CN1617730A - 用于增强皮质类固醇传递的组合物和方法 - Google Patents
用于增强皮质类固醇传递的组合物和方法 Download PDFInfo
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- CN1617730A CN1617730A CNA028277236A CN02827723A CN1617730A CN 1617730 A CN1617730 A CN 1617730A CN A028277236 A CNA028277236 A CN A028277236A CN 02827723 A CN02827723 A CN 02827723A CN 1617730 A CN1617730 A CN 1617730A
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Abstract
本发明包含一种组合物、增强功效的方法和传递位于包含至少两种渗透促进剂和溶剂以及乳化剂的基质中的皮质类固醇的方法。丙二醇和渗透增强剂的存在比例为丙二醇、渗透增强剂、和溶剂以及乳化剂总量的至少约0.70。
Description
技术领域
[1]局部皮质类固醇可以使用其抗炎、抗瘙痒和血管收缩作用。皮质类固醇(或肾上腺皮质激素)是对由垂体所释放的促肾上腺皮质激素或促肾上腺皮质的激素或对任何人工等同物或对血管紧张素II有响应的由肾上腺皮质所加工的任何甾族化合物(包含氢化环戊菲烷环系的脂类)(肾上腺源的性激素除外)。皮质类固醇非限制性地包括阿氯米松、安西奈德、安西法尔(amcinafel)、安西非特、beclamethasone、倍他米松、二丙酸倍他米松、戊酸倍他米松、丙酸氯倍他松、氯泊尼松、氯可托龙(clocortelone)、可的索、可的松、可托多松、difluorosonediacetate、地西龙、地奈德、二氟泼尼酯、二羟可的松、去羟米松、地塞米松、地夫可特、二醋酸二氟拉松、二氯松、倍他米松的酯、flucetonide、氟氯奈德、氟可的松、氟米松、氟尼缩松、醋酸氟轻松、肤轻松、flucortolone、氟培龙、氟泼尼松、fluroandrenoloneacetonide、肤轻松、氟氢缩松、fluorametholone、丙酸氟替卡松、氢化可的松、丁酸氢化可的松、戊酸氢化可的松、氢可他酯、甲羟松、甲泼尼松、甲基强的松、甲泼尼龙、抗酸莫米松、帕拉米松、强的松、泼尼松龙、prednidone、曲安奈德、和曲安西龙。
[2]氢化可的松是被发现局部有效的第一种皮质类固醇。此后,已经研制了是可以影响碳水化合物的代谢、抑制促肾上腺皮质激素分泌、并可以促进所产生的抗炎活性的皮质类固醇子集的其它有效的糖皮质激素。目前,局部甾族化合物在所有皮肤病药品中是最常用的药物。
[3]认为糖皮质激素是通过抑制前列腺素和花生四烯酸途径其它衍生物的形成来发挥其有效的抗炎作用的。已知糖皮质激素可以抑制磷脂酶A2——负责将花生四烯酸从细胞膜中释放出来的酶——的释放,从而可以抑制花生四烯酸途径。目前,认为糖皮质激素在细胞中通过直接诱导该酶的磷酸化而抑制磷脂酶A2。
[4]甾族化合物常被分成两类——氟化和未氟化的。已经对氟化的甾族化合物进行了化学修饰以增加其功效。这些修饰如卤化和甲基化可以改善其在靶细胞内的活性并降低其分解成无活性的代谢物的可能性。这些修饰还可能会导致更多的全身副作用。但是,对甾族化合物的化学结构进行修饰并不是增加其功效的唯一途径。
[5]局部甾族化合物制剂的效力与其通过皮肤的吸收密切相关。在应用该局部甾族化合物之前对皮肤进行的治疗也可以影响皮肤对该化合物的吸收。用角质层分离剂或者用脂肪溶剂(如丙酮)进行的处理破坏了表皮屏障并增加了渗透性。已经表明皮肤的水合也可以增加皮质类固醇类物质的渗透。
[6]一旦通过皮肤被吸收,则通过与全身给药的皮质类固醇相似的药动学途径对局部皮质类固醇类物质进行处理。皮质类固醇的效力差异很大,所以在想要增加任何特定甾族化合物的功效时遇到了挑战。
背景技术
[7]肾上腺皮质激素的临床效力与四种基本性质有关:血管收缩、抗增生作用、免疫抑制、以及抗炎作用。局部甾族化合物会造成浅表真皮中毛细管收缩,从而减少了红斑。给定的糖皮质激素剂引起血管收缩的能力通常与其抗炎效力有关。在现有技术中使用血管收缩药试验并且由U.S.Food and Drug Administration来测定局部皮质类固醇制剂的功效。在该领域中已经根据以双盲临床研究和血管收缩试验为基础的功效将局部糖皮质激素分成了七类。第1类包括效力最高的物质,而第7类包括效力最低的物质。
