CN108992673A - 罗氟司特晶体生长的抑制 - Google Patents
罗氟司特晶体生长的抑制 Download PDFInfo
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- CN108992673A CN108992673A CN201810581282.7A CN201810581282A CN108992673A CN 108992673 A CN108992673 A CN 108992673A CN 201810581282 A CN201810581282 A CN 201810581282A CN 108992673 A CN108992673 A CN 108992673A
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- Prior art keywords
- roflumilast
- composition
- agent
- hexylene glycol
- method described
- Prior art date
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Abstract
已表明罗氟司特晶体在储存中尺寸增大。罗氟司特晶体的尺寸可影响药物组合物的生物利用度和功效。通过在组合物中包含己二醇,可以抑制储存中罗氟司特晶体的生长。所得组合物具有改善的生物利用度和功效,并且可用于抑制需要这样的治疗的患者中的磷酸二酯酶4。
Description
技术领域
本发明涉及抑制储存时从药物产品中悬浮或沉淀的罗氟司特的晶体生长或增加的粒度。更特别地,本发明涉及配制成抑制悬浮或沉淀的罗氟司特颗粒的粒度分布随时间变化的药学上可接受的乳剂、混悬剂、凝胶剂或溶液剂。
背景技术
已知罗氟司特适合作为支气管治疗剂以及用于治疗炎性疾病。含有罗氟司特的组合物用于人类和兽医药物,并已提出用于治疗和预防疾病,所述疾病包括但不限于:炎性和变应原诱导的气道疾病(例如支气管炎、哮喘、COPD);皮肤病(例如增生性、炎性和变应原诱导的皮肤病),以及胃肠区中的普遍性炎症(克罗恩氏病和溃疡性结肠炎)。
罗氟司特及其合成描述于US 5,712,298(“'298专利”)中,其援引加入本文。*长期以来认识到具有磷酸二酯酶(PDE)抑制性质的药物化合物(如罗氟司特)可用于治疗银屑病和特应性皮炎('298专利,第11栏第52-61行)以及其他慢性炎性和变应原诱导的皮肤病。为了治疗这样的皮肤病,已经描述了用于局部施用的罗氟司特乳剂、混悬剂、凝胶剂或溶液剂('298专利,第12栏,第37-64行)。尽管罗氟司特口服片剂已经商品化,但WO95/01338(对应于'298专利并且其全部内容援引加入本文)中已报道化合物的低水溶性在21℃下仅为0.53mg/l。这种低水溶性对于肠胃外制剂和局部用乳剂、混悬剂、凝胶剂或含水溶液剂的开发而言是有问题的。在US 9,205,044(援引加入本文)中,通过使用烷氧基化脂肪,具体为聚氧乙烯化12-羟基硬脂酸作为用于肠胃外给药的共溶剂来克服罗氟司特的差的水溶解度。在EP1511516B1(对应于援引加入本文的公开的美国申请序列号14/075,035)中,通过在保持水重量百分比低于10%的同时用浓度超过62%(w/w)的聚乙二
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*除非另外指明,援引加入本文的参考文献为所有目的并入其全部内容。醇400(PEG 400)配制,从而克服局部用乳剂(霜剂)制剂中罗氟司特的低水溶解度。
已发现局部施用有效的药理学剂如罗氟司特用于治疗皮肤疾病为患者提供较好的递送,较低的全身暴露和较容易的使用。化合物的分子结构最终决定药物穿过施用产品的组织的上皮的能力。对于局部施用至皮肤,制剂组分的选择决定配方能够达到的最大皮肤渗透。霜剂、洗剂、凝胶剂、软膏剂和泡沫剂只是用于施用至皮肤的含有活性药物成分(API)的局部用产品中几种较为熟悉的形式。为确保API向皮肤中或穿过皮肤的连续递送,其必须保持:1)经局部用产品的货架期是溶解的,或2)经局部用产品的货架期作为具有不变的晶体习性和不变的粒度分布的颗粒悬浮。
溶解的活性成分渗透皮肤屏障的能力由其分子结构决定。分子结构和皮肤渗透之间公知的关系是增加分子量会降低活性剂穿过皮肤的速率(JD Bos,MM Meinardi,ExpDermatol.2000Jun;9(3):165-9)。另一种清楚理解的关系是,增加亲水性活性剂的辛醇-水分配系数最初会增加活性剂渗透皮肤的速率,但是一旦活性剂变得太亲脂而不能分配出角质层并进入表皮下层则降低皮肤渗透(D.W.Osborne和W.J.Lambert,用于皮肤递送的前药,K.B.Sloane编,Marcel Dekker,New York 163-178(1992))。最佳的辛醇-水分配系数通常是2-3的log P值。基于局部用产品的组成,可以进一步改变活性成分穿过有活力的表皮的速率。