CN103228281B - 用于局部施用的包含皮质类固醇的药物制剂 - Google Patents
用于局部施用的包含皮质类固醇的药物制剂 Download PDFInfo
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- CN103228281B CN103228281B CN201180056051.0A CN201180056051A CN103228281B CN 103228281 B CN103228281 B CN 103228281B CN 201180056051 A CN201180056051 A CN 201180056051A CN 103228281 B CN103228281 B CN 103228281B
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- fluid oil
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Abstract
即使当通过在包含液态油组分的制剂中提供局部皮质类固醇而显著降低所述皮质类固醇浓度时，药物制剂中的所述皮质类固醇的效力仍得到保持，所述液态油组分包含二羧酸酯和/或单羧酸酯。
Description
发明背景
局部皮质类固醇用于治疗许多急性和慢性皮肤病和粘膜疾病，特别是其中存在瘙痒或炎症的那些疾病。许多这类病症例如湿疹、银屑病和慢性皮炎如手部皮炎是需要长期治疗的慢性病症。
用于局部施用的皮质类固醇在分类系统中基于效力而被分为7类。皮质类固醇的局部效力通过标准测试(被称为血管收缩药分析(vasoconstrictor assay,VCA))进行测定。VCA测试在援引加入本文的Dow等人，第7,300,669号美国专利中有述。
表1示出由VCA测试所测定的基于效力的局部皮质类固醇的分类。
表1
基于VCA而测定的，第1类超高效皮质类固醇为最有效的皮质类固醇组。在本申请说明书中，当标明特定皮质类固醇(例如酯、丙酮化合物、游离醇或二酯形式)的浓度时，则所述皮质类固醇为该皮质类固醇的特定形式。当未标明皮质类固醇的浓度时，或当浓度涉及多于一种形式(例如酯、丙酮化合物、游离醇或二酯形式)的皮质类固醇时，则所述皮质类固醇并非指特定形式。所有已知的丙酸氯倍他索和丙酸卤倍他索的制剂(其浓度均为0.05%w/w)被归类为超高效皮质类固醇。归类为超高效的其它皮质类固醇是浓度为0.05%的二丙酸倍他米松、浓度为0.05%的双醋二氟拉松和浓度为0.1%的醋酸氟轻松的某些制剂。第2类高效的皮质类固醇是次有效的皮质类固醇组。该组包括浓度为0.1%的糠酸莫米松、浓度为0.05%的哈西奈德、双醋二氟拉松、去羟米松、醋酸氟轻松，以及浓度为0.05%的倍他米松乳膏制剂。
超高效皮质类固醇用于对较低效力的皮质类固醇的应答不令人满意的皮肤病症。这类病症包括银屑病和某些严重类型的湿疹。不幸的是，由于第1类皮质类固醇的高效力与全身副作用(包括下丘脑-垂体-肾上腺(HPA)轴抑制)的高发生率和严重性有关，所以使用超高效皮质类固醇的局部治疗通常限于2周的持续时间。这类副作用还可能在用第2类高效皮质类固醇治疗时发生。此外，对于慢性或复发性皮肤病的治疗，局部不良反应的发生限制了使用超高效和高效皮质类固醇的持续时间。
然而，慢性皮肤病(例如银屑病)通常需要长期的治疗(大于2周)以控制这类病症。因此，期望具有降低的全身副作用的发生率和/或严重性的超高效皮质类固醇制剂，以使得治疗能够持续长于2周的持续时间。
Dow的第2006/0239929号美国专利公开披露了包含0.05%的氯倍他索的喷雾制剂，其当给药4周时证明有效且基本不具有严重的副作用。然而，Dow的公开限于喷雾制剂，并且该申请的审查历史表明当施用2周时，含有0.05%的氯倍他索的现有技术制剂与高频率的包括下丘脑-垂体-肾上腺轴抑制在内的严重全身副作用有关。
由于所有超高效皮质类固醇的诱发严重的全身作用的倾向，所以FDA(食品及药品管理局)要求，除特定的氯倍他索喷雾制剂之外，目前市售的超高效类固醇(例如氯倍他索和卤倍他索)的局部组合物的处方信息携带有不建议治疗超过连续2周的警告，并且总剂量不应超过每周50g组合物。对于氯倍他索喷雾制剂，处方信息表明治疗应限于4周，并且超过2周的治疗应限于在两周之后没有得到充份改善的中度至重度斑块状银屑病的局部病变。对于高效皮质类固醇，FDA不要求处方信息携带该警告，但警告医师要意识到且监控HPA轴抑制的发生。
Busse的第4,370,322号美国专利涉及由于局部施用高效力皮质类固醇而引起的全身副作用的问题。Busse公开了包含高效力皮质类固醇和油相的局部药物组合物，所述油相包含低粘度油性溶剂，其中所述液态油相的浓度为完全溶解皮质类固醇所需浓度的至少三倍。Busse披露了当含溶剂的油相对于皮质类固醇的这样高的浓度存在时，皮质类固醇的全身吸收降低，但皮质类固醇的局部、期望的作用得到保持。Busse还披露了该发现使得能够施用相同量的类固醇以实现相同的局部抗炎作用，同时降低不期望的其全身作用。
相对于Busse的公开内容(其公开了当施用于皮肤时高浓度油相会降低皮质类固醇的全身吸收)，Parab的5,326,566号美国专利披露了，当制剂以足以溶解该制剂中的皮质类固醇但小于溶解皮质类固醇所需浓度的1.5倍的浓度包含增强皮肤渗透的量的己二酸二丁酯或者己二酸二丁酯和肉豆蔻酸异丙酯的混合物时，皮质类固醇通过皮肤并进入全身循环的渗透得到增加而非减少。因此，Parab披露了在溶解皮质类固醇所需浓度的1至1.5倍的浓度下，包含皮质类固醇和含己二酸二丁酯的油相的制剂单独地或与肉豆蔻酸异丙酯组合地用于增加局部施用皮质类固醇的全身吸收。
发明内容
出乎预料地发现，如通过上述VCA测试所测定的，即使当通过在包含液态油组分的制剂中提供包括超高效和高效局部皮质类固醇在内的局部皮质类固醇而大大降低所述皮质类固醇的浓度时，所述皮质类固醇的效力仍得到保持，其中所述液态油组分包含二羧酸酯和/或单羧酸酯。因为即使当显著降低所述皮质类固醇的浓度时所述皮质类固醇的效力仍得到保持，所以获得了治疗的期望皮肤病学作用。由于所述皮质类固醇在制剂中的浓度大大降低，所以减少量的所述皮质类固醇可进入全身循环，因此这类制剂引起不期望的全身副作用的趋势应同样降低。因此，本申请的制剂和方法特别用于治疗慢性或顽固性皮肤病(例如银屑病)，这归因于当局部皮质类固醇随时间用于多疗程治疗时与安全性有关的考虑。
