CN107088227A - 用于使治疗剂增溶的药物溶液和方法 - Google Patents
用于使治疗剂增溶的药物溶液和方法 Download PDFInfo
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- CN107088227A CN107088227A CN201610878523.5A CN201610878523A CN107088227A CN 107088227 A CN107088227 A CN 107088227A CN 201610878523 A CN201610878523 A CN 201610878523A CN 107088227 A CN107088227 A CN 107088227A
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- tocopherols
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Abstract
本发明涉及用于使治疗剂增溶的药物溶液和方法。特别地，本发明提供了一种包含疏水性或亲脂性的治疗剂的药物溶液，以及制备该药物溶液的方法。本发明的药物溶液通过将所述治疗剂溶解在一种或多种生育酚类或生育三烯酚类以及一种或多种醇类或二醇类中来制备。这些溶液被用于制备药物组合物。
Description
本申请为国际申请PCT/US2009/038518于2010年9月28日进入中国国家阶段、申请号为200980111145.6、发明名称为“用于使治疗剂增溶的药物溶液和方法”的分案申请。
本发明申请要求在2008年3月28日提交的美国申请序列号61/040,281的权益和优先权，其在此全部引入作为参考。
技术领域和背景技术
每年发现大量的潜在治疗剂，其中很多是水不溶性的或是水溶性差的。对于这样的疏水性的化合物，直接注射是不可能的或是高度危险的，并可能导致溶血、静脉炎、超敏、器官衰竭和/或死亡。这样的化合物被药剂师称作“亲脂性的”、“疏水性的”，或它们中最不可溶的形式，“两憎的”。
这些范畴内的治疗剂的一些例子是布洛芬、地西泮、灰黄霉素、环孢素、可的松、阿地白介素、依托泊甙和紫杉醇(Kagkadis等人，PDA J.Pharm.Sci.Tech.1996 50(5):317-323；Dardel Anaesth.Scand.197620:221-24；Sweetana和Akers PDAJ.Pharm.Sci.Tech.1996 50(5):330-342)。
化疗药的给药是显著的问题。大部分的这些药的溶解性差，因此难以通过水性溶剂递送以及难以以治疗有效水平被供给。此外，水可溶的化疗药一般被癌细胞和非癌细胞两者所吸收，从而导致这类药剂缺乏特异性，并时常有不可接受的毒性。
对于不能被配制成水性溶液的治疗剂，乳剂常常提供了一个成本有效和治疗可接受的选择。然而，使静脉内注射用乳剂无菌和/或不含内毒素是困难的。通常用于药用乳剂的油类包括来自甘油三酯类的可皂化油，例如，大豆油、芝麻油、棉籽油、红花油等(Hansrani等人，J.Parenter.Sci.Technol.1983 37:145-150)。一种或多种表面活性剂用于稳定乳剂，以及加入赋形剂使乳剂更加生物相容、更稳定和毒性更低。来自蛋黄或大豆的卵磷脂是常用的表面活性剂。无菌生产的完成是通过在生产前对所有成分灭菌，随后在生产的各阶段进行无菌操作来进行的。生产简易性的改进和无菌保证是通过加热或过滤的最终灭菌和随后的清洁生产而获得的。然而，通过加热或过滤处理进行的最终灭菌，并不适合所有的乳剂。