[8]在Fitzpatrick,Dermatology in General Medicine,第5版,CD-ROM,1999,表243-1中指定了具有下面分类的下面的糖皮质激素制剂。
[9]表1
皮质类固醇制剂 | 皮质类固醇 | 类别 | 来源 |
Temovate乳膏0.05% | 丙酸氯倍他松 | 1 | Glaxo Wellcome |
Temovate软膏0.05% | 丙酸氯倍他松 | 1 | Glaxo Wellcome |
Diprolene乳膏0.05% | 二丙酸倍他米松 | 1 | Schering Corp. |
Diprolene软膏0.05% | 二丙酸倍他米松 | 1 | Schering Corp. |
Psorcon软膏 | Diflorrasone diacetate | 1 | DermikLaborarories,Inc |
Cyclocort软膏0.01% | 安西奈德 | 2 | Fujisawa |
Diprolene乳膏AF0.05% | 二丙酸倍他米松 | 2 | Schering Corp. |
Diprosone软膏0.05% | 二丙酸倍他米松 | 2 | Schering Corp. |
Elocon软膏0.1% | Mometasone furoate | 2 | Schering Corp. |
Florone软膏 | Diflorasone diacetate | 2 | Dermik |
0.05% | |||
Halog乳膏0.1% | Halcinonide | 2 | Westwood-Squibb |
Lidex凝胶0.05% | 醋酸氟轻松 | 2 | MedicisPharmaceuticalsCorp. |
Lidex乳膏0.05% | 醋酸氟轻松 | 2 | MedicisPharmaceuticalsCorp. |
Lidex软膏0.05% | 醋酸氟轻松 | 2 | MedicisPharmaceuticalsCorp. |
Maxiflor软膏0.05% | Diflorasone diacetate | 2 | Allergan Herbert |
Topicort乳膏0.25% | 去羟米松 | 2 | MedicisPharmaceuticalsCorp. |
Topicort凝胶0.05% | 去羟米松 | 2 | MedicisPharmaceuticalsCorp. |
Topicort软膏0.25% | 去羟米松 | 2 | MedicisPharmaceuticalsCorp. |
Aristocor软膏0.1% | 曲安奈德 | 3 | Fujisawa |
Cutivate软膏0.005% | 丙酸氟替卡松 | 3 | Glaxo Wellcome |
Cyclocort乳膏0.1% | 安西奈德 | 3 | Fujisawa |
Cyclocort洗剂 | 安西奈德 | 3 | Fujisawa |
0.1% | |||
Diprosone乳膏0.05% | 二丙酸倍他米松 | 3 | Schering Corp. |
Florone乳膏0.05% | Diflorasone diacetate | 3 | Dermik |
Halog软膏0.1% | Halcinonide | 3 | Westwood-Squibb |
LidexE乳膏0.05% | 醋酸氟轻松 | 3 | MedicisPharmaceuticalsCorp. |
Maxiflor乳膏0.05% | Diflorasone diacetate | 3 | Allergan Herbert |
Valisone软膏0.1 | 戊酸倍他米松 | 3 | Schering Corp. |
Cordran软膏0.05% | 氟氢缩松 | 4 | Oclassen |
Elocon乳膏0.1% | Mometasone furoate | 4 | Schering Corp. |
Kenalog乳膏0.1% | 曲安奈德 | 4 | Westwood-Squibb |
Synalar软膏0.025% | 肤轻松 | 4 | MedicisPharmaceuticalsCorp. |
Westcort软膏0.2% | 戊酸氢化可的松 | 4 | Westwood-Squibb |
