CN102091090A - 治疗炎症的方法和组合物 - Google Patents
治疗炎症的方法和组合物 Download PDFInfo
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Abstract
本发明包括治疗和预防炎性病症的方法和组合物。该组合物中包含在调节与炎性病症有关的酶中起作用的聚合物和共聚物。所述方法包括在炎症或潜在的炎症部位施用有数量的这种组合物以治疗或预防炎性病症。
Description
本申请是申请号为200580004490.1(PCT/US2005/004113)/申请日为2005年2月10日,发明名称为“治疗炎症的方法和组合物”的专利申请的分案申请。
技术领域
本发明涉及治疗急慢性炎症的组合物和方法。特别是,本发明涉及调节酶的组合物和使用该组合物的治疗方法。
背景技术
急慢性炎症构成了影响所有器官系统的疾病的基础,这些疾病包括但不限于许多皮肤反应、过敏反应、哮喘、肺部疾病或反应、肾病、急性炎性疾病、血管炎性疾病、慢性炎症、动脉硬化症、免疫相关疾病、血管病变、心肌炎、肾炎、克罗恩氏病(节段性回肠炎)、伤口愈合、关节炎、I型和II型糖尿病及相关血管病理。这些炎症状态在人群中的发病率呈上升趋势。
尽管炎症本身是正常的免疫反应,但由于细胞因素如酶和细胞因子相互作用,慢性炎症却导致并发症和不间断的系统损害。慢性炎症在不同组织中引发不同的反应,例如皮肤反应导致牛皮癣或慢性皮炎,或者内皮组织反应导致血管并发症。由于动脉粥样硬化和血栓栓塞性大血管病变而导致的冠状动脉、脑血管和外周血管疾病是慢性炎症疾病中死亡的原因。慢性炎症的结果可视为炎症所致损伤与修复之间的平衡。
通常人们相信炎症是血管化组织对尚不致命的损伤的反应。依据炎症的持续时间将其分为急性或慢性。炎症是一种自平衡反应,目的在于通过分解或修复,破坏或灭活侵入的病原体,去除废物和碎片,并使正常功能得到恢复。在一些反应中,炎症过程显示出与血管发生及其进程共享一个途径,而在其他反应中则互相独立。
所需要的就是直接治疗炎症的组合物和方法,该组合物和方法能够调节由炎性反应或者炎症激动剂成分所引发的细胞成分。
发明内容
本发明包含治疗特别是与炎症疾病相关的生物症状的组合物和方法,所述症状能够影响所有的器官系统,包括但不限于许多皮肤反应、过敏反应、哮喘、肺部疾病或反应、肾病、急性炎性疾病、血管炎性疾病、慢性炎症、动脉硬化症、免疫相关疾病、血管病变、心肌炎、肾炎、克罗恩氏病、伤口愈合、关节炎、I型和II型糖尿病及相关血管病理。
特别地,本发明包括含有聚合物的组合物,该聚合物能够调节炎症相关的酶的活性。本发明组合物一方面包括丙烯酸聚合物或共聚物,包括但不限于公知的称为卡波姆(carbomer)和丙烯酸酯的聚合物和共聚物。在本发明的发现之前以及目前,这些聚合物广泛用作增稠剂、乳化剂和成胶状化妆品制品的辅助成分。聚合物和共聚物被认为是惰性的,像是没有毒性危险。在个人护理品工业中,丙烯酸聚合物被认为是日用聚合物,用作形成结构的组分。
本发明涉及通过施用本发明的组合物影响炎症反应及炎症相关疾病和病理的方法。应用本发明的组合物来调节与炎症相关疾病和病理相关的酶的活性。本发明的组合物可以以特异的或非特异的方式来调节酶的活性。所述方法包括以治疗或预防特定炎性病症有效的方式施用这样的组合物。
附图说明
图5显示ETD 2020和MDI Complex对MMP-9活性的影响。
发明详述
本发明涉及治疗和预防炎性病症的组合物和方法。本发明的组合物包括能够调节与炎性病症相关的酶的活性的聚合物或共聚物。本发明的方法包括以调节涉及炎性病症的酶活性的有效量向有炎性病症的人或动物施用这样的组合物,或者以调节酶活性以预防炎性病症发生的有效量来施用。本发明的方法和组合物对急性和慢性炎性病症均有效。
本发明组合物的一些方面包括聚合物和共聚物。本发明组合物的聚合物和共聚物的例子包括基于丙烯酸的聚合物或共聚物(AAP)。大多数丙烯酸聚合物产品由数家公司生产或销售(表1),这些产品主要用于个人护理产品。
表1:主要公司和AAP产品。
已经生产出许多不同类型的AAP,所有能够调节涉及炎性病症和过程的酶的活性的AAP均打算用于本发明。例如,AAP可以是丙烯酸的线性聚合物,或者是与聚烯烃醚或二乙烯基乙二醇或其他交联剂交联的聚合物。已经有报导,当这些AAP在相同条件下聚合而且使用相同的配方作为交联程度而没有交联的单体时,平均分子量大约500,000。[1]交联聚合物的分子量在数十亿。有两种主要的交联聚合物类型:
a)均聚物,其为丙烯酸与例如烯丙基蔗糖或季戊四醇交联的聚合物,
b)共聚物,其为由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸与例如烯丙基季戊四醇交联的丙烯酸的聚合物,。
虽然线性丙烯酸聚合物可溶于极性溶剂,如水中,但交联聚合物不溶于水,而是溶胀。当用于化妆品制品时,浓度达1%的交联聚合物溶液直到交联聚合物被适当的碱部分中和形成盐时才出现明显溶胀。当该盐溶解并离子化时,交联聚合物溶胀为有效的增稠形式[3],目前在许多局部用药如霜或防晒剂中用作惰性配合剂。
丙烯酸均聚物的主链是相同的,聚合物之间的主要区别与交联密度和分子量有关,而与用作交联试剂的单体的类型无关。对交联剂密度进行非常小的调整,就可以产生大量总体分子结构类似但应用特性(如粘性)不同的AAP产品。可通过稍稍移动交联剂在丙烯酸主链上的位置来改变交联密度。Noveon的文献[2]指出,“因为实际的交联剂本身对特定carbopol树脂的生物学特性的影响即便是有也是非常小,所以对于均聚物树脂,化妆品、化妆用品和香料协会(CTFA)采用了家族专有名称‘卡波姆(carbomer)’”。应注意的是,在本发明之前,用于该文献中的术语“生物学特性”指“生物学惰性”,相信这些聚合物是没有生物学活性的。
