CN104994889B - 用于改善疤痕组织的外观和形成的方法及组合物 - Google Patents
用于改善疤痕组织的外观和形成的方法及组合物 Download PDFInfo
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- CN104994889B CN104994889B CN201480009329.2A CN201480009329A CN104994889B CN 104994889 B CN104994889 B CN 104994889B CN 201480009329 A CN201480009329 A CN 201480009329A CN 104994889 B CN104994889 B CN 104994889B
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Abstract
本发明涉及用于降解哺乳动物皮肤中的胶原的方法和组合物，从而改善闭合的伤口的外观和/或减小其尺寸，该闭合的伤口可为疤痕或瘢痕疙瘩和脂肪团或其中存在过量胶原问题的其它病症。
Description
相关申请的交叉引用
本申请要求2013年2月19日提交的美国临时申请序列号61/766,292以及2013年3月12日提交的美国临时申请序列号61/777,059的优先权，并涉及与本文同时提交的且名称为“Methods and Compositions for Improving Appearance and Formation of ScarTissue”的共同未决的美国专利申请代理人案卷号JCO5096USNP。出于所有目的，将上述相关美国专利申请的全部公开内容以引用的方式并入本文。
技术领域
本发明涉及用于降解哺乳动物皮肤中的胶原的方法和组合物，由此改善闭合的伤口的外观和/或减小其尺寸，该闭合的伤口可为疤痕或瘢痕疙瘩和脂肪团或其中存在过量胶原问题的其它病症。
背景技术
疤痕，作为自然伤口愈合过程的一部分，响应于皮肤损伤而形成。尽管通常被认为是分阶段发生的，但是这是漫长且持续的过程。在损伤后立即开始伤口愈合过程，伴随着炎症阶段。该阶段通常持续两天到一周(依据伤口而定)，在该阶段期间，受损组织和异物被从伤口移除。增生阶段发生在炎症阶段之后某时间，并且特征在于纤维原细胞增生以及产生胶原和蛋白多糖酶。正是在增生阶段期间合成细胞外基质，以便向伤口提供结构完整性。依据伤口性质，增生阶段通常持续约四天到若干周，并且正是在该阶段期间形成肥厚性疤痕。最后阶段被称为重构阶段。在该重构阶段期间，先前构造的并随机组织的基质被重构到经组织的结构中，该经组织的结构高度交联并对齐，以增强机械强度。
在损伤之后的修复期间，连接的组织基质的变化方式需要胶原和蛋白多糖酶的合成及降解之间的精细平衡。在正常情况下，该平衡可被维持，而在许多疾病状态下，该平衡被改变，导致过度沉积胶原、丧失功能性组织、或损形。由于肥厚性疤痕和瘢痕疙瘩，该生物合成阶段持续的时间比修复伤口所需的长。为了保持营养物供应，发生血管向内生长，导致大的、高度血管化疤痕，这是不雅观的并可能致残。瘢痕疙瘩和肥厚性疤痕导致功能和美容上畸形。它们是常见的临床问题。
尽管表征肥厚性疤痕的组织学特征已经很好地被记载，但是潜在的病理生理学不为人所知。肥厚性疤痕是伤口过度愈合的负效应，并且通常导致细胞、胶原和蛋白多糖酶的过度产生。肥厚性疤痕为厚的，并由于细胞、胶原和蛋白多糖酶的过度产生而在皮肤上呈现凸起的疤痕。
瘢痕疙瘩是超过初始损伤处的界限的凸起疤痕(不像肥厚性疤痕，通常留在伤口界限内)，并且很少能被外科干预来修正。通常瘢痕疙瘩的特征在于由高度肥厚性块组成的肿瘤，其发生在易感染个体的真皮和邻近的皮下组织中，最常见地是在外伤之后。瘢痕疙瘩可长成坚固的肿块，其比原始疤痕要长好几倍，并且通常是纤维化增长，包含非典型纤维原细胞的集合和增大量的细胞外基质组分，特别是胶原。
瘢痕疙瘩通常比肥厚性疤痕更严重，因为瘢痕疙瘩趋于侵入正常的相邻组织，而肥厚性疤痕趋于保持限定在原始疤痕边界内。
尽管通常是良性的，但是肥厚性疤痕和瘢痕疙瘩常常引起不适、疼痛、瘙痒、身体损形和受损的生活质量。
大多数减小疤痕的产品包含呈片或凝胶形式的硅氧烷，以及洋葱提取物(Mederma皮肤护理产品)。通常需要超过3个月才看到一些效果，因为这些产品不包含有效活性成分诸如任何形式的胶原酶，其正中疤痕形成的原因。见www.mederma.com/learning/caring_for_scars。