因此，本发明的一个实施方案是用于向皮肤局部施用的药物制剂，其包含浓度低于目前用于局部制剂的浓度的皮质类固醇，并且其提供了与目前所用的具有较高浓度的制剂基本相当的效力。因此，对于除醋酸氟轻松之外的超高效皮质类固醇例如丙酸卤倍他索和丙酸氯倍他索，所述制剂包含浓度小于0.05%w/w的皮质类固醇，并且对于醋酸氟轻松，所述制剂包含浓度小于0.05%w/w的皮质类固醇。同样地，对于除莫米松、哈西奈德和倍氯米松之外的高效皮质类固醇，所述制剂包含浓度小于0.05%的皮质类固醇，并且对于莫米松或哈西奈德，所述制剂包含浓度小于0.1%的皮质类固醇，并且对于倍氯米松，所述制剂包含浓度小于0.025%的皮质类固醇。
本申请的液态油组分包括所述制剂的几乎不溶于水或不溶于水且在22°C室温下为液态的所有成分。除了本文讨论的二羧酸酯和单羧酸酯之外，所述液态油组分可以包含其它组分，例如烃类矿物油、轻质矿物油、角鲨烯和角鲨烷、脂肪醇如辛基十二醇和异硬脂醇、脂肪酸如异硬脂酸和油酸，以及甘油三酯如花生油和分馏椰子油。
除了所述液态油组分，所述制剂还可以包含水不溶性或几乎不溶的在室温下不为液态的成分。然而，如以下更详细讨论的，正是所述制剂的液 态油组分对于该制剂中皮质类固醇的浓度降低而言是重要的。
所述制剂中含二羧酸酯和/或单羧酸酯的液态油组分与该制剂中的皮质类固醇相关联，以使得液态油组分与皮质类固醇可以在制剂中相互作用以溶解或基本溶解皮质类固醇。假设当向患者的皮肤施用制剂时，制剂内的这种溶解提供了皮质类固醇优先进入皮肤的递送，而非提供了通过皮肤并进入全身循环的经皮递送。如本文所用，术语“基本溶解”表示本发明的制剂的液态油组分可在22°C的室温下溶解该制剂中的25%或更多的皮质类固醇。
本发明的制剂中包含的皮质类固醇优选为根据血管收缩药分析(VCA)的超高效皮质类固醇，例如0.1%的氯倍他索、卤倍他索、增强制剂中的二丙酸倍他米松、增强制剂中的双醋二氟拉松，以及醋酸氟轻松；或者为高效皮质类固醇，例如二丙酸倍他米松、糠酸莫米松、双醋二氟拉松、哈西奈德、醋酸氟轻松和去羟米松。
适于本发明制剂的其它皮质类固醇包括除超高效或高效皮质类固醇之外的皮质类固醇。任何适于向人的皮肤或粘膜局部施用的皮质类固醇均可以是所述制剂的皮质类固醇。在较低浓度下效力增加的益处包括降低对皮质类固醇的全身暴露、增加局部以及全身安全性，以及降低用于制备治疗用皮质类固醇制剂的材料的成本。这些益处适用于具有任意效力的皮质类固醇，例如具有第3至7类效力的皮质类固醇，即高中强度至最小效力。例如，地奈德凝胶或泡沫是第6类中度皮质类固醇，而地奈德洗剂为第5类低中强度皮质类固醇。浓度为0.05%的地奈德广泛用于儿童。认为的是，为了降低用地奈德治疗的儿童所经受的类固醇暴露的总量，其中效力与含0.05%地奈德的制剂类似的包含小于0.05%的地奈德浓度的制剂是特别有用的。因此，本发明包括包含表1所示的以下特定皮质类固醇浓度的制剂。例如，本发明涉及丙酸氟替卡松的浓度小于0.005%，氟轻松的浓度小于0.01%，布地奈德、倍氯米松和曲安奈德的浓度小于0.025%，丙酮缩氟氢羟龙、地奈德和二丙酸阿氯米松的浓度小于0.05%，安西奈德、戊酸倍他米松、泼尼卡酯、丁酸氢化可的松和丙酸丁酸氢化可的松的浓度小于0.1%，以及戊酸氢化可的松的浓度小于0.2%。本发明还可用任何形式的皮质类固醇(例如皮质类固醇的酯、二酯、游离醇或丙酮化合物的形式)而实施。
适于本发明的二羧酸酯(DCAE)具有通式R1OOC-(CH2)n-COOR2，其中R1和R2为包含1至4个碳的烷基或芳基，并且可以相同或可以不同，并且其中n为直链或支链，并且为1至12。含有一个或多个芳基的DCAE的实例为二羧酸的二苄基酯。优选的二羧酸酯是癸二酸二乙酯，其具有通式CH3CH2OOC-(CH2)8-COOCH2CH3。癸二酸二乙酯被认为是所公开的典型的二羧酸酯，因为癸二酸二乙酯的参数R1、R2和n各自约处于每个规定参数范围的中心。
其中R1=R2的其它合适的二羧酸酯的实例为二甲酯、二乙酯、二丙酯、二异丙酯、二丁酯和二异丁酯，例如草酸酯、苹果酸酯、琥珀酸酯、戊二酸酯、己二酸酯、庚二酸酯、辛二酸酯和壬二酸酯(azalate)。其中R1≠R2的合适的二羧酸酯的实例为甲基乙基酯、甲基丙基酯、甲基丁基酯、甲基异丙基酯、乙基丙基酯、乙基丁基酯、乙基异丙基酯和丙基丁基酯，例如草酸酯、苹果酸酯、琥珀酸酯、戊二酸酯、己二酸酯、庚二酸酯、辛二酸酯、柳酸己酯和癸二酸酯。
或者，或与DCAE组合地，所述制剂可包含单羧酸酯(MCAE)。适于本发明的MCAE具有通式CH3-(CH2)n-COOR1，其中R1为包含1至4个碳的烷基或芳基，并且其中n为直链或支链的，并且为1至12。这类单羧酸酯的实例包括甲酯、乙酯、丙酯、异丙酯、丁基酯或芳基(如苄基)酯，例如甲酸酯、乙酸酯、丙酸酯、丁酸酯、戊酸酯、月桂酸酯、肉豆蔻酸酯、棕榈酸酯和硬脂酸酯。优选的单羧酸酯的实例为棕榈酸异丙酯和肉豆蔻酸异丙酯。
本发明的皮质类固醇组合物可以是包含DCAE和/或MCAE的任意制剂，例如软膏剂、溶液剂、凝胶剂、泡沫剂和包括乳膏剂和洗剂在内的乳剂。优选地，所述制剂为其中内部油组分分散在外部水相内或内部水相分散在外部油组分内的乳剂。乳剂的实例包括油包水乳剂、水包油乳剂、水包油包水乳剂和油包水包油乳剂。乳剂可以是粗乳剂(macroemulsion)、微乳剂或纳米乳剂。还包括其中油相和水相在制剂内共存的其它制剂，例如在Espinoza的第6,709,663号美国专利中披露的多泡乳剂(multivesicular emulsion)，其并不是真正的乳剂。还包括其中优选DCAE掺入脂质体的脂质组分中的脂质体分散体。还包括其中非极性和极性液态成分在制剂中共 存的其它制剂。
优选地，本发明的制剂包含增稠剂以提供粘性，以使得所述制剂可以洗剂、凝胶剂、乳膏剂或软膏剂的形式提供。优选但非必须地，增稠剂在水性流体中为可混溶或可溶的。合适的增稠剂的实例包括阿拉伯胶、海藻酸、膨润土、卡波姆(还被称为羧基乙烯基聚合物(carboxy vinyl polymer)，例如以商品名(Lubrizol,Wickliffe,Ohio)销售的聚合物)、羧甲基纤维素、乙基纤维素、明胶、羟乙基纤维素、羟丙基纤维素、硅酸镁铝、甲基纤维素、泊洛沙姆、聚乙烯醇、海藻酸钠、黄蓍胶和黄原胶。增稠剂还可以存在于制剂的油或亲脂性部分中。合适的亲脂性增稠剂的实例包括鲸蜡醇、硬酯醇、硬脂酸甘油酯、白蜂蜡、微晶蜡、氢化聚异丁烷聚合物和乳化蜡。
如果期望或需要，为了获得期望的制剂形式，可以包含表面活性剂或乳化剂。乳化剂优选为非离子乳化剂，例如脱水山梨糖醇酯、脱水山梨糖醇酯或甘油酯的聚氧乙烯衍生物；聚合物乳化剂，例如丙烯酸酯/丙烯酸C10-C30烷基酯交联聚合物(crosspolymer)，例如以商品名(The Lubrizol Corporation,Wickliffe,OH)销售的那些；或阴离子乳化剂，例如碱皂(alkali soap)如油酸钠或油酸钾，胺皂(amine soap)如三乙醇胺硬脂酸酯，清洁剂如十二烷基硫酸钠、二辛基磺基琥珀酸钠(sodium dioctyl sulfosuccinate)和多库酯钠。较不优选的是阳离子乳化剂，例如季铵盐。适合的阴离子和非离子乳化剂的特别优选的实例包括单硬脂酸甘油酯、聚氧乙烯单油酸酯、聚氧乙烯单硬脂酸酯、聚氧乙烯单月桂酸酯、油酸钾、十二烷基硫酸钠、油酸钠、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇三硬脂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇三油酸酯、三乙醇胺油酸酯、聚氧乙烯脱水山梨糖醇单月桂酸酯、聚氧乙烯脱水山梨糖醇单棕榈酸酯、聚氧乙烯脱水山梨糖醇单硬脂酸酯、聚氧乙烯脱水山梨糖醇三硬脂酸酯、聚氧乙烯脱水山梨糖醇单油酸酯和聚氧乙烯脱水山梨糖醇三油酸酯。