该制剂的最终pH值可能是关键的,因为溶解的离子化活性成分通常不会像不携带电荷的活性成分一样有效地渗透皮肤(N.Li,X.Wu,W.Jia,M.C.Zhang,F.Tan和J Zhang.DrugDev Indust Pharm 38(8)985-994)。可将功能性成分如皮肤渗透促进剂(D.W.Osborne和J.J.Henke,Pharmaceutical Technology 21(11)58-66(1997))加入到局部用产品中以增加皮肤渗透。对于局部用产品中溶解的活性剂,药物浓度与使药物产品饱和所需的活性剂的量越接近,活性剂穿过皮肤的热力学驱动力越大,即活性剂的皮肤通量越大。科学文献指导配方师如何通过极性途径(polar route)、非极性途径以及细胞间脂质途径或透过滤泡渗透(transfollicular penetration)来增加渗透。虽然这些理论和机制有时是相互矛盾的,但是通常认为,当活性成分溶解在制剂中时,发生药物从局部用产品的最一致的皮肤渗透。为此,配方师通常避免开发如下局部用产品,根据标签储存说明,所述局部用产品会有活性成分的颗粒或晶体在储存中沉淀。活性成分的沉淀可能由于各种原因而发生。当与特定的药物赋形剂配制时,特定的活性成分会倾向于形成过饱和溶液。在制造时,所有的活性成分都会在溶液中。在几天、几周或几个月后,这种亚稳态的局部用产品会平衡并且活性成分颗粒会形成。如果局部用产品含有挥发性溶剂如乙醇,则在储存时溶剂的蒸发可导致活性成分沉淀。溶解性较小的多晶型物(Pudipeddi和Serajuddin,J.Pharm.Sci.,94(5)929-939(2005))可在局部用产品中成核并形成不会再溶解的活性成分颗粒。其他产品可能配制成过于接近活性成分的饱和极限,结果是储存温度的微小变化会导致沉淀。应该注意的是,在运输过程中可能发生的剧烈温度变化预期会导致活性成分的可逆沉淀。不管原因如何,在局部用产品储存期间活性成分的不可逆沉淀可对局部用产品的生物利用度和功效具有深远影响,因为只有溶解的活性成分可渗透到完整的角质层(皮肤上皮的最外层)中。
对于悬浮的活性成分,除分子结构外,性质影响皮肤渗透。溶解与悬浮的活性成分的比率可以对局部施用后递送的活性剂的量具有显著影响。已经表明,对于特定的药物和特定的疾病,通过利用如下局部用组合物可以实现最佳的药物递送,所述局部用组合物包含能够渗透表皮的角质层并变得全身可获得的溶解的活性成分,以及不易穿过表皮的角质层的微粒状态的活性成分(US 5,863,560援引加入本文)。悬浮的活性成分影响其递送的另一性质是悬浮颗粒的粒度分布。已经表明,6微米的颗粒会靶向毛囊并在终毛中渗透至500微米的深度。对于0.75微米至1.5微米尺寸的悬浮颗粒,颗粒渗透终毛干至800微米的深度(A Patzelt,F Knorr,U Blume-Peytavi,W Sterry,J Lademann,Drug Discovery Today:Disease Mechanisms,5(2)2008第e173-e181页)。因此,对于悬浮的活性成分,皮肤渗透性取决于以下性质:1)溶解的活性成分的分子结构,2)悬浮的活性成分的颗粒/晶形结构,3)悬浮的活性成分的粒度,以及4)悬浮的活性成分的粒度分布。局部用产品组合物改变皮肤渗透的能力对于悬浮的活性成分和溶解的活性成分是相似的。因为皮肤渗透性取决于悬浮的活性成分的附加性质,与仅含有溶解的活性成分的局部用产品相比,来自含有悬浮的活性剂的局部用产品的一致递送更难以维持。
通过配制成其中悬浮的颗粒的尺寸或数量经产品的货架期不显著改变的产品来确保悬浮的活性成分从局部用产品的一致递送。溶解的活性成分与颗粒活性成分的比率随时间的变化可以显著改变活性成分的皮肤渗透。可能导致溶解的活性成分沉淀的上述相同机制(过饱和、温度变化、蒸发、多晶型转变)可能改变悬浮的活性成分的溶解与颗粒比率。分散的活性成分的粒度或粒度分布随时间的变化也可以显著改变活性成分的皮肤渗透。有时粒度或粒度分布的这种变化可以通过颗粒的奥斯特瓦尔德熟化来解释。当在局部用产品中的小颗粒溶解并再沉积到悬浮在同一个局部用产品容器中的较大颗粒上时发生奥斯特瓦尔德熟化。随着时间的推移,这种现象会以较小的颗粒为代价将粒度分布向较大的颗粒改变。溶解性较小的多晶型物的奥斯特瓦尔德熟化和沉淀是开发含有悬浮的活性剂的局部用产品中的两个主要问题。
对于无刺激性和无致敏性添加剂存在需要,其可以安全地添加到局部用罗氟司特产品中,以防止悬浮的活性成分颗粒的尺寸变化。这样的添加剂可用于可能在储存过程中经历晶体生长或粒度增加的任何罗氟司特组合物中。晶体生长和粒度变化还会影响除局部用制剂外的罗氟司特药物制剂如肠胃外制剂和肺部制剂的给药和/或生物利用度。
发明内容
根据本发明,已发现己二醇在含有包括水的药学上可接受的溶剂的制剂中抑制悬浮或沉淀的罗氟司特颗粒的结晶生长。由于皮肤渗透性,抑制悬浮或沉淀的罗氟司特颗粒的结晶生长在局部施用制剂中是特别重要的。
附图说明
本专利或申请文件包含至少一个去除了颜色(executed in color)的图形。有彩图的本专利或专利申请出版物的副本会经请求并支付必要的费用而由专利局提供。