一些AAP对酶活性的影响的研究显示出混乱和混杂的结果。尽管生物惰性被断定为用于个人护理用途的卡波姆的基本特性之一,但是一些被选择用于口服药物递送的丙烯酸聚合物却显示出在体外使胰蛋白酶失活[4]。Lueβen等人研究了934P和polycarbophil PCPAA1对胰蛋白酶活性的影响,发现聚合物对酶的显著影响是由于聚合物吸收钙离子,钙的缺乏改变酶的二级结构,因此使酶失活。这不是酶抑制,而只是干扰了酶结合环境中辅助因子的能力。
其他人[5]研究了由两种聚合物,聚丙烯酰胺和聚(氰基丙烯酸异丁酯)其中之一组成的纳米颗粒,这两种聚合物用于口服递送两种肽,人降钙素(hCT)和胰岛素。
Bai等人[6,7]研究了934P、971P和974P阻止胰蛋白酶和胰凝乳蛋白酶对入降钙素、胰岛素、和胰岛素样生长因子I的降解作用。体外研究表明聚合物的存在导致培养基的pH降至低于胰腺酶的最佳pH。所述酶在小于最佳pH情况下不起作用。体内数据没有提供所测试时胰蛋白酶和胰凝乳蛋白酶活性有任何影响的证据。
对聚合物的改性也得出有关活性的不明确的结果。一项研究[8]发现非改性和改性的丙烯酸聚合物都只显示离子结合型抑制。另一研究[9]调查了改性的Carbopol 974P在体外针对氨肽酶N的活性。Carbopol 974P通过碳化二亚胺键共价连接于L-半胱氨酸。氨肽酶N的活性需要Zn2+[10],因此,对该酶的抑制可能是因为如Lueβen等[4]所看到的阳离子结合。
在本发明之前,本发明的聚合物和共聚物与参与炎性过程的酶的活性在公共领域是未知的。特别是,对于治疗或预防的特定方法来说所述活性是未知的。例如,目前认为本发明的聚合物和共聚物是惰性的,不会有益于生物病症的治疗或预防。目前认为丙烯酸聚合物只是生物学上中性的结构组分。据信角质层是由死亡和垂死的皮肤细胞构成,而且包含许多负电荷极性基团的高分子量丙烯酸聚合物,不能够渗过角质层产生任何的相互作用。因此,本发明之前的教导是AAP没有对活的皮肤组织代谢产生任何明显影响的能力。
最近的研究发现有与皮肤相关的酶的活性,当有损害如炎性反应或病症时可见该酶活性。所研究的一种酶是人白细胞弹性蛋白酶(HLE)。[13]HLE是源于嗜中性粒细胞和巨噬细胞的广谱丝氨酸蛋白酶,发现于人皮肤表面。在牛皮癣(31次)、过敏性接触性皮炎(55次)和特应性皮炎(35次)的损伤皮肤上发现HLE活性大大增强,而在患者未受牵连的皮肤上没有发现。患病表皮中蛋白分解活性HLE的存在表明了在牛皮癣、接触性皮炎和特应性皮炎中此酶活性的病理生理学作用。已经发现在一定浓度的、发现于牛皮癣损伤的皮肤表面[14]的酶中,HLE诱导角化细胞增殖。这可以解释牛皮癣中所观察到的表皮过度增殖。
Skytt等人[15]鉴定了另一种皮肤相关的酶,角质层胰凝乳蛋白酶(SCCE),一种由表皮中的角化细胞所表达的丝氨酸蛋白酶。已经表明在细胞从皮肤表面连续脱落过程中,所述酶能够催化皮肤角化层中胞内粘着结构的降解。Horikishi等人[16]也指出了SCCE和成熟形式的组织蛋白酶D的存在。
还证明了[17]另一种重要的细胞表面酶,中性肽链内切酶(NEP)也参与皮肤表面上的过程。这种在物质P的降解中起积极作用的含锌的酶是由角化细胞生产的,能够在正常皮肤尤其是创伤皮肤表面终止神经肽的促炎和促有丝分裂作用。Ludolph-Hauser等人[18]描述了糖尿病患者创伤皮肤表面上的NEP。
在皮肤发炎期间,人嗜中性粒细胞不仅释放HLE,还至少另外释放蛋白酶、组织蛋白酶G。[19]这些酶在糖尿病患者创口中是活化的,治愈这些创口需要同时抑制HLE和组织蛋白酶G。慢性溃疡中基质金属蛋白酶(MMP)水平升高,并且在位于非愈合的上皮之下的细胞中发现了这些酶。[20]已经发现了其他的天然存在于上皮中的酶组织蛋白酶B1和D、内切蛋白酶、非特异性蛋白酶和嗜热菌蛋白酶[21-23]。
由于皮肤炎症、过敏反应、创伤、溃疡和感染,角质层和其他皮肤层的完整性经常被破坏。这种皮肤层扰乱能够引起内源性蛋白酶在表皮和皮肤表面之间的重新分布。皮肤层状结构的破坏程度可能是由于这些酶进入到它们通常不被发现的层面以及可能由于炎症和结构中的最初改变如创伤所释放的因子引发了这些酶结果产生的活性。皮肤层中也可能有常驻酶,因所述部位的损伤或炎性因子的存在,其数量增加,和/或活性水平提高。通常一致认为蛋白水解酶活性水平的升高表示炎症损伤,而其抑制引发抗炎反应。例如,在皮肤发炎部位,嗜中性粒细胞弹性蛋白酶一般以最高浓度存在,而且是针对最多种结缔组织成分包括弹性蛋白的最活跃的蛋白酶。
存在于皮肤表面上的微生物有其自身的酶,所有可能的因子和细胞参与物的完全情形可能非常复杂。每cm2皮肤的平均细菌数取决于身体的部位,包括前额和鼻子,范围是从710到3,900,000。根据皮肤的类型,其他人发现前臂上每cm2的平均细菌数为14,000至87,000。[25]这样的富含酶的细菌群产生出能有助于角质层表面上的活性的蛋白酶和磷脂酶。
表2:酶活性的定位
酶 | 酶的位置 | 参考文献 |
组织蛋白酶B | 皮肤表面 | [15] |
组织蛋白酶D | 皮肤表面 | [21] |
组织蛋白酶G | 皮肤表面 | [21] |
内切蛋白酶 | 皮肤表面 | [23] |
HLE | 皮肤表面 | [13,14,19] |
MMP | 皮肤表面 | [20] |
NEP | 皮肤表面 | [17,18] |
非特异性蛋白酶 | 皮肤表面 | [22] |
SCCE | 皮肤表面 | [15,16] |
嗜热菌蛋白酶 | 皮肤表面 | [23] |