所述制剂可以包含其它药学可接受的赋形剂。优选地，所述制剂包含湿润剂，例如甘油、山梨醇、己二醇、脲或丙二醇。优选地，所述制剂包含软化剂(emollient)，例如凡士林、羊毛脂、矿物油、轻质矿物油、硬脂酸、 环甲硅油或二甲硅油。另外的任选赋形剂包括稳定剂、防腐剂如对羟基苯甲酸甲酯、pH调节剂如氢氧化钠、螯合剂如EDTA及其盐，以及缓冲剂。
所述制剂可以包括足以与二羧酸酯和/或单羧酸酯混溶的量的其它亲脂性液体。亲脂性液体可以是软化剂，例如羊毛脂油、矿物油、轻质矿物油、异硬脂酸、角鲨烯、辛基月桂醇、分馏椰子油、环甲硅油或二甲硅油。
本发明的制剂可以通过任何已知用于制备供局部施用的单相或多相药物制剂的方法而制备。例如，为了制备多相制剂如乳剂，可以将水相和油相的组分分别结合并混合直至获得均匀溶液，然后将水溶液和油溶液结合并混合(例如通过剪切混合)，从而形成制剂。可以向水相中添加油相，或可以向油相中添加水相。例如可以在50-90°C的升高的温度下或室温(即20-30°C)下或在室温与升高的温度之间的温度下结合并混合所述相。
所述制剂可用于局部治疗或预防对施用局部皮质类固醇应答的皮肤病症或粘膜病症。这类病症的实例包括银屑病，皮炎例如特应性皮炎、接触性皮炎或手部皮炎、湿疹和毒葛皮炎。
皮质类固醇在制剂中的浓度为足以对其施用处的皮肤或粘膜区域提供抗炎应答的浓度。该浓度可以根据待治疗的具体病症、所用的具体皮质类固醇和其它参数而变化。
因为考虑本发明所涉及的首要目的是降低在局部施用皮质类固醇之后可进入全身循环的皮质类固醇的量，所以本发明的制剂中皮质类固醇的优选浓度低于在含有相同皮质类固醇的现有技术局部制剂中存在的浓度。例如，丙酸氯倍他索和丙酸卤倍他索局部制剂目前可以0.05%w/w浓度的乳膏剂和软膏剂形式而获得。因此，优选地，本发明制剂中的这种皮质类固醇的浓度低于0.05%w/w。然而，除非权利要求中如此指出，在0.05%的相同水平或更高水平下的皮质类固醇的浓度不从本发明范围内排除。
在一个优选实施方案中，本发明的制剂包含的诸如丙酸氯倍他索或丙酸卤倍他索的皮质类固醇的浓度为目前使用的浓度的80%或更低，即浓度为0.04%或更低。在另一优选实施方案中，所述制剂包含的皮质类固醇的浓度为目前使用的浓度的60%或更低，即浓度为0.03%或更低。在另一优选实施方案中，浓度为目前使用的浓度的50%或更低，即浓度为0.025%或更低。在另一优选实施方案中，本发明的制剂包含的皮质类固醇的浓度 为目前使用的浓度的40%或更低，即浓度为0.02%或更低。在另一优选实施方案中，所述制剂包含的皮质类固醇的浓度为目前使用的浓度的20%或更低，即浓度为0.01%或更低。在另一实施方案中，本发明制剂中的皮质类固醇的浓度为目前使用的浓度的10%或更低，即浓度为0.005%或更低。
包含DCAE和/或MCAE的制剂的液态油组分的浓度至少为足以在22°C室温下溶解制剂中的皮质类固醇总量的至少25%的浓度。在一个实施方案中，液态油组分的浓度足以溶解25%至50%，例如约40%的皮质类固醇。在一个优选实施方案中，液态油组分的浓度足以溶解50%至60%，例如约55%的皮质类固醇。在另一优选实施方案中，液态油组分的浓度足以溶解60%至70%，例如约65%的皮质类固醇。在另一优选实施方案中，液态油组分的浓度足以溶解70%至80%，例如约75%的皮质类固醇。在另一优选实施方案中，液态油组分的浓度足以溶解80%至90%，例如约85%的皮质类固醇。在另一优选实施方案中，液态油组分的浓度足以溶解90%至100%，例如约95%的皮质类固醇。
在一个更优选的实施方案中，液态油组分的浓度足以在22°C的室温下溶解制剂中的100%或更多的皮质类固醇。例如，液态油组分的浓度可以是足以溶解制剂中皮质类固醇总量的浓度的1.0至1.5倍。例如，液态油组分的浓度可以是足以溶解制剂中皮质类固醇总量的浓度的1.5倍以上，例如足以溶解制剂中皮质类固醇的量的浓度的1.5至3.0倍。例如，液态油组分的浓度可以是足以溶解制剂中皮质类固醇总量的浓度的3.0倍以上。对于在室温下溶解制剂中皮质类固醇的总量所需的量，液态油组分的合适的浓度的实例包括比足以在22°C的室温下溶解制剂中皮质类固醇的浓度高0.25、0.4、0.5、0.75、1.0、1.05、1.15、1.25、1.25、1.24、1.45、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5和6.0倍。
在所述制剂的液态油组分中的DCAE和/或MCAE的组合浓度为油组分的至少约10%，例如油组分的至少20%、30%、40%、50%、60%、70%、80%或90%。在一个优选实施方案中，DCAE和MCAE(若存在)构成了制剂的100%的液态油组分。
本发明的制剂保持了与通过施用含有更高浓度的皮质类固醇(例如超高效皮质类固醇)的现有技术制剂而获得的VCA分数一样高或近似的VCA 分数。因为VCA分数是局部效力的决定因素，所以本领域技术人员应理解，甚至在皮质类固醇浓度大大降低的情况下，本发明的制剂通常与目前可获得的含有较高浓度的皮质类固醇的制剂在皮肤中同样局部有效。此外，由于与现有技术组合物相比，所述制剂中皮质类固醇的浓度降低，并且在将该制剂局部施用后进入全身循环的皮质类固醇的量随之降低，所以可认为，与包含较高浓度的皮质类固醇的现有技术制剂相比，所述制剂可具有类似的效力，但具有改善的安全性。因此，本申请的制剂在治疗皮肤病如特应性皮炎方面在婴儿或儿童中具有特定应用，并且对于治疗顽固性或慢性皮肤病如银屑病在成人和儿童中均具有特定应用。本发明提供了与目前可用的局部制剂相比，在治疗类固醇反应性皮肤病方面的相当或更高的效力，并且具有潜在降低的局部和全身副作用。
在下列非限制性实施例中进一步阐述本发明。在实施例中，丙酸卤倍他索用作示例性超高效皮质类固醇，并且癸二酸二乙酯用作示例性二羧酸酯。然而应理解，丙酸卤倍他索是超高效和高效皮质类固醇的示例，癸二酸二乙酯是DCAE的示例，并且肉豆蔻酸异丙酯是MCAE的示例，并且任何皮质类固醇特别是高效或超高效皮质类固醇、DCAE或MCAE可替代所例示的丙酸卤倍他索、癸二酸二酯和/或肉豆蔻酸异丙酯，并具有类似的结果。