治疗肥厚性疤痕和瘢痕疙瘩的其它尝试包括外科手术、机械压力、类固醇、X射线照射和冷冻疗法。存在与这些方法中的每一个方法相关联的许多缺点。外科手术移除疤痕组织常常是不完全的，并可以导致肥厚性疤痕和瘢痕疙瘩在切口和缝合点处进一步发展。类固醇治疗是不可预知的并且常常导致皮肤脱色。X射线疗法仅是至今可预知的且有效的治疗；然而，由于其潜在地引起癌症，通常并不被推荐或接受。控制疤痕且尤其是疤痕过度形成的最常见方法是施用压力，这在许多实例中看起来多少有些效果。该治疗具有有限的应用，通常基于身体上疤痕组织的尺寸和位置。其它常用的治疗方法是施用维他命E和皮质类固醇。
发明内容
本发明涉及改善愈合的伤口和脂肪团的外观和/或显著减少其疤痕形成和其它可见影响的方法，疤痕形成和其它可见影响包括瘢痕疙瘩和肥厚性疤痕，所述方法包括以下、基本上由以下组成、以及由以下组成：利用接触抗病毒组合物接触包含在所述疤痕组织或伤口内的胶原，该抗病毒组合物包含降解所述胶原的有效量的至少一种低分子量疏水改性的聚合物。预想本发明的方法和组合物包括对将得益于通过降解或破坏胶原的治疗模式的任何病症的治疗。
令人惊奇地，发现因温和性质而被熟知的低浓度的某种低分子量疏水改性的聚合物能够成功地降解位于皮肤中或围绕皮肤的、尤其在皮肤上皮层中的胶原。此类聚合物还能够降解细胞外基质中的胶原，诸如与伤口愈合有关和与脂肪团结合而形成那些胶原。
具体实施方式
本发明的方法中的一者涉及用于治疗具有在哺乳类受体的皮肤表面上的疤痕组织的闭合的伤口的方法和组合物。此类疤痕组织可包括肥厚性疤痕和/或瘢痕疙瘩疤痕。
优选地，用于施用本发明的所述组合物的方法包括如下、基本上由如下组成以及由如下组成：将包含低分子量疏水改性的聚合物(低MW HmP)的组合物注射到已形成在闭合的伤口上的疤痕中。
在另一个实施例中，建议该组合物可在疤痕形成之前被施加到开放的伤口。根据本发明的组合物可被直接局部地施加到伤口部位或作为放置到伤口上的绷带的一部分。
优选地，本发明的组合物包含至少一种低MW HmP和水性溶剂。该溶剂可为任何非刺激性溶剂诸如去离子水和磷脂缓冲盐水(PBS)，其对于注射到疤痕中是可接受的。在另一个实施例中，该组合物可为适合直接分配到皮肤的表面的局部组合物，诸如如下文所述的洗剂或霜膏。
本发明的组合物可被部署到能够施加到皮肤的包括粘合剂水凝胶绷带、可注射组合物、套件的装置，以及用于通过降解胶原来改善伤口部位处的疤痕和/或瘢痕疙瘩形成的方法。
如本文所用，术语“伤口”意指一种损伤类型，其中皮肤被撕裂、切割或刺穿(开放的伤口)，或其中钝力创伤引起青肿(闭合的伤口)。
如本文所用，术语“闭合伤口”可包括肥厚性疤痕、瘢痕疙瘩、Dupuytren挛缩、纤维化疤痕或反应性疤痕等等。
优选地，当治疗愈合的和/或闭合伤口的疤痕时，本发明的方法包括如下、基本上由如下组成以及由如下组成：将根据本发明的组合物注射到疤痕组织中。优选地，本组合物应放置在角质层的层下方，即皮肤的最外层。
优选地，本发明的可注射组合物包含至少约0.1％的低分子量疏水改性的聚合物，和优选地至少约50％的溶剂，溶剂包括：悬浮液、胶体、水凝胶和乳液，例如，水或水-丙二醇混合物。此类组合物可制备为可注射物，无论为液体溶液还是悬浮液。也可制备适合于溶解在水凝胶或液体溶液中、或者在使用之前适于悬浮在液体中的固体形式。该制备物也可以是乳化剂。活性成分可与赋形剂混合，该赋形剂为药用的并且与该活性成分相容，并且在量上适于用在本文描述的治疗方法中。合适的赋形剂包括例如水、盐水、右旋糖、甘油、乙醇等、以及它们的组合。另外，如果需要，该组合物可包含增强该活性成分的效果的少量的辅助物质，诸如湿化剂或乳化剂、PH缓冲剂等。关于配方和给药的技术的详细内容可见于最新版本的Remington's Pharmaceutical Sciences(Maack Publishing Co.,Easton,Pa.)。
对于局部给药方法，优选地，包含至少约0.1％的低分子量疏水改性的聚合物和优选地至少约50％的溶剂(包括去离子水和磷酸盐缓冲溶液)的组合物可被结合到绷带中，或者直接施加到伤口的表面。
