CN111107836A - 罗氟司特在水溶性的药学上可接受的溶剂的水性掺合物中的药物组合物 - Google Patents
罗氟司特在水溶性的药学上可接受的溶剂的水性掺合物中的药物组合物 Download PDFInfo
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- CN111107836A CN111107836A CN201880060842.2A CN201880060842A CN111107836A CN 111107836 A CN111107836 A CN 111107836A CN 201880060842 A CN201880060842 A CN 201880060842A CN 111107836 A CN111107836 A CN 111107836A
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- Prior art keywords
- water
- roflumilast
- pharmaceutical composition
- diethylene glycol
- monoethyl ether
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
罗氟司特在肠胃外制剂和局部用乳剂、混悬剂、凝胶剂或溶液剂中的低水溶解度可通过在药物组合物中包含水溶性的溶剂的掺合物来改善。所述水溶性的溶剂的掺合物可包含二乙二醇单***(商品名
缩写DEGEE)和水。二乙二醇单***与水的比率为1∶10至20∶1。所得的组合物具有改善的生物利用度和功效，并可用于抑制需要这样的治疗的患者中的磷酸二酯酶4。
Description
发明领域
本发明涉及罗氟司特在水溶性的药学上可接受的溶剂的掺合物中的药物组合物。更具体地，本发明涉及以下发现：罗氟司特(其为一种水溶性差的药物)在这样的溶剂掺合物中表现出出乎意料的高溶解度。
发明背景
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)。
罗氟司特及其合成记载于US 5,712,298(“＇298专利”)中，将其援引加入本文。*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专利并将其援引加入本文)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助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)的聚乙二醇400(PEG400)配制，来克服局部用乳剂(霜剂)制剂中罗氟司特的低水溶解度。
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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。
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。对于皮肤施用，制剂组分的选择决定了制剂设计者可以达到的最大皮肤通透性。霜剂、洗剂、凝胶剂、软膏剂、泡沫剂和溶液剂只是局部用罗氟司特制剂的一些较熟悉的形式，如′298专利(第12栏第37-64行)中公开，其通常包含完全溶解的活性药物成分(API)以施用至皮肤。为了治疗这样的皮肤病，已经记载用于局部施用的罗氟司特乳剂、混悬剂、凝胶剂或溶液剂，尽管所述化合物的低溶解度限制了这些应用。
已提出数种用于增强具有低水溶解度的活性成分的溶解度的方法。这些方法包括降低粒度、助水溶性(hydrotrophy)沉淀抑制剂(例如HPMC、PVP、PVA、PEG)络合作用、溶剂沉积、改变pH、冷冻干燥、表面活性剂、潜溶(co-solvency)、微乳液、固体分散物和溶剂合物形成。WO 2013/030789公开了具有差水溶性的PDE-IV抑制剂与选自糖(例如蔗糖、乳糖、微晶纤维素、低粘度羟丙基纤维素和/或羟丙甲基纤维素)、蛋白质(例如明胶)或合成聚合物(例如聚乙二醇、聚乙酸乙烯酯、聚乙烯醇和丙二醇)的黏合剂组合。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-羟基硬脂酸作为助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)的聚乙二醇400(PEG 400)配制，来克服局部用乳剂(霜剂)制剂中罗氟司特的低水溶解度。美国专利号7,951,398(援引加入本文)公开了罗氟司特(其被指明为难溶性药物)的固体分散物，其中罗氟司特在高温下分散在包含脂肪醇、甘油三酯和脂肪酸酯的基质中，然后冷却并用亲水性聚合物制粒。美国专利号6,074,670公开了非诺贝特(其为难溶性药物)的组合物，所述组合物具有改善的溶出度。所述组合物包含亲水性聚合物和表面活性剂，其中将非诺贝特用亲水性聚合物(例如聚乙烯吡咯烷酮)的溶液制粒，这导致改善的溶出曲线。美国专利号8,431,154(援引加入本文)公开了通过使用聚乙烯吡咯烷酮(PVP)的水溶液通过制备固体溶液或固体分散物进行罗氟司特制粒而具有改善的释放和改善的药代动力学特性的罗氟司特的组合物。公开的美国申请序列号14/114,541(援引加入本文)公开了新型PI3K抑制剂可以与可溶性大分子实体(例如环糊精及其合适的衍生物或含聚乙二醇的聚合物)组合，以改善其溶解度、溶出速率、掩味、生物利用度和/或稳定性。