Cordran乳膏0.05% | 氟氢缩松 | 5 | Oclassen |
Cutivate乳膏0.05% | 丙酸氟替卡松 | 5 | Glaxo Wellcome |
Diprosone洗剂0.05% | 二丙酸倍他米松 | 5 | Schering Corp. |
Kenalog洗剂0.1% | 曲安奈德 | 5 | Westwood-Squibb |
Locoid乳膏0.1% | 丁酸氢化可的松 | 5 | Ferndale |
Synalar乳膏0.025% | 肤轻松 | 5 | MedicisPharmaceuticalsCorp. |
Valisone乳膏0.1% | 戊酸倍他米松 | 5 | Schering Corp. |
Westcort乳膏0.2% | 戊酸氢化可的松 | 5 | Westwood-Squibb |
Aclovate乳膏0.05% | Alclometasonedipropionate | 6 | Glaxo Wellcome |
Aclovate软膏0.05% | Alclometasonedipropionate | 6 | Glaxo Wellcome |
Aristocort乳膏0.05% | 曲安奈德 | 6 | Fujisawa |
Desowen乳膏0.05% | 地奈德 | 6 | Galderma |
Synalar溶液0.01% | 肤轻松 | 6 | MedicisPharmaceuticalsCorp. |
Synalar乳膏0.01% | 肤轻松 | 6 | MedicisPharmaceuticalsCorp. |
Tridesilon乳膏0.05% | 地奈德 | 6 | Miles |
Valisone洗剂0.1% | 戊酸倍他米松 | 6 | Schering Corp. |
具有氢化可的松、地塞米松、氟米松、泼尼松龙、和甲泼尼龙的局部物质 | 7 |
[10]除非特别说明,否则所给出的所有百分比都是重量百分比。
[11]虽然第2类物质的功效之间没有显著差异,但是在第1类中Temovate乳膏或软膏的功效显著高于第一类中的Diprolone乳膏或Schering的软膏和第1类中的Dermik Laboratories,Inc.的Psorcon软膏。
[12]一些因素如载体、表皮屏障的完整性、以及闭合敷料的应用都对透皮吸收有影响并且所得皮质类固醇类物质的功效可以不考虑糖皮质类固醇(或糖皮质激素)分子的内在功效。此外,皮肤中出现的炎症和/或其它疾病增加了经皮吸收。
[13]因为基质可以影响在任何给定时期内所释放的肾上腺皮质激素的数量及其吸收,所以在决定给定制剂的功效方面肾上腺皮质激素被混入到其中的基质可能与该肾上腺皮质激素分子本身一样重要。在许多皮质类固醇组合物中,该基质多达总组合物的99%。十分闭合的基质如软膏(油和凡士林的水不溶性混合物)可以增加皮质类固醇的作用,这是因为其增加了角质层的水合作用并增加了皮肤的渗透性。通过用闭合敷料如塑料覆盖物对皮肤进行覆盖,这种作用可以被提高多达100倍。肾上腺皮质激素在基质中的溶解度也可以影响向皮肤中的渗透。
[14]作为一种油混悬于水中的形式,已经发现还可以用乳膏作为皮质类固醇类物质的基质。该乳膏的组成可以多种多样并且比软膏的油腻程度低的多,但是其不能提供与软膏所提供的皮肤水合程度相同的水合程度,因此,其可能不具有软膏那么高的渗透性。作为油混悬于水中的形式并且与乳膏相似的洗剂是包含有助于稳定皮质类固醇的物质的基质。溶液已经被用作基质,其是用丙二醇为基础的水。凝胶在室温下是一种固体组分,但是在皮肤上熔化。洗剂、凝胶和溶液的渗透性都低于软膏。
[15]用于皮质类固醇类物质的许多基质包括用于将所说的皮质类固醇类物质溶解于基质中的丙二醇。一般而言,包含较高数量的丙二醇的组合物倾向于更有效。
[16]基质对于皮质类固醇的功效而言也很重要,所以包含相同数量相同皮质类固醇的不同制剂常常是不同的功效类别。例如,可以通过商业途径获得的0.05%二丙酸倍他米松的制剂根据其基质可以被划分为第1类、第2类或第3类(如表1所示)。
本发明的概述
[17]本发明包括一种对于局部应用而言安全、稳定并且可以增加皮质类固醇制剂,尤其是氟化的皮质类固醇的功效的新型基质。