适于本发明的渗透增强剂/溶剂为醇类，包括但不限于乙醇、丙二醇或它们的组合。用于本文的合适的湿润剂/溶剂包括但不限于聚乙二醇、甘油、山梨醇、木糖醇、或前述中的任何物质的任意组合。用于本文的合适的无水载体包括但不限于与醇类渗透增强剂相同或不同的醇类。此类醇类的非限制性示例为异丁醇和异丙醇。也可利用机械性渗透增强剂。渗透增强的方法可见于美国专利7,879,823,7,179,475,6,890,553和美国专利公布2012/0321574中，这些专利以引用的方式并入本文。
如本文所用，术语“表面活性剂”为表面活性制剂或者这样一种物质：当溶解在水或水性溶液中，减少其表面张力或其与另一种液体之间的界面张力的物质。
聚合物材料
在本发明的组合物和方法中有用的聚合物材料的示例包括低分子量丙烯酸、其它烯键式不饱和聚合物、聚酯、聚碳酸酯、聚酸酐、聚酰胺、聚氨酯、聚脲、聚酰亚胺、聚砜、聚硫化物、它们中的两者或更多者的组合等等。合适的低分子量丙烯酸类聚合物的示例包括疏水改性的丙烯酸、多糖、纤维素、淀粉聚合物、它们中的两者或更多者的组合等等。合适的低分子量丙烯酸类聚合物包括疏水改性的丙烯酸类聚合物以及其它丙烯酸类聚合物，它们中的任一者可经由如下形成：溶液、悬浮液、沉淀物、分散体、乳液、反相乳液、微乳液、胶束聚合法、以及它们中的两者或更多者的组合。用于本发明的丙烯酸类聚合物可衍生自选自如下的任意一个或多个单体：(甲基)丙烯酸酯，(甲基)丙烯酰胺，乙烯基醚、酯和酰胺，烯丙基醚、酯、胺和酰胺，衣康酸酯，巴豆酸酯，苯乙烯系，和烯烃。丙烯酸类聚合物可为非离子亲水性的、非离子疏水性的、阳离子的、两性离子的、非缔合型大分子单体、缔合型大分子单体、或多官能/交联的。
如本文所用，术语“低分子量”聚合物指具有约100,000或更低数均分子量(Mn)的聚合物，该分子量是由用聚(甲基丙烯酸甲酯)(PMMA)标准品校准的凝胶渗透色谱法(GPC)测得。在某些优选的实施例中，低分子量聚合物是具有约5,000Mn至约80,000Mn，更优选地约10,000Mn至约50,000Mn，并且更优选地在约15,000Mn和约40,000Mn之间的分子量范围的那些。
制备此类聚合物的某些疏水改性的聚合物和方法描述于授予Marchant等人的美国专利6,433,061中，该专利以引用方式并入本文。在本发明的组合物中有用的聚合物材料优选地为对皮肤和粘膜非常温和的非交联的直链丙烯酸类聚合物。这些非交联的直链聚合物优选地具有较低分子量，通过用聚(甲基丙烯酸甲酯)(PMMA)标准品校准的凝胶渗透色谱法(GPC)测得的数均分子量为100,000或更低(如本文所用，除非另外指明，否则所有数均分子量(Mn)是指以此方式测得的分子量)。因此，该聚合物材料用作共聚物化合物。共聚物化合物由至少两种单体组分聚合而来。第一单体组分选自含有至少一个羧酸基团的一种或多种α,β-烯键式不饱和单体。该酸基团可衍生自一元酸或二元酸、二羧酸的酸酐、二元酸的单酯、以及它们的盐。第二单体组分是疏水改性的(相对于第一单体组分而言)并选自含有C1至C9烷基基团的一种或多种α,β-烯键式不饱和非酸单体，其包括(甲基)丙烯酸的直链和支链C1至C9烷基酯、直链和支链C1至C10羧酸的乙烯酯、以及它们的混合物。在本发明的一个方面，第二单体组分由下式表示：
CH2＝CRX
其中R为氢或甲基；X为–C(O)OR1或-OC(O)R2；R1为直链或支链的C1至C9烷基；并且R2为氢或直链或支链的C1至C9烷基。在本发明的另一方面，R1和R2为直链或支链的C1至C8烷基，并且在另一方面R1和R2为直链或支链的C2至C5烷基。
因此，优选地在本发明的组合物和方法中有用的疏水改性的聚合物包括如下、基本由组成和由如下组成：低分子量非交联直链丙烯酸类共聚物，其衍生自至少一种第一单体组分和至少一种第二单体组分，所述第一单体组分为(甲基)丙烯酸，所述第二单体组分选自一个或多个C1至C9(甲基)丙烯酸烷基酯，其中所述低分子量聚合物具有约100,000或更少的数均分子量。
示例性的第一单体组分包括(甲基)丙烯酸、衣康酸、柠康酸、马来酸、富马酸、巴豆酸、乌头酸、以及它们的混合物。示例性的第二单体组分包括(甲基)丙烯酸乙酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸-2-乙基己酯、甲酸乙烯酯、乙酸乙烯酯、乙酸-1-甲基乙烯酯、丙酸乙烯酯、丁酸乙烯酯、2-乙基己酸乙烯酯、新戊酸乙烯酯、新癸酸乙烯酯、以及它们的混合物。如本文所用，术语“(甲基)丙烯酸”和“(甲基)丙烯酸酯”意在包括相应的丙烯酸甲基衍生物和相应的丙烯酸烷基酯。例如，“(甲基)丙烯酸”是指丙烯酸和/或甲基丙烯酸并且“(甲基)丙烯酸酯”是指丙烯酸烷基酯和/或甲基丙烯酸烷基酯。