WO 2015/132708公开了包含罗氟司特和惰性组分的多颗粒组合物的用途。通过制粒制备惰性组分，然后将其与罗氟司特混合，得到具有改善的溶出度的组合物。所述组合物优选包含聚乙烯醇作为所述惰性组分的一部分。
提高活性成分的溶解度的一项技术是将醇或二醇与水掺合以产生极性比水低的溶剂掺合物。由于药学上可接受的醇(例如乙醇或异丙醇)不是局部施用于发炎性皮肤病的理想赋形剂(因为其趋向于进一步刺激发炎的皮肤)，丙二醇是在用于治疗银屑病或特应性皮炎的局部用霜剂和凝胶剂中常用的助溶剂。丙二醇(缩写为PG)已被用于增加皮质类固醇在局部用凝胶剂、洗剂和霜剂中的溶解度，所述局部用凝胶剂、洗剂和霜剂往往含有大于20％的水和挥发物和/或小于50％的烃、蜡或多元醇(USP<1151>局部用乳剂的定义)。化学上与PG非常相似，并且于2005年首次在FDA批准的局部用产品中使用的另一种溶剂是二乙二醇单***(商品名
)，并且缩写为DEGEE。二乙二醇单***被用作载体并在制备药物组合物中用作增溶剂(例如参见美国申请序列号14/242,973；12/846079和15/376,345，通过援引加入本文)。二乙二醇单***还用作皮肤通透性增强剂(美国申请序列号15/260,554和15/297,998，通过援引加入本文)和表面活性剂(美国9,649,302，通过援引加入本文)。尽管PG已在许多FDA批准的局部用产品中使用，这比DEGEE长数十年，但这两种溶剂却非常相似，如表1中所示。然而，这些溶剂对不同活性成分的溶解度和皮肤通透性具有不同的作用。
表1.用于局部用产品的两种药学上可接受的二醇的比较。
Minghetti等人(J.Pharm.Sci.96(4)814-823，2007)测定了双氯芬酸的四种盐在纯PG和纯DEGEE中的溶解度，并且该溶解度数据汇总于表2中。
表2.双氯芬酸的四种盐的溶解度数据，取自P.Minghetti等人，J.Pharm.Sci96，814-823)
尽管两种溶剂均被认为对于局部施用，在高达且超过约50重量百分比下是安全的，但由于在患者子集中观察到的刺激，药物制剂通常将DEGEE或PG的量限制在约30％。因此，在配制局部用凝胶剂或乳剂(霜剂或洗剂)时，几乎总是将这些二醇与水掺合。当将两种溶剂掺合时，可以根据活性成分在各单独溶剂中的溶解度来计算任何掺合物的理想溶解度。当两种溶剂的物理性质紧密一致时，计算的“理想”溶解度会与观察到的溶解度最一致。J.W.Lorimer关于在混合溶剂***中溶解度的热力学的出版物(Pure&Appl.Chem.65(2)183-191，1993)显示当溶解在水(H2O)和氧化氘(D2O)的掺合物中时NaCl的理想溶解度和测量溶解度之间的精确相关性，以及在水和乙二醇的掺合物中NaCl数据的合理相关性。对于水和乙二醇的掺合物，计算的“理想”溶解度与观察到的溶解度之间最差的相关性出现在两种溶剂的等摩尔混合物中，观察到的饱和溶解度比计算的理想溶解度低18倍(J.SolutionChem.，14，635(1985))。Lorimer根据溶质(API)在溶剂中的化学势(其与溶剂掺合物的摩尔分数线性相关)，使用经典的热力学来得出理想溶解度(在文章中显示为ln(ms (12)/m°)。
在实验确定两种纯溶剂的每一种中的药物溶解度后计算在任何比率的溶剂掺合物下的预期溶解度的能力有助于局部用产品的配制。通常，已经根据API的效力确定了目标浓度。高效药物活性成分(例如一些皮质类固醇或卡泊三醇)在局部用产品中的目标浓度为0.05％至0.5％。大多数局部用产品会为约2％。由于整个皮肤上的最大热力学驱动力在饱和时发生，因此熟练的制剂设计者会想知道在一定范围的溶剂掺合比率下的溶剂掺合物中的饱和药物浓度。通过在建立实验溶解度测定的全矩阵之前计算理想溶解度值，可以将实验次数从数百次减少到少于100次观察饱和药物溶解度测定。
发明概述
根据本发明，已经发现令人惊奇地高浓度的罗氟司特可以溶解在二乙二醇单***(DEGEE)和水的溶剂掺合物中。当将所述溶剂掺合物与高达0.5％的罗氟司特配制在润肤霜中时，罗氟司特的显著提高的溶解度得以维持。
附图简述
本专利或申请文件包含至少一个去除了颜色(executed in color)的图像。有彩图的本专利或专利申请公布的副本会在请求并支付必要的费用下由专利局提供。
图1示出使用配备有10X物镜的偏振光显微镜的制剂1样品的显微图。
图2示出使用配备有10X物镜的偏振光显微镜的制剂2样品的显微图。
图3示出使用配备有10X物镜的偏振光显微镜的制剂3样品的显微图。蓝色箭头指出这五种霜剂的显微照片中五个最大的未溶解的罗氟司特颗粒。
图4示出使用配备有10X物镜的偏振光显微镜的制剂4样品的显微图。蓝色箭头指出这五种霜剂的显微照片中五个最大的未溶解的罗氟司特颗粒。
图5示出使用配备有10X物镜的偏振光显微镜的制剂5样品的显微图。蓝色箭头指出这五种霜剂的显微照片中五个最大的未溶解的罗氟司特颗粒。
发明详述
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)。罗氟司特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)。