[18]本发明的一个实施方案在一种基质中传递了皮质类固醇,所说的基质包含皮质类固醇,和(a)至少两种渗透增强剂,包括丙二醇、二甲基异山梨醇或己二酸二异丙酯,(b)用于皮质类固醇的溶剂和/或乳化剂和可存在或不存在的渗透增强剂和(c)可存在或不存在的非-溶剂/乳化剂成分。该基质具有a∶(a+b)高于或等于0.70的比例,所说的比例优选地高于或等于0.80并且最优选地高于或等于0.90或0.95。
优选实施方案的详细描述
[19]本发明用包含至少两种渗透增强剂的基质增强了皮质类固醇制剂的功效,其中所说的渗透增强剂包括己二酸二异丙酯、二甲基异山梨醇、丙二醇、1,2,6-己三醇、和苄醇。本发明可以使用的皮质类固醇非限制性地包括氟化的皮质类固醇。
[20]本发明的另一个实施方案是一种用于增强皮质类固醇的功效的方法,所说的皮质类固醇优选地是氟化的皮质类固醇。将皮质类固醇与两种或多种渗透增强剂(优选丙二醇和至少一种其它渗透增强剂)、以及一种或多种用于该皮质类固醇的溶剂和乳化剂和可存在或不存在的渗透增强剂相结合,其中所说渗透增强剂的存在比例为所说的渗透增强剂和溶剂以及乳化剂的总量的至少约0.70,优选地至少为其0.80并且最优选地为0.90或0.95。还可以任选地将一种或多种无活性成分与皮质类固醇联用。
[21]本发明的另一个实施方案是一种将皮质类固醇传递到皮肤、指甲或头发上的方法,其优选地将其传递到哺乳动物的皮肤上,最优选地将其传递到人、狗或猫的皮肤上。所说的皮质类固醇优选地是氟化的皮质类固醇。将皮质类固醇与两种或多种渗透增强剂和一种或多种用于皮质类固醇的溶剂和乳化剂相联合,其中所说的渗透增强剂的存在比例为渗透增强剂和溶剂以及乳化剂总量的至少约0.70,优选地为至少0.85并且最优选地为0.90或0.95。还可以任选地将皮质类固醇与一种或多种无活性成分联用。
[22]如上所述的那样,本发明广泛适用于普通的皮质类固醇,特别是氟化的皮质类固醇,最优选地是醋酸氟轻松或肤轻松。下面的实施例表明了其用于一种常用的氟化皮质类固醇——醋酸氟轻松制剂的应用。醋酸氟轻松是一种皮质类固醇,其是肤轻松的21-醋酸酯,其化学名为孕-1,4-二烯-3,20-二酮,21-(乙酰氧基)-6,9-二氟-11-羟基-16,17-[(1-甲基亚乙基)二(氧基)]-,(6α,11β,16α)-。包含0.05%(所有的百分比都是重量百分比)醋酸氟轻松的组合物一般被划分为第2类。
实施例1
[23]用本发明的实施方案和一些对照组合物来进行试验。制备一些组合物并且研究者不知道这些组合物是什么组合物。招募36名健康的志愿者进行两天试验。在第1天,根据计算机所产生的随机代码将约10毫克至少八种组合物单一应用到位于各志愿者前臂下方1cm2的部位上。在使用组合物后,用一种凸起的开口保护物将该部位保护起来。用非-闭合性的带子将该保护物固定到手臂上并在通知其保持该部位干燥后使患者按照预定安排进入到下一天。
[24]在与皮肤进行接触约16小时后,除去该保护性的保护物并通过用温和的肥皂和水进行轻轻洗涤来将组合物从试验部位除去。在使用后约18小时时对皮肤血管收缩进行评分(0-3)。
[25]将各组合物的皮肤血管收缩得分进行总计(将各组合物应用于36名志愿者并且将这36个得分进行合计)。对于各试验组合物而言,计算渗透增强剂(a)与渗透增强剂和溶剂以及乳化剂的和(a+b)的比例(a∶(a+b))。所有的组合物都包含0.10%的醋酸氟轻松。
[26]表2
a∶(a+b)的范围 | 1-0.95 | 0.94-0.90 | 0.89-0.80 | 0.79-0.70 | 0.69-0.60 | 0.59-0.50 |
总血管收缩得分的均值 | 93 | 85 | 71 | 72 | 62 | 58 |
[27]*指没有样品具有0.59至0.55的范围。
[28]正如可以从上表看出的那样,对于a∶(a+b)<0.70的范围而言,平均血管收缩得分显著较低。平局血管收缩得分为58和62的皮质类固醇制剂的效力显著低于平均血管收缩得分为72或更高的这些制剂。62和58的得分没有显著差异。血管收缩得分的这种增加值一般是等级中的增加。
[29]还以相同的方式对一些对照组合物(如下所述的,包括具有0.10%的醋酸氟轻松并且不含渗透增强剂的组合物)的血管收缩得分进行了试验。因此,a∶(a+b)的比为0。血管收缩得分为60.00和59.00,其显著低于本发明实施方案的血管收缩得分。
[30]此外,还对一些其它对照组合物的血管收缩得分(“血管得分”)进行了试验。这些组合物包含0.10%的醋酸氟轻松,并且不含己二酸二异丙酯、丙二醇或二甲基异山梨醇。其得分为49.00、47.00和44.00。
