CN100423717C - 含莫达非尼化合物的药物溶液及其在制备治疗不同疾病的药物中的用途 - Google Patents
含莫达非尼化合物的药物溶液及其在制备治疗不同疾病的药物中的用途 Download PDFInfo
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- CN100423717C CN100423717C CNB2003801026009A CN200380102600A CN100423717C CN 100423717 C CN100423717 C CN 100423717C CN B2003801026009 A CNB2003801026009 A CN B2003801026009A CN 200380102600 A CN200380102600 A CN 200380102600A CN 100423717 C CN100423717 C CN 100423717C
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Abstract
本发明公开了含莫达非尼化合物的药物组合物、在有机溶剂中的含莫达非尼化合物的非水药物组合物、以及它们在制备治疗疾病的药物中的应用。
Description
发明领域
本发明涉及包括在溶液中的莫达非尼化合物的药物组合物,尤其涉及包括至少一种有机溶剂的非水溶液。本发明还涉及包括莫达非尼化合物的固态分散体的药物组合物。本发明还涉及使用该组合物治疗疾病的方法。
发明背景
莫达非尼(C15H15NO2S)为2-(二苯甲基亚磺酰)乙酰胺,也称为2-[(二苯基甲基)亚磺酰]乙酰胺。
据描述,莫达非尼呈现“神经心理学药理学谱,其特征在于,存在伴有活动过度的兴奋和运动过强;以及不存在刻板症(除了高剂量时)和阿扑吗啡和安非他明的效果强化”(美国专利4,177,290;以下称为“‘290专利”,该文献全文引入本文以供参考)。单独服用莫达非尼会引起小鼠的运动力增加以及猴子的夜间活动增加(Duteil et al.,Eur.J.Pharmacol.180:49(1990))。莫达非尼已经被成功试验用于人体,以治疗特发性睡眠过度和发作性睡病(Bastuji et al.,Prog.Neuro-Psych.Biol.Psych.12:695(1988))。
莫达非尼的其它用途已经被提出。美国专利5,180,745被全文引入本文以供参考,其公开了使用莫达非尼为人体提供神经保护作用,特别是用于治疗帕金森病。莫达非尼的左旋形式,即(-)二苯甲基亚磺酰-乙酰胺可能对抑郁、睡眠过度和阿尔茨海默病的治疗具有潜在好处(美国专利4,927,855,该文献全文引入本文以供参考)。欧洲公布申请547952(公布于1993年6月23日)公开了使用莫达非尼作为抗缺血药。欧洲公布申请594507(公布于1994年4月27日)公开了使用莫达非尼治疗尿失禁。
具有限定固体粒子尺寸的莫达非尼制剂描述于美国专利5,618,845,该文献全文引入本文以供参考,莫达非尼的左旋异构体的制剂描述于美国专利4,927,855。莫达非尼的杂环洐生物公开于美国专利申请号60/204,789,该文献全文引入本文以供参考。
在美国,莫达非尼被批准以100mg和200mg固体单位剂型用于人体。将莫达非尼制成液体组合物也是合意的。已观察到,莫达非尼具有非常弱的水溶性和脂溶性,因此难以将莫达非尼溶解在可药用的组合物中。包括莫达非尼的常规固体和液体剂型描述于‘290专利。莫达非尼的液体混悬剂或乳剂描述于美国专利5,618,845中。莫达非尼的混悬剂报道于美国专利5,180,745中。
已经发现,莫达非尼化合物在可药用溶剂中的溶解是困难的和不可预知的。本发明人发现,许多增溶剂或者未列入USP/NF,或者它们具有毒性性质,这种毒性性质不允许将它们以高于百分之零点几的水平使用。本发明的目的是克服这些问题,制备莫达非尼化合物的可药用组合物,并为有需要的患者提供莫达非尼化合物的有效的可生物利用的递送。
发明概述
因此,本发明的一个目的是提供包括在溶液中的莫达非尼化合物的药物组合物。尤其是,本发明的组合物是非水的,并任选地包括其它赋形剂。优选地,组合物包括至少一种有机溶剂。
本发明的另一个目的是提供治疗患者体内的疾病或障碍的方法,该方法包括给患者施用治疗有效量的本发明组合物。