更优选地，所述第一单体组分选自(甲基)丙烯酸，并且所述第二单体组分选自至少一种(甲基)丙烯酸C1至C9烷基酯。
在本发明组合物和方法中有用的未交联的直链丙烯酸类共聚物还可通过本领域已知的自由基聚合技术来合成。在本发明的一个方面，所使用的第一单体组分与第二单体组分的重量比在约20:80至约50:50的范围内。在另一方面，第一单体组分与第二单体组分的重量比为约35:65，并且在又一方面，第一单体组分与第二单体组分的重量比为约25:75。
在本发明的组合物和方法中有用的合成聚合物的方法可见于美国专利6,433,061中，该专利以引用形式并入本文。
在本发明的方法和组合中有用的直链共聚物材料在去离子水中聚合物固体浓度为5重量％且用18重量％的NaOH溶液中和至PH7时，优选地具有500mPa·s或更小的粘度(Brookfield RVT，20rpm，1号转子)。在另一个方面，该粘度可在约1mPa·s至约500mPa·s的范围内，在又一个方面，在约10mPa·s至约250mPa·s的范围内，并且在另一个方面，在约15mPa·s至约150mPa·s的范围内。
优选地，存在于本发明的组合物和方法中的低分子量非交联直链丙烯酸共聚物为丙烯酸钾共聚物。
在本发明的方法和组合中有用的低分子量疏水改性的聚合物优选地以有效地抑制、干扰或降解伤口愈合模型中的胶原基质的量存在于所述组合物中。因此，本发明的组合物和方法降解胶原，并将因此阻止瘢痕疙瘩和肥厚性疤痕的形成。
优选地，它们应按所述组合物重量计以约0.1％至约100％百分比的量存在于本发明的组合物中。更优选地，它们应按所述组合物重量计以约0.1％至约10％百分比的量存在于本发明的组合物中。甚至更优选地，它们应按所述组合物重量计以约0.1％至约5％的量存在。更优选地，它们应按所述组合物重量计以约0.1％至约0.5％的量存在。更优选地，它们应按所述组合物重量计以约0.1％至约0.5％的量存在。
对于可注射应用，低MW HmP可溶解在磷酸盐缓冲盐水(缩写PBS)中。PBS为缓冲溶液，通常用于生物学研究。其为基于水的盐溶液，包含氯化钠、磷酸钠，并且在一些配方中，包含氯化钾和磷酸钾。缓冲液中的磷酸基可帮助维持恒定的PH。溶液的渗透度和离子浓度通常匹配人体(等压的)中的那些。对包含溶解或分散在其中的活性成分的药理学组合物的制备在本领域中是熟知的并且不必限于配方。液体制备物包括溶液、悬浮液、胶体、水凝胶、和乳液，例如，水或水-丙二醇混合物。此类组合物可制备为可注射物，无论为液体溶液还是悬浮液。也可制备适合于溶解在水凝胶或液体溶液中、或者在使用之前用于悬浮在液体中的固体形式。该制备物也可以是乳化剂。活性成分可与赋形剂混合，该赋形剂为药用的并且与该活性成分相容，并且在量上适于用在本文描述的治疗方法中。合适的赋形剂包括例如水、盐水、右旋糖、甘油、乙醇等、以及它们的组合。另外，如果需要，该组合物可包含增强该活性成分的效果的少量的辅助物质，诸如湿化剂或乳化剂、PH缓冲剂等。关于配方和给药的技术的详细内容可见于最新版本的Remington's Pharmaceutical Sciences(MaackPublishing Co.,Easton,Pa.)。
本发明的组合物可以为能够施加在皮肤表面上或在具有伤口的无生气表面的洗剂或液体的形式。也可为直接施加到皮肤或包含在粘合剂绷带中(即，治疗溶液包含在绷带的吸收部分内)并放置在具有伤口的皮肤表面上的组合物。这些类型的组合物可为更粘性的并可基于凝胶或水凝胶组合物。
本发明的该组合物可制成多种多样的产品类型，所述产品类型包括但不限于液体、洗剂、霜膏、凝胶、棒剂、喷剂、剃刮膏、油膏剂、清洁液体洗剂以及固体条棒剂、洗发剂、糊剂、散剂、摩丝、擦拭物、贴剂、伤口敷料和粘合剂绷带、水凝胶和膜。这些产品类型可含有若干类型的美容上可接受的局部载体，包括但不限于溶液、乳液(如微乳液和纳米乳液)、凝胶、固体和脂质体。下面是此类载体的非限制性实例。其它载体可由配制此类产品类型的本领域的技术人员配制。
在本发明的方法中有用的局部用组合物可配制为溶液。这些溶液优选地包含水性溶剂(例如，约50％至约99.99％、或约90％至约99％的美容上可接受的水性溶剂)。