图1显示来自ferrer-Interquim S.A.批次A14367P的样品19-2“干”罗氟司特晶体,该药物物质用于本说明书的所有实施例中。罗氟司特晶体的长度为0.01mm-0.02mm。
图2显示10X倍率的在室温下储存6周后悬浮在等摩尔己二醇:水溶液中的样品20-3罗氟司特晶体。罗氟司特晶体的长度为0.01mm-0.02mm。
图3显示在室温下储存六周后悬浮在等摩尔二乙二醇单乙醚:水溶液中的样品20-2罗氟司特晶体。罗氟司特晶体的长度为0.04mm-0.20mm,宽度为0.01mm-0.02mm。
图4显示4X倍率的在室温下储存6周后悬浮于等摩尔己二醇:水溶液中的样品20-3罗氟司特晶体。罗氟司特晶体的长度为0.01mm-0.02mm。
图5显示在室温下储存六周后悬浮于等摩尔乙醇:水溶液中的样品21-2罗氟司特晶体。罗氟司特晶体的长度为0.05mm-0.25mm,宽度为0.02mm。
图6显示在室温下储存6周后悬浮于等摩尔PEG 400:水溶液中的样品21-3罗氟司特晶体。罗氟司特晶体的长度为0.05mm-0.07mm,宽度为0.02mm。
图7显示在室温下储存6周后悬浮于等摩尔DMSO:水溶液中的样品21-4罗氟司特晶体。罗氟司特晶体的长度为0.10mm-0.67mm,宽度为0.02mm-0.10mm。
图8显示在室温下储存6周后悬浮在等摩尔丙二醇:水溶液中的样品21-5罗氟司特晶体。罗氟司特晶体的长度为0.20mm-1.60mm,宽度为0.02mm。
图9显示在室温下储存6周后悬浮于等摩尔的NMP:水溶液中的样品20-1罗氟司特晶体。罗氟司特晶体的长度为0.10mm-1.55mm,宽度为0.02mm-0.13mm。
图10显示在室温下储存6周后悬浮于HG:NMP:水(水摩尔分数=1.2)溶液中的样品21-1罗氟司特晶体。罗氟司特晶体的长度为0.02mm-0.04mm,宽度为0.02mm。
图11A和11B显示在一次冻融循环后在霜剂组合物中沉淀的罗弗司特颗粒。图11a显示在具有二乙二醇单乙醚(DEGEE)且不含己二醇的霜剂组合物中沉淀的样品36-1罗氟司特颗粒。测量三个最大的罗氟司特颗粒(0.07mm×0.09mm;0.06mm×0.06mm;和0.10mm×0.05mm),发现平均表面积为5,000平方微米。图11b显示在具有二乙二醇单乙醚(DEGEE)和己二醇两者的霜剂组合物中沉淀的样品36-2罗氟司特颗粒。测量三个最大的罗氟司特颗粒(0.05mm×0.03mm;0.05mm×0.03mm和0.05mm×0.03mm),发现平均表面积为1,500平方微米。
具体实施方式
罗氟司特是式(I)的化合物
其中R1是二氟甲氧基,R2是环丙基甲氧基并且R3是3,5-二氯吡啶-4-基。
该化合物的化学名称为N-(3,5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺(INN:罗氟司特)。
己二醇(PharmaGrade.USP/NF)是式(II)的2-甲基-2,4-戊二醇。
本发明涉及将己二醇加入到含有包括水的药学上可接受的溶剂的含罗氟司特的药物组合物中以抑制组合物中罗氟司特晶体的生长。对于设计成含有悬浮的罗氟司特颗粒或晶体的局部用产品,向含有罗氟司特的组合物中加入己二醇会抑制(即,与不含己二醇的组合物相比,防止或实质上减少)粒度分布经货架期的变化并确保一致的生物利用度。对于设计成使罗氟司特完全溶解的局部用产品,己二醇抑制沉淀的罗氟司特颗粒的生长。
如果产品配制成保持显著的热力学驱动力,那么经产品货架期对于标签储存条件具有完全溶解的药物物质的药物产品会具有活性剂沉淀。局部用药物霜剂的典型储存条件为:室温储存:60°F/15℃-80°F/26℃。不要冷冻。产品开发科学家和管理机构审查人员理解,局部用产品不会总是在此温度范围内储存。因此,FDA要求所有局部用产品进行冻融循环和温度漂移研究。当产品暴露于显着低于标签储存条件的15℃(60°F)的-20℃的温度下时,活性剂既不需要也不期望保留在溶液中。由于含有完全溶解的药物的局部用产品通常配制接近饱和,即接近最大热力学驱动力,因此大多数局部用产品在冻融循环或温度漂移研究中经历活性成分的沉淀。当由于标签储存条件以下的温度漂移发生沉淀时,加入己二醇可防止罗氟司特的晶体生长。抑制晶体生长确保一旦产品返回到受控室温下,任何沉淀的活性剂会迅速返回到完全溶解。沉淀的罗氟司特迅速返回到完全溶解状态确保局部施用产品的一致的、可再现的生物利用度、功效和安全性。可以添加基于重量/重量为0.1%至20%,优选基于重量/重量为0.25%至8%,和最优选基于重量/重量为0.5%至2%的己二醇。
受益于己二醇添加的局部用罗氟司特产品制剂包括但不限于气雾剂、泡沫剂、喷雾剂、乳剂(其也可以被称为霜剂、洗剂或软膏剂)、凝胶剂(两相或单相)、液体、软膏剂、糊剂、香波、混悬剂和体系。这些是含有药物活性成分的剂型在药典分类中的二级术语(美国药典<1151>)。
罗氟司特制剂可以通过本领域已知的方法制备(例如参见'298专利和美国申请号14/075,035)。
