CN104363963A - 局部皮肤制剂及皮肤个体化处理的方法 - Google Patents
局部皮肤制剂及皮肤个体化处理的方法 Download PDFInfo
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Abstract
已经开发了含有从成纤维细胞的培养物获得的条件培养基的个体化皮肤特异性局部制剂。不同于其它局部制剂，这些制剂对受体皮肤类型是特异性的，且条件培养基是从具有所需皮肤特征的对象获得的。例如，因为已知非洲裔美国人比白种人皮肤皱纹少且起皱晚，因此条件培养基可从非洲裔美国人皮肤获得，用于施用至发白皮肤。在另一个实施方式中，成纤维细胞是从年轻皮肤获得用于施用至老年皮肤。在又一实施方式中，成纤维细胞是从无痤疮或变色的皮肤获得的，用于施用至容易发生痤疮或变色的皮肤。皮肤供体选择标准的实例包括推迟起皱、小毛孔、抗日晒、抗痤疮、均匀着色或无斑疹或老年斑、以及良好的保湿性。
Description
相关申请的引用
本申请要求2012年3月7日提交的美国临时申请号61/607,883的权益，其全部通过参考并入本文。
技术领域
本发明通常是用于皮肤个体化(personalized)处理的细胞衍生的药用化妆品。
背景技术
皮肤是身体最大的器官，其外貌在大多数文化中是最首要的。已经将皮肤分为不同皮肤类型，其对环境破坏给予不同响应。Fitzpatrick皮肤类型分类通常用于定义皮肤类型。等级为从类型I(乳白色皮肤)到类型VI(深褐色皮肤)范围且基于其对UV光的反应识别皮肤类型。有色皮肤(skin of color)可分类为皮肤类型IV-VI。
皮肤类型间最明显的差别是肤色。皮肤中色素沉着由黑素细胞、在皮肤中形成黑色素或色素的细胞确定。黑素细胞产生被称为黑素体的黑色素组。然后黑素细胞的尖延伸(pointy extension)将黑素体转移至角质细胞。虽然黑素细胞的数目随人种改变，但出生时存在不显著的差异。人们通常具有相同总数的黑素细胞总数，而无论它们的种族；角质细胞中黑素体的分布与皮肤颜色有关。在白色皮肤-通常类型I-III中，黑素体是小的并聚集复合物中。在黑色皮肤-类型V和VI中，存在较大量的黑素体，其单独地分布在角质细胞中。Rosdahl等人，Acta Dermatovenereologica，56(2)：159-61(1979)。皮肤中黑色素的作用是吸收和散射来自UV光的能量以保护表皮细胞免受损伤。黑色素提供相当的保护作用，免受太阳损伤，且保护程度直接与色素沉着程度相对应。该太阳保护可显著预防光老化，这是Fitzpatrick皮肤类型I-III中主要整容考量之一。Woolery-Lloyd的综述“Ethnic Skin Care”，2006年11月，Skin Inc.Magazine。
皮肤质量随年龄、损伤、暴露于太阳和其它环境因素而恶化，且有时，因疾病或自身免疫疾病恶化。很好地确定了皮肤衰老的发病机理，其特征为由金属蛋白酶介导的胶原蛋白合成的减少和胶原蛋白分解的增加((Fisher等人，Arch.Dermatol.，138(11)：1462-70(2002))。皮肤衰老过程是由于内在和外在因素导致的。促成内在或自然衰老的因素是结构性和功能性的。结构上，表皮变薄，角质细胞(corneocyte)粘附性较低，且真皮-表皮结合平坦化。功能上，存在成纤维细胞的数量和生物合成能力的降低，且真皮变得萎缩并相对无细胞和无血管。暴露于紫外光辐射是外在或光老化的主要原因。外在衰老特征是失去弹性、粗糙和干燥增加、不规则的色素沉着、皱纹深、皮似外观、水疱形成和伤口愈合不良。衰老的可见外观，尤其是面部皱纹和褶皱是患者寻求减少的常见效果。
虽然所有皮肤类型对环境损伤都做出反应，但研究表明，不同皮肤类型有不同的反应。皮肤类型IV-VI的整容优势(cosmetic advantage)增加保护免受光老化。然而，有色皮肤的整容缺点是它倾向于形成色素沉着过度或色素沉着不足，这是种族客户经常遇到和最关心的预防。Grimes，Dermatologic Clinics，18(4)：659-65(2000)。色素沉着过度响应的诱导被认为是通过蛋白酶活化受体-2信令实现的，蛋白酶活化受体-2与其活化蛋白酶一起在有色皮肤的对象表皮中增加。Rawlings，Int.J.Cosmetic Science，28：79-93(2006)。