在本发明的方法中有用的局部用组合物可配制成包含润肤剂的溶液。此类组合物优选地包含约2％至约50％的一种或多种润肤剂。如本文所用，“润肤剂”是指用于防止或缓解干燥以及用来保护皮肤的材料。各种各样的合适的润肤剂是已知的，并且可用于本文。Sagarin编写的Cosmetics,Science and Technology,2nd Edition,Vol.1,pp.32-43(1972)；以及Wenninger和McEwen编写的International Cosmetic IngredientDictionary and HandbookWenninger和McEwen，1656-61、1626和1654-55编写的TheCosmetic,Toiletry,and Fragrance Assoc.,Washington,D.C.,7th Edition,1997(本文后文称为“ICI手册”)包含用于本发明的组合物和方法中的材料的大量示例。
洗剂也可由此类溶液制成。洗剂优选地包含约1％至约20％(更优选地，约5％至约10％)的润肤剂和约50％至约90％(更优选地，约60％至约80％)的水。
可由溶液配制的另一产品类型是霜膏。霜膏优选地包含约5％至约50％(更优选地，约10％至约20％)的润肤剂和约45％至约85％(更优选地，约50％至约75％)的水。
还可由溶液配制的另一种产品类型是油膏剂。油膏剂可包含简单的动物或植物油基或半固体碳氢化合物。油膏剂优选地可包含约2％至约10％的一种或多种润肤剂，加上约0.1％至约2％的一种或多种增稠剂。可用于本文的增稠剂或增粘剂在Sagarin编写的Cosmetics,Science and Technology,2nd Edition,Vol.1,pp.72-73(1972)和ICIHandbook pp.1693-1697中有更加全面的公开。
在本发明的方法中有用的局部用组合物也可配制为溶液。如果载体是乳液，则优选地约1％至约10％(例如，约2％至约5％)的载体包含一种或多种乳化剂。乳化剂可为非离子、阴离子或阳离子的。合适的乳化剂在例如美国专利3,755,560、美国专利4,421,769、McCutcheon's Detergents and Emulsifiers，北美版，317-324(1986)和ICI Handbook,pp.1673-1686中已公开，它们以引用的方式并入本文。
洗剂和霜膏也可配制成乳液。优选地，此类乳液包含0.5％至约5％的乳化剂。此类霜膏通常包含约1％至约20％(更优选地，约5％至约10％)的润肤剂；约20％至约80％(更优选地，30％至约70％)的水；以及约1％至约10％(更优选地，约2％至约5％)的乳化剂。
在本发明的方法中有用的其它组合物包括能够施加到粘膜表面以抑制病毒传播的凝胶和液体组合物。粘膜表面包括但不限于阴道、直肠、鼻通道、口和喉咙。优选地，此类化合物应包括至少一种多元醇，包括甘油、聚乙二醇、丙二醇、山梨醇、或它们的组合。可用于本发明的组合物和方法中的本领域技术人员所知的其它多元醇包括分子量在约300至约1450范围内的聚乙二醇。优选地，应该为约0.1至约50重量％的甘油和约2至约40重量％的丙二醇。
本发明的粘膜组合物还应包含一种或多种水溶性的纤维素衍生的聚合物。优选地，此类聚合物应为纤维素胶诸如一种或多种羟烷基纤维素聚合物。更优选地，该羟烷基纤维素为以下中的一种或多种：羟乙基纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素等等。优选地，该纤维素衍生的聚合物应以按组合物的重量计以约0.1％至约2％的量存在于本发明的组合物中。
意在阴道使用的本发明的组合物也可包含一种或多种杀精剂，包括但不限于壬苯醇醚-9等等。尽管此类杀精剂可分类为表面活性剂，但是它们通常具有少于16的HLB并且不用作清洁组合物或用在清洁组合物中，且不起泡沫。
优选地，无机碱基可用于调整将与阴道、口腔或直肠粘膜相容的组合物的PH。氢氧化钾或另一种碱金属或碱土金属碱基可用来提供合适的PH。当然，任何其它生理学可接受的碱基也可以此方式使用。优选地使用约0.05至约5重量％的无机碱基。
可根据本领域技术人员熟知的那些方法和工艺或根据本发明制备方法来制备本发明的组合物。例如，水溶性组分诸如甘油、丙二醇、山梨醇、无机碱基、防腐剂等可溶解在水中，并且可将纤维素衍生的聚合物添加到该组合。另一制备方法是将所有的成分混合成无水的浆料，然后将该浆料添加到水。
该组合物优选地基本上不含表面活性剂，包括阴离子的、阳离子的、两性的或非离子的表面活性剂。