[31]该实验还包括一些第1类的组合物作为比较点。DermikLaboratories,Inc.of Collegeville,PA的具有0.05%二醋酸二氟拉松的Psorcon软膏的血管得分为101。Westwood-Squibb ofEvansville,IN的具有0.05%丙酸halobetasol的Ultravate的血管得分为92。
[32]就(a)∶(a+b)的比例而言,渗透增强剂包括丙二醇、己二酸二异丙酯、二甲基异山梨醇、1,2,6-己三醇、和苄醇中的至少两种(合起来被称为“a”)。用于皮质类固醇的溶剂和乳化剂包括无水乙醇、醇(95%v/v)USP、3-环己烯-1-甲醇、∝4-二甲基-a-(4-甲基-3-戊烯基)-、Steareth-2、Steareth-21、枸橼酸、CPE-215、二异丙醇胺(1∶9)、DIPA/PG(1∶9)、乙氧基二甘醇、氢氧化钾(10%)、PEG-40硬脂酸酯、PEG-7000、聚山梨醇酯60、氢氧化钾(1%)、碳酸丙烯酯USP、丙基乙二醇4、油醇、月桂基硫酸钠、脱水山梨醇单硬脂酸酯、脱水山梨醇硬脂酸酯、和1,2,3-丙三醇酯中的一种或多种(合起来被称为“b”)。
[33]该组合物可以包含或不包含非-溶剂/乳化剂成分,如硬脂酸甘油酯(和)PEG-100硬脂酸酯、卡波普980、环甲基硅油NF、单硬脂酸甘油酯、羟乙基纤维素、羟丙基纤维素、肉豆蔻酸异丙酯、尼泊金甲酯NF、矿物油、油酸NF、PEG-100硬脂酸酯、凡士林、尼泊金丙酯NF、净化水、硬脂醇、白凡士林、和白蜡。
[34]在本发明中所用的渗透增强剂的组合具有显著的和出乎意料的结果。用相似浓度的单一渗透增强剂并不能产生相似高的血管得分(例如用丙二醇作为0.01%醋酸氟轻松唯一的渗透增强剂时,根据所用的溶剂、乳化剂和非-溶剂/乳化剂性组分,产生了72.00和50.00的血管得分)。具有渗透增强剂的组合和小于0.65的处方得分的组合物也具有低血管得分。因此,本发明使得醋酸氟轻松的功效产生了意想不到的增加。
实施例2
[35]在下面的表中对本发明的一个实施方案进行了详细描述。
[36]表3
组分 | %w/w | %w/w |
微粉化的醋酸氟轻松,USP | 0.1 | 0.1 |
丙二醇,USP | 70.0 | 74.9 |
二甲基异山梨醇 | 15.0 | |
己二酸二异丙酯 | 3.0 | |
肉豆蔻酸异丙酯,NF | 5.0 | |
1,2,6-三羟基己烷 | 2.5 | |
卡波普980 | 1.2 | 1.0 |
二异丙醇胺85%∶丙二醇(1∶9) | 1.2 | 1.0 |
枸橼酸,USP | 0.01 | 0.01 |
净化水,USP | 2.49 | 2.49 |
单硬脂酸甘油酯 | 2.5 | 2.5 |
单硬脂酸甘油酯&PEG硬脂酸酯 | 7.5 | 7.5 |
实施例3
[37]在下面的表中对本发明的另一个实施方案进行了详细描述。
[38]表4
组分 | %w/w | %w/w |
微粉化的醋酸氟轻松,USP | 0.1 | 0.1 |
丙二醇,USP | 66.8 | 69.9 |
二甲基异山梨醇 | 5.0 | |
己二酸二异丙酯 | 2.0 | |
肉豆蔻酸异丙酯,NF | 5.0 | 5.0 |
卡波普980 | 0.5 | 0.5 |
二异丙醇胺85%∶丙二醇(1∶9) | 0.5 | 0.5 |
白凡士林,USP | 5.0 | 5.0 |
单硬脂酸甘油酯 | 6.0 | 6.0 |
PEG100硬脂酸酯 | 6.0 | 6.0 |
硬脂醇,NF | 5.0 | 5.0 |
月桂基硫酸钠,NF | 0.1 |
[39]应当清楚的是,虽然已经结合其详细描述对本发明进行了描述,但上述描述是用于对本发明进行说明而不是要对由所附权利要求所取定的本发明的范围进行限制。由下面的权利要求的评述显然可以看出其它的方面、优点和变型。
Claims (60)
1.一种组合物,其包含
一种或多种皮质类固醇;
两种或多种渗透增强剂;和
一种或多种溶剂和乳化剂,其中所说渗透增强剂的存在比例为渗透增强剂、溶剂和乳化剂总量的至少约0.70。
2.如权利要求1所述的组合物,其中所说的皮质类固醇包含氟化的皮质类固醇。
3.如权利要求1所述的组合物,其中所说的皮质类固醇包含醋酸氟轻松。
4.如权利要求1所述的组合物,其中所说的皮质类固醇包含肤轻松。
5.如权利要求1、2、3或4所述的组合物,其中所说皮质类固醇的存在量为约0.10%。
6.如权利要求1、2、3或4所述的组合物,其中所说皮质类固醇的存在量为至少约0.50%。