通常白种人比其他皮肤类型人的皮肤皱纹和松弛较早出现并更严重。在一般情况下，增加的色素问题在有色皮肤中观察到，但一个大研究报告指出，生活在美国的东亚人具有最少的色素斑。皮肤生物物理特性随着年龄的变化证明，相比较轻色素沉着的人群，更暗色素沉着的对象保持较年轻的皮肤特征。相比白种人和非洲裔人皮肤，据报道亚洲人角质层(SC)的天然保湿因子水平减少。报道的非洲裔人皮肤中较深的皮肤类型中减少的表皮组织蛋白酶L2水平促进皮肤灰化问题。增加的毛孔大小、皮脂分泌和皮肤表面的微生物群落以及增加的肥大细胞颗粒大小出在非洲裔的皮肤中。皮肤敏感的频率在不同族群(racial group)间颇为相似，但用于其诱导的刺激显示出细微差异。一些研究表明，亚洲人皮肤可能对外源化学物质更敏感，这可能是由于较薄的SC和较高的小汗腺腺体密度导致的。Rawlings综述，Int.J.Cosmetic Science，28：79-93(2006)。
用于处理脸部线条、皱纹和皱褶的选择包括外科手术、神经毒素、填充剂、激光、非消融性治疗、磨皮(microdermabrasion)和化学脱皮。许多这些处理在衰老迹象处理的安全性、功效和效果的持续时间方面相同。多种物质已被应用于皮肤以对抗环境损伤，其范围从泥浆和草药的混合物、动物脂肪至乳液、洗剂、霜剂、凝胶、以及生物制品。许多药用活性剂已与洗剂、凝胶、霜剂、溶液和喷雾剂混合供局部应用。实例包括减少炎症的可的松和抗组胺药、处理感染的抗生素、抗真菌剂、抗痒剂、以及干燥剂。一些包括处理衰老斑点的漂白剂和去除毛发的化学品。这些制剂对特定的活性成分是非常特异性的，并且对恢复皮肤的质量或降低衰老的效果没有作用。
最近，已经开发了局部生物制剂。例如，生长因子、肽片段、以及其他生物活性分子被掺入抗衰老药用化妆品中，例如，由Mehta等，J DrugsDermatol.，7(9)：864-71(2008)以及Naughton等的美国公开号20090123503中所述。离体培养的活细胞将细胞外蛋白质和肽，包括生长因子分泌到培养于其的营养培养基中。暴露于培养物中细胞的培养基被称为“条件培养基”。这样的条件培养基可以用于制备富含生长因子的药用化妆品组合物，如美国专利号6,372,494中描述。
而使用生长因子来处理老化皮肤正获得皮肤护理专业人员青睐，但对于用于处理和/或预防由于衰老和环境因素导致皮肤损伤、皱纹和/或其他缺陷的更有效的局部制剂，仍然存在是重要且未满足的需求，其对皮肤类型的种族和年龄差异是个体化的。
因此，本发明的目的是提供条件培养基的种族皮肤特异性局部制剂，以便局部施用至患者用于预防和减少衰老迹象，并改善皮肤质量。
本发明的另一目的是提供用于预防或减少衰老迹象并改善皮肤品质的种族皮肤特异性方法。
发明内容
已经开发了含有从成纤维细胞的培养基获得的条件培养基的个体化皮肤特异性局部制剂。不同于其它局部制剂，该局部制剂对受体皮肤类型是特异性的，且条件培养基从具有期望的皮肤特征的对象获得。在一个实施方式中，成纤维细胞是通过来自相同种族背景个体的活组织检查获得。在另一个实施方式中，成纤维细胞是从不同种族背景的个体获得。例如，由于已知非洲裔美国人比白种人皮肤皱纹少且起皱晚，所以条件培养基从非洲裔美国人皮肤获得用于施用于发白(pale)皮肤。在另一个实施方式中，成纤维细胞从年轻皮肤获得用于施用于老年皮肤。在又一实施方式中，成纤维细胞从未患痤疮或变色(discoloration)的皮肤获得，用于施用于易患痤疮或变色的皮肤。皮肤供体选择标准的实例包括推迟起皱、毛孔细小，耐日晒、抗痤疮、均匀着色或无斑疹(blotching)或老年斑且良好保湿。
优选的制剂包括从成纤维细胞的培养基中获得的条件培养基制成的凝胶、霜剂、洗剂和软膏。成纤维细胞是从特定种族群体(ethnic group)筛选的供体获得的，并在培养基中扩张。
该制剂可使用类似于特定皮肤类型的一般人群用途的制造方法大量生产。在该形式的产品中，筛选的供体提供用于成纤维细胞扩张和主细胞库(master cell bank)(MCB)建立的组织。在对MCB进行适当测试后，从主细胞库扩张的细胞用于创建工作细胞库(working cell bank)(WCB)，其进而被扩张用于制造异源局部产品制剂中使用的条件培养基。该制造方法类似于自体方法，具有相同的应用，且所有最终局部产品的制剂都在相同的浓度范围内。