本发明包括影响或调节酶活性的线性聚合物或共聚物的组合物。术语聚合物或共聚物此处可互换使用,聚合物包括共聚物。本发明的实施方案包括调节与炎性病症相关的酶活性的组合物。本发明一方面包括有效调节与人和动物炎性病症或皮肤和表皮系统的反应相关的酶的活性的组合物。受本发明组合物和方法影响的酶包括那些与炎性病症有关的酶,所述炎性病症包括但不限于许多皮肤反应、过敏反应、哮喘、肺部疾病或反应、肾病、急性炎性疾病、血管炎性疾病、慢性炎症、动脉硬化症、免疫相关疾病、血管病变、心肌炎、肾炎、克罗恩氏病、伤口愈合、关节炎、I型和II型糖尿病及相关血管病状。
本发明的组合物包含丙烯酸聚合物和共聚物。组合物包含在药学上可接受的载体或赋形剂组分中的有效量的丙烯酸聚合物或共聚物(此处称为AAP)。例如,组合物包含每个剂量或每次应用约1微克到5g范围的AAP,或者组合物可以包含从约0.001%wt至约99%wt的一种或多种AAP。AAP在组合物中的用量范围包括有效治疗和预防炎性病症的量,包括从约少于0.05%,从约0.001%wt至约少于0.05%wt;从约少于0.1%wt,从约0.001%wt至约少于25%wt;从约0.001%wt至约15%wt;从约0.001%wt至约50%wt;从约0.001%wt至约55%wt;从约0.001%wt至约75%wt;从约0.001%wt至约85%wt;从约0.001%wt至约90%wt;从约0.001%wt至约95%wt,或约少于0.05%wt,约少于0.10%wt,约少于0.5%wt,约少于1.0%wt,约少于5.0%wt,约少于10.0%wt,约少于25.0%wt,约少于50%wt,约少于65%wt,约少于75%wt,约少于80%wt,约少于90%wt,或约少于95%wt。
例如,对于乳液制剂,组合物包含0.01%wt.的丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物。组合物可以包含一种或多种不同的AAP,或AAP的混合物。本发明包含的AAP例如但不限于如下所示的聚合物。
聚(丙烯酸) 聚(乙烯醇)
聚(乙烯基磺酸) 聚(磷酸)
本发明的组合物包含可以在水中溶解或溶胀而形成溶液或水凝胶的AAP聚合物。估计它们的世界市场每年约60亿美元。它们出现在多种多样的产品中,而且发现它们在许多领域的应用,包括:水处理、化妆品、个人护理产品、药品、油回收、纸浆和纸张生产、矿物加工和农业等等。这些聚合物的加工制造一般都是商业化的,通过各种加工处理,包括水溶液聚合、反相悬浮(W/O)聚合、和反相乳液(W/O)聚合它们是由热引发剂或氧化还原耦引发剂引发的来进行。在所有这些聚合物中,基于聚丙烯酸和聚丙烯酰胺的聚合物由于被认为是惰性的,因此在大范围的产品中被使用。
水溶性和溶胀的关键在于沿聚合物的主链或侧链放置足够数量的亲水性功能基。一些具有足够的极性、电荷、或氢键合能力的主要功能基包括但不限于:
-COOH -OH -SO3H
-COOM+ -SO3 -M+
上述功能基不仅提供溶解性,还为聚合物带来许多的有用特性,象螯合、扩散、吸收、絮凝、增稠、拖曳变形等。另外,一些这样的功能基能够进一步反应形成其他种类的功能基,因此发现水溶性和水溶胀聚合物广泛应用于包括水处理、化妆品、个人护理产品、药品、油回收、纸浆和纸张生产、矿物加工和农业的领域。
本发明包括合成的水溶性和水溶胀聚合物。这些聚合物通常由水溶性单体像丙烯酸(AA)及其钠盐、丙烯酰胺(AM)、羟乙基异丁烯酸酯(HEMA)、羟乙基丙烯酸酯(HEA)、乙烯基吡咯烷酮(vinylyyrolidone)(VP)、季铵盐、像二甲基二烯丙基氯化铵(DMDAAC)等合成。通常按照自由基聚合机制进行。此合成是商业化的,通过多种加工处理包括水容液聚合、反相悬浮聚合、和反相乳液聚合来实现。
溶液聚合常用于线性、低分子量水溶性聚合物的合成中。聚(丙烯酸)及其共聚物、聚丙烯酰胺及其与DMDAAC的共聚物在溶液中聚合。采用反相悬浮/乳液聚合方法以合成高分子量的聚丙烯酸、聚丙烯酰胺及其共聚物,在溶液聚合方法中,水溶性单体在自由基引发剂,聚合方法为氧化还原耦的存在下于均质水溶液中聚合。溶液聚合方法需要低操作成本,主要在于避免使用如有机相和乳化剂原料。线性、高分子量的基于聚丙烯酰胺的聚合物商业上通过反相乳液(W/O,0.05-1μm)聚合合成,而轻微交联的、基于聚(丙烯酸)的聚合物一般是通过反相悬浮(W/O,0.05-2mm)聚合来生产。在两种情况下,水合单体混合物(即水相)都乳化/悬浮于脂肪烃或芳香烃相(即油相)中,颗粒的大小特别依赖于所使用的乳化剂或分散剂的化学和物理特性。
受本发明组合物影响的酶的非限制性例子包括肽水解酶、丝氨酸蛋白酶、基质金属蛋白酶、胶原酶、激酶、弹性蛋白酶和过氧化物酶。
本发明的方法包括施用含有能够调节与炎性病症相关的酶的活性的聚合物或共聚物的组合物。这样的聚合物或共聚物的非限制性例子包括在本文的实施例和图表中。本发明的组合物包含的聚合物和共聚物包括,但不限于基于丙烯酸的线性聚合物、基于丙烯酸的交联聚合物、基于丙烯酸的高分子量交联聚合物、丙烯酸与烯丙基蔗糖交联的聚合物、丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-30)丙烯酸酯改性的丙烯酸的聚合物、长链(C10-30)丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-30)烷基丙烯酸酯改性的丙烯酸的共聚物、由长链(C10-30)烷基丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的共聚物、丙烯酸与二乙烯二醇交联的聚合物、丙烯酸与季戊四醇的烯丙基醚、蔗糖的烯丙基醚或丙烯的烯丙基醚交联的均聚物、聚乙烯羧基聚合物、卡波姆,C-10至C-30烷基丙烯酸酯和丙烯酸、甲基丙烯酸、或其简单酯之一的一种或多种单体与蔗糖的烯丙基醚或季戊四醇的烯丙基醚交联的共聚物、具有丙烯酸聚合物主链和二甲基聚硅氧烷侧链的接枝共聚物、亲水/疏水嵌段共聚物如丙烯酸铵和丙烯酰氮(acrylonitrogen)共聚物、丙烯酸与丙烯酰氮(acrylonitrogen)共聚物、丙烯酸聚季铵盐共聚物、聚乙二醇、疏水改性的环氧乙烷聚氨酯、Rohm和Haas的商标名为Acusol的市售的聚合物和共聚物、以及其他能够调节炎性病症相关酶的活性的聚合物和共聚物。