实施例1-制剂
制备表1所示的下列制剂，其包含丙酸卤倍他索(HP)形式的超高效皮质类固醇卤倍他索。制剂A至D为本发明制剂。制剂E为不在本发明范围内的制剂。
表1
实施例2-饱和溶解度和饱和度的测定
如下测定实施例1的制剂A至D中各自的丙酸卤倍他索的饱和溶解度。在22°+/-2°C的温度下，分别制备在液态油组分中含有卤倍他索的制剂A至D的样品，并储存在玻璃小瓶中。使用Burrell Shaker Model75(Burrell Scientific,Pittsburgh,PA)，将样品在395至405次振动/分钟下振摇约72小时。然后，在3500rpm下将样品离心40分钟，并且收集上清液。使用0.45μm PTFE Pall注射过滤器(PallCorporation, Port Washington,NY)过滤上清液。使用在254nm UV检测下监测的反相柱，通过HPLC来分析过滤的样品。然后，通过将液态油组分的浓度(%w/w)乘以液态油组分中的卤倍他索的饱和溶解度并除以制剂中丙酸卤倍他索的浓度，从而计算每一制剂的丙酸卤倍他索的不饱和度。下表2示出数据。
表2
实施例3-VCA分数的测定
按照Dow的第7,300,669号美国专利中所述测定实施例1的每一制剂的平均VCA分数，并且指定为0至4级的半定量主观评价分数。还测定与商购产品0.05%；NDC0072-1400-50(Bristol-Meyers Squibb Company,Princeton,NJ)对应的制剂的平均VCA分数。与测试的其它制剂相比，Ultravate包含0.05%浓度的丙酸卤倍他索。在测定平均VCA分数时，评估员对所测试的制剂是不知晓的。结果在表3中示出。
表3
如表3所示，本发明的制剂A至D中的每一制剂均提供了与现有技术制剂近似的VCA分数。即使本发明制剂的皮质类固醇水平显著 低于现有技术的制剂，但获得了这种高水平的VCA分数(其为皮质类固醇的局部期望应答的指示)。包含与制剂A和D相同的皮质类固醇浓度的制剂E具有显著更低的VCA分数。
实施例4-洗剂制剂
本发明的洗剂制剂4a和4b包含表4中所示的成分。这些制剂可以如下制备。
制备单独的水相。在制备容器中，将纯净水和依地酸二钠二水合物合并并且搅拌混合物直至获得澄清溶液。然后，向混合物中添加山梨醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯。将混合物持续混合并加热至约75°C。将混合物搅拌直至获得溶液。然后将混合物从热源处移开，并且使其在持续搅拌下冷却至低于40°C。在持续推进式搅拌下，向混合物中添加Carbopol981和Pemulen TR-1并分散。继续推进式混合，直至聚合物完全分散并水合。
制备单独的油相。在容器中合并癸二酸二乙酯和丙酸卤倍他索。将混合物搅拌，直至得到溶液。在持续的推进式混合下，添加轻质矿物油和脱水山梨糖醇单油酸酯。继续混合，直至获得溶液。
在单独的容器中，制备1N的氢氧化钠溶液。
在高速转子-定子混合下，向水相中添加含有药物(丙酸卤倍他索)的油相。继续混合，直至获得均质乳液。然后，用推进式混合替代高速转子-定子混合。在持续混合下，递增地添加适量的氢氧化钠溶液以获得5.5±0.5的pH。继续推进式混合，直至获得均质洗剂。
表4
实施例5-稳定性数据
使用表5中所列成分，通过实施例4的方法制备洗剂制剂。
表5
| 成分 | w/w百分比 |
| 丙酸卤倍他索(HP) | 0.025 |
| 癸二酸二乙酯 | 2.10 |
| 轻质矿物油 | 0.70 |
| 单油酸脱水山梨糖醇酯 | 0.10 |
| 丙二醇 | 7.50 |
| 对羟基苯甲酸甲酯 | 0.17 |
| 对羟基苯甲酸丙酯 | 0.03 |
| 依地酸二钠二水合物 | 0.05 |
| Pemulen TR-1 | 0.40 |
| Carbopol981 | 0.60 |
| 氢氧化钠 | 适量，添加至pH5.0 |
| 纯净水 | 适量，添加至100 |
在螺旋盖玻璃广口瓶中封装制剂，并在冷藏箱温度(5°C)、室温(25°C)和加速温度(40°C)下测试制剂的稳定性，并在研究开始以及长达6个月内进行定期测试。通过目测观察进行描述，用校准的pH计来测量pH，并且由使用27号轴和12rpm速率的Brookfield旋转粘度计来测量粘度。通过使用C18柱和UV检测的逆相HPLC来测定丙酸卤倍他索的含量。商购产品所需的卤倍他索洗剂的稳定性规格通常如表6所示。
表6
| 参数 | FDA要求 |
| 描述 | 没有显著变化 |
| pH | 4.0至6.0 |
| 粘度 | 7,500-15,000cps |
| HP含量 | 标称量的90%至110% |
该制剂的物理和化学稳定性测试结果在下面表7中示出。
表7
在所有测试时间下，在通常规格内测定HP洗剂。表6的数据表明，基于在40°C下6个月(由食品及药品管理局接受的用于支持在室温下2年产品保质期的加速条件)后的有利结果，该洗剂产品预期在室温下具有2年的保质期。
本文所述的本发明的其它修改、使用和应用对于本领域技术人员而言是显而易见的。意图这样的修改包括在所附权利要求中。
Claims (25)
1.用于向个体皮肤局部施用的药物组合物，所述药物组合物包含浓度小于0.05％的卤倍他索或其药学可接受的盐，以及液态油组分，所述液态油组分包含一种或多种单羧酸酯和/或二羧酸酯，其中所述单羧酸酯选自肉豆蔻酸异丙酯和棕榈酸异丙酯，并且其中所述二羧酸酯选自癸二酸二乙酯、己二酸二异丙酯和癸二酸二丁酯，其中所述液态油组分的浓度为在22℃的温度下完全溶解所述组合物中卤倍他索的量所需浓度的1.5至3倍，并且其中所述液态油组分中的所述酯的浓度为所述组合物中所述液态油组分浓度的至少10％。
2.如权利要求1所述的药物组合物，所述药物组合物还包含水性组分，所述水性组分包含水。
3.如权利要求1所述的药物组合物，其中所述卤倍他索为丙酸卤倍他索。
4.如权利要求1所述的药物组合物，其中所述卤倍他索的浓度为0.04％或更低。
5.如权利要求1所述的药物组合物，其中所述卤倍他索的浓度为0.025％或更低。
6.如权利要求1所述的药物组合物，其中所述卤倍他索的浓度为0.01％或更低。
7.如权利要求1所述的药物组合物，其中所述卤倍他索的浓度为0.035％。
8.如权利要求1所述的药物组合物，其中所述液态油组分的浓度为在22℃的温度下完全溶解所述组合物中卤倍他索的量所需浓度的1.75至2.75倍。
9.如权利要求1所述的药物组合物，其中所述液态油组分包含二羧酸酯。
10.如权利要求9所述的药物组合物，其中所述二羧酸酯为癸二酸二乙酯。
11.如权利要求1所述的药物组合物，其中所述液态油组分包含单羧酸酯。
12.如权利要求11所述的药物组合物，其中所述单羧酸酯为肉豆蔻酸异丙酯。