本发明的另一个目的是提供包括莫达非尼的固态分散体的药物组合物。尤其是,本发明的组合物包括至少一种固态载体。
本发明的另一个目的是提供治疗患者体内的疾病或障碍的方法,该方法包括给患者施用治疗有效量的莫达非尼化合物的固态分散体的组合物。
在以下的详述中,这些以及其它目的会变得显而易见,它们是通过发明人的如下发现而实现的:尽管莫达非尼化合物有弱的溶解性,但它可以被配制成药物组合物,其中在给有需要的患者施用该组合物后,莫达非尼化合物是可以生物利用的。
发明详述
因而,在第一实施方案中,本发明提供了包括在溶液中的莫达非尼化合物的药物组合物。优选地,药物组合物为非水的。优选地,药物组合物包括莫达非尼。
用于本文时,“药物组合物”是指可药用的组合物。
用于本文时,术语“可药用的”是指那些化合物、材料、组合物、和/或剂型,在合理的医学判断的范围内,它们适于接触人类或动物的组织,而不会有过度的毒性、刺激性、变态反应、或其它与合理的效益/风险比相当的难处理的并发症。
用于本文时,“一种莫达非尼化合物”或“莫达非尼化合物”及其类似物是指莫达非尼、其外消旋混合物、单独的异构体、酸加成盐、如莫达非尼的代谢酸、二苯甲基亚磺酰乙酸、及其砜形式、其羟基化形式、多晶型形式、类似物、衍生物、同源物和其前药。在本领域公知的前药可在患者体内被转化为活性剂(莫达非尼化合物)。这些和其它莫达非尼化合物以及它们的制备公开于美国专利4,177,290、4,927,855、5,719,168和美国专利申请号60/204,789。在优选的实施方案中,莫达非尼化合物为莫达非尼。
用于本文时,“溶液”是指两种或多种物质的化学和物理均一的混合物。溶液可以包括分散在液体、固体或半固体介质中的固体。优选地,溶液包括在液体介质中的固体。在更优选的实施方案中,被溶解的固体是分子尺度的粒子。在本发明的语境中,溶液不包括包合配合物,如药物和环糊精的那些配合物。
用于本文时,“固态分散体”是指药物在固态载体中的分散体。固态分散体可以包括分散系统,其中药物的浓度超过其在室温下的饱和溶解度,从而药物分离为固体相,以晶形或非晶形分散在载体中。优选地,固态分散体为水溶性的和可药用的。
用于本文时,“固态载体”是指在室温下以固态或作为固态基体存在的运载体。固态载体可以包括有机溶剂,尤其是聚合的有机溶剂。典型地,固态载体为生理学惰性的,可以是水溶性或水不溶性的。优选地,固态载体为聚合的、水溶性的并且是可药用的。
用于本文时,“非水”组合物是指包含0-10wt%水的组合物。
用于本文时,“多元醇”是指具有多于一个羟基的醇。例子包括但不限于:二元醇如乙二醇和丙二醇,以及其它二醇;丙三醇,以及其它三元醇洐生物;和糖醇。
用于本文时,“低碳烷基醇”是指包含一个羟基的支链或直链C1-C6烷基,如乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、叔丁醇、戊醇、己醇等;优选的低碳烷基醇包括乙醇、丙醇和异丙醇。
用于本文时,术语“芳基烷基醇”是指包含一个羟基的芳基取代的C1-C6烷基,如苯甲醇、苯乙醇、二苯甲醇(二苯基甲醇)等;优选的芳基烷基醇包括苯甲醇、α-苯乙醇和β-苯乙醇。
用于本文时,“治疗有效量”是指一个量,该量可以有效地减少、消除、治疗、防止或控制本文所述疾病和病症的症状。术语“控制”是指所有过程,其中可能是减慢、中断、阻止、或停止本文所述的疾病和病症的进展,但并不一定表示完全消除所有疾病和病症的症状,并且用于包括预防性治疗。
用于本文时,“可生物利用的”是指被施用剂量的一部分被吸收入血流中,并且可以用本领域中已知的技术如通过测量化合物的血清水平而方便地确定。
用于本文时,术语“患者”是指温血动物如哺乳动物,优选人或人类儿童,其患有、或可能会患有本文所述的一种或多种疾病和病症。
用于本文时,“单位剂量”是指能够施用于患者的单剂量,它易于处理和包装,同时仍保持为物理和化学上稳定的单位剂量,该单位剂量包括莫达非尼化合物、或含有莫达非尼化合物的可药用的组合物。
用于本文时,“赋形剂”是指用于药物组合物剂型的物质,它们本身通常具有很小的治疗价值,或没有治疗价值。典型的赋形剂包括抗氧化剂、抗菌剂和其它防腐剂;螯合剂;缓冲剂;调整毒性的药剂;着色剂、矫味剂和稀释剂;乳化剂和悬浮剂;和有药学应用的其它物质。
用于本文时,术语“约”是指一个特定值的±10%范围的值。例如,短语“约200”包括200的±10%,或从180到220。