其他的肽水解酶,如明胶酶B或基质金属蛋白酶(MMP9)与弹性蛋白酶协同作用,在皮肤炎症中起重要作用。应当注意,MMP-9和弹性蛋白酶均由白血细胞(嗜中性粒细胞)所分泌,而且这些酶是导致炎症的酶。
可同时抑制两种酶,弹性蛋白酶和MMP-9的组合物将会非常有效地治疗或预防炎症过程。老化过程、晒伤、伤口和伤疤的形成具有相同的炎症机制,与MMP-9和弹性蛋白酶均有关。因此,能够同时抑制MMP-9和弹性蛋白酶的组合物有着非常广泛的应用范围。这两种酶共同作用来降解人体组织胞外基质的所有成分。弹性蛋白酶能够使身体自身对MMP-9的抑制性防御失去作用,而MMP-9能够使身体自身对弹性蛋白酶的抑制性防御失去作用。
根据所测得的变化,这里所用的酶活性调节包括活性的抑制和活性的促进。活性变化可以是一种或多种酶的活性的变化,例如底物周转的增加;或者在施用本发明组合物前静止或活跃的一种或多种酶的活性的变化,例如减轻组织破坏的酶的活性的抑制。可以通过测量酶活性或通过炎性病症可测的变化来测定酶活性的改变。用本文所教导的组合物治疗炎性病症包括以有效调节酶活性的量来施用所述组合物,并且可以包括具有炎性病症的人或动物患者可测的变化。例如,如果患者的皮肤正经历炎性反应,那么治疗包括将本发明的组合物施用到该皮肤上,直到该皮肤的外观或功能出现变化,使熟练从业人员不再将皮肤诊断为有炎性病症,例如炎性反应终止或平息为止。
用本文所教导的组合物预防炎性病症包括以有效调节酶活性的量施用所述组合物,并且可以包括预防具有炎性病症的人或动物患者可测量的变化。例如,如果患者的皮肤先前已经遭受炎性反应而目前没有遭受该炎性反应,或者如果患者从未遭受炎性反应,那么预防包括向其皮肤施用本发明的组合物,预防性地阻止炎性反应的发生。
本发明的组合物可以通过包括但不限于口服、肠胃外、表皮、表面、皮下、肌肉内、静脉内、动脉内、支气管内、腹腔内、囊内、软骨内、腔内、体腔内、小脑内、脑室内(intracerebroventricular)、结肠内、宫颈内、胃内、肝内、心肌内、骨骼内、骨盆内、心包内、腹膜内、前列腺内、肺内、直肠内、肾内、视网膜内、脊髓内、滑膜内、胸内、子宫内、膀胱内、快速浓注、阴道、直肠、口腔、合下、鼻内、或透皮的途径施用。
本发明的方法包括施用有效量的本文所教导的组合物以治疗和/或预防炎性病症。本发明的一方面包括施用包含有效量AAP的组合物以治疗皮肤炎症。
包含有效量AAP的化妆品或药物组合物可以以乳液(洗液、霜剂和喷雾剂)、凝胶或溶液形式有效地施用。可以使用乳液,优选水包油型的乳液,包括但不限于油包水、硅氧烷包水,三相乳液、W/O/W或O/W/O,以及微乳液。例子包括AAP,是以治疗炎症有效但不会影响组合物流变学特性的浓度量(例如,低于0.05%wt.)掺入到组合物中的。药物赋形剂是本领域技术人员熟知的,对用于本文教导的施用途径的组合物来说,药物组合物成分是已知的。
乳液或凝胶可以包括下述附加成分中的至少一种:乳化剂、润肤剂、流变性调节剂、肤感助剂、增湿剂、保湿剂、膜形成剂、pH调节剂/螯合剂、防腐剂、香料、效应颜料、着色剂、水或其任意组合。
合适的乳化剂类型包括甘油的酯、丙二醇的酯、聚乙二醇的脂肪酸酯、聚丙二醇的脂肪酸酯、山梨醇的酯、脱水山梨糖醇酐的酯、葡萄糖的酯和醚、乙氧基醚、乙氧基醇、烷基磷酸酯、聚氧乙烯脂肪醚磷酸酯、脂肪酸酰胺、酰基乳酸酯、皂及其混合物。可用于本发明组合物的乳化剂包括但不限于脱水山梨糖醇油酸酯、脱水山梨糖醇倍半油酸酯、PEG-100硬脂酸酯、脱水山梨糖醇异硬脂酸酯、脱水山梨糖醇三油酸酯、聚乙二醇20脱水山梨糖醇单月桂酸酯(聚山梨醇酯20)、聚乙二醇5大豆固醇、Steareth-20、Ceteareth-20、PPG-2甲基葡萄糖醚二硬脂酸酯、Ceteth-10、Polysorbate(聚山梨酸酯)80、十六烷基磷酸酯、十六烷基磷酸钾、十六烷基磷酸二乙醇胺、Polysorbate(聚山梨酸酯)60、硬脂酸甘油酯、聚甘油-3-二硬脂酸酯、油酸/异硬脂酸的聚甘油酯、聚甘油-4-油酸酯、聚甘油-4-油酸酯/PEG-8丙二醇椰油酸酯、甘油油酸酯磷酸钠(sodium glyceryl oleate phosphate)、氢化植物磷酸甘油酯、鲸蜡硬脂基葡糖苷、椰油基葡糖苷、椰油-葡糖苷柠檬酸二钠、椰油基-葡糖苷磺基琥珀酸二钠、油酰乙基葡糖苷(oleoyl ethyl glucoside)、椰油-葡糖苷酒石酸钠、或其任意组合。根据本发明的组合物还可以包含作为皮肤护理活性成分的亲脂性乳化剂。合适的亲脂性皮肤护理活性成分包括阴离子食物等级乳化剂,其包含与单酸甘油酯如琥珀酰单酸甘油酯、单硬脂基柠檬酸酯、甘油单硬脂酸酯二乙酰酒石酸酯(glyceryl monostearate diacetyl tartrate)及其混合物混合的二元酸(di-acid)。存在于本发明乳液中的乳化剂的量优选占组合物总重的0.1wt.%至20wt.%之间,但最优选1wt.%至约12wt.%之间。
本发明的组合物还包括水或其他与水混合的溶剂。含水量优选乳液总重的5wt.%至约95wt.%,但优选45wt.%至90wt.%。
本发明的组合物可以包括一种或多种润肤剂。润肤剂在皮肤表面提供软化或镇定的效果。合适的润肤剂包括但不限于环甲聚硅氧烷、异丙基肉豆蔻酸酯、二甲硅油、马来酸二辛酯、辛酸/癸酸甘油三酯、矿物油、羊毛脂、椰子油、可可脂、牛油树脂、橄榄油、蓖麻油、脂肪酸如油酸和硬脂酸、脂肪醇如十六烷醇和二异丙基己二酸酯、羟基苯甲酸酯、C9-C15醇的苯甲酸酯、烷烃如矿物油、硅氧烷如二甲基聚硅氧烷、醚如聚氧丙烯丁基醚和聚氧丙烯十六烷基醚、C12-C15烷基苯甲酸酯、或其任意组合。根据组合物的总重计算,乳液中存在的润肤剂总量优选在0.1wt.%至70wt.%之间,但最优选在0.1wt.%至约30wt.%之间。