维生素E的乳剂已经公开。例如，可注射维生素E乳剂由Hidiroglou和Karpinski描述(Brit.J.Nutrit.1988 59:509-518)描述用于绵羊的膳食补充，以及用于维生素E及其衍生物的药代动力学研究。用于小鼠的可注射形式的维生素E由Kato等人制备(Chem.Pharm.Bull.1993 41(3):599-604)。胶束溶液是用吐温80、BRIJ 58和HCO-60配制的。异丙醇用作共溶剂，然后经真空蒸发被除去；残留的油玻璃(oil glass)随后通过涡旋被聚集在水中，作为胶束混悬液。乳剂也可以通过用大豆磷脂酰胆碱(卵磷脂)以及大豆油溶解维生素E获得。加入水并超声处理制得乳剂。不含乙醇的α-生育酚乳剂，通过用作治疗性药物的介质或载体的生物相容性表面活性剂来稳定，也已在美国专利号6,667,048和6,660,286中公开了。
E-Ferol，一种用于新生儿维生素E的补充和治疗的维生素E乳剂，也由Alade等人公开了(Pediatrics(1986)77(4):593-597)。用于乳化E-Ferol中25mg/mL的维生素E的表面活性剂混合物是由9％的吐温80和1％的吐温20组成。然而，这种添加物并不安全。
使低溶性化合物增溶的一种备选方式是在非水性环境下直接增溶，例如，醇类(如乙醇)、二甲基亚砜、和/或甘油三乙酸酯。例如，WO 95/11039描述了使用维生素E(100毫克)、卵磷脂(20毫克)、乙醇(100毫克)和EUTANOL(500毫克)作为免疫抑制剂分子环孢素(50毫克)的注射制剂。美国专利号5,689,846描述了紫杉醇的多种醇溶液。美国专利号5,573,781公开了在乙醇、丁醇和己醇中的紫杉醇溶出，同在乙醇中递送相比，当在丁醇、己醇中递送时，增加了紫杉醇的抗肿瘤活性。
WO 95/31217公开了生育酚类可以用作实质上不溶于水的药物的溶剂和/或乳化剂，特别是用于局部用制剂的制备。提及了维生素E-TPGS用作含高浓度α-生育酚的制剂中的乳化剂的应用，由脂质层(α-生育酚)、药物和维生素E-TPGS构成的局部给药用制剂，所述维生素E-TPGS作为乳化剂在该制剂中的量低于25％w/w。
WO 97/03651公开了脂质介质药物递送组合物，其含有至少五种成分：治疗性药物、维生素E、溶解药物和维生素E的油、稳定剂(磷脂、卵磷脂或泊洛沙姆，泊洛沙姆是一种聚氧乙烯-聚氧丙烯的共聚物)和水。
类似地，美国专利号6,962,691教导了由至少十种成分组成的局部用组合物：阿仑膦酸钠、聚维酮、聚维酮乙酸乙烯酯、维生素E、薄荷醇、异山梨酯二甲醚、丙酮、乙醇、四氟乙烷和二氯二氟甲烷。
美国专利号4,393,073也教导了在含乙醇的药物组合物中维生素E作为活性成分。
发明内容
本发明的一个方面涉及一种药物溶液，其包含溶解在一种或多种天然或合成的生育酚类或生育三烯酚类或其任意组合以及一种或多种醇类或二醇类或其任意组合中的治疗剂。在一些实施方案中，生育酚类和/或生育三烯酚类的量为约30％到约99％(重量/重量)以及醇类和/或二醇类的量是约1％至约70％(重量/重量)。
本发明的另一个方面涉及生产这些药物溶液的方法。
本发明的另一个方面涉及用这些药物溶液治疗患者的方法。
具体实施方式
本发明涉及一种或多种生育酚类和/或生育三烯酚类以及一种或多种醇类和/或二醇类作为使治疗剂增溶、特别是使疏水性或亲脂性的治疗剂增溶的药学可接受溶剂的应用。有利地，所得的药物溶液不是乳剂或囊泡，可以直接用于生产药物组合物。此外，相比于纯的醇溶液，生育酚类和/或生育三烯酚类以及醇类和/或二醇类的组合对皮肤和/或粘膜的刺激性更小，通常提供了比乳剂、脂质体、囊封体或环糊精更高的治疗剂载量。