在某些优选的实施方案中,组合物包括在任何可药用溶剂中的莫达非尼化合物。合适溶剂的选择是,它溶解的莫达非尼化合物的量为至少1mg/ml。应该理解,“足够的溶剂”、或“足够的溶解度”是指具有至少1mg/ml溶解度的组合物。“弱溶剂”或“弱溶解度”是指溶解度小于1mg/ml的组合物。
优选地,莫达非尼的溶解度为至少约1mg/ml。在某些实施方案中,莫达非尼化合物的溶解度为约1至约500mg/ml。在某些更优选的实施方案中,莫达非尼化合物的溶解度表现为约1至约200mg/ml。在其它更优选的实施方案中,莫达非尼化合物的溶解度为约5至约100mg/ml,在最优选的实施方案中,莫达非尼化合物的溶解度为约5至约80mg/ml。
在本发明的某些实施方案中,组合物包括至少一种有机溶剂。本领域的技术人员可以容易地确定合适的有机溶剂,该有机溶剂应为可药用的,并能给予莫达非尼化合物足够的溶解度。在某些优选的实施方案中,有三种溶剂,在其它更优选的实施方案中,包括一种或两种溶剂。在某些优选的实施方案中,任何附加溶剂的量占组合物的约0.5%至约50%(v/v),更优选的量为约1%至约50%(v/v),最优选的量为约5%至约20%(v/v)。
在某些优选的实施方案中,有机溶剂为二甘醇一乙醚、碳酸异丙烯酯、二甲基异山梨醇、1-甲基-2-吡咯烷酮(“NMP”)、中等链长的单酸甘油酯、或多元醇。高度纯化的二甘醇一乙醚为TranscutolTM。中等链长的单酸甘油酯包括甘油单辛酸酯()、甘油辛酸酯/癸酸酯(如)和聚氧乙烯甘油己酸酯(如)。多元醇包括丙三醇、丙二醇、1,4-丁二醇、1,3-丁二醇、己二醇、四甘醇(也称为glycofuranol)、或聚乙二醇。优选的多元醇包括聚乙二醇或“PEG”,它是指通式为H(OCH2CH2)nOH的液体或固体聚合物,其中n为至少4。优选PEG的平均分子量为约200至约5000道尔顿,更优选PEG的平均分子量为约300至约2000道尔顿,最优选PEG的平均分子量为约300至约1500道尔顿。市售的PEG材料包括PEG-200、PEG-300、PEG-400、PEG-540、PEG-600、PEG-800、PEG-1000和PEG-1450。所有材料均可以从例如Union Carbide Corporation以食品或药用级别购得。用于本组合物的特别优选的PEG溶剂包括PEG-300、PEG-400和PEG1450,更特别优选PEG-300和PEG-400。
在其它优选的实施方案中,组合物包括附加的溶剂,它可以是充分溶解莫达非尼化合物的任何有机溶剂。本领域的技术人员可以容易地确定合适的附加溶剂,该附加溶剂应为可药用的,并且能够改善莫达非尼化合物的溶解度。优选地,附加溶剂包括有机溶剂。附加溶剂可以选自上述有机溶剂,优选的溶剂为多元醇。在某些优选的实施方案中,附加溶剂或第二溶剂包括低碳烷基醇或芳基烷基醇,更优选芳基烷基醇,如苯甲醇、α-苯乙醇或β-苯乙醇。
在更优选的实施方案中,溶剂系统包括聚乙二醇和芳基烷基醇的混合物。更优选的实施方案包括优选的聚乙二醇和芳基烷基醇的混合物,如PEG-400和苯甲醇、PEG-400和α-苯乙醇、PEG-400和β-苯乙醇、以及PEG-300和苯甲醇等。在其它更优选的实施方案中,组合物包括约80%至约99%PEG-400、和约1%至约20%苯甲醇(v/v)。在更优选的实施方案中,组合物包括约90%至约99%PEG-400、和约1%至约10%苯甲醇(v/v)。在最优选的实施方案中,组合物包括95∶5(v/v)的PEG-400∶苯甲醇。
在某些优选的实施方案中,组合物包括莫达非尼化合物或优选包括莫达非尼,浓度为约1至约100mg/ml,优选约1至约60mg/ml,更优选约20至约50mg/ml;第一有机溶剂选自:丙三醇、丙二醇、二甘醇一乙醚、碳酸异丙烯酯、中等链长的单酸甘油酯、二甲基异山梨醇、和聚乙二醇;第二有机溶剂选自低碳烷基醇和芳基烷基醇。
在某些更优选的实施方案中,第一有机溶剂为聚乙二醇,第二有机溶剂为芳基烷基醇。在更优选的实施方案中,第一有机溶剂为PEG-300或PEG-400,芳基烷基醇为苯甲醇。
在还一些实施方案中,本发明提供了包括莫达非尼化合物的固态分散体的组合物。优选地,组合物为可药用的。优选地,药物组合物包括至少一种固态载体。优选地,药物组合物包括莫达非尼。