通过培养皮肤(真皮，dermal)成纤维细胞得到的条件培养基的局部制剂被局部施用于个体用于预防和/或减少衰老、起皱、起斑疹、弹性损失、干燥、老年斑的迹象、以及皮肤质量的总体改善。在一个实施方式中，将种族皮肤类型特异制剂施用于相同种族的对象。在另一个实施方式中，将种族皮肤类型特异制剂施用于不同种族和皮肤类型的对象。在这些实施方式中，制剂用来补充不同种族和/或类型的皮肤，赋予对其施用的皮肤有利的因素，例如，来自白种人皮肤(其表现出小毛孔)的条件培养基可以施用于有较大毛孔尺寸的非洲裔皮肤。类似地，源自非洲裔(皮肤衰老缓慢)的条件培养基可应用于白种人皮肤，以提供非洲人皮肤的益处，即衰老缓慢。
具体实施方式
I.定义
“两亲”是指结合亲水性和亲油性(疏水性)的特性的分子。
“霜剂(cream)”在本文中用来指“水包油”或“油包水”型粘稠的液体或半固体乳液。
“成纤维细胞”是皮肤中特化细胞(specialized cell)，其产生胶原蛋白和其他细胞外基质成分。它们是结缔组织由其发展，且同样地在人体组织的发展中起着重要作用的细胞，包括合成细胞外基质成分的能力，细胞外基质成分有助于皮肤纹理和基质纤维包括胶原蛋白的分泌。胶原蛋白是构成真皮的主要成分之一的天然存在的蛋白质；它作为纤维的基质存在，可提供结构和支撑。
“凝胶”在本文中用来指胶体，其中分散相已经与连续相结合产生半固体物质，例如，胶状物。
“亲水性”在本文中用来指具有易与水相互作用的强极性基团的物质。
“疏水性”在本文中用来指对水缺少亲和性的物质；其倾向于排斥和不吸收水以及不溶于或不与水混合。
“脂溶性”在本文中用来指在疏水性液体如蓖麻油中具有大于或等于5g/100ml的溶解度的物质。
“洗剂”在本文中用来指低到中等粘度的液体制剂。
“软膏(ointment)”在本文中用来指含有软膏基体和任选的一种或多种活性剂的半固体制剂。
“油”在本文中用来指含至少95 wt％的亲油性物质的组合物。亲油性物质的实例包括但不限于：天然存在的和合成的油、脂肪、脂肪酸、卵磷脂、甘油三酸酯和它们的组合。
在本文中使用的“水可溶”指具有大于或等于至5g/100ml水溶解度的物质。
II.制剂
该制剂是用于局部施用的种族皮肤类型特异性的局部制剂。该制剂包含由在用于局部施用的赋形剂培养活组织检查的成纤维细胞得到的条件培养基。成纤维细胞是从特定种族的皮肤类型的一个或多个个体获得的，并在培养前针对疾病和兼容性筛选。供体个体是基于其特定的种族皮肤类型，并且另外地，根据已知的归因于皮肤类型所需的特性，例如，起皱、小毛孔、耐日晒、抗痤疮、均匀着色或无斑疹或老年斑以及良好的保湿性选择的。
A.条件细胞培养基制剂
成纤维细胞的悬浮液从供体皮肤的活组织检查使用标准组织培养方法生长，并用于制备局部制剂中使用的条件培养基。皮肤组织(真皮和表皮层)是从合适供体的耳后区活组织检查获得的。
异源性细胞系也可以是大量生产的，并扩张建立用于大量生产的局部产品制剂的条件培养基，含有来自特定种族皮肤类型的供体皮肤的介质，已知表现出特定的所需特性如起皱、小毛孔、抗日晒、抗痤疮、均匀着色或无斑疹或老年斑以及良好的保湿性。
条件培养基优选是异源性的。为异源过程建立主细胞库(MCB)的起始物质和细胞扩张过程与自体过程相同。
一旦介质被充分浓缩，粉末或液体与所选择的局部载体混合。混合可手动或使用机械装置进行。形成后，将该产品填充到合适的分配器并运送到最终用户。最终容器的实例可包括泵瓶、挤瓶、罐、管或小瓶。
i.细胞制备
为了生产异源性成纤维细胞的培养物，选择供体提供起始组织。在收集活组织检查皮肤组织之前，针对良好健康，对个体做一般检查，并筛选血液传播的病原性疾病，如HIV和乙型肝炎。一旦供体适合参与，则可以如上面对自体过程的描述的收集并运输活组织检查样品。
提供条件培养基给数量巨大的顾客，首先建立MCB用于随后细胞扩张和介质收集。为了建立MCB，从供体收集的活组织检查使用上述的自体过程扩张。一旦收获完成，可以进行一系列安全测试，以确保该细胞系的纯度，包括下列项：
病毒筛选：测试病毒颗粒组。
无菌度：测试无微生物。
支原体：特别针对无被分类为被认为是在细胞培养中潜在污染物的支原体种类的微生物的测试。
内毒素：测试引起热原性(发热)反应的蛋白质。
此外，还进行效能测试，以确认细胞的质量：
细胞计数：收获的群体中细胞定量。
细胞存活率：群体中活细胞百分比。
同一性(identity)：确定为成纤维细胞的细胞的百分比。
胶原蛋白含量：存在于细胞悬浮液中的胶原蛋白量，其指示细胞生物活性群体。
最终收获后，将细胞等分并在液氮的蒸汽相中低温保存，如上面对自体过程的描述。这些细胞代表MCB，并在后面用来接种用于条件介质收集的额外培养。多个供体细胞系的维持提供持续的生产库存。