13.如权利要求1所述的药物组合物，其中所述液态油组分包含二羧酸酯和单羧酸酯。
14.如权利要求13所述的药物组合物，其中所述液态油组分包含癸二酸二乙酯和肉豆蔻酸异丙酯。
15.如权利要求1所述的药物组合物，其中所述液态油组分还包含矿物油。
16.如权利要求1所述的药物组合物，其中所述液态油组分还包含轻质矿物油。
17.如权利要求1至16中任一项所述的药物组合物，其中所述液态油组分中的所述酯的浓度为所述组合物中所述液态油组分浓度的至少30％。
18.如权利要求17所述的药物组合物，其中所述液态油组分中的所述酯的浓度为所述组合物中所述液态油组分浓度的至少50％。
19.如权利要求18所述的药物组合物，其中所述液态油组分中的所述酯的浓度为所述组合物中所述液态油组分浓度的至少70％。
20.如权利要求19所述的药物组合物，其中所述液态油组分中的所述酯的浓度为所述组合物中所述液态油组分浓度的至少90％。
21.如权利要求20所述的药物组合物，其中所述液态油组分中的所述酯的浓度为所述组合物中所述液态油组分浓度的100％。
22.如权利要求1所述的药物组合物，其中所述卤倍他索是浓度为0.025％或更低的丙酸卤倍他索，所述液态油组分包含癸二酸二乙酯，并且至少50％的所述卤倍他索在室温下溶解在所述液态油组分中。
23.权利要求1至16中任一项所述的药物组合物在制备用于治疗顺应使用局部皮质类固醇治疗的皮肤病症的药物中的用途。
24.权利要求17所述的药物组合物在制备用于治疗顺应使用局部皮质类固醇治疗的皮肤病症的药物中的用途。
25.权利要求22所述的药物组合物在制备用于治疗顺应使用局部皮质类固醇治疗的皮肤病症的药物中的用途。
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| PCT/US2011/059861 WO2012087443A1 (en) | 2010-11-22 | 2011-11-09 | Pharmaceutical formulations containing corticosteroids for topical administration |
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Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8809307B2 (en) | 2010-11-22 | 2014-08-19 | Dow Pharmaceutical Sciences, Inc. | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| CN103705440B (zh) * | 2012-10-08 | 2017-05-10 | 天津金耀集团有限公司 | 一种哈西奈德乳膏 |
| CN103705441B (zh) * | 2012-10-08 | 2017-06-23 | 天津金耀集团有限公司 | 一种丙酸倍氯米松乳膏 |
| US20140112959A1 (en) | 2012-10-18 | 2014-04-24 | MiCal Pharmaceuticals LLC - H Series, a Series of MiCal Pharmaceuticals LLC, a Multi-Division Limite | Topical steroid composition and method |
| US10111956B2 (en) | 2013-06-03 | 2018-10-30 | Tolmar, Inc. | Corticosteroid compositions |
| CN104095805B (zh) * | 2014-01-02 | 2016-08-24 | 江苏知原药业有限公司 | 地奈德乳膏及其制备方法 |
| US20160184431A1 (en) * | 2014-03-11 | 2016-06-30 | Promius Pharma Llc | Topical compositions comprising a corticosteroid |
| AU2016279801B2 (en) * | 2015-06-18 | 2021-09-09 | Valeant Pharmaceuticals North America | Topical compositions comprising a corticosteroid and a retinoid for treating psoriasis |
| US20190133943A1 (en) * | 2015-06-18 | 2019-05-09 | Valeant Pharmaceuticals North America | Topical compositions and methods for treating skin diseases |
| CN106474052B (zh) * | 2016-12-16 | 2019-10-25 | 重庆华邦制药有限公司 | 二丙酸阿氯米松乳膏及其制备方法 |
| US11311482B2 (en) | 2017-05-12 | 2022-04-26 | Bausch Health Us, Llc | Topical compositions and methods for treating skin diseases |
| US10653656B2 (en) | 2018-04-05 | 2020-05-19 | Bausch Health Ireland Limited | Topical pharmaceutical compositions for treating skin conditions |
| CA3133174A1 (en) | 2019-03-14 | 2020-09-17 | Crescita Therapeutics Inc. | Rinse-off compositions and uses thereof for delivery of active agents |
| WO2021162796A1 (en) * | 2020-02-11 | 2021-08-19 | Taro Pharmaceutical Industries Ltd. | Compositions comprising desoximetasone and tazarotene |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5326566A (en) * | 1991-05-17 | 1994-07-05 | Bristol-Myers Squibb Company | Use of dibutyl adipate and isopropyl myristate in topical and transdermal products |