包括在本组合物的液体或洗剂形式中的可为水、油、防腐剂、乳化剂、增粘剂润肤剂、电解质、芳香剂、缓冲剂、PH调整剂、皮肤保护剂、金属离子整合剂等等。
伤口护理绷带
吸收性制品诸如绷带也可用来覆盖开放性伤口以及递送包含低MWHmP的治疗溶液。在本发明中，可使用任何吸收性绷带。通常，绷带具有三层：皮肤面对层、和吸收性层、以及顶层，该顶层面对远离使用者皮肤。绷带的底层取向成朝着使用者的皮肤，并且可由带孔膜或不粘到伤口但允许治疗溶液透过的其它材料制成。吸收性层可由吸收性纤维制成并包含治疗溶液。顶层可为带孔膜。顶层相较于底层可具有较小开口区域；这将阻止治疗溶液从吸收层不期望的逸出。绷带形状上可为方形的、矩形的、圆形的、椭圆形的或三角形的。绷带可大体上具有0.25mm至5mm范围内的厚度。
材料
丙烯酸钾共聚物(Lubrizol,Wickliffe,OH)作为30％的活性制剂供应。用蒸馏水、磷酸盐缓冲盐水(PBS)或丙烯酸盐交联聚合物-4(SF2)将溶液稀释到0.5％活性和5％活性。以不同浓度供应下面的溶液，并且用水都稀释成0.5％活性制剂。EDP200脲基丙烯酸/甲基丙烯酸共聚物(Rhodia,Aubervillier,Cedex)以17.7％的活性制剂供应。EDP300脲基N,N-二甲基丙烯酰胺甲基丙烯酸共聚物(Rhodia,Aubervillier,Cedex)以16.4％的活性制剂供应。聚丙烯酸酯-33(Rhodia,Cranbury,NJ)以29％的活性制剂供应。丙烯酸共聚物4(Lubrizol,Wickliffe,OH)以32％的活性制剂供应。丙烯酸共聚物(Lubrizol,Pedricktown,OH)以30％的活性制剂供应。菊粉月桂基氨基甲酸酯(Beneo-Bio BasedChemicals(Belgium))以100％的活性制剂供应。水解马铃薯淀粉十二烯基琥珀酸钠(AkzoNobel,Salisbury,NC)以100％的活性制剂供应。十八烯/MA共聚物(Chevron-Phillips,TheWoodlands,Texas)以2％的活性制剂供应。对于本实验，以水或磷酸盐缓冲盐水(PBS)(Mattek,Ashland,MA)进一步制备次级稀释液。
实例1
伤口愈合试验：
下文描述的伤口愈合实验用来评估根据本发明的材料的上皮再形成特性。实验也可用来确定制剂的胶原降解性。
全厚度皮肤等同物在载有纤维原细胞的人体胶原基质上制成。在胶原基质的顶部上培养人体角质细胞，然后从培养基取出，以生成分化的角质层。全厚度等同物从Mattek(Ashland,MA)制造和定购，并且定购培养基以包括额外生长因子。培养基还补充有2％的人血清(Lonza,Gampel,Valais)。接收等同物并根据制造商说明来培养等同物。在皮肤组织等同物的中部制有3mm的活检穿孔器(Miltex,Plainsboro,NJ)，用于移除表皮层但使胶原层完整。将6μL的表面活性剂溶液施加到活检穿孔器区域。根据制造商的说明来培养等同物五天。在第五天，收获细胞，并转移至10％福尔马林缓冲剂溶液(VWR,Bridgeport,NJ)。用苏木精和伊红(H&E)染色剂(American Histolabs,Gaithersburg,MD)来对样本染色。使用带活动台的Olympus BH2显微镜(Center Valley,PA)在4倍下扫描样本。然后使用Nikon成像软件(NIS)(Melville,NY)分析样本。使用校准的NIS软件来分析表面积和微米计算。
表1
通过伤口床的中部中的胶原基质的长度来测定胶原基质的降解。
通过单因素方差分析比较来报告数字为±SEM,*p<0.001。
结果
当在伤口愈合模型中测试时，0.5％的活性丙烯酸钾共聚物引起胶原基质显著的降解。表1示出在伤口床的中部中测得的胶原基质的深度。将丙烯酸钾共聚物与另一卡波姆聚合物即丙烯酸盐交联聚合物-4进行比较。与磷酸盐缓冲盐水(PBS)混合的丙烯酸钾共聚物或者与丙烯酸盐交联聚合物-4混合的丙烯酸钾共聚物引起胶原基质的显著降解(p<0.001)。有趣地是，仅胶原被降解，胶质细胞保持完好。
实例2
明胶降解试验
明胶是胶原的不可逆水解形式，并因此是胶原水凝胶的较好模型。该实验检查根据本发明的包含不同浓度的丙烯酸钾共聚物的组合物如何随时间来液化明胶。