优选地,将己二醇加入到含有0.005-2.0%罗氟司特的组合物中,所述组合物可以是以下形式之一:
水包油乳剂:产品可以是其中将己二醇添加到乳剂中的制剂,所述乳剂包含疏水性组分的分散相和包含水和任选存在的一种或多种极性亲水性赋形剂的连续水相,以及溶剂、共溶剂、盐、表面活性剂、乳化剂和其他组分。这些乳剂可以包括有助于稳定乳剂的水溶性或水溶胀性聚合物。
增稠的含水凝胶剂:这些体系包括已经通过诸如下述的合适的天然、改性天然或合成的增稠剂增稠的水相。或者,可以使用合适的聚乙氧基化烷基链表面活性剂或其他非离子、阳离子或阴离子体系增稠该增稠的含水凝胶剂。
增稠的水醇凝胶剂:这些体系包括水和醇的混合物作为极性相,其已经通过诸如下述的合适的天然、改性天然或合成的聚合物增稠。或者,可以使用合适的聚乙氧基化烷基链表面活性剂或其它非离子、阳离子或阴离子体系增稠该增稠的水醇凝胶剂。该醇可以是乙醇、异丙醇或其他药学上可接受的醇。
亲水性凝胶剂:这些是其中连续相包括至少一种水以外的水溶性或水分散性亲水性组分的体系。该制剂还可任选地含有至多60重量%的水。较高的水平可能适用于某些组合物。合适的亲水性组分包括一种或多种二醇,诸如多元醇如甘油、丙二醇、丁二醇、聚乙二醇(PEG),环氧乙烷、环氧丙烷和/或环氧丁烷的无规或嵌段共聚物,每分子具有一个或多个疏水部分的聚烷氧基化表面活性剂,硅酮共聚多元醇,鲸蜡硬脂醇聚醚-6和硬脂醇的混合物以及它们的组合等。
油包水乳剂:组合物可以是其中将罗氟司特掺入乳剂中的制剂,所述乳剂包含疏水性组分的连续相和包含水和任选存在的一种或多种极性亲水性载体的水相,以及盐或其他组分。这些乳剂可以包括油溶性或油溶胀性聚合物以及一种或多种有助于稳定乳剂的乳化剂。
亲水性或疏水性软膏剂:将组合物用任选地具有少量水溶性相的疏水性基质(例如矿脂、增稠或凝胶化的水不溶性油等)配制。亲水性软膏剂通常含有一种或多种表面活性剂或润湿剂。
溶剂
根据本发明的组合物可包含一种或多种溶剂或共溶剂以获得活性成分在局部用产品中的期望水平的溶解度。溶剂还可以改变皮肤渗透或制剂中所含的其他赋形剂的活性。溶剂包括但不限于丙酮、乙醇、苯甲醇、丁醇、癸二酸二乙酯、二乙二醇单乙醚、己二酸二异丙酯、二甲基亚砜、乙酸乙酯、异丙醇、异硬脂酸异丙酯、肉豆蔻酸异丙酯、N-甲基吡咯烷酮、聚乙二醇、甘油、丙二醇和SD醇。
保湿剂
根据本发明的组合物可以包括保湿剂以增加水合的水平。保湿剂可以是包括湿润剂的亲水性材料,或者它可以是包括润肤剂的疏水性材料。合适的保湿剂包括但不限于:1,2,6-己三醇、2-乙基-1,6-己二醇、丁二醇、甘油、聚乙二醇200-8000、硬脂酸丁酯、鲸蜡硬脂醇、鲸蜡醇、十六烷基酯蜡、棕榈酸鲸蜡酯、可可脂、椰子油、环甲基硅油、二甲基硅油、二十二烷醇、羟基硬脂酸乙基己酯、脂肪酸、异硬脂酸甘油酯、月桂酸甘油酯、单硬脂酸甘油酯、油酸甘油酯、棕榈酸甘油酯、乙二醇二硬脂酸酯、乙二醇硬脂酸酯、异硬脂酸、异硬脂醇、羊毛脂、矿物油、柠烯、中链甘油三酯、薄荷醇、肉豆蔻醇、辛基十二烷醇、油酸、油醇、油酸油醇酯、橄榄油、石蜡、花生油、矿脂、Plastibase-50W和硬脂醇。
表面活性剂和乳化剂
根据本发明的组合物任选地可以包含一种或多种表面活性剂以乳化组合物并帮助润湿活性剂或赋形剂的表面。如本文所用,术语“表面活性剂”是指能够降低水的表面张力和/或水与不混溶的液体之间的界面张力的两亲分子(同时具有共价结合的极性和非极性区域的分子)。表面活性剂包括但不限于烷基芳基磺酸钠、Amerchol-CAB、月桂基硫酸铵、杏仁油PEG-6酯、Arlacel、苯扎氯铵、鲸蜡硬脂醇聚醚-6、鲸蜡硬脂醇聚醚-12、鲸蜡硬脂醇聚醚-15、鲸蜡硬脂醇聚醚-30、鲸蜡硬脂醇/鲸蜡硬脂醇聚醚-20、鲸蜡硬脂醇乙基己酸酯、鲸蜡醇聚醚-10、鲸蜡醇聚醚-2、鲸蜡醇聚醚-20、鲸蜡醇聚醚-23、胆甾醇聚醚-24、椰油酰胺醚硫酸盐、椰油胺氧化物、椰油基甜菜碱、椰油酰二乙醇胺、椰油酰单乙醇胺、椰油醇辛酸酯/椰油醇癸酸酯、椰油酰两性基二乙酸二钠、月桂醇聚醚磺基琥珀酸酯二钠、月桂醇磺基乙酸酯二钠、月桂醇磺基琥珀酸酯二钠、油酰胺基单乙醇胺磺基琥珀酸酯二钠、多库酯钠、月桂醇聚醚-2、月桂醇聚醚-23、月桂醇聚醚-4、月桂酰二乙醇胺、卵磷脂、甲氧基PEG-16、甲基葡糖醇聚醚-10、甲基葡糖醇聚醚-20、甲基葡糖倍半硬脂酸酯、油醇聚醚-2、油醇聚醚-20、PEG 6-32硬脂酸酯、PEG-100硬脂酸酯、PEG-12月桂酸甘油酯、PEG-120甲基葡糖二油酸酯、PEG-15椰油胺、PEG-150二硬脂酸酯、PEG-2硬脂酸酯、PEG-20甲基葡糖倍半硬脂酸酯、PEG-22甲醚、PEG-25丙二醇硬脂酸酯、PEG-4二月桂酸酯、PEG-4月桂酸酯、PEG-45/十二烷甘醇共聚物、PEG-5油酸酯、PEG-50硬脂酸酯、PEG-54氢化蓖麻油、PEG-6异硬脂酸酯、PEG-60氢化蓖麻油、PEG-7甲醚、PEG-75羊毛脂、PEG-8月桂酸酯、PEG-8硬脂酸酯、Pegoxol 7硬脂酸酯、季戊四醇椰油酸酯、泊洛沙姆124、泊洛沙姆181、泊洛沙姆182、泊洛沙姆188、泊洛沙姆237、泊洛沙姆407、聚甘油-3油酸酯、聚氧乙烯醇、聚氧乙烯脂肪酸酯、聚氧乙烯20鲸蜡硬脂基醚、聚氧乙烯40氢化蓖麻油、聚氧乙烯40硬脂酸酯、聚氧乙烯6和聚氧乙烯32、聚氧乙烯硬脂酸甘油酯、聚氧乙烯硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨酸酯60、聚山梨酸酯65、聚山梨酸酯80、PPG-26油酸酯、PROMULGENTM 12、丙二醇二乙酸酯、丙二醇二辛酸酯、丙二醇单硬脂酸酯、二甲苯磺酸钠、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、硬脂醇聚醚-2、硬脂醇聚醚-20、硬脂醇聚醚-21,硬脂醇聚醚-40、牛脂甘油酯和乳化蜡。