每个MCB小瓶能够接种新的成纤维细胞传代培养系(subculture line)从而建立工作细胞库(WCB)。成纤维细胞将在传统的培养容器传代，以产生足够的细胞以充分接种大规模培养生物反应器。从培养物收获的小瓶被冷冻并置于低温保存，从而形成最终WCB。
来自WCB的冷冻细胞解冻，并用常规的细胞培养扩张。细胞传代，直到有足够细胞形成从而接种生物反应器。该生物反应器通常用在生物技术产业中，以支持疫苗、抗体和小分子生产。为了建立用于局部产品制剂的大量条件培养基，生物反应器可用于生产大规模培养物从而最大化收集的介质量。
在生物反应器中贴壁细胞培养是可以直接应用到本申请的现有技术。大量现成单元以不同尺寸存在，其持续监测培养条件如温度、CO2、pH和溶解氧，确保不同批次的一致性。实例包括：
系列(New Brunswick Scientific，Edison，NJ)
WAVETM生物反应器系统(GE Healthcare，Piscataway，NJ)
生物反应器采用微载体充当用于贴壁细胞如成纤维细胞的生长表面。载体是支撑细胞直接扩张到表面的小2D或3D结构。在大数量时，微载体为细胞提供大量的生长表面积，以附着在生物反应器内。潜在的载体包括：
多混合物，如BioNOC(Cesco Bioengineering，由BellcoBiotechnology，Vineland，NJ分销)和(New Brunswick Scientific，Edison，NJ)
明胶，如Cultispher-G(Percell Biolytica，Astrop，Sweden)
纤维素，如CytoporeTM(GE Healthcare，Piscataway，NJ)涂覆/未涂覆聚苯乙烯，如2D MicroHexTM(Nunc，Weisbaden，Germany)、(GEHealthcare，Piscataway，NJ)或Hy-Q SphereTM(Thermo Scientific Hyclone，Logan，UT)
一旦接种到含有微载体的反应器中，在该处理过程中为培养供给新鲜介质。每隔几天，培养过程中进行多次供给。条件培养基在无菌条件下收集，分装到适当的容器中并冷冻供后续处理。
可替换地，经典培养瓶如组织鳞片(tissue flaks)和细胞培养室(CellStacks)可用于取代生物反应器扩张WCB，并收集用于局部制剂中的介质。
ii.条件介质表征
总胶原蛋白：
测试总胶原含量是可注射自体细胞治疗产品的发布标准(releasecriteria)的一部分，其表明成纤维细胞在培养中是生物活性的。作为表征测试的一部分，也已经针对胶原蛋白含量对条件介质做了历史测试。测试可以使用Sicrol测定试剂盒(Biocolor Life Science Assay，United Kingdom)进行。该试剂盒测量胶原蛋白I-V，并报告总胶原蛋白含量值。
氨基酸
完全生长培养基的IMDM组分包含氨基酸以支持细胞扩增。收集的条件介质样本可使用已知方法对氨基酸含量进行测试，例如尺寸排阻色谱法(size exclusion chromatography)。
B.载体和赋形剂
载体可以是任何凝胶、软膏、洗剂、乳液、霜剂、泡沫、摩丝(mousse)、液体、喷雾剂、悬浮液、分散体或气雾剂，其能够将活性剂从细胞培养基递送到组织。在一个实施方式中，载体是凝胶，它是无臭且无味的，并迅速溶解，例如水醇凝胶。
洗剂
洗剂可含有细粉末状物质，其通过使用助悬剂和分散剂在分散介质中可溶。可替换地，洗剂可以具有如分散相液体物质，所述物质与载体不混溶，且通常通过乳化剂或其它合适的稳定剂分散。在一个实施方式中，洗剂是粘度在100至1000厘沱之间的乳液的形式。洗剂的流动性允许快速和均匀地施加在广泛表面积上。洗剂通常倾向于在皮肤上干燥留下其药用成分的薄涂层。
霜剂
霜剂可含有乳化剂和/或其它稳定剂。在一个实施方式中，所述制剂是具有粘度大于1000厘沱，通常在20,000-50,000厘沱范围内的霜剂形式。霜剂通常时间优选于软膏，因为它们通常更容易扩散且更容易除去。霜剂和洗剂的基本区别是粘度，其是依赖于各种油的量/使用以及用于制备该制剂的水的百分比。霜剂通常比洗剂更厚，可具有各种用途，且常常使用更多样化的油/黄油，这取决于皮肤上所需的效果。霜剂制剂中，水基百分比为总的约60-75％，且油基为总的约20-30％，其他的百分比是乳化剂、防腐剂和添加剂，总共为100％。