在某些实施方案中,有机溶剂可以额外地起固态载体的作用,以形成固态分散体。前述有机溶剂中的任一种,只要是聚合的或在室温下以固态存在,就可以起固态载体的作用。合适的固态载体是那些物质,当它们与莫达非尼化合物混合时,以及任选地与其它载体、表面活性剂、或其它赋形剂混合时,能产生固态分散体。通过使用常规技术并观察所得组合物的特性,本领域的技术人员可以容易地确定合适的固态载体或固态载体的组合、它们的相对量,以及它们与其它合意的表面活性剂、或其它赋形剂之间的相互作用。
额外地起固态载体作用的有机溶剂包括:二甘醇一乙醚、碳酸异丙烯酯、二甲基异山梨醇、1-甲基-2-吡咯烷酮(“NMP”)、中等链长的单酸甘油酯、或多元醇。高度纯化的二甘醇一乙醚为TranscutolTM。中等链长的单酸甘油酯包括甘油单辛酸酯()、甘油辛酸酯/癸酸酯(如)和聚氧乙烯甘油己酸酯(如)。多元醇包括丙三醇、丙二醇、1,4-丁二醇、1,3-丁二醇、己二醇、四甘醇(也称为glycofuranol)、或聚乙二醇。
用于固态分散体的优选PEG包括那些在室温下以固态存在的PEG。这些PEG典型地包括平均分子量为约600至约35,000道尔顿的PEG,更优选PEG的平均分子量为约1,000至约20,000道尔顿,最优选PEG的平均分子量为约3,000至约8,000道尔顿。市售的固态PEG材料包括PEG-600、PEG-900、PEG-1000、PEG-1450、PEG-3350、PEG-4500、和PEG-8000。
其它载体包括但不限于:有机酸,如柠檬酸、和琥珀酸;明胶;糖类,如木糖醇、D-甘露醇、右旋糖、半乳糖、蔗糖、山梨醇、乳糖、环糊精;聚乙烯衍生物,如聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)、和聚氯乙烯;聚氧化乙烯;聚丙烯;聚原酸酯;聚酐类(polyanhydrate);CarbopolTM,AlbuminTM;ChitosanTM;Dextran;Dextrin(淀粉糊精);纤维素衍生物,如甲基纤维素、羧甲基纤维素钠、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、邻苯二甲酸醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸丁酸纤维素;乳酸-乙醇酸共聚物;硅氧烷弹性体;滑石;脂质,如三硬脂精、β-谷甾醇、胆固醇;天然甘油酯;和聚(L-乳酸)。
优选的固态载体为聚乙二醇,或者单独使用,与其它聚乙二醇组合使用,或者与包括以下物质的载体中的一种或多种组合使用:聚乙烯吡咯烷酮、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、氧化乙烯和氧化丙烯的嵌段共聚物、右旋糖酐、和乳糖。
在其它实施方案中,本发明的组合物包括至少一种表面活性剂。某些表面活性剂,特别是聚合物表面活性剂,也可以起固态载体的作用。优选地,表面活性剂为可药用的。合适的表面活性剂是那些物质,当它们与莫达非尼化合物混合时,以及任选地与溶剂、赋形剂或固态载体混合时,产生溶液、或固态分散体。通过使用常规技术并观察所得组合物的特性,本领域的技术人员可以容易地确定合适的表面活性剂或表面活性剂的组合、它们的相对量、以及它们与其它合意的溶剂、赋形剂或固态载体之间的相互作用。
表面活性剂包括但不限于:聚氧乙烯山梨糖醇酐脂肪酸酯、聚乙二醇醚、饱和的聚乙二醇化甘油酯、聚乙二醇的脂肪酸酯、中等链长的单酸甘油酯、中等链长的脂肪酸酯、d-α-生育酚聚乙二醇琥珀酸酯、聚乙二醇/丙二醇共聚物、氧化乙烯和氧化丙烯的嵌段共聚物、硬脂酸聚烃氧基酯、聚氧乙烯硬脂酸酯、乙氧基化蓖麻油、和乙氧基化羟基硬脂酸。其它的表面活性剂可以在The Handbook of Pharmaceutical Excipients,2nd ED.,(The Pharmaceutical Press,London and AmericanPharmaceutical Association(1994))中找到,它是本领域中普通的课本,该文献全文引入本文以供参考。