聚合物和增稠剂
对于某些施用,可能需要配制用以下增稠的产品:可溶性、可溶胀性或不溶性的有机聚合物增稠剂如天然和合成聚合物或无机增稠剂,诸如丙烯酸酯共聚物、卡波姆1382、B型卡波姆共聚物、A型卡波姆均聚物、B型卡波姆均聚物、C型卡波姆均聚物、羧基乙烯基共聚物、羧甲基纤维素、羧基聚亚甲基、卡拉胶、瓜尔胶、羟乙基纤维素、羟丙基纤维素、微晶蜡和甲基纤维素。
附加组分
根据本发明的组合物可以用化妆品和药物局部用产品中常规存在的附加组分如填充剂、载体和赋形剂配制。附加组分包括但不限于消泡剂、防腐剂(例如对羟基苯甲酸酯、苯甲醇、苯基汞盐、氯甲酚)、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节溶液、皮肤渗透增强剂、成膜剂、染料、颜料、稀释剂、膨松剂、芳香剂和改善稳定性或美观性的其它赋形剂,可以添加至组合物中。
根据本发明的组合物可以依据所治疗的病症用附加活性剂配制。附加活性剂包括但不限于蒽林(地蒽酚)、硫唑嘌呤、他克莫司、煤焦油、氨甲蝶呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙基硫氧嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、霉酚酸酯、富马酸酯、皮质类固醇(例如阿氯米松、安西奈德、倍他米松、氯倍他索、氯可龙(Clocotolone)、莫米松、曲安西龙、氟轻松、醋酸氟轻松、氟氢缩松、二氟拉松、地奈德、去羟米松、地塞米松、哈西奈德、乌倍他索、氢化可的松、甲基泼尼松龙、泼尼卡酯、泼尼松)、促肾上腺皮质激素、维生素D类似物(例如卡泊三醇、钙三醇)、阿维A酸、他扎罗汀、环孢素、间苯二酚、秋水仙碱、阿达木单抗、优特克单抗、英夫利昔单抗、支气管扩张剂(例如β-激动剂、抗胆碱药、茶碱)和抗生素(例如红霉素、环丙沙星、甲硝唑)。
给药和剂量
根据本发明的组合物可以通过任何合适的给药途径给药,包括但不限于口服、直肠、肠胃外(例如皮内、皮下、肌内、静脉内、髓内、动脉内、鞘内、硬膜外)、眼部、吸入、雾化、皮肤(局部用)、透皮和粘膜(例如舌下、口、鼻)。在优选的实施方案中,组合物局部给药。
合适的药物剂型包括但不限于乳剂、混悬剂、喷雾剂、油剂、软膏剂、脂肪软膏剂、霜剂、糊剂、凝胶剂、泡沫剂、透皮贴剂和溶液剂(例如注射、口服)。
组合物每剂量单位优选含有0.005-2%w/w,更优选0.05-1%w/w,最优选0.1-0.5%w/w的量的罗氟司特、罗氟司特的盐、罗氟司特的N-氧化物或其盐。
组合物优选含有0.1%至20%w/w,更优选0.25%至8%w/w,最优选0.5%至2%w/w的量的己二醇。
组合物可以每天给药一次或多次,优选组合物每天给药1-2次。
组合物可用于兽医和人类医学,用于治疗和预防所有通过使用罗氟司特视为可治疗或可预防的疾病,包括但不限于急性和慢性气道疾病;增生性、炎性和变应性皮肤病;基于TNF和白三烯过度释放的疾病;可以用PDE抑制剂治疗的心脏疾病;胃肠系统或中枢神经系统中的炎症;眼疾病;关节炎疾病;和可通过PDE抑制剂的组织松弛作用治疗的疾病。优选地,组合物用于治疗增生性、炎性和变应性皮肤病,诸如银屑病(寻常性)、湿疹、痤疮、单纯性苔癣、晒斑、瘙痒、斑秃、肥厚性瘢痕、盘状红斑狼疮和脓皮病。
组合物可以包含适合于治疗患者病症的附加活性剂。例如,当治疗增生性、炎性和变应性皮肤病时,组合物可以另外包括蒽林(地蒽酚)、硫唑嘌呤、他克莫司、煤焦油、氨甲喋呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙基硫氧嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、霉酚酸酯、富马酸酯、皮质类固醇(例如阿氯米松、安西奈德、倍他米松、氯倍他索、氯可龙、莫米松、曲安西龙、氟轻松、醋酸氟轻松、氟氢缩松、二氟拉松、地奈德、去羟米松、地塞米松、哈西奈德、乌倍他索、氢化可的松、甲基泼尼松龙、泼尼卡酯、泼尼松)、促肾上腺皮质激素、维生素D类似物(例如卡泊三醇、钙三醇)、阿维A酸、他扎罗汀、环孢素、间苯二酚、秋水仙碱、阿达木单抗、优特克单抗、英夫利昔单抗和/或抗生素。
提供以下实施例以使本领域普通技术人员能够制备和使用本发明的方法和组合物。这些实施例并不意在限制发明人视为发明的内容的范围。对于本领域技术人员而言,其他优点和修改会是显而易见的。