二乙二醇单***是式(II)的化合物
本发明涉及罗氟司特溶解于二乙二醇单***(DEGEE，Gattefosse商品名
)和水的掺合物中的药物组合物，其任选地包含一种或多种药学上可接受的载体。可以使用任何合适等级的
包括
和
DEGEE和水的该掺合物可以加入赋形剂并进行进一步加工，以形成一系列药物剂型，并在药物产品的货架期内保持溶解或分子分散的罗氟司特。
本发明对于局部用制剂特别有用。可以基于DEGEE-水掺合物的局部用罗氟司特药物产品制剂在美国药典USP<1151>中进行了定义，并包括气雾剂、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用于局部施用于哺乳动物(包括人)的典型剂型。
局部施用是指向会受益于用药物产品的治疗的患者的皮肤、毛发或指甲给药。局部也可以表示施用于患者的上皮以进行局部递送。这包括经眼、耳、口腔粘膜、***粘膜、直肠粘膜或尿道施用罗氟司特。局部的最广泛定义会包括使用患者的上皮作为给药途径以获得治疗性全身水平的活性成分。局部的该定义通常被称为治疗活性成分的透皮递送。
在局部用制剂中，经常将DEGEE配制成10-30％(w/w)，优选15-20％(w/w)。类似地，在局部用产品中，将水配制为约20-90％(w/w)。对于DEGEE和水的掺合物，比率范围为1∶10至20∶1。在含有罗氟司特的制剂中，DEGEE：水的比率优选为1∶4至9∶1。
通常，DEGEE-水掺合物可用于溶解高达2.0％的罗氟司特(在成品中)或优选高达0.5％的罗氟司特(在成品中)。所述成品优选为以下形式之一：
水包油乳剂：所述局部用产品可以是乳剂，其包含分散疏水相和包含DEGEE-水掺合物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、助溶剂、盐、表面活性剂、乳化剂和其他组分。这些乳剂可以包含有助于稳定所述乳剂的水溶性或水溶胀性聚合物。
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，所述乳剂包含连续疏水相和包含DEGEE-水掺合物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。这些乳剂可以包含油溶性或油溶胀性聚合物以及一种或多种有助于稳定所述乳剂的乳化剂。
对于水包油乳剂和油包水乳剂，添加顺序可能是重要的。可以添加预先溶解在含有DEGEE-水掺合物的连续水相中的罗氟司特。类似地，可将罗氟司特预先溶解在乳剂的疏水分散相中，然后与不包含活性成分的DEGEE-水掺合物和任选存在的亲水性赋形剂混合。可将罗氟司特预先溶解在乳剂的油相和水相中，也可以在乳剂形成后添加预先溶解在DEGEE或DEGEE-水掺合物中的罗氟司特。在乳剂冷却期间，一些乳剂在特定温度范围内发生相转变。因此，可以将罗氟司特在高于相转变温度的情况下添加至油包水乳剂中，最终药物产品是在受控室温下的水包油乳剂，反之亦然。
增稠的含水凝胶剂：这些***包含DEGEE-水掺合物与溶解的罗氟司特和任选存在的一种或多种极性亲水性载体(如己二醇)，其已通过如下文所述的合适的天然、改性的天然或合成增稠剂增稠。或者，可以使用合适的聚乙氧基化烷基链表面活性剂或其他非离子、阳离子或阴离子体系增稠所述增稠的含水凝胶剂。
增稠的水醇凝胶剂：这些***包含DEGEE-水-醇掺合物与溶解的罗氟司特和任选存在的一种或多种极性亲水性载体(如己二醇)作为极性相，其已通过如下文所述的合适的天然、改性的天然或合成聚合物增稠。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所述增稠的水醇凝胶剂。所述醇可以是乙醇、异丙醇或其他药学上可接受的醇。
亲水性或疏水性软膏剂：将组合物用疏水性基质(例如矿脂、增稠或凝胶化的水不溶性油等)配制，并任选地具有少量DEGEE-水掺合物与溶解的罗氟司特。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
本发明的组合物可包含一种或多种溶剂或助溶剂以获得活性成分在产品中的期望水平的溶解度。所述溶剂还可以改变皮肤通透或局部用产品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***、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、丙二醇和SD醇。
保湿剂
本发明的组合物可以包含保湿剂以提高水合的水平。对于乳剂，保湿剂通常是分散或连续疏水相的组分。所述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
