 (en) * | 2000-05-19 | 2003-09-11 | Ralf Piotrowiak | Pharmaceutical and/or cosmetic composition containing an organosiloxane and a phospholipid |
| US20070149448A1 (en) * | 2001-01-29 | 2007-06-28 | Mona Stahle-Backdahl | Use of the cathelicidin ll-37 and dervicaties thereof for would healing |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1269634B (it) * | 1994-05-06 | 1997-04-08 | Indena Spa | Medicamento topico ad attivita' cicatrizzante |
| US6183766B1 (en) * | 1999-02-12 | 2001-02-06 | The Procter & Gamble Company | Skin sanitizing compositions |
| BRPI0211282B8 (pt) * | 2001-07-24 | 2021-05-25 | Advanced Biotechnologies Inc | curativo compreendendo composição de fluido de silicone não volátil e seu método de manufatura, uso de composição para tratamento de cicatriz e de infecção por patógeno, bem como aplicador |
| US6835536B2 (en) * | 2001-08-21 | 2004-12-28 | Micrologix Biotech Inc. | Antimicrobial cationic peptides and formulations thereof |
| FR2856301B1 (fr) * | 2003-06-23 | 2007-08-03 | Galderma Res & Dev | Composition sous forme de spray comprenant un actif pharmaceutique, au moins un silicone volatile et une phase non polaire non volatile |
| GB0426010D0 (en) * | 2004-11-26 | 2004-12-29 | Britannia Pharmaceuticals Ltd | Improvements in or relating to organic materials |
| AU2006279369B2 (en) * | 2005-08-17 | 2011-09-08 | Rochal Partners, Llp | Conformable solvent-based bandage and coating material |
-
2010
- 2010-11-03 JP JP2012536746A patent/JP2013510085A/ja active Pending
- 2010-11-03 WO PCT/SE2010/000269 patent/WO2011056116A1/en active Application Filing
- 2010-11-03 CA CA2779433A patent/CA2779433A1/en not_active Abandoned
- 2010-11-03 CN CN2010800499024A patent/CN102665765A/zh active Pending
- 2010-11-03 EP EP10828611.3A patent/EP2496264A4/en not_active Withdrawn
- 2010-11-03 AU AU2010316006A patent/AU2010316006B2/en active Active
- 2010-11-03 US US13/505,502 patent/US20120213843A1/en not_active Abandoned
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2012
- 2012-04-25 IL IL219439A patent/IL219439A0/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030170194A1 (en) * | 2000-05-19 | 2003-09-11 | Ralf Piotrowiak | Pharmaceutical and/or cosmetic composition containing an organosiloxane and a phospholipid |
| US20070149448A1 (en) * | 2001-01-29 | 2007-06-28 | Mona Stahle-Backdahl | Use of the cathelicidin ll-37 and dervicaties thereof for would healing |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105939726A (zh) * | 2013-11-19 | 2016-09-14 | 利波佩普泰德公司 | 慢性溃疡的新治疗 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2496264A4 (en) | 2014-03-26 |
| IL219439A0 (en) | 2012-06-28 |
| WO2011056116A1 (en) | 2011-05-12 |
| EP2496264A1 (en) | 2012-09-12 |
| AU2010316006A1 (en) | 2012-05-17 |
| AU2010316006B2 (en) | 2013-09-26 |
| JP2013510085A (ja) | 2013-03-21 |
| US20120213843A1 (en) | 2012-08-23 |
| CA2779433A1 (en) | 2011-05-12 |
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