实施例1
将几mg的罗氟司特API(来自Interquim S.A.的批次A14367P)干粉末轻拍到显微镜载玻片上,将盖玻片移动到位并且使用偏振光显微术使用10X物镜检测API的晶体习性和粒度(图1,显微镜样品19-2)。
将0.0092克的罗氟司特(来自Interquim S.A.的批次A14367P)称重入液体闪烁小瓶中。将等摩尔的己二醇(批次1AC0818,Spectrum)与蒸馏水的混合物在混合下滴加到含有罗氟司特的小瓶中,以产生超过溶解度极限的罗氟司特的悬浮液。基于重量/重量百分比,等摩尔的混合物是86.7%己二醇和13.3%水。在将每次添加的己二醇:水混合物混合后,将密封的小瓶返回到设定在25℃的水浴中。它需要0.7962克等摩尔的己二醇:水混合物以完全溶解0.0092克的罗氟司特,并得到等摩尔的己二醇:水(wt/wt%)溶液中的1.14%罗氟司特。在25℃下,向该样品(标记为12-3)中加入0.0064克的罗氟司特以形成精细分散的悬浮液,然后在约15-18℃下将小瓶不受干扰避光保存六周。将罗氟司特晶体样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用10X物镜检测(图2,显微镜样品20-3)。
将0.0111克的罗氟司特(来自Interquim S.A.的批次A14367P)称重入液体闪烁小瓶中。将等摩尔的二乙二醇(DEGEE)(Transcutol P,批次146063,Gattefosse)与蒸馏水的混合物在混合下滴加到含有罗氟司特的小瓶中,以产生超过溶解度极限的罗氟司特的悬浮液。基于重量/重量百分比,等摩尔的混合物为88.3%DEGEE和11.7%水。在将每次添加的DEGEE:水混合物混合之后,将密封的小瓶返回到设定在25℃的水浴中。它需要0.2477克等摩尔的DEGEE:水混合物以完全溶解0.0111克罗氟司特,并得到等摩尔的DEEEE:水(wt/wt%)溶液中的4.29%罗氟司特。该样品(标记为13-1)是罗氟司特在25℃下的溶液,然后在约15-18℃下将小瓶不受干扰避光保存六周。由于储存温度较低,罗氟司特晶体沉淀。将罗氟司特晶体样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用10X物镜检测(图3,显微镜样品20-2)。
实施例2
将0.0092克的罗氟司特(来自Interquim S.A.的批次A14367P)称重入液体闪烁小瓶中。将等摩尔的己二醇(批次1AC0818,Spectrum)与蒸馏水的混合物在混合下滴加到含有罗氟司特的小瓶中,以产生超过溶解度极限的罗氟司特的悬浮液。基于重量/重量百分比,等摩尔的混合物是86.7%己二醇和13.3%水。在将每次添加的己二醇:水混合物混合后,将密封的小瓶返回到设定在25℃的水浴中。它需要0.7962克等摩尔的己二醇:水混合物以完全溶解0.0092克罗氟司特,并得到等摩尔的己二醇:水(wt/wt%)溶液中的1.14%罗氟司特。在25℃下,向该样品(标记为12-3)中加入0.0064克的罗氟司特以形成精细分散的悬浮液,然后在约15-18℃下将小瓶不受干扰避光保存六周。将罗氟司特晶体样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用4X物镜检测(图4,显微镜样品20-3)。
将0.0260克的罗氟司特(来自Interquim S.A.的批次A14367P)称重入液体闪烁小瓶中。加入1.0705克乙醇:水混合物(Everclear,其基于重量/重量百分比为74.98%乙醇和25.02%水,或按体积计为95%乙醇)以产生罗氟司特在乙醇:水混合物中的超过溶解度极限的分散体。然后在约15-18℃下将该样品(标记为“Alc”,第2页)不受干扰避光保存6周。将罗氟司特晶体样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用4X物镜检测(图5,显微镜样品20-3)。
将0.0180克的罗氟司特(来自Interquim S.A.的批次A14367P)称重入液体闪烁小瓶中。将聚乙二醇400(批次1DE0880,Spectrum)在混合下滴加到含有罗氟司特的小瓶中以产生超过溶解度极限的罗氟司特的悬浮液。在将每次添加的聚乙二醇400混合后,将密封的小瓶返回到设定在25℃的水浴中。它需要0.5486克的丙二醇400来完全溶解0.0180克罗氟司特并得到聚乙二醇400溶液中的3.18%罗氟司特。该样品(标记为“PEG 400”,第1页)是在25℃下的溶液,然后在约15-18℃下不受干扰避光保存六周。由于储存温度较低,罗氟司特晶体沉淀。将罗氟司特晶体的样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用4X物镜检测(图6,显微镜样品21-3)。