本发明的组合物可以包括一种或多种流变性调节剂。用于本发明组合物的合适的流变性调节剂包括但不限于增稠剂、合成的和天然的树胶或聚合物产品、多糖增稠剂、缔合性增稠剂、改性淀粉或其任意组合。可用于本发明组合物的合适的流变助剂和稳定剂包括合成的和天然的树胶或聚合物产品、多糖增稠剂、缔合性增稠剂、阴离子缔合性流变性调节剂、非离子缔合性流变性调节剂、多糖、聚醚-1、硅酸镁钠、角叉菜胶、羧甲基葡聚糖钠、羟乙基纤维素、羟丙基环糊精、膨润土、三羟硬脂精、氢氧化铝镁硬脂酸酯、黄原胶或其任意组合。根据组合物的总重计算,乳液中所含的流变性调节剂总量优选在0.1w t%至5wt%之间,最优选在0.1wt.%至约2wt.%之间。
也可以包括肤感助剂。肤感助剂包括但不限于聚合物、硅氧烷、酯、微粒、或其任意组合。优选地,根据组合物的总重计算,肤感助剂以约1wt.%至约5wt.%的量存在。
可以用一种或多种已知的pH调节剂和/或螯合剂调节本发明组合物的pH。例如,氢氧化钠、柠檬酸、三乙醇胺、乙二胺四乙酸二钠、或其任意组合都是可以包含在本发明乳液中的合适的pH调节剂/螯合剂。用有效量的可包含的pH调节剂和/或螯合剂将最终组合物的pH调至大约3至大约8。
增湿剂如保湿剂可用于本发明的组合物中。保湿剂包括但不限于甘油、聚乙二醇、聚丙二醇、penthylene glycol、山梨醇或其任意组合。
可选地,本发明的组合物包含占组合物总重约1wt.%至约20wt.%的一种或多种增湿剂。
可用于本发明乳液中的另一种成分是膜形成剂。膜形成剂是赋予乳液膜形成和持续释放特性的疏水性物质。根据组合物的总重计算,本发明的组合物中可以含有约1wt.%至约5wt.%量的一种或多种膜形成剂。
可选地,本发明的组合物可以包含一种或多种防腐剂和抗氧化剂。例子包括重氮烷基脲、碘代丙炔基氨基甲酸丁酯、氯甲基异噻唑啉酮、甲基异噻唑啉酮、维生素E及其衍生物包括维生素E醋酸酯、维生素C、丁基化羟基甲苯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸钠、山梨酸钾、苯氧乙醇或其任意组合。
本发明的组合物中可以包含约0.01wt.%至约1wt.%的防腐剂和抗氧化剂。
乳液也可以含有其他的可选添加剂。例如,乳液中可以包含一种或多种防晒活性成分、香料、着色剂、植物提取物、吸收剂、增稠剂、水杨酸、α和β羟基酸、维生素包括维生素A、C和E、视黄醇、视黄醇棕榈酸酯、生育酚或其任何混合物。
包含任何具有止汗活性的化合物、组合物或其混合物的成分适合用于本发明,它们可能具有炎性潜力。收敛性金属盐是比处优选使用的止汗物质、特别是铝、锆和锌的无机和有机盐,及其混合物。尤其优选的是铝和锆的盐如铝卤化物、铝羟基卤化物、氧化氧锆卤化物、碱式卤化氧锆及其混合物。
这里也可以使用可能具有炎性潜力的防晒剂,像2-乙基己基对甲氧基肉桂酸酯、2-乙基己基N,N-二甲基-对氨基苯甲酸酯、对氨基苯甲酸、2-苯基苯并咪唑-5-磺酸、氰双苯丙烯酸辛酯、羟苯甲酮、水杨酸高基酯(homomenthylsalicylate)、水杨酸辛酯、4,4′-甲氧基-叔丁基二苯甲酰甲烷、4-异丙基苯甲酰甲烷、3-苯亚甲基樟脑、3-(4-甲基苯亚甲基)樟脑、二氧化钛、氧化锌、硅石、氧化铁、及其混合物。
本发明组合物中有用的药物活性成分包括炎性潜力激活剂如抗痤疮角质软化剂,如水杨酸、硫磺、乳酸、羟基乙酸、丙酮酸、尿素、间苯二酚、和N-乙酰半胱氨酸;类维生素A(retinoid)例如视黄酸及其衍生物(例如,顺式和反式的);抗生素和抗微生物剂如过氧化苯甲酸、羟甲辛吡酮、红霉素、锌、四环素、三氯生、壬二酸及其衍生物、苯氧乙醇和苯氧丙醇、乙酸乙酯、克林霉素和甲氯环素;sebostats如黄酮甙;α和β羟基酸;和胆酸盐如鲨胆甾醇硫酸盐及其衍生物,脱氧胆酸盐、和胆酸盐。本发明组合物中有用的药物活性成分包括止痛活性成分。
适合用于本发明组合物的止痛活性成分包括水杨酸衍生物如水杨酸甲酯、辣椒属的种类和衍生物如辣椒素和非甾族抗炎药(NSAIDS),而上述本发明组合物可以从包括本发明实施方案的载体组合物中获益。NSAIDS可选自以下类别:丙酸衍生物;乙酸衍生物;芬那酸(fenamic acid,N-苯基氨茴酸)衍生物;联苯基甲酸衍生物;和昔康类(oxicam,苯并噻嗪类)。最优选丙酸NSAIDS包括但不限于阿斯匹林、对乙氢基酚(acetaminophen)、布洛芬(ibuprofen)、萘普生(naproxen)、苯恶洛芬(benoxaprofen)、氟比洛芬(flurbiprofen)、非诺洛芬(fenoprofen)、芬布芬(fenbufen)、酮洛芬(ketoprofen)、吲哚洛芬(indoprofen)、吡洛芬(pirprofen)、卡洛芬(carprofen)、奥沙普秦(oxaprozin)、普拉洛芬(pranoprofen)、吡恶芬(miroprofen)、硫恶洛芬(tioxaprofen)、舒洛芬(suprofen)、阿明洛芬(alminoprofen)、噻洛芬酸(tiaprofenic acid)、氟洛芬(fluprofen)和布氯酸(bucloxic acid)。也可使用甾族抗炎药包括氢化可的松等类似药。
本发明组合物中的有用药物活性成分包括止痒药。优选包含于本发明组合物中的止痒活性成分包括甲地嗪(methdilizine)和异丁嗪(trimeprazine)的药学上可接受盐。本发明组合物中的有用药物活性成分包括麻醉活性成分。优选包含于本发明组合物中的麻醉活性成分包括利多卡因(lidocaine)、布比卡因(bupivacaine)、氯普鲁卡因(chlorprocaine)、地布卡因(dibucaine)、依替卡因(etidocaine)、甲哌卡因(mepivacaine)、丁卡因(tetracaine)、达克罗宁(dyclonine)、海克卡因(hexylcaine)、普鲁卡因(procaine)、可卡因(cocaine)、氯胺酮(ketamine)和普莫卡因(pramoxine)的药学上可接受盐。