本发明上下文中的溶液是均匀的混合物，其由三种或更多种的物质组成。在这样的混合物中，溶质溶解在被称为溶剂的其它物质中。根据本发明，药物溶液通过在作为溶剂的生育酚类和/或生育三烯酚类以及醇类和/或二醇类中溶解治疗剂来形成。在本发明的一个实施方案中，治疗剂完全溶解在生育酚类和/或生育三烯酚类以及醇类和/或二醇类的溶剂中。在本发明的另一实施方案中，治疗剂可能不完全溶解，从而部分地溶解在生育酚类和/或生育三烯酚类以及醇类和/或二醇类溶剂中。在这个具体实施方案中，治疗剂的微粒可能存在于药物溶液中。任一实施方案所得的药物溶液可用于采用多种给药方式的多种药物组合物中。
生育酚类和/或生育三烯酚类以及醇类和/或二醇类的组合还用于使至少部分两憎的治疗剂增溶。在此实施方案中，溶液作为一种运输相，通过部分增溶来增加来自于治疗剂的细分散混悬液中的两憎治疗剂的生物利用度。
依照本发明中使用的生育酚类和/或生育三烯酚类包括天然和合成的化合物家族，以母育酚或维生素E的通用名为人所知。α-生育酚是这个化合物家族中最丰富和最具活性的形式，它由以下化学结构表示：
这个家族的其他成员包括β-、γ-和δ-生育酚，α-、β-、γ-和δ-生育三烯酚，tocopsoralen，α-生育酚衍生物和/或类似物例如维生素E的乙酸酯、磷酸酯、琥珀酸酯、烟酸酯和亚油酸酯，以及其异构体及其酯。在此使用生育酚类和/或生育三烯酚类术语，指的是被包含这个家族中的任何单独或组合的成员。在本发明的一个实施方案中，所用的生育酚类和/或生育三烯酚类是α-生育酚。
本发明使用的醇类的例子包括但不限于乙醇、丙醇、丁醇、戊醇、苯甲醇以及其任何异构体，以及其任何组合。本发明使用的二醇类的例子包括但不限于乙二醇、丙二醇、丁二醇、戊二醇以及其任何异构体，以及其任何组合。在本发明的一个实施方案中，醇类是乙醇。优选使用乙醇，其是生物相容的，在某种意义上，其是无毒的，不会造成任何生理或药理影响。在这方面，乙醇期望是180至200标准加仑的乙醇，即在90-100％乙醇的范围内。有利地，用醇类或二醇类稀释生育酚类或生育三烯酚类，大幅减少生育酚类或生育三烯酚类的特性粘度，进而产生可喷雾剂型。
根据本发明，一种或多种生育酚类和/或生育三烯酚类以及一种或多种醇类和/或二醇类的溶液被用于使疏水性或亲脂性的治疗剂增溶，从而提供了治疗剂的增加的生物利用度。在某些实施方案中，生育酚类和/或生育三烯酚类的量是约30％到约99％(重量/重量)，以及醇类和/或二醇类的量是约1％到约70％(重量/重量)。
作为一个非限制的例子，在室温下地西泮的溶解度在190标准加仑的乙醇中小于或等于6.67％。然而，发现生育酚类和乙醇的组合能使地西泮的溶解度接近10％的水平。通过具体说明，在70％的生育酚：30％的乙醇(200标准加仑)中，地西泮以大于或等于8％溶解；在95％的生育酚：5％的乙醇(200标准加仑)中，地西泮以大于或等于9％溶解。
相应地，对一些实施方案，优选的是α-生育酚和乙醇分别占药物溶液的60％至99％和1％至40％。在其它实施方案中，α-生育酚和乙醇分别占药物溶液的约70％至90％及10％至30％。还有一些实施方案中，使用生育酚类和乙醇的比例分别为约95:5、90:10、85:15、80:20、75:25、70:30、65:35或60:40。
本发明的药物溶液通过在作为药学上可接受的溶剂的一种或多种生育酚类和/或生育三烯酚类以及一种或多种醇类和/或二醇类中溶解任何难溶解的治疗剂(例如，疏水性或亲脂性的治疗剂)制得。对于治疗剂，指的是包括，但不限于，有机小分子、治疗性的肽、非肽和核苷酸。水溶性分子的疏水衍生物如脂质结合物/前药也属于治疗剂的范畴。