聚氧乙烯山梨糖醇酐脂肪酸酯(聚山梨酸酯)是非离子型表面活性剂(洗涤剂),它可以包括脂肪酸的混合物。市售的例子为:聚氧乙烯(20)山梨糖醇酐单月桂酸酯(如20)、聚氧乙烯(40)山梨糖醇酐单棕榈酸酯(如40)、聚氧乙烯(80)山梨糖醇酐单油酸酯(如80)、和失水山梨糖醇单月桂酸酯(如20)。优选的聚氧乙烯山梨糖醇酐脂肪酸酯为聚氧乙烯(80)山梨糖醇酐单油酸酯(尤其是80)和失水山梨糖醇单月桂酸酯(尤其是20)。聚乙二醇醚包括Triton x-100、TritonTM x-114、TritonTM x-405、TritonTM N-101。饱和的聚乙二醇化甘油酯包括,例如甘油单酯、甘油二酯、或甘油三酯。聚乙二醇的二脂肪酸酯包括,例如44/14(主要是PEG-1500的脂肪酸酯,购自Gattefossé,Saint-Priest,France)和50/13。中链的单酸甘油酯(其中链长为6至10个碳原子)包括例如甘油单辛酸酯(308)、甘油单己酸酯(MCM C-8)、甘油辛酸酯/癸酸酯(MCM)和聚氧乙烯甘油辛酸酯和聚氧乙烯甘油己酸酯的混合物()。中链的脂肪酸酯包括中等链长的甘油三酯,如三癸酸甘油酯和三辛酸甘油酯的混合物(602)。氧化乙烯和氧化丙烯的嵌段共聚物包括例如聚氧乙烯-聚氧丙烯嵌段共聚物(F-68)。硬脂酸聚烃氧基酯包括聚乙氧基化(40)硬脂酸(52)。乙氧基化蓖麻油包括例如聚乙氧基化(60)氢化蓖麻油(EL)。乙氧基化羟基硬脂酸包括例如聚乙二醇660羟基硬脂酸酯(HS 15)。在室温下一些表面活性剂是固体或半固体,如甘油单辛酸酯、44/14、和50/13。
其它表面活性剂包括卵磷脂,如磷脂、双肉豆蔻酰DL-α-磷脂酰胆碱、和羟基化卵磷脂(如Centrolene A);其它离子型表面活性剂,如十二烷基硫酸钠(SDS),和十二烷基三甲铵(DTAB);和胆汁盐,如胆酸、脱氧胆酸、胆酸钠、牛磺胆酸钠和脱氧胆酸钠等。
优选的表面活性剂包括:十二烷基硫酸钠(SDS)、聚乙二醇/丙二醇共聚物(如)、饱和的聚乙二醇化甘油酯(如)、十二烷基三甲铵(DTAB)、聚氧乙烯山梨糖醇酐脂肪酸酯,如聚氧乙烯(80)山梨糖醇酐单油酸酯、尤其是80;聚乙氧基化(40)硬脂酸,尤其是52;失水山梨糖醇月桂酸酯,尤其是20;和卵磷脂。
在本发明的某些实施方案中,莫达非尼化合物占组合物重量的约1-50wt%。在某些更优选的实施方案中,莫达非尼化合物占组合物重量的约3-40wt%,更优选的范围为组合物重量的约5-25wt%。在其它更优选的实施方案中,莫达非尼化合物占组合物重量的约7-12wt%。
在某些优选的实施方案中,组合物包括至少一个单位剂量的莫达非尼化合物。在某些更优选的实施方案中,组合物包括一个单位剂量的莫达非尼化合物。优选地,莫达非尼化合物为莫达非尼。莫达非尼每日剂量的优选范围为约0.01至100mg/kg体重。按照常规指导,人的每日剂量范围为约0.1mg至约2000mg。优选地,单位剂量范围为约1至约500mg,每天给药一至四次,甚至更优选地,单位剂量范围为约10mg至约400mg,每天给药一至两次。在某些优选的实施方案中,单位剂量为100或200mg。在其它优选的实施方案中,单位剂量为在患者体内达到约0.05至约30μg/ml、更优选约1至约20μg/ml的血清水平所必需的剂量。
在本发明的其它实施方案中,提供了治疗患者体内疾病或障碍的方法,该方法包括给有需要的患者施用治疗有效量的莫达非尼化合物、或优选莫达非尼化合物的非水药物组合物。在优选的实施方案中,组合物为溶液。
在本发明的另一个实施方案中,提供了治疗患者体内疾病或障碍的方法,该方法包括给有需要的患者施用治疗有效量的组合物,该组合物包括莫达非尼化合物的固态分散体、或优选莫达非尼。
在某些其它实施方案中,本文所述的药物组合物用于治疗嗜睡,如发作性睡病相关的过度日间嗜睡,或与睡眠呼吸暂停相关的嗜睡、疲劳、帕金森病、脑缺血、脑卒中、睡眠呼吸暂停、进食障碍、注意缺陷/多动障碍、认知功能不良或疲劳,如多发性硬化所致的疲劳(“MS”疲劳);和用于促进觉醒、刺激食欲、或刺激体重增加。
作为本领域的技术人员,主治医师可以通过使用常规技术并观察在类似环境下所得的结果,容易地确定治疗有效量的组合物的施用。确定治疗有效量时,主治医师会考虑许多因素,这些因素包括但不限于:患者的物种;其大小、年龄、和全身健康;患有的具体疾病;所得疾病的牵累程度和严重性;个体患者的反应;所施用的具体化合物;施用方式;所施用制剂的生物利用度特性;所选择的给药方案;同时使用的药物治疗;和其它相关环境。
莫达非尼化合物的治疗有效量会根据许多因素而改变,这些因素包括:将被施用的药物剂量、所使用化合物的化学特性(如疏水性)、化合物的效能、疾病种类、患者的疾病状态、和给药途径。一般地,以小剂量开始治疗,然后少量增加剂量,直到在该环境下获得最优的期望效果。