7.如权利要求1、2、3或4所述的组合物,其中所说皮质类固醇的存在量为至少约0.25%。
8.如权利要求1、2、3或4所述的组合物,其中所说的渗透增强剂包含丙二醇、己二酸二异丙酯、二甲基异山梨醇、1,2,6己三醇、和苄醇中的两种或多种。
9.如权利要求1、2、3或4所述的组合物,其中所说的渗透增强剂包含丙二醇、己二酸二异丙酯和二甲基异山梨醇中的两种或多种。
10.如权利要求1、2、3、或4所述的组合物,其中一种渗透增强剂包含丙二醇。
11.如权利要求1所述的组合物,其中所说的比为至少约0.80、
12.如权利要求1所述的组合物,其中所说的比为至少约0.90。
13.如权利要求1所述的组合物,其中所说的比为至少约0.95。
14.如权利要求1所述的组合物,其中所说的溶剂和乳化剂包含无水乙醇、乙醇(95%v/v)USP、3-环己烯-1-甲醇、∝4-二甲基-a-(4-甲基-3-戊烯基)-、Steareth-2、Steareth-21、枸橼酸、CPB-215、二异丙醇胺(1∶9)、DIPA/PG(1∶9)、乙氧基二甘醇、氢氧化钾(10%)、PEG-40硬脂酸酯,PBG-7000、聚山梨醇酯60、氢氧化钾(1%)、碳酸丙烯酯USP、丙基乙二醇4,油醇、月桂基硫酸钠、脱水山梨醇单硬脂酸酯、脱水山梨醇硬脂酸酯、和1,2,3-丙三醇(Propanetriyl)酯中的一种或多种。
15.如权利要求1所述的组合物,其进一步包含一种或多种非-溶剂/乳化剂成分。
16.如权利要求14所述的组合物,其中所说的非溶剂/乳化剂成分包括硬脂酸甘油酯(和)PBG-100硬脂酸酯、卡波普980、环甲基硅油NF、单硬脂酸甘油酯、羟乙基纤维素、羟丙基纤维素、肉豆蔻酸异丙酯、尼泊金甲酯NF、矿物油、油酸NF、PBG-100硬脂酸酯、凡士林、尼泊金丙酯NF、净化水、硬脂醇、白凡士林、和白蜡中的一种或多种。
17.如权利要求1所述的组合物,其中所说的溶剂和乳化剂的存在量为约4-5%。
18.如权利要求15所述的组合物,其中所说的非-溶剂/乳化剂成分的存在量为约11%至约53%。
19.如权利要求15所述的组合物,其中所说的非-溶剂/乳化剂成分的存在量为约11%至约27%。
20.一种包含约0.10%醋酸氟轻松、约74.9%丙二醇、约3.0%己二酸二异丙酯、约5.0%肉豆蔻酸异丙酯、约2.5%1,2,6三羟基己烷、约1.0%卡波普980、约1.0%二异丙醇胺85%∶丙二醇(1∶9)、约0.01%枸橼酸、约2.49%净化水、约2.5%单硬脂酸甘油酯、和约7.5%单硬脂酸甘油酯&PEG硬脂酸酯的组合物。
21.一种包含约0.10%醋酸氟轻松、约70.0%丙二醇、约15.0%二甲基异山梨醇、约1.2%卡波普980、约1.2%二异丙醇胺85%∶丙二醇(1∶9)、约0.01%枸橼酸、约2.49%净化水、约2.5%单硬脂酸甘油酯、和约7.5%单硬脂酸甘油酯&PEG硬脂酸酯的组合物。
22.一种包含约0.10%醋酸氟轻松、约66.8%丙二醇、约5.0%二甲基异山梨醇、约5.0%肉豆蔻酸异丙酯、约0.5%卡波普980、约0.5%二异丙醇胺85%∶丙二醇(1∶9)、约5.0%白凡士林USP、约6.0%单硬脂酸甘油酯、约6.0%PEG100硬脂酸酯、约5.0%硬脂醇、和约0.10%月桂基硫酸钠的组合物。
23.一种包含约0.10%醋酸氟轻松、约69.9%丙二醇、约2.0%己二酸二异丙酯、约5.0%肉豆蔻酸异丙酯、约0.5%卡波普980、约0.5%二异丙醇胺85%∶丙二醇(1∶9)、约5.0%白凡士林USP、约6.0%单硬脂酸甘油酯、约6.0%PEG100硬脂酸酯、和约5.0%硬脂醇的组合物。
24.一种用于增强皮质类固醇的功效的方法,其包括
将一种或多种皮质类固醇与两种或多种渗透增强剂和一种或多种溶剂和乳化剂相结合,其中所说渗透增强剂的存在比例为渗透增强剂和溶剂以及乳化剂总量的至少约0.70。
25.如权利要求24所述的方法,其中所说的皮质类固醇包含氟化的皮质类固醇。
26.如权利要求24所述的方法,其中所说的皮质类固醇包含醋酸氟轻松。
27.如权利要求24所述的方法,其中所说的皮质类固醇包含肤轻松。
28.如权利要求24、25、26或27所述的方法,其中所说皮质类固醇的存在量为约0.10%。
29.如权利要求24、25、26或27所述的方法,其中所说皮质类固醇的存在量为至少约0.50%。
30.如权利要求24、25、26或27所述的方法,其中所说皮质类固醇的存在量为至少约0.25%。