示例性的疏水性或亲脂性的治疗剂，根据本发明能够被增溶的，包括但不限于，甾族化合物如地塞米松、17-β-雌二醇；苯并二氮杂卓类诸如地西泮、阿普唑仑、溴西泮、氯氮卓(chlordiazepoxidem)、氯硝西泮、艾司唑仑、氟硝西泮、氟西泮、劳拉西泮、氯甲西泮、美沙唑仑、硝西泮，奥沙西泮、替马西泮和三唑仑；雷帕霉素及类似物；泰素(紫杉醇)及类似物；放线菌素D；前列腺素(PGEl)；维生素A；普罗布考；巴马司他；他汀类药物(HMG-CoA还原酶抑制剂；曲匹地尔(和其他抗增殖生长因子抑制剂)；细胞松弛素B；以及微管结合剂如艾普赛隆(epothilones)、艾鲁赛宾(elutherobin)和地松莫莱(discodermolide)。本发明的药物溶液和用这些溶液配制成的组合物可以在溶液中包含一种或多种治疗剂。进一步地，由本发明的药物溶液配制成的药物组合物可以进一步含有囊封的或微粉化(不溶的)形式的一种或多种附加治疗剂。
本发明还提供了生育酚类和/或生育三烯酚类以及醇类和/或二醇类的组合用于使至少部分两憎的治疗剂增溶的应用。在此实施方案中，溶液作为一种运输相，通过部分增溶来增加来自于治疗剂的细分散混悬液中的两憎治疗剂的生物利用度。
本发明的药物溶液可被配制成通过血管内、经口、肌肉内、皮肤和皮下途径给药至动物(优选人类)的药物组合物。具体来说，本发明的药物组合物可以通过以下非限制性的示例性途径中的任意一种来给药，腹内、动脉内、关节内、囊内、宫颈内、颅内、导管内、硬膜内、病灶内、小房内、腰椎内、壁内、鼻内、眼内、手术中、顶骨内(intraparietal)、腹膜内、胸膜内、肺内、脊椎内、胸内、气管内、鼓室内、子宫内和心室内。本发明的药物组合物可以使用机械喷雾器或合适的气雾喷射剂雾化，这是亲脂化合物的肺递送的现有技术中已知的。在任何特定情况下最合适的途径将取决于接受治疗的病症的性质和严重度，以及取决于正在使用的特定的治疗剂的性质。
本发明的药物溶液特别适用于粘膜给药的制剂，例如通过任何适合方式的鼻粘膜或肺粘膜给药。对于许多治疗剂而言，通过鼻途径给药使得能够更快地全身性地达到治疗剂的治疗水平。然而，许多治疗药物是如此的微溶于水，以致在一定体积的、能顺应于粘膜使用的水性溶剂中不能溶解治疗有效量。然而，使用本发明的药物溶液，能提供使亲水性和亲脂性的治疗剂溶解的能力提高，从而提供了一种有用的递送系统，用于向一种或多种粘膜包括鼻粘膜给药这类治疗剂。这种溶液能够通过，例如计量式吸入器或雾化器，或在喷雾器中给药。
本发明的药物溶液，包括治疗剂、一种或多种生育酚类和/或生育三烯酚类和一种或多种醇类和/或二醇类，也可被配制成注射用药物组合物，通过使本发明的药物溶液组合如生理盐水或水及维生素E增溶剂如克列莫佛(Cremophor)。这种药物组合物可进一步含有其它药学上可接受的添加剂，例如，但不限于，酸化剂、碱化剂、缓冲剂、螯合剂、络合剂和增溶剂、抗氧化剂和抗菌剂、防腐剂、渗透增强剂、保湿剂、助悬剂和/或粘度调节剂、张力剂和润湿剂或其他生物相容的材料。
当用于口服治疗给药时，本发明的药物溶液可以与一种或多种载体结合，以及以可摄取的片剂、口颊片、锭剂、胶囊、酏剂、混悬剂、糖浆剂、薄片剂、咀嚼胶、食品等形式使用。这样的组合物和制备物应包含至少0.1％的活性化合物。片剂、锭剂、丸剂、胶囊等等也可以包含下述的一种或多种：粘合剂如黄蓍树胶、阿拉伯树胶、玉米淀粉或明胶；赋形剂如磷酸二钙；崩解剂诸如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂如硬脂酸镁；以及甜味剂如蔗糖、果糖、乳糖或阿斯巴甜或调味剂如薄荷、冬青油或樱桃调味剂。上述清单只是一个代表，本领域技术人员可以想到其他粘合剂、赋形剂、甜味剂等等。当单位剂量形式是胶囊时，它可以包含，除了上述类型材料之外的液体载体如植物油或聚乙二醇。其他各种材料可以作为包衣存在或以其它方式改变固体单位剂量形式的物理形态。例如，片剂，丸剂或胶囊，可以用明胶，蜡，虫胶或糖等来包衣。
糖浆剂或酏剂可以包含本发明的药物溶液，蔗糖或果糖作为甜味剂，甲酯和对羟苯甲酸丙酯作为防腐剂，染料和调味剂例如樱桃或柑橘香料。当然，制备任何单位剂量形式的任何材料，应当以实质上无毒的量使用。
此外，本发明的药物溶液能够被配制成缓释制剂和装置，包括但不限于依靠渗透压来获得期望的释放曲线的那些。