Family Cites Families (66)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU75903A1 (zh) | 1976-09-29 | 1978-05-16 | ||
| NL7105591A (en) | 1971-04-24 | 1972-10-26 | Topical antiphlogistic compsns - contng 3, 20-diketo-9 alpha, 11 beta-dichloro - 16 alpha, 17 alpha-dimethyl-21-hydroxy pregna-1,4- | |
| DE2655570A1 (de) | 1975-12-12 | 1977-06-16 | Ciba Geigy Ag | Neue polyhalogensteroide und verfahren zu ihrer herstellung |
| US4048310A (en) | 1976-02-24 | 1977-09-13 | E. R. Squibb & Sons, Inc. | Topical steroid formulation in form of lotion or cream |
| US4083974A (en) | 1977-03-07 | 1978-04-11 | The Upjohn Company | Topical steroidal anti-inflammatory preparations containing polyoxypropylene 15 stearyl ether |
| JPS5850964B2 (ja) * | 1978-03-07 | 1983-11-14 | 東興薬品工業株式会社 | ステロイド含有クリ−ム製剤およびその製造方法 |
| US4299828A (en) * | 1979-05-31 | 1981-11-10 | E. R. Squibb & Sons, Inc. | Corticosteroid stick formulations |
| AU5794680A (en) | 1979-05-31 | 1980-12-04 | E.R. Squibb & Sons, Inc. | Corticosteroid stick formulations |
| US4233295A (en) | 1979-05-31 | 1980-11-11 | E. R. Squibb & Sons, Inc. | Corticosteroid formulations containing sebacate carrier |
| CH649923A5 (de) * | 1980-10-06 | 1985-06-28 | Glaxo Group Ltd | Topisch verabreichbare pharmazeutische zusammensetzungen, enthaltend anti-inflammatorische steroide. |
| JPS58225009A (ja) | 1982-06-23 | 1983-12-27 | Shionogi & Co Ltd | コルチコステロイド外用製剤 |
| DE3225848A1 (de) | 1982-07-07 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | Kortikoidhaltige zubereitung zur topischen applikation |
| US4552872A (en) | 1983-06-21 | 1985-11-12 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing corticosteroids |
| GB8401965D0 (en) | 1984-01-25 | 1984-02-29 | Beecham Group Plc | Composition |
| JPH0764734B2 (ja) * | 1986-03-17 | 1995-07-12 | 大正製薬株式会社 | 経皮投与製剤 |
| CA1303991C (en) | 1986-03-31 | 1992-06-23 | Chung H. Cheng | Composition and method for delivering a steroid active ingredient |
| JPS62238216A (ja) * | 1986-04-03 | 1987-10-19 | Otsuka Pharmaceut Factory Inc | ステロイドクリ−ム製剤 |
| US5019569A (en) | 1986-11-03 | 1991-05-28 | Ortho Pharmaceutical Corporation | Reversal of glucocorticoid-induced skin atrophy |
| JPH0676327B2 (ja) | 1987-04-14 | 1994-09-28 | 株式会社大塚製薬工場 | ステロイド軟膏製剤 |
| JPH0676328B2 (ja) * | 1987-04-14 | 1994-09-28 | 株式会社大塚製薬工場 | ステロイドクリ−ム製剤 |
| JPH07116026B2 (ja) | 1987-07-07 | 1995-12-13 | 株式会社資生堂 | ジクロフェナックナトリウム含有乳化外用剤 |
| AU6974191A (en) * | 1989-12-20 | 1991-07-18 | Schering Corporation | Stable cream and lotion bases for lipophilic drug compositions |
| CA2051621C (en) | 1990-03-02 | 2001-06-05 | Shiseido Company, Ltd. | Oil-in-water type emulsified composition comprising non-steroidal antiphlogistic and analgesic drug |
| TW218849B (zh) * | 1991-05-17 | 1994-01-11 | Bristol Myers Squibb Co | |