本发明组合物中的有用的药物活性成分包括抗微生物剂(抗细菌、抗真菌、抗原生动物和抗病毒药)。优选包含于本发明组合物的抗微生物活性成分包括b-内酰胺类药物、喹诺酮类药物、环丙沙星(ciprofloxacin)、噻吩草胺(norfloxacin)、四环素、红霉素、阿米卡星(amikacin)、三氯生、强力霉素(doxycycline)、卷曲霉素(capreomycin)、氯己定(chlorhexidine)、金霉素(chlortetracycline)、土霉素(oxytetracycline)、克林霉素、乙胺丁醇(ethambutol)、甲硝唑(metronidazole)、喷他脒(pentamidine)、庆大霉素(gentamicin)、卡那霉素(kanamycin)、lineomycin、甲烯土霉素(methacycline)、乌洛托品(methenamine)、米诺环素(minocycline)、新霉素(neomycin)、奈替米星(netilmicin)、巴龙霉素(paromomycin)、链霉素(streptomycin)、妥布霉素(tobramycin)、咪康唑(miconazole)和amanfadine的药学上可接受盐。优选包含于本发明组合物中的抗微生物药包括盐酸四环素、依托红霉素、硬脂酸红霉素(盐)、硫酸阿米卡(amikacin sulfate)、盐酸多西环素(doxycycline hydrochlori de)、硫酸卷曲霉素、葡萄糖酸氯已定、盐酸洗必泰(chlorhexidine hydrochloride)、盐酸金霉素、盐酸土霉素、盐酸克林霉素、盐酸乙胺丁醇、盐酸甲硝唑、盐酸喷他脒、硫酸庆大霉素、硫酸卡那霉素、盐酸lineomycin、盐酸甲烯土霉素、马尿酸乌洛托品、扁桃酸乌洛托品、盐酸米诺环素、硫酸新霉素、硫酸奈替米星、硫酸巴龙霉素、硫酸链霉素、硫酸妥布霉素、盐酸咪康唑、盐酸amanfadine、硫酸amanfadine、三氯生、吡啶酮乙醇胺盐、对氯间二甲苯酚、制霉菌素(nystatin)、托萘酯(tolnaftate)和克霉唑(clotrimazole)。
本发明的组分可以组合起来构成稳定的乳液、凝胶或溶液。将AAP掺入到水相,其后可以与其他成分合并。
所述组合物每天至少向皮肤感染区施用一次,至少施用一天。治疗皮肤烧伤及所致炎症的例子包括施用霜剂组合物,直至皮肤不再发炎,所述组合物包含0.01%的丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物(见实施例4)。
必须注意,如本说明书和所附权利要求书中所使用的,除非上下文清楚地说明了,否则单数形式的“a”、“an”、和“the”包括复数指代。
特别将此处的所有专利、专利申请和参考文献整体一并作为参考。
当然,应当理解,前述只与本发明的优选实施方案有关,可以在其中作大量修改或改动而不背离本说明书所公开的发明的精神和范围。
通过下述实施例来进一步阐述本发明,这些实施例不以任何方式构成对其范围的限制。相反,应清楚理解,读了本说明书之后,可能会有这些实施例的其他不同实施方案、修改、和等价方式,其本身就向本领域技术人员作出了提示,并不脱离本发明的精神和/或所附权利要求的范围。
实施例
实施例1
表3:所选AAP的特性。
*0.5%溶液 **中和溶液 ***活性成分含量85-100%
基于RITA和Noveon的丙烯酸聚合物之间的特定相似性,用下述AAP产品评估其酶抑制活性(表4)。
表4:选择用于评估抑制活性的AAP产品
因为所选AAP具有有限且非常不同的溶胀能力,所以开发了下述方法以补偿样品制备物的条件。通过慢慢向12mL缓冲液中加入6mg的干燥原料,同时缓慢涡旋,将和聚合物悬浮于pH 7.3的50mMTris-HCl缓冲液中。悬浮液置于末端复末端(end-over-end)的摇摆器上1小时,以确保彻底分散,然后置于37C保温箱中48小时达到完全溶解。这段时间结束时,任一制品中都没有明显可见的聚集体或不溶性残留。每种这样的母液都有500μg/mL浓度的丙烯酸聚合物。
实旋例2
用合成的、特异于人嗜中性粒细胞弹性蛋白酶(HNE)的可溶性肽底物与源于人炎性流体的酶活性源一起测定弹性蛋白酶的抑制。底物(甲氧琥珀酰-Ala-Ala-Pro-Val-对硝基苯胺)用于这些测试,HNE源是源于囊肿性纤维化患者导气管分泌物的纯化的酶制品。随着时间推移,底物的酶裂解导致出现黄色的不断加深;通过增加含抑制活性的测试样品的浓度来减小颜色的产生速率。对抑制的浓度依赖性分析不仅可以使抑制活性潜力量化,以在每个部分中达到50%抑制(IC50)时所需干物质的浓度来表示,还提供了有关抑制模式的信息。当抑制常数Ki的值明显低于IC50的值时,至少部分的抑制机制与酶活性位点的阻断有关,即“竞争性”抑制。抑制数据的图表分析还提供了抑制模式是否可逆的线索。由于嗜中性粒细胞弹性蛋白酶以受控水平存在时具有一些积极的生理学作用,因而不加选择地使用不可逆的抑制剂可能危及酶的这些正常功能。
将多聚体母液(丙烯酸聚合物浓度为500μg/mL)稀释到相同的Tris-HCl缓冲液中,在96孔微板上,将50μL等分试样的系列稀释液加至50μl等分试样的、在相同的缓冲液中人嗜中性粒细胞弹性蛋白酶(HNE)浓度为4.5μg/mL的溶液中。混合以确保聚合物均匀分布后,加入50μL等分试样的、在含10%DMSO的Tris缓冲液中显色底物甲氧琥珀酰-Ala-Ala-Pro-Val-对硝基苯胺浓度为450μM的溶液中(最终底物浓度=150μM),通过在405nm下记录10分钟期间光密度的增长来测试孔中的弹性蛋白酶活性。所有测量均用多孔微板读取器进行。所有观测到的酰胺裂解速率均与含酶、缓冲液和底物但不含聚合物的对照进行对比。