在磷酸盐缓冲盐水(Mattek,Ashland,MA)中制备2.5％(w/v)纯净的明胶(Amresco,Solon,OH)，并加热到80℃直到融化。将溶液冷却并放置到6井凹或24井凹的板中。使溶液在室温下固化最低24小时。在形成固体凝胶之后，将包含丙烯酸钾共聚物的100μL各种组合物添加到固化的明胶。在不同的时间点，对样本送气并在分析天平上称重，以测定液化的明胶的量。在称重后将送气的量抽取回井凹中。在不超过6天后，结束实验。
为证实丙烯酸钾共聚物能够降解胶原，将丙烯酸钾共聚物的稀释液施加到纯净的明胶基质。100μL的丙烯酸钾共聚物以不同的浓度施加到明胶水凝胶，在施加后48小时，测定的液化的明胶的量示于表2中。
表2丙烯酸钾共聚物示出在施加后48小时液化的明胶剂量依赖性增加。
| 材料 | 液化的明胶的量(g) |
| 在水中5％活性的丙烯酸钾共聚物 | 0.2457±0.0175** |
| 在水中0.5％活性的丙烯酸钾共聚物 | 0.1099±0.0046** |
| 在水中0.25％活性的丙烯酸钾共聚物 | 0.0629±0.0030** |
| 在水中0.1％活性的丙烯酸钾共聚物 | 0.0353±0.0037* |
| 在水中0.05％活性的丙烯酸钾共聚物 | 0.0244±0.0028 |
| 在水中0.005％活性的丙烯酸钾共聚物 | 0.0142±0.0025 |
| 水 | 0.0190±0.0021 |
通过单因素方差分析，报告数字为与水比较±SEM,*p＝0.05，与水比较**p<0.001。
在施加后48小时，丙烯酸钾共聚物引起依赖于剂量的胶原的降解；以0.1％活性制剂的丙烯酸钾共聚物引起比水更多的对明胶基质的显著的降解。随着溶液中丙烯酸钾共聚物的浓度增加，使这种趋势持续。
HMP的降解胶原基质的能力是与所有HMP不同的专门功能。这种能力最可能与HMP的大小和形状有关。
例如，丙烯酸钾聚合物，温和的疏水改性的聚合物表面活性剂，示出以广泛浓度范围有效降解胶原的惊人能力。这具有从减少瘢痕疙瘩疤痕形成到减少胶原植入物的广泛临床应用范围。
Claims (3)
1.一种降解胶原的方法，包括使胶原与有效量的包含至少一种低分子量的疏水改性的聚合物的组合物相接触以降解所述胶原，其中，所述低分子量的疏水改性的聚合物是丙烯酸钾共聚物。
2.根据权利要求1所述的方法，其中所述低分子量的疏水改性的聚合物按所述组合物的重量计以0.1％至10％的量存在于所述组合物中。
3.根据权利要求1所述的方法，其中所述低分子量的疏水改性的聚合物具有100,000或更少的数均分子量。
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| US8329626B2 (en) | 2010-06-24 | 2012-12-11 | Johnson & Johnson Consumer Companies, Inc. | Low-irritating, clear cleansing compositions with relatively low pH |
| ES2442928T3 (es) | 2010-07-08 | 2014-02-14 | Devirex Ag | Composiciones de polietilenglicol para controlar las recidivas de herpes labialis, herpes genitalis y herpes zoster |
| US8778864B2 (en) | 2010-11-15 | 2014-07-15 | Johnson & Johnson Consumer Companies, Inc. | Polyglyceryl compounds and compositions |
| US8338348B2 (en) | 2010-12-21 | 2012-12-25 | Johnson & Johnson Consumer Companies, Inc. | Skin cleansing compositions with polyglycerol esters and hydrophobically modified polymers |
-
2014
- 2014-02-18 RU RU2015139585A patent/RU2673342C2/ru not_active IP Right Cessation
- 2014-02-18 JP JP2015558189A patent/JP6284956B2/ja active Active