合适的软膏基质的实例包括烃类基质(例如，凡士林、白凡士林、黄色软膏、和矿物油)；吸收基质(亲水性凡士林、无水羊毛脂、羊毛脂和冷霜)；驱水基质(例如，亲水性软膏)，和水溶性基质(例如，聚乙二醇软膏)。糊剂(paste)通常与软膏不同，在于它们含有较高百分比的固体。糊剂通常比相同组分制备的软膏吸收性更高且油腻性较低。
凝胶
一些乳液可以是凝胶，或否则包括凝胶组分。然而，一些凝胶并不是乳液，因为它们不含有不混溶组分的均匀混合物。合适的胶凝剂包括，但不限于，改性纤维素如羟丙基纤维素和羟乙基纤维素；卡波普均聚物(聚羧乙烯均聚物，Carbopol homopolymer)和共聚物；以及它们的组合。液体载体中的合适溶剂包括，但不限于，二甘醇单乙醚；亚烷基二醇如丙二醇；异山梨醇二甲醚(dimethyl isosorbide)；醇如异丙醇和乙醇。溶剂通常针对其溶解药物的能力选择。改善皮肤感觉和/或制剂的润肤性的它添加剂也可加入。这类添加剂的实例包括，但不限于，肉豆蔻酸异丙酯、乙酸乙酯、C12-C15烷基苯甲酸酯、矿物油、角鲨烷、环甲硅油、癸酸/辛酸甘油三酯，以及它们的组合。
泡沫
泡沫由乳液结合气态推进剂组成。气态推进剂主要由氢氟烷(HFA)组成。合适的推进剂包括HFA如1，1，1，2-四氟乙烷(HFA 134a)和1，1，1，2，3，3，3-七氟丙烷(HFA 227)，但这些物质和当前被批准或可被批准用于医疗用途的其它HFA的混合物和掺合物是合适的。推进剂优选不是烃推进气体，其可在喷射过程中产生易燃或易爆蒸气。此外，该组合物优选不含有挥发性醇，它可在使用过程中产生易燃或易爆蒸汽。
赋形剂
合适的赋形剂是根据制剂的类型选择的。标准的赋形剂包括明胶、酪蛋白、卵磷脂、阿拉伯树胶、胆固醇、黄蓍胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、鲸蜡硬脂醇(cetostearyl alcohol)、聚西托醇乳化蜡、脱水山梨醇酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨醇脂肪酸酯、聚乙二醇、聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸盐(磷酸酯)、十二烷基硫酸钠、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非结晶纤维素、硅酸镁铝、三乙醇胺、聚乙烯醇、聚乙烯吡咯烷酮、蔗糖、和淀粉。
“稀释剂”可包括在制剂中以溶解、分散或并入载体。稀释剂的实例包括，但不限于，水，缓冲水溶液，有机亲水性稀释剂如一元醇、和低分子量二醇和多元醇(如丙二醇、聚丙二醇、甘油、丁二醇)。
“润肤剂”是软化或舒缓皮肤的外加剂，并且通常是本领域已知的并在一览表中列出，如“药用赋形剂手册”，第4版，医药出版社，2003。这些包括，但不限于，杏仁油、蓖麻油、角豆提取物、鲸蜡硬脂醇、鲸蜡醇、十六烷基酯蜡、胆固醇、棉籽油、环甲硅油、乙二醇棕榈酸甘油酯、甘油、甘油单硬脂酸酯、甘油单油酸酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、羊毛脂、卵磷脂、轻质矿物油、中链甘油三酯、矿物油和羊毛脂醇、凡士林、凡士林和羊毛脂醇、大豆油、淀粉、硬脂醇、葵花籽油、木糖醇和它们的组合。在一个实施方式中，润肤剂是硬脂酸乙基己基酯和棕榈酸乙基己基酯。
“表面活性剂”是降低表面张力并因此增加产品乳化、发泡、分散、铺展和润湿特性的表面活性的药剂。合适的非离子表面活性剂包括乳化蜡、甘油单油酸酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚山梨酯、山梨坦酯、苄醇、苯甲酸苄酯、环糊精、甘油单硬脂酸酯、泊洛沙姆(poloxamer)，聚维酮和它们的组合。在一个实施方式中，非离子表面活性剂是硬脂醇。
“乳化剂”是表面活性物质，其促进一种液体在另一种液体中的悬浮，并促进油和水的稳定混合物或乳液的形成。常见的乳化剂是：金属皂、某些动物油和植物油、和各种极性化合物。合适的乳化剂包括阿拉伯胶、阴离子乳化蜡、硬脂酸钙、卡波姆(carbomer)、鲸蜡硬脂醇、鲸蜡醇、胆固醇、二乙醇胺、硬脂酸棕榈酸乙二醇酯、甘油单硬脂酸酯、甘油单油酸酯、羟丙基纤维素、羟丙基甲基纤维素、羊毛脂、水合物、羊毛脂醇、卵磷脂、中链甘油三酯、甲基纤维素、矿物油和羊毛脂醇、磷酸二氢钠、单乙醇胺、非离子乳化蜡、油酸、泊洛沙姆、泊洛沙姆类、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯硬脂酸酯、藻酸丙二醇酯、自乳化型单硬脂酸甘油酯、柠檬酸钠脱水物、十二烷基硫酸钠、山梨坦酯、硬脂酸、向日葵油、黄蓍胶、三乙醇胺、黄原胶以及它们的组合。在一个实施方式中，乳化剂是硬脂酸甘油酯。