适合于胃肠外给药的制剂可以是水性或非水性的注射溶液，其通常与预期的接受者的血液等渗。这些制剂可以含有抗氧化剂，缓冲剂，抑菌剂和使制剂与预期的接受者的血液等渗的溶质。水性的和非水性的无菌混悬剂可以包括助悬剂和增稠剂。所述制剂可以存在于单位剂量和多剂量的容器，例如密封的安瓿和小瓶。
适合在皮肤上局部应用的制剂，可以以膏、霜、洗液、糊剂、凝胶剂、喷雾剂、气雾剂、油或其他药物制剂的形式使用，从而实现治疗剂和皮肤的直接接触。适合封闭疗法的局部用制剂也可以被制得。
膏、霜、洗液和糊剂形式的制剂通常具有油性基质(如白凡士林和白膏)形式的载体；通过加入油包水乳化剂到油性基质(如亲水凡士林，AQUABASE和AQUAPHOR)中形成吸收基质；油包水乳剂基质，通过向吸收基质(如HYDROCREAM，EUCERIN，妮维雅和冷霜)中加水而形成；水包油乳剂基质(如DERMABASE，UNIBASE，VELVACHOL和亲水性膏)；以及水溶性基质(例如，聚乙二醇膏，如PEG 400-600G或PEG 3350-400G)。适合生产喷雾剂、凝胶剂、或气雾剂的载体是本领域已知的。
局部应用的载体也可以包含其他的成分例如其他载体、保湿剂、渗透增强剂、湿润剂、润肤剂、分散剂、辐射阻断剂、清洁剂、抗感染药物(如抗生素、杀真菌剂、灭疥癣药或灭虱药)、抗炎药(如皮质类固醇)、角质层分离剂(能软化，松动，并促进表皮的上皮细胞脱落的药剂)以及对局部用组合物的活性没有显著副作用的其他合适的材料。附加成分可以包括，例如，酸式磷酸钠保湿剂，金缕梅提取物、甘油保湿剂、杏核仁油润肤剂或玉米油分散剂。其他材料可以任选地被包括在含有肌醇或复合B族维生素的局部用组合物中。
适合于经皮给药的制剂可以作为适合与接受者的表皮保持直接接触的，并可保持长时间的离散的贴剂存在。适合于经皮给药的制剂也可以通过电离子透入法被递送(例如见，Pharmaceutical Research 3(6)：318(1986))，以及通常采取可选的经缓冲的水性溶液的形式。本发明的制剂同样适合于经由微针递送技术进行递送用于皮肤给药。
Claims (13)
1.药物溶液，其包含溶解在一种或多种生育酚类或生育三烯酚类以及一种或多种醇类或二醇类中的一种或多种治疗剂。
2.根据权利要求1的药物溶液，其中一种或多种生育酚类或生育三烯酚类的量是30％到99％，以及一种或多种醇类或二醇类的量是1％到70％，所述量基于药物溶液的体积计。
3.根据权利要求1的药物溶液，其中一种或多种生育酚类或生育三烯酚类是α-生育酚。
4.根据权利要求1的药物溶液，其中一种或多种醇类或二醇类是乙醇。
5.药物溶液，由溶解在α-生育酚和乙醇中的治疗剂组成。
6.药物组合物，包含权利要求1-5中任一项的药物溶液。
7.权利要求6的药物组合物，进一步包含囊封的或微粉化形式的一种或多种附加治疗剂。
8.权利要求1-5中任一项的药物溶液，其中一种或多种治疗剂部分地溶解在一种或多种生育酚类或生育三烯酚类以及一种或多种醇类或二醇类中。
9.使治疗剂增溶的方法，其包括将治疗剂溶解在一种或多种生育酚类或生育三烯酚类以及一种或多种醇类或二醇类中形成药物溶液。
10.根据权利要求9的方法，其中一种或多种生育酚类或生育三烯酚类的量是30％到99％，以及一种或多种醇类或二醇类的量是1％到70％，所述量基于药物溶液的体积计。
11.根据权利要求9的方法，其中一种或多种生育酚类或生育三烯酚类是α-生育酚。
12.根据权利要求9的方法，其中一种或多种醇类或二醇类是乙醇。
13.权利要求9-12中任一项的方法，其中治疗剂部分地溶解在一种或多种生育酚类或生育三烯酚类以及一种或多种醇类或二醇类中。