在还一个实施方案中,本发明提供了包括莫达非尼化合物的可药用组合物,其中在给患者施用该组合物后,莫达非尼化合物在所述患者体内具有约0.05至约30μg/ml的血清水平。在优选实施方案中,莫达非尼化合物在所述患者体内具有约1至约20μg/ml的血清水平。在另一个优选的实施方案中,被施用以达到期望的血清水平的组合物是包括莫达非尼化合物的非水药物组合物。在更优选的实施方案中,莫达非尼化合物为莫达非尼。
在还一个实施方案中,本发明提供了适于患者口服给药的组合物。口服给药包括以液体组合物的形式摄取,所述形式包括糖浆剂、酏剂、或乳剂;或作为胶囊摄取。
预计所述组合物适于以胶囊形式施用,如硬明胶胶囊和软明胶胶囊和淀粉胶囊。硬明胶胶囊和软明胶胶囊从明胶混合物中制备,这在The Theory and Practice of Industrial Pharmacy,3d Ed.,Lachman et al.,p.374-408(Lea & Febiger,1986)中被充分地讨论,该文献全文引入本文以供参考。明胶被与增塑剂,如丙三醇USP和山梨醇USP,和水相混合。明胶胶囊也可以包含这些添加剂如防腐剂、着色剂、矫味剂等。市售的明胶胶囊是由CAPSUGEL,Warner-Lambert Co.的一个分公司制备的那些,可以在#5至#000的普通胶囊尺寸范围内获得,其体积为约0.1至约1.4ml。此外,本发明组合物的胶囊可以用肠溶衣包衣,这可以抑制胶囊在胃的酸性环境中降解。这种肠溶衣在本领域中广泛知名,如在美国专利5,206,219中,该文献内容被引入本文以供参考。
在某些实施方案中,组合物任选地包括其它赋形剂。本领域的技术人员可以容易地确定合适的赋形剂,它们也可以包括抗菌剂,如羟苯甲酸甲酯;抗氧化剂,如抗坏血酸、亚硫酸氢钠、和抗坏血酸的脂肪酸酯,如棕榈酸抗坏血酸酯;螯合剂,如乙二胺四乙酸;缓冲剂,如乙酸盐、柠檬酸盐或磷酸盐;用于调节毒性的药剂,如氯化钠或右旋糖;矫味剂;甜味剂和着色剂;稀释剂和粘合剂;乳化剂和悬浮剂;和本领域的技术人员认为有用的其它赋形剂,如The Handbook of Pharmaceutical Excipients,2nd Ed.,(The Pharmaceutical Press,Londonand American Pharmaceutical Association,1994)中发现的那些,该文献全文引入本文以供参考。
本发明的组合物包括莫达非尼化合物,它可以被本领域的技术人员使用常规方法容易地制备。制备莫达非尼和各种衍生物的方法出现在美国专利4,177,290中,制备其它莫达非尼化合物的方法出现在美国专利4,927,855、5,719,168和美国专利申请号60/204,789中。
本发明的组合物具有很宽的剂型范围。在室温下,本发明的组合物可以是液体、半固体、或固体。例如,较高分子量的PEG,如PEG-600在室温下是固体,可能需要加热以使PEG液化并溶解莫达非尼化合物。可以将这些PEG溶液保持温暖,或冷却至室温,这由所期望的施用模式所要求。例如,明胶胶囊形式的口服剂型可以利用PEG-600的冷却溶液。根据本发明的组合物在室温下是否为液体、半固体、或固体,这取决于组分的选择,或其它考虑因素如商业生存力、给药等。
其惰性或非活性组分(即莫达非尼之外的组分)在室温下均为液体的组合物可以通过简单地混合组分就可制得,无需加热。将所需量的莫达非尼化合物称出,溶解在惰性组分的混合物中,不经加热。可以使用适度的加热,优选地低于60℃,以加快惰性组分的完全混合,加快莫达非尼化合物的溶解,或同时进行。
在适度升高的温度,优选低于60℃下,制备包括一种或多种在室温下为固体的组分的组合物。例如,PEG-1450在室温下为固体,以约40至约60℃轻微加热,使PEG-1450液化,从而用作溶剂。然后将莫达非尼化合物搅拌到被加热的液体PEG溶液中,直到溶解。冷却至室温后,溶液固化,轻微加热至40-45℃,获得莫达非尼化合物在PEG-1450中的清澈溶液。必须小心避免过度加热,因为这会导致剂型中一种或多种组分的分解。
制备本发明的固态分散体的方法包括本领域的技术人员公知的那些方法。例如,参见Serajuddin,A.T.M.J.Pharm.Sci.1999,88(10),1058-1066。两种普通的技术包括“熔化”或“熔融”方法、和“溶剂”方法。在每一种方法中,将莫达非尼化合物研磨至微粉化形式都是有益的。