对于每个单独试验,图中的结果以对照孔的酰胺裂解速率百分数表示。所有例子中,聚合物的终浓度均以μg/mL的单位表示。
抗弹性蛋白酶的活性按以下顺序下降:501ER>940>980>PNC-EG。IC50值之间的差异非常显著。因此,最有效的抑制活性与501ER相关,IC50=0.3μg/ml,为与PNC-EG相关的弹性蛋白酶抑制活性(IC50=0.9μg/ml)的三分之一。505E和940的IC50范围为0.5-0.6μg/ml。
表5:所选AAP产品的IC50值。
或都不能完全抑制弹性蛋白酶活性:在高于IC50值两个数量级的AAP浓度下,仍然可以检测到大约5-20%的残留活性。高浓度的ETD 2020,可以达到大约95%的抑制。最高浓度的940可以抑制大约90%的酶活性。用另一种多阴离子聚合物也看到了该效果。
发现丙烯酸聚合物的酶抑制特性可能依赖于电解质的浓度。因此在高浓度(1.0M NaCl)中,AAP的抑制作用被完全消除。虽然不希望受任可降定理论的束缚,但还是认为酶和AAP的极性基团之间的静电相互作用可能影响所测试聚合物抑制作用。应当注意到,只在证明抑制机制的性质时电解质1.0M浓度的效果才是显著的,因为其与非生理学条件的利用有关。0.15M的生理学浓度远低于消除AAP抑制作用所需的1.0M的电解质浓度。因此,在生理学条件下,丙烯酸聚合物能够有效地抑制弹性蛋白酶。
AAP的弹性蛋白酶抑制活性可以与不含丙烯酸聚合物的弹性蛋白酶抑制剂如(Pentapharm,瑞士)的特异活性相比较。对比试验显示(制品含大约2.5%(w/v)的活性大豆肽)的IC50=3.5μg干物质/ml。这种特殊的化妆品成分是为501ER有效性十分之一以下的弹性蛋白酶抑制剂。被认为与蛋白酶之间有明显的非静电相互作用,因此是一种不可逆的、可能产生调节性问题的酶抑制剂。对于显示出其抑制作用是可逆的。
实施例3
选择MMP-9用于下一步的AAP酶抑制特性平估。有趣的是,MMP-9和弹性蛋白酶具有非常不同的物理化学和生物化学特性。例如,MMP-9是一种在酶活性中心含14个离子(10Cu+&4Zn2+)的复杂的酶。MMP-9由两个肽链构成,分子量>90,000道尔顿。而弹性蛋白酶是一种活性中心不含离子的简单的酶。弹性蛋白酶只由一个肽链构成,分子量<30,000道尔顿。因此,如果丙烯酸聚合物能够同时抑制这两种差异极大的酶,那么这样的聚合物就能够全身作用于皮肤疾病最基本的问题。
发现AAP产品(如卡波姆)能够显示出明显的MMP-9抑制活性,如图5所示。
将AAP的MMP-9抑制活性与基质金属蛋白酶酶抑制剂(如MDI(Atrium Biotechnologies,Inc.,加拿大))的特异活性作了比较,MIDI为不含丙烯酸聚合物的成分。这样的对比试验显示出ETD 2020的IC50=0.19μg干物质/ml,而MIDI显示出IC50=4.2μg干物质/ml。表明卡波姆的酶抑制比MDI Complex高出几乎20倍。
卡波姆和特异性抑制剂的抑制活性对比列于表6。
表6:卡波姆和酶抑制剂的IC50值。
*IC50μg/ml
发现丙烯酸聚合物的MMP-9抑制特性可能浓赖于电解质的浓度。因此,在高浓度(1.0M NaCl)中,AAP的抑制作用被完全消除。虽然不希望受任何特定理论的束缚,但还是认为酶和AAP的极性基团之间的静电相互作用可能影响所测试聚合物抑制作用。应当注意到,只在显示抑制机制的性质时电解质1.0M的浓度的作用才是显著的,因为其与非生理学条件的利用有关。0.15M的生理学浓度远低于消除AAP抑制作用所需的1.0M电解质浓度。因此,在生理学条件下,丙烯酸聚合物能够有效地抑制MMP-9。
可以将AAP的MMP-9抑制活性与MMP-9抑制剂如MDI(AtriumBiotechnologies,Inc.,加拿大)的特异活性进行比较。发现在1.0M的电解质浓度中,MDI的抑制作用完全被消除。表明AAP和MDI对MMP-9的抑制作用都是可逆的。
实施例4
下面的实施例阐述了AAP在代表敏感的皮肤面部增湿品乳液中的应用。推荐在太阳曝晒后和红斑痤疮症状时使用。
乳液组成:
%wt.
水相
纯净水(足量至100%) 70.54
丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物 0.01
甘油 7.50
Phenonip 0.20
油相
异丙基豆蔻酸酯 18.50
聚山梨醇酯80 1.50
Span 80 0.50
鲸蜡醇 3.00
十八烷醇 3.50
Arlacel 165(甘油硬脂酸酯和PEG 100硬脂 4.50酸酯)
二甲硅油 0.25
100.00
制备过程包括将两相加热到80℃,通过高剪切混合将油乳化到水中。应当在持续混合的同时将混合液缓慢冷却到25℃。使用前必须好好晃动乳液。
实旋例5
下述实施例阐述了AAP在杀虫凝胶中的应用。推荐用于保护皮肤不被虫咬。凝胶的组成为:
%wt.
A相
纯净水(足量至100%) 73.05
戊二醇 10.00
Ethoxydigidroglycol 5.00
尿囊素 0.50
Aloe Vera Extract 0.25
Phenonip 0.20
B相
卡波姆 0.01
C相
羟丙基纤维素 1.00
D相
SDA Alcohol 3A 10.00
100.00
制备过程包括将B相撒在A相上,同时高速混合。在持续高速混合的同时加热至65℃,加入C相。混合30分钟,冷却至30℃。加入D相,冷却至室温。
实施例6
下述实施例阐述了AAP在喷雾剂中的应用。推荐用作头皮止痒喷雾剂。凝胶的组成为:
%wt.