31.如权利要求24、25、26或27所述的方法,其中所说的渗透增强剂包含丙二醇、己二酸二异丙酯、二甲基异山梨醇、1,2,6己三醇、和苄醇中的两种或多种。
32.如权利要求24、25、26或27所述的方法,其中所说的渗透增强剂包含丙二醇、己二酸二异丙酯和二甲基异山梨醇中的两种或多种。
33.如权利要求24、25、26或27所述的方法,其中一种渗透增强剂包含丙二醇。
34.如权利要求24所述的方法,其中所说的比为至少约0.80。
35.如权利要求24所述的方法,其中所说的比为至少约0.90。
36.如权利要求24所述的方法,其中所说的比为至少约0.95。
37.如权利要求24所述的方法,其中所说的溶剂和乳化剂包括无水乙醇、乙醇(95%v/v)USP、3-环己烯-1-甲醇、∝4-二甲基-a-(4-甲基-3-戊烯基)-、Steareth-2、Steareth-21、枸橼酸、CPE-215、二异丙醇胺(1∶9)、DIPA/PG(1∶9)、乙氧基二甘醇、氢氧化钾(10%)、PEG-40硬脂酸酯、PEG-7000、聚山梨醇酯60、氢氧化钾(1%)、碳酸丙烯酯USP、丙基乙二醇4、油醇、月桂基硫酸钠、脱水山梨醇单硬脂酸酯、脱水山梨醇硬脂酸酯、和1,2,3-丙三醇酯中的一种或多种。
38.如权利要求24所述的方法,其中所说的组合物进一步包含一种或多种非-溶剂/乳化剂成分。
39.如权利要求38所述的方法,其中所说的非-溶剂/乳化剂成分包含硬脂酸甘油酯(和)PBG-100硬脂酸酯、卡波普980、环甲基硅油NF、单硬脂酸甘油酯、羟乙基纤维素、羟丙基纤维素、肉豆蔻酸异丙酯、尼泊金甲酯NF、矿物油、油酸NF、PEG-100硬脂酸酯、凡士林、尼泊金丙酯NF、净化水、硬脂醇、白凡士林、和白蜡中的一种或多种。
40.如权利要求24所述的方法,其中所说的溶剂和乳化剂的存在量为约4-5%。
41.如权利要求39所述的方法,其中所说的非-溶剂/乳化剂成分的存在量为约11%至约53%。
42.如权利要求39所述的方法,其中所说的非-溶剂/乳化剂成分的存在量为约11%至约27%。
43.一种将皮质类固醇传递到皮肤上的方法,其包括
局部应用一种包含一种或多种皮质类固醇和两种或多种渗透增强剂、以及一种或多种溶剂和乳化剂的组合物,其中所说渗透增强剂的存在比为渗透增强剂和溶剂以及乳化剂总量的至少约0.70。
44.如权利要求43所述的方法,其中所说的皮质类固醇包含氟化的皮质类固醇。
45.如权利要求43所述的方法,其中所说的皮质类固醇包含醋酸氟轻松。
46.如权利要求43所述的方法,其中所说的皮质类固醇包含肤轻松。
47.如权利要求43、44、45或46所述的方法,其中所说皮质类固醇的存在量为约0.10%。
48.如权利要求43,44,45或46所述的方法,其中所说皮质类固醇的存在量为约0.50%。
49.如权利要求43、44、45或46所述的方法,其中所说皮质类固醇的存在量为至少约0.25%。
50.如权利要求43、44、45或46所述的方法,其中所说的渗透增强剂包含丙二醇、己二酸二异丙酯二甲基异山梨醇、1,2,6己三醇、和苄醇中的两种或多种。
51.如权利要求43、44、45或46所述的方法,其中所说的渗透增强剂包含丙二醇、己二酸二异丙酯和二甲基异山梨醇中的两种或多种。
52.如权利要求43、44、45或46所述的方法,其中一种渗透增强剂包含丙二醇。
53.如权利要求43所述的方法,其中所说的比为至少约0.85。
54.如权利要43所述的方法,其中所说的比为至少约0.90。
55.如权利要求43所述的方法,其中所说的溶剂和乳化剂包含无水乙醇、乙醇(95%v/v)USP、3-环己烯-1-甲醇、∝4-二甲基-a-(4-甲基-3-戊烯基)-、Steareth-2、Steareth-21、枸橼酸、CPE-215、二异丙醇胺(1∶9)、DIPA/PG(1∶9)、乙氧基二甘醇、氢氧化钾(10%)、PEG-40硬脂酸酯、PEG-7000、聚山梨醇酯60、氢氧化钾(1%)、碳酸丙烯酯USP、丙基乙二醇4、油醇、月桂基硫酸钠、脱水山梨醇单硬脂酸酯、脱水山梨醇硬脂酸酯、和1,2,3-丙三醇酯中的两种或多种。
56.如权利要求43所述的方法,其中所说的组合物进一步包含一种或多种非-溶剂/乳化剂成分。
57.如权利要求56所述的方法,其中所说的非-溶剂/乳化剂成分包含硬脂酸甘油酯(和)PEG-100硬脂酸酯、卡波普980、环甲基硅油NF、单硬脂酸甘油酯、羟乙基纤维素、羟丙基纤维素、肉豆蔻酸异丙酯、尼泊金甲酯NE、矿物油、油酸NF、PEG-100硬脂酸酯、凡士林、尼泊金丙酯NF、净化水、硬脂醇、白凡士林、和白蜡中的一种或多种。