在熔化方法中,允许莫达非尼化合物和载体以稍高于最高熔点的固体的熔点的温度熔化,直到形成清澈液体。可以将莫达非尼化合物与载体混合在一起,然后将所得浆液加热,或者先将载体熔化,随后将莫达非尼化合物搅拌到液化载体中。在每一种情况下,可以将液化混合物迅速冷却,以提供冻凝块,然后将之研磨以产生粉末,用于制作成片剂或装入胶囊。
在溶剂方法中,通过将组分溶解在普通有机溶剂中并充分掺合混合物,使莫达非尼化合物分散到载体中。然后蒸发除去溶剂,用常规方法类似地制备最终的固体组合物。
本文提到的材料、方法、和实施例是为了说明的目的,不应被理解为限制本发明的范围或内容。除非另有说明,所有技术和科学术语旨在具有它们在本领域中公认的意思。
实施例
A.材料:
在下列实施例中所有的材料均为市售,或可由本领域的技术人员用已知的或可容易获得的文献方法容易地制备。溶剂为USP/NF级别或更高级别。
B.方法:
1.HPLC
下列HPLC方法可用于测量组合物中莫达非尼化合物的含量。将莫达非尼化合物的饱和溶液通过1.2μm针筒过滤器进行过滤。用990μl二甲亚砜(Fischer Certified ACS级别)将10μl澄清溶液稀释至1ml。取10μl稀溶液用于HPLC分析,使用以下典型的柱条件:
流速:1.2ml/min。
色谱柱:ODS,4.6×20mm,柱温30℃
流动相:80%(65%乙腈/35%1M磷酸盐缓冲液)20wt%水
分析时间:5分钟
波长:222纳米
通过将在0.4mg/ml下使用的莫达非尼化合物标准物经的所得面积与适当的稀释物进行比较,计算浓度。
2.在给予莫达非尼溶液的大鼠中血液水平的测量方法
在给药前将成年雄性Sprague-Dawley大鼠禁食过夜。通过经口管饲法给大鼠施用每种剂型,莫达非尼化合物的剂量为100mg/kg,剂量体积为3.3ml/kg。给药后,在0.25、0.5、1、2、4和6小时从外侧尾静脉收集血液。将血液集中在湿冰上,以13,000RPM旋转10分钟。收集上清液(血浆)并冷冻在干冰上,保存在-70℃直到分析。这些实验中莫达非尼化合物的血清水平可以用LC/MS测量。
实施例1:制备95∶5(v/v)PEG-400∶苯甲醇
将95ml PEG-400和5ml苯甲醇的混合物在室温下搅拌直到均匀。称量0.1克莫达非尼,加入至单独容器中,在搅拌和加热至55-60℃下,加入1ml经混合的溶剂。允许溶液冷却至室温,通过过滤溶液除去任何不溶解的固体。对于粘性溶液或在室温下固化的溶液,进行加热直到获得自由流动的溶液,然后过滤得到不含微粒物质的溶液。
用HPLC测量,莫达非尼的溶解度为61mg/ml。
实施例2:大鼠中莫达非尼的血清水平
施用实施例1的组合物后,大鼠中莫达非尼的血清水平示于下表1中。组合物用于模拟以口服形式如片剂施用的固体莫达非尼的生物利用度,但没有给大鼠施用片剂的困难。是一种市售(Paddock Laboratories,Minneapolis,MN)的口服悬浮运载体,主要由纯化水、微晶纤维素、羧甲基纤维素钠、黄原胶、角叉菜胶、柠檬酸和磷酸钠(作为缓冲盐)、西甲硅油(消泡剂)、和山梨酸钾和羟苯甲酸甲酯(防腐剂)组成。
表1:大鼠中莫达非尼的血清水平
实施例3:固态分散体组合物
表2
组合物编号 | 莫达非尼%(微粉化) | PEG 1000% | PEG 8000% | PVP% | 方法 |
1 | 10 | 90 | - | - | A |
2 | 10 | 50 | 40 | - | B |
3 | 10 | 70 | 20 | - | B |
4 | 10 | 65 | 20 | 5 | C |
5 | 7 | 63 | 30 | - | D |
6 | 10 | 70 | 20 | - | D |
7 | 7 | 63 | 25 | 5 | C |
8 | 10 | 65 | 20 | 5 | C |
9 | 10 | 20 | 70 | - | D |
10 | 10 | 45 | 40 | - | D |
11 | 10 | 45 | 40 | 5 | C |
12 | 12 | 70 | 18 | - | D |
其中组合物使用下列方法中的一种制备:
A.将莫达非尼和PEG-1000混合,在微波炉中加热,直到混合物被液化(加热时间为约13秒)。
B.将莫达非尼和PEG-1000混合,形成浆液,然后加入熔化的PEG-8000,在微波炉中加热,直到混合物被液化(加热时间为约17秒)。
C.将莫达非尼和PEG-1000混合,形成浆液,然后向浆液中加入PVP,之后加入熔化的PEG-8000,在微波炉中加热,直到混合物被液化(加热时间为约10秒)。