A相
纯净水(足量至100%) 54.94
1-3丁二醇 4.00
聚丙烯酸钠 0.01
B相
SDA Alcohol 3A 40.00
氢化可的松 1.00
香料
0.05
100.00
制备过程包括混合A相的组分同时混合B相的组分。然后混合A相和B相直至均匀。
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Claims (15)
1.基于丙烯酸的聚合物在制备用于向人或动物皮肤角质层给药来治疗皮肤炎性病症的药物组合物中的用途,其中所述药物组合物中基于丙烯酸的聚合物的有效量为有效调节至少一种与皮肤炎性病症有关的酶的活性的量,
其中所述基于丙烯酸的聚合物选自基于丙烯酸的线性聚合物、基于丙烯酸的交联聚合物、基于丙烯酸的高分子量交联聚合物、丙烯酸与烯丙基蔗糖交联的聚合物、丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-C30)丙烯酸酯改性的丙烯酸的聚合物、由长链(C10-C30)丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸的共聚物、由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的共聚物、丙烯酸与二乙烯醇交联的聚合物、丙烯酸与季戊四醇的烯丙基醚、蔗糖的烯丙基醚或丙烯的烯丙基醚交联的均聚物、聚乙烯羧基聚合物、卡波姆,C-10至C-30烷基丙烯酸酯和丙烯酸、甲基丙烯酸、或其简单酯之一的一种或多种单体与蔗糖的烯丙基醚或季戊四醇的烯丙基醚交联的共聚物,具有丙烯酸聚合物主链和二甲基聚硅氧烷侧链的接枝共聚物、丙烯酸铵或丙烯腈共聚物、丙烯酸与丙烯腈共聚物、丙烯酸聚季铵盐共聚物、聚乙二醇、疏水改性的环氧乙烷聚氨酯、聚合物或共聚物。
2.权利要求1的用途,其中在组合物中,所述至少一种丙烯酸聚合物的量从大约0.001%wt至95%wt。
3.权利要求1的用途,其中所述的至少一种酶是肽水解酶、丝氨酸蛋白酶、基质金属蛋白酶、胶原酶、激酶、弹性蛋白酶或过氧化物酶。
4.权利要求1的用途,其中所述皮肤炎性病症包括皮肤反应、过敏性皮肤反应、急性皮肤炎性疾病、慢性皮肤炎性病症、免疫相关皮肤疾病、和伤口愈合。
5.权利要求1的用途,其中所述组合物进一步包含一种或多种制剂组分,包括药物赋形剂、防腐剂、乳化剂、润肤剂、流变性调节剂、肤感助剂、增湿剂、保湿剂、膜形成剂、pH调节剂/螯合剂、香料、效应颜料、着色剂、水或其任意组合。
6.权利要求1的用途,其中所述组合物包含含有0.01%wt丙烯酸聚合物的油和水乳液,其中丙烯酸聚合物为丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物。
7.基于丙烯酸的聚合物在制备用于预防皮肤炎性病症的药物组合物中的用途,其中所述药物组合物中基于丙烯酸的聚合物的量为有效调节至少一种与皮肤炎性病症有关的酶的活性的量,
其中所述基于丙烯酸的聚合物选自基于丙烯酸的线性聚合物、基于丙烯酸的交联聚合物、基于丙烯酸的高分子量交联聚合物、丙烯酸与烯丙基蔗糖交联的聚合物、丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-C30)丙烯酸酯改性的丙烯酸的聚合物、由长链(C10-C30)丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸的共聚物、由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的共聚物、丙烯酸与二乙烯醇交联的聚合物、丙烯酸与季戊四醇的烯丙基醚、蔗糖的烯丙基醚或丙烯的烯丙基醚交联的均聚物、聚乙烯羧基聚合物、卡波姆,C-10至C-30烷基丙烯酸酯和丙烯酸、甲基丙烯酸、或其简单酯之一的一种或多种单体与蔗糖的烯丙基醚或季戊四醇的烯丙基醚交联的共聚物,具有丙烯酸聚合物主链和二甲基聚硅氧烷侧链的接枝共聚物、丙烯酸铵或丙烯腈共聚物、丙烯酸与丙烯腈共聚物、丙烯酸聚季铵盐共聚物、聚乙二醇、疏水改性的环氧乙烷聚氨酯、聚合物或共聚物。
8.权利要求7的用途,其中在组合物中,所述至少一种丙烯酸聚合物的量从大约0.001%wt至95%wt。
9.权利要求7的用途,其中所述的至少一种酶是肽水解酶、丝氨酸蛋白酶、基质金属蛋白酶、胶原酶、激酶、弹性蛋白酶或过氧化物酶。
10.权利要求7的用途,其中所述皮肤炎性病症包括皮肤反应、过敏性皮肤反应、急性皮肤炎性疾病、慢性皮肤炎性病症、免疫相关皮肤疾病、和皮肤伤口愈合。
11.权利要求7的用途,其中所述组合物进一步包含一种或多种制剂组分,包括药物赋形剂、防腐剂、乳化剂、润肤剂、流变性调节剂、肤感助剂、增湿剂、保湿剂、膜形成剂、pH调节剂/螯合剂、香料、效应颜料、着色剂、水或其任意组合。
12.权利要求7的用途,其中所述药物组合物用于施用到皮肤表面。
13.权利要求7的用途,其中所述组合物包含含有0.01%wt丙烯酸聚合物的油和水乳液,其中丙烯酸聚合物为丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物。
14.一种组合物,包含至少一种有效调节至少一种与皮肤炎性病症有关的酶的活性量的基于丙烯酸的聚合物,其中基于丙烯酸的聚合物的量低于组合物的95%wt,其中所述基于丙烯酸的聚合物选自基于丙烯酸的线性聚合物、基于丙烯酸的交联聚合物、基于丙烯酸的高分子量交联聚合物、丙烯酸与烯丙基蔗糖交联的聚合物、丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-C30)丙烯酸酯改性的丙烯酸的聚合物、由长链(C10-C30)丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的聚合物、由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸的共聚物、由长链(C10-C30)烷基丙烯酸酯改性的丙烯酸与烯丙基季戊四醇交联的共聚物、丙烯酸与二乙烯醇交联的聚合物、丙烯酸与季戊四醇的烯丙基醚、蔗糖的烯丙基醚或丙烯的烯丙基醚交联的均聚物、聚乙烯羧基聚合物、卡波姆,C-10至C-30烷基丙烯酸酯和丙烯酸、甲基丙烯酸、或其简单酯之一的一种或多种单体与蔗糖的烯丙基醚或季戊四醇的烯丙基醚交联的共聚物,具有丙烯酸聚合物主链和二甲基聚硅氧烷侧链的接枝共聚物、丙烯酸铵或丙烯腈共聚物、丙烯酸与丙烯腈共聚物、丙烯酸聚季铵盐共聚物、聚乙二醇、疏水改性的环氧乙烷聚氨酯、聚合物或共聚物。
15.权利要求14的组合物,其中所述基于丙烯酸的聚合物的量少于组合物的0.05%wt。
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