| EP0610401A1 (en) * | 1991-10-29 | 1994-08-17 | Audio Authority Corporation | Apparatus and method for interconnecting electronic products |
| JP4387463B2 (ja) | 1997-02-20 | 2009-12-16 | アラーガン、インコーポレイテッド | タザロテンおよびコルチコステロイドによる乾癬の処置 |
| US5972920A (en) * | 1998-02-12 | 1999-10-26 | Dermalogix Partners, Inc. | Formulation containing a carrier, active ingredient, and surfactant for treating skin disorders |
| SE9800729L (sv) | 1998-03-06 | 1999-09-07 | Scotia Lipidteknik Ab | Ny topikal formulering I |
| US5990100A (en) * | 1998-03-24 | 1999-11-23 | Panda Pharmaceuticals, L.L.C. | Composition and method for treatment of psoriasis |
| GB9823036D0 (en) | 1998-10-22 | 1998-12-16 | Glaxo Group Ltd | Fluticasone lotion having improved vasoconstrictor activity |
| WO2000040250A1 (fr) * | 1999-01-06 | 2000-07-13 | Taisho Pharmaceutical Co.,Ltd. | Lotion a base d'amelometasone |
| AU2877800A (en) | 1999-02-12 | 2000-08-29 | Susan Bershad | Short contact treatment of psoriasis with topical retinoids |
| DK1194109T3 (da) | 1999-06-25 | 2004-10-25 | Durham Pharmaceuticals Ltd | Topiske formuleringer omfattende hud-gennemtrængningsmidler samt anvendelse deraf |
| US6479058B1 (en) | 1999-09-02 | 2002-11-12 | Mccadden Michael E. | Composition for the topical treatment of poison ivy and other forms of contact dermatitis |
| US6656928B1 (en) * | 1999-09-02 | 2003-12-02 | Mccadden Michael E. | Composition for the topical treatment of rashes, dermatoses and lesions |
| US6387383B1 (en) | 2000-08-03 | 2002-05-14 | Dow Pharmaceutical Sciences | Topical low-viscosity gel composition |
| US6579512B2 (en) * | 2001-06-15 | 2003-06-17 | Crutchfield, Iii Charles E. | Topical steroid spray |
| US6709663B2 (en) | 2001-08-31 | 2004-03-23 | Healthpoint, Ltd. | Multivesicular emulsion drug delivery systems |
| ES2298438T3 (es) * | 2001-12-21 | 2008-05-16 | Rhodia Inc. | Composiciones estables combinadas de tensioactivos cationicos y anionicos. |
| US6765001B2 (en) | 2001-12-21 | 2004-07-20 | Medicis Pharmaceutical Corporation | Compositions and methods for enhancing corticosteroid delivery |
| US20060018937A1 (en) | 2002-10-25 | 2006-01-26 | Foamix Ltd. | Steroid kit and foamable composition and uses thereof |
| US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
| US7544674B2 (en) | 2002-10-25 | 2009-06-09 | Galderma S.A. | Topical skin care composition |
| US9265725B2 (en) | 2002-10-25 | 2016-02-23 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
| JP2004359585A (ja) | 2003-06-03 | 2004-12-24 | Medorekkusu:Kk | 被膜形成型の副腎皮質ステロイド薬含有外用製剤 |
| US20050101582A1 (en) | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
| US8741333B2 (en) | 2004-06-07 | 2014-06-03 | Nuvo Research Inc. | Compositions and methods for treating dermatitis or psoriasis |
| US8449867B2 (en) * | 2004-08-31 | 2013-05-28 | Stiefel Research Australia Pty Ltd | Microemulsion and sub-micron emulsion process and compositions |