在25℃下,将0.0103克的罗氟司特(来自Interquim S.A.的批次A14367P)称重入液体闪烁小瓶中并与0.2501克的二甲基亚砜(批次US150,Gaylord Chemical)混合,以得到28.5%的罗氟司特溶液。然后在约15-18℃下将该样品(标记为“DMSO”,第2页)不受干扰避光保存6周。将沉淀的罗氟司特晶体样品从小瓶中取出,置于显微镜载玻片上(有盖玻片),然后使用偏振光显微术使用4X物镜检测(图7,显微镜样品21-4)。
在25℃下,将0.0061克的罗氟司特(来自Interquim S.A.的批次A14367P)、1.9332克的丙二醇(批次1EC0004,Spectrum)和0.2335克蒸馏水混合以初始形成澄清溶液。基于重量/重量%,样品的组成为0.28%的罗氟司特、88.97%的丙二醇和10.75%的水。在25℃下储存105分钟后,在小瓶底部观察到细罗氟司特晶体的“粉化(dusting)”。六天后,另外的晶体沉降到小瓶的底部。然后,在约15-18℃下将该样品(标记为7-2)不受干扰避光保存6周。将沉淀的罗氟司特晶体样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用4X物镜检测(图8,显微镜样品21-5)。
实施例3
与添加有超过溶解度极限的罗氟司特的12:4:3(wt/wt/wt)的己二醇:N-甲基吡咯烷酮:水(1.2摩尔分数的水)的混合物溶液相比,在含有超过药物饱和度的罗氟司特的等摩尔的N-甲基吡咯烷酮:水溶液中观察到显着更大的罗氟司特结晶生长。
将0.0202克的罗氟司特(来自Interquim S.A.的批次A14367P)与0.0682克等摩尔的N-甲基-2-吡咯烷酮:水混合物在液体闪烁小瓶中混合。基于重量/重量百分比,等摩尔的混合物是84.5%的N-甲基-2-吡咯烷酮(批次SYYN-HJ,TCI)和15.5%的水。在等摩尔N-甲基-2-吡咯烷酮:水中的22.85%罗氟司特在25℃完全溶解。然后,在约15-18℃下将该样品(标记为13-2)不受干扰避光保存6周。由于储存温度较低,罗氟司特晶体沉淀。将罗氟司特晶体的样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用4X物镜检测(图10,显微镜样品20-1)。
基于重量/重量百分比,将3.6%罗氟司特(来自Interquim S.A.的BatchA14367P)、60.8%己二醇(批次1AC0818,Spectrum)、20.0%N-甲基-2-吡咯烷酮(批次SYYN-HJ,TCI)和15.6%蒸馏水的0.8152克样品混合。该样品(标记为13-4)是在25℃下罗氟司特的细分散的悬浮液。然后在约15-18℃下将样品不受干扰避光保存6周。将罗氟司特晶体的样品从小瓶中取出,置于显微镜载玻片(有盖玻片)上,然后使用偏振光显微术使用4X物镜检测(图11,显微镜样品21-1)。
实施例4
根据以下制剂制备罗氟司特霜剂。
制剂1(比较的)
制剂2
制备后,将0.4222克的制剂1密封在1.0mL CryoTubeTM小瓶中并标记为36-1。同样,将0.3961克的制剂2密封在1.0mL CryoTubeTM小瓶中并标记为36-2。将两个CryoTubeTM小瓶用封套端对端固定并放入冷冻器中17.5小时。从冷冻器中快速取出后,制备每个样品的显微镜载玻片,并且在将样品“解冻”至室温(18℃)后,捕获显微照片图像以表征沉淀的罗氟司特晶体生长中的差异。参见图11A和11B。
Claims (45)
1.用于抑制组合物中罗氟司特晶体生长或粒度变化的方法,其包括在含有罗氟司特的组合物中包含己二醇。
2.根据权利要求1所述的方法,其中所述组合物包含悬浮的罗氟司特颗粒。
3.根据权利要求2所述的方法,其中所述悬浮的罗氟司特颗粒的尺寸变化在20-26℃下储存6周期间被抑制。
4.根据权利要求1所述的方法,其中所述己二醇以0.1-20%w/w的量加入。
5.根据权利要求4所述的方法,其中所述己二醇以0.5-2%w/w的量加入。
6.根据权利要求1所述的方法,其中所述罗氟司特组合物包含0.005-2%的罗氟司特。
7.根据权利要求1所述的方法,其中所述罗氟司特组合物选自水包油乳剂、增稠的含水凝胶剂、增稠的水醇凝胶剂、亲水性凝胶剂和亲水性或疏水性软膏剂。
8.根据权利要求1所述的方法,其中所述罗氟司特组合物还包含至少一种选自以下的附加组分:溶剂、保湿剂、表面活性剂或乳化剂、聚合物或增稠剂、消泡剂、防腐剂、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节溶液、皮肤渗透增强剂、成膜剂、染料、颜料和芳香剂。
9.根据权利要求1所述的方法,其中所述罗氟司特组合物还包含选自以下的附加活性剂:蒽林、硫唑嘌呤、他克莫司、煤焦油、氨甲蝶呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙基硫氧嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、霉酚酸酯、富马酸酯、皮质类固醇、促肾上腺皮质激素、维生素D类似物、阿维A酸、他扎罗汀、环孢素、间苯二酚、秋水仙碱、阿达木单抗、优特克单抗、英夫利昔单抗、支气管扩张剂和抗生素。