58.如权利要求43所述的方法,其中所说溶剂和乳化剂的存在量为约4-5%。
59.如权利要求57所述的方法,其中所说非-溶剂/乳化剂成分的存在量为约11%至约53%。
60.如权利要求57所述的方法,其中所说非-溶剂/乳化剂成分的存在量为约11%至约27%。
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US10/037,360 | 2001-12-21 | ||
US10/037,360 US6765001B2 (en) | 2001-12-21 | 2001-12-21 | Compositions and methods for enhancing corticosteroid delivery |
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US (8) | US6765001B2 (zh) |
EP (2) | EP2363150A1 (zh) |
JP (2) | JP2005524614A (zh) |
CN (1) | CN1617730A (zh) |
BR (1) | BR0215254A (zh) |
CA (1) | CA2471041C (zh) |
IL (1) | IL162581A0 (zh) |
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2001
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- 2002-12-12 EP EP20100184291 patent/EP2363150A1/en not_active Withdrawn
- 2002-12-12 CN CNA028277236A patent/CN1617730A/zh active Pending
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102988992A (zh) * | 2011-09-13 | 2013-03-27 | 日东电工株式会社 | 用于增强酸性药物的透皮吸收的组合物和贴片制剂 |
CN104884043A (zh) * | 2012-10-18 | 2015-09-02 | 米卡尔制药有限公司-H系列 | 局部类固醇组合物和方法 |
CN104884043B (zh) * | 2012-10-18 | 2018-12-11 | 米卡尔制药有限公司-H系列 | 局部类固醇组合物和方法 |
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US20070142343A1 (en) | 2007-06-21 |
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WO2003055445A3 (en) | 2003-10-09 |
IL162581A0 (en) | 2005-11-20 |
US20120289490A1 (en) | 2012-11-15 |
EP1465636A4 (en) | 2006-04-05 |
AU2002360589B2 (en) | 2007-03-15 |
US20030186951A1 (en) | 2003-10-02 |
EP2363150A1 (en) | 2011-09-07 |
CA2471041A1 (en) | 2003-07-10 |
AU2002360589A1 (en) | 2003-07-15 |
US7220424B2 (en) | 2007-05-22 |
CA2471041C (en) | 2012-07-03 |
US20070142344A1 (en) | 2007-06-21 |
BR0215254A (pt) | 2005-02-01 |
MXPA04006014A (es) | 2005-07-13 |
US20100210609A2 (en) | 2010-08-19 |
US20100210614A2 (en) | 2010-08-19 |
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