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| US6696413B2 (en) * | 1995-06-16 | 2004-02-24 | Hexal Ag | Pharmaceutical preparation with cyclosporin A |
| US6395770B1 (en) * | 1995-10-26 | 2002-05-28 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
| HUP0000116A3 (en) * | 1996-10-01 | 2000-08-28 | Stanford Res Inst Int | Taste-masked microcapsule compositions and methods of manufacture |
| US6458373B1 (en) * | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| IL131217A0 (en) * | 1998-03-10 | 2001-01-28 | Napro Biotherapeutics Inc | Novel methods and compositions for delivery of taxanes |
| WO2000001351A1 (en) | 1998-07-07 | 2000-01-13 | Transdermal Technologies, Inc. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
| US6962691B1 (en) * | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
| US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
| WO2003020318A1 (en) * | 2001-09-04 | 2003-03-13 | Lipocore Holding Ab | A topical w/o-emulsion composition |
| CA2471572A1 (en) | 2001-12-28 | 2003-07-17 | Ivax Research, Inc. | Taxane based compositions and methods of use |
| BR0313024A (pt) * | 2002-07-30 | 2005-07-12 | Wyeth Corp | Formulações parenterais contendo um hidroxiéster de rapamicina |
| US20080045559A1 (en) * | 2003-10-29 | 2008-02-21 | Sonus Pharmaceuticals, Inc. | Tocopherol-modified therapeutic drug compounds |
| WO2006133349A2 (en) * | 2005-06-08 | 2006-12-14 | Alpharma, Inc. | Orally disintegrable sleep aid formulations |
| US20060287301A1 (en) * | 2005-06-17 | 2006-12-21 | Mcnair Douglas | Novel formulations for phenothiazines, including fluphenazine and its derivatives |
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