本发明的组合物可任选地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成分或赋形剂的表面。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-10磷酸酯、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、二鲸蜡醇磷酸酯、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、PROMULGENTM12、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局部用产品：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，包括但不限于丙烯酸酯共聚物、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、聚羧乙烯、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
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配制。附加组分包括但不限于消泡剂、防腐剂、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节溶液、透皮吸收促进剂、成膜材料、染料、色素、芳香剂和改善产品的稳定性或美观性的其它赋形剂。在优选的实施方案中，添加己二醇以在组合物的货架期内抑制粒度分布的变化。己二醇可以按重量/重量计添加0.1％至20％，优选按重量/重量计添加0.25％至8％，并且最优选按重量/重量计添加0.5％至2％。
本发明的组合物可以依据所治疗的病症与附加活性剂配制。所诉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、甲氨蝶呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙硫氧嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、吗替麦考酚酯、延胡索酸酯、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、***、去羟米松、***、哈西奈德、乌倍他索、氢化可的松、甲基***龙、泼尼卡酯、***)、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、他扎罗汀、环孢素、间苯二酚、秋水仙碱、阿达木单抗、乌司奴单抗、英利昔单抗、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
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、含服、鼻)。在优选的实施方案中，将所述组合物局部给药。
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)。
所述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，并且最优选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。
所述组合物优选含有5％至50％w/w，更优选20％至30％w/w，并且最优选22.5％至27.5％w/w的量的二乙二醇单***。
所述组合物可以每天给药一次或多次，优选所述组合物每天给药1-2次。
所述组合物可用于兽医和人类医学，用于治疗和预防所有认为通过使用罗氟司特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***或中枢神经***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，所述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。
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0.0061克的罗氟司特(来自Interquim S.A.的批次A14367P)称量入液体闪烁小瓶中。将PG(丙二醇，Spectrum Chemical批次IEC0004)在混合下滴加到含有罗氟司特的小瓶中。在将每次添加的PG混合之后，将盖紧的小瓶放回至设定为25℃的水浴中。它需要1.9332克PG才能完全溶解0.0061克的罗氟司特，这等于在25℃下罗氟司特在PG中的0.3w/w％的观察到的饱和溶解度。将WO95/01338中记载的值0.53mg/l(在21℃下)用作罗氟司特在水中的饱和溶解度的观察值，其等于0.000053w/w％。使用Lorimer方程、在PG中的观察到的饱和溶解度(0.3％罗氟司特)和在水中的观察到的饱和溶解度(0.000053％)，罗氟司特在等摩尔PG：水中的计算的理想溶解度为0.0040w/w％。
制备2.3200克PG(Spectrum Chemical批次IEC0004)与蒸馏水的等摩尔掺合物，并将其加入到含有0.0012克罗氟司特(来自Interquim S.A.的批次A14367P)的闪烁小瓶中。平衡至25℃后，罗氟司特完全溶解，形成0.052％的溶液。按重量/重量百分比计，等摩尔掺合物是80.7％PG和19.3％水。在25℃下添加2.2696克等摩尔PG∶水未完全溶解0.0017克罗氟司特(0.075％罗氟司特)。实验确定的罗氟司特等摩尔PG∶水在25℃下的观察到的饱和溶解度为0.06w/w％。