| WO2006098353A1 (ja) | 2005-03-15 | 2006-09-21 | Kyowa Hakko Kogyo Co., Ltd. | 外用剤 |
| US20060239929A1 (en) | 2005-04-25 | 2006-10-26 | Dow Gordon J | Use of a clobetasol spray formulation to treat psoriasis |
| CA2632616A1 (en) | 2005-12-09 | 2007-06-21 | Nycomed Us Inc. | Topical glucocorticosteroid formulations |
| CA2633464A1 (en) | 2005-12-14 | 2007-09-07 | Zars Pharma, Inc. | Compositions and methods for dermal delivery of drugs |
| PT2494959E (pt) | 2006-07-05 | 2015-02-20 | Foamix Pharmaceuticals Ltd | Veículo formador de espuma de ácido dicarboxílico e suas composições farmacêuticas |
| EP2097065A2 (en) | 2006-11-29 | 2009-09-09 | Foamix Ltd. | Foamable waterless compositions with modulating agents |
| US20100323998A1 (en) * | 2007-08-06 | 2010-12-23 | Glenmark Pharmaceuticals Ltd. | Topical composition containing the combination of mupirocin and beclomethasone |
| MX2010002592A (es) | 2007-09-10 | 2010-03-30 | Glenmark Pharmaceuticals Ltd | Composicion farmaceutica topica para la combinacion de acido fusidico y corticoesteroides. |
| WO2009084020A2 (en) | 2007-10-18 | 2009-07-09 | Glenmark Pharmaceuticals Limited | Topical composition comprising halobetasol and salicylic acid |
| BRPI0914630A2 (pt) | 2008-06-26 | 2019-09-24 | Anterios Inc | liberação dérmica |
| WO2010039251A1 (en) * | 2008-10-03 | 2010-04-08 | Nexmed Holdings, Inc. | Stabilized composition for treating psoriasis |
| US20100249060A1 (en) * | 2009-02-23 | 2010-09-30 | Smith Jan G | Topical formulation of low level clobetasol propionate for treating disorders of the skin and mucous membranes |
| WO2010096868A1 (en) | 2009-02-25 | 2010-09-02 | Stiefel Research Australia Pty Ltd | Topical foam composition |
| US20130310355A1 (en) | 2009-12-15 | 2013-11-21 | Young Pharmaceuticals, Inc. | Low toxicity topical active agent delivery system |
| WO2012051614A2 (en) | 2010-10-15 | 2012-04-19 | Kulesza John E | Delivery of hydrophobic bioactive agents |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| US8809307B2 (en) | 2010-11-22 | 2014-08-19 | Dow Pharmaceutical Sciences, Inc. | Pharmaceutical formulations containing corticosteroids for topical administration |
| US20140112959A1 (en) | 2012-10-18 | 2014-04-24 | MiCal Pharmaceuticals LLC - H Series, a Series of MiCal Pharmaceuticals LLC, a Multi-Division Limite | Topical steroid composition and method |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5326566A (en) * | 1991-05-17 | 1994-07-05 | Bristol-Myers Squibb Company | Use of dibutyl adipate and isopropyl myristate in topical and transdermal products |
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Effective date of registration: 20190912 Address after: Ai Er Landubailin Patentee after: Bosch Health Ireland Ltd. Address before: American California Patentee before: Dow Pharmaceutical Sciences, Inc. |
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