“缓冲剂”用于控制组合物的pH值。优选地，缓冲剂将组合物缓冲为约4的pH值到约7.5的pH值，更优选约4的pH值到约7的pH值，且最优选在约5的pH值到约7的pH值。在一个优选实施方式中，缓冲剂是三乙醇胺。
“防腐剂”可用于防止真菌和微生物生长。合适的抗真菌和抗菌剂包括，但不限于，苯甲酸、对羟基苯甲酸丁酯、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸钠、丙酸钠、苯扎氯铵、苄索氯铵、苄醇、西吡氯铵、三氯叔丁醇、苯酚、苯乙醇和硫柳汞。
“渗透促进剂”经常被用来促进药物通过皮肤，特别是穿过角质层的经皮递送。可加入渗透促进剂以使活性剂能够跨过角质层的屏障。一些渗透促进剂造成皮肤刺激、皮肤毒性和皮肤过敏。然而，更常用的渗透促进剂包括尿素(碳酰二胺脲(碳酰二胺，carbonyldiamide))、咪脲、N，N-二乙基甲酰胺、N-甲基-2-吡咯烷、1-十二烷基-氮杂环戊烷-2-酮(1-dodecal-azacyclopheptane-2-one 1-dodecal-azacyclopheptane-2-one)、巯基乙酸钙(calcium thioglycate)、2-吡咯烷、N，N-二乙基间甲苯甲酰胺、油酸及其酯衍生物，如甲基、乙基、丙基，异丙基、丁基、乙烯基和丙三基单油酸酯，山梨坦酯如脱水山梨糖醇单月桂酸酯和脱水山梨糖醇单油酸酯，其它的脂肪酸酯如月桂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、己二酸二异丙酯、丙二醇单月桂酸酯、丙二醇单油酸酯和非离子型去污剂如(硬脂基聚(10)氧乙烯醚)、(硬脂基聚(20)氧乙烯醚)、(油基聚(10)氧乙烯醚)、和(硬脂基聚(21)氧乙烯醚)(ICI Americas公司)。
III.施用和处理方法
本文使用的制剂可用于局部递送到任何位置，特别是由于年龄皮肤已经变薄、变色或皱褶的区域。该方法是个体化的，即，成纤维细胞条件培养基的来源是基于受体需要选择的。在一个实施方式中，选择的是种族皮肤类型特异性，其中基于受体的特定的皮肤类型和存在于相同或不同种族的皮肤类型的互补的特性选择制剂。在一个实施方案中，制剂是从与被处理皮肤相同种族的皮肤类型的供体皮肤获得。在其他实施方式中，制剂来自与被处理皮肤不同种族的皮肤类型的供体皮肤。供体皮肤是基于受体皮肤的所需和缺失特性选择的，供体皮肤已知拥有所述特性。示范性特性包括推迟起皱、小毛孔、抗日晒、抗痤疮、均匀着色或缺乏斑疹或老年斑和良好的保湿性。例如，由具有小毛孔的供体皮肤制成的制剂可施用于具有大毛孔的受体皮肤。可替换地，由具有良好的遗传和晚发生起皱特性的供体皮肤制成的制剂可以施用于早发生起皱的受体皮肤。
不必表征细胞培养基中特定分子的存在或不存在或其数量。人们只选择来源。据认为，由细胞培养介质中多种因素的组合负责提供所需的效果。该制剂可通过刺激真皮中细胞生长和分裂、通过增加细胞外基质组分(例如，胶原蛋白)的产生、和/或通过刺激现有细胞外基质的重组发挥作用，其可以具有用于改善皮肤的多因素效果。
Claims (19)
1.一种个体化皮肤类型特异性局部制剂，包括：
用于局部施用的赋形剂，以及
通过培养活组织检查的成纤维细胞获得的条件培养基，其中，所述成纤维细胞是从特定种族群体、年龄、抗感染、抗变色、或皮肤质量的一个或多个个体中获得，所述个体在培养前针对疾病和兼容性被筛选，其中所述赋形剂与所述条件培养基或其中的物质混合以形成所述制剂。
2.根据权利要求1所述的制剂，选自由凝胶、软膏、洗剂、乳液、霜剂、泡沫、摩丝、液体、喷雾剂、悬浮液、分散体和气雾剂组成的组中。
3.根据权利要求1所述的制剂，其中，所述成纤维细胞已经多次传代以产生所述条件培养基。
4.根据权利要求3所述的制剂，其中，所述成纤维细胞达到40％融合后传代。
5.根据权利要求1所述的制剂，其中，所述制剂含有从1.5升其中细胞生长到至少80％细胞融合的条件细胞培养基中获得的物质。
6.一种制备个体化皮肤类型特异性局部制剂的方法，包括：