在25℃下，罗氟司特在等摩尔PG∶水中的观察到的饱和溶解度比罗氟司特在等摩尔PG∶水掺合物(80.7∶19.3PG∶水w/w)中的计算的理想溶解度高15倍。
实施例2
将0.0205克的罗氟司特(来自Interquim S.A.的批次A14367P)称量入液体闪烁小瓶中。将DEGEE(Transcutol P，批号146063，Gattefosse)在混合下滴加到含有罗氟司特的小瓶中。在将每次添加的DEGEE混合之后，将盖紧的小瓶放回至设定为25℃的水浴中。它需要0.2699克DEGEE才能完全溶解0.0205克的罗氟司特，这等于在25℃下罗氟司特在DEGEE中的7.1w/w％的观察到的饱和溶解度。将WO95/01338中记载的值0.53mg/l(在21℃下)用作罗氟司特在水中的饱和溶解度的观察值，其等于0.000053w/w％。使用Lorimer方程、在DEGEE中的观察到的饱和溶解度(7.1％罗氟司特)和在水中的观察到的饱和溶解度(0.000053％)，罗氟司特在等摩尔DEGEE：水中的计算的理想溶解度为0.019w/w％。
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。制备DEGEE(Transcutol P，批次146063，Gattefosse)与蒸馏水的等摩尔掺合物，并将其在混合下滴加到含有罗氟司特的小瓶中。按重量/重量百分比计，等摩尔掺合物是88.3％DEGEE和11.7％水。在将每次添加的等摩尔DEGEE：水混合之后，将盖紧的小瓶放回至设定为25℃的水浴中。在添加0.2337克等摩尔DEGEE∶水后0.0111克罗氟司特未溶解(4.53％罗氟司特)，但在添加0.2477克等摩尔DEGEE∶水后溶解(4.29％罗氟司特)。实验确定的罗氟司特等摩尔DEGEE∶水在25℃下的饱和溶解度为4.4w/w％。
在25℃下，罗氟司特在等摩尔DEGEE∶水中的观察到的饱和溶解度比罗氟司特在等摩尔DEGEE∶水掺合物(88.3∶11.7DEGEE∶水w/w)中的计算的理想溶解度高232倍。
实施例3
0.5％罗氟司特霜剂根据以下配方制备。在密闭的玻璃容器中存放至少一个月后，将稀薄的霜剂涂片放在玻璃显微镜载玻片上，并将盖玻片放在样品上。使用配备有10X物镜的偏振光显微镜获得样品的显微图(图1-5)。检查显微图显微照片以确定霜剂中是否存在未溶解的罗氟司特。蓝色箭头指出这五种霜剂的显微照片中五个最大的未溶解的罗氟司特颗粒。只有两个含有Transcutol(25％)的霜剂不含未溶解的活性剂。
制剂1
*(鲸蜡硬脂醇、二鲸蜡醇磷酸酯和鲸蜡醇聚醚-10磷酸酯的Croda乳化剂掺合物的商品名)
制剂2
制剂3
**(鲸蜡硬脂醇聚醚-6和硬脂醇的BASF乳化剂掺合物的商品名)
制剂4
***(Croda乳化剂PEG-75羊毛脂的商品名)
制剂5
Claims (19)
1.药物组合物，其包含罗氟司特，并包含水溶性的药学上可接受的溶剂的掺合物，其中所述掺合物包含二乙二醇单***和水，其中所述二乙二醇单***的量为10-30％(w/w)，并且所述水的量为20-90％(w/w)。
2.权利要求1的药物组合物，其中所述二乙二醇单***的量为15-20％w/w。
3.权利要求1的药物组合物，其中所述罗氟司特的量为0.005-2％w/w。
4.权利要求1的药物组合物，其中二乙二醇单***与水的比率为1∶10至20∶1。
5.权利要求4的药物组合物，其中所述二乙二醇单***与水的比率为1∶4至9∶1。
6.权利要求1的药物组合物，其中所述药物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、亲水性凝胶剂以及亲水性或疏水性软膏剂。
7.权利要求1的药物组合物，其中所述药物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、透皮吸收促进剂、成膜材料、染料、色素和芳香剂。
8.权利要求1的药物组合物，其中所述药物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、甲氨蝶呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙硫氧嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、吗替麦考酚酯、延胡索酸酯、皮质类固醇、促肾上腺皮质激素、维生素D类似物、阿维A、他扎罗汀、环孢素、间苯二酚、秋水仙碱、阿达木单抗、乌司奴单抗、英利昔单抗、支气管扩张剂和抗生素。
9.权利要求1的药物组合物，其中所述药物组合物包含适用于局部、肠胃外或肺部给药的载体。
10.权利要求9的药物组合物，其中所述药物组合物包含适用于局部给药的载体。
11.权利要求1的药物组合物，其中所述药物组合物还包含量为0.1-20％w/w的己二醇。
12.克服罗氟司特制剂的低水溶解度的方法，其包括在包含罗氟司特的组合物中组合二乙二醇单***和水，其中所述二乙二醇单***的量为10-30％(w/w)，所述水的量为20-90％(w/w)，并且所述罗氟司特处于饱和浓度。
13.权利要求12的方法，其中二乙二醇单***与水的比率为1∶10至20∶1。
14.权利要求13的方法，其中所述二乙二醇单***与水的比率为1∶4至9∶1。