10.根据权利要求1所述的方法,其中所述己二醇在储存之前加入到所述组合物中。
11.根据权利要求1所述的方法,其中所述组合物包含一种或多种适用于局部、肠胃外或肺部给药的载体。
12.根据权利要求1所述的方法,其中所述组合物包含一种或多种适用于局部给药的载体。
13.根据权利要求1所述的方法,其还包括将二乙二醇单乙醚加入到所述组合物中。
14.根据权利要求1所述的方法,其中所述组合物包含罗氟司特、白矿脂、棕榈酸异丙酯、鲸蜡硬脂醇、磷酸二鲸蜡酯、鲸蜡醇聚醚-10磷酸酯、己二醇、二乙二醇单乙醚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和纯化水。
15.根据权利要求14所述的方法,其中所述组合物包含:
16.根据权利要求4所述的方法,其中所述己二醇以0.25-8%w/w的量加入。
17.药物组合物,其包含罗氟司特和己二醇。
18.根据权利要求17所述的药物组合物,其中所述己二醇的量足以抑制罗氟司特的晶体生长或粒度变化。
19.根据权利要求17所述的药物组合物,其中所述己二醇的量为0.1-20%w/w。
20.根据权利要求17所述的药物组合物,其中所述罗氟司特的量为0.005-2%w/w。
21.根据权利要求17所述的药物组合物,其还包含药学上可接受的填充剂、载体和/或赋形剂。
22.根据权利要求17所述的药物组合物,其还包含二乙二醇单乙醚。
23.根据权利要求21所述的药物组合物,其中所述药学上可接受的填充剂、载体和/或赋形剂适用于局部给药。
24.根据权利要求17所述的药物组合物,其中所述组合物为乳剂、混悬剂、凝胶剂、喷雾剂、油剂、软膏剂、脂肪软膏剂、霜剂、糊剂、泡沫剂、透皮贴剂或溶液剂的形式。
25.根据权利要求17所述的药物组合物,其包含罗氟司特、白矿脂、棕榈酸异丙酯、鲸蜡硬脂醇、磷酸二鲸蜡酯、鲸蜡醇聚醚-10磷酸酯、己二醇、二乙二醇单乙醚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和纯化水。
26.根据权利要求25所述的药物组合物,其包含以下组分:
27.根据权利要求19所述的药物组合物,其中所述己二醇的量为0.25-8%w/w。
28.根据权利要求27所述的药物组合物,其中所述己二醇的量为0.5-2%w/w。
29.抑制患者中的磷酸二酯酶4的方法,其包括将包含罗氟司特和己二醇的组合物给药至有此需要的患者。
30.根据权利要求29所述的方法,其中所述患者患有炎性病症。
31.根据权利要求30所述的方法,其中所述患者患有特应性皮炎。
32.根据权利要求29所述的方法,其中所述组合物包含悬浮的罗氟司特颗粒。
33.根据权利要求29所述的方法,其中所述己二醇以0.1-20%w/w的量加入。
34.根据权利要求33所述的方法,其中所述己二醇以0.25-8%w/w的量加入。
35.根据权利要求34所述的方法,其中所述己二醇以0.5-2%w/w的量加入。
36.根据权利要求29所述的方法,其中所述罗氟司特组合物包含0.005-2%的罗氟司特。
37.根据权利要求29所述的方法,其中所述罗氟司特组合物选自水包油乳剂、增稠的含水凝胶剂、增稠的水醇凝胶剂、亲水性凝胶剂和亲水性或疏水性软膏剂。
38.根据权利要求29所述的方法,其中所述罗氟司特组合物还包含至少一种选自以下的附加组分:溶剂、保湿剂、表面活性剂或乳化剂、聚合物或增稠剂、消泡剂、防腐剂、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节溶液、皮肤渗透增强剂、成膜剂、染料、颜料和芳香剂。
39.根据权利要求29所述的方法,其中所述罗氟司特组合物还包含选自以下的附加活性剂:蒽林、硫唑嘌呤、他克莫司、煤焦油、氨甲蝶呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙基硫氧嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、霉酚酸酯、富马酸酯、皮质类固醇、促肾上腺皮质激素、维生素D类似物、阿维A酸、他扎罗汀、环孢素、间苯二酚、秋水仙碱、阿达木单抗、优特克单抗、英夫利昔单抗、支气管扩张剂和抗生素。
40.根据权利要求29所述的方法,其中所述组合物通过局部、肠胃外或肺部给药来给药。
41.根据权利要求29所述的方法,其中所述组合物通过局部给药来给药。
42.根据权利要求29所述的方法,其还包括将二乙二醇单乙醚加入到所述组合物中。
43.根据权利要求29所述的方法,其中所述组合物包含罗氟司特、白矿脂、棕榈酸异丙酯、鲸蜡硬脂醇、磷酸二鲸蜡酯、鲸蜡醇聚醚-10磷酸酯、己二醇、二乙二醇单乙醚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和纯化水。
44.根据权利要求43所述的方法,其中所述组合物包含:
45.根据权利要求29所述的方法,其中所述组合物每天给药1-2次。
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