选择特定种族群体、年龄、抗感染、抗变色、或皮肤质量的一个或多个个体，
从所述一个或多个个体获得成纤维细胞，
在细胞培养物中培养所述成纤维细胞，并混合条件培养基、或其中的物质和赋形剂，以制备用于局部施用的制剂。
7.根据权利要求6所述的方法，其中，所述一个或多个个体是基于通过Fitzpatrick皮肤类型分类表征的他们的种族皮肤类型选择。
8.根据权利要求6所述的方法，其中，所述皮肤类型具有选自由以下所组成的组中的一种或多种所需特征：起皱、小毛孔、抗日晒、抗痤疮、均匀着色或无斑疹或老年斑、以及良好的保湿性。
9.根据权利要求6所述的方法，其中，所述成纤维细胞是在达到40％融合后传代的。
10.根据权利要求6所述的方法，其中，所述自体成纤维细胞是从三个3毫米穿孔皮肤活组织检查获得。
11.根据权利要求6所述的方法，其中，所述制剂含有从1.5升其中细胞生长到至少80％细胞融合的条件细胞培养基中获得的物质。
12.根据权利要求6所述的方法，其中，所述条件细胞培养基被干燥以产生与所述赋形剂混合的物质。
13.一种用于处理皮肤的个体化皮肤类型特异性方法，包括将通过培养皮肤成纤维细胞获得的条件培养基的制剂局部施用至需要其的皮肤，所述皮肤成纤维细胞是从特定种族群体、年龄、抗感染、抗变色、或皮肤质量的一个或多个个体获得。
14.根据权利要求13所述的方法，其中，来自供体皮肤的制剂来自比被处理皮肤的人更年轻的供体。
15.根据权利要求14所述的方法，其中，所述供体与晚起皱或最少起皱有关。
16.根据权利要求13所述的方法，其中，所述供体皮肤表现出选自由以下所组成的组中的所需特性：起皱、小毛孔、抗日晒、抗痤疮、均匀着色或无斑疹或老年斑、以及良好的保湿性。
17.根据权利要求13所述的方法，其中，将制剂施用至与所述成纤维细胞的来源具有相同种族起源的受体皮肤。
18.根据权利要求17所述的方法，其中，所述供体皮肤的所述制剂是非洲裔起源的并施用至非洲裔起源的皮肤。
19.根据权利要求13所述的方法，其中，制剂施用至受体皮肤，并且其中所述制剂是权利要求1至5中任一项所述的制剂。
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| CN108283648A (zh) * | 2018-04-11 | 2018-07-17 | 广东颜值科技有限公司 | 一种促进皮肤痤疮治愈的贴膜制剂及其制备方法和应用 |
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| US10736653B2 (en) | 2013-12-06 | 2020-08-11 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US11000310B2 (en) | 2010-12-17 | 2021-05-11 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US11612410B2 (en) | 2010-12-17 | 2023-03-28 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US11103275B2 (en) | 2010-12-17 | 2021-08-31 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US11278309B2 (en) | 2010-12-17 | 2022-03-22 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US10368904B2 (en) | 2013-12-06 | 2019-08-06 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US10702684B2 (en) | 2010-12-17 | 2020-07-07 | Srgi Holdings, Llc | Systems, devices and methods for fractional resection, fractional skin grafting, fractional scar reduction and fractional tattoo removal |