15.权利要求12的方法，其中所述二乙二醇单***的量为15-20％(w/w)。
16.权利要求12的方法，其中所述罗氟司特组合物包含0.005-2％的罗氟司特。
17.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二乙二醇单***的组合物向所述患者给药。
18.权利要求17的方法，其中所述患者患有炎性病症。
19.权利要求18的方法，其中所述患者患有特应性皮炎。
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| US15/712,900 US11534493B2 (en) | 2017-09-22 | 2017-09-22 | Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents |
| US15/712,900 | 2017-09-22 | ||
| PCT/US2018/051691 WO2019060379A1 (en) | 2017-09-22 | 2018-09-19 | PHARMACEUTICAL COMPOSITIONS OF ROFLUMILAST IN AQUEOUS MIXTURES OF PHARMACEUTICALLY ACCEPTABLE SOLVENTS MISCIBLE TO WATER |
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| US20210161870A1 (en) | 2017-06-07 | 2021-06-03 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
| US20200155524A1 (en) | 2018-11-16 | 2020-05-21 | Arcutis, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
| US11129818B2 (en) | 2017-06-07 | 2021-09-28 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
| US9895359B1 (en) * | 2017-06-07 | 2018-02-20 | Arcutis, Inc. | Inhibition of crystal growth of roflumilast |
| KR20210044191A (ko) | 2018-06-04 | 2021-04-22 | 아큐티스, 인크. | 로플루밀라스트 피부 침투 지연 시간의 개선 방법 및 제형 |
| CN114828840A (zh) * | 2019-10-11 | 2022-07-29 | 泽威恩制药有限责任公司 | 秋水仙碱的改进的局部用组合物 |
| MX2022009399A (es) * | 2020-01-31 | 2022-09-19 | Arcutis Biotherapeutics Inc | Formulacion topica de roflumilast que tiene mayor liberacion y semivida plasmatica. |
| WO2022169615A1 (en) * | 2021-02-05 | 2022-08-11 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
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| IL273376B1 (en) | 2024-03-01 |
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| US20190091333A1 (en) | 2019-03-28 |
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| ES2972843T3 (es) | 2024-06-17 |
| EP4316590A2 (en) | 2024-02-07 |
| CA3076002A1 (en) | 2019-03-28 |
| MX2020003001A (es) | 2020-09-28 |
| KR102681877B1 (ko) | 2024-07-04 |
| JP7402301B2 (ja) | 2023-12-20 |
| JP7191944B2 (ja) | 2022-12-19 |
| JP2023027195A (ja) | 2023-03-01 |
| EP3684334B1 (en) | 2023-12-06 |
| US11534493B2 (en) | 2022-12-27 |
| BR112020005421A2 (pt) | 2020-09-29 |
| IL273376A (en) | 2020-05-31 |
| AU2018337752A1 (en) | 2020-04-09 |
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