- 2014-02-18 MX MX2015010650A patent/MX362459B/es active IP Right Grant
- 2014-02-18 BR BR112015019598-9A patent/BR112015019598B1/pt not_active IP Right Cessation
- 2014-02-18 AU AU2014219132A patent/AU2014219132B2/en not_active Ceased
- 2014-02-18 EP EP14709034.4A patent/EP2958598B1/en not_active Not-in-force
- 2014-02-18 US US14/182,427 patent/US9084740B2/en active Active
- 2014-02-18 WO PCT/US2014/016834 patent/WO2014130432A1/en active Application Filing
- 2014-02-18 CN CN201480009329.2A patent/CN104994889B/zh not_active Expired - Fee Related
- 2014-02-18 CA CA2899424A patent/CA2899424A1/en not_active Abandoned
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2016
- 2016-05-13 HK HK16105486.2A patent/HK1217453A1/zh unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051326A1 (en) * | 2001-12-14 | 2003-06-26 | Medtrade Products Ltd. | Cosmetic scar management composition |
| WO2005105115A1 (en) * | 2004-05-04 | 2005-11-10 | Queensland University Of Technology | Functionalised siloxanes for scar tissue treatment |
| WO2010131032A2 (en) * | 2009-05-11 | 2010-11-18 | Pharmapatents Global Ltd | Novel polymers |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2958598B1 (en) | 2018-11-21 |
| RU2015139585A (ru) | 2017-03-23 |
| RU2673342C2 (ru) | 2018-11-26 |
| CA2899424A1 (en) | 2014-08-28 |
| US9084740B2 (en) | 2015-07-21 |
| BR112015019598B1 (pt) | 2020-06-23 |
| EP2958598A1 (en) | 2015-12-30 |
| WO2014130432A1 (en) | 2014-08-28 |
| CN104994889A (zh) | 2015-10-21 |
| HK1217453A1 (zh) | 2017-01-13 |
| JP2016509026A (ja) | 2016-03-24 |
| MX362459B (es) | 2019-01-18 |
| RU2015139585A3 (zh) | 2018-03-01 |
| US20140234249A1 (en) | 2014-08-21 |
| MX2015010650A (es) | 2016-06-06 |
| AU2014219132B2 (en) | 2017-10-19 |
| AU2014219132A1 (en) | 2015-08-13 |
| JP6284956B2 (ja) | 2018-02-28 |
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