| ES2827049T3 (es) | 2013-10-02 | 2021-05-19 | Srgi Holdings Llc | Dispositivos médicos de conjunto de píxeles |
| CA2926322C (en) | 2013-10-02 | 2022-10-18 | Srgi Holdings, Llc | Pixel array medical devices and methods |
| WO2015073778A1 (en) * | 2013-11-14 | 2015-05-21 | Dermarche Labs, Llc | Fibroblast mixtures and methods of making and using the same |
| US11937846B2 (en) | 2013-12-06 | 2024-03-26 | Srgi Holdings Llc | Pixel array medical systems, devices and methods |
| US11229452B2 (en) | 2013-12-06 | 2022-01-25 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| EP3253308A4 (en) | 2015-02-05 | 2018-10-24 | SRGI Holdings LLC | Pixel array medical systems, devices and methods |
| GB201504124D0 (en) | 2015-03-11 | 2015-04-22 | Proqr Therapeutics B V | Oligonucleotides |
| US11759231B2 (en) | 2015-08-31 | 2023-09-19 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| US11490952B2 (en) | 2015-08-31 | 2022-11-08 | Srgi Holdings, Llc | Pixel array medical devices and methods |
| JP2019500418A (ja) * | 2015-11-30 | 2019-01-10 | デルマフォース・ホールディングス、エルエルシー | タンパク質を有する局所皮膚組成物および使用方法 |
| US11564706B2 (en) | 2019-10-28 | 2023-01-31 | Srgi Holdings, Llc | Pixel array medical systems, devices and methods |
| WO2018217479A2 (en) | 2017-05-11 | 2018-11-29 | Srgi Holdings, Llc | Systems, devices and methods for fractional resection, fractional skin grafting, fractional scar reduction and fractional tattoo removal |
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| HK1205707A1 (zh) | 2015-12-24 |
| US20130236427A1 (en) | 2013-09-12 |
| EP3542866A1 (en) | 2019-09-25 |
| JP2018039819A (ja) | 2018-03-15 |
| HK1207330A1 (zh) | 2016-01-29 |
| EP2822659A2 (en) | 2015-01-14 |
| WO2013134248A3 (en) | 2013-11-07 |
| WO2013134248A2 (en) | 2013-09-12 |
| KR20150009521A (ko) | 2015-01-26 |
| CA2866563A1 (en) | 2013-09-12 |
| JP2015510884A (ja) | 2015-04-13 |
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