D.用微波炉加热PEG-1000直到液化(约20秒)。在热水浴上将莫达非尼搅拌到PEG-1000中,形成浆液,然后加入熔化的PEG-8000。
本领域的技术人员可知,根据上述教导,本发明的许多变更和变化是可能的。因此可以理解,在所附权利要求书的范围内,可以不同于本文的具体描述的其他方式实施本发明,本发明的范围旨在包括所有的这些变化。
Claims (25)
1. 一种包括莫达非尼化合物在至少一种固态载体中的固态分散体的药物组合物,其中莫达非尼化合物以超过其在室温下的饱和溶解度的浓度存在于固态载体中,从而莫达非尼化合物分离为在组合物中分散的固体相,并且其中固态载体包括平均分子量3,000到8,000道尔顿的聚乙二醇,并且其中莫达非尼化合物选自莫达非尼、其外消旋混合物、单独的异构体、酸加成盐、砜形式、和多晶型形式。
2. 如权利要求1所述的组合物,其中组合物包括莫达非尼。
3. 如权利要求1所述的组合物,其中固态载体还包括聚乙烯吡咯烷酮、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、氧化乙烯和氧化丙烯的嵌段共聚物、右旋糖酐、和乳糖。
4. 如权利要求1所述的组合物,其中聚乙二醇选自:PEG-1000、PEG-3350、和PEG-8000。
5. 如权利要求4所述的组合物,其中聚乙二醇选自PEG-1000和PEG-8000。
6. 如权利要求1所述的组合物,其中固态载体进一步包括聚乙烯吡咯烷酮。
7. 如权利要求6所述的组合物,其中固态载体为PEG-1000、PEG-8000和聚乙烯吡咯烷酮。
8. 如权利要求1所述的组合物,还包括至少一种表面活性剂。
9. 如权利要求8所述的组合物,其中表面活性剂选自:十二烷基硫酸钠、聚乙二醇/丙二醇共聚物、饱和的聚乙二醇化甘油酯、十二烷基三甲铵、聚氧乙烯山梨糖醇酐脂肪酸酯、和卵磷脂。
10. 如权利要求6所述的组合物,其中组合物还包括至少一种表面活性剂。
11. 如权利要求10所述的组合物,其中表面活性剂选自:十二烷基硫酸钠、聚乙二醇/丙二醇共聚物、饱和的聚乙二醇化甘油酯、十二烷基三甲铵、聚氧乙烯山梨糖醇酐脂肪酸酯、和卵磷脂。
12. 如权利要求11所述的组合物,其中表面活性剂为十二烷基硫酸钠。
13. 如权利要求1所述的组合物,其中莫达非尼化合物占组合物重量的1wt%至50wt%。
14. 如权利要求13所述的组合物,其中莫达非尼化合物占组合物重量的3wt%至40wt%。
15. 如权利要求14所述的组合物,其中莫达非尼化合物占组合物重量的5wt%至25wt%。
16. 如权利要求15所述的组合物,其中莫达非尼化合物占组合物重量的7wt%至12wt%。
17. 如权利要求1所述的组合物,包括一个单位剂量的莫达非尼化合物,其中单位剂量为1mg到500mg。
18. 如权利要求17所述的组合物,其中单位剂量为10mg到400mg。
19. 如权利要求18所述的组合物,其中单位剂量为200mg。
20. 如权利要求18所述的组合物,其中单位剂量为100mg。
21. 如权利要求17所述的组合物,其中组合物为片剂或胶囊。
22. 如权利要求3-21中任一项所述的组合物,其中莫达非尼化合物为莫达非尼。
23. 莫达非尼化合物在至少一种固态载体中的固态分散体在制备用于治疗嗜睡、疲劳、帕金森病、脑缺血、脑卒中、睡眠呼吸暂停、进食障碍、注意缺陷/多动障碍、认知障碍或疲劳的药物中的应用,其中莫达非尼化合物选自莫达非尼、其外消旋混合物、单独的异构体、酸加成盐、砜形式、和多晶型形式,并以超过其在室温下的饱和溶解度的浓度存在于固态载体中,从而莫达非尼化合物分离为在组合物中分散的固体相,并且其中固态载体包括平均分子量3,000到8,000道尔顿的聚乙二醇。
24. 莫达非尼化合物在至少一种固态载体中的固态分散体在制备用于促进觉醒、刺激食欲、或刺激体重增加的组合物中的应用,其中莫达非尼化合物选自莫达非尼、其外消旋混合物、单独的异构体、酸加成盐、砜形式、和多晶型形式,并以超过其在室温下的饱和溶解度的浓度存在于固态载体中,从而莫达非尼化合物分离为在组合物中分散的固体相,并且其中固态载体包括平均分子量3,000到8,000道尔顿的聚乙二醇。
25. 如权利要求23或24所述的应用,其中莫达非尼化合物为莫达非尼。
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